Document 9Jeb491p7zwN2nVJe9w8xQ6w3

ABDOOO19431 Draft TL Vfor P VC Dusts The Sapphire Croup Inc February 4, 2002 DRAFT TLV DOCUMENTATION FOR POLYVINYL CHLORIDE (PVC) DUST Preparedfor: The Vinyl Institute Prepared by: The Sapphire Group, Inc. Beachwood, OH and Dayton, OH February 4, 2002 ABDOOO19432 Draft TL Vfor PVC Dusts The Sapphire Croup, Inc February 4, 2002 PVC Dust CAS Number 9002-86-2 Synonyms chloroethene polymer, ethylene chloro-polymer, chloroethene homopolymer, polychloroethylene, vmyl chloride polymer Molecular formula (C2-H-Cl)n Structural formula (-CH=CCl-)n TLV-TWA To be determined A4 - Not Classifiable as a Human Carcinogen Summary PVC dusts are particulates generated from PVC resin prior to compounding with other agents The size of the particulates, which determines its deposition, clearance, and ultimately its toxicity in the lung, is strongly dependent upon the polymerization process used during resin synthesis The majority of the PVC produced in the US occurs by a suspension polymerization method which results in particle sizes that are generally too large to be respired Ammal and epidemiology data indicate that the lung is the primary target organ affected by exposures to respirable dusts Prolonged exposures to high concentrations of PVC dusts can overwhelm the clearance mechanisms of the lung, resulting m a benign pneumoconiosis In this condition, PVC dust particles can be found in alveolar macrophages, and may be associated with small decrements in pulmonary function, an increased frequency ofcoughing or wheezing, and an increase in the prevalence of small opacities visible upon chest radiography Chemical and Physical Properties At room temperature, PVC is an odorless solid plastic that can be colorless to amber in color Chemical and physical properties for PVC dust are listed below (HSDB, 2001, Hams and Sarvadi, 1994) Molecular weight 60,000-150,000 (average) Melting Pomt 212-310C Density 1 406 Refractive index 1 54 Solubility High molecular weight PVC soluble in cyclohexanone, methylcyclohexanone, dimethyl formamide, nitrobenzene, tetrahydrofuran, isophorone, mesityl oxide, low molecular weight PVC soluble in dipropyl ketone, methyl amyl ketone, methyl isobutyl ketone, acetonylacetone, methyl ethyl ketone, dioxane, methylene chloride Decomposition products When heated to decompose, PVC can emit toxic fumes of hydrogen chloride and phosgene One of the key properties that impacts its kinetics and toxicity of PVC dust is particle size The particle size distribution for PVC dusts differs greatly from one resin to another, and depends upon the polymerization process used to make PVC resin The two primary polymerization methods include (1) suspension polymerization, which accounts for approximately 96% of U S production, and (2) emulsion polymerization, which accounts for approximately 4% of U S production (VI, 2000) Resin particles generated by the suspension methods are generally large in diameter (50 to 200 um) (Hams and Sarvardi, 1994), and as such the majority are not considered to be respirable Resin particles generated by the emulsion method generally have a much smaller diameter (0 05 to 30 um) (Hams and Sarvardi, 1994), and are therefore more easily respired [VI ANY ADDITIONAL INFO ON PARTICLE SIZE DISTRIBUTIONS WOULD BE USEFUL, KEEP IN MIND 0 1 UM SERVES AS ACGIH'S REDLINE VALUE FOR ULTRAFINE PARTICLES IN THEIR PNOS GUIDELINE] -2- ABDOOO19433 PVC dusts may contain one or more additives or impurities that may affect its toxicity For example, vinyl chloride monomer (VCM), a known human cancinogen, is present m PVC resin However, the levels of VCM contained in PVC resin has changed substantially over the past 30-40 years Prior to 1975, residual VCM levels of 1,000 to 2,000 ppm were commonly detected in PVC resin (Clayton, 1977, Burgess, 1982, USFDA, 1986) Efforts to reduce the levels of residual monomer by improved stripping techniques resulted in levels below 5 to 10 ppm in 1975-1976 A recent survey of four PVC resin types revealed residual VCM monomer concentrations ranging from 0 09 to 3 ppm, with arithmetic means ranging from 0 32 to 1 45 ppm (VI, 2000) PVC dusts may also contain one or more surfactants used to facilitate the polymerization process, such as sodium lauryl sulfate [VI ARE THERE OTHERS WE SHOULD CONSIDER SPECIFYING9 SHOULD WE INCLUDE INFORMATION ON RESIDUAL LEVELS & HOW THEY HAVE CHANGED OVER TIME9] Some in vitro studies have suggested that extractable