Toxicology Summary

1. Toxicology (Summary) Exposure + Hazard = Risk All substances can be a poison Dose determines the response Pathway, duration and frequency of exposure and chemical determine dose Absorption, distribution, metabolism & excretion The extent of the effect is dependent upon the concentration of the active compound at site of action over time Bioactivation: compounds to reactive metabolites Individual variation of the organism will affect ADME

2. Dose (intake) X Toxicity = Risk The does makes the poison Dose/intake are exposure That is: no matter how dangerous the toxicant no risk without exposure

3. Risk Technical # of people that will be injured, become ill, or die Non-Technical Upsetting, frightening, or enraging

4. Risk Assessment A process or method by which we assess the nature and magnitude of risk. hazardous waste disposal and chemicals new and existing technologies site facilities set priorities develop cleanup goals

5. Risk- the likelihood or possibility of suffering injury, disease, or death from a hazard Hazard-a source of risk, refers to a substance or action that can cause harm a hazard can not constitute a risk unless there is exposure

6. 1983 NRC Report- Risk Assessment in the Federal Government: Managing the Process 1. Hazard identification 2. Dose-response assessment 3. Exposure assessment 4. Risk characterization

7. Congressional Commission on Risk Assessment � Risk Assessment and Risk Management in Regulatory Decision-Making (1997)

8. Hazard Identification Determining whether a chemical, under plausible circumstances, may cause harm to human health or the environment

9. Types of Information 1. Epidemiological studies 2. Animal bioassays 3. In vitro tests 4. SAR analyses

10. Animal Bioassays acute studies subchronic studies chronic studies

11. Acute studies single exposure, multiple doses observed up to 14 days LD50, LC50

12. Subchronic Studies Repeated exposures, 5 to 90 days variable exposure routes 3 doses NOEL, LOEL vs. NOAEL, LOAEL determine MTD

13. Chronic Studies Several doses- MTD, 1/2 or 1/4 MTD, 0 majority of lifetime (2 years rodent) lower doses, larger N = subtle effects long time, high cost

14. Exposure Assessment Estimate or directly measure the quantities of chemicals received by individuals, populations, or ecosystems no risk without exposure output is quantitative, used in Risk Charterization

15. Questions to Answer Which chemicals reach target? How much exposure? In what way? For how long? Under what circumstances?

16. Biomonitoring- measuring a chemical or its byproducts in tissues or fluids as an indicator of exposure (exposure vs effect) rarely done- expensive, limited tests time issues

17. Ambient Monitoring Monitoring contaminants in media (soil, air, water, etc.) to estimate exposure point concentrations (EPCs) when inadequate, often use modeling

18. Goal of modeling or ambient monitoring calculate an intake or dose for organism Dose (intake, exposure) x Toxicity = Risk

19. Intake = C x CR x EFD BW x AT  I is intake or dose C is chemical concentration CR is contact rate EFD is exposure frequency and duration BW is body weight AT is averaging time

20. These equations are used to calculate doses from exposure pathways values for inputs are as realistic as research allows (Exposure Factors Handbook) but many uncertainties exist

21. At GAEPD, evaluate Reasonably Maximally- Exposed Individual (RME) not a worst case scenario may be appropriate to contrast with exposure estimates calculated from central tendency estimates Probability Density Functions (Monte Carlo simulations)

22. Total Dose (Intake) = sum of all doses from individual pathways chronic versus intermittent exposures? aggregate

23. DOSE-RESPONSE ASSESSMENT Intake x Toxicity = Risk often must extrapolate from animal studies two important assumptions 1. Thresholds for non-cancer 2. No thresholds for cancer

27. Thresholds exist for most biological effects Doses exist below which no adverse effects are observable in a population of exposed individuals

28. Thresholds do not exist for carcinogens. Any level of exposure to the chemical corresponds to some non-zero increase of inducing genotoxic effects.

29. Non-cancer evaluation Reference Dose- an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily or continuous exposure for human populations, including sensitive subgroups, that is likely to be without appreciable risks of deleterious effects occurring in a lifetime.

