biological monitoring a practical field manual

Biological MonitoringA Practical Field Manual

A Publication of the

American Industrial Hygiene Association

AIHA Guideline 1—2004

AIHA Guideline 1 — 2004

Biological MonitoringA Practical Field Manual

Approval date: 02/27/2004American Industrial Hygiene Association

About this DocumentAIHA guidelines are developed through a consensus process that involves review by internal AIHA technical committeesand external review by outside experts. Through this process, AIHA brings together volunteers with varied backgroundsand viewpoints. The intent of this document is to provide practical guidance to the practicing OEHS professional. Thisdocument is not a standard.

DisclaimerAIHA did not independently test the methods or verify the accuracy of recommendations contained in this document.Specific mention of manufacturers and products in this book does not represent an endorsement by AIHA.

CopyrightCopyright 2004 by the American Industrial Hygiene Association. All rights reserved. No part of this publication may bereproduced in any form, by photostat, microfilm, retrieval system, or any other means, without prior permission from thepublisher.

Available from:American Industrial Hygiene Association

2700 Prosperity Avenue, Suite 250Fairfax, VA 22031(703) 849-8888www.aiha.org

Stock #: EBMG04-654ISBN #: 1-931504-51-2

Printed in the United States of America

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Table of ContentsFOREWORD/ HOW TO READ THIS GUIDELINE ..................................................................................................ivACKNOWLEDGMENTS ...........................................................................................................................................v

1. PURPOSE ..............................................................................................................................................................12. SCOPE ..............................................................................................................................................................13. DEFINITIONS AND ABBREVIATIONS ...................................................................................................................14. SIGNIFICANCE AND USES....................................................................................................................................45. ELEMENTS OF A BIOLOGICAL MONITORING PROGRAM IN AN OCCUPATIONAL AND

ENVIRONMENTAL HYGIENE PROGRAM .............................................................................................................55.1 Objective............................................................................................................................................................55.2 Defining Biological Monitoring ...........................................................................................................................55.3 When is Biological Monitoring Appropriate?......................................................................................................65.4 Cautionary Notes on Biological Monitoring .......................................................................................................65.5 Roles and Responsibilities ................................................................................................................................65.6 Developing a Process to Create a Biological Monitoring Program ...................................................................75.7 Elements of a Written Biological Monitoring Protocol .......................................................................................8

5.7.1 Objective ...............................................................................................................................................85.7.2 Process Summary ................................................................................................................................85.7.3 Participants ...........................................................................................................................................85.7.4 Collection Schedule ..............................................................................................................................95.7.5 Collection Procedure ..........................................................................................................................105.7.6 Questionnaire Administration..............................................................................................................105.7.7 Quality Control (QC) ...........................................................................................................................105.7.8 Documentation....................................................................................................................................105.7.9 Analytical Procedures .........................................................................................................................105.7.10 Reviewing and Reporting Results ......................................................................................................105.7.11 Follow-Up Actions...............................................................................................................................11

5.8 Sampling and Analytical Method Issues.......................................................................................................115.9 Implementation of a Biological Monitoring Program.....................................................................................115.10 Data Analyses, Reporting, and Periodic Review .........................................................................................115.11 Reports to Participants and Management ....................................................................................................125.12 Stopping a Program......................................................................................................................................12

6. SAMPLING AND ANALYSIS.................................................................................................................................126.1 Introduction to Sampling...............................................................................................................................12

6.1.1 Sampling Personnel................................................................................................................................126.1.2 Sample Collection and Shipping ............................................................................................................136.1.3 Field Blanks and Other Blanks...............................................................................................................136.1.4 Labels .....................................................................................................................................................136.1.5 Baseline Sampling..................................................................................................................................146.1.6 Sampling Other than for Biological Monitoring.......................................................................................146.1.7 Documentation........................................................................................................................................146.1.8 Safety......................................................................................................................................................14

6.2 Urine Collection ............................................................................................................................................156.2.1 Trace Metals ........................................................................................................................................156.2.2 Organic Analytes.................................................................................................................................15

6.3 Blood Collection............................................................................................................................................166.3.1 Metals..................................................................................................................................................166.3.2 Organics ..............................................................................................................................................16

6.4 Breath Collection ..........................................................................................................................................176.5 Saliva Collection ...........................................................................................................................................176.6 Hair Collection ..............................................................................................................................................176.7 Laboratory QC/QA........................................................................................................................................17

6.7.1 Definitions and Basics.........................................................................................................................176.7.2 Analytical Chemistry Laboratories and Biological Monitoring ................................................................20

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7. USING RESULTS ..................................................................................................................................................247.1 Control Programs..........................................................................................................................................24

7.1.1 Exposure Assessment ........................................................................................................................247.1.2 Health Surveillance and Medical Surveillance ....................................................................................28

8. ETHICAL AND LEGAL ASPECTS OF BIOLOGICAL MONITORING .................................................................328.1 Ethical and Legal Basics .................................................................................................................................328.2 Ethical and Legal Considerations for Implementing Biological Monitoring ......................................................34

8.2.1 Before Biological Monitoring...................................................................................................................348.2.2 Performing Biological Monitoring............................................................................................................358.2.3 After Biological Monitoring......................................................................................................................35

9. NORMATIVE REFERENCES ................................................................................................................................36

APPENDIX I: Introduction to Biological Monitoring; Questions and Answers ....................................................................39APPENDIX II: Case Studies

Case Study 1: Importance of Biological Monitoring for Urinary 1-Hydroxypyrene (1HP) in Assessing Dermal Exposure for Coke Oven Workers: Biological Monitoring to Represent a Class of Compounds...........................63

Case Study 2: Biological Monitoring for Estrogens and Progestins as Indicators of Occupational Exposure in the Reformulation of Hormone Replacement Therapy Products: Saliva Biological Monitoring .........................64

Case Study 3: 4,4’-Methylene Dianiline Spill at a Large Chemical Manufacturing Facility in the Southwest United States: Urine Monitoring as an Index of Exposure.....................................................................................64

Case Study 4: Protectiveness of Negative and Positive Pressure Respirators and Contribution of Dermal Exposure to Carbon Disulfide Exposure in the Viscose Rayon Industry: Urine Monitoring for TTCA in Tandem with Personal Air Sampling...................................................................................................................65

Case Study 5: N,N-Dimethylacetamide Dermal Exposure to Workers in the Acrylic Fiber Manufacturing Industry...........................................................................................................................................67

Case Study 6: Cadmium and Past Exposures .............................................................................................................68Case Study 7: Workplace Protection Factors for Lead Fume for Powered Air-Purifying Respirators in a Brass

Foundry: Blood Lead Must Be Used to Ascertain True Protectiveness of Respirators..........................................68Case Study 8: 2-Butoxyethanol Exposure for Window Cleaners: Urine Monitoring as a Means to Gauge

Noninhalation Exposure .........................................................................................................................................69Case Study 9: Urine Biological Monitoring after Hexamethylene Diisocyanate Exposure During Motor Vehicle

Repair Spray Painting to Test PPE Protectiveness................................................................................................70Case Study 10: Effect of Respirator Use on Exposure to 2-Methoxyethanol ..............................................................71Case Study 11: Death by Dimethylmercury Poisoning in a Laboratory Researcher: The Utility of Hair Analysis

to Reconstruct Metal Exposures ............................................................................................................................72Case Study 12: Exhaled Breath Measurements for Tetrachloroethylene Exposures in Dry-Cleaning Shops .............72Case Study 13: Breath Analysis for Freon-113 as a Tool for Evaluating Respirator Performance...............................73Case Study 14: Personal Exposure to JP-8 Jet Fuel at Air Force Bases: Exhaled Breath Analysis Versus

Breathing Zone Air Sampling Results for a Relatively Nonvolatile Fuel ................................................................74Case Study 15: Air and Biological Monitoring of Solvent Exposure During Graffiti Removal ......................................75Case Study 16: Biological Monitoring and Air Sampling for Thorium for Mineral Sands Workers:

Biological Monitoring and Radioactive Elements ...................................................................................................76Case Study 17: Organocarbamate Pesticide Exposure Assessment: Carbaryl Exposure to Farmer Applicators

and Their Families..................................................................................................................................................77Case Study 18: Organophosphate Intoxication of a Worker in a Plastic Bottle Recycling Plant:

Unexpected Events Can Lead to Health Problems................................................................................................78Case Study 19: Methylene Chloride, Carbon Monoxide, and Carboxyhemoglobin: The Same Marker but

Different Kinetics ....................................................................................................................................................79Case Study 20: Aplastic Anemia in a Petrochemical Factory Worker..........................................................................80

APPENDIX III: Bibliography of Some Key Works in the Field ............................................................................................81APPENDIX IV: Background Concentrations for Biological Monitoring of Environmental Chemicals ................................91APPENDIX V: Consents Forms for Biological Monitoring .................................................................................................93Appendix VI: Some Important Internet URLs for Biological Monitoring Information .......................................................101APPENDIX VII: Biological Monitoring for Evaluating Occupational Exposure to Toxic Chemicals...................................103

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EditorShane S. Que Hee, MS, PhD, RPIH, FAIC, FAIHA, Department of Environmental Health Sciences and UCLA Center forOccupational and Environmental Health, School of Public Health, University of California at Los Angeles

Contributing AuthorsThis guideline is sponsored and maintained by the American Industrial Hygiene Association (AIHA) Biological MonitoringCommittee.Present and former committee members who contributed (in parentheses) include the following.

Mark Boeniger, CIH, NIOSH (Appendix VII)Tim Buckley, PhD, CIH, Johns Hopkins University SPH, Dept of Env Health Sciences (Appendix VII)James Calpin, CIH, Analytics Corporation (Appendix IV)Kevin Cummins, CIH, OSHA Health Response Team (Section 5; Case Studies 1–3)Jean Grassman, PhD, Brooklyn College CUNY (Section 8.2)Larry K. Lowry, PhD, ABCC, Occupational Health Sciences, Univ Texas Health Center at Tyler (Appendix VII)Paul R. Michael, PhD, CIH, Monsanto Company (Section 6)Dan Napier, MS CIH CSP, DNA Industrial Hygiene (Appendix V-2)Shane Que Hee, MS, PhD, RPIH, FAIC, FAIHA, Department of Environmental Health Sciences and UCLA

Center for Occupational and Environmental Health, School of Public Health, University of California at Los Angeles (Sections 5–8; Case Studies; Appendices I, III, and VI)

P. Jenny E. Quintana, MPH PhD, Graduate School of Public Health, San Diego State University (Appendix V-1)Garry Spies, CIH, CSP, Pharmacia (Section 5; Case Studies 5 and 6)Reggie Suga, SC, CIH, CHMM, Tetra Tech NUS (Sections 6 and 7)Glenn Talaska, PhD CIH, Department of Environmental Health, University of Cincinnati Medical Center

(Appendix VII)Paul Ullucci, ESA Laboratories (Section 6)Albert M. Zielinski, CIH, GE Lighting (Section 6)

Staff LiaisonsMargaret A. Breida, MS, American Industrial Hygiene AssociationMili Mavely, American Industrial Hygiene Association

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Foreword

The Biological Monitoring Committee prepared this document to be used as a guide and reference for entry-level industri-al hygienists and occupational health specialists. The committee worked for several years preparing this text. The con-tributing authors are recognized individually, but many other volunteers spent countless hours assisting and working withthe listed authors.

We hope industrial and environmental hygienists, those intending to become occupational safety and health personnel,practicing public health professionals, and informed members of the general public will use this manual to orient them-selves relative to the practice and theory of biological monitoring. Although it is impossible to have all the answers, theBiological Monitoring Committee tried to address many of the major issues according to the perspective of the industrialhygienist with as little technical content as possible at a level also appropriate for students studying for bachelor of sci-ence degrees.

How to Read this GuidelineReaders with various levels of experience can use this manual.

Appendix VII provides a Power Point™ slide show (see enclosed CD) that can be used as an introduction for entry-levelindustrial and environmental hygienists or for experienced occupational health professionals as a review or for training pur-poses. Entry-level industrial hygienists should also attempt their own answers to the questions posed in Appendix I, whichprovides an introduction and answers to the most commonly asked questions in biological monitoring. They should thencompare their answers with those provided in Appendix I, and then read the applications of each question to the biologicalmonitoring of benzene and lead. The same set of questions should then be applied to another exposing chemical forfamiliarization with the basics of biological monitoring and the kinds of documentation necessary for each chemical.

Hygienists familiar with the basics of biological monitoring may wish to begin with how a biological monitoring program isconceptualized, developed, and implemented in the workplace (Section 5). Others with specific questions may wish toconsult specific sections directly, for example, how to do sampling (Section 6) or how to interpret results (Section 7). Ineach case it is important that each section be read through from the beginning.

Staff note: This guideline was developed using AIHA’s guideline procedures, which include peer review by AIHA techni-cal committees and outside experts.

Comments are welcome and should be directed to AIHA Scientific and Technical Initiatives Staff at 2700 Prosperity Ave.,Suite 250, Fairfax, VA 22031.

Dan Napier, Chairperson, 2004Shane Que Hee, Editor

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Acknowledgments

Thanks to all who helped create this guide:• To Jenny Quintana, who did the early heavy lifting.• To the committee chairpersons—Paul Ullucci, Kevin Cummins, Tim Buckley, Jim Calpin, Jean Grassman, and Dan

Napier—who must have wondered if the project would ever be completed.• To the American Industrial Hygiene Association’s Margie Breida, who patiently listened to all of our excuses.• To the American Industrial Hygiene Association for its support.• To all the contributing authors.• To all the production people.• To all spouses and significant others who had to support their partners.• To Mark Boeniger of NIOSH for his indefatigable optimism.

The editor and authors acknowledge and thank everyone who helped, assisted, or otherwise aided and abetted them.Special thanks go to Margie Breida of AIHA who was indispensable in facilitating the task. We also thank the AmericanIndustrial Hygiene Association for having faith in our committee.

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Biological Monitoring—A Practical Field Manual

1. PurposeThis guide is written to be a text for undergraduatecourses in industrial hygiene and as a practical fieldmanual for the entry-level and experienced practicingindustrial hygienist. This guide, along with the mostcurrent methods for specific biological monitoringprotocols and more theoretical texts, will enable thepracticing professional to further excel in the conduct ofgood science in the field.

2. ScopeThis guide covers the general basics of biologicalmonitoring from the perspective of a field industrialhygienist and also constitutes a field manual for thetrainee industrial hygienist. The guide is also suitable forundergraduate students because it contains a slide showand question and answer sections. It cannot answeradvanced questions about all of biological monitoring, butmany books and scientific articles are available for thatpurpose. Such advanced questions include analyticalmethods, advanced toxicological mechanisms, andadvanced risk assessment for specific chemicals.

3. Definitions and AbbreviationsFor the purposes of this guideline document, the followingterms and definitions apply. The AIHA Glossary ofOccupational Hygiene Terms should be referenced forany terms not defined in this section.

3.1 Absorbed dose: the amount (mass ormoles) of exposing compound that actuallyenters into the bloodstream through anyexternal routes of exposure; the absolutebioavailability.

3.2 Accuracy: how close the data are to the truevalues. Accuracy is usually expressed as the% relative error and is positive or negative.

3.3 Action level: the trigger level to start controlprocedures.

3.4 Adduct: the product of a reaction between amacromolecule of the body and an exposingchemical or its metabolite.

3.5 Administrative rotation: rotating the workerthrough different job descriptions to reduceexposure.

3.6 Aerodynamic diameter for an aerosol: thediameter of the equivalent sphere of a waterdroplet at the same conditions.

3.7 Aerosol: airborne solid or liquid.3.8 Alveoli: the anatomical sites in the lungs

where oxygen and carbon dioxide exchangeoccur.

3.9 Analysis: identification and quantification ofan element, compound, or material.

3.10 Antibody: the protein that a living organismis stimulated to make from B lymphocyteswhen a foreign antigen is present.

3.11 Antigen: a large macromolecule that triggersan immune response.

3.12 Baseline sampling: sampling the biologicalfluid immediately before worker exposure.

3.13 Behavioral change: a change in attitude,nervous state, or behavior.

3.14 Biochemical epidemiology: the correlationof chemical markers measured in bodilymedia with epidemiologic variates.

3.15 Biologically effective dose: the amount(mass or moles) of exposing compound thatactually reaches a target organ.

3.16 Biological equivalent values: values ofbiological markers that correlate to exposureguidelines.

3.17 Biological exposure index: the guidancepublished by ACGIH for biological fluids thatis the biological equivalent of the airthreshold limit value–time weighted average

3.18 Biological monitoring: the measurement ofchemical markers in body media that areindicative of external exposure to chemical,physical, or biological agents.

3.19 Biomarker: the determinant or marker to bemeasured in a biological system.

3.20 Blank: a sample that does not contain theanalyte; there are many possible blanks.

3.21 Blood: the red fluid contained in arteries andveins that is pumped by the heart.

3.22 Boiling point: the temperature at which aliquid completely changes into the gaseousstate at a specified external pressure, andthe temperature at which the vapor pressureof an analyte becomes equal to the externalpressure.

3.23 Breathing zone air sampling: the airsampling that is done near the worker’s lapel.

3.24 Cancer: uncontrolled growth and division ofcells.

3.25 Chelate: the compound formed when ametal bonds with organic functional groups.

3.26 Chromatography: a technique to separate ahomogeneous mixture of compounds.

3.27 Circadian rhythm: unique cycling of aprocess in a living organism that could be onthe scale of minutes to decades.

3.28 Coefficient of variation: the standarddeviation divided by the representative value(often the arithmetic mean), all multiplied by 100.

3.29 Conjugate: the product of a reaction of anexposing chemical or its metabolite with anendogenous biochemical pathway.

3.30 Control chart: a plot of marker concentra-tion versus time for a worker or a group ofworkers.

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3.31 Detection: qualitative analysis of acompound, element, or material.

3.32 Detection limit: the concentration or amountthat corresponds to four times thebackground signal or a signal/noise ratio of 3;this is a laboratory-dependent variable. Alsocalled the limit of detection (LOD).

3.33 Determinant: the substrate, marker, orindicator to be measured in a biologicalsystem.

3.34 Dipstick: an impregnated stick that changescolor when exposed to the analyte at adesignated concentration.

3.35 Direct-reading instruments: Instrumentsthat give almost instantaneous readings.

3.36 Dose response: the linear correlation of abiological effect or biological parameter withexposure dose.

3.37 Dynamic air sampling: air sampling with apump.

3.38 Edema: swelling from fluid accumulation incells or tissues.

3.39 Element: an atom with a characteristicatomic number (number of protons).

3.40 Elimination: internal clearance of a markerfrom an internal organ.

3.41 End-exhaled breath (alveolar exhaledbreath): the exhaled breath forced from thelungs after natural exhalation.

3.42 End-of-shift sampling: sampling at the endof the work shift.

3.43 Endogenous: intrinsic; found naturally in theliving system under study.

3.44 Engineering controls: controls thatmanipulate the physical work environmentand that do not involve personal protectionequipment.

3.45 Enzyme: an agent that catalyzes a biologicalreaction and that is not itself consumed in thereaction.

3.46 Ethics: the discipline of the conduct of aperson or the members of a professiondealing with what is good and bad, and withmoral duty and obligation.

3.47 Excretion: appearance of a marker outsideof the body.

3.48 Exposure: how a material contacts the bodyand how much.

3.49 Field blank: a sampling container (and anypresampling contents) that is subjected tothe same operational sampling procedures inthe field as the real sample in parallel withoutactually taking the sample.

3.50 Fluids: a state of matter that flows underpressure; that is, gas and liquid states.

3.51 Formulation: a mixture of compounds usedfor specific industrial or user purposes.

3.52 Fume: aerosol that is produced fromcondensation of vapor or gas.

3.53 Gas: the standard state of matter that amaterial or compound has that is whollygaseous at a specified temperature andpressure.

3.54 Genetic factors: determined by the genes(DNA).

3.55 Glutathione: the tripeptide Glu-Cys-Glywhere Glu is glutamic acid, Cys is cysteine,and Gly is glycine.

3.56 Hair: the flexible shaft of distinct coloring thatprotrudes from the skin surface.

3.57 Half-time (pseudo first order): t0.5 = 0.693/kwhere k is the pseudo first-order process rateconstant in units of time-1.

3.58 Health surveillance: the measurement ofchemical markers in body media that may beindicative of health effects to chemical,physical, and biological agents.

3.59 Homeostasis: the normal state of stablecontrol of various body parameters liketemperature, osmotic pressure, and so forth.

3.60 Hormone: a chemical agent secreted by onegland to act at another gland or organ.

3.61 Hydrolysis: reaction of a molecule withwater.

3.62 Hypersensitivity: a state of susceptibilityabove the norm.

3.63 Immune response: chemical/cellularresponse of the body to an antigen orinvading microorganism.

3.64 Informed consent: written consent providedby the worker for procedures that will involvethe worker before they are instituted.

3.65 Inhalation: the inspiration or breathing in ofair into the body.

3.66 Inorganic: a compound that does notcontain carbon.

3.67 Interindividual variation: variation ofmarker concentrations between individualsexposed to the same concentration ofexposing agent.

3.68 Internal dose: the amount of xenobioticactually absorbed by the body.

3.69 Internal standard method: the standardcurve is constructed by plotting the ratio ofthe analyte response relative to that of aspecific amount of a reference compoundadded to all samples versus analyteconcentration.

3.70 Intrinsically safe: conditions that are notimmediately dangerous to life and healthwithin 30 min.

3.71 Ionizing radiation: radiation that ionizes theoxygen of air.

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3.72 Kidneys: the pair of organs responsible forconserving body macromolecules, excretinglow molecular weight end products ofmetabolism and catabolism in the urine, andmaintaining body salt balance.

3.73 Label: (1) the identifiers on an individualsample container; (2) the identifier insertedinto an atom or molecule that allowsdetection.

3.74 Lean body mass: mass of body muscle.3.75 Limit of detection (LOD): see detection

limit.3.76 Limit of quantitation (LOQ): see lower

quantifiable limit.3.77 Liver: the major organ of metabolism,

catabolism, and anabolism of the body andthe major one for conjugation; it excreteshigh molecular weight conjugates in the bile.It also stores glycogen.

3.78 Lower quantifiable limit (LQL): theconcentration or amount that corresponds to11 times the background level or asignal/noise ratio of 10. Also called the limitof quantitation (LOQ).

3.79 Lungs: the pair of organs responsible foroxygen and carbon dioxide exchange for theblood of the body through inhalation andexhalation.

3.80 Macromolecules: high molecular weightbiochemicals such as proteins,phospholipids, glycosides, nucleic acids, andtheir mixed analogs such as glycolipids,lipoproteins, and chromatin (nuclearprotein/DNA complex).

3.81 Marker: the determinant to be measured inhuman body media.

3.82 Matrix spike: a known amount of analytespiked into the sample that is to bereanalyzed. Also called “spiking.”

3.83 Medical monitoring: the measurement ofchemical markers in body media known to beindicative of adverse health effects (clinicalmarkers).

3.84 Medical removal: the removal of the workerfrom the workplace for medical reasons.

3.85 Medical screening: a method to detectdisease or body dysfunction before medicalcare is sought (OSHA).

3.86 Medical surveillance: the measurement ofchemical markers in body media that indicateexternal exposure to chemical, biological,and physical agents and/or of potentiallyadverse effects.

3.87 Medical surveillance: the analysis of healthinformation to look for workplace problemsthat require targeted prevention (OSHA,NIOSH).

3.88 Metabolite: a stable product of thebiochemical alteration of an exposingchemical.

3.89 Midstream urine: a urine sample taken withthe first couple of milliliters discarded toeliminate potential microorganisms or sperm.

3.90 Mixed exhaled breath: the breath that isnaturally exhaled without forcing.

3.91 Molecular epidemiology: epidemiologystudies on populations concerning biologicalmonitoring and genetic markers.

3.92 Molecular weight: the weight of all theatoms in a molecule relative to carbon 12C6.

3.93 Mutagenicity: altered DNA.3.94 Negative interference: an interference that

causes the observed value to be decreasedrelative to its true value.

3.95 Occupational illness: an abnormal healthcondition caused or contributed to by anoninstantaneous event or exposure in thework environment (OSHA).

3.96 Octanol/water coefficient: the ratio of thesolubility of analyte in octanol to that in waterat the same temperature.

3.97 Odor threshold: the air concentration atwhich odor can be perceived.

3.98 Oxidation: gain of oxygen or loss ofhydrogen for a compound or atom, or loss ofelectrons or gain in oxidation number for anatom.

3.99 Oxide: the compound that results afterreaction of a metal element with oxygen.

3.100 Passive air sampling: air sampling withouta pump; also called diffusive air sampling.

3.101 Pathogen: an agent that causes disease.3.102 Personal breathing zone air sampling: the

sampler is located on the lapel of the workerduring integrated air sampling.

3.103 Personal protective equipment (PPE):materials or equipment worn to protect theworker.

3.104 Pesticide: an agent that controls or killspests.

3.105 pH: the minus logarithm to base 10 of thehydrogen ion activity (which for the pH range1–11 at 25°C is equal to the hydrogen ionmolar concentration in aqueous solution).

3.106 Phase I process: biotransformationresulting in reduction, oxidation, orhydrolysis, of a xenobiotic.

3.107 Phase II process: bioconjugation of axenobiotic and its Phase I metabolites by anonmacromolecule biochemical.

3.108 Plasma (blood): the liquid that does notcontain the cellular components of blood onsitting or mild centrifugation of a bloodsample. It contains the ionic fraction of blood.


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3.109 Positive interference: an interference thatcauses the observed value to be increasedover its true value.

3.110 Precision: how reproducible the data are.Precision is usually expressed as thecoefficient of variation (CV) of the data. Thereare several types of precision: intrarun, theCV of the same sample run multiple times;interrun, the CV of replicates of the samesample or concentration.

3.111 Preservative: a compound added to asampling container to preserve the analyteand its concentration and to preventmicrobial growth in aqueous and biologicalmedia.

3.112 Quality assurance: the proof of theaccuracy and precision of the measurementsprocess.

3.113 Quality control: the written program or setof operating procedures to achieve control ofthe measurements process.

3.114 Relative response factor: the detectorresponse relative to that for a referencecompound.

3.115 Replicate analysis: the analysis of splitsamples.

3.116 Respirable aerosol: the aerodynamicdiameter is <10 µm.

3.117 Sampling: to collect or take a portion of thewhole.

3.118 Sebum: the waxy excretion on the skinsurface.

3.119 Selectivity: specificity.3.120 Semen: the viscous creamy fluid obtained

from the penis on ejaculation.3.121 Serum (blood): the clear liquid that appears

on blood coagulation.3.122 Skin: the outer solid layers of the body; that

is, the stratum corneum, the epidermis, andthe dermis.

3.123 Solubility: the maximum (saturation)amount of a solid that a specified solutionvolume can contain without a precipitatebeing evident.

3.124 Specific gravity: the density of a material orcompound relative to that of water at thesame conditions.

3.125 Spectroscopy: the use of electromagneticradiation for detection and quantitation ofmatter.

3.126 Sperm: the cell of the semen that containsthe male contribution to genetic inheritance.

3.127 Spot urine sample: urine sample collectedas a single void at a designated time.

3.128 Sputum: watery fluid with solids excretedfrom the throat and upper lungs onexpectoration.

3.129 Standard operating procedures (SOPs):the procedures that are used routinely, inwritten form.

3.130 Standard reference material (SRM): a bulkmaterial that has been analyzed by severaldifferent analytical techniques for use inquality assurance.

3.131 Symbiotic: living in mutual association.3.132 Time and motion study: a study to assess

how much time and how much motion aworker expends during the work shift orduring unit processes.

3.133 Trace metals: the metals that are not in highconcentrations in the body.

3.134 Twenty-four hour urine sample: acumulative urine sample taken (all voidscollected) over 24 hours.

3.135 Unit process: a characteristic sequence ofsteps.

3.136 Uptake: analyte mass absorbed divided byanalyte mass exposed to over a specific timeperiod.

3.137 Urine: the yellowish, watery nonviscousexcretion from the bladder voided by thepenis in males and by the urethra in females.

3.138 Vapor: the gaseous state of a compoundabove its standard state liquid or solid at aspecified temperature and pressure.

3.139 Vapor pressure: the pressure exerted by acompound at a specific temperature andexternal pressure when the air is saturatedwith the compound.

4. Significance and UsesSignificance• This is the first field manual on biological monitoring for

field and intending industrial and environmentalhygienists and for other occupational healthprofessionals.

• Previous books on biological monitoring haveconcentrated on the science associated with the field;this manual considers management, policy, ethics,legal issues, and other issues germane to the practiceof industrial hygiene and occupational health.

• The language in this manual is as nontechnical aspossible to allow use by many different people and atmore levels of education.

• The manual employs a multidisciplinary andinterdisciplinary holistic approach.

• The manual contains the first case studies of biologicalmonitoring in any book on the subject.

• The manual contains the first slide show to bepublished on the principles of biological monitoring.


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Uses• The manual contains information to allow a field

occupational health professional to set up, run, andterminate a biological monitoring program.

• The manual contains information pertinent to theinteraction of the health professional, the worker,unions, and corporate administration relative to abiological monitoring program.

• Case studies are provided to illustrate the practical useof biological monitoring.

• The manual contains a question and answer section onbiological monitoring that focuses on lead andbenzene, two major toxicants with which alloccupational health professionals must be able to cope.

• The manual contains citations to reviews on biologicalmonitoring appropriate for all levels of scientificknowledge to facilitate further information on broadissues being obtained.

• The manual contains an example of consent forms asmodels.

• The manual contains pictorial material in the form ofslides to allow beginners to grasp the essentialscientific principles of biological monitoring, and thentests this knowledge applied to benzene and lead in aquestion and answer format.

• The manual contains essential knowledge for industrialhygienists to help them communicate with industrialhygiene chemists.

5. Elements of a BiologicalMonitoring Program in anOccupational and EnvironmentalHygiene Program5.1 ObjectiveBiological monitoring is the measurement of compoundsin, or the affected components of, body fluids of thehuman body by chemical or physical methods.

Biological monitoring is an important tool in anoccupational and environmental hygiene program. Undercertain exposure scenarios, such as when a chemicalagent is absorbed through the skin, air monitoring resultsare not adequately related to exposure or health risk.However, because biological monitoring involves uniqueethical issues, more planning and more resources arerequired to ensure valid results than for air monitoring.For these reasons and others, the occupational andenvironmental health function within an organization mustdefine the role of biological monitoring before programdevelopment.

Among the issues that should be resolved prior toimplementing biological monitoring programs is to definethe position of an organization’s top management onbiological monitoring. Very few regulations in the United

States require biological monitoring. These includebenzene,(1) lead,(2) and cadmium.(3) Under mostcircumstances biological monitoring is consideredbecause it will provide a more accurate measurement ofhealth risk than air sampling. Management may wish tolimit the role of biological monitoring in an occupationaland environmental hygiene program to a certain set ofcircumstances to ensure ethical issues are addressed, tolimit legal liabilities that might arise from the data, and todeploy scarce resources wisely. It will be necessary forthe occupational and environmental hygiene professionalto explain the value of biological monitoring to facilitymanagement in terms of worker productivity, cost/benefit,and company aims, and to help define the potential roleof biological monitoring within the existing occupationaland environmental hygiene program.

If the work force of a facility has a union, the unionleadership should be consulted in the planning phase toensure that the union is convinced that adequateprotections guaranteeing the confidentiality of the workerare in place. The understanding and support of a unioncan help enlist the cooperation of the work force in abiological monitoring program. It will be necessary for theoccupational and environmental hygiene professional toexplain the value of biological monitoring to unionleadership in terms of worker health and union aims.

Proposed training programs at all administrative andworker levels must also be integrated within the biologicalmonitoring program during the planning stages.

5.2 Defining Biological MonitoringA definition of biological monitoring must be developed toexplain the explicit role of biological monitoring within theoccupational and environmental hygiene program and toexplain to management and to the workers whatbiological monitoring is, and what it is not. Generally,biological monitoring is defined as the assessment ofhuman exposure through the measurement of internalchemical markers of exposure, such as the chemicalagent itself and/or one of its metabolites or an exposure-related biochemical change unrelated or related todisease, in human biological samples. Biologicalmonitoring is not air monitoring for microbes.

It is important to place biological monitoring inperspective relative to health monitoring and medicalmonitoring. The latter two can be defined as periodicassessment of the health status of workers to detect earlyeffects (health) or clinical effects (medical). Biologicalmonitoring is generally not intended to detect the earlymedical signs or effects of chemical exposure and isconsidered part of health monitoring. This distinction canhave implications on record keeping and confidentiality.Frequently, occupational and environmental hygieneprofessionals are not given access to the results ofmedical monitoring (clinical chemistry results) because ofpatient confidentiality. To implement exposure controls,


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hygienists must have access to exposure monitoringresults, which include data from biological monitoring.Unfortunately, the situation is not necessarily clear-cut inthe cases of blood acetylcholinesterase activity,methemoglobin content, carboxyhemoglobin content, andβ2-microglobulin urine concentration, which are markersof adverse effect also utilized in biological monitoringprograms and which have American Conference ofGovernmental Industrial Hygienists Biological ExposureIndex (ACGIH BEI) guidance.(4,5)

Like air monitoring results, biological monitoringresults of occupational exposure to a specific chemicalare considered to be exposure monitoring, not medicalresults.(6) As such, they can be communicated topersonnel who were not monitored but similarly exposed.However, some parameters that are measured in abiological monitoring program, such as β2-microglobulinin the case of cadmium exposure, are not unique to aspecific exposure and may be a result of a preexistingmedical condition. Therefore, careful consideration mustbe given when communicating results to employees whowere not monitored, taking care to protect the privacy ofthose who were monitored.

5.3 When is Biological MonitoringAppropriate?The definition of biological monitoring adopted by theorganization and the role of biological monitoring in theoccupational hygiene program will determine whichexposure scenarios are selected for further evaluationusing biological monitoring. In the industrial setting,biological monitoring is often an adjunct exposureassessment tool to air monitoring. For exposurescenarios in which air monitoring does not adequatelymeasure exposure from all routes, biological monitoringshould be considered.

Exposure scenarios in which air monitoring isinadequate include the following.• When the chemical agent is known to pass through the

skin or is ingested• When the chemical agent possesses a long biological

half-life• When respiratory protection or other personal

protective equipment (PPE) such as gloves or otherprotective garments are used.

Major instances in which biological monitoring isjustified occur when symptoms of overexposure areevident or are experienced by the worker when airmonitoring results imply that inhalation exposure is nothazardous. The definition of biological monitoring and therole biological monitoring plays within the occupationaland environmental hygiene program should clarify whenbiological monitoring is justified within an organization.

Biological monitoring also may be dictated bygovernment regulation.(1–3) In the United States biological

monitoring for lead,(2) cadmium,(3) and benzene(1) arerequired by the federal Occupational Safety and HealthAdministration (OSHA) under certain conditions. See theQ&A section in Appendix I for requirements for lead andbenzene.

To ensure that scenarios justifying biologicalmonitoring are effectively and consistently identified, fieldhygienists should be trained in the role of biologicalmonitoring in their specific occupational andenvironmental hygiene programs.

5.4 Cautionary Notes on BiologicalMonitoringBiological monitoring must be approached with greatercare than air monitoring. Because the data are directmeasures of the intakes or biological effects of absorptionof chemicals after exposure, biological monitoring resultsare generally more meaningful to worker health than areair monitoring data. The sampling procedures are moreinvasive. Urine, breath, or blood sampling are generallyinvolved in a biological monitoring program. Workers maybe concerned that the samples might be used for drugtesting or other purposes unrelated to workplacechemical biological monitoring.

Biological monitoring data can be highly variable,with elevated levels one day followed by low levels thenext. This may be caused by differences in exposure time;exposure frequency; exposure intensity during workshifts; work practices; the protection afforded by PPE;occurrence of spills and accidents; and differences ineach worker’s absorption, metabolism, and excretion ofthe exposing chemical; or a mixture of all these factors.The effects of confounding exposures, both on and off thejob, must also be considered. This variability makes theinterpretation of results and communication to workerschallenging. The hygienist’s task is to assign thecontribution of the workplace exposure and recommendcontrol and prevention measures.

The sampling and analytical procedures of abiological monitoring program can be more complicatedand critical to the interpretation of the results than thoseof an air monitoring program. The timing of samplecollection relative to exposure can affect the validity of theinterpretation for some chemical agents. The mediasampled, generally urine or blood, are complex. Thisplaces unique demands on the analytical method andincreases the need for an effective program of qualityassurance/quality control (QA/QC). Lastly, analyticalcosts generally are higher. All of these factors togetherhighlight the need to plan a biological monitoring programcarefully to achieve the objectives.

5.5 Roles and ResponsibilitiesBiological monitoring requires input from a number oftechnical disciplines. The hygienist is required to definethe objectives of the program and the sampling strategy


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and to recommend control and preventive measures.Having a capable occupational physician as a resource isessential. Other resource personnel may be necessarydepending on the task at hand.

Questions that should be addressed prior to thedevelopment of a program include the following.• How will situations justifying biological monitoring be

identified? If the organization intends to place theresponsibility on field hygienists to identify exposurescenarios for which biological monitoring is justified,training and guidance will be required to ensure aconsistent approach is applied throughout theorganization.

• Who will be involved in program development? Someorganizations may choose to centralize the process ofbiological monitoring program development to ensurethat ethical issues are adequately addressed, that theapproach is consistent companywide, and thatresources are effectively used. A central steering teammay coordinate and approve biological monitoringprograms and new biological monitoring requests. Aconsulting team consisting of an analytical chemist,toxicologist, epidemiologist, biostatistician, andoccupational physician may need to be assembled.

• Who will review and approve the program? In additionto an occupational and environmental hygienist and anoccupational physician/nurse if available, it is useful toinclude representatives from human resources, thelegal department, and a respected high administrator.Another alternative is to seek biological monitoringprogram accreditation on important activities fromaccrediting bodies outside the organization.

• What is management’s role? Management must beintimately involved in all phases of the biologicalmonitoring program.

• Who pays for method development and sampleanalysis? Resources should not be a limiting factor forthose scenarios in which biological monitoring isjustified and necessary to answer key questions aboutexposure. Consultation with an analytical chemistryresource may be required to choose, evaluate, ordevelop the sampling and analytical methods and todesign the QC/QA procedures. High methoddevelopment costs may delay the implementation of abiological monitoring program. A cost/benefit analysis isusually crucial to obtain management support.

• Who interprets the results? A consulting team ishelpful. A physician may be needed to interpret theresults for legal purposes. To communicate the resultseffectively to the worker, the aid of hygienists isessential, and nurses may also be effective. The help oftoxicologists, biostatisticians, and epidemiologists mayalso be necessary. Analytical chemists are useful toensure sampling and analytical results are adequate.Results must be communicated to the appropriateparties as soon as practical, but they must be accurate

and readily understandable. Any supporting data andinformation such as for QC, questionnaires, andobservations from the field must be reviewed to ensurean accurate, thorough, and balanced interpretation.

• How will results be reported to participants? Tomanagement? How will confidentiality be assured?Biological monitoring data should be communicated ina manner that protects individual confidentiality butallows everyone to understand the impact of workpractices on exposure levels. Exposure assessmentdata, including biological monitoring data, can motivategood workplace hygiene practices.

5.6 Developing a Process to Create aBiological Monitoring Program

Before any sampling is conducted, the exposureconditions and biological monitoring index, determinant,or marker must be carefully evaluated to determine ifbiological monitoring is scientifically justified for theexposure scenario. It is absolutely necessary thatmanagement be supportive of the program. Ifmanagement has already taken a position on the role ofbiological monitoring in the facility’s occupational andenvironmental hygiene program, this position should bereviewed and used as a basis for starting or expandingother biological monitoring programs.

All in-house exposure data should be reviewed. If airmonitoring data have been adequate and low relative tothe exposure limit, and dermal absorption or ingestion arenot relevant routes of entry, biological monitoring may notprovide additional useful exposure information unlessclinical symptoms and health complaints have occurred.The current exposure assessment methodologies should,in some way, require biological monitoring to provide amore complete exposure assessment.

The source of the request for biological monitoringshould also be considered. If a group of workers or aworkers’ union expresses concern about an exposurescenario, biological monitoring might be a goodtechnique to reinforce the existing exposure assessment.Because biological monitoring is a more direct measureof chemical intake from all routes, the results might bemore persuasive than air monitoring results.

The current biological monitoring indices andanalytical methods should also be read and evaluated.The index should be appropriate to the exposurescenario. For example, the ACGIH BEI for chromium iscurrently applicable to only a specific type of chromiumexposure, manual metal arc stainless steel welding.Certain BEIs require a month or two of exposure prior tobiological monitoring to build up the body burden to asteady state level. Likewise, the analytical methodreferenced in the BEI or other source should beevaluated, and a laboratory capable of performing themethod should be identified. If possible, the laboratoryshould be accredited. An initial determination should be


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performed to assess whether the sampling and analyticalmethods recommended in the BEI are feasible in thefacility and for the actual workplace exposure scenario.

If these evaluations conclude that biologicalmonitoring is justified for the exposure scenario, it isrecommended that a team be assembled to develop,review, and implement the biological monitoring program.The team must include representatives from the facility’soccupational and environmental hygiene andoccupational medicine functions, as well as from uppermanagement. An analytical chemist is necessary toconsult on the sampling and analytical chemistrymethods and the QC and QA procedures. Otherpersonnel, such as toxicologists, biostatisticians,epidemiologists, or medical specialists, might bevaluable.

The exposure scenario must be thoroughlyevaluated. A summary of the work process should bedone to reveal the degree of dermal contact, and themetabolic load or work required to complete the tasks.Groups of workers who appear to be similarly exposedshould be defined. Exposure variability within eachapparently similar group should be assessed. Forexample, exposure of maintenance personnel who mayperform many different tasks may vary greatly. In contrast,the exposure of a group of workers that performs a singleset of simple tasks on a continuous process may varylittle during the work shift or even from day to day.Variability of exposure during the work shift andworkweek should be assessed and used to define asampling strategy.

If exposure to other compounds is possible duringwork, the exposure potential to these other compoundsmust also be assessed. The type and efficacy of PPEshould be recorded. It is desirable to observe the work tojudge whether PPE are being used properly. The numberof workers involved in the process and the length of thework shift and workweek schedule must be obtained.Workers should be categorized based by their productionresponsibilities (such as maintenance, production, orsupervision).

Information on the relevant biological monitoringindex or marker should be assembled. The most commonsource for biological monitoring indices are the ACGIHBEIs and the German Biologische Arbeitsstoff Toleranz—Werte (BATs). The documentation that describes thejustification for the index and the key parameters on howthe index is to be applied must be thoroughly reviewed.The documentation will include a review of theabsorption, toxicokinetics, metabolism, and excretion ofthe chemical agent. Other issues that can be found in thedocumentation include information on compounds thatcan confound the results from occupational,nonoccupational, and endogenous sources; medicalconditions and medical remedies that can influence theresults; and the requirements and interferences of theanalytical methods

The information assembled should be reviewed todetermine if biological monitoring is necessary. The teammust determine if there is anything to be gained bybiological monitoring. Some crucial questions to beanswered relative to conditions in the specific workplaceinclude the following.• Is the index appropriate for the exposure scenario?• Are sample collection and the analytical method

feasible and cost effective?• Can potential confounding exposures or medical

conditions or treatments be controlled or determined?

The critical decision, at this point, is to determine whetherthe current exposure scenario justifies biologicalmonitoring and whether biological monitoring is feasible.

5.7 Elements of a Written BiologicalMonitoring ProtocolIf the exposure scenario justifies biological monitoringand the program is feasible, a written protocol should bedeveloped. This protocol will guide all facets of thesampling and analytical method and will be used as thebasis to inform management and employees about theprogram and its results.

The following elements should be included in aprotocol.

5.7.1 ObjectiveThe protocol should define why biological monitoringis being conducted and what questions the programwill answer. Defining the purpose of the biologicalmonitoring program is essential to ensure theprogram answers the proper exposure questions andto know when the program can be stopped.

5.7.2 Process SummaryThis describes the process and the exposurescenario, including the activities of each group ofsimilarly exposed workers, the potential for dermalcontact or ingestion, and the PPE used. Informationcollected on the degree and duration of exposure tothe compound of interest and any compounds thatcan potentially confound the results should besummarized in the protocol.

5.7.3 ParticipantsThe workers to be included in the biologicalmonitoring program must be clearly defined. Amongthe questions to address include: How manyparticipants are necessary to answer the purpose forbiological monitoring? Will every worker in anexposure group participate or only a portion of thegroup? Will workers from all shifts and work groupsbe included? Will participation be voluntary? Is a no-exposure negative control group needed? Willbaseline samples be taken? A checklist approach willbe valuable.


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One advantage of biological monitoring over airmonitoring is that the cost of the program willincrease with the number of analyses and number ofsample containers. There will be no large extra costssuch as for sampling pumps: the number of workerssampled is not limited by that of the sampling pumpsavailable, for example.

The number of participants included in theprogram from each similarly exposed group is afunction of the expected variability within each group.Everyone within groups that perform highly variabletasks from day to day or week to week such asmaintenance workers should be included. All workersexposed to unknown amounts of many chemicalsshould also be included, as for hazardous wasteworkers. Workers who perform similar tasks day inand day out could be represented by a randomsample. Because of individual differences in personalhygiene, absorption/metabolism/elimination ofexposing compound, and nonoccupationalconfounding exposures, the usual practice is toinclude everyone initially within the exposure group inthe biological monitoring protocol. All work shiftsshould be included in the program. Once it isdetermined who absorbs the most and whether theseexposures are near any guidelines, some changescan be made as to which workers need continuedsampling.

The above then leads to the question of whetherparticipation should be voluntary. In the UnitedStates, OSHA and the courts have generally said thatworker participation in occupational hygiene andoccupational medicine programs is voluntary. U.S.regulations require that the employer make certainhygiene and occupational medicine programsavailable to the employee, but do not require thatworkers participate in these programs unless theemployer requires participation as a condition ofemployment. A full discussion of these issues is notwithin the scope of this guideline. Any employerconsidering requiring worker participation in abiological monitoring program should obtain aqualified legal opinion to ensure that the properdocumentation and communications are made. SeeSection 8.2 on Ethical and Legal Aspects.

If participation in the biological monitoringprogram is voluntary, there is a risk that workers withthe highest exposures may elect not to participate forfear of losing their jobs. Effective communication ofthe value of the program to the participants throughin-depth training on the topic should help maximizethe number of participants. The industrial hygienistwill usually be the person to do worker training, andhe or she must be able to articulate the concepts inlanguage, symbols, and terms the workerunderstands. It is also important to communicate toworkers what will happen to their individual and group

results, and the ultimate impact. Ideally,understanding the reasons behind the program andwhat it is trying to do will have a beneficial effect onworkers by improving their knowledge of theprocedures for handling hazardous chemicals. Thismay also lead to greater productivity.

5.7.4 Collection ScheduleThe hygienist will be required to define the monitoringstrategy. Will participants be sampled every day,every week, every 6 months? How manyweeks/years will the program last? When will it end?A checklist for each marker and worker monitored ishelpful to define confounders and interferences suchas smoking, medicinal drugs, alcohol, health status,hobbies, and transit mode.

A permanent biological monitoring program isvery rare. The sampling strategy should be designedto answer the purpose for biological monitoringefficiently. The number of samples and length of theprogram should take into account the variabilityexpected in the sample results. If variability is low,meaning exposure is consistent throughout the workshift and workweek, a lower number of samples willbe required to complete the exposure assessment.Characterizing exposure in a worker population withwidely variable biological monitoring results will takemore samples, more time, and will be moreexpensive.

A collection schedule for a work group with littleexposure variability may involve collecting samplesevery work shift from every worker for 2 weeks. Ifexposure variability from the work tasks performed bythe group is higher, the duration of the program mayneed to be extended.

It is often useful to analyze samples obtainedpreshift or at the beginning of the workweek toestablish a baseline for measuring a rise of thedeterminant during the work shift or workweek. Apreexposure sample is useful to show thatnonoccupational exposure is contributing to thebiological monitoring results. Such a sample is alsouseful to demonstrate holdover from the previousday’s workshift exposure for markers of half-timegreater than 5 hours.

