Clinical Effects

After completing this section, you will be able to explain potential health effects of exposure to elevated levels of TCE.

TCE is carcinogenic to humans by all routes of exposure and poses a potential human health hazard for noncancer toxicity to the nervous system, kidneys, liver, immune system, male reproductive system, and the developing embryo/fetus. These conclusions are based on analyses of a broad spectrum of information from thousands of scientific studies and input from numerous scientific reviews (Chiu et al., 2013).

As TCE toxicity and carcinogenicity are generally associated with TCE metabolism, susceptibility to TCE health effects might be modulated by factors affecting toxicokinetics, including lifestage, gender, genetic polymorphisms, race/ethnicity, preexisting health status, lifestyle, and nutrition status. Although some of these factors are known risk factors for effects associated with TCE exposure, but how TCE interacts with known risk factors for human diseases is not known.

An underlying assumption in deriving reference values for noncancer effects is that the dose-response relationship for these effects has a threshold. For some effects, a practical threshold (i.e., a threshold within the range of environmental exposure levels of regulatory concern) might not exist (EPA, 2011c). This is particularly true for effects on very sensitive processes (e.g., developmental processes) or effects for which there is a nontrivial background level and even small exposures might contribute to background disease processes in more susceptible people.

Human and animal studies have associated TCE exposure with effects on several neurological domains (Chiu et al., 2013; EPA, 2011c).

Strong evidence, based on multiple human and experimental animal studies, shows that TCE might cause

• Changes in trigeminal nerve function or morphology
• Impairment of vestibular function

Limited evidence, primarily from experimental animal studies, with fewer or more-limited human studies, shows that TCE might cause

• Delayed motor function, including during neurodevelopment
• Changes in auditory, visual, and cognitive function or performance

Non-cancer toxicity

Limited evidence in humans and strong evidence from experimental animal studies show that, at effect levels, TCE causes hepatotoxicity but not necrosis.

Mice appear to be more sensitive than other experimental species, and hepatotoxicity is likely mediated through oxidative metabolites including, but not exclusively, TCA.

The hepatotoxicity shown in laboratory animals includes increased liver weight, small transient increases in DNA synthesis, cytomegaly in the form of swollen or enlarged hepatocytes, increased nuclear size (probably reflecting polyploidization), and proliferation of peroxisomes (EPA, 2011c).

Cancer toxicity

Limited evidence suggests liver carcinogenicity in humans. Positive associations have been observed in some cohort studies. However, there were few cases of liver cancer among study participants, which limits the ability to determine exposure-response relationships and causality. A consistent hepatocarcinogenic response has been observed using mice of differing strains and genders and from differing routes of exposure, although some studies were confounded by various limitations (Chiu et al., 2013; EPA, 2011c).

Non-cancer toxicity

Strong evidence indicates that TCE might cause nephrotoxicity, particularly by damaging renal tubules. This is based on mechanistic studies, animal experiments, and a few human studies. Kidney damage is likely mediated by S-(1,2-dichlorovinyl)-L-cysteine (DCVC), a metabolite of TCE formed via glutathione conjugation and further enzyme activity (Chiu et al., 2013).

Cancer toxicity

Strong evidence shows a causal association between TCE exposure and kidney cancer in humans across 15 independent epidemiologic studies of different study designs and populations from different countries. Convincing evidence from animal studies provided further biological plausibility for the epidemiologic findings of TCE-induced kidney cancer. (EPA, 2011c; Fevotte et al., 2006; Moore et al., 2010; Scott & Jinot, 2011).

Strong evidence, based on multiple human and animal studies, shows that TCE might cause fetal cardiac malformations.

Limited evidence, primarily from experimental animal studies, with limited epidemiologic studies, indicates that TCE might cause other fetal malformations (in addition to cardiac), prenatal losses, decreased growth or birth weight of offspring, and alterations in immune system function (Chiu et al., 2013; EPA, 2011c).

Strong evidence, based on multiple human and experimental animal studies, shows that TCE might cause male reproductive toxicity, primarily through effects on the testes, epididymides, sperm, or hormone levels.

Limited evidence, based on few and limited human and experimental animal studies, indicates that TCE might cause female reproductive toxicity (Chiu et al., 2013; EPA, 2011c).

Strong evidence, based on multiple human and experimental animal studies, shows that TCE exposure might cause autoimmune disease, including scleroderma, and a specific type of generalized hypersensitivity disorder.

Limited evidence, primarily from experimental animal studies, with fewer or more limited human studies, indicates that TCE might cause immunosuppression (Chiu et al., 2013; EPA, 2011c).

EPA conducted a systematic review of 76 human epidemiologic studies on TCE and cancer (EPA, 2011c; Scott & Jinot, 2011). A meta-analysis of these studies was conducted for liver cancer, kidney cancer, and non-Hodgkin lymphoma.

A summary of the weight of evidence on consistency of the observed association between TCE exposure and cancer follows (Chiu et al., 2013; EPA, 2011c):

Strong evidence of consistency for kidney cancer (consistently elevated relative risks [RR]). Meta‑analysis yielded robust, statistically significant summary RR, with no evidence of heterogeneity or potential publication bias.

Moderate evidence of consistency for non-Hodgkin lymphoma (consistently elevated RR): RR estimates more variable compared with kidney cancer. Meta-analysis yielded robust, statistically significant summary RR, with some heterogeneity (not statistically significant) and some evidence for potential publication bias.

Limited evidence of consistency for liver cancer (fewer studies overall, more variable results): Meta-analysis showed no evidence of heterogeneity or potential publication bias.

Supported by the analyses described above and following the EPA’s Guidelines for Carcinogen Risk Assessment (U. S. EPA, 2005), EPA concludes that TCE is characterized as “carcinogenic to humans” by all routes of exposure (EPA, 2011c). The International Agency for Research on Cancer has concluded that TCE is carcinogenic to humans (Group 1) (IARC, 2018). The U.S. Department of Health and Human Services considers TCE to be a known human carcinogen (NTP, 2016).

Respiratory: Suggestive evidence, primarily from short-term experimental animal studies, shows that TCE might cause respiratory tract toxicity, primarily in Clara cells, and pulmonary tumors in mice only (Chiu et al., 2013).

Skin: Like other organic solvents, TCE can produce contact dermatitis, rashes, and burns. The defatting dermatitis resulting from prolonged contact might reduce resistance to skin infections (ATSDR, 2019; EPA, 2011c).

• Strong evidence shows that TCE is a potential human health hazard to the nervous system, kidneys, liver, immune system, male reproductive system, and the developing embryo/fetus.
• TCE is carcinogenic to humans by all routes of exposure.
• Even small exposures might contribute to disease processes in more susceptible people.