Trichloroethylene nervous system

AH volatile organic solvents are toxic to some degree. Excessive vapor inhalation of the volatile chloriaated solveats, and the central nervous system depression that results, is the greatest hazard for iadustrial use of these solvents. Proper protective equipment and operating procedures permit safe use of solvents such as methylene chloride, 1,1,1-trichloroethane, trichloroethylene, and tetrachloroethylene ia both cold and hot metal-cleaning operations. The toxicity of a solvent cannot be predicted from its chlorine content or chemical stmcture. For example, 1,1,1-trichloroethane is one of the least toxic metal-cleaning solvents and has a recommended threshold limit value (TLV) of 350 ppm. However, the 1,1,2-trichloroethane isomer is one of the more toxic chloriaated hydrocarboas, with a TLV of only 10 ppm. 

Trichloroethylene is acutely toxic, primarily because of its anesthetic effect on the central nervous system. Exposure to high vapor concentrations is likely to cause headache, vertigo, tremors, nausea and vomiting, fatigue, intoxication, unconsciousness, and even death. Because it is widely used, its physiological effects have been extensively studied. 

Trichloroethylene levels in the workplace are regulated by the Occupational Safety and Health Administration (OSHA). The occupational exposure limit for an 8-hour workday, 40-hour workweek, is an average concentration of 100 ppm in air. The 15-minute average exposure in air that should not be exceeded at any time during a workday is 300 ppm. The OSHA standards are based on preventing central nervous system effects after trichloroethylene exposure. For more information, see Chapter 7. 

Animal experimentation has revealed inhaled concentrations that result in death following acute, intermediate, and chronic exposure. An LC50 value for acute exposure in rats was reported as 12,500 ppm for a 4-hour exposure (Siegel et al. 1971). Two out of 10 mice died after a 4-hour exposure to 6,400 ppm trichloroethylene (Kylin et al. 1962). Death was often caused by the central nervous system depression that... 

Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after inhalation exposure to trichloroethylene. Trichloroethylene exposure can result in nervous system effects that result in secondary effects on muscle strength, especially in the face (Leandri et al. 1995). See Section 2.2.1.4 for further discussion of nervous system effects following trichloroethylene exposure. 

A study that examined the interaction between exposure concentration and time of exposure on nervous system function found that concentration, rather than time of exposure, was more important in determining effects (Bushnell 1997). Rats were trained to press two levers for food reward one lever when a light flashed, the second lever produced food when there was no signal. The trained rats were exposed to 0,400, 800, 1,200, 1,600,2,000, or 2,400 ppm trichloroethylene for 0.33, 0.67, or 1 hour. Response times were signiflcantly increased only at 2,400 ppm at 0.67 and 1 hour. Sensitivity was significantly decreased at 2,400 ppm at all exposure times. At 0.33 hour, sensitivity was not affected at the other concentrations. At 0.67 hour, sensitivity was significantly decreased at 2,000, and 1,200 ppm, and at 1 hour, sensitivity was... 

Route Dependent Toxicity. The toxicity of trichloroethylene does not seem to be heavily dependent upon its route of entry. Inhalation and ingestion are the primary exposure routes, and the liver, heart, and central nervous system are the primary targets for both routes (Candura and Faustman 1991). Renal toxicity results principally from oral exposure, and dermal exposure generally confines its toxic effects to the skin, although broad systemic effects can be induced imder conditions of high exposure (Bauer and Rabens 1974). Attributing such effects solely to dermal exposure, however, is difficult because inhalation exposure is often a factor in these cases as well. 

The liver is an organ that shows variable effects from trichloroethylene among species, and this can probably be attributed to interspecies differences in metabolism (see Section 2.4.2.1). Specifically, the apparent difference in susceptibility to trichloroethylene-induced hepatocellular carcinoma between humans and rodents may be due to metabolic differences (see Section 2.4.2.3). Kidney effects are also variable among species. Humans and mice are less sensitive than rats. In rats exposed chronically to trichloroethylene, toxic nephrosis characterized as cytomegaly has been reported (NTP 1988). The kidney effects in rats do not seem to be related to an increase in alpha-2 -globulin (Goldsworthy et al. 1988). Effects on the nervous system appear to be widespread among species, presumably due to interactions between trichloroethylene and neuronal membranes. 

In the past, trichloroethylene was used as a human anesthetic. Trichloroethylene has also been used by individuals who intentionally inhale it for its narcotic properties. Therefore, most of the information regarding the effects of trichloroethylene in humans comes from case studies and experiments describing effects of trichloroethylene after inhalation exposure. These studies indicate that the primary effect of exposure to trichloroethylene is on the central nervous system. Effects include headache, vertigo, fatigue, short-term memory loss, decreased word associations, central nervous system depression, and anesthesia. 

