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r* KJ Te> /? /Y /f/ 5m* &y &CAt/*e#0 & 7~jA-J<-- ENVIRONMENTAL HEALTH PERSPECTIVES Volume 41# October 1981 ucc 057046 # t 057047 I 1 i t SUBSCRIPTION INFORMATION Subscription rates are as follows: Single copies $7.00, foreign $8.75, domestic $41.00 per year, foreign $51.25 per year. The yearly subscription is for 6 regular issues. Please send check or money order, in advance to the Superintendent of Docu ments, U.S. Government Printing Office, Washing ton, D.C. 20402. The Secretary of Health and Human Services has determined that the publication of this periodical is necessary in the transaction of the public business required by law of this Department. Use of funds for printing this periodical has been approved by the Director of the Office of Management and Budget through January 31, 1983. ENVIRONMENTAL HEALTH PERSPECTIVES is a publication of the National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services. 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In addition. Executive Order 1141 prohibits discrimination on the basis of age by contractors and subcontractors in the performance of Federal contracts, and Executive Order 11246 states that no federally funded contractor may discriminate against any employee or applicant for employment because of race, color, religion, sex, or national origin. Therefore, the National Institute of Environmental Health Sciences must be operated in compliance with these laws and Executive Orders. ucc 057048 David P. Rail, Director, National Institute of Environmental Health Sciences EDITORS ; George W. Lucier Gary E. R. Hook BOARD OF EDITORS Richard Bates Colin F. Chignell Robert L. Dixon Hans L. Falk Lawrence Fishbein Robert Goyer a Larry Hart Joseph Haseman David Hoel James Huff Heinrich Mailing H. B. Matthews Ernest E. McConnell James D. McKinney Clifford L. Mitchell John A. Moore Warren Piver Robert Staples Ray Tennant EDITORIAL STAFF Martha H. Dockery, Assistant Managing Editor Ruth Krigman, Copy Editor Sharon Barber ENVIRONMENTAL HEALTH PERSPECTIVES i Volume 41, October 1981 > U.S. DEPARTMENT OP HEALTH AND HUMAN SERVICES Public Health Service i National Institutes of Health CONTENTS t Conference to Reevaluate the Toxicity of Vinyl Chloride, Poly(vinyl Chloride) and Structural Analogs R. J. Waxweiler, P. J. Landrigan, P. Infante and R. Shapiro. Introduction......... 1 C. Maltoni, G. Lefemine, A. Ciliberti, G. Cotti and D. Carretti. Carcinogenicity bioaasays of vinyl chloride monomer a model of risk assessment on an experimental basis ........................................................... 3 Y. Suzuki. Neoplastic and nonneoplastic effects of vinyl chloride in mouse lung ..... 31 D. H. Groth, W. B. Coate, B. M. Ulland and R. W. Homung. Effects of aging on the induction of angiosarcoma................................................................................................. 53 M. J. Radike, K. L. Stemmer and E. Bingham. Effect of ethanol on vinyl chloride carcinogenesis...................................................................................................................... 59 R. M. Hehir, B. P, McNamara, J. McLaughlin, Jr., D. A. WUligan, G. Bierbower and J. F. Hardisty. Cancer induction following single and multiple exposures to a constant amount of vinyl chloride monomer .................................................................. 63 i D. H. Groth, D. W. Lynch, W. J. Moorman, L. E. Stettler, T. R. Lewis, W, D. Wagner and C. Konunineni. Pneumoconiosis in animals exposed to poly(vinyl chloride) dust........................................................................................................................ 73 J. C. Wagner and N. F. Johnson. Preliminary observations of the effect of inhalation of PVC in nuuvand experimental gnimals ...................................................................... 83 C. Maltoni and P. Lodi. Results of sputum cytology among workers exposed to vinyl chloride monomer and to polyfvinyl chloride) .................................................................... 85 P. F. Infante. Observations of the site-specific carcinogenicity of vinyl chloride to humans.................................................................................................................................. 89 H. Weber, W. Reinl and E. Greiser. German investigations on morbidity and mortality of workers exposed to vinyl chloride ............................................................ 95 W. C. Cooper. Epidemiologic study of vinyl chloride workers: mortality through December 31, 1972 ............................................................................................................. 101 H. Falk, J. Herbert, S. Crowley, K. G. Ishak, L. B. Thomas, H. Popper and G. G. Caldwell. Epidemiology of hepatic angiosarcoma in the United States: 1964-1974 .... 107 P. J. Baxter. The British Hepatic Angiosarcoma Register........................................... 115 C. H. Tamburro and R. Greenberg. Effectiveness of federally required medical laboratory screening in the detection of chemical liver iqjury.................................... 117 R. N. Wheeler, Jr. Polyfvinyl chloride) processes and products .................................. 123 J. H. Jones. Worker exposure to vinyl chloride and polyfvinyl chloride).................... 129 L. Chiazze, Jr., and L. D. Ference. Mortality among PVC-fabricating employees .... 137 G. Molina, B. Holmberg, S. Elofsson, L. Holmiund, R. Moosing and P. Westerholm. Mortality and cancer rates among workers in the Swedish PVC processing industry....... ..................................................................................................... 145 G. Mastrangelo, B. Saia, G. Marcer and G. Piazza. Epidemiological study of pneumoconiosis in the Italian poly(vinyl chloride) industry ........................................ 153 R. J. Waxweiler, A. H. Smith, H. Falk and H. A. Tyroler. Excess lung cancer risk in a synthetic chemicals plant................................................................................................ 159 R. Lilis. Review of pulmonary effects of polyfvinyl chloride) and vinyl chloride exposure................................................................................................................................ 167 ucc 057050 #I * J I'i } 1; J. A. John, F. A. Smith and B. A. Schwetz, Vinyl chloride: inhalation teratology study in mice, rats and rabbits ........................................................................................ J. M. Rice. Prenatal susceptibility to carcinogenesis by xenobiotic substances including vinyl chloride...................................................................................................... J. D. Fabricant and M. S. Legator. Mutagenicity studies of vinyl chloride ............. M. Hatch, J. Kline and Z. Stein. Power considerations in studies of reproductive effects of vinyl chloride and some structural analogs .................................................. W. F. Dimmick. EPA programs of vinyl chloride monitoring in ambient air............ N. J. Vienna, J. Brady and P. Harper. Angiosarcoma of the liven a signal lesion of vinyl chloride exposure...................................................................................................... K. C. Chu and H. A. Milman. Review of experimental carcinogenesis by compounds related to vinyl chloride........ ............................................................................................ ' R. Apfeldorf and P. J. Infante. Review of epidemiologic study results of vinyl chloride*related compounds .............................................................................................. 0. Hattis. Needs for public health intervention and needs for new research on vinyl halides and their polymers: a public policy perspective .............................................. 171 179 189 195 203 207 211 222 227 Contributed Articles R. M. Stern. Process-dependent risk of delayed health effects for welders ............... J. H. Ware, L. Thibodeau, F. Speizer, S. Colome and B. G. Ferris, Jr. Assessment of the health effects of atmospheric sulfur oxides and particulate matter evidence from observational studies.................................................................. R. Jourmard, M. Chiron, R. Vidon, M. Maurin and J.-M. Rouzioux. Mathematical models of the uptake of carbon monoxide on hemoglobin at low carbon monoxide J. C. Westman and J. R. Walters. Noise and stress: a comprehensive approach .... 235 255 277 291 311 312 1 ill i tr-*i**_ ucc 057051 1 # IN THE NEXT ISSUE A Symposium on Environmental Epidemiology N. A. Esmen. Limitations on dose estimation. Y. Alarie. Dose response analysis in animal studies: prediction of human responses. C. E. Land. Statistical limitations in relation to sample size. B. Altshuler. Modeling of dose-response relationships. H. E. Griffen. Discussion: Detection of health effects of exposure to low doses of agents--epidemiologic problems. M. A. Schneiderman. Extrapolation from incomplete data to total or lifetime risks at low doses. P. E. Enterline. Extrapolation from occupational studies--a substitute for environmental epidemiology. E. P. Radford. Sensitivity of health end points: effect on conclusions of studies. R. J. Waxweiler. Epidemiologic problems associated with exposure to several agents. P. E. Enterline. Discussion: Policy issues ^applying epidemiologic evidence. V. R. Hunt. Epidemiological studies for regulatory agencies. M. Bundy. When are studies adequate for regulatory purposes: view of one regulated. I. H. Billick. Lead: a case study in interagency policy-making. L. H. Kuller. Who should provide research initiative and support? J. H. Turner Discussion: New approaches to detecting low-dose effects. N. L. Fetrakis. Genetic-environmental interactions in relation to low dose stud ies. A possible model from breast cancer. J. C. Christian. Use of twins to study environmental effects. M. K. Conner. Chromosomal methods in population studies. V. Hunt. Discussion: Epidemiologic investigation of special groups. E. A. Murphy. Detection of genetic effects of environmental agents. J. Kline. Epidemiologic detection of low dose effects on the developing fetus. C. K. Redmond. Sensitive population subsets in relation to effects of low doses. Contributed Articles J. I. Rader. Comparative toxicity and tissue distribution of lead acetate in weanling and adult rats. B. E. Vaughan. Problems in evaluating radiation dose via terrestrial and aquatic pathways. F. Perera. The carcinogenicity of airborne fine particulate benzo(a)pyrene: an appraisal of the evidence and the need for control. * . St. ucc 