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CHLOROFORM

BACKGROUND INFORMATION

PHYSICAL AND CHEMICAL PROPERTIES

Structural Formula:

CHCl3

Molecular weight:

119.39

Chemical Names:

Chloroform, Trichloromethane

CAS number:

67–66–3

Physical state:

Colorless liquid

Specific gravity:

1.49845 (15°/4°C)

Melting point:

−63.5°C

Boiling point:

61.2°C

Vapor pressure:

200 Torr (25°C)

Solubility:

1.0/100 ml of water at 15°C; soluble in ethanol, ethyl ether, benzene, acetone, and CS2

Flammability:

Not flammable by standard tests in air.

Conversion factors:

ppm=0.2 (mg/m3)

mg/m3=5.0 (ppm)

OCCURRENCE AND USE

Chloroform was widely used for many years as an anesthetic. Because it led to liver injury (often delayed) and cardiac sensitization, this use has been generally eliminated. Chloroform has some use as a solvent, but most of it is used as a chemical intermediate. Although its use as a solvent in industry is not extensive, it may be found as a constituent in solvent mixtures, and it is still commonly used as a laboratory solvent. Until recently, it was used as a flavoring agent in toothpaste. Chloroform is a contaminant of submarine atmospheres. It arises mainly from “off-gassing” of adhesives and plastics and possibly from medical uses (National Research Council, 1970).

Although the resulting concentrations are low, the process of chlorinating water yields chloroform at a few parts per billion. Higher quantities are produced during chlorination of sewage. Some chloroform appears to be produced by microorganisms in soil and water.

SUMMARY OF TOXICITY INFORMATION

EFFECTS ON HUMANS

Much of the toxicologic information on chloroform has been developed because of its use as an anesthetic. The literature is replete with papers on anesthetic potency and liver injury.

High concentrations of chloroform result in narcosis and anesthesia. The most outstanding effect of acute exposure is depression of the central nervous system (see Table 13). Responses associated with exposure at less than anesthetic or preanesthetic concentrations are typically inebriation and excitation passing into narcosis. Vomiting and gastrointestinal upset may be observed.



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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 CHLOROFORM BACKGROUND INFORMATION PHYSICAL AND CHEMICAL PROPERTIES Structural Formula: CHCl3 Molecular weight: 119.39 Chemical Names: Chloroform, Trichloromethane CAS number: 67–66–3 Physical state: Colorless liquid Specific gravity: 1.49845 (15°/4°C) Melting point: −63.5°C Boiling point: 61.2°C Vapor pressure: 200 Torr (25°C) Solubility: 1.0/100 ml of water at 15°C; soluble in ethanol, ethyl ether, benzene, acetone, and CS2 Flammability: Not flammable by standard tests in air. Conversion factors: ppm=0.2 (mg/m3) mg/m3=5.0 (ppm) OCCURRENCE AND USE Chloroform was widely used for many years as an anesthetic. Because it led to liver injury (often delayed) and cardiac sensitization, this use has been generally eliminated. Chloroform has some use as a solvent, but most of it is used as a chemical intermediate. Although its use as a solvent in industry is not extensive, it may be found as a constituent in solvent mixtures, and it is still commonly used as a laboratory solvent. Until recently, it was used as a flavoring agent in toothpaste. Chloroform is a contaminant of submarine atmospheres. It arises mainly from “off-gassing” of adhesives and plastics and possibly from medical uses (National Research Council, 1970). Although the resulting concentrations are low, the process of chlorinating water yields chloroform at a few parts per billion. Higher quantities are produced during chlorination of sewage. Some chloroform appears to be produced by microorganisms in soil and water. SUMMARY OF TOXICITY INFORMATION EFFECTS ON HUMANS Much of the toxicologic information on chloroform has been developed because of its use as an anesthetic. The literature is replete with papers on anesthetic potency and liver injury. High concentrations of chloroform result in narcosis and anesthesia. The most outstanding effect of acute exposure is depression of the central nervous system (see Table 13). Responses associated with exposure at less than anesthetic or preanesthetic concentrations are typically inebriation and excitation passing into narcosis. Vomiting and gastrointestinal upset may be observed.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 Exposure at high concentrations may result in cardiac sensitization to epinephrine and similar compounds, as well as liver and kidney injury (see Table 14). In cases of chronic or repeated exposure to chloroform, liver injury is most typical (cf. the effects of carbon tetrachloride). Although injury to the kidney is not as common as that to the liver, it may be observed from either acute or chronic exposure. Numerous reviews on the toxicity of chloroform are available (Challen et al., 1958; Davidson et al., 1982; NIOSH, 1974; Scholler, 1968; Van Dyke et al., 1964; Von Oettingen, 1955; Winslow and Gerstner, 1978; Zimmerman, 1968). Considering the long history of chloroform, there is surprisingly little epidemiologic literature on chronic exposure to it. There have been almost no quantitative toxicologic studies of human responses to chronic exposure to chloroform. Challen et al. (1958) studied an industrial operation in which chloroform was being used. Groups exposed at 77–237 ppm exhibited definite symptoms. Apparently, there were also some high peak concentrations for very short periods. Symptoms were gastrointestinal distress and depression. Another group with shorter service was exposed at 21–71 ppm and had comparable symptoms. Both groups were tested for liver injury, but none was found. The authors believed, however, that there may have been mild liver injury, and they recommended that atmospheric exposure be kept below 50 ppm. Bomski et al. (1967) reported on an investigation of a pharmaceutical plant that used chloroform as a solvent. Smaller amounts of methanol and methylene chloride were also used. Estimates of the airborne chloroform varied from 2 to 205 ppm (0.01–1.0 mg/L). Actual time-weighted average exposures of the workers were not reported; it is not clear if the room concentrations adequately described the workers’ actual exposure. Complaints of headache, nausea, eructation, and loss of appetite were reported, as well as enlargement of the liver (25% of workers) and spleen. Results of liver function tests were not remarkable. EFFECTS ON ANIMALS Acute Exposure When chloroform was given by gavage to male rats, an LD50 of 2,000 mg/kg (confidence range, 1,050–3,800 mg/kg) was determined (Torkelson et al., 1976). Deaths generally occurred in 2.4 h, but some were delayed as long as 2 wk after treatment. Gross pathologic examination showed liver and kidney changes at doses as low as 250 mg/kg. Thompson et al. (1974) fed chloroform to pregnant rats at 20 mg/kg per day for 10 d without effect on the dams; 50 mg/kg appeared to cause fatty changes. These data are discussed in more detail in the section on teratology below. Oettel (1936) indicated that chloroform was more irritating to the skin and eyes than many other chlorinated solvents. Oettel’s conclusions have been confirmed by Torkelson et al. (1976), One or two 24-h applications on the skin of rabbits resulted in hyperemia and moderate necrosis. Healing of abraded skin appeared to be delayed by

