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HERAGHealth Risk Assessment Guidance for Metals

Contents

Foreword 1

Acknowledgements 2

Abbreviations 4

01. Purpose and Intended Use 5

02. Scope and Organization 72.1 Scope 82.2 Organization – building block approach 8

03. Exposure Assessment 113.1 Assessment of occupational exposure 12

3.1.1 Inhalation exposure 123.1.2 Dermal exposure 143.1.3 Exposure via ingestion 17

3.2 Indirect exposure via the environment and consumer exposure 173.2.1 Indirect exposure via the environment 183.2.2 Consumer exposure 20

04. Effects Assessment 214.1 Toxicokinetics 22

4.1.1 Inhalation absorption 224.1.2 Oral absorption 224.1.3 Dermal absorption 23

4.2 Acute toxicity, irritation and corrosivity 244.3 Sensitization 244.4 Repeated-dose toxicity 244.5 Mutagenicity/genotoxicity 254.6 Carcinogenicity 274.7 Reproductive toxicity 284.8 Quality screening procedures for health effects literature 29

05. Risk Characterization 315.1 Proposed scheme for the refinement of occupational inhalation

exposure and subsequent systemic absorption 325.2 Proposed tiered-approach for dermal exposure assessment 325.3 General considerations for the choice of assessment factors in risk

characterization of metals 345.4 The influence of essentiality on risk assessment of metals 35

06. References 37

Credits 40

Assessing and managing potential risks from the production and use of metalsand inorganic metal compounds is an increasingly important consideration formining and metals companies. As well as demonstrating enhanced responsibility,it is becoming necessary to perform such assessments to align practices withnew trends in chemicals management policies – for example the RegistrationEvaluation and Authorisation of Chemicals (REACH) legislation in the EU and bythe UN’s Strategic Approach to International Chemicals Management (SAICM)globally.

Access to markets will become ever more dependent on the ability of companiesto prove a substance can be produced and used safely, and this in turn requiresaccurate and robust risk assessment methodologies. The Health RiskAssessment Guidance for Metals (HERAG) has been published in response tothese challenges. Launched jointly by ICMM, Eurofer and Eurometaux, it hasassembled a set of the most advanced and appropriate methods available forhuman-health based risk assessment of metals.

HERAG is intended to address the specific properties of metals, metal compounds,alloys and other naturally occurring inorganic substances. It describes currentknowledge on metal-specific human health risk assessment approaches andprovides guidance for the scientific and regulatory community with the aim ofreducing uncertainty in future risk assessments. This is crucial because, in manycases, existing guidance focuses on organic chemicals and fails to adequatelyaddress specific characteristics that must be taken into account when assessingmetals.

The critical scientific concepts are presented in the series of ‘fact sheets’ on theCD-ROM inside the back cover of this publication. Each fact sheet has beenreviewed by a panel of leading independent scientists.

It is our intention that this publication, through periodic updates, will continue to provide a solid basis for sound health risk assessment processes for metalsand we encourage all parties to use the material (for updates please visitwww.metalsriskassessment.org). We welcome any comment on the publicationas feedback enables us to provide further guidance as the science evolves.

Guy Thiran Secretary General, Eurometaux

Gordon Moffat Director General, Eurofer

Paul MitchellPresident, ICMM

Foreword

HERAG Health Risk Assessment Guidance for Metals 1

HERAG Health Risk Assessment Guidance for Metals

HERAG Project Team

Dr William Adams (Rio Tinto)Dr Scott Baker (ICA)Dr Hudson Bates (NiPERA)Dr Andy Bush (LDAI)Mr Peter Brewin (EPMA)Dr Tom Brock (CDI)Ms Sandra Carey (IMOA)Mr Terrence Civic (Brush Wellman)Dr Ruth Danzeisen (ICA)Mr Grant Darrie (Elementis)Dr James Deyo (Eastman Chemical Company)Dr Richard Gaunt (Rio Tinto)Dr Wouter Ghyoot (Umicore)Dr Kate Heim (NiPERA)Ms Agnieszka Herok (Tin Technology)Ms Jenny Holmqvist (Eurofer)Ms Sophie Le Pennec (Eramet)Dr Christina Messner (WVM)Dr Adriana Oller (NiPERA)Mr Wieslaw Piatkiewicz (EGGA/IMoA)Mr Eric Pezennec (Arcelor Mittal)Mr Christian Plazanet (Eramet)Ms Ilse Schoeters (ECI)Ms Lydie Servant (Arcelor Mittal)Dr Frank Van Assche (IZA Europe)Ms Nadia Vinck (Euroalliages)Mr Martin Wieske (VWM)

2

Acknowledgements

Principal Authors

EBRC ConsultingDr Rodger Battersby Dr Kevin Klipsch Mr Daniel VetterDr Craig Boreiko (ILZRO)

Project Management Group

Dr John Atherton (ICMM)Dr Benjamin Davies (ICMM)Dr Patricia Koundakjian (Eurofer)Mr Eirik Nordheim (Project Chairman, EAA)Dr Violaine Verougstraete (Eurometaux)Mr Hugo Waeterschoot (ENIA)


Scientific Review Panel Members

Dr John Cherrie Institute of Occupational Medicine Edinburgh, UK

Dr Thomas Gebel Federal Institute for Occupational Safety andHealthDortmund, Germany

Dr Daniel Krewski Institute of Population and Health University of Ottawa, Canada

Prof Len Levy Institute of Environment and Health Cranfield University, UK

Prof Dominique Lison Université catholique de Louvain Brussels, Belgium

Prof Harry McArdle Rowett Research Institute Aberdeen, UK

Dr James Parry University of Wales Swansea, UK

Prof Eric Smolders Katholieke Universiteit Leuven, Belgium

Dr Karl Summer Institute of Toxicology Neuherberg, Germany

Prof Jan Willems Ghent University, Belgium

The participants of the October 2006 ScienceConsolidation Workshop are thanked for theirimportant contribution towards the completion ofthe HERAG factsheets.

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HERAG Health Risk Assessment Guidance for Metals4

Abbreviations

CMRCarcinogenic, Mutagenic and/or Reproductive toxin

EASEEstimation and Assessment of Substance Exposure(model), see reference Creely et al. (2004)

ESR‘Existing Substances Regulation’: European CouncilRegulation No 793/94 on the evaluation and controlof the risk of existing substances. May also refer tothe associated Commission Regulation EC 1488/94laying down the principled for the assessment ofrisk to man and the environment of existingsubstances in accordance with Council Regulation(EEC) No793/93.

GHSGlobally Harmonized System of Classification andLabelling of Chemicals

GIGatro-Intestinal (tract)

IWGTInternational Working Group on GenotoxicityTesting

LOAELLowest Observed Adverse Effect Level

MMADMass Median Aerodynamic Diameter

MPPDMultiple Path Particle Deposition (Model), name ofthe current version

MWMolecular Weight

OECDOrganisation for Economic Co-operation andDevelopment

OELOccupational Exposure Limit

PSDParticle Size Distribution

QSARQuantitative Structure Activity Relationship

RA(R)Risk Assessment (Report)

RWCReasonable/Realistic worst case exposure value(usually the 90th or 95th percentile of a data set ofmeasured values)

TDITolerable Daily Intake

TGDTechnical Guidance Document in support ofCommission Directive 93/67/EEC on RiskAssessment for new notified substances,Commission Regulation (EC) No 1488/94 on Risk Assessment for existing substances andDirective 98/8/EC of the European Parliament and of the Council concerning the placing ofbiocidal products on the market.

TLVThreshold Limit Value

TYPTypical exposure value (usually derived from themedian of a set of measured exposures)

VRAVoluntary Risk Assessment

WELWorkplace Exposure Limit

01HEALTH RISK ASSESSMENT GUIDANCE FOR METALS

PURPOSE AND INTENDED USE


Several of the fact sheets that accompany thispublication have identified the need for furtherresearch and model development specifically formetals and inorganic compounds. In view of thisand considering that the science of metalscontinues to evolve, it is anticipated that some ofthe recommendations presented in this documentand the corresponding fact sheets will, in thecourse of time, require modification or updating.

The principal purpose of this Health RiskAssessment Guidance for Metals (HERAG) is toprovide the worldwide regulatory and scientificcommunity with an overview of the most recentdevelopments in risk assessment methodologiesfor metals and inorganic metal compounds, withthe aim of reducing uncertainty in future riskassessments.

The guidance and concepts presented have beenbuilt on the experience gained with previous orongoing risk assessments for metals under the EU Existing Substances Regulation (ESR, CouncilRegulation EEC 793/93) and of voluntary riskassessments conducted in the EU in accordancewith the same legislation. However, reference hasalso been made to other national or internationalinstitutions (e.g. US EPA, WHO, OECD).

To allow for adaptation of this guidance and theunderlying concepts to a broader legislative context,HERAG follows a ‘building block’ approach (see‘Scope and Organization’). Each building blockaddresses a particular aspect of risk assessment,which enables the methodologies to be used inother applications, such as chemicals managementsystems and occupational exposure monitoring.

HERAG is intended to aid professionals in the fieldof human health risk assessment, particularlyregulatory authorities and industry professionals,either at a national or international level. Whereasthe general concepts presented may be useful foranyone interested in human health assessment ofmetals and inorganic compounds, it is assumedthat the reader already has a good understandingof the basic principles of human health riskassessment.

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01. Purpose and Intended Use


SCOPE AND ORGANIZATION


2.1 Scope

Experience in recent risk assessments of metalsand their inorganic compounds has led to therecognition that existing frameworks andassociated guidance (e.g. US-EPA, EU TGDguidance) are not appropriate. This is largelybecause these systems for assessing the riskassociated with the production and use ofchemicals were initially developed with anemphasis on organic chemicals.

HERAG was therefore established to summarizeexisting knowledge on metal-specific issues thatare relevant to human health risk assessment.Furthermore, some of the concepts presented mayalso be applied in chemicals management and inoccupational exposure surveillance in particular.

To facilitate this, a team of metal industry expertsfrom companies and associations previously orcurrently involved in metal risk assessments,conducted a point-by-point analysis of existingconcepts on exposure assessment and hazardcharacterization to identify those that are trulyspecific for metals.

For the purpose of this document, the term ‘metal(s)’ refers also to semimetals (metalloids).For increased readability, this term also frequentlyrefers to inorganic metal compounds as well as thepure metal. However, organometallic compounds1

are currently outside of the scope of HERAG.

HERAG specifically focuses on risk assessmentissues associated with inorganic metal compounds.However, some elements addressed in HERAG are not essentially unique to metals and may also be applied to a wider range of compounds. For example, the data-richness of some metals inprevious risk assessments has required a specificfocus on quality screening of available data,accordingly this topic is addressed in a separatefact sheet.

2.2 Organization – building block approach

The HERAG project employs a building blockapproach (see Figure 1) to ensure that itsmethodologies are useful for different jurisdictions and that the presented concepts are also useful forchemicals management in general. Nevertheless,the established building blocks were based ongeneral risk assessment methodology, which isprincipally conducted in three steps: effectsassessment, exposure assessment and riskcharacterization.