057052 J. Miller. Cadmium, lead and zinc in growing rats fed com leaf tissue grown on soil amended with sewage sludge or heavy metal salts. S. Lan. Effect of air pollution on chronic respiratory disease in the New York City metropolitan area, 1972. <a ucc 057053 > I Conference to Reevaluate the Toxicity of Vinyl Chloride Monomer, Poly(vinyl Chloride) and Structural Analogs National Institutes of Health, Bethesda, MD March 20-21,1980 Sponsored by National Institute of Environmental Health Sciences, National Institute for Occupational Safety and Health and Occupational Saffcty and Health Administration ucc 057054 Environmental Health Perspective* Vol. il. p. 1, mi Introduction It has been over 30 years since the first sugges tive evidence was published by Tribukh to indicate that vinyl chloride monomer (VCM) is acutely toxic in man. Chronic toxicity in animals was subse quently demonstrated by Torkelson in 1961, but it was an outbreak to VCM-induced acroosteolysis in the 1960's that focused attention for the first time on the occupational toxicity of this important indus trial chemical. The carcinogenicity of VCM was recognized in 1974 following the nearly simulta neous reports of an association between exposure to VCM and angiosarcoma of the liver (ASL) in man (reported by Creech and Johnson) and in animals (reported by Maltoni). These reports precipitated a thorough international review of the toxicity of VCM at the New York Academy of Sciences. Since then, enormous research efforts have been under taken to expand our knowledge of the toxicity of vinyl chloride. Many of the research efforts stimu lated by the events of the 1970's have now come to fruition, and are appropriately brought together in these proceedings. The proceedings begin with a presentation of the most extensive animal research on the carcinoge nicity of VCM ever published. In these data, dose-response curves can be examined by site and type of tumor, by route and schedule of exposure, and by species and strain of animal. This study and other research on the carcinogenicity of VCM reported in this volume indicate the importance of cofactors such as age at exposure and simultaneous exposure to ethyl alcohol in VCM toxicity. Evi dence that even a single exposure to VCM induces experimental neoplasia is significant from the standpoint of both occupational and nonoccupational exposures. The updated epidemiologic studies presented in this volume of mortality among workers exposed to vinyl chloride reinforce the laboratory findings of multisite carcinogenicity. Data demonstrating the mutagenic and transplacental effects of VCM are also updated and summarized. The lack of predictivity of one prospective liver screening program sug gests the need for further work in identifying effective medical surveillance techniques for early recognition of liver abnormalities. While thousands of workers are exposed to VCM vapor, many more are exposed to its polymer, poly(vinyl chloride) (PVC). The carcinogenicity of PVC dust is evaluated both experimentally and epidemiologicaily in these proceedings. The results are not definitive. Nonmalignant respiratory sys tem effects from PVC dust are suggested by a number of papers at this conference. Finally, the extension of the findings of carcino genicity of VCM to its structural analogs, vinylidene chloride, trichloroethylene and tetrachloroethylene, and its brominated equivalent, vinyl bromide, serves as another lead in our effort to understand some fundamental concepts of chemical carcinogenesis. Richard J. Waxwkilek Philip J. Landrican Peter Infante Raymond Shapiro October 1981 1 Envtrvnmtnial Htalth Ptrtpcctivtt Vot. il, pp. 3-ti, MSI Carcinogenicity Bioassays of Vinyl Chloride Monomer: A Model of Risk Assessment on an Experimental Basis by Cesare Maltoni,* Giuseppe Lefemine,* Adriano Ciliberti,* Giuliano Cotti* and Donata Carretti* Data art praamtad rvgxrting the (Inal remit* ot the Bentitoclio (Bolofna) project an lone-term <^fcinofni<rity bioeueyt of vinyl chloride (VC). The experimental project studied the effect* of the monomer, administered by different route*, concentrations and schedules of treatment to animals (near 7000) of different specie*, strains, sex and eg*. To our knowledge this is the tartest experimental carcinofenkity study performed on a sin(i* compound by a single institution. The remits Indicate that VC is a multipotential carcinogen, affecting a variety of organ* and tissues. In the experimental conditions studied, the neoplastic effects of the monomer were also detected at low doses. The experimental and biological factors greatly affect the neoplastic response to VC. Long-term carcinogenicity bfoassays are, at present, a unique tool for the identification and quantification of environmental and occupational risks. Precise and highly standardised experimental procedure* are needed to obtain data for risk assessment. Introduction The present report deals with the presentation of the final results of our project on the long-term carcinogenicity bioassays of vinyl chloride (VC) (BT project). To our knowledge this project is the most exten sive experimental carcinogenesis study ever per formed on one industrial compound by a single institution. Planning, Materials, Methods and Performance of the Experiment Planning The experiments of the project were planned (a) to test the carcinogenicity of the compound; 'Institute of Oncology snd Tumor Center' Botokfy,, Italy. (b) to obtain information on the site and type of tumors; (c) to evaluate the possible effects of the routes of administration, with particular regard to the ones reproducing potential human exposure; (d) to assess, in quantitative terms, the level of risk. The planning of the experiments was aimed at achieving these goals. The compound was tested on animals of different species, strain, sex and age (Table 1), since it is known that these factors may modify the neoplastic response qualitatively and quantitatively. The choice of the animals was made with the intention of having an integrated system of complementary biological models which could express a range, as wide as possible, of neoplastic responses. VC was sdministered by different routes: intraperitoneal (IP) injection, subcutaneous (SC) injec tion, inhalation and ingestion (by stomach tube), the latter two being the major routes of potential human exposure. The monomer was administered at different concentrations: 14 by inhalation levels and 6 inges tion levels for various periods of time, by continu ous or intermittent treatment (Table 2). October 1981 ......... ,v 3 ucc 057056 Table 1. BT project on VC: animal* uacd. Sped** Strain Sex Age Rat SpragueDawley Rat Mouse Hamster Wistar Swiss Golden M.F M M, F M Adult (10-21 wk) Newborn (1 day) Embryo (12 day* pregnancy) Aduh Adult Adult The plan of the project is presented in Tables 3-9. Material VC was supplied from the same source in all cases, and it contained very low amounts of impuri ties (Table 10). The oil employed as a vehicle in the ingestion and injection experiments was pure vir gin olive oil from Tuscany. The animals (except for the golden hamsters) were breeds which have been routinely employed in our laboratory for many years. It should be pointed out that, whatever their use, all the animals of our colony undergo periodic examination and complete autopsy, giving us extensive information concern ing their pathology. The chambers for inhalation exposure were built basically of stainless steel and glass. For the ingestion treatment glass syringes and stainless steel needles with round tips were used. To control the level of exposure in the inhalation experiments, an automatic gas chromatography system was used. Rome Inhalation Ingeetion IP injection SC injection Table 2. BT project on VC: routes, concentration* and schedules. Concentration Schedule 30.000, 10,000, 6000, 2500, 500, 250, 200, 150,100, 50, 25,10, 5,1 ppm 10,000, SOW, 2500, 500, 250. 50 ppm 10,000, 6000 ppm 10,000, 0000 ppm 10,000, 6000 ppm 10,000, 6000 ppm 50,16.66, 3.33,1.0, 0.3,0.03, mg/kg body weight 4.26 mg 4.26 mg 4.26 mg 4 hr/day, 6 days/wk, 52 wk 4 hr/day, 5 days/wk, 17 wk 4 hr/day, 6 dayt/wk, 5 wk 4 hr/day, 1 day/wk, 26 wk 1 hr/day, 4 days/wk, 26 wk 4 hr/day, 7 day* 5 tiraes/wk, 62 wk 4, S, or 2 time* at 2 month intervals Once only Once only Table 3. Plan of lone-tana experiment* on the effects of exposure by Inhalation far 1 year to different doaaa of VC on adult Sprague-Dawiey rat* (basic txperimanta). ExpL no. TVcfltSMOt Route VC doss Duration Sptciat Strain Age, weeks Animals No. 9 No. i Total No. per group BTl BT2 BT6 BT> BTl5 Inhalation 10,000,6000,2600,500 4 hr/day, 250, 50 ppm 5 dayt/wk. Untreated controls 62 wk Treated controls VA. 2500 ppm Inhalation 200, 150, 100 ppm 4 hr/day, 6 Untreated control* days/wk, 52 wk Inhalation 30,000 ppm 4 hr/day, 6 days/wk, 62 wk Inhalation 50 ppm 4 hr/day, 6 Untreated controls days/wk, 62 wk Inhalation 25,10, 5,1 ppm 4 hr/day, 5 Untreated controls dayt/wk, 52 wk Rat Spngua- IS Dawley Rat SpragueDsedey Rat SpragueDawley Rat Spngnt* Dtwtty Rat SpragueDewiey IS 17 11 IS 240 240 460 60 280 266 546 120-185 30 30 60 60 200 200 400 900 300 600 100 (c) 300 (t) 120 4 Environmental Health Perspectives TS) 1 in ted 3ur ete m- uih and ad. tion *'hy Table 4. Flu of long-term experiment* on Um effect* of length of VC expoeure on VC carcinogenicity. Expt. no. BT3 BT10 Route Treatment__________________ ___ ___________ _____________ Animeie VCdoee Duration Age, Spedea Stnin week* No. 9 No. i Inhalation 10,000, 6000, 2500, 600, 250, 60 ppm Untreated controla Inhalation 10,000, 6000, ppm Untreated controla 4 hr/day, 5 daya/Wk, 17 wk 4 hr/day, 5 day*/ wk, 5 wk; 4 hr/ day, 1 d*y/wk, 25 wk; 1 hr/day, 4 daya/wk, 25 wk Rat SpragueDawley Rat SpngueDawley 12 11 262 288 420 420 No. per Total group 550 60-190 840 120 Table 5. Plan of long-term experiment* on the effect* of af* on rinyl chloride carcinofenkity. Expt. no. Treatment Route VCdoee Duration Specie* Strain Animal* Age, week* No. 9 No. i No. per Total group BT5 Tranapla. 