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197706 
Journal Article 
Mode of action frameworks: a critical analysis 
Guyton, KZ; Barone, S; Brown, RC; Euling, SY; Jinot, J; Makris, S 
2008 
1 
Journal of Toxicology and Environmental Health, Part B: Critical Reviews
ISSN: 1093-7404
EISSN: 1521-6950 
11 
1 
16-31 
English 
18176885 
WOS:000252343800002 
Mode of action (MOA) information is increasingly being applied in human health risk assessment. The MOA can inform issues such as the relevance of observed effects in laboratory animals to humans, and the variability of response within the human population. Several collaborative groups have developed frameworks for analyzing and
utilizing MOA information in human health risk assessment of environmental carcinogens and toxins, including the International Programme on Chemical Safety, International Life Sciences Institute, and U.S. Environmental Protection Agency. With the goal of identifying gaps and opportunities for progress, we critically evaluate several of these MOA frameworks. Despite continued improvement in incorporating biological data in human health risk assessment, several notable challenges remain. These include articulation of the significant role of scientific judgment in
establishing an MOA and its relevance to humans. In addition, binary (yes/no) decisions can inappropriately exclude consideration of data that may nonetheless be informative to the overall assessment of risk. Indeed, the frameworks lack a broad consideration of known causes of human disease and the potential for chemical effects to act additively with these as well as endogenous background processes. No integrated analysis of the impact of multiple MOAs
over the same dose range, or of varying MOAs at different life stages, is included. Separate consideration of each MOA and outcome limits understanding of how multiple metabolites, modes, and toxicity pathways contribute to the toxicological profile of the chemical. An extension of the analyses across outcomes with common modes is also needed.