Introduction

Some occupational studies have shown that TCE produces

• CNS effects
• decreased appetite
• gastrointestinal irritation
• headaches
• mucous membrane
• skin irritation

Hepatotoxicity has been associated primarily with TCE inhalation and ingestion of very large amounts.

Renal failure has been reported in concert with confirmed hepatic damage.

Cardiac dysrhythmias may be induced by heavy TCE exposure.

Neurological Effects

TCE-induced CNS symptoms depend on both concentration and exposure duration.

Acute Exposure

In one study of human volunteers, exposure to TCE air levels of 27 ppm for one to four hours caused drowsiness and mucous membrane irritation, and at 81 ppm, headaches (Nomiyama and Nomiyama 1977).

In another study, an 8-hour exposure (two 4-hour exposures separated by 1.5 hours) to 110 ppm TCE for two 4-hr periods resulted in decreased performance on tests of perception, memory, reaction time, and dexterity (Salvini, Binaschi et al. 1971). However, a later attempt to replicate these results found no effects other than fatigue and drowsiness (Stewart RD 1974a).

The available data suggest that the threshold for CNS effects in humans is in the range 81-110 ppm TCE, although the effects observed at these exposure levels reflected only mild symptoms of CNS depression (Brown, Farrar et al. 1990).

Symptoms due to short-term exposures typically resolve within a few hours of exposure. However, one report demonstrated evidence of long-term residual oculomotor and ciliary reflex dysfunction as well as impaired neuropsychological performance as a result of acute TCE intoxication (Feldman, White et al. 1985).

Chronic Exposure

In a study of 73 workers employed from one month to 15 years in various industrial cleaning and degreasing operations using TCE, complaints due to chronic exposure included:

• a reduced number of word associations
• ataxia
• decreased appetite
• headache
• short-term memory loss
• sleep disturbances
• vertigo

Greater frequency of symptoms was noted in workers exposed to higher (85 ppm) than lower (14 ppm) mean TCE concentrations (Grandjean, Munchinger et al. 1955).

Some of the observed neurological effects from long-term exposure to TCE indicate impaired trigeminal nerve function (e.g., blink reflex and masseter reflex) (Buxton and Hayward 1967; Agency for Toxic Substances and Disease Registry 1997). This is thought to be neurotoxicity induced dichloroacetylene, a breakdown product of TCE (Armstrong and Green 2004).

A study found neurobehavioral deficits from exposures to drinking water contaminated with to TCE (Reif, Burch et al. 2003).

Deliberate Abuse

Abuse of volatile chlorocarbon solvents is a risk factor for development of cerebellar damage and ataxia.

Animal Studies

Studies on the neurological effects of acute TCE inhalation in animals have produced results similar to human studies (Agency for Toxic Substances and Disease Registry 1997).

Hepatic and Renal Effects

When swallowed, TCE causes gastrointestinal (GI) irritation, with possible inflammation of the GI tract, manifested as:

• abdominal pain
• diarrhea
• nausea
• vomiting

Hepatotoxicity has been associated primarily with intentional TCE inhalation abuse. In these cases, hepatic histological examination has revealed centrilobular necrosis with fatty infiltration (Joron, Cameron et al. 1955; Thiele, Eigenbrodt et al. 1982).

Chronic TCE exposures at concentrations currently permissible in the workplace or at those expected in ambient air are not likely to cause liver damage (Agency for Toxic Substances and Disease Registry 1997).

Studies that have examined exposure to TCE and development of kidney disease (Lash, Parker et al. 2000).

• One case report links acute renal failure with normal liver function in a male worker opening bins containing 7.5 L of a nearly pure solution of TCE (David, Wolman et al. 1989).
• One study reports that adverse kidney effects associated with occupational exposure to TCE are very mild (Nagaya, Ishikawa et al. 1989).
• Another study of a small group of male metal degreasers in Sweden observed no increase in N-acetyl-β-glucosamineidase (NAG) excretion into urine, and concluded that TCE was not nephrotoxic at low exposures levels (Selden, Hultberg et al. 1993).
• A retrospective study was performed on 39 workers who were exposed to high levels of TCE from 1956 to 1975. The study concluded that chronic exposure to high doses of TCE causes persistent changes to the proximal tubules (Bruning, Sundberg et al. 1999).
• In a recent cross-sectional study of 70 workers currently exposed to TCE, the mean exposure to TCE, estimated from urinary trichloroacetic acid concentrations, was 32 ppm (range 0.5 – 252 ppm) with average duration of exposure of 4.1 years (range 1-20 years). The results suggested that kidney damage could occur at exposure concentrations higher than 250 ppm (Green, Dow et al. 2004).
• A study reports on a 17-year-old male who ingested approximately 70 ml TCE in a suicide attempt. This study first demonstrated that a single, oral dose of TCE can produce nephrotoxicity in humans (Bruning, Vamvakas et al. 1998).

