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

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

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.

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.

Health Statutes & Regulations Toxicity Studies/Data Research Developments

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

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

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

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

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

Regulatory Guidance for Toxicity Testing U.S. FDA’s Redbook.U.S. FDARedbook U.S. EPA’s testing guidelines.U.S. EPAtesting guidelines OECD’s testing guidelines.OECDtesting guidelines Japan’s MAFF testing guidelines.MAFF

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

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

Health Statutes & Regulations Toxicity Studies/Data Research Developments

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