components (: e , surfactants) can contribute to the cytotoxicity of PVC dusts at relatively high concentrations (Richards et al 1975, Pigott and Ishmael, 1979) Regardless, it should be noted that the contributions to toxicity from either residual VCM or surfactants are intrinsically included in the toxicity and epidemiology studies that have evaluated PVC dusts In this way, PVC dusts may be viewed as a simple mixture ' After synthesis, PVC resins may be shipped as pellets, powders, or liquid latex to other facilities where the PVC resin undergoes compounding with plasticizers, stabilizers, filling agents, flame retardants, biocides and/or pigments to modify the properties of the resin prior to forming a final product For this reason, compounded PVC may be viewed as a mixture that is considerably more complex than the original PVC resin The potential interactions of these agents on the toxicity of PVC dusts are not known For the purposes of documenting a TLV, the term "PVC dust'' is defined here to refer specifically to dusts generated from PVC resin, pnorto compounding Therefore, any TLV value derived for PVC dust is not necessarily protective of dusts generated from compounded PVC The need to assess individual additives within compounded PVC, by comparing concentrations to their individual TLV Draft TLVfor PVC Dusts The Sapphire Group Inc February 4, 2002 values, should be considered on a case by case basis Major Uses The annual production of PVC in North America has been estimated to be approximately 15 billion pounds, and has generally been increasing at a rate of 5 to 6% per year (Lewis, 1999) PVC resins are used in a wide variety of applications Major uses of PVC resin (as a percentage of North American consumption) include pipes and fittings (47%), siding (15%) windows and doors (9%), flexible film and sheeting (7%), wire and cable coverings (4%), rigid film and sheeting (3%), flooring (3%), bottles (1%), and miscellaneous products (11%) (VI, 2001) Animal Studies Acute Information regarding the acute toxicity of PVC dust following inhalation exposure is limited, and suggest that the respiratory tract is the principal target of toxicity following exposure to high concentrations of dust In rats exposed to 50 to 60 mg/m3 for one hour/day, for one to three days (geometric mean diameter = 1 2 um), some evidence of cellular proliferation was observed in the lungs (Snvastava et al 1980) This effect was resolved following a 30-day recovery period These results are in sharp contrast to the more severe effects (interstitial fibrosis and granulomatous lesions) which were observed in rats receiving the same delivered dose of PVC dust via intratracheal instillation (Agarwal et al 1978), suggesting that intratracheal instillation is not a suitable model for PVC dust delivery to the lung Dermal application of PVC dust to rabbit ears, five days/week for two weeks, did not produce dermal lesions (Goh and Ho, 1988) Subchronic Limited information suggest that subchronic inhalation exposures to high concentrations PVC dusts are associated with effects on the lung Small lung lesions were observed in rats exposed to 10 mg/m3 PVC dust for six hours/day, five days/week for 15 weeks (Richardsetal 1981) TheauthorsconcludedthatPVC -3- ABDOOO19434 dust at this concentration was best characterized as a "nuisance" dust with weak biological activity Chronic Rats and guinea pigs exposed to PVC dusts (concentrations not specified) continuously for two to seven months at a facility where workers were exposed (Frongia et al 1974) developed lung lesions The response in exposed animals was characterized initially as an alveolar-lobular macrophagic reaction, more so in guinea pigs than rats, followed by the formation of granulomatous foci and septal thickening in the lungs No indication of significant pulmonary disease was evident in rats exposed to 12 mg/m3 PVC dust (average diameter = 0 15 um) for seven hours/day, five days/week for seven months (Wagner and Johnson 1981) However, a slight proliferation of reticulin fibers was observed, and PVC dust particles were found in macrophages Several species (rat, guinea pig, monkey) were exposed to 13 mg/m3 PVC dust (90% of particles with a diameter less than 1 5 um) 6 hours/day, five days/week for up to 22 months (Groth et al 1981) No fibrosis, cellular infiltration, or deficits in pulmonary function were observed in any species Aggregates ofPVC dust particles were found in