10,000, 6000 ppm cental 4* BT14 Inhalation 10,000, 6000 ppm 4 hr/day, 7 day* Rat Sprague- 19 110 36 146 30-64 (from 12th to IStfa Dawley (bread- day of pregnancy) era) 12 ilay* (em bryo*) 4 hr/day, 5 Rat Sprague- 1 day 45 44 89 43-46 daya/wk, 5 wk Dawley dull tp > > 0 (e) 0 (t) 0 Table 5. Plan of lone-term experiment* on the effect* of (train on rinyl chloride carcinogenicity. Expt. no. BT7 BT17 Treatment Route VCdoee Duration Inhalation 10.000, 6000, 2500, 500, 250, 50 ppm Untreated control* Inhalation 1 ppm Untreated control* 4 hr/day, 5 daya/wk, 52 wk 4 hr/day, 6 daya/wk, 52 wk Spade* Strain Animal* Age, week* No. 9 No. a Rat Wiatar 11 0 220 Rat Wiatar IS 0 250 No. pir Total group 220 30-40 250 120-130 Table 7. Plan of long-term experiment* on the effect* of ipecie* on rinyl chloride carcinogenicity. Expt. no. Treatment Route VC darn Duration Sptda* Strain Animal* Age, week* No. 9 No. a No. per Total group BT4 Inhalation 10,000, 6000, 2500, 250, SO ppm Untreated control* BT8 Inhalation 10,000, 6000, 2500, 500, 250, 50 ppm Untreated control* 4 hr/day, 6 daya/wk, 30 wk 4 hr/day, 5 daya/wk. 30 wk Mouae Swim 11 500.250 260 510 60-150 Hamater Golden 11 10 268 268 30-62 October 1981 5 UCC 057058 1 Table 8. Plan of lonf-term Ingestion experiments on vinyl chloride carcinogenicity. Expt. no. BTll BT27 Treatment Routo VC doae Duration Spado* Strain Animal* Aft, w*aka No. 9 No. $ Ingestion 50, 16.85, 3.38 mg/kf 5 timee/wk, Ret Sprague- body weight in olive oil 52 wk Dawiey Control*, olive oil Infection 1, 0.3, 0-08 mg/kg body 5 times/wk, 52 wk Ret Sprague- weight in olive oil or 59 wk* Control*, alive ail IS 10 160 160 300 300 No. par Total group 820 80 600 150 For 10 animal* of aaefa of th* three expoeed and control group* the treatment vaa planned to laat 104 week*, but it had to be (topped becsuie of animal intolerance. Expt. DO. BT12 BT1S Table I. Plan of long-term injection experiment* on vinyl chloride eatcinageatettp. Route IP in jection SC in jection Treatment VCdoee Duration Specie* Strain Animal* Age, week* No. 9 No. t 4.25 mg in 1.0 olive oil Control*, 1.0 ic olive oil 4.25 mg in 1.0 cc olive oO Control*, 1.0 cc olive oil 4, 8, 2, or 1 time*; two month interval* 1 injection Rat SpngueDuwley Rat SpragueDawley 13 21 150 150 80 70 No. per Total group 800 60 150 75 Table 10. Maximum lead of impuritie* in the VC need. Impurity Conen, ppm HiO Acetic aldehyde Acetylene Alien* Butane 1,3-Butadiane Cbloropban* Diacetykn* Vinyl acetylene Propine Methyl chloride 10 5 2 6 8 10 10 4 10 8 100 Methods and Procedures For the experiment on VC, as well as for any other long-term experimental bioassaya performed in our laboratory, the procedure has been always the same highly standardized and controlled one. In particular, the following points in our laboratory standard procedures, should be emphasized. Compounds. All shipments of VC used were examined in order to determine whether they meet the required standards. Concentrations. The concentrations, particularly when VC was given by inhalation, were controlled by continuous gas chromatographic monitoring. Modalities of Treatment Treatment was al ways performed by the same people. This is par ticularly important for gavage, since the animals become accustomed to the same operator. Control of the Animals. The conditions of the animals checked three times daily. Every two weeks the animals were examined to detect any gross changes. Weight of the Animals. The animals were weighed every two weeks during treatment and every eight weeks after the end of treatment. Duration of the Experiments. In the VC pro ject, as in any other long-term bioassays performed in our laboratory, the animals were kept alive until spontaneous death. Autopsg. Full autopsy was performed on each animal All parts of the body were explored, including the central nervous aystem. Specimens for histology included the brain, Zymbal glands, interscapular brown fat, salivary glands, tongue, lungs, liver, kidneys, adrenals, spleen, pancreas, stomach, intestine, bladder, uterus, gonads and any other organ with pathological lesions. Histologg. Specimens were trimmed in the standard way. Sections were routinely stained with Haematoxylin-Eosin and, when necessary, with special techniques. Histopathologicat Examination. All sides were screened by a junior pathologist and then reviewed Environmental Health Perspectives by a the 1 Cl Co< ___ 1 2 3 6 9 10 11 12 13 14 16 16 17 18 19 20 21 24 25 26 27 28 29 80 31 Code r 2 8 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Octobt ucc 057059 No. per group 80 150 had to be No. per group SO 75 was al'ar- ; of the ay two set any i were ait and nt proformed ve until m each plored, `cimens glands, tongue, ncreas, Js and in the ed with with "s were viewed .ives b> a senior pathologist. The same classification of the lesions were used by all pathologists. l lastiftcation of Data. All the anatomical sites and the gross and microscopic observations were classified and coded following our laboratory codes (Tables 11-13). Table 11. Code* of organs considered (sequence). < udt Organ Code Organ 1 Skin (epidermis end dermis) O Epidermal sppendages 3 Zymbsl glands 4 Subcutaneous tissues 5 Mammary glands 6 Pirotid glands " Submaxillary glands * Nasal and paranasal cavities 9 Orel cavity 10 Tongue 11 Lung 13 Pleura end pleural cavity 13 Esophagus 14 Foreitomaeh 15 Glandular stomach 16 Intestine 17 Liver 18 Pancreas 19 Peritoneum and peritoneal cavity 20 Kidneys 21 Pelves 22 Ureters 23 Bladder 24 Ovaries 25 Uterus 26 Seminal vesicles 27 Prostate 28 Testicles 29 Epididymis 30 Hypophysis 31 Thyroid 32 Adrenals 33 Cerebrum 34 Cerebellum 35 Spinal marrow 36 Peripheral nervous system: ganglia 37 Peripheral nervous system: nerves 38 Eyss 39 Hsrdsrian glands 40 Skeletal musdae (diaphragm not included) 41 Diaphragm 42 Bones 43 Articulations 44 Heart 46 Pericardium and pericardial cavity 46 Largs vassals 47 Thymus 48 Spleen 49 Axillary and inguinal lymph nodes 50 Head-neck lymph nodes 61 Interthoradc and peratbymic lymph nodes St Intrabdominal lymph nodes 68 Lymph nodes of other site* 64 Bone marrow 56 Soft tissues of support 66 Intarscapular fat pad 67 Trachea 68 Ear 60 Female external sex organs 60 Male external sex organs 61 Odontogenic apparatus 62 Gall bladder Table It. Codes of macroscopic changes. Code Change Code Change 1 No change 2 Alopeda 3 Kemoaie 4 Degenerative pathoaii 5 Ukeratiaa 6 Hyperemia, edema and hemorrhage 7 Phlogotis (including of ibicim) 8 Pulmonary bepatintion 9 Pulmonary emphysema 10 Irregular surface 11 Granulations and plaques 12 Simple thickening 13 Thickening of cspsuls 14 Fihroeis 15 In toto reduction 16 Atrophy 17 In Unto enlargement 18 Augmentation in consistency 19 Dilatation of organ with cavity to Protrusion of eyeball 21 Simple cyst a Hemorrhagic cyst a Multiple simple cyst 24 Multiple hemorrhagic cyst a Polypoid formation a Papillomatous formation and ham 27 Solid nodule a Hemorrhagic nodule a Cystic maae 30 Solid mass 21 Solid necrotic man a Hemorrhagic mass a Ossifying man 34 Serous eAuion a Fibrinous-purulent effusion a Hemorrhagic effusion October 1981 7 ucc 057060 i Table 13- Code* of microscopic chance*. Code Chance Code Change 1 No change* 57 Fibroangiomatosis 2 Mild regressive change* 58 Simple polyp 3 Serious regressive change* 59 Polyp with cellular diatypia* 4 Necrosis 60 Papilloma .5 Ulcer 61 Fibrapapilkmu 6 Amyloidosis 62 Acanthoma 7 Hyalinosis 63 Trichoepithelioma 8 Colloid-cystic degeneration 64 Simple adenoma 9 Calcifications 65 Muciparous adenoma 10 Emphysema 66 Colloid-cystic adenoma 11 Vascular changes (hyperemia, dilatation of sinusoids 67 Exocrine pancreas adenoma and other vessels, edema and hemorrhage) 68 Endocrine pancreas adenoma (Islet cell adenoma) 12 Hematic cytt 69 Chromophobe adenoma 13 Organised fibrinous coaguhnn 70 Chromophibe adenoma 14 Hemorrhagic effusion 71 Cortical adenoma IS Acute phlogistic changes (including sbecess) 72 Medullary adenoma 16 Chronic phlogistic change* (also reactive) 73 Cholangioma 17 Particular granulomatous chsnges 74 Hepatocellular adenoma or hepatoma 18 Phlogistic effusion 75 Tumor of granulosa and of theca 19 Thickening of capeuie 76 Leydig cell tumor 20 Thickening of submeeothelial tiseues 77 Other epithelial benign turnon 21 Fibroeis ,s 78 Fibroma 22 Poet necrotic fibrosis (comprehensive of drrboais) 79 UbUMBI 23 Fibrous thickening of vessels 80 Lipoma 24 Cystic ectasia of blood vessels with fibrosis 81 Leiomyoma 2S Cystic tctaai* of blood vessels with fibrosis and 82 Rhabdomyoma hyperplasia of perithelial cells 88 Chondroma 28 Cystic ectasia of blood vessels with fibrosis and 84 Osteoma dysplasia of peritbelial cells 86 Angioma 27 Cellular depletion and atrophy (with or without 86 Fibroangionia fibrosis) 87 Ossifying angioma 28 Simple cytt 88 Other benign turnon of connective tissue 29 Hemorrhagic cyst 89 Fibroadenoma 30 Multiple simple cyst 90 Adenoroyoma 31 Multiple hemorrhagic cyst 91 Benign turnon of nervous ganglia (ganglioneuroma) 32 Dilatation of organa with cavity (including and benign sympathetic tumor* of adrenal medulla hydronsphroaii) 92 Benign turnon of peripheral nerves (neurilemoma) 33 Hyperplasia and squamous metaplasia 96 Cardnoma 34 Glandular simple and cystic hyperplasia 94 Carcinoma with metastaaee 36 Diffused parenchymal hyperplasia 96 BssoceUular cardnoma 36 Nodular parenchymal hyperplasia 96 Baaocellular cardnoma with metaataaes 37 Cortical hyperplasia 97 Squamoeelhilar carcinoma 38 Medullary hyperplasia 39 Hyperplasia of stroma 40 Reactive hyperplasia ................ . 98 98 100 Squamocellular cardnoma with metastaaee Transitional cell cardnoma Transitional cell carcinoma with metastases 41 Simple proliferation of tymphoreticular cells with 101 Adenocarcinoma myelopoiesis 102 Adenocarcinoma with metaataaaa 42 Proliferation of angioblastk eoDa 108 Biliary duct adenocarcinoma 43 FibroangMlastk proliferation 104 Biliary duct adenocarcinoma with metastases 44 Proliferation of lipocytee 105 Hepatocellular carcinoma or hepatocardnoma 45 Proliferation of biliary ducts 106 Hepatocardnoma with metaataaaa 46 Proliferation of renal tubules and/or of 107 Exocrine pancreas adenocarcinoma nephroblastoma 108 Exocrine pancreas adenocarcinoma with metaitaMs 47 Adenomatous hyperplasia 108 Cortical adenocarcinoma 48 Cholangiofibrosis 110 Cortical adenocarcinoma with metastases 49 Dysplasia (comprehensive of neoplastic parenchymal 111 Phcochromoblaatoma nodule of liver) 112 Pheochromobiaatoma with metastaaee 50 Simple and cystic glandular dysplasia 113 Nephroblastoma 61 Cortical dysplasia 114 Nephroblastoma with metastaaai 52 Medullary dysplasia 115 Seminoma 53 Dysplasia of angioblastk cells 116 Seminoma with metaataaes 54 Papillomatosis 117 Melanoma 55 Acanthomatoaia US Melanoma with metaataaes 56 Angiomatosis - --- ----- - - 119 Other malignant epithelial tumor* Environmental Health Perspective* Co. "12 12 12 12 12 12 12 12 12 1213. 13 13; 13: 13 13 13> 13: 13r 13! 