A screening strategy for identifying the developmental and reproductive toxicity potential of botanicals

Botanicals are widely consumed as dietary supplements and traditional medicines, yet their developmental and reproductive toxicity (DART) potential is often inadequately characterized. Botanicals are chemically complex and variable, complicating traditional in vivo testing and interpretation. There is a need for fit-for-purpose new approach methodologies (NAMs) to evaluate DART hazards of complex mixtures while reducing reliance on mammalian models.

This review describes the Botanical Safety Consortium (BSC) DART Working Group strategy to evaluate a battery of NAMs for screening botanical extracts and outlines the botanicals selected as case studies to assess assay suitability for complex mixtures.

Available NAMs relevant to DART were identified and reviewed, including human induced pluripotent stem cell assays (e.g., devTox Quick Predict), zebrafish embryos, Caenorhabditis elegans, transcriptomics with Connectivity Map analysis, in vitro pharmacology profiling, and selected in silico tools. Assays were selected to provide complementary functional, mechanistic, and biomarker coverage across biological levels. Eighteen botanicals were chosen based on published in vivo, mechanistic, livestock, or in vitro evidence indicating no concern, uncertain effects, or established DART hazards.

The selected NAM battery captures diverse mechanisms relevant to DART. The case study botanicals span clear positives (e.g., locoweed, poison hemlock, cottonseed), suspected positives based on limited data (e.g., bitter melon, goldenseal, rue), and low concern examples (e.g., Asian ginseng), enabling evaluation of assay performance for complex mixtures.

This strategy paper lays the groundwork to assess the suitability of integrated NAMs for screening botanical DART potential and establishes the foundation for subsequent testing and case study evaluation.