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Background: Trichloroethylene (TCE) was negative for developmental toxicity after inhalation and oral gavage exposure of pregnant rats but fetal cardiac defects were reported following drinking water exposure throughout gestation. Because of the deficiencies in this latter study, we performed another drinking water study to evaluate whether TCE causes heart defects., Methods: Groups of 25 mated Sprague Dawley rats consumed water containing 0, 0.25, 1.5, 500, or 1,000 ppm TCE from gestational day 1-21. TCE concentrations were measured at daily formulation, when placed into water bottles each day and when water bottles were removed from cages. Four additional mated rats per group were used for plasma measurements. At termination, fetal hearts were carefully dissected fresh and examined., Results: All TCE concentrations were >90% of target when initially placed in water bottles and when bottles were placed on cages. All dams survived with no clinical signs. Rats in the two higher dose groups consumed less water/day than other groups but showed no changes in maternal or fetal weights. The only fetal cardiac observation was small (<1 mm) membranous ventricular septal defect occurring in all treated and water control groups; incidences were within the range of published findings for naive animals. TCE was not detected in maternal blood, but systemic exposure was confirmed by detecting its primary oxidative metabolite, trichloroacetic acid, although only at levels above the quantitation limit in the two higher dose groups., Conclusions: Ingesting TCE in drinking water ≤1,000 ppm throughout gestation does not cause cardiac defects in rat offspring., (© 2019 The Authors. Birth Defects Research published by Wiley Periodicals, Inc.)

An evaluation of the scientific literature for trichloroethylene (TCE) identified two reports of ocular defects, specifically microphthalmia/anophthalmia, following prenatal TCE exposure in rats. Herein, these reports are analyzed in detail and interpreted within the context of other developmental TCE exposure studies. The ocular findings following prenatal TCE exposure are reported in studies that were not designed specifically for developmental safety assessment, and thus did not use standard experimental practices. Furthermore, these findings most commonly occurred at TCE doses associated with considerable maternal toxicity. Among the 18 published studies using developmental TCE exposures, only 3 used doses sufficiently high enough to result in maternal toxicity, and of these, only the 2 discussed in detail in this paper demonstrated ocular defects in the offspring. Furthermore, statistically significant effects were only observed at doses that were above the currently accepted guideline limit dose of 1000 mg/kg body weight. All other TCE developmental exposure studies failed to demonstrate ocular defects as a result of prenatal exposure. These results suggest that the micro-/anophthalmia findings were likely a consequence of delivery of an extremely high bolus TCE dose that is irrelevant to human environmental exposure scenarios.

The organic solvent trichloroethylene (TCE) is a metal degreasing agent and an intermediate in the production of fluorochemicals and polyvinyl chloride. TCE is also a common, persistent drinking water contaminant. Several epidemiological studies have alleged links between TCE exposure during pregnancy and offspring health problems including congenital heart defects (CHDs); however, the results of these studies are inconsistent, difficult to interpret, and involve several confounding factors. Similarly, the results of animal studies examining the potential of TCE to elicit cardiac anomalies have been inconsistent, and they have often been performed at doses far exceeding the highest levels ever reported in the drinking water. To determine what is known about the relationship between TCE and the incidence of CHDs, a comprehensive analysis of all available epidemiological data and animal studies was performed. Additionally, in vivo and in vitro studies examining possible mechanisms of action for TCE were evaluated. The specific types of heart defects alleged to have been caused by TCE in animal and human epidemiology studies were categorized by the morphogenetic process responsible for the defect in order to determine whether TCE might disrupt any specific developmental process. This analysis revealed that no single process was clearly affected by TCE, providing support that gestational TCE exposure does not increase the prevalence of CHDs. As a final evaluation, application of Hill's causality guidelines to the collective body of data revealed no indication of a causal link between gestational TCE exposure at environmentally relevant concentrations and CHDs.