The U.S. Environmental Protection Agency Strategic Plan for Evaluating the Toxicity of Chemicals

Abstract

In the 2007 report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences envisioned a major transition in toxicity testing from cumbersome, expensive, and lengthy in vivo testing with qualitative endpoints, to in vitro robotic high-throughput screening with mechanistic quantitative parameters. Recognizing the need for agencies to partner and collaborate to ensure global harmonization, standardization, quality control and information sharing, the U.S. Environmental Protection Agency is leading by example and has established an intra-agency Future of Toxicity Testing Workgroup (FTTW). This workgroup has produced an ambitious blueprint for incorporating this new scientific paradigm to change the way chemicals are screened and evaluated for toxicity. Four main components of this strategy are discussed, as follows: (1) the impact and benefits of various types of regulatory activities, (2) chemical screening and prioritization, (3) toxicity pathway-based risk assessment, and (4) institutional transition. The new paradigm is predicated on the discovery of molecular perturbation pathways at the in vitro level that predict adverse health effects from xenobiotics exposure, and then extrapolating those events to the tissue, organ, or whole organisms by computational models. Research on these pathways will be integrated and compiled using the latest technology with the cooperation of global agencies, industry, and other stakeholders. The net result will be that chemical toxicity screening will become more efficient and cost-effective, include real-world exposure assessments, and eliminate currently used uncertainty factors.

Toxicologic Pathology in the 21st Century

“…The intra-agency Future of Toxicity Testing Workgroup looked into four main aspects of the future strategy to render toxicity testing of environmental chemicals more efficient and cost effective and to eliminate uncertainty factors (Firestone et al 2010 (Bhogal et al 2005). FRAME says that without a shift from checklist in vivo testing to inclusion of alternative methods using a case-by-case risk assessment strategy, the REACH program to assess tens of thousands of chemicals is unrealistic.…”

Implementing toxicity testing in the 21st century: challenges and opportunities

“…The first tier of testing would be generalised and contain a battery of tests that analyse all possible conditions of toxicity. The purpose of the first tier would be to rank tens of thousands of substances based on their bioactivity profile (Dix et al, 2007;Firestone et al, 2010;Judson et al, 2010;Krewski et al, 2010). Potentially hazardous substances would then move to the next tiers of testing and undergo a more thorough analysis including animal studies.…”

Pathways of Toxicity

“…A critical overview of the extensive dialog that ensued after the publication of the report has been compiled by Andersen and Krewski (2010). Within a few years, the discussion has moved from whether the field of toxicology should change to discussions on how and when to do so – from the call for a Human Toxicology Project (Seidle and Stephens, 2009; http://www.humantoxicologyproject.org) to ongoing programs of US federal agencies (Judson et al, 2010; Knudsen et al, 2011) and the redefinition of the EPA toxicity-testing paradigm (Firestone et al, 2010). …”