Document zQmpj994vkR17VRaOygGGa8Z6

R&S 108034 5* 0--KZDI CAL RZS ZARCH * DOCtMZKT DESCRIPTION FORM . 4 63 68 69 000016376 Duplicate in all cards:--5> /?yo year as-1961- File number [Right justify [Numeric only] vi_____ 73 l/CL- } Suh-Inde^ Code Author(s), as Last Name FS (No Punctuation) and coden for journal as JAKA preceeded-by. one blank space 1______ 20-21 40 41 _____________ 60 It'? -fe '*?. - /r . n i 61 62*' u 12 13 Title___o__f___R___e_p__o___r_t_; end wwiitohi, issppatiucee---huy^pphneu-iijrpneu--sptiue.* xuixww wxlii xnaex iem separated fron each other with -comma-space. Avoid other punctuation; do 'not abbreviate. 12 61 62 21 5- to r--> Oo c/ r ir~lc <_C /! / C_J ui ]~h-\ fci 'I'Z </ a. ~T^_<r/ ~o/^y-- p -r> A i' / t:(J / ' C/A ) /'UwA^y;i. / Ac- Ay A?l /(jaAis h^i-L { 7, ^ Cj_ ^QC /* /'/ ^. ' e_c/ 22 23 24 l/ rce (Journal, Vol., Number, Pages, Late) 12 CT/?t'/sc.o/?/S/'r/pc//i'es A ~2_/ A (j 7LZT/-23-y 61 62. 31 32 Brief Sunnary' 12 10 IsUHMARY': 61 62 61 62 63 64 J tM l\i\i o0 \fr "* *,*.-'**'+*' fv-7?- / <f-, ii<->r / &5-/3?' /?7'i Environmental Health rcr.ipectivc\ Vol. 21. ;>p, 251-254, 197/ 0000163 M143= i.% f} t ,?fv r> ^-'3 -r`` ^ s' ^ n rpt\ f52\ o-xv fO S g? r-'f v$ ^'J5 v>j iCSWlVk tl S3a4i? CailavUA! e^Cdl; w*&u mT'C-.-) v** J ij '.;*? b 'i}.4twi!s& ^ui' 4^ U vf^i la ^r%i3 ^'?a^p$p^ cy U h ft U Wk v**3 Vl^sSBh^ bv Peler F. Infante* R&S 108035 Recvnt cxpci imf!\U! evidence indlcsies th.it structural onaloji ,<f vinyl chloride namely, vinylidene chloride and trieh'oieethylene, are mutasez.ie. Careinoqenie rrsponss uivo has been observed in experi mental animals followin'! exposure to vinyi.'drnc chloride, trichloroethylene, and perdilorocthjlcno. More -,. recent observations demonstrate bu-ievel vinyl eliioridc-induced mammary carcinoma. An additional rhiot inoted olefin. cliloroprcne, has demonstruted a mutagentc response in several test systems. Li.VcH t.se, several stuoies imve iiidicatctl .significant excesses of chromosomal aberrations as well as adverse effects on reproductive function following male exposure to cliloroprcne. Although reports have indicated an increased incidence of hint; and sJtir. cancer among workers occupationally exposed to ciiloruprvtic, adequately dcvier.ed studies have not been carried out which would allow the dtvelopmcnt cf _ valid inferences regarding its carcinogenicity. The question facing the scientific community and society is whether observations in subhuman species are adequate to institute prudent public health practice by controlling these agents as carcinogens or mutagens or whether, once again, post-hoc epidemiologic enumeration of the tell will be required. Since the early !940's, there has been a tremen dous proliferation of man-made chemicals into the workplace. Because of the lack of concern or knowledge of the adverse effects of these 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 major ity of these chemical', has not been evaluated for potential danger as carcinogens, mutagens or teratogens. Although carcinogens have been iden tified b urn studies of finite occupational groups, the insensitivity of currently employed epidemiologic methods as well as the kick of a national policy for letcution of personnel and medical records in the occupational setting necessitate the use of and re liance upon laborat-'ry assay for the detection and prevention cf adverse health effects to humans. The observation of vinyl chloride (VC)-iuduced cancer, first in animals [1,2) and subsequently in human*- (*', 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 tf ' struc tural analogs of VC: vinylidene chloride (VDC). trichloroethylene (TCE), and perehIroe:hyIeae (PCE). With regard to mutagenicity, both vinyi- idene chloride and trichloroethylene have tested positive in .V. ty/.