Document 6woKVgLzp9bQB6vgMMrjKr7Y4

bt vro^ted *T oopyxlbt i CARCINOGENICITY OrVlNYL CHLO^RRIjxS' vinyL*CJMa**V< AND VINYUPENE-CHLftilIPE . C C Lee, J. C Bhandari,). M. Winston,W.B. House Pharmacology and Toxicology; fffisgsffitcscarch & Institute, Kansas City, Missouri -- ' . -V- . R. L. Dixon,). S. Woods : Environmental Toxicology Bran Environmental Health Scien North Carolina institute of e Park, f i i t j Cxpeeun of mice to 50, 250, or WOO ppm of vinyl chloride (VC) in the air for 6 h/d, 5 d/wk, caused a high incidence of bronchioloalveolar adenoma, mammary gland tumors, and hemenglosarcoma. Mammary gland tumors occurred in the femcles end included ductuhr adenocarcinoma and squamous and anaplastic cell carcinomas with metastasis to the lung. Hemenglosarcoma occurred in the liver and, to a lesser extent, hi various other organs. The incidence and verity of these tumors increased with the concentration of VC and the length of exposure. Malignant lymphoma involving various organs was observed in several mite. Rots were more resistant to the carcinogenic effects of VC. Exposure of rats to 2S0 or WOO ppm of VC caused hemanglosarcoma in the fiver. Stony rets with hepatic hemcngiasorcomo also developed hemangiosarcome ln` the lung. Extrahepetic hentangiosorconia also occasionally occurred tn other organs. Exposure to 55 ppm of vinylidene chloride (VDC) coused hepatic hemangiosoriomo and probably bronchioloalveolar adenoma in mice. Jlemangiosorcomo also occurred in the mesenteric lymph node or subcutaneous tissue In two rats txposed to 55 ppm of VDC. I i > i li it . i t i INTRODUCTION In 1971, the carcinogenic effect of vinyl chloride (VC) was first reported in animals (Viola et al., 1971). Male Ar/IRE rats exposed to 30,000 ppm of VC, 4 h/d, 5 d/wk, for 12 mo, developed epidermoid The author* are indebted to Dr. P. J. Peters and Mr. J. K. Hagensen for their assistance on inhalation and chamber monitoring operations and to Mrs. E. R. Eliis tor her supervision of histology preparation. This research was supported by contract NO1-ES-2-2084 from the National Institute of Environmental Health Sciences. Preliminary results were presented to the 197G Fall meeting of the American Society lor Pharmacology and Experimental Therapeutics, August 15-19, 1970, Tulane University, New Orleans, Louisiana, and to the First International Congress on Toxicology, March 30-April 2, 1977, Toronto, Canada, Requests for reprints should be sent to Cheng-Chtm Lee, Midwest Research Institute, <25 Volker Boulevard, Kansas City, Missouri 64110. 15 Journal of Toxicology and Environmental Health, 4:15-30,1978 Copyright O 197S by Hemisphere Publishing Corporation 0028-410S/78f04 01 >0015J 2.25 RSV 0019405 I I| t Iti ^99P7 ?l&e t*lu Raprintad from the Archives of Enviranmaatat Hearth January 1971, Volume 22 Copyright 1971, American Medical Association 't E. P. Whaeijr 'J Occupational Acroosteolysis II. An Industrial Hygiene Study Warren A. Cook; Paul M. Giever, MPH; Bertram b. Dinman, Mb, ScD; and Harold J. Magnuion, Mb, MPH, Ann Arbor, Mich RSV 0019420 74 Occupational Acroosteolysis II. An Industrial Hygiene Study Warren A. Cook; Paul M. Gieoer, MPH; Bertram D. Dinman, MD, ScD; and Harold J. Magnueon, MD, MPH, Ann Arbor, Mich An Industrial hygiene survey was conductsd In respect to occupational eeroosteotysis (AOL) in 32 plants engaged in production and compound ing of polyvinyl chloride. This survey was limited to inspection of facilities, interrogation of tech nical personnel, end statistical analyses. Alt manufacturing processes and chemicals utilized were explored. A major objective was the MenUficalion of variables In processes and chemicals that war# peculiar to thoaa plants affording known cases of AOL No such processes or chemicals won found. The survey brought to light a manbar ol situations suspected of relationship to the precise cause of AOL soma of which require additional exploration. Most positive of these was the finding that essentially alt of the persona who developed AOL had served as reactor eieaners using manual methods. Polyvinyl chloride fPVC) has been in production and widespread use for more than 30 years. An extensive account of the chemistry, methods of production, materials utilized, properties, and uses of the PVC resins was recently published in a series of technical articles by Albright.1'9 Uses in clude such diverse products as floor tiles, films for food wrappings, sheeting for show er curtains, phonographic records, and coat ings for cables. As an indication of the magnitude of the PVC industry, the average operating capaci ty in this country for the year 1969 was about 3 billion lb. Much PVC is produced in other countries. Even with this extensive production involving thousands of operators, the occurrence of occupational acroosteolysis (AOL) among these workers was not recog nized until about 1961.T Pubroittfcd for publication Feb 9. 