title: A systematic evaluation of the potential effects of trichloroethylene exposure on cardiac development.
abstract: The 2011 EPA trichloroethylene (TCE) IRIS assessment, used developmental cardiac defects from a controversial drinking water study in rats (Johnson et al. [51]), along with several other studies/endpoints to derive reference values. An updated literature search of TCE-related developmental cardiac defects was conducted. Study quality, strengths, and limitations were assessed. A putative adverse outcome pathway (AOP) construct was developed to explore key events for the most commonly observed cardiac dysmorphologies, particularly those involved with epithelial-mesenchymal transition (EMT) of endothelial origin (EndMT); several candidate pathways were identified. A hypothesis-driven weight-of-evidence analysis of epidemiological, toxicological, in vitro, in ovo, and mechanistic/AOP data concluded that TCE has the potential to cause cardiac defects in humans when exposure occurs at sufficient doses during a sensitive window of fetal development. The study by Johnson et al. [51] was reaffirmed as suitable for hazard characterization and reference value derivation, though acknowledging study limitations and uncertainties.
authors: U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Washington, DC 20460, United States. Electronic address: makris.susan@epa.gov.
authors: Susan L
authors: SL
authors: Makris
authors: U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Washington, DC 20460, United States.
authors: Cheryl Siegel
authors: CS
authors: Scott
authors: U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Washington, DC 20460, United States.
authors: John
authors: J
authors: Fox
authors: U.S. Environmental Protection Agency, Office of Research and Development, National Center for Computational Toxicology, Research Triangle Park, NC 27711, United States.
authors: Thomas B
authors: TB
authors: Knudsen
authors: U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Research Triangle Park, NC 27711, United States.
authors: Andrew K
authors: AK
authors: Hotchkiss
authors: U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Washington, DC 20460, United States.
authors: Xabier
authors: X
authors: Arzuaga
authors: U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Washington, DC 20460, United States.
authors: Susan Y
authors: SY
authors: Euling
authors: U.S. Environmental Protection Agency, Office of Transportation and Air Quality, Assessment and Standards Division, Ann Arbor, MI 48105, United States.
authors: Christina M
authors: CM
authors: Powers
authors: U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Washington, DC 20460, United States.
authors: Jennifer
authors: J
authors: Jinot
authors: U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Washington, DC 20460, United States.
authors: Karen A
authors: KA
authors: Hogan
authors: U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711, United States.
authors: Barbara D
authors: BD
authors: Abbott
authors: U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711, United States.
authors: E Sidney
authors: ES
authors: Hunter
authors: U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711, United States.
authors: Michael G
authors: MG
authors: Narotsky
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000009:adverse effects*; D004785:Environmental Pollutants / Q000633:toxicity*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000196:embryology; D006801:Humans; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012997:Solvents / Q000633:toxicity*; D014241:Trichloroethylene / Q000633:toxicity*
chemical_list: D004785:Environmental Pollutants; D012997:Solvents; D014241:Trichloroethylene
keywords: AOP; Cardiac; Malformations; TCE; Trichloroethylene