Hexabromocyclododecane (HBCD): A case study applying tiered testing for human health risk assessment. (September 2019)

• Record Type: Journal Article
• Authors: Gannon, Anne Marie; Moreau, Marjory; Farmahin, Reza; Thomas, Russell S.; Barton-Maclaren, Tara S.; Nong, Andy; Curran, Ivan; Yauk, Carole L.
• Is Part Of: Food and chemical toxicology. Volume 131(2019)
• Publication Date: 2019-09
• Subjects: Tiered testing -- Risk assessment -- Transcriptomics -- Highthroughput screening -- In vitro-in vivo extrapolation -- Bioactivity exposure ratio; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2019.110581
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Current global efforts are aiming to increase use of mechanistic information in regulatory testing. In tiered testing paradigms, in vitro, in silico, and in vivo studies are employed progressively to identify and classify health hazards, which are then compared against human equivalent doses. We used data from three companion papers on the brominated flame retardant hexabromocyclododecane (HBCD) to conduct a case study on tiered testing. We included ToxCast™ and in vitro-in vivo extrapolation (Tier 1), rat liver transcriptomic (Tier 2), and conventional rat (Tier 3) data. Bioactivity-exposure ratios (BERs) were derived by comparing human administered dose equivalents of the measured effects to Canadian exposure levels. Biological perturbations were highly aligned between Tiers 1/2, and consistent with apical effects in Tier 3. Tier 1 had the smallest BERs, and Tiers 2/3 were similar. The study demonstrates the promise of using physiologically-based pharmacokinetic modeling and mechanistic analyses in a tiered framework to identify pathways through which chemicals exert toxicological effects; however, they also point to some shortcomings associated with in vitro and in silico approaches. Additional case studies of chemicals from multiple classes are required to define optimal tiered screening procedures to reduce future in vivo requirements in health hazard assessments. Highlights: We applied a tiered paradigm to evaluate the toxicity of the flame retardant HBCD. Tiers 1-3 were ToxCast and in vitro-in vivo extrapolation, rat liver transcriptomic and conventional data, respectively. Administered dose equivalents were derived to generate bioactivity-exposure ratios (BERs) against human exposure values. Biological perturbations identified in Tiers 1 and 2 were highly aligned, and consistent with apical effects. Tier 1 had smaller BERs than Tiers 2/3 as expected, and the latter two tiers were highly concordant.