Elsevier

Reproductive Toxicology

Volume 21, Issue 2, February 2006, Pages 117-147
Reproductive Toxicology

Review
Trichloroethylene-contaminated drinking water and congenital heart defects: A critical analysis of the literature

https://doi.org/10.1016/j.reprotox.2005.07.013Get rights and content

Abstract

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.

Introduction

Trichloroethylene (TCE) is a halogenated hydrocarbon solvent primarily used as a metal degreasing agent and produced as an intermediate in the production of fluorochemicals and polyvinyl chloride (PVC). Historically, TCE has been used as an anesthetic, an antiseptic, and a solvent for use in dry cleaning and coffee decaffeination [1]. During biotransformation in humans, TCE is converted to chloral hydrate, a substance that is frequently prescribed for insomnia in the elderly as well as to sedate children undergoing CAT scans [2]. The terminal products of oxidative biotransformation are trichloroacetic acid (TCA) and dichloroacetic acid (DCA). TCE is volatile, and therefore most TCE released into the environment evaporates. However, in certain groundwater environments, TCE has limited contact with the air, and will therefore persist for years. For this reason, it is found as a contaminant in groundwater supplies.

According to the Toxics Release Inventory compiled by the Environmental Protection Agency, 291,000 pounds of TCE were released into water and onto land between 1987 and 1993. States with the largest releases to water include Pennsylvania, Illinois, and Georgia [3]. The American Conference of Governmental Industrial Hygienists (ACGIH) has established an 8-h time-weighted average (TWA) threshold limit value (TLV) of 50 ppm TCE vapors, and a 15-min short-term exposure limit (STEL) of 100 ppm TCE vapors. The current EPA-defined maximum contaminant level (MCL) for TCE is 0.005 mg/L (5 ppb), and the maximum contaminant level goal is 0 ppb [3]. EPA established the aforementioned regulatory levels based on the rationale that long-term exposure to TCE at levels above the MCL might contribute to an increased risk of liver problems and cancer. Additionally, the limit of detection of TCE in the water was 5 ppb at the time this MCL was determined, and this conservative limit is likely to have been selected due to the dearth of robust data on TCE's effect on human health.

Due to its occurrence in the water supply, it is important to identify and characterize any risks to human health attributed to TCE. Accordingly, several epidemiological studies have been conducted, some of which have linked TCE to health problems including, but not limited to, cancer, spontaneous abortions, and congenital heart defects (CHDs). Despite the plethora of adverse effects purportedly attributed to TCE exposure, analysis of the body of studies available fails to establish a clear cause and effect relationship [4], [5]. As a result, there is a great deal of confusion regarding the toxicity of TCE. In order to assess risk and to identify appropriate avenues for future research, it is necessary to evaluate the current state of the data to determine what exactly is known about each of TCE's alleged effects on human development. In the present analysis, emphasis is placed on TCE's impact on the developing heart.

Section snippets

Etiology of CHDs

Due to the potential for dire outcomes associated with CHDs, any potentially causative factor should be investigated. In some cases CHDs are minor or treatable, but CHDs can be fatal or have a marked adverse effect on one's quality of life. According to the American Heart Association [6], at least 8/1000 infants are born with a CHD. Although certain genetic conditions (e.g., down syndrome) and drugs (e.g., isotretinoin [Accutane®]) are linked to CHDs, rarely is the cause of a CHD understood.

Types of epidemiology studies

Epidemiology identifies factors that differ between two populations and are sufficiently important to play a causative role in the genesis of a disease. Several epidemiological studies have been conducted to determine if there is a link between TCE exposure during pregnancy and an increased prevalence of CHDs. To accurately evaluate these studies, it is important to recognize the various types of epidemiological study designs and to what extent conclusions can be drawn from them. The five major

Epidemiological studies of TCE exposure during pregnancy

Epidemiological information is available for several locations where pregnant women were likely to have been exposed to TCE or related substances, predominantly through groundwater contamination. These locations include Tucson, AZ; Northern NJ; Woburn, MA; Milwaukee, WI; Santa Clara, CA; San Francisco, CA; Baltimore, MD/Washington, DC area as well as regions of Finland and France. A total of 16 studies were reviewed, 5 of which addressed the potential cardiac toxicity of TCE alone, and 11 of

Animal studies

In order to investigate whether exposure to TCE can adversely impact normal heart development, research has been conducted using various experimental animal models. Although such studies are necessary to gauge the risk TCE poses to humans, especially in light of the equivocal epidemiological information, there are important caveats involved with extrapolating results of experimental animal exposures to humans. To begin with, there are notable differences in how rodents and humans metabolize TCE

An examination of possible biological mechanisms of TCE in the heart

Only a handful of studies have attempted to identify a biological mechanism underlying the purported cardiac-specific teratogenic effect of TCE (Table 5). Boyer et al. [69] examined TCE's impact on epithelial-mesenchymal cell transformation in an in vitro system wherein cardiac endothelial cells were isolated from chicken embryo hearts and exposed to 50–250 ppm of TCE. In this model, TCE inhibited epithelial-mesenchymal cell transformation in a dose-dependent manner at all concentrations, and

Does TCE exposure cause an increase in CHDs?

As previously noted, none of the epidemiological studies was sufficiently robust to indicate a link between TCE exposure and CHDs. A major obstacle in interpreting most of the animal and in vitro studies was the lack of data at the concentrations of TCE that have been reported in contaminated water. The need for generating toxicological data at “real-world” exposure levels in order to provide information useful in making regulatory decisions is paramount for several dimensions of risk

Conclusion

CHDs are the most frequent form of birth defects, affecting nearly 1% of newborns [6]. Because the underlying cause of the CHDs is rarely understood, any indication that an environmental contaminant might increase the prevalence of CHDs warrants further investigation. Several studies attempted to address the question of whether TCE is likely to contribute to CHDs; however, in no case was a strong, reliable correlation substantiated.

The epidemiology studies alleging a possible link between TCE

Acknowledgements

We are grateful to Dr. Jeffrey Fisher of the University of Georgia and Teri Sterner of the Wright Patterson Air Force Base Toxicology Lab for their calculation of the amount of TCE in the drinking water needed to achieve a specific in vitro concentration.

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