Critical review of dose-response options for F344 rat mammary tumors for acrylamide - additional insights based on mode of action.

Previous risk assessment reviews analyzed the potential for dietary acrylamide to increase breast cancer risk. Here, we critically review acrylamide animal bioassay data on mammary tumors for human relevance. We applied a systematic evaluation using reasonable standards of scientific certainty and a systematic weight of evidence (WOE) approach to evaluate several hypothesized modes of action (MOA), including (1) genotoxicity related to glycidamide formation and oxidative stress, (2) endocrine effects due to age-related hyperprolactinemia or secondary to neurotoxicity, and (3) epigenetic effects. We conclude that the appropriate approach for low-dose extrapolation of the rat mammary tumors can be narrowed to two options: (1) linear low-dose extrapolation (i.e., based on a MOA of mutagenicity from direct DNA interaction) from a point of departure (POD) for the combined incidence of adenomas and adenocarcinomas, since these tumor types are related; or (2) non-linear extrapolation, using uncertainty factors to estimate a Reference Dose (RfD) from a POD for tumor promotion derived using the combined fibroadenoma, adenoma and adenocarcinoma data. Non-linear extrapolation is used in the latter approach because these combined tumor types are unlikely to be exclusively caused by mutagenicity. Comparison of the WOE for each alternative MOA indicates that a non-linear approach (option 2) is more appropriate for evaluation of acrylamide-induced mammary tumors; a linear approach (option 1) is shown for comparison.