Formatted Title
The Role of Trichloroethene in Congenital Heart Defects: Updated Weight of Evidence Shifts Risk Management
Background/Objectives
In September 2011, the United States Environmental Protection Agency (USEPA) released an updated Toxicological Review of Trichloroethylene (TCE) (USEPA, 2011) which established a lowered chronic (i.e., long-term) non-cancer inhalation toxicity criterion (reference concentration [RfC]) for the compound of 2 micrograms per cubic meter (µg/m3). The USEPA’s RfC for trichloroethylene (TCE) is based, in part, on a controversial study (Johnson et al., 2003) in which congenital heart defects (CHDs) observed in the offspring of Sprague-Dawley rats following oral (TCE in drinking water) exposure during the 21-day rodent gestational period were deemed a critical effect. Subsequent to the adoption of the RfC, concern from the USEPA Region 9 regarding the CHDs led to the development of interim short-term exposure limits for TCE in indoor air as low as 2 µg/m3 (under a residential exposure scenario) to 8 µg/m3 (under an 8-hour per day commercial/industrial exposure scenario), to prevent against possible CHDs in women. The rationale for this approach was predicated on the recognition that the fetal heart is susceptible to teratogenic effects during a specific period within the first trimester; hence, a short-term exposure to TCE of between a day and a few weeks could hypothetically induce CHDs. Multiple states and other USEPA regions subsequently adopted the USEPA Region 9 action levels or developed their own short-term exposure limits based on the concern over CHDs. However, there are challenges with communicating risk management decisions to the public where a concentration of, for example, 2 µg/m3 is considered safe for long-term exposure, but a concentration only slightly higher than 2 µg/m3 is considered indicative of a need for immediate response actions, including evacuation from buildings. This can create substantial anxiety, particularly for pregnant women, because parental concerns about pregnancy and unborn children are emotionally sensitive topics. In fact, the anxiety in and of itself poses a mental health risk.
Approach/Activities
To help to evaluate the plausibility that TCE can induce CHDs, a weight of evidence (WOE) evaluation was synthesized from the literature, including animal bioassay, epidemiological, and mechanistic evaluations. The Johnson et al. (2003) study that has served as the basis for short-term exposure limits has numerous limitations, including the use of a non-standardized dissection technique, lack of positive controls, and the lack of verification of administered dose levels. These study deficiencies, combined with the irreproducibility of the critical effect in other animal studies (including inhalation studies) and the general lack of epidemiological evidence to support the possible effect, has led several investigators to conclude that the weight of evidence from human and animal data does not support a role for TCE in CHDs. A recently completed study by DeSesso, et al. (2019) that was specifically designed to evaluate the hypothesis advanced in the Johnson study that TCE exposure is linked to CHDs, while at the same time correcting the defficiences of the Johnson study, casts further doubt on the link between TCE exposure and CHDs. The study found no evidence of a significant increase in the incidence of cardiac malformations in the TCE-treated groups compared to the control group and demonstrated that it is not dosimetrically plausible for TCE to induce CHDs within the dose ranges studied in the Johnson study.
Results/Lessons Learned
The WOE evaluation demonstrates that the association of TCE exposure with CHDs at environmentally relevant concentrations is not scientifically supported. The same conclusion was recently articulated in the Toxic Substances Control Act (TSCA) Risk Evaluation for TCE, in which EPA cited their charge under TSCA to use the best available science and weight of scientific evidence, and therefore did not use the CHD endpoint for making risk management decisions. As noted above, EPA regional and state-specific risk management frameworks are currently built around the concept that immediate response actions are necessary should TCE concentrations exceed CHD-based exposure limits. In the absence of using CHDs to inform risk management for TCE, response actions could be built around protection against risks for chronic health effects. This in turn could translate to risk management decisions that are based on seasonal/long-term air monitoring as opposed to single sampling events, and response actions that could focus on engineering-based mitigation, as opposed immediate response actions that involve evacuations.