Revisiting the evidence for genotoxicity of acrylamide (AA), key to risk assessment of dietary AA exposure

The weight of evidence pro/contra classifying the process-related food contaminant (PRC) acrylamide (AA) as a genotoxic carcinogen is reviewed. Current dietary AA exposure estimates reflect margins of exposure (MOEs) 7-GA-Gua adducts dose-dependently in the high dose range (> 100 µg/kg b w). At variance, in the dose range below 100 µg/kg b.w. down to levels of average consumers exposure, DNA N7 -Gua lesions were found only sporadically, without dose dependence, and at levels close to the lower bound of similar human background DNA N7-Gua lesions. No DNA damage was detected by the comet assay within this low dose range. GA is a very weak mutagen, known to predominantly induce DNA N7-GA-Gua adducts, especially in the lower dose range. There is consensus that DNA N7-GA-Gua adducts exhibit rather low mutagenic potency. The low mutagenic potential of GA has further been evidenced by comparison to preactivated forms of other process-related contaminants, such as N-Nitroso compounds or polycyclic aromatic hydrocarbons, potent food borne mutagens/carcinogens. Toxicogenomic studies provide no evidence supporting a genotoxic mode of action (MOA), rather indicate effects on calcium signalling and cytoskeletal functions in rodent target organs. Rodent carcinogenicity studies show induction of strain- and species-specific neoplasms, with MOAs not considered likely predictive for human cancer risk. In summary, the overall evidence clearly argues for a nongenotoxic/nonmutagenic MOA underlying the neoplastic effects of AA in rodents. In consequence, a tolerable intake level (TDI) may be defined, guided by mechanistic elucidation of key adverse effects and supported by biomarker-based dosimetry in experimental systems and humans.