Pathway Based Toxicology and Fit-for-Purpose Assays.
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.
ScitoVation, 6 Davis Drive, 110566, Research Triangle Park, NC, 27709, USA. rclewell@scitovation.com.
Rebecca A
RA
Clewell
ScitoVation, 6 Davis Drive, 110566, Research Triangle Park, NC, 27709, USA.
Patrick D
PD
McMullen
Unilever Safety and Environmental Assurance Centre, Colworth Science Park, Sharnbrook, Bedfordshire, UK.
Yeyejide
Y
Adeleye
Unilever Safety and Environmental Assurance Centre, Colworth Science Park, Sharnbrook, Bedfordshire, UK.
Paul L
PL
Carmichael
ScitoVation, 6 Davis Drive, 110566, Research Triangle Park, NC, 27709, USA.
Melvin E
ME
Andersen
D000826:Animal Testing Alternatives; D000818:Animals; D004249:DNA Damage; D057166:High-Throughput Screening Assays; D006801:Humans; D066298:In Vitro Techniques; D047493:PPAR alpha / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology; D018675:Toxicity Tests / Q000379:methods*; D014116:Toxicology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D047493:PPAR alpha; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
Case study approach; DNA damage; Estrogen signaling; Fit-for-purpose safety assessment; In vitro toxicity testing; Nuclear receptor activation; Toxicity pathways