Regulatory Toxicology James Swenberg, D.V.M., Ph.D.
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
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)
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
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
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
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
Survival Body weight Variability of endpoints Pathology Working Group MTD Statistics vs biology Dose-response Mechanistic factors Carcinogenicity Study Evaluation Issues
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).
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
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
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.
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.
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
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
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
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
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
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
Consistency Strength Specificity Temporality Coherence Dose Response Biological Plausibility Experimental Support Analogy Bradford Hill Criteriafor Cancer Causation
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 IPCS/EPA Framework for Evaluating Mechanistic Data
Systematic Characterization of Comprehensive Exposure-Dose-Response Continuum and the Evolution of Protective to Predictive Dose-Response Estimates
Helpful Web Sites • http://cfpub.epa.gov/ncea/ • www.fda.gov/cder/ • www.ovpr.uga.edu/qau/index.html
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.
Risk Assessment AssignmentsFriday & 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
Risk Assessment AssignmentsMonday • 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