30. RfD = NOAEL or LOAELUFs x MFs NOAEL OR LOAEL for critical effect

31. UF 1 to 10 to account for: Variation in humans extrapolation from animals to humans subchronic instead of chronic LOAEL instead of NOAEL

32. Assumptions Population threshold exists RfD estimate represents subthreshold doses preventing critical effect protects against all effects

33. CANCER EVALUATION EPA�s guidelines published in 1986 weight of evidence- all human and animal

34. �86 Scheme Group A- known human carcinogen sufficient human data Group B- probable human carcinogen B1- limited human, sufficient animal data B2- inadequate human, sufficient animal data

35. Group C- possible human equivocable animal data Group D- not classifiable inadequate or no data Group E- evidence of noncarcinogenicity

36. Current practice Data (usually animal) fit with model to extrapolate into low dose range EPA uses Linearized Multistage Model

37. LMS Accommodates nonlinearity at high doses Constrains results to linear form at low doses Based on current understanding of cancer as multistage process

38. LMS Output in form of �slope factor� Represents steepness of dose-response curve (larger number = more potent) Slope factor represents upper bound (95th percentile) caner risk per unit dose

39. Risk Characterization Where all components of assessment are brought together in a quantitative evaluation and transparent qualitative discussion

40. Integrate information from Haz ID, Dose-Response, and Exp Assess discuss overall quality, degree of confidence in estimates and conclusions (uncertainty) describe risk to individuals and populations (extent, severity, probable harm)

41. Calculating risk (numeric) and hazard indices Non-cancer- hazard quotient, hazard index HQ = intake/ RfD Both intake and RfD have units of mg/kg-day

42. HQ < 1.0 � no detrimental effects HQ > 1.0 � potential for effects to occur HI is sum of HQs Summing based on assumption of additivity of effects

43. Cancer risk Calculate �theoretical lifetime� Cancer risk from estimated exposure or intake Excess or additional risk Upper-bound on risk

44. Risk = Intake x SF Intake units of mg/kg-day SF units of 1/(mg/kg-day) Risk is unitless (probability) Sum cancer risk for all chemicals

45. Risk Char Discussion Confidence in key site-related chemical identity and conc. relative to background Describe types of cancer and health effects, distinguish between known effects in humans versus animal derived or predicted

46. Confidence in quantitative tox info used to estimate risk, and qualitative info on chemicals not included in assessment Confide in exposure estimates for key pathways and inputs Magnitude of cancer risks and non-cancer HIs

47. Major factors driving risk (chem., pways, and pway combinations) Major factors reducing certainties and the significance of uncertainties (ex. adding risk over chemicals and pways) Exposed population characteristics

48. Risk = Hazard + Outrage(the non-technical side) Voluntary vs. Involuntary Natural vs. Industrial Familiar vs. Exotic Dreaded or Not The last thing that I want to discuss is the non-technical side of risk - the emotional side. There are a number of factors that influence how people feel about risk. In fact, if you ranked hazards by mortality and ranked them by outrage they don�t line up. (BULLET) The first point to consider most are aware of. Is the risk voluntary or involuntary? People are willing to take much greater risks if it is their choice. Smoking is a great example. 350,000-450,000 people die each year from smoking, but how many of those people would �freak out� if they learned their water was contaminated with a carcinogen? (BULLET) Is the exposure due to natural causes or industrial causes? In New Jersey 30% of the homes have enough radon in them to increase their risk of cancer to 1 in 200, yet most people won�t spend $20 to test for radon. But if radon was a byproduct from some industry down the street, you can bet there would be law suits galore. (BULLET) Is the substance familiar or exotic? TCE vs. air pollution (BULLET) Is the health effect dreaded? Cancer vs. asthma The last thing that I want to discuss is the non-technical side of risk - the emotional side. There are a number of factors that influence how people feel about risk. In fact, if you ranked hazards by mortality and ranked them by outrage they don�t line up. (BULLET) The first point to consider most are aware of. Is the risk voluntary or involuntary? People are willing to take much greater risks if it is their choice. Smoking is a great example. 350,000-450,000 people die each year from smoking, but how many of those people would �freak out� if they learned their water was contaminated with a carcinogen? (BULLET) Is the exposure due to natural causes or industrial causes? In New Jersey 30% of the homes have enough radon in them to increase their risk of cancer to 1 in 200, yet most people won�t spend $20 to test for radon. But if radon was a byproduct from some industry down the street, you can bet there would be law suits galore. (BULLET) Is the substance familiar or exotic? TCE vs. air pollution (BULLET) Is the health effect dreaded? Cancer vs. asthma

49. WEB RESOURCES www.epa.gov/ncea/raf/cancer.htm Draft revised guidelines for carcinogenic risk assessment (1999) www.epa.gov/iris/ Methylmercury Polychorinated biphenyls