Theoretical and Experimental Approaches to Address Possible Thresholds of Response in Carcinogenicity

Abstract

The determination and utilization of the actual low dose-response relationship for chemical carcinogens has long interested toxicologists, experimental pathologists, modelers and risk assessors. To date, no unequivocal examples of carcinogenic thresholds in humans are known. However, at least 5 examples of thresholds of preneoplastic foci or tumors have been observed in animals. The two largest dose-response studies utilized 20,880 mice (2-acetylaminofluorene) and 7,200 rainbow trout fry (aflatoxins). In both of these studies linear relationships were observed for DNA adducts and for liver tumors. A threshold relationship was observed for 2-acetylaminofluorene induced mouse urinary bladder cancer. Other comprehensive dose-response studies have examined the chemicals 2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline, 2-amino-1-methyl-6-phenolimidazo[4,5-b]pyridine and diethylnitrosamine. Taken collectively, the DNA adduct data for these 6 well studied chemicals are fairly linear. The foci and tumor data show either supralinear, linear or threshold curves, making it difficult to generalize. All the 6 studied chemicals cause multiple biological effects including genotoxicity, cytotoxicity and cell proliferation in complex dose and time dependent patterns that are not fully understood. We do know that there are multiple possible biological defenses (at least 7 pharmacokinetic and 7 pharmacodynamic) against the development of cancer. Currently, we have limited scientific and regulatory understanding of chemicals that act simultaneously or sequentially via both linear and nonlinear carcinogenic pathways (genotoxic and nongenotoxic). If an 100% experimental approach is used to elucidate the dose-response of chemicals of dual carcinogenic dose-response properties (linear and non linear), this would require studying 2 or more such chemicals in a large scale coordinated fashion employing at least 1,000 animals, 5 different treatment groups, 7 different study parameters and 8 different scientific disciplines.