Current Intelligence Bulletin 9: Chloroform (DDM)

Department of Health, Education, and Welfare
Public Health Service
Center for Disease Control

National Institute for Occupational Safety and Health
5600 Fishers Lane
Rockville, Maryland 20852

The enclosed background material an chloroform has been prepared by the Office of Extramural Coordination and Special Projects, National Institute for Occupational Safety and Health, to alert members of the occupational health community to new information on a potential occupational hazard.

Your comments and suggestions for changes to future reports are solicited.

Sincerely yours,
[signature]
John F. Finklea, M.D.
Director

Summary

Chloroform has been shown to be carcinogenic by ingestion in laboratory mice and rats, according to a report recently released by the National Cancer Institute. Because of the uses of chloroform in the work environment and the potential for cancer induction in humans, the National Institute for Occupational Safety and Health (NIOSH) is alerting the occupational health community as part of its Current Intelligence System. In addition, NIOSH is attempting to identify a worker population at risk of chloroform exposures for epidemiologic study.

Introduction

On March 1, 1976, the National Cancer Institute released its report on the carcinogenic bioassay of chloroform.¹ According to this report, chloroform ingestion produced malignant kidney tumors in rats and hepatocellular carcinoma in mice.

Background

Chloroform is a colorless volatile liquid, has a normal boiling point of 61°C, and is miscible with the principal organic solvents. Chloroform is manufactured by the chlorination of methane in a process which can be made to yield varying proportions of methyl chloride, methylene chloride, chloroform, and carbon tetrachloride. A list of domestic manufacturers and producers of chloroform is presented in Table 1 and the domestic distributors of chloroform are listed in Table 2.

During 1974, 302 million pounds of chloroform were produced in the United States. Domestic sales for the same year were 252 million pounds.³

Most of the chloroform produced is consumed as a raw material in the preparation of fluorocarbons. [Fluorocarbons are used as aerosol propellants, refrigerants, and blowing agents as well as in the manufacture of fluorocarbon resins such as polytetrafluoroethylene].

Other applications⁵ of chloroform have included use in the extraction and purification of penicillin and other antibiotics, in the purification of alkaloids, in the solvent extraction of vitamins and flavors, as a general solvent, as an intermediate in the preparation of dyes, drugs, and pesticides, and as an anesthetic. Chloroform is currently found in cough and cold preparations, dental preparations (tooth-ache drops, toothpastes, mouthwashes) and topical liniments. Chloroform would be found in most chemistry laboratories.

Toxicity

Human

Chloroform was first used as an anesthetic in 1847. Its narcotic effects on the central nervous system have been well-documented.^6,7,8 Toxic hepatitis has been reported among chemical workers exposed to chloroform⁹ and, in addition, cardiac irregularities during anesthesia, and local irritation when applied to skin, have also been reported.¹⁰

Two epidemiologic studies of occupational exposure to chloroform found episodes of lassitude, dry mouth, depression, irritability and painful urination.^9,11

To date, there have been no published reports of any association between chloroform and cancer in humans.

Animal

Depression of the central nervous system has been seen in a number of animal studies of effects of chloroform inhalation.¹² Inhalation of chloroform also produces dilation of pupils of the eyes, reduced reaction to light, and reduced intraocular pressure. Fatty degeneration and necrosis of the liver as well as kidney impairment have been seen in experimental animals after ingestion, inhalation, and intravenous administration.¹³

Carcinogenic effects of chloroform in laboratory animals have been reported in two published studies. Eschenbrenner, in 1945, produced hepatomas in 7 of 10 female mice fed 30 doses at 4-day intervals of approximately 600 to 1200 mg/kg/dose over a four-month period. The other three female mice died within the first week of the experiment. Male mice receiving similar doses also died within the first week.¹⁴

In the recent National Cancer Institute study, Osborne-Mendel rats were fed chloroform in corn oil (at 90 and 180 mg/kg body weight for males and at 100 and 200 mg/kg for females) for 111 weeks. A significant increase in epithelial tumors of the kidney in treated male rats was observed. Of the 13 tumors of renal tubular cell epithelium observed in 12 of the 50 high dose male rats, ten were carcinomas and three adenomas; two of the carcinomas were found to have metastasized. Two carcinomas and two adenomas of renal tubular epithelium were observed among the 50 low dose male rats. The tubular cell adenocarcinoma widely metastasized. An increase in thyroid tumors in chloroform-treated female rats was also seen; however, NCI does not consider these to be significant findings.

