Follow‐up actions from positive results of in vitro genetic toxicity testing

Abstract

Appropriate follow-up actions and decisions are needed when evaluating and interpreting clear positive results obtained in the in vitro assays used in the initial genotoxicity screening battery (i.e., the battery of tests generally required by regulatory authorities) to assist in overall risk-based decision making concerning the potential effects of human exposure to the agent under test. Over the past few years, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) Project Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity (IVGT) Testing developed a decision process flow chart to be applied in case of clear positive results in vitro. It provides for a variety of different possibilities and allows flexibility in choosing follow-up action(s), depending on the results obtained in the initial battery of assays and available information. The intent of the Review Subgroup was not to provide a prescriptive testing strategy, but rather to reinforce the concept of weighing the totality of the evidence. The Review Subgroup of the IVGT committee highlighted the importance of properly analyzing the existing data, and considering potential confounding factors (e.g., possible interactions with the test systems, presence of impurities, irrelevant metabolism), and chemical modes of action when analyzing and interpreting positive results in the in vitro genotoxicity assays and determining appropriate follow-up testing. The Review Subgroup also examined the characteristics, strengths, and limitations of each of the existing in vitro and in vivo genotoxicity assays to determine their usefulness in any follow-up testing.

Genotoxicity Expert Panel review: weight of evidence evaluation of the genotoxicity of glyphosate, glyphosate-based formulations, and aminomethylphosphonic acid

“…The universally recommended method for evaluating the databases of the type associated with glyphosate (including GBFs and AMPA), involves the application of a WoE approach as discussed recently for genetic toxicology testing (US FDA 2006;Dearfield et al 2011). Many of the principles of the WoE analysis indicated here are consistent with and included in the very recently issued endpoint specific guidance document of the European Chemicals Agency (ECHA 2015).…”

A review of the carcinogenic potential of glyphosate by four independent expert panels and comparison to the IARC assessment

“…The universally recommended method for evaluating the databases of the type associated with glyphosate (including GBFs and AMPA), involves the application of a WoE approach as discussed recently for genetic toxicology testing (US FDA 2006;Dearfield et al 2011). One of the most important requirements of a WoE approach is that individual test methods should be assigned a weight that is consistent with their contribution to the overall evidence, and different types of evidence or evidence categories must be weighted before they are combined into a WoE.…”

Quantitative approaches for assessing dose–response relationships in genetic toxicology studies

“…Two workgroups have published critical evaluations of emerging technologies to assist genetic toxicologists in improving the scientific basis of sound in vitro genetic toxicity testing for more accurate human risk assessment [Lynch et al, 2011], and a follow-up strategy for determining the relevance of in vitro test results to human health [Dearfield et al, 2011], respectively. The present report is based on the work of the third workgroup (the ''Quantitative Analysis Workgroup'') whose primary objectives are to develop strategies for the quantitative analysis of in vitro and in vivo genotoxicity dose-response data, and moreover, to consider critically how quantitative analyses might be used to assess human risk.…”