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.

Keywords: AOP; Cardiac; Malformations; TCE; Trichloroethylene.

Fig. 1.

Conceptual view of a Weight-of-Evidence evaluation. Considerations within a WOE evaluation of toxicity data are shown. The relative weight of each consideration can vary, based upon the data [86], Fig. 4–4). Temporality is the premise that the exposure must occur prior to the outcome. Strength of association is the consideration of study rigor and statistical power. Variability analysis considers the source of variability within individual studies. Uncertainty analysis considers information or data gaps in individual studies and in the comprehensive database of information. Qualitative dose-response relationship is the change in an effect, and the degree of the change, as a function of exposure or dose. Experimental evidence is the alterations in response or rate of response resulting from manipulation of exposure. Reproducibility is the observation of specific effects under varied conditions. Bio-logical plausibility is the determination of whether an observed outcome could be attributed to the toxicological insult, given the currently known science. Alternative or multiple explanations are other explanations for the observed outcome(s) following the exposure of interest. Specificity refers to determination of the relationship between one exposure, the effect(s), and whether each effect is mediated through a single or alternative MOAs. Coherence is the extent to which the data are similar in outcome and exposure/dose and whether they support each biologically plausible hypothesis or MOA.

Fig. 2.

TCE inhalation developmental toxicology studies. Effects on fetal/offspring survival, growth, and morphology following maternal inhalation exposures to TCE during gestation. Boxes indicate the doses at which maternal toxicity was observed.

Fig. 3.

TCE oral developmental toxicology studies. Effects on fetal/offspring survival, growth, and morphology following maternal oral exposures to TCE during gestation. Boxes indicate the doses at which maternal toxicity was observed. ¹Maternal toxicity was not reported in Johnson et al. [51]. * Doses at which cardiac defects were observed.

Fig. 4.

DCA and TCA oral developmental toxicology studies. Effects on fetal/offspring survival, growth, and morphology following maternal oral exposures to TCE metabolites, DCA and TCA, during gestation. Boxes indicate the doses at which maternal toxicity was observed. ¹ Maternal toxicity was not reported in Epstein et al. [27]. *Doses at which cardiac defects were observed.

Fig. 5.

Control vs. TCE treatment groups and dates of exposure. During the duration of the University of Arizona (UA) research program on TCE (1989–1995), a number of developmental toxicology studies were conducted on TCE and its metabolites. Control animals (red blocks) were on study when treated animals (blue blocks) were being exposed. The blocks are general representations of time frames and are not presented to exact scale. The dates that cohorts of animals were on study (as well as dose levels and the number of dams/litters for each cohort) are shown. In three cases, information on the exact month and day of animal receipt was not available (indicated by dotted lines). Exclusively pregnancy-only TCE-treated groups are included in this figure; however, other treatment regimens were also being conducted during the time period of 6/12/89 to 10/6/95 (i.e., 3 months pre-pregnancy-only, 2 months pre-pregnancy + pregnancy). Additionally, during this time period, TCE metabolites and other toxicokinetically related chemicals were studied: dichloroacetic acid (DCA), trichloroacetic acid (TCA), monochloroacetic acid (MCAA), trichloroethanol (TCEth), trichloroacetaldehyde (TCAld), dichloroacetaldehyde (DCAld), carboxy methylcystine (CMC), dichlorovinyl cystine (DCVC), dichloroethylene (DCE). The control animal cardiac malformation incidence data were combined for statistical comparison with incidence data for pregnancy-only TCE-treated groups. Sources of information used to compile this figure: [53,52,50,51,49,20].

Fig. 6.

Percent of Offspring with Cardiac Defects [51]. The dose is on log scale. The inset figure shows the same data on the untransformed scale. Confidence limits (95%) for percentages are also shown. The solid points identify the treated groups and the open points identify the control.