-liittittritiin (5-8) (C. Kamel, per sonal communication) in E. coli (9), and TCE has tested positive in Tradcscaittia (A. H. Sparrow, personal communication). Mutagenicity testing with perchloroethylenc has been negative (9). 'Industry-wide St.idiv' brunch, Division of Smvodl.itice, I Lizard t-tv'.iluiiUunv unu Kidd Sttidirv, N.uiorul It; tang lor Occnp.iu.rn.d K.ilcty nnd llo.ilth, (.'enter lor llivctivc Control. Dv'ptminonl of lleullh. education and Woll'.ne. Cincinnati, Oluo 4.1:0:. December 1977 251 I i Table l. Laboratory studies indicating cytogenetic. mutagenic, or reproductive effects of eliloropreiic. Laboratory test system Mouse, rat Rat Rat Rat Rat S. lyrhhnurkin: S. typhinutnttm DrowphiUt Observation Steiility --" Dominant lethal; effects on sperm: testicular atrophy dominant lethal: chromosomal aberrations in bone m.urovv cells Chromosomal aberrations in bone marrow cells Chromosomal aberrations in bone marrow cells Mutagenic in TA 100 or TA 15.10 Mutagenic in TA 15,15 Roecsxi* e loiiuit ---------------------- ------------- -------------------------------- Investigators von Oettineen et al. (IJ) DavMan (N) Davtian et al. (15) -, Bagramian ami Babaian (16) Volkova et al. (17) Bartsch et al. (ft. IS, 19) Brustek (personal communication) Vogel (20) ZZ r '>% T3 .Z _e5 0*5 OO3?.CO3s #-* ~L- Sj? * _ * \ R&S 108036 With regard to caicinogemcity, VDC. TCE, and PCI: till have induced cancer in experimental ani mals. VDC h;\.s induced angiosarcoma (10) and adenocarcinoma of kidney (II) in the mouse. TCE (12) and 1'CE (unpublished observations. NCI) have induced hepatocellular carcinoma in the mouse. An additional chlorinated olefin, 2-chloro-l, 3-hutadiene, ntoie commonly called chloroprene, htts demonstrated adverse effects on reproduction and a mutagenic response in several test systems. Chloroprene is a colorless liquid which is polymerized into polychloroprene. a synthetic rub ber. Table ! shows reports indicating cytogenetic, mutagenic or adverse reproductive effects of chloroprene in subhuman species. As far back as 1936. von Oettingen (13) induced sterility in made mice at air concentrations ranging from 12-132 ppm. Sterility in rats was obseived at higher concemiations. In the rat. atmospheric chloroprene concentra tions ranging from 0.04 to 1.0 ppm have resulted in a dominant lethal effect (N, 15). effects on sperm (l-l\. testicular atrophy (/-/!. and chromosomal aberiations in bone marrow cells (15-17). Chloro prene also has demonstrated a mutagenic response in several strains of .V. typhhmiriuni (6, IS. 19; D. Urtisick. personal communication). The report by Harlsch et al. (!l>) indicates that the mutagenic action of chloiopicne is .S'. t\phiminium was four times that of VC without metabolic activation and eight times greatei with activation. In l)n>\<>i>hilti. chloroptene litis induced sex-linked iccessive lethal mutations (2d). Obseivutioiis in humans tire consistent with Imdings in subhuman experimental systems. Table 2 lists repoits indicating the cytogenetic and adverse reproductive effects of chloroprene on workers. Three studies indicate a significant excess of chromosomal aberrations in workers exposed to chloroprene or.chloroprene latexes (17, 21, 22). Even more significant are the observations by Sanotskii (23). He reported a decrease in motility of sperm after 6-10 years of work in chloroprene and morphological disturbances of sperm after 11 years of exposure to ehloroprenc-hased latex. He also re ported that cases of spontaneous abortion occurred three times mote frequently in the wives of chloro prene