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Hexabromocyclododecane (HBCD): A case study applying tiered testing for human health risk assessment
Citation:
Gannon, A., M. Moreau, R. Farmahin, R. Thomas, T. Barton-Maclaren, A. Nong, I. Curran, AND C. Yauk. Hexabromocyclododecane (HBCD): A case study applying tiered testing for human health risk assessment. FOOD AND CHEMICAL TOXICOLOGY. Elsevier Science Ltd, New York, NY, 131:110581, (2019). https://doi.org/10.1016/j.fct.2019.110581
Impact/Purpose:
This manuscript describes approaches for using tiered toxicity testing to inform chemical safety decisions. This case study uses the flame retardant hexabromocyclodecane (HBCD) as a case study using physiologically-based pharmacokinetic modeling and mechanistic analyses to inform chemical safety decisions. This manuscript will be of interested to our partners that have a general interest in the evaluation and regulatory application of NAM data. In addition, HBCD is a potential endocrine disrupting compound and may be of interest to our partners in the Endocrine Disruptor Screening Program (EDSP). This manuscript supports the hypothesis that tiered toxicity testing strategies can be used for chemical screening and priority setting, resulting in a protective indication of potential risk from chemical exposure.
Description:
Over a decade ago the National Research Council published “Toxicity Testing in the 21st Century: A Vision and a Strategy,” which sought to increase the use of mechanistic information in regulatory testing to address deficiencies in existing approaches. Under the paradigm, in vitro, in silico, and in vivo studies are employed in a progressive manner to identify and classify human health hazards. Tiered testing paradigms expanded upon this by defining the order of conduct of specific types of mechanistic tests and how to relate these to human exposures to identify potential chemical hazards. Herein we employ the data from three companion papers on a brominated flame retardant, hexabromocyclododecane (HBCD), to conduct a case study on tiered testing. We used ToxCast data and in vitro-in vivo extrapolation (Tier 1), rat in vivo transcriptomic data (Tier 2), and conventional rat data (Tier 3) to assess potential hazards and identify the concentrations/doses at which these effects occurred. Bioactivity-exposure ratios (BERs) were derived by comparing the doses at which effects occurred to human administered dose equivalents. There was remarkable consistency in the biological perturbations identified within Tiers 1 and 2, which were consistent with apical effects in Tier 3 tests. Tier 1 had smaller BERs than Tiers 2/3 as expected. The data provide a case example of the utility of using physiologically-based pharmacokinetic modeling and mechanistic analyses in a tiered testing framework to identify potential pathways through which chemicals act in biological system; however, they also point to some shortcomings associated with in vitro and in silico approaches that, at present, can only be addressed through in vivo studies. Therefore, further population of robust databases with integrated studies using numerous chemicals from multiple classes will enhance development of Tier 1 and 2 screening procedures and reduce future in vivo requirements in health hazard assessments.
URLs/Downloads:
DOI: Hexabromocyclododecane (HBCD): A case study applying tiered testing for human health risk assessment
https://pubmed.ncbi.nlm.nih.gov/31202941/