The following key building blocks were established:

Exposure AssessmentThe quantification (by measuring or modelling) ofhuman exposure to a chemical is called exposureassessment. Conventionally, this assessment isperformed for three human population subgroups:(i) those occupationally exposed during productionor use of the substance;(ii) those exposed because the chemical iscontained in and potentially released fromconsumer products; and,(iii) those exposed indirectly via the environment, to which the chemical is emitted during productionand use and may reach the individual for examplevia food, water or air.

As for the effects assessment, three routes ofexposure (inhalation, oral, dermal) are considered.Previous metals risk assessment experience hasshown that for the following topics there is a clearneed for metal-specific guidance:• inhalation and dermal exposure, both especially

relevant under occupational conditions;• oral exposure, including the fate of metals once

they reach the gastrointestinal tract (systemic absorption and use of toxicokinetic models).

Though not strongly metal-specific, theassessment of consumer exposure and indirectexposure via the environment is addressed in somedetail by HERAG, particularly since conventionaldiffusion-based exposure models are found to beinapplicable to metals, and numerous metal-specific consumer scenarios have been identified.

Effects AssessmentEffects assessment involves the investigation of theeffect that a chemical exerts on human healthbecause of its intrinsic toxicological propertiesusing in vitro or in vivo methods (also called hazardidentification). The effects assessment furthermore

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02. Scope and Organization

1 IUPAC Definition of ‘Organometallic Compounds’ (abbreviated):Classically compounds having bonds between one or more metal atomsand one or more carbon atoms of an organyl group. (…) In addition to thetraditional metals and semimetals, elements such as boron, silicon,arsenic and selenium are considered to form organometallic compounds(…). The status of compounds in which the canonical anion has adelocalized structure in which the negative charge is shared with an atommore electronegative than carbon, as in enolates, may vary with thenature of the anionic moiety, the metal ion, and possibly the medium; inthe absence of direct structural evidence for a carbon–metal bond, suchcompounds are not considered to be organometallic.


Risk Characterization A risk assessor finally compares the quantitativeand/or qualitative information on human exposurefor the human population to the no-adverse-effectlevels established in the effects assessment for thevarious effects, a process called risk characterization.In consideration of the uncertainties that areassociated with both the effects assessment andthe exposure assessment, so-called assessmentfactors (or safety factors) are usually introduced. In this context, experience has shown that specialattention is required for metals to ensure a realisticrisk assessment. In contrast to most anthropogenicorganic substances, several metals play anessential role for the functioning of life and areubiquitous in the environment. The choice of

includes the investigation of a dose (concentration)– response (effect) relationship and the derivationof no-adverse-effect levels/concentrations, whereappropriate. Three routes of exposure need to beconsidered: inhalation, ingestion and dermalexposure. The spectrum of possible health effectsthat need to be covered are acute toxicity, repeateddose toxicity, irritation/corrosivity, sensitization,mutagenicity, carcinogenicity and reproductivetoxicity. Of these effects, particularly the last fourwere identified as needing metal-specific attentionand are therefore addressed separately withinHERAG.

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Figure 1: Overview of key building blocks


assessment factors in risk assessments for metals should therefore take into account thesometimes low margin between toxicologicalendpoints and deficiency levels, and the existenceof natural background levels.

Fact SheetsBased on these building blocks, a series of factsheets was developed (these are included as pdffiles on the enclosed CD-ROM). The fact sheetscontain the core guidance elements and provide the reader with state-of-the-art techniques andtools for assessing metals.

In contrast to the more elaborate and detailedguidance provided in the extensive fact sheets(which mostly also include concise summaries of relevant aspects from previous metal riskassessments), the subsequent chapters of thissummary document outline the main concepts and key conclusions on metal-specificmethodologies referred to in the different factsheets. Suggestions for further research,indications of currently developed models andlimitations in the application of methods areaddressed where relevant.

Finally, some of the topics initially identified wereconsidered not to warrant the publication of a fullfact sheet at this time, either because they werejudged not intrinsically metal-specific, or becausethe status of development based on availableknowledge is insufficient. However, furtherdevelopment of these fact sheets is foreseen in the future. Whereas these are not included on the attached CD-ROM, working documents areavailable upon request from ICMM/EBRC andfurther comment or input to these fact sheets iswelcomed. Further details of these fact sheets areincluded on the enclosed CD-ROM.

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EXPOSURE ASSESSMENT


For human health risk assessment, a correctassessment of exposure is essential and formetals, a considerable improvement of existingknowledge has occurred recently during theevaluation of zinc, nickel, lead, copper andantimony (as trioxide).

Inhalation is a key route of exposure, especially atthe workplace, since metals and inorganic metalcompounds are frequently produced and used inpowdery, dusty forms. A considerable portion of the material entering the body through the nose ormouth is translocated to the gastro-intestinal tractand this indirect route of ingestion may contributesignificantly to total systemic exposure.

Discussion among industry experts also identifiedingestion by hand-to-mouth transfer, as well asinadvertent ingestion from the peri-oral regionafter facial deposition as additional routes ofexposure with a need for further research.

Further to exposure via inhalation, the handling ofpowdery substances can also lead to exposure ofthe skin, followed by percutaneous absorption.Three separate HERAG fact sheets extensivelydiscuss the metal industry’s experience concerning‘dermal exposure’ (No. 01), ‘inhalation exposure’(No. 02), and ‘gastrointestinal uptake’ (No. 04). The key concepts and guidance elements withrespect to exposure assessments are summarizedbelow. However, because of the complex nature ofthese topics, it is explicitly recommended that thereader and users of the given guidance refer to thefull fact sheet.

Finally, in addition to the workforce, consumersand humans indirectly exposed via the environmentalso need to be considered in chemicals riskassessments. HERAG addresses these issues in a further, separate fact sheet (No. 03).

3.1 Assessment of occupational exposure

3.1.1 Inhalation exposure

Inhalation is probably the most important exposureroute to consider in the assessment of human riskfrom solid inorganic substances – in particularfrom metals in the workplace, and to a certainextent where consumer products entail exposure to an aerosol.

For some substances (examples: lead and cadmium),a large amount of biomonitoring data may beavailable. Given that biomonitoring data reflectactual body burdens most correctly by reflectingintakes as well as absorption/toxicokinetics, theseshould be given preference over ‘external’ exposuredata that are intrinsically affected by uncertainties,and which require ‘translation’ into systemic bodyburdens via absorption factors which add to theuncertainty of any assessment. The priority ofexposure data according to their relevance for riskcharacterization can be schematically summarizedin Figure 2.

For many metal compounds however, biomonitoringdata will not be readily available or at least not toan extent that it allows a thorough risk assessment.Furthermore, even when biomonitoring is available,this data considers the sum of all routes of exposure.Thus, a quantitative assessment of externalexposures is required to identify the mostquantitatively relevant sources of exposure, so that, if required, correct recommendations forappropriate risk reduction measures can be given.

The focus therefore of the fact sheet on inhalationexposure is on the collection of data of highrelevance. The concepts and methodologiespresented are based on the experience gainedduring previous risk assessments for metals andmetals compounds, with a strong emphasis on the assessment of occupational exposure.

Another key issue is the influence of particle-sizedistribution of any inhaled material on its fractionaldeposition in the various regions of the respiratorytract. The use of particle-size distribution data forthe assessment of inhalation absorption has beensuccessfully used in previous risk assessments,and is described in detail in the toxicokineticssection of the fact sheet.

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03. Exposure Assessment


particles (<100nm) are given in this fact sheet(such as zinc and lead), but none of theseessentially qualify as what is commonly designateda ‘nanoparticle’. Since nanoparticles and theirtoxicological characterization are currently subjectof extensive research without definitive conclusionsbeing available at this time, the aspect has not yetbeen considered within HERAG.

Aerosol sampling techniques and methodologyReviews of available measurement techniques andcomparisons of sampling equipment have beenconducted previously for various purposes, andextracts of these are summarized in the fact sheet.On workplace inhalation exposure sampling,Witschger (2001) extensively reviewed themonitoring devices and methods used in aerosolsampling studies in workplaces for exposureassessment. Whereas small parts of the documentdeal with radiation dosimetry issues, the majorpart addresses aerosol sampling issues in general.This exercise was conducted in the context of theSMOPIE3 project.

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2 Towards a harmonized approach to setting occupational exposure limits,Report of an ICMM-sponsored workshop (9–11th November 2005), ICMM,London, May 2006.

3 SMOPIE: Strategies and Methods for Optimisation of Internal Exposuresof workers. Funded by the European Commission in 2001. For moreinformation see www.nrg-nl.com/product/re/norm/smopie001.html

1Biomonitoring data (e.g. blood, urine)

2Inhalation exposure data, preferably with information on particle size distribution

3Analogous data (measured for similiar substances or under similiar conditions)

4Modelled data (e.g. EASE) for missing sectors/activities

Figure 2: Priority ranking of exposure data by relevance for risk assessment of occupational inhalation exposure

Increasingpriority forselection of

exposure data

Historically, there are regulatory limits (designatedas OELs, TLVs or WELs, etc.) in place for manymetals or metal compounds, which are generallyaimed at the control of airborne dust or fumeconcentrations. As a consequence, a large body ofdata exist that were generated to monitor compliancewith these levels. However, the existing differencesin methods of sampling which influence the qualityand relevance of these data has been recognizedand methodological issues of aerosol samplingtechniques have been addressed in detail.

In this context, it is noted for the sake ofcompleteness, that the International Council onMining & Metals (ICMM) has recently launched aninitiative to promote a global harmonization of theway in which such regulatory limits on workplaceexposure are set2. Further information may beobtained from ICMM (www.icmm.com). The issue of the setting of regulatory limits is not furtheraddressed within HERAG, since the setting of suchlimits and the conduct of risk assessment occursaccording to different legal standards.

Finally, whereas this chapter addresses particle-size as relevant for occupational inhalation riskassessment, nanoparticles are not currentlyconsidered; under most (albeit not all) occupationalcircumstances, particles in workplace aerosolsaggregate or agglomerate to rather large particles.However, some exceptions for much smaller


Different measurement methods and samplingdevices are in use across the EU for the assessmentof inhalation exposure at the workplace, andseveral studies were conducted to describe theperformance of sampling devices in relation to the three biologically relevant aerosol fractions(inhalable, thoracic and respirable fraction (CEN, 1993; ISO, 1992)). The focus of most studiescomparing the various types of samplers is on the sampling efficiency for the inhalable fraction. This specific methodical aspect of samplingefficiency has been discussed in the sections onoccupational exposure assessment in the EU RARson nickel and copper, and is further discussed inthe HERAG fact sheet and its appendices.

Collection of occupational monitoring data for riskassessment purposesFor many metals or metal compounds, a large bodyof occupational exposure data exist that weregenerated in the past during compliancemonitoring. However, for the purpose ofretrospective analysis of such existing data, notonly the measurement result itself is required, butfurther information on the situation under whichthe sample was taken, e.g.• process descriptions,• frequency and duration of exposure,• amount and nature of substance handled,• engineering controls and PPE in use,• sampling details and quality controls.

Based on the principles given in the EU TGD, theexperiences gained in previous data collectionexercises and a consideration of available scientificliterature (Ritchie and Cherrie 2001; Rajan et al.1997; Vincent 1998), a generic questionnairetemplate has been developed within HERAG and isprovided in the fact sheet as a starting point forfuture data collection exercises.