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 application of a cotton pad soaked in chloroform. Absorption through the intact skin of rabbits was indicated by weight loss and degenerative changes in the kidney tubules, but the animals survived doses as high as 3,980 mg/kg. When the liquid was instilled into the eyes of rabbits, some corneal injury was evident, in addition to conjunctivitis. The authors concluded that chloroform was more irritating to rabbit skin and eyes than most common fat solvents tested by the same technique in their laboratory. Chronic Exposure Several studies describing long-term oral administration of chloroform are available, but they were designed to evaluate carcinogenic response and have limited value in evaluating noncarcinogenic effects. They are discussed in the following section. Despite its long use, few reports on inhalation of chloroform are available. Repeated 7-h exposures to chloroform at 85, 50, or 25 ppm 5 d/wk for 6 mo resulted in adverse effects in all or some of the species studied: rats, rabbits, guinea pigs, and dogs. The effects at 25 ppm were slight and reversible. Rats exposed 1, 2, or 4 h/d were not adversely affected. Cloudy swelling of the kidneys and centrilobular granular degeneration and necrosis of the liver were the principal adverse effects (Torkelson et al., 1976). The effects of chloroform exposure in animals are summarized in Table 15. Teratogenesis Chloroform appears to be unique among the smaller chlorinated aliphatics, in that it is the only one that appears to be somewhat teratogenic and highly embryotoxic in animals. Schwetz et al. (1974) exposed pregnant Sprague-Dawley rats to chloroform vapor at 0, 30, 100, or 300 ppm 7 h/d. Exposures were given on days 6–15 of gestation, and cesarean sections were done to evaluate embryonal and fetal development. According to the authors: Exposure to chloroform caused an apparent decrease in the conception rate and a high incidence of fetal resorption (300 ppm), retarded fetal development (30, 100, 300 ppm), decreased fetal body measurements (30, 300 ppm) and a low incidence of acaudate fetuses with imperforate anus (100 ppm). Chloroform was not highly teratogenic but was highly embryotoxic. The results of this study disclosed no relationship between maternal toxicity and embryo or fetotoxicity as the result of exposure to chloroform by inhalation. In another inhalation study, Murray et al. (1979) evaluated the effect of inhaled chloroform on embryonal and fetal development in CF-1 mice. Pregnant mice were exposed to chloroform at 0 or 100 ppm 7 h/d on days 1–7, 6–15, or 8–15 of gestation. Exposure on days 6–15 or 1–7 produced a significant decrease in the incidence of pregnancy, but did not cause significant teratogenicity. A significant increase in the incidence of cleft palate was observed among the offspring of mice

