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Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

B11 Trichloroethylene

John T. James, Ph.D., Harold L. Kaplan, Ph.D.,

and Martin E. Coleman, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

National Aeronautics and Space Administration

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Trichloroethylene (TCE) is a colorless, nonflammable, volatile liquid, with a sweetish odor resembling chloroform (ACGIH, 1986).

Synonyms:

Ethylene trichloride, trilene

Formula:

CHC1=CCl2

CAS number:

79-01-6

Molecular weight:

131.4

Boiling point:

87°C

Melting point:

-87°C

Conversion factors at 25°C, 1 atm:

1 ppm = 5.38 mg/m3 1 mg/m3 = 0.19 ppm

OCCURRENCE AND USE

TCE is widely used as an industrial solvent, particularly in metal degreasing and extraction processes (Torkelson and Rowe, 1981). Other less toxic chemicals have replaced it in some of its former uses, including that as an anesthetic. Although TCE is not used in the spacecraft, it has been found in numerous atmospheric samples collected from the cabin of the space shuttle (Coleman, 1984). In contact with alkaline materials, especially at high temperatures, TCE can be convert-

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

ed into more toxic compounds. Dichloroacetylene (DCA) is the major product formed from TCE in carbon dioxide scrubbers containing alkaline materials (Saunders, 1967). In an experiment by the Toxicology Laboratory at the National Aeronautics and Space Administration, all the TCE disappeared upon passage over heated alkaline adsorbent, with at least 75% conversion to DCA (Rippstein, 1980). The SMAC limits developed here are only applicable to a spacecraft environment in which an alkaline air scrubber is not present. If an alkaline air scrubber is present, the SMAC values for DCA are applicable to TCE (see Chapter B5).

TOXICOKINETICS AND METABOLISM

Absorption and Distribution

TCE is readily absorbed from the lungs of humans and distributed throughout the body (Waters et al., 1977). Most blood-borne TCE reaches the liver where the majority of its metabolism occurs (Steinberg and DeSesso, 1993).

Elimination

Approximately 20% to 30% of the absorbed chemical is excreted unchanged in the expired air, mostly during the first 24 h, with the rest metabolized and excreted in the urine (Ogata and Bodner, 1971). Because of its high lipid solubility, a portion of the absorbed TCE is stored in tissues, principally fatty tissues, from which it is slowly released and then metabolized and excreted (Müller et al., 1974). After a 4-h exposure of human volunteers to TCE at 100 ppm, trichloroacetic acid (TCA) and trichloroethanol glucuronide accounted for about 20% and 80%, respectively, of the total urinary trichloro compounds (Sato et al., 1977). In contrast to the rapid excretion of trichloroethanol glucuronide by the kidneys, renal clearance of TCA is delayed because of its high degree of protein-binding (Müller et al., 1974).

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×
Metabolism

TCE that is not excreted from the lungs is converted enzymatically in several steps to the principal urinary metabolites, trichloroethanol, trichloroethanol glucuronide, and trichloroacetic acid (Waters et al., 1977), and a minor metabolite, dichloroacetic acid (DCA) (Hathway, 1980). Cytochrome P-450 systems are the primary metabolizing systems in the liver (Steinberg and DeSesso, 1993). In the first metabolic step, TCE is oxidized through intermediates to chloral hydrate, which undergoes reduction to trichloroethanol as well as further oxidation to TCA (Byington and Leibman, 1965; Sellers et al., 1972). Most of the trichloroethanol is conjugated with glucuronic acid in the liver before being excreted in the urine (Waters et al., 1977). Other pathways for trichloroethanol are oxidation to TCA and excretion of unchanged trichloroethanol in the urine. The proportion of urinary metabolites excreted as TCA was predicted to increase in a chronic exposure. TCA and DCA have recently been shown to be complete hepatocarcinogens in male B6C3F1 mice (Herren-Freund et al., 1987; Bull et al., 1990; DeAngelo et al., 1991). Thus, these metabolites might be responsible for hepatic tumors produced in B6C3F1 mice treated with TCE (NCI, 1976). In rodents, DCA can be converted to S-(1, 2-dichlorvinyl)-L-cysteine and subsequently by ß-lyase to the reactive mercaptan (Steinberg and DeSesso, 1993). The pathway to DCA is much more heavily used in rodents than in humans. The biological half-life of trichloroethanol in humans is relatively short compared with that of TCA. In humans exposed to TCE at 50 ppm for 6 h/d for 5 d, the half-lives of trichloroethanol and TCA were approximately 12 h and 99 h, respectively (Müller et al., 1974). For exposures at 100 ppm for 6 h/d for 10 d, the half-lives were 13 h and 86 h, respectively. Physiologically based pharmacokinetic (PB-PK) models of the toxicokinetics and metabolism of TCE in humans (Sato et al., 1977; Fernandez et al., 1977) and in animals (Fernandez et al., 1977; Andersen et al., 1987; Fisher et al., 1989, 1990, 1991; Dallas et al., 1991) have been developed by several groups of investigators. These models have enabled a better understanding of the uptake, distribution, and metabolism of TCE as well as of the kinetics of formation, distribution, and excretion of its metabolites TCA and trichloroethanol.