macrophages in all three species, but were more numerous in monkeys The authors concluded that PVC dust produces a benign pneumoconiosis under the conditions tested Lung inflammation and hyperplasia were observed in some rats exposed to either 3 2, 8 0, or 20 mg/m3 PVC dust (mean diameter =131 um) five hours/day, five days/week for eight months (Takenaka et al 1981) The lack of specific information regarding the dosedependency ofthe incidence or severity ofthese effects precludes defining a NOAEL or LOAEL value from this study Genotoxicity Studies No data were located regarding the potential genotoxicity of PVC dust Reproductive Toxicity Studies Draft TL Vfor PVC Dusts The Sapphire Croup, Inc February 4, 2002 No data were located regarding the potential reproductive toxicity of PVC dust However, a few epidemiology studies have evaluated reproductive endpoint in PVC workers (see Human Studies below) Pharmacokinetic/Metabolism Studies In rats exposed to 50 to 60 mg/m3 PVC dust (geometric mean diameter = 1 2 um) one hour/day, for one to three days, the authors noted that the lung retention rate was approximately 21 to 25 mg/hour (Snvastava et al 1980) PVC dust was present in the airways immediately following exposure However, the airspaces were free ofdust following a 30-day recovery period Some infiltration of PVC dust into lymphatics and epithelial lining of the bronchioles was evident The alveolar clearance of PVC dust (median diameter = 1 3 um) was found to be increased over control rats (halftime=57 days) in a concentration-dependent manner in rats exposed to 3 3, 8 33, or 20 2 mg/m3, 25 hours/week for seven months (Muhle et al 1990) Halftimes of 71, 122, and 184 days were reported for the low, medium, and high concentration groups, respectively The authors attributed the impairment of alveolar clearance to dust overload In an analysis of these data, Yu and Rappaport (1996) were able to describe the clearance of PVC dust from rat lung in terms of Michaehs-Menten kinetics with a maximum rate of clearance (kmax) of 0 0089 day 1 and a lung burden at which the clearance rate is equal to one half of its maximum value (M,/2)of 2 9 mg/lung Human Studies A number of epidemiology studies are available for workers exposed to PVC dusts Like many epidemiology studies, interpretation of the results is limited due to the presence of confounders, lack of information on exposure, particularly historical exposures, and small sample size For the few studies in which exposure information is presented, the concentrations generally reflect levels present at the tune of study, and do not necessarily reflect historical exposure levels For this reason it is difficult to attribute any of the effects observed to the reported concentrations Collectively the epidemiology studies suggest that prolonged exposures to PVC dusts at high -4- r ABDOOO19435 concentrations are associated with effects on the lung, including decrements in pulmonary function radiographic opacities, and subjective symptoms Subjective symptoms (complaints of wheezing) were increased and pulmonary function parameters were lower in 70 Canadian PVC wire and plastic wrapping workers exposed to 8-hour TWA concentrations of up to 21 mg/m3 when compared to 48 controls (Ernst et al 1988) The authors suggested that there may be two different pulmonary reactions associated with exposure, including an obstructive and a restrictive defect At a facility in Singapore, pulmonary function parameters (forced expiratory volume, FEV, forced vintal capacity, FVC) were lower, while radiological opacities and subjective symptoms (wheezing, chest tightness) were more frequent in 171 PVC compounding workers exposed to 0 2-1 55 mg/m3 PVC dust when compared to 48 controls (Ng et al 1991) No difference in lung function was reported between 104 PVC coated fabrics and wall coverings workers exposed to 0 2-11 5 mg/m3 PVC dust when compared to 112 workers exposed to non-chlonnated solvents in the United Kingdom (Chivers et al 1980) Twenty cases of pneumoconiosis were identified in a health survey of more than 1,216 Italian PVC production workers with exposures estimated to exceed 10 mg/m3 for at least five years (Mastrangelo et al, 1981) Subjective symptoms (complaints of wheezing) were more frequent and pulmonary function parameters (FEV) were decreased in 24 PVC compounding mixers (mean exposure = 1 6 mg/m3) but were not significantly changed in 24 non-mixers (mean =04 mg/m3) when