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 exposed on days 8–15 of gestation; no effect on the incidence of pregnancy was discerned. A significant increase in serum glutamic pyruvic transaminase (SGPT) activity was observed in mice exposed on days 6–15. Bred mice that were not pregnant had significantly higher SGPT activity than pregnant mice. Similar results were reported by Dilley et al. (1977), who exposed pregnant rats to chloroform vapor at 4,441 ppm (duration of daily exposure not stated) and produced increased fetal mortality and decreased fetal weight gain, but no teratologic effects. Thompson et al. (1974) failed to produce teratogenic effects in Sprague-Dawley rats given chloroform by intubation at 0, 20, 50, or 126 mg/kg/per day on days 6–15 of gestation or in Dutch belted rabbits given chloroform at 0, 20, 35, or 50 mg/kg/per day on days 6–18. These authors stated: The occurrence of anorexia and weight gain suppression in dams of both species, as well as subclinical nephrosis in the rat and hepatotoxicity in the rabbit, indicated that maximum tolerated doses of chloroform were used. Fetotoxicity in the form of reduced birth weights was observed at the highest dose level in both species. There was no evidence of teratogenicity in either species at any dose tested. It appears that chloroform has more fetotoxic effect when inhaled than when given by gavage. Thompson et al. (1974) speculated that doses given by gavage may result in different blood chloroform contents; that accounts for the apparent discrepancy with the effects seen after inhalation. Mutagenesis Chloroform failed to produced mutagenic changes in cultures of Chinese hamster lung fibroblast cells (Sturrock, 1977) or in the Salmonella/microsome test with typhimurium strains TA1535, 1537, 1538, 98, and 100 (Simmon et al., 1977). Carcinogenesis The available data from carcinogenicity studies in mice were summarized by IARC (1972). Chloroform has since been studied in Osborne-Mendel rats and B6C3F1 mice in the NCI bioassay program (Weisburger, 1977). Male (but not female) rats developed kidney epithelial tumors at 180 and 90 mg/kg per day. Mice of both sexes developed hepatocellular carcinomas at 138 and 277 mg/kg per day (males) and 238 and 477 mg/kg per day (females). The relationship of this study (in which the maximal tolerated dose was given by repeated gavage) to industrial exposure (in which vapors were inhaled) has been questioned (Reitz et al., 1978; Roe et al., 1979; Stokinger, 1977). Data are available from long-term studies in rats, mice, and dogs fed a toothpaste base containing chloroform (Heywood et al., 1979; Palmer et al., 1979; Roe et al., 1979). Rats, mice, and dogs were fed lower doses than those used in the NCI bioassay study. Table 16 summarizes the studies. The males of only one of four strains of mice

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 developed an excess of tumors. No excess was found in the females of any strain, nor in the dogs and rats. Adenomas in the renal cortex and hypernephromas regarded as possibly malignant occurred in male mice fed 60 mg/kg per day, but not 17 mg/kg per day (Roe et al., 1979). The importance of these tumors in indicating a carcinogenic effect is not clear, inasmuch as they had not spread to other organs and have since been observed in control mice of the same strain (ICI-Swiss). The metabolic relationship of the data from high-dose studies in animals to man as discussed by Reitz et al. (1978), is presented in the following section. PHARMACOKINETICS AND MOLECULAR INTERACTION There are so many references to the absorption, excretion, and metabolism of chloroform that the data are at times understandably contradictory. There is no question but that chloroform is rapidly absorbed through the lungs, GI tract, and to some extent the skin; that some is metabolized; and that some is excreted in expired air. Chloroform has been shown to be metabolized by microsomal mixed-function oxidases (MFOs) to CO2 (Paul and Rubinstein, 1963; Van Dyke et al., 1964) and by a sulfhydryl-dependent pathway to CO (Stevens and Anders, 1979). Differences in doses may account for the apparent discrepancies in routes of elimination proposed by various investigators and there are wide differences between species in ability to excrete unchanged chloroform (see Table 17, from Reitz et al., 1978). These data suggest that chloroform metabolism is less efficient in man than in the rodent species. Because metabolism of chloroform to a reactive intermediate is likely to mediate toxicity (discussed below), the metabolism data suggest that man would be less sensitive than rodents; this is generally consistent with the available data (Reitz et al., 1978). The mechanism of action of toxicity of chloroform has been studied by several investigators. All data tend to support the hypothesis that microsomal-enzyme-mediated metabolism of chloroform to a reactive intermediate is responsible for its hepatoxic and nephrotoxic effects (Ilett et. al., 1973; Lavigne and Marchand, 1974; Pohl, 1979). Ilett et al. (1973) have shown that the microsomal MFO inducer, phenobarbital, increases toxicity, whereas piperonyl butoxide—an inhibitor of MFOs—inhibits toxicity in mice treated with chloroform. Furthermore, induction and inhibition of MFOs is correlated with intracellular macromolecular binding reactions in the liver and kidneys; that suggests formation of a reactive intermediate. It has been postulated that phosgene is the reactive intermediate formed from chloroform (Bhooshan et al., 1977; Pohl, 1979) and that intracellular glutathione is the primary nucleophile responsible for detoxification (Brown et al., 1974a; Docks and Krishna, 1976). Reitz et al. (1980) and Moore et al. (1980) have postulated that the carcinogenic effect observed in animals after oral administration of chloroform has an epigenetic mechanism. This conclusion was based on the lack of genotoxic activity of chloroform and the pronounced cytotoxicity in the target organs susceptible to tumor formation.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 Chloroform has not been shown to be active in in vitro mutagenicity tests, and this is consistent with its low interaction with DNA in vivo (fewer than 3 alkylations/106 DNA nucleotides), compared with dimethylnitrosamine (900 alkylations/106 DNA nucleotides), which mediates its carcinogenic effect through direct interaction with DNA (Reitz et al., 1980). DNA damage measured by DNA repair was not observable when carcinogenic doses of chloroform were administered to mice. In contrast with the lack of genotoxic activity of chloroform at carcinogenic doses, cytotoxicity observed histopathologically and indicated by increased DNA synthesis (regeneration after cellular death) was marked in the liver and kidneys of mice that received carcinogenic doses (Reitz et al., 1980; Moore et al., 1980). These data suggest that the tumors induced by chloroform may have been secondary to tissue toxicity and thus that the risk of carcinogenesis may be diminished below cytotoxic doses. INHALATION EXPOSURE LIMITS Work place inhalation exposure limits recommended for chloroform are summarized in Table 18. COMMITTEE RECOMMENDATIONS EXPOSURE LIMITS In 1970, the Committee on Toxicology recommended EELs and CEL for chloroform as follows: 1-h EEL: 200 ppm 24-h EEL: 30 ppm 90-d CEL: 3 ppm Chloroform is easily absorbed, and substantial amounts are retained during inhalation. It concentrates heavily in adipose and adrenal tissues, but much is also retained by brain, kidney, and blood. There are qualitative and quantitative differences in metabolism between man and animals, and humans metabolize it more slowly. CO2 is a major metabolite in all species, with the liver and to some extent the kidneys being involved. Metabolism also results in formation of small amounts of phosgene, carbenes, and free radicals. Covalent binding to DNA or nucleic acids is not an important aspect of metabolism. Exposure to chloroform at high concentrations produces anesthesia. After acute high doses or repeated at lower doses, hepatotoxicity is the major effect in humans and is, sometimes, accompanied by renal toxicity. Chloroform is fetotoxic in animals, in four of six studies, with effects at 100 ppm but not 30 ppm in rats (Schwetz et al., 1974). It is not teratogenic. Long-term studies in animals demonstrated that chloroform has a carcinogenic potential (Davidson et al., 1982). Epidemiologic studies