3.1.2 Dermal exposure

Uptake of metals through skin has been a majorfactor contributing to predicted risk in previous EUrisk assessments, particularly when insufficientmeasured data was available and highly conservativedefault model predictions of exposure were coupledwith current guidance on defaults for dermalabsorption (i.e. 10%). Therefore, this topic isaddressed in HERAG with the aim of providingguidance on how to assess occupational dermalexposure more precisely. The project findings focusprimarily on solid, powdery/dusty, inorganic

contaminants, and do not consider liquids orvapours of any kind.

Whereas very little published information onmonitoring of dermal exposure for metals and theirinorganic compounds is available, such data weregenerated only very recently within EU RARs orVRA processes, usually in the form of unpublishedreports which are not generally accessible to thescientific community.

As a consequence of the lack of measured dermalexposure data, model calculations have often beenused as an alternative in regulatory assessments.For EU Risk Assessments, extensive use has beenmade of the EASE model, the validity of which isuncertain because the dermal exposure componentis partly based on experiments conducted withliquids and partly on expert judgement – with littleactual measured data to support it. Anotherweakness is that EASE merely assigns a ratherwide ‘range’ of exposures (based on a simpledecision tree). In the absence of measured dataand as an alternative to modelled exposure,increasing use is being made of ‘analogous’ dermalexposure data. For this purpose, either potentialdermal exposure 4 data on calcium carbonate(Lansink, 1996), or the only publicly available dataset (to date) on actual dermal exposure to zincoxide (Hughson and Cherrie, 2002) have been usedpreviously. For obvious reasons, it is necessary tounderstand whether it is appropriate to extrapolatefrom such data to other compounds, and basedupon which argumentation.

Available dermal exposure data from EU RARs andcomparison to EASE predictionsThe HERAG fact sheet on occupational dermalexposure and absorption provides a comprehensivecompilation of actual dermal exposure datagenerated in the context of risk assessment in thezinc, lead, nickel and antimony trioxide industries.Together with the exposure data, detailedinformation is available on the tasks performedwith the compounds at the workplaces where theexposure was measured. Since EASE described thetasks only by a set of rather simplistic exposuredescriptors (as presented in Table 1), it wastherefore possible to compare the measuredexposure with the exposure modelled by EASE.

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4 Definitions: Potential exposure is measured with surrogate techniquessuch as patches, cotton gloves etc. outside the clothing and any protectiveequipment. In contrast, actual exposure is measured by sampling anymaterial that is actually deposited on the skin of a volunteer, e.g. bywipe-sampling, and is thus more reflective of practical workplaceconditions.


make a substantial impact on levels of dermalexposure.

Dermal exposure measurements – methodologicalaspectsFurther to the compilation of measured dermalexposure data and its comparison with EASE modelpredictions, the HERAG fact sheet addresses keymethodological aspects of dermal exposuremeasurements. Existing sampling techniquescannot continuously sample the changing dynamicsof surface deposition and clearance of the skincontaminant layer. Saturation phenomena mayoccur, and thus dermal loading may not increaselinearly with time. For this reason, samples takenduring the course of a shift should preferably notbe pooled in order to avoid potential over-sampling.The collection of individual samples should begiven preference also because it allows for anassessment of variation of exposure during a shift.Based on a methodical comparison of availablesampling techniques and in particular inconsideration of the more recent experience gainedfrom dermal exposure monitoring in various lead,antimony, nickel and zinc industries, it is concludedthat neither the use of cotton gloves nor the bag-wash method with their inherent limitations arepreferable methods. Particularly in the case ofdermal exposure monitoring of inorganiccompounds, it is proposed for future measurementsto make use of the wipe-sampling methodology.The degree of standardization and validationobtained with this method to date should facilitatethe collection of a comparable dataset for thefuture.

The selection of ‘no direct handling’ as a pattern ofcontrol leads to the qualitative prediction ‘very low’independently of the two other parameters.Therefore, a comparison of EASE predictions tomeasured data in various industries was conductedonly for ‘direct handling’. For the pattern of use,either non-dispersive or wide dispersive use wasselected (abbreviated ‘Wide’ or ‘Non’), whereas forthe contact level, distinction was made betweenintermittent and extensive contact only (abbreviated‘Int’ or ‘Ext’). See Figure 3.

A key finding is that EASE consistently over-predictsdermal exposure to metals and their inorganiccompounds, in many cases by up to two orders ofmagnitude. The fact that EASE predicts the highestrange of exposure for a workplace where thehighest exposures are actually measured showsthat some of the factors that determine exposureare indeed captured by the model’s simplisticexposure descriptors. However, the absolute,quantitative figures are obviously inappropriate and it is therefore concluded that the dermalmodule of EASE is not suitable for regulatory risk assessment.

Perception of hazard and resulting pattern ofcontrol as an exposure modifierThe differences between actual measured dermalexposure data for zinc, lead, antimony and nickelcompounds may be hypothesized to reflect the levelof control implemented in these industries,resulting from the perception of risk associatedwith the skin contact with these substances – whichis low for zinc and zinc oxide, medium for lead andantimony compounds, and high for nickel and itscompounds. This is mirrored by the observationthat the correct use of gloves (low usage for zinc,higher usage for lead, antimony, nickel or therespective compounds) and even beyond this, otherlevels of control (automated packaging for nickel)

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Table 1: EASE exposure descriptors

Pattern of use (PU)

closed system

inclusion onto matrix

non-dispersive use

wide dispersive use

Pattern of control (PC)

no direct handling

direct handling

Contact level (CL)

none

incidental

intermittent

extensive


Alternative model approach (screening model)Considering the limitations of existing models asoutlined above, but also the time, effort and costfor properly conducted sampling, a screeningmodel approach was suggested, which utilizes an‘analogous’ approach for (occupational) scenarioswith an absence of measured data.

In the case that exposure data for a particularsubstance are not available, but data do exist eitherfor other substances derived from the same metal,or for completely different metals/substances, then an ‘analogous approach’ can be taken,provided a subset of data can be selected from the data base which comply with the exposurecharacteristics outlined as follows, and which mayjustify the choice of a particular analogy. Two maincharacteristics which are thought to influence thelevel of dermal exposure can be summarized asfollows:

(i) Intrinsic substance properties:• physical form, dustiness, particle size,

hygroscopicity, agglomeration tendency;• chemical speciation, water solubility.

(ii) Process conditions and pattern of control:• conditions of handling, use of tools and PPE

(such as gloves);• degree of involvement (i.e., direct handling vs.

use of automation);• where no direct occurs, indirect exposure may

result, for example from contaminated surfaces; thus, the level of ventilation controls and resulting air may influence deposition.

There is no single criterion that can be applied tojustify the extrapolation from one data set toanother. Instead, a combination of the aspectsabove should be considered. In the case that nodata for a particular substance or any othersubstance derived from the same metal are

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EASE use pattern: wide or non-dispersive use; contact level (direct handling): Ext = extensive, Int=intermittent

Figure 3: Dermal exposure levels for different chemical agents and activities, in comparison to EASE predictions

Der

mal

expo

sure

[µg/

cm2 ]

toco

ntam

inat

ing

subs

tanc

e

1000

10000

100000

1

10

0.1

100

0.01EASE

Wide.Extn=17Zinc

EASEWide.Int

n=27Zinc

EASENon.Ext

n=103Lead

n=51Antimony

n=33Nickel

EASENon.Int

n=39Zinc

n=71Lead

n=54Antimony

n=159Nickel

Bar: Median, Cross: Mean, Box: [P25; P75], Whiskers: [P10; P90]

Substance + EASE scenario (Dispersivity.Contact Level)


Another route of exposure is inadvertent ingestionfrom the peri-oral region after facial depositionthat occurs as a function of airborne level ofcontaminants. None of the previous metal riskassessments have addressed this however, andalthough HERAG does not contribute to this,concepts are being developed elsewhere (Cherrieet al. (2006).

3.2 Indirect exposure via the environment andconsumer exposure

Exposure to chemical substances duringproduction and subsequent downstream or end-use may affect the general population in two ways:• humans may be exposed to chemical substances

released to the environment during production and/or use, which may reach humans indirectlyvia the environment, primarily through inhalation of ambient air, or ingestion of water and food;

• consumers may be exposed to hazardous substances intentionally or unintentionally released from consumer products or articles.

Whereas both aspects are not strictly metal-specificand extensive risk assessment guidance is alreadyavailable, it was considered that there are severalissues which are particularly relevant for metalsand which are not appropriately covered by thestandard TGD assessment approaches. Therefore,the aim was to capture these metal-specific issuesin order to facilitate exchange of such knowledgeon a broader basis for the metals industry in orderto improve further risk assessment exercises (factsheet No. 03).

available, then the following ‘screening model’approach is suggested, by comparing thecircumstances under which any particular‘analogous’ data set was collected, with featurescharacteristic of the ‘new’ occupational setting tobe modelled. Then, the three ranges of exposureset forth in Table 2 may be used for modelscreening purposes.

The proposed typical (TYP) values were based on alevel with greatest proximity to the median of aparticular group of data sub-sets. The worst-case(RWC) values were selected because of proximity tothe 90th percentile of the underlying data sub-sets.Whereas the use of EASE as a model is explicitlydiscouraged for metals, the advantage of the above‘screening model’ approach is that it allocates datato several of the relevant exposure categories ofEASE, thus facilitating continued use ofconventional risk assessment considerations.

This model approach is intended to be of use in, forexample, iterative approaches as foreseen in thedevelopment of exposure scenarios under REACH.Although this provides a valuable initial tool, it wasrecognized within HERAG that there is a clearfuture need to generate further dermal monitoringdata, and to facilitate the development of moremetal-specific dermal exposure models.

3.1.3 Exposure via ingestion

It is well-known that ingestion can play a majorrole in the way a metal may enter the body. Forexample, during occupational exposure to lead,poor personal hygiene behaviour can contribute to systemic intake, by inadequate washing ofhands, poor maintenance of work clothing, and(previously) lack of control of feeding and drinkinghabits as well as smoking during work. As a result,ingestion by hand-to-mouth transfer can occur.There is to date no accepted methodology toquantity this route of exposure.

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Table 2: Ranges of exposure

Range

0-5 µg/cm2

5-50 µg/cm2

50-500 µg/cm2

RWC

5

50

500

TYP

1

10

100

Description

Low dermal loading, no direct handling (analogy: Ni)

Medium dermal loading, limited direct handling (analogy: Pb, Sb, etc.)

High dermal loading, direct handling (analogy: Zn compounds)


3.2.1 Indirect exposure via the environment

Indirect exposure of humans may, in principle,occur via the typical exposure pathways – inhalation,ingestion and dermal contact. The followingexposure scenarios are most commonly consideredfor the general public:• exposure via inhalation of air;• exposure via drinking water; and• exposure via food intake.

In some instances, further exposure routes mayneed consideration for sub-groups of the population,e.g. intake by infants via mother’s milk. In currentEU TGD guidance, exposure via soil ingestion anddermal contact is discounted because it isconsidered to be very unlikely (extremely pollutedsoils e.g. land fill sites or accidental releases arelisted as exemptions). However, whereas thedermal route has indeed been shown to beirrelevant for ‘indirect exposure’ to metals becauseof their very low dermal absorption (see section4.1.3), the ingestion of soil and dust has been found to be worthy of consideration especially forchildren as further discussed below.

