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Problems in extrapolating toxicity data for laboratory animals to man

R L Dixon

    Environmental Health Perspectives
    |February 1, 1976
    PubMed
    Summary
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    Extrapolating animal toxicity data to humans is challenging. Using the maximum tolerated dose (MTD) in the most sensitive animal species (dogs or monkeys) improves prediction for anticancer drugs, with a 3% risk of toxicity in humans.

    Area of Science:

    • Pharmacology
    • Toxicology
    • Drug Development

    Background:

    • Extrapolating preclinical toxicity data from animals to humans presents significant challenges.
    • The quantitative predictiveness of animal models for anticancer drug efficacy and safety in humans requires careful examination.

    Purpose of the Study:

    • To evaluate the predictability of preclinical anticancer drug studies in dogs and monkeys for human application.
    • To compare dose expression methods (mg/kg vs. mg/m2) for predicting clinical doses.
    • To introduce a method for assessing the statistical risk of extrapolating animal toxicity data to initial human clinical doses.

    Main Methods:

    • Comparison of maximum tolerated dose (MTD) in dogs and monkeys with clinical observations.
    • Analysis of dose expression based on body weight (mg/kg) and body surface area (mg/m2).

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  • Development of a statistical risk assessment for dose extrapolation from animal models to Phase I clinical trials.

    • Main Results:

    • The most reliable clinical dose prediction is achieved using the MTD in mg/kg for the most sensitive animal species (dog or monkey).
    • Administering a new anticancer agent at 1/10th of the MTD in the sensitive species carries an approximate 3% statistical risk of human toxicity.
    • The findings were theoretically extended to general toxic chemicals and the broader human population.

    Conclusions:

    • Utilizing the MTD from the most sensitive animal species in mg/kg provides the best prediction for initial human clinical doses of anticancer drugs.
    • A 3% statistical risk is associated with initiating anticancer drug treatment based on this animal data extrapolation.
    • Accurate extrapolation necessitates a deeper understanding of structure-activity relationships, pharmacokinetics, and toxicity mechanisms.