compared to 24 controls (Lee et al 1991) Decrements in pulmonary function (FEV, FVC) were associated with PVC dust levels (mean shift levels up to 2 88 mg/m3), after adjusting for age, height, and smoking habit, in 818 workers at a PVC manufacturing plant (Soutar et al, 1980) Decreases in pulmonary function (forced expiratory flow at 75% of FVC, FEF75) were associated with duration of exposure in 81 U S PVC resin workers Draft TLVfor PVC Dusts The Sapphire Group, Inc February 4, 2002 (Gambleetal 1976) The authors estimated the rate of diminishing pulmonary function due to PVC exposure to be approximately 1% per year, after adjusting for age, height, and smoking Duration of employment was associated with decrements in cross-shift lung function in 133 US vinyl sheeting and wall covering production workers compared to 41 controls (Baser et al 1985) A significant increase in the prevalence of chest X-ray abnormalities was associated with duration ofexposure to PVC dust (concentrations not determined) in U S production plant workers (Lilis et al 1976, 1977) The prevalence of pulmonary function impairment (decreased maximum mid-expiratory flow, forced expiratory flow) was correlated with duration of exposure in a health survey of 354 U S PVC polymerization workers, regardless of smoking status (Miller etal 1975) Decrements in pulmonary function (FVC, FEV) were associated with duration ofexposure, after adjusting for height, smoking, and age (Siracusa etal, 1988) With respect to reproductive endpoints, an increased odds ratio for spontaneous abortion (95% Cl = 1 0-5 1) was observed in Swedish women working in the PVC plastics industry (Ahlborg etal, 1987) Conversely, no increased risk of spontaneous abortions was found in Finnish women workers who process polymerized plastics (Lindbohm et al, 1985) A large number of cancer mortality studies have been conducted on PVC production workers, but have generally been focused on exposures to VCM rather than PVC dust For this reason, these studies are not summarized here, but are included m the TLV documentation for VCM (ACGIH, 1997) Relative risk of breast cancer mortality was not significantly increased in female workers from 17 PVC fabrication factories (Chiazze and Ference 1981) TLV Recommendation [TO BE DETERMINED] References -5- ABDOOO19436 ACGIH 1997 TLV Documentation for particulates (insoluble) not otherwise classified (PNOC) Agarwal DK, Kaw JL, Snvasta SP, et al 1978 Some biochemical and histopathological changes induced by polyvinyl chloride dust in rat lung Environ Res 16(13) 333-341 Agarwal DK 1983 Biochemical Assessment of the Bioreactivity ofIntratracheally Administered Polyvinyl Chloride Dust in Rat Lung Chem Biol Interact 44 195201 Ahlborg Jr G, Bjerkdal T, Egenaes J 1987 Delivery outcome among women employed in the plastics industry in Sweden and Norway Am J Ind Med 12 507-517 Antti-Poika M, Nordman H, Nickels J, et al 1986 Lung disease after exposure to polyvinyl chloride dust Thorax 41(7) 566-567 Amaud A. Pommer de Santi PP, Garbe L, et al 1978 Polyvinyl chloride pneumoconiosis Thorax 33(1) 1925 Baser ME, Tockman MS, Kennedy TP, et al 1985 Pulmonary function and respiratory symptomatology in polyvinyl chloride fabrication workers Amer Rev Resp Dis 131(2)203-208 Burgess RH (Ed) 1982 The Toxicity of Vinyl Chloride and Its Removal from PVC In, Manufacture and Processing of PVC edited by R H Burgess, Applied Science Publishers pp 101-120 Chiazze L, Nichols W, and O Wong 1977 Mortality Among Employees of PVC Fabricators Journal of Occupational Medicine 19(9) 623-62S Ciazze Jr L, Ference LD 1981 Mortality among PVC-fabncating employees Environ Health Perspect 41 137-143 Chivers CP, Lawrence-Jones C, and GM Paddle 1980 Lung function in workers exposed to polyvinyl chloride dust BntJ Ind Med 37(2) 147-151 Clayton HM 1977 Toxicity and Vinyl Chloride In, Draft TL Vfor P VC Dusts The Sapphire Group, Inc February 4, 2002 Developments in PVC Production and Processing Edited by A Whelan and J L Craft, Applied Science Publishers pp 43-61 Ernst P, De Guirel L, Armstrong B, et al 1988 Obstructive and restrictive ventilatory impairment in polyvinyl chloride fabrication workers Amer J Ind Med 14(3) 273-279 Frongia N, Spinazzola A, and A Bucarelli 1974 Experimental lung damage from prolonged inhalation of airborne polyvinyl chloride dust Med Lav 65(910) 321-342 Goh CL, Ho SF, 1988 An outbreak of acneiform eruption in a polyvinyl chloride manufacturing factory