Systematic evaluation of mechanistic data in assessing in utero exposures to trichloroethylene and development of congenital heart defects

• Published in: Toxicology (Amsterdam) Vol. 436; p. 152427
• Main Authors: Urban, Jonathan D., Wikoff, Daniele S., Chappell, Grace A., Harris, Craig, Haws, Laurie C.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 30.04.2020
• Subjects: adverse outcome pathways; Cardiac defects; chickens; Congenital heart defects; data collection; Developmental toxicology; Emergency; experimental design; health effects assessments; heart abnormalities; human health; humans; In utero; in vitro studies; laboratory animals; maternal exposure; Mechanistic evidence; progeny; rats; Risk assessment; Systematic review; TCE; Trichloroethylene; AOPKB; EndoMT; HH; OPPT; RoB; PBPK; Trichloroethylene; EtOH; LOEL; Systematic review; GLP; NOEL; USEPA; OECD; TUNEL; Developmental toxicology; ESC; LOAEL; RT-PCR; Risk assessment; KE; Mechanistic evidence; Cardiac defects; OFT; GD; hpf; AOP; DCA; ppb; ADME; NTP-OHAT; hrs; MIE; ppm; EMT; In utero; RfC; Congenital heart defects; IRIS; RfD; TCA; AV; NOAEL; TCE; CHD; MoA; no observed adverse effect level; physiologically-based pharmacokinetic; absorption distribution, metabolism, and excretion; AOP Knowledge Base; lowest observed effect level; trichloroethylene; good laboratory practice; parts per billion; adverse outcome pathway; gestation day; Reference Concentration; outflow tract; congenital heart defect; Hamburger and Hamilton stages of chick embryo; no observed effect level; key event; trichloroacetic acid; Integrated Risk Information System; ethanol; reverse transcriptase polymerase chain reaction; epithelial-mesenchymal transition; endothelial-mesenchymal transition; hours; U.S. Environmental Protection Agency; hours post-fertilization; mechanism of action; risk of bias; terminal deoxynucleotidyl transferase dUTP nick end labeling; Reference Dose; lowest observed adverse effect level; National Toxicology Program Office of Health Assessment and Translation; molecular initiating event; atrioventricular; parts per million; embryonic stem cell; Organisation for Economic Co-operation and Development; Office of Pollution Prevention and Toxics; dichloroacetic acid
• ISSN: 0300-483X; 1879-3185; 1879-3185
• DOI: 10.1016/j.tox.2020.152427

The hypothesis that in utero exposures to low levels of trichloroethylene (TCE) may increase the risk of congenital heart defects (CHDs) in offspring remains a subject of substantial controversy within the scientific community due primarily to the reliance on an inconsistent and unreproducible experimental study in rats. To build on previous assessments that have primarily focused on epidemiological and experimental animal studies in developing conclusions, the objective of the current study is to conduct a systematic evaluation of mechanistic data related to in utero exposures to TCE and the development of CHDs. The evidence base was heterogeneous; 79 mechanistic datasets were identified, characterizing endpoints which ranged from molecular to organismal responses in seven species, involving both in vivo and in vitro study designs in mammalian and non-mammalian models. Of these, 24 datasets were considered reliable following critical appraisal using a study quality tool that employs metrics specific to the study type. Subsequent synthesis and integration demonstrated that the available mechanistic data: 1) did not support the potential for CHD hazard in humans, 2) did not support the biological plausibility of a response in humans based on organization via a putative adverse outcome pathway for valvulo-septal cardiac defects, and 3) were not suitable for serving as candidate studies in risk assessment. Findings supportive of an association were generally limited to in ovo chicken studies, in which TCE was administered in high concentration solutions via direct injection. Results of these in ovo studies were difficult to interpret for human health risk assessment given the lack of generalizability of the study models (including dose relevance, species-specific biological differences, variations in the construct of the study design, etc.). When the mechanistic data are integrated with findings from previous evaluations of human and animal evidence streams, the totality of evidence does not support CHDs as a critical effect in TCE human health risk assessment.