TITLE: Trichloroethylene--A Review of the Literature in View of the Results of the Trichloroethylene Subregistry Results
AUTHORS: Ginger L. Gist, Ph.D.
JeAnne R. Burg, Ph.D.
AFFILIATIONS: Exposure and Disease Registry Branch, Division of Health Studies, Agency for Toxic Substances and Disease Registry, Atlanta, Georgia
CORRESPONDENCE: Ginger L. Gist, Ph.D., Exposure and Disease Registry Branch, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road, Mailstop E-31, Atlanta, GA 30333
(404)639-6202
ABBREVIATIONS: Agency for Toxic Substances and Disease Registry (ATSDR), Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA), confidence interval (CI), National Center for Health Statistics (NCHS), National Exposure Registry (NER), National Health Interview Survey (NHIS), National Household Survey on Drug Abuse (NHSDA), trichloroethylene (TCE), Superfund Amendments and Reauthorization Act (SARA)
KEY WORDS: National Exposure Registry, environmental exposures, trichloroethylene, hazardous substances, CERCLA, SARA
RUNNING TITLE: TCE Review
ABSTRACT
BACKGROUND
Since it was first described by Fischer in 1864 (Hewer, 1975), TCE has been used for a wide variety of purposes. TCE was initially used as a degreaser for both metal fabrication and dry cleaning of clothes. In 1911, Lehmann reported the use of TCE as an anesthetic, which was soon followed by its use as an analgesic, specifically for the treatment of trigeminal neuralgia (Hewer, 1975). It was at that time that TCE was first reported to have neurological effects.
In the United States today, TCE is mainly used as a degreaser for metal parts, which is closely associated with the automotive and metals industries (CMR, 1983). Other uses of TCE include use as an extraction solvent and as a chemical intermediate; in the textile industry TCE is used as a scouring agent and as a solvent. TCE is also used as a component in adhesives, lubricants, paints, varnishes, paint strippers, pesticides, and cold metal cleaners (ATSDR, 1993).
The atmosphere is the primary recipient of environmental releases of TCE. The major emission source for TCE into the atmosphere is vapor degreasing operations (ATSDR, 1993), accounting for approximately 90% of TCE emissions. Other sources include solvent losses from adhesives, paints, and coatings; TCE manufacturing; manufacturing of other chemicals such as polyvinyl chloride; and releases from publicly owned treatment works. (Note: TCE may be formed as the result of water chlorination (National Research Council, 1977; EPA, 1984, 1985; Borzelleca et al., 1990); however, it is not considered to be a common breakdown product.) Releases to aquatic systems and soils are primarily from industrial discharges of wastewater streams and leachate from landfills.
Background levels of TCE in the environment vary according to media and location. For example, TCE background levels in air ranged from 0.03 parts per billion (ppb) for rural areas, 0.04 to 0.71 ppb for urban/suburban areas, and 1.2 ppb for areas near emission sources. With respect to water, TCE backgrounds levels ranged from 0.001 ppb in the Gulf of Mexico, 0.007 ppb in the northeastern Atlantic, to 0.0008 to 0.039 ppb in rainwater or snow. Sixteen percent of the groundwater sampled in the US has detectable levels of TCE compared with 28% of surface water samples; however, TCE was not detectable in 90.4% of samples taken from drinking water systems. Finally, 6% of soil samples in the US had less than 5 ppb TCE (ATSDR, 1993).
Humans may be exposed to TCE in the environment from the above named sources; in addition, consumer products such as typewriter correction fluids, paint removers, strippers, adhesives, spot removers, and rug-cleaning fluids may also contain TCE. TCE has been reported at 801 of the 1408 National Priorities List sites (ATSDR, 1994). In addition, 401,373 workers at 23,225 plant sites in the United States are potentially exposed to TCE (NOES, 1991), mainly through degreasing operations. Certain foods (Table 1) may also contain TCE.
According to ATSDR (1993), the average daily intake of TCE in the US is 11-33 micrograms per day; average daily water intake is 2-20 micrograms per day.
TABLE 1. Foods containing TCE (ATSDR, 1993).
| Food | TCE Concentration (ppb) |
| Fish Chinese style sauce Quince jelly Crab apple jelly Grape jelly Chocolate sauce Dairy products Meats Oils and fats Fresh bread US margarine Yellow cake mix Yellow corn meal Fudge brownie mix Beverages (canned fruit drink, light ale, instant coffee, tea, wine) Fruits and vegetables (potatoes, apples, pears, tomatoes) Bleached flour |
10-100 28 40 25 20 50 0.3-13 12,000-22,000 0-19 7 440-3,600 1.3 2.7 2.4 0.02-60 1.7-5 0.77 |
Metabolism
The percentage of inhaled TCE that is absorbed by the pulmonary vasculature ranges from 50% to 76% (Walder, 1983; Flanagan et al., 1990); of the retained dose, between 40% and 75% is metabolized (ATSDR, 1993). The oil vs. water partition coefficient for TCE of 900:1 favors deposition in the lipophilic organs, including the liver and brain (Miller et al., 1975; Kilburn and Warshaw, 1993). TCE has also been shown to concentrate in the ovary (Manson et al., 1984) and spermatocytes (Land et al., 1979). Metabolites have been shown to cross the placenta readily into the fetal circulation and amniotic fluid (Goldberg et al., 1990).
The principal site of metabolism of TCE is the liver, although the lung also metabolizes TCE to trichloroacetic acid or trichloroethanol. Other tissues, such as the kidney, spleen and/or small intestine, are also involved in metabolism of TCE as these tissues are sites of cellular protein binding of metabolites from TCE (Bolt and Filser, 1977; Dalbey and Bingham, 1978; Bergman, 1983; Davidson and Beliles, 1991). Cytochrome P-450 mediated metabolism plays an important role in the toxicity of TCE (Fort et al., 1993; EPA, 1985; Bruckner et al., 1989; Bonse and Henschler, 1976; Henschler et al., 1979; Miller and Guengerich, 1982, 1983; WHO, 1985; Fan, 1988; Odum et al., 1992; Ikeda and Ohtsuji, 1972; Dekant et al., 1984; Prout et al., 1985). The probable route of metabolism in mammals is presented in Figure 1. The primary metabolites of TCE are 2,2,2-trichloroethanol (45%), and trichloroacetic acid (32%) (Flanagan et al., 1990; Toftgard and Gustafsson, 1980; Baselt,1982), with other minor metabolites formed via dechlorination reactions (see Table 2) (EPA, 1985; Dekant et al., 1986). Biotransformation
FIGURE 1. The metabolic pathways of trichloroethylene (ATSDR,1993).
TABLE 2. Demonstrated metabolites of TCE (Davidson and Beliles, 1991).
| Metabolites of Trichloroethylene | ||
| Trichloroacetic acid
Trichloroethanol Chloral hydrate TCE-epoxide Glyoxylic acid |
Carbon dioxide Monochloroacetic acid
Dichloroacetic acid N-Acetyl dichlorovinyl-cysteine N-(Hydroxyacetyl) aminoethanol Trichloroacetic acid-glucuronide > |
Trichloroacetic acid-CoA Chloroform
Oxalic acid Dichlorovinyl-cysteine Carbon monoxide |
of TCE via the p-450 system ultimately produces dichloroacetic acid, trichloroacetic acid, trichloroethanol, and oxalic acid (EPA, 1985).
Following inhalation, unmetabolized TCE is exhaled; metabolites are excreted primarily in the urine. Trichloroethanol (glucuronide) is the major urinary metabolite of TCE (90%), with trichloroacetic acid accounting for approximately 8% of the urinary metabolites (Green and Prout, 1985). In addition, excretion in the bile may account for up to 30% of TCE metabolite elimination. The terminal half-life of TCE is 30-38 hours (Flanagan et al., 1990); however, the half-time for renal elimination of trichloroethanol and trichloroethanol glucuronide is approximately 10 hours (Monster et al., 1979; Sato et al, 1977).
Alcohol consumption
Ethanol can either increase or decrease the metabolism of TCE, depending on the doses administered and the time interval between ethanol and TCE administration. For example, Sato et al. (1991) found that ingestion of moderate amounts of ethanol before the start of work or at lunchtime, but not at the end of work, caused pronounced increases in blood TCE concentrations and decreases in the urinary excretion rates of TCE metabolites. This work supported the findings of others (Mueller et al., 1975, Stewart et al., 1974b); however, with a longer time interval after ethanol administration TCE metabolic rates would be expected to increase. It is certain that consumption of alcohol can alter the metabolism of organic solvents in animals; a single dose of ethanol consumed the day before exposure to TCE enhanced the TCE metabolism in vivo as shown by a faster disappearance of TCE from blood as well as an increased urinary excretion of TCE metabolites (Sato et al., 1981).
THE TCE SUBREGISTRY
In 1988, TCE was selected as the primary contaminant for the first subregistry of the National Exposure Registry. At the time of its selection, TCE was the most prevalent contaminant found at National Priorities List (NPL) sites having been identified at 37% (n = 355) of all NPL sites; TCE was a groundwater contaminant at 91% (n = 322) of these TCE sites.
A key purpose of the TCE Subregistry is to determine if there is an excess of adverse health conditions for registrants when compared with a national sample. To date, this objective has been pursued by comparing TCE Subregistry data about health conditions with National Health Interview Survey (NHIS) data; comparing TCE cancer outcomes with cancer incidence data from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program; and comparing TCE Subregistry mortality rates with National Center for Health Statistics (NCHS) published rates. Health, demographic, occupational, and environmental information was collected on 4,280 TCE-exposed persons (4,041 living, 239 deceased) who met the eligibility criterion for the National Exposure Registry participation; resided for more than 30 consecutive days during the period of exposure at a site address. The site information and data analyses are discussed in detail elsewhere (ATSDR 1994). The comparisons of TCE Subregistry and NHIS data on reported health conditions revealed several statistically significant differences (Table 3).
The purpose of this paper is to review findings in the literature relative to the findings of health outcomes from the TCE Subregistry.
TABLE 3. Summary results of TCE Subregistry - NHIS comparisons.
Disease Category |
Age Groups (years) | ||||||||||||||||||
| 0-9 | 10-17 | 18-24 | 25-34 | 35-44 | 45-54 | 55-64 | 65 | All | All | ||||||||||
| M | F | M | F | M | F | M | F | M | F | M | F | M | F | M | F | M | F | ||
| Speech impairment | X | X | |||||||||||||||||
| Hearing impairment | X | X | R | R | R | R | R | R | R | R | R | R | |||||||
| Stroke | X | X | X | X | X | X | |||||||||||||
| Liver problems | X | ||||||||||||||||||
| Anemia and other blood disorders | X | X | X | X | X | X | X | ||||||||||||
| Diabetes | X | X | |||||||||||||||||
| Kidney disease | X | ||||||||||||||||||
| Urinary tract disorders | X | X | X | X | X | X | X | X | |||||||||||
| Skin rashes | X | ||||||||||||||||||
| Asthma, emphysema | R | ||||||||||||||||||
| Arthritis | R | R | |||||||||||||||||
| Respiratory allergies | R | R | |||||||||||||||||
X = Statistically significant differences, TCE subregistry rate higher.
R = Statistically significant differences, NHIS rate higher.
= Insufficient data.