Dermatosen36 53-57 Gamble J, Liu S, McMichael AJ, et al 1976 Effects of occupational and nonoccupational factors on the respiratory system of vinyl chloride and other workers J Occup Med 18 659-670 Groth DH, Lynch DW, Moorman WJ, et al 1981 Pneumoconiosis in animals exposed to poly (vinyl chloride) dust Environ Health Perspect 4 73-81 Hams LR, Sarvadi DG 1994 Synthetic Polymers In Patty's Industrial Hygiene and Toxicology, Volume II, PartE pp 3760-3775 Hilado CJ, and NV Hutthnger 1978 Toxicity of Pyroysis Gases from Some Synthetic Polymers J Combust Toxicol 5 361-369 HSDB 2001 retrieval Hazardous Substance Database Hunter AM, Wagner JC, Johnson N, et ai 1981 Lung fibrosis in polyvinyl chloride workers Thorax 36(9)711-712 ^International Labour Office (ILO) 1972 ILO U/C international classification of radiographs of the pneumoconiosis, 1971 Occupational Safety and Health Senes No 22 Geneva Interagency Regulatory Liaison Group (IRLG) 1981 Guidelines for documentation of epidemiological -6- ABDOOO19437 studies American Journal of Epidemiology 114(5) 609-613 Jaeger RJ, et al 1975 Short-term Inhalation Toxicity of Halogenated Hydrocarbons Effects on Fasting Rats Arch Environ Health 30( 1) 26-31 Jones JH 1981 Worker Exposure to Vinyl Chlonde and Poly(vinyl Chlonde) Environmental Health Perspectives 41 129-136 Lazard P, Guigou C, Capo C, et al 1980 Pneumoconiosis and polyvinyl chlonde Arch Mai Prof Med Trav Secur Soc 41(6-7) 339-340 Lee HS, Ng TP, Ng YL, et al 1991 Diurnal vanation in peak expiratory flow rate among polyvinyl chlonde compounding workers Brit J Ind Med 48(4) 275-278 Lee HS, Yap J, Wang YT, et al 1989 Occupational asthma due to unheated polyvinyl chlonde resin dust Brit J Ind Med 46 820-822 Leith DE 1984 Mass transport in mammalian lungs Comparative physiology J Toxicol Environ Health 13 251-271 Lewis 1999 Vinyl chlonde and polyvinyl chlonde Occup Med 14(4) 719-741 Lilis R, Anderson H, Miller A, etal 1976 Pulmonary changes among vinyl chlonde polymerisation workers Chest 69(Suppl 2) 299-303 Lilis R, Anderson H, Miller A, etal 1977 Pulmonary modifications and exposure to vinyl chloride and poly (vinyl chlonde) Med Hyg 35(1238) 1542-1545 Lilis R 1981 Review of Pulmonary Effects of Polv(vinyl Chlonde) and Vinyl Chlonde Exposure Environmental Health Perspectives 41 167-169 Lilis R 1980 Vinyl Chlonde and Polyvinyl Chloride Exposure and Occupation Lung Disease Chest 78 826828 Lindbohm ML, Hemmink K, Kyyronen P 1985 Spontaneous abortions among women employed in the plastic industry Am J Ind Med 8 579-586 Draft TLVfor PVC Dusts The Sapphire Croup, Inc February 4, 2002 Lloyd MH, Gauld S, Copland L, et al 1982 An epidemiological study ot the lung function of workers at a factory manufacturing polyvinyl chlonde IOM Report No TM/82/4 Lloyd MH, Gauld S, Copland L, et al 1984 Epidemiological study of the lung function of workers at a factory manufacturing poly (vinyl chlonde) Brit J Ind Med 41(3) 328-333 Magnavita N, MondeJIo M, Bergamaschi A, et al 1983 Ventilating changes in a PVC compounds factory A longitudinal study Arch Mai Prof 44(8) 543-549 Magnavita N, et al 1986 Vasculitic Purpura m vinyl chloride disease a case report Angiology 37(5) 382-388 Markowitz JS 1989 Self-Reported Short-and LongTerm Respiratory Effects Among PVC-Exposed Firefighters Archives of Environmental Health 44(1) 30-33 Markowitz JS, et al 1989 Acute Health Effects Among Firefighters Exposed to a Polyvinyl Chloride (PVC) Fire Amencan Journal of Epidemiology 129(5) 1023-1031 Mastrangelo G, et ai 1980 Polyvinyl chlonde pneumoconiosis epidemiological study of exposed workers Hazards Rev 1(11) 11-12 Mastrangelo G, Manno M, MarcerG, etal 1979 Poly (vinyl chlonde) pneumoconiosis epidemiologic study of exposed workers J Occup Med 21(8) 540-542 Mastrangelo G, Saia B, Marcer G, et al 1981 Epidemiological study ofpneumoconiosis in the Italian poly (vinyl chlonde) industry Environ Health Perspect 41 153-157 McMahon TA, Brain JD, and SR LeMott 1977 Species differences in aerosol deposition In Inhaled Particles IV, Part 1 WH Walton, ed Pergamon Press, Oxford, UK pp 23-33 Miller A 1980 Airway obstruction m workers exposed to vinyl chionde and polyvinyl chlonde In -7- ABDOOO19438 Occupational Asthma CA Frazier, ed Van Nostrand Reinhold Co pp 179-185 Miller A 1975 Pulmonary function defects in non smoking vinyl chloride workers Environ Health Perspect 11 247-250 Miller A, Teirstem AS, Chuang M, et al 1975 Changes in pulmonary function in