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Acute Toxicity Studies

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 - rat, mouse (5-10/sex/dose), dog, monkey (2/sex/dose)

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Acute Toxicity Studies

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  1. 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

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

  3. Acute LD50 Values vs Toxicity

  4. 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

  5. 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

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

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

  8. 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 of decreasing survival (except due to tumor induction).

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. Consistency Strength Specificity Temporality Coherence Dose Response Biological Plausibility Experimental Support Analogy Bradford Hill Criteriafor Cancer Causation

  14. 1986 EPA Cancer Risk Assessment Guidelines

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

  16. 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

  17. 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

  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

  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. Helpful Web Sites • www.epa.gov/ncea/ • www.fda.gov/cder/ • www.ovpr.uga.edu/qau/

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