workers as computed to the control group. Furthermore, an industrial hygiene assessment in dicated that chloroprene levels in the process ranged fiom only 0.2K to 1.94 ppm. This is in con trast to the current OSH A standard which allows for a 23 ppm S-hr time-weighted average concentra tion. Although no single study clearly establishes that chloroprene is mutagenic, the consistency of positive mutagenic response over the numerous test systems in addition to observations, which indicate that chloroprene affects the sperm, testicles, and reproductive function as a result of male exposure only, indicates the need to control chloroprene as a potential mutagenic agent to man. Table 2. Cvto^emtic or rcpmdncfiw.* effect* amon^ worker* exposed to diloniprcne. Atmospheric chlou'prene concent! at ion. ppm Observation InvcNli^nlnr 5.0 No data tl.K-2.0 0.1-1. ; ('hivmoMHiu! .iherrattmis K.i[os()x;i {?/) ( hmmoMHiKu jl'cn.ilMiis Bochkov (107ft) (22) Chiomosomnl jhcn.ilinns Volko'a. el al. (17) Decrease m tuoli!il> anil Sanotskii u'.f) number ofsperm; threefold e\ces\ol iniscariiiii:o* * in v. ives of ii'hlc u 01 kor\ 252 Environmental Health Perspectives 1 .With regard to eaicinogenieity. two studies re ously of concern. port tin excess of limy and skin cancer among work Although this conference pertains to VC-relalcd ers exposed to chloroprene in the Yerevan district compounds, new observations related to VC are of the Soviet Union (37, 25). also of interest. After 87 weeks of observations, More recently, Pell (26) reported preliminary Maltoni (unpublished observations) has observed analyses from a study of mortality among workers angiosarcoma in ruts exposed to 25 ppm VC. exposed to chloroprene in the U. S. Although no Mammary carcinomas were observed at lower significant excesses were reported, inspection of levels, liven at 1 ppm. t lie re appears to be a 2-fold the data indicates an excessive risk of respiratory risk of mammary carcinoma; with 120 animals ex cancer for each of three 6-yr calendar time peiiods posed at each concentration, at 25 ppm there were 9 between 1957 and 1974 for the total study cohort. observed (871). at 10 ppm there were 11 observed These excesses however, were not statistically sig (971), at 5 ppm there weic 13 observed (1191), at I nificant. In addition, four deaths from cancer, plus pom there were 7 observed (671), as compared to 4 four cases of lung cancer among currently active observed (371) in the control group. In another _ mainteivance mechanics have been observed. The series of experiments by Maltoni, a 50 ppm expo- eight lung cancels in this subcohort account for 4071" 7"sure to^VCMesulted in 43/300 (147-1.) ofthe rats de (8/20) of the lung cancer cases in the total study veloping mammary carcinoma as compared to 3/100 cohort. Since only 1771 of the tota.l study cohort is (371) in controls (2<S). Thuis/'there.appears to be a " composed of maintenance mechanics, this observa dose-response relationship in the induction of tion may be highly significant. Since the task of the mammary carcinomas with a 371 tumor rate in each maintenance mechanics is to replace" leaking control group. pipe-fittings, to install equipment and to do general In 1976, the results of a study of PVC fabricators maintenance in the reactor areas, this group of conducted by Organization Resources Counselors workers would be expected to have relatively high (29) was transmitted to NIOSH, An estimated- chloroprene exposures. However, limitations in 700,000 to two million workers are employed in the methodology and study design in these reports pre production of 3.5 million tons of PVC annually. VC clude tin assessment of the carcinogenic