1970; accepted April 16, 1970. From the Institute of Environmental and Indus, (rial Health, University of Michigan, Ann Arbor. Read before the American Industrial Hygiene Conference, Denver, May 15,1969. Reprint requests to School of Public Health. University of Michigan. Ann Arbor, Mich 48104 (Dr. Dinman). The clinical and epidemiological aspects of this condition are discussed in separate papers in this issue of the archives.^ Industrial Hygiene Survey Surveys were made of 32 plants by the authors of this paper, most of the plants being visited by a team of one physician and one industrial hygienist Twenty-six of these were polymer production plants. Vinyl chloride mon omer production plants and plants engaged in compounding and fabricating of the polymer ized resin were a part of the manufacturing complex at a number of these locations. Five plants conducted compounding and fabricating operations only, and one plant produced only the vinyl chloride monomer. These plants were located throughout the United States and one in Canada. This survey was designed to obtain informa tion on equipment used, procedures followed, materials involved, extent of exposure to these, and names and descriptions of jobs in order to compare practices in the plants where cases of AOL occurred with those in plants experienc ing no cases. The extent of exposures was estimated on the basis of general observation, a knowledge of the physical, chemical, and physiological prop- Arch Environ Health--Vol 22. Jan 197] RSV 0019421 76 OCCVPATIONAL ACROOSTEOLYSJS--COOK ET Ah Fig 2.--Charging floor of PVC production plant showing top portion of reactors. in Fig 2. The reactors extend lor ten feet or so down to the floor below. The polymer slurry is pumped to blend tanks, then to centrifuges for removal of much of the water. The dewatered polymer is passed through a rotary dryer with heated air, the temperature of the polymer being kept below 140 F to avoid degradation. The dried granular polymer is pneumatically conveyed into a cy clone separator, with finer particles being re moved from the air stream by means of a filter-type collector. The polymer particles are sized by vibrating screens, then bagged for transfer to compounding and fabricating plants or shipped in bulk. In some plants, the polymer is stored in bins prior to being shipped. In the emulsion process, the equipment and process is essentially the same as in the suspen sion process up to the drying operations. In order to produce the finer polymer particles characteristic of the .emulsion process, a wide variety of emulsifying agents is used. These may be soaps such as ammonium or sodium laurate. surfactants such as salts of naphthalene sulfonic add, or various synthetic detergents. Water-soluble initiators such as ammonium persulfate and hydrogen peroxide are used as catalysts. Since the fine polymer particles can not be readily separated from the emulsion by centrifuging or filtering, a spray dryer is em ployed in this process. The bulk process is similar to suspension polymerization but is characterized by the pre- cipitation of the polymer from the liquid phase, as about 10% of the vinyl chloride becomes polymerized. Solution polymerization is much the same as suspension polymerization, but no water is in troduced. Instead, the polymerization is con ducted in such solvents as cyclohexane, acetone, or n-butane. Copolymer and Terpolymer Production. --In addition to the production of the homopolymer PVC, many of the plants also produce copolymer and terpolymers, includ ing vinyl chloride. The greater percentage of the monomer tends to be the vinyl chloride in all of these. The copolymer vinyl chloride-vinyl acetate is in highest production Arch Environ Health-- Vo! 22. Jan 1971 RSV 0019423 78 OCCUPATIONAL ACROOSTEOLYS1S--COOK ET AL Table 3.--MapnHuda of Deaapa Expressed at Single Concept at a weekly, monthly, or Severtty/Ouration Exposure Parameters other period. A classification of 26 job Magnitude* of Dosage Slight 1 2 3 4 5 6 intermediate 7 8 9 IQ 11 12 Less Than 1 hr/Week Negligible Moderate Moderate Moderate Appreciable Appreciable Appreciable 1-8 hr/Week None Negligible None Negligible None Negligible Moderate Moderate More Then 8 hr/Week None None Negligible None None Negligible None None Negligible None Negligible Moderate titles for the statistical pur poses of this study was pre pared (Table 1). These job titles corresponded to com parable operations in all the plants and to a common group of types of exposures to production materials. Ev ery job in each of the plants was given its fraction of time related to the job title as defined for the study. De Ma>or 13 14 IS 16 17 18 Appreciable Appreciable Moderate Appreciable Appreciable Appreciable None Moderate None Negligible Moderate Appreciable * Expressed in order of increasing dosage received from exposure, which is the summation of the three columns to the right. t Severity of exposure is estimated at none, negligible, moderate, or appreciable for indicated durations. tails of the manner in which this was done are discussed in the accompanying paper on epidemiological aspects of AOL. Job Progression.