Mode of action human relevance (species concordance) framework: Evolution of the Bradford Hill considerations and comparative analysis of weight of evidence
Article first published online: 10 FEB 2014
Copyright © 2014. The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Journal of Applied Toxicology
Volume 34, Issue 6, pages 595–606, June 2014
How to Cite
Meek, M. E., Palermo, C. M., Bachman, A. N., North, C. M. and Jeffrey Lewis, R. (2014), Mode of action human relevance (species concordance) framework: Evolution of the Bradford Hill considerations and comparative analysis of weight of evidence. J. Appl. Toxicol., 34: 595–606. doi: 10.1002/jat.2984
- Issue published online: 25 APR 2014
- Article first published online: 10 FEB 2014
- Manuscript Accepted: 3 DEC 2013
- Manuscript Revised: 28 NOV 2013
- Manuscript Received: 2 NOV 2013
- human relevance framework;
- mode of action;
- weight of evidence;
- key events;
- evolved Bradford Hill considerations
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.