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Theoretical and experimental approaches to possible thresholds of response in carcinogenicity
Citation:
KITCHIN, K. T. Theoretical and experimental approaches to possible thresholds of response in carcinogenicity. Genes and Environment. Japanese Environmental Mutagen Society, Tokyo, Japan, 30(4pp):150-159, (2008).
Impact/Purpose:
For the six selected experimental studies of low dose-response relationships, the individual studies are presented in respect to the study chemical, number and type of experimental animals used, length of chemical exposure, doses selected and biological endpoints. This comparison allows the reader to see areas where past studies might have been designed better and how future studies might be designed to maximize the chances of useful outcomes. Examples of better possible past experimental designs would include adduct and foci work in studies were it was not performed, longer exposure times for animals in certain experiments and better spacing of doses in several cases. This type of experimental dose-response work is expensive in time, animals and money. Therefore, review articles such as this may help the design, execution and interpretation of any such possible future dose-response studies.
Description:
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.