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Results from carcinogenicity studies are generally not available for drugs until the time of approval. Many people, including healthy volunteers are often exposed to pharmacologically active doses of the drug before carcinogenicity results are available. The Food and Drug Administration (FDA) Center for Drug Evaluation and Research uses results of genetic toxicology studies as a surrogate for carcinogenicity during the drug development phase (clinical trials). A number of issues are considered in deciding whether drugs that give positive results in genetic toxicology studies can be given to subjects in clinical trials. These relate to the drug indication, the target population, duration of treatment, and importance of the drug. In general, single-dose clinical studies are permitted regardless of the genetox results. In situations where a genetic toxicology assay showed a positive result, some review divisions have asked sponsors to perform a Syrian hamster embryo (SHE) cell transformation assay or a p53 carcinogenicity study prior to allowing repeat-dose clinical trials to proceed. This paper discusses alternatives to SHE cell and p53 assays when faced with a positive result in a genetic toxicology assay. In addition, this paper discusses factors to consider when setting limits for genotoxic impurities in drug substances and products. [ABSTRACT FROM AUTHOR]

The concept of hormesis has been receiving greater interest in the biomedical and toxicological research communities over the past decade. Of particular importance has been how the hormesis concept may affect risk assessment practices, litigation, and regulation. This paper identifies and discusses what may be the first application of the hormesis concept in environmental assessment and litigation. This occurred in California within the context of an assessment of alleged continuing smelter contamination nearly a century ago. [ABSTRACT FROM AUTHOR]