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 revealed that anesthesiologists from the chloroform era had a higher cancer mortality rate than those of the postchloroform period (Linde and Mesnick, 1980). However, confounding factors limit interpretation of these findings. Acute human studies showed that 390 ppm is tolerated for 30 min without complaint, whereas 1,030 ppm results in dizziness, intracranial pressure, and nausea in 7 min, with headache for several hours (Lehmann and Flury, 1943). Symptoms were experienced by workers in a plant manufacturing chloroform-containing lozenges when the chloroform concentration was 21–71 ppm and exposure was for 4 h/d over a period of 10–24 mo (Challen et al., 1958). Severe symptoms occurred in other workers in this plant exposed at 77–232 ppm for 3–10 yr. The aforementioned acute and chronic information, taken with data on the fetotoxic potential of chloroform, appears to support a 1-h EEL of 100 ppm and a 24-h EEL of 30 ppm. The reduction of the 1-h EEL from 200 to 100 ppm is based on the fetotoxic potential of chloroform, as related to possible exposure of women of childbearing-age. The long-term studies are more difficult to evaluate. Because a carcinogenic potential cannot be excluded, caution is required in the interpretation of the findings. Furthermore, all sources of chloroform contamination of the atmosphere should be minimized in confined areas where workers are exposed for long periods. The data of Roe et al. (1979) show that mice given chloroform by gavage (in toothpaste) at 17 mg/kg per day were not affected, whereas those exposed at 60 mg/kg per day developed tumors. The data of Torkelson et al. (1976) showed that rats inhaling chloroform at 50 and 85 ppm 7 h/d, 5 d/wk for 6 mo developed liver and renal histopathologic conditions, whereas adverse effects produced at 25 ppm were reversed when exposure was stopped. These rats were exposed 21% of the time (35 of a possible 168 h/wk) Exposure in this manner at 50 ppm (the lower of the first two concentrations) would be equivalent to continuous exposure at 10 ppm. Use of a 10-fold uncertainty factor yields a concentration of 1 ppm. With exposure at 1 ppm, a human breathing at 10 L/min (an average resting rate) would inhale 70.4 mg of chloroform over a 24-h period (1 ppm=4.89 mg/m3), or about 1 mg/kg per day. Gavaged mice exposed at 60 mg/kg per day developed tumors; those exposed at 17 mg/kg per day did not. Therefore, exposure at 1 ppm would be considerably less than the long-term exposure of mice that did not develop tumors. The Committee suggests that the 90-d CEL for chloroform be reduced from 3 ppm to 1 ppm, on the basis of the long-term animal studies. In summary, the Committee recommends the following EELs and CEL: 1-h EEL: 100 ppm 24-h EEL: 30 ppm 90-d CEL: 1 ppm

