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Evaluation of food-relevant chemicals in the ToxCast high-throughput screening program
Citation:
Karmaus, A., D. Filer, M. Martin, AND K. Houck. Evaluation of food-relevant chemicals in the ToxCast high-throughput screening program. FOOD AND CHEMICAL TOXICOLOGY. Elsevier Science Ltd, New York, NY, 92:188-196, (2016).
Impact/Purpose:
This study evaluates the food-relevant chemical landscape using cheminformatics approaches and subsequently identifies food-relevant chemicals in the ToxCast program. For the food-relevant chemicals evaluated in ToxCast, the cytotoxicity and bioactivity of chemicals is summarized.
Description:
There are thousands of chemicals that are directly added to or come in contact with food, many of which have undergone little to no toxicological evaluation. The ToxCast high-throughput screening (HTS) program has evaluated over 1,800 chemicals in concentration-response across ~820 assay endpoints and continues to grow; with all data completely available to the public, this resource serves as a unique opportunity to evaluate the bioactivity of chemicals in vitro. This study investigated the chemical landscape of the food-relevant chemical universe using cheminformatics analyses, and subsequently evaluated the bioactivity of food-relevant chemicals included in the ToxCast HTS program. Initially, a list of 9,437 food-relevant chemicals was compiled by comprehensively mining publicly available sources for direct food additives, food contact substances, indirect food additives, and pesticides. Of these food-relevant chemicals, 4,638 were associated with curated structure definition files amenable to defining physical/chemical features used to generate chemical fingerprints. Clustering was conducted based on the chemical fingerprints using a self-organizing map approach. This revealed that pesticides, food contact substances, and direct food additives generally clustered apart from one another, supporting that these categories reflect not only different uses but also distinct chemistries. Subsequently, 967 of the 9,437 food-relevant chemicals were identified in the ToxCast HTS program, comprising 321 direct food additives, 255 food contact substances, and 391 pesticides. Chemical bioactivity in ToxCast was filtered for cytotoxicity to identify specific chemical effects. By initiating analyses from a strictly chemical structure-based methodology, as well as bioactivity/cytotoxicity-driven evaluation, we demonstrated unbiased approaches for identifying food-use chemicals of interest. Although bioactivity in vitro is not necessarily predictive of adverse effects or toxicity in vivo, these data provide insight into the chemical properties and the cellular targets through which food-relevant chemicals elicit bioactivity.