The timing of sample collection is a keyparameter of the biological monitoring program. Thedocumentation of the biological monitoring index willinclude the recommended timing of samplecollection. Generally, samples are collectedimmediately at the end of the work shift for biologicalmonitoring indices with elimination half-times lessthan 5 hours. For markers with elimination half-timesbetween 5 and 20 hours some accumulation duringthe workweek is likely, and samples are collected atthe end of the work shift at the end of the workweek,


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or prior to the last shift of the workweek. The timing ofsample collection is less critical for markers withelimination half-times longer than 20 hours, althoughadequate sensitivity could then become a problem.Coordinating biological monitoring sample collectionwith air monitoring is desirable to allow directcomparison of air monitoring and biologicalmonitoring data.

5.7.5 Collection ProcedureThe sample collection procedure must be developed.Will samples be collected in a clinic or in anotherlocation? How will contamination of the sample beprevented? If the biological monitoring indexcompound is the marker of interest, such as cadmiumor lead, strict procedures to prevent thecontamination of the biological monitoring samplemust be in place. If the marker is a metabolite, the riskof contamination is reduced.

Instructions to participants on how to collect thesample should be developed. If contamination of thesample is a concern, it might be desirable to have theworkers shower, or at least wash their hands, prior tosample collection. Markers with very fast eliminationhalf-times might require participants to refrain fromurine voiding for a period up to 4 hours prior tosample collection to permit a time-weighted averagemeasurement. The alternative is to collect all voidsduring the work shift. Some markers may require 24-hour urine sampling. Generally, the worker shouldempty the bladder just before the work shift. Thissample can be retained as a baseline sample.

The collection vessel must be specified and howthe sample is to be collected documented. Certainblood collection tubes contain stabilizers that canaffect the concentration of the determinant andshould be avoided (see Section 6.3). Samplepreservatives may be required for certaindeterminants to prevent degradation. Storagerequirements and shipping conditions must bespecified. Is refrigeration adequate, or will storage at–70°C be required to minimize degradation? Howlong can samples be stored before degradation issignificant? Sample labeling and chain of custodyprocedures should be defined. To preserve theconfidentiality of the participants, it is good practice tocode the samples rather than marking them with thename of the participant.

5.7.6 Questionnaire AdministrationTo document the effects of confounding exposures,the tasks performed during the exposure period, thetime-course of the participant’s day, any observationsof participants, and PPE used during the work shift,an is effective to ask the participant to complete aquestionnaire or checklist at the time of sampling. Fora determinant with a short elimination half-time lessthan 5 hours, it is necessary to document when

during the work shift the exposure occurred. Forexample, if the majority of exposure occurred in thefirst hours of the work shift and sample collectionoccurred at the end of the work shift, urine markerresults will underestimate exposure unless nourination has occurred. Also, exposures in the secondhalf of an 8-hour shift may also cause exposureunderestimation for urine markers of half-livesgreater than 5 hours because there has not beentime for metabolism or excretion.

5.7.7 QCThe procedures to be used to assess confidence inthe analytical results should be documented. QC canbe assessed throughout the program by the use ofblanks, samples from personnel who are not knownto be exposed to the agent of interest, duplicates(where a sample is split into two samples andanalyzed separately), and spiked samples (where aknown concentration of the analyte is added to onesample of a split). The QA program should describehow the QC results are to be interpreted and theactions that will be taken if results are not acceptable.

5.7.8 DocumentationThe protocol should describe the documentation tobe created and retained from the program. At aminimum, analytical results and reports to theparticipants should be retained during theemployment period of each worker. OSHA requiresthat exposure monitoring records be retained for thelength of the employment plus another 30 years.Computer skills are now essential for industrialhygienists in the documentation, review, andreporting results segments.

5.7.9 Analytical ProceduresThe analytical procedures to be used to find theconcentration of the determinant in the sampleshould be documented. The limit of quantification(LOQ) should be determined and included in theprocedures.

5.7.10 Reviewing and Reporting ResultsPrior to implementing the program, the process to befollowed to evaluate QC, questionnaire, and rawexposure analytical data should be defined. Theprotocol should also describe how results will bereported to the participants. For biological monitoringprograms that will be completed in a matter of weeks,it might be acceptable to report all results toparticipants at one time at the completion of thestudy. If the program is to last for several months oryears, participants should receive their resultsperiodically but at specified intervals. If results are tobe collected and reported at the end of the program,it might be necessary to define a trigger value forimmediate reporting to the participant. The protocolshould also describe the method by which results will


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be reported to participants and supervisors. Theprotocol should also define how confidentiality ofparticipants will be assured. If a biological monitoringmarker concentration regarded as cause for medicalattention is exceeded, the physician who is toexamine the worker should be named together withcontact information. Similar information should beprovided for the threshold for medical removal.

5.7.11 Follow-Up ActionsThe protocol should address when continuedbiological monitoring is justified. Programs involvingcompounds on the U.S. Environmental ProtectionAgency Toxic Substances Control Act (TSCA) 8E listmay need to be reported to a regulatory agency.

The protocol should be at least annually reviewedand approved by appropriate worker representatives,technical resources, and management.

5.8 Sampling and Analytical Method IssuesContract labs generally are not as proficient withbiological monitoring samples as with samples from airmonitoring. Media sampled for biological monitoring,generally blood or urine, are complex. This can placedemands on the analytical method and the analyst. Inaddition, there are few proficiency test programs forbiological monitoring indices (Pb in blood, and Cd in urinehave such programs). To assure confidence in the results,labs must be prequalified

Elements of a prequalification program include thefollowing.• The prequalification samples must be the media to be

sampled in the biological monitoring program. Spikedsamples of water or solvent will not result in anadequate challenge of the lab.

• The analyte sent to the lab should be the chemical formof the analyte seen in the biological medium. Forexample, if the analyte is excreted conjugated, methoddevelopment and validation should use the conjugatedanalyte. This may not always be possible.

• The sampling and analytical method should always bethe method referenced in the documentation for theindex. The index was based on the analytical resultsobtained in studies referenced in the documentation.Different analytical methods might yield differentanalytical results. If a new method is developed, it mustbe compared with the method referenced in thedocumentation on a performance basis.

• The analytical method should be validated to at least10% of the index. The LOQ and accuracy of themethods should be determined. The intrarun precisioncoefficient of variation should never exceed 10% in theworking range.

• If the medium is urine, and creatinine corrections will beused, the creatinine analytical method must also bevalidated. If urine volume is to be utilized, a specific

gravity correction must be applied, meaning that themethod of measurement of specific gravity must bevalidated, and that the specific gravity must bemeasured on the fresh urine sample.

• The stability of the analyte in the storage conditionsexpected in the study should also be assessed andcontrolled.

• Pretreatment of the sample with citric acid or otherpreservative might be required. The efficacy of thepretreatment procedures should be assessed on thesame types of samples to be analyzed.

A large potential source of variability in a biologicalmonitoring program is the sampling and analyticalmethod combination. With proper prequalification and on-going QC this variability can be nearly eliminated, so thatthe observed variability arises from the person sampledand not the methods used to sample and analyze theperson’s sample. This becomes an important factor todecide the extent of interindividual variability and whetherthe biological monitoring program should be modified.

5.9 Implementation of a BiologicalMonitoring ProgramPrior to taking the first sample, the protocol and the resultsof method development should be presented toappropriate worker representatives, technical resourcepersonnel, and management. Thorough communication atthis early stage will minimize controversy and variability.

The first step in implementing a protocol is to educateand address the concerns of the participants. Theparticipants must understand the purpose of the programand the advantages of biological monitoring over airmonitoring in this circumstance. They need to be familiarwith the sample collection and analytical procedures andbe assured of confidentiality. It might be necessary todevelop a procedure covering the disposition of unusedportions of samples that includes assurances thatadditional analyses will not be performed without theindividual’s approval. If the latter instance arises, theindustrial hygienist may have to develop a consent form(see Appendix V for examples).

The communication sessions should allow questionsso the expectations and concerns of participants areunderstood, and to facilitate trust.

5.10 Data Analyses, Reporting, and PeriodicReviewOSHA regulations require that, at a minimum,participants need to have access to their results. OSHA’slead and cadmium standards require that employeesshall be informed of their results. It is good practice tonotify each individual of his or her results as soon aspossible. For projects that are limited to a few weeks,reporting cumulative results for the entire study periodmay be desirable.


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Data from QC samples and information aboutconfounding exposures should be reviewed. The effectthese data may have on an individual’s results should beevaluated and reported to the participant. The creatininelevels of urine samples should be reviewed, with resultsdiscounted if the creatinine concentration is less than 0.5g/L or greater than 3 g/L. Urine specific gravity resultsshould be 1.003–1.030. The National Institute forOccupational Safety and Health (NIOSH) in its Manual ofAnalytical Methods(7) recommends normalization to1.024 specific gravity. Data outside of these referenceranges mean the urine sampling must be repeated. Ifvalues outside the reference range are again obtained,the worker should be referred to a physician to ascertainwhether kidney and liver functions are adequate. If theperson is healthy, then use of out-of-reference-rangevalues is appropriate. Good judgment should prevail insuch cases.

5.11 Reports to Participants andManagementAll of a participant’s results should be reported to theparticipant. For those samples that are discounted, anexplanation of the reasons for discounting the sampleshould be provided.

Include the reference value (for example, the BEI) orthresholds for medical attention and medical removal withthe report to assist the participant in interpreting theresult. If there is no reference value, each worker shouldbe told the range of values in his or her workplace.

Providing an anonymous summary of all results fromthe monitoring project may also help a particularparticipant interpret his or her results and place them incontext. For this step the individuals reported on must becoded to preserve confidentiality or, alternatively, somestatistics and control charts should be provided thatguarantee individual confidentiality.

Anonymous summary reports of the project can beprovided to plant and company management as anelement of the industrial and environmental hygienestatus of the plant.

Another effective reporting method for employeesmonitored over time is to present past and present resultsas a control chart (for example, urine concentrationversus time) with reference values clearly indicated.

5.12 Stopping a ProgramThe program should be stopped when the reason forinitiating the program has been fulfilled. The reason fordoing biological monitoring should be part of the protocol.When that justification is no longer valid, stop theprogram.

Some biological monitoring programs need to beopen-ended because the purpose is surveillance. Forthese programs the data should be summarized at least

annually as part of the overall exposure assessmentprocess, and the results should be compared against thejustification and purpose of the program. A permanentbiological monitoring program is rare.

6. Sampling and Analysis6.1 Introduction to SamplingSample collection is a most important part of thesampling–analysis chain and can be a majorresponsibility of the industrial hygienist like traditional airsampling.

6.1.1 Sampling PersonnelBecause biological monitoring involves biologicalfluids, only properly accredited personnel can takeblood, urine, and breath samples. Blood sampling,being invasive of the body, must be left to physicians,nurses, and phlebotomists for legal reasons. Thetraining of an industrial hygienist facilitates exhaledbreath sampling methods. However, there are fewnumerical guidelines for exhaled breath(4) (see Q&AQuestions 13 and 14 in Appendix I), unlike urinesampling (see Q&A Questions 8 through 12).

An informed consent approach under thesupervision of an on-call clinician together with theindustrial hygienist is the best method to prepare theworker for urine and breath sampling. See alsoSection 5 for the broad overall elements of abiological monitoring program to see where thesampling and analysis effort fits in.

At present, the major sampling and analyticalconcerns of industrial hygiene personnel in biologicalmonitoring relate to the following.

• Training and educating the worker and theadministration in the need for the sampling

• Procuring and managing the samplingcontainers for use for biological monitoring

• Sending the collected sample for analysis inthe appropriate containers and with theappropriate labeling

If there is an OSHA-mandated regulation that isapplicable (for benzene,(1) lead,(2) and cadmium(3))you must be able to perform the stated aspects of theappropriate standard. See also Q&A Question 5 inAppendix I relative to the requirements for lead andbenzene.

You, being often the only on-site occupationalhealth specialist, need to ensure the workerunderstands what he or she has to do in the samplingscheme, and why. The consent process (Appendix Vcontains sample Consent Forms for Unregulated andRegulated Chemicals) is an effective way to informthe worker what is to happen and allow questionsbefore the sampling occurs. Because such a formusually has to be approved by your company¢s


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lawyers, the process will help your administrationunderstand the need for biological monitoring also.

If the worker has already given blanket consent atthe initial time of employment to provide whateversamples the employer requests, the samplingprocedure information in the appropriate consentform, BEI documentation, or laboratory directions canbe provided to generate questions before thesampling begins.

6.1.2 Sample Collection and ShippingBecause sample contamination and shipping arealways concerns, it is best to contact your analyticallaboratory, which will inform you of the correctcontainers, preservatives, labeling, holding times,shipping containers, and insulation. Somelaboratories even provide the samplingcontainers/preservatives, labels, insulation, andshipping containers as part of the analysis price.Some laboratories provide free preservatives whenrequested. The laboratory should also supply detailedwritten instructions concerning the proper use of thesample containers, timing of the sample, andshipping precautions.

Immediately before collecting samples, it isimportant to make adequate preparations such asremoving contaminated clothing, washing hands orskin, showering, and so forth. It is important to collectsamples using only the specified container(s),avoiding any intermediate collection vessels orsample transfers that have not been specificallydesignated in the sampling plan. Extra steps orapparatus increase the possibility of samplecontamination, especially in the case of metals ornonmetabolized organic compounds. The analyticallaboratory should always be asked for anyrecommended sampling procedure guidelines,because the laboratory is usually up to date on thelatest requirements or may have further optimizedtheir procedures.

Holding times (the maximum time from samplecollection to sample analysis that assures accurateresults) and storage conditions may differ for eachmarker. Metabolites and organic analytes generallyhave shorter holding times than metals. Somemarkers may require refrigeration immediately aftersample collection. Storage conditions also apply tothe time the samples spend in shipment to theanalytical lab, sometimes requiring overnightshipment on ice or dry ice. The specific regulation ordocumentation supporting the BEIs usually hasguidance on holding times and storage conditions.Breath samples can present special problemsbecause of the possibility of the analyte condensingor reacting with the walls of the sample container.These difficulties can be decreased by minimizingsample holding time or analyzing the samples

immediately if possible. To account for the possibleeffect of storage times and conditions, QA samplesshould be prepared or obtained at the same time thesamples are collected and should be stored andshipped with the samples.

Sources of metal contamination include thesample collection device (needles for bloodcollection), sample collection containers, theenvironment in which the sample was collected, andthe hands of the person collecting the sample. Fororganic analytes, contamination is generally not asmuch of a problem, but sample preservation andshipping take on added concern. Thus, a written QCprogram should specify what blanks are to besampled and why, what is to be done with them, andhow their results are to be used in the QAdocumentation.

6.1.3 Field Blanks and Other BlanksA field blank (container with the appropriatepreservative or solvent that is opened, manipulated,and closed in parallel with the sample containers tocontain the real samples) is essential for each type ofsample to detect any problems in the sampling chainof custody. The field blank constitutes the “fieldmethod blank” or “negative control.” An unopenedsampler can also be sent for analysis to ascertaincontainer cleanliness (“container blank”). Whenpreservatives are used, an extra “preservativesblank” in its unopened container also can be sent foranalysis if it is made up off-site before field sampling.

Although the field blank is the chief QA/QCmeasure in sampling, analytical costs may precludeany blank analysis in smaller companies. The bestway to cope with this situation is to take the blanksamples, but not send them for analysis until resultsfrom the real sample indicate a problem relative toworker exposure that requires confirmation that theresults are not artifacts of the chain of custody. Thiswould mean that adequate storage conditions at theworkplace facility must be present, for example, arefrigerator or freezer dedicated to sample holding(not food!) and a storage cabinet used only forsample storage. Such a strategy may be effective forsmall companies.

6.1.4 LabelsThe final general consideration during field samplingis to decide what information should be on the label.You will need to plan ahead if no worker names are tobe on the sample. How will you code the sample, andwho will have access to the code? How you will storeand use the results are also importantconsiderations. Are you going to use control charts toshow the progress of the sampling relative to timeand to personal breathing zone exposures? Are yougoing to use computerized data management (withbackup?), are computer bar codes to be used, and


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what aspects need to be hard copy (such as labelsand reports to workers and management)? Be sureto double-check all information on labels and enteredin computers as part of the written QA/QC program.

6.1.5 Baseline SamplingOne difficulty with biological monitoring that is

different from airborne exposure monitoring is thatbiological monitoring reflects all exposures,nonoccupational as well as occupational. Therefore,exposure to chemicals also present in the home,recreational, or transport vehicle environments cancomplicate the interpretation of results. The analyticalchemist can provide a result, but how is it to beinterpreted? Heavy metals, for example, can be foundin nonoccupational settings causing exposures thatmay result in elevated concentrations in the blood orurine of workers. Elevated concentrations of lead inblood can be a result of exposure to lead from waterin residential plumbing or from leaded paint dust,from ammunition used in recreational firearms, oreven ceramic vessels that contained acidic materialssuch as tomatoes, strawberries, vinegar, orcarbonated soda. Elevated mercury levels have beenfound to correlate with consumption of seafood orfrom taking folk medicine remedies. Mercury has alsobeen found to be elevated above its reference rangefollowing dental work with mercury amalgams.

To assess the true occupational exposure,samples need to be collected prior to exposure toestablish “baseline” data. The sample to clear thebladder before the shift will suffice for a baselineurine. For rapidly metabolized markers (for example,urine and blood half-times ≤5 hours) this can beaccomplished simply by sampling immediately priorto the beginning of the work shift. Baseline samplescan reflect holdover from the previous workday orrecent nonworkplace exposures. Baseline data forslowly metabolized materials may only be availableby sampling at the beginning of employment or priorto a new work assignment. The baseline sampleneeds to be analyzed only if the sample reflectingexposure is above a reference value. Thus, baselinesamples need to be stored appropriately in theinterim.

No employer wants to have a worker be absentfrom the workforce for exposures that occurredoutside the workplace, and they certainly do not wantto pay workers’ compensation for this cause ifmedical removal occurs. Thus, periodic baselinesamples should be taken, and certainly should betaken when a change of process or work routineoccurs. A baseline sample is part of the BEI protocolfor total chromium in urine for chromium VI water-soluble fume exposure. The urine baseline samplecan be the urine sample used to empty the bladderbefore the worker begins the shift.

6.1.6 Sampling Other than for BiologicalMonitoringConcurrent personal breathing zone air monitoringshould always be conducted. The timing of the airmonitoring may vary, however, depending on whetherthe exposure is short (acute) or long term (chronic).For instances in which biological monitoring is ameasure of acute exposure (marker half-times ≤5hours), it is important that air monitoring be done veryclose in time to the biological monitoring, preferablycovering the identical exposure period. When themarker being evaluated reflects a chronic exposure(for example, for the BEIs designated “not critical” insampling time, such as for cadmium in urine andblood for cadmium, lead in blood for lead), the timeoverlap between biological and air monitoring is notas critical. In this case air monitoring must besufficiently detailed to adequately characterize theoverall level of exposure and be able to differentiatebetween dissimilar employee exposure populations.

Measuring other routes of exposure, such as theskin surface or saliva in the mouth, can be attempted,but procedures for doing so are much less developedthan for air monitoring and are beyond the scope ofthis guideline.

6.1.7 DocumentationDocumentation of the sampling conditions and thework environment is required to allow a meaningfulinterpretation of the data. It is especially important tonote whether the sampling was done as part of aroutine effort to monitor normal working conditions orif unusual events occurred during the work period.Any pre- or post- sampling questionnaires, shippingdocuments, and analytical lab report forms should bearchived as well. Many testing laboratories are alsomedical labs and provide an analysis request formwith spaces for the following: patient information;sample collection information; name of therepresenting physician; specimen description; nameof the person collecting the specimen; anddescriptions of the tests requested. In lieu ofpreprinted laboratory forms, a custom form can bedeveloped, which should include the above items andaddress sample chain-of-custody.

6.1.8 SafetyAll personnel involved with the biological monitoringprogram—employees as well as employers,chemists, or health professionals—must be familiarwith OSHA regulations on bloodborne pathogens.(8)

Hazards associated with handling of biological fluidsmust be explained to each employee during trainingsessions. Methods to minimize exposure such asengineering and work practice controls, PPE,housekeeping, and proper labeling must be part ofthe overall program.


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6.2 Urine CollectionWhen ACGIH developed the BEIs using the GermanBATs as the model, timed spot urine collection using200–300 mL volume containers was used, because allthe urine collection could be done on the workplace siteand only one sample was necessary. Spot samples aretypically collected at preshift, postshift end-of-day, andpostshift end-of-week depending on the marker to bemeasured (see Q&A Question 8 in Appendix I).Containers should be wide-mouth to allow women to besampled.

The disadvantage of a spot urine as a specimen isthe variation in the concentration of its constituents due tovariable worker fluid intake and sweating. This hasnecessitated the use of normalization procedures (seeQ&A Question 9 in Appendix I).

The most common approach to normalization is acreatinine correction. Creatinine is a normal constituent ofurine that is excreted at a constant rate in people of aboutconstant muscle mass (“lean weight”). The concentrationof the marker is divided by the concentration of creatininein the same sample:

Amt. of marker Vol. of urine Amount of marker——————— x ———————— = —————————Vol. of urine Amt. of creatinine Amount of creatinine

Common units are milligrams of marker per gram ofcreatinine; micrograms of creatinine per milligram ofcreatinine; and milligrams of marker per millimolecreatinine.

There are limits to the use of this correction. It cannotbe used if body weight is not relatively constant, or if theworker has kidney damage, for example, excess proteinin the urine (proteinuria). The correction should be usedwhen creatinine concentration is within the range of 0.5 to3 g/L, but not outside this range. For instance, in the caseof a dilute urine of 0.2 g/L, the uncorrected markerconcentration will be multiplied by a factor of 5, oftenresulting in a falsely elevated result. It is advisable to usea creatinine dipstick just after sample collection at thesampling site to determine if the fresh urine sample isvalid or if another sample needs to be collected onanother exposure day. There is no point to an expensivemarker analysis when the sample is invalid.

Another normalization procedure is by specificgravity, the density of the urine relative to that of water atthe same temperature.

It is advisable to check the specific gravity at the siteand time of collection with a dipstick, just as for thecreatinine concentration above. If the urine specificgravity is greater than 1.015, the creatinine concentrationis usually greater than 0.5 g/L. This procedure also avoidsinconsistent results and unnecessary expense frominvalid urine samples. The specific gravity correction isnot applicable below a value of 1.010. The NIOSHreference specific gravity is 1.024, and:

Corrected specific gravity = (observed value × 24)/last two digits of the observed specific gravity

Samples that are not frozen should have theircreatinine or specific gravity checked by the analyticallaboratory to ensure sample integrity during storage,transport, and analytical laboratory reception. If urinesamples need to be frozen, ensure that the bottom part ofthe sample is cooled first to prevent container breakage,especially for glass and low-density polyethylenecontainers. Creatinine concentration or specific gravity dochange after freezing relative to fresh urine. Becauselabels tend to fall off at or below freezing, the label shouldbe taped securely in a way that does not obscure thelabel.

6.2.1 Trace MetalsFor trace metals in urine, samples are collected inplastic cups or bottles that have been acid washed orpreviously analyzed to ensure that they are free oftrace metals. Preservation of urine samples for tracemetals usually involves acidification of the samplewith dilute nitric acid. Acidification should never bedone in the field because of possibility ofcontamination and acid burns. An alternative is tosend the samples to the laboratory refrigeratedovernight, and for the acidification to be done at thelab. Several cold packs are available to cool thesample. If dry ice (–70°C) is specified, specialshipping requirements and documentation arenecessary. Express mail that involves a signedreceipt at the sample destination is recommended.

Another approach is for the laboratory to providetwo containers: a wide mouth acid-washed containerfor sample collection and a leak proof transport bottlecontaining an acid preservative for shipping that thecollected sample is poured into for storage andtransport. Samples should be packed in a cooler withrefrigerant using an appropriate shipping containerthat meets the regulations covering shipping ofbiological samples. Samples should be sent off bynext day or second day delivery.

6.2.2 Organic AnalytesUrine collection procedures for organic analytes varydepending on the marker of interest. For organicsolvent metabolites such as trichloroacetic acid,hippuric acid, methylhippuric acid, phenol,pentachlorophenol, mandelic acid, N-methylacetamide, hexanedione, and so forth,samples are collected in plastic containersunpreserved. Samples should be frozen asrecommended and then sent to the laboratory byovernight carrier.

For the determination of volatile organics in urine,the sample is collected in a urine cup and promptlytransferred to two 40-mL, Teflon® lined, screw-capvials. The vials are filled to near overflow level, and


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the caps replaced and tightened firmly. It is essentialthat there are no bubbles present. Vials should bewell protected from breakage and sent to thelaboratory in coolers with refrigerant by next dayservice. Do not allow freezing.

Urine samples for aromatic aminesdetermination—aniline, o-toluidine, methylenedianiline, β-naphthylamine, and so forth—arestabilized by the addition of citric acid to the urinesample at approximately 1 g to every 100 mL of urine.The citric acid should be added to the transport bottleby the laboratory or in an on-site laboratory but not inthe field. Urine samples for the analysis of alkoxyacetic acid metabolites of glycol ethers should bepreserved and acidified with hydrochloric acid.Numerous other collection methods exist dependingon the nature of the analyte. Users should consult thelaboratory for specific details on sample collection,preservation, and shipping. Alternatively, the writtenguidelines that cover this process should be followedmeticulously.

6.3 Blood CollectionCollection of blood is usually by venipuncture into avacuum-collection tube (“Vacutainer®”) of approximatevolume 15 mL, containing anticoagulant to preventclotting. As a rule of thumb, the volume of blood drawnshould be equal to 2.5 times the volume required foranalysis. After the blood is sampled, it must be rocked10–20 times to mix the blood thoroughly with theanticoagulant. Whole blood samples generally are notfrozen. Blood for serum samples is metered into twotubes (for example, “red-top” Vacutainers) with noanticoagulant and allowed to clot for 30 min. The tubesare then centrifuged at 1500 g for 15–20 min. The cleartop layer is transferred by pipet (plastic for metals) to aclean glass vial or centrifuge tube, which is closed with aTeflon-lined screw cap. The sample is then cooled for 1hour at 4°C, then frozen at –20°C, with shipping at –20°C.Industrial hygienists need to check for the proper shippingrequirements for their samples.

6.3.1 MetalsThe most convenient method for the collection of tracemetals in blood is the use of an Evacuated Tube,Vacutainer, Venoject®, or other similar brand name.Although convenient, these tubes are known sourcesof contamination for a number of metals, particularlyaluminum (Al) and zinc (Zn). For metals such as lead(Pb), cadmium (Cd), mercury (Hg), and arsenic (As),contamination is not an issue, and evacuated tubescontaining ethylene diamine tetraacetic acid (EDTA)disodium salt as an anticoagulant are routinely used (“purple top” Vacutainer). Dipotassium EDTA salt is thefavored anticoagulant for plastic “tan top” Vacutainersfor blood lead analysis. EDTA provides longeranticoagulant action than heparin (“green top”

Vacutainer), and is recommended when there is adelay between sample collection and analysis.Stability is not an issue for these metals, but microbialgrowth must be inhibited. Samples should always beshipped in insulated containers to avoid temperatureextremes.

For metals such as Al, cobalt (Co), chromium(Cr), nickel (Ni), and manganese (Mn), extremecaution must be taken to avoid contamination in allaspects of sample collection. Glass Vacutainer tubesshould not be used for these metals. PlasticVacutainer tubes have been found to be virtually freeof metal contamination and are recommended.

Contamination of the blood sample with metalsfrom needles is also an issue of concern. Foroccupational exposure purposes, flushing of theneedle by taking a preliminary blood sample beforethe actual trace metal sample is taken is effective inlimiting needle contamination.

For determinations requiring plasma or serum,an additional source of contamination must be dealtwith. After collection in an appropriate tube, thesample is centrifuged and the plasma/serum layertransferred to another tube. This step must be done ina laboratory environment (not the field) using aplastic transfer pipet and a plastic tube known to bemetal free. Glass transfer pipets and glass tubesshould never be used.

All containers, evacuated tubes, transfer pipets,transport tubes, and other sampling accessoriesshould be checked for metal contamination regularlyby analysis of several samples from each lot asblanks.

6.3.2 OrganicsThe most common organic analyses performed onwhole blood is the determination of volatile organiccompounds such as benzene, toluene,trichloroethylene, xylene, perchloroethylene, andsimilar industrial solvents. For this determinationwhole blood is collected in glass Vacutainers withanticoagulant, and transferred to Teflon-lined screw-cap glass vials. The blood is added to the vial until italmost overflows, and the cap is screwed on tightly.Ensure that no air bubbles remain in the vial.Samples should be kept cold (but not frozen) andshipped cold to the laboratory, taking everyprecaution to prevent breakage of the glass vials.

For the determination of PCBs and pesticides,blood serum is used. For this determination bloodshould be collected in glass “red top” Vacutainers.Samples are allowed to clot for 15–30 min and thencentrifuged. The serum layer is removed with a glasstransfer pipet and placed in a glass transport tube.Plastic should be avoided for organic analytes. Glassshould be handled with extreme caution.


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Biological monitoring of organophosphoruscompounds usually also requires the determination ofcholinesterase activity in red cells. For this determinationthe plasma must be separated from the red cells.Samples are collected in Vacutainer tubes containingEDTA. After collection the samples are centrifuged at2500 rev/min for 5–7 min. The upper yellow plasma layeris completely removed from the red cells. Red cellsamples should be refrigerated and not frozen. Sendsamples on cold packs by overnight delivery.

6.4 Breath CollectionThe most convenient breath collection container is aclean 5–10 L Tedlar® gas bag that has been filled andevacuated at least three times with medical grade air. Thesample can be taken after the end of the shift, afterworker exposure for 15 min to an uncontaminatedatmosphere or preferably to pure medical air breathed inunder a Tyvek® hood. The sampling procedure is toexhale normally and then blow the end-exhaled air of thelungs through a Teflon or polyethylene 0.5 inch/0.25 inchconnector attached to the bag by 0.25 inch inner diameterTeflon tubing that is as short as possible. Tygon® butt-to-butt collars need to be used to ensure there are no leaks(test with soap solution). Fill the bag at least half full. If theworker feels there is too much resistance to blowing, awider diameter Teflon tubing is required. Any othercollection device that features valves will require medicalcertification of worker lung function. The carbon dioxideconcentration is measured with a detector tube to ensurethe end-exhaled sample is a valid one, and to normalizebreath concentrations, if desired.

Some other methods that could be used dependingon the analyte might be sampling the analyte with a solidsorbent the analyte capacity of which is independent ofrelative humidity (for example, Tenax® polymers andXAD® resins), or with an evacuated Summa™ canister oran evacuated glass container. The solid sorbent methodwould require the use of an instrument such as a wet testmeter to measure breath volume.

6.5 Saliva CollectionTeflon preweighed containers (10–25 mL) are preferredfor whole saliva collection. The worker sits with the headtilted forward so that the saliva moves anteriorly in themouth. After an initial swallow, the saliva should beallowed to drain continuously for 5 min from the lower lipinto a clean funnel sitting in the container neck. Theworker then expectorates the residual mouth saliva intothe funnel. This particular method is called the “draining”method. Other methods are also used, but the fewerforeign objects in the mouth as for the so-calledstimulated sampling methods, the fewer potentialcontamination problems there are.

6.6 Hair CollectionHair is collected from the back of the head at the

nape. Stainless steel scissors should be used, and thehair should be cut as close to the scalp as possible. Thehair length should be no longer than 1–2 inches, with theend closest to the scalp being retained. About 0.5–1 ghair (1–2 tablespoons) should be cut and placed into azip-top plastic bag (if metals are being analyzed) forshipment in an appropriate container, such as a plasticbottle. If organics are to be analyzed, the containershould be Teflon or acid-washed Pyrex®. As shampoos,hair tinters, conditioners, suntan lotions, or other haircosmetics affect trace metal analysis, the use of theseagents should also be ascertained, with specific brandnames.

6.7 Laboratory QC/QA

6.7.1 Definitions and Basics• QC is the means by which accurate and

precise results are obtained. The QC programis a written set of standard operatingprocedures (SOPs).

• QA is the documentation that shows that theQC program works.

Both QC and QA are essential parts of anydetermination, no matter which matrix is beinganalyzed or which chemical or hazard is beingmeasured. Every laboratory, whether it is analyzingair or water or dirt or blood, must have a formalwritten QA/QC program in place to ensure the validityof the data. Although QA/QC falls under the primaryresponsibility of the laboratory, industrial hygienists,occupational physicians, nurses, and others who relyon contract laboratories for biological monitoringdeterminations should be aware of basic QA/QC andshould use basic QA/QC in their sampling protocols,as discussed in Section 6.1.

Laboratory SOPs provide the formaldocumentation of how the laboratory functionsincluding the following.

• Sample collection; labeling; sample log-in;sample storage; holding times; preservationmeasures; sample analysis and data reduction;archiving data; disposal of biological waste andhazardous chemicals; and so forth

• SOPs must be regularly reviewed by thelaboratory QA/QC manager and laboratorydirector and the formal program revisedwhenever a change or update is required.

The QA manual should describe the procedures usedto assure high-quality data (e.g., personnelqualifications and training, documentation oflaboratory procedures, instrument calibration andmaintenance) and the control measures taken tomonitor, and when necessary, to improve the


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laboratory’s results (e.g., QC samples, control charts,resolution of deficient performance).(9–12) Alaboratory should be able to specify its criteria foraccuracy and precision of results and how they areapplied to each set of samples analyzed. To allow formeaningful interpretation, the data must haveaccuracy and precision sufficient to allow samplesfrom unexposed individuals to be clearlydistinguished from regulatory levels or BEIconcentrations.

The limit of detection (LOD) and the LOQ dependon the method being used for the analysis. They canvary from laboratory to laboratory. The usualdefinition of LOD is the concentration that causesthree times the signal-to-noise ratio or four times thetotal response-to-noise ratio. The usual definition ofLOQ is the concentration that causes 10 times thesignal-to-noise ratio, or 11 times the total response-to-noise ratio. The latter can be defined operationallyas the concentration that causes an intraruncoefficient of variation (100 × [standard deviation/mean]) of 10%. Consult the laboratory for its LOD andLOQ and how they are determined for the particularanalyte and matrix involved. As a general guide, theLOQ should be lower than one-tenth the regulatorylevel or exposure index. The LOQ is the mostimportant parameter to ascertain.

The industrial hygienist should ask for the latestversion of the laboratory’s QA/QC plan anddocumentation. Safety concerns should berecognized by all laboratory personnel, such as thetechnicians and laboratory analysts, being trained onthe OSHA requirements for bloodborne pathogens.(8)

Methods to minimize exposure such as engineeringand work practice controls, personal protectiveequipment, housekeeping, and proper labeling mustbe part of the overall program. Compliance withOSHA’s laboratory standard(13) is useful in meetingsuch objectives.

Laboratory analytical QA/QC can be divided intotwo major areas: preanalytical and analytical.

Preanalytical parameters deal with the QA/QCthat must be in place before a laboratory can performany analyses, whereas analytical parameters dealwith the determination itself. The first part of anyQA/QC program is the preparation of SOPs, whichcover every aspect of laboratory operation. Thepreanalytical QC plan may be very similar to thatoutlined for field sampling by health professionals inSection 6.1. However, many laboratories also havepersonnel who go out into the field to sample, andtheir QA/QC is generally more complex than used byfield-only personnel, because the field actions havecorresponding laboratory analytical procedures. TheirQA/QC may also include evaluations of new samplingcontainer products and direct-reading devicedevelopment, for example, field immunoassay and

colorimetric kits. Direct-reading devices will becomemore important in the future.

Analytical method SOPs provide the step-by-stepprocedures to determine a particular substance in aparticular matrix. They include standardizationprocedures, QC measures, sample analysis, LOQs,LODs, working ranges, data reduction/calculations,and data acceptance/rejection criteria. The mostimportant part of a method SOP is the methodvalidation study. This is the initial demonstration bythe laboratory that the method does indeed work, thatit is both accurate and precise, and that it will givereproducible results in an intrarun and interrunmanner.

A QA/QC system is the formal program that alaboratory establishes to monitor quality. The majorsteps, in order, are as follows.

• Documentation of all methods and procedures• Establishment of an analyst’s training program

that sets qualification standards and thetraining; requirements for all analysts

• Certification or accreditation of the laboratory,as appropriate for each analyte

The most important function of a QA/QC system is tomonitor quality. Quality can be monitored by

(1) the various inter- and intralaboratory QCprograms,

(2) QC charts (plots of detector responses to known concentrations of analytes over time), and

(3) QA audits (usually at least one a year).

All laboratory testing falls under the jurisdiction ofsome certifying or accrediting organization. Thesame is true of laboratories performing biologicalmonitoring. Under the Clinical LaboratoryImprovement Act (CLIA) of 1988 (Code of FederalRegulations [CFR] Title 42, Part 493 [LaboratoryRequirements]), any laboratory analyzing biologicalsamples must obtain a CLIA certificate. Laboratoriesperforming biological monitoring analyses require ahigh-complexity testing certificate. Laboratories canbe accredited by the College of AmericanPathologists (CAP), by individual states, or by anyother accrediting agency approved by CLIA. Inaddition, laboratories must be licensed in theirindividual states or any state where they obtainsamples, for example, laboratories analyzingsamples from New York State must be licensed byNew York State. Industrial hygienists should alwaysask a prospective laboratory whether it has a CLIAcertificate.

If there is a need to analyze biological samplesfor drugs, National Institute on Drug Abuse (NIDA)certification may be required for drug testing ofcertain occupations (truck drivers, airline pilots) but is


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not necessary for all situations. For many laboratoriesthe College of American Pathologists drug testingaccreditation assures quality testing without the highexpense of the annual NIDA certification. Thelaboratory must be licensed by the Federal NuclearRegulatory Commission to analyze for radioactivematerial. Some state regulatory agencies may alsorequire licenses.

An important requirement of certification/accreditation is proficiency testing. Industrialhygienists are familiar with the PAT (ProficiencyAnalytical Testing) program run by NIOSH in whichAIHA accredited laboratories are required toparticipate. The OSHA lead standard requireslaboratories to participate successfully in anapproved blood lead proficiency program. (See theOSHA list of laboratories approved for blood leadanalysis at http://www.osha.gov/SLTC/bloodlead/index.html.)

CLIA registered laboratories are required toparticipate in an approved proficiency test programfor every determination that the laboratory performs.In the case of biological monitoring, there are twoproficiency test programs other than blood lead forwhich participation is required by CLIA. The cadmiumprograms include blood and urine cadmium, urine β2-microglobulin, and urine creatinine. The tracemetal program includes Al, Cr, Cu, selenium (Se),and Zn in plasma. Laboratories are encouraged toparticipate in proficiency testing programs even if notrequired by law to do so.

The final preanalytical parameter is samplecollection, which is discussed at length in Sections6.1 through 6.6. Sample and reagent blankdeterminations are necessary for any analysis, butespecially for trace metal analyses in which samplecollection containers (particularly needles and bloodcollection tubes) can be a source of contamination. Itis up to the industrial hygienist to ensure that theenvironment is not a source of contamination bytaking field blanks in parallel with the sample.

Calibration standards are important, becausequantitative determinations are only as accurate asthe standard on which they are based. In the area oftrace metal determinations the National Institute ofStandards and Technology (NIST) provides 67different standard reference materials (SRMs)consisting of individual certified metal standardsolutions that are used as primary metal standards.In addition, standard solutions of most metals areavailable from a number of manufacturers at variousconcentrations that are certified against these NISTSRMs. NIST also provides a blood lead SRMconsisting of four whole-blood calibrators that can beused as calibration standards or QC samples.

In the case of organic analytes such as organicsolvents, pesticides, phenols, and other organics,

standard solutions in methanol/methylene chlorideare available from a number of suppliers. Mostanalytes have a certificate of analysis provided by themanufacturer or supplier. For solvent metabolites andmost organics the pure compound is the onlymaterial available for standardization. Thus, theissues of purity, stability, and solubility must be dealtwith.

A calibration verification standard is a standardobtained from a different source of material than thatused for the calibration standard. It is a single pointstandard that verifies the primary standard. A numberof manufacturers provide individual standards andmixed standards for both metals and organicscreated for this purpose. All of the standard materialsmentioned previously could be used, too. The ideahere is that if the calibration standard is purchasedfrom a manufacturer, the calibration verificationstandard should be prepared internally or purchasedfrom a different manufacturer and vice versa. If thepure chemical is the only standard material available,the chemical could be purchased from two differentmanufacturers. One source would be the calibrationstandard and the other the verification standard.

Matrix matched QC materials provide the bestmeans to assess the overall accuracy of a biologicalmonitoring determination and should be included inevery analytical run. Disguised as samples, thesematerials can be sent to contract laboratories tocheck the accuracy of the values reported. A numberof QC materials are available for the determination oftrace metals in blood/urine/serum/plasma, especiallyfrom NIST.

In addition to the NIST blood leadstandards/controls mentioned earlier, urine basedstandards are available for a number of metals andfluoride. NIST materials are the gold standard andcan be used with confidence. The bi-level controlsinclude a normal control and an elevated control. Forany other level the elevated control can be dilutedwith the normal control to obtain the desiredconcentration. Many commercial QCs are availablefor blood lead, urine metals, whole blood metals, andserum metals. Most of these controls are also bi-level(include a unexposed reference and elevated level).

Documentation of analysis of QC materials isdone through QC charts. Every time the analysis isperformed, the value is recorded on a statistical chartthat displays high and low acceptance levels for theparticular control. From these charts the laboratorydetermines if an assay is “in control” or not. Out ofcontrol samples must be rerun.

Replicate analysis is running a sample twice fromthe first step of the analysis. Duplicate analysis isrunning the final prepared sample twice. Replicateanalyses should be done at a frequency of 10% ormore of the sample load, or at least every 10


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samples. Replicate analyses are plotted on a differenttype of QC chart so that a lab can monitor precision.Replicate analysis is a simple way contract laboratoryusers check on laboratory performance. A generalrule for the industrial hygienist would be to split onesample in every batch of urine or blood samples intotwo equal aliquots and then send them to thelaboratory for analysis. Results of the replicateanalyses should be recorded.

Matrix spike analysis is a valuable method tocheck on the accuracy of any analytical method. Amatrix spike is a sample to which a known amount ofthe analyte of interest is added. For biologicalmonitoring markers, this must be the marker itself,which is not necessarily the same as the chemicalthat exposes the worker. The original sample and this“spiked” sample are then analyzed. The differenceshould correspond to the amount spiked. Acceptablerecovery ranges from 75–125%. Although using 10%spikes is normal in an analysis day, for highly criticalanalyses it is not unusual to perform 20% spikes(every fifth sample). As mentioned in the calibrationverification section, a different source of materialshould be used for the spike than used for thecalibration standard. However, in many cases thisalso is not possible. Matrix spike values are plottedalso using the same procedure used for QCmaterials.

6.7.2 Analytical Chemistry Laboratories andBiological MonitoringCurrently, nearly all markers in urine, breath, andblood require analysis by analytical chemistrylaboratories because sensitivity, selectivity, accuracy,and precision can be attained only by such means.Development of direct-reading methods or near real-time biological monitoring methods will occur in thefuture, and this will allow biological monitoring to beused much as detector tubes are used for grab airsampling. Dipsticks, for example, are currentlyavailable for urinary creatinine.

6.7.2.1 Identifying Laboratories Initially. Identifyingand choosing a laboratory or laboratories is a criticalpart of the project and should be completed beforesamples are collected from the employees. Manylaboratories, when approached with a request foranalysis, will receive the samples and provide results.However, if the samples are unusual or the analysesrequested are not frequently performed by thelaboratory, the primary lab may subcontract samplesto another laboratory more familiar with the analysis.Although this may not be a problem, and in fact mayimprove the reliability of the results, the submittershould be aware that this is happening, because thesublaboratory is not necessarily CLIA accredited.

Most commercial laboratories that analyzebiological samples are familiar with urine, blood,tissue, and so forth. Many are not prepared to dealwith breath samples. Because of handling, shipping,and storage problems, breath sample analysis isprobably best performed by an in-house or on-sitelaboratory.

Commercial laboratories and, when possible, in-house industrial labs should participate in a variety ofQA programs, both internal and external. Althoughformal programs are not available for all analytes, theparticipation in some aspects of a formal programprovides an indication that the appropriate QA andQC procedures are in place at the laboratory tosupport the reliability of the data.

The laboratory review should include adiscussion of such issues as the following.

• Does the laboratory provide sampling andshipping containers, with any neededpreservatives and instructions?

• Have chain-of-custody procedures beenestablished for handling of samples?

• Does the laboratory provide adequateturnaround of samples?

• Are “rush” analyses available?• Can the laboratory provide results by fax,

telephone, or electronic mail?• Will the laboratory provide summary reports

monthly, quarterly, or annually, as desired?• Will the laboratory provide reports of

excursions above your preset limits?• Is technical support available for discussion of

results?• How responsive is the laboratory to efforts to

resolve problems?• Will the laboratory provide a list of references,

analytical methods used, QA/QC procedures,and internal QC data, such as control charts?

• What outside proficiency testing programsdoes the laboratory participate in, and howhave their results been?

• Does the laboratory have a written QA/QCsystem? Will they allow you to read it?

• Is the laboratory and its subcontractorlaboratories CLIA-accredited?

• Is the laboratory’s computer system secure?• And, of course, cost, volume discount, multisite

discount, and so forth

The ultimate test is laboratory performance. Ifpossible, before the final laboratory selection is made,a set of samples having known concentrations in thedesired biological matrix or a matrix spike (and itsunspiked counterpart) should be submitted to thelaboratory disguised as actual biological monitoring


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samples. Another method is to combine samples ofknown content in the same matrix, accounting fordilution effects. Sample stability is the major variablethat must be assessed for this method. Theseprocedures allow the accuracy of the laboratory ‘sanalyses to be evaluated prior to the start of thebiological monitoring program. Although sometimesdifficult to perform, matrix spiking is another waycontract laboratory users can check on laboratoryperformance. A sample from an unexposed workercould be spiked and sent to the laboratory along withan aliquot of the unspiked sample. Consult with yourchoice of laboratory on how to do matrix spiking. Mostlabs would be happy to show you how, as well asprovide you with the appropriate standard. In thelaboratory, matrix spike analysis is very important formethods in which matrix-matched QC materials arenot available. Unfortunately for most organic analyses,this is the usual case, and matrix spike analysisprovides the major measure of accuracy available.

In the laboratory, matrix spiking is also often doneat two to three different concentration levels within thelinear dynamic range of the analyte; that is, theoriginal sample is split into three or four equal aliquotsbefore spiking with various masses of the analyte. Thetechnique is then called the method of standardadditions when the sample content is defined as thenegative intercept on the X-axis after extrapolation ofthe straight line that results. Time and economicconstraints often limit the application of this technique,but when all else fails, its result is defined as thecorrect answer. Laboratories must be able to use thistechnique for the most intractable quantitation cases.

Once a laboratory has been selected, it shouldbe considered an integral part of the biologicalmonitoring program. Collaboration with laboratorypersonnel regarding the scope and objectives willlead to significant improvements in the overallbiological monitoring program. If deficiencies arefound, corrective action can be taken, such asworking with the lab to improve results. If you are notsatisfied, select and test another lab.

6.7.2.2 Selecting the Marker. To an analyticalchemist, accurate and precise identification andquantification of the marker or analyte is the solescientific goal for a laboratory’s analysis and QA/QCprogram. From the industrial hygienist’s point of view,as discussed in Section 5, the analytical chemistry isbut one of the variables, albeit one of greatimportance, that must be considered in a biologicalmonitoring program. Most health professionals onlyreally want to have the result rather than have tounderstand the basis of the result. Such thinkingcauses the role of an analytical chemist to bedevalued. The formal biological monitoring programmust include laboratory analysis to assure that the

biological monitoring results will be useful accuratedata, and will allow appropriate interpretation toaccomplish the objectives, because the healthprofessional usually does not analyze the samples.

However, the industrial hygienist has to knowenough to either select the appropriate marker or tounderstand the advice of others, including laboratorypersonnel experienced in the analyses. For biologicalmonitoring data to be meaningful, a detailedunderstanding is also required of a chemical’smetabolism and elimination kinetics in the humanbody. Fortunately, this information already exists forchemicals that have established BEIs(4,5) orregulatory biological monitoring requirements.(1–3)

The difficulty of choosing a marker is much greaterwhen the literature is contradictory or not sufficient,or if other chemicals can be metabolized to the samemarker. In general, the exposing chemical is alwaysthe most selective and specific marker, whereasmetabolites may have many possible precursors.