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 TABLE 13 Chloroform Inhalation Exposures and Effects in Humans Concentration, ppm Exposure Duration, min Effects Ref. 20,000 30–24 Anesthesia; nausea; vomiting; jaundice; delayed chloroform poisoning Whitaker and Jones (1965) 922 3 Dizziness, vertigo Lehmann and Schmidt-Kehl (1936) 1,107 2 Dizziness, vertigo 7,236 15 Dizziness, light intoxication Lehmann and Hasegawa (1910) 205 approx. 1 Perception of light transient odor Lehman and Schmidt-Kehl (1936) 14,420–16,480 NGa Limited narcotic concentration Lehman and Flury (1943) 4,120   Fainting sensation; vomiting   1,483   Dizziness and salivation after a few minutes   1,030   Dizziness, intracranial pressure, and nausea in 7 min; after-effect of fatigue and headache for several hours   391   Tolerated for 30 min without complaint   206–309   Lowest concentration detected by smell   aNot given, except as listed under “effects.”

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 TABLE 14 Six Cases of Delayed Chloroform Poisoning Age, yr Dosage Effects Laboratory Test and Autopsy Findings Ref. 37 3 administrations: 3 capsules, each 20 minims; “very little” from drop bottle; 3 capsules, each 20 minims and anesthesia on open mask Restless, coma and convulsions, on 2nd postpartum day, vomiting, jaundice; increased pulse and temperature; died on 8th postpartum day Blood urea: 198/100 cc on 3rd day, 303 mg/100 cc on 5th day; blood NPN: 187 mg; amino acid nitrogen: 8.2 mg %; urine: acid, albumin, red blood cells, pus, high urobilinogen; liver: soft, yellow, advanced necrosis, and fatty degeneration; kidneys: swollen, fatty deposits, necrosis; heart: fatty degeneration Gibberd (1935) 30 2 inhalations of unspecified amount separated by 2 h, and anesthesia on open mask Drowsy, swelling of hands, jaundice; coma; increased temperature and pulse; extreme hyperpnea; no vomiting; died 5th postpartum day blood urea: 105 mg/100 cc on 2nd day; 360 mg/100 cc on 5th day; plasma bicarbonate: 0.003 m; urine: uric acid, albumin, pus, 2.35% urea on 3rd day; liver: yellow, mottled, soft, diffuse centrilobular necrosis, fat mostly in periphery Gibberd (1935) 25 Full anesthesia on open mask “long time” Drowsy, jaundice; coma on 4th day, muscular twitching; increased temperature, vomiting; died on 6th postpartum day Blood: 0.093% sugar, urea at 60 mg/100 cc; urine: deep orange, pH 6.0, 0.4% albumin, diacetic acid; liver: soft, flabby, recent shrinkage, yellow, widespread necrosis; kidneys: congestion of cortical vessels; heart: fatty changes Gibberd (1935)

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 Age, yr Dosage Laboratory Test Effects And Autopsy Findings Ref. 24 Unspecified Restless; delirium; coma; jaundice; drowsy, increased temperature; muscle twitching; no vomiting; recovered Urine: albumin, bilirubin, urobilin Lunt (1953) 35 2 doses, unspecified Drowsiness, mental confusion, coma, jaundice, tenderness over liver, hiccups; restless, no vomiting; recovered Urine: albumin bilirubin, urobilin Lunt (1953) 23 2 doses, unspecified Jaundice; nausea; general weakening; slight icterus; recovered No observations Lunt (1953)

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 TABLE 15 Chloroform Inhalation Exposure and Effects in Animals Species Dosages Exposure Duration Effects Ref. Dog 1–2 oz. (total) 1–2 h Anesthesia; central hyaline necrosis; acute yellow atrophy and fatty degeneration of the kidneys Whipple and and Sperry (1909) Dog 13,450–15,546 ppm 60–285 min Narcosis; respiratory rate fluctuation; decrease in blood pressure and body temperature; death von Oettingen et al. (1949) Mouse 6,765 ppm 0.5 h Narcosis; death Fuhner (1923) Cat 7,175 ppm 7.8 Light narcosis Lehmann and Schmidt-Kehl (1936) Mouse 400 and 800 ppm 4 h Fatty infiltration of liver, liver necrosis, increased SOCT activity Kylin et al. (1963) Mouse 100 ppm 200 ppm 4 h 4 h Moderate fatty infiltration of liver Some liver necrosis, increased SOCT activity Kylin et al. (1963) Rat 85 ppm 6 mo 7 h/d 5 5 d/wk, 6 mo Male: increased mortality (pneumonia), centrilobular degeneration in liver, and renal histopathology; female: liver and kidney effects similar to those in males Torkelson et al. (1976) Guinea pig 85 ppm 7 h/d, 5 d/wk, 6 mo Male: no effects; Female: slight pneumonitis Torkelson et al. (1976) Rabbit 85 ppm 7 h/d, 5 d/wk, 6 mo Male: marked pneumonitis and liver necrosis; female: liver and kidney pathologic conditions Torkelson et al. (1976)

