Abstract
The Human Toxicology Project Consortium (HTPC) was created to accelerate implementation of the science and policies required to achieve a pathway-based foundation for toxicology as articulated in the 2007 National Research Council report, Toxicity Testing in the 21st Century: a Vision and a Strategy. The HTPC held a workshop, "Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action," in January, 2013, in Baltimore, MD, to further the science of pathway-based approaches to liver toxicity. This review was initiated as a thought-starter for this workshop and has since been updated to include insights from the workshop and other activities occurring in 2013. The report of the workshop has been published elsewhere in this journal (Willett et al., 2014).
Highlights
Experience over several decades of characterizing chemical toxicity has led to the realization that a new approach is warranted
The idea of incorporating mechanistic biochemical information into toxicological assessment is not new; it began with dose-response modeling efforts and mode-of-action frameworks, such as those developed by the International Program on Chemical Safety (IPCS) to determine human relevance of modes-of-action of pesticides and industrial chemicals leading to carcinogenic (Boobis et al, 2006) and non-carcinogenic (Boobis et al, 2008) toxicity, and the creation of mode-of-action pathways commonly used in drug development (e.g., Iorio et al, 2010) and applied to human disease (e.g., Schadt and Lum, 2006)
Several overlapping and related frameworks have been proposed over time, including modes of action, adverse outcome pathways, toxicity pathways and pathways of toxicity
Summary
Experience over several decades of characterizing chemical toxicity has led to the realization that a new approach is warranted. Such factors as the large number of relatively uncharacterized chemicals that are already in the environment, the need to generate information for extensive regulatory programs such as the European Union’s Registration, Evaluation, Authorization and Restriction of Chemical substances (REACH) program, the high cost and slow pace of animal experimentation and the need to improve the certainty of safety decisions have made it necessary to rethink the traditional approach to hazard and risk assessment, which has generally relied on an extensive array of empirical animal test data (Bradbury et al, 2004) These findings, combined with advances in biological understanding and in experimental technologies (e.g., omics tools, stem cell culturing, reconstructed tissues), have allowed the contemplation of dramatically different approaches to toxicology than those traditionally practiced. From this thinking the mode of action (MoA), toxicity pathway, and adverse outcome pathway (AOP) approaches have evolved (Ankley et al, 2010; Boobis et al, 2008; NRC, 2007; US EPA, 2006)
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