Although knowing the specific marker to bemeasured may seem too simple in defining the scopeof the actual analytical chemistry program, there is anintimate tie between which information you wish togain from the monitoring, what you will monitor for,and how you will obtain the information. In somecases it is possible to evaluate a combination ofacute, intermediate, and chronic exposures. This canby done by appropriately selecting the specificmarkers and sample types with an understanding ofthe biological and metabolic half-lives. An excellentdiscussion of this can be found in the Introduction tothe Biological Exposure Indices in ACGIH’sDocumentation of the TLV®s and BEIs.(5)

Another aspect of selecting a marker is whetherthe free marker, conjugate, or both together (“total”)should be measured. Usually in the BEIs the latter ismeant: for example, total p-aminophenol in urine foraniline; total 4-chlorocatechol and total 4-chlorophenol in urine for chlorobenzene; total furoicacid in urine for furfural; total trichloroethanol in urineand blood for methyl chloroform; total 4,4’-methylenebis(2-chloroaniline) in urine for 4,4’-methylenebis(2-chloroaniline); total p-nitrophenol inurine for nitrobenzene and parathion; totalpentachlorophenol in urine for pentachlorophenol;total phenol in urine for phenol; total 1,2 –cyclohexanediol and total cyclohexanol in urine forcyclohexanol and cyclohexanone; and all metals inurine and blood. The markers are analyzed by ahydrolysis procedure that converts all conjugates tothe free form for organics and by a digestiveprocedure that converts all organometallics to metalnitrates before analysis for metals. You should askwhat the recovery of the laboratory method is for aspiked conjugate for the above organics. This is not tosay that BEIs specify “total” always. For example, free


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trichloroethanol in blood for trichloroethylene is a BEImarker, as is free pentachlorophenol in plasma forpentachlorophenol and 1-hydroxypyrene in urine forpolycyclic aromatic hydrocarbons. The healthprofessional must be specific about what is asked for,and that means a basic knowledge of the termsinvolved is essential.

In some cases the biological monitoring markeris not specific for a particular chemical but may be fora metabolite or an indicator of the chemical’s effect.An example is the testing required under the OSHAstandard for cadmium,(3) which includes a test for β2-microglobulin in urine as well as cadmium in urineand blood. The β2-microglobulin is a protein that isused as an indicator of adverse effect on the kidneys.It is not, however, specific to an effect on the kidneysby cadmium and may be the result of other kidneyproblems. Other similar tests exist (for example,cholinesterase activity in red blood cells for pesticidesthat inhibit acetylcholinesterase can also be inhibitedby the anesthetic succinyl choline) that evaluate theimpact on an organ or tissue where the effect may befrom more than one cause.

Another important concern is to decide whichmarker value takes precedence when guidelines arenot the same, for example, for lead the OSHAmedical removal threshold of 50 µg/dL blood or theBEI of 30 µg/dL. Another example is for urinarycadmium; the OSHA threshold is 3 µg/g creatininecompared with the BEI of 5 µg/g creatinine, thoughthe blood cadmium guidelines are the same. OSHAregulations have primacy.

6.7.2.3 Availability of Standard Reference Materials.NIST currently provides a number of biologicalstandards containing a variety of toxic materials ofknown concentrations.(14) These materials are allcertified and include acceptable ranges around thereference value. The SRMs for urine are normallysupplied as a dried material requiring only theaddition of high-purity water to reconstitute thesample. Once in liquid form, they can then besubmitted to the laboratory as if they were a routinesample. In some cases dried blood specimens aresimilarly available.

In addition to NIST, the following locations,among others, provide urine and blood containingknown concentrations of contaminants, either as partof an interlaboratory proficiency test program or as aservice.

Centre de Toxicologie du QuebecLe Centre Hospitalier de l’Universite Laval2705 Boul. LurierQuebec, Quebec GIV 4G2 Canada418-654-2100

Kaulson Laboratories, Inc.691 Bloomfield Ave. Cauldwe11, NJ 07006 201-226-9494

Biorad, ESC Division3726 E. Miraloma Ave.Anaheim, CA 92806800-854-6737

Utak Laboratories, Inc.26752 Oak Ave., Suite JCanyon County, CA 91351805-251-9654

Accurate Chemical and Scientific Corp.300 Shames Dr.Westbury, NY 11590516-333-2221

Reference materials for breath analysis are notcommercially available. Standard gas mixtures canbe purchased, but they do not contain the potentiallyinterfering species in human breath. Standard gassamples can be used to spike breath samples bystandard additions, which can provide an indicationof the accuracy of the analysis.

6.7.2.4 Proficiency Testing. Participation in anapproved proficiency program (run by CAP, New YorkState Department of Health, or the Wisconsin StateLaboratory of Hygiene) for blood lead is mandatoryfor laboratories conducting analyses in support of therequirements for testing under OSHA’s leadstandard.(2) A number of other interlaboratory testingprograms are available for analytes other than lead.The CAP has proficiency testing for several tracemetals in urine, serum, and blood. However, not allcompounds or markers are the objects of proficiencytesting.

The Centre de Toxicologie du Quebec,referenced previously, conducts interlaboratorystudies on arsenic; lead; mercury; chromium;selenium; fluorides; cadmium; and others. Samplesare provided bimonthly. The participating laboratory isprovided with both a bimonthly and annual report ofthe laboratory’s results. The Finland Institute ofOccupational Health runs a program that includesseveral organic solvent metabolites: mandelic acid,methylhippuric acid, phenol, phenylglyoxylic acid,trichloroacetic acid, and 2,5-hexanedione.

Although NIOSH’s PAT program is aimed atproviding QA for analysis of a limited number ofmaterials (asbestos, cadmium, lead, zinc, silica, anda small number of organics) using air samplingmedia, it is a requirement that laboratories in theprogram participate in those areas in which they


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routinely do analyses. Similarly, a laboratoryconducting biological monitoring should alsoparticipate in a proficiency test program for thosematerials for which it routinely conducts analyses.Customers of a laboratory should request summariesof the lab’s performance in the testing program tohelp assess the lab’s accuracy and precision. If notdone as a matter of course by the laboratory,participation in proficiency testing should be includedas part of your contract for services, where available.

6.7.2.5 Preparation of Spiked Samples. Because ofdifficulties involved in accurately spiking biologicalsamples with known concentrations of chemicals, it isusually preferable to purchase samples of knownpurity or composition. If samples of knownconcentration are not available, then spikes shouldbe prepared only by qualified laboratory personnel,such as analytical chemists. Spiked biologicalsamples should be generated with routines similar tothose used for preparing spikes of other liquid media.The form present in the biological medium must bethe chemical species that is spiked. This means thatspiking tetrachloroethylene instead of 1,1,1-trichloroethanol or trichloroacetic acid and theirglucuronides is a systematic error for urine analysisunless tetrachloroethylene is the marker. Similarly,the recovery of spiked lead chloride in blood may notbe the same as for the lead organometalic formactually in red blood cells.

The least difficult medium to handle is urine.Standard concentrations of metals in urine can beprepared from commercial concentrated standardsfor atomic absorption or inductively coupled plasmaspectroscopy, using urine as the final diluent. Ifpossible, the volume of the spiking solution addedshould be less than 1% of total solution volume. Insome cases it will be necessary to choose thecontaminant species carefully to be sure it remainssoluble at the urine’s pH. Solubility is usually not aproblem if an aliquot of the spiked urine is transferredto a standard sample container with preservativeimmediately after it is spiked. The sample must beshaken.

Because of the limited volume of availablematerial, at least in comparison to urine, thetechniques for spiking blood samples are somewhatdifferent. To calculate the quantity of analyte to add,the amount of blood in the tube can be estimated towithin 5% by filling a spare tube with water to anequivalent level and then measuring the amount ofwater in a graduated cylinder. To have the minimumeffect on the sample, the spiking solution should be ofminimum volume with a correspondingly higherconcentration, for example, 10–20 µL spiked into5–10 mL of blood. The sample must be shaken.

In any event, the actual concentration of thematerial of interest should be determined for aportion of unspiked sample as well. This allows thedetermination of the recovery from the spikedsample. Ideally, spikes should be submitted induplicate unless the reproducibility of the analysis isknown.

Spiked samples should be prepared over a rangeof concentrations, for example, 0.1, 0.5, 1, and 2times the regulatory level or BEI guideline. To be areliable indicator of method performance, the spikedsample concentration should be at least 2 to 5 timesgreater than the unspiked sample. Spikes at lowlevels (0.1) are best prepared using samples from thecontrol population for which the backgroundconcentration is expected to be lowest.

All handling of potentially infectious biologicalfluids must be done in compliance with OSHA’sbloodborne pathogens standard.(8)

6.7.2.6 Frequency of QA Samples. The frequency ofsubmitting samples of known concentration, blanks,and duplicates normally reflects the availability of thesamples and the ease and expense of obtaining them.Duplicates will normally be most easily obtained,followed by blanks. Commercially available or speciallyprepared spikes can be difficult to obtain and are moreexpensive, and may not be utilized as frequently.

On a routine basis, at least one set of duplicatesand preferably a blank as well should accompanyeach set of samples submitted to the laboratory. Thisallows an ongoing evaluation of the reproducibility ofthe laboratory’s testing. Due to the difficulties involvedin preparing the samples, spikes may be used on aless frequent basis. However, the routine submittal ofeither known spikes or purchased standard referencematerials should be a part of a periodic evaluation ofthe laboratory. Depending on the numbers of samplessubmitted and the criticality of the analytical results,the submission of spikes may be done at a frequencythat varies from monthly to annually.

6.7.2.7 Corrective Actions. If some data points aresuspected to be erroneous, it may be possible for thelab to reanalyze the sample(s) in question. This maynot be possible if the lab discards samples soon afteranalysis or if the sample is totally consumed in theanalysis. If the parameter being measured is used toassess chronic exposure and the half-life of theparameter is very long compared with the timeelapsed since the sample was taken, another samplecan be collected from the individual for analysis.

Poor results on QA samples or unexpectedresults from the control population may require thebasic design of the biological monitoring effort to bereconsidered. Consult the documentation for the BEIsor the analytical lab for “reference” (non-occupationally exposed) concentration ranges.


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Elevated control values can be caused bycontaminated sampling equipment, inadequateanalytical methodology and method, exposure fromunanticipated sources, or, especially in the case of anonspecific parameter such as β2-microglobulin forcadmium, confounding effects possibly unrelated tothe compound of interest. Recoveries from referenceor spiked samples should generally fall in the rangeof 75 to 125% of the nominal value. Intraruncoefficients of variation should be less than 10%.Values outside these ranges can be caused byinadequate analytical method, sample decomposition(especially if the analyte is an organic compound), orimproper spiking technique.

7. Using Results7.1 Control ProgramsThe results of biological monitoring reflect exposure fromall routes, such as inhalation, oral ingestion, and skinabsorption, as tempered through marker half-times thatare dependent on(15) the following.• Exposing a chemical and the physical state of its

challenge (solid, liquid, or gas)• Physical activity (workload) and whether heat stress is

present for the worker• PPE, local emission source controls, general workplace

controls, and general worker training regarding theiruse

• Validity of sampling, storage, transport, and analyticalprocedures for the marker

These specific areas are under the control of hygienists. Other factors that may be important include the

following.• Genetic factors of the worker including gender, race,

ethnicity, and family traits• Homeostatic factors such as body temperature, pH of

blood and urine, circadian rhythms, type of symbioticmicroorganisms in the body, and integrity of theimmune system

• Lifestyle controllable factors such as diet; tobaccousage, alcohol, caffeine, and drug intake; and chemicalexposures in the home, during commuting, and duringrecreation

• Uncontrollable factors such as medications; medicalconditions; shock; depression; schizophrenia; trauma;oxygen lack; aging; seasonal factors; injury; andenvironmental factors such as geography; altitude; localtemperature and humidity; indoor air pollution; homepollution; commuting mode; types of recreation; andpast workplace exposures

The practicing industrial hygienist should seek the help ofphysicians, chemists, toxicologists, epidemiologists,biostatisticians, and experienced professionals to cope

with the full list of factors. The hygienist must know how toask for help in language that can communicate with otherexperts as well as with workplace management andworkers.

7.1.1 Exposure Assessment The specific areas under the control of hygienists arethe first four bullets in 8.1.1, that is, exposureassessment. The following paragraphs consider eachbullet with the role of biological monitoring specified.

7.1.1.1 The exposing chemical and physical state ofits challenge (solid, liquid, or gas). Determination asto whether inhalation or skin exposure mightdominate as exposure routes may be determined by(1) reference to the appropriate currentdocumentation of the threshold limit values,(5) (2)knowledge of the specific unit processes,(16) and (3)an understanding of the physical and chemicalproperties of the material safety data sheets for thechemicals used in the unit process and whether theyare known to permeate the skin.

Some generalizations include the following.

• Unenclosed hot processes usually signal agreat potential for inhalation exposure, as dodusty workplaces and use of solvents withvapor pressures >10–3 mm Hg at 25°C. Themajor role of biological monitoring would be toconfirm inhalation exposure as obtainedconcurrently by personal breathing zone airsampling.

• Handling solvents without PPE such as theappropriate gloves or clothing implies potentialfor contact with exposed skin. The hygienistmust observe the exposure situation to identifypotential sampling sites on the exposed or ill-protected skin for skin patch placement(17) ordirect sampling of the exposed skin(17) usingNIOSH methods, if possible.(7) The major roleof biological monitoring in this case would be toshow whether the lack of PPE contributed toskin absorption after skin exposure throughsolvent splashes in addition to the knowninhalation exposure. Even if PPE are worn,biological monitoring would show whether thePPE is an effective barrier to exposure.

• The chemicals that expose the skin willprobably have a much longer body half-time(t0.5) than the same chemical that is inhaled,unless skin absorption occurs fast, as, forexample, for dimethyl sulfoxide or materialsthat also contain dimethyl sulfoxide. Some timeis usually necessary to permeate the skin layerthat consists of the outer cuticle (epidermis orstratum corneum), the underlying dermis,which contains sweat glands, hair roots, fat


25

glands, and blood capillaries in a matrix ofcollagen and elastin; and then through the nextlayer, the hypodermis, which containsconnective tissue, fat, arterioles, and venules.The t0.5 is longer for water-soluble neutral andweakly acidic compounds that are resisted bythe cuticle. In contrast, exposure to organicbases such as aniline; basic aqueous solutionssuch as alkali salts of organic carboxylic acids;strong detergents; desiccant chemicals suchas acetone and concentrated sulfuric acid; andorganic solvents such as benzene causebreaching and abrading of the cuticle, allowingpenetration and permeation into the inner skinlayers, and so show shorter body t0.5. Themajor role of biological monitoring for thissituation would be to assess whether suchchemicals could be detected in the baselinesample of the next workday; an end-of-shiftsample might not reflect the skin absorptioncontribution because of the long half-time.

7.1.1.2 Whether physical activity (workload) and heatstress are factors for each worker. Increases in bothfactors cause increases of absorbed dose breathedin and hence biological monitoring markerconcentrations in urine, blood, and exhaled breath.

This is essentially an observational task for ahygienist.

The following qualitative scheme has been founduseful for workload.

• Resting: Sedentary, with little physical activityfor <30% of the time over the work shift

• Light: No sweating, with physical activity atleast 70% of the time over the work shift

• Average or moderate: Sweating just begins,without puffing and panting

• Heavy: Puffing and panting also occur withprofuse sweating

• Very heavy: Wheezing and gulping air occurwith copious sweating

There are two major semiquantitative scales ofworkload, one developed by the InternationalOrganization for Standardization (ISO) in 1990(18)

and another that dates from 1982.(19) Table 7-1 showswhat internal metabolic energy was formulated byISO, as apportioned for a 70 kg standard man,assuming a 1.8 m2 skin surface area. Each of thework contributions is additive.

The other major metabolic energy scheme is thefollowing.(19)

• Resting, <117 watt or a level of 0 relative toresting

• Light, 117–232 watt (a midpoint of 175 watt ora level of 58 watt relative to resting)


Table 7-1. Workload Contributions Suggested by the InternationalStandards Organization(18)

Cumulative WorkloadWork Metabolic Rate Workload Above RestingType (watt/m2) (wattA) (wattA) (watt)A

Resting (basal) 44 79 79 0Sitting 10 18 97 18Kneeling 20 36 115 36Crouching 20 36 115 36Standing 25 45 124 45

HandworkLight 15 (<20) 27 (<36) 106–151B 27–72 Average 30 (20–35) 54 (36–63) 133–178B 54–99Heavy 40 (>35) 72 (>63) 151–196B 72–117

One-arm workLight 35 (<45) 63 (<81) 142–187B 63–108 Average 55 (45-65) 99 (81-117) 178–223B 99–144Heavy 75 (>65) 135 (>117) 214–259B 135–180

Two-arm work Light 65 (<75) 117 (<135) 196–241B 117–162Average 85 (75-95) 153 (135-171) 232–277B 153–198Heavy 105 (>95) 189 (>171) 268–313B 189–234

Trunk workLight 125 (<155) 225 (<279) 304–349B 225–270Average 190 (155-230) 342 (279-414) 421–466B 342–387 Heavy 280 (230-330) 504 (414-594) 583–628B 504–549Very heavy 390 (>330) 702 (>594) 781–826B 702–747

Work speed as to distance Walking, 2–5 km/hour 110 198 277–322B 198–243

Walking uphill 2–5 km/hourInclination 5° 210 378 457–502B 378–423Inclination 10° 360 648 727–772B 648–693

Walking downhill 5 km/hourDeclination 5° 60 108 187–232B 108–153Declination 10° 50 90 169–214B 90–135

Walking 4 km/hour, backload10 kg 125 225 304–349B 225–27030 kg 185 333 412–457B 333–37850 kg 285 513 592–637B 513–558

Work speed as to heightWalking upstairs 1725 3105 3184–3229B 3105–3150Walking downstairs 480 864 943–988B 864–909

Mounting inclined ladder Without load 1660 2988 3067–3112B 2988–3033With 10 kg load 1870 3366 3445–3490B 3366–3411With 50 kg load 3320 5976 6055–6100B 5976-6021

Mounting vertical ladderWithout load 2030 3654 3733–3778B 3654–3699With 10 kg load 2335 4203 4282–4327B 4203–4248 With 50 kg load 4750 8550 8629–8674B 8550–8595

AAssuming a 70-kg reference man of 1.8 m2 skin areaBAssuming mean values between basal rate and standing are additive with mean values for body posture, type of work, and work speed

• Moderate, 233–348 watt (a midpoint of 291watt or a level of 174 watt relative to resting)

• Heavy, 349–465 watt (a midpoint of 407 watt ora level of 290 watt relative to resting)

• Very heavy, >465 watt or a level of >290 wattrelative to resting

To complicate matters, workers who do the sameapparent external work at the same work rate mayexperience different body workloads and hencedifferent absorbed doses of the chemicals to whichthey are exposed. Each worker should be classifiedas to average body workload in defined exposuresituations with the classification system specified.Individual body workload can also be calibrated byblood oxygen or by individual noninvasive bloodpressure measurements (fingercuff or arm cuff).

Heat stress from exposure to workplace hotprocesses and from wearing PPE also contributes tobody workload. Wet/dry bulb assessment of heatstress is recommended for hot workplaces, andsimilar type measurements within PPE encasing thebody at the end of shifts.(20) If real heat stress issuspected, the worker should be sent to a physician.

Workload and heat stress scales are heavilyinfluenced by personal factors such as pulmonaryfunction, personal fitness, and healthiness. Suchfactors are assessed in a conventional medicalexamination that is part of the health surveillanceprogram.

7.1.1.3 PPE, local emission source controls, generalworkplace controls, and worker training in their use.The biological monitoring data in conjunction withobservational data may suggest which of thesefactors should be tried first to control anyoverexposure as signaled by biological markerconcentrations that are greater than are expectedfrom the inhalation exposure alone.

The hygienist’s traditional job is to(1) identify the need for personal and

environmental controls;(2) institute such measures along with the

appropriate worker training; and(3) test whether these measures are effective

and communicate the findings to the worker and supervisors.

Personal controls may include any or variouscombinations of the following.

• Respirators• Gloves• Chemically protective clothing• Face shields• Personal showering• Hand and face washing at breaks

• Intake of fluids at breaks• Personalized break intervals• Daily changing of clothing

Personal breathing zone air sampling and personalbiological monitoring programs are beneficial inevaluating the effectiveness of personal andenvironmental controls, and training.

Training may be in any or various combinations ofthe following.

• PPE cleaning and maintenance• Donning, doffing, and disposing of PPE• Local exhaust and building ventilation• Workplace sanitation/cleaning• Personal air sampling program• Personal biological monitoring program

7.1.1.4 Validity of sampling, storage, transport, andanalytical procedures for the marker. In the absenceof a physician or an occupational nurse (the vastmajority of workplaces), the hygienist must identifythe appropriate biological monitoring marker, itscollection in the appropriate biological medium, itssafe storage, and its safe transport to an identifiedanalytical chemistry laboratory that will do theanalysis as outlined in the Question and Answersection of Appendix I. Beforehand, the worker mustprovide consent, be told why the monitoring isnecessary, and what the results may mean. Thisprocedure could be short-circuited by referring theworker to a medical clinic, which has to follow thesame procedure when the sample is taken. Thehygienist still must justify to the worker why thesampling is necessary and what the results maymean in conjunction with air sampling and ventilationresults and any skin exposure sampling.

The major role of the hygienist in skin sampling isto identify the most exposed site of the skin. This isoften the face, neck, wrists, arms, and hands inworkers with long-sleeved shirts, long trousers,socks, and chemical impermeable shoes. Table 7-2shows the accepted surface areas of body parts for a70-kg reference man, and for a 60-kg referencewoman.(21)

The major hygienist tasks are the following.• Sampler placement must be ascertained by

close observation and/or by using avisualization technique such as fluorescence,reflectance, or chemical spot tests. Use offluorescence is possible for aromaticcompounds, and if not aromatic, by use of afluorescent tracer such as uranine orfluorescein.

• The skin should be inspected before samplingfor cuts, abrasions, and eczema. Theseconditions invalidate the use of organic

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solvents for pads, wipes, or hand washes.According to the California EPA, no organicsolvents should be used for skin sampling,even if the skin surface is healthy.

• The worker should be asked whether there isany known allergy to any organic solvent usedin the sampling, and if that solvent coexposureis contraindicated for any medication that isbeing taken.

The important points for hygienists include thefollowing.

• The hygienist must wear the appropriate glovesduring sampling to prevent samplecontamination. Glove manufacturers’permeation/chemical degradation chartsshould be used, or the hygienist shouldreference either books of data on glovepermeation(22) or their Internet equivalent.

• Filters and gauze pads must not drip solventduring wetting or sampling. NIOSHrecommends that at least 80% of the centralsurface of the wipe or pad be moistened, withno excess liquid.

• The appropriate blank (two samplers exposedto the air environment by being cradled in theglove type worn for the length of the duration ofsampling after being moistened with theappropriate solvent) should also be analyzedand its mean analyte content corrected for inthe actual sample.

• Skin or surface area sampled must bemeasured, or better, defined beforehand.Repetitive skin sampling with pads and filtersshould be at constant speed (with pressure)from the outside margins of any samplingtemplate into its center, not the reverse.

• Any exposed side of any filter or pad used forsampling should be folded inward beforeplacement inside the sample container.

• The sample container should be an acid-washed Pyrex screw-cap tube or jar, the cap ofwhich is Teflon-lined. Plastic bag or plastic tubecontainers should be avoided for organics, butare adequate for inorganic analytes such aslead and cadmium. Secondary containment bymaterials of the same type as used for thesample container should be used in case ofbreakage.

• The storage and transport container must belabeled appropriately and insulated properly fortransport at the correct temperature.

• The initial survey should involve separateanalysis of each pass filter, gauze, or handwash to assess recovery for each method thatshould involve at least five sampling passes toassess whether more than one pass isnecessary for adequate recovery.(23)

There are only four NIOSH methods for skinsampling.(7)

(1) For aniline, o-toluidine and nitrobenzene(Method 2017): gauze wipes (4-inch × 4-inch)are used for surface and wipe sampling, andthe passive skin sampler is 1 g of silica gelcontained in a cotton pouch. Recoveries for thepassive dermal sampler spiked with 27–31 µgnitrobenzene, aniline, and o-toluidine andequilibrated for 1 hour varied between 88 and100%. Recoveries for similarly spiked gauzewipes after equilibration for about 8 hoursvaried between 83 and 88%. Ultrasonication in2 mL ethanol for 60 min is the desorption stepbefore capillary gas chromatography (GC)/flame ionization detection. The hygienist shouldwear butyl gloves or a laminated glove such asSilver Shield® during sampling.(24) The wipesshould be moistened with distilled water beforesampling.

(2) For lead in surface wipe samples (Method 9100):2-inch × 2-inch sterile cotton gauze (Curity®,Johnson & Johnson, or equivalent) or ashlessquantitative filter paper (for example, Whatman40) are recommended using a minimum 100-cm2 surface area sampled to detect at least 2µg Pb by flame atomic absorption (AAS) orinductively coupled plasma (ICP)-atomicemission spectroscopy. If graphite furnace AASor ICP-mass spectrometry are used, theminimum amount to be sampled decreases toabout 100 ng, and smaller surface areas can besampled. The gauze pad or paper should bemoistened with 1–2 mL distilled water. Wearingdustless disposable latex gloves is adequate. Inthe laboratory, sample treatment involvesdigestion in concentrated nitric acid beforespectroscopic analysis.

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Table 7-2. Mean Skin Surface Areas and 90% Confidence Ranges (...)for 70-kg Reference Man and 60-kg Reference Woman(21)

Body Region Men Women(cm2) (cm2)A

Arms 2280 (1090–2920) 2100 (1930–2350)Upper 1430 (1220–1560) NAForearms 1140 (945–1360) NA

Feet 1120 (611–1560) 975 (834–1150)Hands 840 (596–1130) 746 (639–824)Head 1180(900–1610) 1100(953–1270)Legs 6360 (2830–8680) 4880 (4230–5850)

Thighs 1980 (1280–4030) 2580 (2580–3600)Lower legs 2070 (930–2960) 1940 (1650–2290)

Trunk 5690 (3060–8930) 5420 (4370–8670)Total 19,400 (16,600–22,800) 16,900 (14,500–20,900)

ANA, Not available

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(3) Hand wash method for chlorinated andorganonitrogen herbicides (Method 9201 foralachlor, atrazine, cyanazine, metolachlor,simazine, and 2,4-dichlorophenoxyacetic acid(2,4-D) nonsalt derivatives): A volume of 150-mL isopropanol is poured into a 12-inch × 8-inch, 4-mL polyethylene bag (Scienceware® orequivalent). The hand is then inserted into thebag and the bag wrapped securely around theforearm several inches above the wrist. Thehand is shaken for about 30 sec. The hand isthen removed and dried. If the hand appearsdry, apply hand lotion. The solution istransferred to an acid-washed 250-mL Pyrexjar with a Teflon-lined screw cap lid, the lidsecured, and the container labeled and packedfor storage and transport to the laboratory. A150-mL blank poured into a plastic bag,shaken, and transferred to its Pyrex containermust also be analyzed. In the laboratory analiquot is methylated, the solution is cleaned upon a silica gel column and filtered, and thepesticides are quantified in an aliquot bycapillary gas chromatography with an electroncapture detector. The sample must be analyzedwithin 30 days of the sampling. The hygienistshould wear nitrile, Teflon, or laminated glovesduring sampling and transfer operationsinvolving these pesticides and isopropanol.(24)

(4) Patch method for chlorinated and organonitrogenherbicides (Method 9201 for alachlor, atrazine,cyanazine, metolachlor, simazine, and 2,4-dichlorophenoxyacetic acid (2,4-D) nonsaltderivatives): The dermal patch here is a 10-cm ×10-cm polyurethane foam pad, 3–4 mm thick,placed in an aluminized card holder with a 7.6-cm diameter circle cut in one side, and thenaffixed to the skin or the worker’s clothing. Thepads are transferred with 2-propanol-washedforceps to wide-mouth acid washed 120-mLPyrex jars with Teflon-lined screw caps. The capsare closed, the jars are labeled and insulated for4°C transport, and then sent to the laboratory foranalysis. Sample solubilization in the laboratoryis with 20 mL isopropanol, and then subsequentmethylation is with 20 mL methylating agent inthe same sample treatment and analysis as forMethod 9200. The method has been validated(>90% recovery) for 30-day storage except forthe 2,4-D acid (80% recovery) and metolachlor(86% recovery). Hygienists should wear nitrile,Teflon, or laminated gloves for protection againstthe pesticides.(24)

These basic field sampling methods can be adaptedfor almost any nonvolatile chemical with judiciousselection of patch, wipe, or filter types and theirsolvents, and also the appropriate hand-wash

solvents. The hygienist should consult with thechemist who will quantify the analyte.

7.1.2 Health Surveillance and MedicalSurveillance

8.1.2.1 Scientific Definitions. Health surveillanceand medical surveillance are interlinked and are oftenthought of as being the same. The basic difference isthat medical surveillance involves clinical markersthat physicians use to detect adverse effects ofexposure in individuals as based on a markerreference range, whereas health surveillanceconcerns all other markers, including biologicalmonitoring markers of dose, effect (nonclinical), andpredictive effect. When there is a definite adversehealth effect, the process of medical surveillancebecomes medical monitoring or medical screening.The marker of health surveillance may or may nothave a reference range or be dose-related.

Medical surveillance is the procedures involvedwith the panel of markers that physicians utilize forblood, urine, and other body fluids and tissues togauge whether a person is healthy via evaluating thefunction of the vital organs. This is the examinationthat physicians do before worker employment and toend employment and is the examination thatphysicians do on hygienists and any lay person toascertain their health.

Health surveillance is the procedures involvedwith markers that are not used clinically to assesshealth. A marker of health surveillance may becomeclassified as a medical surveillance marker when itproves its clinical worth through time. These markersare therefore medical surveillance markers at theirresearch (validation) stage.

To make things more complicated, governmentshave their own definitions of these terms. Hygienistsin every country have to abide by the regulations (andlegal definitions) that govern their activities. The restof this section discusses the present requirements inthe United States. Hygienists of other countries mustreplace the following section with those for their owncountries.

7.1.2.2 OSHA Medical Screening and MedicalSurveillance. In the United States, OSHAdistinguishes(25) between medical screening andmedical surveillance in its own manner(http//www.osha.gov/SLTC/medicalsurveillance/index.html).

Medical screening, according to OSHA, is “amethod for detecting disease or body dysfunctionbefore an individual would normally seek medicalcare. Screening tests are usually administered toindividuals without current symptoms, but who maybe at high risk for certain adverse health outcomes.”This is very close to the previously stated definition


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for medical surveillance used in its predictive guisefor supposedly healthy people. OSHA further states:“The fundamental purpose of medical screening isearly diagnosis and treatment of the individual andthus has a clinical focus.” This purpose reinforces theprimacy of the physician in the testing and brings intoeffect physician-patient confidentiality.

Medical surveillance, according to OSHA, is “theanalysis of health information to look for problemsthat may be occurring in the workplace that requiretargeted prevention, and thus serves as a feedbackloop to the employer.” OSHA elaborates:“Surveillance may be based on a single case orsentinel event, but more typically uses screeningresults from the group of employees being evaluatedto look for abnormal trends in health status.Surveillance can also be conducted on a singleemployee over time. Review of group results helps toidentify potential problem areas and the effectivenessof existing worksite preventive strategies.” Thisdefinition of medical surveillance therefore involvessingle cases, single sentinel events, or prospectiveepidemiology-type studies at one point in time orthrough time. OSHA adds: “The fundamental purposeof medical surveillance is to detect and eliminate theunderlying causes (i.e., hazards/exposures) of anydiscovered trends and thus has a prevention focus.”This purpose broadens the scope of medicalsurveillance to the whole program that prevents,identifies, controls, and manages health effects in theworkplace, even though prevention is stated to be thesupposed focus. This broadened scope for medicalsurveillance is also utilized by NIOSH(http://www.cdc.gov/niosh). Thus, personal airsampling, ventilation, hygiene, training, safety, andadministrative issues are included in addition tospecific clinical and health issues related to chemical,physical, and biological exposures. This purpose ofmedical surveillance allows hygienists and safetyengineers to be the primary decision-makers relativeto preventive measures in the workplace.

Interestingly, OSHA provides the major medicalscreening and surveillance endpoints together in itsguidance.(25) Table 7-3 summarizes these markers forthe 14 specific chemical hazards that are relevant tobiological monitoring. The tabulated endpoints are formedical screening except for the ones required forfitness to wear respirators (“Pulmonary functiontesting” and “Evaluation of ability to wear arespirator”), and “Additional tests if deemednecessary.” The category “Other required tests” oftenalso contains specific medical monitoring markers forthe exposure chemical. The category “Additional testsif deemed necessary” allows the full range of healthsurveillance markers (that include markers forbiological monitoring) to be used “if deemednecessary” by a physician.

OSHA also provides general medical screeningand medical surveillance guidance (Table 7-4) forgeneral chemical exposure in the following situationsrelated to chemical exposures.

• Asbestos in general industry (29 CFR1910.1001(l)) and in construction andshipyards (29 CFR 1926.1191(m)/1915.1001)

• Hazardous wastes in HAZWOPER (29 CFR1910.120(f)/1926.65)

• Hazardous chemicals in laboratories (29 CFR1910.1450(g))

• Respiratory protection (29 CFR 1910.134(e)/1926.103)

Tables 7-3 and 7-4 summarize OSHA guidance onmedical screening and medical surveillance relatedto chemical exposure. It should be noted that medicalscreening and surveillance guidelines also exist forbloodborne pathogens,(26) compressed airenvironments,(26) cotton dust,(26) noise,(26) andionizing radiation (as contained in 10 CFR 835 for theDepartment of Energy and as memorialized betweenOSHA and the Nuclear Regulatory CommissionOSHA Directive CPL 2.86 of 1989). Any knowntoxicologic interactions with the toxic effects ofchemicals bring these other medical screening andmedical surveillance endpoints into effect also.

Previously, according to 29 CFR 1910, anyoccupational illness, no matter how transient or short-lived, had to be recorded by the employer in its OSHA200 log. The legal definition of an occupational illnesswas then “an abnormal health condition caused orcontributed to by a non-instantaneous event orexposure in the work environment”(http://www.osha.gov). Subjective symptoms such asthe feeling of malaise, headache, or nausea were notrecordable if there was no apparent association withthe work environment. These guidelines have nowchanged.

According to the current 29 CFR 1904.39, theemployer must orally report to OSHA (nearest officeor 800-321-6742) within 8 hours a fatality orhospitalization of three or more employees as a resultof a work-related incident. This includes heart attacksand any fatality or multiple hospitalizations within 30days of the incident. Employers must record in theOSHA 300 log new work related injuries and illnessesthat meet one or more of the general recordingcriteria or meet the recording criteria for specifictypes of conditions. An injury or illness is now anabnormal condition or disorder. Injuries include casessuch as, but not limited to, a cut, fracture, sprain, oramputation. Illnesses include both acute and chronicillnesses, such as, but not limited to, a skin disease,respiratory disorder, or poisoning (including that afterexcess exposure to lead, cadmium, or benzene).Regardless of where signs or symptoms surface, a


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Table 7-3. Major Nonconstruction Industry Medical Screening and Surveillance Endpoints Recommended by OSHA for Chemical Hazards that CauseSystemic Effects(25)

Endpoint Chemical1 2 3 4 5 6 7 8 9 10 11 12 13 14

Preplacement Exam +a +a +a,k,l +a,k,l +a,k,l + +a + +a +a,l + +a,k,l +a,l +aPeriodic exam +a,b +a +b,l +b,l +b,l +b +a +a +b +a,l +a,l +a,b,l +a,l +aEmergency/Exposure examination/Tests + + +b,l,m +b,l,r +b,l +a,z – +F +a +l +a,l +a,l +a,l +Termination exam + +h – +s +a – +h – +a – – – +h –Exam emphasis c i n t w A C G I K L P R TWork and medical history +d +b,j +o +b,d +d +d +a +d +d +d +d,M +d +d +d,UChest X-ray + + – – + – + – – – – – – –Pulmonary Function tests – – +p – + – + – – + – – – –Other required tests e – q u x – D H J – N Q S VEvaluate Ability to Wear respirators + + + + + + + + + + + + + +Additional tests if deemed necessary + + + + + + + + + + + + + +Written medical opinion +f +f +f +g,v +f +B +f +f +f +f +f +f +g,v +f Counselling +g +g +g +g,v +g,y – +g,E +g +g +g +g,O +g +g,v – Medical removal plan – – + – + – – – – + + + + +

Key:1=acrylonitrile 29 CFR 1910.1045(n)/1926.1145/1915.10452=Arsenic 29 CFR 1910.1018(n)/ 1926.1118(n)/1915.10183=Benzene 29 CFR 1910.1028(i)/1926.1128/1915.10284=1,3-Butadiene 29 CFR 1910.1051(k)/1926.11515=Cadmium 29 CFR 1910.1027(l)/1926.1127/ 1915.1027/1928.10276=Carcinogens (Suspect) 29 CFR 1910.1003-1016(g)/1926.1103/1915.1003-10167=Coke oven emissions 29 CFR 1910.1029(j)8=1,2-Dibromo-3-chloropropane 29 CFR 1910.1044(m)/1926.1144/1915.10449=Ethylene oxide 29 CFR 1910.1047(i)/1926.114710=Formaldehyde 29 CFR 1910.1048(l)/1926.1148/1915.104811=Lead 29 CFR 1910.1025(j)/1926.6212=Methylenedianiline 29 CFR 1910.1050(m)13=Methylene chloride 29 CFR 1910.1052(j)/1926.115214=Vinyl chloride 29 CFR 1910.1017(k)/ 1926.1117

a, Standard specifies particular factors such as personal air exposures and/or years of exposure, biological indices, employee age, amount of time/year, andperiodic exams may be required at varying time intervals depending on exposure circumstances; b, annual; c, lung, gastrointestinal tract, thyroid, skin, neurological(peripheral and central); d, standard requires focus on specific body systems, symptoms, personal habits, family history, environmental history, and occupationalhistory; e, fecal occult blood; f, physician to employer; employer to employee; g, by physician; h, if no exam within 6 months of termination; i, skin, nose; j, smokinghistory included; k, no examination is required if previous exam occurred within a specific time frame and provisions of the standard were met; l, additional medicalreview by specialist physician(s) may be necessary for workers with abnormalities; m, includes urinary phenol; n, blood cell forming system, cardiopulmonary (ifrespirators used at least 30 days/year initial year, and then every 3 years); o, required for initial and periodic exams, and the preplacement exam requires a specialhistory; p, initially and every 3 years if respirators worn 30 days/year and with special requirements; q, complete blood count and differential; specific blood testsrepeated as required; r, within 48 hours of exposure; s, if 12 months and beyond last exam; t, liver, spleen, lymph nodes, skin; u, complete blood count withdifferential count and platelet both annually and 48 hours after exposure in an emergency situation and then repeated monthly for 3 more months; v, other licensedhealth care professional; w, lung, cardiovascular system, kidney and urine, and for males over 40 prostate palpation; x, annually: cadmium in urine, ß-2-microglobulinin urine, cadmium in blood, complete blood count, blood urea nitrogen, serum creatinine, urinalysis; y, specific requirements; z, special medical surveillance occurswithin 24 hours; A, determination for increased risk, for example, target organs, reduced immune system competence, reproductive/developmental systemcompetence, and known interacting factors, for example, smoking; B, physician to employer; C, skin; D, weight, urine cytology, urinalysis for sugar, albumin,hemoglobin; E, employer must inform employee of possible health consequences if employee refuses any required medical exam; F, male reproductive repeatedevery 3 months; G, male reproductive and genitourinary system; H, sperm count, follicle stimulating hormone, luteinizing hormone, total estrogen for women andmen; I, nose/lung, skin, neurologic, blood, reproductive, eyes; J, complete blood count with differential, hematocrit, hemoglobin, red cell count; if requested by theemployee, pregnancy testing and male fertility testing “as deemed appropriate by the physician”; K, skin irritation or sensitization; lung/nose; eyes; shortness ofbreath; L, teeth, gums, blood cell forming system, gastrointestinal, kidney, cardiovascular, and neurological; M, includes reproductive history, past lead exposure(work and nonwork), and history of specific body systems; N, blood hemoglobin, hematocrit, zinc protoporphyrin, urea nitrogen, serum creatinine, lead, peripheralblood cell smear morphology, red cell indices; urinalysis with microscopic examination; also, if requested by the employee: pregnancy testing and fertility testing inmales; O, includes advising the employee of any medical condition, occupational or nonoccupational, requiring further medical examination or treatment; P, skin andliver; Q, liver function tests and urinalysis; R, lungs, cardiovascular (including blood pressure and pulse), liver, nervous, skin; extent and depth depends onemployee’s health status, work, and medical history; S, before and after shift tests are included in the standard; T, enlargement of kidneys, spleen, and liver or theirdysfunction; abnormalities in skin, connective tissue, and lungs; U, includes alcohol intake, history of hepatitis, exposure to compounds that cause liver damage,blood transfusions, hospitalizations, and work history; V, blood tests for total bilirubin, alkaline phosphatase, serum aspartate aminotransaminase (glutamic-oxalotransaminase ), alanine aminotransferase (glutamic-pyruvic transaminase ), and γ-glutamyl transferase(γ-glutamyl transpeptidase)

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case is recordable in the OSHA 300 log only if a workevent or exposure is a discernable cause of the injuryor illness or of a significant aggravation to apreexisting health condition.

Recordable work related injuries and illnessesare those that result in one or more of the following:death; days away from work; restricted work; transferto another job; medical treatment beyond first aid;loss of consciousness; or diagnosis of a significant

injury or illness. Work is considered restricted when,as a result of a work related injury or illness, (a) theemployer keeps the employee from performing one ormore of the routine functions of his or her job (jobfunctions that the employee regularly performs atleast once per week), or from working the fullworkday that he or she would otherwise have beenscheduled to work; or (b) a physician or otherlicensed health care professional recommends thatthe employee not perform one or more of the routinefunctions of his or her job, or not work the full workdaythat he or she would otherwise have been scheduledto work. Medical treatment means any treatment notcontained in the list of first aid treatments. Medicaltreatment does not include visits to a health-careprofessional for observation and counseling ordiagnostic procedures. First aid means only thosetreatments specifically listed in 29 CFR 1904.7.Examples of first aid include the use ofnonprescription medications at nonprescriptionstrength, the application of hot or cold therapy, eyepatches or finger guards, and others.

Because of its broad nature, OSHA’s GeneralDuty Clause can also be used to ensure safeworkplaces. OSHA has cited employers under thisclause for failing to protect workers from dermalexposure that led to health effects, even though airconcentrations were below the permissible exposurelimit and respiratory PPE were properly used.Because biological monitoring could have led to thedetection of the exposure, but air sampling could not,biological monitoring could be required to test theeffectiveness of any control measures.

If the hygienist wishes to determine whichmedical screening and surveillance endpoints mightbe used for a specific chemical other than in Tables 7-3 and 7-4, the following procedure is suggested.

• Read the current ACGIH documentation of thethreshold limit values and BEIs(5) and notewhich target organs and blood and urinemarkers are mentioned.

• Consult a textbook,(26) OSHA publications,(25)

other books, or the most recent scientific reviewthat provide blood, breath, and urine targetorgan markers for the exposing chemical. If thebiological sample collection is noninvasive of thebody, the hygienist may be able to collect thesample. But if blood sampling is involved, theworker must be referred to a physician or otherlicensed health professional, as set out in theQuestion and Answer Section of Appendix I.

• Discuss your findings with a physician orcertified health professional, especially theones that your company uses. Failing asympathetic ear here, discuss your findingswith friendly nearby academics, personnel inindustrial hygiene organizations who specialize


Table 7-4 Medical Screening and Medical Surveillance Endpoints forGeneralized Chemical Exposure and to Asbestos(25)

Endpoint Chemical Exposure1 1A 2 3 4

Preplacement exam +a,b +a,b +a -q +s,tPeriodic exam +c +c,l +c,l -q +t,uEmergency/Exposure – – +a +a –

exam and testsTermination exam +d – +n – –Exam emphasis e m o -q +a,tWork/Medical history +f +f +p -q +aChest X-ray +g +g -,o -q -vPulmonary function test +h +h -,o -q -vOther required tests – – -,o -q -vEvaluate ability to + + + +q +

wear respiratorsAdditional tests if + + + + +

deemed necessaryWritten medical opinion +i +i +i +r +wEmployee counseling +j,k +j,k +j +j +xMedical removal plan – – – – –

1=Asbestos workers (General Industry)1A=Asbestos workers in Construction and Shipyards2=HAZWOPER workers3=Laboratory personnel4=Personnel who need to wear respirators for protection

a, Standard specifies specific factors such as personal air exposures and/oryears of exposure, biological indices, employee age, amount of time/year,and periodic exams may be required at varying time intervals depending onexposure circumstances; b, no examination is required if previous examoccurred within a specific time frame and provisions of the standard weremet; c, annual; d, within ±30 days of termination; e, respiratory,cardiovascular, gastrointestinal; f, standard form required; g, specializedrequirements; h, B reader, board eligible/certified radiologist or physicianwith expertise in pneumoconioses required for X-ray interpretation andclassification; h, forced vital capacity (FVC) and forced expired volume inone second (FEV1) measurements; i, physician to employer; employer toemployee; j, by physician; k, includes informing employee of increased riskof lung cancer from combined effect of smoking and asbestos exposure; l,can be more frequent if determined be necessary by physician; m,pulmonary and gastrointestinal; n, if no exam within 6 months oftermination/reassignment; o, determined by physician; p, emphasis is onsymptoms related to handling and exposures to hazardous substances andhealth hazards, fitness for duty, and ability to wear PPE; q, when required byspecific standards in Table 8-3 or others; r, physician to employer; s,evaluation questionnaire or exam required or follow-up exam when deemednecessary by physician or other licensed health professional; t, specificprotocol required; u, specific protocol required; v, as determined by physicianor other licensed health care professional; w, by physician or other licensedhealth care professional to employer and to employee; x, by physician orother licensed health care professional

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in the biological monitoring area(http://www.acgih.org and http:/www.aiha.org),and government bodies at the federal(http://www.cdc.gov/niosh; http://www.osha.gov)and state levels. It is a good idea to have aconsulting team of an analytical chemist,toxicologist, occupational physician,epidemiologist, and biostatistician.

It is important to realize that new physicians are nottrained in occupational medicine and the influence ofchemical exposures on target organs. Experiencedphysicians and licensed health professionalsincluding occupational physicians are the mostvaluable resources in deciding which medicalscreening is necessary, as well as deciding whichmedical surveillance markers are appropriate. Thesepersonnel may be useful in deciding what healthsurveillance markers are appropriate too, butbiological monitoring specialists are probably morelikely to know up-to-date information.

The hygienist is the crucial link between thelicensed health professional or physician andemployer, and between the employer and workersbecause of his or her

(1) training and their training skills;(2) knowledge about the interactions of the roles of

ventilation, enclosure controls, PPE, and theirmeasurement; and

(3) experience in the importance of personalhygiene. Part of the hygienist’s professionalrole is effective communication betweenemployer, worker, and licensed health careprofessionals.

8. Ethical and Legal Aspects ofBiological MonitoringBiological monitoring creates both ethical and legalchallenges for the industrial hygienist.(27,28) You mayoversee the collection of human blood or waste samples,activities that are usually associated with medicaldiagnostics.(27) If all potentially exposed employeesparticipate in the biological monitoring program, you willacquire information about inadvertent dermal exposuresand unanticipated failures in controls.(29) This knowledgewill make it possible to improve controls and reduce therisk of adverse health effects.

From the employee’s point of view, biologicalmonitoring outside of a strictly medical setting oftenprovokes anxiety. Workers may not be comfortableproviding blood samples. They may worry that theirtissues may be sampled for illicit drugs rather than toconfirm specified workplace exposures. They may haveconcerns that their ability to obtain health insurance maybe affected after being found highly exposed. Regulationssuch as the lead standard(2) provide basic protections,

including requiring that employees will not be financiallypenalized for medical removal. However, even the bestregulatory standard does not fully protect employees fromnegative outcomes when they participate in biologicalmonitoring. Therefore, protections guided by theprinciples of ethical conduct are needed. Adherence toethical conduct will ultimately make the industrialhygienist’s task easier.