Mice (B6C3F) were fed chloroform for 92-93 weeks at 138 and 277 mg/kg doses for males and at 238 and 477 mg/kg doses for females. A highly significant increase in hepatocellular carcinomas was observed in both sexes of treated mice when compared with control animals. The incidence of hepatocellular carcinoma was 98% for males and 95% for females at the high dose, and 36% for males and 80% for females at the low dose compared with 6% in both matched and colony control males, none in matched control females, and 1% in colony control females. Nodular hyperplasia of the liver was observed in many low dose male mice that had not developed hepatocellular carcinoma.

Occupational Exposure

The National Institute for Occupational Safety and Health estimates that 40,000 persons are exposed occupationally to chloroform. The majority of these are workers in industries where chloroform is used in small amounts. These industries include those producing biological products, pharmaceutical preparations, paint and allied products, and surgical supplies, as well as hospitals, paper milling, petroleum refining and metal industries.

The current Occupational Safety and Health Administration ceiling value standard for workplace air is 50 ppm.¹⁵

On September 11, 1974, the National Institute for Occupational Safety and Health transmitted criteria for a recommended standard on chloroform to the Department of Labor, NIOSH’s recommendations included that no worker be exposed to chloroform in excess of 10 ppm determined as a time-weighted average exposure for up to a 10-hour workday, 40-hour work week, or for any 10-minute period to more than 50 ppm.¹⁰

Epidemiologic Studies

The Division of Surveillance, Hazard Evaluations, and Field Studies, NIOSH, is planning to conduct environmental and mortality studies in industries in which people are exposed to chloroform. Efforts are now in progress to identify worker populations at risk of chloroform exposures for epidemiologic study.

TABLE 1 Domestic Manufacturers and Producers of Chloroform

Adapted From:
1975 Directory of Chemical Producers, United States of America, Stanford Research Institute, Menlo Park, California, 1975, p. 478.

Synthetic Organic Chemicals, U.S. Production and Sales, 1973, U.S. International Trade Commission, ITC Publication 728, Washington, D.C., 1975, p. 231.

TABLE 2 Domestic Distribution of Chloroform

Adapted from: Chem. Sources U.S.A., 1976 Edition, Directories Publishing Company, Flemington, New Jersey.

References

1. Carcinogenesis Program, Division of Cancer Cause and Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Report on Carcinogenesis Bioassay of Chloroform. March 1, 1976.
2. Number not used.
3. Synthetic Organic Chemicals, United States Production and Sales of Miscellaneous Chemicals, 1974. Preliminary, United States International Trade Commission, Washington, D.C., p. 9, January 1976.
4. Number not used.
5. Hardie, D.W.F. in Kirk-Othmer Encyclopedia of Chemical Technology, Second Edition. Interscience Publishers, New York, New York, Volume 5, pp. 119-127, 1964.
6. Lehmann, K.B. and Hasegawa. Studies of the absorption of chlorinated hydrocarbons in animals and humans. Arch. Hyg., 72:327-42, 1910.
7. Lehmann, K.B. and Schmidt-Kehl, L. The thirteen most important chlorinated aliphatic hydrocarbons from the standpoint of industrial hygiene. Arch. Hyg., 116:131-200, 1936.
8. Heilbrunn, G., Liebert, E., Szanto, P.B. Chronic chloroform poisoning — Clinical and pathological report of a case. Arch. Neurol. Psych., 53:68-72, 1945.
9. Bomski, H., Sobolewska, A., and Strakowski, A. Toxic damage of the liver by chloroform in chemical industry workers. Arch. Gewerbepathol. Gewerbehyg., 24:127-34, 1967.
10. U.S. DHEW/PHS/CDC/NIOSH. Criteria Document: Recomendations for an occupational exposure standard to chloroform. HEW (NIOSH), 75-114, 1974
11. Challen, P.J.R., Hickish, D.E., Bedford, J. Chronic chloroform intoxication. Br. J. Ind. Med., 15:243-49, 1958.
12. Fuhner, H. The intensity and action of chloroform and carbon tetrachloride. Arch. Exp. Pathol., 97:86-112, 1923.
13. Whipple, G.H. and Sperry, J.A. Chloroform poisoning — Liver necrosis and repair. Bull. Johns Hopkins Hospital, 20:278-89, 1909.
14. Eschenbrenner, A.B. Induction of hepatomas in mice by repeat oral administration of chloroform, with observations on sex differences. J. Nat’l. Cancer Inst., 5:251-55, 1945.
15. Federal Register. Vol. 39, No. 125 PartII, page 23451, June 27, 1974.
16. Number not used.