1 141 141 14. ' 141 F01 preps iactoi and a showi Pn of all exper prese same Thi by th arums proxii Sue amort} same study InU subjet analy.c interp bioass smalls group, while from the cs animal Oct b< ucc 057061 9 Table 13. (cont.) ( '-If Change Code Change Other malignant epithelial turnon with metaataaea l.'l Mesothelioma 1" Mesothelioma with metaataaea Fibrosarcoma 4 Jw Fibrosarcoma with metaataaea 1-1 Mixoaarcoma l.'v Mixosarcoma with metaataaea Lipoiarcoma U' Liposarcoma with metaattaaa Leiomyosarcoma Leiomyosarcoma with metaataaea 1 ` 1 Rhabdomyosarcoma Rhabdomyosarcoma with metastaaas Chondrosarcoma ^ Chondrosarcoma with metaataaea ; Osteosarcoma ) i'. Osteosarcoma with metaataaea Angiosarcoma 1 > Angiosarcoma with metastaaas ; Ossifying angiosarcoma 14" Ossifying angiosarcoma with metaataaea ! ;i Angiopericytoiarcoma iJ Angiopericytosarcoma with metaataaea Other malignant turnon of connective tissue 144 Other malignant turnon of connective tissue with metastases .* 146 Carcinosarcoma 146 Carcinosarcoma with metaataaea 147 Neuroblastoma 148 Neuroblastoma with metaataaea 149 Glioma (astrocytoma, oligodendroglioma, microglioma) 160 Ependymoma 151 Meningioma 162 Malignant turnon of nervous ganglia and malignant sympathetic turnon of adrenal medulla 168 Malignant turnon of nervous ganglia and malignant sympathetic turnon of adrenal medulla with metaataaea 164 Malignant turnon of peripheral nerves (malignant schwannoma) 166 Malignant tuman of peripheral nerves (malignant schwannoma) with metaataaea 168 Characteristic turnon of eyes 167 Lymphoreticular neoplastic localisations 188 Secondary localizations of tumors from other anatomical districts 168 Neoplastic effusions 180 Odontoma 161 Chondromatosis 162 Histiocytosis and benign histiocytoma 168 Metothelia) hyperplasia t-nr each animal an individual final card was !>' siared. which included data on experimental f.. >>rs, survival, weight at , 12,18 and 24 months, i any gross and microscopic lesions. Samples are - u n in Figures 1 and 2. 1'n M ntation of Pathological Data. Hie results * f J! VC experiments, as well as those of any other i \i, riment performed in our laboratory, will be ! >t-nied in the final report (now in press) with the types of tables, in the same sequence. I nis type of presentation has been made possible I . ' he knowledge of the basic pathology of the ial used, which enabled us to make an ap 1 ; imated census of the expected lesions. s a h a procedure permits a quick comparison a-:, nj: the results of different experiments of the project and possibly of the results of projects >' : ing different compounds. Init rpretation of tike Data. The data were vital to statistical analysis. Although statistical . >is provides an extremely important tool for is ' ivting the meaning ofthe results of long-term h. .--ays. it should be stressed that there may be Ur differences between exposed and control c p- which do not reach statistical significance, > these differences could still have meaning :> an oncological point of view (particularly in thi vase of tumors which are infrequent in the colony). Oc tuber 1981 Therefore, the most important data should be commented on both in the light of the statistical analysis performed and from a biological point of view. The methodological protocol adopted meets the requirements of the recent Good Laboratory Practice Act. Results Part of these results, namely those dealing with seven basic experiments on the effects of long-term exposure to a range of 14 doses by inhalation (from 30,000 to 1 ppm) and of six doses by ingestion (from 50 mg to 0.03 mg/kg bw), on Sprague-Dawley rates, were presented previously (1, t). A report, for limited circulation, dealing with part of the results his also appeared (3). The results of the whole project, with detailed tables, will appear in a monograph which will encompass data on survival rate, body weight, regressive and inflammatory changes, benign and malignant tumors, neoplastic precursors, and the most important proliferative changes. With this report we are presenting only tables summarizing the most outstanding results and information, and what we do believe to be the integrative documentation and strictly necessary comments. 9 IJCC 051062 1 Agent Vinyl chloride Experiment No.: BT 6 Group No.: 1 No. animal: 10 Typt of txpoturt Inhalation Concentration. 30,000 ppm Treatment protocol: 4 hr/day, 6 day*/ week, S3 weeka Specie*: Rat Strain: Sprague-Dawley Stx: Female Aft at atari of experiment (tootle*): 17 Total do** received: Cod* XVIII, 1 1,1 II. 1 VI, 6 X, 1 XI. 1 XII, 1 XIII, 10 Age at death (week*): 86 Period from etart of treatment (week*): 68 Weight (g) t month*: 247 It month*: 278 IS month*: 290 tk month*: Fiouu 1. Sample treatment protocol card. Tables 15-31 presented data on the incidence of the tumors which have been considered as depen dent or possibly correlated to VC exposure, in 17 different experiments on the effects of VC in different animal systems, by different routes, at different doses and with various schedules of treat ment. Explanations of abbreviations used in the tables are given in Table 14. The possible leukemogenic effect of VC in golden hamsters is expressed both by the slight increase in incidence but more by the decrease in latency time (from 16 weeks in animals treated at 10,000 ppm to 36 weeks in control animals). Examples of the most characteristic microscopic features of these tumors were given in a previous publication U). The data on dose-response relationship in long term treatment experiments, by inhalation and by ingestion, in Sprague-Dawley rata, Wistar rats and Swiss mice, with reference to the incidence of total malignant and benign tumors, and the most impor- 10 tant neoplasias observed, are shown in Tables 32-63. The striking effect of the influence of scheduled treatment is pointed out by the results shown in Table 64. Examples of the marked influence of the animals used in determining the neoplastic response ire shown in Tables 65-67, which point out the effects of species, strain and age. Conclusions VC-dependent turnon are identified on the basis of one or more of the following parameters: (a) sharply enhanced incidence; (b) rare or excep tional occurrence in the colony of the animal used; (c) dose-response relationship; (d) association of precursor lesions. From the presented data the following conclu sions may be drawn. (1) VC causes turnon in all the different animal systems tested. (2) VC is a multipotential carcinogen, since it causes turnon of different types in different sites (Table 68). (3) Some types of tumors are observed in all the animals studied, i.e., liver angiosarcoma, whereat othen an observed in only one animal system. (4) The degree of evidence of correlation be tween VC treatment and the turnon considered as VC-dependent varies from tumor to tumor. (5) VC shows carinogenic effects both when given by inhalation and ingestion and possibly by injection. (6) Both through inhalation and ingestion exper iments there is a clear-cut dose-response relation ship. (7) The duntion of treatment and schedule of treatment greatly affects the neoplastic response. (8) The neoplastic response, in qualitative and quantitative terms, is greatly affected by the spe cies, the strain and the sex of the animals studied. (9) Newborn animals appear to be extremely responsive and easily develop liver tumors, both hepatocardnomas and angiosarcomas. (10) VC produces carcinogenic effects on em bryos via the placenta. (11) With the above criteria for identifying VCdependent tumors, VC shows carcinogenic effects even at low doses, namely down to 50 ppm and less. (12) The results of the seven basic experiments studying the effects of doses of VC as given by inhalation (BT1, 2, 6, 9, 15), and ingestion (BT11, 27), have been subject to statistical analysis follow ing the Fisher exact probability test (p 0.05). The total cancer-bearing animals and the turnon Environmental Health Perspective* .1 c 1s L P f L jP A 1H Ii :M \ SI Sl : L: I ' PI : F. Pc i 1 A< Hi In' I Fuji Abbr. T Ca EpT P Ac Ad AdT MT BT US U ELAP EU Xtphr XeuK A AT Neap. Nod. t Dif. h;. n* a* the bear ir lh* tit tumor The animal alive * Octofc ucc 057063 i ^ 4-iL'5?&.*a. 99 'SS t v? issr t*- 6. f ^ M ils , tropic ehanQtt: <u < jk jtaneou* tiaaue* Lur.t FIvjv and pleural cavity Kurt-iwnach Ln.r K--"neum and peritoneal cavity A'i'vnai* H*' It-rian gland* Ii-Tithoracic and parathymk i vmph nod* Type Hemorrhagic nodule Hemorrhagic nodule Hemorrhagic effusion No change* Hemorrhage No change* Hemorrhagic maa* No change* In toto enlargement M mucopic change*; -..t-ciuaneou* tiaaue* Lji, 1'i. jra and pleural cavity V -cnomadi Liver IVntoncum and lientoneal cavity A, i renal* Hjrrleriin gland* Imrethoracic and parathymia lymph node Type Fibroangioma Secondary neoplaatk localisation (liver angioaareoros) Secondary neoplaatk locahaation (liver angioearcoma) Papilloma Hepatocardnoma Angioaarcoma with metaataae* Secondary neoplaatie localisation (liver angioaarcoma) Cortical adenoma Abaeeta , Jio change* Sid* Sn Sn Sid* Sn Sn No. Cod* I 4. 28, D1 11. 28, D12 12, 36 14.1 17,6 19.1 1 32, 32, Cl, Dl 39.1, Cl 61, 17 No. Cod* 4,86 11,168 (17,188) 12, 168 (17,138) 14,60 17,106 17,188 19,158 (17,188) 32,71, Cl 89, 1$, Cl 61,1 Ki .ikeI Sample record of macruecopic and microacopic change*. Table 14. Abbreviation! uaed In tablet.* Abbreviation T Tumor (. 4 Carcinoma Ki>T Epithelioma I'd Papilloma Ac Acanthoma Ail Adenoma A'l T Adenoma in malignant tranafonnation MT Malignant turnon (total ft not otherwiae apedflad) HT Benign tumor* (total if not otherwiae specified) LAS Liver angioearcoma LA Liver angioma KLAS Extra-liver angfeearama t'LA Extra-liver angioma Nephro-BL Nephroblastoma Neuro-BL Neuroblastoma A Angioblastie hyperplasia ia Over A 1 Angioblastic dytplaaia in liver Neop. nod. Neoplastic nodule* of liver Nod. hyp. Nodular hyperplasia of Hear Dif. hyp. - Diffused hyperplasia of Beer Marked -+ Very marked 'The incidence of total malignant and benign tumour* it given a> the total number of tumor* per 100 animal* (one animal may t*ar more than on* malignant or benign tumor) on the baaii at >* tumor* obterved among the animal* alive, when the firtt '-"nor *u obaerved in the experiment. The incidence of specific tumour ia given, aa percent at the animal* bearing the tumor considered, referred to the animal* alive when the lint tumor wa* obaerved (in parentheaea). October 1981 significantly in excess in these experiments, in relation to doee, are given in Tables 69 and 70. The Fisher exact probability test at 96% confidence is, in relation to the above, not "sensitive" enough, in our experimental conditions. Biologically, in our opinion, the following results, although not statistically significant according to the test used, should be given proper attention. Extrahepatic angiosarcomas of different sites are observed at a very low incidence doee in untreated Sprague-Dawley rats of our colony. Results of experiments BT1 and particularly BT9, however, strongly suggest a relationship between these tu rnon and VC exposure. This relationship is supprated by the excessive incidence of extrahepatic vascular turnon in mice treated with VC (BT4). Few cases of hepatomas have been observed in treated groups, particularly in BT1. This tumor is exceptionally rare in our colony of animals, and none have been observed in the control group of the 17 experiments. Moreover the relationship with treatment ia supported by the fact that a high incidence of hepatomas has been obaerved in Sprague-Dawley nts, following neonatal exposure to s high dose for s short period (BT14). In view of their rareness or nonobservstion in the colony of animal used, for the following tumors it should be stressed that attention should be paid to 11 \!