risk. None exposures are thought to have been low (5-15 ppm) of the epidemiologic studies gives adequate consid and to have lesuited oniy from the release of un eration to environmental concentrations, job clas reacted monomer trapped in the resin. Study results, sification, intensity or duration of exposure, or la arc based on deaths which occurred between 1964 tency, all factors known to influence the risk of and 1973. Causes of death for selected types of cancer. In each of these studies, the investigators cancer in female employees are shown in Table 3. A did not analyze their data separately for chioro- 3871 excess of breast cancer is seen among women prene polymerization workers. (The greatest risk in the vinyl chloride industry was identified in Tiil'l'1 3. Obs-rwd and expected deaths due to selected causes polymetization workers, not in monomer produc among employees of 17 PVC fabricators, 1964-1973." 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 White females Ohsetvcd Inspected PMR'' cers. All cancers More recently, a confirmed case of angiosarcoma Selected types of cancer 179 135.933 1.32 of the liver in a worker who had extensive exposure to finished polychloroprenc 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 buccal cavity and pharynx Digestive Respiratory Breast Genital* Uriaaiy 3 1.872 1.60 53 34.929 1.52 12 1 1.715 1.02 44 31.907 1.38 19 22.971 0.83 ! I 4.487 _2.4S later vulcanized. A history of exposure indicated Lymphatic and leukemia 10 12.481 0.80 that this worker never had occupational exposure to "Unpublished data (39). vinyl chloride, nor had he ever received Thorolrast, ''Proportionate mortality ratio. an agent also associated with angiosarcoma of the liver (27). An industrial hygiene assessment con employed in the fabrication of PVC into finished ducted by NIOSH at the plant where this employee products.* These observations, combined with aniworked 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 chloropiene and the rare oc currence of angiosarcoma, this observation is obvi- *The author has recently become aware of it limited cascconlrol study which suggests that the increased risk of breast cancer among PVC f.ibucators may not lie related to vinyl cldo, ide exposure. Dccembcr 1977 253 u mal studies indicating VC-induced mammary car cinomas at 1 ppm. raise serious health concern for the possibility of yet another type of cancer induced by vinyl chloride from low level exposures. Tlte 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 1. Viola. P. L., Bigotti. A., and Caputo, A. Oncogenic re sponse of rat skin, lungs and bones to vinyl chloride. Cancer Res. 31: 516 (1971). 2. Maltoni, C., and Lefemine, G. Carcinogenicity bioassays of vinyl chloride: current results. Ann. N. Y. Acad. Sci. 226: 195 (1975). 3. Creech, J, L.. Jr., and Johnson. M. N. Angiosarcoma of liver in the manufacture of polyvinyl chloride. J. Occup. Med. 16: 150 (1974). 4. Waxwciler, R. J., et at. Neoplastic risk among workers ex posed to vinyl chloride. Ann. N. Y. Acad. Sci. 271: 39 0976). 5. McCann, J., et at. Detection uf carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals Proc. Nat. Acad. Sci. (U. S.) 72: 5135 (1975). 6. Bartsch, H., et al. Tissue mediated mutagenicity of vinylidene chloride and 2-chIorobutadiene in S. tvpltimurium. Nature 255: 641 (1975). 7. Raden, J., et al. Mutagenicity of volatile anesthetics. Fed. Proc. 35: 410 (1976). 8. Simmon. V., Kauhaneri. K.. and Tardiff, R. G. Mutagenic activity of chemicals identified in drinking water. In: Prog ress in Genetic Toxicology. D. Scott, B. A. Bridges, and F. H. Sobcls. Eds., Elsevier/North-Hollaud, New York, 1977. d. 249. 