The scope of this discussion is limited to humanbiomarkers of exposure and biomarkers of effect that arebeing used as part of routine industrial hygiene programs.This discussion does not address the ethical or legalissues associated with the use of biomarkers in molecularepidemiological studies.(30) Research contexts may useeither validated or experimental biomarkers to studydisease processes. These research programs generallydiffer from routine biological monitoring because thebiomarkers may not be validated, medical removal is notan issue, and the presence of external funding makes itless likely that the biological monitoring activity willcompete with other industrial hygiene activities. Thisdiscussion also does not address biomarkers ofsusceptibility (genetic testing) that measure either geneticor functional variations that affect the metabolism oftoxicants or predispose an individual to disease.(30) Theimportance of the legal, ethical, and social implications ofgenetic testing is acknowledged. However, genetic testingis predominantly aimed at testing the suitability of theemployee for work. In contrast, the biomarkers ofexposure and biomarkers of effect discussed in followingparagraphs reflect the impact of the workplace on theemployee.

8.1 Ethical and Legal BasicsThe Merriam-Webster dictionary defines ethics as “thediscipline of the conduct of a person or the members of aprofession dealing with what is good and bad and withmoral duty and obligation.”

The ethical principles presented here are based onthe conventional medical ethics developed to administermedical tests.(27) These include(1) autonomy (the right to refuse a test in a voluntary

program);(2) the right to have notification of results;(3) the right to confidentiality; and(4) the right to equity/lack of harm.

These principles provide general guidance that can beexpanded and adapted for biological monitoring. Inparticular, biological monitoring may challenge theprinciples of equity and lack of harm in ways that aredistinctly different from those encountered with medicaltesting. For instance, critics have warned that biologicalmonitoring uses employees as sampling devices (“guineapigs”). They are concerned that biological monitoring maycompete or replace other activities, such as air area


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monitoring and prevention-control activities. An ethicallydesigned biological monitoring program recognizessituations in which there is a potential for employee harmand appropriately use biological monitoring to provideadditional information rather than supplant otherimportant industrial hygiene activities. However, in somecases biological monitoring may be the only way toassess whether an exposure situation is in control or not,for example, blood lead or blood/urine cadmiumconcentrations when PPE are worn, or when skinabsorption is the dominant exposure route.

The legal guidelines for biological monitoring arementioned here, but for compliance purposes thehygienist is referred to the regulatory standard. DirectOSHA oversight of biological monitoring is limited to threechemical-specific standards (cadmium, 29 CFR1910.1027;(3) lead, 29 CFR 1910.1025;(2) and benzene,19 CFR 1910.1028(1)) and the rules regarding access toexposure and medical records (29 CFR 1910.1020).(6)

OSHA also provides nonmandatory biological monitoringguidelines for a number of chemicals, including mercuryand vinyl chloride (see Section 7.1.3.2 and Tables 7-3and 7-4). Depending on the standard, there may beprovisions for confidentiality, notification of individualresults, controlled access, and medical removal withoutpenalty.

The Americans with Disabilities Act (ADA),administered by the Equal Employment OpportunitiesCommission (EEOC), gives civil rights protections similarto those provided on the basis of race, color, sex, nationalorigin, age, and religion to individuals with disabilities. Arecent court case is pertinent to the use of medicalscreening and, possibly, biological monitoring. In ChevronU.S.A. Inc. v. Echazabal (2002 DJDAR 6379 [06/10/02]),a Californian had been employed by a maintenancecontractor in a coker unit since 1972. The worker, MarioEchazabal, applied for a full-time position with Chevron in1992. However, he failed Chevron’s medical examinationon the basis of high liver enzymes, which indicated theliver ailment would be aggravated by continued exposureto coker toxins. Echazabal continued to work at themaintenance position, but was found to have had liverdamage from a past hepatitis C infection. He againapplied for a full-time position in 1995 and was rejectedagain, because he still had high liver enzymes.Furthermore, Chevron asked the maintenance companyto remove Echazabal to a safer job that did not involveexposure to coking unit solvents, or to remove him fromthe refinery altogether. To make matters morecomplicated, the EEOC had issued a regulation [29 CFRU 1630.15(b)(2)(2001)] stating that a threat to oneselfwould be a reason for disqualifying someone from a job.By this guideline Chevron could refuse to hire Echazabal.In addition, California Labor Code, Sections 6402, 6403,and 6423, also forbids any workplace that “is not safe andhealthful” and states that the employer must not “permit”an employee to work in such a place. Furthermore, a

“serious” violation (defined as a risk to life) is a crimeunder this California Labor Code. After being laid off in1996, Echazabal sued on the basis of the violation of theprovisions of the ADA, with the result that the district courtruled in favor of Chevron. On appeal, the Ninth CircuitCourt of Appeals in a split decision ruled that anemployee with a medical condition cannot be excludedfrom the workplace even if continued employment placeshis or her health at risk. The Supreme Court appeal wasdecided in June 2002 by reversing the Ninth Circuit Courtof Appeals decision on the basis that the ADA covers notonly a potential employee’s “threat to others in theworkplace” but also “risks to the potential employee’s ownhealth and safety as well.” The precursor to ADA, theRehabilitation Act of 1973, recognized an employer’s rightto consider threats to self and others as grounds fordenying employment. Although the ADA does notspecifically mention “threat to self,” the policies of theEEOC do include such directives. Chevron had alsoargued that the refusal was reasonable because thecompany had an interest in avoiding time lost to sickness,excessive turnover from medical retirement or death,litigation under state tort law, and risk of violating OSHA.The Supreme Court rejected the charge that Chevronhad reacted in a “paternalistic manner.” However, theSupreme Court did ask the Ninth Circuit Court toconsider whether Chevron engaged in the type ofindividualized medical assessment required by ADA inorder for a “direct threat” argument to be used asjustification for not hiring a potential employee.

On remand, in July 2003 the Ninth Circuit Court ruledagainst Chevron saying that there was not adequateevidence to conclude that Echazabel’s medical conditionposed a significant hazard to his health and safety, andtherefore there was no basis for the “direct-threat”decision. They rejected the “direct threat” argumentprimarily because Chevron failed to perform “individualassessment.” It was concluded that the assessment ofEchazabel’s liver enzymes by Chevron’s physicians wasnot adequate evidence of future risk to himself, especiallyas Echazabel’s specialists had discounted the healthrisks. Rather, the evidence of “direct threat” would need tobe based on an assessment of liver function or toxicity byspecialists. This revives the case, which can once againbe taken up by the Supreme Court if Echazabel choosesto do so. Chevron may still appeal the Ninth CircuitCourt’s decision.

The outcome of this case may serve as a precedentfor potential employees with high body burdens oftoxicants, and who wish to work at a job where there isthe likelihood of further exposure. The lead and cadmiumstandards prevent the continued working of theoverexposed employee even under the protection of ADAbecause the criteria for mandatory medical removal arethe objective levels of lead or cadmium in blood. However,in general the case for use of data for biologicalmonitoring markers of dose or susceptibility has not been


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legally tested in a similar manner. There is concern thatshould the “direct threat” argument be established as aprecedent, employers could use biological monitoringresults in hiring and job assignment situations.

Before discussing the guidelines for performingethical and legal biological monitoring, OSHA’sclassification scheme for biological monitoring activitiesshould be clarified. OSHA considers biological monitoringresults as either exposure records or medical recordsdepending on whether the chemical or its effects arebeing measured. Biological monitoring results that areconsidered medical records have a greater degree ofconfidentiality and more stringent requirements foraccess by individuals other than the employee than doexposure records. According to OSHA, “biologicalmonitoring results which directly assess the absorption ofa toxic substance or harmful physical agent by bodysystems (e.g., the level of a chemical in the blood, urine,breath, hair, fingernails, etc) but not including resultswhich assess the biological effect of a substance or agentor which assess an employee’s use of alcohol or drugs”are considered to be exposure records. In contrast,biological monitoring for biomarkers of effect isconsidered to be medical records, which are the results ofmedical examinations (pre-employment, preassignment,periodic, or episodic) and laboratory tests (includingchest and other X-ray examinations) taken for thepurpose of establishing a baseline or detectingoccupational illnesses, and all biological monitoring thatis not defined as an “employee exposure record.”(25)

Mandatory medical removal at designated bloodconcentrations of lead and cadmium cause these recordsto become medical records, so that the classification isnot as clear cut as it seems. However, it is clear that theexposure records of workers who do not suffer medicalremoval are not medical records.

8.2 Ethical and Legal Considerations forImplementing Biological MonitoringThe process of biological monitoring can be divided intothe ethical and legal considerations encountered before,during, and after the biological monitoring is performed.Throughout the process, steps should be taken to ensureequity and lack of harm among those participating in theprogram.

8.2.1 Before Biological MonitoringDevelop an industrial hygiene program that ensuresthe ethical treatment of employees. Ethical conflictsarise when industrial hygiene programs rely solely onbiological monitoring rather than integrating biologicalmonitoring into a comprehensive program ofevaluation and controls. When biological monitoringis used in place of environmental monitoring,hazardous conditions are detected only byoverexposing employees. The problem of

overreliance on biological monitoring is compoundedwhen financial resources for a comprehensiveindustrial hygiene program are scarce or unavailable.

Industrial hygiene programs should be designedto accomplish the following.(28)

• Whenever possible, environmental monitoringshould be the principal mode of assessment,with biological monitoring as the secondaryindicator of failures in control.

• The biological monitoring program should notdivert resources from other industrial hygieneactivities that reduce toxicants throughengineering or other controls; that is, it shouldbe cost-effective.

Choose biological monitoring tests that are accurate,reliable, and have high predictive values.(29) Biologicalmonitoring tests that meet these requirementsconstitute a good use of resources by the employerand help employees by informing them about themagnitude and circumstances of their exposures.See Section 5 and Appendix I for more details.

Employees should have the right to choosewhether to participate. Although it is beneficial tohave the participation of all workers, they may bereluctant to participate because of personal, cultural,or religious reasons. Employees who choose not toparticipate should not be identified or penalized.Continuation of employment or job access should notbe contingent on participation in the biologicalmonitoring program. Employers have madeparticipation in biological monitoring programs acondition of employment, a practice that may be legalbut is not ethical.

Employers should inform employees in writingabout the risks and benefits of any planned biologicalmonitoring. Some employers have institutional reviewboards to manage informed consent. The informedconsent should convey

(1) that participation is voluntary (this assumesthat the requirement for autonomy is fulfilled);

(2) information about the chemical(s) that will bemeasured;

(3) information about the media in which theagents will be collected (exhaled air, blood,urine, etc.);

(4) information about the risk(s) associated withthe biological monitoring sampling;

(5) a summary of how results will be reported(individual vs aggregate and the times thereports will be issued); and

(6) the benefits and disadvantages of the plannedsampling to the worker.

Some examples of informed consent forms areprovided in Appendix V.


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8.2.2 Performing Biological MonitoringBiological monitoring should be performed using theleast invasive method possible.(28,29) The biologicalmaterial collected from the worker should beanalyzed only for the chemicals about which theemployee was informed. Biological monitoringanalysis for additional substances, such as drugs orfor other chemicals about which the employee wasnot informed, should not be performed. Doing so willdamage employee trust and undermine the biologicalmonitoring program. See Sections 6.1 through 6.6 formore details on how to do sampling for specificbiological materials.

8.2.3 After Biological Monitoring8.2.3.1 Timely Notification. Workers should benotified of their biological monitoring results in atimely manner. The form of reporting should beguided by the ethical principles of equity and lack ofharm. Biological monitoring results can be reported toemployees as individual results, or the group resultscan be reported in the aggregate as the maximum,mean, geometric mean, range, and medianexposures. Biomarkers of effect often predict grouprather than individual risk, and therefore, aggregateresults should be reported as well as individualresults. Aggregate results also can be reported forbiomarkers of exposure, because this type ofreporting can supply useful information about theoccurrence of dermal exposures or failures incontrols. This avoids ostracizing individual employeesand provides a signal to the industrial hygienist thatthe workplace controls need to be reevaluated.

For lead and cadmium there are regulatoryrequirements as to how the notification is performed.The cadmium standard mandates that individualresults be reported.

8.2.3.2 Right to Know. Employees should haveaccess to their biological monitoring records. Here,whether OSHA considers the biological monitoring tobe exposure or medical records affects the terms ofthe access. The general rule is that data for markersof dose in medical surveillance are consideredaccessible, but not data for markers of adverse effectused in medical screening.

8.2.3.3 Confidentiality of Results. Biologicalmonitoring data are descriptive of an individual’sbodily fluids and wastes, and therefore, should beconfidential. This statement reflects ethical ratherthan legal considerations. In reality, biologicalmonitoring records that are considered to beexposure records have no guarantee of

confidentiality according to OSHA, althoughconfidentiality is required of all medical records.Health professionals and union representatives musthave the written consent of the employee to gainaccess to biological monitoring results that areconsidered medical records. In contrast, no suchwritten consent is necessary for biological monitoringfor exposure. The exception is cadmium, for which theurine and blood levels are considered to beconfidential.

The lack of legal confidentiality of biologicalmonitoring data considered to be part of exposurerecords does not preclude some confidentiality. Onestrategy would be to remove the personal identifierswhen reporting the results to unions or otheragencies authorized to have access to exposurerecords.

8.2.3.4 Administrative Removal. Employees found bybiological monitoring to be highly exposed should beremoved from further risk of exposure. Removalunder these circumstances would constitute medicalremoval (MR) and redesignation of the exposurerecord as a medical record. There are severalconditions that should be satisfied when MR isnecessary.

• Employees should not be penalized eitherfinancially or in terms of employment orseniority.

• Controls should be instituted to preventexposures for future employees when theyperform the tasks that resulted in theoverexposure of the employee who wasmedically removed.

These protections are mandatory under the leadstandard.(2) Other preventative measures mayinclude job rotation (“administrative controls”), or jobreassignment.

8.2.3.5 Responsible Employer Use of BiologicalMonitoring Data. It is unethical to use biologicalmonitoring as a way to identify unexposed employeesfor jobs or tasks with a high risk of exposure withoutseriously attempting to institute effective controls.

8.2.3.6 Preemployment Testing. It is still unethical touse biological monitoring results to make decisionsabout whether to offer employment to job applicants.Preplacement biological monitoring can be done afterthe offer of employment to avoid placing previouslyexposed workers at greater risk. If there is an existingbiological monitoring program, baseline biologicalmonitoring should be performed prior to commencingthe job to establish each individual’s baseline.


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9. Normative References

Codes, regulations, standards, and guidelines in this listcontain provisions that, through reference in thisguideline, constitute provisions of the guideline. Whenpublished requirements are in conflict, the more stringentshould be used.

1. “Benzene.” Code of Federal Regulations Title 29, Part1910, section 1028, 1992. “Lead.” Code of FederalRegulations Title 29, Part 1910, section 1025, 1992;“Lead Exposure in Construction.” Code of FederalRegulations Title 29, Part 1926, section 62, 1993.

2. “Lead.” Code of Federal Regulations Title 29, Part1910, section 1025, 1992; “Lead Exposure inConstruction.” Code of Federal Regulations Title 29,Part 1926, section 62, 1993.

3. “Occupational Exposure to Cadmium; Final Rule.”Federal Register 57:178 (14 September 1992), pp.42102-42463.

4. American Conference of Governmental IndustrialHygienists (ACGIH): 2003 TLV®s and BEIs.Cincinnati, Ohio: ACGIH, 2003.

5. American Conference of Governmental IndustrialHygienists (ACGIH): Documentation of the ThresholdLimit Values and Biological Exposure Indices. 6th ed.Cincinnati, Ohio: ACGIH, 1991 and updates.

6. “Access to Employee Exposure and MedicalRecords.” Code of Federal Regulations Title 29, Part1910, section 20, 1992.

7. There are very few direct-reading methods in theNIOSH Manual of Analytical Methods (NMAM) in thefourth edition: Method 9100 for lead surface and handwipes; Method 2017 for surface wipes and skinbadges for aromatic amines; Method 9200 forchlorinated and organonitrogen herbicides (handwash); and Method 9201 for chlorinated andorganonitrogen hericides (patch). For the up-to-dateNMAM on the web, seehttp://www.cdc.gov/niosh/nmam/nmammenu.html.

8. “Bloodborne Pathogens.” Code of FederalRegulations Title 29, Part 1910, section 1030, 1992.

9. American Industrial Hygiene Association (AIHA):Quality Assurance Manual for Industrial HygieneChemistry. Fairfax, Va.: AIHA, 1988.

10. U.S. Environmental Protection Agency (EPA):Handbook for Analytical Quality Control in Water andWastewater Laboratories (EPA-600/4-79-091).Cincinnati, OH: Environmental Monitoring andSupport Laboratory, EPA, 1979.

11. National Institute for Occupational Safety and Health:Industrial Hygiene Laboratory Quality Control Manual(Technical Report 78). Washington, D.C.:Government Printing Office, 1976.

12. Schlecht, D.C., J.V. Cradle, and W.D. Kellogg:Industrial hygiene. In Quality Assurance Practices forHealth Laboratories. Washington, D.C.: AmericanPublic Health Association, 1978.

13. “Occupational Exposure to Hazardous Chemicals inLaboratories.” Code of Federal Regulations Title 29,Part 1910, section 1450, 1992.

14. National Institute of Standards and Technology(NIST): Catalog of Standard Reference Materials.Gaithersburg, Md.: NIST, 1993.

15. Que Hee, S.S.: Biological Monitoring: An Introduction.New York: Van Nostrand Reinhold/John Wiley, 1993.

16. Burgess, W.A.: Recognition of Health Hazards inIndustry, 2nd ed. New York: Wiley, 1995.

17. Ness, S.A.: Surface and Dermal Monitoring for ToxicExposures. New York: Van Nostrand Reinhold/Wiley,1994.

18. International Organization for Standardization (ISO):Determination of Metabolic Rate (ISO 8996).Geneva: ISO, 1990.

19. Smith, J.L., and J.D. Ramsey: Designing physicallydemanding tasks to minimize levels of worker stress.Ind. Eng. 14:44–50 (1982).

20. Ramsey, J.D., and M.Y. Beshir: Thermal standardsand measurement techniques. In S.R. DiNardi, editor,The Occupational Environment: Its Evaluation andControl, pp. 660–690. Fairfax, Va.: AmericanIndustrial Hygiene Association, 1997.

21. U.S. Environmental Protection Agency: Developmentof Statistical Distributions of Ranges of StandardFactors Used in Exposure Assessment (EPA 600/8-85/010). Washington, D.C.: Office of Health andEnvironmental Assessments, Exposure AssessmentGroup, 1985.

22. Forsberg, K., and L.H. Keith: Chemical ProtectiveClothing. Boca Raton, FL: Lewis Publishers, 1995,pp. 105–106 and 247–249.

23. Que Hee, S.S., B. Peace, C.S. Clark, J.R. Boyle, R.L.Bornschein, and P.B. Hammond: Evolution of efficientmethods to sample lead sources, such as house dustand hand dust, in the homes of children. Environ.Res. 38:77–95 (1985).

24. Lin, Y.W., and S.S. Que Hee: Glove permeation testsusing novel microchemical techniques for 2,4-dichlorophenoxyacetic acid (2,4-D) derivatives. Arch.Environ. Contam. Toxicol. 36:485–489 (1999).

25. Occupational Safety and Health Administration:Screening and Surveillance: A Guide to OSHAStandards (OSHA 3162). Washington, D.C.: U.S.Department of Labor, 1999.

26. Que Hee, S.S.: Biological Monitoring: An Introduction.New York: Van Nostrand Reinhold/John Wiley, 1993.Part 3, pp. 187-299, and Part 4, pp. 301–357.


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27. Engelhardt, H.T. Jr.: The Foundation of MedicalEthics. New York: Oxford University Press, 1986.

28. Ashford, N.A., C.J. Spadafor, D.B. Hattis, and C.C.Caldart: Monitoring the Worker for Exposure andDisease. Baltimore: Johns Hopkins University Press,1990.

29. National Institute for Occupational Safety and Health(NIOSH): Manual of Analytical Methods, 4th ed., byA.W. Teass, R.E. Biagini, G. DeBord, and R.D. Hull.Cincinnati, Ohio: NIOSH, 1998. Appendix F.,Application of Biological Monitoring Methods.

30. Schulte, P.A.: Biomarkers in epidemiology: Scientificissues and ethical implications. Environ. HealthPerspect. 98:143–147 (1992).


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The information in Appendix I is provided for those whorequire basic biological monitoring information. Thereader who has no background in biological monitoringshould first view the CD slide show. This appendix shouldthen be read and questions Q1 through Q18 thenanswered. The answers should then be checked againstyour replies. Then you should answer these questionsagain relative to lead and benzene and check youranswers against the Appendix I answers. Keep repeatingthis until you get the answers right. Once you feel youhave a good grasp of the scientific principles, thenSections 6 through 8 should be read plus the casestudies of interest. Then you are ready to do a questionand answer series on another chemical of interest. Thereferences for Appendix I apply only to this appendix.

The following background is necessary for industrialhygienists who want to understand or do biologicalmonitoring.• Sufficient chemistry to understand units and chemical

notation• Practical personal breathing zone air sampling

experience• An understanding of industrial unit processes• Comprehension of the principles of toxicology• Knowledge of data management• Ability to use the literature of industrial hygiene,

including material safety data sheets (MSDSs), to findinformation

• U.S. industrial hygienists also should possess (1) themost recent Documentation of the TLVs and BEIs of theAmerican Conference of Governmental IndustrialHygienists (ACGIH);(1) (2) the most recent edition of theannual ACGIH TLV®s and BEIs;(2) and (3) the mostrecent NIOSH Pocket Guide to Chemical Hazards.(3)

Hygienists in other countries should have their country’sequivalent publications. If there are no such publications,use the same-language publications of an appropriatecountry near you.

A textbook on industrial hygiene is also useful. Thetwo of note in English are

(1) B.A. Plog, J. Niland, and P.J. Quinlan,Fundamentals of Industrial Hygiene, 4th ed.(Itasca, Ill.: National Safety Council, 1996); and

(2) S.R. DiNardi (editor), The OccupationalEnvironment—Its Evaluation, Control, andManagement, 2nd ed. (Fairfax, Va.: AmericanIndustrial Hygiene Association, 2003).

Industrial hygienists must use professionalobservational judgment in assigning the importance ofexposure routes, because this is a major trigger for theuse of biological monitoring. Judgment requires a mixtureof theoretical knowledge, practicality, and experience.

Understanding of some basic concepts, as discussedin the following paragraphs, also is required for everyexposure chemical before biological monitoring iscontemplated.

The essential uses and relevant physical propertiesof the specific compound in the specific workplace(1) mustbe considered. At 25°C, compounds with vapor pressures>10-3 mm Hg pose primarily a vapor inhalation hazard.When hot processes are present, some chemical vaporsmay condense to produce both fume and vapor inhalationexposures together. The use of dusts, sprays, nozzles,and moving vehicles can produce aerosols that cause aparticle inhalation hazard as well as simultaneous skindeposition. All chemicals, whether they are volatile or not,pose skin irritation/absorption problems on skin contact.Poor personal workplace hygienic practices andinadequate housekeeping may allow the oral and skinroutes of exposure to be important to the dose ultimatelyabsorbed by the body.

Knowledge of specific exposure scenarios,conditions, and symptoms of overexposure for eachspecific workplace exposure is needed. This alsopresupposes knowledge of the specific unit processes inthe workplace(1,4) and that MSDSs are available to defineand state the composition of the chemicals used. Thenearer the worker is to the emission source, and thelonger the worker is exposed near the source, the higheris the exposure potential. This is the classic time-and-motion workplace study.

An understanding of data from analytical chemistrylaboratories is necessary. The analytical methods musthave sufficient sensitivity (How much can be reliablyquantified?) and selectivity or specificity (What else is inthe workplace that might interfere?).(5,6) This is oftenworkplace, analytical method, and sampling methoddependent as well as being workplace chemical-dependent.

Regulatory or recommended guidelines(2,3) must beknown. These differ from country to country. Eachdocumentation in reference 1 has a section devoted tonon-U.S. guidelines.

Every chemical to be monitored should have itsindividual information available or compiled.


Appendix I: Introduction to Biological Monitoring; Questions and Answers

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The detailed examples here will focus on the organicaromatic compound, benzene (C6 H6), a carcinogen, andlead (Pb), a metal.(7,8) Summaries for benzene and leadfollow for illustrative purposes for each question. TheBackground Note on Intrinsically Safe WorkplaceExposures to Benzene and Lead should be read beforereading about benzene and lead in the biologicalmonitoring questions and answers.

A1.1 Some Important Questions andAnswers on Biological Monitoring

The question-and-answer session is gradated, that is,questions follow from the answers. See Table A1.1 for acomplete list of questions.

Q1: What Is Biological Monitoring?Biological monitoring is the measurement of compoundsin, or the affected components of body fluids of, thehuman body by chemical or physical methods afterabsorption of an exposing chemical or interaction with aphysical or biological agent.(9)

The measured compound or affected component isalso often termed a biological monitoring marker, oftenshortened to marker or biomarker. Marker can mean anymeasured or correlated factor relative to an agent’sabsorbed dose and hence exposure. Biomarker limits thefactor to living things. Biomarker also covers geneticchanges and products, and chemicals indicative ofmicrobial and viral exposures.

There are two types of biological monitoring markers.

(1) Of dose, sometimes also called “internal dose.”The concentration of the marker is correlated to theabsorbed dose of the exposing chemical. The marker andthe exposing chemical may or may not be the same.

If inhalation is the dominant contribution to theabsorbed dose (>70%), the marker concentration is alsocorrelated to the personal breathing zone concentrationsof the exposing chemical. If skin and/or oral exposure arethe dominant contributions to the absorbed dose (>70%),there may be no correlation of the marker to personalbreathing zone concentrations of the exposing chemical.Guideline “biological equivalent values” are used thatcorrespond to specific personal breathing zone airconcentrations of the vapor or aerosol under specifiedexposure conditions. These biological equivalent valuesshould be consistent with the findings of otherinvestigators who measure markers of dose under similarinhalation exposure conditions, and when other routes ofexposure are not important.

(2) Of effect, sometimes also related to the“biologically effective exposure dose.” The concentrationor magnitude of the marker is related to the magnitude ofa biological effect in the target organ or tissue. If theexposing agent is the culprit, the biological effect in atarget organ will be better correlated to the dose ofexposing chemical absorbed by that target organ ratherthan a surrogate such as blood concentration, themeasure of absorbed or internal dose for the body.

The effect can be any of the following: reversible (amarker of health surveillance); irreversible (a marker ofadverse effect, also called a medical monitoring ormedical screening marker); predictive of impending effect(a predictive marker of effect). Predictive markers of effectmay or may not be reversible. Markers that predicthypersensitivity (or sensitivity) to the exposing agent thatare not observed in most other exposed people are calledmarkers of susceptibility.

All of these markers of effect may also be markers ofdose.

Clinical symptoms—for example, pain, headache,insomnia, irritation, bleeding, or crying—are not biologicalmonitoring markers. Quantitative measurements ofbiochemical and biophysical markers as surrogates orcorrelates of clinical symptoms are biological monitoringmarkers. Most biological monitoring markers are not usedto correlate to acute adverse effects such as clinicalsymptoms, or to short-term exposure limits (STELs) orceiling limits. Biological monitoring is impractical underimmediately-dangerous-to-life-and-health (IDLH)conditions. Intrinsically safe conditions of exposure andsample collection are required.

The markers (sometimes termed “chemical markers”if the marker is the exposing chemical or is derived fromthe exposing chemical, or “biochemical markers” ifproduced from native or modified biochemicals of thehuman body) may be any of the following.


Table A1-1 Index of Questions

Q1: What is biological monitoring?Q2: When should I use biological monitoring? Is personal breathing zone

air monitoring inadequate?Q3: Do I have to take any biological monitoring samples?Q4: I want to do biological monitoring. What compounds have guidelines?Q5: What biological monitoring am I legally required to do?Q6: What is a BEI?Q7: Is there a difference between a BEI and biological monitoring?Q8: When do I sample?Q9: Why per gram for creatinine and per liter for urine sampling?Q10: If workers are exposed to a specific chemical, why is another chemical

often chosen as biomarker instead?Q11: How do I begin to take urine samples?Q12: How do I interpret the results of urine testing? Q13: When and how should I do breath sampling?Q14: What factors affect the concentrations of breath markers?Q15: Are the BEI guidelines still applicable if a worker is exposed at the

same time to other chemicals or exposed to other chemicals prior to the work shift?

Q16: What should I do when I cannot find guidelines for an exposing chemical?

Q17: What are my responsibilities to the worker and my employer relative to biological monitoring?

Q18: What is my function in the effort to do biological monitoring?

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The Marker as Absorbed Exposing ChemicalBenzene (concentration in urine, blood, or breath).The analytical methods to measure benzene withselectivity (specificity) depend on thechromatographic method used and the complexity ofthe sample. The sensitivity depends on thechromatographic detector and the actual amount ofbenzene detected in the end determinative step ofthe analysis. The latter is related to benzene airconcentration, air volume sampled, and analyterecovery from the air sampler. Other compounds inthe sample matrix may interfere at low benzenelevels. In general, the more complex the biologicalmedium, the more chance is there of interference.Thus, breath is the simplest convenient biologicalfluid, followed by saliva; urine; plasma; sputum;sperm; hair; and then blood in order of increasingcomplexity.

Lead (total concentration in blood [PbB] andurine [PbU]. The analytical chemistry methods (suchas those for filter air samples for metallic lead or leadoxides in metal fume or dust exposure) usedigestions to measure total Pb rather than the actualmolecular form of lead in the biological fluid.(10–12)

Tetraethyl lead (TEL) and tetramethyl lead (TML),specific lead covalent compounds that are alsovolatile, can be analyzed as themselves in breath,blood, and urine. Guidelines are in leadequivalent(13,14) to be uniform with metal fumesampling.

The Marker as a MetaboliteThis metabolite is a product of oxidation (gain ofoxygen, loss of hydrogen, loss of electrons, orincrease in oxidation number of an element), or ofreduction (loss of oxygen, gain of hydrogen, gain ofelectrons, or a decrease in oxidation number of anelement), or of hydrolysis (reaction with water) of theexposing chemical. Such a metabolite is commonlycalled a “product of a Phase I process” in toxicology.Such reactions are enzyme catalyzed and requirecofactors and high-energy compounds.

Benzene. Urinary free phenol concentration forbenzene(15,16) (see Equation A1-1):

[O] = oxidationC6H6 → C6H5OH A1-1

Lead. The Pb in urine, blood, and bone has thePb(II) oxidation state. These lead compounds maydiffer from those in the exposure (Equation A1-2).

Pb(IV) or Pb(III) → Pb(II) A1-2

The chemical forms of Pb in blood and urine arenot known. TEL and TML degrade to otherorganolead compounds that can be analyzed inblood and urine. Trialkyl, dialkyl, monoalkyl, andinorganic Pb result from tetraalkyl lead metabolismand can be detected in urine and blood.

The Maker as a Product of Reaction with a SmallBiomolecule of the Body via Enzyme Catalysiswith Subsequent Clearance of the Product fromthe Cell and OrganThis metabolite type is produced from the “Phase II”or “conjugating” systems of the body. The xenobioticor its Phase I product are processed by the enzyme-catalyzed mechanisms of the body that promotemetabolism, catabolism, anabolism, and transport ofsmall inorganic and organic biochemical substrates,which the xenobiotic resembles chemically.

Benzene. Urinary phenol is not only free, but alsois present as sulfate and ß-glucuronide conjugateforms, the latter being important only at highexposure concentrations of benzene.(17) Thus, in thiscase the Phase I product is conjugated rather thanthe benzene itself. Analytical methods for phenol withacid or alkaline hydrolysis steps produce total phenolcontent.(15) The ratio of free-, sulfated- (Equation A1-3), and ß-glucuronidated (Equation A1-4) forms varywith age, ethnicity, gender, diet, genetic factors, andexposure concentrations. The total phenol contentvaries less than its original precursors and is a moresensitive marker than the other three markers.

C6H5OH + sulfate group donor molecule ? C6H5OSO2O- phenol sulfate A1-3

C6H5OH + C6H8O7 →C6H5OC6H6O6

- ß-glucuronide of phenol A1-4ß-glucuronic acid

Lead. Pb is transported in the body as a Pb(II)organic chelate rather than as a Pb2+ cationassociated with an inorganic anion such as chloride,bicarbonate, or phosphate.(16) Pb is excreted in thebile into the small intestine as a lead glutathioneconjugate (Equation A1-5). Pb substitutes for calciumin bone marrow.(17) These same processes occur forTEL and TML after total dealkylation. No conjugationsexcept with glutathione (GSH) have been reported forTEL or TML and their less alkylated metabolites.

Pb(II) + 2Glu-Cys-Gly → Glu-Cys-Gly Glu-Cys-Gly A1-5| | |

SH S— Pb(II) —S GSH conjugate of Pb (G-S-Pb-S-G)

A tripeptide

where Glu=glutamic acid; Cys=cysteine; and Gly=glycine.


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Affected Components of Body FluidsThe “affected components of body fluids” mentionedin the definition of biological monitoring givenpreviously can be normal blood constituents, urineparameters, or chemicals naturally breathed out; seeTable A1-2 for a representative list of thesecomponents.

Such biological monitoring markers are often notspecific to the exposing chemical. These markers areoften measured in routine medical checkups asmedical monitoring markers or as biologicalmonitoring markers of effect, medical screening,medical surveillance, or health surveillance ratherthan just dose.

Benzene• Number of white blood cells (WBC) and

differential count: Leukemia, WBC uncontrolledincrease, may occur after chronic exposure for2–5 years.(18,19) For high short-term doses >10ppm (acute exposure), WBC numberdecreases (leukopenia), and in extreme casesall blood cells decrease (pancytopenia). Short-term aplastic anemia may develop afterexposure to high benzene concentrations.

• Products of reaction with large molecules intissues (adducts): Benzene in the blood reactswith the protein albumin in blood plasma andhemoglobin (Hb) in red blood cells (RBC) toform protein adducts.(20,21) Similar reactionsoccur with cellular DNA in WBC to formmodified DNA (DNA adducts).(21)

More details can be found in criteria documents andreviews on benzene.(22)

Lead• RBC zinc protoporphyrin (ZPP): There is a

dose-response above PbB 15 to 20 µg/dL inadult women, and above 25 to 30 µg/dL in adultmen. It integrates exposure effects on boneover the lifetime of blood cells (90–120 days).Peaks in ZPP lag behind those of PbB by 90-120 days. The marker is related to the effect ofPb on the bone enzyme ferrochelatase.

• RBC δ-aminolevulinic acid (ALA): ALA is anintermediate in Hb biosynthesis. ALA in bloodincreases nonlinearly with PbB.

• RBC δ-aminolevulinic acid dehydratase(ALAD): ALAD is an enzyme in Hbbiosynthesis. The decrease in blood ALAD isinversely related to PbB at least as far down as10–12 µg/dL. It is the most sensitive marker ofabsorbed Pb. It is not specific for Pb, but it is abiological monitoring marker of effect on theblood forming system.


Table A1-2. Affected Components of Body Fluids

Normal blood constituents such as(7)

• EnzymesSerum γ-glutamyltranspeptidase (the serum is the clear fluid after blood clotting) and red blood cell (RBC) acetylcholinesterase

• Nonenzyme proteinsSerum albumin, plasma immunoglobulins (the plasma is the clear top fluid when a blood sample is allowed to stand or is centrifuged), and hemoglobin (Hb) of RBC

• LipidsPlasma triglycerides

• CarbohydratesGlucose, fructose, galactose

• Blood cellsRBC, reticulocytes (immature RBC with nuclei), white blood cells (WBC), and hematocrit (the volume of blood cells to total blood volume on standing or centrifugation of blood)

• End products of nitrogen metabolismCreatinine, urea, uric acid, bilirubin

• Specific types of HbMethemoglobin [Fe (II) is oxidized to Fe (III)], carboxyhemoglobin (Hb binds with carbon monoxide), and carbon dioxide bound to Hb

• Serum and RBC Fe and blood iron binding capacityIndicators of a relationship to anemia (<35% hematocrit)

Urine parameters such as(7)

• End products of nitrogen metabolismCreatinine, urea, uric acid, urobilin (yellow color of urine), and bile salts

• Urine sedimentThe greater the sediment the more likely is kidney damage

• Cast-off (“exfoliated”) cells (examined microscopically)• Protein to identify proteinura

Indicates kidney damage, now easily detected by a dipstick test• End products of the liver

Bile salts, porphyrins, and urobilin• End products of sulfur metabolism

Bile salts, sulfates, and thioethers (mercapturic acids)• End products of sugar metabolism

D-glucaric acid and ß-glucuronides indicate induction of the ß-glucuronic acid pathway; glycosides; glucose to indicate diabetes (a dipstick test is available); and insulin to indicate integrity of the kidney

• Hemoglobin “Occult blood,” a sign of kidney damage

• Ketones Acetone, acetoacetic acid. Ketones indicate ketone body accumulation. There is a dipstick test.

• Hydronium ion.Constancy of pH indicates homeostassis. There is a dipstick test.

• Specific gravityReflects urine concentration and fluid intake. There is a dipstick test.

• NitriteIndicates bacterial infection. There is a dipstick test.

• Leukocyte esteraseLeukocytes (WBC) are increased in urinary tract infection. There is a dipstick test.

Chemicals naturally breathed out such as(7)

• Products of carbon metabolismCarbon dioxide, carbon monoxide, acetone, methane, pentane, alkylamines, thiols, and isoprene

• Products of nitrogen metabolismAmmonia, nitrogen dioxide, and alkyl amines

• Products of symbiotic bacteria metabolismHydrogen, hydrogen sulfide, ammonia, and methane

• Products of sulfur metabolismThiols (mercaptans), hydrogen sulfide, sulfur dioxide, alkyl thioethers, and carbon disulfide

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• RBC δ-aminolevulinic synthase (ALAS):Another enzyme in Hb biosynthesis. Therelationship with PbB is not as sensitive as thatfor ALAD.

• Oxygen carrying capacity decrease of theblood (anemia): Anemia increases for PbB >80µg/dL. Susceptible workers can show anemiadown to 14 µg/dL PbB.

• Urinary coproporphyrins: These increase withPbB >60 µg/dL, and there is considerablevariation among individuals (interindividualvariation).

• Urinary ALA: ALA increases with PbB >40µg/dL.

• Urinary and serum creatinine: These indicatorsof muscle (lean body mass) and liver functiondecline at high Pb doses >60 µg/dL.(16)

All of these effects have different Pb air exposure andPbB thresholds for a dose response. There are manybooks and reviews on the consequences of leadexposure to humans.(23)

TEL and TML both tend to accumulate in thebrain rather than in the bone and cause changes incatecholamines (adrenaline/noradrenaline) in bloodand urine. TEL elevates blood urea nitrogen andcauses urine proteinuria.(24)

All of these parameters are not the direct concernof the industrial hygienist, but do concern physiciansbecause these changes are related to adverse healtheffects. The industrial hygienist should understandwhat these parameters signify so that he or she canexplain the exposure situation to the worker and whyinvasive testing rather than noninvasive urine andbreath sampling is necessary. For legal reasons, youcannot take the place of a physician to provide adetailed explanation of these markers of adverseeffect.

Q2: When Should I Use BiologicalMonitoring? Is Personal Breathing Zone AirMonitoring Inadequate?

Most workplace trigger situations involve a threshold airconcentration called the action level. There are severalsituations in which biological monitoring must beconsidered.(25)

Required by the Occupational Safety and HealthAdministration (OSHA) or the StateBenzene. OSHA medical removal for benzeneoccurs(2) for a urinary phenol concentration of 75mg/L using urine specific gravity normalization to1.024. The urine sample is to be taken within 72hours after the end of the work shift. The sample istermed a “spot sample,” because it is an individual

urine void and not a cumulated sample over a timeinterval. The National Institute for OccupationalSafety and Health (NIOSH) recommends at leastquarterly biological monitoring. Sampling at intervalsof 2 weeks is recommended near and above 10 ppmvbenzene in air. Note that the medical removalguideline is independent of exposure route.

The triggers for initiating the medical surveillanceprogram for benzene exposures to workers are asfollows.

• More than 10 ppmv air benzene for 30 or moredays in a previous year before the currentstandard (1 ppmv) came into effect

• Air benzene concentrations above the actionlevel (0.5 ppmv) for at least 30 days per year

• Tire building machine operations that usesolvents of benzene >0.1% v/v

The minimum number of biological monitoringmarkers of effect that are mandated by OSHA(http://www.osha.gov under benzene in the SubjectIndex) to be measured for medical surveillance are asfollows.

• RBC number• WBC number• Platelet number• WBC differential count• Hematocrit• RBC indices

The blood markers of impending leukemia (WBCincrease) in benzene medical surveillance are thefollowing.

• Pancytopenia• Anemia• Macrocytosis (giant cells)• Abnormal WBC differential count• Decreased serum iron• Increased reticulocytes• Peripheral blood smear that shows stippled

basophils, and low peroxidase and alkalinephosphatase enzyme activities in peripheralgranulocytes

Lead. OSHA medical removal occurs at or above thearithmetic mean of 50 µg Pb/dL blood (dL=0.1 L=100mL) for a worker exposed at or above the air actionlevel of 30 µg/m3 for the last three blood tests or forblood tests over the last 6 months, unless the mostrecent blood test result was at or below 40 µg/m3 (29CFR 1910.1025, 1979).(3) Medical chelation mayensue. Regular measurement of PbB and othermedical surveillance markers is triggered when airexposures above 30 µg/m3 occur for at least 30 daysin a year that cause PbB to be more than 40 µg/dL.


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The blood markers required by OSHA(http://www.osha.gov under lead in the Subject Index)for PbB above 40 µg/dL are the following.

• Pressure• Hb• Hematocrit• RBC indices• Peripheral smear morphology• ZPP• Urea nitrogen• Serum creatinine

OSHA also mandates routine urinalysis, includingmicroscopic examination.

Routes of Exposure Other Than InhalationIf more than 30% of the exposure can be attributed toroutes other than alveolar inhalation—that is, skin andoral exposure—biological monitoring is recommended,if it is feasible. Also, if more than 30% of an inhalableaerosol exposure has aerodynamic diameters abovethe respirable aerodynamic diameter threshold of 10µm that corresponds to the thoracic fraction, thenbiological monitoring should be considered, becauseoral ingestion is likely.

Benzene. Vapor inhalation should be the majorroute of benzene exposure because of its high vaporpressure. Direct skin contact with liquids containingbenzene must be verified through direct observationby the hygienist, because this is better than anycurrent skin sampling method.

Lead. Inhalation is the major route of exposurefor lead fume aerosol, TEL, and TML. Vaporinhalation is negligible for metal fume, but dominatesfor TEL and TML, especially for the latter. Absorptioninto the bloodstream is efficient for aerosol particlesof respirable size for lead fume.

Lead exposure by the oral route is very importantin hot, dusty workplaces where poor hygiene andpoor housekeeping (no showering, no independenteating rooms, no regular floor cleaning, no hand-washing facilities, and contaminated water fountains)is present. The effectiveness of these amenities mustbe also known, if they are present.

Absorption by skin exposure is usually negligiblefor inorganic Pb compounds unless they are in mediathat facilitate skin absorption. Organoleadcompounds such as TEL and TML are rapidlyabsorbed through the skin. If there is any doubt,biological monitoring is recommended if feasible.

Use of Personal Protective Equipment (PPE),Especially RespiratorsIf the protective equipment is truly protective, thenexposure should be reduced; but this should be

proven rather than assumed. This is especiallyimportant for both lead and benzene exposure. Airsampling also should be performed inside the mask,preferably with passive samplers proven to beunaffected by high humidity and high carbon dioxideconcentrations, because dynamic sampling mayblunt the protectiveness of the respirator.

Nonworkplace Sources of ExposureThe analysis of markers of samples taken before thework shift allow detection of this factor. Workplaceguidelines relate only to workplace air exposures.

Unanticipated ExposuresTell-tale signs of trouble, such as worker symptomsand behavioral changes, may call for a screeningmedical examination of the usual blood and urinenonspecific biological monitoring markers. Thehygienist is therefore the first line of medicalsurveillance.

Q3: Do I Have to Take Any BiologicalMonitoring Samples?No. You are not allowed to take blood samples unless youare also a certified phlebotomist. This is the job usually formedical personnel such as nurses, physicians, orcertified phlebotomists. Urine samples are to be taken bymedical personnel. For privacy reasons, the industrialhygienist cannot be in the same cubicle as the workerwhen the latter is urinating into a sample container.However, worker urine samples can be sent by theindustrial hygienist for subsequent analysis if workerconsent is provided. If there is a drug policy in theworkplace that involves urine and blood sampling, themechanism for collecting, storing, and transporting urineor blood samples may already exist. Breath samples alsoare collected by medical personnel. If the workerconsents, or it is a condition of employment, the industrialhygienist can take gas-bag samples of expired breath.Use of a valved sampling system for breath collectionrequires validation of pulmonary function by a physician,as for wearing negative pressure respirators.

The author recommends that industrial hygienistssample breath and urine in the presence of a registerednurse or physician. This is possible if a company has amedical department, but only large companies have thatluxury. Hygienists can arrange the date and time forsampling with a nearby clinic, a consultant nurse orphysician, or a hospital on an ad hoc basis. However,these links and arrangements must be made well beforeexposure and sampling begin. The samples can be senteither by the medical personnel (more expensive), or bythe hygienist, if a laboratory to do the analysis is known.


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Q4: I Want To Do Biological Monitoring.What Compounds Have Guidelines?The best U.S. guidelines are those recommended byACGIH through their biological exposure indices (BEIs).OSHA-mandated actions for benzene, lead, andcadmium must be done, however. The BEI guidelines forthese compounds also may be instituted.

The BEIs can be found in the current threshold limitvalue (TLV®) and BEI booklet. In 2003 there were 39compounds or compound groups withrecommendations,(4) plus 7 compounds with intendedchanges, 4 being new. Guidelines are available for othercountries as well. Each BEI documentation contains thereference values of other countries, and whether othermarkers are recommended.

Benzene.(2) Guidelines: (1) 25 µg S-Phenylmercapturicacid/g creatinine in urine: spot sample taken at the end ofshift; requires a baseline sample determination; (2) 500µg trans, trans-muconic acid/g creatinine in urine: spotsample taken at the end of shift; requires a baselinesample determination.

Lead.(2) Guideline: 30 µg Pb/dL blood sampled at anytime because of its long body half-time of >30 years.

Women of child-bearing potential, whose PbBexceeds 10 µg/dL, are at risk of delivering a child withPbB over the current Centers for Disease Control andPrevention guideline of 10 µg/dL. If the PbB of suchchildren remains elevated, they may be at increased riskof cognitive deficits. The PbB of these children should beclosely monitored, and appropriate steps should be takento minimize the child’s exposure to environmental lead.

Note that the BEI marker for benzene and the BEImarker concentration for lead differ from the OSHAmandates. This is because the OSHA thresholds forbiological monitoring are related to medical removal,whereas the ACGIH air concentrations require onlycontrols, not medical removal. Thus, whereas the current8 hour TLV®-time-weighted average (TWA) for benzene is0.5 ppm with BEIs based on urinary S-phenylmercapturicacid and trans, trans-muconic acid, the OSHA biologicalmonitoring guideline is based on medical removal at orbeyond a threshold total phenol urine concentration of 75mg/L at high benzene air exposures beyond 10 ppmv. TheOSHA and ACGIH criterion for the air lead 8-hour TWA is50 µg/m3, but whereas the OSHA medical removalthreshold PbB is 50 µg/dL with action level 40 µg/dL formedical screening, the BEI PbB is 30 µg/dL.

Q5: What Biological Monitoring Am ILegally Required To Do?The only OSHA regulations that include mandatorybiological monitoring are for benzene, lead, andcadmium. A physician may require “any appropriate test”in the medical surveillance of any agent. See Question 2for benzene and lead details.

Q6: What Is a BEI?It is the biological equivalent value to the 8-hour ACGIHTLV®-TWA on which it was set. It is based only oninhalation exposure and on the biological effect to whichthe TLV® is keyed. TLV®s are not designed to protect thehealth of all workers, so the hygienist must observeclosely any other routes of workplace exposure, workersymptoms, and changes in worker behavior. The lattercould be a result of exposures other than workplaceinhalation or hypersensitivity. Biological monitoring andwell-placed questions may provide the ultimate controlstrategy: administrative rotation, exposure controlmeasures, or medical intervention.

