Document jgOn4aovqjrMgj3JDGO49VrqN

tn*. WfCnOB78 "V&zssr cfi5 (3>oJ Emimnmeittat HeahhfmptciSvts Vot. 21. pp. 2S1-3X.WVff7,A Mutagenic and Carcinogenic Risks Associated With Halogenated Olefins by Peter F. Infante* Recent experimental evidence indicate* that structural analogs or vinyl chloride namely, vtsyUdcoe chlorEdc and trlchloro*ihykae, are mutagenic. Carcinogenic mtponi* aUo hat been observed In expert* mental an(malt foRftwtoi exposure to Ytnytidrne chloride, trichloroethylene, and perchUjroetbyknt More recent observations demorntrott low-Wvel vinyl chloride-induced mammary cardnoma. A* addUianat chlorinated delta, cfeloroprene, has demonstrated a mutagenic response la several test systems. Likewise, several studies have indicated significant exeat*** of chromosomal aberrations ai well as advene effects on reproductive (knctloe foHewing nek exposure to cphimpme. Although reports have indicated an Increased incidence of lung and skin cancer among workers occupationally rxposed to ehtoroprsne, adequately designed studies have not been carried out which would allow the development of valid inferences regarding H* carcinogenicity. The question betas the scientific community and iwkiy c whether observation* Is subhuman specks an adcqnste to Institute prudent public health practice by toutrolling these agents as carcinogen* or mutagens or whither, once again, post-hoc epidemiologic enumeration of the tod will be required. Since the early 1940's, there has been a tretnendons proliferation of man-made chemicals into the workplace. Because of the lack of concern or knowledge of the adverse effects ofthese chemicals on workers, this proliferation of toxic agents has extended into the environment from out-plant emis sions and from consumer end-product use. A majority of these chemicals has not been evaluated for potential danger as carcinogens, mutagens or teratogens. Although carcinogens have been iden tified from studies of finite occupational groups, the insensitivity of currently employed epidemiologic methods as well as the lack of a national policy for retention of personnel and medical records in the occupational setting necessitate the use of and re liance upon laboratory assay for the detection and prevention of adverse health effects to humans. The observation of vinyl chloride (VCHnduced cancer, first in animals (/, 1) and subsequently in humans (f,4) had a profound effect on the need for a rapid reduction of VC levels in the industrial setting and on the value of laboratory assay. Subsequently, investigators have assessed the mutagenic and carcinogenic potential of the struc tural analogs of VC: vinylidene chloride (VDC), trichloroethylene (TCE), and perchioroethylene (PCE). With regard to mutagenicity, both vinyl idene chloride and trichloroethylene have tested positive in S. typhimurium (j-d) (C. Ramel, per sonal communication) in E. coll (9), and TCE has tested positive in Tradescantia (A. H. Sparrow, personal communication). Mutagenicity testing with perchioroethylene has been negative (P). *i ndustry-wide Studies Branch, Division of Surveillance. Hazard Evaluations and Field Studies, National Institute for Occupational Safety and Health, Center for Ditease Central, Department of Health, Education and Welfare, Cincinnati, Ohio 45202. December 1977 251 i AP00007001 Tiblt 1. Laboratory (Indict Indicating cytogenetic, muugenic, or reproductive affects of chtoroprene. Laboratory test system Mouse,rat Rat Rft! Rat Rat S. tYphirtwrinm S. tvphlmuriifin DroxtfphiJa Observation Sterility Dominant lethal: effects on sperm: ttsiicular atrophy dominant lethal; chromosomal aberrations in hone marrow cells Chromosomal aberrations in bone marrow cells Chromosomal aberrations in hone marrow celt* Mutagenic inTA 100 or TA 15JO Mutagenic in TA 1535 Recessive lethal Investigators von Oeuingen *1 at. (13) Davtfan (fd) Davtian etal. (11) Bagramian and Babaian (J6l Volkova el al. iJ7} Bartsch ei al. (6. IS. I9i Brusick (personal communication^ Vogel (20 > With regard to carcinogenicity. VDC. TCE. and reproductive effects of chloroprene on workers. PCE all have induced cancer in experimental ani Three studies indicate a significant excess of mals. VDC has induced angiosarcoma (/<?) and chromosomal aberrations in workers exposed to adenocarcinoma of kidney (//). in the .mouse. TCE . chloroprene or chloroprene Jatexes (17, 21,22). (121 and PCE (unpublished observations. NCI I Even more significant are the observations by have induced hepatocellular carcinoma in the Sanotskii (23). He reported a decrease in motility of mouse. sperm after 6-10 years of work in chloroprene and An additional chlorinated olefin. 