Evaluation of 5-day In Vivo Rat Liver and Kidney With High-throughput Transcriptomics for Estimating Benchmark Doses of Apical Outcomes

• DOI: 10.1093/toxsci/kfaa081
• Publication Date: 2020-05-29T03:33:56Z
• Authors: William M Gwinn; Scott S Auerbach; Fred Parham; Matthew D Stout; Suramya Waidyanatha; Esra Mutlu; Brad Collins; Richard S Paules; Bruce Alex Merrick; Stephen Ferguson; Sreenivasa Ramaia...; John R Bucher; Barney Sparrow; Heather Toy; Jenni Gorospe; Nick Machesky; Ruchir R Shah; Michele R Balik-M...; Deepak Mav; Dhiral P Phadke; Georgia Roberts; Michael J DeVito
• Keywords: Benchmark (surveying); Toxicogenomics

Abstract A 5-day in vivo rat model was evaluated as an approach to estimate chemical exposures that may pose minimal risk by comparing benchmark dose (BMD) values for transcriptional changes the liver and kidney BMD toxicological endpoints from traditional toxicity studies. Eighteen chemicals, most having been tested National Toxicology Program 2-year bioassays, were evaluated. Some of these chemicals are potent hepatotoxicants (eg, DE71, PFOA, furan) rodents, some exhibit but have hepatic effects acrylamide α,β-thujone), little overt ginseng milk thistle extract) based on evaluations. Male Sprague Dawley rats exposed once daily 5 consecutive days oral gavage 8–10 levels each chemical. Liver collected 24 h after final exposure total RNA assayed using high-throughput transcriptomics (HTT) with S1500+ platform. HTT data analyzed Express 2 determine gene set values. BMDS used histopathological chronic or subchronic For many lowest BMDs assays within a factor These suggest provides reasonable estimates apical endpoints. This be useful prioritize further testing while providing actionable timely cost-effective manner.