The metabolism and elimination pattern for TCE is conducive to exposure monitoring with the use of biological markers. The parent com-

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

pound can be monitored in the breath, blood, or urine (Stewart et al., 1970; Kimmerle and Eden, 1973; Monster et al., 1979), or the metabolites trichloroacetic acid and trichloroethanol can be monitored in the urine (Inoue et al., 1989). Use of these markers might be confounded by interindividual variation and by the presence of other chlorinated hydrocarbons (Inoue et al., 1989). Air monitoring near the breathing zone of exposed persons is still the best predictor of inhalation exposure to TCE. Biological markers of TCE toxicity have focused on nervous system injury or kidney injury (Feldman et al., 1988; Nagaya et al., 1989); however, those markers do not appear to be widely used and are not specific for TCE exposure.

TOXICITY SUMMARY

Acute Exposures

Many cases of accidental acute poisoning by TCE are described in the literature (Cotter, 1950). The predominant physiological effect is depression of the central nervous system (CNS), with reported symptoms of inebriation, loss of coordination, dizziness, visual disturbances, mental confusion, headache, nausea, vomiting, and loss of consciousness (Waters et al., 1977; Cotter, 1950). In one TCE exposure accident, two workmen rapidly lost consciousness upon re-entry into an atmosphere containing TCE at an estimated 3000 ppm after an earlier, less severe exposure (Longley and Jones, 1963). In a controlled laboratory study with a human volunteer, a 2.75-h exposure to TCE at 100 ppm did not cause any significant effects on psychomotor performance (Stopps and McLaughlin, 1967). At 200 ppm, there was a slight decline in performance, which became more pronounced at 300 and 500 ppm. In another study, a 2-h exposure at 100 or 300 ppm did not affect visual-motor performance, but 1000 ppm significantly impaired performance and resulted in subjective responses of light-headedness and dizziness or lethargy (Vernon and Ferguson, 1969). A longer exposure of 8 h at 110 ppm resulted in a significant decrease in the performance of volunteers in various psychophysiological tests, the greatest decrease being in the more complex tests (Salvini et al., 1971). However, performance decrements were not found in a repeat of this study with an additional concentration of 50 ppm and more end points (Stewart et al.,

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

1974). It has been suggested that drowsiness can occur at 27 ppm during acute exposures and headaches can occur at 81 ppm (Nomiyama and Nomiyama, 1977). Those conclusions were based on subjective reports of three volunteers; however, because no dose-response relationship was shown for drowsiness (i.e., no drowsiness after 3 h in persons exposed at 200 ppm), the observation is suspect. Even though the prevalence of headache shows a dose response, many other symptoms do not show a dose response, so that the findings must be questioned.

There are reports that cardiac arrhythmias induced by inhaled TCE have resulted in human deaths (Kleinfeld and Tabershaw, 1954; Bell, 1951). TCE has been shown to be have the capability to cause cardiac sensitization to epinephrine in the dog. After a 10-min exposure to 5000 or 10,000 ppm, a challenge injection of epinephrine produced ventricular fibrillation in 1 of 12 and 7 of 12 dogs, respectively (Reinhardt et al., 1973). Those findings in animals are particularly significant in view of the cardiac dysrhythmias seen periodically in crew members of U.S. spaceflights as well as in at least one Soviet cosmonaut (Bungo, 1989; NASA, 1991). Whether spaceflight-associated conditions, such as gravitational stress, thermal load, electrolyte changes, fluid shifts, or catecholamine alterations, caused those cardiac rhythm irregularities is unknown at this time (NASA, 1991).

Short-Term and Subchronic Exposures

Repeated exposures for 7 h/d for 5 consecutive days to TCE at 200 ppm did not adversely affect performance or neurological or biochemical tests in human volunteers, but they elicited a consistent subjective response of a sensation of mild fatigue and sleepiness during the fourth and fifth days (Stewart et al., 1970). In subsequent better-controlled studies, the same investigators did not find objective or subjective adverse effects after repeated 7.5-h daily exposures at 100 or 200 ppm and concluded that 100 ppm probably has a threefold to fourfold margin of safety for most individuals (ACGIH, 1986). According to studies cited by the American Conference of Governmental Industrial Hygienists, daily exposures to TCE at 100 ppm caused no impairment in mental or psychological capabilities in one European study (Triebig et al., 1976), but in a similar study, it caused fatigue, lassitude, and headaches (Ertle et al., 1972).

