Mode of action human relevance (species concordance) framework: Evolution of the Bradford Hill considerations and comparative analysis of weight of evidence

Abstract

The mode of action human relevance (MOA/HR) framework increases transparency in systematically considering data on MOA for end (adverse) effects and their relevance to humans. This framework continues to evolve as experience increases in its application. Though the MOA/HR framework is not designed to address the question of “how much information is enough” to support a hypothesized MOA in animals or its relevance to humans, its organizing construct has potential value in considering relative weight of evidence (WOE) among different cases and hypothesized MOA(s). This context is explored based on MOA analyses in published assessments to illustrate the relative extent of supporting data and their implications for dose–response analysis and involved comparisons for chemical assessments on trichloropropane, and carbon tetrachloride with several hypothesized MOA(s) for cancer. The WOE for each hypothesized MOA was summarized in narrative tables based on comparison and contrast of the extent and nature of the supporting database versus potentially inconsistent or missing information. The comparison was based on evolved Bradford Hill considerations rank ordered to reflect their relative contribution to WOE determinations of MOA taking into account increasing experience in their application internationally. This clarification of considerations for WOE determinations as a basis for comparative analysis is anticipated to contribute to increasing consistency in the application of MOA/HR analysis and potentially, transparency in separating science judgment from public policy considerations in regulatory risk assessment. Copyright © 2014. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd.The potential value of the mode of action (MOA)/human relevance (species concordance) framework in considering relative weight of evidence (WOE) amongst different cases and hypothesized MOA(s) is explored based on the content of several published assessments. The comparison is based on evolved Bradford Hill considerations rank ordered to reflect their relative contribution to WOE determinations for MOA based on experience internationally.

Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance

“…Considerations related to weight of evidence for MOA have been additionally articulated in a subsequent publication (Meek et al 2014b) and evolved in international collaborative efforts on adverse outcome pathways (AOPs) (OECD Handbook 2016;Becker et al 2015;Edwards et al 2016). The US EPA (2014) guidance on Data-Derived Extrapolation Factors also contributes significantly to CSAF evolution by encouraging the identification and use of TK or TD data to inform the magnitude of interspecies differences and human variability (e.g.…”

Differential genotoxicity of acrylamide in the micronucleus andPig-a gene mutation assays in F344 rats and B6C3F1 mice

“…DNA damage) are expected to appear at doses below or similar to those associated with later key events (e.g. tumour formation) (61). In mice, no mutagenic response was detected up to tested concentrations of acrylamide almost an order of magnitude higher than the BMDs for tumour induction.…”

Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water

“…To derive a MOA based on the International Programme on Chemical Safety (IPCS)/ (ILSI) MOA framework (Meek et al 2014; Boobis et al, 2006; Meek et al, 2003; Sonich-Mullin et al, 2001), key events were identified by interrogating all genomics data based on functional annotation. Key events are empirically observable, necessary precursor events in the MOA or biologically based markers for such events (US EPA, 2005).…”