title: Using ToxCast to Explore Chemical Activities and Hazard Traits: A Case Study With Ortho-Phthalates.
abstract: US EPA's Toxicity Forecaster (ToxCastTM) is a tool with potential use in evaluating safer consumer products, conducting chemical alternatives analyses, prioritizing chemicals for exposure monitoring, and ultimately performing screening-level risk assessments. As a case study exploring a potential use of ToxCast, we evaluated ToxCast results for ortho-phthalates focused on the well-established toxicological endpoints of some members of this class. We compared molecular perturbations measured in ToxCast assays with the known apical toxicity endpoints of o-phthalates reported in the open literature to broadly reflect on the predictive capability of the high-throughput screening (HTS) assays. We grouped the ToxCast assays into defined sets to examine o-phthalate activity and potency. This study revealed several links between key molecular events assayed in vitro and chemical-specific hazard traits. In general, parent o-phthalates are more active than their monoester metabolites. The medium-chain length o-phthalate group is also more active than other o-phthalate groups, as supported by Toxicological Priority Index ranking and statistical methods. Some HTS assay results correlated with in vivo findings, but others did not. For example, there was a notable lack of assay activity to explain the known male reproductive toxicity of these compounds. Ultimately, HTS data resources such as ToxCast may inform us of sensitive upstream toxicity endpoints and may assist in the rapid identification of environmental chemical hazards for screening and prioritization. However, this case study shows that the absence of positive results in ToxCast in vitro assays cannot be interpreted as absence of related in vivo toxicity, and limited biological coverage by the assays remains a concern.
authors.affiliation: *California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, Sacramento, California 95814; California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, Oakland, California 94612; Nathalie.pham@oehha.ca.gov ntnpham@gmail.com.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pham
authors.affiliation: *California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, Sacramento, California 95814; California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, Oakland, California 94612;
authors.forename: Shoba
authors.initials: S
authors.lastname: Iyer
authors.affiliation: *California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, Sacramento, California 95814; California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, Oakland, California 94612;
authors.forename: Edward
authors.initials: E
authors.lastname: Hackett
authors.affiliation: *California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, Sacramento, California 95814; California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, Oakland, California 94612;
authors.forename: Bennett H
authors.initials: BH
authors.lastname: Lock
authors.affiliation: *California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, Sacramento, California 95814; California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, Oakland, California 94612;
authors.forename: Martha
authors.initials: M
authors.lastname: Sandy
authors.affiliation: *California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, Sacramento, California 95814; California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, Oakland, California 94612;
authors.forename: Lauren
authors.initials: L
authors.lastname: Zeise
authors.affiliation: California Environmental Protection Agency, Sacramento, California 95814; and California Environmental Protection Agency, Oakland, California 94612.
authors.forename: Gina
authors.initials: G
authors.lastname: Solomon
authors.affiliation: *California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, Sacramento, California 95814; California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, Oakland, California 94612;
authors.forename: Melanie
authors.initials: M
authors.lastname: Marty
mesh_terms: D000818:Animals; D016208:Databases, Factual; D052244:Endocrine Disruptors / Q000737:chemistry / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D015394:Molecular Structure; D010795:Phthalic Acids / Q000737:chemistry / Q000633:toxicity*; D010968:Plasticizers / Q000737:chemistry / Q000633:toxicity*; D012098:Reproduction / Q000187:drug effects; D018570:Risk Assessment; D013329:Structure-Activity Relationship; D018675:Toxicity Tests
chemical_list: D052244:Endocrine Disruptors; D010795:Phthalic Acids; D010968:Plasticizers
keywords: ToxCast; hazard traits.; high-throughput screening; phthalates