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

Several studies of worker complaints have been published involving industrial exposure to TCE; however, the findings are often uncertain and do not agree with results of volunteer exposures. The prevalence of symptoms (e.g., sleepiness, fatigue, nausea, and irritation) was reduced in nine workers after TCE exposures were reduced from 38 ppm TWA (average of 200 ppm for short-term exposure) to 16 ppm TWA (average of 74 ppm for short-term exposures) by improving ventilation and work practices (Landrigan et al., 1987). The reported symptoms probably were elicited by the high-concentration short-term exposures rather than the low-concentration sustained exposures. The National Institute for Occupational Safety and Health (NIOSH) has reviewed a number of work sites because of worker complaints of excess chemical exposure. In one investigation, the TCE exposures were confounded by the presence of other chemicals, and the magnitude of worker complaints did not compare well with the exposure concentrations (Bloom et al., 1974). Three workers reported occasional light-headedness and headache in a degreasing operation, which had a TWA TCE concentration at 47 ppm, with 1-h maximum exposures up to 94 ppm (Hervin et al., 1974). In a study of printed circuit-board processors, average breathing-zone concentrations of TCE ranged from 29 to 62 ppm, and symptoms reported were nausea (71%), headache (54%), and fatigue and drowsiness (25%) (Okawa and Bodner, 1973). The authors concluded that the symptoms were due to toxic exposures to TCE in the workplace.

The difficulty of interpreting workplace results is indicated by subjective responses reported by volunteers even when not exposed to TCE. For example, two of two test subjects reported headaches; irritation of the eyes, nose, and throat; and odor when no exposures to TCE had occurred (Stewart et al., 1974). In another group of test subjects, only odor was reported, even at exposure concentrations of 50 and 110 ppm (Stewart et al., 1974). Objectively measurable performance decrements were absent.

Chronic Exposures
Noncarcinogenicity

Neurological symptoms, including vertigo, fatigue, insomnia, and

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

memory loss, have been reported in epidemiological studies of workers chronically exposed to TCE in industry (Grandjean et al., 1955; Bardodej and Vyskocil, 1956). The incidence of these symptoms correlated with the duration of exposure of the workers. Although biochemical tests have also suggested possible hepatic and renal effects in workers chronically exposed to TCE, the evidence is not conclusive (Waters et al., 1977; NIOSH, 1978). In chronic exposure studies with animals, TCE appears to be a weak hepatotoxin and renal toxin because high doses produced mild effects in the liver and kidney. Exposure for 8 h/d, 5 d/w, for 6 w at 730 ppm or for 24 h/d for 90 d at 35 ppm did not result in any evidence of injury to the liver or kidneys of rats, guinea pigs, rabbits, dogs, and monkeys (Prendergast et al., 1967). Exposure of rats, guinea pigs, rabbits, and monkeys for 7 h/d, 5 d/w, for 148 to 178 d at 200 ppm also caused no adverse effects, except decreased growth and body weights in guinea pigs (Adams et al., 1951). Exposure of these species for 7 h/d, 5 d/w, for 161 to 175 d at 400 ppm caused increased liver and kidney weights in rats, increased liver weights in male and female guinea pigs, depressed growth in male guinea pigs, and a slight increase in liver weights of rabbits, but no adverse effects in monkeys (Adams et al., 1951).

Carcinogenicity

The results of most of the carcinogenicity studies with animals show that TCE is a potential carcinogen. TCE produced an increased incidence of hepatocellular carcinomas in B6C3F1 mice subjected daily for their lifetime to high oral doses of the chemical (NCI, 1976; NTP, 1988, 1990). An increased incidence of these tumors was not detected in rats, but the results indicated the possibility of renal tumorigenic effects in rats. Studies also showed that inhalation exposure to TCE can be carcinogenic in animals (Fukuda et al., 1983; Maltoni et al., 1988). In a recently completed European bioassay, exposure of Swiss and B6C3F1 mice to TCE for 7 h/d, 5 d/w, for 78 w at 100, 300, or 600 ppm resulted in a significant increase in the incidence of pulmonary tumors (from 11.1% in controls to 25.5% in males exposed at 300 ppm and 30.0% in mice exposed at 600 ppm) and hepatomas (from 4.4% in controls to 14.4% in males exposed at 600 ppm) in male Swiss mice (Maltoni et al., 1988). In female B6C3F1 mice, there was a significant

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

increase in the number of total malignant tumors per 100 animals (from 54.4 in controls to 70.0 in mice exposed at 100 ppm, 68.9 at 300 ppm, and 77.7 at 600 ppm) and in the incidence of pulmonary tumors (from 4.4% in controls to 16.7% in mice exposed at 600 ppm). In male and female B6C3F1 mice combined, the increase in incidence of hepatomas from 2.2% in controls to 8.3% in those exposed at 600 ppm was significant. It should be noted that the time of sacrifice of these animals was not specified; however, the reported incidence of hepatomas at 600 ppm appears low compared with the historical lifetime incidences of 20% to 30% and 5%, respectively, in male and female B6C3F1 mice.

