Exposure Assessment

Thanks to Marc Rigas, PhD for an earlier version of this lecture

Much of the materials is drawn from

Paustenbach, DJ. (2000) The practice of exposure assessment: a state-of-the-art review. J Toxicol Env Health,

3:179-291

Goals of this lecture

• Outstanding issues?

• Explore issues and methods in exposure assessment– Pathways of exposure– Pathways following exposure

• Explore some data sets!

Exposure and Dose-Response

• If Risk = Exposure × Potency

• Epidemiology and Toxicology provide potency data

• Exposure assessment explores exposure!

• In reverse, dose reconstruction is essential to good epidemiology

Definitions

• Exposure– The contact with a chemical, biological, or physical agent

at the boundary of the body over a specified time.

• Exposure Route– How a substance contacts the body and results in an

internal dose (inhalation, ingestion, dermal penetration).

• Boundaries of the body– By Exposure Route: For inhalation, could be the tissue

in the lung separating air from blood. For ingestion, the layer of cells, lining the gastrointestinal tract.

Definitions II

• Exposure Pathway– How a substance moves from the source to the

receptor (in this case, people).

• Intake– Amount of substance that is inhaled or consumed

• Uptake– Amount or fraction of intake that passes through a

boundary of the body

Definitions III

• Dose– Applied Dose: amount available at a boundary– Potential Dose: amount ingested or inhaled– Internal Dose: the amount of a substance

crossing one of the route barriers into the body

– Biologically-effective dose: the amount of a substance reaching a target organ.

Definitions IV

• Bioavailability– Most research is on ORAL, but also some on

dermal and inhalation– Fraction of the administered dose that

reaches the central (blood) compartment– Relative bioavailability compares different

FORMS or MEDIA

Why assess exposure?(Isn’t it EASY?!)

• Determine factors that put segments of the population at higher risk to chemical toxicity

• Help establish dose-response relationships in the “real world”

• Hazard = Toxicity x Exposure

Three elements of exposure assessment

• Transportation, transformation and fate processes – Before it meets up with people

• Exposures– As it meets up with people

• Physiologically based pharmacokinetics (PBPK)– What goes on IN people

Exposure Elements

SOURCE/STRESSORFORMATION

DOSE

EFFECT

AcuteChronic

DispersionKineticsThermodynamicsSpatial variabilityDistributionMeteorology

AirWaterDietSoil and dustGroundwater

TargetAbsorbedApplied

ChemicalMicrobial

TRANSPORT/TRANSFORMATION

ENVIRONMENTALCHARACTERIZATION

EXPOSURE

PathwayDurationFrequencyMagnitude

Statistical profileReference populationSusceptible individualSusceptible subpopulationsPopulation distributions

• Individual• Community• Population

Transport, Transformation,and Fate Process Models

ExposureModels

PBPKModels

ACTIVITYPATTTERN

Uses of Exposure Assessment in Risk Assessment

• Used to estimate internal dose which, with dose response data (usually in animals), is used to estimate risk.

• For risk-based regulations, provides the link to emissions (point source, consumer products, area sources).

• Evaluation of efficacy of cleanup (risk to most exposed subgroup).

Hazard IdentificationDose-response assessmentExposure AssessmentRisk CharacterizationRisk Communication

From:Paustenbach, DJ. (2000) The practice of exposure assessment: a state-of-the-art review. J Toxicol Env Health, 3:179-291

Exposure Pathways

Use Exposure Assessment for Status and Trends

• Determine exposure at a particular place and time as well as trends over time.

• Provide a profile of a population or a population segment.

• Establish effectiveness of risk mitigation strategy (regulations).

Exposure Assessment in Epidemiology

• A goal of epidemiology is to establish a dose-response relationship to a contaminant and to identify an exposed population.

• Improve the chances of identifying a valid dose-response relationship.

• Reduces misclassification in epidemiological studies.

