Genotoxic carcinogenicity of pyrrolizidine alkaloids: relevance of potency factors for the risk assessment.

Pyrrolizidine alkaloids represent a large group of substances synthesized as secondary plant metabolites. The subgroup of the 1,2-unsaturated pyrrolizidine alkaloids (PAs) can induce acute and chronic liver toxicity in humans and livestock, and many of them are considered to be genotoxic and carcinogenic. Currently, the risk assessment is based on carcinogenicity data for the relatively potent PA riddelliine, and on the assumption that all PAs, regardless of their chemical structure, have the same potency. However, results from in vitro and in vivo studies indicate that the severity of the effects depends on the alkaloids' structure and, thus, varies for different congeners. To align the concept of potency factors with risk assessment, we analysed the available studies and selected those that best reflect the human situation or mode of action, and that included riddelliine in their study design. Based on the selected studies, we used riddelliine as a reference point to calculate the relative potencies of the PAs also used in the corresponding study. Further, we propose conservatively derived relative potency factors for certain PA congeners and evaluated the impact when applying them to real food samples considering tea and food supplements as examples. Our evaluation demonstrates that the inclusion of relative potency factors for PAs has generally only a minor influence on the final risk assessment, especially when conservative factors are used. However, this approach may be of great importance in certain situations where the PA spectrum consists mainly of PAs with low potency, such as the monoester lycopsamine.