Chemicals for evaluating the sensitivity and specificity of reduced/transgenic rodent cancer bioassay protocols

Abstract

The standard two-species/two-gender lifetime carcinogenicity bioassay protocol is not practical when assessing the possible carcinogenicity of a large number of chemicals. This has led to consideration of reduced cancer bioassay protocols (e.g., male rat/female mouse), or to the use of genetically altered rodents that succumb to chemically induced cancer in a fraction of their lifespans. Two uncertainties accompany these endeavours. First, that use of reduced protocols may lead to the non-detection of some weak or tissue-specific carcinogens. Second, that genetically altered rodents may be so sensitive to chemical disturbance of homoeostasis that their carcinogen specificity may be low. Such uncertainties lead to the requirement that the modified test protocols should be validated using appropriate carcinogens and non-carcinogens. Given that several such studies may take place over the coming years it seems appropriate that a common pool of chemicals should be agreed upon for this purpose. To this end a selection of human carcinogens, and rodent carcinogens/non-carcinogens defined by the US National Toxicology Program (NTP), have been collected together. Six categories of chemicals are listed: (1) representative human carcinogens; (2) representative trans-species genotoxic carcinogens; (3) all two-species non-carcinogens reported to be negative in the Salmonella mutation assay and lacking structural alerts to electrophilicity; (4) representative single-species/presumed non-genotoxic carcinogens; (5) all two-species non-carcinogens that are mutagens in the Salmonella mutation assay and which are structurally alerting; (6) all chemicals possessing equivocal evidence of carcinogenicity and which are both structurally alerting and mutagenic to Salmonella. Chemicals in the first four groups provide robust calibrants for determining the sensitivity and specificity of reduced/accelerated rodent carcinogenicity bioassay protocols. Chemicals in the last two groups may be of value when studying the interface between the sensitivity and the specificity of modified rodent carcinogenicity bioassay protocols.