Q7: Is There a Difference Between a BEIand Biological Monitoring?Yes. A BEI is a biological equivalent guideline thatcorresponds to a workday (8-hour) inhalation TLVexposure followed by 16 hours of no exposure for that dayover 5 consecutive days followed by a weekend of noexposure, and is related to the occurrence of the specifictoxic effect on which the TLV is set. Biological monitoringsamples reflect the net result of all modes of absorption,redistribution, and clearance. Thus, the measuredconcentration of a marker that is at the BEI guidelineconcentration does not necessarily imply that the workeris exposed to the air TLV. If the simultaneous personalbreathing zone air sampling concentration agrees within30% of the TLV guideline, then probably most of themeasured concentration in the biological fluid is in factfrom alveolar inhalation. If an air exposure at the TLVoccurs, the biological monitoring results should be within30% of the BEI guideline. Only if inhalation is thedominant route of exposure is the personal breathingzone air concentration an adequate surrogate of workerexposure risk.

If there is a greater than 30% difference in the markerconcentration relative to what is expected from themeasured air concentration, other modes of absorptionmay be present. The hygienist must then more closelyobserve the worker to identify these noninhalationprocesses of exposure for control purposes. A baselinesample should also be taken to check fornonoccupational exposures or for holdover from pastworkplace exposures. Any baseline sample that is 30% ormore of the BEI or biological guideline indicates thenecessity for continued baseline sampling. It is the usualpractice to empty the bladder before work starts. Thissample can be the baseline urine sample.

Q8: When Do I Sample?The time to sample is a function of the body half-time ofthe marker and how sensitive and selective the analyticalmethod for it is. Regarding the analysis, if the markercannot be adequately detected and quantified there is nopoint submitting the sample for analysis. All samples must


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be collected in an uncontaminated area away from theexposure area (usually within 15 to 30 min of leaving theexposure area).

The marker half-time can be a complex function ofmany factors. Usually the absorbed exposing compoundis removed from blood in three phases, the earliest beingthe quickest, which influences end-of-work shiftcollection, and the third (which can influence next dayholdover) being the slowest phase. The middle phasemay also influence end-of-work shift collection if the firstphase is shorter than 2–3 hours. Each phase is usuallycharacterized by its own half-time, the time to reach 50%of the initial concentration at the start of the phase. Thephase durations are defined by log cmarker versus timelinear segments. The time boundary conditions other thanzero and the last collection time are found by theintersections of the linear regression lines of best fit.

For cases of holdover from previous work shiftexposures and for markers with long half-times >12hours, the blood baseline value can be subtracted fromthe end-of-work shift value to obtain the current dayworkplace contribution. However, if exposure occurswithin 8 hours of the baseline sample, the initial fastphase governs the baseline sample. If the half-time andprecise time and duration of exposure are known, thebaseline sample value can be corrected beforesubtraction from the end-of-shift value to obtain theworkplace contribution. The hygienist must determinewhich situation is relevant for each worker monitored.Bloods need to be stored and transported at 4°C.

The same reasoning applies for urine and breathsamples, except that instead of half-times ofdisappearance, the half-times for complete excretion ofthe marker (appearance half-times) for each phase inurine and breath are used.

For breath sampling it is usual to wait at least 15–30min in an uncontaminated setting, or compressedmedical grade air is breathed in for at least 10 min beforebeginning sampling, to ensure removal of any deadvolume holdover.

If possible, the worker should not urinate during thelast 4 hours of the work shift before taking the spot urinesample. If the worker is willing, urine void collectionduring the work shift and breaks is recommended toprovide extra samples should the end-of-shift sampleindicate problems or if it cannot be procured. In the eventof the latter, the last sample taken should be selected foranalysis.

The same marker in each biological fluid generallyhas different half-times. The appearance half-times ofmetabolites in urine may have no relationship at all tohalf-times for the decrease of the exposing compound inblood, unless most of the compound is excreted in urinein the form of the urinary marker being measured. Thus,blood disappearance half-times also match breathappearance half-times only when exhalation dominates

as the excretion route for the marker, as for example, forabsorbed perchloroethylene and methyl chloroform,which resist metabolism and are volatile.

The major times to take spot samples of urine andblood and grab samples of breath are shown for the BEIsin Table A1-3. The end-of-shift sample is typically used formarker half-times of less than 12 hours. Some 30 BEImarkers including both benzene markers share thissampling time. The markers sampled at the end of ashift(2) are mostly for organic chemicals.

The end-of-shift, end-of-week sampling time isgenerally used for markers that have long half-times ofover 12 hours and that tend to accumulate (Table A1-3).Some 23 BEI markers(3) share this sampling time, manybeing for metals or organics.

An anomaly is the “end-of-workweek” designation forinorganic arsenic plus methylated metabolites in urine (35µg As/L) as markers after exposure to elemental arsenicand water- soluble inorganic arsenic compounds.

Baseline sampling involves sampling the same fluidin the same uncontaminated area as end-of-shift or end-of-workweek samples. However, the time for samplingrelative to end-of-shift samples is just before thebeginning of the work shift to be evaluated. For end-of-week sampling when holdover is known to occur, thebaseline sample is taken preshift on the first working dayafter the 2-day weekend. In addition,(2) some prior-to-shift, preshift, and increase-during-shift samples arerecommended (Table A1-3).

Prior-to-last-shift, end-of-workweek sampling is avariant of baseline sampling, but this sampling time isalso for markers of long half-time with holdover. Theconcentrations obtained at this time correlate better withpersonal breathing zone air sampling concentrations thanat other times. Some markers that are sampled at thistime(2) are shown in Table A1-3.

“Noncritical” means that the sample can be taken atany time during a work shift. Cadmium in blood (5 µg/L)and urine (5 µg/g creatinine), and lead in blood (30 µg/dL)share this sampling designation in the BEIs.

Q9: Why per Gram Creatinine and per Literfor Urine Sampling?The creatinine term corrects for urine dilution from fluidsintake better for a marker than the specific gravityadjustment (normalization) for volume. This also meansthat the fresh urine sample must be analyzed forcreatinine or have its specific gravity measured to be ableto compare with the BEI guideline. There are dipsticks foreach parameter. Thus, in Equation A1-6:

Marker weight/g creatinine = marker concentration/creatinine concentration =(marker weight/L urine)/(L urine/g creatinine) A1-6


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End-of-Shift Samples• Acetone in urine (50 mg/L) after acetone exposure• Total p-aminophenol in urine (50 mg/g creatinine) after aniline exposure;

a proposed guideline is 50 mg/L. • S-Phenylmercapturic acid (25 µg/g creatinine) and trans, trans-muconic

acid (500 µg/g creatinine) in urine after benzene exposure• 2-Thiothiazolidine-4-carboxylic acid in urine (5 mg/g creatinine) after

exposure to carbon disulfide• Carboxyhemoglobin (3.5% of hemoglobin) in blood, and carbon monoxide

in end-exhaled air (20 ppmv) for carbon monoxide• Total 4-chlorocatechol (150 mg/g creatinine) and total p-chlorophenol

(25 mg/g creatinine) in urine after chlorobenzene exposure• N-Methylformamide in urine (15 mg/L) after N, N-dimethylformamide

exposure• Fluorides in urine (10 mg/g creatinine) after exposure to fluorides• Total furoic acid in urine (200 mg/g creatinine) for furfural• Methanol in urine (15 mg/L) after methanol exposure• Total 4,4’-Methylene bis (2-chloroaniline) [MBOCA] in urine (no guidance)

for exposure to MBOCA• Methyl ethyl ketone in urine (2 mg/L) for methyl ethyl ketone• Methyl isobutyl ketone (2 mg/L) after methyl isobutyl ketone exposure• Methemoglobin in blood (1.5% of hemoglobin) for aniline, nitrobenzene

and methemoglobin inducers• Total p-nitrophenol in urine (0.5 mg/g creatinine) after exposure to

parathion• Free pentachlorophenol in plasma (5 mg/L) after pentachlorophenol

exposure• Total phenol in urine (250 mg/g creatinine) after exposure to phenol• Mandelic acid plus phenylglyoxylic acid in urine (400 mg/g creatinine),

and styrene in venous blood (0.2 mg/L) after styrene exposure• Tetrahydrofuran in urine (8 mg/L) for tetrahydrofuran• o-Cresol (0.5 mg/L) and hippuric acid (1.6 g/g creatinine) in urine after

toluene exposure• Methyl hippuric acids in urine (1.5 g/g creatinine) after exposure to

technical xylene· Cyclohexanol in urine (no guideline) after exposure to cyclohexanol (proposed)

· Cyclohexanol in urine (8 mg/L) after exposure to cyclohexanone (proposed)

· Dichloromethane in urine (0.4 mg/L) after exposure to dichloromethane (proposed)

End-of-Shift, End-of-Week SamplesMetals:• Total chromium in urine (30 µg/g creatinine; 25µg/L proposed) after

exposure to chromium (VI) water-soluble fume• Total cobalt in urine (15 µg/L) and blood (1 µg/L)• Total inorganic mercury in blood (15 µg/L)• Total vanadium in urine (50 µg/g creatinine) after exposure to vanadium

pentoxideOrganics:• N-methylacetamide in urine (30 mg/g creatinine) after exposure to N,N-

dimethylacetamide• 2-Ethoxyacetic acid in urine (100 mg/g creatinine) after exposure to 2-

ethoxyethanol and/or 2-ethoxyethyl acetate• Mandelic acid in urine (1.5 g/g creatinine), and ethyl benzene in end-

exhaled air (no guidance) after exposure to ethyl benzene• 2,5-Hexanedione in urine (0.4 mg/L) after exposure to n-hexane or methyl

n-butyl ketone• 2-Methoxyacetic acid in urine (no guidance) after exposure to

2-methoxyethanol and/or 2-methoxyethyl acetate• Total trichloroethanol in urine (30 mg/L) and blood (1 mg/L) after exposure to

methyl chloroform• Total p-nitrophenol in urine (5 mg/g creatinine) after exposure to nitrobenzene• Trichloroacetic acid in urine (3.5 mg/L) after exposure to tetrachloroethylene• Trichloroacetic acid/trichloroethanol in urine (300 mg/g creatinine),

a proposed trichloroacetic acid urine guideline of 80 mg/L, and free trichloroethanol in blood (4 mg/L; 2 mg/L proposed) after exposure to trichloroethylene), as well as proposed trichloroethylene in blood and end-exhaled air (no guidance).– 1,2 - Cyclohexanediol in urine (no guidance) after exposure to cyclohexanol

(proposed)– 1,2 - Cyclohexanediol in urine (80mg/L) after exposure to cyclohexanone

(proposed)– 1 - Hydroxypyrene in urine (no guidance) after exposure to polycyclic

aromatic hydrocarbons (proposed)

Baseline Sampling• A prior-to-shift sampling time is recommended for fluorides in urine

(3 mg/g creatinine)• A “preshift” sampling time is given for total inorganic mercury in urine

(35 µg/g creatinine)• An increase-during-shift notation occurs for total chromium in urine

(10 µg/g creatinine) with a 2002 proposed change to 10 µg/L• A baseline sample is required to demonstrate 70% decrease in baseline for

cholinesterase activity in red blood cells after exposure to acetylcholinesterase inhibiting pesticides. A “Discretionary” designation exists for sampling blood for cholinesterase activity.

Prior-to-Last-Shift, End-of-Workweek• N-acetyl-S-(N-methylcarbamoyl) cysteine in urine (40 mg/L) as a marker for

N,N-dimethylformamide• Methyl chloroform in end-exhaled air (40 ppmv)• Total pentachlorophenol in urine (2 mg/g creatinine)• Tetrachloroethylene in end-exhaled air (5 ppmv) and tetrachloroethylene in

blood (0.5 mg/L)• Toluene in blood (0.05 mg/L)

Noncritical• Cadmium in blood (5 µg/L) and urine (5 µg/g creatinine)• Lead in blood (30 µg/dL)

Table A1-3. Major Times to Take Spot Samples of Urine and Blood and Grab Samples of Breath

48

The creatinine normalization is valid only for compoundsthat are filtered through the kidney glomeruli, forcreatinine concentrations >0.3 g/L, and for healthyworkers whose body weight is relatively constant, do notwork near their physical upper limit, and do not eatexcessive amounts of meat or fish.

If the marker is in units of per unit volume of urine, thespecific gravity of urine must be measured with ahydrometer, urinometer, or a dipstick test, and themeasured concentration corrected (normalized) to aNIOSH reference specific gravity(5) of 1.024 as in thefollowing equation:

Corrected concentration = Observed concentration × 24/(last two digits of observed specific gravity) A1-7

The correction is valid in the range 1.003 to 1.030according to the BEI Committee,(1) though Lauwerys andHoet(26) do not recommend analysis of urines withspecific gravity <1.010. The present author supports therange 1.010 to 1.030. Interestingly, the BEI Committeeprefers a reference specific gravity value of 1.020, themidpoint of the latter range, rather than NIOSH’s 1.024.(5)

The present author prefers the NIOSH reference value,which is also used by OSHA(6) to normalize urinarycadmium.

Sometimes a mass of marker collected over 24 hoursor some other time period is used for urine, but especiallywith regard to pesticide and pesticide metaboliteexcretion. This is the standard unit to use whenappearance half-times exceed 12 hours.

BEIs focus on end-of-shift sampling using spotsamples of blood, urine, and breath, therefore, short half-times <12 hours are usually involved for markers, so thatspot sampling can be representative and sensitive. Thus,8-hour, 12-hour, or 24-hour integrated (combined orcomposite) sampling is not used for most workplacesampling. Other reasons to prefer spot samples areconvenience, work productivity, and legal responsibility.The choice of whether to use the specific gravity orcreatinine normalization is based on the best correlationbetween the absorbed dose and the normalizedparameter.

Q10: If Workers Are Exposed to a SpecificChemical, Why Is Another Chemical OftenChosen as a Marker Instead?If the chemical is metabolized quickly and a metaboliteconcentration correlates to the absorbed dose, thatmetabolite is a candidate biological monitoring marker. Ifthere is a variable background (for example, phenol forbenzene exposure), or if the marker is not selective (forexample, phenol is a marker for benzene, phenol,chlorobenzene, and bromobenzene), the choice of

marker may be more complicated. For lead exposure,total lead in blood is the accepted marker. The mostspecific marker is always the original exposing chemicalin the biological fluid sampled. However, sensitivity andbackground noise become major factors at low exposingchemical concentrations in biological fluids.

The two benzene BEI markers are metabolites ofbenzene, S-phenylmercapturic acid being from theglutathione conjugation (Phase II) pathway, and the trans,trans-muconic acid being from opening of the benzenering to form a conjugated unsaturated straight chaindicarboxylic acid with six carbons and two C=C.

Either marker may have a background concentrationsin benzene-unexposed workers through the markersbeing produced from precursor biomolecules other thanbenzene. These backgrounds are not as high as for thephenol marker, so there is better correlation betweenurinary marker concentration and air benzeneconcentration about the TLV for these two markers thanfor phenol. Phenol is an acceptable marker for highbenzene air concentrations >5 ppmv.

Q11: How Do I Begin to Take UrineSamples?There are several steps.

(1) You need a laboratory that analyzes themarkers and creatinine (if applicable) within thesame sample.

(2) If possible, this laboratory should be certifiedfor analysis of the marker.

(3) The laboratory should send you the containersfor sampling with detailed instructions on howto sample, how to store and transport, and thetransport packaging. Spot sample urinecontainer volumes should be 250–500 mL withwide mouths to allow women to urinate. Acid-washed glassware or Teflon® containers withTeflon-lined screw cap lids are necessary fororganics. High-density polyethylene containersare used for metals. Containers for 24-hoururines should be 2.5 L. The bladder needs tobe emptied just before the shift, and thissample should be retained to assess theworker’s baseline.

(4) You must have enough background about thebiological monitoring markers to be able toidentify and, if necessary quantify,interferences and nonworkplace factors, andassess whether holdover from previousworkplace exposures is occurring. Thisbackground information will enable the posingof specific questions to assure that the resultswill be interpreted adequately.

Relative to the first three points, you must select anadequate laboratory for analysis of the samples you


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collect. More detail on laboratory adequacy and selectionis contained in Section 7 on Sampling and Analysis.

The major organization that accredits laboratories inroutine medical blood and urine testing is the College ofAmerican Pathologists (325 Waukegan Road, Northfield,IL 60093; 800-323-4040, http://www.cap.org). The Website allows you to locate certified laboratories in your areaincluding commercial laboratories and hospitallaboratories

The major organization that accredits laboratories inbiological monitoring for workplace chemicals and theirmetabolites is the Centre de Toxicologie du Quebec(2705 Blvd Laurier, Sainte-Foy, Quebec G1V 4G2Canada; 418-654-2254; fax: (418) 654-2148;http://www.ctq.qc.ca).

The Centre de Toxicologie has accredited 170laboratories, mostly for metals such as Pb, 26% being inCanada, 33% in the United States, and 32% in Europe.They also have their own commercial laboratory thatanalyzes samples, including drugs and industrialchemicals and their metabolites. Contact them to ask forthe nearest accredited laboratory for the markers ofinterest or retain them to analyze your samples.

Many states have an accreditation program for PbB,so use the Web site of the state government to findcertified laboratories. A list of OSHA-approvedlaboratories for PbB and blood cadmium is available fromits analytical center (OSHA, Salt Lake Technical Center,Quality Control Division, 781 South 300 West, Salt LakeCity UT 84115-1802; 801-487-0073, extension 271;http://www.osha.gov, then use the alphabetic subjectindex to locate lead and cadmium).

Some U.S. commercial laboratories that have theresources to analyze urine and blood samples for manymetabolites and exposing compounds are the following.

• Pacific Toxicology Laboratories, 6160 Variel Ave.,Woodland Hills CA 91367; 800-328-6942, fax: 818-598-3116; http://www.pactox.com, e-mail: [email protected]

• ESA Laboratories, 22 Alpha Rd, Chelmsford MA01824; 978-250-7000, fax: 978-250-7090;http:/ /www.esainc.com/products/ lab_services/esa_labs.htm; e-mail: [email protected]

• National Medical Services, 3701 Welsh Road, WillowGrove PA 19090; 800-522-6671 or 215-657-4900; fax:215-657-2972; [email protected]. Also: 1600 HarborBay Parkway, Suite 150, Alameda CA 94502; 866-522-6672; fax: 510-523-1800; [email protected]

These three laboratories may help you locate othercommercial laboratories that perform analyses they maynot do themselves.

It should be noted that standardized methods forurinary S-phenylmercapturic acid and t,t-muconic acidamongst other methods are provided in the followingreference.

• J. Angerer and K.H. Schaller (eds.), Analyses ofHazardous Substances in Biological Materials, vol 5(Weinheim, Germany: Wiley-VCH, 1996).

Some laboratories will do analyses if you provide thestandardized method as a basis.

Q12: How Do I Interpret the Results of UrineTesting?This is related also to the discussion of Question 11. Moredetail is provided in Appendix II in the Case Studies.

You must first have documentation for the specificbiological monitoring marker that covers interferences,nonoccupational exposures, skin/oral/inhalationexposures, sampling times, sampling methods, and unitprocesses.

The best single documentation in the United States isissued by ACGIH.(1) The interferences can be positive ornegative. Positive interferences may includenonoccupational exposures or holdover from previousworkday exposures. Negative interferences may involveother chemicals to which workers may be exposed. Thehygienist must locate, read, and list all existinginformation on this topic. The BEI documentation is thestarting point, but new research results appear all thetime, and the hygienist needs up-to-date information to beeffective. Animal interaction information does not directlyrelate to human interactions unless the animal is a goodmodel for humans. The hygienist should seek help from atoxicologist to apply animal results to humans.

You also should have an understanding of the basicsof biological monitoring. A textbook is available.(9) Shortcourses on the topic are held at the annual AmericanIndustrial Hygiene Conference and Exposition. TheAmerican Industrial Hygiene Association (AIHA)Biological Monitoring Committee has developed anintroductory slide show that will change in time (seeAppendix VI for the 2003 version). There is also a revieworiented to practicing industrial hygienists.(25) The bestadvanced reference book emphasizing the chemical sideis by Lauwerys and Hoet.(26)

The analytical laboratory that quantifies your samplesmay be helpful. Good laboratories often can performanalyses on multiple chemicals, and it is efficient to seekhelp from such laboratories. In addition, it is always lessexpensive to have one laboratory do all your samples,because you may then qualify for a bulk rate.

Asking experts of the ACGIH BEI(http://www.acgih.org) and the AIHA Biological Monitoring(http://www.aiha.org) committees, government (forexample, NIOSH), and in universities are options. Theexpert should be experienced in biological monitoringand listen well to your problems.

Knowing the relationship between the marker and thepersonal breathing zone air concentration from theliterature will allow you to assess whether inhalation is the


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dominant absorption pathway in your particular case. Thecalculated concentration of the marker should be within30% of the observed answer. If it is not, then other routesor sources of exposure may exist if the calculated markerconcentration is too low. If it is too high, assess theworkload (physical activity) rate and baseline sampleresults.

BenzeneCorrelations of markers cmarker with 8-hour shiftbenzene personal air sample concentrations cair inppmv:

Urinary S-phenylmercapturic acid(27,28)

log cmarker = 0.712 log cair + 1.644 A1-8

cmarker: nonsmokers, 1.0; smokers >20 cigarettes/day,7.8; for cmarker geometric means or medians inmicrograms per gram of creatinine.(27) Note EquationA1-8 implies that an endogenous baseline may existof log cmarker=1.644 or cmarker=44 µg/g creatinine. Thisshould be verified for each individual to replace theconstant value of Equation A1-8.

About 0.11% of absorbed benzene is excreted asurinary S-phenylmercapturic acid in an end-of-shiftsample. The appearance half-time is about 9.1 hoursand is specific down to 0.3 ppmv air benzene.(29)

Other data(30) show cmarker for nonsmokers, 3.6 (1.0-19.6); smokers, 5.8 (not detectable to 33.4) µg/gcreatinine.

Urinary t,t-muconic acid(28)

log cmarker = 0.429 log cair - 0.304 A1-9

where cmarker is in milligrams per gram of creatinine.

Equation A1-9 implies an endogenous baseline ofabout 0.5 µg/g creatinine, which is quite low. Thisshould be verified with a baseline sample.

About 3.9% of absorbed benzene is excretedwith an appearance half-time of about 5.0 hours andis specific above 1 ppmv air benzene.(29)

From Reference 47, cmarker: nonsmokers, 30 (notdetectable to 480); smokers, 110 (5–340) µg/gcreatinine(30)

From Reference 48, cmarker: nonsmokers, 65(20–590); smokers, 130 (60–390) µg/g creatinine.(31)

Urinary Benzene(28)

log cmarker = 0.681 log cair + 4.018 A1-10

where cmarker is in nanograms per liter.

Eqn A1-10 implies the urinary benzenebackground is about 10.4 µg/L. This is high.

Equations A1-8 through A1-10 were obtained formedian air benzene values of about 0.1 ppmv for 145workers.(28)

The S-phenylmercapturic acid marker is to bepreferred over t,t-muconic acid because thefrequently used food preservative, sorbic acid, is anuncontrolled positive interference for t, t-muconicacid.(31–33) About 0.12% of absorbed sorbic acid isconverted to t,t-muconic acid, and 500 mg sorbic acidincreased urinary t,t-muconic acid concentrations by800 mg/d (5301360). A dietary intake of 6–30 mgsorbic acid/d accounts for between 10–50% of the t,t-muconic acid background in nonsmokers and 5–25%in smokers.(31) When food preservatives are notingested, the t,t-muconic acid marker is probablyadequate and is more sensitive than the S-phenylmercapturic acid marker.

A workplace study(34) showed the followingequivalencies to 1 ppmv benzene TWA over 8 hours.

• S-Phenylmercapturic acid, 58 µg/g creatinine,0.4 µmol/L, 95.7 µg/L

• trans,trans-Muconic acid, 2,000 µg/gcreatinine, 23 µmol/L, 3300 µg/L

• Blood benzene, 8.6 µg/L, 0.110 µmol/L

• Urine benzene, 39 µg/L, 0.499 µmol/L

• Breath benzene, 0.2 µg/L, 0.0028 µmol/L

If your measured personal breathing zone airconcentration does not result in a markerconcentration within 30% of the marker concentrationon substitution into the above regression equationsA1-8 through A1-10, then routes of exposure otherthan inhalation should be suspected if the calculatedmarker concentrations are low.

A review of these biological monitoring markersand others in humans and the relationship of animalresults to humans for benzene is the subject of awhole volume of Environmental Health Perspectives(volume 104, supplement 6, December 1996).

LeadUrinary lead (PbU) is not a BEI marker. Most of thePb in blood is in RBC, with <1% present as plasmaPb, which can be filtered through the kidneys into theurine. The correlation between air Pb and PbU hasmuch less precision than air Pb and PbB or RBC Pbrelative to recent exposures. Linear (Equation A1-11)and curvilinear relationships between PbB and PbUhave been found.

PbB = 0.265 PbU - 3.305 for PbB and PbU both in µg/dL A1-11


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was found for 170 lead battery workers.(35) Therelationship between urinary ALA and PbB in thesame workers was curvilinear above PbB 40µg/dL.(35) Other studies did not show any relationship.However, some investigators believe that plasma Pb,and hence, PbU, may be related more to long-termadverse Pb effects than PbB or RBC Pb, the latterbeing more important for effects on the RBC formingsystem.

PbU is better correlated with air TEL than PbU iswith air Pb metal fume.(24)

The classic 1969 study by Williams andcolleagues(36) found the following for the arithmeticmean PbB (in µg/dL) and PbU (in µg/L) relationshipswith arithmetic mean air lead (PbA) in mg/m3:

PbB = 201 PbA + 30.1 r=0.90, n=39 A1-12PbU = 486 PbA + 45.5 r=0.82, n=39 A1-13PbB = 0.333 PbU + 21.5 r=0.90, n=39 A1-14

The “baseline” PbB is 30.1 µg/dL and that forPbU is 45.5 µg/L, which imply significantbackgrounds. Personal baseline data must bemeasured again to replace the constants inEquations A1-12 and A1-13.

A checklist is a good method of covering allbases before sampling. Such a checklist for benzeneis shown in Figure A1-1.

Q13: When and How Should I Do BreathSampling?Breath analysis is useful to confirm exposure to volatilesolvents and gases that are not metabolized extensively.

The only numerical breath BEIs in 2003 are for end-exhaled air for the following materials.• Carbon monoxide (20 ppmv end of shift); a baseline

also needs to be measured• Methyl chloroform (40 ppmv prior to the last shift of the

workweek)• Tetrachloroethylene (5 ppmv prior to the last shift of the

workweek)

Nonnumerical breath BEIs are for end-exhaled air forethyl benzene and trichloroethylene (end of shift at endof workweek in the List of Intended Changes).

There are two types of exhaled breath samples: (1)“mixed exhaled” is the naturally expired breath and (2)“end exhaled” or “alveolar” is the portion forced from thelungs after normal exhalation.

There are several possible sampling alternatives: (1)using Tedlar® bags as containers; or (2) using anevacuated valved container such as a Summa® canisteror an evacuated glass bulb. A vacuum source is requiredfor the latter, which many workplaces do not have. Thisalternative will not be presented here.


Positive Benzene Interferences andSourcesNonoccupational exposureTake a baseline urine sample. If positive, ask specific questions aboutexposures to gasoline, kerosene, naphtha, or other sources ofbenzene, and record how long the exposure occurred and when wasthe last time of the exposure.

Holdover from previous occupational exposuresTake a series of consecutive baseline samples over one workweek.The baseline before each work shift will increase on each succeedingday if holdover is occurring. The baseline should decrease after the 2-day nonexposure weekend as evaluated with a preshift sample of thefirst day of the next workweek. This procedure should be done initiallyin the first week of employment and again after about 6 months onthe job after the enzyme systems of the body have been induced,because considerable interindividual variation can occur amongpreviously exposed and unexposed workers.

Identify and list any chemical-containing sources in theworkplace from MSDSs and knowing the specific unit processesThe hygienist should compile a worker-specific list of potential andknown sources.

Identify exposed workers who have greater workload (physicalwork) than othersWorkers who do more physical work absorb more benzene vaporthan those who are exposed to the same air benzene concentrationbut who do not work as hard.

Assess how close and for how long workers are near sources,and whether they are wearing respirator and hand protection.Also determine whether any PPE is effective.List the results of these factors. These items should already be part ofthe air-sampling program.

Identify smokersBenzene and many other chemicals are components of tobaccosmoke. There should be no smoking in the work area, but workerscan smoke during recreation breaks, and benzene from this sourcecontributes to urine marker levels.

Known positive interferences on marker: sorbic acid on t,t-muconic acidNote whether the food workers consume at breaks contains sorbicacid preservative, and note how much was eaten, if t, t-muconic acidis used as a marker.

Negative Benzene InterferencesKnown negative interferencesCoexposure to phenol (for example, in cough medicines and coughcandies, and in cleaners) causes the metabolism of benzene tophenol to be delayed. This lengthens the time for benzene to bedetoxified, and the phenol exposure also constitutes a positiveinterference for a phenol marker.

Coexposure to toluene vapor inhibits metabolism of benzene anddecreases benzene toxicity. This is an interaction.

Possible negative interferencesThe phenol effect on t, t-muconic acid and S-phenylmercapturic acidmarkers has not been investigated, but phenol exposure may elevatetheir urine concentrations, so that the normal dose response tobenzene air concentration is not obeyed.

Figure A1-1. Presampling Checklist for Benzene

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It is easiest to use a Tedlar gas-bag container,because hygienists have received training in its handlingand maintenance. It can be emptied manually. A 10-L bagusually suffices. Use of a valved respirator-type system toregulate inhalation and collection requires pulmonaryfunction testing before it can be used. Of course, workerscleared to use respirators can use such an arrangement.

Tedlar Bag Sampling(1) You first need to set up a clean, leakproofcollection system. You need 6.4 mm interior diameter(i.d.) Teflon tubing to connect the gas bag (clean firstby three fillings/evacuations with compressed air of atleast medical grade quality, and ensure there are nopinholes by immersing the bag in water and assessingwhether water gets inside) to a midget impinger (tocollect excess moisture). The midget impinger shouldbe connected by 6.4 mm i.d. Teflon tubing to a Teflonadapter of greater than 1.2 cm diameter into which theworker blows exhaled breath by mouth.(25) The tubingsystem must be shown to be leakproof by placing thesystem under slight pressure and applying soapsolution at the joints. If the worker experiencesdifficulty in blowing breath through the system, themidget impinger can be dispensed with. If difficulty isstill experienced, Teflon tubing of greater diametershould be used and the tubing length shortened asmuch as possible. A cylinder of medical grade air canbe used to test the collection apparatus for leaks.

(2) You need to collect sufficient volume. Avolume of 1 to 5 L should be collected with at leasthalf the bag filled. It is helpful to know any breathguidelines before collection, to be able to collect alarge enough volume to detect 0.1 of the guidelinerelative to the end analysis method.

(3) The collection must be done in anuncontaminated setting 15–30 min after the end ofany occupational exposure. It is essential to do thesampling on the worker at rest in an uncontaminatedenvironment, and preferably, to have a compressedgas cylinder of air of at least medical grade quality forbreathing purposes for 10 min before the samplingand during the sampling. A convenient inexpensivebreathing enclosure is a Tyvek® powered air-purifyingrespirator visor/hood.

(4) A calibrated pump and solid sorbent can thenbe used to collect a known volume of the exhaledbreath in the bag for analysis using EnvironmentalProtection Agency (EPA) air sampling methods(37)

that are not dependent on relative humidity. Solidsorbents based on Tenax, XAD,™ and Porapak®

resins are recommended. Usually the sample has tobe thermally desorbed in the laboratory analysis,Because breath guidelines are generally in the parts-per-billion-by-volume to low parts-per-million-by-volume range. The laboratory should be accreditedby EPA to do purge-and-trap or thermal-desorption

types of gas chromatography-mass spectrometryanalyses. EPA’s National Environmental LaboratoryProgram has approved states as accreditingauthorities for analytical laboratories(http://www.epa.gov/ttnnela1). ASTM-accreditedlaboratories in thermal desorption(http://www.astm.org/labs) may also be acceptable.

Breath concentrations are often normalized tothe parts-per-million-by-volume of carbon dioxide inthe same sample to account for differences inexhaled breath relative to alveolar air proportion.

Benzene. Inhaled benzene is between 10–50%exhaled depending on physical activity and theamount of body fat.(26) At moderate physical activity,about 30 to 65% of the inhaled benzene is absorbedinto the blood.(8) Of the benzene absorbed into theblood, about 12% is exhaled.(8) About 13% of theabsorbed benzene is excreted into the urine asphenol, <1% as unchanged benzene, 1.6% ascatechol (2 hydroxy groups on a benzene ring), 10%as quinol, 0.5% as trihydroxybenzene, and 1.9% ast,t-muconic acid at the end of a shift on a workday.(26)

The benzene content of breath in nonsmokers is 1-2ppbv compared with 2–6 ppbv in smokers.Occupational exposure to 10 ppmv over a workdaycauses a concentration of 50–120 ppbv 16 hoursafter the end of an 8-hour workday. A similarexposure to 1 ppmv causes breath concentrations ofabout 22–220 ppbv at the end of a work shift.(26)

To detect 20 ppbv of benzene from a TWA airexposure of 1 ppmv, an actual method to detect atleast 2 ppbv is required. Because 2 ppbv (U.S.)=6.38µg/m3, a 5-L air sample contains 32 ng, which thethermal desorption technique must be able toquantify. If the least quantifiable limit (LQL) of theanalytical technique is beyond one order ofmagnitude the mass in the collected volume, then thevolume of the breath sample must be increasedaccordingly. If the LQL is lower or within an order ofmagnitude higher, a smaller defined volume thancontained in the bag can be subsampled onto a solidsorbent for thermal desorption so as to be above thethermal desorption technique LQL. Photoionizationdetection (PID) usually provides sufficient sensitivityto quantify benzene adequately. A portable PID fieldgas chromatographic method also exists for benzeneif the hygienist wants to do the analysis in the field.(7, pp. 73–93) Do not use direct-reading infraredbased methods for organic compound analysis ofbreath samples because of large water vapor andcarbon dioxide interferences.

Lead. Because lead fume is not volatile,negligible lead fume is breathed out. TEL and TMLare much more likely to be breathed out because oftheir volatility. Because the Pb-C bond is weak, TELand TML also react with aqueous media and blood toform progressively dealkylated analogs.


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Q14: What Factors Affect theConcentrations of Breath Markers?All the factors previously mentioned as affecting urinemarker concentrations also affect concentrations ofbreath markers.

It is often unclear whether breath markerconcentrations are from the last workplace exposure orare truly from the excreted absorbed exposing chemical.To solve this complication, noting when the last definiteexposure occurred aids in interpretation of the results.Therefore, direct-reading instrument or data logginginformation may be helpful. Taking the sample in anuncontaminated area is clearly essential.

Q15: Are the BEI Guidelines Still ApplicableIf a Worker Is Exposed at the Same Time toOther Chemicals or Exposed to OtherChemicals Prior to the Work Shift?This is an exposing agent-specific problem. If a worker isexposed only to the guideline chemical, clearly theguidelines apply.

Therefore hygienists need(1) to know what other major chemicals expose

the worker, using MSDSs;(2) an understanding of the unit process involved;

and(3) to know the extent of exposure as mitigated by

PPE, proximity to the emission source, and theduration of exposure.

The more chemicals that are involved, the more likely is itthat toxicologic interactions may occur, for example, iftobacco smoke exposure is also a factor where at least5000 chemicals are involved. The definitions of theinteraction types are as follows.• An interaction is additive if the combined effect of the

constituent chemicals is additive.• An interaction is potentiative if the combined effect of

the constituent chemicals is more than additive, whensome of the chemicals have no biological activity alone.

• An interaction is synergistic if the combined effect of theconstituent chemicals is more than additive.

• An interaction is antagonistic if the combined effect ofthe constituent chemicals is less than additive.

Thus, the known interactions for the guideline chemicalneed to be compiled from the literature into the abovecategories, using the newest reference in the BEIdocumentation as the starting year for the search to thepresent. Free computer searches operated by theNational Library of Medicine such as MEDLINE athttp://www.nlm.nih.gov/hinfo.html or TOXNET athttp://toxnet.nlm.nih.gov are the best choices initially.

Some generalizations can be made. The majorinteractions are most likely caused by agents of nearly

comparable or above-exposure concentrations in termsof absorbed moles, or if inhalation is dominant, in termsof parts per million by volume of vapors, or moles percubic meter for aerosols. This means that compoundspresent at parts-per-trillion by volume vapor ornanograms per cubic meter concentrations are not likelyto interact appreciably with the guideline chemical relativeto those at parts per million by volume, percentage, ormilligrams per cubic meter concentrations.

Some important interference factors not related to thework shift are heavy smoking, medications, high alcoholintake, recreational drugs, and diet. The hygienist shouldbe prepared to administer a questionnaire regarding suchfactors if necessary. Verbal questions are easiest, but thehygienist should write them out beforehand so that all thedesired information is obtained in one session.

No interactions are expected if the metabolism of apotential interferent is different from that of the guidelinechemical. The familiar situation of calculating mixtureTLVs for air exposure to mixtures is applicable for thissituation if BEIs exist for the compounds. Naturally, themechanism of metabolism must be known to determinethis. You may find the information in the scientificliterature. You must have a basic understanding oftoxicological terms to interpret the literature. Often rat andprimate data are used as a first approximation when thereare no human data. The correct animal model for humansmust be used to make human extrapolation possible. Ifthe difficulty in interpretation is insurmountable, ask anearby toxicology expert at a university, governmentagency, or an experienced industrial hygienist withknowledge in toxicology.

Interactions may occur if the potential interference ismetabolized by the same mechanism. Again, most of thedata is animal-based. This is a competitive effect. Thus,these interferents should be chemically similar to theguideline chemical, for example, an isomer such as o-xylene and m-xylene, or a near member in thehomologous series of the guidance chemical such as n-hexane and n-octane. This is not infallible, however.Dissimilar chemicals also can cause interactions,because agents that affect regulation of genes, theinsertion of metals into enzymes, and the cofactors ofenzymic reactions have had documented interactions,(1)

as have common toxic metabolites. An example of thelatter instance in rats is the antagonism between n-hexane and methyl n-butyl ketone in producing theircommon neurotoxic metabolite, 2,5-hexanedione.(1)

Interactions also arise from genetic defects anddifferences.

In molecular terms, interactions are likely if there iscompetition for the same cytochrome P450 isozymeimplicated in the Phase I processes for the guidelinechemical.

Benzene. It has been postulated that benzene,phenol, and hydroquinone are oxidized by the samecytochrome P450 isoenzyme (Type 2E1), and, therefore,


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exposure to the metabolites phenol and hydroquinoneshould cause competition for oxidation.(38,39) The currenttheory(39) is that phenol synergistically oxidizeshydroquinone to the active chemical that causesleukemia, p-benzoquinone. An alternative theory is thatmuconaldehyde, the precursor to t,t-muconic acid,causes leukemia.(7) Both candidate compounds are 1000times more erythropoietic than benzene itself in the short-term 59Fe uptake assay.

Ikeda observed that when benzene and toluenecoexpose human workers, compared with singleexposures alone, the resulting urinary phenol (frombenzene) and hippuric acid (from toluene) concentrationsare both lower than expected from single exposures atgeometric mean air concentrations of 20 and 86 ppmv ofbenzene, and 38 and 86 ppmv toluene.(40) This is mutualantagonism. The biological marker is lowered, rather thanremaining the same or being raised, and is the worstsituation predictive of risk using only biological monitoringdata. This emphasizes the need to also do simultaneouspersonal breathing zone air sampling. The decrease maybe related to the capacity of the metabolic systemsinvolved, and this effect has not yet been investigatedbelow 1 ppmv. It is also unknown whether coexposures ofbenzene and toluene at these high concentrationsincrease, decrease, or do not affect toxicity relative tosingle compound exposures at the same concentrations.

Lead. Exposure to metal fume in a nonferrousfoundry often involves not only lead fume, but also zinc,copper, and manganese fume.(41) Though PbB is notexpected to be affected by coinhaled Zn, Cu, and Mnspecies, the toxic effects of Pb may be influenced, andthence the interpretation of the levels of any biologicalmonitoring markers of effect. Zinc supplementationreduced the effects of lead on the testis in rats relative topathology, and decreases of ALAD and superoxidedismutase enzyme activity.(42) Experiments in-vitro haveshown that 60 mM ethanol and nerve endings from ratsexposed to 500 ppm lead acetate for 56–70 days togetheraffect long-term nerve ending potential over 1 hour,whereas either alone does not.(43) Iron deficiency in ratsalso results in increased Pb absorption duringdevelopment but with no increased accumulation in thebrain.(44) Cognitive development in children affected bylead exposure also depends on iron nutritional status,and those children with dietary iron deficiency havehigher PbB.(45)

Lead also stimulates adrenaline/noradrenalinesecretion in vitro in pheochromocytoma cells through thecalcium/calmodulin protein kinase II system and notthrough the protein kinase A or C systems. However, thisstimulation depends on the presence of Ca2+.(46) Tounderstand interactions, a strong toxicology backgroundis essential, and the hygienist should usually seek experthelp.

Q16: What Should I Do When I Cannot FindGuidelines for an Exposing Chemical?There are several possibilities.

Consult the most recent TLVs and BEIs list. Notewhether your exposing compound has a TLV or ceilinglimit. If it has a ceiling limit (as is common for irritants),there is no BEI because the latter is set on the TLV. Thisdoes not mean biological monitoring cannot be done, butend-of-shift sample concentrations may have norelationship to the acute effect on which the air ceiling orSTELs are based. There may be a correlation if the doseabsorbed parallels the exposure dose.

If the exposing compound has a TLV, thoroughly readits documentation and note any possible biologicalmonitoring markers mentioned in the section on humanstudies. Note which metabolites are of highest molarconcentration or highest percentage yield in urine orblood (these will be the most sensitive markers), and alsoany comments on marker selectivity. When there are nobiological monitoring markers in the human studiessection, read similarly through the section on animalstudies. However, these markers may or may not apply tohumans. In either case, note the most recent date of thereference that refers to any potential biological monitoringmarker. Also, if the information is promising, a copy of anyreferences should be procured for detailed instructions onsampling and analysis. Only the data from the correctanimal model for humans should be used. Thisnecessitates consultation with a toxicologist.

If the compound contains a metal or an element otherthan C, H, N, and O, then the analytical methods for totalmetal or total element in your biological fluid may beadequate using a baseline/end-of-shift samplingcomparison.

If there are no markers mentioned and no referencesin the TLV documentation, consult standard textbooksand biological monitoring sources (see the bibliographyfor this book in Appendix III) and experts in biologicalmonitoring.

Q17: What Are My Responsibilities to theWorker and My Employer Relative toBiological Monitoring?Every situation has to be assessed on its own merits.

You are an employee and you can be fired for beingincompetent or for other “good cause,” the latter coveringa number of employer-sensitive factors. You have to thinkabout how to handle every sensitive situation, especiallywhen legalities are involved.

You must tell the exposed worker enough informationso that the actual risk relative to the exposure situation isunderstood, as well as the meaning of any exposuremonitoring and biological monitoring results. The authorrecommends the written informed consent route as theeducational tool. If the worker does not understand the


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information, training needs to be done. If the employer oryour supervisor does not clearly understand the actualsituation, training (“education”) needs to be done therealso. Read the Section 6 of this guideline also.

When BEIs are just exceeded, tell the worker that thismeans that workplace exposure is uncontrolled, andsome exposure control measures need to be initiated. Ifthe BEI is exceeded twofold or more, an immediatemedical examination referral is recommended if theworker shows symptoms of overexposure. You must havea medical contact in place.

Confidential information between the worker and thehygienist, and between the hygienist and his or hersupervisor/employer, must be respected and keptconfidential. Lack of respect or trust can escalate quicklyinto an untenable situation for the hygienist.

If the situation is life-threatening, you should take thebull by the horns and immediately initiate action tomitigate the situation, with appropriate protection foryourself. Otherwise, get immediate but appropriate help,also informing your onsite key personnel.

Any other situation can be approached in a mannerthat befits its urgency, a political decision that weighs theprevailing overall situation and mood of all personnel inthe involved workplace.

You as a professional have to provide your expertiseto your employer/supervisor. You should double-checkthat all biological monitoring procedures have a soundscientific basis, and be able to articulate that basis to youremployer/supervisor, the worker, nurses, physicians,other workplace professionals, and to governmentagencies. You need to be able to function in a very diverseprofessional realm.

You also need to protect the individual legal rights ofthe worker. The best way to ensure this is to have aconsent form signed by the worker that codifies anagreement between worker and employer in everydaylanguage to ensure the following.• The worker understands the purpose of the tests and

procedures.• The worker understands the test results and what

resulting actions might be taken.• The worker names the people who have access to any

personal results (for example, physician, hygienist,safety engineer, health and safety manager, unionrepresentative).

• The worker agrees to whether personal results can bepooled anonymously with the results of other workers.

• The worker has agreed to personal results beingidentified by name, number, or code.

• The worker has stipulated that the sample can beanalyzed only for the exposing chemical and its relatedbreakdown products that result from work exposures.

• The employer has assured the worker that any testresult will not affect condition of employment.

• The worker is aware of the stated risks of sampling thebiological fluids involved.

• The worker understands that designated employerpersonnel or consultants may ask questions on relatedmatters at any time with the specific contactinformation.

Some sample consent forms can be found in Appendix V.

Q18: What Is My Function in the Effort ToDo Biological Monitoring?You are the first line of screening relative to worker safetyand health. You have to look after the property andinterests of your employer as set out in the legal terms ofemployment.

Industrial Hygienists’ ResponsibilitiesThe hygienist must be able to do environmentalsampling, store and organize transport of thesamples for analysis, and be able to interpret theresults, whether from chemical, biological, or physicalhazards, in the context of biological monitoring data.You have to keep up-to-date records and be currentwith the relevant regulations, guidelines, and science.

See also Section 6 on the elements of abiological monitoring program.

Hygienists must make the decision to seekmedical personnel help, whether because of workersymptoms, if help is needed in an unfamiliar situation,or to assure there are no legal ramifications from thetaking of biological monitoring samples. These linksmust be in place before any biological monitoring isdone.

You must prevent adverse health effects andexposures by diligent observation and monitoring ofthe target worker during the job to formulate a controlplan through source reduction; engineering controls;optimization of the unit process; chemical agentsubstitution; waste minimization; pollution prevention;and administrative control and removal of the worker.The observational component should already be builtin to nonbiological monitoring standard operatingprocedures. The biological monitoring program partof medical surveillance requires standard operatingprocedures in a written program just asenvironmental sampling does.

The hygienist must balance responsibilities to theworker and to his or her employer, and act withpersonal integrity, organization, sensitivity, andtechnical skill that induce respect.


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A1.2 Background Note onIntrinsically Safe WorkplaceExposures to Benzene and LeadA1.2.1 Benzene

A1.2.1.1 UsesBenzene is present as a component of petroleum,kerosene, naphtha, and gasoline; in cigarette smoke;and as a solvent in old formulations of paints,lacquers, varnishes, adhesives, glues, linoleum,putty, fats, inks, oils, plastics, and rubber. It is used inthe industrial synthesis of many aromatic compoundsincluding detergents, explosives, pharmaceuticals,dyestuffs, and in chemical laboratories.

The hygienist should compile here a list ofworker-specific uses of the chemical at thelocations/processes of the workplace to bemonitored.

A1.2.1.2 Relevant Physical Properties(7)

Benzene (molecular weight 78.11) is a colorlessliquid organic chemical compound at 25°C and 760mm Hg, but freezes at 5.5°C. The vapor pressure is75 mm Hg at 25°C and 760 mm Hg atmosphericpressure, and the boiling point at 760 mm Hg is80.1°C. The water solubility at 25°C is 180 mgbenzene/100 mL water. The liquid specific gravity at20°C is 0.87865. The odor threshold is about 12ppmv.

The hygienist should compile a list of potentialemission sources specific to each worker and keyedby physical state (gas, liquid, solid).

If the source is a liquid, note whether it containsmore than 1% benzene, because OSHA has specialprovisions for this situation.

A1.2.1.3 Exposures(7–9)

Benzene exposure can occur by any of the followingpathways.

