Abstract
The ToxCast program has generated in vitro screening data on over a thousand chemicals to assess potential disruption of important biological processes and assist in hazard identification and chemical testing prioritization. Few results have been reported for complex mixtures. To extend these ToxCast efforts to mixtures, we tested extracts from 30 organically grown fruits and vegetables in concentration-response in the BioMAP® assays. BioMAP systems use human primary cells primed with endogenous pathway activators to identify phenotypic perturbations related to proliferation, inflammation, immunomodulation, and tissue remodeling. Clustering of bioactivity profiles revealed separation of these produce extracts and ToxCast chemicals. Produce extracts elicited 87 assay endpoint responses per item compared to 20 per item for ToxCast chemicals. On a molar basis, the produce extracts were 10 to 50-fold less potent and when constrained to the maximum testing concentration of the ToxCast chemicals, the produce extracts did not show activity in as many assay endpoints. Using intake adjusted measures of dose, the bioactivity potential was higher for produce extracts than for agrichemicals, as expected based on the comparatively small amounts of agrichemical residues present on conventionally grown produce. The evaluation of BioMAP readouts and the dose responses for produce extracts showed qualitative and quantitative differences from results with single chemicals, highlighting challenges in the interpretation of bioactivity data and dose-response from complex mixtures.
Highlights
Political, scientific, financial, and ethical pressures have all contributed to global efforts to transition away from animal-based toxicity testing toward incorporation of in vitro and alternative testing approaches to inform chemical safety
The biological activity of complex mixtures, i.e., fruit and vegetable extracts, were characterized using the BioMAP assays and the results were compared with agrichemicals tested in ToxCast
The intent of the comparison was to provide better context for the bioactivities ob-served in the ToxCast chemicals since the produce extracts represent substances to which humans are routinely exposed and are generally considered safe
Summary
Scientific, financial, and ethical pressures have all contributed to global efforts to transition away from animal-based toxicity testing toward incorporation of in vitro and alternative testing approaches to inform chemical safety. To build confidence in applying in vitro tools to this task, a range of issues need to be considered to relate activity of compounds in in vitro assays to potential human health ef-ects and real-world exposures. Validation of in vitro tools designed to predict therapeutic effects of drugs for which intake doses, systemic concentrations and biomarker studies can be evaluated using clinical study data is more straightforward than validation of in vitro tools designed to predict human toxicological effects of environmental, commercial and industrial chemicals, where controlled study in vivo data are lacking. As new in vitro assays come into practice for measuring molecular and cellular responses, un-certainty in the relationship between measurable bioactivity and potential adversity needs to be carefully considered, when considering risk from complex environmental exposures
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