Comparison between endocrine activity assessed using ToxCast/Tox21 database and human plasma concentration of sunscreen active ingredients/UV filters.

Sunscreen products are composed of ultraviolet (UV) filters and formulated to reduce exposure to sunlight thereby lessening skin damage. Concerns have been raised regarding the toxicity and potential endocrine disrupting (ED) effects of UV filters. The ToxCast/Tox21 program, that is, CompTox, is a high-throughput in vitro screening database of chemicals that identify adverse outcome pathways, key events, and ED potential of chemicals. Using the ToxCast/Tox21 database, octisalate, homosalate, octocrylene, oxybenzone, octinoxate, and avobenzone, 6 commonly used organic UV filters, were found to have been evaluated. These UV filters showed low potency in these bioassays with most activity detected above the range of the cytotoxic burst. The pathways that were most affected were the cell cycle and the nuclear receptor pathways. Most activity was observed in liver and kidney-based bioassays. These organic filters and their metabolites showed relatively weak ED activity when tested in bioassays measuring estrogen receptor (ER), androgen receptor (AR), thyroid receptor, and steroidogenesis activity. Except for oxybenzone, all activity in the endocrine assays occurred at concentrations greater than the cytotoxic burst. Moreover, except for oxybenzone, plasma concentrations (Cmax) measured in humans were at least 100× lower than bioactive (AC50/ACC) concentrations that produced a response in ToxCast/Tox21 assays. These data are consistent with in vivo animal/human studies showing weak or negligible endocrine activity. In sum, when considered as part of a weight-of-evidence assessment and compared with measured plasma concentrations, the results show these organic UV filters have low intrinsic biological activity and risk of toxicity including endocrine disruption in humans.

Identifying chemicals based on receptor binding/bioactivation/mechanistic explanation associated with potential to elicit hepatotoxicity and to support structure activity relationship-based read-across.

The liver is the most common target organ in toxicology studies. The development of chemical structural alerts for identifying hepatotoxicity will play an important role in in silico model prediction and help strengthen the identification of analogs used in structure activity relationship (SAR)- based read-across. The aim of the current study is development of an SAR-based expert-system decision tree for screening of hepatotoxicants across a wide range of chemistry space and proposed modes of action for clustering of chemicals using defined core chemical categories based on receptor-binding or bioactivation. The decision tree is based on âˆ¼ 1180 different chemicals that were reviewed for hepatotoxicity information. Knowledge of chemical receptor binding, metabolism and mechanistic information were used to group these chemicals into 16 different categories and 102 subcategories: four categories describe binders to 9 different receptors, 11 categories are associated with possible reactive metabolites (RMs) and there is one miscellaneous category. Each chemical subcategory has been associated with possible modes of action (MOAs) or similar key structural features. This decision tree can help to screen potential liver toxicants associated with core structural alerts of receptor binding and/or RMs and be used as a component of weight of evidence decisions based on SAR read-across, and to fill data gaps.

An interim internal Threshold of Toxicologic Concern (iTTC) for chemicals in consumer products, with support from an automated assessment of ToxCast™ dose response data.

Additional non-animal methods are urgently needed to meet regulatory and animal welfare goals. TTC is a broadly used risk assessment tool. TTC based on external dose has limited utility for multi-route exposure and some types of structure activity relationship assessments. An internal TTC (iTTC), where thresholds are based on blood concentration, would extend the applicability of TTC. While work is on-going to develop robust iTTC thresholds, we propose an interim conservative iTTC. Specifically, an interim iTTC of 1 µM, supported by the published experience of the pharmaceutical industry, a literature review of non-drug chemical/receptor interactions, and analysis of ToxCast™ data. ToxCast™ data were used to explore activity versus the 1 µM interim iTTC and recommendations for the analysis and interpretation of HTS data. Test concentration-based points of departure were classified to identify quality of fit to the Hill Model. We identified, for exclusion from the approach, estrogen receptor and androgen receptor targets as potent chemical/receptor interactions potentially associated with low dose exposure to non-pharmaceutical active ingredients in addition to the original TTC exclusions. With these exclusions, we conclude that a 1 µM plasma concentration is unlikely to be associated with significant biological effects from chemicals not intentionally designed for biological activity.