In rats similarly exposed for 104 w, there were significant dose-related increases in the incidence of Leydig-cell tumors of the testis from 4.4% in controls to 12.3%, 23.1%, and 23.8% in rats exposed at 100, 300, and 600 ppm, respectively (Maltoni et al., 1988). There was also a non-dose-related increase in the incidence of hemolymphoreticular neoplasias as well as a low incidence of renal adenocarcinomas at the highest dose in male rats.

In humans, two Scandinavian cohort studies did not find an increase in cancer-related mortality in workers exposed to TCE for up to 13 and 20 y (Axelson et al., 1978; Tola et al., 1980).

Genotoxicity

TCE was weakly positive or negative in numerous mutagenicity bioassays (Stott et al., 1982). Those results and a low level of in vivo TCE-DNA binding observed in B6C3F1 mice indicate a weak genotoxic potential of TCE (Stott et al., 1982). Many of the studies did not report purity of test material; hence, it is possible that mutagenic epoxide stabilizers caused false positives (Brown et al., 1990).

Reproductive and Developmental Effects

TCE was found not to be a developmental toxicant in mice or rats exposed to TCE by inhalation at 300 ppm (Schwetz et al., 1975). In more recent studies, administration of TCE to the developing rat fetus in utero and injection into the air sacs of fertilized chick eggs resulted in cardiac teratogenic effects (Dawson et al., 1990; Loeber et al.,

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

1988). Additional evidence of the possible cardiac teratogenicity of TCE was provided by recent epidemiological studies showing a greater-than-expected number of pediatric patients with congenital heart disease in areas where the drinking water of their parents near the time of conception was contaminated by TCE and other halogenated aliphatic hydrocarbons (Goldberg et al., 1990). The authors noted important limitations to their study that preclude the conclusion of a cause-and-effect relationship.

Interactions with Other Chemicals

Biological interactions between TCE and other chemicals and drugs, such as ethyl alcohol and phenobarbital, have been reported in humans and animals. Degreaser's flush, a transient vasodilation of the skin, occurs in some TCE-exposed workers or subjects after ingestion of even small quantities of ethanol (Müller et al., 1975). Small quantities of ethanol also might increase the concentration of TCE in the blood, suggesting a lower rate of metabolism of TCE in the presence of alcohol (Müller et al., 1975). In Wistar rats, pre-exposure with ethanol or phenobarbital can enhance hepatic damage induced by exposure to TCE vapor (Okino et al., 1991).

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

TABLE 11-1 Toxicity Summarya

Concentration, ppm

Exposure Duration

Species

Effects

Reference

NS

Up to 13 y

Human (workers)

No increase in mortality or cancer-related mortality

Tola et al., 1980

NS

Up to 20 y

Human (workers)

No increase in cancer-related mortality

Axelson et al., 1978

1-335

Up to 15 y

Human (workers)

Nervous disorders increased with exposure duration and levels greater than 40 ppm

Grandjean et al., 1955

5-630

0.5-25 y

Human (workers)

Various symptoms; some correlated with exposure duration

Bardodej and Vyskocil, 1956

29-62 (averages)

Work site

Workers

Nausea, headache, dizziness

Okawa and Bodner, 1973

20, 100, or 200

7.5 h/d, 5 d

Human

No adverse subjective or objective behavioral effects

ACGIH, 1986

50 or 110

8 h

Human

No impairment of performance

Stewart et al., 1974

100

h/d NS, 5 d

Human

No impairment in mental performance

ACGIH, 1986

100, 200, 300, or 500

165 min

Human

Slight decrease in psycho-motor performance at 200 ppm, more pronounced at 300 and 500 ppm

Stopps and McLaughlin, 1967

100, 300, or 1000

2 h

Human

Impairment of visual-motor performance, dizziness, lightheadedness at 1000 ppm

Vernon and Ferguson, 1969

110 average (90-130)

8 h

Human

Significant decrease in psychomotor performance; slight dizziness at 130 ppm

Salvini et al., 1971

200

7 h/d, 5 d

Human (n = 5)

No adverse effects on performance, neurological or clinical chemistry tests

Stewart et al., 1970

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

Concentration, ppm

Exposure Duration

Species

Effects

Reference

1000

2 h

Human

CNS effects indicated by optokinetic nystagmus test

Kylin et al., 1967

3000

10 min

Human (workers)

Unconsciousness in two workers exposed previously

Longley and Jones, 1963

10 or 600

6 h

Rat (O-M), mouse (B6C3F1)

Reactive metabolite formation and hepatic macromolecular binding greater in mouse than rat

Stott et al., 1982

35

24 h/d, 90 d continuous

Monkey, dog, rabbit, guinea pig, rat

No deaths, hematological changes, or toxic signs except depressed body-weight gain in rabbits