2-chloro-t. morphological disturbances of sperm after II years 3-butadiene, more commonly called chloroprene. of exposure tochloroprene-based latex. He also re has demonstrated adverse effects on reproduction ported that cases of spontaneous abortion occurred and a mutagenic response in several test systems. three times more frequently in the wives of chloro Chloroprene is a colorless liquid which is prene workers as Compared to the control group. polymerized into polychloropiene. u synthetic rub Furthermore, an industrial hygiene assessment in ber. dicated that chloroprene levels in the process Table l shows reports indicating cytogenetic, ranged from only 0.28 to 1.94 ppm. This is in con mutagenic or adverse reproductive effects of trast to the current OSHA standard which allows chloroprene in subhuman species. As far back as for a 25 ppm 8-Hr time-weighted average concentra 1936. von Oettingen (13) induced sterility in male tion. Although no single study clearly establishes mice at air concentrations ranging from 12-152 that chloroprene is mutagenic, the consistency of ppm. Sterility in rats was observed at higher con positive mutagenic response over the numerous test centrations. systems in addition to observations, which indicate In the rat. atmospheric chloroprene concentra that chloroprene affecis the sperm, testicles, and tions ranging from 0.04 to 1.0 ppm have resulted in a reproductive function as a result of male exposure dominant lethal effect (14, 15). effects on sperm only, indicates the need to control chloroprene as a (14). testicular atrophy (74). and chromosomal potential mutagenic agent to man. aberrations in bone marrow cells (15-17). Chloro prene also has demonstrated a mutagenic response in several strains of S. typhhnurium (6. 18, 19: Tabic 1 Cytogenetic or reproductive effects among workers exposed to chloreprtite. D.Brusick, persona! communication!. The report Atmospheric by Bartsch el al. (19) indicates that the mutagenic action of chloroprene is S. lypliimarium was four limes that of VC without metabolic activation and chloroprene concentration. Observation ppm Investigator eight times greater with activation. In Drosophila, chloroprene has induced sex-linked recessive lethal mutations (20). Observations in humans are consistent with find 5.0 No data 0.8-2.0 0.3-1.9 Chromosomal aberrations Katosova (7/) Chromosomal aberrations Bochkov (1976) {22\ Chromosomal aberrations Volkova, et at. (77i Decrease in motility and San(i(skir<23) number of sperm: threefold ings in subhuman experimental systems. Table 2 lists reports indicating the cytogeneiic and adverse excess of miscarriages in wives of male workers 252 Environmental Health Perspectives AP00007002 With regard to carcinogenicity, two studies re port an excess of lung and skin cancer among work ers exposed to chloroprene in the Yerevan district of the Soviet Union (24, 25). More recently, Pell (26) reported preliminary analyses from a study of mortality among workers exposed to chloroprene in the U. S. Although no significant excesses were reported, inspection of the data indicates an excessive risk of respiratory cancer for each of three 6-yr calendar time periods between 1957 and 1974 for the total study cohort. These excesses however, were not statistically sig nificant. In addition, four deaths from cancer, plus four cases of lung cancer among currently active maintenance mechanics have been observed. The eight lung cancers in this subcohort account for 40% (8/20) of the lung cancer cases in the total study cohort. Since only 17% of the total study cohort is composed of maintenance mechanics, this observa tion may be highly significant. Since the task of the maintenance mechanics is to replace leaking pipe-fittings, to install equipment and to do general maintenance in the reactor areas, this group of workers would be expected to have relatively high chloroprene exposures. However, limitations in methodology and study design in these reports pre clude an assessment of the carcinogenic risk. None of the epidemiologic studies gives adequate consid eration to environmental concentrations, job clas sification, intensity or duration of exposure, or la tency, all factors known to influence