title: A predictive data-driven framework for endocrine prioritization: a triazole fungicide case study.
abstract: The US Environmental Protection Agency Endocrine Disruptor Screening Program (EDSP) is a tiered screening approach to determine the potential for a chemical to interact with estrogen, androgen, or thyroid hormone systems and/or perturb steroidogenesis. Use of high-throughput screening (HTS) to predict hazard and exposure is shifting the EDSP approach to (1) prioritization of chemicals for further screening; and (2) targeted use of EDSP Tier 1 assays to inform specific data needs. In this work, toxicology data for three triazole fungicides (triadimefon, propiconazole, and myclobutanil) were evaluated, including HTS results, EDSP Tier 1 screening (and other scientifically relevant information), and EPA guideline mammalian toxicology study data. The endocrine-related bioactivity predictions from HTS and information that satisfied the EDSP Tier 1 requirements were qualitatively concordant. Current limitations in the available HTS battery for thyroid and steroidogenesis pathways were mitigated by inclusion of guideline toxicology studies in this analysis. Similar margins (3-5 orders of magnitude) were observed between HTS-predicted human bioactivity and exposure values and between in vivo mammalian bioactivity and EPA chronic human exposure estimates for these products' registered uses. Combined HTS hazard and human exposure predictions suggest low priority for higher-tiered endocrine testing of these triazoles. Comparison with the mammalian toxicology database indicated that this HTS-based prioritization would have been protective for any potential in vivo effects that form the basis of current risk assessment for these chemicals. This example demonstrates an effective, human health protective roadmap for EDSP evaluation of pesticide active ingredients via prioritization using HTS and guideline toxicology information.
authors.affiliation: a Human Safety, Bayer CropScience LP, Research Triangle Park , NC , USA ;
authors.forename: Katie
authors.initials: K
authors.lastname: Paul Friedman
authors.affiliation: b Human Health Assessment, Dow AgroSciences LLC , Indianapolis , IN , USA ;
authors.forename: Sabitha
authors.initials: S
authors.lastname: Papineni
authors.affiliation: c Toxicology & Environmental Research and Consulting, The Dow Chemical Company , Midland , MI , USA ;
authors.forename: M Sue
authors.initials: MS
authors.lastname: Marty
authors.affiliation: d Toxicology and Health Sciences, Syngenta Crop Protection LLC , Greensboro , NC , USA.
authors.forename: Kun Don
authors.initials: KD
authors.lastname: Yi
authors.affiliation: d Toxicology and Health Sciences, Syngenta Crop Protection LLC , Greensboro , NC , USA.
authors.forename: Amber K
authors.initials: AK
authors.lastname: Goetz
authors.affiliation: b Human Health Assessment, Dow AgroSciences LLC , Indianapolis , IN , USA ;
authors.forename: Reza J
authors.initials: RJ
authors.lastname: Rasoulpour
authors.affiliation: a Human Safety, Bayer CropScience LP, Research Triangle Park , NC , USA ;
authors.forename: Pat
authors.initials: P
authors.lastname: Kwiatkowski
authors.affiliation: d Toxicology and Health Sciences, Syngenta Crop Protection LLC , Greensboro , NC , USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wolf
authors.affiliation: a Human Safety, Bayer CropScience LP, Research Triangle Park , NC , USA ;
authors.forename: Ann M
authors.initials: AM
authors.lastname: Blacker
authors.affiliation: d Toxicology and Health Sciences, Syngenta Crop Protection LLC , Greensboro , NC , USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Peffer
mesh_terms: D001681:Biological Assay; D052244:Endocrine Disruptors / Q000145:classification / Q000592:standards / Q000633:toxicity*; D005659:Fungicides, Industrial / Q000145:classification / Q000592:standards / Q000633:toxicity*; D009570:Nitriles / Q000633:toxicity; D018675:Toxicity Tests / Q000379:methods*; D014230:Triazoles / Q000145:classification / Q000592:standards / Q000633:toxicity*; D014481:United States
chemical_list: D052244:Endocrine Disruptors; D005659:Fungicides, Industrial; D009570:Nitriles; D014230:Triazoles; C045950:propiconazole; C032910:triadimefon; C446685:systhane
keywords: Endocrine Disruptor Screening Program; ExpoCast; Tox21; ToxCast; high-throughput screening; myclobutanil; propiconazole; triadimefon