_ ucc 057064 # r Table 15. Experiment BT1.* Group and concentration Turoon/100 animal* MT BT LAS Animala with turnon. % Fort- MamHepa- Nephro- Neuro- Zymbal Skin atomic!) nury LA ELAS ELA tomaa BL BL Gl.Ca EpT PaAAc MT I 10,000 ppm II 6000 ppm III 2500 ppm IV 500 ppm V 250 ppm VI fiO ppm VII No treatment (control) 81.7 60.0 63.3 51.7 30.0 15.0 13.3 23.3 88.3 20.0 13.3 25.0 86.7 43.8 11.7 am 22.0 (13/60) 21.7 (13/60) 10.0 (6/60) 5.1 (3/50) 1.7 (1/60) 3.4 (2/50) 1.7 (1750) -r _ 5.0 (3/60) 6.1 (8/50) 5.0 (8/60) 1.7 (1/60) 8.4 (2/50) 1.7 (1/60) _ 5.0 (3/60) 6.8 (4/50) 3.3 (2/60) 1.7 (1/60) 8.8 (2/60) 8.4 (2/56) 1.7 (1/60) 1.7 (1/GO) 3.3 (2/80) 8.3 (5/60) 1.7 (1/50) - 8.8 (5/50) 8.5 (6/68) 10.0 (6/60) 10.0 (6/60) 8.6 (5/80) 1.7 (1/60) 11.7 (7/60) 5.1 (8/58) 6.7 (4/60) - 26.7 (16/60) 11.0 (7/SO) 8.3 (2/60) 6.7 (4/60) - 5.0 (3/60) 3.4 (2/59) 1.7 (1/60) 1.7 (1/60) 3.4 (2/59) 1.7 (1/60) 1.7 (1/58) 1.7 (1/59) * _ 1.7 (1/60) _ 5.0 (3/60) _ 3.3 (2/60) 1.7 (1/60) 34 (2/59) 3.3 (260) 'Expoaure by inhalation to VC in air at 10,000, 6000. 2500, 500, 250, and 50 ppm; 4 hr/day, 5 days/weak, for 52 week*. Sprvfue-DawUy nti, M and F* 18 weeks old. Results alter 185 weeks (end of experiment). 4 Table 16. Experiment BTT* Group and concontntion Tumora/100 animala MT BT LAS Animala with turnon, % Fore- Mam- Hepa- Nephro- Neuro- Zymbal Skin atomach maiy LA ELAS ELA tomaa BL BL Gl.Ca EpT PiAAc MT I 200 ppm II ISO ppm III 100 ppm IV No treatment (control) 35.0 86.0 21.7 15.7 - 21.7 25.0 27.S 10.0 3.3 (12/120) (4/120) $.0 (6/110) 0.8 0.8 (1/120) (1/120) 0.8 (1/120) * 0.8 (1/120) 0.8 (1/119) 2.5 5.8 (3/120) (7/120) - 9.2 (11/110) 8.8 (10020) 21.6 1.1 (2086) - 3.3 (4/120) 3.4 (4a 19) 0.8 (1/120) 4.2 (5020) 8.4 (4019) 0.8 (1020) 1.7 (2/119) 8.8 (4/120) 5.0 (6 120) 5.0 (6119) 3.3 <4 120) 1.1 1.1 1.6 1.0 (2085) (2086) (8086) (2185) 'Expoeureby inhalation to VC bi air at 200, ISO, 100 ppm; 4 hr/dxy, 5 dayvweek, for 52 week*. Spncue-Dawley rata, M and F, IS weeks old. Results after 143 weeks (end of experiment). -- R we i Table IT. Experiment BT*.* Group and concentration TuroonOOO animala MT BT LAS Animal* with turnon. % Fore- MamHepa- Nephro- Neuro- Zymbal Skin atomach miry LA ELAS ELA tomaa BL BL Gl.Ca EpT PalAc MT I 30,000 ppm 100.0 50.0 30.0 1.7 1.7 5.0 1.7 - 1.7 58.8 1.7 18.3 3.3 (18/60) (1/60) (160) (3/60) (1/60) (1/60) (36/60) (1/60) (11/60) (2 60) Expoaure by inhalation to VC in air at 30,000 ppm; 4 hr/day, 5 daya/week, for 52 week*. Spncue-Dawley rata, M and F, 17 w eda old. Results after 66 weeks (end of experiment). 12 Environmental Health Perspective* N E aprx Oct ucc 057065 * % ! Table 18. Experiment BT9.* -- Animals with tumor*, % Group and f^rC(.ntrttion Tumon/100 ifiipfii vr it us Fora- HamHapa- Nephro- Neuro- Zymbal Skin stomach miry LA ELAS ELA tomaa BL BL GLCa EpT PaAAc MT i 44.3 41.7 4.8 2.7 3.1 8.7 - 0.3 - 3.1 1.0 0.4 21.7 > 51> ppm (14/294) (8/294) (9/294) (11/294) (1*94) (9/294) (3/294) (1/294) (62294) 11 S'' treatment 23.0 24.0 1.0 10.2 icontrol) (1*8) (10*8) *t m--ure bv inhalation to VC in air at SO ppm; 4 hr/day, 6 daya/watk, for 52 waoka. Sprague-Dawiey rata, If and F, 13 week* old. > Rr-after 142 weak* (and of experiment). Table 19. Experiment BT15.* i Animala with turnon, % Tumon/100 animala Fora- Mam- Group and Hapa- Nephro- Neuro- Zymbal Skin ttflffiiffa miry i. concentration KT ST US LA ELAS ELA tomaa BL BL GLCa EpT PaAAe MT i 33.3 58.3 4.2 0.8 - 2.5 - 0.8 - 8.8 _ 15.0 23 ppm (5/120) (1/120) (8/120) (1/120) (4/120) (17/120) 11 31.7 53.3 0.8 1.7 2.5 - 1,7 _ * 17.6 10 ppm s (1/119) (2/119) (3/119) (2119) (21/119) 111 35.8 55.0 ------ 0.8 0.8 -- 18.6 _ 5 ppm (1119) (1/119) (22/119) IV 22.5 44.2 ------ 0.8 0.8 _ 12.7 1 ppm v (1/118) (1/118) (15/118) No treatment (control) 23.S 37.5 0.8 (1120) 1.7 (2/120) 5.8 (7/120) -- K\|iorure by inhalation to VC in air at 25,10, 5.1 ppm; 4 hr/day, 5 days/waek, for 52 weeks. Sprague-Dawley rata, M and F, 13 ) >* ). old. Results after 14? waaka (and of experiment). ) Table 20. Experiment BTS-* Animala with turnon, * Tumon/100 animala Fora- Mam- Group and Hapa- Nephro- Neuro- Zymbal Skin stomach mity 3 concentration KT BT LAS LA ELAS ELA tomaa BL BL GLCa EpT PaAAe MT I 45.0 20.0 1.7 1.7 1.7 16.6 16.6 8.8 1.7 1.7 10,000 ppm (1*8) (1*8) (1*8) (9*8) (9*8) (5*8) (1*8) (1*8) 11 58.3 25.0 1.7 8.8 1.7 1.7 20.0 15.0 &S 8.8 1.7 6000 ppm (1*0) (2*0) (1*0) (1*0) (12*0) (9*0) (6*0) (2*0) (1*0) 111 41.7 85.0 1.7 - 3.3 8.8 8.8 11.7 3.8 -- 8.7 2500 ppm (1*0) (2*0) (2*0) (5*0) (7*0) (2*0) (4*0) -- IV 15.0 36.0 1.7 ------ 1.7 * _ 5.0 _ 500 ppm (1*0) (1*0) (8*0) V 21.7 25.0 1.7 - 1.7 - 10.2 - 1.7 5.1 1.7 250 ppm (1/50) (1/50) (6/50) (1/50) (8*0) (1*0) VI 18.3 25.0 1.7 - 1.7 6.2 1.7 1.7 50 ppm _ VII (1*8) (1*8) (8*8) (1*8) (1*8) No treatment (control) 14.7 20.0 - 0.5 - - - - 1.0 0.6 (1/190) (2/190) (1/190) 2.6 (5/190) ft "Exposure by inhalation to VC in air at 10,000, 6000, 2500, 500, 250, and 50 ppm; 4 hr/day, 5 days/week, for 17 waaka. -'Prague-Dawley rata, If and F, 12 waaka old. Raaulta altar 156 waaka (and of axporimant). October 1981 13 1 ' i OCC Group and concentration Tumora/100 XT BT LAS Tablt II. Experiment BT10.* Animals with tumor*. % Fore- Mam Hep*-, Nephro- Neuro- Zymbal Skin stomach mary LA ELAS ELA tomaa BL BL Gl.Cs EpT PaAAc MT I 10,000 ppm II 6000 ppm III 10,000 ppm IV 6000 ppm V 10,000 ppm VI 6000 ppm VII No treatment (control) 33.8 30.0 85.8 30.8 41.7 38.3 16.6 41.7 45.0 45.0 38.2 45.0 50.8 0.8 (1/118) - 0.8 (1/119) 2.5 (3/118) 0.8 (1/119) 0.8 (1/120) - 0.8 (1/120) 1.7 (2/119) _ 1.7 (2/119) 1.7 (2/120) - - 1.7 (2/118) - 0.8 (1/120) 0.8 (1/118) 1.7 (2020) 0.8 (1019) - 0.8 (1019) - 0.8 (1018) - - -- - 1.7 (2020) _ 0.8 (1020) - 0.8 (1019) 0.8 (1020) * 0.8 (1020) - - 0.8 (1019) - 7.6 (9018) 7.5 (9020) 7.6 (9019) 4.2 (5018) 6.7 (8019) 7.6 (9020) - 2.5 (3019) 3.4 (4018) 0.8 (1019) - 2.5 11.0 (3/118) (13/118) 1.7 10.8 (2/120) (13/120) 2.5 13.4 (3/119) (16/119) 1.7 9.3 (2/118) (11/118) 0.8 16.8 (1019) (20/119) 0.8 10.0 (1020) (12/120) 41.0 _ * 0.4 - - - - 0.9 2.2 7.5 (1/227) (2/227) (5027) (17/227) Exposure by inhalation to VC in air at 10,000, 6000, ppm; 4 hr/day, 5 daya/waak, for 5 waaka (groupa I and II) or 1 hr/day, 4 daya/waak, for 25 waaka (group* III and IV) or 4 hr/day, once weakly, for 25 waaka (group* V and VI) (100 hr). Sprague-Dawley rata, X and F, 13 waaka old. Result* after 154 weeks (and of experiment). Group and concentration Tumora/100 iffiimilt MT BT LAS Table 22. Experiment BT5.* Animals with tumors. % Fort- MamHep*- Nephro- Neuro* zyntbel Skin stomach mary LA ELAS ELA tomas BL BL GLCa EpT PaAAc MT I 10.000 ppm II 6000 ppm III 10,000 ppm IV 6000 ppm 6.7 86.7 - * _ _ - 3.3 - (1/30) 6.7 28.8 - 29.6 22.2 _ - - - 5.9 * 9.8 - 10 10 (3/51) (5/51) (1/51) (1/51) 21.9 46.9 _ _ - 11 - - * 9.4 11 3.1 6.2 (1/32) am (1/32) (1/32) (2/32) Exposure by inhalation to VC in air at 10,000. and 8000 ppm of breeders; 4 hr/day for 1 weak (from 12th to 18th day of pregnancy). Sprague-Dswicy rata. M and F, 1* weeks old (breeders). Breeder* (group* I and 11) and offspring* (groups III and IV). Results after 148 weeks (and of experiment). Table 21 Experiment BT14.* Group and eoneentntioB Tiumm/IOO XT BT LAS Animal* with tumors. % Fore MamHp*~ Ntpnro- Nuro* zymsai Skin stomach marv LA ELAS ELA tomaa BL BL Gl.Ca EpT PaAAc MT I 10,000 ppm (breeders) II 6000 ppm (breeders) III 10,000 ppm (newborn) IV 6000 ppm (newborn) 16.7 617 - 100.0 109.8 56.6 34.1 (15/44) - - 6.8 46.4 (3/44) (20/44) 511 40.5 14 14 14 47.6 (17/42) (1/42) (1/42) (1/42) (20/42) - - - 18 13 (1/44) (1/44) - 4.8 4.8 (2/42) (2/42) 2.4 (1/42) `Exposure by inhalation to VC in air at 10,000 and 6000 ppm, 4 hr/day, 5 daya/waak. for 5 waaka (from 1 day to 5 waaka of age). Sprague-Dawley rata, X and F, 21 waaka old (breeder!) (groupa I and II) and newborn (groupa III and IV). Results after 124 waaka (and of experiment). 14 Environmental Health Perspective! ucc 057067 no (13/118) 10.5 (13/130) 134 16/119) 93 11/118) 16.8 20/118) 10,0 12/120) 7.5 17/227) day. 4 yrau. Table 24. Experiment BT7.* Group and r -contrition I In.ml) ppm II ppm 111 ppm IV ppm V iVi ppm VI 5/i ppm VII N` treatment i control) Tumora/100 animala MT BT 60.0 10.0 53.3 20.0 26.7 13.3 30.0 10.0 13.8 16.7 16.7 6.7 16.0 16.0 LAS Animals with tumors. * Fore- Hepa Nephro- Neuro- Zymbal Skin ttomach LA ELAS ELA tomas BL BL Gl.Ca EpT PaAAc 29.6 (8/27) 11.5 (3/26) 12.0 (3/25) 10.7 (3*8) 3.7 (1/27) - 7.7 (226) 3.6 (1/28) - 3.8 (126) 4.0 (1/25) 3.7 (127) 3.8 (126) _ 3.7 (127) * 7.7 (226) 4.0 (125) . 3.7 (127) 7.7 (226) 7.1 (228) 3.6 (128) 1U (827) 8.8 (128) 4.0 (125) 7.4 (227) 7.7 (228) 4.0 (125) 3.7 (127) 2.6 (1/38) -jrr by inhalation to VC in air at 10,000,6000,2500,600.260, and 60 ppm; 4 hr/day, 6 days/week, for 52 waaka. Wiatar rata, M, old. Results alter 186 weeka (end of experiment). Table 26. Experiment BT17.* roup and uentration animala MT BT LAS Animala with turnon, 81 Fare- Hepa Ntghro- Neuro- Zymbal Skfai stomach LA ELAS ELA tomas BL GLCa EpT PaAAc I 24.2 29.2 1.0 3.0 5.0 1.0 - 1 ppm (129) (329) (629) (129) II Nn treatment 30.0 18.6 * - -- - i control) - to " (229) - 8.2 - u (324) (124) ).\ii?ureby inhalation to VC in air at 1 ppm; 4 hr/day, 6 dtys/week, for 52 week*. Wiatar rata, M, 18 weeks old. Results alter 184 . - - /end of experiment). _________________________________________ Table 28. Experiment BT4.