workers exposed to vinyl chloride and poly (vinyl chlonde) Ann NY Acad Sci 246 42-52 Molina G, et al 1981 Mortality and Cancer Rates Among Workers m Swedish PVC Processing Industry Environ Health Perspect 41 145-51 Morgan RH, Donner MW, Gaylor BW, et al 1973 Decision processes and observer error in the diagnosis of pneumoconiosis by chest roentgenography American Journal of Roentgenology, Radium Therapy and Nuclear Medicine 117 757-764 Muhle H, Bellmann B, Creutzenberg 0, Heinrich U, Ketkar M, Mermelstein R 1990 Dust overloading of lungs after exposure of rats to particulates of low solubility comparative studies J Aerosol Sci 21 374377 Muhle H, Creutzenberg 0, Bellmann B, Heinnch U, Mermelstein R 1991 Dust overloading of lungs investigations of various matenals, species differences and irreversibility of effects J Aerosol Med National Health Council ofthe The Netherlands 1987 A Scientific Basis for the Risk Assessment of Vinyl Chlonde Reg Toxicol Pharmacol 7 120-127 Ng TP, Lee HS, Low YM, et al 1991 Pulmonary effects of polyvinyl chlonde dust exposure on compounding workers Scand J Work Environ Health 17(1) 53-59 Nielsen J, Fahraeus C, Bensryd I, et al 1989 Small airways function in workers processing polyvinyl chlonde Int Arch Occup Environ Health 61 427-430 Oleru UG, and C Onyekwere 1992 Exposures to polyvinyl chlonde, methyl ketone and other chemicals Int Arch Occup Environ Health 63 503-507 Draft TLVfor PVC Dusts The Sapphire Group, Inc February 4, 2002 Pigott GH, and J Ishmael 1979 A Companson Between In Vitro Toxicity of PVC Powers and Their Tissues Reation in Vivo Ann Occup Hyg 22 111-126 PopowJ 1969 Effect ofPoly(Vinyl Chlonde) (PVC) Dust on the Respiratory System ofthe Rat Rocz Akad Med Bialymstoku 24 5-48 Prodan L, Suciu I, et al 1975 Expenmental Chronic Poisoning with Vinyl Chlonde (Monochloroethene) Ann NY Acad Sci 246 159-163 Richards RJ, Desai R, Hext PM, et al Biological reactivity of PVC dust 256(5519) 664-665 1975 Nature Richards RJ, Rose FA, Tetley TD, et al 1981 Effects in the rat of inhaling PVC dust at the nuisance dust level (10 mg/m3) Arch Environ Health 36(1) 14-19 Saunn JC, Taniere P, Mion F, et al 1977 Pnmary hepatocellular carcinoma in workers exposed to vinyl chlonde-a report oftwo cases Cancer 79 1671-1677 Simonato L, L'Abbe KA, Anderson A, et al 1991 A collaborative study of cancer mcidence and mortality vinyl chlonde workers Scan J Work Environ Health 17(3) 159-169 Siracusa A, Ciciom C, Volpi R, et al 1984 Lung function among asbestos cement factory workers crosssectional and longitudinal study Amer J Ind Med 5(4)315-325 Siracusa A, Forcina A, Volpi R, et al 1988 Anilyear longitudinal study of the occupational dust exposure and lung function of polyvinyl chlonde, cement and asbestos cement factory workers Scan J Work Environ Health 14(3) 181-188 Smith AJ, Li Y, Whitley R, et al 1998 Molecular epidemiology of p53 mutations in pnmary hepatic angiosarcomas not associated with vinyl chlonde exposure Am J Epidem 147 302-8 Smulevich VB, Fedotova IV, and VS Filatova 1988 Increasing evidence of the nse of cancer in workers exposure to vinyl chlonde Br J Ind Med 45 93-97 -8- ABDOOO19439 Snipes MB 1989 Species comparisons for pulmonary retention ofinhaled particles In Concepts in Inhalation Toxicology Chapter 7 RO McClellan and RF Henderson, eds Hemisphere Publishing Corporation, London (ISBN 0-89116-805-2) Soini Y, Welsh JA, Ishak KG, and WP Bennett 1995 p53 mutations in primary hepatic angiosarcomas not associated with vinyl chloride exposure Carcinogenesis 16 2879-2881 Soutar C, Copland L, Thomley P, et al 1981 An epidemiological study ofrespiratory disease in workers exposed to polyvinyl chloride dust Chest 80(Suppl 1)60 *Soutar C, Copland L, Thomley P, et al 1979 An epidemiologic study of respiratory disease in workers exposed to polyvinyl chloride dust IOM Report No TM/79/2 October Soutar C, Copland L, Thomley P, et al 1980 Epidemiology study of respiratory disease in workers exposed to polyvinyl chloride dust Thorax 35(9) 644652 Soutar CA, and S Gauld 1983 Clinical studies of workers exposed to polyvinyl chloride dust Thorax 38(11) 834-839 *Soutar C, Gauld S, Lloyd M, et al 1981 Epidemiological and clinical studies of polyvinylchloride workers IOM Report No TM/81/8 July Snvasta RK, Sachan AS, Sharma SK, et al 1980 Effect of inhaled polyvinyl chloride dust on lungs of rats Indian J Physiol Pharmacol 24(5) Suppll,Abstr 124 Storetvedt S, et al 1984 Incidence of Cancer