9. Greim, 5!.. et al. Mutagenicity in vitro and potential car cinogenicity of chlorinated cthylenes and a function of metabolic oxiranc formation. Biochcm. Pharmacol. 24: 2013 (1975). 10. Lee, C. C-, et al. Inhalation toxicity of vinyl chloride and vinylidene chloride. Environ. Health Pcrspect. 21: 25(1973). 11. Maltoni, C. Recent findings on the carcinogenicity of chlori nated olefins. En iron. Health Pcrspect. 21: ! (1978). 12. U, S. Dept. H.E.W., National Cancer institute. Car cinogenesis bioassay of triehlomethylene. Technical Report 2. CAS No. 79-01-6. NCl-CG-TR-2, 1976. 13. Voit Ocltingcn, W. f-'.. et al. 2-chloro-butadicne (chloropicno): Its toxicity and pathology and the mechanism of its action. J. Ind. Hyg. Toxicol. IS: 240 (1936). 14. Daxfian, R. M. Toxicological characteristics of the action of chloroprcnc on the reproductixe function of nude rats (in Russian). In: Reports of Toxicology and Hygiene of the Products of Petroleum Chemistry and Petrochemical Pioductions. All Union Conference. Yaroslavc, USSR, Yaro slavskii Mcditsitiskii Iitstitut, 1972. pp 95-97. 15. Davtian, R. M.. Fomenko. V. N.. and Andreyva, G. P. Question of the effect of chloroprcnc on the generative func tion of mammals (males) (in Russian). Toksikol. Nov. Prom. Ishim. Veschesiv 13:58 (|973). 16. Bagramian, S. B., and Babaian, E. A. Cytogenetic study of the mutagenic activity of chemical substances isolated from nairet latexes MKh and LNT-I tin Armenian).'Biol. Zh. Arm. 27: 102 (1974). -17. Volkoxa. Z. A., et al. De'erminatioti of the maximum per missible concentration of chloroprcnc in the air of working areas (in Russian). Gig. Trud. Piof. Zabol. 20: 31 (1976). 13. Bartsch, H. Mutagenicity tests in chemical carcinogenesis. IARC Inxerm Symp. Ser. No. 13. (Environmental Pollution and Carcinogenic Risks) 52: 229 (1976). 19. Bartsch. H.. et al. Alkylating and mutagenic metabolites of halogenuted olefins produced by human and animal tissues. Proc. Am. Assoc. Cancer Res. 17:17 (1976), 20. Vogel. E. Mutagenicity of caicinogcns in Drosophila as function of genotype-controlled metabolism. Paper pre sented at Conference On In Vitro Metabolic Activation, NIFJIS. Research Triangle Park. N. C., 1976. 21. Katosova, L. D. Cytogenetic analysis of peripheral blood of workers encaged in the production of chloroprcnc (in Russian). Gig. Trud. Prof. Zabol. 10: 30 (1973). 22. Eochkov, N. P._ (Director, Institute Medical Genetics, Moscow). Letter dated March 22. 1976, re chromosomal aberrations in lymphocy tes of workers exposed to chloroprenc. . 23. Sanotskii. I. V. Aspects of the toxicology of chloroprcnc: Immediate and long-term effects. Environ. Health Pcrspect. 17: 85 (1976). 24. Khachutnan, E. A. The occurrence of lung cancer among people woi king w ith chloroprcnc (in Russian), Vopr. Onkol. 18: 85 (1972). ~ 25. Khachatrian. E. A. The role of chloroprcnc in the process of skin neoplasm formation (in Russian). Gig. Trud. Prof. Zabol. IS: 54 (1972). 26. Pell, S. Mortality of workers exposed to chloroprcnc at the Louisville Works, 1957-74. A preliminary study. E. 1, du Pont de Nemotus & Co. Unpublished manuscript. 27. da Silva Horta. J., cl al. Malignancy and othej late effects following administration of Thoiotrast. Lancet, ii: 201 (1965). 28. Maltoni, C. Vinyl chloride (VC) carcinogenicity: An ex perimental model for carcinogenesis studies. 1 r.: Origin of Human Cancer. H. H. Hiatt, J. D. Watson, and J. A. Wins ton, lids., Cold Spring Harbor, in press. 29. Organization Resources Counselors, Inc. Report on a mor tality study covering employees of PVC fabricators. Un published report transmitted to NIOSH, Washington, D. C., Feb. 1976. 3 CO O 00 O CO 254 oo Environmental Health Perspectives