--Often the first job assignment of the new employee is that of reactor cleaner. Unless there pounding consists of mixing PVC with a multi are many reactors, this work does not require plicity of plasticizers, antioxidants, pigments, the entire time of the employee. Part of his emulsifiers, stabilizers, and other special com pounds in ribbon blenders and mills. The mix tures are then passed through roll milii or mixers, such as are used in the rubber industry, where the temperature may rise sufficiently to vaporize some of the plasticizer and other vola tile constituents. The compounded polymer is then extruded through rolls or dies to form time may be spent in bagging or shipping finished polymer or in the handling of cata lysts and other additives. As job openings arise and with accretion of seniority, this employee may progress to higher skilled jobs such as reactor, monomer recovery or dryer operator, or any combina sheets, films, or pellets. These are used in tion of these at any one time. fabricating operations. In plants producing other products in ad Job Classification dition to vinyl chloride polymers, employees may transfer between these product areas Many variables were introduced in the either as full time for a period of months or plants surveyed and even in different units dividing their time within a given week or of the same plant in regard to nearly every even day. The latter occurs particularly phase of the operations. Investigation of among maintenance personnel. unit jobs in the plants disclosed a wide Where production of vinyl chloride is part assortment of job titles. In fact, a job title as of the operation, operators may rotate be used by the technical supervisors often dif tween jobs in the production of the mono fered from that for the same job in the mer and those associated with the produc same plant as listed by the personnel de tion of the polymer. partment. The length of time spent at various jobs is Furthermore, a job assignment in one a function of production needs, economic plant might include a different group of unit conditions, plant growth rates, and activity operations than in another plant. Also, the of other product lines. proportion of time devoted to the several unit operations often differed. To compound Occupational Exposures to Materials the difficulties of classification, workers Extent of Exposures.'--Information was would frequently rotate through several jobs obtained not only on each of the materials Arch Environ Health--Vo! 22, Jan 1971 RSV 0019425 80 OCCUPATIONAL ACROOSTEOLYSIS--COOK ET AL TaM* 8.->AMCtor Coining Procadufts as a possible factor in the Want .-- -- -Hand Scraping --- After Every Less tlwn Cleaning by Water jet Cleaning by Solvent causation of AOL. Contact with these inorganic and or* garlic peroxides occurs as Code Batch Plants with AOL cases BX EX Every Cycle they are handled prior to their introduction into the reactor and also during re* FX KX (through 1964) From 1965 actor cleaning if any unre acted catalyst remains in the residue. Twenty-two of the aX u Every 5-12 cycles From )962 (building A) (building BJ EE X -- 26 plants used lauroyl perox ide. Eight of thee were plants with AOL cases or Plants with possible AOL cases B6 Every ''several" cycles On glass-lined. intermittently possible AOL cases, and 14 were plants without AOL in 1966. entirely Plents with no AOL cases AX by December 1966 From September mon organic peroxide was the IPP, and it, too, was in use in both the positive and (to September 1964) CX D From 1962 1964 the negative plants, in four of the former and in eight of the latter. No catalyst or HX J Every 216 cycles L Every 4-8 days NX group of catalysts was used in all positive plants and in no negative plants. P Weekly From 1965 through 1964, every 2 weeks Constituents of Scrapings. --Other suspect materials 1965-1966 QX sX T X Every 1-3 cycles are constituents of scrapings removed from the reactors during manual cleaning. (emulsion) (suspension) V Every 10 cycles zX AA Every 4 or more These are believed to include some partially polymerized resins, along with some un 00 X GG cycles From start Of operations reacted catalysts and addi tives, and unpolymerized vinyl chloride. Little specif ic information is currently vinyl chloride to prevent spontaneous poly available concerning these constituents. It has merization in storage. An inhibitor may also been reported that lauroyl peroxide is definite be added to the vinyl chloride recovered ly associated with residual PVC particles, from the reactor. The phenol is removed by whereas little of the IPP remains unreacted treatment with caustic soda prior to its in the polymer. * transfer to the reactor. The practice over