title: A Comparison of ToxCast Test Results with In Vivo and Other In Vitro Endpoints for Neuro, Endocrine, and Developmental Toxicities: A Case Study Using Endosulfan and Methidathion.
abstract: BACKGROUND
  The U.S. Environmental Protection Agency's (EPA's) Toxicity Forecaster (ToxCast) is a potential tool for chemical prioritization, hazard identification, and risk assessment. We conducted a case study to compare ToxCast data with endpoints from other in vitro and in vivo studies for two data-rich pesticides: endosulfan and methidathion.
  
  
  METHODS
  ToxCast assays for endocrine disruption, development (zebrafish), and neurotoxicity were qualitatively compared to traditional neurotoxicity, developmental and reproductive toxicity findings. We also used in vitro-in vivo extrapolation to convert half-maximal activity concentrations in active ToxCast assays to rat oral equivalent doses, and quantitatively compared these to the lowest observable effect level (LOEL) from in vivo studies.
  
  
  RESULTS
  Endosulfan was inactive for GABAA R, unlike in vivo; but active with dopamine transporter assays and was neurotoxic in zebrafish as expected. Methidathion was not active for these endpoints in vivo or in vitro. Acetylcholinesterase inhibition was ToxCast-inactive, although both pesticides are inhibitors in vivo. ToxCast results were generally inactive for endosulfan estrogen receptor agonism and androgen receptor antagonism unlike in vivo. Calculated oral equivalent doses for estrogen receptor and androgen receptor pathways and for zebrafish assays for both compounds were generally consistent with in vivo LOELs. Endosulfan showed neurotoxicity and both pesticides showed developmental effects in the zebrafish assays, although methidathion is not developmentally toxic in vivo.
  
  
  CONCLUSIONS
  ToxCast's predictions showed concordance on some endpoints and nonconcordance, consisting mainly of false inactives, in several critical endpoints, likely due to a lack of metabolic activation and limitations in assay design. Zebrafish assays were good predictors of developmental toxicity and neurotoxicity for endosulfan.
authors.affiliation: Department of Pesticide Regulation, California Environmental Protection Agency (CalEPA), Sacramento, California.
authors.forename: M
authors.initials: M
authors.lastname: Silva
authors.affiliation: CalEPA's Office of Environmental Health Hazard Assessment (OEHHA), Sacramento, California.
authors.forename: N
authors.initials: N
authors.lastname: Pham
authors.affiliation: Department of Pesticide Regulation, California Environmental Protection Agency (CalEPA), Sacramento, California.
authors.forename: C
authors.initials: C
authors.lastname: Lewis
authors.affiliation: CalEPA's Office of Environmental Health Hazard Assessment (OEHHA), Sacramento, California.
authors.forename: S
authors.initials: S
authors.lastname: Iyer
authors.affiliation: Department of Pesticide Regulation, California Environmental Protection Agency (CalEPA), Sacramento, California.
authors.forename: E
authors.initials: E
authors.lastname: Kwok
authors.affiliation: Office of the Secretary, CalEPA, Sacramento, California.
authors.forename: G
authors.initials: G
authors.lastname: Solomon
authors.affiliation: CalEPA's Office of Environmental Health Hazard Assessment (OEHHA), Sacramento, California.
authors.forename: L
authors.initials: L
authors.lastname: Zeise
mesh_terms: D000818:Animals; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects*; D004703:Endocrine System / Q000187:drug effects*; D004726:Endosulfan / Q000633:toxicity*; D057166:High-Throughput Screening Assays; D006801:Humans; D066298:In Vitro Techniques; D007306:Insecticides / Q000633:toxicity; D051379:Mice; D009420:Nervous System / Q000187:drug effects*; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D018570:Risk Assessment; D018675:Toxicity Tests / Q000379:methods*; D015027:Zebrafish / Q000254:growth & development*
chemical_list: D007306:Insecticides; D009946:Organothiophosphorus Compounds; D004726:Endosulfan; C005828:methidathion
keywords: ToxCast; dopamine/dopamine transporter; endocrine disruptor; endosulfan; estrogen/androgen receptors; high-throughput screening; methidathion; neurotoxicity