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Pathway Based Toxicology and Fit-for-Purpose Assays

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Validation of Alternative Methods for Toxicity Testing

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 856))

Abstract

The field of toxicity testing for non-pharmaceutical chemicals is in flux with multiple initiatives in North America and the EU to move away from animal testing to mode-of-action based in vitro assays. In this arena, there are still obstacles to overcome, such as developing appropriate cellular assays, creating pathway-based dose-response models and refining in vitro-in vivo extrapolation (IVIVE) tools. Overall, it is necessary to provide assurances that these new approaches are adequately protective of human and ecological health. Another major challenge for individual scientists and regulatory agencies is developing a cultural willingness to shed old biases developed around animal tests and become more comfortable with mode-of-action based assays in human cells. At present, most initiatives focus on developing in vitro alternatives and assessing how well these alternative methods reproduce past results related to predicting organism level toxicity in intact animals. The path forward requires looking beyond benchmarking against high dose animal studies. We need to develop targeted cellular assays, new cell biology-based extrapolation models for assessing regions of safety for chemical exposures in human populations, and mode-of-action-based approaches which are constructed on an understanding of human biology. Furthermore, it is essential that assay developers have the flexibility to ‘validate’ against the most appropriate mode-of-action data rather than against apical endpoints in high dose animal studies. This chapter demonstrates the principles of fit-for-purpose assay development using pathway-targeted case studies. The projects include p53-mdm2-mediated DNA-repair, estrogen receptor-mediated cell proliferation and PPARα receptor-mediated liver responses.

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Acknowledgments

The ACC-LRI (Long Range Research Initiative of the American Chemistry Council), Dow Chemical, Unilever, the ExxonMobil Foundation, Dow Corning have supported method development and data generation needed in pursuing case study approaches to bringing the TT21C vision to life more quickly. Unilever has supported the p53-case study activities at The Hamner.

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Authors and Affiliations

  1. ScitoVation, 6 Davis Drive, 110566, Research Triangle Park, NC, 27709, USA

    Rebecca A. Clewell, Patrick D. McMullen & Melvin E. Andersen

  2. Unilever Safety and Environmental Assurance Centre, Colworth Science Park, Sharnbrook, Bedfordshire, UK

    Yeyejide Adeleye & Paul L. Carmichael

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  1. Rebecca A. Clewell
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  2. Patrick D. McMullen
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  3. Yeyejide Adeleye
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  4. Paul L. Carmichael
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Correspondence to Rebecca A. Clewell .

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Editors and Affiliations

  1. SeCAM Services & Consultation on Alternative Methods, Magliaso, Switzerland

    Chantra Eskes

  2. European Commission Joint Research Centre (JRC), Ispra, Italy

    Maurice Whelan

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Clewell, R.A., McMullen, P.D., Adeleye, Y., Carmichael, P.L., Andersen, M.E. (2016). Pathway Based Toxicology and Fit-for-Purpose Assays. In: Eskes, C., Whelan, M. (eds) Validation of Alternative Methods for Toxicity Testing. Advances in Experimental Medicine and Biology, vol 856. Springer, Cham. https://doi.org/10.1007/978-3-319-33826-2_8

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