Non-genotoxic mechanisms

Mutagenicity and carcinogenicity are generally considered to be non-threshold effects, unless a non-genotoxic mechanism can be established with a NOEL (or NOAEL or LOAEL). Risk assessment is based on establishing whether exposure is prevented. A similar process of preventing exposure also applies for skin and respiratory sensitisers, since there is no means of identifying a dose or concentration below which adverse effects will not occur in someone already sensitised to a particular substance. 

However, it was found that there is also substantial overlap between Mnt and iTP, the latter being a non-genotoxic phenomenon (Table 19.7) (66). This finding suggests that Mnt can occur by genotoxic as well as non-genotoxic mechanisms. Thus, a positive Mnt response by a chemical that does not induce mutations in Salmonella does not necessarily represent a carcinogenic risk to humans. 

Many compounds can lead to cancer via non-genotoxic mechanisms, rendering the evaluation and assessment of their toxic potential rather complex. The primary action of these compounds is not DNA reactivity they do not directly interact to alter chromosome architecture or number furthermore, genotoxic events... 

Melnick, R. L., Kohn, M. C., and Portier, C. J. (1996). Implications for risk assessment of suggested non-genotoxic mechanisms of chemical carcinogenesis. Envirrm Health Perspect 104(Suppl 1), 123-134. 

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