Among Vinyl Chloride and Polyvinyl Chloride Workers British Journal of Industrial Medicine 41 25-30 Studnicka MJ, Menzinger G, Drlicek M, Maruna H, and MG Neumann 1995 Pneumoconiosis and systemic sclerosis following 10 years of exposure to polyvinyl chloride dust Thorax 50(5) 583-5, discussion 589 Draft TL Vfor PVC Dusts The Sapphire Group, Inc February 4, 2002 Sulotto F, Romano C, Peruccio G, et al 1985 A case of pneumoconiosis caused by polyvinyl chloride Med Lav 76(4) 304-308 Styles JA, and J Wilson 1973 Companson between in vitro toxicity of polymer and mineral dusts and their fibrogemcity Ann Occup Hyg 16(3) 241-250 Szende B, Lapis K, Nemes A, and A Pinter 1970 Pneumoconiosis caused by the Inhalation of Polyvinyl Chloride Dust Med Lav 61(8-9) 433-436 Takenaka S, Rittinghausen S, Bellmn B, et al 1987 Morphological effects of `nuisance' dusts on the respiratory system in rats J Aerosol Sci 18(6) 717-720 Tetley TD, et al 1981 Biochemical and Cellular Reaction of PVC Paste Polymer and latex following Intratracheal Instillation into Rats Inflammation 5 137 *U S Code of Federal Regulations Title 29 Part 1910 1000 1992 29 CFR 1910 1000, Table 1 USFDA 1986 US Food and Drug Administration Proposed Rule "Proposed Uses of Vinyl Chloride Polymers" 51 Federal Register 4177, at 4178 (Feb 3, 1986) Vamiotalo S, andP Pfaffli 1990 Air Impurities in the PVC Plastics Processing Industry Ann Ind Occup Hyg 34 585-590 Vertkin YI, and YP Mamontov 1970 State of the bronchopulmonary apparatus in workers engaged in the manufacture ofarticles made ofpolyvinyl chloride Cig Tr Prof Zabol 14(10) 29-32 Vertkin YI, and AA Nikonov 1981 Nature of the Action of Poly(vinyl Chloride) Dust on Lungs Gig Tr Prof Zabol 7 48 VI 2001 Personal communication from the Vinyl Institute VolkheimerG 1975 Hematogenous Dissemination of Ingested Polyvinyl Chloride Particles Ann NY Acad Sci 246 164-171 Volpi R, Siracusa A, Ciciom C et al 1986 Lung -9- ABDOOO19440 function among PVC, cement and asbestos cement factorv workers A longitudinal studv Med Lav 77(1) 106 Wagner JC, Johnson NF 1981 Preliminary observations of the effect of inhalation ot PVC in man and experimental animals Environ Health Perspect 41 83-84 Wagoner IK 1983 Toxicity of Vinyl Chloride and Poly(Vinvl Chloride) A Critical Review' Environ Health Perspect 52 61-66 Waxweiler R, Allan J et al 1981 Excess Lung Cancer Risk in a Synthetic Chemicals Plant Environmental Health Perspectives 41 159-165 White NJ and RI Ehrlich 1997 Regression of polyvinvlchlonde polymer pneumoconiosis Thorax 52(8) 748-9 Wibowo AAE 1993 Health based recommended occupational exposure limit for polyvinyl chloride (PVC) Dust Dutch Expert Committee on Occupational Standards Sdu Uitgcvenj Plantijnstraat Afdeling Verkoop Publikaties Arbeidsinspectie Den Haag, Netherlands Wong KL et al 1983 Evaluation of the Pulmonary Toxicitv ot Plasticized Polwmvl Chloride Thermal Decomposition in Guinea Pigs bv Repeated CO; Challenges Toxicology and Applied Pharmacology 70 236-248 Yu RC, and SM Rappaport 1996 Relation between pulmonary clearance and particle burden a MtchaelisMenten-like kinetic model Occupational and Environmental Medicine 53(8) 567-72 G \Project\Vinyl Institute\master\reports\PVC TLV wpd Draft TLV for PVC Dusts The Sapphire Group Inc February 4, 2002 -10- ABDOOO19441 TLV Recommendation Draft TLVRecommendation The Sapphire Croup, Inc February 4, 2002 The quantitative data available for PVC dusts, including epidemiological and toxicological studies, from which a TLV could be derived are extremely limited Epidemiology studies, while providing suggestive evidence of pulmonary function changes, radiographical abnormalities, and subjective symptoms, generally do not provide adequate information regarding exposures to provide an adequate charactenzation of an exposure-response relationship Two animal studies which serve as potential candidates for deriving a TLV include (1) a study in rats, guinea pigs, and monkeys that identifies a chronic LOEL of 13 mg/m3 for benign pneumoconiosis without change in pulmonary function (Groth et al 1981), and (2) a study in rats that reports a concentration dependent increase in lung inflammation and hyperplasia following chronic exposure to 3 2-20 mg/m3 (Takenaka et al 1987) The strengths of the former study include its use of primates as one of the test species, thereby making the results potentially of greater relevance to human exposures The primary weakness of this study, however, is