Prendergast et al., 1967

100

7 h/d, 5 d/w, 132 d

Guinea pig

No adverse effects

Adams et al., 1951

100, 300, or 600

7 h/d, 5 d/w, 78 w

Mouse (Swiss, B6C3F1)

In Swiss males, significant increase in incidence of pulmonary tumors from 11.1% (controls) to 25.5% (300 ppm) and 30.0% (600 ppm), and of hepatomas from 4.4% (controls) to 14.4% (600 ppm); in B6C3F1, females significant increase in total number of malignant tumors per 100 animals from 54.4 (controls) to 70.0 (100 ppm), 68.9 (300 ppm) and 77.7 (600 ppm) and in incidence of pulmonary tumors from 4.4% (controls) to 16.7% (600 ppm); significant increase in hepatomas at 600 ppm in male plus female mice

Maltoni et al., 1988

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

Concentration, ppm

Exposure Duration

Species

Effects

Reference

100, 300, or 600

7 h/d, 5 d/w, 104 w

Rat (S-D)

Significant dose-response related increase in incidence of Leydig cell tumors of testis from 4.4% (controls) to 12.3% (100 ppm), 23.1% (300 ppm), and 23.8% (600 ppm)

Maltoni et al., 1988

100 or 500

6 h/d, 5 d/w, 18 mo

Rat, hamster, mouse

Dose-dependent decrease in survival rate of mouse

Henschler et al., 1980

100 or 500

6 h/d, 5 d/w, 18 mo

Rat, hamster, mouse

No tumorigenic effects except for significant increase in incidence of malignant lymphomas in female mice, from 9/29 (controls) to 17/30 (100 ppm) and 18/28 (500 ppm)

Henschler et al., 1980

100 or 600

7 h/d, 5 d/w, 8 w

Rat (S-D), mouse (Swiss)

No tumorigenic effects

Maltoni et al., 1988

200

7 h/d, 5 d/w, 148-178 d

Monkey, rabbit, guinea pig, rat

No adverse effects on appearance, behavior, hematology, clinical chemistry, histology, or organ/body weights except decreased growth and body weights of guinea pigs

Adams et al., 1951

400

8 h/d, 5 d/w, 10 mo

Rat

No effects on general condition, weight, mortality; swimming speed decreased, exploratory behavior increased

Battig and Grandjean, 1963

400

7 h/d, 5 d/w, 161 d

Monkey

No adverse effects on appearance, behavior, hematology, clinical chemistry, or histology

Adams et al., 1951

400

7 h/d, 5 d/w, 161 d

Rabbit

Slight increase in liver weight

Adams et al., 1951

400

7 h/d, 5 d/w, 167 d

Guinea pig

Increased liver weight, depressed growth in males

Adams et al., 1951

400

7 h/d, 5 d/w, 173 d

Rat

Increased liver and kidney weights

Adams et al., 1951

730

8 h/d, 5 d/w, 6 w

Monkey, dog, rabbit, guinea pig

No effects except on liver enzymes and cofactors in rats and growth depression in dogs

Prendergast et al., 1967

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

Concentration, ppm

Exposure Duration

Species

Effects

Reference

1250 or 2500

Variable

Mouse

Motor activity increased with rapid increase in TCE concentration

Kjellstrand et al., 1990

3000

7 h/d, 5 d/w, 27 d

Rabbit, rat

Mild impairment of equilibrium and coordination; increased liver and kidney weights

Adams et al., 1951

5000

10 min

Dog

Ventricular fibrillation on epinephrine challenge in 1/12

Reinhardt et al., 1973

9000

15 min

Rat (W-M)

Slight difficulty in locomotion

Utesch et al., 1981

10,000

10 min

Dog

Ventricular fibrillation on epinephrine challenge in 7/12

Reinhardt et al., 1973

12,000

10 min

Rat (W-M)

2/6 lost righting reflex

Utesch et al., 1981

14,000

5 min

Rat (W-M)

6/6 lost righting reflex

Utesch et al., 1981

15,000

Until loss of righting reflex

Rat (W-M)

Loss of reflex 3.5 min; recovery 1.25 min

Utesch et al., 1981

a Only results of inhalation studies are included.

Strains: S-D (Sprague-Dawley); O-M (Osborne Mendel); W-M (Wistar-Munich); NS, not specified.

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

TABLE 11-2 Exposure Limits Set or Recommended by Other Organizations

Agency or Organization

Exposure Limit, ppm

Reference

ACGIH's TLV

50 (TWA)

ACGIH, 1995

 

100 (STEL)

 

OSHA's PEL

50 (TWA)

U.S. Dept. of

 

200 (STEL)

Labor, 1995

NIOSH's REL

25 (TWA)

ACGIH, 1991

NRC's EEGL

200 (1 h)

NRC, 1988

 

10 (24 h)

 

TLV, Threshold Limit Value; TWA, time-weighted average; STEL, short term exposure limit; PEL, permissible exposure limit; REL, recommended exposure limit; EEGL, emergency exposure guidance level.