HEALTH CONDITIONS
Anemia or Other Blood Disorders
As seen in Table 3, anemia and other blood disorders were significantly increased for specific subpopulations within the TCE Subregistry. Most hematological findings reported in the literature have been the result of occupational exposures. Mild macrocytic anemia has been observed in some workers (Defalque, 1960; Sotarieni et al., 1982), in addition to intolerance to alcohol, abnormal liver function tests, and an increase in total blood lipids. White corn wet-milling workers exposed to solvents and other chemicals, experienced excess mortality from lymphatic and hematopoietic malignancies (Thomas et al., 1985). Other hematological effects reported following TCE exposure include thrombocytopenia (Czirjak et al., 1993); microangiopathic hemolytic anemia (Lockey et al., 1987); polycythemia, eosinophilia, and aplastic anemia (Walder, 1983); and "low blood counts" (Kilburn and Warshaw, 1992). In contrast, Stewart et al. (1970) reported that acute exposures to TCE resulted in no adverse hematological effects on blood cell counts, sedimentation rates, serum lipid levels, serum proteins, or serum enzymes.
Changes in lymphocyte subpopulations have also been reported in solvent-exposed workers. A decrease in the OKT11 (all) T cell fraction, a decrease in the OTK4 helper cells, and an increase in the anti-Leu 7 positive cells (mostly natural killer cells), an increase in anti-Leu 12 labeled T cells (that is, human B-lymphocytes) and no differences in the OKT8 suppressor cells were among the alterations reported (Denkhaus et al., 1986). It should be noted the authors felt these changes to be similar to those found in states of immunodeficiency and immunogenetic forms of aplastic anemia. Immunological abnormalities, including persistent lymphocytosis, increased numbers of T-lymphocytes, and a depressed helper:suppressor T-cell ratio, were also found in adults in Woburn, Massachusetts, who were family members of children with leukemia (Byers et al., 1988). It should be noted, however, that there was a possible bias in reported risk factors as well as other limitations (MacMahon, 1986; Prentice, 1986; Rogan, 1986; Swan, 1986; Whittemore, 1986).
In animal studies, TCE was reported to have direct action on the bone marrow of rabbits, causing myelotoxic anemia (Mazza and Brancaccio, 1967). Mice exposed to a mixture of organic solvents in their drinking water developed suppressed marrow granulocyte macrophage progenitors (Hong et al., 1991); residula effects (lower progenitor cell numbers following irradiation) were seen up to 10 weeks following exposure.
Mice, following intermediate oral exposure, showed minor changes in hematology, including a 16% reduction in rbc counts, increased fibrogen in males, decreased white cell counts in females, and decreased prothrombin times in females; however, no changes in platelet counts were found (Tucker et al., 1982). The changes were not considered to be toxicologically significant since they were not dose related and were within normal values for mice. Various hematological effects have been reported in other animal studies (Fujita et al., 1984; Koizuma et al., 1984; Goel et al., 1992), but since hemoglobin concentration in erythrocytes did not change, the changes were not considered to be adverse. Goel and coworkers (1992) did, however, report a dose-related increase in cell density and related parameters in bone marrow, an observation the authors believed to be responsible for the hematological alterations seen, such as a significant increase in red blood cell counts and a reduction in white blood cell counts without any statistically significant change in the hemoglobin, urea nitrogen, uric acid, and creatinine levels, seen in male mice orally administered TCE.
Arthritis
Arthritis was significantly reduced in the TCE Subregistry population (all males and all females). Only one study was located that included arthritis in the health outcomes noted. Arthritis was reported to be elevated 2 to 5 times in a self-selected resident study population in Tucson, Arizona, reportedly exposed to TCE and other chemicals and metals at levels ranging from 6 to >500 parts per billion (ppb) for up to 25 years (Kilburn and Warshaw, 1992). No animal studies were located.
Asthma, emphysema, chronic bronchitis, respiratory allergies, such as hay fever
Reports of asthma, emphysema, and chronic bronchitis were reduced for the overall TCE Subregistry population; reports of respiratory allergies or other problems such as hay fever were reduced for all males and females. Similarly, in a detailed analysis of the 6929 employees occupationally exposed to TCE, the most widely used solvent at Hill Air Force Base during the 50s and 60s, Spirtas and coworkers (1991) found significant deficits occurred for mortality from non-malignant respiratory disease. The authors found their results to be consistent with other cohort studies of TCE exposed workers (Axelson et al., 1978; Tola et al., 1980).
Positive findings have also been reported for these conditions following TCE exposure. In a study of Woburn, Massachusetts residents exposed to unknown levels of TCE and other solvents in their drinking water, Lagakos et al. (1986) and Byers et al. (1988) reported finding an increase in the risk of asthma, chronic bronchitis, pneumonia, and pulmonary infections to be associated with long-term exposure to the water. Kilburn and Warshaw (1992) reported the incidence of pleurisy to be increased 2 to 3 times in the Tucson population; however, systemic lupus erythmatosis, which may contribute to pleurisy, was also increased in this population. TCE has also been reported to cause pulmonary edema (Seage and Burns, 1971; Walder, 1983), however it has been demonstrated that this effect is due to the oxidation of TCE to phosgene (Wodka, 1991).
In mice, TCE selectively binds to pulmonary epithelial cells and may become pneumotoxic (Forkert et al., 1985). This was confirmed in a further study by Forkert and Birch (1989) in which pulmonary toxicity was demonstrated by histologic studies and covalent binding to pulmonary tissues including tracheal and epithelial lining cells, after intraperitoneal administration of TCE. Nichols et al., (1992), however, in a study using enriched subpopulations of isolated rabbit lung cells incubated with TCE, found TCE to be a nonselective pneumotoxin that appears to be bioactivated by a non P-450-mediated enzymatic pathway to a cytotoxic intermediate.
Odum and coworkers (1992), in a study of female CD-1 mice exposed to TCE via inhalation, found that the mice developed a highly specific lung lesion of the Clara cells after a single exposure. Isolated mouse lung Clara cells were shown to metabolize trichloroethylene to chloral, trichloroethanol and trichloroacetic acid. Chloral was the major metabolite and was believed to be responsible for the lesion. No morphological changes were seen in the lungs of rats exposed to either 500 or 1000 ppm trichloroethylene, indicating a clear species difference in the effects of TCE on rat lungs. Prendergast et al. (1967) also found no histopathological changes in the lungs of rats chronically exposed to TCE.
It is important to note that human Clara cells are known to be relatively few in number and are morphologically different from those in rodents. "In attempting to assess the relevance of the mouse data to humans exposed to TCE these parameters must be considered although the available data is very limited. However given the lack of effect of TCE in the rat lung, a species whose Clara cells morphologically more closely resemble those of the mouse than the human, it seems unlikely that the effect of TCE on human lung would resemble that of the mouse rather than the rat" (Odum et al., 1992).
It is interesting to note that, in an animal study of TCE-induced bradyarrhythmogenesis, Arito et al. (1993) explained the process as follows: TCE exerts its facilitatory action on the paradoxical sleep-generating mechanism and its inhibitory action on the respiratory center. These actions would independently or synergistically attenuate the respiratory drive, developing into apnea during paradoxical sleep. Possible hypoxemia due to paradoxical sleep apnea would stimulate both the carotid chemoreceptors and the pulmonary vagus receptors, thereby affecting the cardiovascular center controlling sympatheto-parasympathetic tone. Bradyarrhythmia is elicited by the increased vagal tone.
Dermal Effects
Skin rashes were reported in excess by the overall TCE Subregistry population. Effects seen following dermal exposure to TCE are usually the consequence of direct skin contact with concentrated solutions, but occupational exposure also involves vapor contact. Individuals occupationally exposed to TCE for intermediate periods sometimes develop skin burns or primary irritant contact dermatitis, as well as exfoliative dermatitis and scarlatiniform reaction (Bauer and Rabens, 1974; Schirren,1971). Nakayama et al. (1988) reported that some people may be particularly sensitive to TCE and develop allergies when exposed to high levels during occupational exposures of intermediate duration; however, allergies have not been reported following exposure to dilute aqueous solutions (ATSDR, 1993). Phoon et al. (1984) reported the development of Stevens-Johnson syndrome, a severe erythema, in five individuals following intermediate duration exposure to 19-164 ppm TCE. Although this particular condition has not been reported historically (ATSDR, 1993), "degreasers' flush", an erythematous cutaneous reaction of the face, neck, and shoulders due to ingestion of ethanol following TCE exposure, is well known (Stewart et al., 1974). Finally, in a study of workers with exposures to many solvents and heavy metals, Dubrow and Gute (1987) found excess deaths due to diseases of the skin and subcutaneous tissue (PMR=383).
In a study of individuals potentially exposed to TCE in drinking water, exposed women reported more skin rashes than the controls (Kilburn and Warshaw, 1992). Malar rash and heliotropic skin lesions were also reported in excess by this population.
Some of the participants in the Woburn, Massachusetts study reported skin lesions (maculopapular rashes) that occurred approximately twice yearly and lasted from 2 to 4 weeks (Byers et al., 1988). These lesions ceased from 1 to 2 years after cessation of exposure to TCE.
One study (Kronevi et al., 1981), in which TCE was applied to the skin of guinea pigs, reported the presence of karyopyknosis, karyolysis, spongiosis, and pseudoeosinophilic infiltration in biopsies taken at different times of exposure. Another animal study reports that guinea pigs exhibited considerable erythema, edema, and increased epidermal thickness following an uncovered, dermal exposure to TCE (Anderson et al., 1986). The reports of TCE-induced scleroderma-like illnesses may also have biological plausibility since sclerotic skin changes can be induced experimentally in mice with aliphatic hydrocarbons (Sverdrup, 1984).
Diabetes
Diabetes was reported in excess by females 18 through 24 years and 45 through 54 years of age in the TCE Subregistry population; however, few studies are available that explore a possible relationship between environmental chemical exposure and the development of diabetes. One of the potential precursors of diabetes, pancreatic cancer, was addressed. In a study of workers in the corn wet-milling industry, who were occupationally exposed to solvents, along with a variety of other chemical and physical agents, Thomas et al. (1985) reported an elevated frequency of deaths due to diabetes and a threefold excess of pancreatic cancer deaths among blacks. Ijsselmuiden and coworkers (1992) conducted a case-control study of individuals exposed to chlorinated drinking water and found a significant odds ratio (2.2) for pancreatic cancer among exposed individuals. The study was limited, however, in exposure assessment.
Much of the recent literature concerning insulin dependent diabetes mellitus (IDDM) points to a role for an environmental factor of some sort, in addition to the genetic factors, in the etiology of the disease. The supporting evidence for this conclusion is the low concordance rate of IDDM for identical twins, the increasing incidence of IDDM in several countries, the association of IDDM with epidemic-like outbreaks in certain years, and the seasonal pattern to the incidence of IDDM (Todd, 1991). The most commonly reported environmental factors include viruses, such as cause mumps, Coxsackie infections, cytomegalovirus infections, and rubella (Harris, 1987; Kemper, 1947; Sultz et al., 1975; Helmke et al., 1986; Gamble et al., 1984; Yoon et al., 1979, 1987ab; Forrest et al., 1971; Ginsberg-Fellner et al., 1985; Pak et al., 1988; Loria et al., 1986; Banatuala, 1987; Rayfield and Ishmura, 1987; Suenaga and Yoon, 1988; Ciampolillo et al., 1989); environmental toxins, such as Alloxan, streptozotocin, Vacor, nitrosamines (Karam et al., 1980, 1979; Bouchard et al., 1982; Helgason and Jennasson, 1981; Helgason et al., 1982), arsenic (Lai et al., 1994), and diazoxide and corticosteroids (Ferner, 1992); nutrients, such as foods containing N-nitroso compounds (Helgason et al., 1982); and stress (Drash, 1990).
Cardiovascular Effects
The rate of heart disease or other heart problems in the TCE Subregistry when compared with the NHIS could not be assessed since a comparable heart response rate could not be created for the TCE Subregistry file. It should be noted, however, that this variable will be addressed in future data analyses.