• Breathing in (inhalation) of the vapor (dominantbecause the vapor pressure is high and theboiling point low) or aerosol (droplets producedby spray nozzles or splashes; adsorbedbenzene on dust particles)

• Skin exposure (dermal exposure) to benzeneliquid, benzene in solvent mixtures, or tobenzene vapor

• Exposure by mouth (oral exposure) to benzenein contaminated food, dust, and from inhalationof aerosols >10 µm in aerodynamic diameter(the nonrespirable size component that doesnot reach the lung alveoli)

The hygienist should compile a list of exposuresituations specific to location and worker within the

workplace. This should be keyed to whether potentialexposure is most likely through inhalation or spills orboth, and whether PPE is worn. A qualitative estimateof exposure potential should be assigned based onnearness to an emission source, length of time nearthe emission source, and the degree of physicalactivity of the worker. A time and motion study may benecessary to make the assignments morequantitative and discriminative. For those workerswith respirator PPE, only workers wearingquantitatively fitted negative pressure respirators orthose wearing supplied air types should be assignedas having low risk from inhalation. For those workerswearing gloves, the gloves must be known to protectagainst both benzene and the major othercomponents in the liquid, to be assigned as havinglow risk from skin absorption. Consult the literature ofthe glove manufacturer to assess this situation,because the same glove types from different glovemanufacturers differ in protectiveness.

A1.2.1.4 Symptoms of OverexposureThese symptoms are important to know, because theTLVs are not protective of all workers, and certainlynot susceptible ones. Therefore, the hygienist mustbe aware of the following clinical symptoms ofbenzene toxicity.

• Irritation to the mucus membranes• Lung congestion• Headache• Dizziness• Nausea• Dry skin• Scaly dermatitis• Very high benzene exposures induce a

condition identical to scurvy caused by vitaminC deficiency. This is a classical effect.

The above items should be used as a checklist foreach worker.

A1.2.1.5 Air Sampling and AnalysisWorkplace air analysis for benzene is either bycalibrated direct-reading devices,(47) calibratedportable gas chromatographs,(48) area airsampling,(49) or personal breathing zone airsampling.(50,51)

Many air monitoring guidelines for worker healthare shown as personal breathing zone samples over8 hours.(1,2) Industrial hygienists who do personalbreathing zone air sampling must ensure that theminimum/maximum air volumes, minimum/maximumsampling flow rates, storage, transport, labeling, fieldblank, and reporting requirements are met as statedin the appropriate NIOSH method.(50,51) Passivesamplers and dynamic samplers may be used, and


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industrial hygienists must be aware of the strengthsand weaknesses of these techniques. An increasingtrend is to use data logging capability for personaldirect-reading breathing zone air sampling thatprovides the exposure profile relative to time as wellas time-integrated data for any time range sampled,for example, any 15 or 30 min range. The industrialhygienist must directly calibrate the direct-readingdevice and not just assume the accuracy of relativeresponse factors.

The hygienist should compile here the airsampling methods for the chemical that are actuallyused in the specific workplace keyed to the workersampled.

A1.2.1.6 Workplace Air Sampling GuidelinesFor guidelines from OSHA, NIOSH, and ACGIH, seeTable A1-4.

Most STEL sampling time periods are 15 min inlength. The IDLH relates to a 30 min time period. TheTLV, PEL, and recommended exposure levelparameters all relate to exposures at the guidelineconcentration for 8 hours/day and 5 days/week,followed by 2 consecutive days of nonexposure.

All of these may need to be updated periodically,but especially the annual TLVs.

A1.2.2 LeadA1.2.2.1 UsesLead is used to manufacture brass and bronze metalarticles and batteries. Some other uses are bullets;ceramic glazes; radioactive source shielding;pigments; lead solder; linings of metal tanks; piping;flint glass; vitreous enamels; litharge rubber; plastics;microelectronic circuits; metallizing; wire drawing; andimitation pearl. Lead arsenite is a pesticide. Leadpigments in paint still occur for nonhome utilization.Leaded gasoline is still used in the United States forvehicles and craft that are not family vehicles. Leadsoaps are sometimes used.

The hygienist should compile a list of uses keyedto each worker and unit process.

A1.2.2.2 Relevant Physical Properties(52)

Lead (atomic weight 207.2) is an inorganic metalsolid at 25°C and 760 mm Hg, because the meltingpoint is 327.5°C. The vapor pressure at 1000°C is1.77 mm Hg; the boiling point at 760 mm Hg is1740°C. The specific gravity is 11.34. The solubility oflead metal in water depends on the pH,(4) withsolubility favored in aqueous strong inorganic acidssuch as nitric or hydrochloric to form Pb2+, and inaqueous strong inorganic bases such as sodium andpotassium hydroxide to form plumbates PbO3

2- andspecies such as [Pb (OH)6] 2-. Rapid formation of an

oxide coating on the surface at pH 7.0 protects leadmetal from hydrolysis (reaction with water).Confusingly, lead as a metal is usually notdistinguished from lead the element withincompounds. The industrial hygienist must be awareof the exposure context to determine if chemicalspeciation is important.

The lead aerosol component of fume is a mixtureof oxides (PbxOy) and the metal (oxidation state,zero).

Lead in lead oxides has oxidation states rangingfrom I to IV,(53) as follows.

• Black Pb2O (the suboxide form) is in negligibleamounts unless materials of high carboncontent are also present in the hot process thatgenerates the fume.

• Brown Pb (IV) form (Plattnerite, the rutile form) asPbO2 is much more chemically inert than PbO;(4)

specific gravity 9.38; molecular weight 239.21.Reacts with air at 300–450°C to form Pb3O4 thatat 530°C decomposes to PbO and O2.

• Yellow PbO, the Pb (II) monoxide, dominatesmetal fume and dust. Litharge and orangemassicot are the two major isomers; specificgravity 9.53; molecular weight 223.21. Theyellow form reacts with air at 300–450°C toform Pb3O4 that at 530°C decomposes to PbOand O2.

• Red Pb3O4, minium, consists of 2PbO.PbO2and Pb2O3.PbO mixtures; specific gravity 9.1.Decomposes at 530°C to PbO and O2.

• Orange-yellow Pb2O3, lead sesquioxide or leadtrioxide, can be regarded as PbO.PbO2;molecular weight, 462.42. Reacts at 370°C withair to form Pb3O4 that at 530°C decomposes inturn to PbO and O2.

All the oxides are nonvolatile and are solids that havedecomposition temperatures or melting points>300°C.(53) Lead hydroxide is actually lead oxidehydrate 3PbO.H2O (molecular weight 687.59; specificgravity 7.41).


Table A1-4. Workplace Air Sampling Guidelines

Occupational Safety and Health Administration (OSHA)(3)

• Permissible exposure limit (PEL), 1 ppmv• Short-term exposure limit (STEL), 5 ppmv

National Institute for Occupational Safety and Health (NIOSH)(3)

• Recommended exposure limit (REL), 0.1 ppmv• STEL, 1 ppmv• Immediately dangerous to life and health (IDLH), 5 ppmv

American Conference of Governmental Industrial Hygienists (ACGIH)(2)

• Threshold limit value (TLV®), 0.5 ppmv (skin; A1 cancer)• STEL, 2.5 ppmv• TLV BASIS: cancer

Note: 1 ppmv = 3.19 mg/m3

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The water solubilities of the oxides also dependon pH. The solubilities at pH 7.0, in milligrams ofoxide per 100 mL water,(53) are as follows.

• PbO litharge, 1.7 (20°C) • PbO massicot, 2.3 (22°C)• PbO2, 0.16 (18°C)

Tetraethyl Lead. The organolead compound,tetraethyl lead Pb(CH2CH3)4 or TEL, is the majorantiknock compound in leaded gasoline for theinternal combustion engine.(24) The molecular weightis 323.45. Because the freezing point is -136.8°C andthe boiling point is 200°C with decomposition above100°C, TEL is a liquid at 25°C and 760 mm Hg withvapor pressure 0.20 mm Hg at 20°C. The watersolubility is 0.2 mg/L at 25°C. The specific gravity is1.659 at 11°C.

Tetramethyl Lead. Tetramethyl lead, Pb(CH3)4 orTML, is also used as an antiknock compound oftentogether with TEL. The molecular weight is 267.33.Because the freezing point is -27.5°C and the boilingpoint is 110°C, TML is a liquid at 25°C and 760 mmHg with vapor pressure 22 mm Hg at 20°C. The watersolubility is <18 mg/L at 25°C. The specific gravity is1.995.

A1.2.2.3 Workplace ExposureLead exposure in the workplace is usually as a metalfume aerosol(52) from hot processes or as a dust fromone of the follow.

• Liquid metal pouring in nonferrous foundriesmaking brass and bronze

• Lead material welding• Lead-soldering• Firing lead bullets of guns• Striking leaded surfaces with electric arcs or

discharges or by intense heat, for example,heat stripping old leaded paint from surfaces

• Abrasive cleaning or blasting of materialscontaining lead

• Exposure to leaded automobile, truck, airplane,rocket, or boat engine exhaust fallout.

• Firing ceramics with lead glazes in kilns

Aerosols containing lead compounds can also begenerated during the following processes.

• Leaded paint spraying operations• Sandblasting surfaces covered by leaded paint• Contaminated dust resuspension• Automated or manual emptying of

contaminated dusts into containers

Each potential exposure situation should be assignedas a vapor or liquid aerosol or fume exposuresituation for each worker.

A1.2.2.4 Exposure Routes(9,24,52)

Lead exposure can occur via several pathways.• Inhalation of the vapor (negligible except for

TEL and TML) or aerosol (dominant for metalfume and dusts; the respirable fraction <10 µmin aerodynamic diameter is absorbed into theblood through the alveolar membranes and thelymphatic system)

• Skin exposure to solvents and solutions thatpermeate the skin and that contain leadcompounds. Organolead compounds such asTEL and TML are absorbed rapidly. Organicsalts such as lead soaps and soluble salts areabsorbed more rapidly from aqueous solutionthan are inorganic salts.

• Oral exposure to lead in contaminated food,fluids, dust, fingers, and from inhalation ofaerosols >10 µm in aerodynamic diameter (thenonrespirable size component)

The hygienist should augment the list of exposuresituations specific to location and worker within theparticular workplace by exposure potential. See TableA1-5 for a list of symptoms of lead overexposure.

A1.2.2.6 Air Sampling and AnalysisInorganic Lead. The current analytical methods forlead in metal fume or dust measure the total leadindependent of its oxidation state or original chemicalform because of sample nitric acid or other colddigestion.(54–56)

Personal direct-reading instrumentation involvingX-ray fluorescence is now available to assess lead on


Table A1-5. Symptoms of Lead Overexposure

Inorganic Lead• Decreased physical fitness• Fatigue• Insomnia• Headache• Aching bones and muscles• Digestive upset (wind and constipation)• Pains in the abdomen• Decreased appetite• Pallor• Anemia• Blue “lead line” where the teeth meet the gums• Decreased hand grip strength• Wrist drop

Tetraalkyl Lead• Nervous irritability• Tremors• Dizziness• Insomnia• Psychosis• Mania• Argumentativeness

Note: The above items should be used as a check list for each worker.

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collected filter samples. The industrial hygienist mustunderstand and calibrate the instrumentation.(57,58)

Tetraalkyl Lead. TEL and TML can be measuredas a vapor by air sampling methods for organics onXAD-2 solid sorbent because they are volatile.(13,14)

Thus, gas chromatographic methods are the mostuseful ones as discussed for benzene, with PIDrecommended.(13,14)

The hygienist should compile the air samplingmethods for the chemical that are actually used in thespecific workplace keyed to the worker sampled. SeeTable A1-6 for guidelines.

References1. American Conference of Governmental Industrial

Hygienists (ACGIH): Documentation of the ThresholdLimit Values and Biological Exposure Indices, 6th ed.Cincinnati, Ohio: ACGIH, 1991.

2. American Conference of Governmental IndustrialHygienists (ACGIH): 2003 TLVs and BEIs. Cincinnati,Ohio: ACGIH, 2003.

3. National Institute for Occupational Safety and Health(NIOSH): NIOSH Pocket Guide to Chemical Hazards(DHHS [NIOSH] Pub. no 2002-140). Cincinnati, Ohio:NIOSH, 2002.

4. Burgess, W.A.: Recognition of Health Hazards inIndustry, 2nd ed. New York: Wiley, 1995.

5. Eller, P.M., and M.E. Cassinelli: NIOSH Manual ofAnalytical Methods, 4th ed. (DHHS [NIOSH] Pub. no94-113). Cincinnati, Ohio: National Institute forOccupational Safety and Health, 1994.

6. Occupational Safety and Health Administration(OSHA): OSHA Analytical Methods Manual, 2nd ed.Salt Lake City, Utah: OSHA, 1990.

7. American Conference of Governmental IndustrialHygienists (ACGIH): Benzene. In Documentation ofthe Threshold Limit Values and Biological ExposureIndices, 6th ed., pp. 108–120. Cincinnati, Ohio:ACGIH, 1991.

8. American Conference of Governmental IndustrialHygienists (ACGIH): BEI-41 to BEI-45. InDocumentation of the Threshold Limit Values andBiological Exposure Indices, 6th ed., pp. 108–120.Cincinnati, Ohio: ACGIH, 1991.

9. Que Hee, S.S. (ed.): Biological Monitoring: AnIntroduction. New York: Van Nostrand Reinhold, 1993.

10. National Institute for Occupational Safety and Health(NIOSH): Lead in blood and urine, Method 8003. InNIOSH Pocket Guide to Chemical Hazards (DHHS[NIOSH] Pub. no 2002-140). Cincinnati, Ohio:NIOSH, 2002.

11. National Institute for Occupational Safety and Health(NIOSH): Elements in blood or tissue, Method 8005.In NIOSH Pocket Guide to Chemical Hazards (DHHS[NIOSH] Pub. no 2002-140). Cincinnati, Ohio:NIOSH, 2002.

12. National Institute for Occupational Safety and Health(NIOSH): Metals in urine, Method 8310. In NIOSHPocket Guide to Chemical Hazards (DHHS [NIOSH]Pub. no 2002-140). Cincinnati, Ohio: NIOSH, 2002.

13. National Institute for Occupational Safety and Health(NIOSH): Tetraethyl lead (as Pb), Method 2533. InNIOSH Pocket Guide to Chemical Hazards (DHHS[NIOSH] Pub. no 2002-140). Cincinnati, Ohio:NIOSH, 2002.

14. National Institute for Occupational Safety and Health(NIOSH): Tetramethyl lead (as Pb), Method 2534. InNIOSH Pocket Guide to Chemical Hazards (DHHS[NIOSH] Pub. no 2002-140). Cincinnati, Ohio:NIOSH, 2002.

15. National Institute for Occupational Safety and Health(NIOSH): Phenol and o-cresol in urine, Method 8305.In NIOSH Pocket Guide to Chemical Hazards (DHHS[NIOSH] Pub. no 2002-140). Cincinnati, Ohio:NIOSH, 2002.

16. American Conference of Governmental IndustrialHygienists (ACGIH): BEI-99 to BEI-104; Supplement:Lead. In Documentation of the Threshold Limit Valuesand Biological Exposure Indices, 6th ed. Cincinnati,Ohio: ACGIH, 1991.


Table A1-6. Guidelines for Lead and Compounds in Personal BreathingZone Air Samples as Total Lead

InorganicOSHA(3)

• PEL, 0.050 mg/m3

NIOSH(3)

• REL, 0.100 mg/m3

• IDLH, 100 mg/m3

ACGIH(2)

• TLV, 0.05 mg/m3

TELOSHA(3)

• PEL, 0.075 mg Pb/m3 (skin)NIOSH(3)

• REL, 0.075 mg Pb/m3 (skin)• IDLH, 40 mg Pb/m3

ACGIH(2)

• TLV, 0.1 mg Pb/m3 (skin)

TMLOSHA(3)

• PEL, 0.075 mg Pb/m3 (skin)NIOSH(3)

• REL, 0.075 mg Pb/m3 (skin)• IDLH, 40 mg Pb/m3

ACGIH(2)

• TLV, 0.15 mg Pb/m3 (skin)

Note: These guidelines may have to be updated periodically, but especiallythe annual ACGIH guidelines.

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17. American Conference of Governmental IndustrialHygienists (ACGIH): BEI-41 to BEI-45. InDocumentation of the Threshold Limit Values andBiological Exposure Indices, 6th ed. Cincinnati, Ohio:ACGIH, 1991.

18. Rinsky, R.A., B. Alexander, M.D. Smith, et al.:Benzene and leukemia: An epidemiologic riskassessment. N. Engl. J. Med. 316:1044–1050 (1987).

19. Paustenbach, D.J., P.S. Price, W. Ollison, et al.:Reevaluation of benzene exposure for the pliofilm(rubberworker). J. Toxicol. Environ. Health 36:177–231(1992).

20. Rappaport, S.M., and K. Yeowell-O’Connell: Proteinadducts as dosimeters of human exposure tostyrene, styrene-7,8-oxide, and benzene. Toxicol.Lett. 108:117–126 (1999).

21. Medeiros, A.M., M.G. Bird, and G. Witz: Potentialbiomarkers of benzene exposure. J. Toxicol. Environ.Health 51:519–539 (1997).

22. International Programme on Chemical Safety:Benzene (Environmental Health Criteria 150).Geneva: World Health Organization, 1993.

23. Agency for Toxic Substances and Disease Registry:Toxicological Profile for Lead. Atlanta: U.S.Department of Health and Human Services, 1990.

24. American Conference of Governmental IndustrialHygienists (ACGIH): Tetraethyl lead. InDocumentation of the Threshold Limit Values andBiological Exposure Indices, 6th ed., pp. 1513–1516.Cincinnati, Ohio: ACGIH, 1991.

25. Que Hee, S.S.: Biological monitoring. In S.R. DiNardi,editor, The Occupational Environment—ItsEvaluation and Control, 1st ed., pp. 262–283. Fairfax,Va.: AIHA Press, 1997.

26. Lauwerys, R.R., and P. Hoet: Industrial ChemicalExposure: Guidelines for Biological Monitoring, 2nded. Boca Raton, Fla.: Lewis Publishers, 1993.

27. Ghittori, S., M. Imbriani, L. Maestri, E. Capodaglio,and A. Cavalleri: Determination of S-phenylmer-capturic acid in urine as an indicator of exposure tobenzene. Toxicol. Lett. 108:329–334 (1999).

28. Ghittori, S., L. Maestri, M.L. Fiorentino, and M.Imbriani: Evaluation of occupational exposure tobenzene by urinalysis. Int. Arch. Occup. Environ.Health 67:195–200 (1995).

29. Boogaard, P.J., and N.J. Van Sittert: Suitability of S-phenyl mercapturic acid and trans, trans-muconicacid as biomarkers for exposure to lowconcentrations of benzene. Environ. Health Perspect.104(suppl 6):1151–1157 (1996).

30. Melikian, A.A., R. O’Connor, A.K. Prahalad, et al.:Determination of the urinary benzene metabolites S-phenylmercapturic acid and trans, trans-muconicacid by liquid chromatography-tandem massspectrometry. Carcinogenesis 20:719–726 (1999).

31. Ruppert, T., G. Scherer, A.R. Tricker, and F. Adlkofer:Trans,trans-muconic acid as a biomarker of non-occupational environmental exposure to benzene. Int.Arch. Occup. Environ. Health 69:247–251, 1997.

32. Pezzagno, G., L. Maestri, and M.L. Fiorentino: Trans,trans-muconic acid, a biological indicator to low levelsof environmental benzene: Some aspects of itsspecificity. Am. J. Ind. Med. 35:511–518 (1999).

33. Scherer, G. T. Renner, and M. Meger: Analysis andevaluation of trans, trans-muconic acid as abiomarker for benzene exposure. J. Chromatogr. B717:179–199 (1998).

34. Kivisto, H., K. Pekari, K. Peltonen, et al.: Biologicalmonitoring of exposure to benzene in the productionof benzene and in a cokery. Sci. Total Environ.199:49–63 (1997).

35. Selander, S., and K. Cramer: Interrelationshipsbetween lead in blood, lead in urine, and ALA in urineduring lead work. Br. J. Ind. Med. 27:28–39 (1970).

36. Williams, M.K., E. King, and J. Walford: Aninvestigation of lead absorption in an electricaccumulator factory with the use of personalsamplers. Br. J. Ind. Med. 26:202–216 (1969).

37. U.S. Environmental Protection Agency (EPA):Compendium of Methods for the Determination ofToxic Organic Compounds in Ambient Air, 2nd ed.(EPA/625/R-96/010b). Cincinnati, Ohio: EPA, 1999.

38. Medinsky, M.A., E.M. Kenyon, M.J. Seaton, and P.M.Schlosser: Mechanistic considerations in benzenephysiological model development. Environ. HealthPerspect. 104(suppl 6):1399–1404 (1996).

39. Medinsky, M.A., E.M. Kenyon, and P.M. Schlosser:Benzene: A case study in parent chemical andmetabolite interactions. Toxicology 105:225–233(1995).

40. Ikeda, M.: Exposure to complex mixtures:Implications for biological monitoring. Toxicol. Lett.77:85–91 (1995).

41. Que Hee, S., and P. Lawrence: Inhalation exposure oflead in brass foundry workers: The evaluation of theeffectiveness of a powered air-purifying respiratorand engineering controls. Am. Ind. Hyg. Assoc. J.44:746–751 (1983).

42. Batra, N., B. Nehru, and M.P. Bansal: The effect ofzinc supplementation on the effects of lead on the rattestis. Reprod. Toxicol. 12:535–540 (1998).

43. Grover, C.A., and G.D. Frye: Ethanol effects onsynaptic neurotransmission and tetanus-inducedsynaptic plasticity in hippocampal slices of chronic invivo lead-exposed adult rats. Brain Res. 734:61–71(1996).

44. Crowe, A., and E.H. Morgan: Interactions betweentissue uptake of lead and iron in normal and iron-deficient rats during development. Biol. Trace Elem.Res. 52:249–261 (1996).


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45. Ruff, H.A., M.E. Markowitz, P.E. Bijur, and J.F. Rosen:Relationships among blood lead levels, irondeficiency, and cognitive development in two-year oldchildren. Environ. Health Perspect. 104:180–185(1996).

46. Ramin, M., and J.C. Porter: A study of the cellularmechanism by which lead affects catecholaminesecretion. Life Sci. 61:1313–1321 (1997).

47. Draeger: Draeger-Tube Handbook, 11th ed. Lubeck,Germany: Draeger Sicherheitstechnik GmkH, 1998.

48. National Institute for Occupational Safety and Health(NIOSH): Benzene by Portable GC, Method 3700. InNIOSH Pocket Guide to Chemical Hazards (DHHS[NIOSH] Pub. no 2002-140). Cincinnati, Ohio:NIOSH, 2002.

49. U.S. Environmental Protection Agency (EPA): MethodTO-1. In Compendium of Methods for theDetermination of Toxic Organic Compounds inAmbient Air (EPA-600/4-89-017). Cincinnati, Ohio:EPA, 1989.

50. National Institute for Occupational Safety and Health(NIOSH): Hydrocarbons, BP 36-126°C, Method 1500.In NIOSH Pocket Guide to Chemical Hazards (DHHS[NIOSH] Pub. no 2002-140). Cincinnati, Ohio:NIOSH, 2002.

51. National Institute for Occupational Safety and Health(NIOSH): Hydrocarbons, Aromatic, Method 1501. InNIOSH Pocket Guide to Chemical Hazards (DHHS[NIOSH] Pub. no 2002-140). Cincinnati, Ohio:NIOSH, 2002.

52. American Conference of Governmental IndustrialHygienists (ACGIH): Supplement to Lead; BEI-99;BEI-Supplement. Documentation of the ThresholdLimit Values and Biological Exposure Indices, 6th ed.Cincinnati, Ohio: ACGIH, 1991.

53. Lide, D.R. (ed.): CRC Handbook of Chemistry andPhysics, 71st ed. Boca Raton, Fla.: CRC Press,1990.

54. National Institute for Occupational Safety and Health(NIOSH): Lead by FAAS, Method 7082. In NIOSHPocket Guide to Chemical Hazards (DHHS [NIOSH]Pub. no 2002-140). Cincinnati, Ohio: NIOSH, 2002.

55. National Institute for Occupational Safety and Health(NIOSH): Lead by HGAAS, Method 7105. In NIOSHPocket Guide to Chemical Hazards (DHHS [NIOSH]Pub. no 2002-140). Cincinnati, Ohio: NIOSH, 2002.

56. National Institute for Occupational Safety and Health(NIOSH): Elements by ICP, Method 7300. In NIOSHPocket Guide to Chemical Hazards (DHHS [NIOSH]Pub. no 2002-140). Cincinnati, Ohio: NIOSH, 2002.

57. National Institute for Occupational Safety and Health(NIOSH): Lead by Field Portable XRF, Method 7702.In NIOSH Pocket Guide to Chemical Hazards.Cincinnati, Ohio: NIOSH, 1998.

58. Morley, J.C., C.S. Clark, J.A. Deddens, K. Ashley, andS. Roda: Evaluation of a portable X-ray fluorescenceinstrument for the determination of lead in workplaceair samples. Appl. Occup. Environ. Hyg. 14:1–11(1999).


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Case Study 1Importance of Biological Monitoring for Urinary 1-Hydroxypyrene in Assessing Dermal Exposure forCoke Oven Workers: Biological Monitoring toRepresent a Class of Compounds

Despite the fact that it has long been recognized thatairborne polynuclear aromatic hydrocarbons (PAHs) posea health risk, the industrial hygiene community has beenslow to recognize the importance of dermal exposure asa significant route for these substances. This is in spite ofnumerous studies that have called attention to theimportance of dermal exposure as a significant, if not themajor, route of exposure for most occupational settingsinvolving PAHs. These studies have focused onmonitoring for a metabolite of pyrene, 1-hydroxypyrene(1-HP) that is excreted in the urine of exposed workers.Although pyrene has much less carcinogenic potentialthan other components of PAHs, it predominates in PAHsand is useful as a marker of exposure to PAHs as a class.Recently, Jongeneelen summarized the results of studiesinvolving PAH exposure and published guidelinerecommendations for 1-HP in the urine of workers for twoindustries, coking and primary aluminum production.(1)

The concentration that corresponded to no genotoxiceffect was 1.4 µmol/mol creatinine. The 95 percentile innonoccupational exposed nonsmoker controls was 0.24µmol/mol creatinine, but was 0.76 µmol/mol creatinine forsmokers. Other markers for biological monitoring havehad limited application. Some used have included urinaryhydroxyphenanthrenes, thioethers, and mutagenicity; andblood hemoglobin-benzo(a)pyrene protein adduct andwhite cell PAH-DNA adducts. All the markers areconfounded by smoking or exposure to products ofcombustion outside of the workplace.

Several occupational studies emphasize the value ofmonitoring for 1-HP in the urine of workers in assessingthe importance of controlling dermal exposure and theefficacy of personal protective equipment and workpractices in limiting exposure. In one study of coke ovenworkers, a 37% reduction in the amount of increase of 1-HP over a 4-day workweek was measured on average forworkers who used “extra” hygienic measures (clean workclothing, new gloves, and daily face washings) versus aworkweek in which these hygienic measures were notenforced.(2)

In another study by the same author a 35% reductionin 1-HP levels was demonstrated for creosote workerswho wore coveralls to reduce dermal exposure.(3) Theauthors noted that additional reductions in exposure were

probably needed because significant skin exposure wasstill evident even with the wearing of the coveralls.

A dramatic demonstration of the importance ofbiological monitoring in assessing dermal exposure wasa study in which a “shadow” control was used to measuredifferences in 1-HP levels between a coal liquefactionworker who performed normal work tasks and the 1-HPlevels in the urine of an occupational physician whofollowed the worker on his work routine over the course offour 12-hour work shifts but avoided skin contact.(4)

Although a similar upward trend in the levels of 1-HPpresent in the urine was seen over the workweek for boththe operator and the shadow control, an order ofmagnitude higher level of 1-HP (15.83 mmole/molecreatinine for operator versus 1.07 mmole/mole for theshadow control) was measured at the end of theworkweek for the operator who had dermal contact withwork surfaces during the workweek. In this same studyother workers performing similar work indicatedcomparable 1-HP levels in their urine over a workweek.Based on the measurement of the inhaled dose duringthe workweek for these workers, the authors calculatedthat the dermal route of exposure accounted for morethan 70% of the total exposure to the coal liquefactionproducts.

There is a biological exposure index proposed that isnot quantitative for a urine sample at the end of a shift atthe end of a workweek.(5)

References1. Jongeneelen, F.J.: Benchmark guideline for urinary 1-

hydroxypyrene as biomarker of occupationalexposure to polycyclic aromatic hydrocarbon. Ann.Occup. Hyg. 45:3–13 (2001).

2. Van Rooij, J.G.M., M.M. Bodelierbade, P.M.J.Hopmans, and F.J. Jongeneelen: Reduction ofurinary 1-hydroxypyrene excretion in coke-ovenworkers exposed to polycyclic aromatic hydrocarbonsdue to improved hygienic skin protection measures.Ann. Occup. Hyg. 38:247–256 (1994).

3. vanRooij, J.G.M., E.M.A. van Lieshout, M.M.Bodelier-Bade, and F.J. Jongeneelen: Effect of thereduction of skin contamination on the internal doseof creosote workers exposed to polycyclic aromatichydrocarbons. Scand. J. Work Environ. Health19:200–207 (1993).

4. Quinlan, R., G. Kowalczk, K. Gardiner, I.A. Calvert, K.Hale, and S.T. Walton: Polycyclic aromatichydrocarbon exposure in coal liquefaction workers:


Appendix II:Case Studies

64

The value of urinary 1-hydroxypyrene excretion in thedevelopment of occupational hygiene controlstrategies. Ann. Occup. Hyg. 39:329–346 (1995).

5. American Conference of Governmental IndustrialHygienists (ACGIH): Threshold Limit Values andBiological Exposure Indices. Cincinnati, Ohio:ACGIH, 2003.

Case Study 2Biological Monitoring for Estrogens and Progestinsas Indicators of Occupational Exposure in theReformulation of Hormone Replacement TherapyProducts: Saliva Biological Monitoring

At a pharmaceutical facility located in the midwesternUnited States, a compliance officer for the U.S.Department of Labor, Occupational Safety and HealthAdministration (OSHA) responded to an employeecomplaint related to overexposure to estrogens andprogestins.(1) Estrogens are natural or synthetic steroidsthat promote growth and development of the femalereproductive system. Progestin is a generic term referringto steroids that have a biological activity similar toprogesterone that acts to prepare the uterus forpregnancy. Overexposures in men to these compoundscan produce enlargement of the breasts and decreasedlibido. In women overexposures can cause menstrualirregularities, breast tenderness, and edema. Estrogensand progestins may also pose a cancer risk either actingdirectly as carcinogens, or as promoters.

The company supplied hormone replacementtherapy products to customers via a mail order service.The drugs were reformulated to produce capsules,creams, dermal patches, and suppositories and wereused for therapeutic purposes to relieve postmenopausalsymptoms and osteoporosis in women. The hormonesconsisted of very fine powders compounded into the finaldrug form. A variety of work operations including sievingand blending were performed, which created respirableaerosols that posed a respiratory hazard to theemployees. The powder also deposited on surfaces andwas readily absorbed by the skin to pose an additionalhazard due to skin contact.

One of the tests used to regulate dosage forcustomers was a saliva test that was submitted to thecompany for analysis. One employee, concerned abouther exposure, submitted saliva samples collected duringher menstrual cycle for analysis of progesterone andestradiol. Progesterone levels ranging from 25–900pg/mL were detected, well above normal progesteronelevels, which peak below 200 pg/mL during the menstrualcycle. Estradiol levels for this same individual measuredfrom undetectable to 25 pg/mL versus normal levels ofundetectable to 5 pg/mL.

Based on these biological monitoring results, acomplaint was filed with OSHA, and an inspection by

OSHA was initiated. As a part of the inspection thecompliance officer measured surface contaminationlevels in office areas for progesterone of 300 µg/100 cm2,and surface area levels averaged over 1000 µg/100 cm2

in the laboratory and inventory areas of the facility.Personal air sampling of two employees measured 53and 80 mg/m3 based on an 8-hour time-weightedaverage, well in excess of a manufacturer’srecommended exposure limit of 12.5 µg/m3. Short term,higher exposures were measured during someoperations. A personal air sample from an employeesieving progesterone powder was 1700 µg/m3.

Deficiencies in personal protective equipment, workpractices, and lack of ventilation controls weredetermined to be significant causes of theoverexposures. The saliva testing for hormones proved tobe a definitive indication of overexposure anddemonstrated the need for better controls to limit bothinhalation and dermal routes of exposure.

Reference1. Presented by Michael Wacker, U.S. Department of

Labor, OSHA, Madison, Wisc., at the GlenWilliamson Forum: Most Interesting OSHA HealthCases 1998–2000, June 4, 2001, New Orleans, La.

Case Study 34,4’-Methylene Dianiline Spill at a Large ChemicalManufacturing Facility in the Southwest UnitedStates: Urine Monitoring as an Index of Exposure

On an early June morning at a large chemicalmanufacturing facility in Texas an employee inadvertentlyoverfilled a railcar with hot, molten 4,4’-methylenedianiline (MDA), resulting in a spill of the material onto theloading rack scales. The majority of the spill was removedwith shovels shortly after the incident, and the MDA wasplaced in plastic barrels for disposal. Several hours afterthe incident the safety and health manager met with otherplant management personnel, and the decision wasmade to remove the remaining amounts of solidified MDAmaterial from the area using sodium bicarbonate as anabrasive blasting agent. This represented a change inprocedure, because for prior spills of MDA high-pressurewater was used to remove the material. In this instancethere was a concern that the loading rack scales could bedamaged by water. In an effort to contain the MDA atarpaulin was placed around the area, and contractorswore Tyvek® suits, rubber boots, gloves, and fullfacepiece respirators to perform the blasting.

Shortly after the blasting began, maintenancecontractors located downwind of the loading rack noticeda white cloud drifting toward the maintenance shop andreported that the powder was accumulating on surfacesinside the shop. The abrasive blasting continued into thenext day and was completed on the following day.


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Numerous complaints of eye, nose, and throat irritation;nausea; and headaches were made by the employeeswho were working in the maintenance shop during theabrasive blasting. One employee reported that both heand his wife became nauseated after eating a gumbosoup that was prepared in the maintenance shop duringthe incident. On the final day of the blasting an industrialhygienist was called in. The shop area was evacuated,and wipe samples were taken from surfaces, although noair sampling was conducted during the release.

Urine monitoring for MDA was conducted for many ofthe exposed workers on the final day of the incident.Follow-up urine monitoring for MDA was conducted onthese same employees approximately 2 weeks later. TotalMDA was reported after analysis was made for both freeMDA and acetylated MDA. Additional testing for serumliver enzyme activities was also conducted to determine ifthere was any indication of abnormal liver function as aresult of MDA exposure, jaundice also having beenreported in acutely exposed workers in the scientificliterature.(1)

Based on the assumption that a worker absorbed50% of the inhaled dose of MDA at the OSHA permissibleexposure limit (PEL; 80 µg/m3), and assuming that aworker inhaled 10 m3 air per work shift at moderateworkload and excreted 1.2 L of urine containing 1.2 gcreatinine per day, it was estimated that 140 µg/gcreatinine would be the urinary equivalent of the air PELfor MDA. Urinary analysis indicated that six employeesreceived an exposure in excess of this dose. There wasno direct evidence linking abnormal liver function testresults to exposure. However, several individuals hadelevated liver enzyme activities. The highest MDAexposure level measured (636 µg/g creatinine) was for anemployee who had eaten the gumbo prepared in themaintenance shop during the release. Follow-up urinetesting of exposed employees (at least 59 employeeswho were tested had MDA levels above background)approximately a week after exposure indicated that MDAlevels had generally dropped into the range of 1 mg/gcreatinine or lower.

Although the study did not address the contribution ofdermal exposure to these employees, a significantportion of the exposure may have resulted from dermalcontact with the MDA material as it deposited on surfacesin the maintenance shop area. The use of bicarbonate asa blasting agent would have facilitated dermal absorption,because this chemical would have maintained anelevated pH on surfaces in which MDA was deposited.MDA is an aromatic amine, and as such it is more readilyabsorbed through skin in its “free base” form, thechemical form of MDA that would be on surfacescontaining sodium bicarbonate residues. Ingestion of theMDA in the soup may also have represented an oral routeof exposure, but no testing was done to verify this.Gumbo soup would most probably represent an acidic(tomato-based) mixture that may reduce the tendency for

absorption of MDA, because the MDA would be presentin the salt form of the base. However, it is known that thesalt form is absorbed orally from animal experiments.(2)

It might be noted that a proposed biological exposureenvironmental limit of 70 µg/L has been proposed for a24-hour urine sample.(3)

References1. Dunn, G.W., and S.S. Guirguis: p,p’-Methylene

dianiline (MDA) as an occupational health problem. Asuggested time-weighted average exposure level andmedical program. In R. Plestina, editor, Proceedingsof the International Congress on OccupationalHealth, 19th ed. Zagreb, Yugoslavia: Institute ofMedical Research and Occupational Health, 1980.(In English)

2. National Toxicology Program: CarcinogenesisStudies of 4,4’-Methylenedianiline Dihydrochloride(CAS No 13552-44-8) in F344/N rats and B6C3F1Mice (Drinking Water Studies), (Technical ReportSeries vol. 248). Research Triangle Park, NC:National Toxicology Program, 1983.

3. “Basis of the Proposed Biological-BasedEnvironmental Exposure Level (BEEL) for 4,4’-Methylene Dianiline.” Forum presented at theAmerican Industrial Hygiene Conference andExhibition, San Diego, June 1–6, 2002.

Case Study 4Protectiveness of Negative and Positive PressureRespirators and Contribution of Dermal Exposure toCarbon Disulfide Exposure in the Viscose RayonIndustry: Urine Monitoring for TTCA in Tandem withPersonal Air Sampling

Workers at a Virginia viscose rayon plant (SIC 2823)were monitored for air carbon disulfide (CS2) and urinary2-thiothiazolidine-4-carboxylic acid (TTCA) in 1989.(1) Atthe time, the Occupational Safety and HealthAdministration (OSHA) permissible exposure limit (PEL)was 4 ppmv (skin) recommended (1 ppmv=3.11 mg/m3),revised to 20 ppmv effective July 1, 1993, after asuccessful legal challenge in 1992; the National Institutefor Occupational Safety and Health (NIOSH)recommended exposure limit (REL) was 1 ppmv (skin);the American Conference of Governmental IndustrialHygienists (ACGIH) threshold limit value/time-weightedaverage (TWA) was 10 ppmv (skin); and the ACGIHbiological exposure index was 5 mg TTCA/g creatinine,end-of-shift.

Exposure to vapor was expected at the hot processsteps, pouring liquid CS2, and if inadequate respiratorswere worn or if they were worn improperly. Skin exposurewas considered likely by condensation of hot vapor onunprotected skin, spilling liquid CS2 on skin, or


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inadequate glove or skin protection. Little spillingoccurred in this workplace. Oral exposure was possible ifthere were contaminated aerosols in the nonrespirablesize range, and contaminated food. No eating wasallowed. Housekeeping was regular and effective.Therefore, the NIOSH industrial hygienist consideredinhalation exposure to be the most likely exposure route.The workload was estimated to be light (0–50 watt).

The most likely work practices were then targetedrelative to inhalation exposure potential. One chargehand (CH) added CS2 into “white crumbs” of wood chipsheets steeped in lye (sodium hydroxide solution) in theabsence of air, and then milled to form cellulose xanthate(“yellow crumbs”) that was dissolved in lye to form theorange-brown gooey “viscose.” A qualitatively fittednegative pressure respirator with charcoal cartridge wasworn along with gloves.

Two spinners supervised viscose extrusion throughfine spinnerettes into dilute, buffered, sulfuric acid(50–100°C) to form long separate “green” fibers, whichwhen not sticky were spun inside a spinning machine.These fibers formed a tow that was handled regularlywithin and outside the spinning machine to retain its form.The machine’s inner rollers needed to be cleared often.Qualitatively fitted negative pressure respirators withcharcoal cartridges and gloves were worn.

Two cutters supervised cutting of the fiber towthreaded at >100 m/min out of the spinning machine to aventilated cutting machine to form rayon staples. Cutterheads were cleaned inside an enclosed cutting house,where each worker wore a self-contained breathingapparatus. They wore qualitatively fitted negativepressure respirators with charcoal cartridges outside thecutting house. Gloves were also worn.

NIOSH Method 1600 was used for air CS2measurement, involving sampling with 270 mg sodiumsulfate foretube/150 mg charcoal tube at 0.2 L/min,(3)

desorbing with 1 mL 5% methanol-toluene, and analyzingwith a 30 m × 0.24 mm DB-1 capillary column and a flamephotometric sulfur detector.

Spot urine samples were taken in 500 mLpolyethylene containers at the end and beginning of eachshift. The samples were stored and transported frozen.After thawing and extraction, analysis was by reversephase (C8/C18 in series) high performance liquidchromatography with ultraviolet detection (272 nm).(4)

Creatinine was also determined.The air and urine results for these workers are

summarized in Table A2-1.No worker exceeded the postshift ACGIH 5.0 mg

TTCA/g creatinine guideline equivalent to a 10 ppmvTWA, or 4.9 mg TTCA/g creatinine increase from theregression relationship.(6) Also, no worker was exposed tothe equivalent of a 20 ppmv OSHA PEL. The personalprotective equipment program was effective for theseconditions.

If the rescinded OSHA PEL of 4 ppmv was used asthe guideline, the equivalent TTCA increase is 2.7 mg/gcreatinine from the regression relationship.(6) Only Cutter7 on September 21 exceeded this value.

If the NIOSH REL of 1 ppmv was used as theguideline, the equivalent TTCA increase is 1.7 mg/gcreatinine from the regression relationship.(6) Only Cutter7 on September 21 exceeded this guideline. Correctionfor baseline gives the workplace contribution, if thepreshift contribution does not change appreciably overthe sampling time. The fast t0.5 for urinary TTCA is 6hours; the second t0.5 is 68 hours.(7) For the first t0.5, about6.3–16% is in a sample taken t=16 to 24 hours later (e-0.693t/t0.5).

The maximum workplace contribution is the postshiftTTCA value uncorrected for preshift value. For therescinded OSHA PEL, only Cutter 7 on September 20also exceeded 2.7 mg/g creatinine equivalent. For theNIOSH REL guideline equivalent of 1.7 mg/g creatinine,no other workers exceeded this guideline.

No workers were adversely exposed, except possiblyfor Cutter 7. The calculated respirator workplaceprotection factor was <7 on September 21, even thoughthe qualitative fit test was adequate.

Skin exposures were not sufficient to warrantchanges in the protective clothing program.

Another case study for carbon disulfide biologicalmonitoring in the viscose rayon industry is available.(2)

References1. Cox, C., S.S. Que Hee, and W.P. Tolos: Biological

monitoring of workers exposed to carbon disulfide.Am. J. Ind. Med. 33:48–54 (1998).

2. Drexler, H., T. Goen, J. Angerer, S. Abou-el-ela, andG. Lehnert: Carbon disulfide. I. External and internalexposures to carbon disulfide of workers in the


Table A2-1. Air and Urine Results for Viscose Rayon Plant Workers

Worker Date Air CS2 TTCA(mg/g creatinine) WPF

9/89 (ppmv) Preshift Postshift Increase CalculatedA

Spinner 1 20 5.80 <0.02 0.62 0.61 3.4 5.621 2.90 0.70 1.20 0.50 2.4 4.8

Spinner 2 20 8.60 <0.02 0.91 0.90 4.4 4.921 3.70 0.10 0.67 0.57 2.7 4.7

CH 3 20 7.40 <0.02 0.26 0.25 4.0 16Cutter 4 20 17.7 <0.02 0.72 0.71 7.5 11

21 10.3 0.45 0.97 0.52 5.0 9.6Cutter 7 20 15.1 2.20 2.70 0.50 6.6 13

21 13.6 0.06 2.90 2.84 6.1 2.2

Notes: CH, charge hand; Air CS2, personal breathing zone time-weightedaverage air concentration sampled full-shift; WPF, workplace protectionfactor=calculated/increase. The <0.02 mg TTCA/g creatinine value is the limitof detection, but 0.014 (0.02/20.5) was used to calculate increase.(5)

ACalculated from the air CS2 using the regression relationship: Increase in

TTCA=1.387+0.347 air CS2 at 50 watt physical activity.(6)

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viscose industry. Int. Arch. Occup. Environ. Health65:359–365 (1994).

3. National Institute for Occupational Safety and Health(NIOSH): Method 1600. In Manual of AnalyticalMethods (DHHS [NIOSH] Pub. no. 84-100).Cincinnati, Ohio: ACGIH, 1984.

4. Cox, C., and S.S. Que Hee: Synthesis of 2-thiothiazolidine-4-carboxylic acid and itschromatography in rat and human urine. J.Chromatogr. B. 679:85–90 (1996).

5. Hornung, R., and L. Reed: Estimation of averageconcentration in the presence of nondetectablevalues. Appl. Occup. Environ. Hyg. 5:46–51 (1990).

6. Cox, C., L.K. Lowry, and S.S. Que Hee: Urinary 2-thiothiazolidine-4-carboxylic acid as a biologicalindicator of exposure to carbon disulfide: derivation ofa biological exposure index. Appl. Occup. Environ.Hyg. 7:672–676 (1992).

7. Riihimaki, V., H. Kivisto, K. Peltonen, E. Helpio, and A.Aitio: Assessment of exposure to carbon disulfide inviscose production workers from urinary 2-thiothiazolidine-4-carboxylic acid determinations. Am.J. Ind. Med. 22:85–97 (1992).

Case Study 5N,N-Dimethylacetamide Dermal Exposure to Workersin the Acrylic Fiber Manufacturing Industry

N, N-Dimethylacetamide (DMAC) is a solvent used inthe acrylic fiber manufacturing industry, among manyothers. The threshold limit value/time-weighted averagefor 8 hours at the time of monitoring was and still is (2003)10 ppmv (skin). The American Conference ofGovernmental Industrial Hygienists biological exposureindex (BEI) is 30 mg N-methylacetamide (NMAC)/gcreatinine at the end of shift at the end of the workweek.DMAC can also permeate skin rapidly.

One repetitive unit process step in the manufacturingof acrylic fiber where exposure is likely is threading theextruded DMAC-containing “dope” through a water bath.Though the personal sampling air concentrations at thisstep were consistently below 1 ppmv, the workers stillreported some DMAC overexposure symptoms. This ledto the site industrial hygienist and physician becomingconcerned about the degree of possible permeation ofDMAC through the shoulder-length neoprene glovesutilized in the threading bath operation, and subsequentskin absorption.

An analytical method for NMAC in urine wasdeveloped in the plant’s industrial hygiene laboratoryusing the references in BEI documentation.(1) A samplingand analytical protocol was developed with help from theproduction staff, the site’s physician, the industrialhygienist, and the laboratory. The protocol called forcollecting a postshift urine sample from every worker on

the water baths every shift during a 2-week period. Inaddition, air-sampling using diffusion badges was to beperformed on the workers to be monitored. In addition tothe laboratory QC samples certain urine samples were“split” and urine also collected from workers known not tobe exposed to DMAC (site safety personnel). These extraQC samples were sent to the laboratory “blind.”

During the 2-week period, 98 urine samples and 82air samples were collected from exposed workers. The airsamples had concentrations less than 5 ppmv, and mostwere less than 1 ppmv. There was no correlation betweenpersonal air concentrations and urinary NMAC. Most ofthe urine samples were below the limit of detection of themethod. Six samples contained measurable NMAC, and2 samples exceeded the BEI.

The integrity of the gloves and work practices wasexamined for the workers who showed measurableNMAC in urine. The most likely explanation was skinexposure caused by failure to remove the glovesimmediately following contamination of the inside of thegloves with water from the water bath. These results andrecommendations to prevent dermal contact with DMACwere summarized and communicated to the workers.

A different data set on a similar population is reportedin the literature.(2)

Note: At the time of this case study, very littleinformation was available on the permeation of DMACthrough gloves. Now the permeation and penetrationcharts of solvents for a glove manufacturer also would beconsulted. Such consultation in 2003 would show thatneoprene is not recommended for protection against pureDMAC,(3) as is also true for nitrile, polyvinyl alcohol, andpolyvinyl chloride. This does not mean that DMAC inwater would permeate, but this is a strong signal to useother glove materials for optimum safety. In this caselaminated gloves are the best (pure DMAC breakthrough>480 min with permeation rate less than 0.9 µg/cm2/min),followed by neoprene/natural rubber blend (breakthroughat 30 min after exposure with permeation rate 9–90µg/cm2/min), and then natural rubber (breakthrough at 15min with permeation rate 9–90 µg/cm2/min). Doublegloving with relatively resistant gloves may be effective(and economical) with glove protection time dependingon the duration of contact and the concentration of DMACin water. This latter stratagem is much more cumbersomeand less practical for shoulder-length gloves than forhand and hand-forearm gloves.

