Chemically induced cancer is a major concern of the National Toxicology Program (NTP). The mechanisms by which cancer is induced following exposure to chemicals are diverse and not well understood. Further, there are very few good model or test systems for studies of chronic insult by chemicals. Present work by this group has focused on the induction of cancer in the forestomachs of experimental animals receiving oral doses of test chemicals. This work was designed to follow the development of the early stages of these lesions in an effort to characterize their development from early lesions to fullscale cancers. The purpose of this work has been to determine the relevance of these lesions to human exposure to chemicals and evaluate the suitability of this lesion as a short term test for chemical toxicity and carcinogenicity. Results of this work have shown that a series of chemicals which have been characterized as stomach carcinogens induce hyperplasia and hyperkeratosis on acute exposure at doses which induced cancer in chronic studies. These lesions were dose dependent and significantly increased over those observed in controls in every case in which a known forestomach carcinogen was studied. Further, structurally related chemicals which did not induce cancer in chronic studies did not induce similar lesions when administered at comparable doses. This work is being extended to further characterize the development of these lesions following exposure to additional chemicals and to more closely examine development of these lesions in the course of repeated dosing over a period of several months and to determine the effect of coadministration of other drugs and chemicals.