TCE and related compounds cause acute and chronic cardiotoxicities via mechanisms that are still obscure (Tse et al., 1990). Cardiac arrhythmias (sometimes resulting in cardiac arrest) due to TCE exposure have been reported frequently in the literature (Bell, 1951; Dhuner, 1957; Flanagan et al., 1990; Huff, 1971; Kleinfield and Tabershaw, 1954; Smith, 1966; Hantson et al., 1990; Nakajima et al., 1987). Other heart problems have also been reported, including disturbances in cardiac conduction (Hantson et al., 1990), pericarditis with effusion (Lockey et al., 1987), myocardial injury (Wodka and Jeong, 1991), significantly elevated risk of arteriosclerotic heart disease (Zoloth et al., 1986), erratic heart action and abnormal electrocardiogram readings (Milby, 1968), and myocardial infarction (Morreale, 1976). It is interesting to note that, according to Hantson et al. (1990), cardiac arrhythmias in humans occur after a variable delay, thus they are more likely due to the metabolites, trichloroethanol and trichloroacetic acid, than to TCE itself.
In one study of persons exposed to TCE in drinking water (Byers et al., 1988), the parents of children with leukemia complained of unexplained rapid heart rates at rest, palpitations, or near syncope. Of the 11 adults tested, 8 had serious ventricular dysfunctions and 7 had multifocal premature ventricular beats and required cardiac medication. None of the subjects had clinically significant coronary artery disease. It is important to note, however, that the study has been declared flawed by other researchers (ATSDR, 1993) since no background information was taken on the subjects.
Goldberg et al. (1990) found a significant association, but not cause and effect relationship, between maternal exposure during the first trimester of pregnancy and congenital heart disease in children whose parents drank water contaminated with TCE and other substances. Worker solvent exposure has also been associated with an increased prevalence of congenital heart disease (Zieler et al., 1988). It should be noted that Swan et al. (1985) have shown a possible association between TCA and human congenital cardiac disease.
Cardiovascular disease is the most frequent and costly complication of diabetes (Barrett-Conner and Wingard, 1976; CDC, 1990; Ford and Stefano, 1991) and is the leading cause of mortality among persons with diabetes. Diabetes was increased in certain subgroups of the TCE Subregistry. It should be noted that persons with undiagnosed diabetes or impaired glucose tolerance are at increased risk for macrovascular complications, that is, coronary heart disease (Jarrett et al., 1982).
Decreases in the incidence of heart conditions following TCE exposure have also been reported. Reports of health problems requiring medical treatment by current and former employees of a manufacturing plant using TCE indicated that there were only one- third as many persons with heart disease or hypertension as were reported in a comparable reference population studied over a 5-year span. For the white male cohort, there were fewer deaths than expected from heart disease, cancer, and trauma (Shindell and Ulrich, 1985). Spirtas et al. (1991) found that significant deficits occurred for mortality from all causes, all malignant neoplasms, ischemic heart disease, nonmalignant respiratory disease, and accidents in workers exposed to solvents, particularly TCE. The inconsistent mortality patterns by sex, multiple and overlapping exposures, and small numbers make it difficult to ascribe these excesses to any particular substance, however. In addition, the "healthy worker effect" may contribute to the reported decreases.
In animals, TCE elicits depression of the central nervous system and inhibits cardiac function (Safe Drinking Water Committee, 1980). For example, dogs and rabbits exposed to TCE via inhalation and subsequently challenged with epinephrine have been demonstrated to experience premature ventricular contractions (Reinhardt et al., 1973; White and Carlson, 1979). Some studies (Grandjean, 1960, 1966; Kylin et al., 1963; Mikiskova and Mikiska, 1966; Reinhardt et al., 1973; Savolainen et al., 1977) delineate apparent "minimum-effect levels" of TCE. It should be noted, however, that marked species differences have been reported to exist in types and frequencies of cardiac arrhythmias between rats and humans (Arito et al., 1993).
The findings of congenital heart disease in humans have been supported by animal studies. Loeber et al. (1988) found that TCE was associated with three times (p < 0.005) as many cardiac defects as occurred for control solutions when injected into the air sacs of fertilized eggs at 5 to 25 µmol/egg. Other studies of chick embryos have also demonstrated significant general and cardiac teratogenesis (Elovaara et al., 1979; Bross et al., 1983; Smith et al., 1968). In a mammalian study in which TCE was delivered to developing rat fetuses under provocative circumstances, Dawson et al. (1990) also found a dose-dependent increase in cardiac anomalies. TCA, a major metabolite of TCE, has also been demonstrated to cause soft tissue malformations, particularly of the cardiovascular system, in fetal rats following oral administration to pregnant dams during oncogenesis (Smith et al., 1989). In addition, a highly toxic epoxide intermediate has been identified in rats, rabbits, and mice and may be partially responsible for inducing developmental toxicity (Bruckner et al., 1989; Bonse and Henschler, 1976; Henschler et al., 1979). This epoxide intermediate has also been shown to play a significant role in the developmental toxicity of TCE in vitro via the FETAX (Xenopus) test system (Fort et al., 1993). It should be noted, however, that some inhalation studies in mammals have produced no observable teratogenesis (Dorfmuller et al., 1979; Healy et al., 1982; Schwetz et al., 1975).
The mechanism by which TCE causes acute and chronic cardiotoxicities is unknown. Various theories have been advanced, however. For example, Tse et al. (1990) have demonstrated that in the presence of low levels of iron, all five agents promoted lipid peroxidation up to 200% of control. Honma (1990) reported that TCE inhibited the formation of very low density lipoproteins. Cardiotoxicities induced by halogenated hydrocarbons, such as TCE and TCA, have been shown to mimic those induced by free radicals. For example, the superoxide anion and hydroxyl radical are known to be potent vasodilators--a mechanism that has been demonstrated to be one of the manifestations of acute TCE poisoning (Aviado, 1976b; Tse et al., 1990). Halogenated hydrocarbons also sensitize the heart to catecholamines (Boon, 1987; Wodka, 1991), which can result in cardiac arrhythmias.
Studies have shown that ethanol competitively inhibits the metabolism of TCE. White and Carlson (1981) showed that rabbits given ethanol 30 minutes before exposure to high levels of TCE (6000 ppm) experienced epinephrine-induced cardiac arrhythmias sooner and at lower epinephrine doses than did rabbits exposed to trichloroethylene without ethanol. Because ethanol exposure apparently increases the cardiovascular toxicity of TCE, workers exposed to both solvents simultaneously may have a higher risk of cardiac arrhythmias than do those exposed to TCE alone (Wilcosky and Simonsen, 1991).
High Blood Pressure (Hypertension)
Hypertension could not be investigated appropriately using the NHIS as a compariosn population; the NHIS 12-month response rate was calculated using the "ever had" positive responses. In addition, the positive response was retained in the file only if the respondent answered positively to one or more of nine other selected questionnaire items (NCHS, 1990). This additional restriction might have altered the NHIS response rate for this condition. Without considering these problems, however, hypertension was significantly elevated for those 18 through 64 years of age.
Many of the reports in the literature of hypertension following exposure to TCE are case reports. For example, following a single dermal exposure to TCE for 2.5 hours, one woman developed systemic sclerosis with renal insufficiency and severe hypertension (Lockey et al., 1987). Eskenazi et al. (1988) reported that solvent-exposed women were approximately four times more likely to develop preeclampsia, a disorder of pregnancy characterized by hypertension, edema, and proteinuria. Because hypertension alone, without edema or proteinuria, was also more likely to be reported in solvent-exposed women lent additional support to the association of solvent exposure and hypertensive disorders of pregnancy. Two patients who drank either 350 or 500 ml TCE experienced delayed but profound hypotension and cardiac arrhythmias (Dhuner et al., 1957).
Workers studies have been mixed. A slight depression in pulse rate and/or blood pressure was also observed in persons inhaling TCE at levels as low as 170 ppm (Ogata et al., 1971) and 200 ppm (Nomiyama and Nomiyama, 1977). One cohort study of current and former employees of a manufacturing plant who were exposed to TCE and who reported health problems requiring medical treatment showed that there were only one-third as many persons with heart disease or hypertension as were reported in a comparable reference population studied over a 5-year span (Shindell and Ulrich, 1985). This result, however, could have been partially due to the so-called "healthy worker" effect.
Hypertension is a common condition associated with diabetes (Bild and Teutsch, 1987, Christleib et al., 1981; Dupree and Myer, 1980; Horan, 1984), occurring approximately twice as frequently in persons with diabetes as in persons without diabetes (NCHS, 1990). The proportion of complications in the diabetic population attributable to hypertension range from 33% to 75% (Dupree and Myer, 1980; Pell and D'Alonzo, 1970), increasing with age. Diabetes has been reported in excess in certain subgroups of the TCE Subregistry population.
Effects of Stroke
Stroke was reported in excess in the TCE Subregistry; however, only one study was located that reported a borderline significance for relative risk of stroke in a population that had been potentially exposed for 12 years to TCE by means of chlorinated domestic drinking water (Wilkins and Comstock, 1981). (Note: The byproducts of chlorination may include TCE, although it is considered unusual.) Convulsions associated with cerebral infarction have been associated with long term TCE exposure (Parker et al., 1984). Abuse of typewriter correction fluid has been reported to cause cerebral edema and coma, along with cardiac arrhythmias (Pointer, 1982; King et al., 1985; Banathy and Chan, 1983; Boon, 1987); vascular-like syndromes have also been reported in solvent abusers (Wiseman and Banin, 1987).
It is important to note that hypertension--which occurs approximately twice as frequently in persons with diabetes (Horan, 1985)--contributes to stroke, the incidence of which is also twice as high among diabetics as among non-diabetics (Kannell et al., 1976; Kannell and McGee, 1979). In the TCE subregistry population, of the 32 individuals reporting stroke, 11 were diabetic (6 males and 5 females, all over age 55). No animal studies were located specific to the effects of a stroke following exposure to TCE.
Kidney Disease
Kidney disease was significantly elevated in females in the TCE Subregistry population who were 55 through 64 years of age. Long-term exposure to TCE has been associated with hepatorenal damage (Flanagan et al., 1990; Baerg and Kimberg, 1970; Clearfield, 1970; Litt and Cohen, 1969; Pozzi et al., 1985). David et al. (1989) studied one worker in a degreasing operation who developed acute renal failure due to acute allergic interstitial nephritis with secondary tubular necrosis, however this reaction could not be definitely attributed to TCE. Slight renal effects, indicated by changes in urinary proteins and enzymes, have been reported in workers exposed to TCE in mixtures with other substances in the workplace (Brogren et al., 1986; Nagaya et al., 1989).
Dubrow and Gute (1987) reported elevated PMRs for nonmalignant kidney disease in males in the jewelry industry; however, exposure to known renal toxins, such as heavy metals and solvents, was thought to possibly account for the excess numbers of deaths from kidney disease. The authors cautioned that, because of the lack of information about specific occupational exposures of the decedents, their study should be viewed as an exploratory investigation requiring further follow up.
In a study assessing early tubular dysfunction by urinary enzymes, Rasmussen et al. (1993a) found indications that subclinical tubular dysfunction is nonsignificantly associated with long-term and peak exposure to degreasing solvents. In addition, in a review of the literature, Kluwe et al. (1984), reported that causal associations appear to exist between occupational exposure to some hydrocarbon solvents and chronic kidney disease, although the data on humans are not definitive. They reviewed studies that they believe indicate a potential for organic chemicals, especially halogenated hydrocarbons and aromatic amines, to produce chronic kidney injury in humans and other mammalian species.
