Article

Predictive Model of Rat Reproductive Toxicity from ToxCast High Throughput Screening

National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Biology of Reproduction (Impact Factor: 3.32). 05/2011; 85(2):327-39. DOI: 10.1095/biolreprod.111.090977
Source: PubMed

ABSTRACT

The U.S. Environmental Protection Agency's ToxCast research program uses high throughput screening (HTS) for profiling bioactivity and predicting the toxicity of large numbers of chemicals. ToxCast Phase I tested 309 well-characterized chemicals in more than 500 assays for a wide range of molecular targets and cellular responses. Of the 309 environmental chemicals in Phase I, 256 were linked to high-quality rat multigeneration reproductive toxicity studies in the relational Toxicity Reference Database. Reproductive toxicants were defined here as having achieved a reproductive lowest-observed-adverse-effect level of less than 500 mg kg(-1) day(-1). Eight-six chemicals were identified as reproductive toxicants in the rat, and 68 of those had sufficient in vitro bioactivity to model. Each assay was assessed for univariate association with the identified reproductive toxicants. Significantly associated assays were linked to gene sets and used for the subsequent predictive modeling. Using linear discriminant analysis and fivefold cross-validation, a robust and stable predictive model was produced capable of identifying rodent reproductive toxicants with 77% ± 2% and 74% ± 5% (mean ± SEM) training and test cross-validation balanced accuracies, respectively. With a 21-chemical external validation set, the model was 76% accurate, further indicating the model's potential for prioritizing the many thousands of environmental chemicals with little to no hazard information. The biological features of the model include steroidal and nonsteroidal nuclear receptors, cytochrome P450 enzyme inhibition, G protein-coupled receptors, and cell signaling pathway readouts-mechanistic information suggesting additional targeted, integrated testing strategies and potential applications of in vitro HTS to risk assessment.

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Available from: Robert Kavlock, Nov 30, 2015
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    • "The Tox21 10 K chemical library consists of ∼10,500 plated compound solutions, consisting of 8311 unique chemical substances, including pesticides, industrial chemicals, food-use additives and drugs (Huang et al., 2014). Acquired activity data can serve not only as in vitro signatures that could be used to predict in vivo toxicity endpoints (Martin et al., 2011; Sipes et al., 2011) and to prioritize chemicals for extensive toxicity testing (Judson et al., 2010), but also to provide the scientific community with training data sets for developing reliable in silico toxicity models (Sun et al., 2012). Also, many attempts toward development of new computational methods for high-throughput toxicity prediction have been made and many techniques and algorithms have been proposed (Deeb and Goodarzi, 2012; Bakhtyari et al., 2013; Cheng et al., 2013; Valerio, 2013; Low et al., 2014; Omer et al., 2014; Toropov et al., 2014; Rouquie et al., 2015). "
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    • "This includes the development of in vitro testing databases for hundreds of assays and thousands of chemicals in the ToxCast and Tox21 programs (Attene-Ramos et al. 2013; Kavlock et al. 2012). This has fostered development of computational models predicative of in vivo adverse outcomes (Martin et al. 2011; Rotroff et al. 2013; Sipes et al. 2011). The lack of adequate data sets for large numbers of chemicals from in vitro DNT assays has severely hampered the development of computational models. "
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    • "Reproductive and developmental toxicity were even estimated to become the largest animal user for safety testing within REACH (Pedersen et al., 2003; Van der Jagt et al., 2004) since approximately 10,000 chemicals with an annual volume of >100 tonnes would have to be tested on reproductive toxicity. The estimates ranged from 40% to 90% of the total number of animals to comply with REACH that would be needed for reproductive toxicity testing purposes (Van der Jagt et al., 2004; Spielmann and Vogel, 2006; Hartung and Rovida, 2009; Martin et al., 2011). At about the same time, several studies became available that questioned the added value of the second generation (Cooper et al., 2006; Janer et al., 2007a,b; Martin et al., 2009; Piersma et al., 2011) and criticized the limited predictive value of the OECD TG 416 for developmental immunotoxic and neurotoxic parameters (See Section 2.1.). "
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