Carcinogenic chemical-response "fingerprint" for male F344 rats exposed to a series of 195 chemicals: implications for predicting carcinogens with transgenic models.
Transgenic model systems have recently been advocated as replacements for traditional methods of testing chemicals for carcinogenicity in rodents. To shed light on the diversity of responses induced by chemicals in natural whole animal systems, a type of "fingerprint" is devised and, in turn, applied to describe the results of testing approximately 200 chemicals in male F344 rats. Such focus helps develop an appreciation of the complexity involved in the chemical carcinogenic response. When we ask transgenic systems to serve as replacements for natural whole animals, for predicting the risk of chemically induced cancer, we are asking them somehow to reflect or express this complexity so that the effects of exposure in humans can be realistically appraised. For the fingerprint, a graphic data display is used to represent the different tissues and organs that show statistically significant, chemically related tumor increases. Chemicals vary extensively according to the particular sites and the array of sites that display a carcinogenic response; but any given site may also show a carcinogenic response to a variety of different chemicals. The data suggest that a large number of different genetic factors may underlie the determination of the chemical carcinogenic response. This apparent genotypic variability and complexity in phenotypic expression would seem to make it quite difficult, if not impossible, to decide on the specific performance requirements of transgenic systems for detecting carcinogens. Unless this and other obstacles can be overcome, the transgenic approach to identifying carcinogenic chemicals for regulatory purposes may best be abandoned. Published 1999 Wiley-Liss, Inc.
Johnson
F M
FM
Environmental Toxicology Program, Toxicology Operations Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA. johnson1@niehs.nih.gov
D000818:Animals; D030801:Animals, Genetically Modified; D015197:Carcinogenicity Tests / Q000379:methods*; D002273:Carcinogens / Q000633:toxicity*; D005260:Female; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000139:chemically induced; D011237:Predictive Value of Tests; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
D002273:Carcinogens