Solvent Blog Post: Trichloroethylene

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Background:

Trichloroethylene was cultivated in 1864 by a German chemist by the name of Emil Fischer. Fischer came across trichloroethylene as a by-product of reducing hexachloroethane with hydrogen. Its commercial use was not in effect until the early 1920s. Trichloroethylene became an industrial solvent primarily used to create hydrofluorocarbon synthetics, cooling agents, and an addictive for cleaning supplies. Due to its multifaceted use within the manufacturing industry and to consumer goods; the product was produce in large amounts as a supplemental agent. Even to the extent of being used as an anesthetic, intended to be used as a deterrent to that of chloroform (due to high levels of hepatotoxicity).

The expansion to healthcare and pharmaceutical use is where the promise for trichloroethylene began to diminish. Researchers were able to correlate exposure levels to the substance to that of morbidity and mortality in 1979. This caused the product to be solely used for consumerism and not as a medical synthetic. Widely used from the 1908’s until 2007, trichloroethylene number one consumer was The United States. The decline from 2007 on stemmed from further research supporting past articles to current oncology studies.

Pharmacodynamic Distribution of TCE in major Target Organs

Pharmacodynamic Distribution of TCE in major Target Organs

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No studies have provided evidence of saturation of TCE metabolism in humans, at least for short-term inhalation exposure to high concentrations up to 315 ppm (Agency for Toxic Substances and Disease Registry 1997).

Target Organs:

  • Liver
  • Kidney
  • Thyroid
  • Lungs
  • Heart
  • Blood/Plasma
  • Reproductive Organs
  • Muscle Tissue
  • Gastrointestinal

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Biotransformation/Toxicokinetics:

Absorption: Trichloroethylene is a lipophilic solvent of low relative molecular mass, and can readily cross biological membranes. It is taken up in the lungs, with pulmonary absorption approaching steady-state within a few hours after the start of exposure (IACR, 2014). Most methods of exposure are occupational hazards caused by inhaling trichloroethylene as a vapor.

Distribution: The distribution of trichloroethylene in the body is instantaneous through inhalation, diffusing through pulmonary circulation to the blood the stream. It has been discovered in autopsies that the chemical agent can reside an adipose tissue, cranial tissue, liver, and kidneys. The molecular weight of trichloroethylene as a vapor, 131.38 g/mol, allows the substance to freely distribute throughout body circulation. Accumulation in the blood plasma allows for the bioavailability of the substance to bind throughout different organ systems.

Metabolism: Metabolism plays a key role in the carcinogens, endocrine irregularities, and the occurrence of mutation in the exposure of trichloroethylene.  Experimental animal and human data indicate that TCE metabolism occurs through two major pathways: cytochrome P450 (CYP)-dependent oxidation and glutathione (GSH) conjugation catalyzed by GSH S-transferases (GSTs). Herein we review recent data characterizing TCE processing and flux through these pathways, (Lash, 2014). The disruption in both metabolic pathways causes toxicity within organ systems due to the disruption of enzymes to degrade and catalyze.

Elimination: TCE kinetics between absorption-distribution play a vital role in its elimination. After exposure to air concentrations between 50 and 380 ppm, approximately 58% of an absorbed dose appears in urine as metabolites (Monster, Boersma, et al. 1976; Monster, Boersma et al. 1979). These metabolites are in the form of trichloroacetic acid and trichloroethanol one degraded through the liver through CYP-oxidation pathway and GSH. A small fraction has been tested to be eliminated through exhalation but not significant enough to deter from wide-body distribution.

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Cariogenicity:

The Department of Health and Human Services (DHHS) has listed trichloroethylene as a known carcinogen. There has been substantial evidence through epidemiological reports in humans that trichloroethylene causes kidney cancer and mild evidence that the substance causes non-Hodgkin Lymphoma humans. Animal models in in-vivo studies have shown that TCE causes several malignant sites in murine tissue.

Teratotoxicity:

Through reservoir contamination, TCE has shown a correlation to congenital heart defects and damage to cardiac tissue in children. While there are several developmental disorders and defects stemming from TCE, there is a long occurrence of cardiac failure in the pediatric population. Below is an attachment provided through the Environmental Protection Agency that discusses the exposure and effects of TCE.

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Mechanism of Action/Genetic Susceptibility:

TCE suppresses mitochondrial complex I, this is a key factor in the mutagenic properties of TCE and genetic polymorphism. The high rate of distribution in blood plasma and tissue causes further influence to disrupt systemic regulation. The alteration of CYP and GSH are studied not only in the accumulation of proteins causing toxicity but the disruption of catecholamines through paracrine and autocrine signaling.  Genetic polymorphisms in several of the key enzymes metabolizing TCE and its intermediates contribute to variability in metabolic profiles and rates. In all, the evidence characterizing the complex metabolism of TCE can inform predictions of adverse responses including mutagenesis, carcinogenesis, and acute and chronic organ-specific toxicity (Lash, 2014).

CDC Illustration of TCE Entering the Body:

Treatment:

There is no known treatment for Trichloroethylene, the best form of treatment is to provide support to cardiovascular and pulmonary function.

Biomarkers:

Trichloroethylene may be present in:

  • Whole-body systemic tissue –> high level contaminates
  • Pericardial fluid –> low level contaminates
  • Urine –> seen through elimination, high level contaminates
  • Fecal matter –> seen through elimination, high level contaminates
  • Prostate –> site of mild exposure

Interesting Case:

The Legacy of Woburn, MassachusettsImage Source

Woburn, Massachusetts in the early 1900s was a suburban town that was the epicenter of industrialization for the state outside of Boston. The town based its economic prosperity through factory jobs throughout the next century. This resulted in years of toxic solvent exposure; Trichloroethylene was found in two of the town’s reservoir(s) as a high level contaminate. In 1981, locals express that the water tasted out of the ordinary and the general population showed high morbidity for childhood leukemia. This was an issue that was neglected from reports shown in 1958 that stated the water supply is unsuitable for human use. Below is an article that discusses the history of  Woburn, Massachusetts, and its ordeal with TCE contamination.

https://www.webpages.uidaho.edu/etox/resources/case_studies/woburn.pdf

References:

  1. Cichocki JA, Guyton KZ, Guha N, Chiu WA, Rusyn I, Lash LH. Target Organ Metabolism, Toxicity, and Mechanisms of Trichloroethylene and Perchloroethylene: Key Similarities, Differences, and Data Gaps. J Pharmacol Exp Ther. 2016;359(1):110-123. doi:10.1124/jpet.116.232629

  2. IARC Working Group on the Evaluation of Carcinogenic Risk to Humans. Trichloroethylene, Tetrachloroethylene, and Some Other Chlorinated Agents. Lyon (FR): International Agency for Research on Cancer; 2014. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 106.) TRICHLOROETHYLENE. Available from: https://www.ncbi.nlm.nih.gov/books/NBK294285/

  3. Lash LH, Chiu WA, Guyton KZ, Rusyn I. Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity. Mutat Res Rev Mutat Res. 2014;762:22-36. doi:10.1016/j.mrrev.2014.04.003

  4. Seven substances added to 14th Report on Carcinogens (Environmental Factor, December 2016). (2016, November). Retrieved July 09, 2020, from https://factor.niehs.nih.gov/2016/12/science-highlights/carcinogens/index.htm