Gene expression profiling of short-term (2-, 7- or 30-day) exposures can predict chemical mode of action (MOA), temporality of key events, and tumorigenic potency after utilizing only a small fraction of the time and resources (including animal use) of a chronic bioassay. Transcriptional benchmark dose (BMDT) estimates for key genes and pathways after short-term exposures were consistent with potency estimates for the tumorigenic outcome or precursor key events such as hyperplasia. Further, unlike traditional apical responses to short-term exposures, BMDT could distinguish tumorigenic and non-tumorigenic class members, at times in the absence of measurable apical responses. Case studies to be presented include liver gene expression for nuclear receptor (CAR and PPARα) agonists in mice and urinary bladder gene expression for a substituted urea pesticide associated with urinary bladder cytotoxicity and tumorigenesis in rats. By encompassing multiple rodent species, target tissues, MOA, chemical classes, and exposure durations, this approach illustrates how BMD modeling of short-term data is a reliable and efficient chemical testing, prioritization and safety assessment paradigm for future data-poor chemicals with high exposure potential.

Benchmark dose modeling and 21st century application in predictive safety assessment

2019 Fall National Meeting

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