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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
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Goals of this lecture
• Outstanding issues?
• Explore issues and methods in exposure assessment– Pathways of exposure– Pathways following exposure
• Explore some data sets!
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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
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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.
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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
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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.
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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
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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
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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
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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
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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
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From:Paustenbach, DJ. (2000) The practice of exposure assessment: a state-of-the-art review. J Toxicol Env Health, 3:179-291
Exposure Pathways
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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).
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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.
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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
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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.
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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)
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Integrated Exposure
• “Area under the curve” or AUC
• Exposure profile
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Issues in Dose and ResponseB
lood
lead
leve
ls
Time (Days)
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Time-Weighted Average
• TWA
• Total dose divided by time period of dosing
• This is what we used for toxicology assumption
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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
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Empirical Data
• Direct measurement
• Usually measures applied dose
• A variety of methods and equipment have been developed
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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
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Modeling Exposure
• “Exposure Scenarios”
• Recreating past doses
• Predicting future doses
• Two major components– Chemical concentrations (including time
trends)– Population characterizations
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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
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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
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Dermal exposure
• Cutaneous permeability
• Dermal bioavailability
• Skin surface area
• Soil loading on the skin
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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)
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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?
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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
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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
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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
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It’s all about the algebra
• http://www.epa.gov/epaoswer/hazwaste/combust/tech/risk/apx_c-e.pdf