TABLE 11-3 Spacecraft Maximum Allowable Concentrations

Exposure Duration

Concentration, ppm

Concentration, mg/m3

Target Toxicity

1 h

50

270

Cardiac arrhythmias, CNS effects

24 h

11

60

CNS effects

7 d

9

50

Liver and kidney effects

30 d

4

20

Liver and kidney effects

180 d

2

10

Liver and kidney effects, cancer

RATIONALE FOR ACCEPTABLE CONCENTRATIONS

CNS Effects

Five available human inhalation studies could potentially provide data pertinent to setting short-term SMACs for TCE. Each of the human inhalation studies was reviewed for a number of quality factors as follows: purity of test material, method of exposure-concentration measurement, appropriateness of toxic end point, number of subjects, and statistical methods. The study by Stopps and McLaughlin (1967) is flawed because only one test subject was exposed, the end points were

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

subjective, and chamber concentrations were nominal. The study by Stewart el al. (1962) is somewhat better but is of limited value because the exposure concentrations were ramped, subjective end points were used, and no statistical analyses were conducted. The study by Vernon and Ferguson (1969) was found to be of high quality and is used as the basis for setting the 1-h AC (CNS effects). The TCE used for exposure was pharmaceutical grade, the exposure concentrations were measured analytically (halide meter), the end points were thorough and objective, there were eight subjects, and a suitable statistical analysis (ANOVA/ Dunnett's test) was done. Human subjects were exposed to 0, 100, 300 or 1000 ppm for 2 h, and six visual-motor performance tests were administered. No statistically significant effects (p < 0.05) were reported at concentrations below 1000 ppm; however, one subject with a preexisting visual perception deficit was found to be more susceptible to TCE as measured in a Howard-Dolman depth perception test. Because 1000 ppm caused significant effects in visual perception, steadiness, and coordination, 300 ppm was concluded to be a no-observed-adverse-effect level (NOAEL) for TCE-induced performance decrements for normal individuals in 2-h exposures. To set the 1-h AC (CNS effects), no factor was applied for the greater length of the 2-h exposure to give additional safety below the NOAEL of 300 ppm. Because only eight human subjects were evaluated, the 300-ppm NOAEL was reduced by a factor of 3.5 (approximately 10/√n) to give a 1-h AC (CNS effects) of 90 ppm.

The 24-h AC (CNS effects) is based on studies in which performance of mental and motor tests was measured in human volunteers exposed to TCE for approximately 8 h. In an early study, exposure of volunteers for 7 h to 100 or 200 ppm did not result in performance or behavioral effects (Stewart et al., 1970). The study was slightly flawed for our purposes in having few objective end points for measuring performance and no statistical analysis. Concentrations were measured analytically (IR spectroscopy), and an adequate number of subjects (five) were studied. In contrast, a statistically significant reduction in efficiency of performing psychophysiological tasks was reported in humans exposed at 110 ppm for 8 h (24-h exposures separated by a 1.5-h break) (Salvini et al., 1971). The concentrations were measured analytically (GC), the number of subjects (12) was adequate, the end points were objective, and the data were subjected to statistical analysis (ANOVA). However, a well-controlled repeat of this study with nine

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

subjects, an additional TCE concentration (50 ppm), and two additional performance tests did not confirm the results (Stewart et al., 1974). Questionable statistical analysis of the data, inaccurate TCE vapor exposure, or poor experimental execution was suggested as responsible for the positive effects in the original study (Stewart et al., 1974). Other investigators have also been unable to confirm decremental performance effects at 100 to 300 ppm (Annau, 1981). Because the findings of decremental performances at 110 ppm are suspect (Stewart et al., 1974), 110 ppm is concluded to be the NOAEL for TCE-induced performance decrements in 8-h exposures. The 24-h AC (CNS effects) was calculated by dividing the NOAEL of 110 ppm for 8 h by 3 to extrapolate from 8 to 24 h in accordance with Haber's rule and by 3.3 (10/√n, where n = 9) (Stewart et al., 1974). Consideration was given to combining earlier data on nine subjects exposed at 100 ppm (Stewart et al., 1970) with these data (Stewart et al., 1974); however, the end points measured were more extensive in the later study, and a statistical analysis was not given in the earlier paper. The 24-h AC (CNS effect) was calculated as follows:

C = 110 ppm (NOAEL) × 8 h/24 h (Haber's rule) 1/3.3 = 11 ppm.