that only a single test concentration of PVC dust was examined The strengths of the latter study include the testing ofthree dust concentrations and the availability of kinetic information in a companion study (Muhle et al 1990), which could be used to assess the importance of lung burden and clearance in toxicity [VI WE HAVE ORDERED A FEW STUDIES CITED IN MUHLE ET AL , WHICH MIGFIT CONTAIN ADDITIONAL TOXICITY DATA WE EXPECT TO RECEIVE SHORTLY IF ADDITIONAL TOXICITY DATA FOR THE TAKENAKA STUDY ARE AVAILABLE, IT COULD IMPACT TLV RECOMMENDATION] The critical weaknesses of this study, however, include the lack of specific information regarding the incidence and/or seventy of the lung effects observed at each concentration, and the difficulties encountered when attempting to extrapolate information from rats, whose respiratory tract and breathmg patterns (obligate nose breathers) are fundamentally different from humans In our opinion, neither of these studies are well suited for denvmg a TLV A tentative TLV value could be denved from the results of Groth et al (1981), however, confidence in the value would be considered low The LOEL value of 13 mg/m3, when divided by an uncertainty factor of 3 (3 for LOEL to NOAEL extrapolation, 1 for interspecies extrapolation), could be used to support a TLV of 4 3 mg/m3 An uncertainty factor of 3 for LOEL to NOAEL extrapolation is justifiable since no decrease in pulmonary function was reported in the exposed animals (Groth et al 1981) An uncertainty factor of 1 is considered to be appropriate for interspecies extrapolation smce the architecture of the respiratory tract and breathing patterns (ability to mouth breathe) m monkeys is similar to that for humans For this reason, depositional processes for PVC dusts are expected to be similar between the two species However, differences may exist between non-human -2- ABDOOO19442 Draft TLVRecommendation The Sapphire Group, Inc February 4, 2002 primates and humans with respect to clearance rates A potential indicator of relative clearance between mammalian species can be made by comparing the relative volume occupied by macrophages in the alveolar region Macrophages comprise approximately 2 3% of the lung cell population m non-human primates (baboon), compared to 9 4% of the lung cell population in humans, indicating a 4-fold difference in favor of humans (CRC, 1995) Furthermore, the average volume of lung macrophage m humans is approximately 2 5 times higher than the corresponding volume in non-human primates (2,492 versus 1,059 urn3) (CRC, 1995) Together, these two factors suggest that when compared to non-human primates, pulmonary clearance of dust is expected to be greater m humans by a factor of approximately 10 (4x2 5) In this case, application of an uncertainty factor of 1 for mterspecies extrapolation can be considered conservative However, at least one review of lung clearance data across species has suggested that particle overloading might occur at lower concentrations in humans than other species (Kreyhng et al, 1990) [VI WE HAVE ORDERED THIS REFERENCE, WHICH IS CITED ACGIH PNOS DOCUMENTATION, SINCE IT COULD IMPACT THE TLV RECOMMENDATION] Under this alternative assumption, an uncertainty factor for mterspecies extrapolation greater than 1 would need to be considered Currently ACGIH recommends a TLV of 10 mg/m3 for inhalable particulates and 3 mg/m3 for respirable particulates not otherwise specified (PNOS) (ACGIH, 2001) These TLV values are considered to be protective of "toxicity caused by physical overloading of the normal clearance mechanisms of the respiratory tract" (ACGIH, 1997) As such, use of these TLV values for exposures to PVC dusts is considered to be appropriate, and is supported by the tentative value of 4 3 mg/m3 derived above from the data of Groth et al (1981) References ACGIH 2001 TLVs and BEIs Threshold limit values for chemical substances and physical agents & biological exposure indices Cincinnati, OH American Conference of Governmental Industrial Hygienists ACGIH 1997 TLV Documentation for particulates (insoluble) not otherwise classified (PNOC) CRC 1995 CRC Handbook of Toxicology Edited by Derelanko MJ, Holhnger MA CRC Press Groth DH, Lynch DW, Moorman WJ, et al 1981 Pneumoconiosis in animals exposed to poly (vinyl chloride) dust Environ Health Perspect 4 73-81 Kreyhng WG 1990 Interspecies comparison of lung clearance ofinsoluble particles J Aerosol Med 3(Suppl 1) S93S107 o-