title: Using In Vitro High-Throughput Screening Data for Predicting Benzo[k]Fluoranthene Human Health Hazards.
abstract: Today there are more than 80,000 chemicals in commerce and the environment. The potential human health risks are unknown for the vast majority of these chemicals as they lack human health risk assessments, toxicity reference values, and risk screening values. We aim to use computational toxicology and quantitative high-throughput screening (qHTS) technologies to fill these data gaps, and begin to prioritize these chemicals for additional assessment. In this pilot, we demonstrate how we were able to identify that benzo[k]fluoranthene may induce DNA damage and steatosis using qHTS data and two separate adverse outcome pathways (AOPs). We also demonstrate how bootstrap natural spline-based meta-regression can be used to integrate data across multiple assay replicates to generate a concentration-response curve. We used this analysis to calculate an in vitro point of departure of 0.751 μM and risk-specific in vitro concentrations of 0.29 μM and 0.28 μM for 1:1,000 and 1:10,000 risk, respectively, for DNA damage. Based on the available evidence, and considering that only a single HSD17B4 assay is available, we have low overall confidence in the steatosis hazard identification. This case study suggests that coupling qHTS assays with AOPs and ontologies will facilitate hazard identification. Combining this with quantitative evidence integration methods, such as bootstrap meta-regression, may allow risk assessors to identify points of departure and risk-specific internal/in vitro concentrations. These results are sufficient to prioritize the chemicals; however, in the longer term we will need to estimate external doses for risk screening purposes, such as through margin of exposure methods.
authors.affiliation: U.S. Army Engineer Research and Development Center, Research Triangle Park, NC, USA.
authors.forename: Lyle D
authors.initials: LD
authors.lastname: Burgoon
authors.affiliation: Oak Ridge Institute for Science and Education assigned to the U.S. Environmental Protection Agency, National Center for Environmental Assessment, Research Triangle Park, NC, USA.
authors.forename: Ingrid L
authors.initials: IL
authors.lastname: Druwe
authors.affiliation: Oak Ridge Institute for Science and Education assigned to the U.S. Environmental Protection Agency, National Center for Environmental Assessment, Research Triangle Park, NC, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Painter
authors.affiliation: Oak Ridge Institute for Science and Education assigned to the U.S. Environmental Protection Agency, National Center for Environmental Assessment, Research Triangle Park, NC, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Yost
mesh_terms: D000465:Algorithms; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000139:chemically induced; D005449:Fluorenes / Q000633:toxicity*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D018384:Oxidative Stress; D016016:Proportional Hazards Models; D012306:Risk; D018570:Risk Assessment / Q000379:methods*; D018675:Toxicity Tests
chemical_list: D005449:Fluorenes; C007738:fluoranthene; C022921:benzo(k)fluoranthene
keywords: H3PV; High-throughput screening; human health hazard prioritization values; risk assessment; risk screening