Risk Assessment

• Typically decomposed into four steps:– Hazard Identification– Dose-Response Assessment– Exposure Assessment– Risk Characterization

Hazard Identification

• Determine the nature of the hazard:– Exposure pathways of concern, e.g.

• Ingestion

• Inhalation

• Dermal contact

• Puncture

– Toxic endpoints, e.g.• Lethal vs. non-lethal

• Chronic vs. Acute

Acute Toxicity

• Acute toxins result in observed endpoints after few exposures, in short timeframe

• For lethal endpoints, toxicity is a measure of the amount of exposure required to produce death– Example endpoints: chemical poisoning,

radiation sickness

Chronic Toxicity

• Chronic toxins produce observed endpoints only after repeated exposures and/or considerable elapsed time

• Like acute toxicity, may be lethal or non-lethal

• Toxicity may be cumulative or not (e.g. mercury vs. carbon monoxide)– Example endpoints: cancer, birth defects

Measuring Toxicity

• Need measures of dose which causes toxic endpoint

• Measurements for ingested toxins ordinarily normalized for body weight (e.g. mg/kg)

• Must generalize from populations of experimental subjects

• For lethal endpoints can use LD50

But LD50 is limited!

e.g.: here A is always more toxic than B

but A can be less toxic than C, even with lower LD50

Toxicology vs. Epidemiology

• Toxicology answers the wrong question well

• Epidemiology answers the right question poorly

Toxicology

• Controlled laboratory experimental conditions

but

• Surrogate subjects (usually animals)

• Exaggerated doses

Extrapolating High to Low Dose

• Experimental studies produce minimum detectable responses on order of a percent

• Desire information on order of 10-6

• It’s virtually impossible to perform lab studies with N large enough (e.g. megarat)

We need a mathematical model to perform extrapolation

Designing Toxicology Experiments

• Selection of subject species

• Control design

• Multiple dose levels (at high levels to produce observable effect in relatively small number of subjects)

Epidemiology

• Human subjects

• Realistic doses

but

• Uncontrolled experimental conditions

Dose-Response Assessment

• Relating Dose to (adverse) response

• “Response” typically described as a probability (unitless fraction or percent)

• Dose-Response Curve– Dose on the abscissa– Response on the ordinate– Intercept with abscissa is “threshold dose”

Potency Factors(a.k.a. Slope Factors)

• For chronic chemical toxicity (e.g. cancer),Potency Factor slope of the low dose DR curve

where Chronic Daily Intake (CDI) is measured in units of mg/kg/day

Potency Factors (cont’d)

• Re-arranging,Incremental Lifetime Cancer Risk = CDI PF

• Potency Factors are available from EPA’s Integrated Risk Information System (IRIS):

http://www.epa.gov/iris

Exposure Assessment

• Risk has two components:– Toxicity of the substance– Exposure of humans to substance

• Exposure often forgotten (see, for example, the Scientific American article comparing indoor pollution to outdoor pollution)

Exposure Pathways

• The route by which a toxin or hazard reaches the human influences its impact

• Internal factors would include the human contact route (e.g. inhalation, ingestion, &c)

• External factors would include the physical transport (e.g. distance and travel time in air or water, &c)

Exposure Routes and Effects

• Principle routes for chemicals:– Ingestion– Dermal– Inhalation

• Other routes for hazard exposure:– Puncture– Eyes– Ears

Gastrointestinal Exposures

• Chemicals gain direct access to mucous membranes in stomach and intestines, allowing transfer of chemical to bloodstream

• Digestive processes can transform chemicals into others

• Physical hazard endpoints can apply (e.g. with ingested acids)

Dermal Exposure

• Epidermis consists of former living cells– Removed from blood vessels to some extent– Acts as barrier to loss of fluids and entry of

contaminants

• Some materials are able to pass this barrier– Solvents which can be absorbed into the skin– Pores and hair follicles

Inhalation

• Rapid route of entry to bloodstream

• Alveoli designed to facilitate transfer of gases (oxygen and carbon dioxide)– Effectively transfer other materials too

Distribution of Toxicants

• Two factors govern transport:– Protein binding -

• Toxicants can bind to proteins in the blood, thus preventing their access to surrounding cells through capillary walls

• But access to kidneys (for removal) is also inhibited

– Polarity -• Polar toxicants obstructed by non-polar membranes• Nonpolar toxicants dissolve through readily and can be

stored in body fat

Metabolism

• Conversion of materials through reaction

• For toxicants, tendency is to increase polarization (and therefore reduce bio-uptake)

• In some cases chemicals can be converted into more toxic materials

Pollution Control in the Body

• Kidneys

• Liver

Kidney Function

• Blood flowing through kidneys is exposed to porous membrane– the (relatively) small molecules of toxins pass

– substantial quantities of water also pass

• Aqueous solution passes along tubes which selectively retrieve desirable nutrients, water &c

• Concentrated aqueous toxins expelled as urine

Liver Function

• Metabolize toxicants into more polar structures

• Some substances removed from blood and transformed into bile, stored in gall bladder

• Gall bladder sends bile into small intestine to assist with digestion

• Toxins therefore eliminated with feces (unless resorbed by intestinal walls)

Lifetime Exposure

where a 70-year lifetime is assumed

Risk Characterization

• Bring Dose-Response together with Exposure assessment to estimate risk

Example: Chloroform in Drinking Water

• Suppose your drinking water has 0.10 mg/L concentration of chloroform (CHCl3)

• From IRIS, PF = 6.1x10-3 (mg/kg/day)-1

• So incremental lifetime cancer risk is

Chloroform Example (cont’d)

• In a city of 500,000 people:

General Exposure

Example: Occupational Exposure

• A 60 kg person works 5 days/week, 50 weeks/yr, for 25 years

• Each workday they breathe 20/3 m3 of air containing 0.05 mg/m3 of toxin

Example (cont’d)

• If the Potency Factor is 0.02 (mg/kg/day)-1:

Non-carcinogenic Doses

• Metrics from toxicity experiments include– Lowest Observed Effect Level (LOEL)– Lowest Observed Adverse Effect Level (LOAEL)– No Observed Effect Level (NOEL)– No Observed Adverse Effect Level (NOAEL)

• Note: NOEL and NOAEL are the highest experimental doses at which no (adverse) effect was seen

Reference Dose

• The Reference Dose (RfD) is taken from the NOAEL:

• Where Uncertainty Factors are 10 each fordifferences across populationusing animal data to estimate human endpointsusing only a single species of animal

Hazard Quotient

• Compares exposure to Reference Dose:

• HQ < 1 should be free of significant risk of toxicity

Hazard Index

• Considers multiple risks (e.g. from multiple chemical toxins)

• The sum of the Hazard Quotients:

Other Factors in Risk Characterization

• Also consider– Statistical uncertainties– Biological uncertainties– Selection of applicable dose-response and

exposure data– Selection of population groups toward which

the risk assessment should be targeted

Occupational Standards revisited

• The standards set by OSHA (and ACGIH and NIOSH) are based upon such risk assessment analyses

Occupational Standards: TWA

• The Time-Weighted Average (TWA) assumes an 8-hour day and 40-hour week

TWA Example

So TWA = 120 ppm / 40 hours = 3 ppm

Occupational Standards: STEL

• Short Term Exposure Level

• Calculated as a 15-minute TWA

• Allowed no more than four such exposure periods per day, separated by at least 1 hour

Occupational Standards: Ceiling

• Concentration which must not be exceeded, regardless of duration of exposure.