One study reported hepatorenal failure as the cause of death following oral exposure to TCE, but a dose was not determined (Kleinfield and Tabershaw, 1954); however, another case report stated that urine and blood analyses revealed no hepatic or renal injury in a man who drank several tablespoons of TCE (Todd, 1954). In Woburn, MA, an increased risk of kidney and/or urinary tract infections was associated with long-term exposure to TCE-contaminated water (Lagakos et al., 1986).
Renal failure is one of the major chronic complications of diabetes (Christleib et al., 1981; Knowler et al., 1980), a condition that was reported in excess in certain subpopulations of the TCE Subregistry. Compared with the rest of the population, people who have diabetes are at a seventeen fold increased risk for end-stage renal disease (Herman and Teutsch, 1986) related to hypertension. Finally, proteinuria, a clinical marker for nephropathy, develops in from 18 to 30 percent of persons who have had Type I or Type II diabetes for 15 up to 19 years (Herman and Teutsch, 1986).
In animal studies, renal enlargement has been associated with acute or intermediate duration inhalation or oral exposure. Kidney enlargement seems to be less pronounced and occurs less consistently than liver enlargement. Enlargement was associated with altered biochemical indices of renal function, but not abnormal histology in some of the intermediate-duration animal studies (ATSDR, 1993; Brown et al., 1990; Kjellstrand et al., 1983ab; Nomiyama et al., 1986).
Chronic experiments also revealed toxicity. Administration of high doses of TCE by gavage for 78 weeks to Osborne-Mendel rats and B6C3F1 mice resulted in treatment-related chronic nephropathy, characterized by degenerative changes in the tubular epithelium (NCI, 1976). In two carcinogenicity studies of rats and/or mice, nonneoplastic renal effects included toxic nephrosis (characterized as cytomegaly) at doses of 500 and 1,000 mg/kg (NTP, 1982, 1990), and cytomegaly of the renal tubular cells coupled with toxic nephropathy (NTP, 1988). Wodka (1991) has postulated that the renal damage arising from renal tubular necrosis is possibly due to the generation of free radicals. Oral administration of TCE (2000 mg/kg/day) to male mice once daily, 5 days a week for a period of 28 days, caused an increase in kidney weight, glomerular nephrosis, degeneration/desquamation of tubular epithelium and characteristic amyloid deposition in glomeruli (Goel et al., 1992). These changes occurred concurrently with a significant increase in total protein and free sulphydryl contents, elevated activities of acid phosphatase and catalase and decreased activity of delta-aminolevulinic acid dehydratase (d-alad) indicating the sensitivity of liver and kidney as target tissues in tce-toxicity.
Liver Damage
Females 55 throguh 64 years of age in the TCE Subregistry population reported an excess of liver problems when compared with the comparable population from the NHIS. As early as 1962 (Takamatsu, 1962) hepatotoxicity following TCE exposure was being assessed in humans. Since that time, TCE has been found to cause liver damage (Bai and Stacey, 1993; Brown et al., 1990; Flanagan et al., 1990; Baerg and Kimberg, 1970; Clearfield, 1970; Litt and Cohen, 1969; Pozzi et al., 1985; Nethercott et al., 1982; Sax, 1975; Allemand et al., 1978; Commission of the European Communities, 1976, 1986; Wang and Stacey, 1990; Davidson and Beliles, 1991; Fielder et al., 1982). It should be noted, however, that hepatotoxicity is generally believed to be reversible upon the cessation of exposure (Davidson and Beliles, 1991).
Exposure to TCE has also been reported to result in hepatitis (McCunney, 1988; Herdman, 1945; Priest and Horn, 1965; Baerg and Kimberg, 1970; Clearfield, 1970; Kleinfield and Tabershaw, 1954); however, hepatitis from exposure to TCE in industrial settings is considered to be extremely rare. Other reports of liver damage following exposures to TCE have included fatal hepatic necrosis (Joron et al., 1955), liver dysfunction (Nakayama et al., 1988), hepatomegaly and icterus (Phoon et al., 1984), and increased neutrophilic infiltration in liver sinusoids (Klaassen and Plaa, 1967).
Driscoll and coworkers (1992) found TCE to be associated with highly significant increases in a number of individual and summed bile acid measures in workers; however, no association was found between any of the exposures and any of the standard tests of liver function. The authors believed these findings to reflect early and small disturbances in liver function. Liver function abnormalities have also been reported following abuse of solvents containing TCE. For example, Litt and Cohen (1969) reported of ten illnesses found secondary to sniffing spot remover, liver function abnormalities were noted in 5 patients, two of whom exhibited proteinuria and a rise in blood urea nitrogen. Rasmussen et al. (1993c) found a nonsignificant association between solvent exposure and tests screening for early liver dysfunction.
The hepatotoxic effect of TCE is believed to be mediated through the production of toxic metabolites and/or reactive free radicals (Tse et al., 1990; Wodka, 1991; Poyer et al., 1981; McCay et al., 1984; Tomasi et al., 1985; Goel et al., 1992; Bruckner et al., 1989; DeAngelo et al., 1989). Goel and coworkers (1992) believe that a build-up of TCE's toxic metabolites in the liver may be responsible for the lysosomal damage seen, as evidenced by increased acid phosphatase activity. The authors of this study further believed the potential of TCE and/or its metabolites to induce peroxisome proliferation and oxidative stress in the liver was evidenced by a significant increase in the activity of catalase, a marker of peroxisomes (de Duve, 1969). It should be noted that administration of ethanol or other hepatotoxins may potentiate TCE toxicity for the liver (Cornish and Adefuin, 1966; Candura and Faustman, 1991).
The hepatic effects in animals following exposure to TCE are not well understood. Kylin et al. (1962, 1963) observed only "slight" fatty infiltration of the liver; however, when the experiment was repeated no marked difference was seen in the livers between treated and control mice. In other studies, rodents have been shown to develop hepatic toxicity following exposure to TCE under a variety of conditions (Candura and Faustman, 1991; Green and Prout, 1985; Buben and O'Flaherty, 1985; Rouisse and Chakrabarti, 1986). An increase in liver weight and associated histopathological and biological changes have been reported in rats and mice exposed to TCE at relatively low concentrations for periods up to 14 weeks (Brown et al., 1990; Kjellstrand et al., 1983ab; Kimmerle and Eben, 1973). Hepatocellular injury, including hypertrophy and hyperplasia, have also been observed in both rats and mice (Stott et al., 1982; Elcombe, 1985).
In another study, Goel and coworkers (1992) reported that TCE, administered orally to male mice at 0, 500, 1000, and 2000 mg/kg/day, 5 days a week for a period of 28 days, caused a significant increase in liver weight, degeneration/necrosis of hepatocytes and characteristics proliferation of endothelial cells of hepatic sinusoids. These changes occurred concurrently with a significant increase in total protein and free sulphydryl contents, elevated activities of acid phosphatase and catalase and decreased activity of delta-aminolevulinic acid dehydratase (d-alad) indicating the sensitivity of liver and kidney as target tissues in TCE-toxicity.
In a study of rats injected with TCE, Honma (1990) found that TCE impaired very low density lipoprotein formations at low doses. The decreases in high density lipoproteins (hdl) at high doses of TCE resulted from the inhibition of hdl synthesis. Liver-to-body weight ratios were raised with increasing doses and believed to be related to the changes in lipoproteins. In addition, plasma GOT and GPT activities rose at much higher doses of TCE than dose levels which produced the changes in lipoproteins and the increases in liver weights.
Dees and Travis (1993) found that liver cell DNA synthesis and mitosis in male and female mice were stimulated by TCE; these effects may be in part responsible for the transformation of liver cells. The authors noted, however, that these effects appeared to be associated with a mature hepatocyte population.
In a study of the effects of TCE on bile acid transport in isolated rat hepatocytes, Bai and Stacey (1993) found that TCE caused a dose-related suppression of initial rates of uptake of cholic acid and taurocholic acid with no significant effect on enzyme leakage and intracellular potassium ion contents. The authors believed their data supported the contention that it is an interface with bile acid uptake, rather than actual cell damage, that is responsible for TCE-induced increases in serum bile acids (SBA). The authors further believed their data to be data consistent with a rise in SBA concentrations in the systemic circulation being explained by an impairment of transport mechanisms for the bile acids, as seen in similar studies (Franco, 1991; Kukongviriyapan et al., 1990). In a related study, Hamdan and Stacey (1993) found TCE to have a rapid and specific effect on SBA levels by a mechanism other than liver cell damage. In rats treated with TCE via injection or inhalation, SBA were found to be elevated in response to TCE, but at doses below those at which other parameters of liver function were increased (Wang and Stacey, 1990).
Bioactivation of TCE via B-cysteine lyase has been reported to be required for cytotoxicity to liver tissue after in vivo exposure (Nichols et al., 1992; Forkert et al., 1985; Kowalski et al., 1985). In a study in which TCE was orally administered, Borzelleca et al. (1990) found that, in combination, carbon tetrachloride and TCE displayed a synergistic (supraadditive) response for peak plasma enzyme activity.
Neurological Effects
In the past TCE was used as a general anesthetic in dental and surgical procedures; however, due to reported complications of the cranial nerves (Jackson, 1934; Hewer, 1943; Humphrey and McClelland, 1944; Carden, 1944; Enderby, 1944; Buxton and Hayward, 1967) its use as an anesthetic was restricted by the American Medical Association in 1936 (Mitchell and Parsons-Smith, 1969). Following its introduction as a degreasing agent, reports of neurological sequela began to appear in the literature (Mitchell and Parsons-Smith, 1969; Hunter, 1944; Flinn, 1946; Hartgarten et al., 1961; Plessner, 1915). Stuber (1931) described 284 cases, of which 182 were chronic and had presented either with a functional neurosis or with cranial nerve involvement. Later reports stressed organic mental deterioration as the most serious complication (Grandjean et al., 1955). Since then, numerous epidemiologic studies have suggested a possible link between occupational exposures to solvents and dementia (Arlien-Soborg et al., 1979; Axelson et al., 1976; Bruhn et al., 1981; Elofsson et al., 1980; Hanninen et al., 1976; Husman, 1980; Lindstrom, 1980; Mikkelsen, 1980; Struwe, 1980) or encephalopathy (Barret et al., 1984; Ruijten et al., 1991; Rasmussen et al., 1993). Shalat et al. (1988), however, reported no apparent increased risk of Alzheimer's disease following occupational exposure.
Chronic signs and symptoms reported following TCE exposure include fatigue, dizziness, lethargy, lightheadedness, weakness, sleepiness, nausea, blurred vision, numbness and tingling in arms and legs, poor concentration, emotional lability, poor short-term memory, headache, confusion, muscle cramps, difficulty solving sequential problems, drowsiness, abnormal electroencephalogram, and deficits in psychomotor performance (Hartman, 1988; NIOSH, 1973, 1977ab; Struwe and Wennberg, 1983; Baker et al., 1985; Bowler et al., 1991; Defalque, 1961; Hane et al., 1977; Arlien-Soborg et al., 1979, 1981; Nomiyama and Nomiyama, 1977; Nomiyama, 1978; Stewart et al., 1970; Landrigan et al., 1987; Mikiskova and Mikiska, 1968; Konietzko et al., 1976; Stopps and McLaughlin, 1967; Vernon and Ferguson, 1969; Salvini et al., 1971; Odkvist et al., 1983; Yamakaga and Ishikawa, 1982; Seppalainen and Annti-Poika, 1983; Bardodej and Vyskocil, 1955). Several reports suggest that non-accidental industrial exposure to TCE may also result in some nerve impairment (Barret et al., 1984, 1987; Ruijten et al., 1991; Seppalainen et al., 1978).
