Hexabromocyclododecane (HBCD): A case study applying tiered testing for human health risk assessment
- DOI
- Language of the publication
- English
- Date
- 2019-06-13
- Type
- Article
- Author(s)
- Gannon, Anne Marie
- Moreau, Marjory
- Farmahin, Reza
- Thomas, Russell S.
- Barton-Maclaren, Tara S.
- Nong, Andy
- Curran, Ivan
- Yauk, Carole L.
- Publisher
- Elsevier
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.
Plain language summary
Health Canada is responsible to the risk assessment of chemicals in the Canadian environment to protect human health. Conventional regulatory toxicology tests that rely on the measurement of diseases in animals are time consuming, expensive, and require many animals. Current global efforts are aiming to increase use of novel sources of information in regulatory testing. In tiered testing paradigms, in vitro (cell culture), in silico (computer), and short-term animal studies are employed progressively to identify and classify health hazards, which are then compared against human equivalent doses (i.e., the doses humans would need to be exposed to in order to reach the same in vitro or animal levels of exposure). Health Canada collaborated with the US Environmental Protection agency in this study to use data from three companion papers on the brominated flame retardant hexabromocyclododecane (HBCD) to conduct a case study on tiered testing. We included cell culture data and computer models (Tier 1), rat liver genomic (Tier 2), and conventional rat (Tier 3) data. Bioactivity-exposure ratios were derived by comparing human equivalent doses of the measured effects within each tier to Canadian exposure levels. Biological perturbations were highly aligned between Tiers 1/2, and consistent with effects in short term rat tests in Tier 3. Tier 1 had the smallest BERs, and Tiers 2/3 were similar. The study demonstrates how a tiered framework can be applied to identify pathways through which chemicals exert toxicological effects. Additional case studies of chemicals from multiple classes are required to define optimal tiered screening procedures to reduce future reliance on conventional long-term animals tests currently required in health hazard assessments. This case study provides a critical model for how to use these novel sources of information for human health risk assessment at Health Canada.
Subject
- Health,
- Health and safety