the Further investigation of the scrapings years covered by the study is presented in from the reactor may be expected to furnish Table 3. The use of the inhibitor in the information that may lead to a better under virgin vinyl chloride at two of the positive standing of the factors involved in causation plants and three of the negative plants, with of AOL. A difficulty in such investigation is inhibitor being added in the vinyl chloride that the composition of the scrapings is recovery operation in two positive plants continually changing from the time they are and four negative plants, leads to the con* removed from the surfaces of the reactor. It elusion that inhibitors probably are not a is obvious that comparatively small mole factor in AOL causation. cules of partially polymerized vinyl chloride Catalyst Exposures.--Since the catalysts are increasing in size with passage of time, are all active compounds, they were suspect and active constituents such as residual cat* Arrh Knviron Health--Vol 22. Jan .1971 RSV 0019427 82 OCCUPATIONAL ACROOSTEOLYSIS--COOK ET AL figure derives from the paper on epidemio Preventive Measures logical aspects of AOL8 which reports the The present knowledge as to AOL is such prevalence of AOL or possible AOL as one that categoric statements as to preventive case per 37 reactor cleaners at risk. measures are not justified. However, on a Of the negative plants with an AP-T val somewhat speculative basis, some measures ue of 10 or more, none of those in operation are indicated that may be conducive to AOL earlier than 1965 had enough reactor clean prevention: ers at risk to expect an AOL case, whereas 1. Although some manual removal of resi two of the four plants with an AP-T value due from reactor surfaces may be required under 10 have enough workers to expect when solvents or high-pressure water jets cases. Cases would be expected from the are used for cleaning, the more extensive total population of reactor cleaners in the - employment of these methods would greatly entire group of the seven negative plants reduce the number of man hours required with AP-T values of 10 or more, but the for conducting this operation by manual total number would be 3.6, as compared methods. with 5.3 expected cases from the entire 2. The adequacy of ventilation of reactors group of four negative plants with an AP-T prior to entry should be checked with value of less than 10. This contrasts with flammable vapor indicator equipped with a expected cases in the group of positive scale of greater sensitivity than 1% of the plants with an AP-T value of less than 10 as lower explosive limit of vinyl chloride or 1.7, compared with 11.8 in such plants with with other instruments of such sensitivity. an AP-T value of 10 or more. 3. Further investigation of the constituen The proportion of the number of reactor cy of the scrapings from the reactor surfaces cleaners in the negative plants with an AP-T should be considered, as such information value of less than 30 to the total number might disclose the factor responsible for the in 6uch plants was 193 to 325. This propor causation of the disease. tion for the positive plants was 63 to 499. A X3 test demonstrated that the probability of References this difference between the negative and the positive plants occurring by chance is less than 0.001. In order to make this comparison between the positive and negative plants with AP-T values below and above 10, it was necessary to oversimplify a multiplicity of varying de tails of operational procedures from the time the polymerization is completed to the time the cleaner enters the reactor. Accordingly, any interpretation of the findings that re duction of the AP-T value below 10 by reducing the absolute pressure or keeping the reactor at reduced pressure for a longer time or both may results in reduction in development of AOL cases should be ap proached with great caution. 1. Albright LF: Vinyl chloride processes. Chem Eng 74:123-130, 1967. 2. Albright LF: Manufacture of vinyl chloride. Chem Eng 74:219-226. 1967. 3. Albright LF: Polymerization of vinyl chloride. Chem Eng 74:151-158. 1967. 4. Albright LF: Vinyl chloride polymerization by suspension processes yields polyvinyl chloride res ins- Chem Eng 74:145-152, 1967. 5. Albright LF: Vinyl chloride polymerization by emulsion, bulk and solution processes. Chem Eng 74:85-92. 1967. 6. PVC producers. Chem Eng New 47:18-19, 1960. 7. Wilson RH. McCormick WE. Tatum CF. at at: Occupational acroosteolysis: Report of 31 cases. JAMA 201:577-581, 1967. 8. Dinman BD, Cook WA, Whitehouae WM, et al: Occupational acroosteolysis: I. An epidemiologi cal studv. Arch Environ Health 22:61-73, 1971. 9. Dodson VN. Dinman BD, Whitehouse WM, et at: Occupational acroosteolysis: III. A clinical study. Arch Environ Health 22:83-91. 1971. Arch Environ Health--Vol 22, Jan 1971 Printed end Published m the United States of America RSV 0019429