Integration of new approach methods for the assessment of data-poor chemicals.

The use of new approach methods (NAMs), including high-throughput, in vitro bioactivity data, in setting a point-of-departure (POD) will accelerate the pace of human health hazard assessments. Combining hazard and exposure predictions into a bioactivity:exposure ratio (BER) for use in risk-based prioritization and utilizing NAM-based bioactivity flags to indicate potential hazards of interest for further prediction or mechanism-based screening together comprise a prospective approach for management of substances with limited traditional toxicity testing data. In this work, we demonstrate a NAM-based assessment case study conducted via the Accelerating the Pace of Chemical Risk Assessment initiative, a consortium of international research and regulatory scientists. The primary objective was to develop a reusable and adaptable approach for addressing chemicals with limited traditional toxicity data using a NAM-based POD, BER, and bioactivity-based flags for indication of putative endocrine, developmental, neurological, and immunosuppressive effects via data generation and interpretation for 200 substances. Multiple data streams, including in silico and in vitro NAMs, were used. High-throughput transcriptomics and phenotypic profiling data, as well as targeted biochemical and cell-based assays, were combined with generic high-throughput toxicokinetic models parameterized with chemical-specific data to estimate dose for comparison to exposure predictions. This case study further enables regulatory scientists from different international purviews to utilize efficient approaches for prospective chemical management, addressing hazard and risk-based data needs, while reducing the need for animal studies. This work demonstrates the feasibility of using a battery of toxicodynamic and toxicokinetic NAMs to provide a NAM-based POD for screening-level assessment.