Dose–response approaches for nuclear receptor-mediated modes of action for liver carcinogenicity: Results of a workshop

Abstract

A public workshop, organized by a Steering Committee of scientists from government, industry, universities and research organizations, was held at the National Institute of Environmental Health Sciences (NIEHS) in September, 2010. The workshop explored the dose–response implications of toxicant modes of action (MOA) mediated by nuclear receptors. The dominant paradigm in human health risk assessment has been linear extrapolation without a threshold for cancer, and estimation of sub-threshold doses for non-cancer and (in appropriate cases) cancer endpoints. However, recent publications question the application of dose–response modeling approaches with a threshold. The growing body of molecular toxicology information and computational toxicology tools has allowed for exploration of the presence or absence of sub-threshold doses for a number of receptor-mediated MOAs. The workshop explored the development of dose–response approaches for nuclear receptor-mediated liver cancer, within a MOA Human Relevance Framework (HRF). Case studies addressed activation of the AHR, the CAR and the PPARα. This article describes the workshop process, key issues discussed and conclusions. The value of an interactive workshop approach to apply current MOA/HRF frameworks was demonstrated. The results may help direct research on the MOA and dose–response of receptor-based toxicity, since there are commonalities for many receptors in the basic pathways involved for late steps in the MOA, and similar data gaps in early steps. Three additional papers in this series describe the results and conclusions for each case-study receptor regarding its MOA, relevance of the MOA to humans and the resulting dose–response implications.

• Aryl hydrocarbon receptor (AHR)
• constitutive androstane receptor (CAR)
• dose–response
• liver carcinogenicity
• mode of action
• nuclear receptor
• peroxisome proliferator-activated receptor-alpha (PPARα)
• risk assessment

Acknowledgements

The authors wish to thank the Nuclear Receptor Steering Committee (Dr. Melvin Andersen, Dr. Richard Becker, Dr. Robert Budinsky, Dr. Michael Cunningham, Dr. Vicki Dellarco, Dr. Michael Dourson, Dr. Cliff Elcombe, Dr. Michael Honeycutt, Dr. James Klaunig and Dr. Julian Preston) for its vision and efforts organizing the workshop, the workshop participants for contributing their expertise and insights; the case study chairs for leading each case study team through the workshop process and manuscript preparation and all the authors of the individual case study papers. Special thanks to Dr. Lynne Haber for her very helpful technical review of the manuscript.

Notes

¹The NAS committee authors used the term “low-dose linear” to describe the shape of the curve in the range of background exposures (i.e. no sub-threshold or non-adverse effect dose exists), rather than intending that linear extrapolation be used from the range of the animal data, but the authors did not provide a recommendation on how to draw the dose-response curve based on data that are typically available from animal studies.

²Examination of the literature revealed that while an extensive database is available on the effects of CAR activators on liver tumor formation in rodents, comparatively little information is available on the corresponding effects of compounds that specifically activate PXR. A MOA for PXR activators was not established owing to a lack of suitable data at this time.