Various tests have been used to attempt to assess the level of TCE neurotoxicity in humans. Beginning in the late 1960s adverse effects on performance in behavioral tests were reported following acute experimental exposure to TCE (Rasmussen et al., 1993b, Stopps and McLaughlin, 1967; Vernon and Ferguson, 1969). Since then, numerous neuropsychological and behavioral studies (Olson et al., 1981; Elofsson et al., 1980; Baker and Fine, 1986; Hane et al., 1977; Valciukas et al., 1985; Bowler et al., 1986; Ryan et al., 1987; Triebig et al., 1988; Knave et al., 1978; Gregersen et al., 1984; Hanninen et al., 1976; Winneke, 1982), as well as various experimental models (Goldberg et al., 1964; Grandjean, 1960; Ikeda et al., 1980; Kulig, 1987), have been used in the study of the disorder of neurobehavioral function caused by the exposure to TCE. Examples of tests in which TCE-exposed individuals have differed significantly from non-exposed individuals include Dynamometer, Fingertapping, and simple and choice reaction time tests (Bowler et al., 1991), visual suppression test, the saccade test, the interrupted speech test, and responses to frequency glides (Odkvist et al., 1982, 1987), sural nerve conduction velocity, sural refractory period, and masseter reflex (Ruijten et al., 1991), perception, memory, reaction time, and dexterity tests (Salvini et al 1971), blink reflex (Feldman et al., 1992), tachistoscopic perception, immediate memory, and complex reaction time (Salvini et al., 1971), the Romberg test (Stewart et al., 1970), the Mental Control test (Digit Span and Visual Memory Span subtests) and the Wechsler Memory Scale Index (Bowler et al., 1991).
Decreased reaction time speed (Eskelinen et al., 1986; Gamberale, 1985; Gyntelberg et al., 1986; Mikkelsen, 1980; Juntunen et al., 1980; Grasso et al., 1984) and decreased visuomotor and psychomotor speed and visuospatial function (Hanninen, 1979; Elofsson et al., 1980; Mikkelsen, 1980; Harkonen et al., 1978; Seppalainen et al., 1978; Lindstrom, 1980; Hanninen et al., 1976) have also been reported following exposure to solvents, such as TCE. The apparent threshold for CNS effects is in the range of 81-300 ppm (Brown et al., 1990; Fielder et al., 1982). Exact dose-response relationships in humans are not known (Antti-Poika, 1982), although it is believed that the intensity of the exposure determines the degree of damage. Peripheral nervous system effects have also been associated with exposure to specific solvents such as TCE (Spencer et al., 1980; Ruff et al., 1981; Johnson, 1987; Jung-Der Wang et al., 1986). In addition, ethanol consumption has been found to potentiate TCE-related CNS effects (Candura and Faustman, 1991; Ferguson and Vernon, 1970; Savolainen, 1980). It should be noted that some studies have not found CNS effects following TCE exposure (Holonen et al., 1986; Maizlish et al., 1985; Cherry et al., 1985; Fielder et al., 1982; Stewart et al., 1974; Koniezko et al., 1976; Ettema and Zielhuis, 1975; Gamberale et al., 1976).
The neurotoxicity of TCE is manifested mainly in the cranial nerves, predominantly the trigeminal, but dysfunction of cranial nerves I, VII, X, and XII have also been reported (Rasmussen et al., 1993; Konietzko et al., 1975, 1979; Humphrey and McClelland, 1944; Vernon and Ferguson, 1969, Byers et al., 1988; Lawrence and Partyka, 1981; Feldman et al., 1985; Spencer and Schaumburg, 1985). Although the actual mode of action of TCE has not been identified, several mechanisms, such as demyelination (Barret et al., 1992), axonal or neuronal alterations due to metabolic dysfunctions (Savolainen et al., 1977; Kjellstrand et al., 1980; Haglid et al., 1982), viral action (Humphrey and McClelland, 1964; Cavanagh and Buxton, 1989), and receptor alterations (Feldman et al., 1970) have been proposed. Other evidence, such as disturbed physical-chemical properties of the nerve membrane (Juntunen, 1986; Barret et al., 1992), variations in the activity in one or more of the phosphoinositide linked neurotransmitter systems (Barret et al., 1992; Subramoniam et al., 1989), a loss of myelin in the brain stem and hippocampus, as well as effects on myelin sheaths in the temporal and occipital cortex, spinal cord, and cranial nerves (Isaacson and Taylor, 1989; Spohler et al., 1987; Barret et al., 1991; Buxton and Hayward, 1967; Baker, 1958; Isaacson et al., 1990), modification of lipid content of the trigeminal nerve (Barret et al., 1992), peroxidation effects in the brain (Kyrklund et al., 1983), degeneration of the distal long, myelinated sensory fibers (Fagius and Gronquist, 1978; Feldman et al., 1992; Feldman and Lessell, 1967), also indicate TCE is a neurotoxicant.
TCE uptake in the brain has also been demonstrated (U.S. Environmental Protection Agency, 1984); however, researchers have noted that different areas of the brain react differently to this exposure (Haglid et al., 1982; Kyrklund et al., 1984ab). Biochemical changes which occur in the brain as a result of this uptake include a decrease brain RNA content (Savolainen et al., 1977), a decrease in soluble proteins (Haglid et al., 1980) and an increase in dopamine and norepinephrine synthesis (Patrick et al., 1980).
TCE's neurotoxicity has also been proposed to be related to its metabolites. Chlorinated epoxides, similar to the first intermediate metabolite of TCE, have been shown to bind to CNS macromolecules, including neurofilaments, resulting in demyelination (Savolainen, 1977). Also, recent evidence for the production of free radicals from metabolites of TCE, such as trichloroethanol, in both brain and liver microsomes could perhaps account for the CNS effects seen (Gonthier and Barret, 1989; Barret et al., 1992).
There are some studies indicating that CNS effects related to TCE exposure may in actuality be due to decomposition products, especially dichloroacetylene (DCA) in addition to metabolites of TCE (Buxton and Hayward, 1967; Defalque, 1961; Ertle et al., 1972; Bonse and Henschler, 1976; Leighty and Fentiman, 1981; Cavanaugh and Buxton, 1989; Humphrey and McClelland, 1944). According to Barret and coworkers (1992), the rationale for proposing DCA as the causative agent for neurotoxicity is based the following observations: mixtures containing DCA and TCE are more toxic than pure TCE (Siegel et al., 1971); the human clinical picture of DCA exposure is very close to that of TCE exposure (Henschler et al., 1970); and severe pathological trigeminal nerve lesions can result from inhalation of DCA (Reichert et al., 1976), while pure TCE exposure produces less severe lesions (Adams et al., 1952; Baker, 1958). Finally, DCA is a recognized neurotoxicant, as is TCA (Defalque, 1961; Barret et al., 1992; Hamdan and Stacey, 1993).
Occupational studies and case reports have also shown TCE to be a neurotoxicant (Morrow et al., 1990; McCunney, 1988; Barret et al., 1982, 1984; Buxton anf Hayward, 1967; Feldman and Lessell, 1967; Feldman et al., 1985; Lawrence and Partyka, 1981; Martinelli et al., 1984; Mitchell and Parsons-Smith, 1969; Plessner, 1915; Sagawa et al., 1973). A consistent correlation between exposure to organic solvents and two cognitive disturbances, decreased concentration ability and memory difficulties, was found for both workers and retirees following occupational exposures to mixed solvents (Hein et al., 1990).
In a historical cohort study of metal degreasers, Rasmussen and coworkers (1993b) found a highly significant dose-response relation between solvent exposure and clinical neurological signs of motor dyscoordination--a finding that was retained after multivariate control of relevant confounders. Although no significant cranial nerve dysfunction was found, histologically verified symmetrical sensory-motor peripheral neuropathy was reported. The authors noted several shortcomings of the study, however, including a short follow up period, a possible healthy worker bias, and difficulty in obtaining accurate information on alcohol consumption. In addition, age was a problematic confounder in that it was strongly correlated to cumulative exposure; genuine age adjustment could only be done by the relatively few old workers with low cumulative exposure. In another study of this cohort, Rasmussen et al. (1993c) found a significant dose-response relation between increasing cumulative solvent exposure and impaired psychometric test performance. After control for confounding factors the strongest associations were found for the acoustic-motor function test, the Paced Auditory Serial Addition test, and the visual gestalt test.
Neurological impairments have also been reported following exposure to TCE in drinking water. In Woburn, MA, CNS anomalies were found in children born after 1970 (Lagakos et al., 1986). Also in Woburn, Feldman et al. (1992) found reflex abnormalities in 92.8% of the group; a diagnosis of peripheral neuropathy was made in 75% of the group. Individual cases of abnormalities in proximal motor amplitude, distal sensory amplitude, distal motor and sensory latency, and prolonged direct responses of the trigeminal-facial blink reflex circuit were also reported. Encephalopathy, characterized by deficits in the behavioral domain, were also reported for other individuals exposed to TCE and other contaminants in their drinking water (Feldman et al., 1992). Kilburn and Warshaw (1993) found statistically significant impairments of neurophysiological and neuropsychological status in a self-selected population potentially exposed to TCE-contaminated water for 1 to 25 years. Finally, neurological impairments were reported for 21 of 22 persons exposed to 800-1400 ppb TCE for 5-20 years (Bernad et al., 1987).
The CNS is also a target of TCE exposure in animals (Brown et al., 1990; Fielder et al., 1982; Baker, 1958; Bartonicek and Brun, 1970), even at levels as low as 200 ppm (Savolainen et al., 1977) to 400 ppm (Grandjean, 1966). CNS toxicity in animals is characterized by ataxia, lethargy, hindlimb paralysis, and convulsions; irreversible CNS lesions with accompanying behavioral changes have been induced in several species by chronic exposure to TCE (Kjellstrand 1980, 1981ab).
Arito and coworkers (1993) reported abnormal EEG activity, incapacitation of postural maintenance, decreasing waking time, lowered heart rate, and increased numbers of bradyarrhythmic episodes in electrode-implanted and freely moving rats exposed to 3000 and 6000 ppm TCE. Studies of the rat mental nerve found the myelin thickness in the largest myelinated fibers to be somewhat decreased by TCE, whereas the myelin thickness in the smallest fibers was significantly increased by TCE (Barret et al., 1991; Barret et al., 1992). As indicated previously, the reason for this variability is unknown, but has also been seen in various brain areas (Haglid et al., 1982; Kyrklund et al., 1983, 1984ab). In vitro studies also support the neurotoxicity of TCE. For example, TCE has been shown to decrease squid axonal potentials in proportion to the concentration of TCE (Shrivastav et al., 1976). In an animal study, Kossler (1991) reported that TCE depressed the force development of both twitch and tetanic tension of isolated muscles, prepared from frogs and rats, in a dose-dependent manner. The results suggested that the interaction of TCE with membrane sites is responsible for Ca2+ release for contractile processes.
In many species these effects have not been reported to be persistent (Rebert et al., 1991; Kjellstrand et al., 1980; Kulig, 1987). In addition, some animal studies have found TCE to be either non-neurotoxic or weakly neurotoxic (Rebert et al., 1991; Kulig, 1987; Dorfmueller et al., 1979).
Speech Impairment
As previously mentioned, TCE produces selective analgesia of the face in the area of the trigeminal nerve (Glaser, 1983); that is, the nerve providing sensory function for the face, teeth, mouth, and nasal cavity, and motor function for the muscles of mastication. TCE has also been used as an inhalant analgesic-anesthetic for dental procedures because of its recognized analgesic properties (Firth and Stuckey, 1945); however, due to residual neuropathy, characterized by nerve damage (Camden, 1994; Dillon, 1959; Enderby, 1944; Hewer, 1943; Humphrey and McClelland, 1944; McAuley, 1943), TCE is no longer employed as a general anesthetic or an analgesic. Neuropathy of this type is characterized by facial numbness (indicating damage to cranial nerve VII), and jaw weakness and facial discomfort (indicating damage to cranial nerve V, which is the trigeminal nerve) which can persist for several months (Buxton and Hayward, 1967; Feldman et al., 1970). In addition, Feldman et al. (1970) reported a patient with symptoms, including extensive anesthesia of the face, oral cavity, and tongue mucosa, similar to those reported by Plessner in 1915.