In the case of the shoulder-length gloves, duct-tapingthe gloves to the protective suit ensemble may be moreprotective, but this does not allow a very flexible situationin the workplace, and in some cases may lead to tearingof the protective suit. Any unavoidable contamination ofthe insides of the gloves can be followed by glovedisposal and DMAC decontamination of the exposed skinwith cool flowing water.


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References1. American Conference of Governmental Industrial

Hygienists (ACGIH): N, N-dimethylacetamide(DMAC). In Documentation of the BEIs. Cincinnati,Ohio: ACGIH, 1996.

2. Spies, G.J., R.H. Rhyne, Jr., R.A. Evans, et al.:Monitoring acrylic fiber workers for liver toxicity andexposure to dimethylacetamide. I. Assessingexposure to dimethylacetamide by air and biologicalmonitoring. J. Occup. Environ. Med. 37:1093–1107(1995).

3. Ansell Protective Products: Ansell ProtectiveProducts Chemical Resistance Guide: Permeationand Degradation Data, 6th ed. Coshocton, Ohio:Ansell Protective Products, 1998.

Case Study 6Cadmium and Past Exposures

Cadmium (Cd) is used to stabilize plastics and as apigment,(1) most notably for polyvinyl chloride (PVC).Cadmium-in-air assessments in PVC plants havegenerally found little exposure.(2)

A plastics manufacturing plant had used cadmium-containing pigments for more than 20 years. Thepigments had been replaced with those that did notcontain Cd about 5 years prior to this study. Past personalair sampling showed only a few isolated instances inwhich the air permissible exposure limit (PEL) wasexceeded, but most results were below the limit ofdetection. Workers in the plant still expressed concernabout past Cd exposure because conditions had beenvery dusty, with extensive dermal contact with pigmentdust, and Cd has a long body biological half-time of about20 years. To address these concerns, a study wasdesigned to determine urine Cd in every worker still in theplant who may have had contact with Cd-containingpigments. Cd has an Occupational Safety and HealthAdministration (OSHA) air PEL of 5 µg/m3 and an OSHAaction level for the PEL for Cd in urine of 3 µg Cd/gcreatinine.

The plant industrial hygienist identified three contractlaboratories that claimed to be able to determine Cd inurine. With the help of the corporate industrial hygienelaboratory, urine specimens with known levels of Cd werecreated and sent to these contract laboratories foranalysis. Only one of the laboratories returnedsatisfactory results. None of the real samples fromexposed workers contained Cd above the limit ofdetection of the analytical method. Because the biologicalhalf-time is about 20 years and it is known most of the Cdaccumulates in the kidney except when kidney damagehas occurred, the industrial hygienist informed theworkers that past Cd exposures appeared to be withinacceptable limits.

This case study shows that biological monitoring canbe used to satisfy workers that past exposures have notbeen important.

References1. Batzer, H.: Use and possibilities for substitution of

cadmium stabilizers. Ecotoxicol. Environ. Safety7:117–121 (1983).

2. Chan, O.Y., K.T. Tan, S.F. Kwok, and L.F. Chio: Studyon workers exposed to cadmium in alkaline storagebattery manufacturing and PVC compounding. Ann.Acad. Med. Singapore 11:122–129 (1982).

Case Study 7Workplace Protection Factors for Lead Fume forPowered Air-Purifying Respirators in a BrassFoundry: Blood Lead Must Be Used to Ascertain TrueProtectiveness of Respirators

The major exposure concern leading to this studywas why blood lead concentrations were still well abovethe Occupational Safety and Health Administration(OSHA) blood permissible exposure limit (PEL) of 50µg/dL when the workers were equipped with powered air-purifying respirators.(1,2)

The industrial hygienists firstly examined theseven most exposed workers, their work practices,and their personal protective equipment. The ladleattendants (LA) transported the molten metal in theladle (it contained its own local exhaust system thattraveled on a monorail) for pouring into the molds.The furnace attendants (FA) tended the gas-firedfurnaces and tapped the molten metal into the ladle.It was determined that the filters and flow rates of thehelmets of the powered air-purifying respirators werewithin specification and that there were no leaks up tothe helmets. Sampling cellulose acetate filtercassettes were placed inside the helmet facepiece(13 mm diameter) and at the lapel, both connectedwith calibrated pumps. The lead analysis was done byatomic absorption spectroscopy. The airconcentration at the lapel divided by the insideconcentration provided the workplace protectionfactor (WPF). In addition, the velocity of airflowthrough the holes of the facepieces and masks weremeasured with a calibrated hot wire anemometer.

The results are provided in Table A2-2.

Most of the measured WPFs were less than 10,but were always so for the FAs. Whenever a highWPF was measured for the LAs, the blood leadconcentrations decreased. The FAs often raised theirrespirator face shields because of the dusty and hotconditions and often did not ensure the side shieldsfitted properly when they lowered their shields. Low


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air face velocities below the nose at mask holes alsocoincided with dusty masks after work. Thissuggested that much of the protective airflow was notreaching the nose, and in a few cases this wasdemonstrated directly. The major defect was that theairflow entered the helmet at the top of the head andhad to find its way down to the nose for the respiratorto be protective. Although the worker felt cooler andmore comfortable with this arrangement, the workerwas not protected optimally from metal fume. Betterfitting side shields addressed some of the problems.It was suggested that the respirator design bechanged so that the air entered the helmet near thenose. This had the disadvantage of impeding theworker’s line-of-vision somewhat.

The WPFs for metal fume were usually in thefollowing decreasing order: zinc, lead, and copper, theorder of decreasing particle size of the metal fume.Recommendations were, among others, to replace thegas-fired furnaces with an electric furnace, and shorten

the distance to transport the ladle as much as possible.The LA was advised to pull the ladle rather than push itso that the attendant was downstream of the ladle as littleas possible. More rigorous cleaning of the helmet wasrecommended. These measures, plus a rigoroushousekeeping and personal hygiene program thatincluded washing hands and faces at breaks in additionto showering, eventually allowed the blood leadconcentrations to be lowered to below the OSHA actionlevel.

The situation of WPF of negative pressure andpositive air-purifying respirators not always agreeing withassigned fit factors was still current in 2000 for leadfume.(3)

References1. Que Hee, S.S., and P. Lawrence: Inhalation exposure

of lead in brass foundry workers: The evaluation ofthe effectiveness of a powered air-purifying respiratorand engineering controls. Am. Ind. Hyg. Assoc. J.44:746–751 (1983).

2. McQuiston, T.H., S.S. Que Hee, and B.E. Saltzman:Lead exposures during the segments of the ladlingcycle at a non-ferrous foundry. Ann. Occup. Hyg.30:41–49 (1986).

3. Spear, T.M., J. DuMond, C. Lloyd, and J.H. Vincent:An effective protection factor study of respiratorsused by primary lead smelter workers. Appl. Occup.Environ. Hyg. 15:235–244 (2000).

Case Study 82-Butoxyethanol Exposure for Window Cleaners:Urine Monitoring as a Means to Gauge NoninhalationExposure

2-Butoxyethanol (2-BE) is widely used as a solventin paints, varnishes, inks, and cleaning fluids. About 50%of the latter for window cleaning contain 2-BE at 1–30%(v/v). Absorption of the vapor and the compound whenapplied to the skin can occur. The major metabolite inhumans is butoxyacetic acid (BAA), and it has a urinaryelimination half-time of 5.8 hours. The AmericanConference of Governmental Industrial Hygienists(ACGIH) 2003 threshold limit value/time-weightedaverage of 2-BE for 8 hours is 20 ppm (97 mg/m3). The2003 National Institute for Occupational Safety andHealth (NIOSH) recommended exposure limit is 5 ppm(skin), whereas the Occupational Safety and HealthAdministration permissible exposure limit is 50 ppm(skin). There is no ACGIH biological exposure index, butone does exist for 2-ethoxyethanol. NIOSH has estimatedthat 60 mg BAA/g creatinine postshift is equivalent to a 2-BE exposure of 5 ppmv over 8 hours.(1)

A group of 29 cleaners of cars and offices wassampled for breathing zone 2-BE by the charcoal tube


Table A2-2. Results of Examination of Brass Foundry Workers

Employee Title Air Pb WPF FV Comments(mg/m3) (m/sec)

Lapel Inside

1 LA 2316 78 30 nm Long thin side shields; shield down continuously

288 230 1.3 0.4–0.6 Wrong side shields; low flow due to low battery

530 19 28 5.6–7.6 Long thin side shields; shielddown continuously

2 LA 485 <5 >97 nm Sample collected at air inlet

800 12 67 5–6

3 LA 320 57 5.6 1.5–1.8 Wide shields; shield down continuously

4 FA 97 92 1.1 nm Shield up often; wide face

190 160 1.2 0.7–1.0 Shield up often196 70 2.8 2-3 Shield up less20 8 2.5 5-6 Rest period in

ventilated room

5 FA 84 19 4.4 1.7–2.0 Wide face; shield down continuously

6 FA 46 25 1.8 7–12 Wide face; shield up often

7 FA 36 7 5.1 7–14 Narrow face; shield up often

Abbreviations: WPF, workplace protection factor; FV, face velocity; nm=notmeasured; LA, ladler; FA, furnace attendant

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method, and also preshift and postshift urine samples in150 mL polyethylene bottles.(2) 2-BE concentrations incleaning solutions were also determined. A questionnaireon job category, type of window cleaning agent used, anduse or nonuse of protective gloves was administered.

2-BE content in cleaning fluids ranged from 0.9 to21.2% (v/v). The volume of cleaning agent used duringthe work shift ranged from 50 mL to 1200 mL/workingday, with variable daily exposure times of 20 to 320 min.Only one set of the six sets of workers evaluated woreprotective “rubber gloves.”

Although many preshift urine samples were belowdetection (<2 mg BAA/g creatinine), this was not alwaysso. In fact, one cleaner of used cars had a preshift valueof 33 mg BAA/g creatinine compared with 24 mg BAA/gcreatinine for postshift. Eight of 24 urine samples showedBAA postshift concentrations above 60 mg/g creatinine.Only 2 personal air concentrations exceeded 5 ppmv; 7 of22 showed air concentrations below detection (0.1ppmv). Air concentrations alone could not account for theurine levels.

Considering just the two workers with personalbreathing zone concentrations above 5 ppmv, onecleaner of new cars exposed to 5.44 ppmv of 2-BE hadpreshift/postshift BAA urine concentrations of 21.8/114.8mg/g creatinine, a difference of 93 mg/g creatinine,leading to a workplace exposure of between 70%inhalation and 30% noninhalation or 57% inhalation and43% noninhalation. The worker exposed to 7.33 ppmv 2-BE had preshift/postshift BAA urine concentrations of98.6/371 mg/g creatinine, a difference of 272.4 mg/gcreatinine, leading to a workplace exposure of between32% inhalation and 68% noninhalation or 24% inhalationand 76% noninhalation. Either way, for the last worker thenoninhalation route dominates, as it does for the rest ofthe exposed workers.

For example, a cleaner of new cars was exposed to a2-BE air concentration of 0.91 ppmv, yet showed apreshift/postshift BAA urine concentrations of <2/178.2mg/g creatinine. The inhalation component of theexposure comprised about 6%.

References1. National Institute for Occupational Safety and Health

(NIOSH): Criteria for a recommended standard. InOccupational Exposure to Ethylene Glycol MonobutylEther and Ethylene Glycol Monobutyl Ether Acetate.(DHHS [NIOSH] Pub. no. 90-118). Cincinnati, Ohio:NIOSH, 1990.

2. Vincent, R., A. Cicolella, I. Subra, B. Rieger, P. Poiret,and F. Pierre: Occupational exposure to 2-butoxyethanol for workers using window cleaningagents. Appl. Occup. Environ. Hyg. 8:580–586 (1993).

Case Study 9Urine Biological Monitoring after HexamethyleneDiisocyanate Exposure During Motor Vehicle RepairSpray Painting to Test Personal Protective EquipmentProtectiveness

1,6-Hexamethylene diisocyanate (HDI) is used inspray paint operations and as a substitute for the moretoxic toluene diisocyanate.(1) The technical preparationcontaining HDI in two-component spray paints alsocontains monomers, polymers, biurets, as well as freeHDI.(1) The diisocyanates are well-known inducers ofchemical asthma. The Occupational Safety and HealthAdministration has no recommendations. The NationalInstitute for Occupational Safety and Health has arecommended exposure limit of 0.005 ppmv and a 10-minceiling value of 0.020 ppmv. The American Conference ofGovernmental Industrial Hygienists recommends a 2003threshold limit value/time-weighted average of 0.005ppmv.

Workers in five British motor vehicle repair shops thatused isocyanate paints in spray painting operations weremonitored, along with bystanders and unexposedcontrols. Urines and area air samples were taken beforeand after the work shift and at midday for each person.This was necessary because the urinary marker ofexposure, 1,6-hexamethylene diamine (HDA), has a shorthalf-time of about 1.5 hours. Workers also filled in aquestionnaire concerning the amount of time spentspraying and the personal protective equipment worn.

Urine samples were frozen at the work site;transported frozen; thawed in the laboratory; acidhydrolyzed; extracted; reacted with heptafluorobutyricanhydride; and quantified using the internal standardmethod by gas chromatography-mass spectrometry (GC-MS) at m/z 449.

In the initial pilot study in one dealer, no urinary HDAwas detected in bystanders or unexposed people. Only 1and 2 nmol HDA/L was detected in two paint sprayers.

In the full study with 11 sprayers, 3 bystanders, and 8unexposed persons, none of the unexposed workersshowed detectable HDA. One bystander hadundetectable (before shift), 6 (midday) and 12 (after shift)mmol HDA/g creatinine in three urine samples on thesame day. Only 4 workers showed detectable urinaryHDA. One worker showed 11 (before shift), 10 (midday),and 4.0 (after shift) mmol HDA/g creatinine. Anothershowed undetectable (before shift), 6.0 (midday), and 12(after shift) mmol HAD/g creatinine. Another showed 1.0(before shift), not detectable (midday and after shift)mmol HAD/g creatinine. The fourth sprayer showed notdetectable (before shift), 3.0 (midday), and 1.0 (after shift)mmol HAD/g creatinine. All sprayers wore full-facepositive pressure respirators and sprayed in anadequately ventilated environment.

The industrial hygienists thought the major exposurewas through inhalation after lifting the respirator visor to


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inspect the quality of the spraying. Air monitoring showedthat HDI concentrations of >20 µg/m3 persisted in spraybooths and spray spaces. Clearance times of 5 and 30min were also measured for booths and spacesrespectively. Lifting the respirator visor prematurely inthese spaces could lead to exposure. Another source ofinhalation exposure was the emission of HDI during thespray bake cycle. In one workplace, trucks rather thancars were being spray-painted. This involved a lot ofspraying above head height.

The two sprayers who showed detectable urinaryHDA before the shift were thought to have had a recentinadvertent short-term high exposure or were showingholdover from exposures that produced protein HDAadducts that were later hydrolyzed in a reversibleprocess. The exposed bystander recalled that he hadspoken to a sprayer while he was spraying.

The study shows that personal monitoring is requiredto assess whether personal protective equipment andhygienic measures are adequate for each worker.Furthermore, the work practices and hygienic measuresof each worker must be evaluated.

Reference1. Williams, N.R., K. Jones, and J. Cocker: Biological

monitoring to assess exposure from use ofisocyanates in motor vehicle repair. Occup. Environ.Med. 56:598–601 (1999).

Case Study 10Effect of Respirator Use on Exposure to 2-Methoxyethanol

2-Methoxyethanol or ethylene glycol monomethylether is a solvent used in producing 2-methoxy acetate,plasticizers, insulation, high-flash coatings, photoresists,and in the coating or lamination resins of circuit boards.The Occupational Safety and Health Administration hasno requirements. The 2003 American Conference ofGovernmental Industrial Hygienists threshold limitvalue/time-weighted average is 5 ppmv (skin). Thebiological exposure index is a “not quantitative”concentration of 2-methoxyacetic acid (MAA) in urine atthe end of a shift at the end of a workweek. The NationalInstitute for Occupational Safety and Health hasrecommended that 0.8 mg MAA/g creatinine signalsmore than background exposure. The urinary half time forMAA of about 77.1 hours implies accumulation during theworkweek can occur.

In this study 2-methoxyethanol was used in dippingand oven heating operations in a copper laminatesemiconductor facility in Taiwan. The coating gluecontained 70% 2-methoxy-ethanol and 30% acetone. Atotal of 18 regular workers who did not wear respiratorsbut wore rubber gloves were studied. A further 9 special

operations workers also mixed raw materials, chargedreactor, cleaned machines, and did maintenance work:they wore respirators and rubber gloves. Twentyunexposed administrative workers were chosen asnegative controls, and 10 workers in the heat pressoperations were also evaluated.

Daily personal 8-hour breathing zone airconcentrations using charcoal tubes and urine samplesbefore and after each shift were obtained from Monday toSaturday for exposed workers, and urines on Fridays for30 negative control workers. The charcoal tubes weredesorbed by 95:5 methylene chloride/methanol andanalyzed by gas chromatography/flame ionizationdetection (GC/FID). The urine was acidified, extractedwith 2:1 methylene chloride/isopropanol, and reacted with(trimethylsilyl)diazomethane. The resultant methyl esterof MAA was quantified by GC/FID. Urinary creatinine wasalso measured.

No urinary MAA was detected in unexposed controlworkers, but low concentrations (0.4-0.5 mg/mL) werefound in three heat press workers. Regular operationalworkers were exposed from 0.72 to 9.73 ppmv in thebreathing zone, whereas the special operations workerswere exposed from 24 to 268 ppmv. End-of-shift MAAconcentrations were 10–45 mg/g creatinine.Concentrations for the special operations workers rangedfrom 10-27 mg/g creatinine. These results implyinhalation exposure was important for the regular workersbecause they did not wear respirators, which wereapparently protective for most of the special operationsworkers in spite of much higher 2-methoxyethanol airconcentrations.

There was a dose response between Friday urinaryMAA in mg/g creatinine and weekly mean air 2-methoxyethanol in ppmv for the regular workers (r=0.702)but not for the special operations workers. The regressionequation for the regular workers was log MAA = 0.0893(air 2-methoxyethanol + 1.142. The correlation was less ifcreatinine correction was not done (r=0.601).

The recommended end-of-shift guidance value thatcorresponded to 5 ppmv was 40 mg MAA/g creatinine.On this basis, two regular workers and no specialoperations workers were overexposed. Another criterionadvanced by the authors was 20 mg MAA/g creatininebefore the shift of the next workweek.

Some inadvertent skin contact with glue was notedduring the study when workers were not wearing gloves.The contribution of permeation of 2-methoxyethanolvapor through the skin was not defined.

Reference1. Shih, T.S., S.H. Liou, C.Y. Chen, and J.S. Chou:

Correlation between urinary 2-methoxy acetic acidand exposure of 2-methoxy ethanol. Occup. Environ.Med. 56:674–678 (1999).


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Case Study 11Death by Dimethylmercury Poisoning in a LaboratoryResearcher: The Utility of Hair Analysis toReconstruct Metal Exposures

Researcher and professor, Dr. Karen Wetterhahn, 48,of Dartmouth College, Hanover, New Hampshire, died ofdimethylmercury poisoning On June 8, 1997, 298 daysafter the exposure.(1–4)

She was wearing disposable latex or vinyl medicalexamination gloves when she tried to fill her samplecapillary tube for nuclear magnetic resonance analysis onAugust 14, 1996. She was also wearing a face shield andworked in a fume hood. She spilled a few drops of liquidon the back of her left glove from her pipet. She cleanedup the spill and then removed and disposed of her gloves.

In January 1997, 154 days after exposure, she beganexperiencing difficulty with balance, speech, vision, andhearing. She had also lost 15 lb over the previous 2months. After hospitalization on January 20, she wasdiagnosed with mercury poisoning on January 28,because the blood levels were much higher than thethreshold levels for toxicity (>200 µg/L). On February 6,176 days after exposure, she lapsed into a coma. Hairanalysis (assuming 1.38 cm/month hair lengthening) wasconsistent with just one acute exposure, the maximumhair concentration of 1100 ng/mg (toxic level >50 ng/mg)occurring 54 days postexposure followed by a slowdecline in mercury levels in the appropriate hair 2-mmsegments. At the time of diagnosis, urine mercury was234 µg/L (toxic level, >50 µg/L), and blood mercury was4000 µg/L compared with background levels of 4–5 µg/Land 1–8 µg/L, respectively. The bile contained 30–99 µgHg/L. Aggressive chelation therapy with oral succimerand vitamin E failed to stop the adverse effects, althoughit was initially successful. It was estimated that theoriginal exposure dose was about 1344 mg, equivalent toabout 0.44 mL of dimethyl mercury.

Subsequent tests on the gloves Dr. Wetterhahn waswearing revealed that dimethylmercury permeated thedisposable latex gloves used by her in 15 sec or less. Italso permeated through latex, polyvinyl chloride, butyl,and neoprene gloves almost as quickly as through thedisposable latex gloves. Silver Shield bilaminate gloveswere impervious for at least 4 hours. The compound alsoquickly permeated through the skin.

The Occupational Safety and Health Administration(OSHA) issued three citations with fines totaling $13,500.One citation was for improper training on the limitations ofpersonal protective equipment (PPE) or on how tochoose the appropriate PPE. On September 15, 1997,OSHA reduced the number of citations and penaltiesbecause of the college’s quick response.

OSHA recommended(3) compound substitution;double gloving with Silver Shield gloves, the outer one tobe disposed of appropriately after a single wearing; liquidtransfers by syringe rather than by pipet; working within a

fume hood because of the vapor hazard; training in thetoxicity of the materials handled and on how to protectoneself adequately; and immediate reporting of anycontact, real or suspected, with immediate medicalattention sought.

Once dimethylmercury is absorbed, it is metabolizedto the monomethyl form that can cross the blood-brainbarrier to bond to sulfur-containing amino acids, aprocess that kills nerve cells. Other known fatalities fromexposure to dimethylmercury include(2) two laboratoryworkers in England who originally synthesized thecompound in 1865; two secretaries in Canada whoinhaled vapors from a leaking vial in a warehouse; and achemist working without adequate protection inCzechoslovakia. The lethal dose is about 5 mg/kg bodyweight.

The material safety data sheet for thedimethylmercury used at Dartmouth College read “Wearappropriate chemical-resistant gloves.” This is far toovague for adequate guidance for glove selection. Materialsafety data sheets should provide the specific glove typesknown to be protective.

References1. Death from lab poisoning. Science 276:1797 (1997).2. Nierenberg, D.W., R.E. Nordgren, M.B. Chang, et al.:

Delayed cerebellar disease and death afteraccidental exposure to dimethylmercury. N. Engl. J.Med. 338:1672–1676, 1998.

3. Occupational Safety and Health Administration(OSHA): Hazard Information Bulletins: HazardInformation Bulletin for: Dimethylmercury, March 9,1998. http://www.oshaslc.gov/dts/hib/hib_data/hib19980309.html

4. Lewis, R.: Researchers’ deaths inspire actions toimprove safety. Scientist 11(21):1 (1997).

Case Study 12Exhaled Breath Measurements for Tetra-chloroethylene Exposures in Dry-Cleaning Shops

Tetrachloroethylene (TCE) or perchloroethylene isstill much used for dry-cleaning purposes, even though itis an animal carcinogen. The 2003 American Conferenceof Governmental Industrial Hygienists (ACGIH) 8-hourthreshold limit value/time-weighted average (TLV®-TWA)is 25 ppmv (170 mg/m3). The Occupational Safety andHealth Administration (OSHA) air permissible exposurelimit (PEL) is 100 ppmv, and the National Institute forOccupational Safety and Health (NIOSH) recommendedexposure level (REL) is as low an exposure as possible.The 2003 ACGIH biological exposure indices (BEIs) are5 ppmv tetrachloroethylene in end-exhaled air prior to thelast shift of the workweek; 0.5 mg/L tetrachloroethylene inblood prior to the last shift of the workweek; and 3.5 mg/L


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for total trichloroacetic acid in urine at the end of shift atthe end of the workweek.

About 70% of the dry-cleaning shops in the UnitedStates have one to four workers. In the cramped,confined-space like environments of these shops,exposures to tetrachloroethylene can be quite high,especially if workers put their heads into the washer toretrieve clothes, a situation in which lapel air samplersmight not be representative of air exposure. The aim ofthe study was to assess the effectiveness of inexpensiveengineering controls (refrigerated condenser or a closed-loop carbon adsorber) retrofitted onto existing dry-cleaning machines to reduce exposures during loadingand unloading clothes.(1)

Breathing zone personal air samples using NIOSHMethod 1003 and exhaled breath concentrations usingNIOSH Method 3704 were the parameters chosen formeasurement at three small shops over 3.5 months.Relative to the latter parameter, next morning end-exhaled breath concentrations were compared beforeand after installation of engineering controls and beforeand after opening the dry-cleaning machine door.

The major dry-cleaning machine used was the “dry-to-dry” variant, a single combination washer/dryer thatvents TCE on opening the door. Previous studiesindicated that up to 70% of a worker’s exposure mayoccur on opening the door of the machine.(2)

The breath samples were taken in the followingmanner. Workers were asked to move outside the shop toan area of expected low TCE concentration. Theybreathed normally several times, and then held theirbreath for 10 sec to allow the alveolar air to come intoequilibrium with the blood. The breath was exhaledthrough a tube containing Dry-Rite® desiccant into aTedlar bag. Each bag contained three breath exhalations.Analysis was performed with a calibrated portablePhotovac10S plus Digital Gas Chromatograph with aphotoionization detector of 10.6 eV energy.

Personal breathing zone air samples containedbetween 0.54 and 94 ppmv before the interventions. Novalues exceeded the OSHA PEL, but 44% exceeded theACGIH TLV-TWA. After the interventions only twosamples (25.2 and 26.8 ppmv) exceeded the TLV-TWA.Breath concentrations ranged between 0.18 and 10.7ppmv, with the same number of samples exceeding theACGIH breath BEI. The breath samples were lognormallydistributed, necessitating a log transformation of the datafor statistical comparisons. Thus, although the personalbreathing zone sampling indicated improvement, this wasnot supported by the breath sampling except in someindividual cases. In some cases the breathconcentrations were higher after the intervention.

Study of each shop and worker revealed that workpractices were important in affecting breath sampleconcentrations. For example, truncating the dry cleaningcycle was observed, and having to do maintenance on

inoperative machines. Other significant factors werephysical layout of the shops, leaking of the machines,machine age (the older the machine the more prone theywere to leaks), and the season of the year.

The equivalence of personal breathing sampling atthe lapel with what is breathed in has been a basicassumption of most industrial hygiene air sampling. Thisstudy demonstrated that decrease of air samplingbreathing zone concentrations at the lapel do notnecessarily correlate with exhaled breath concentrationsthat measure actual exposure.

References1. Ewers, L.M., A.M. Ruder, M.R. Peterson, G.S.

Earnest, and L.M. Goldenhar: Effects of retrofitemission controls and work practices onperchloroethylene exposures in small dry-cleaningshops. Appl. Occup. Environ. Hyg. 17:112–120 (2002).

2. Earnest, G.S., A. Beasley Spencer, W.A. Heitbrink, etal. Control of Health and Safety Hazards inCommercial Drycleaners: Chemical Exposures, FireHazards, and Ergonomic Risk Factors (DHHS[NIOSH] Pub. no. 97-150). Cincinnati, Ohio: NationalInstitute for Occupational Safety and Health, 1997.

Case Study 13Breath Analysis for Freon-113 as a Tool for EvaluatingRespirator Performance

For volatile chemicals the analysis of end-exhaledbreath can be used to indicate exposure to the chemical.End-exhaled breath represents the air volume from thelungs that is in contact with the alveoli, where volatilechemicals exchange between air and the blood. Thus, it isthe last volume of air expelled from the lungs and is areliable indicator of the amount of volatile chemicalpresent in the blood stream after a chemical has beenabsorbed.

The National Institute for Occupational Safety andHealth used breath analysis of subjects exposed to Freon-113 as a means of evaluating respirator fit-testmethodologies.(1) Breath analysis was selected becauseother methods to measure the efficacy of respiratorperformance during exposure required sampling inside therespirator, which has inherent biases. In this study,volunteers donned respirators, performed a fit-seal check,and then entered an exposure chamber of 500 ppm Freon-113. While in the chamber for 30 min the subjects performeda series of movements to simulate work performed by healthcare workers. Following the exposure the subjects werequantitatively fit-tested using corn oil aerosol, and then end-exhaled breath analysis was performed 30 min after thesubjects left the exposure chamber.

The end-exhaled breath was collected after havingthe subjects inhale deeply and hold their breath for 10


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sec. The subjects then exhaled as long and as hard aspossible, in the same fashion as is done for spirometrytesting, into a device that captured the end-exhaledbreath for analysis. Analysis of breath collected in the 3-L balloon was performed by either Fourier transforminfrared or gas chromatography equipped with a massselective detector. In practice in the field, breath analysisfor workers can be performed with less sensitive and lessexpensive instrumentation such as detector tubes. Theexposures of interest in the workplace are much greaterthan the low concentrations of Freon-113 used in thisstudy, in which relatively high protection factors wereachieved because subjects wore well-fitted respirators.

The authors concluded that the breath analysismethod allowed them to obtain an unbiased measure ofexposure to Freon-113 for the subjects who performedsimulated work exercises in the exposure chamber. Fromthese results the authors were able to show that the cornoil aerosol quantitative fit-test method provided reliableindicators of actual protection factors that can beachieved by a subject using a respirator. The breathanalysis also provided the authors with a plausibleexplanation for the failure of workplace protection factorsto predict actual protection factors while a respirator is inuse. The authors concluded that the failure to perform aqualitative fit-test after donning a respirator may result inan actual fit factor that is well below the workplaceprotection factors achieved if the respirator is properlyfitted as verified by quantitative fit-testing.

Validation of the end-breath analysis methodologywas performed prior to the respirator study.(2) Thisvalidation determined that skin exposure to a 500 ppmvatmosphere of Freon-113 was minimal (equivalent to 9ppm or less exposure via the lung), and that breathanalysis was not dependent on the need for a constantexposure. In other words breath analysis was a reliableindicator of total dose and not dependent on the rate ofexposure.

The study did indicate that end-breath analysis forFreon-113 exhibited a significant degree of individualvariability for the 11 subjects tested. For the equationY=A(X), where X represents the air exposureconcentration and Y the concentration in end-exhaledbreath, the researchers determined coefficients of A for11 subjects with a mean of 0.014 and a standarddeviation of 0.0047 (range=0.0086 to 0.0256). The datasuggest that individual characterization of air exposuresmay be necessary for the assessment of individualexposure in the workplace. However, the data do notpreclude valid inferences based on mean exposures togroups of workers in the absence of information aboutindividual variability.

References1. Coffey, C., D.L. Campbell, and W.R. Myers:

Comparison of six respirator fit-test methods with anactual measurement of exposure in a simulated

health care environment: Part III—Validation. Am. Ind.Hyg. Assoc. J. 60:363–366 (1999).

2. Coffey, C., D.L. Campbell, W.R. Myers, Z. Zhuang,and S. Das: Comparison of six respirator fit-testmethods with an actual measurement of exposure ina simulated health care environment: Part I—Protocol development. Am. Ind. Hyg. Assoc. J.59:852–861 (1998).

Case Study 14Personal Exposure to JP-8 Jet Fuel at Air ForceBases: Exhaled Breath Analysis Versus BreathingZone Air Sampling Results for a RelativelyNonvolatile Fuel

This study assessed how breathing zone dynamicand grab air sampling of JP-8 jet fuel at 12 U.S. Air Forcebases correlated with exhaled breath concentrations inthe presence of a potentially significant skin andcontaminated clothing exposure.(1)

JP-8 fuel is the most used fuel at military installations(as of 2002) not only for Air Force jets, but also for allmilitary vehicles. It is a complex mixture of aliphatic (28%in the C9-C14 range), alicyclic, and aromatichydrocarbons (about 15% in the C6–C18 range) andsome oxygenated derivatives. The airborne exhaust ispresent both as an aerosol and vapor. Specific markercompounds (including benzene; toluene; ethylbenzene;xylenes; styrene; n-alkanes from C6 to C12; andchlorinated compounds such as chloroform,trichloroethylene, tetrachloroethylene, and p-dichlorobenzene) were analyzed in both the breath andbreathing zone air samples (dynamic and grab samplingmethod using evacuated 1 to 6 L evacuated stainlesssteel Summa™ canisters and calibrated portablesampling pumps). The self-sampled exhaled breathsamples were contained in valved 1-L stainless steelSumma canisters that had been evacuated beforeexhaled breath collection via breathing tubes. Air Forceworkers who were directly exposed and not directlyexposed were sampled. Analyses were in accordancewith a modified Environmental Protection Agency (EPA)Method TO-14 by capillary gas chromatography-massspectrometry using cryogenic concentration and thermaldesorption. Carbon dioxide concentration was alsodetermined, and the normalization factor for the latterwas set at 5%. There were 162 breath samples fromexposed workers and 19 from negative controls. Forambient passive exposures to fuel there were 53 airsamples for those exposed and 44 for negative controls.

All subjects were volunteers with informed consentunder standard Air Force and U.S. EPA protection ofhuman subjects certification procedures withconfidentiality maintained. The subjects were trained inthe breath sampling technique. Respirator tests, heatstress testing, and meteorological measurements were


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also included. Broadly, the cohorts were classified assmokers and nonsmokers, and subclassified as to jobtype. For the latter, these were job-related fuel exposure,ground crew, and no direct exposure.

The highest air exposures were for fuel tankmaintenance inside fuels tanks and around aircraft. Theconfined space type conditions inside fuel tanks led toarithmetic means for C9–C11 of 31–34 ppmv, benzene atabout 3 ppmv, and hexane at about 4.3 ppmv.Chromatograms showed enrichment in the most volatilecomponents of the fuel. Ambient air concentrations weregenerally higher than indoor air concentrations. Smokersalways showed higher mean benzene breathconcentrations than nonsmokers on the same job.

The highest arithmetic means of the breath sampleswere 36 and 41 ppbv for C9 and C10 n-alkanes for all fueltank entry workers and who all wore positive pressurerespirators (control means were 0.12 and 0.16 ppbv,respectively). All workers who were directly exposed tofuel showed higher breath concentrations after their workthan before their work except for benzene in smokers.The tank entry workers showed higher relativeconcentrations of the less volatile components in theirbreath than in the corresponding air samples, and thebreath concentrations did not correlate with thecorresponding breathing zone air concentration. This wasprobably because of dermal exposure, and indicated thatthe positive pressure respirator program was effective.The breath concentrations before work for the indoorworkers were generally higher than after work, indicativeof exposures traveling to work or at home and generallylow indoor exposures of fuel.

Further work on the importance of dermal absorptionand on the workplace protection factors of respiratorswas recommended.

Reference1. Pleil, J.D., L.B. Smith, and S.D. Zelnick: Personal

exposure to JP-8 jet fuel vapors and exhaust at airforce bases. Environ. Health Perspect. 108:183–192(2000).

Case Study 15Air and Biological Monitoring of Solvent ExposureDuring Graffiti Removal

Workers routinely have to remove graffiti, especiallyin large cities. This Stockholm Sweden study(1) sought toidentify the solvents used for graffiti removal and toestimate exposure through personal dynamic airsampling in the breathing zone and blood and urinebiological monitoring.

Thirty-eight workers removed graffiti from subwaystations, elevators, or outside and inside trains at thedepots. Small areas to be cleaned were generally

sprayed and then the surfaces wiped off with a cloth.Large areas were cleaned by applying viscous detergentswith a brush, scrubbing, and then spraying with jets of hotwater. Such spraying caused aerosol exposure thatcontaminated clothes and the skin. Usually the areas tobe cleaned were poorly ventilated, confined-type spaces.A variety of personal protective equipment (PPE) wasworn. A questionnaire was administered to determinepast exposures and PPE used. An unexposed controlgroup of 10 was used for depot workers, and 18 forunexposed subway office workers.

The cleaning solutions contained N-methylpyrrolidone (NMP); propylene glycol monomethylether (PGME); dipropylene glycol monomethyl ether(DPGME); diethylene glycol monoethyl ether (DEGEE);ethylene glycol monobutyl ether; dipropylene glycolmonobutyl ether; aliphatic hydrocarbons (nonane,decane, undecane, hexadecane); gamma-butyrolactone;alicyclic hydrocarbons; aromatic hydrocarbons (toluene,xylenes and ethylbenzene, pseudocumene,hemimellitene, mesitylene); methylene chloride; sodiummetasilicate; organic fatty esters; sodium hypochlorite;sodium hydroxide; Colza oil ester; wax; and formic acid.The most frequently used cleaner contained NMP,DPGME, and PGME. The concentrations found bychemical analyses often disagreed with material safetydata sheet specifications.

XAD-7 tubes allowed dynamic air sampling of NMPand the glycol ethers. Charcoal tubes were used for therest of the organics. At the end of each shift, blood andspot urine samples were collected to determineabsorption of NMP, glycol ethers, and their metabolites.The blood samples were collected by venipuncture inevacuated heparinized tubes. Urines were collected inpolyethylene bottles. The NMP metabolites analyzedwere 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP), N-methylsuccinimide (MSI), 2-hydroxy-N-methylsuccinimide(2-HMSI). NMP readily permeates the skin. The NMPmetabolites were derivatized with bis-trimethylsilyltrifluoroacetamide before capillary gas chromatography-mass spectrometry.

The air concentrations never exceeded 18% of theSwedish permissible exposure limit of the appropriatechemical. Short-term air samples were generally belowthe Swedish short-term exposure limit value, except forpseudocumene and PGME. NMP and its metaboliteswere found in all workers, exposed at work or not. Thearithmetic means and ranges of NMP and its metabolitesfor the exposed group were as follows.• Plasma (µmol/L) for 35 workers: NMP, 2 (not detected:

22.6); 5-HNMP, 1.82 (0.05–6.89); MSI, 0.4 (0.01–1.36);2-HMSI, 0.36 (not detected: 2.84); Sum, 4.58(0.12–27.4).

• Urine (mmol/mol creatinine) for 36 workers: NMP, 0.059(not detectable: 0.22); 5-HNMP, 3.31 (0.03–18.3); MSI,0.04 (not detectable: 0.15); 2-HMSI, 2.19 (0.05–8.89);Sum, 5.59 (0.12–27.4).


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For the exposed workers, the summedconcentrations of NMP and its metabolites correlated to8-hour time-weighted averages (TWAs). The negativecontrol background for the summed concentrations hadan arithmetic mean and range of 0.17 and 0.09–0.31µmol/L for plasma, and 0.54 and 0.08–3.53 mmol/molcreatinine for urine, mostly from 5-HNMP and 2-HMSIwith NMP undetectable in “unexposed” negative controls.

For sum of the plasma NMP and metabolites inmicromols per liter (SumP) and NMP air TWAs inmilligrams per cubic meter (NMP):

SumP = 0.88 NMP + 3.9

For sum of the urine NMP and metabolites inmillimols per mol of creatinine (SumU) and NMP personalbreathing zone air concentrations in milligrams per cubicmeter (NMP):

SumU = 1.00 NMP + 4.7

PPE use varied: 87% used gloves (only three usedbutyl gloves, considered the most chemically resistantones, with many wearing cloth or leather gloves that willabsorb solvents); 42% used protective garments; and42% wore respirators. Over 50% of the workers reportedsplashes on hands, face, and body. Workers who worePPE had lower absorbed NMP and 2-ethoxyethanol thanthose who did not wear PPE, even though the airexposure was about the same. This varied, however, fromindividual to individual and depended on the type of PPE.

No glycol ethers were detected in the urine samples,but acid metabolites were detected in both exposed andunexposed workers. Graffiti workers showed five timesthe depot control mean for urinary 2-ethoxyacetic acid,and only about twice that for the office controls. Only twoexposed workers were above 3 µmol/L, because onlysome were exposed to DEGEE at 1–17 mg/m3 for a fewminutes.

Dermal exposure was estimated by counting dropletson the skin, and by wet porous clothing area. There wasno correlation between air NMP and urinary NMP plusmetabolites for workers who wore respirators, eventhough most still showed the presence of absorbed NMP,and this was ascribed to dermal absorption.

Reference1. Anundi, H., S. Langworth, G. Johanson, et al.: Air and

biological monitoring of solvent exposure duringgraffiti removal. Int. Arch. Occup. Environ. Health73:561–569 (2000).

Case Study 16Biological Monitoring and Air Sampling for Thoriumfor Mineral Sands Workers: Biological Monitoring andRadioactive Elements

Defining the relationships between airconcentrations, blood serum concentrations, and urineconcentrations of thorium in mineral sands workers inWestern Australia were the major objectives of thestudy.(1)

The mineral monazite contains 5-7% thorium (Th; 220Rn)and 0.1–0.3% uranium (U), mostly as phosphates, withother rare earth metals (Ce, La, Nd, Y). The predominantexposure route was thought to be through inhalation ofalpha activity associated with airborne dust.(2) Monazite(0.2–2%) was associated also with the minerals ilmenite(FeO.TiO2; 70 ilmenite 80%), rutile (TiO2; 5–10%), andzircon (ZrSiO4; 10–20%). Because monazite is softer andfiner than its other associated minerals, it may becomepreferentially concentrated in air samples relative to itsassociated minerals. It was estimated that some workersapproached or exceeded the then-standard of 50mSv/year. Most of the Th resided in small crystals ofcheralite, monazite, and zircon, with the most inert formbeing in monazite. It was assumed that six alpha particleswere associated with the decay chain of 232Th, and thatthe mass median aerodynamic diameter of the aerosolwas 10 mm. In addition, because thorium has longeffective half-times in the body, the activity excreted isthought to reflect the long-term accumulation of theradionuclide in the body.

All thorium measurements were performed based onradiochemical separation following neutron activationanalysis. Aerosol sampling was performed on 34 workerswhose employment period ranged from 367–7387 days(geometric mean, 1383 days). A sample of 25 mL blood(no anticoagulant in Vacutainer®) was collected beforeand after shifts. A volume of 10 mL of serum wascollected after clotting and centrifugation. Each serumsample was lyophilized before neutron irradiation. Avolume of 1 L of urine was taken at home to collect >12hours of urine voids the day preceding the bloodsampling, and after the work shift. The urine sample wasshipped with dry ice. In the laboratory, thawed urinesamples were scavenged with calcium phosphate andthe thorium coprecipitated with calcium oxalate beforeneutron activation.

Committed effective dose equivalents of the workerswere estimated to range from 12–400 mSv/year(geometric mean, 65 mSv/year). The daily intake of eachworker was estimated by dividing by 6 and by theemployment time period. The mean daily intakes rangedfrom 0.15–1.4 Bq/day (geometric mean, 0.43 Bq/day).The measured urine concentrations varied from 3–210ng/L (geometric mean, 31 ng/L; n=34), whereas serumthorium ranged from 170–2000 ng/L (geometric mean,480 ng/L; n=25). No correlation was found between air


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measurements and serum and urine concentrations.There was no correlation between urine concentrationand employment period. The geometric mean ratio ofdaily excretion of thorium in the urine to total thorium inthe serum was 2.5%, much lower than the value of 10%proposed by the International Commission onRadiological Protection. For individual workers the ratiovaried between 0.3 and 25%.

Thorium concentrations in the urine of unexposedpersons ranged between <1 to 20 ng/L (geometric mean,5 .0 ng/L; n=5). Similarly, thorium concentrations in theserum of unexposed persons ranged between 200–480ng/L (geometric mean, 320 ng/L; n=7).

Serum measurements appear to be less variablethan urine measurements, probably because of the extrasteps involved in the analytical method, the lowerconcentration of thorium, and variability of fluid intake andperspiring of the workers.

In a plant where mandatory half-mask respiratorprotection was in force, the workplace protection factors(WPF) were above 3.5.(2) Where respirator usage wasintermittent, WPFs above 2 occurred. Both dust andradiological WPFs were compared, and the WPF forradiological protection (WPF 2.5–21) were always higherthan for dust protection (WPF 1.8–13). Such WPFs werenot factored into the data analysis as previouslydescribed.

This same research group has published on thoriumconcentrations in feces(3) and breath.(4,5) In the fecesstudy using inductively coupled-mass spectrometrymeasurements, the thorium content of feces correlatedwith air sampling of two workers. In the breath studies, athoron exhalation rate of 4.7% was obtained,(4) comparedwith 3.7±1.2% from the other study.(5)

A study on the relationship between airconcentration, hand coverage, and urinary concentrationof uranium is also available.(6)

References1. Hewson, G.S., and J.J. Fardy: Thorium metabolism

and bioassay of mineral sand workers. Health Phys.64:147–156 (1993).

2. Hewson, G.S., and M.I. Ralph: Determination ofprogram protection factors for half- mask respiratorsused at a mineral sands separation plant. Am. Ind.Hyg. Assoc. J. 53:713–720 (1992).

3. Terry, K.W., G.S. Hewson, and G. Meunier: Thoriumexcretion in feces by mineral sands workers. HealthPhys. 68:105–109 (1995).

4. Terry, K.W., and G.S. Hewson: Thorium lung burdensof mineral sands workers. Health Phys. 69:233–242(1995).

5. Terry, K.W., G.S. Hewson, and P.A. Burns: Furtherthorium lung burden data on mineral sands workers.Rad. Protect. Dosim. 71:297–304 (1997).

6. Yu, R.C. and R.J. Sherwood: The relationshipsbetween urinary elimination, airborne concentration,and radioactive hand contamination for workersexposed to uranium. Am. Ind. Hyg. Assoc. J.57:615–620 (1996).

Case Study 17Organocarbamate Pesticide Exposure Assessment:Carbaryl Exposure to Farmer Applicators and TheirFamilies

This study investigated the exposure of the pesticidecarbaryl to 6 farmer applicators and their families.(1) Themethodologies involved would also be applicable to farmworkers and pesticide sprayers and take-homeexposures.

Carbaryl is an organocarbamate insecticide thatcauses “reversible” cholinesterase inhibition at highdoses but also quickly metabolizes to 1-naphtholexcreted in the urine as a glucuronide and sulfate.

During the application season four biological samples(24-hour urine and blood) were collected from eachparticipant and two personal breathing zone air, dermal,and hand-wipe samples were collected from the farmerapplicator, all with informed consent. One biologicalsample was collected on the day prior to pesticideapplication and another on the day of pesticideapplication. Another sample was taken on each of the twofollowing days also. One hand-wipe sample (detectionlimit 1.7 ng/sample) was taken from each family memberand one household indoor air sample (detection limit 0.7 ng/m3) was taken on the day of application. Theapplicator wore a portable air sampler and an a-cellulosedermal patch (detection limit of 14 ng/sample) during theentire sampling period. Hand-wipe samples werecollected with cotton swabs and isopropanol (rubbingalcohol). Carbaryl was analyzed in isopropanol solutionby gas chromatography-mass spectrometry (GC-MS).Urine sample (10 mL) 1-naphthol was analyzed byderivatization and then GC-MS (detection limit 1.2ng/mL). Serum sample analysis involved proteindenaturation and solid phase extraction before GC-MSanalysis (detection limit, 19 ng/L).

One farmer applicator actively sprayed carbarylduring the study. For this applicator the baseline valuesfor carbaryl were as follows: personal air, 8–16 ng/m3;dermal patch, 1.4–10 ng/cm2; hand-wipe, 9–20µg/sample; urinary total 1-naphthol, 270 µg/g creatinineor 860 µg/L; serum 1-naphthol, 0.26 µg/L. On applicationday these values were personal air, 640,000 ng/m3;dermal patch, 11 µg/cm2; hand-wipe, 20,100 µg/sample;urinary 1-naphthol morning, 140 µg/g creatinine or 500µg/L; urinary naphthol evening, 9,300 µg/g creatinine or22,000 µg/L; serum 1-naphthol, 510 µg/L; and serumcarbaryl, 120 ng/L.


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Urinary 1-naphthol on postapplication day 1 was7100 µg/g creatinine or 12,000 µg/L and onpostapplication day 2 was 1500 µg/g creatinine or 2600µg/L. Serum 1-naphthol on postapplication day 1 was 1.9µg/L and on postapplication day 2 was 0.56 µg/L. Familymembers showed no urinary 1-naphthol levels abovebackground.

