Academic journal article Environmental Health Perspectives

On the Utility of ToxCast[TM] and ToxPi as Methods for Identifying New Obesogens

Academic journal article Environmental Health Perspectives

On the Utility of ToxCast[TM] and ToxPi as Methods for Identifying New Obesogens

Article excerpt

Introduction

In 1996, the Food Quality Protection Act (FQPA 1996) and the Safe Drinking Water Act Amendments (SDWA Amendments 1996) directed the U.S. Environmental Protection Agency (EPA) to develop a screening program that would identify endocrine-disrupting chemicals (EDCs) targeting the androgen, estrogen, and thyroid signaling pathways. One key outcome is that the U.S. EPA developed the Toxicity Forecaster (ToxCast[TM]) program in 2007 (Dix et al. 2007). The stated goal of ToxCast[TM] was to employ high-throughput screening (HTS) assays to prioritize chemicals and use this information to inform regulatory decisions regarding thousands of environmental contaminants (Dix et al. 2007). The rationale was that a vanishingly small number of chemicals had been tested adequately for toxicity, and even fewer for endocrine-disrupting end points. Currently, 8 million unique organic compounds are available for purchase (Chuprina et al. 2010), and approximately 84,000 chemicals are registered with the U.S. EPA under the Toxic Substances Control Act of 1976 (TSCA 1976). The U.S. EPA Chemical Data Reporting revealed that over 7,000 chemicals are in wide use (annual production volume > 100,000 lbs) (U.S. EPA 2014b). Other estimates that include data sources from the United States, Canada, and Europe conclude that 30,000 chemicals are in wide commercial use (> 1 ton/year) (Muir and Howard 2006). Health and toxicity data for most chemicals remains elusive because TSCA grandfathered tens of thousands of chemicals that were already on the market before 1976, none of which underwent U.S. EPA review and for which scant safety data are available.

In 2007, the National Research Council recommended in vitro assays to determine which toxicity pathways contribute to human disease (Collins et al. 2008; Kavlock et al. 2009). As a result, ToxCast[TM] implemented Phase 1 in vitro testing. ToxCast[TM] Phase 1 was a proof-of-concept study whereby 320 pesticides, mostly agrochemicals, were selected based on historical toxicological evidence, including in vivo carcinogenicity, reproductive, and developmental defects (Dix et al. 2007). Phase 1 chemicals were subjected to > 450 assays and prioritized by cluster and discriminant analysis using multiple inputs: in silico predictions from physicochemical properties, radioligand/enzyme biochemistry, transcription reporter assays, microarray, cytotoxicity, cell growth kinetics, and more (Dix et al. 2007). In Phase 2, 700 additional chemicals (for which toxicological data is more sparse compared to Phase 1) were tested (Kavlock et al. 2012). Since its 2007 inception, ToxCast[TM] has been reformulated as a prescreening effort to the U.S. EPA Endocrine Disruptor Screening Program (EDSP) to prioritize chemicals for subsequent, in vivo testing.

The peroxisome proliferator-activated receptor gamma (PPAR[gamma]) is a key regulator of adipogenesis (Tontonoz and Spiegelman 2008). PPAR[gamma] heterodimerizes with the 9-cis retinoic acid receptor (RXR) and directly promotes transcription of such key adipogenic genes as fatty acid binding protein 4 (Fabp4), lipoprotein lipase (Lpl) and adiponectin (Adipoq) (Tontonoz and Spiegelman 2008). Some environmental EDCs activate PPAR[gamma] and RXR, thereby promoting adipogenesis, whereas others promote adipogenesis by as yet unknown pathways (Janesick and Blumberg 2011b). These obesogens typically act at low, environmentally relevant doses [often below the established no-observed-adverse-effect-level, (NOAEL)] during critical windows of prenatal or postnatal development to promote obesity later in life (Grun and Blumberg 2006; Janesick and Blumberg 2011a). Obesogens can also alter the epigenetic memory of cells, creating lasting, transgenerational effects on obesity and metabolic end points (Chamorro-Garcia and Blumberg 2014; Chamorro-Garcia et al. 2013; Janesick et al. 2014).

When we began this project, there were no published studies investigating the reliability of ToxCast[TM] assays. …

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