Cardiac Sensitization to Arrhythmia

In addition to the CNS effects of TCE, the cardiac sensitizing properties of TCE must be considered for short-term SMACs. A lowest-observed-adverse-effect level (LOAEL) for cardiac sensitization to epinephrine injection in dogs was 5000 ppm (10-min exposure) because 1 of 12 animals exhibited serious arrhythmias (Reinhardt et al., 1973) defined in the study as multiple consecutive ventricular beats or, more seriously, ventricular fibrillation. It was assumed that the potential for cardiac sensitization depended on blood concentrations that would be near equilibrium after only 10 min of exposure on the basis of data from rats exposed at 50 ppm (Dallas et al., 1991). Hence, length of exposure is not a major factor unless the concentration of TCE is high. The NOAEL was estimated to be a factor of 2 below 5000 ppm on the basis of the observation that a doubling of the dose to 10,000 ppm caused the frequency of serious arrhythmias to increase to 7 of 12. A halving of the concentration to 2500 ppm should be a NOAEL for this

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

end point. The 1-h AC (cardiac effects) was calculated using a species extrapolation factor of 10 and a spaceflight factor of 5 because of the reports of cardiac arrhythmias during both Soviet and U.S. missions (Bungo, 1989; NASA, 1991). The value was calculated as follows:

C = 5000 ppm × 1/2 × 1/10 × 1/5 = 50 ppm.

The U.S. data come primarily from experience in Skylab where all crew members exhibited some form of rhythm disturbance. Most were premature ventricular contractions; however, one crew member had a five-beat run of ventricular tachycardia and another had occasional wandering supraventricular pacemaker (Bungo, 1989). One cosmonaut has experienced more serious cardiac arrhythmias, including atrial extrasystoles, episodes of trigeminy, and a ''significant number'' of supraventricular extrasystoles (associated with exercise) (NASA, 1991). While such rhythm disturbances are not serious themselves, they should be considered warning signals that whatever activity elicits the disturbance should be stopped as soon as possible.

Because the AC for cardiac effects was below the AC for CNS effects, the 1-h SMAC was set at 50 ppm to protect against cardiac effects. The 24-h to 180-d ACs for cardiac effects are the same as the 1h AC for cardiac effects (i.e., 50 ppm) because the extended length of exposure is not a major factor in the cardiac sensitizing potential of TCE.

Hepatotoxicity and Nephrotoxicity

Setting longer-term SMACs is complicated by the fact that the only long-term continuous inhalation exposure study is of limited quality. The study by Prendergast et al. (1967) involved exposures of rats, guinea pigs, squirrel monkeys, rabbits, and dogs to TCE at 0 or 35 ppm for 90 d. Chamber concentrations were monitored analytically (GC) and compared with nominal values (data not given). The shortcomings of the study are as follows: the number of animals of each species was extremely small (e.g., three rabbits and two dogs), the end points measured were of limited value (body weights, few biochemical and histological measurements, and gross necropsy), and statistical techniques were not described. Even with those few measurements, the data were

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

not reported consistently. The body of the paper asserts that the bodyweight gain was lower in exposed rabbits when compared with controls, whereas the discussion asserts that a slight growth depression occurred in all species except the dog. Because slight growth depression in the absence of other effects is not considered an adverse effect, a 35-ppm exposure for 90 d was considered a NOAEL. To protect against expected liver and kidney effects, which were reported in intermittent, long-term exposures to TCE (Adams et al., 1951), the 30-d AC was set at 4 ppm by starting with the 35-ppm NOAEL and adjusting it by a factor of 10 for species extrapolation.

The 180-d AC was derived in the same way as the 30-d value except that a time factor of 1/2 was used to estimate a 180-d NOAEL from the 90 d NOAEL observed at 35 ppm. The 180-d AC was set at 2 ppm to protect against liver and kidney effects.

The 7-d AC was based on a human NOAEL observed using clinical laboratory methods to detect liver or kidney injury during exposure of five subjects exposed to TCE at 200 ppm 35 h (7 h/d, 5 d) (Stewart et al., 1970).

The 7-d AC (for liver and kidney) was calculated as follows:

Carcinogenesis

The potential for TCE to cause cancer in humans is a controversial issue, because cohort and case-control epidemiological studies are generally negative for cancer; however, a few studies suggest an association (Brown et al., 1990). In the largest of the studies with negative results, a cohort of almost 7000 workers exposed for many years to TCE exhibited no "significant or persuasive" associations between exposure and excess cancer (Spirtas et al., 1991). Unfortunately, the magnitude of the TCE exposures could be estimated only in relative terms (Stewart et al., 1991). The studies with positive results are of limited value because of poorly characterized exposure history or small sample sizes. Animal data do little to resolve the issue. A number of studies in rodents show a potential for TCE to induce cancer; however, applying those data to human risk is difficult for the following reasons:

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×
  1. Some studies used mutagenic epoxide stabilizers in the TCE test material.

  2. Some studies used unconventional protocols and incomplete reporting methods or did not comply (apparently) with good laboratory practices.