Trigeminal nerve impairment is frequently seen in chronic trichloroethylene intoxication (Barret et al., 1987; Feldman et al., 1988, 1992). Facial hypesthesia, when present, is typically predominant in the mandibular and maxillary nerve areas and may or may not be associated with absent reflexes. Chronic exposure in the workplace has also been associated with damage to cranial nerves in several cases (Barret et al., 1982, 1984, 1987; Cavanaugh and Buxton, 1989; Lawrence and Partyka, 1981; Martinelli et al., 1984; Mitchell and Parsons-Smith, 1969) and has more recently been evaluated by means of the masseter and blink reflex (Ruijten et al., 1991). Reported neuropathies can persist for several months (Buxton and Hayward, 1967; Feldman et al., 1970). Persons who have died from overexposure have shown degeneration of cranial nuclei in the brain stem (Buxton and Hayward, 1967).
Specific impairments of verbal ability have also been reported. Bowler and coworkers (1991) used the California Neuropsychological Screening Battery-Revised to test a group of former microelectronics assembly plant workers and found significantly lower performance on tests of verbal ability. Neurological disorders resembling dementia, with loss of cognitive and verbal ability, have been described as an effect of more chronic and severe stages of exposure (Baker and Fine, 1986; Gregersen et al., 1987; Johnson, 1987; Lindstrom et al., 1982; White and Feldman, 1987). Although word knowledge (verbal ability) is generally considered to deteriorate only in advanced stages of neurotoxic disease (Ron, 1986).
Trigeminal nerve impairment has also been reported in populations exposed to TCE in drinking water. Residual damage to facial and trigeminal nerves, measured by a decreased blink reflex (indicating damage to cranial nerves V and VII), was reported 6 years after exposure in 28 persons in Woburn, Massachusetts, who had alleged exposure to TCE in their drinking water (Feldman et al., 1988), however, dose-response relationships could not be determined. For other individuals exposed via drinking water, language/verbal function was almost always within expected limits (Feldman et al., 1992). In the Woburn, MA, population, analyses restricted to births occurring after 1970 revealed increases in oral/cleft anomalies (Lagakos et al., 1986), which could potentially contribute to speech impairments.
Trigeminal nerve impairment is not as evident in animals exposed to TCE (Adams et al., 1952; Baker, 1958; Bartonicek and Brun, 1970). In a morphometric study of the effects of TCE and DCA on the mental nerve (a branch of the trigeminal leading to the chin and lips), Barret et al. (1992) reported that both compounds altered the external and axonal diameters and myelin thickness, but had only a slight effect on fatty acid content in the brain. The authors noted that TCE exposure increased the fatty aldehydes in the trigeminal nerve by 18%, compared to 64% for DCA. It should be noted that some authors (Spencer and Schaumburg, 1985; Lash and Green, 1993; Reichert et al., 1976) have postulated that dichloroacetylene, a breakdown product of TCE, is probably responsible for trigeminal nerve toxicity.
Hearing Impairment
As early as 1955, hearing loss has been reported in association with exposure to solvents such as TCE (Rebert et al., 1991). In 1971, Tomasini and Sartorelli reported symmetrical bilateral eighth cranial nerve deafness, with subsequent recovery, in a patient who had been overexposed to TCE during operation of a dry-cleaning unit (U.S. Environmental Protection Agency, 1985). Other examples of deafness following occupational exposure to TCE (Mitchell and Parsons-Smith, 1969) and organic solvents, including TCE, with noise (Barregard and Axelson, 1984; Bergstrom and Nystrom, 1986) have been reported. In a study of 40 TCE-exposed workers, Szulc-Kuberska et al. (1976) reported 26 of the 40 had bilateral, sensorineural hearing loss. Workers with long-term occupational to solvents, including TCE, were reported to have significantly abnormally distorted speech audiometry results (Odkvist et al., 1987).
Flanagan et al. (1990) reported tinnitus in patients following acute poisoning with organic solvents from consumer products. Morrow et al. (1992) determined that the latencies of the N250 and P300 components of the auditory event-related potential were significantly delayed in organic solvent-(including TCE) exposed patients when compared with those in normal controls. This is in keeping with the findings of El Massioui and coworkers (1986). The delay in N250 and P300 provides evidence that solvent exposure slows central system mechanisms that evaluate and/or process relevant auditory stimuli. In addition, complaints such as fewer word associations and increased misunderstanding have been reported in workers exposed for longer than 15 years to TCE (Grandjean et al., 1955). Under conditions of longer exposure, complaints such as vertigo, fatigue, and headache and short-term memory loss, fewer word associations, and increased misunderstanding occurred with higher frequencies in workers exposed for up to 15 years to a mean of 167 parts per million (ppm) TCE than in lower exposure categories. Workers with discontinued exposure, however, were not evaluated (Grandjean et al., 1955).
TCE has been shown to be ototoxic in rats (Pryor et al., 1987, 1991; Rebert and Becker, 1986; Rebert et al., 1983, 1991, 1993). Hearing loss in rats has been found to be restricted to the mid-frequencies (4-20 kHz) (Crofton et al., 1993) at a threshold concentration of 2,000 ppm (Rebert et al., 1991). Intensity-amplitude function shows the greatest reduction at 16 kHz (Rebert et al., 1991). Another study found an antagonistic interaction between TCE and noise at varying levels and durations of exposure to solvents, including TCE (Kurnayeva et al., 1986). Finally, the vestibulo-oculomotor system has been found to be affected in animals (Larsby et al., 1976; Odkvist et al., 1977, 1980, 1987).
Gastrointestinal Effects
Little is known about the gastrointestinal effects of TCE exposure. Fredriksson et al. (1989) reported an especially high risk for colon cancer among dry cleaners exposed to TCE. Pneumocystosis of the colon and/or intestine may also be related to TCE exposure (Sata et al., 1987; Yamaguchi et al., 1985). In a worker population exposed to many solvents and heavy metals, Dubrow and Gute (1987) found excess stomach cancer (PMR=174) in females and excess peptic ulcer (PMR=235); since death certificates were used, their limitations were noted. Sparks and Wegman (1980) also found an elevated PMR for stomach cancer in male jewelry polishers exposed to TCE. Logue and coworkers (1985) reported "significantly more" exposed than control individuals experienced diarrhea following exposure to TCE-contaminated water. Nausea and vomiting have been reported following TCE exposure; however, it is likely these symptoms are secondary to vestibular effects.
Urinary Tract Disorders, Including Prostate Trouble
Urinary tract disorders were more common in many subpopulations in the TCE Subregistry than in the NHIS population; however, few studies are available that investigate the potential impact of TCE exposure on the urinary tract. A significant excess of urinary tract tumors was reported for dry cleaners exposed to TCE for up to 24 years (Axelson 1985, 1986, et al., 1978, 1984). In a study of workers exposed to solvents in the paint industry, Lundberg (1986) reported that three cleaners had died from infectious urinary tract disease, in comparison to 0.2 deaths expected from all genitourinary diseases. Although the population was small and very heavily exposed, the author believed this association might possibly indicate a modifying effect on the prognosis of urinary tract morbidity from solvents. One study is available that suggests an association between cumulative exposure to solvent-contaminated well water and increased urinary tract infection in children (Lagakos et al., 1986), however exposure was to a number of solvents and no clinical tests were run on the urine.
Urinary tract infection have been noted to occur more frequently in diabetics than in nondiabetics. (Diabetes was reported more frequently in the TCE Subregistry population than in the NHIS population.) The prevalence of infection is higher in female diabetics (18% to 41%) than in male diabetics (1% to 18%) (Kass, 1962; Vejlsgaard, 1966). Bladder paralysis and urinary retention, which contribute to infections, have also been reported with diabetes (Herman and Teutsch, 1986; Sepe and Teutsch, 1988).
Immune System Effects
Some of the conditions reported in excess by the TCE Subregistry population when compared with the NHIS population may have an immune component. These conditions include arthritis, anemia, skin conditions, and diabetes, and infections of the urinary tract, ear, kidney, and respiratory system. For example, a case study involving excessive skin contact showed that 1 man out of 11 studied may have had an allergic response to TCE (Nakayama et al., 1988). As mentioned previously, Dubrow and Gute (1987) found excess deaths due to diseases of the skin and subcutaneous tissue among solvent-exposed (including TCE-exposed) workers; bullous pemphigus and bullous pemphigoid, which both appear to be autoimmune in nature (Jordan, 1979ab), were particularly noted.
Although neither the etiology nor pathogenesis of progressive systemic sclerosis (scleroderma) has been established, this disease has been associated with a wide variety of seemingly unrelated compounds, including exposure to organic solvents (Rush et al., 1984; Walder, 1965, 1983; Ward et al., 1976). Flindt-Hansen and Isager (1987) reported three cases of scleroderma which developed after occupational exposure to TCE and trichloroethane (TCA). Lockey et al. (1987) reported a case of progressive scleroderma that developed in a previously healthy 47-year-old woman who was occupationally exposed to TCE. Renal and skin biopsies were consistent with progressive systemic sclerosis. Saihan et al. (1978) reported scleroderma, pigmentation, and Raynaud's phenomenon in a middle-aged man following prolonged exposure to TCE. Other cases of progressive systemic sclerosis have also been reported as being TCE-induced (Yanez et al., 1992; Yamakage and Ishikawa, 1982; Czirjak et al., 1989, 1993; Haustein and Ziegler, 1985; Perry, 1992; Fleming et al., 1991).
Significantly increased symptoms of lupus erythematosus were reported in the Tucson, Arizona self-selected study population. Women in the group potentially exposed to TCE in drinking water reported more symptoms than the controls (Kilburn and Warshaw, 1992). The authors indicated that antinuclear antibodies had been induced in this population.
The immunological aspects of both diabetes and TCE exposure are of interest. Type I, insulin-dependent diabetes (IDDM), which is typified by an abrupt onset during the first two decades of life, appears to have an autoimmune basis (National Diabetes Data Group, 1984). Risk of development of IDDM is highly associated with the human leukocyte antigen (HLA) system. The HLA system appears to be related to chronic disorders with unclear etiologies that may have an autoimmune basis. Research in IDDM has lead to the discovery that antibodies appear to develop in the pancreas in individuals who develop diabetes (Irvine et al., 1978; Lernmark et al., 1981). Of particular relevance is that these autoantibodies, which are specific to the insulin secreting beta cells, seem to appear prior to the onset of the disorder suggesting that pathological damage is occurring before the onset of symptoms (Gorsuch et al., 1982; MacCuish et al., 1974; Yoon and Ray, 1985).
IDDM is characterized by both cellular and humoral immune changes, including increased numbers of activated T-lymphocytes expressing the HLA-DR antigen on their cell surface, decreased levels of complement C4, alterations in both the number and function of immunoregulatory T-lymphocytes and natural killer cells, and production of islet cell autoantibodies at the time of clinical onset (Lo et al., 1991; Scherbaum, 1992). Ninety percent of IDDM patients carry HLA type DR3, DR4, or both (Drash, 1990). It is interesting to note that sclerosis, which has been associated with TCE exposure (Flindt-Hansen and Isager, 1987; Czirjak et al., 1989; Yanez et al., 1992), has HLA-DR5 as a marker of susceptibility to the disease; HLA-B8 and -DR3 have been associated with progression of the disease (Black et al., 1986; Yanez et al., 1993).
