The Environmental Protection Agency (EPA) provides access to information on a variety of topics related to the environment and strives to inform citizens of health risks. The EPA also has an extensive library network that consists of 26 libraries throughout the United States, which provide access to a plethora of information to EPA employees, scientists, and researchers. The EPA implemented a reorganization project to digitize their materials so they would be more accessible to a wider range of users, but this plan was drastically accelerated when the EPA was threatened with a budget cut. It chose to close and reduce the hours and services of some of their libraries. As a result, the agency was accused of denying users the “right to know” by making information unavailable, not providing an adequate strategic plan, and discarding vital materials. This case study explores the background of the digitization project, the practices implemented, and the critiques of the project.

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The Environmental Protection Agency

There are thousands of environmental chemicals, including many industrial chemicals and pesticidal active and inert ingredients, with the potential for significant human exposures but for which toxicity information is either limited or nonexistent (Judson et al. 2009). This data gap is due largely to the high cost and length of time required to conduct animal testing in rodents and other species. A complete set of regulatory tests for a single chemical (including those for carcinogenicity and for chronic, reproductive, and development toxicity) uses thousands of animals and costs millions of dollars. In addition, traditional animal tests often yield limited information on mechanism of action, and hence on the cellular pathways that could lead to toxicity in humans. Such mechanistic information is key to moving beyond default approaches for extrapolating from high-dose animal toxicity tests to estimation of human risk at realistic exposure levels.

There is a pressing need to screen the large backlog of chemicals for their potential toxicity and, ultimately, their contribution to human diseases. The National Research Council (2007) advocated the use of mechanistically informative in vitro assays based on human cells or human cell constituents that measure effects on “toxicity pathways” leading to human disease. The U.S. Environmental Protection Agency (EPA), through its ToxCast program (Dix et al. 2007) and the Tox21 collaboration with the National Toxicology Program and the National Institutes of Health Chemical Genomics Center, is pursuing similar objectives and applying many of the ideas represented in the National Research Council report (Collins et al. 2008; Kavlock et al. 2009).

ToxCast is a large-scale experiment using a battery of in vitro, high-throughput screening (HTS) assays, applied to a relatively large and diverse chemical space, to develop methods to predict potential toxicity of environmental chemicals at a fraction of the cost of full-scale animal testing. Three major goals of ToxCast are to a) identify in vitro assays that can reliably indicate alterations in biological processes of relevance to in vivo toxicity; b) develop signatures or prediction models based on multiple assays, along with computed or available chemical properties, that can achieve higher predictive power than single assays or chemical structure alone; and c) use these combined in silico and in vitro assay-based signatures to screen large numbers of previously untested environmental chemicals. The ToxCast data set provides a rich resource for identifying chemically induced changes in biological pathways that are associated with in vivo end points and that could potentially lead to human disease. Chemicals whose properties and assay profiles match these predictive signatures can be prioritized for more in-depth testing, which may include nontraditional, mechanism-focused in vivo tests. In this article, we provide an overview of the entire ToxCast phase I assay results data set and present initial analyses and findings.

In Vitro Screening of Environmental Chemicals for Targeted Testing Prioritization: The ToxCast Project

The U.S. Environmental Protection Agency’s (EPA) ToxCast program is testing a large library of Agency-relevant chemicals using in vitro high-throughput screening (HTS) approaches to support the development of improved toxicity prediction models. Launched in 2007, Phase I of the program screened 310 chemicals, mostly pesticides, across hundreds of ToxCast assay end points. In Phase II, the ToxCast library was expanded to 1878 chemicals, culminating in the public release of screening data at the end of 2013. Subsequent expansion in Phase III has resulted in more than 3800 chemicals actively undergoing ToxCast screening, 96% of which are also being screened in the multi-Agency Tox21 project. The chemical library unpinning these efforts plays a central role in defining the scope and potential application of ToxCast HTS results. The history of the phased construction of EPA’s ToxCast library is reviewed, followed by a survey of the library contents from several different vantage points. CAS Registry Numbers ar...

http://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.6b00135

ToxCast Chemical Landscape: Paving the Road to 21st Century Toxicology

Phthalates impact human health: Epidemiological evidences and plausible mechanism of action.

Over the years, various liver-derived in vitro model systems have been developed to enable investigation of the potential adverse effects of chemicals and drugs. Liver tissue slices, isolated microsomes, perfused liver, immortalized cell lines, and primary hepatocytes have been used extensively. Immortalized cell lines and primary isolated liver cells are currently the most widely used in vitro models for liver toxicity testing. Limited throughput, loss of viability, and decreases in liver-specific functionality and gene expression are common shortcomings of these models. Recent developments in the field of in vitro hepatotoxicity include three-dimensional tissue constructs and bioartificial livers, co-cultures of various cell types with hepatocytes, and differentiation of stem cells into hepatic lineage-like cells. In an attempt to provide a more physiological environment for cultured liver cells, some of the novel cell culture systems incorporate fluid flow, micro-circulation, and other forms of organotypic microenvironments. Co-cultures aim to preserve liver-specific morphology and functionality beyond those provided by cultures of pure parenchymal cells. Stem cells, both embryonic- and adult tissue-derived, may provide a limitless supply of hepatocytes from multiple individuals to improve reproducibility and enable testing of the individual-specific toxicity. This review describes various traditional and novel in vitro liver models and provides a perspective on the challenges and opportunities afforded by each individual test system.

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In vitro models for liver toxicity testing.

ObjectiveThousands of chemicals are in common use, but only a portion of them have undergone significant toxicologic evaluation, leading to the need to prioritize the remainder for targeted testing...

Todd Holderman

Papers

The Toxicity Data Landscape for Environmental Chemicals