  3. Some tumors appear to be due to metabolic pathways in the test species that differ from those in human beings.

  4. Some tumors might involve cytotoxic mechanisms and are not relevant to risk at much lower human exposures.

Despite those uncertainties, we have chosen to calculate a cancer risk based on an estimate by the U.S. Environmental Protection Agency (EPA, 1987). A continuous lifetime exposure to TCE at 1 µg/m3 (0.00019 ppm) was estimated to yield an excess tumor risk of 1.7 × 10-6 in humans. Using the approach of the National Research Council (NRC, 1992) and setting k = 3 (stages in process), t = 25,550 d (70-y lifetime), and s1 = 10,950 d (earliest exposure, 30 y of age), the adjustment factor was calculated to be 26,082 for a near instantaneous exposure concentration that would yield the same excess tumor risk as a continuous lifetime exposure. The 24-h TCE exposure concentration that would yield an excess tumor risk of 10-4 was equal to the following:

1.9 × 10-4 ppm × 26082 × 10-4 ÷ (1.7 × 10-6) or 290 ppm.

For the 7-d, 30-d, and 180-d SMACs, adjustment factors were calculated on the basis of the NRC (1992) approach and setting k = 3, t = 25,550 d, and s1 = 10,950 d. The adjustment factors are 3728, 871, and 146.7 for continuous 7-d, 30-d, and 180-d exposures, respectively, that would yield the same excess tumor risk of 1.7 × 10-6 as a continuous lifetime exposure. The 7-d, 30-d, and 180-d exposure concentrations that would yield an excess tumor risk of 10-4 are equal to the following:

1.9 × 10-5 ppm × 3728 × 10-4 ÷ (1.7 × 10-6) = 42 ppm (7 d).

1.9 × 10-5 ppm × 871 × 10-4 ÷ (1.7 × 10-6) = 9.7 ppm (30 d).

1.9 × 10-5 ppm × 146.7 × 10-4 ÷ (1.7 × 10-6) = 1.6 ppm (180 d).

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

It must be pointed out that the original EPA estimate was withdrawn, and a revised estimate has not been determined as of this writing (EPA, 1993). Some authors suggest that a threshold model might be more appropriate than a linear extrapolation to low doses to set exposure limits (Steinberg and DeSesso, 1993).

Summary

The 1-h SMAC of 50 ppm was based on cardiac sensitization in dogs and the occurrence of arrhythmias in some crew members during missions. The 24-h SMAC of 12 ppm was based on CNS and neurobehavioral effects in humans rather than on cardiac sensitization in dogs.

The 7-d and 30-d SMACs of 9 and 4 ppm, respectively, were set to protect against liver and kidney injury. Those concentrations protect against cancer at a risk predicted to be below 0.01%. The 180-d SMAC of 2 ppm protects against liver and kidney injury and against cancer at the 95% limit of 0.01% risk per mission.

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

TABLE 11-4 Acceptable Concentrations

 

 

Uncertainty Factors

 

 

Small n

To NOAEL

 

 

Spaceflight

Acceptable Concentrations, ppm

Effect, Data, Reference

Species

Species

Time

1 h

24 h

7 d

30 d

180 d

CNS effects

 

NOAEL = 300 ppm, 2 h (Vernon and Ferguson, 1969)

Human

3.5

1

1

-

1

90

-

-

-

-

NOAEL = 100 ppm, 8 h (Stewart et al., 1974)

Human

3.0

1

1

3 (HR)

1

-

11

-

-

-

Cardiac arrhythmia

 

1/12 at 5000 ppm, 10 min (Reinhardt et al., 1973)

Dog

-

2

10

1

5

50

50

50

50

50

Hepatotoxicity and nephrotoxicity

Rat, guinea

-

1

10

-

1

-

-

-

4

2

NOAEL = 35 ppm, 7 h/d, 5 d (Stewart et al., 1970)

pig, monkey, rabbit, dog

 

 

 

 

 

 

 

 

 

 

NOAEL = 200 ppm, 7 h/d, 5 d (Stewart et al., 1970)

Human

4.5

1

1

5 (HR)

1

-

-

9

-

-

Carcinogenesis

 

1.7 × 10-6a at 0.00019 ppm, life continuous (EPA, 1987)

Human

-

NA

1

NA

1

-

300

40

10

2

SMACs

 

 

 

 

 

 

50

11

9

4

2

a Excess tumor risk of 1.7 × 10-6.

—, Data not considered applicable to the exposure time; HR, Haber's rule.

Suggested Citation:"B11: Trichloroethylene." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

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The National Aeronautics and Space Administration (NASA) has measured numerous airborne contaminants in spacecraft during space missions because of the potential toxicological hazards to humans that might be associated with prolonged spacecraft missions.

This volume reviews the spacecraft maximum allowable concentrations (SMACs) for various contaminants to determine whether NASA's recommended exposure limits are consistent with recommendations in the National Research Council's 1992 volume Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants.

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