Challenges and opportunities of read-across for the tumor promotion effects of microcystins

Abstract

The microcystins (MCs) are a family of cyclic oligopeptides toxins expressed in at least 30 cyanobacterial species and are liable to pose significant hazard to human health due to hepatotoxicity. Microcystin-leucine arginine (MC-LR) is the most extensively studied and toxic congener and classified as possibly carcinogenic to humans based on tumor promotion activity in the liver. Given the substantial toxicity data gaps for the MCs, read-across was assessed to evaluate the tumor promotion effects of a series of data-poor MC congeners based on in vivo information for MC-LR as the source molecule. Lines of evidence from in silico estimates of structural similarity, physico-chemical properties, hepatotoxicity, genotoxic and carcinogenicity were compiled to support the filling of data gaps. Uncertainties were evaluated according to scenario 4 of the European Chemicals Agency's (ECHA's) Read-Across Assessment Framework (RAAF). The read-across process followed a previously proposed harmonized framework to apply the common principles together with information from new approach methodologies (NAMs). Lines of evidence were consistent across the MC congeners and the uncertainties were found to be acceptable for data gap filling. Read-across strategies, with known caveats and restrictions, were shown to be applicable for large, complex molecules such as the MCs.