* Animala with tumors. % Group and c"Mentratia) Tumore/100 animals MT BT LAS Mammery LA ELAS ELA Lunf T Ca Skin EpT stomach PaAAc I In.000 ppm 11 two ppm 111 3500 ppm IV 5oppni V 250 ppm VI 50 ppm VII No treatment (control) 60.0 984 17.8 10.7 1.8 7.1 82.1 23.2 7.1 1.8 am(10/56) (6/56) (4/86) (4626) (1220) (420) (120) n.758.7 100.0 11.7 1.7 5.0 784 18.3 11.7 1.7 (1820) (720) (120) (320) (4720) (820) (720) (120) 584 0.0 27.1 8.6 13.6 1.7 <7.8 18.5 U 1.7 (16/SO) (620) (820) (120) (4020) (820) (420) (120) 584 100.3 23.3 84 11.7 5.0 83.3 18.8 84 _ (1420) (520) am (320) (6020) (820) (220) 634 96.3 80.0 184 6.0 6.0 684 80.0 1.7 1.7 (1820) (1120) (320) (320) (4120) (1220) (120) (120) 284 284 1.7 1.7 1.7 84 10.0 80.0 * 1.7 (120) (120) (120) (620) (620) (1220) - (120) 14.7 14.7 _ 0.7 0.7 10.0 0.7 14 (1/150) (1/150) (16/160) (1/150) (8/160) *E \ poaure by inhalation to VC in air at 10,000,6000,2600,500,260, and 50 ppm; 4 hr/day, 5 daya/woak, for 30 weeks. Swiss mice. X andF. 11 weeka old. Results after 81 weeka (end of experiment). October 1981 IS ucc 057068 i Table 27. Experiment BT8.' Group and concentration I 10,000 ppm II 6000 ppm HI 2500 ppm IV 600 ppm V 260 ppm VI 50 ppm VII No treatment (control) Tumon/100 animala MT BT 60.0 73.3 40.0 83.3 48.8 108.3 58.3 68.8 30.0 60.0 48.8 40.0 20.0 46.7 LAS - 8.8 (D30) - 6.7 (2/80) - - LA 3.3 (1/30) 8.8 (1/30) 6.7 (2/30) - - - - ELA 6.7 (2/30) - - 3.3 (1/30) 3.3 (1/30) - - Animals with turnon, % Acoustic Hepa- Cholan- ChoUn- Duct tomaa gio-Ca giomaa EpT Skin EpT Fore- Uk- stomach Leukaenomu PaAAc miasb - 3.8 (1/80) 6.7 (2/80) 6.7 (2/80) _ * 13.3 (4/80) 16.7 (5/80) 26.7 (800) 20.0 (6/80) 20.0 (6/80) 2S.S (7/80) 8.8 (1/80) 6.7 (2/80) 8.8 (1/80) 10.0 (3/80) - - 28.3 (7/80) 8.8 (1/80) 10.0 (M0) 2S.S a/80) 10.0 (8/80) 80.0 (9/80) 3.3 (1/80) 6.7 (2/80) 8.8 (1/80) * - 8.8 (1/80) S.S a/80) 33.3 (10/30) 33.3 (10/80) 66.7 (17/30) 30.0 (9/30) 13.8 (4/30) 10.0 (3/80) 16.7 (5/30) 20.0 (630) 30.0 (9/30) 16.7 (5/30) 20.0 (6/30) 20.0 (6/30) * - 86.7 -- 5.0 6.0 13.3 (22/60) (8/60) (3/60) (8/60) `Exposure by inhalation to VC in air at 10,000, 0000, 2500, 500, 250, and 50 ppm; 4 hr/day, 6 daya/week. for SO weeks. Golden hamsters, M, 11 waalca old. Results after 109 weeks (and of experiment). `Latency time in weeka: Group 1,10.7; Group II, 27.2; Group III, 80.8; Group IV, 19.0; Group V, 22.5; Group VI, 86.8; Group VII, 86.6. 1s Table 28. Experiment BT11.* Group and concentration I 60.00 mg/kg II 16.66 mg/kg III 8.33 mg/kg IV Olive oil (control) Tumort/100 animala MT BT LAS Animals with turoora, ** Fore- Mam Hepa Ntphro- Neuro- Zymbul Skin stomach mary LA ELAS ELA tomas BL BL GLCa EpT PaAAc MT 88.7 36.0 21.2 8.7 2.5 2.5 - 2.6 - 1.2 1.2 2.5 5.0 (170) (3/80) (2/80) (2/80) (2/80) (1/80) (1/80) (2/80) (4/80) 30.0 17.5 12.5 a* " " 3.7 " 2.5 * 1.2 7.5 (10/80) (MO) (2/80) (1/80) (6/80) 10.0 26.0 "" 2.5 1.2 " " " 3.7 (2/80) (1/80) (3/80) 18.7 22.5 - - - - - - - 1.2 1.2 - 5.0 (1/80) (1/80) (4/80) `Exposure by ingestion (stomach tuba) ofVC in oliva oil at 80.00,10.06 and 8.88 rag/kg body weight, onea daily, 4-6 daya/week. for 52 weeks. Sprague-Dawley rata, X and F, 18 weaka old. RaaulU after 188 weeks (and of experiment). Table 28. Experiment BT27.* Group and concentration I 1.0 mg/kg 11 0.3 m^/kg 0.08 mg/kg IV Olive ofl (control) tumonaOQ animala MT BT LAS Animals witb tumors. % Fore- MamHepe- Nephro- Neuro- Zymbul Skin stomach mary LA ELAS ELA tomaa BL BL GLCa EpT PaAAc MT 24.7 18.8 18.0 86.8 28.0 81.8 2.0 - 0.7 (3/149) (1/148) 0.7 0.7 " (1/148) (1/148) 0.7 (1/149) 0.7 (1/148) - 8.8 - 2.0 8.0 (5/149) (3/149) (12/149) - - 0.7 1.8 2.7 (1/148) (2/148) (4/148) 0.7 0.7 9.8 (1/150) (1/150) (14/160) 16.0 28.7 - 1.8 4.7 (1/150) 0150) (7150) `Exposure by ingestion (stomach tuba) ofVC in olive oil at 1.0,0.8,0.08 mg/kg body weight, once daily, 4-6 daya/waek, for 69 weaka. Sprague-Dawley rata, M and F, 10 weeka old. Results after 180 weeks (end of experiment). 1C Environmental Health Perspective* Spi ii Ref Tat Ex, BT BT BT BT BT BT Co. I i l E Oc ucc 057069 1 Leulutmut1 16.7 (530) 20.0 (630) 30.0 (830) 16.7 (5 30) 20.0 (6 30) 20.0 (630) 13.3 (8/60) Golden )p VIJ, 4IDlarv 4T T 80) .7 80) 0 80) it 52 1 -- D7r --* ) 49) 48) 50) 0) --* * Tab)* 30. Experiment BT12.* Gr jp and animals MT BT LAS Animal* with tumor*, % Fore- MamHepa iNpnro- neuro- lymoai Skin atomach miry LA ELAS ELA tomas BL BL Gl.C* EpT PaftAc MT I 4 S my * 4 II 4 Si mg x 3 HI 4 S> mg * 2 IV 4 Si mg * 1 V i line oil cntrol) 13.8 25.0 16.7 2S.S 11.7 18.3 20.0 35.0 8.3 81.7 1.8 1.8 1.9 _ - (1/56) (1/56) 1.9 1.9 (1/53) 1.8 _ _ we (1/53) (1/53) 1.8 5.3 (1/56) 1.8 (1/56) (3/56) _ 1.8 3.6 3.6 (1/55) (1/55) (2/56) (2/55) 8.6 (2/56) i,: -Jn bv uitraperitoneal injection of VC, 4.25 mg in olive oil (1 ml). 4, 8, 2 time*, at two month interval* or one* only. ' . .. Hawley rat*. M and F, 17 week* old. Result* after 144 week* (end of experiment). Table SI. Experiment BT1J.* ormjp and do#* Tumor*/!00 animals MT BT ______________________________ Animal* with tumor*. <k LAS Hepe- Nephro- Nauro- Zymbal LA ELAS ELA tfTTHf BL BL GLCa Fore- Mam Skin atomach mary EpT PaAAc MT I 16.0 I7!8 - - 1.8 * - " 4.0 4.25 mg (1/75) (3/75) II Oh\e oil 13.3 26.7 1.3 - - 1.3 - 1.3 i control) (1/75) (1/76) (1/75) I. Mf.-ure by tubcutaneou* injection of VC. 4.25 rag, m olive oil (1 ml), tingle dote. Sprague-Dawlty rat*, M and F, 21 week* old. I.- after 145 week* (end of experiment). T.ihl* 32. Incidence of total MT and BT in Sprague-Dawley rats, in relation to concentration of VC administered by inhalation for 52 weeks. h\|*-nment* Concentration (ppm) M Tumora'100 animals MT F Total M BT F Total ri RT 1 1;T2 BT 1 BT 9 BT 15 Commit BT 1 BT2 BT9 BT 15 30,000 10,000 6,000 2,500 500 250 200 150 100 50 to 25 10 5 1 0 0 0 0 76.7 80.0 46.7 53.8 23.8 23.8 40.0 21.7 22.2 6.7 20.7 20.0 18.3 25.0 15.0 15.3 10.0 18.3 128.8 88.8 73.3 73.8 80.0 36.7 80.0 48.3 20.0 23.3 <8.0 48.7 45.0 46.7 30.0 26.7 16.0 30.0 28.8 100.0 81.7 00.0 63.8 51.7 30.0 86.0 35.0 21.7 16.0 44.3 83.8 81.7 36.8 22.5 18.S 16.7 22.0 22.8 40.0 20.7 12.8 16.7 18.8 28.3 10.0 21.7 20.0 23.8 23.3 81.7 30.0 28.3 18.8 23.8 21.2 4.0 20.0 60.0 20.0 63.8 23.3 13.3 26.7 88.2 28.8 86.0 50.0 <0.0 85.0 76.7 81.7 70.0 68.8 22.0 44.0 55.0 50.0 23.8 38.3 20.0 18.3 25.0 21.7 25.0 27.5 36.7 41.7 58.3 53.3 55.0 44.2 43.3 21.6 24.0 37.5 October 1981 17 ucc 057070 Tabic S3. Incidence of LAS. LA, A+ 4/4 + + f and A+ +/+ + + In Sprague-Dawley rata in relation to concentration of VC administered by inhalation for 52 weeks. Experiments BT 6 BT 1 BT 2 BT 1. BT 8 BT 15 Control BT t, BT 15 Concentration, ppm 80,000 10,000 6,000 2,600 600 250 200 150 100 50 25 10 6 1 0 Animals with tumors and correlated chances. % LAS LA A4 4/4 4 4 t A + +/+ + 4* M F Total U F Total M F Total If F Total 16.6 43.8 80.0 8.3 1.7 6.7 6.7 6.7 6.7 13.3 10.0 10.0 13.3 11.7 - * - * 3.8 1.7 3.8 6.7 5.0 10.3 33.3 22.0 - 6.7 8.4 -- * 20.0 16.7 18.3 20.0 23.3 21.7 * - - - . 13.8 18.3 13.3 - 20.0 10.0 * - - 8.3 1.7 18.8 6.7 10.0 3.4 6.7 5.1 - 3.3 1.7 _ _ _ 20.0 10.0 15.0 11.7 8.8 10.0 8.3 8.8 8.8 6.6 5.0 5.8 18.3 10.0 14.1 1.7 8.8 6.0 - - 8.8 10.0 9.2 18.8 6.6 12.5 - 1.7 0.8 1.7 * 0.8 1.7 6.6 4.2 8.8 6.0 6.6 1.1 7.2 4.2 1.1 8.3 2.2 1.7 1.1 1.4 5.6 15.5 10.5 1.7 6.7 4.2 - 1.7 0.8 1.7 - 0.8 8.3 6.0 4.2 1.7 0.8 " " " 1.7 - 0.8 1.7 1.7 1.7 2.5 1.3 Table 34. Incidence of ELAS, and' ELA in Sprafue-Dewley rata in relation to concentration of VC administered by inhalation for 52 weeks. n BT6 BT 1 BT2 BT 1, BT8 BT 15 Controls BT1.BT2, BT#, BT 15 Concentration, ppm ELAS f Animals with tumors, ft TOW ELA Total 30,000 10,000 6,000 2,500 500 250 200 ISO 100 50 2S 10 5 1 0 3.3 1.7 3.3 6.7 5.0 6.7 3.3 5.0 8.7 3.8 5.0 3.4 6.7 5.1 6.9 6.7 6.8 6.7 3.8 5.0 8.3 3.3 3.3 - 3.3 1.7 3.3 - 1.7 3.4 8.8 8.4 _ * _ 1.7 - 0.8 1.7 0.8 * _ 1.7 0.8 _ __ * . 2.8 3.8 2.8 4.6 2.8 3.7 _ 5.0 - 2.5 8.3 - 1.7 3.3 1.7 2.5 ---- - _--_ 0.9 0.4 0.4 0.8 0.6 Table 35. Incidence of hepatomas, neoplastic liver nodules, nodular hyperplasia of the liver and diffuse hyperplasia of the Uver in Spratue-Dnwley rut* in relation to concentration of VC administered by inhalation for 52 weeks. Exportmonu Concentration, ppm Animals with tumors and correlated chances Hemtomaa Noool. nod. Nod. hyp. Diff. hyp. M F Total M F Total 11 F Total M F Tout BT 6 BT 1 18 30,000 10,000 6,000 2.500 GOO 250 3.8 1.7 8.8 * 1.7 3.3 1.7 6.7 3.3 - 16.7 8.3 8.8 r 1.7 3.3 18.8 8.8 18.8 10.0 11.7 _ - 8.8 3.3 3.3 3.8 3.3 _ 1.7 18.3 6.7 10.0 8.3 3.8 1.7 6.7 18.8 10.0 - - * 10.0 5.0 13.3 - - - 28.3 - U.7 8.8 _ 17 5.0 3.3 3.3 8.3 1.7 17 10.0 - 1.7 Environmental Health Perspective* Expert' BT 2 BT1.B BT 15 ControlBT 1. BT#. Table 3 Expertr BT 6 BT 1 BT 2 BT1, B BT 15 Controls BT 1. BT 9. Table 37 Experim BT 6 BT 1 BT2 BT1, BT BT 15 Control# BT 1,1 October ucc 0S7071 f it I >tal ).0 i.O I i.3 t .3 I '0 .0 .1 .5 ,.6 >,5 i-2 .7 .3 i Experiments BT 2 BT 1. BT 9 BT 15 C octrois BT 1. BT2, BT 9. BT 15 Concentration, ppm BOO ISO 100 50 25 10 $ 1 0 Table S$ (cant) Animals with turnon and correlated change*. % Hepatoma* Neopl. nod. Nod, hvn. Dig, hvt>. If F Total If F Total If F Total If F Total 1.7 3.8 2.5 8.8 1.7 2.5 20.0 18.8 15.7 38.3 18.3 28.3 -- 1.7 * 0.8 8.8 18.8 10.8 18.7 25.3 20.8 - -- * - 5.0 28.8 14.2 26.7 13.3 20.0 - - * 0.5 - 0.8 18.8 9.4 11.4 2.8 3.3 3.0 - -- - * - 15.0 8.8 11.7 5.0 10.0 7.5 - -- - * - 20.0 5.0 12.5 10.0 6.7 8.3 - -- - . 1.7 0.8 _ . - - - - - 8.8 _ 1.7 1.7 _ 0.8 " " - - 0.4 0J 0.4 0.8 0.6 0.9 2.9 1.9 Tahir 3t. Incidence of nephrobiaatom* in SprafwDawley rata in relation to concentration of VC adminiatemd by inhalation for 52 week*. Experiment BT 6 BT 1 BT 2 BT 1. BT9 BT 15 Control* BT 1. BT 2, BT 9. BT 15 Concentration, ppm 80.000 10,000 . * 6.000 2,500 500 250 BOO 150 100 50 BS 10 5 1 0 Ajumato with NEPHRO-BL. * If F Total _ _ 10.0 6.7 8.3 18.8 8.8 8.5 16.7 8.8 10.0 8.7 13.3 10.0 3.4 13.3 8.5 8.8 3.8 5.8 13.8 6.0 9.2 13.8 8.8 8.8 . M 0.6 1.7 _ 0.8 *" " *- " Table 37. Incidence of neuroblaatomo in Spracue-Oawley rata in relation to concentration of VC adminiaterad by inhalation for 52 weak*. Animal* with NEURO-BL. % Experiment* Concentration, ppm M F Total BT6 BT 1 BT2 BT1.BT8 BT 15 Control* BT l, BT 2, BT 9, BT 16 80,000 10,000 8,000 2,500 500 250 200 150 100 50 25 10 5 1 0 18 _ 1.7 8.7 18.7 11.7 6.9 8.8 5.1 8.7 6.7 8.7 - -- _ -- _ -- - -- __ _ _- _ *- - -- -- _ -- "" October 1981 19 # ucc 057072 Ttbte 3*. Incidence of zrmbal (land carcinoma in Spnguc-Dawley tiU in relation to concentration of VC adminiatered br inhalation for 32 week*. Experiment BT 6 BTl BT2 BT 1, BT 9 BT IS Control* BT 1, BT 2, BT 9. BT 15 Concentration, ppm 90.000 10,000 6,000 2,300 BOO 230 200 ISO 100 GO 23 10 5 1 0 Animals with Zymbal stand CA. * M F Total 56.6 33.3 10.8 3.3 10.0 _ 3.0 - - 2.8 3.0 1.7 - 1.7 0.9 60.0 20.0 13.8 3.3 8.3 1.7 6.7 1.7 2.8 1.7 1.7 1.7 0.8 58.3 26.7 11.9 3.3 6.7 8.3 3.4 0.8 2.6 8.8 1.7 0.8 0.8 0.9 Tablo . Incidane* of foreetonj^ph papilloma and acanthoma in Spragvo-Dawlap rata in rolation to concentration of VC administarad by inhalation for 32 wotha. Experiment BT 6 BTl BT2 BT1.BT9 BT 16 Control BTl, BT2, BT9, BT 15 Concentration, ppm 30,000 10,000 6,000 2,500 300 230 200 150 100 SO 23 10 5 1 0 Animals with forestomacb Pa and Ac uS________ M F Total 16.7 - _ 20.0 3.3 * _ 18.3 1.7 *. . * 8.8 1.7 3.3 3.8 3.3 1.1 -- 0.6 __ -*. * 1.8 0.4 0.9 Tabic Sprar Expcr BT6 BT1 BT2 BTl BT 9 BT 15 Conrn BTl BT; BT!BTl TabU 4 relatio Expert BT 7 BT 17 Contn.' BT 7 BTl their onset, even it doses below the ones with statistically significant results. An excess of Zymbal gland carcinomas la ob served down to 50 and 25 ppm. Liver angiosarcomas are extremely tare in the colony used (4 cases over several thousand un treated animals). Therefore, one must consider the onset of these tumors as important even at doses not shown by statistical analysis, and particularly below 50 ppm (5 liver angiosarcomas out of 120 animals at 25 ppm, and 1 liver angiosarcoma out of M 120 animals at 10 ppm), and at 1 mg/kg (3 liveangiosarcomas out of 150 animals), and at 0.3 mg/kg (1 liver angiosarcoma out of 150 animals). The onset of a few nephroblastomas observed slter inhalation treatment at doses below 100 ppm and in groups treated by ingestion with 50 and 16.65 mg/kg, is not casual in our opinion, given the extreme rarity of these tumors in rats. Neuroblastomas have never been observed by us, up to the present, in the Sprague-Dawley nti used in our laboratory as control or otherwise Environmental Health Perspective! Tal Experii BT 7 BT 17 Control BT 7 Octob' ucc 057073 ~T t I I ---------tai 1' .7 .9 .3 7 - .3 4 8 5 .8 7 8 9 f VC :-------- Tehlct* Incidence of mammary malitnant tumor in famalo !VWWt.