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Issues in carcinogenicity testing: dose selection.

J K Haseman

    Fundamental and Applied Toxicology : Official Journal of the Society of Toxicology
    |February 1, 1985
    PubMed
    Summary
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    Selecting the maximum tolerated dose (MTD) for rodent carcinogenicity studies is debated. Data suggest MTDs are crucial for detecting chemical carcinogenicity, especially in dietary studies, and reducing doses risks missing effects.

    Area of Science:

    • Toxicology
    • Carcinogenesis Research
    • Animal Study Design

    Background:

    • Dose selection for rodent carcinogenicity testing remains a contentious issue.
    • The definition and application of the maximum tolerated dose (MTD) are central to this debate.
    • Disagreements may stem from differing MTD definitions rather than fundamental dose selection philosophies.

    Purpose of the Study:

    • To examine the definition, advantages, and disadvantages of using MTD in chemical carcinogenicity testing.
    • To analyze dose selection challenges in National Toxicology Program (NTP) studies.
    • To evaluate the impact of dose reduction on the detection of carcinogenic effects.

    Main Methods:

    • Review of the definition and application of MTD in toxicological studies.

    Related Experiment Videos

  • Analysis of data from 52 NTP carcinogenicity studies, differentiating between gavage and dietary exposure routes.
  • Evaluation of the potential impact of reducing the highest dose level on detecting carcinogenic responses.

    • Main Results:

    • No universal definition of MTD exists, contributing to dose selection controversies.
    • Dose selection posed challenges in NTP gavage studies but less so in dietary studies.
    • Reducing the highest dose from the MTD to 1/2 MTD would have missed over two-thirds of detected carcinogenic effects in feeding studies.
    • The insensitivity of animal studies for weak carcinogens supports using higher doses.

    Conclusions:

    • The MTD is critical for identifying chemical carcinogenicity in rodent studies.
    • Dietary exposure studies appear more robust regarding MTD selection than gavage studies.
    • Improving MTD estimation, particularly for gavage, and incorporating pharmacokinetic data are recommended.
    • Adding a lower-dose group enhances safety against MTD overestimation.