Use of Exposure Assessment in Epidemiology

• Case-Control studies: relates disease incidence to exposure by comparing health outcomes in a group that has exposure and one that doesn’t

• Reconstruction based on questionnaire– Questions asked concerning activities or

locations that may result in exposure

Population based studies

• Exposure reconstruction or assignment of exposure classification (i.e., high, medium, low)

• Personal monitoring– I.e. collect water at home along with water use

information– Time period? Latency?

• Exposure modeling– Assess individual exposure OR generate a population

base distribution for boundaries on risk assessment.

Aggregate Exposure

• Sum total of exposure to a chemical via ALL routes of exposure and in all media

• Concentration times duration

• DDT:– 6 to 10 sources (fruits and veggies)– Three routes (air, food, water)

Integrated Exposure

• “Area under the curve” or AUC

• Exposure profile

Issues in Dose and ResponseB

lood

lead

leve

ls

Time (Days)

Time-Weighted Average

• TWA

• Total dose divided by time period of dosing

• This is what we used for toxicology assumption

Lifetime Average Daily Dose

• 72 year old person• Has eaten lettuce

since age 4 (14,000 kg)

• Bioavailability• 4 mg Aldrin per kg

lettuce

LTBW

BDIRCLADD

Empirical Data

• Direct measurement

• Usually measures applied dose

• A variety of methods and equipment have been developed

Biological Monitoring

• Body burden levels or biomarkers• Concentration of chemical in tissues or sera

– Usually not the tissue of concern– Need to understand internal dose relationship

• Concentration of the chemical’s metabolites• Biological response chemicals• Chemical or metabolites bound to target

molecules

Modeling Exposure

• “Exposure Scenarios”

• Recreating past doses

• Predicting future doses

• Two major components– Chemical concentrations (including time

trends)– Population characterizations

Exposure Factors Handbook

• Drinking water consumption rates

• Breast milk consumption rates

• Consumption rates of foods

• Soil ingestion rates• Breathing rates

• Body surface areas• Body weights• Shower times,

intensities, temperatures

• Animal exposures– Domestic– Wildlife

Standard Regulatory Defaults

• Point estimates– 2 L water / day, RME adult– 1.4 L water / day, Avg. adult– 1.0 L water / day, avg child

• Variability?– Geographic– Cultural

• Variability versus central tendencies

Dermal exposure

• Cutaneous permeability

• Dermal bioavailability

• Skin surface area

• Soil loading on the skin

Skin uptake of a chemical in soil

• Uptake = C × A × r × B

• C in mg material per kg soil

• A in cm2

• r in mg / cm2

• B is unitless (bioavailability)

Monte Carlo Analysis

• Uptake = C × A × r × B

• What if we know distributions of C, A, and r, and uncertainty surrounding B!

• MEI (maximally exposed individual)

• 95% worst case for each?

• 1 - (1-0.95)4 = 99.9994 case?

Monte Carlo Analysis

• A taste:

• C = lognormal (12 mg / kg, 3 mg / kg)

• A = 500 cm2

• r = uniform (0.015 kg / cm2,0.025 kg / cm2)

• B = lognormal (0.75, 0.02)

• Mean Uptake = 70 mg

• Upper 95%? = 180 mg / kg

Monte Carlo Analysis

• 95% upper CI?

• C = lognormal (12 mg / kg, 3)

• A = 500 cm2

• r = uniform (0.015 kg / cm2,0.025 kg / cm2)

• B = lognormal (0.75, 0.02)

• Uptake = 70 mg

Monte Carlo Uptake?

Frequency Chart

Certainty is 95.00% from 49.19 to 151.37 mg

.000

.006

.013

.019

.025

0

63

126

189

252

26.86 59.54 92.22 124.90 157.58

10,000 Trials 9,828 Displayed

Forecast: Uptake

It’s all about the algebra

• http://www.epa.gov/epaoswer/hazwaste/combust/tech/risk/apx_c-e.pdf