In general terms, a risk characterization forindirect exposure via the environment can beconducted at several different levels, as shown inFigure 4, in hierarchical order of complexity andrelevance.

If regulatory limit values like air quality standardsor food limits exist for a given substance, a directcomparison with environmental concentrationsmay be feasible at the first level. As a more refinedapproach, a comparison of actual intake with limitvalues such as a TDI (tolerable daily intake) can beperformed. At the final and principally mostaccurate level, the actual internal dose (biomarkers)of individuals is compared with the lowest observedadverse effect level (LOAEL), preferably in a specifictarget organ for repeated dose toxicity.

For metals, preference should be given (whereavailable) to internal over external concentrationsfor risk characterization; the evaluation ofbiomonitoring data is discussed further in the HERAGfact sheet, based on examples from the riskassessments of lead (blood data) and cadmium(urinary data).

18

Figure 4: Conduct of risk characterization for indirect exposure at different levels of accuracy

Emission

Environmental concentrations(air, water, soil, dust, crops,...)

Indirect exposure for the individual(intake of air, food,...)

Internal concentration/dose(biomonitoring data)

Level of exposureassessment

e.g. food limits, air quality standards

e.g. TDI

LOAEL (in target organ)

Corresponding level of effects assessment

comparevs.

Increased accuracy of risk

assessment


In contrast, the main body of the fact sheet focuseson deviations from the TGD approach andsummarizes metal specific issues (by route ofexposure) which have been identified to requirespecial attention in future metal risk assessments.

For example, for the assessment through theintake of drinking water, a set of definitions anddefaults was proposed that may allow a moreconsistent approach to metals for which this is arelevant route of exposure. In addition, default(age-dependant) uptake factors beyond theabbreviated approach in the TGD are proposed fordrinking water. Among other scenarios, furtherguidance is given on the assessment of metalexposure via cigarette smoking, via ingestion of soil and via consumption of food.

General recommendationsThe assessment of indirect exposure to humans via the environment employs a considerableoverlap with the assessment of possible risk toenvironmental ecosystems. Therefore, reference is made at this point to the MERAG5 project. This project aims to provide the regulatorycommunity at regional and international level withscientific and regulatory guidance on the mostadvanced status of environmental risk assessmentconcepts for metals and inorganic metal compounds.The included concepts of bioavailability,bioconcentration, bioaccumulation andbiomagnification of metals and/or metal compoundsare also applicable when assessing the possibleexposure of humans via the environment, e.g. viathe ingestion of food.

A further general conclusion is that the modelapproaches suggested by the EU TGD, which arebased on partition equilibria, are applicable tometals only to a very limited degree. Depending onthe level of data available, it may be possible toassess indirect exposure to some metals at a rathersophisticated level (i.e. using biomonitoring data)compared to the basic modelling of concentrationsin air, water and food. Where relevant, theassessment of indirect exposure via the environmentshould be performed separately for susceptible orparticularly sensitive sub-populations (for anexample, please refer to the VRA for lead, whereexposure of children is addressed in detail).

If such biomarkers of exposure are not availablethen accurate absorption factors are required for areliable conversion of external exposures (via food,water and air) into systemic uptakes. It is notuncommon for absorption to vary as a function ofthe level of intake (i.e., saturation; for examples,refer to the risk assessments on zinc and copper).Thus, precise oral absorption factors are likely tobe required to assess intake from dietary sources(relevant for consumers and indirect exposure) and these will differ considerably from thoseapplicable to occupational circumstances forexample. For more details, please refer also tosection 4.1.2 and to the separate fact sheet on GIuptake and toxicokinetic models.

Similarly, inhalation uptake will vary considerablybetween the occupational setting and situationswhere humans are exposed via ambient air. In thelatter case, chemicals are commonly assumed tobe adsorbed onto fine (sub-micron) particulatematter, which is assumed to penetrate to a highextent to the pulmonary region of the lung, withpotentially very high uptake rates, for which 100%absorption is often assumed by default (forexamples, refer to the EU risk assessment on lead). In contrast, workplace aerosols are oftencharacterized by the mass-median aerodynamicdiameters of airborne particles well above 10 microns. This means that the bulk of inhaledmaterial will usually be redirected to the GI tract,with absorption rates usually much lower than100% (for more details, see fact sheet on inhalationexposure/absorption).

Even when biomonitoring is available however, thequantitative assessment of external exposures isessential to identify the most relevant sources ofexposure, so that if required, correctrecommendations for appropriate risk reductionmeasures can be given.

Metal specific issues and exposure routesIn order to facilitate the indirect exposureassessment section, previous risk assessmentsreports conducted under the ESR or as voluntaryrisk assessments were screened for issues of‘indirect exposure via the environment’, and inaddition key metal industries provided input ontheir direct experience with these issues. For easeof reference to these previous metal riskassessments, the fact sheet contains an extensiveappendix, giving detailed extracts of the indirectexposure assessments for individual metals.

19

5 The scientific and technical recommendations of MERAG can be found atwww.metalsriskassessment.org


The general use of 90th percentiles of quantitativeexposure measures as recommended in the EUTGD is likely not to be applicable to metals. This is because a multiplication of such values forconcentration in environmental media and theirintake rates may result in overestimates of internalexposure. However, the use of RWC values may,under certain circumstances, allow considerationto be given to (potentially sensitive) known sub-populations.

Metals are natural components of the earth andtherefore reflection must be given to a correctdistinction between natural ambient andanthropogenic concentrations. This will be ofparticular relevance when certain CMR labelledmetals are discussed for risk through indirectexposure because of the conflict with the ‘nothreshold concept’ for genotoxicity andcarcinogenicity.

3.2.2 Consumer exposure

Similar to ‘indirect exposure via the environment’,the assessment principles for ‘consumer exposure’are not metal-specific per se. Nevertheless, theexperience in previous metal risk assessments hasshown that several individual scenarios exist,where consumers are in (sometimes regular andextensive) contact with metals in products andarticles of daily life.

The currently available risk assessment reports on metals and metal compounds were thereforescreened for consumer exposure issues whichwere deemed to be quantitatively relevant forhuman health risk assessment. In the attached fact sheet, the resulting (non-exhaustive) tabularsummary of consumer exposure scenariospotentially relevant for metals is presented, as well as a discussion of several aspects of commoninterest for which discrepancies between variousexisting metal risk assessments have beenobserved. Examples for metal specific scenariosaddressed in previous assessments are contactwith batteries, jewellery, coins, food-packagingmaterials, crystal-glassware, soldering material,household and artist’s paints.

In the appendix to the fact sheet, more extensivesummaries of previously undertaken consumerexposure assessments are given as a backgrounddocument, from which more detailed informationmay be extracted as guidance for futureassessments.

This compilation of scenarios may be helpful infuture assessments, particularly because existingmodel concepts (such as ConsExpo) were designedfor organic substances, and are based on diffusion-related calculation models. Since these relypredominantly on physico-chemical properties(such as vapour pressure and octanol/waterpartition coefficient), they are considered to beunsuitable for metals and metal compounds.

Based on a retrospective analysis of the way inwhich consumer exposure was addressed inseveral risk assessments, some general guidancefor the future assessment of consumer exposure to metals and metal compounds is summarized in this fact sheet, as follows:• It is recommended to conduct a quantitative

exposure assessment for each consumer scenario, and not to exclude any particular use a priori. Previous experience with metals for example has shown that the designation of a particular scenario as ‘negligible’ inevitably opens a discussion on the ‘cut-off’ value for the metal, since the various existing routes of exposure may cumulate to critical total body burdens.

• The assessment of exposure via dermal contact should make use of default assumptions for release rates only for initial screening purposes; for a refined assessment, it is recommended to rely on (experimentally verified) release rates of the metal from the product (preferably in appropriate physiological media).

20


EFFECTS ASSESSMENT

4.1 Toxicokinetics

4.1.1 Inhalation absorption

Inhalation absorption factors are not commonlyavailable for most metals, and are also difficult tomeasure. In the absence of substance-specificinhalation absorption factors, the initial approach in previous EU risk assessments has been to use100% as a default absorption factor (75% isrecommended for inhalation absorption for indirectexposure via the environment). For occupationalrisk assessment of metals, this is an unrealisticand unnecessarily conservative assumption.

The fundamental basis for assessment ofabsorption of inhaled particles is the aerodynamic-size dependant deposition of the particles in threedistinct zones of respiratory tract. This has beenelaborated upon in detail elsewhere (ICRP, 1994).This model leads to the conclusion that (i) largeinhaled material is deposited in the extra-thoracicregion by impaction, subject to rapid clearance tothe gastro-intestinal (GI) tract; (ii) materialdeposited in the tracheo-bronchial region bysedimentation is similarly subject to clearance(although somewhat more slowly) to the GI tract;(iii) finally, the retention of material that penetratesto the alveolar/pulmonary fraction of the lung issubject to diffusion, so that as a conservativedefault assumption, 100% of this material mayassumed to be absorbed.

In the case that detailed particle size distribution(PSD) data for a particular substance and a specificoccupational setting are available, then a mass-median-aerodynamic diameter together with itsgeometric standard deviation can usually becalculated. Fractional deposition in the respiratorytract can then be predicted with the aid of theMPPD model (Asgharian and Freijer, 19996). Sinceworkplace aerosols commonly are composed ofrather large particles (i.e. MMAD >10 microns), and if a precise rate of oral absorption is available,then such particle size distribution data togetherwith deposition modelling can be used to refine therisk characterization considerably. A fully workedexample of fractional deposition and inhalationabsorption using workplace particle sizedistribution data as used in the (EU) zinc riskassessment is given in the HERAG fact sheet onthis subject (No. 02).


4.1.2 Oral absorption

Ingestion is a relevant route of exposure not onlyfor dietary intake (relevant for consumer andindirect exposure), but is also of importance in theoccupational setting (hand-to-mouth transfer,inadvertent intake from peri-oral exposure viafacial deposition). In addition, translocation of largeinhaled particles to the GI tract renders this themost relevant route of intake.

Absorption after intake via ingestion is known tovary strongly between metals, and is can beinfluenced considerably by chemical speciation,solubility, dietary composition and nutritionalstatus. Metal-metal interactions are also known tooccur: examples are copper-zinc or copper-ironwhere any one of these essential elements at highintakes is thought to compete with transportmechanisms of the other and thereby possiblyinduce deficiency; an alternative example is lead,which has no known physiological function in thehuman body, but partly enters the body by utilizingcalcium transport mechanisms. Finally, non-linearkinetics usually govern the absorption of metalsfrom the GI tract, with saturation occurring athigher intake rates.

Thus, for metals it is relevant to distinguish between(i) usually low intakes of the general population via food, ambient air, drinking water, or consumerarticles/products, and (ii) usually considerablyhigher intakes from occupational exposure. Inorder to develop this issue further, metal- or metalcompound-specific information on oral bioavailabilitywas collected to derive general conclusions on GIuptake as well as information on modifying factors,such as speciation, particle size, solubility etc.

