Michael H. Dong MPH, DrPA, PhD

1. Toxicology and Risk Assessment (3rd of 10 Lectures onToxicologic Epidemiology) Michael H. Dong MPH, DrPA, PhD  readings

2. Taken in the early ’90s, when desktop computers were still a luxury.

3. Learning Objectives • Learn the close linkages among health risk perception, regulatory statutes, toxicity studies, and related research developments. • Learn how the above four (4) elements anchor the intimate interrelationship between toxicology and health risk assessment.

4. Performance Objectives • Able to list the factors of risk and health perceptions which have a great impact on health statues. • To describe the spectrum of toxicity studies for health risk assessment. • To appreciate the need for research developments related to toxicity data and assessment techniques.

5. Health Risk Perception Health Statutes & Regulations Toxicity Studies/Data Research Developments

6. Risk Perception high uncontrollable, not observable Risk Perceived uncontrollable, observable controllable, not observable controllable, observable low

7. Health Perception (I) • Fundamental to risk perception. • Based on a broad spectrum of toxic reactions. • Definitions of adverse health effects not uniformly accepted.

8. Health Perception (II) • Problems with interpretation of adverse health effects. • Effects on health risk assessment and toxicity studies. • Different terminology for safe human dose.

9. Impacts of Health Risk Perception • Ways in which NOAEL and uncertainty/safety factors used. • Technology-based vs. risk-based health standards. • Risks: assessment priority.

10. Impacts of Health Statutes & Regulations • Mitigation feasibility with demonstration of risk. • Zero tolerance for carcinogens (de minimus risk of cancer). • Balance of risk and benefit. • Aggregate and cumulative exposure/risk assessment.

11. Effects on Health Statutes & Regulations • Effects of advances in assessment methodologies and other sciences. • Toxicity assessment as key step in health risk assessment. • Toward more realistic health policy agenda and programs.

12. Effects on Toxicity Assessment • On hazard identification and dose-response evaluation. • Especially on carcinogenic, neurotoxic, developmental, and reproductive effects. • Demanding valid biologic models and high quality toxicity data.

13. Effects on/of Toxicokinetics Data • Related to cumulative exposure and risk assessment. • To interspecies extrapolation for equivalent dose. • To strength-of-evidence and weight-of-evidence analysis. • To understanding the toxic agent.

14. Effects on/of Exposure Assessment • On aggregate exposure with probabilistic analysis. • On biomonitoring to measure total internal dose. • Limitations of biomonitoring. • Using PB-PK modeling as an aid in biomonitoring.

15. Effects on/of Low-Dose Extrapolation Models • Mechanistic models (one-hit, multi-hit, multistage). • Statistical models (Probit, Logit, Weibull). • Built on biological considerations. • Aided with biologic models and pharmacokinetics data.

16. Physiological-Based Pharmacokinetic (PB-PK) Modeling (I) • A set of complex mass-balance differential equations offering a time course of a chemical’s disposition. • Chemical’s disposition is followed in accord with PK rate laws. • Requiring intensive iterations with a computer for simulation.

17. Physiological-Based Pharmacokinetic (PB-PK) Modeling (II) • Powerful tools for interpretation of biomarker data. • For better use of spot sample results where complete urine (or other type of sample) collection not practical. • For estimation of internal dose and of timed tissue concentrations.

18. Toxicity Testing (I): Irritation, Sensitization, Immunotoxicity • Guidance on protocols for testing. • Skin and eye irritation in rabbits. • Skin sensitization test in guinea pigs. • Tests on the immune system.

19. Toxicity Testing (II): Mutagenicity, Developmental, Reproductive, Others • Gene mutation; genome mutation; Ames test; transgenic mice. • General fertility; reproductive performance; teratogenic potential; multigeneration studies. • Toxicity on other organs.

20. Toxicity Testing (III): Acute, Subchronic, Chronic, Carcinogenicity • Acute lethality; acute toxicity. • Subchronic exposure in two species; for 90 days or less. • Chronic exposure typically in rats or mice; may extend to lifetime for carcinogenicity.

21. Regulatory Guidance for Toxicity Testing • U.S. FDA’s Redbook. • U.S. EPA’s testing guidelines. • OECD’s testing guidelines. • Japan’s MAFF testing guidelines.

22. U.S. Regulatory Actions on Risk Assessment • FQPA on aggregate/cumulative risk assessments. • Delaney clause on carcinogen risk assessment. • The Benzene Decision.

23. World Actions on Risk Assessment • WHO’s efforts and influences. • International comparison. • WTO’s harmonization of risk assessment. • USA/OECD’s good laboratory practices.

24. Health Risk Perception Health Statutes & Regulations Toxicity Studies/Data Research Developments

25. Overview of Next Lecture Epidemiology and Risk Assessment • Epidemiologic advances in health risk assessment. • Epidemiologic approaches to exposure assessment. • Biomarkers used in epidemiology.