Cardiac Effects

A few case studies of persons who died following acute occupational exposure to TCE have revealed cardiac arrhythmias to be the apparent cause of death.

Inhalation of very high concentrations of TCE in incidents of poisonings or during its use as an anesthetic agent has been reported to lead to cardiac arrhythmias.

When TCE was administered as an anesthetic agent, serious ventricular arrhythmias and cardiac arrests were rare and were nearly always associated with hypoxia (Norris and Stuart 1957; Agency for Toxic Substances and Disease Registry 1997).

Significant ventricular ectopy would not be expected from TCE exposure at background environmental levels or those currently allowed in the workplace (Candura and Faustman 1991).

Hypertension, enlarged heart, and arrhythmia were seen in some workers accidentally exposed to TCE at a level that was unspecified but at least 15 ppm (ATSDR 1997).

The underlying mechanism of these cardiac effects of TCE exposure might be due to changed sensitization of the heart to catecholamines.

Reproductive and Developmental Effects

Adverse effects were noted in residents of several communities where TCE was found to be present in drinking water (Bove, Shim et al. 2002). The Tucson study (1990) (Goldberg, Lebowitz et al. 1990) reported a higher risk of congenital cardiac defects associated with exposure to TCE-contaminated drinking water. The New Jersey study (1995) (Bove, Fulcomer et al. 1995) reported a strong association between exposure to TCE-contaminated drinking water and oral clefts as well as neural tube defects (NTDs). The Woburn study (1996) (Massachusetts Department of Public Health 1996) found associations between exposures to TCE-contaminated well water and small for gestational age (SGA), fetal deaths, eye defects, choanal atresia, NTDs, cleft lip, and hypospadias. The Camp LeJeune study (1998) also found increased risk of SGA associated with TCE (Bove, Shim et al. 2002).

One retrospective occupational study suggested an increased risk of spontaneous abortion in women exposed to TCE, but the result was not statistically significant, and the effect disappeared when odds ratios were adjusted for potential confounders (Windham, Shusterman et al. 1991).

In animals, some abnormalities (decreased fetal body weight, ossification anomalies, and cardiac defects) have been reported infrequently (Agency for Toxic Substances and Disease Registry 1997).

Carcinogenic Effects

Evidence for the carcinogenicity of TCE in humans comes from several cohort studies where specific TCE exposures were well characterized for individual study subjects.

A meta-analysis of these cohort studies found that occupational exposure to TCE was associated with excess incidences of liver cancer, kidney cancer, non-Hodgkin's lymphoma, prostate cancer, and multiple myeloma, with the strongest evidence for the first three cancers (Wartenberg, Reyner et al. 2000; NTP 2004). It is important to note that the conclusions drawn in these studies were based on a relatively small number of exposed workers and were confounded by exposure to other solvents and other risk factors. Other studies did not reveal any excess cancer mortality from low exposures to TCE (Axelson, Andersson et al. 1978; Tola, Vilhunen et al. 1980; Shindell and Ulrich 1985; Spirtas, Stewart et al. 1991; Axelson, Selden et al. 1994).

A study (Massachusetts Department of Public Health 1996) performed in Woburn, Massachusetts by the Massachusetts Department of Health (1996) found an elevated risk of childhood leukemia in a group exposed to TCE in utero.

The New Jersey study (Bove, Fulcomer et al. 1995) found associations with childhood leukemia among females and with non-Hodgkin's lymphoma.

A review on mutagenicity of TCE and its metabolites indicated that TCE and its metabolites are not potent genotoxic agents and require high doses to induce a response (Moore and Harrington-Brock 2000). The full tumor development is likely to require promotional stimuli under high (suggested: >500 ppm peak exposures) and long-term (several years) exposure to TCE (Bolt, Lammert et al. 2004).

A cohort study of 169 male workers having been exposed to unusually high levels of TCE in Germany between 1956 and 1975 supported a nephrocarcinogenic effect of TCE in humans. A further case-control study confirmed the results of the previous cohort study, supporting the concept of involvement of prolonged and high-dose TCE exposures in the development of renal cell cancer (Bruning and Bolt 2000). The finding of a TCE-specific mutation of the von Hippel-Landau (VHL) tumor suppressor gene, a gene associated with kidney tumors, provides strong evidence that TCE causes kidney cancer (Brauch, Weirich et al. 1999).