As a background document to the underlying factsheet (No. 04), a collection of information availableon gastro-intestinal uptake of several metals ispresented in an appendix, this comprises extractsfrom previous and current risk assessments andother sources.

22

04. Effects Assessment

6 In the meantime, a revised version of the original MPPDep v1.11 modelis available (MPPD 2.0, see annex A2.2 to the HERAG fact sheet andwww.ciit.org/techtransfer/tt_technologies.asp


4.1.3 Dermal absorption

Current guidance documents suggest that in theabsence of data on dermal absorption, a choicebetween two default values (10% and 100%) may be made, based on observations with organicmolecules where substances with MW >500 andextreme log Pow values (under -1 or above +4)display a limited extent of skin permeation. These considerations do not apply to metals asinorganic compounds require dissolution involvingdissociation to metal cations prior to being able topenetrate skin by diffusive mechanisms.

However, current (EU TGD) guidance also suggeststhat where data are available (e.g. data on watersolubility, ionic state, ‘molecular volume’, oralabsorption and dermal area dose in exposuresituations in practice) which indicate that the use of an alternative dermal absorption percentagevalue is appropriate, then this alternative value can be used, and scientific justification for the useof alternative values should be provided. A factsheet on this aspect has therefore been developedwithin HERAG to provide such argumentation. For this purpose, all previously available information(as validated during recent or on-going riskassessments) on dermal absorption of metals was collected, and alternative default absorptionfactors were proposed.

Current models8 for the prediction of dermalabsorption were found to be inappropriate formetals, since they are also based on considerationsof diffusion-mediated processes, depending on theliphophilicity (i.e. log Pow) and molecular weight of acompound, and in some instances also to a certaindegree on concentration. It may also be questionedwhether the establishment of such QSARs is at allfeasible, since (i) metals and their compounds maydeposit on skin in many different physical forms(fine powders, coarse crystalline materials, orliquid paste or solubilized forms) which in turn willinfluence the availability of ‘free’ metal ions, and (ii) the solubility in water or a physiological mediumsuch as sweat will vary strongly, depending on thesolubility product of any given metal compound andthe possible anions present in such a medium.

The focus of the work in preparation of this factsheet (No. 01) was therefore on the collation andscreening of the relevance of existing data on

The second focus of this fact sheet is onphysiologically based toxicokinetic andtoxicodynamic models, which are in most casesintrinsically linked to the aspect of GI uptake. Such models use mathematical descriptions of theuptake and distribution of chemical substances toquantitatively describe the relationships amongcritical biological processes. A catalogue of suchtoxicokinetic models for metals was collected fromthe industries participating in the HERAG project in order to extract any aspects available for aparticular metal that are of a more general natureand perhaps useful for other metals. Whether thebasic input parameters of any of these modelscould be used for future human health riskassessments for other metals was also considered.Summaries of such models and where available orfeasible, the underlying principles together withadvantages and disadvantages are discussedmetal-by-metal in appendices to this fact sheet.

In risk assessment for a wide range of metalcompounds, extrapolation between different metalcompounds is necessary and the fact sheet givesthe following recommendations:• For a differentiation between soluble vs. poorly

soluble or insoluble forms, water solubility is often used as a surrogate for bioavailability. For example in the assessment of nickel and zinc, it has been experimentally verified (in vivo)that large variations exist between soluble salts of a metal, and the metal itself, or the oxides or other very poorly soluble substances. This principle has also been established for cobalt, based on in vitro data.

• As a warning, it has also been shown that this concept is not applicable to all metals. For example, the VRA for lead has shown that these differences in solubility do not necessarily impact bioavailability under physiological circumstances. In consequence, extrapolation based on solubility alone can not be assumed a priori, but should be demonstrated to exist as a phenomenon for a particular metal on a case-by-case basis.

• Where robust toxicokinetic data are not available, in vitro ‘bioaccessibility’7 testing may be performed to substantiate read-across arguments.

23

7 The term ‘bioaccessibility’ refers to experimental (in vitro) testing ofsolubility in synthetic physiological media.

8 SKINPERM (ten Berge, 2006); Corish and Fitzpatrick, 2002; Moss et al.2002; Krüse et al (2007); Cleek and Bunge (1993); Bunge and Cleek(1995); Bunge et al. (1995).

dermal absorption of metals. Test systems forpercutaneous transfer have now been standardizedto allow reliable measurement. In vitro studies ofseveral metals (Zn, Ni, Cd, Sb, Cu, Pb) havedemonstrated that the penetration of the dermis by dissolved metal cations is generally low, i.e. inthe range of 0.1-1%, depending on the resolution ofthe test system. In the case of lead, a combinationof in vitro testing plus toxicokinetic modelling hasdemonstrated that the assumption of a dermalabsorption rate in excess of 0.01% would be inconflict with available biomonitoring data (bloodlead) and is therefore implausible.

The fact sheet on dermal absorption however alsoconcludes that future studies of metals and metalcompounds could be undertaken with a view toestablishing the maximum transfer rate of metalions through skin, and the extent of dermal loadingrequired to achieve the concentration gradient that is the determinant of this maximum. It is alsoproposed that an extensive validation exercise onexisting dermal absorption studies should beundertaken with the purpose of proposingalternative, more realistic default dermalabsorption factors.

Based on currently available data which were alsovalidated and used for risk characterization incurrent EU risk assessments, the followingconclusions were derived:• Considering that under industrial circumstances

many applications involve handling of dry powders, substances and materials, and since dissolution is a key prerequisite for any percutaneous absorption, a lower default absorption factor may be assigned to such ‘dry’ scenarios where handling of the product does not entail use of aqueous or other liquid media (like in the in vitro experiments).

• The following default dermal absorption factors (reflective of full-shift exposure) for metal cations may be tentatively proposed for screening risk assessment purposes, until more sophisticated guidance becomes available:• from exposure to liquid/wet media: 1.0%• from dry (dust) exposure: 0.1%

It remains a matter for debate in dermalabsorption testing whether the assessment ofmaterial retained in the skin (and not released tothe receptor fluid during the exposure period orthereafter) must be considered as ‘potentiallyabsorbable’.

4.2 Acute toxicity, irritation and corrosivity

This aspect is mentioned here merely for reasonsof completeness. Discussions during the HERAGproject did not identify any points of particularrelevance to metals. One point worthy of mentionhowever is that for acute inhalation toxicity testing,and for interpretation and extrapolation of testresults for one compound to others, use should bemade of the detailed particle-size argumentation in the fact sheet on inhalation exposure andabsorption, as well as the fact sheet on classification,read-across and derogation (currently underdevelopment).

4.3 Sensitization

For the numerous metals, positive confirmation ofsensitizing effects have been reported, theseinclude beryllium, vanadium, chromium(VI), cobalt,nickel and platinum. In contrast, previous as wellas current EU ESR and VRAs have concluded on alack of sensitization for the metals copper, lead,cadmium and antimony. Only for nickel is a detailed risk assessment available. Within HERAGa retrospective analysis of experience from EU riskassessments on skin sensitization was undertakenwith the exercise restricted to Cd, Zn, Ni, Cu, Sband Pb. Since only one of these metals withsensitizing properties was reviewed within EU RARprocedure (nickel), the sensitization fact sheet was deemed upon peer review to be insufficientlydeveloped for publication. Further input on thissubject from beyond the current framework of theHERAG project is however welcome and interestedparties can obtain the draft fact sheet from ICMMor EBRC.

4.4 Repeated-dose toxicity

At an early stage in the HERAG project, thisendpoint was deemed not to be associated withmany metal-specific aspects. Nevertheless, metal-metal interactions were identified as onemajor area of relevance. Whereas one metal maynot exert any particular toxic effect at a givenconcentration, it may nevertheless modify theeffect of another in situations of co-exposure.

Further, the relevance of particle-size dependantdeposition on the respiratory tract was recognizedfor its relevance for route-to-route extrapolation,and for the correct assessment of target tissue(lung) dose assessment.

24 HERAG Health Risk Assessment Guidance for Metals

This decision tree for metals and metal compoundseliminates mutagenicity testing in bacterialsystems due to a lack of sensitivity related to either probable mechanism of action or lack ofmetal uptake. Although some metals will inducemutations in bacteria, this would appear to bemore the exception than the rule. Testing inmammalian cell culture assays for forwardmutations is instead proposed as part of the basetesting data set, preferably in a system sensitive to the large DNA deletions believed to thepredominant form of damage induced by theindirect mechanisms of action that characterizemany metals. In addition to a gene mutation assay, chromosome effects would be assessed in mammalian cells. The micronucleus test,incorporating appropriate staining procedures todistinguish aneugens from clastogens, would beappropriate for use as a second test.

Further testing might not be required if thematerials tested were negative in both type of invitro assays. However, based upon the collectiveexperience of metal risk assessments conducted to date, it is expected that most metals will elicitresponses in the micronucleus test and potentiallyassays for gene mutations. The tendency of metalsto produce positive in vitro assay results is likelydue to the high metal concentrations that can beachieved in cell culture and the multiple metalbinding sites that exist on key cellularmacromolecules. Indirect mechanisms forgenotoxicity, triggered by either nonspecific metalbinding or substitution of metals being tested foressential metals contained within metalloproteins,are expected to produce positive responses thatwill require follow-up in appropriately designed in vivo systems. The challenge that is presented for follow-up testing is a determination of whetheror not positive in vitro responses are induced viamechanisms that are plausible for intact organisms.

Follow-up in vivo studies would ideally be conductedto evaluate the genetic endpoint of concern from in vitro testing (gene mutations or chromosomeeffects), coupled with an understanding of thetoxicokinetic properties of the substance understudy. Tissues known to accumulate highconcentrations of metal, or to be the targets ofmetal toxicity, would be assigned priority forevaluation. If toxicokinetic information is lacking,indicator tests such as the Comet assay could beapplied to identify potential target tissues for indepth study with mutagenicity tests. The route,

4.5 Mutagenicity/genotoxicity

The mutagenic and/or genotoxic properties of asubstance are an important property upon whichhazard classification of substances is based.Although new classification criteria may evolve with the progressive adoption of the United Nations’ Globally Harmonized System (GHS),criteria for mutagenicity classification should besimilar to those presently in place within the EU.Mutagenic properties will also be of fundamentalimportance with the adoption of REACH, serving as a potential mandatory ‘trigger’ for REACHauthorization provisions. In addition, mutagenicpotential can also be of importance within riskassessments and can affect the fashion in whichdose response relationships are evaluated for other health endpoints. For example, genotoxiccarcinogens can be presumed to exert this effectwithout a threshold dose/concentration, which is in contrast to ‘No Observable Effect Levels’ thatcharacterize several other end-points like acutetoxicity or irritation.

The mutagenic effects of metals and theircompounds have been evaluated within the contextof several EU Risk Assessments and were furtherthe subject of a workshop convened in Hannover,Germany on 28–29 November 2005. The workshopassembled external independent experts fromgovernment and academia to address key issuessuch as testing strategies, classification criteriaand risk assessment principles that might beappropriate for metals. From this workshop, and asrefined in subsequent stakeholder consultations,the conclusion has emerged that testing strategiesdeveloped for the classification of organicsubstances are not fully appropriate for metals andthat alternate approaches for in vitro and in vivogenotoxicity testing should be adopted.

