Procedural application of mode-of-action and human relevance analysis: styrene-induced lung tumors in mice

Abstract

Risk assessment of human health hazards has traditionally relied on experiments that use animal models. Although exposure studies in rats and mice are a major basis for determining risk in many cases, observations made in animals do not always reflect health hazards in humans due to differences in biology. In this critical review, we use the mode-of-action (MOA) human relevance framework to assess the likelihood that bronchiolar lung tumors observed in mice chronically exposed to styrene represent a plausible tumor risk in humans. Using available datasets, we analyze the weight-of-evidence 1) that styrene-induced tumors in mice occur through a MOA based on metabolism of styrene by Cyp2F2; and 2) whether the hypothesized key event relationships are likely to occur in humans. This assessment describes how the five modified Hill causality considerations support that a Cyp2F2-dependent MOA causing lung tumors is active in mice, but only results in tumorigenicity in susceptible strains. Comparison of the key event relationships assessed in the mouse was compared to an analogous MOA hypothesis staged in the human lung. While some biological concordance was recognized between key events in mice and humans, the MOA as hypothesized in the mouse appears unlikely in humans due to quantitative differences in the metabolic capacity of the airways and qualitative uncertainties in the toxicological and prognostic concordance of pre-neoplastic and neoplastic lesions arising in either species. This analysis serves as a rigorous demonstration of the framework’s utility in increasing transparency and consistency in evidence-based assessment of MOA hypotheses in toxicological models and determining relevance to human health.

Keywords:

• Human relevance of animal carcinogens
• carcinogenic mode of action
• human relevance framework
• weight of evidence analysis
• styrene

Acknowledgements

Draft versions of this manuscript received scientific and editorial comment from the NIOSH Division of Science Integration’s Christine Whittaker (Division Director) and Kathleen McMahon (Associate Director of Science) as a part of NIOSH’s internal review process. This manuscript also received scientific comment from Dr. Jennifer Seed, retired from US EPA, and Dr. Lynne Haber, University of Cincinnati as part of NIOSH’s review processes. The authors acknowledge expert input from four anonymous peer reviewers assigned by the editor and thank them for their detailed critique. Revisions made in response to peer review comments were drafted and reviewed by the authors without additional contributions.

Declaration of interest

This review was developed by the authors out of collegial interest and prepared within the context of normal employment activities at their respective institutions. The authors did not receive any compensation specific to this work and have not previously and do not plan to participate in any legal or regulatory proceedings related to the content.

The conclusions and findings in this work are those of the authors and do not represent NIOSH positions or policy. NIOSH manuscripts are developed on the initiative of the authors and undergo clearance by the offices of division and institute directors.