the risk of cancer. In each of these studies, the investigators did not analyze their data separately for chloro prene polymerization workers. (The greatest risk in the vinyl chloride industry was identified in polymerization workers, not in monomer produc tion workers). The studies also do not mention the method by which the cancers were diagnosed, nor are the cell types indicated for skin and lung can cers. More recently, a confirmed case of angiosarcoma of the liver in a worker who had extensive exposure to finished polychloroprene has been identified. The worker had been employed as a roll builder during the period 1952-1967. During this period, he applied neoprene to metal cylinders, which were later vulcanized. A history of exposure Indicated that this worker never had occupational exposure to . vinyl chloride, nor had he ever received Thorotrast, an agent also associated with angiosarcoma of the liver (27). An industrial hygiene assessment con ducted by N105H at the plant where this employee worked indicates average chloroprene air levels of 0.2 ppm from personal sampling and 0.14 ppm from area sampling. Because of the structural similarity of vinyl chloride and chloroprene and the rare oc currence of angiosarcoma, this observation is obvi- ously of concern. Although this conference pertains to VC-related compounds, new observations related to VC are also of interest. After 87 weeks of observations, Mahoni (unpublished observations) has observed angiosarcoma in rats exposed io 25 ppm VC. Mammary carcinomas were observed at lower levels. Even at I ppm, there appears to be a 2-fold risk of mammary carcinoma; with 120 animals ex posed at each concentration, at 25 ppm there were 9 observed (8%), at 10 ppm there were 11 observed (9%), at 5 ppm there were l3 observed (11%), at 1 ppm there were 7 observed (6%), as compared to 4 observed (3%) in the control group. In another series of experiments by Maltoni, a 50 ppm expo sure to VC resulted in 43/300(14%) of the rats de veloping mammary carcinoma as compared to 3/100 (3%) in controls (28). Thus, there appears to be a dose-response relationship in the induction of mammary carcinomas with a 3% tumor rate in each control group. In 1976, the results of a study of PVC fabricators conducted by Organization Resources Counselors (29) was transmitted to NIOSH. An estimated 700,000 to two million workers are employed in the production of 3.5 million tons of PVC annually. VC exposures are thought to have been low (5-15 ppm) and to have resulted only from the release of un reacted monomer trapped in the resin. Study results are based on deaths which occurred between 1964 and 1973. Causes of death for selected types of cancer in female employees are shown in Table 3. A 38% excess of breast cancer is seen among women Table 3. Observed and expected dtathi due 1o selected cause* among employees of 17 PVC fabricators, 1964-1973.* White females Observed Expected PMR* All cancers Selected types of cancer 179 135.933 1,32 Buccal cavity and pharynx Digestive Respiratory Br Genitals Urinary Lymphatic and leukemia Unpublished data {29). ^Proportionate mortality ratio. 3 1.672 S3 34.929 12 11.715 44 31.907 19 22.971 II 4.4S7 to . IZ.4S1 1.60 1.52 1.02 I.3B 0.83 2.45 0.80 employed In the fabrication of PVC into finished products.* These observations, combined with ani- The author ha* recently become aware of a limited case' control Mudy which suggests that the increased risk of breast cancer among PVC fabricator* may not be related to vinyl chloride exposure. December 1977 253 AP00007003 mal studies indicating VC-induced mammary car cinomas at] ppm, raise serious health concern for the possibility of yet another type of cancer induced by vinyl chloride from low level exposures. The question facing the scientific community is whether observations in subhuman species are adequate to institute prudent public health practice by controlling these agents as carcinogens or muta gens or whether, once again, post-hoc epi demiological enumeration of the toll will be re quired. REFERENCES I. Viola, P. L., Blgotti. A.. and Capulo, A. Oncogenic response of rat akin, lungs and bones to vinyl chloride. Cancer Rei. 31: 316(1971). 2- Maltoni, C., and Lefemine, C. Carcinogenicity bioassays of vinyl chloride: current results. Ann. N. Y. Acad. Sci. 246: 195(1973). 3. Creech. J. L,, Jr., and Johnson, M. N. Angiosarcoma of liver in the manufacture of polyvinyl chloride. J. Occup. Med. Wj.150(1974). 