The attached HERAG fact sheet (No. 05) reviews the experience with test systems currently andpreviously applied to metals and metal compounds,focusing upon the findings of recent EU riskassessments. The response profile for these metalsis presented and metal-specific mechanisms ofmutagenicity are discussed. From theseconsiderations, a mutagenicity testing strategyspecifically for metals and metal compounds isproposed in the format of a decision tree (seeFigure 5).

25HERAG Health Risk Assessment Guidance for Metals

26

Figure 5: Proposed mutagenicity testing strategy for metals and metal compounds


Mec

hani

stic

stud

ies

Haz

ard

clas

sifi

cati

on

Start

in vitro tests

in vivo tests

No furthertesting

Dose response comparisonbetween mutagenic effects and

putative mechanisms

Classification

Dose response formicronucleus or genemutation induction inrelevant tissues

If in vivo tests (+), futherstudies with relevantexposure routes andendpoints are required

If in vivo tests (+), futher studies with relevantexposure routes and endpoints are required

In vivo MN test in relevant tissue if in vitro MN test was (+). Distinguish betweenstructural and numericalchromosome effects.

COMET assay if targettissue(s) need to bedetermined

Gene Mutation Assaysensitive to point andlarge mutations (e.g.mouse lymphoma assay)

Mammalian cell(preferably human)micronucleus test

Toxicokinetic evaluationof relevant tissues andexposure routes forsubsequent in vivo tests

One or more (+) results

In vivo dose response for ROS metabolismeffects

Dose response for DNA repair effects:1. in vitro2. in vivo

All tests(-)

Yes

within risk assessments, with the potential for riskbeing introduced for individuals experiencingoccupational exposure, exposure from consumerproducts, and indirect exposure via the environment.The manner in which dose response relationshipsare evaluated for carcinogenic substances is in partinfluenced by mechanistic assumptions maderegarding the induction of carcinogenic responses.For example, genotoxic/mutagenic carcinogens arecurrently presumed to exert effects without athreshold and to exhibit low dose linearity for theinduction of effects. Conversely, for non-genotoxiccarcinogens, thresholds may be presumed to existif adequate dose response and/or mechanisticinformation is available to support this contention.

Existing guidelines for classification and riskassessment for the carcinogenicity of metals andmetal compounds are less than optimal andconsideration needs be given to the specialproperties of metals when deciding upon strategiesfor testing. This consideration should focus uponboth practical complexities of the occupationalexposure environments for metal production anduse, and the mechanistic complexity (i.e. indirectmechanisms) that may underlie the carcinogenicpotential of some metals.

A number of metals have been demonstrated to becarcinogenic in animals, but the mechanism bywhich carcinogenic responses are induced, and the significance of animal responses for humans,must be conducted via a careful weight-of-evidenceevaluation. Indirect mechanisms appear to beresponsible for many carcinogenic responses.Given that the mechanism of action of many metalsstudied to date appears to be unique, demonstrationthat a given mechanism of action is, or is not,relevant to human must be conducted on a case-by-case base. The principal probable exception tothis would be instances of pulmonary tumoursproduced by particulate overload mechanisms inthe rat. The ‘generic’ mechanism would be commonto inert, poorly soluble substances that inducetumour of alveolar origin in the rat following chronicinhalation exposure to high (e.g. 50 mg/m3) levelsof a given substance. Such substances would notinduce tumour in other experimental animal speciesand could produce a stronger response in femalerats than male rats. Substances exhibiting such aresponse profile should be carefully evaluated andpotentially exempted from classification.

Distinctions between genotoxic and non-genotoxiccarcinogens are also problematic when applied to

intensity and duration of exposure would beselected with a view to both maximizing mutagenicresponses and avoiding high dose effects (such astissue necrosis or apoptosis) that may produceartifactual false positives. While control for sourcesof artifactual responses is advised for any substance,it is particularly important in the testing of metalssince essential metals appear to be involved in keyprocesses that regulate cell division, differentiationand apoptosis.

Since the uptake and distribution of many metals isgoverned by specific metal-binding carrier proteins,use of physiological routes of exposure would bemost likely to yield exposure in tissues of greatestrelevance to both hazard identification andsubsequent risk assessment. Non-physiologicalroutes of exposure (e.g. intravenous or intraperitonealinjection) can increase the precision of dosing butmay bypass physiological carrier systems and failto reproduce patterns of tissue specificity thatwould characterize oral or inhalation exposures.There may further be concern that non-physiologicalexposure routes, in bypassing carrier proteinsystems, result in levels of internal exposure tofree metal ions and induce indirect mechanisms ofeffect that could not be plausibly achieved via oralor inhalation exposure.

Should positive findings be obtained during in vivotesting, appropriately designed tests will have laidthe foundations for follow-up studies that would be critical for quantitative risk assessment. Forexample, if indirect mechanisms for mutagenicityare suspected, the induction of mutations mayoccur with sharply non-linear or quasi-thresholdeddose response functions. An evaluation of the doseresponse functions for both suspected mechanismsand mutagenic effects could be initiated in relevanttarget tissues with guidance from the base settesting data.

4.6 Carcinogenicity

The ability of a substance to induce the cellularchanges which lead to cancer (i.e. its carcinogenicproperties) is an important factor for hazardclassification within the context of the ExistingSubstances Regulation (ESR) of the EU. Carcinogenicproperties will also be of fundamental importancewith the adoption of REACH, serving as a potentialmandatory trigger for REACH authorizationprovisions whereby classified substances mustobtain approval prior to use in consumer products.Carcinogenic potential can also be of importance


metals. Virtually all metals tested are genotoxic in vitro and most will also induce weak positiveresponses for in vivo genotoxicity. The presence of in vitro genotoxicity, and potentially in vivogenotoxicity, is thus uninformative with respect todetermining whether or not a metal is carcinogenic.Given the uncertain relationships betweengenotoxicity and carcinogenicity for metals, itfurther follows that carcinogenic metals should notbe automatically assumed to exert effects via agenotoxic mechanism. Alternate rules of procedureare needed whereby the relevance of genotoxicityfor metal carcinogenicity can be assessed andapplied to risk assessment. These might include,but would not be limited to, similarity in the doseresponse for induction of carcinogenic andgenotoxic effects and patterns of tissue specificityfor both effects.

Epidemiology studies have suggested associationsbetween numerous metals and human cancer.However, in a number of striking cases, initialassumptions regarding causal relationshipsbetween specific metals and human cancer havebeen shown to be the result of co-exposures toother metals in the workplace. While confoundingby co-exposures is not a specific property of metalsper se, it is reflective of the long industrial historyof metal production and a failure to fully recognizeand evaluate the complex co-exposures associatedwith metallurgical processes. The older humanepidemiology literature must thus be viewed withcaution. In particular, co-exposures to arsenic mayhave been responsible for some of the associationsthat have been reported. Better understanding ofthe dosimetry of arsenic’s effects would aidinterpretation of the historical literature as well asfuture epidemiology studies. This highlights theneed for more comprehensive and refined exposureassessments to be incorporated into futureepidemiological studies of metals. Metal ore bodiesare, by their intrinsic nature, extremely complexmixtures and the exposure environments atprimary metallurgical facilities are more complexthan had been initially realized. While excesscancer may exist at a number of primarymetallurgical facilities, the causative agents thatare responsible for these excesses can only bedefined if more comprehensive and refinedexposure assessments are conducted.

4.7 Reproductive toxicity

The reproductive effects of exposure to anysubstance (loosely defined as any adverse impactupon any aspect of mammalian reproduction) canbe an important property upon which hazardclassification and risk assessment are based. This is true within the context of the ESR, and isexpected to be of fundamental importance with theadoption of provisions within the new EU ChemicalsPolicy (REACH). Thus, impacts upon the ability toconceive (fertility) or upon pregnancy outcome(inclusive of developmental effects) will be criticaldeterminants of classification.

The reproductive effects of metals have beenevaluated within the context of EU RiskAssessments (e.g. Cd, Cu, Ni, Pb, Zn). Throughexamination of existing risk assessments, and onthe basis of consultations with experts who haveevaluated the reproductive effects of metals, itwould appear that technical procedures for theevaluation of reproductive risk developed for organicsubstances are largely suited for the evaluation ofmetals and their compounds. However, the designand interpretation of studies of reproductive impactsneeded to consider the toxicokinetic properties ofmetals and, in certain instances, the uniquemechanisms through which metal interactionscould influence reproductive system function.

Metals are diverse in their ability to impact onreproductive organs and/or to cross the placenta to impact upon the developing foetus, but it hasbecome evident that specific mechanisms existthat can regulate the ability of metals to reachtarget tissues. This is most evident for metals thatare under tight homeostatic control (e.g. copper,zinc) or which bind to common carrier systems and sequestration proteins that modulate thepharmacokinetics and homeostasis of essentialmetals. Under conditions of excessive exposure,this binding can in result in perturbations of tracemineral homeostasis that can have adverseimpacts upon development through indirectmechanisms of action. Thus excessive amounts ofzinc can induce copper deficiency in the developingfoetus and it is suspected that cadmium may exertadverse impacts via the induction of zinc deficiency.In the instance of both cadmium and zinc, effectsare not mediated by the intrinsic capacity of thematerial to impair processes such as foetaldevelopment but by indirect mechanisms (disruptionof homeostatic control mechanisms for tracemineral metabolism) that may be more properly


4.8 Quality screening procedures for healtheffects literature

Prior to initiating the effects assessment for achemical, the data and information available maysafely be assumed to vary considerably in extentand quality. As one extreme, there may be little or no information at all, meaning that newexperimental data needs to be generated before an assessment is possible. On the other hand,‘data-rich’ substances may exhibit a wealth of dataon various health end-points.

This could include toxicological studies, publishedarticles, earlier toxicological review, hand bookdata and even epidemiological studies forsubstances available and used for a longer periodof time, requiring for a scoring for reliability andquality. Depending on the extent of the data set,systematic evaluation procedures need to beapplied, which may differ in detail and extentbetween e.g. animal toxicity testing reports, humanepidemiological studies and other publishedliterature. The need for a relevance and reliabilityscreening for health effects literature may notintrinsically appear to be a metal-specific issue inrisk assessment. However, since some metals(such as lead and copper) have been found to bevery data-rich in previous EU risk assessments,specific quality and relevance scoring and evaluationsystems have already been developed in thiscontext. To support similar such efforts in thefuture, the HERAG fact sheet (No. 06) providessome generic guidance and also provides specificexamples of systematic health effects dataevaluation procedures.

Animal test dataHERAG has acknowledged the continued usefulnessof the scheme by Klimisch et al. (1997) for animalstudies to assess data for reliability, relevance andadequacy, as also endorsed by the OECD in theirExisting Chemicals Programme, as reflected intheir ‘Manual for Investigation of HPV Chemicals’.This ranking of individual experimental data isrecommended since it has facilitated transparencyin documenting how health end-points for riskcharacterization were selected based upon aweight-of-evidence approach.

Human (epidemiological) dataThe assessment of the quality and relevance ofhuman data is a more complex matter that hasbeen dealt with at varying levels of detail inprevious EU risk assessments. The examples for

regarded as manifestations of maternal toxicity.That cadmium should be classified for reproductivetoxicity, and zinc is not, in part reflects the qualityof the data demonstrating the probable mechanismof zinc’s impact relative to that for cadmium.Essential nutrients required for reproductive functionare also less likely to be classified as toxic forreproduction if the public health risks associatedwith deficiency are perceived to be greater thanthose associated with exposure excess.