Gastrointestinal Effects. Case reports indicate that acute inhalation exposure to trichloroethylene results in nausea and vomiting (Buxton and Hayward 1967 Clearfield 1970 David et al. 1989 DeFalque 1961 Gutch et al. 1965 Milby 1968). Anorexia, nausea, vomiting, and intolerance to fatty foods have also been reported after chronic occupational exposure to trichloroethylene (El Ghawabi et al. 1973 Schattner and Malnick 1990 Smith 1966). Trichloroethylene-induced efiects on the autonomic nervous system may contribute to these effects (Grandjean et al. 1955). Some of the people exposed to trichloroethylene and other chlorinated... 

Alcohol can affect the metabolism of trichloroethylene. This is noted in both toxicity and pharmacokinetic studies. In toxicity studies, simultaneous exposure to ethanol and trichloroethylene increased the concentration of trichloroethylene in the blood and breath of male volunteers (Stewart et al. 1974c). These people also showed "degreaser s flush"—a transient vasodilation of superficial skin vessels. In rats, depressant effects in the central nervous system are exacerbated by coadministration of ethanol and trichloroethylene (Utesch et al. 1981). 

Attempts to diminish the overall metabolism of trichloroethylene might be useful (e.g., hypothermia, mixed-function oxidase inhibitors, competitive inhibitors of trichloroethylene metabolism [i.e., P-450 substrates]), if instituted soon enough after trichloroethylene exposure. Catecholamines (especially beta agonists) act in concert with trichloroethylene, increasing the risk of cardiac arrhythmias. Hence, catecholamines should be administered to patients only in the lowest efficacious doses and for certain limited presentations of trichloroethylene poisoning. Ethanol should also be avoided because concurrent exposure to trichloroethylene and ethanol can cause vasodilation and malaise and may potentiate central nervous system depression at high dosage levels of either compound. 

Effect. Biomarkers of effects are not available for trichloroethylene. There is no clinical disease state that is unique to trichloroethylene exposure. Interpretation of the behavioral observations in humans is complicated by many factors, such as possible irritant effects of the odor and nonspecific effects on the nervous system (e.g., fatigue). Further studies in this area would be useful in determining the exposure levels that may be... 

Comparative Toxicokinetics. In humans, the targets for trichloroethylene toxicity are the liver, kidney, cardiovascular system, and nervous system. Experimental animal studies support this conclusion, although the susceptibilities of some targets, such as the liver, appear to differ between rats and mice. The fact that these two species could exhibit such different effects allows us to question which species is an appropriate model for humans. A similar situation occurred in the cancer studies, where results in rats and mice had different outcomes. The critical issue appears to be differences in metabolism of trichloroethylene across species (Andersen et al. 1980 Buben and O Flaherty 1985 Filser and Bolt 1979 Prout et al. 1985 Stott et al. 1982). Further studies relating the metabolism of humans to those of rats and mice are needed to confirm the basis for differences in species and sex susceptibility to trichloroethylene s toxic effects and in estimating human heath effects from animal data. Development and validation of PBPK models is one approach to interspecies comparisons of data. 

Baker AB. 1958. The nervous system in trichloroethylene. An experimental study. J Neuropath Exp Med 17 649-655. 

Bardodej Z, Vyskocil J. 1956. The problem of trichloroethylene in occupational medicine trichloroethylene metabolism and its effect on the nervous system evaluated as a means of hygienic control. AMA Arch Ind Health 56 581-592. 

Toxicology. Trichloroethylene (TCE) is primarily a central nervous system (CNS) depressant. Although it is carcinogenic at high doses in experimental animals, it is not considered to be a human carcinogen at low exposure levels. 

CONSENSUS REPORTS lARC Cancer Review Group 3 IMEMDT 7,56,87 Animal Limited Evidence IMEMDT 39,369,86. OSHA PEL CL 0.1 ppm ACGIHTLV CL 0.1 ppm DFG MAK Animal Carcinogen, Suspected Human Carcinogen DOT CLASSIFICATION Forbidden SAFETY PROFILE Confirmed carcinogen with experimental carcinogenic data. Poison by inhalation. Central nervous system effects. Can be formed by thermal decomposition (>70°) from trichloroethylene. Symptoms include a disabling nausea and intense jaw pain. 

Acute and high-dosage intoxication by trichloroethylene leads to severe symptoms associated with the central nervous system, but not to (noteworthy) liver damage. 

The chlorinated hydrocarbons trichloroethylene and perchloroethylene (Fig. 2) are widely used as solvents and cleaners. They may be considered closely related to VC because of the clinical similarity of the disorders caused by these compounds to VC disease. Trichloroethylene is more volatile (boiling point 87.2 °C) and much more toxic than perchloroethylene (boiling point 121.1 " C). It penetrates the skin and, in its vaporous state, is also absorbed by the alveolar capillaries. Prolonged contact with the skin will induce irritative dermatitis (Schirren 1971 Bauer and Rabens 1977). Besides the well-described toxic effects in the nervous system, liver, kidney, and bone marrow, several reports on SLD resembling VC disease have been published (Reinl 1957 Saihan et al. 1978). Sparrow (1977) observed a SLD similar to VC disease, probably caused by perchloroethylene. 

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