Given the current speculation on the association of diabetes and immunological abnormalities, it is of interest to note that immunological abnormalities were found in 23 adults in Woburn, Massachusetts, who were allegedly exposed to TCE contaminated water and who were family members of children with leukemia (Byers et al., 1988). These immunological abnormalities, tested for 5 years after exposure ceased, included persistent lymphocytosis, increased numbers of T-lymphocytes, and a depressed helper: suppressor T-cell ratio. Auto-antibodies, particularly antinuclear antibodies, were detected in 11 of 23 adults tested. Interpretation of this study is limited, however, due to the possible bias in identifying risk factors for immunological abnormalities in a small, non-population-based group identified through association with patients with leukemia.
Other studies have reported changes in lymphocyte subpopulations in solvent-exposed workers that are similar to those found in states of immunodeficiency and immunogenetic forms of aplastic anemia (Denkhaus et al., 1986). In contrast, Stewart et al. (1970) reported that humans acutely exposed to TCE exhibited no adverse hematological effects on blood cell counts, sedimentation rates, serum lipid levels, serum proteins, or serum enzymes.
The immunotoxic effects of TCE were evaluated in CD-1 mice following exposure for 14 days by gavage or for 4 and 6 months in drinking water (Sanders et al., 1982). The investigators concluded that none of the effects were remarkable, but that both humoral and cell-mediated immunity are sensitive to TCE; however, the results of this study are considered inconclusive (ATSDR, 1993). It is interesting to note that this study found females to be more susceptible to immune alterations than males--a finding supported by Henschler and coworkers (1980) and Maltoni and coworkers (1986). In another study, mice exposed to TCE for 3 hours at 10 ppm had increased susceptibility to experimentally induced respiratory streptococcus infection (Aranyi et al., 1986).
The in vivo functions of natural immunity are thought to include immune surveillance against tumors and the early protection against viral infections (Burton, 1986). The liver has only recently received attention as a tumor cell killing organ, mainly due to the observation that the liver contains more natural killer (NK) cells than the peripheral blood and harbors Kupffer cells (Malter et al., 1986). In a study of immune function in rodents, Wright and coworkers (1991) found the highest TCE dose resulted in inhibition of hepatic NK activities in both rats and mice. High dose TCE in vitro resulted in marked inhibitions of NK activities in all groups of effector cells. At the lowest in vitro dose mouse hepatic NK activity was still inhibited. Significant atrophy of the spleen was reported in mice; spleen cell number was reduced in rats. It should be noted, however, that none of the animal treatments resulted in a significant inhibition of either T cell-mediated immunity or humoral immunity.
Cancer
The potential carcinogenicity of TCE is still in question. Currently, some researchers believe that TCE exerts its carcinogenicity through its metabolites, such as trichloroacetic acid (TCA), by means of peroxisome proliferation (Prout et al., 1985; Bruckner et al., 1989; Hamdan and Stacey, 1993; Goel et al., 1992; DeAngelo et al., 1990; Elcombe et al., 1985). Other researchers (Bull et al., 1993; Brown et al., 1990; Conway et al., 1989) believe this response to be of no significance to human risk assessment. TCE and/or its metabolites may also interact with cellular macromolecules and interfere with membrane signal transduction (Stott et al., 1982; Banki and Anders, 1989; Subramoniam et al., 1989; Goel et al., 1992). The literature is also varied on the mutagenicity of TCE, containing both positive (Brown et al., 1990) and negative reports (Fielder et al., 1982).
Hematolymphatic. Initial concerns of cancer in humans following TCE exposure stemmed from studies showing excesses of hematolymphatic malignancies (Blair et al., 1979). (Selected studies of cancer outcomes can be found in Tables 4 and 5). Two studies that reviewed mortality statistics for the period 1969 through 1979 for a population in Woburn, Massachusetts, that drank water from a domestic water supply reported to be contaminated with industrial solvents (including TCE, tetrachloroethylene, and 1,2-trans-dichloroethylene) concluded that there was a significantly elevated rate of childhood leukemia (Kotelchuck and Parker, 1979; Parker and Rosen, 1981), however, etiologic factors were not identified.
Another study (Lagakos et al., 1986) found a potential association between ingestion of drinking water contaminated with solvents in Woburn and increased risk of childhood leukemia, particularly acute lymphocytic leukemia. Other researchers (MacMahon, 1986; Prentice, 1986; Rogan, 1986; Swan and Robins, 1986; Wittemore, 1986) reevaluated the data and did not concur because of the numerous problems associated with this study, including residents' exposure to a mixture of chemical contaminants and the use of inadequate statistical methods. Another study of the Woburn population also found an unusually high incidence of leukemia in children
TABLE 4. Cancers associated with TCE exposure.
| Cancer type | Reference | Exposure Source |
| Leukemia | Kotelchuck and Parker 1978
Parker and Rosen 1981 Lagakos et al., 1986 Byers et al., 1988 Fagliano et al., 1990 Thomas et al., 1985 |
Water
Water Water Water Water Occupational |
| Bladder | Wilkins and Comstock, 1981
Mallin 1990 Cantor et al., 1987 Axelson 1986 |
Chlorinated water
Water Chlorinated water Occupational |
| Urinary tract | Wilkins and Comstock, 1981
Axelson 1985, 1986 Axelson et al., 1978, 1984 |
Chlorinated water
Occupational Occupational |
| Breast | Wilkins and Comstock, 1981 | Chlorinated water |
| All | Zoloth et al., 1986 | Occupational |
| Colorectal | Zoloth et al., 1986
Spiegelman and Wegman 1985 Fredriksson et al., 1989 Maizlish et al., 1988 |
Occupational
Occupational Occupational Occupational |
| Lymphatic | Zoloth et al., 1986
Axelson et al., 1984 Axelson 1986 Maizlish et al., 198 8 |
Occupational
Occupational Occupational Occupational |
| Hematopoietic | Zoloth et al., 1986 | Occupational |
| Liver | Wilkins and Comstock, 1981
Zoloth et al., 1986 Hernberg et al., 1984, 1988 Dubrow and Gute, 1987 Hardell et al., 1984 Stemhagen et al., 1983 Blair et al., 1979 |
Chlorinated water
Occupational Occupational Occupational Occupational Occupational Occupational |
| Pancreas | Zoloth et al., 1986
Thomas et al., 1985 |
Occupational
Occupational |
| Skin | Maizlish et al., 1988 | Occupational |
| Brain | Maizlish et al., 1988 | Occupational |
| Stomach | Dubrow and Gute, 1987
Sparks and Wegman, 1980 |
Occupational
Occupational |
| Testicular | Garland et al., 1988 | Occupational |
| Multiple myeloma | Lundberg 1986 | Occupational |
TABLE 5. Studies reporting negative cancer findings in association with TCE exposure.
| Reference | Cancer Type |
| Shindell and Ulrich, 1985
Zoloth et al., 1986 Axelson 1986 Axelson et al., 1978 Tola et al., 1980 Paddle 1983 Austin et al., 1987 Brown and Kaplan, 1987 Duh and Asal, 1984 Katz and Jowett 1981 Malek 1979 Harrington et al., 1990 Spirtas et al., 1991 Novotna et al., 1979 |
Total
Bladder, lung, leukemia Total Total, liver Total, liver Liver Liver Liver Liver Liver Total Renal Total Liver |
exposed in utero (Byers et al., 1988). However, the study was also found to be flawed (ATSDR, 1993).
An ecologic study of persons exposed to VOCs, particularly TCE, in drinking water supplies (Fagliano et al., 1990) found the standardized incidence ratio of leukemia was elevated for females in towns in the highest of three exposure categories. No association was observed in males in any of the exposure categories. The increase in risk among females with increasing level of contamination appeared to be distributed evenly among all age groups. The observed association appeared to suggest that drinking water contaminated with VOCs might increase the incidence of leukemia among exposed females, but caution was advised in the interpretation of the results due to uncertainties inherent in ecologic studies.
Elevated frequencies of deaths from leukemia have been reported among white maintenance workers in the corn wet-milling industry who were exposed to multiple chemicals, including solvents (Thomas et al., 1985). In a study of workers exposed to TCE in the paint industry, Lundberg (1986) reported three workers had died from multiple myeloma (0.6 expected) and related the excess number of deaths to solvent exposure. In a study of commercial pressmen, Zoloth et al. (1986) found a significantly elevated risk of cancers of the lymphatic and hematopoietic system, with non-Hodgkin's lymphoma responsible for much of the excess. Pressmen who had been employed for 20 or more years, however, had no excess risk of leukemia. Axelson (1986) found a significant excess of lymphomas in a male cohort occupationally exposed to unspecified levels of TCE. White women occupationally exposed to TCE and other solvents were also reported to have increased mortality due to multiple myeloma and non-hodgkin's lymphoma (Spirtas et al., 1991). Finally, an excess number of deaths due to lymphosarcomas was reported for white retired highway workers exposed to TCE and other chemicals (Maizlish et al., 1988).
Urinary tract. In a nonconcurrent prospective study of persons who used chlorinated surface water as a domestic water source for 12 years versus persons who used unchlorinated well water as a domestic water source, Wilkins and Comstock (1981) reported that incidence rates for cancer of the bladder among men was nearly twofold for persons exposed to the chlorinated water. A comparative mortality study also suggested an association of chlorinated water with cancer of the urinary tract.
Mallin (1990) reported a high incidence of bladder cancer in a section of Winnebago County in northwest Illinois. One of four drinking water wells had been closed in that area due to contamination with TCE, tetrachloroethylene, and other solvents. The reported excess in the number of bladder cancers was primarily confined to one town in which standardized incidence ratios were significantly elevated in males (1.7) and females (2.6). Investigation of this cluster is ongoing.
Previous studies have also detected associations between chlorinated water and genitourinary and gastrointestinal cancers, but most of the studies have been ecologic in design (Shy, 1985; Wilkins et al., 1979). One case control study, however, detected a two fold relative risk for bladder cancer cases with 40 or more years of exposure to chlorinated surface water, after adjusting for known risk factors (Cantor et al., 1987). Excess numbers of bladder cancers have also been reported for males occupationally exposed to unspecified levels of TCE (Axelson, 1986).
Kluwe et al. (1984) found preliminary evidence that suggested an association between organic chemical exposure and cancers of the urinary tract in humans. Many literature reports, indicating that short-chain halogenated hydrocarbons appear to have a propensity for causing low incidence of renal tubular carcinoma in exposed rodents, tend to support these findings. Comparative analyses of the NTP/NCI studies did not indicate consistent sex or species differences in the nonneoplastic chronic toxic response, but chemically induced urinary tract cancers occurred more commonly in rats than in mice and chemically induced cancers of the kidney occurred more commonly in males than in females. Viewed collectively these data may indicate a potential for organic chemicals, especially halogenated hydrocarbons and aromatic amines, to produce chronic kidney injury in humans and other mammalian species. Harrington et al. (1990) found no relation between occupational exposures to solvents and renal cancer. However, the statistical power of this observation has been questioned. Finally, no excess risk of bladder cancer was seen for commercial pressmen occupationally exposed to solvents, including TCE, for 20 or more years (Zoloth et al., 1986).
Total cancers. Results from occupational studies have also been mixed. Following a report of a cancer cluster, Zoloth et al. (1986) initiated a proportionate analysis of cause of death in 1,401 commercial pressmen who were occupationally exposed to solvents. They found a significantly elevated risk of all cancers.