Interactions are to be expected between metalsand, when these interactions mediate effects uponreproduction though the induction of trace mineraldeficiency or perturbations in basic homeostaticcontrol mechanisms, such fundamental mechanismsshould be more explicitly and transparentlyconsidered in the evaluation of data for classificationand risk characterization. Towards this end,guidelines should acknowledge that nutritionaldeficiency and perturbations in basic homeostaticcontrol mechanisms for essential metals are bothmanifestations of systemic toxicity. Careful weight-of-evidence evaluations can thus be required todetermine whether reproductive effects reflectunusual sensitivity of the developing foetus (orplacenta) to a metal or are reflective of a moregeneralized systemic perturbation in homeostasis.Specific examples illustrating this are limited, butshould be expected to increase in number astesting is extended to a broader range of metalsand their compounds. Guidelines for the definitionand demonstration of toxicity mediated throughinduction of perturbations in homeostasis foressential metals, and the subsequent induction ofnutritional deficiency are needed.

Interpretation of toxicological studies, andextrapolation from animal studies to humans, isalso facilitated if the basic dose response fordeficiency and the regulation of metal uptake,distribution, and excretion by homeostatic controlmechanisms is fully documented. Such informationfacilitates understanding of the potential mechanismsthat may underlie adverse effects, sets bounds tothe exposure levels that may or may not be ofconcern, and assists in the identification of effectsthat may reflect gross perturbations in fundamentalhomeostatic control mechanisms that should beregarded as systemic toxicity.


Cu, Zn, Pb, Cd and Ni presented in the fact sheetillustrate that the diversity between nature andextent of data sets for various metals implies thatthere likely cannot be one common approach for all metals, and that a case-by-case approach needsto be developed. In some cases, an end-point byend-point scheme had to be developed. No singleapproach was found to be clearly superior to theothers. The examples presented may help to selectthe most suitable approach, or at least provideguidance on relevant aspects which need to beconsidered in such an exercise. In doing so, oneneeds to consider the level of detail required forsome of the approaches given in the fact sheet. If too much detail is required, the screening criteriamay become so burdensome that they will beunlikely to be readily adopted. Therefore, the finalprocedure should be simple enough to not requireexcessive resources to complete while providingsufficient clarity regarding the quality of the study.Finally, for data rich substances, the application ofscreening criteria provide the basis of establishingexclusionary criteria for the conduct of sophisticatedstatistical exercises (e.g. meta-analyses) that canbe used to integrate estimates of effect and/ordose response from multiple studies of exposurehuman populations.

Genotoxicity/mutagenicity dataNumerous test systems have been developed forthe detection of mutagenic and genotoxicproperties of substances, and test systems evolveon a continuous basis. No single set of qualityassessment criteria can be applied to all testingdata, and studies must be evaluated on a case bycase basis. OECD protocols exist for some testsand OECD guideline compliance can be determinedas a first step in study quality assessment. Othertests have been evaluated by groups such as theInternational Working Group on Genotoxicity Testing(IWGT) and detailed protocol recommendationspublished. IWGT recommendations, which tend tobe published as separate papers as opposed tobeing compiled in a single repository for easyreference, serve as an additional useful source ofquality screening criteria.

As a generalization, higher quality tests examinethe effects of multiple doses in an effort todetermine whether dose-dependent effects can bedetected using concentrations of a test substancethat extend into cytotoxic ranges while at the sametime avoiding excessive cytotoxicity. Inclusion ofpositive and negative controls further aids in theevaluation of test data and controls for conditions

known to produce artefactual positive responses(e.g. necrosis or apoptosis). As further addressedin section 3.2 and the corresponding mutagenicityfact sheet, special consideration should be given tothe properties of metals when planning, conductingand evaluating experimental investigationsconcerning their mutagenic and/or genotoxicpotential. Although no single set of metal specificguidelines can be put forward, due considerationmust be given to the observation that most metalsappear to act via indirect mechanisms which, inmany instances, entail perturbations in metalcontrol mechanisms and/or the ability ofnonessential metals to substitute for essentialmetals in processes related to DNA repair and themetabolism of reactive oxygen species.

Metals also modulate processes (e.g. apoptosis andmitogenesis) that may influence assay outcomesand which therefore must be controlled if assaydata are to be interpreted in an appropriate fashion.Finally, an understanding of metal toxicokinetics,and the capacity-limited processes that govern theuptake, transport, distribution, and excretion canbe critical for the design of adequate in vivostudies. Combined, these factors introduce studyquality issues different from those that would beimportant for the study of organic substances.



RISK CHARACTERIZATION

Extensive debate during the HERAG project did notyield major concerns for the application of currentmethodologies to metals and their inorganiccompounds. However, some aspects of exposureassessment were thought to be of particularrelevance for the refinement of the riskcharacterization and these are summarized below.

5.1 Proposed scheme for the refinement ofoccupational inhalation exposure and subsequentsystemic absorption

The risk assessment of inhalation exposure (seefact sheet No. 02) for any hazardous substance mayultimately lead to a decision about which controlmeasures are required, and which exposure limitstandards need to be met to ensure adequatecontrol. For this, a most precise assessment ofexposure is needed, together with correspondinglyaccurate predictions of systemic intake and/or lungtissue target dose. For this purpose, a step-wiseprocedure was developed as shown in Figure 6.

The individual stages of this stepwise procedureare described in detail in the fact sheet. In principle,the scheme proposes a logical sequence startingwith highly conservative assumptions for exposureand absorption, leading in an iterative process tothe use of more sophisticated modelling and acombination of particle-size distribution andworkplace monitoring data.

5.2 Proposed tiered-approach for dermalexposure assessment

Similar to inhalation exposure, a tiered approachfor the refinement of systemic uptake via the dermalroute was developed, as presented in Figure 7 (see also fact sheet No. 01). This approach reflectsthe consideration that currently existing modelsprovide little guidance for metal-specific exposurescenarios, and also the necessary time, effort andcosts for a properly conducted sampling campaign.

This tiered approach proceeds through varioushypothetical situations, starting from the idealposition that adequate monitoring data areavailable, through to where assumptions can bemade based upon available data on analogousmaterials, and finally to the extreme, wheresuitable data neither exist nor can be modelled,and where generation of monitoring data is the only alternative. The various steps including thescreening model for dermal exposure are describedin detail in the corresponding fact sheet

For risk characterization, these exposure estimatesmust be coupled to appropriate values for the likelydermal absorption; again, the fact sheet makesrecommendations on the choice of default dermalabsorption factors, or (where required) on theexperimental design suitable for the investigationof measure uptake rates.

32

05. Risk Characterization



Figure 6: Decision tree for the refined assessment of inhalation absorption using particle size distribution data

Proceed to riskcharacterization

If available, useadequate experimentalanimal inhalationabsorption data torefine assessment ofdeposition andabsorption

Generate WORKPLACEPSD data using multi-stage cascadeinpactors or respiconsamplers

Use MPPD model withWORKPLACE PSD datato estimate fractionaldeposition andsystemic absorption

Conduct screeninglevel assessment usingavailable inhalationexposure data andassuming 100%systemic absorptionfrom inhalation

Use MPPD model with LABORATORYPSD data to estimatefractional depositionand systemicabsorption

Generate LABORATORYPSD data

Refinement of systemic absorption

necessary?

Workplace exposure data with

adequate PSD information

available?

Yes

No

Yes

No

Yes

OrEither

Further refinement of systemic absorption

necessary?No

5.3 General considerations for the choice ofassessment factors in risk characterization ofmetals

In several of the previous and current EU riskassessments, considerable deviations from‘conventional’ approaches of applying a standardset of assessment factors have been made. The intention of setting assessment factors is toaccount for uncertainty (see fact sheet No. 08).

This uncertainty may result from the reliability and quality of data that form the basis of a riskassessment; for this reason, such procedures weredescribed in a separate fact sheet on ‘qualityscreening of published data’. Similarly, uncertaintymay also arise from inadequate or modelledexposure data – for this purpose, separate factsheets on dermal, inhalation, indirect and consumerexposure were generated. Uncertainty in exposureassessment will be lowest when systemic exposurebiomarkers (e.g. levels of a metal in blood) areavailable. Finally, uncertainty may also originatefrom the need to extrapolate from observationsbased upon experimental animals to humans.However, several metals have a substantial database of human data, these include cadmium andlead, from which effect levels for different healthendpoints based upon measures of systemic

exposure can reliably be established. For thesereasons, a fact sheet was established to documentthese approaches with the aim of providing guidancefor future metal risk assessments. Some of theconclusions reached can be summarized asfollows:

The choice of assessment factors in riskassessments for metals should consider theexistence of natural background levels – theassumption of ‘zero’ exposure is irrelevant for most metals, because humans are subjected to amultitude of metal compounds through ambientenvironmental concentrations. This necessitates averification of no-effect-levels against environmentalbackground for plausibility; the documentation of‘baseline intake rates’ and resulting body burdensfor metals should be envisaged in futureassessments.

In addition, the occasionally small differences inexposure levels that separate toxicological effectsfrom exposure excess and deficiency for essentialtrace elements also need to be addressed (seesection 5.4). The application of traditionalassessment factor approaches to such substancesresults in permissible exposure levels that may bedetrimental to health since they would inducedeficiency.


Figure 7: Tiered approach for the assessment of dermal exposure

Tier (1)

Monitoring data are available for ametal/compound andthe scenario to beassessed

Tier (2)

Monitoring data are available for anothercompound of the metalwhich is used in acomparable scenario

Tier (3)

No monitoring data are available for anycomparable compoundof this metal

Tier (4)

A suitable analogy can not be found, or thescreening modelapproach yieldsinsufficient safetymargin

Proceed to riskcharacterization

Define exposuremodifiers and use‘analogous’ data,where available

Define exposuremodifiers and apply‘screening model’approach

Refine exposureassessment bygenerating appropriatemonitoring data

For acute effects, HERAG does not provide anyrelevant basis for setting of such values in additionto that of the TGD, recognizing at the same timethat there is currently no uniform, standardizedapproach available.

A systematic approach is however suggested in thefact sheet for the deviation from standardassessment factors for repeated dose toxicity, inthree different situations:• For non-essential elements with toxicity data

largely derived from animal testing, the application of the standard (EU TGD) approach is recommended (example: nickel).

• For non-essential elements with relevant human data, it may argued (depending on data quality and extent) for a considerable reduction of assessment factors down to as little as 1-3 (example: cadmium and lead).

• For essential trace elements, where adequate human data are available for relevant endpoints, a minimal assessment factor of ‘1’ may be adopted (example: zinc).

Particle size and chemical speciationThe extrapolation of effects seen in animal studiesto human exposure situations should recognize thedifferences in particle sizes between laboratoryexperiments (usually micronized materials) andworkplace exposures (usually much larger aerosolparticles). As an example, the zinc RAR clearlydistinguishes between effects elicited by ultra-finezinc oxide particles and by aerosols reflective of the occupational setting.