4. Waxweifer, R. J.. at al. Neoplastic risk among workers ex posed to vinyl chloride. Arm. N. Y. Acad. Sci. 271: 39 (1976). 5. McCann. J., et al. Detection of carcinogens as mutagens in the SaJmoaeJia/mlcrosome lest: Assay of 300 chemicals. Proc, Nat. Acad. Sci. (U, S.) 72: 5135 (1975). 6. Bartsch. H.. el al. Tissue mediated mutagenicity of vinylidetie chloride and 2-chlorobutadiene in 5. typhimurium. Nature 255:641 (1975). 7. Baden, J. et al. Mutagenicity of volatile anesthetics. Fed. Pros. 33:410(1976), 8. Simmon. V., Kauhanen, K-. and TardifT, R. C- Mutagenic activity of chemical* identified io drinking water. In: Prog ress in Genetic Toxicology. D. Scott, B. A. Bridges, and F. H. Sobeh, Eds., ElsevicifNorth-Holl&nd, New York, 1977.. 1*9. 9. Oreim, H., at al. Mutagenicity in vitro and potential car cinogenicity of chlorinated ethylene* and a function of metabolic oxirane formation. Biochtm. Pharmacol. 24:2013 (1975). 10. Lee, C- CM et al. Inhalation toxicity of vinyl chloride pad vinyLidene chloride. Environ. Health Penpect 21:23 (1978). 11. Maltoni, C. Recent findings on the carcinogenicity of chlori nated olefin*. Environ. Health Perepect. 21:1 (197ft). 12. U. S. Dept. H.E.W., National Cancer Institute. Car cinogenesis hioaseay of trichloroethylene. Technical Report ,,2, CAS No. 7941-6. NC4-CG-TR-2, 1976. 13. Von Oeuingen, W. F., et *1. 2-chloro-butadiene (chloroprene): Its toxicity and pathology and ihe mechanism of its action. J. Ind. Hyg. Toxicol. 18: 240 < 19361, 14, Davtim.R. M. Toxicological characteristics ofihe action of chloroprene on Ihe reproductive function of male rats (in Russian). In: Reports of Toxicology and Hygiene of the Products of Petroleum Chemistry and Petrochemical Pro duction*, All Union Conference, Yaroslave, USSR. Yaro slavskii Meditsinskii Insthui, 1972, pp 95-97. 13. Davtian, R. M,. Fomenko. V. N., and Andreyva. G. P. Question of the effect ofchloroprene on the generative func tion ofmammals (males) (in Russian). Tok sfkoJ. Nov. Prom. Khim. Veschestv 13:38 11973). 16. Bagramian, 5- B., and Babaian, E. A. Cytogenetic study of the mutagenic activity of chemical substances isolated from nalret latexes MKh and LNT-1 (in Armenian). Biot, Zh. Arm. 27; 102(1974). 17. Volkova, Z. A., ct al. Determination of the maximum per missible concentration ofchloroprene rn (he air of working areas (in Russian). Gig. Trud. Prof. Zabol. 20: 31 (1976). 18. Bartsch. H. Mutagenicity tests in chemical carcinogenesis, I ARC Intern Symp. Ser. No. 13. (Environmental Pollution and Carcinogenic Risks) 52: 229 (1976). 19. Bartsch, H., et a). Alkylating and mutagenic metabolites of halogenated olefins produced by human and animal tissues. Proc, Am. Assoc. Cancer Res. 37:17 (1976). 20. Vogel, E. Mutagenicity of carcinogens in Drosophila as function of genotype-controlled metabolism. Paper pre sented at Conference On in klrfro. Metabolic Activation, NIEHS, Research Triangle Park, N. C,, 1976- 21. Kaiosova, L. D. Cytogenetic analysis of peripheral blood of workers engaged in the production of chloroprene (in Russian). Gig. Trud. Prof. Zabol. 10: 30 (1973). 22. Bochkov, N. Pv (Director, Institute Medical Genetics, Moscow). Letter dated March 22, 1976, re chromosomal aberrations in lymphocytes of workers exposed to chloro prene. 23. Sanotsktf, 1. V. Aspects of the toxicology ofchloroprene: Immediate and long-term effects. Environ. Health Perspect. 17: 85 (1976). 24. Khachatrian, E. A, The occurrence of lung cancer among people working with chloroprene (in Russian). Vopr. Onkol. 18: *5 (1972). 25. Khachatrian, E. A. The role ofchloroprene In the process of skin neoplasm formation (in Russian). Grg. Trod. Prof. Zabol. 18:54(1972). 26. Pell, S. Mortality of workers exposed to chloroprene at the Louisville Works, 1957-74. A preliminary study. E. 1. du Pontdc Nemours A Co. Unpublished manuscript. 27. da Silva Horta. J., et al. Malignancy and other Isle effects following administration of Thorotrast. Lancet, ii: 201 (1965). 2ft. Maltoni, C. Vinyl chloride (VC) carcinogenicity: An ex perimental model for carcinogenesis studies. In: Origin of HusninCancer. H. H. Hiatt, J. D. Watson, and J. A. Wins ton, Eds., Cold Spring Harbor, in press. 29. Organization Resource! Counselors, Inc. Report on a mor tality study covering employe*! of PVC fabricators. Un published report traatshttd to NIOSH, Washington, D. C,, Feb. 1976, i254 Environmental Health Perspectives AP00007004