|il.lt, rats in r*1***0" to eoncantration of VC edministered hr inhalation for SI waaka. Concentration, Animal* with - PPI*1 Mammary MT, % KT * FT 1 FT.' FT 1 FT s* ft r* FT 1 FT 1 FT ' FT r 30,000 10,000 6,000 1,600 600 260 200 160 100 60 60 26 10 6 1 0 0 0 0 6.7 10.0 - 6.7 3.3 6.7 8.3 10.0 6.7 6.7 40.7 28.8 35.0 38.3 28.8 _ 2.0 18.0 10.0 13 TaMt It I n> idrnre of total MT and BT Hi male Wistar nti in rrleiion t unrentration of VC administered by inhalation for 62 veelu. FT 7 ic r { . . - . ft : ft :: Concentration, ppm 10,000 6.000 2.600 600 260 50 1 0 0 Tumors/150 Animals MT BT 60.0 58.3 28.7 30.0 13.3 16.7 24.2 10.0 80.0 18.8 10.0 16.7 17 29.2 15.0 20.0 16.0 18.3 Wit 43. Incidence of ELAS and ELA in male Wistar rata in relation to coneantration of VC adminiaterad bgr Inhalation for 52 wocka. Experiment . Animals with tumors, % Concentration, PP ELAS ELA BT 7 BT 17 Controls BT7.BT17 10,000 6,000 2,600 600 2B0 60 1 0 _ 3.8 4.0 8*.7 8.0 0.7 3.8 8_.7 6.0. treated. Therefore we coniider aa dependent on treatment the onaet of these tumors, even at doses below 10,000 ppm, i.e., 6000 and 2500 ppm. The meaning in oncological terns of the results at the lowest doses may be better evaluated in consid ering, not singly, but together, the tumors found to be VC-dependent (Table 71). None (or no increase) of the specifically VC related tumors shown in Table 71, observed in the seven basic experiments, was found at doses of 5 and 1 ppm (by inhalation) and 0.03 mg/kg (by ingestion). General Comments VC long-term experimental study led to the discovery of VC carcinogenicity, and as a direct consequence, to what probably has been the great est effort ever made at controlling the exposure to an industrial carcinogen in the workplace (Table 72). Moreover, long-term carcinogenicity bioassays on VC are a crucial step in the field of environmen tal and occupational carcinogenesis which, in turn, liver gkt ved jpm and the by ise i:. Incident* of LAS, LA, A* +/+ + T M4A++/+ + + in mai* Wiatar rats in relation to concentration of VC administered hr Inhalation for 62 weeks. ft: BT ift: ftn Concentration, ppm 10,000 6,000 2,600 600 260 60 1 0 Animals with turnon and correlated chants*. * LAS LA A-f +/* -f + f 29.6 11.6 12.0 10.7 8.7 7.7 - 16 - IS - 3.8 18 18 * 1.0 1.7 18 - 18 -- 18 October 1981 21 ucc 057074 Tabic 44. Incidence of hepatomas, neoplastic Ibar nodules, nodular hyperplasia of the liver and diffuse hyperplasia of the liver in male Wistar rats in relation to concentration of VC administered by inhalation for 62 weeks. Experiment Concentration, ppm Animals with tumors and correlated chanaes. % Hepatomas Neop.nod. Nod.hyp. Dif.hvp, BT 7 BT 17 Control! BT 7, BT 17 10,000 6,000 2,600 600 250 60 1 0 - 6.7 7.7 6.7 3.8 6.7 4.0 6.7 6.7 - 6.7 3.3 * 16.7 - 10.0 1.0 6.0 4.2 * - 1.3 2.3 Table 4S. Incidence of NEPHRO-BL in male Wistar rets in relation to concentration of VC administered by inhalation for S3 weeks. Experiment Concentration, ppm Animal* with NEPHRO-BL, ft BT 7 BT 17 Control* BT 7. BT 17 10,000 6,000 2,500 flOO 260 60 1 0 8.7 7.7 7.1 * 3.6 _ _ Table 47. Incidence of Zymbai gland CA In male Witter nil In relation to concentration of VC administered by inhalatieo for S3 weeks. Experiment Concentrotian, Animal* with ppm Zymbai gland CA, * BT 7 BT 17 Controls BT 7, BT 17 10,000 6,000 2,500 600 260 60 1 0 7.4 7.7 - - - - 2.0 2.3 T. Tol Tabl Table 46. Incidence of NEURO-BL in male Wistar rata in relation to concentration of VC administered by inhalation for S3 week*. Experiment BT 7 BT 17 Controls BT 7. BT 17 Concentration, ppm 10,000 6,000 2,500 600 250 60 1 ft Animal* with NEURO-BL, ft 11.1 3.8 4.0 -e - Table 48. Incidence of forestomach Pa and Ac in mol* Wistar rata in relation to concentration of VC administered by Inhalation for 63 watka. Experiment Concentration, ppm Animate with forestomach Pa and Ac. 5 BT 7 BT 17 Controls BT 7. BT 17 10,000 6.000 2,600 600 260 60 1 0 * V_ _ 0.7 Table are among the most important areas of public health nowadays. These studies have demonstrated that long-term carcinogenicity bioassays: may predict carcinogenic risk for humans; may give indication of the level of risk, in relation to dose; may provide information on 22 possible target organs and, in general terms, on the quality of neoplastic response; may represent a tool for obtaining information on the relative risk repre sented by different compounds, provided that they are tested under the same standard conditions (Table 73); have revealed the need to identify Environmental Health Perspectives Octob ucc 057075 i - , 1 \ , ` Table 49. Incidence of total JIT and BT fat Swiaa mice in relation to concentration of VC adminietend by inhalation for 30 woeka. Experiment Concentration, ppm M Tumora/100 animala MT BT F Total H F Total BT4 10,000 6,000 2,500 600 260 50 0 16.6 26.7 40.0 36.7 36.7 6.7 6.2 83.3 86.6 76.7 80.0 90.0 60.0 24.3 60.0 66.7 66.8 68.3 63.3 28.3 14.7 88.3 100.0 80.0 98.8 116.7 20.0 13.7 113.8 100.0 100.0 113.3 80.0 26.7 16.7 98.3 100.0 90.0 103.3 98.3 28.3 14.7 Table 50. Incidence of LAS and LA in Swim mica in relation to concentration of VC odminiatorod by inhalation for SO vaaka. Animala with turnon. % fl LAS LA Experiment Concentration, ppm M F Total 11 F Total 0 BT4 10,000 3.8 30.0 17.8 3.8 16.7 10.7 6400 .300 6.7 20.7 36.7 83.3 21.7 27.1 6.7 16.7 11.7 6.9 10.0 8.6 600 20.0 26.7 28.3 8.3 13.3 8.3 260 50 30.0 3.3 30.0 * 30.0 1.7 20.0 * 16.7 3.3 18.3 1.7 0 " ne -- " " Table 51. Incidence of ELAS and ELA in Swiaa mica in relation to concentration of VC adminietend by inhalation for 30 waaka. Experiment Concentration, ppm 11 ELAS F Animala with turnon. % Total If ELA F Total BT 4 10,000 6,000 - 2.800 500 280 60 0 * 3.3 1.8 7.7 6.7 7.1 _ 3.3 1.7 6.7 3.3 5.0 18.8 13.3 13.6 - 8.8 1.7 6.7 16.7 11.7 3.3 6.7 5.0 6.7 3.3 5.0 6.7 8.3 6.0 3.3 1.7 3.8 13.8 8.3 * 1.4 0.7 1.2 0.7 Table 51. Incidence oflnactnMta (A4 and Ad t) in Swiaa mica in relation to concentration ofVC admlniatarad by inhalation for * 5 1 *<n ii Experiment BT 4 October 1981 Concentration, ppm 10,000 6,000 2,500 600 260 60 0 u 76.9 76.7 62.1 80.0 80.0 10.0 10.0 F 817 80.0 73.3 817 517 10.0 10.0 Total 811 718 67.8 83.8 68.3 10.0 10.0 23 ucc OS7076 Table S3. Incidence of mammary CA in female Swim mice in relation to concentration of VC adminlatarad by inhalation for 30 wocka. Experiment Animals with Concentration, ppm mammary CA, % BT 4 10,000 6,000 2.600 500 250 50 0 43.3 26.7 26.7 23.3 40.0 40.0 1.4 animal systems more equivalent to humans in neoplastic response, which in turn depends on partly-known factors, such as basic "spontaneous" tumorigram and enzymatic profiles. Prospects At present the most important goal of research on environmental and occupational carcinogenesis is, in our own view, the extrapolation of results Table 54. Incidence of for*tomach Pa and Ca in Swiu mice in relation to concentration ofVC administered by inhalation for a week*. BT 4 d Concentration, ppm 10,000 6.000 2,500 500 250 SO 0 Animal* with toreatomacb Pa and Ac.*...... M F Total _ 3.3 1.8 3.3 _ 1.7 - 3.3 1.7 -._ 3.3 - 1.7 3.3 - 1.7 "" TabU 58. Incidence of total MT and BT in Spragua-OawUy rata in relation to concentration of VC admlnirtered by ingeation far 52 (or 51) week*. Experiment BT 11 BT 27 Control* BT 11 BT 27 Concentration, mg/kf 50.00 16.65 3.38 1.0 0.8 0.06 0 0 M 35.0 22.5 5.0 13.8 12.0 8.0 12.5 8.0 MT F 42.5 37.5 15.0 36.0 14.7 28.0 15.0 24.0 Tumors/100 animal* Total 38.7 80.0 10.0 24.7 13.8 18.0 18.7 16.0 M 20.0 - 2.5 12.0 20.0 14.7 10.0 9.2 BT F 50.0 35.0 47.5 58.7 38.0 48.0 85.0 48.0 Total 35.0 17.5 25.0 35.3 28.0 31.3 22.5 28.7 TabU SS. Incidence of LAS, LA, 4+ +(+1- + f and A+ +/+ + + in Sprasne-Dawley rata in relation to concentration of VC adminiatend by inteatinn for 52 (or 55) week*. Experiment AniinoU with tumor* and correlated chancoo, % LAS LA A+ f/ + + T A-e +/* * M F Total M F Total M F Total M F Total BT 11 BT27 Control* BT 11, BT27 50.00 16.66 3.32 1.0 0.3 0.01 0 20.0 22.5 21.2 2.5 5.0 3.7 7.5 10.0 15.0 as * * 5.0 2.5 1.3 2.7 2.0 1.4 0.7 ew 1.4 0.7 * ------- 5.0 12.6 7.5 10.0 8.7 5.0 5.0 7.5 15.0 11.2 7.5 6.0 15.0 22.5 18.7 _ - 1.2 6.7 4.0 1.3 0.7 1.3 1.3 1.3 0.8 0.4 - 0.9 0.4 24 Environmental Health Perspectives ucc 057077 i wins in ends on a"' -is* 1 i j ! i search renesig * iSUltS i nforM , TmW, incidence of ELAS and ELA in Sprafue-Dmwlcy rata in relation to concentration of VC adminiatarad by ingestion for 52 (or 59) waaka. Eprnr,-i BT 11 err CuKf.1- KT 1) BT 27 Concentration, mg/kg 50.00 16.65 3.33 1.0 0.3 0.08 0 M - " _ ELAS F 5.0 - 5.0 1.3 * Animala with tumor*. % Total 2.5 - 2.5 0.7 * M 2.5 * - * ELA F 2.5 - 2.6 - * Total 5 1.2 ' Tahir >. Incidence of hepatoma*. neoplastic liver nodult*. nodular hyperplasia oftha liver, and dlffuaa hypoplasia of the liver in Spmgue-Dawley rata in relation to coneantration of VC adminiatarad by ingaation for 52 (or il) waaka. F-m- '-n: Concentration, mg/kg Animal* with tumora and correlated ebangaa. % Hccatoma* Neop.nod. Nod-hyp. Dif-hyp- M F Total M F Total M F Total 11 F Total BT i: HT i for Cpi.-*.;- HT !l. BT27 50.00 16.66 3.33 'F.O 0.3 0.03 0 - - - 6.0 2.5 17.5 17.6 17.5 15.0 15.0 15.0 - - - - - - 17.5 30.0 23.7 25.0 32.6 28.7 - - * 2.5 - 1.2 10.0 20.0 15.0 15.0 42.5 28.7 1.3 - 0.7 1.5 2.7 2.0 6.7 18.3 10.0 6.7 14.7 10.7 1.3 - 0.7 - 1.8 0.7 9.3 6.7 8.0 10.7 5.8 - - * - - _ 4.0 6.7 6.8 10.7 5.3 0.9 0.4 5.2 6.1 6.6 7.0 8.7 7.8 TaM. ,*H. Incidence of NEPHRO-BL in Spragua-Dmwleynt* m ri ution to concentration of VC adminiatarad by ingaation for 52 (or 59) waaka. Animaia with NEPHRO-BL, 1 1 J E\|* r:menu BT II BT 2" Control* BT 11, BT 27 50.00 16. 