oa Low-Dose Carcinogenicity Studies and Mechanisms

One of the major deficiencies of cancer risk assessments is the lack of low-dose carcinogenicity data. Most assessments require extrapolation from high to low doses, which is subject to various uncertainties. Only four low-dose carcinogenicity studies and five low-dose biomarker/pre-neoplastic studies have been performed. The four carcinogenicity studies involved exposures of 24,192 mice to two acetylaminofluorene, 4,080 rats to nitrosamines (NDMA and NDEA), 40,000 rainbow trout to dibenz[a,l]pyrene, and 20,00 trout to aflatoxin B1. The low-dose biomarker/pre-neoplastic studies involved exposure of 1,145 rats to MeIQx, 2,000 rats each to DEN or DMN, 1,920 rats to PhIP, and 50 rats to potassium bromate. In most cases there was some evidence for a threshold effect for the induction of cancer or biomarkers of cancer. However, absolute proof of a threshold effect for carcinogenicty could not be demonstrated unambiguously by any of the carcinogenicity studies due to the limited number of animals used. The induction of stable DNA adducts was not predictive of tumors in the mouse and trout studies. All of the biomarkers evaluated, including stable DNA adducts, oxidative damage, mutation, and pre-neoplastic foci, exhibited threshold effects, ie, they were not inducible or detectable at the lowest doses tested. Clear proof of a threshold effect for any of the carcinogens tested is lacking. However, the limited data available suggest that these carcinogens may exhibit threshold effects for the induction of carcinogenic biomarkers and cancer. Given the fact that some mutagens clearly show threshold effects and that cancer is a multi-step process, it is possible that carcinogens may also show a threshold effect.