1. Regulatory Toxicology James Swenberg, D.V.M., Ph.D.

2. Acute Toxicity Studies Single dose - rat, mouse (5/sex/dose), dog, monkey (1/sex/dose) 14 day observation In-life observations (body wt., food consumption, clinical observations) Necropsy

3. Acute LD50 Values vs Toxicity

4. Acute Toxicity Studies Repeated dose studies (usually 14 days) - rat, mouse (5-10/sex/dose), dog, monkey (2/sex/dose) In-life observations Necropsy Histopathology Clinical pathology (optional)

5. Subacute Toxicity 28 day study (3 doses and control) Species - rat (10/sex/dose), dog or monkey (2/sex/dose) In-life observations Clinical pathology Necropsy Histopathology

6. Subchronic Toxicity 13 week study +/- 4 wk recovery (3 doses and control) Species - rat (10/sex/dose), dog or monkey (2/sex/dose) In-life observations (+/- ophthamology) Clinical pathology Necropsy Histopathology Used to set doses for carcinogenicity studies

7. Chronic Toxicity 1 year study +/- 4-13 wk recovery (3 doses and control) Species - rat (10-15/sex/dose), dog or monkey (2-3 /sex/dose) In-life observations including ophthalmology Necropsy Histopathology

8. Carcinogenicity Study 2 years (3 doses and control) Species - rats and mice (50/sex/dose) In-life observations Toxicokinetic studies Clinical pathology (rats, optional) Necropsy Histopathology

9. Carcinogenicity Study Evaluation Issues Survival Body weight Variability of endpoints Pathology Working Group MTD Statistics vs biology Dose-response Mechanistic factors

10. MTD ISSUE The Maximum Tolerated Dose is defined as the highest dose of a chemical or drug that can be administered for the animal’s life without causing excessive toxicity or decreasing survival (except due to tumor induction).

11. Current MTD Debate “Normal physiology, homeostasis and detoxification or repair mechanisms may be overwhelmed and cancer, which otherwise might not have occurred, is induced or promoted.” OSTP, 1985

12. Current Debate “More than two-thirds of the carcinogenic effects detected in feeding studies would have been missed had the high dose been reduced from the estimated MTD to 1/2 the MTD.” Haseman, FAAT, 1985

13. MTD Issue The problem is not testing for carcinogenic potential at the Maximum Tolerated Dose, it is how those data are used in risk assessment. The proper interpretation and use requires an understanding of the mechanism(s) of action.

14. Overview The integration of metabolism, toxicity, pathology and mechanism is playing a much greater role today than ever before. A better understanding of these areas is essential for proper regulation of chemicals and drugs. It can also play an important role in the development of backup drugs and chemicals.

15. General Approaches To Risk Assessment Qualitative approach using scientific judgment Quantitative approach using safety factors Quantitative approach using mathematical models Quantitative approach using linear extrapolation Biologically-based quantitative risk assessment

18. Cancer Risk Assessment Population risks for environmental carcinogens are usually set at one additional cancer per 100,000 or 1,000,000 individuals Occupational risks are frequently much higher, with one additional cancer per 1,000 workers being not uncommon

19. Hazard Identification A qualitative risk assessment Does an agent have the potential to increase the incidence of cancer under any conditions Hazard Characterization takes into consideration the conditions under which the cancer was induced

20. Dose-Response Assessment The relationship between dose and response (cancer incidence) Two sets of data are usually available –Data in the observable range –Extrapolation to responses below the observable range

21. Exposure Assessment EPA uses the cumulative dose received over a lifetime This is expressed as the average daily exposure Occupational exposures are usually based on exposure during the work week

22. Risk Characterization Provides an overall conclusion and confidence of risk for the risk manager Gives the assumptions made Explains the uncertainties Outlines the data gaps

23. 1986 EPA Cancer Risk Assessment Guidelines

24. Bradford Hill Criteria for Cancer Causation Consistency Strength Specificity Temporality Coherence Dose Response Biological Plausibility Experimental Support Analogy

25. IPCS/EPA Framework for Evaluating Mechanistic Data Introduction Postulated mode of action Key events Dose-response relationship Temporal association Strength, consistency and specificity of association with key events Biological plausibility and coherence Other modes of action Assessment of mode of action Uncertainties, inconsistencies and data gaps

26. Systematic Characterization of Comprehensive Exposure-Dose-Response Continuum and the Evolution of Protective to Predictive Dose-Response Estimates

27. Helpful Web Sites http://cfpub.epa.gov/ncea/ www.fda.gov/cder/ www.ovpr.uga.edu/qau/index.html

28. Risk Assessment Assignments Review the Guidelines for Cancer Risk Assessment, March 2005 at http://cfpub.epa.gov/ncea/ We will compare these guidelines with the 1986 Cancer Risk Assessment Guidelines on Friday. We will also discuss the Draft Supplemental Guidance for Assessing Cancer Susceptibility from Early-Life Exposure to Carcinogens on Monday. We will DISCUSS the issues in the next two class periods. It will NOT be lectures.

29. Risk Assessment Assignments Friday & Monday Hazard Identification vs Hazard Characterization Extrapolation: Linearized multistage vs Biologically-based vs Linear vs Non-linear Framework analysis of Mode of Action Dose-response assessment: Extrapolation within and below the observable data Susceptible populations Use of defaults Why not use safety factor? Uncertainties

30. Risk Assessment Assignments Monday Factors that affect early-life susceptibility Evidence for increased early-life susceptibility Mode of action vs default in early-life susceptibility Quantitative effects of early-life exposure on risk assessment Uncertainties associated with the supplemental guidance Science vs science policy