1. 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

2. Goals of this lecture Outstanding issues? Explore issues and methods in exposure assessment –Pathways of exposure –Pathways following exposure Explore some data sets!

3. 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

4. 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.

5. 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

6. 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.

7. 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

8. 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

9. 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

10. Exposure Elements

11. 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 Identification Dose-response assessment Exposure Assessment Risk Characterization Risk Communication

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

13. 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).

14. 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.

15. 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

16. 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.

17. 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)

18. Integrated Exposure “Area under the curve” or AUC Exposure profile

19. Issues in Dose and Response Blood lead levels Time (Days)

20. Time-Weighted Average TWA Total dose divided by time period of dosing This is what we used for toxicology assumption

21. Lifetime Average Daily Dose 72 year old person Has eaten lettuce since age 4 (14,000 kg) Bioavailability 4 mg Aldrin per kg lettuce

22. Empirical Data Direct measurement Usually measures applied dose A variety of methods and equipment have been developed

23. 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

24. Modeling Exposure “Exposure Scenarios” Recreating past doses Predicting future doses Two major components –Chemical concentrations (including time trends) –Population characterizations

25. 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 –WildlifeWildlife

26. 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

27. Dermal exposure Cutaneous permeability Dermal bioavailability Skin surface area Soil loading on the skin

28. Skin uptake of a chemical in soil Uptake = C × A × r × B C in mg material per kg soil A in cm 2 r in mg / cm 2 B is unitless (bioavailability)

29. 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?

30. Monte Carlo Analysis A taste: C = lognormal (12 mg / kg, 3 mg / kg) A = 500 cm 2 r = uniform (0.015 kg / cm 2,0.025 kg / cm 2 ) B = lognormal (0.75, 0.02) Mean Uptake = 70 mg Upper 95%? = 180 mg / kg

31. Monte Carlo Analysis 95% upper CI? C = lognormal (12 mg / kg, 3) A = 500 cm 2 r = uniform (0.015 kg / cm 2,0.025 kg / cm 2 ) B = lognormal (0.75, 0.02) Uptake = 70 mg

32. Monte Carlo Uptake?

33. It’s all about the algebra http://www.epa.gov/epaoswer/hazwaste/combust/tech/risk/apx_c-e.pdf