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 Species Dosages Exposure Duration Effects Ref. Rat 50 ppm 7 h/d, 5 d/wk 60 mo Male: similar to effects at 85 ppm but less in degree, decreased body weight, and liver and kidney pathologic conditions; female: less affected than male liver/kidney pathology Torkelson et al. (1976) Guinea pig 50 ppm 7 h/d, 5 d/wk 60 mo No effects Torkelson et al. (1976) Rabbit 50 ppm 7 h/d, 5 d/wk 60 mo No effects Torkelson et al. (1976) Rat 25 ppm 7 h/d, 5 d/wk 6 mo Slight histopathologic effects in liver and kidney effects, but not considered significant, because no dose-response relation   Guinea pig 25 ppm 7 h/d, 5 d/wk 6 mo Some liver and kidney effects, but not considered significant, because no dose-response relation Torkelson et al. (1976) Rabbit 25 ppm 7 h/d, 5 d/wk 6 mo Male: Some tubular nephritis; female: some tubular nephritis and liver and other kidney effects (no dose-response relation) Torkelson et al. (1976) Dog 25 ppm 7 h/d, 5 d/wk 6 mo Male: no change; female: swelling of renal tubular epithelium Torkelson et al. (1976) Rat 25 ppm 4, 2, or 1 h/d 5 d/wk, 6 mo No adverse effects Torkelson et al. (1976)

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 TABLE 16 Summary of Carcinogenicity Studies of Chloroform Carried Out at Huntingdon Research Center Species Dosage, mg/kg per daya No. Animals Duration of Exposure Excess of Neoplasms Reference Male Female Rat:   Sprague/Dawley 60 50 50 95 wk None Palmer et al. (1979) Mouse:   ICI-Swiss 17 52 52 80 wk None Renal tumors Roe et al. (1979)     60 52 80 wk   60 52 80 wk None C57BL 60 52 — 80 wk None   CBA 60 52 — 80 wk None   CF/1 60 52 — 80 wk None   Dog:   Beagle 15 8 8 7–1/2 yr None Heywood et al. (1979)   30 8 8 7–1/2 yr None a6 d/wk.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 TABLE 17 Interspecies Comparisons of Chloroform Excretiona Species Oral Dose, mg/kg CHCl3 Excreted Unchanged, % of dose Ref. Mouse 60 6 Brown et al. (1974b) Rat 60 20 Brown et al. (1974b) Monkey 60 78 Brown et al. (1974b) Man 7 7–66 Fry et al. (1972) aAdapted from Reitz et al. (1978)

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 TABLE 18 Chloroform Inhalation Exposure Limits Institution Kind of Limit Concentration Reference ACGIH TLV-TWA 10 ppm ACGIH (1980) OSHA Ceiling 50 ppm OSHA (1981) NRC   Panel on Air Standards for Manned Space Flight 90 d 5 ppm NRC (1968) 1,000 d 1 ppm Italy MAC 20 ppm Soc. Ital. Med. Lav. (1975) Japan MAC 50 ppm Jap. Assoc. Ind. Health (1971)

