Cancer Risk Assessment Approaches at the FDA/CDER: Is the Era of the 2-Year Bioassay Drawing to a Close?

Determining the carcinogenic potential of materials to which humans have significant exposures is an important, complex, and imperfect exercise. Not only are the methods for such determinations protracted and expensive and use large numbers of animals, extrapolation of data from such studies to human risk is imprecise. With improved understanding of oncogene activation and tumor suppressor gene inactivation, a number of animal models have been developed to dramatically reduce latency for chemically induced cancers and has led to the development and use of shorter carcinogenicity assays. Recent studies by a number of investigators suggest that specific gene signature patterns seen after short-term exposure of rats to test chemicals can predict long-term outcomes in cancer bioassays with relatively high accuracy. In addition, a recent survey performed by PhRMA member companies examined two hundred drug years to determine whether histological biomarkers seen at the end of a six- or twelve-month toxicology study in rats can predict the outcome of a two-year carcinogenicity study. With only a handful of exceptions, chronic studies appear capable of predicting effects at the end of two years with good accuracy. It is hoped that the combination of results from transgenic mouse assays and six-month rat studies will soon supplant the need for most two-year bioassays.