The one exposed applicator showed higherparameters on application day than on the preapplicationday. However, the high preapplication day urinarynaphthol is suggestive of holdover exposure fromprevious exposure days. Although urinary 1-naphthol offamily members (spouse and two children) doubled onthe day of exposure, the values were still within thereference range of the U.S. population. Home indoor airand house dust showed no detectable carbaryl.

Although the serum and urine concentrations of 1-naphthol correlated, so did hand-wipe carbaryl andurinary 1-naphthol. There was no correlation betweenurinary 1-naphthol and 2-naphthol, to be expected ifsmoking was a significant source of 1-naphthol, but thiscorrelation was positive for unexposed control populationmembers. The correlation between personal breathingzone carbaryl and urinary 1-naphthol was not reported.

Reference1. Shealy, D.B., J.R. Barr, D.L. Ashley, D.G. Patterson

Jr., D.E. Camann, and A.E. Bond: Correlation ofenvironmental carbaryl measurements with serumand urinary 1-naphthol measurements in a farmerapplicator and his family. Environ. Health Perspect.105:510–513 (1997).

Case Study 18Organophosphate Intoxication of a Worker in aPlastic Bottle Recycling Plant: Unexpected EventsCan Lead to Health Problems

A 24-year-old Taiwanese man was sent to a medicalclinic because he had suffered from vomiting, coldsweating, dizziness, and poor appetite for 2 days.(1)

A physical examination revealed a heart rate of 100beats/min and a respiratory rate of 20/min. The skin wasmoist and flushed, and the eye pupils were normal insize. A panel of clinical tests showed reference rangecomplete blood cell count, liver and kidney tests, andelectrolytes.

An interview established that the man suffered fromno allergies or systemic diseases, and his family had noremarkable diseases. He had been working in a plasticbottle-recycling factory for 6 years, his first and only job.He collected the used bottles, transported them to thefactory, and washed the bottles in an automatic washingmachine. The bottles were then conveyed to a grindingmachine that crushed them into small pieces. These

chips were then sent to other companies to make plasticutensils. Plastic pesticide bottles were processed everyTuesday, Wednesday, and Thursday. He and his sixcoworkers had periodic health examinations that showedno remarkable data.

He remembered that his symptoms first appeared ona rainy afternoon when he was handling pesticide bottles,and that the left sole of his shoe had been damaged andhis foot had been wet all day from the rainwater on thefactory floor. His sock remained wet throughout. Thisimplied that dermal exposure through the foot in thedamaged shoe might have occurred. The fact that none ofthe other workers showed symptoms ruled out inhalationas the major exposure route for the workers, becausethey all performed similar jobs in the same work area. Theplasma acetylcholinesterase level was found to be 1498.6µU/L on day 1 of examination and 1379.7 µU/L on day 2(reference range: 2000–5000 µU/L). On treatment withatropine, the man’s symptoms disappeared 3 days later.After 2 more days the acetylcholinesterase level was2309.8 µU/L. This implied that the worker had at least65% of baseline activity on the first measurement and60% on day 2. The threshold adverse activity is 70% ofbaseline.

Personnel from the clinic did a walkthrough of thefactory on a rainy day after the worker recovered.Because the floor was not level, water had pooled aroundthe machines and in low areas. Blood samples werecollected before and after the work shift. There were nodifferences in acetylcholinesterase activity for eachworker.

In successful suicide cases with organophosphatepesticides the plasma acetylcholinesterase activity isgenerally <1000 µU/L, with the occurrence of pinpointeyes, and hypernervousness.

The employer was advised to supply the workers withgloves and waterproof shoes. Training in the occupationalhazards of their work was also recommended. The latterwas to include pesticide toxicity, adverse pesticidesymptoms, personal protection, first aid for exposure, andpersonal hygiene (washing hands before eating andsmoking, removing boots and socks in an area away fromthe worksite, and being careful to step on a clean floor).Inclusion of the acetyl cholinesterase test in the periodicmedical examination was recommended.

Reference1. Wang, C.L., H.Y. Chuang, C.Y. Chang, et al.: An

unusual case of organophosphate intoxication of aworker in a plastic bottle recycling plant: An importantreminder. Environ. Health Perspect. 108:1103–1105(2000).


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Case Study 19Methylene Chloride, Carbon Monoxide, andCarboxyhemoglobin: The Same Marker but DifferentKinetics

This case study of one 26-year-old cabinet worker(1)

started with a complaint to a physician of persistentheadaches no longer relieved by nonprescription drugs. Aheadache specialist opined that “stress” was the culpritand that “fumes” in the workplace exacerbated thecondition. The patient had a history of occasionalheadaches since adolescence, but these had increasedin intensity for November 1995 to February 1996. Theheadaches were retro-orbital with radiation to the back ofthe head and were associated with sensitivity to brightlights and noise, occasionally with nausea.

The man had worked the previous 6 months as acarpenter in a laminating manufacturing company. Heworked with 10 other cabinet workers in a building 50 ft ×200 ft in size. There was an unenclosed spray booth withsome local exhaust ventilation and with gas-poweredheating fans hanging from ceilings. The doors were keptclosed during winter months to prevent heat loss. Theworker’s job involved lacquer thinner to clean cabinetsurfaces. No personal protective equipment was worn. Heand other workers had noticed drying and cracking of theskin on their hands from touching lacquer thinner. Someof the other workers suffered from headache. He was anonsmoker, drank one beer per week, and denied takingillicit drugs. His medications were amitriptyline anddiphenylhydramine. His mother suffered from migraineheadaches. He sustained a skull fracture at age 8 from abicycle accident, causing residual hearing loss on the leftside. He had suffered a motor vehicle accident 18 monthsbefore, but this did not cause increase in headaches afterthe accident.

He brought along the material safety data sheets fortwo materials he often used: a clear, noninflammablespray contact cement (containing 70% methylenechloride, toluene, and methyl ethyl ketone), and a lacquerthinner (containing toluene, isopropyl alcohol, ethylacetate, isobutyl alcohol, and isobutyl acetate). Heshowed normal physical parameters but thickened handskin with fissures and cracking. Initial laboratory workrevealed a normal complete blood count, normal liverfunction tests, and a blood carboxyhemoglobin content of2.8% (normal is <3% for nonsmokers).

The patient was instructed to have hiscarboxyhemoglobin analyzed by his primary carephysician just after a work shift, particularly if he hadheadache. On the next workday he had a mild headache,even though the doors of the workplace were open, anda carboxyhemoglobin content of 6.4%. Four days laterwhen the doors were closed, he had a violent headacheand experienced nausea and vomiting. He had acarboxyhemoglobin content of 21% approximately 35 minafter leaving work early. He received normobaric oxygen

therapy, and carboxyhemoglobin content reverted alongwith the headaches. Grab air samples revealedmethylene chloride at concentrations of 300–500 ppmvand carbon monoxide concentrations of 28 ppmv. Thecompany immediately substituted a water-based processinstead of using methylene chloride. A secondexamination 8 days later, after the new process wasinitiated, showed low concentrations of solvent vaporsand a peak carbon monoxide concentration of 8 ppmv,this appearing to come mostly from a propane-poweredfork lift inside the plant and the gas-powered heating fans.

A number of fatalities caused by methylene chloridehave been reported, most associated with paint orfurniture stripping and/or in enclosed spaces.Unconsciousness has been reported atcarboxyhemoglobin levels as low as 5%.

Because carboxyhemoglobin formed from methylenechloride vapor (elimination half-time is about 13 hours) orother nonfluorinated halogenated methanes occurs moreslowly than from carbon monoxide exposure (eliminationhalf-time is about 4 hours), the most acute threat is fromcarbon monoxide. Skin-absorbed methylene chloride hasa longer body half-time except when the skin is crackedand fissured, as was the case here. Thus, prolongedtreatment with normobaric oxygen may be necessary forsolvent-related high exposures. There appears to be highinterindividual variation in susceptibility to the sameabsorbed dose of methylene chloride.

The International Agency for Research on Cancerconsiders methylene chloride to be a possible humancarcinogen, whereas the U.S. Environmental ProtectionAgency classifies it as a probable human carcinogen. TheOccupational Safety and Health Administration (OSHA)permissible exposure limit (PEL) is now 25 ppmv, with anOSHA PEL carboxyhemoglobin level of 2.3% (at the timethe values were 500 ppmv and >12% carboxyhemo-globin). The American Conference of GovernmentalIndustrial Hygienists (ACGIH) threshold limit value(TLV®)/time-weighted average (TWA) was then 50 ppmv,with a recommended carboxyhemoglobin biologicalexposure index (BEI) of 3.5%. The 2003 intended BEI isend-of-shift dichloromethane in urine at 0.4 mg/Lcorresponding to a TLV of 50 ppmv. The National Institutefor Occupational Safety and Health (NIOSH)recommends the lowest feasible air exposure.

The OSHA PEL for carbon monoxide is 50 ppmv, witha recommended carboxyhemoglobin content of 7%. TheACGIH TLV-TWA was 25 ppmv, with a recommendedcarboxyhemoglobin BEI of 3.5%. NIOSH has arecommended exposure limit of 35 ppmv, with arecommended carboxyhemoglobin content of 5%.

A NIOSH study for the correlation of personalbreathing zone concentrations to bloodcarboxyhemoglobin, blood methylene chloride, andalveolar air methylene chloride is also available.(2)


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References1. Mahmud, M., and S.N. Kales: Methylene chloride

poisoning in a cabinet worker. Environ. HealthPerspect. 107:769–772 (1999).

2. McCammon Jr, C.S., R.A. Glaser, V.E. Wells, F.C.Phipps, and W.E. Halperin: Exposure of workersengaged in furniture stripping to methylene chlorideas determined by environmental and biologicalmonitoring. Appl. Occup. Environ. Hyg. 6:371–379(1991).

Case Study 20Aplastic Anemia in a Petrochemical Factory Worker

A 45-year-old petrochemical worker in Korea withaplastic anemia (the stage before leukemia) was referredto the Department of Industrial Medicine of the CatholicUniversity of Korea in November 1998 to determine whathad caused the disease.(1) He worked in a petroleumresin-producing factory that used heavy raw pyrolysisgasoline containing 0.3% benzene. These resins wereused primarily in the production of paints and adhesives.

In 1977 he began working in an indoor packaging-process area where he packed powder resin into 80-kgbags. In May 1993 he moved to an outdoor deactivation-process area where he poured lime into a deactivationtank twice a day, 40 kg each time, and drained the tankafter the chemical reaction. This comprised <30 min/workday, and the rest of the time was spent in a control room.Other than doing routine work in the packaging anddeactivation processes, he occasionally cleaned thereaction tank. While working he wore a facial mask.

In September 1998 he complained of fatigue andlethargy. A visit to a physician showed possiblepancytopenia (<500 neutrophils/mm3; <20,000platelets/mm3) in the complete blood count test. A bonemarrow biopsy then showed hypocellularity with fattyinfiltration, confirming aplastic anemia. There were nochromosomal aberrations. He did not smoke or drinkalcohol. No drug or radiation exposures were evident.There were no abnormal complete blood counts beforethe onset of symptoms.

Because there was no matching compatible bonemarrow donor, he was given blood transfusions,antilymphocyte immunoglobulins, and cyclosporin, andsymptoms disappeared, discharged in December 1998.In January 1999 he was readmitted and treated foropportunistic herpes zoster infection (shingles).

Industrial hygienists performed routine environmentalsurveillance of the factory twice each year from 1993 to1998. The air benzene was generally about 0.28 ppmv.

The authors then performed an environmental surveyof the factory after the patient was referred, andmeasured trans, trans-muconic acid in the urine ofworkers to assess exposure. Air benzene concentrationswere higher for workers in the deactivation process(0.07–0.40 ppmv) than in the packing process (<0.04ppmv), but urinary trans, trans-muconic acidconcentrations were higher in packaging workers(0.03–0.18 mg/L) relative to the deactivation processworkers (0.03–0.08 mg/L). This could imply that otherexposure routes such as skin exposure may haveoccurred. Area sampling in the drainage tank arearevealed air concentrations of benzene between 0.19 to0.26 ppmv, and 0.02 ppmv in the packaging process inNovember 1998.

It is known that for >100 ppmv benzene inhaled, theincidence of aplastic anemia in workers is about 1/100.Between 10-20 ppmv, the incidence is 1/10,000.(2) Thus,the worker must either have been exposed to high airbenzene concentrations in the past, or a high exposureskin contact might also have been a possibility.

References1. Baak, Y.M., B.Y. Ahn, H.S. Chang, J.H. Kim, K.A. Kim,

and Y. Lim: Aplastic anemia in a petrochemical factoryworker. Environ. Health Perspect. 107:851–853(1999).

2. Smith, M.T.: Overview of benzene-induced aplasticanemia. Eur. J. Haematol. 57:107–110 (1996).


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Further Reading: Ethical Issues (Section 8.2)

• Schulte, A. Biomarkers in epidemiology:Scientific issues and ethical implications.Environ. Health Perspect. 98:143–147 (1992).

Some Key General References• Baselt, R.C. Biological Monitoring Methods for

Industrial Chemicals, 2nd ed. Littleton, Mass.:PSG Publishing, 1988.

• Carson, B.L., H.V. Ellis IV, and J.L. McCann.Toxicology and Biological Monitoring of Metalsin Humans. Boca Raton, Fla.: LewisPublishers, 1987.

• Clarkson, T.W., L. Friberg, G.F. Nordberg, andR.R. Sager. Biological Monitoring of ToxicMetal. New York: Plenum Press, 1988.

• Ho, M.H., and H.K. Dillon (eds.). BiologicalMonitoring of Exposure to Chemicals: OrganicCompounds. New York: John Wiley & Sons,1987.

• Ho, M.H., and H.K. Dillon (eds.). BiologicalMonitoring of Exposure to Chemicals: Metals.New York: John Wiley & Sons, 1991.

• Kneip, T.J., and J.V. Crable (eds.). Methods forBiological Monitoring. New York: John Wiley &Sons, 1988.

• Lauwerys, R.R., and P. Hoet. IndustrialChemical Exposure Guidelines for BiologicalMonitoring. Boca Raton, Fla.: LewisPublishers/CRC Press, 1993.

• Que Hee, S.S. (ed.). Biological Monitoring: AnIntroduction. New York: Van Nostrand Reinhold,1993. A bibliography of books and reviews(summaries) on biological monitoring and onspecific chemicals and techniques before 1990is available in Appendix C.

• Ryan, R.P., and T.F. Shults. The OccupationalDesk Reference (ODR). New York: QuadrangleResearch, LCC, 1993.

• Sheldon, L., M. Urama, J. Bursey, et al.Biological Monitoring Techniques for HumanExposure to Industrial Chemicals: Analysis ofHuman Fat, Skin, Nails, Blood, Urine, andBreath. Park Ridge, N.J.: Noyes Publications,1986.

Research Reviews and Books Since 1989Some major research reviews and books since 1989follow. Unless specified otherwise, all references arewritten in English and are reviews. Books are listed atthe beginning for each year. The list allows the readerto gauge what was “hot” for each year, to assess thegrowth of the field, and to locate the most up-to-dateperspectives quickly.

2002• Mutti, A. (ed.). Biomarker Research in

Occupational and Environmental Toxicology.Shannon, Ireland: Elsevier, 2002. Proceedingsof the Fifth International Symposium onBiological Monitoring, September 19–21, 2001,Banff, Alberta, Canada.

• Priezzhev, A.V. (ed.). Optical Diagnostics andSensing of Biological Fluids and Glucose andCholesterol Monitoring II. Bellingham, Wash.:SPI, 2002. Proceedings of SPIE, theInternational Society for Optical Engineering,held January 23–24, 2002, San Jose, Calif.

• Trull, A.K., L.M. Demers, D.W. Holt, et al. (eds.).Biomarkers of Disease: An Evidence-BasedApproach. Cambridge, UK: CambridgeUniversity Press, 2002.

• Wilson, S.H., and W.A. Suk (eds.). Biomarkersof Environmentally Associated Disease. BocaRaton, Fla.: Lewis Publishers, 2002.

• Cerna, M., and A. Pastorkova. Bacterial urinarymutagenicity test for monitoring of exposure togenotoxic compounds: A review. Cent. Euro. J.Public Health 10:124–129 (2002).

• Cocker, J., H.J. Mason, S.J. Garfitt, and K.Jones. Biological monitoring of exposure toorganophosphate pesticides. Toxicol. Lett.134:97–103 (2002).

• Viau, C. Biological monitoring of exposure tomixtures. Toxicol. Lett. 134:9–16 (2002).

• Amacher, D.E. A toxicologist’s guide tobiomarkers of hepatic response. Human Exp.Toxicol. 21:253–262 (2002).

• Sato, H., and Y. Aoki. Mutagenesis byenvironmental pollutants and biomonitoring ofenvironmental mutagens. Curr. Drug Metabol.3:311–319 (2002).


Appendix III:Bibliography of Some Key Works in the Field, 1990–2002

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• Aprea, C., C. Colosio, T. Mammone, and C.Minoia, M Maroni. Biological monitoring ofpesticide exposure: A review of analyticalmethods. J. Chromatogr. B 769:191–219 (2002).

2001• Manno, M. (ed.). Bioactivation and

Biomonitoring of Volatile Organic Chemicals.Shannon, Ireland: Elsevier Science Ireland Ltd,2001. Proceedings of the project “Liver EnzymeInduction and Inhibition as a Biological Markerof Occupational Exposure to VolatileAnesthetics and Other Volatile Chemicals.”

• Crews, H.M., A.B. Hanley, H. Verhagen, and C.Wild (eds.). Biomarkers of Exposure and Effectin Relation to Quality of Life and Human RiskAssessment (European Union “ConcertedAction” ERB-FAIR CT 961176). Wallingford,UK: CABI Publishers, 2001.

• Honer, A. Polycyclic aromatic hydrocarbon(PAH) metabolites. In Handbook of AnalyticalSeparations 3(Environmental Analysis):99–121, 2001.

• Majer, B.J., B. Laky, S. Knasmuller, and F.Kassie. Use of the micronucleus assay withexfoliated epithelial cells as a biomarker formonitoring individuals at elevated risk ofgenetic damage and in chemoprevention trials.Mutation Res. 489(2–3):147–172 (2001).

• Schaller, K.H., J. Angerer, D. Weltle, and H.Drexler. External quality assurance program forbiological monitoring in occupational andenvironmental medicine. Rev. Environ. Health16:223–232 (2001).

• Aprea, C., G. Sciarra, L. Lunghini, and N. Bozzi.Biological monitoring of pesticide exposure:occupationally exposed workers and generalpopulation. Annali dell’Istituto Superiore diSanita 37:159–174 (2001).

• Moretto, A., and M. Lotti. Monitoringoccupational exposures to organophosphoruscompounds. In L. Karalliedde, editor,Organophosphates and Health, pp. 407–429.London: Imperial College Press, 2001.

• Gil, F., and A. Pla. Biomarkers as biologicalindicators of xenobiotic exposure. J. Appl.Toxicol. 21:245–255 (2001).

• Thier, R., and H.M. Bolt. European aspects ofstandard setting in occupational hygiene andmedicine. Rev. Environ. Health 16:81–86 (2001).

• Au, W.W., B. Oberheitmann, M.Y. Heo, W.Hoffmann, and H.Y. Oh. Biomarker monitoringfor health risk based on sensitivity toenvironmental mutagens. Rev. Environ. Health16:41–64 (2001).

2000• Diplock, A.T., and B. Nielsen (eds.). Markers of

Oxidative Damage and Antioxidant Protection:Relation to Health and Well-Being. Amsterdam:Harwood, 2000. Proceedings of the ILSIEurope Workshop, May 28-30, 1999, Prague,Czech Republic.

• Maroni, M., C. Colosio, A. Ferioli, and A. Fait(eds.). Special Issue on Biological Monitoringof Pesticide Exposure: A Review. Shannon,Ireland: Elsevier, 2000.

• Angerer, J. Possibilities and limits of humanbiomonitoring. Umwelthygiene:Standortbestimmung und Wege in die Zukunft106:42–48 (2000). Review in German.

• Heinrich-Ramm, R., M. Jakubowski, B.Heinzow, J.M. Christensen, E. Olsen, and O.Hertel. Biological monitoring for exposure tovolatile organic compounds (VOCs). Pure Appl.Chem. 72:385–436 (2000).

• Fiserova-Bergerova, V., and J. Mraz. Biologicalmonitoring of exposure to industrial chemicals.In R.L. Harris, editor, Patty’s Industrial Hygiene,5th ed., vol. 3, pp. 2001–2060. New York: JohnWiley & Sons, 2000.

• Carter, S., M.S. Morgan, S. Que Hee, and T.Buckley. Biological monitoring. In MK Harris,editor, Essential Resources for IndustrialHygiene: A Compendium of Current PracticeStandards and Guidelines, pp. 131–139.Fairfax, Va.: American Industrial HygieneAssociation, 2000.

• Que Hee, S.S., and M.F. Boeniger. Dermalchemical hazards. In MK Harris, editor,Essential Resources for Industrial Hygiene: ACompendium of Current Practice Standardsand Guidelines, pp. 141–154. Fairfax, Va.:American Industrial Hygiene Association,2000.

• Determination of parent and progenycompounds in exhaled breath. In R.A. Meyers,editor, Encyclopedia of Analytical Chemistry,pp. 4718–4733. Chichester, Sussex, UK: JohnWiley & Sons, 2000.

1999• Baan, R.A., and K. Szyfter (eds.). Biomarkers

in Monitoring of Occupational andEnvironmental Exposure to Organic GenotoxicSubstances. Amsterdam: Elsevier, 1999.Proceedings of a Workshop, held October 23-27, 1997, in Ustron, Poland.

• Mutti, A., S.H. Lee, and M. Ikeda (eds.).Biological Monitoring in Occupational andEnvironmental Toxicology. Shannon, Ireland:


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Elsevier, 1999. Proceedings of the 4thInternational Symposium on BiologicalMonitoring, September 23–25, 1998, in Seoul,Korea.

• Baan, R.A., and K. Szyfter (eds.). Biomarkersin Monitoring of Occupational andEnvironmental Exposure to Organic GenotoxicSubstances. Amsterdam: Elsevier, 1999.Proceedings of a workshop, held October 23-27 1997, in Ustron, Poland.

• Buszewski, B., and H. Brygiert. Biologicalmonitoring in industrial toxicology as illustratedby assessment of occupational exposure tostyrene. Chemia i Inzynieria Ekologiczna6:1139–1147 (1999). Review in Polish

• Benford, D.J., J. Cocker, P. Sartorelli, T.Schneider, J. Van Hemmen, and J.G. Firth.Dermal route in systemic exposure. Scand. J.Work Environ. Health 25:511–520 (1999).

• Menditto, A., F. Chiodo, S. Palleschi, B. Rossi,A. Minoprio, and M. Mosca. The role ofbiological monitoring in the assessment ofchemical exposure. Annali dell’IstitutoSuperiore di Sanita 35:145–151 (1999).Review in Italian.

• Colosio, C., E. Corsini, W. Barcellini, and M.Maroni. Immune parameters in biologicalmonitoring of pesticide exposure: Currentknowledge and perspectives. Toxicol. Lett.108:285–295 (1999).

• He, F. Biological monitoring of exposure topesticides: current issues. Toxicol. Lett.108:277–283 (1999).

• Ong, C.N. Reference values and action levelsof biological monitoring in occupationalexposure. Toxicol. Lett. 108:127–135 (1999).

• V.K. Bhatnagar and G. Talaska. Carcinogenexposure and effect biomarkers. Toxicol. Lett.108:107–116 (1999).

• Lison, D. Importance of biotransformationpathways for interpreting biological monitoringof exposure. Toxicol. Lett. 108:91–97 (1999).

• Mutti, A. Biological monitoring in occupationaland environmental toxicology. Toxicol. Lett.108:77–89 (1999).

• Wilson, H.K. Biological monitoring values foroccupational exposure. A United Kingdomperspective. Int. Arch. Occup. Environ. Health72:274–278 (1999).

• Omae, K., T. Takebayashi, and H. Sakurai.Occupational exposure limits based onbiological monitoring. The Japan Society forOccupational Health. Int. Arch. Occup. Environ.Health 72:271–273 (1999).

• Morgan, M.S., and K.H. Schaller. An analysis ofcriteria for biological limit values developed inGermany and in the United States. Int. Arch.Occup. Environ. Health 72:195–204 (1999).

• Roels, H.A., P. Hoet, and D. Lison. Usefulnessof biomarkers of exposure to inorganicmercury, lead, or cadmium in controllingoccupational and environmental risks ofnephrotoxicity. Renal Failure 21:251–262(1999).

• Krieger, R.I. Biomonitoring human pesticideexposures. In D.J. Ecobichon, editor,Occupational Hazards of Pesticide Exposure:Sampling, Monitoring, Measuring, pp. 187–208.Philadelphia: Taylor & Francis, 1999.

• Bouchard, M., and C. Viau. Urinary 1-hydroxypyrene as a biomarker of exposure topolycyclic aromatic hydrocarbons: Biologicalmonitoring strategies and methodology fordetermining biological exposure indices forvarious work environments. Biomarkers4:159–187 (1999).

• Andrzejak, R., W. Kucharski, and J.Mioduszewska. Cytostatic drugs: Occupationalhazard to health care workers. MedycynaPracy 50(1):61–65 (1999). Review in Polish.

• Mason, H., and K. Wilson. Biological monitoring:The role of toxicokinetics and physiologicallybased pharmacokinetic modeling. Am. Ind. Hyg.Assoc. J. 60:237–242 (1999).

• Sessink, P.J.M., and R.P. Bos. Drugshazardous to healthcare workers: Evaluation ofmethods for monitoring occupational exposureto cytostatic drugs. Drug Safety 20:347–359(1999).

• Marczynski, B., V. Van Kampen, and X. Baur.Exposure determination and biologicalmonitoring of diisocyanates and theirmetabolites. A literature review. Zentralblattfuer Arbeitsmedizin, Arbeitsschutz undErgonomie 49:2–8 (1999). Review in German.

• Barr, D.B., J.R. Barr, W.J. Driskell, et al.Strategies for biological monitoring of exposurefor contemporary-use pesticides. Toxicol. Ind.Health 15:168–179 (1999).

1998• Mendelsohn, M.L., L.C. Mohr, and J.P. Peeters

(eds.). Biomarkers: Medical and WorkplaceApplications. Washington, D.C.: Joseph HenryPress, 1998.

• Neumann, D.A., and C.A. Kimmel (eds.).Human Variability in Response to ChemicalExposure. Boca Raton, Fla.: CRC Press, 1998.


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• Greim, H., and G. Lehnert (eds.). BiologicalExposure Values for Occupational Toxicantsand Carcinogens: Critical Data Evaluation forBAT and EKA Values, vol. 3. New York: JohnWiley & Sons, 1998.

• Perbellini, L., and S. Ghittori. Biologicalmonitoring of occupational exposure tosolvents using their urinary concentration.Medicina del Lavoro 89:375–386 (1998).Review in Italian.

• Brondeau, M.T. Novel developments inbiological monitoring. Cahiers de NotesDocumentaires 170:107–109 (1998). Review inFrench.

• Lof, A., and G. Johanson. Toxicokinetics oforganic solvents: A review of modifying factors.Crit. Rev. Toxicol. 28:571–650 (1998).

• Hoet, P., and R. Lauwerys. Biologicalmonitoring of occupational neurotoxicants. InL.G. Costa and L. Manzo, editors, OccupationalNeurotoxicology, pp. 49–74. Boca Raton, Fla.:CRC, 1998.

• Dock, L. Human exposure monitoring andbioavailability issues. In Contaminated Soil ‘98.London: Telford, 1998. Proceedings of the 6thInternational FZK/TNO Conference onContaminated Soil, Edinburgh, Scotland, May17–21, 1998.

• Van Delft, J.H.M., R.A. Baan, and L. Roza.Biological effect markers for exposure tocarcinogenic compound and their relevance forrisk assessment. Crit. Rev. Toxicol. 28:477–510(1998).

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MetalsMetal Specimen Units Geometric 95% Conf.

Mean Interval

Antimony urine µg/L 0.1 0.09–0.12Barium urine µg/L 1.6 1.5–1.7

µg/g creatinine 1.5 1.3–1.6Cadmium blood µg/L 0.3 0.2–0.3A

urine µg/L 0.32 0.3–0.33Cesium urine µg/L 4.7 4.2–5.2

µg/g creatinine 4.3 3.8–4.7Cobalt urine µg/L 0.36 0.32–0.40

µg/g creatinine 0.33 0.29–0.36Lead blood µg/L 1.6 1.4–1.8B

urine µg/L 0.8 0.68–0.91C

Mercury blood µg/L 1.2 0.9–1.6D

Molybdenum urine µg/L 48.4 43.6–53.2µg/g creatinine 43.9 40.6–47.2

Thallium urine µg/L 0.19 0.17–0.20µg/g creatinine 0.17 0.16–0.18

Tungsten urine µg/L 0.10 0.09–0.12Uranium urine µg/L 0.008 0.006–0.011

Organophosphate Pesticides—MetabolitesDimethyl phosphate urine µg/L 1.84 1.10–2.59 Diethyl phosphate urine µg/L 2.55 1.33–3.78

µg/g creatinine 2.24 1.11–3.37Dimethylthio phosphate urine µg/L 2.61 1.77–3.45Diethylthio phosphate urine µg/L 0.81 0.69–0.94

µg/g creatinine 0.71 0.56–0.87Dimethyldithio phosphate urine µg/L 0.51 0.39–0.62Diethyldithio phosphate urine µg/L 0.19 0.14–0.23

µg/g creatinine 0.16 0.12–0.21

Phthalate Ester—MetabolitesMono-benzyl phthalate urine µg/L 17.4 14.1–20.7

µg/g creatinine 15.0 12.8–17.2Mono-butyl phthalate urine µg/L 26.7 23.9–29.4

µg/g creatinine 23.0 20.9–25.0Mono-ethyl phthalate urine µg/L 176.0 132–220

µg/g creatinine 151.5 121–182Mono-2-ethylhexyl phthalate urine µg/L 3.5 3.0–4.0

ACadmium in blood data is not the geometric mean, but the 50th percentile(median).BFrom people aged 1 year and olderCFrom urine in a subset of people 6 years and olderDFemales, 16–49 years

Source: National Report on Human Exposure to Environmental Chemicals,Centers for Disease Control and Prevention, March 2001


Appendix IV:Background Concentrations for Biological

Monitoring of Environmental ChemicalsA

This table lists the levels of 21 environmental chemicals(or their metabolites) measured in the blood and/or urineof a representative sample of the U.S. population. Thesedata are taken from the National Report on HumanExposure to Environmental Chemicals published by theCenters for Disease Control and Prevention in March2001. The referenced report provides exposureinformation about people participating in an ongoingnational survey of the general U.S. population, theNational Health and Nutrition Examination Survey. Thefollowing data lists only those chemicals studied that havedata on the geometric mean and the 95% confidenceinterval. Limited data on 6 other metals,organophosphates, and phthalate esters are listed in thecomplete report. The complete report also lists the 10th,25th, 50th, 75th, and 90th percentiles and their 95%confidence intervals as well as the geometric mean. Thepeople chosen for this study were from a group not knownto have any specific exposure to the chemicals beyondthat experienced by the general population.

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1. Template for compounds without aspecific OSHA health interview form

a. General Format

1. PurposeUse company letterhead for all forms. In this

section provide information as to what will be tested,and why.

You may wish to include a statement such as“These samples will not be used for other purposessuch as drug testing or genetic testing.”

2. Description of ProceduresIn this section describe in detail what the worker

will be asked to do, how long the procedure will take,and how often he/she will be asked to provide asample. Also state how soon results will be available.

It is advisable to separate the sampling andtesting processes into two paragraphs.

3. Access to Results In this section describe who will have access to

individual results, how the worker will be informed ofthe results, and who else will have these personalresults.

Describe next who will have access to theaggregate data without identifiers for all the workers,where it will be kept, and how to ask for the aggregatedata.

Entities who might have an interest in access tothe aggregate data include

• Workers at this facility

• Union representatives

• Management (local and corporate)

• Health and safety officers and healthprofessionals

• Government agencies

4. Confidentiality of DataIdentify specific procedures that will maintain

confidentiality, or state that test results will not beconfidential. Identify where test results will be kept.As data are not protected from subpoena in mostcases, you may wish to include a statement such as“Confidentiality will be maintained to the extentallowed by law.”

5. Risks and DiscomfortsIdentify known physical, social, legal and

psychological risks here, along with procedures tominimize risks (for example, for blood collection statethat “there is a slight risk of bruising and infection atthe site, but the risks will be minimized by having acertified phlebotomist, nurse, or physician [whoeveris appropriate] draw the blood”).

6. Additional InformationIdentify a contact person to answer questions.

For example, say “If you have questions now, pleaseask. If you wish to have further information, pleasecall the Health and Safety Office (or other, contactinfo here).”

7. Right to Refuse TestingState the company policy on the right to refuse

testing, and consequences of refusing testing.

8. SignatureInclude a statement such as “Your signature

below indicates that you have read the information inthis agreement and have had a chance to ask anyquestions you have about the testing. Your signaturealso indicates that you agree to participate in thistesting program. You will be given a copy of thisagreement.” Workers should sign two copies-one forthemselves and one for the person collecting thesample. You may wish to have a witness signatureline as well, but especially if the worker asks for it.

b. Specific Example of a Consent Form forCompounds Without a Specific OSHAHealth History Interview Form

Consent Form for Biological Monitoring (UseCompany Letterhead)

1. Purpose (sample text) In this workplace, there is a

biological monitoring program for the followingchemical exposures (insert chemicals/materials/exposures here). In our biological monitoringprogram, measurements are performed on humansamples such as urine, blood, breath, hair, or saliva(select the biological media that are applicable).These measurements are made to assess yourexposure to workplace chemicals so that theappropriate control measures can be decided on.


Appendix V:Consent Forms for Biological Monitoring

94

These samples will not be used for other purposessuch as drug testing or genetic testing.

2. Description of Procedures(sample text) Urine Sampling: The sampling

process will take approximately 10 minutes of yourtime and will be performed up to four times per year.You will be provided with a container and asked tourinate in the cup at the (end or beginning) of yourshift. Please wash your hands or shower beforeproviding the sample, if you have just finishedworking. If your urine is determined to be unusuallyconcentrated or dilute, you may be asked to provideanother sample on another day, as such samplescannot be used for testing.

Urine Testing: Your sample will be labeled with acode and sent to Laboratory X, and the results will beavailable in 2 weeks from (contact information).

3. Access to Results(sample text) Only you and the industrial

hygienist will know your personal test result. You willbe informed of your individual result by the industrialhygienist in the facility, and he/she will inform yourphysician if you give permission for this to happen inwriting. Other persons can also be informed if you askthis in writing.

The test results will also be reported as groupresults, without your name being linked to any oneresult. The following will have access to the groupresults

• Yourself and other workers at this facility

• Union representatives

• Management (local and corporate)

• Health and safety officers

• Government agencies

These group results will be kept in the Health andSafety Office (insert contact information) and will beavailable on a written request to (contact informationhere).

4. Confidentiality of DataTo make sure that your test result is private, the

sample will be given a code when it is collected. Thelist that links your name with the sample code will bekept in a locked filing cabinet in the Health and SafetyOffice (insert contact information or insert otherplace/contact information here). To prevent any othertesting being done on your sample, we will destroythe sample when the test is completed. Informationthat might specifically identify you (such as datecollected) will be removed from group (aggregate)data. Confidentiality will be maintained to the extentallowed by law.

5. Risks and DiscomfortsThere are no physical risks associated with urine

collection. You may feel embarrassed at being askedto provide a urine sample. To minimize this risk, wewill provide a private area for sample collection.

6. Additional InformationIf you have questions now, please ask. If you wish

to have further information, please call the Health andSafety Office (contact information or other/ contactinfo here).

7. Right to Refuse TestingOur company policy is that you have the right to

refuse to participate in this testing program. You alsohave the right to withdraw at any time.

8. SignatureYour signature below indicates that you have

read the information in this agreement and have hada chance to ask any questions you have about thetesting. Your signature also indicates that you agreeto participate in this testing program. You will be givena copy of this agreement.

Signature Date

Job Title

(Agreement administered by ____________________ )

2. Occupational Health HistoryInterview Form with Reference toCadmium Exposure

OSHA standards for lead and cadmium have a healthhistory interview form that should be completed. Anexample for cadmium exposure follows.

Directions(Determine if the employee can read and understandEnglish. If not, the employer should provide a translationof the document into an idiom/language that theemployee can understand. The following information is tobe explained and understood by the employee andsigned prior to the interview)

Please answer the questions you will be asked ascompletely and carefully as you can.


95

These questions are asked of everyone who workswith cadmium. You will also be asked to give blood andurine samples. The doctor will give your employer awritten opinion on whether you are physically capable ofworking with cadmium. Legally, the doctor cannot sharepersonal information you may tell him/her with youremployer. The following information is considered strictlyconfidential. The results of the tests will go to you, yourdoctor, and your employer. You will also receive aninformation sheet explaining the results of any biologicalmonitoring or physical examinations performed.

If you are just being hired, the results of thisinterview and examination will be used to

(1) establish your health status and see if workingwith cadmium might be expected to cause unusualproblems;

(2) determine your health status today and see ifthere are changes over time; and

(3) see if you can wear a respirator safely.If you are not a new hire:OSHA says that everyone who works with cadmium

can have periodic medical examinations performed by adoctor.

The reasons for this are(1) if there are changes in your health, either because

of cadmium or some other reason, to find them early; and(2) to prevent kidney damage.

Please sign below.I have read these directions and understand them:

Employee Signature Date

Thank you for answering these questions.

(Suggested Format)

Name _______________________________________Age ________________________________________Social Security #_______________________________Company ____________________________________

Job _________________________________________Type of Preplacement Exam:

[ ] Periodic[ ] Termination[ ] Initial[ ] Other

Blood Pressure __________ Pulse Rate ___________

1. How long have you been employed at the abovelisted job?

[ ] not yet hired

[ ] number of months

[ ] number of years

2. Job Duties, etc.:

____________________________________________

____________________________________________

____________________________________________

____________________________________________

____________________________________________

____________________________________________

____________________________________________

____________________________________________

____________________________________________

____________________________________________

3. Have you ever been told by a doctor that you hadbronchitis?

[ ] yes

[ ] no

If yes, how long ago?

[ ] number of months [ ] number of years

4. Have you ever been told by a doctor that you hademphysema?

[ ] yes

[ ] no

If yes, how long ago?

[ ] number of years [ ] number of months

5. Have you ever been told by a doctor that you hadother lung problems?

[ ] yes

[ ] no

If yes, please describe type of lung problems and whenyou had these problems.

____________________________________________

____________________________________________

____________________________________________

____________________________________________

____________________________________________

____________________________________________

____________________________________________


96

6. In the past year, have you had a cough?[ ] yes[ ] noIf yes, did you cough up sputum?[ ] yes[ ] noIf yes, how long did the cough with sputum production last?[ ] less than 3 months [ ] 3 months or longerIf yes, for how many years have you had episodes of cough with sputum production lasting this long?[ ] less than one [ ] 1 [ ] 2 [ ] longer than 2

7. Have you ever smoked cigarettes?[ ] yes [ ] no

8. Do you now smoke cigarettes?[ ] yes [ ] no

9. If you smoke or have smoked cigarettes, for howmany years have you smoked, or did you smoke?

[ ] less than 1 year [ ] number of years What is or was the greatest number of packs per day that you have smoked?[ ] number of packs If you quit smoking cigarettes, how many years ago did you quit?[ ] less than 1 year [ ] number of years How many packs a day do you now smoke?[ ] number of packs per day

10. Have you ever been told by a doctor that you hada kidney or urinary tract disease or disorder?

[ ] yes [ ] no

11. Have you ever had any of these disorders?Kidney stones [ ] yes [ ] no Protein in urine [ ] yes [ ] no Blood in urine [ ] yes [ ] no Difficulty urinating [ ] yes [ ] no Other kidney/ urinary disorders [ ] yes [ ] no

Please describe problems, age, treatment, and follow upfor any kidney or urinary problems you have had.________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

12. Have you ever been told by a doctor or otherhealth care provider who took your blood pressurethat your blood pressure was high?

[ ] yes [ ] no

13. Have you ever been advised to take any bloodpressure medication?

[ ] yes [ ] no

14. Are you presently taking any blood pressuremedication?

[ ] yes [ ] no

15. Are you presently taking any other medication?[ ] yes [ ] no

16. Please list any blood pressure or othermedications and describe how long you have beentaking each one.

Medicine How long taken?____________________ ________________________________________ ________________________________________ ________________________________________ ____________________

17. Have you ever been told by a doctor that you havediabetes? (sugar in your blood or urine)?

[ ] yes [ ] no

If yes, do you presently see a doctor about yourdiabetes?

[ ] yes [ ] no


97

If yes, how do you control your blood sugar?[ ] diet alone [ ] diet plus oral medicine [ ] diet plus insulin (injection)

18. Have you ever been told by a doctor that you had:anemia [ ] yes [ ] no low blood cell count? [ ] yes [ ] no

19. Do you presently feel that you tire or run out ofenergy sooner than normal or sooner than otherpeople your age?

[ ] yes [ ] no

If yes, for how long have you felt that you tire easily?[ ] less than 1 year [ ] number of years

20. Have you given blood within the last year?[ ] yes [ ] no If yes, how many times?[ ] number of times How long ago was the last time you gave blood?[ ] less than 1 month [ ] number of months

21. Within the last year have you had any injuries withheavy bleeding?

[ ] yes[ ] noIf yes, how long ago?[ ] less than 1 month [ ] number of months

Describe: ____________________________________________________________________________________________________________________________________________________________________________________________________________________________

22. Have you recently had any surgery?[ ] yes[ ] no

If yes, please describe:________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

23. Have you seen any blood lately in your stool orafter a bowel movement?

[ ] yes[ ] no

24. Have you ever had a test for blood in your stool?[ ] yes[ ] no

If yes, did the test show any blood in the stool?[ ] yes[ ] no

What further evaluation and treatment were done?____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

The following questions pertain to theability to wear a respirator.

Additional information for the physician can be found inThe Respiratory Protective Devices Manual.

25. Have you ever been told by a doctor that you haveasthma?

[ ] yes[ ] noIf yes, are you presently taking any medication for asthma? Mark all that apply.[ ] shots[ ] pills[ ] inhaler

26. Have you ever had a heart attack?[ ] yes[ ] noIf yes, how long ago?[ ] number of years [ ] number of months


98

27. Have you ever had pains in your chest?[ ] yes[ ] noIf yes, when did they usually happen?While resting [ ]While working [ ]While exercising [ ]Activity didn’t matter [ ]

28. Have you ever had a thyroid problem?[ ] yes[ ] no

29. Have you ever had a seizure or fits?[ ] yes[ ] no

30. Have you ever had a stroke (cerebrovascularaccident)?

[ ] yes[ ] no

31. Have you ever had a ruptured eardrum or aserious hearing problem?

[ ] yes[ ] no

32. Do you now have claustrophobia, meaning fear ofcrowded or closed in spaces, or any psychologicalproblems that would make it hard for you to wear arespirator?

[ ] yes[ ] no

The following questions pertain toreproductive history.

33. Have you or your partner had a problemconceiving a child?

[ ] yes[ ] noIf yes, specify:[ ] self [ ] present mate [ ] previous mate

34. Have you or your partner consulted a physicianfor a fertility or other reproductive problem?

[ ] yes[ ] no

If yes, specify who consulted the physician?[ ] self [ ] spouse/partner [ ] self and partner

If yes, specify the diagnosis made by the doctor.____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

35. Have you or your partner ever conceived a childresulting in a miscarriage, still-birth, or deformedoffspring?

[ ] yes[ ] noIf yes, specify.[ ] miscarriage[ ] still-birth[ ] deformed offspring

If the outcome was a deformed offspring, please specifytype of deformation.________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

36. Was this outcome a result of a pregnancy of[ ] yours with present partner[ ] yours with a previous partner

37. Did the timing of any abnormal pregnancyoutcome coincide with present employment?

[ ] yes[ ] no

List dates of occurrences:________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________


99

38. What is the occupation of your spouse or partner?____________________________________________

For Women Only

39. Do you have menstrual periods?[ ] yes[ ] noHave you had menstrual irregularities?[ ] yes[ ] no

If yes, specify type.____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

If yes, what was the approximate date this problembegan?________________________________________________________________________________________

Approximate date problem stopped?____________________________________________

For Men Only

40. Have you ever been diagnosed by a physician ashaving prostate gland problem(s)?

[ ] yes[ ] no

If yes, please describe type of problem(s) and what wasdone to evaluate and treat the problem(s).____________________________________________________________________________________________________________________________________________________________________________________________________________________________


101

Web URLs are an important aid to obtaining up-to-dateinformation. A problem has always been that InternetWeb addresses change regularly. If any of the links do notwork, the best thing is to back up to the link of the homeagency and work from there, and also use any searchcapabilities of the agency site.

All links begin with “http://”.

American Conference of GovernmentalIndustrial Hygienists BEI Committee

www.acgih.orgClick on “Leadership” then “Committees”

American Industrial Hygiene AssociationBiological Monitoring Committee

www.aiha.orgClick on “Committees/SIGs” then “AIHA

Committees” and “Biological Monitoring Committee”

American Industrial Hygiene Conferenceand Exposition abstracts

www.aiha.orgClick on “Meetings and Education” then “AIHce” and

AIHceAbstracts”

Centro de Toxicologic du Quebecwww.ctq.qc.ca/pciendes.htmlInterlaboratory program for metals and inorganics

Environmental Protection Agencywww.epa.govwww.epa.gov/pesticides/safety/workers/part170.htm

(for the worker protection standard for pesticide workers)www.epa.gov/nceawww/dermal.html (for dermal

exposure assessment)

European Community Materialseuropa.eu.int/index_en.htmUse search engine

Finnish Occupational Hygiene Societywww.occuphealth.fi/ttl/osasto/tt/bio/qceng.htm (for

QA program for organic solvents metabolites in urine)

www.occuphealth.fi/tt/bio/guide346.htm (forsummaries of guidelines and analytical procedures)

Health Care Financing Administrationwww.hcfa.gov/medicaid/clia/prodesc.htm (to obtain

U.S. requirements for laboratories analyzing humanspecimens)

National Institute for Occupational Safetyand Health (NIOSH)

www.cdc.gov/niosh

www.cdc.gov/niosh/nmed/medstart.html (forliterature references and analytical methods for OSHAregulated substance)

www.cdc.gov/niosh/nmammenu.html (for NIOSHanalytical methods including biological monitoringmethods)

www.cdc.gov/niosh/nrderm.html (for the NIOSHresearch agenda for skin absorption research)

www.cdc.gov/niosh/pubs.html (to search NIOSHpublications)

Occupational Safety and HealthAdministration (OSHA)

www.osha.gov

Use Site Search for OSHA list of approvedlaboratories for blood lead analyses

www.osha.gov

Use Site Search for OSHA guidance on dermalexposure

www.osha.gov

Use Site Search for OSHA guidance on biologicalmonitoring and medical surveillance

World Health Organizationwww.who.int/peh/gelnet/hlm97occ.htm (for WHO

guidelines on biological monitoring in the workplace)


Appendix VI:Some Important Internet URLs for Biological Monitoring

Information

103

You should print out a black and white copy of thePowerPoint® slide show to complement the full color CDof the slide show inside the book cover and to free up theviewer from taking notes. Slides 1–62 comprise the coremodule that represents the most important concepts.Slides 63–72 introduce absorption, distribution, storage,metabolism, and excretion. Different types of markers arediscussed in Slides 73–77. Some examples of biologicalmonitoring are then presented in Slides 78–110,

including OSHA monitoring for lead, cadmium, andbenzene. Slides 111–118 summarize when and how todo biological monitoring and with what. The CD allowsyou to move slides around in line with your needs andaudience types.

You should become thoroughly familiar with this slideshow and Appendix I before going on to the othersections.


Appendix VII:Biological Monitoring for Evaluating Occupational Exposure to

Toxic Chemicals Slide Show: An Introduction

American Industrial Hygiene Association2700 Prosperity Ave., Suite 250Fairfax, VA 22031(703) 849-8888(703) 207-3561 faxwww.aiha.orgStock #EBMG04-654

biological monitoring a practical field manual

Documents