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 REFERENCES American Conference of Governmental Industrial Hygienists. 1980. Documentation of the Threshold Limit Values. 4th ed. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists. Bhooshan, B., Pohl, L.R., and Krishna, G. 1977. A biochemical mechanism for chloroform activation. Fed Proc. 36:396, abstr. no. 674. Bomski, H., Sobolewska, A., and Strakowski, A. 1967. [Toxic injury of the liver due to chloroform in workers in the chemical industry.] Int. Arch. Gewerbepathol. Gewerbehyg. 24:127–134. [Abstr. Hyg. 43:1009–1010, abstr. no. 3330, 1968] Brown, B.R., Jr., Sipes, I.G., and Sagalyn, A.M. 1974a. Mechanisms of acute hepatic toxicity: Chloroform, halothane, and glutathione. Anesthesiology 41:554–561. Brown, D.M., Langley, P.F., Smith, D., and Taylor, D.C. 1974b. Metabolism of chloroform-I. The metabolism of [14C] chloroform by different species. Xenobiotica 4:151–163. Challen, P.J.R., Hickish, D.E., and Bedford J. 1958. Chronic chloroform intoxication. Br. J. Ind. Med. 15:243–249. Davidson, I.W.F., Sumner, D.D., and Parker, J.C. 1982. Chloroform: A review of its metabolism, teratogenic, mutagenic, and carcinogenic potential. Drug Chemical Toxicol. 5:1–87. Dilley, J.V., Chernoff, N., Kay, D., Winslow, N., and Newell, G.W. 1977. Inhalation teratology studies of five chemicals in rats. Toxicol. Appl. Pharmacol. 41:196, abstr. no. 154. Docks, E.L., and Krishna, G. 1976. The role of glutathione in chloroform-induced hepatotoxicity. Exp. Mol. Pathol. 24:13–22. Fry, B.J., Taylor, T., and Hathway, D.E. 1972. Pulmonary elimination of chloroform and its metabolite in man. Arch Int. Pharmacodyn. 196:98–111. Fuhner, H. 1923. Relative potencies of chlorform and carbon tetrachloride. Arch. Exp. Pathol. Pharmacol. 97:86–112. [Chem. Abs. 17:2454, 1923] Gibberd, G.F. 1935. Delayed chloroform poisoning in obstetric practice; clinical study, with reports on 3 cases. Guy’s Hosp. Rep. 85:142–160. [Qtly. Cumul. Ind. Med. 18:519, 1935] Heywood, R., Sortwell, R.J., Noel, P.R.B., Street, A.E., Prentice, D.E., Roe, F.J.C., Wadsworth, P.F., Worden, A.N., and Van Abbe, N.J. 1979. Safety evaluation of toothpaste containing chloroform. III. Long-term study in beagle dogs. J. Environ. Pathol. Toxicol. 2:835–851.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 Ilett, K.F., Reid, W.D., Sipes, I.G., and Krishna, G. 1973. Chloroform toxicity in mice: Correlation of renal and hepatic necrosis with covalent binding of metabolites to tissue macromolecules. Exp. Mol. Pathol. 19:215–229. International Agency for Research on Cancer. 1972. Chloroform. In IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Volume 1. Lyon, France: International Agency for Research on Cancer. p. 61–65. Japan Association of Industrial Health. 1971. Recommendations for permissible concentrations, etc. Transl. of Sangyo Igaku, (Jpn. J. Ind. Health) 13:475–484. Kylin, B., Reichard, H., Sumegi, I., and Yllner, S. 1963. Hepatotoxicity of inhaled trichloroethylene, tetrachloroethylene and chloroform. Single exposure. Acta Pharmacol. Toxicol. 20:16–26. Lavigne, J.G., and Marchand, C. 1974. The role of metabolism in chloroform hepatotoxicity. Toxicol. Appl. Pharmacol. 29:312–326. Lehmann, K.B., and Flury, F., eds. 1943. Toxicology and Hygiene of Industrial Solvents, Translated by E.King and H.F.Smyth, Jr. Baltimore: Williams & Wilkins. [378 p.] Lehmann, K.B., and Hasegawa. 1910. The absorption of chlorinated hydrocarbons from the air by animals and man: Chloroform, carbon tetrachloride and tetrachloroethane. Arch. Hyg. 72:327–342. [Chem. Abs. 4:2949, 1910] Lehmann, K.B., and Schmidt-Kehl, L. 1936. Thirteen most important chlorohydrocarbons of the paraffin series from the standpoint of industrial hygiene. Arch. Hyg. Bakteriol. 116:131–268. [Chem. Abs. 31:4774, 1937] Linde, M.W., and Mesnick, P.S. 1980. Causes of death of anesthesiologists from the chloroform era. Gov’t Reports Announcements and Index 80:1148. Lunt, R.L. 1953. Delayed chloroform poisoning in obstetric practice. Br. Med. J. 1:489–490. Moore, D., Chasseaud, L.F., Majeed, S.K., Prentice, D.E., Roe, F.J.C., and Van Abbe, N.J. 1980. Effect of dose and vehicle on early tissue damage and regenerative activity after chloroform administration. Abstracts of the Second International Congress on Toxicology, Brussels, July 6–11, 1980. Toxicol. Lett., Special Issue 1:234, abstr. no. P. 214. Murray, F.G., Schwetz, B.A., McBride, J.G., and Staples, R.E. 1979. Toxicity of inhaled chloroform in pregnant mice and their offspring. Toxicol. Appl. Pharmacol. 50:515–522.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 National Institute for Occupational Safety and Health. 1974. Criteria for a Recommended Standard…Occupational Exposure to Chloroform. Cincinnati, Ohio: U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health. (HEW Publ. No. (NIOSH) 75–114. 120 p. [PB-246 695] National Research Council, Space Science Board. 1968. Atmospheric Contaminants in Spacecraft. Washington, D.C.: National Academy of Sciences. [86 p.] National Research Council, Committee on Toxicology. 1970. Letter to Chief, Bureau of Medicine and Surgery, Dept. of the Navy, Washington, D.C. 20390, dated 4 Sept. 1970. (File P-551) Occupational Safety and Health Administration. 1981. Air Contaminants. 29 CFR 1910:1000. Oettel, H. 1936. Actions of organic liquids upon the skin. Arch. Exp. Pathol. Pharmakol. 183:641–696. [Chem. Abs. 31:63344, 1937] Palmer, A.K., Street, A.E., Roe, F.J.C., Worden, A.N., and Van Abbe, N.J. 1979. Safety evaluation of toothpaste containing chloroform. II. Long term studies in rats. J. Environ. Pathol. Toxicol. 2:821–833. Paul, B.B., and Rubinstein, D. 1963. Metabolism of carbon tetrachloride and chloroform by the rat. J. Pharmacol. Exp. Ther. 141:141–148 Pohl, L.R. 1979. Biochemical toxicology of chloroform. Rev. Biochem. Toxicol. 1:79–107. Reitz, R.H., Gehring, P.J., and Park, C.N. 1978. Carcinogenic risk estimation for chloroform: An alternative to EPA’s procedures. Food Cosmet. Toxicol. 16:511–514. Reitz, R.H., Quast, J.F., Stott, W.T., Watanabe, P.G., and Gehring, P.J. 1980. Pharmacokinetics and macromolecular effects of chloroform in rats and mice: Implications for carcinogenic risk estimation. In R.L.Jolley, W.A.Brungs, and R.B.Cumming, eds. Water Chlorination: Environmental Impact and Health Effects, vol. 3. Proc. of the Third Conf. on Water Chlorination: Environmental Impact and Health Effects. Colorado Springs, Colo. Ann Arbor, Mich.: Ann Arbor Science, p. 983–993. Roe, F.J.C., Palmer, A.K., Worden, A.N., and Van Abbe, N.J. 1979. Safety evaluation of toothpaste containing chloroform. I. Long-term studies in mice. J. Environ. Pathol. Toxicol. 2:799–819. Scholler, K.L. 1968. Electron-microscopic and autoradiographic studies on the effect of halothane and chloroform on liver cells. Acta Anaesthesiol. Scand. V. 12, Suppl. 32. [62 p.]