An update of the Axelson et al. (1978) epidemiologic study of occupational exposures, which evaluated an expanded cohort of 1,424 men (levels of TCE not specified), found a lower than expected incidence of total cancer mortality, possibly due to the "healthy worker effect" (Axelson, 1986). Malek (1979) also did not find significant increases in the overall incidence of cancer following occupational exposure to TCE. These studies, however, were limited by relatively small numbers of subjects and lack of lengthy follow-up periods; thus, such studies would not be expected to detect uncommon cancers or weak carcinogens (ATSDR, 1993).
Spirtas et al. (1991) investigated whether working with solvents, particularly TCE, posed any excess risk of mortality. Significant deficits occurred for mortality from all causes and all malignant neoplasms in solvent-exposed workers. Other researchers have also reported negative findings for overall cancer (Shindell and Ulrich, 1985; Tola et al., 1980; Novotna et al., 1979).
Colorectal. Spiegelman and Wegman (1985) reported hypotheses for colon cancer risk in males with potentially high exposure to solvents, abrasives, and fuel oil, and those with jobs with high stress, while hypotheses emerged for females with potentially high exposure to dyes, solvents, and grinding wheel dust. Fredriksson et al. (1989) found a slightly increased risk for colon cancer following exposure to TCE in general. In a study of highway workers exposed to solvents, herbicides, asphalt and welding fumes, diesel and auto exhaust, asbestos, abrasive dusts, hazardous materials spills, and moving motor vehicles, white retirees with 5 or more years of service experienced an excess number of deaths due to colon cancer (Maizlish et al., 1988). In a study of commercial pressmen, Zoloth et al. (1986) found a significantly elevated risk of death due to colorectal cancer. Other studies have also reported elevated colon cancer rates in occupationally exposed cohorts (Greene et al., 1979; Morgan et al., 1981).
Liver. In the follow up and confirmation of a previous study of occupational exposures to solvents, Hernberg et al. (1988) reported the odds ratio for liver cancer cases as greater than 3 for solvent-exposed women irrespective of reference group, with no increase for men. Among jewelry workers, an elevated PMR was reported for liver cancer in males (Dubrow and Gute, 1987). The elevated PMR for liver cancer may have been due to exposure to solvents, such as TCE, tetrachloroethylene, and carbon tetrachloride, that cause liver cancer in animals; however, because of the lack of information about specific occupational exposures of the decedents, the authors felt their findings should be viewed as an exploratory investigation requiring further follow up.
Wilkins and Comstock (1981) reported a twofold incidence of liver cancer among women using chlorinated water for household uses. Their comparative mortality study also suggested an association of chlorinated water with liver cancer. In a proportionate mortality study among pressmen, Zoloth et al. (1986) found a significantly elevated risk for cancers of the liver for men who had been employed for 20 or more years. Other studies (Stemhagen et al., 1983; Blair et al., 1979; Hardell et al., 1984) have also reported positive results; however, the literature also contains reports of negative findings for cancer of the liver (Austin et al., 1987; Duh and Asal, 1984; Brown and Kaplan, 1987; Katz and Jowett 1981).
Testicular. Garland et al. (1988) found a significantly elevated age-adjusted rate of testicular cancer in naval aviation support equipment technicians, enginemen, and construction mechanics when compared with the US population and the total Navy population. These occupations involve maintenance of internal combustion engines and exposure to the attendant lubricants, solvents, paints, and exhausts.
Pancreas. Thomas et al. (1985) reported a threefold excess number of pancreatic cancer deaths among black maintenance workers in the corn wet-milling industry. Pressmen who had been employed for 20 or more years had a significantly elevated risk for cancers of the pancreas (Zoloth et al., 1986).
Other cancers. Various other cancers have been reported following exposure to TCE. Maizlish et al. (1988) found that white male highway workers exhibited a statistically significant excess number of cancers of the digestive organs, while Dubrow and Gute (1987) reported an elevated PMR for stomach cancer among female jewelry workers. A significantly elevated risk of mortality due to cancer of the breast was suggested for women exposed to chlorinated drinking water (Wilkins and Comstock, 1981). No excess deaths due to lung cancer were reported for workers exposed to solvents for 20 or more years (Zoloth et al., 1986). Finally, in a study of highway workers exposed to solvents and a variety of other substances, white retirees with 5 or more years of exposure experiences an excess number of deaths due to cancers of the skin and brain (Maizlish et al., 1988).
O'Leary et al. (1991) studied the relationship of parental occupational exposures to childhood malignancies and concluded that the preponderance of evidence supported the hypothesis that occupational exposures of parents to chemicals increased the risk of malignancies in their children. The parental occupational exposures implicated in childhood malignancy risk were exposure to chemicals including paints, petroleum products, solvents (especially chlorinated hydrocarbons), and pesticides, and metals. The available data, however, did not allow the identification of specific etiologic agents. Odom et al. (1990) reported that the occurrence of acute monoblastic leukemia in young children appeared to be associated with in utero exposure to marijuana and parental exposure to pesticides and solvents. In another study, paternal occupational exposures to chlorinated solvents was associated with excess childhood leukemia (Lowengart et al., 1987).
Other studies of childhood cancers have also reported associations with parental occupational exposure to TCE, but in combination with other compounds. The reported cancers include urinary tract tumors (Kwa and Fine, 1980; Bunin et al., 1989), brain tumors (Hemminki et al., 1981; Peters et al., 1981, 1985; Olshan et al., 1986; Wilkins and Sinks, 1990; Wilkins et al., 1991), central nervous system and lymphatic (Hicks et al., 1984), acute non-lymphocytic leukemia (Buckley et al., 1989), and neuroblastomas (Spitz and Johnson, 1985). Parents may expose their children in utero or through exhaled air or breast milk.
No studies were located regarding cancer in humans after dermal exposure to TCE. In three animals studies, no significant tumor incidences were observed and doses were well below the maximum tolerated level following dermal exposure to TCE (ATSDR, 1993).
Animal studies. Animal studies have linked TCE exposure to various types of cancers in rats and mice. Statistically significant increases in cancers include renal tubular cell adenocarcinomas in male rats but not female (Maltoni et al., 1986; U.S. National Toxicology Program, 1982), lung adenocarcinomas in female ICR mice (Fukuda et al., 1983), and mouse hepatocellular carcinomas, forestomach tumors in Swiss mice, increased incidence of leukemia in male but not female rats, renal tubular cell adenomas in male rats but not female, interstitial cell tumors of the testis in rats, and mouse hepatocellular carcinomas and hepatocellular adenomas (ATSDR, 1993). Crebelli and Carere (1989) reported that exposure to high doses of TCE, administered to rodents during long-term carcinogenicity studies, resulted in the induction of liver and lung tumors in the mice, and tumors of the kidney and testes in rats. Among TCE metabolites, trichloroacetic acid was reported to be carcinogenic to the livers of mice. The incidence data for lung tumors in female Swiss mice, together with other tumor incidences, were used by the U.S. Environmental Protection Agency (1987) to derive a carcinogenicity potency estimate; however, this cancer rating has recently been withdrawn (IRIS, 1990). Other studies (Maltoni et al., 1986; Henschler et al., 1980) did not find excess lung tumors in various strains of mice.
One problem with some animal studies is the use of TCE containing small amounts of epoxide stabilizers to preserve the TCE from rapid degradation. Since these epoxides form free radicals, they themselves may be carcinogens, and may have contributed to the carcinogenic potential of industrial TCE. Thus, the significance of these studies cannot be determined. Another serious problem with many of the studies is the poor survival rate (Maltoni et al., 1986; NTP 1988, 1990).
One study that did use epoxide-free TCE showed liver tumors in mice, some indication of renal tumors in male rats, and no evidence of carcinogenicity in female rats (National Toxicology Program, 1990). Acute oral exposure to TCE or its metabolites preferentially induces peroxisome in the liver of mice, which may be related to the carcinogenic response in the liver of mice (Goldsworthy and Popp, 1987); however, both TCA and DCA, metabolites of TCE, are capable of inducing liver tumors in B6C3F1 mice, but not rats (Bull et al., 1990, 1993; Herren-Freund et al., 1987). It should be noted that this mouse strain has a high spontaneous rate of liver tumors (Elashoff et al., 1979). In addition, Dees and Travis (1993) found no evidence for increased lipid peroxidation in TCE-treated animals, using histologic confirmation. Other metabolites of TCE are known to be genotoxic (chloral) (Odum et al., 1992) or carcinogenic (1,2-dichlorovinyl-N-acetyl-cysteine) (Meadows et al., 1988); however, TCE oxide (epoxide) was negative in a mouse carcinogenicity bioassay (VanDuren et al., 1983).
Chromosome studies of workers exposed to TCE have found an increased prevalence of sister chromatid exchanges (Gu et al., 1981), increased prevalence of chromosomal aberrations (Konietzko et al., 1978), and unscheduled DNA synthesis (Perucco and Prodi 1981); however, in vivo assays, such as mouse liver unscheduled DNA synthesis (Mirsalis et al., 1985), mouse bone marrow chromosome aberration (Loprieno and Abbandandolo, 1980), and dominant lethals (Slacik-Erben et al., 1980), have shown TCE to be without effect. The literature also contains a number of reports of positive findings relating to in vitro genotoxicity assays with Salmonella typhimurium (Simmon et al., 1977; Baden et al., 1979), Saccharomyces cerevisae (Bronzetti 1978), Escherichia coli (Greim et al., 1975), and Aspergillus nidulans (Candura and Faustman, 1991). A similar number of studies reporting no activities are also described (Fielder et al., 1982). The conclusion of most researchers is that TCE is a very weak mutagen, therefore an epigenetic mechanism, such as peroxisome proliferation, is most likely responsible for the experimental carcinogenicity of TCE (Brown et al., 1990).
Sprague-Dawley rats and B6C3F1 mice administered TCE intraperitoneally displayed minor decreases in splenocyte viability, inhibition of LPS-stimulated mitogenesis in rat cells, and marked inhibition of rat and mouse hepatic natural killer cells and rat natural cytotoxic cell activities in all groups of effector cells (Wright et al., 1991). These results indicate that TCE is able to inhibit the activity of lymphocytotoxic cells which are involved in the immune surveillance of cancerous cells, thus suggesting the possibility that compromised immune function may play a role in the carcinogenic responses in experimental animals following exposure to TCE.
The carcinogenic status of TCE is currently being reviewed by the USEPA.
CONCLUSIONS
The TCE Subregistry population reported more adverse health outcomes when compared with a national sample. The adverse health outcomes reported in excess of those reported by the national sample, for all or specific age groups, included speech impairment, hearing impairment, stroke, liver disease, anemia and other blood disorders, diabetes, kidney disease, urinary tract disorders, and skin rashes.
Many of the effects seen in the TCE Subregistry have also been reported in the literature. The limitations of both the TCE Subregistry data and tmany of the studies cited above should be taken into account when assessing the value of the findings. Epidemiological studies are frequently limited by multiple and/or mixed exposures to many chemicals (as was the Subregistry), inadequate latency periods, small cohorts, healthy-worker effect. Additional limitations of the TCE Subregistry data include the comparability of the questions between the Subregistry and the NHIS, recall bias, frequency of health care utilization, and underrepresentation of children younger than 5 years of age in the TCE Subregistry population. Also, because of the many comparisons carried out, some of the positive results might have been chance occurrences, or might have occurred because the true causal factors (confounders) were not identified.
Cause and effect relationships cannot be determined from simple analyses of the subregistry-based information; however, information obtained from this database can and will be used to determine appropriate future activities and research. Considerations for further research using this database include modification of the current data collection procedures and methods; exploration of recognized sources of bias and reduction or elimination of these biases; acquisition of additional definitive information on and confirmation of selected outcomes that appear to be in excess; and substance-specific research with specific hypotheses clearly identified.
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