Abstract
Throughout the history of rodent carcinogenicity studies, scientists have been seeking better methods to understand human risk for chemically induced neoplasia and mechanisms of carcinogenesis (Alden et al., 2011). Public concern regarding adverse effects of chemicals for humans resulted in the passage of the Food, Drug, and Cosmetic Act of 1938. Human risk assessment based on rodent carcinogenicity studies was mandated for the first time by the Delaney clause that prohibited the use of food additives that cause neoplasia in animal studies. The National Cancer Institute’s bioassay program (the predecessor of the National Toxicology Program) was initiated in 1961. Standardization of carcinogenicity study designs and practices continued into the 1980s. The FDA Red Book containing guidance for the design of rodent carcinogenicity studies and requiring carcinogenicity studies in 2 species for new food additives was first published in 1982. For small organic pharmaceutical compounds, 2-year studies in both rats and mice traditionally have been required for new drugs intended for chronic or repeated intermittent use. In 1997, a significant new option was incorporated into ICH guidance that permitted replacement of the 2-year mouse study with an alternative in vivo carcinogenicity model if a robust 2-year rat carcinogenicity study was conducted. This was the first major change in carcinogenicity assessment methods in animals since the 1960s.
One of the major criticisms of the rodent bioassay is the lack of mechanistic information generated in most of these studies. Without knowledge of mechanisms, determination of the relevance of findings in rodents for human risk assessment is uncertain. The Ames bacterial reverse mutagenesis assay, introduced in 1973, provided the first rapid in vitro screening method to identify mechanisms contributing to carcinogenicity. In the 1980s, exciting new advances in genetics, genomics, and biomarker development raised hopes that the rodent bioassays would soon be replaced with shorter, less expensive, mechanism-based assays that would more effectively predict human risk. Despite more than two decades of additional advances in molecular biology, the rodent bioassay remains a standard and required assay to predict the potential carcinogenic risk of drugs and other chemicals for humans. New strategies are needed to improve the effectiveness and efficiency of cancer hazard identification.
The paper by Sistare et al. in this issue of Toxicologic Pathology recommends a substantive improvement over current practice by expanding the factors used to determine if a 2-year rat carcinogenicity study should be required for registration of a new pharmaceutical. This decision tree uses knowledge of data from chronic rodent studies, genetic toxicity assays, and mechanism of action to identify compounds that are highly likely to be negative in a rodent carcinogenicity study and to have low risk for carcinogenicity in humans. If this proposal is accepted by regulatory agencies, the requirement for rat carcinogenicity studies could be waived for about 40% of new small organic drugs intended for chronic or repeated intermittent use without compromise to human risk assessment. This is in part true because most treatment-related neoplastic findings in rodents are not considered relevant for human risk (Alden et al., 2011). While Sistare et al. provide no mechanistic or scientific quantum leap in the assessment of human risk for carcinogenicity, their data demonstrate that drugs with minimal risk of human carcinogenicity can be identified in routine shorter -term studies and do not require lifetime dosing in the rat. Acceptance of the proposed risk management strategy will improve the efficiency and effectiveness of carcinogenicity testing and conserve resources for those chemicals more likely to pose significant risk for humans.
Footnotes
Acknowledgements
The authors of this letter are also coauthors of the paper by Sistare et al. and the reference cited at the end of the letter.