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 Schwetz, B.A., Leong, B.K.J., and Gehring, P.J. 1974. Embryo- and fetotoxicity of inhaled chloroform in rats. Toxicol. Appl. Pharmacol. 28:442–451. Simmon, V.F., Kauhanen, K., and Tardiff, R.G. 1977. Mutagenic activity of chemicals identified in drinking water. In D.Scott, B.A. Bridges, and F.H.Sobels, eds. Progress in Genetic Toxicology. Developments in Toxicology and Environmental Science. Vol. 2. New York: Elsevier/North-Holland, p. 249–258. Societa Italiana di Medicina del Savora: Associazione Italiana degli Igienisti Industriali. 1975. Valori Limite Ponderati degli Inguinanti Chimici e Particolati degli Ambrenti di Lavoro Per IL. 1975. Med. Lav. 66:361–371. Stevens J.L., and Anders, M.W. 1979. Metabolism of haloforms to carbon monoxide-III. Studies on the mechanism of the reaction. Biochem. Pharmacol. 28:3189–3194. Stokinger, H.E. 1977. Toxicology and drinking water contaminants. J. Am. Water Works Assoc. 69:399–402. Sturrock, J. 1977. Lack of mutagenic effect of halothane or chloroform on cultured cells using the azaguanine test system. Br. J. Anaesth. 49:207–210. Thompson, D.J., Warner, S.D., and Robinson, V.B. 1974. Teratology studies on orally administered chloroform in the rat and rabbit. Toxicol. Appl. Pharmacol. 29:348–357. Torkelson, T.R., Oyen, F., and Rowe, V.K. 1976. The toxicity of chloroform as determined by single and repeated exposure of laboratory animals. Am. Ind. Hyg. Assoc. J. 37:697–705. Van Dyke, R.A., Chenoweth, M.B., and Van Poznak, A. 1964. Metabolism of volatile anesthetics. I. Conversion in vivo of several anesthetics to 14CO2 and chloride. Biochem. Pharmacol. 13:1239–1247. Von Oettingen, W.F. 1955. The Halogenated Aliphatic, Olefinic, Cyclic, Aromatic, and Aliphatic-Aromatic Hydrocarbons Including the Halogenated Insecticides, Their Toxicity and Potential Dangers. Washington, D.C: U.S. Department of Health, Education, and Welfare. Public Health Service Publication No. 414. [430 p.] Von Oettingen, W.F., Powell, C.C., Sharpless, N.E., Alford, W.C., and Pecora, L.J. 1949. Relation Between the Toxic Action of Chlorinated Methanes and Their Chemical and Physicochemical Properties. Washington, D.C.: Federal Security Agency, U.S. Public Health Service. National Institutes of Health Bulletin No. 191. [85 p.] Weisburger, E.K. 1977. Carcinogenicity studies on halogenated hydrocarbons. Environ. Health Perspect. 21:7–16.

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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Volume 1 Whipple, G.H., and Sperry, J.A. 1909. Chloroform poisoning. Liver necrosis and repair. Bull. Johns Hopkins Hosp. 20:278–289. Whitaker, A.M., and Jones, C.S. 1965. Report of 1500 chloroform anesthetics administered with a precision vaporizer. Anesth. Analg. (Cleveland) 44:60–65. Winslow, S.G., and Gerstner, H.B. 1978. Health aspects of chloroform. A review. Drug Chem. Toxicol. 1:259–275. Zimmerman, H.J. 1968. The spectrum of hepatotoxicity. Perspect. Biol. Med. 12:135–161.