A study of three Michigan communities exposed to chlorinated solvents, including TCE in drinking water, showed no significant increase in cancers, including leukemia, among the exposed population. However, the cohort size in the study was only 223 (Agency for Toxic Substances and Disease Registry 1997). A study of 4,280 people exposed to TCE and other contaminants in drinking water in three states reported an increase in respiratory tract cancer in males. The study authors concluded that, based on the incidence of smoking in the population, “it would be inappropriate to relate this excess solely to TCE exposure” (Agency for Toxic Substances and Disease Registry 1997).

The findings in humans are supported by evidence of carcinogenicity in experimental animals, in which tumors occurred at several of the same sites as in humans. Inhalation or oral exposure to high doses of TCE produces liver and lung tumors in mice (Maltoni, Lefemine et al. 1988), and renal adenocarcinomas, testicular tumors, and possibly leukemia in rats (Maltoni, Lefemine et al. 1988).

However, it is important to understand interspecies differences in TCE metabolism and pharmacokinetics in order to reduce uncertainties inherent in species-to-species extrapolations (Bruckner, Davis et al. 1989).

Many studies reviewed by the International Agency for Research on Cancer (IARC) examined the relationship between TCE exposure and kidney and liver cancer mortality or incidence. Most of studies were of occupational exposures (Bull 2000; Lash, Parker et al. 2000).

In conclusion, TCE is reasonably anticipated to be a human carcinogen based on limited evidence of carcinogenicity from studies in humans, sufficient evidence of carcinogenicity from studies in experimental animals, which indicates there is an increased incidence of malignant and/or a combination of malignant and benign tumors at multiple tissue sites in multiple species of experimental animals, and information suggesting TCE acts through mechanisms that indicate it would likely cause cancer in humans (NTP 2004).

Other Effects

Respiratory

TCE produces minimal irritation of the respiratory tract at concentrations that do not exceed current workplace standards (Waters, Gerstner et al. 1977).

TCE is not a sensitizing agent, and bronchospasm is unlikely to occur except after exposure to high concentrations (Agency for Toxic Substances and Disease Registry 1997). Reactive Airway Dysfunction Syndrome (RADS) or Irritant Induced Asthma (IIA) has been attributed to exposure to very high concentrations of solvents (Rosenman, Reilly et al. 2003).

In a study conducted with human volunteers, 200 ppm TCE was inhaled simultaneously with ethanol ingestion, an increase in both heart rate and breathing rate was observed. However, when 200 ppm TCE was inhaled in the absence of ethanol ingestion, these TCE-related effects did not occur (Agency for Toxic Substances and Disease Registry 1997).

TCE is both acutely toxic and carcinogenic to the mouse lung following exposure by inhalation. Toxicity to the mouse lung is confined almost exclusively to the nonciliated Clara cell (Forkert, Sylvestre et al. 1985).

Comparisons between species suggest that the ability of the human lung to metabolize TCE is approximately 600-fold less than that in the mouse.

In addition, the human lung differs markedly from the mouse lung in the number and morphology of its Clara cells. Thus, risks from TCE exposure to human lung damage are minimal (Green 2000).

Skin

Like other organic solvents, TCE may produce contact dermatitis, rashes, and burns. The defatting dermatitis resulting from prolonged contact may reduce resistance to skin infections. An irritant reaction resembling an exfoliative dermatitis or scarlatiniform reaction can occur from dermal contact with contaminated clothing (Waters, Gerstner et al. 1977; Agency for Toxic Substances and Disease Registry 1997).

A syndrome called degreaser's flush (Stewart, Hake et al. 1974) has been associated with the interaction of ingested ethanol and inhaled TCE. Typically, erythema resulting from vasodilation develops around the face, back, and shoulders within 30 minutes of exposure and resolves in about an hour.

Immune System

The immunotoxic effects of TCE were evaluated in an animal study. The investigators concluded that, although the effects observed were not remarkable, the immune system does appear to be sensitive to the chemical (Sanders, Tucker et al. 1982). A few reports have been found on human immunological abnormalities related to usage of TCE contaminated well water (Agency for Toxic Substances and Disease Registry 1997). A recent study of TCE exposed workers has found immune abnormalities (Iavicoli, Marinaccio et al. 2005).

Progress Check