In addition, particle-size dependant deposition may deviate considerably in view of the variances in airway morphometry between animals andhumans. Furthermore, chemical speciation anddissolution kinetics will influence the translocationof deposited particles in the respiratory tract.


5.4 The influence of essentiality on riskassessment of metals

The World Health Organization regards thefollowing trace elements as essential for humanhealth: copper, zinc, iron, chromium, molybdenum,selenium, cobalt and iodine; a second group ofelements is classified by the WHO as ‘probablyessential for humans’: silicon, manganese, nickel,boron and vanadium.

Previous risk assessments have focused primarilyon the effect of high doses of chemicals, whichultimately may induce toxicity; however, for severalmetals which are essential to life, harmful effectsalso occur at very low levels of intake due todeficiency. This challenges risk assessmentparadigms that aim to minimize exposure as far as possible. Unbalanced concern over high doseeffects of essential elements may result inrecommendations that lead to harm from deficiency.

Therefore, a separate HERAG fact sheet (No. 07)has been prepared with the aim of providingguidance for careful consideration of bothnutritional essentiality and high dose toxicity in theoverall risk assessment and risk characterizationprocedures for essential metals and theircompounds. The reader is cautioned to the fact thatthis fact sheet was largely based on a retrospectiveanalysis of the zinc and copper risk assessments.Whereas it is acknowledged that the aspect ofessentiality has also been recognized for othermetals (such as iron and selenium), none of thesehave been subject to a comprehensive (EU) riskassessment, and therefore experience in thereflection of this aspect in the establishment ofassessment factors is not available.

In brief the definition of essentiality for humanhealth is that absence or deficiency of any suchelement from diet produces either functional orstructural abnormalities related to or a consequenceof specific biochemical changes that can bereversed by the presence of the essential metal.Essential trace elements are subject to homeostaticcontrol mechanisms that may include regulation ofabsorption and/or excretion and tissue retention,and enable adaptation to varying nutrient intakes to ensure a safe and optimum systemic supply.


A structured scheme for the assessment ofessentiality (depending on the quality and extent of data available) is suggested. In this, in order toavoid confusion with the concept of ‘no effect levels’used for high dose toxicity, the new terms‘sufficient dietary intake9’ (SDI) and ‘deficiencyeffects level10’ (DEL) as developed in the copper VRA are proposed as boundary terms for effects at low intakes.

For such an assessment, data need to be extractedlargely from nutritional studies, which have intrinsiclimitation; therefore, a separate set of qualityscreening criteria (Plunkett, 2004) have beendeveloped. Klimisch criteria are not useful in thiscontext as they were not designed to assess thepotential adverse consequences of deficientexposures.

Given the current restriction of previously conductedwork to copper, it would be desirable to have thesame concept and level of detail applied to otherelements such zinc and possibly also iron asfurther examples. It was recognized that such workis outside the current scope of the HERAG project,and is therefore highlighted as an issue for futureconsideration.

9 The dose/intake level in a given study at which no adverse healthconsequences associated with intake are observed in any of themeasured endpoints.10 The dose/intake level at which potentially adverse health consequencesassociated with deficiency are first observed. For studies with only oneexperimental dose, the DEL is considered to be that dose if adversehealth consequences are observed relative to controls (basal diet).


REFERENCES


Hughson and Cherrie (2002)Identification of practical maximum levels ofdermal dust exposure for zinc oxide and zinc metaldusts. Institute for Occupational Medicine, Edinburgh, UK.Report No. TM/02/03, September 2002.

ICRP (1994)Human Respiratory tract model for radiologicalprotection.ICRP Publication 66, Annals of the ICRP 24 (1-3),22-25, Pergamon/Elsevier Science, UK, USA,Japan.

ISO (1992)Air quality – particle size fraction definitions forhealth-related sampling. Technical report ISO/TR/7708-1983, ISO, Geneva,1983 (revised 1992).

Klimisch H.J. et al. (1997)A systematic approach for evaluating the quality ofexperimental and ecotoxicological data.Reg. Tox. and Pharm. 25, 1-5 (1997).

Krüse et al (2007)Analysis, Interpretation, and Extrapolation ofDermal Permeation Data Using Diffusion-BasedMathematical Models.J. Pharm. Sci., Vol. 96, No. 3, 682-703, 2007.

Lansink (1996)Skin exposure to calcium carbonate in the paintindustry. Preliminary modelling of skin exposurelevels to powders based on field data. TNO Nutrition and Food Research Institute, The Netherlands. Report No. V 96.064, June 1996.

Moss et al. (2002)Quantitative structure-permeability relationships(QSPRs) for percutaneous absorption. Toxicology In Vitro 16, 299-317, 2002.

Plunkett (2004)Personal communication, criteria developed forrating the utility and quality of studies of excess ordeficiency of essential.Presented at the U.S. Society of Toxicology Meeting,Baltimore, MD, March, 2004.

38

06. References

Asgharian and Freijer (1999)Multiple-Path Particle Deposition Model (MPPDep). Chemical Industry Institute of Toxicology (CIIT), USA;National Institute of Public Health and theEnvironment (RIVM), the Netherlands, and The Ministry of Housing, Spatial Planning and theEnvironment, the Netherlands, version 1.11.

Bunge and Cleek (1995)A New Method for Estimating Dermal Absorptionfrom Chemical Exposure: 2. Effect of MolecularWight and Octanol-Water Partitioning. Pharmaceutical Research. Vol. 12, No. 1, 88-95,1995.

Bunge et al. (1995)A New Method for Estimating Dermal Absorptionfrom Chemical Exposure: 3. Compared withSteady-State Methods for Prediction and DataAnalysis. Pharmaceutical Research. Vol. 12, No. 7, 972-982,1995.

CEN (1993) Workplace atmospheres – size fraction definitionsfor measurement of airborne particles.CEN, European Committee for Standardisation,European Standard EN 481.

Cherrie et al. (2006)How Important is Inadvertent Ingestion ofHazardous Substances at Work?Ann Occup Hyg. 50, 693-704, 2006.

Cleek and Bunge (1993)A New Method for Estimating Dermal Absorptionfrom Chemical Exposure: 1. General Approach. Pharmaceutical Research Vol. 10, No. 4, 497-506,1993.

Corish and Fitzpatrick (2002)Theoretical Models of Percutaneous Absorption.Proceedings of the International Conference onOccupational & Environmental Exposure of Skin toChemicals.Science & Policy. Arlington, 8-11 September 2002.

Creely et al. (2005)Evaluation and Further Development of EASEModel 2.0.Annals of Occupational Hygiene, Vol. 49, No. 2,2005.


Rajan et al. (1997)European Proposal for Core Information for the Storage and Exchange of Workplace Exposure Measurements on Chemical Agents. Applied Occupational and Environmental Hygiene 12(1), 31-39, 1997.

Ritchie and Cherrie (2001)The Development of a Prototype Database for the Voluntary Reporting of Occupational Exposure Data on Chemicals. Applied Occupational and Environmental Hygiene 16(2), 295-299, 2001.

ten Berge (2006)Skin permeation model.Last updated 25 July 2007.http://home.wxs.nl/~wtberge/qsarperm.html

Vincent (1998)International Occupational Exposure Standards: A Review and Commentary. American Industrial Hygiene Association Journal 59, 729-742, 1998.

Witschger (2001)Sampling for particulate airborne contaminants – Review and analysis of techniques.Report IRSN No. DPEA/SERAC/LPMAC/02-18 in the final report on the SMOPIE project (Annex 3, Appendix 1). Available for download atwww.nrg-nl.com/docs/smopie2004/SMOPIE_Annex3_Appendix1.pdf

39

Credits

The views expressed in this publication do notnecessarily reflect those of ICMM.

Published: September 2007 by ICMM, London, UK.

©2007, the International Council on Mining andMetals

Reproduction of this publication for educational orother non-commercial purposes is authorizedwithout prior written permission from the copyrightholders provided the source is fully acknowledged.Reproduction of this publication for resale or othercommercial purposes is prohibited without priorwritten permission of the copyright holders.

ICMM (2007). HERAG: Health Risk AssessmentGuidance for Metals

ISBN: 978-0-9553591-4-9

Design: DuoPrint: Quadracolor Limited

Available online and in hard copy from ICMM,www.icmm.com, [email protected]

This book is printed on Challenger Offset 250gsmand 150gsm. The paper is made from ECF(Elemental Chlorine Free) wood pulps, acquiredfrom sustainable forest reserves, and is fullyrecyclable with no harmful residue. Accordant toEMAS and ISO 14001 the international standardthat specifies a process for controlling andimproving a companies environmental performance.


The content of the HERAG fact sheetsreflects the recent experience andprogress made with human health riskassessment methods and concepts formetals. Since the science constantlyevolves these fact sheets will be updated and supplemented as required to take into account new developments.To ensure that you have the most recentfact sheet please check the website:www.metalsriskassessment.org

This CD-ROM also contains the output of the related MERAG project (MetalsEnvironmental Risk AssessmentGuidance). MERAG is available as aseparate publication and furtherinformation can be obtained from ICMM or found at the website shown above.

FACT SHEETSVersion 01

Metals Environmental Risk Assessment Guidance

MERAG

Health Risk AssessmentGuidance for Metals

HERAG

ICMM35 Portman SquareLondon W1H 6LRUnited Kingdom

Phone: +44 (0) 20 7467 5070Fax: +44 (0) 20 7467 5071Email: [email protected] [email protected]

www.icmm.com

ICMMThe International Council on Mining and Metals (ICMM) is theindustry’s peak CEO-led organization. It comprises the leadinginternational mining and metals companies as well as regional,national and commodity associations. ICMM’s vision is arespected leadership group that is recognized as a keycontributor to sustainable development, in a mining and metalsindustry whose activities and products are widely regarded asessential for society.

Our library at www.goodpracticemining.com has case studiesand other examples of leading practices.

EurometauxEurometaux constitutes the interface between the Europeannon-ferrous metals industry and the European authorities andinternational or intergovernmental bodies. It is committed toestablishing dialogue with the latter in order to ensure earlyconsultation in all fields of policy and legislation that may affectindustry and to asserting the sector’s views and positions in thisrespect. It asserts the contribution of the European industryand its products to sustainable development, as well as thisindustry’s views and positions, whenever the opportunity to doso arises across all sectors of society.

www.eurometaux.org

EuroferEurofer is the European Confederation of Iron and SteelIndustries; founded in 1976, its offices are located in Brussels.The objectives of Eurofer are the co-operation amongst thenational federations and companies in all matters thatcontribute to the development of the European steel industry,and the representation of the common interests of its membersvis-à-vis third parties, notably the European institutions andother international organizations.

www.eurofer.org

EBRCEBRC is a privately-owned consulting organisation based inHannover, Germany, providing consulting services with a focuson chemical, biocidal and agrochemical industries. EBRC wasestablished in 1993 as a spin-off from a former contractresearch organisation and has specialized scientific experiencein all key disciplines relevant for product safety with respect tohuman health and environment. EBRC has acted as a keyconsultant in several EU risk assessments for metals, includingzinc, copper, lead and antimony, among others. In addition,EBRC has provided complete dossiers for a wide range ofbiocidal and plant protection agents within the EU existingsubstances review programme.

www.ebrc.de

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