3.38 1.0 0.3 0.03 0 M F Total 2.5 2.5 2.6 6.0 2.5 17 ** * * Table 10. Incidence ofNEURO-BL in Sprague-Dawlcy rata in relation to concentration of VC adminiatarad by ingaation for 52 (or 59) waaka. Animaia with NEURO-BL, % Experiments BT 11 BTEf Control* BT 11, BT 7 Coneantration, mg/kg M 50.00 16.85 133 1.0 0.3 0.08 0 * * * F Total _ _ _ - _ _* from animal to human, both in qualitative and in quantitative terms. VC carcinogenicity may again provide an importam tool towards solving this problem. We now know a great deal about the effects of VC in experimental animal systems, both in quailtati\e and quantitative terms. On the other hand, epidemiological investigations October 1981 on occupationally exposed population groups have been made and are being carried out in different parts of the world, particularly in Western Europe and in the U.S.A., with reference to general pathology and neoplasias. If these epidemiological investigations provide precise figures on the whole group considered, including figures on the level and length of expo* 25 ucc 057078 TabU 61. Incident! of Zymbal gland CA in Serague-Dawley ret* in relation to concentration of VC adminietered by ingeation for St (or 59) weak*. Experiment! Animala with Zymbal gland CA, ft _____________ Concentration, mg/kg If F Total BT 11 BT 27 Control* BT 11, BT 27 60.00 16.66 8.38 1.0 0.8 0.08 0 2.6 1.2 2.6 2.5 2.5 *- 2.7 4.0 8.2 *_ -_ 1.7 0.9 TabU tt. Incidence of mammary MT in female Sanaa Dawley mta in relation to concentration of VC by inteatton for S2 (or $t> week*. Experiment BT 11 BT27 ControU BT 11 BT 27 Concentration mg/kg 60.00 16.66 3.83 1.0 0.3 0.06 0 0 Animal* with "* mammary KT, t 10.0 16.0 5.0 16.0 5.6 18.7 10.0 9.3 TabU 62. Incidence of foreetomach Pa and Ac In 8praneOawUy rata in relation to concentration of VC adminietered by infection far S3 (or St) week*. Eatparimonta Animala with farea atomachPaandAc-ft Concentration, mg/kg If F Total BT 11 BT 27 Contrail BT 11, BT 27 60.00 16.66 3.28 1.0 0.8 0.06 0 5.0 _ 2.5 - 2.6 1.2 _ e 1.8 2.7 2.0 2.7 l.S 1.8 0.7 1.7 0.9 sure (so at to define homogeneous exposed group), and collect all poesible available data on pathology, we shall have an opportunity, unique at present, t* compare animal and human data, both in quabtatm and quantitative terms, and to help find a posttir key for extrapolating from animala to humans. The Cost With the presentation made in Paris last Novem ber () and with today's report, ten years of wot on our VC experimental project seem to be neatly concluded. After having presented the results, w also wish to present the data of the cost of the project, which cannot be expressed only in financial terms. The cost of the BT project of long-term carcino genicity bioaaaaya on vinyl chloride includes the coat of (1) the planning and setting-up of experi mental apparatus, including inhalation facilities, of TabU 14. Incidence of LAS and Zymbal aland CA in Spracna-DawUy rata in ralatien to achaduU of treatment with VC administered by inhalation. Experiment BT 1 BTS BT 10 BT 1 BTS BT 10 Animal* with turner*, ft LAS Zymbal d.ca VC concentration, ppco SdMdnU* it F Total M F Total 10,000 10,000 10,000 6,000 6,000 6.000 I 10.0 18.8 11.7 33.3 20.0 26.7 II - 17.8 13.3 15.6 III 1.7 * 0.8 18.6 1.7 7.6 IV 1.7 0.8 8.6 6.7 7.6 V 1.7 0.8 8.8 10.2 6.7 I 10.8 88.3 22.0 10.8 18.8 11.9 a 8.8 1.7 20.0 10.0 15.0 in 10.0 5.0 7.5 IV 8.4 1.7 2.5 8.5 - 4.2 V 1.7 0.8 10.0 5.0 7.5 Schedule*.- (1) 4 hr/day, 6 dayv/wk, S3 woclca; (11)4 hr/day, 5 daya/wk, 17 waoka; (III) 4 hr/day, S dayt/wk, 5 waeka; (IV) 1 hr/day, 4 daya/wk, 25 weak*; (V) 4 hr/day, 1 day/wk; 2$ week*. S Environmental Health Perspectives ucc 057079 dnuniuo* mala with ; nary MT, f : 10.0 15.0 5.0 16.0 5.5 18.7 10.0 9.3 -ed groups. i pathology present, u qualitative a possible unans. at Novemrs of wort > *" near!} . u, we ost of the Lnfinandi m cartino:ludes the of expert tdlities, of nt w ith Vf Tout 26.7 15.5 7.6 7.6 6.7 11.9 15.0 7.5 4.2 7.5 ')lhrd*.v.< p.jtiv*s . ... c- tnr nitnet of LAS in relation to apecies (male Sprafue-Dawley Rats, Wfstar rata, Swias mice and folden hamster*), TM traatad with VC administered by inhalation. ` K7: H77 F T 4 HTb Concentration, PPra 10,000 6,000 2,500 600 250 50 0 Spngue-Dawley rata 10.0 10.8 20.0 * 8.4 " Animals with LAS. % Wistsr rats . Swiss mice 29.6 3.8 11.5 6.7 12.0 20.7 10.0 20.0 8.7 80.0 8.3 Golden hamsters _ 3.3 4* 6.7 _ " TsMrM 1m id* m r of Zymbal (land CA In r*1stion to strain mole >pretui liiilv tnd Wistsr rats) traatad wtth VC administered by inhalation. Animals with Zymbal aland CA. % i r.centration. Sprefueppm Dawley rats Wistsr rats i:: i ._. t 10.000 6.000 2.500 500 250 50 0 33.3 10.3 3.3 10.0 _ - - 7.4 7.7 - _ _ a type uncommon in 1971, and the working out of a protocol for long-term bioassays; (2) the study of nearly 7000 animals up to the point of their natural death, equivalent to more than 3,000,000 rodent days; (3) ten years of work; (4) the routine exami nation of some 200,000 histological slides; (5) a financial commitment equivalent to more than $2,000,000 U.S. at present prices (the average cost of a rat throughout the world in this type of experiment is $300 U.S.); (6) the availability of the same team of scientists throughout the entire 10 years of the project, a prerequisite which may be difficult or even impossible to ensure in many countries at the present time; (7) the highly moti vated commitment of those scientists to a type of work which is long-lasting, onerous and often tedious; (8) the effort involved in maintaining the Tthir 67. in< nil net of LAS in relation to if* (newborn and adult) Sprague-Dawley rata traatad with VC administered hr inhalation 4 hr/day, 5 days/week, 52 weeks. t S- vm i,i NT T ITTt Concentration, ppm 10,000 6,000 If 2&0 27.8 Animals with LAS, *4_______________________ Newborn rata_______________________11 weak old rata F Total If F Total 45^0 STI L7 I 5T" 50.0 40.5 Table 18. Tumor* presently correlated to VC exposure, by experiments on rodents. W-.- Tumors Tumors Lympbo- mas of of mas and Hepa- rr brain lung ieuktmia* toma* Anglo- sarcomas and an- gioroai Nephro- of other blasto- sites mv Sefaaceous cuts1MOOS cardnomas Other rata- Foraato- ntous mach pa- epith- Mam* pilkmaa elial mary car- and scan- tumors dnomaa thomas Melanomas t..y - + <+) ++ + <+> (--) (+) (-*-) + (+) + (+) October 1 MSI 27 ucc 057080 Table *# Total cancer-bearing animal* significantly in new by Fisher exact probability test if 0.05). Doee level at which total cancer Sex boring animal* in exeeaa Male Female 30,000 10,000 6,000 2,500 500 260 200 50 ppm 50 mg/kg 30,000 10,000 6.000 2,500 500 200 150 50 ppm 50 mg/kg Table 70. Tumor* (ignifleantly in extern by Fisher exact probability test (y * 0.05). ------------------------------- L Dom it which tumor* Tumor type Sex in ixctu Zymbal gland carcinoma Uver angiosarcoma Nephroblastoma Neuroblastoma Mammary gland adenocarcinoma Fortstomach papilloma M 30.000,10,000 ppm F 30,000; 10,000 ppm M 30,000; 2500; 200 ppm 50 mg/kg F 30,000; 6000; 2500; 500 200; ISO; 50 ppm 50; 16.65 mg/kg M 2500:200: 150; 100 ppm F 500; 250 ppm F 10,000 ppm F 160; SO; 26; 10; 5 ppm M 30,000 ppm F 30,000 ppm Table 71. Onset of tumors considered VC-correlated at the Table 73. History of vinyl chloride carcinogenicity Date 1961 1970 1970 July 1971 August 1972 April 1973 1973 December 1973 February 1974 February 1974 1974 1974 1974-73 1976 VC was found to produce liver enUrgenee and mkroacopk hepatic degenerative change* (5) Zymbal gland carcinoma* were reported a rat* exposed to 30,000 ppm of VC, by inhalation (6) An increase in atypia* in respiratory cellst* observed among worker* heavily expoatd a. VC (7) A vast project of long-term carcinogenidtr bioaaaays on VC was started in BeMivgfja, near Bologna, Italy (BT project) Zymbal gland carcinomas, nephroblastoma and liver angiosarcomas were observed a rat* exposed to VC by inhalation (Malum, BT project) The 3r*t data ofthe BT project were relawt to the sdentifle community: the oncogene effect was observed up to 250 ppm U) Splenomegalic liver disease war found aaw polytvinyl chloride) production workers (1) For the first time a case of liver angioasmat in a potytvinyl chloride) production warier was correlated to VC exposure <) On the basis of the BT project data indicate! a carcinogenic effect at 250 ppm. OSHA proposed a TLV of 50 ppm The BT project data showed that VC i* a multipotential carcinogen, producing a variety of tumor*, in different animal tprae The BT project data indicated a carnnofr* effect at 50 ppm M0); OSHA proposed arc stricter rules Early epidemiological observations (parallel ing the experimental information) indicated an increase in tumors other than liver an| sarcomas (of brain, lung, liver, hemotympifr reticular tissue*) among worker* of VC-FVC industries Mi) BT project data showed that VC had ordnogenk effect* in rata also when givmty ingestion (li) In rata of the BT project exposed to VC by inhalation, angiosarcoma* were observed dawn to the level of 25 ppm, end Zymbal gland eardnomae down to the level oflOppn (IS) Does 25 ppm 10 ppm 1 mg/kg 0.3 mg/kg 28 Tumor* Over 120 animals, 6 Uver angiosarcomas, 4 Zymbal gland mrdnotnas and 1 naphrcblastama Ovr 120 animals, 1 Uver angiosarcoma, 2 extnhepstk angiosarcomas, and 2 Zymbal gland carcinomas Over 150 animals, 3 Uver angiosarcomas, 1 extrahepatk angiosarcoma, 1 hepatoma, and 5 Zymbal gland carcinomas Over 150 animals, 1 Uver angiosarcoma and 1 hepatoma consistency of the methodology, which has as iu reverse side the limits placed on the exercise of imagination--the most positive element in scientific life; (9) the effort involved in establishing ud preserving objectivity and balance in the evaluation and interpretation of data; (10) and finally, the strength required to withstand the sense of loneli ness arising from the lack ofco-operation of many of those bodies which should properly be concerned with the progress of science in this field, not excluding part of the scientific community whose Environmental Health Perspectives it t w C; li S'. I 3 4. ucc 057081 1 niciw itudia. r enJrgennr. i erative `reported*, ! VC, by | story cells**' ily exposed u rrinogenidti 1 Bemjvogi* -t) iroblutona.* baerved in on (Maitoni, ** release; oncogen* >pn> U) found unoej worker? (i) 'ngioMTconu ion worker (*) itaindicniiw . OSHA t VC ifi dnga w ipeae; a. .ogenit poMd new rw (panDe). ) indicated liver angiocmolympbo. cfVC-PVC , had urT giver by to VC by rnerved Zymbel I of jo p| i a as its ^rcise of : dentiflc ing nnd aluation ; Uy, the f lonelimany of ncemed JH not j .ose ectives Table 73 (.omparstlv* effect! of three related compound*--vinyl chloride (VC), vinylidene chloride (VDC) and ethylene dlchloride (CDC) on the nine animal eyitcma. (Vi p.jr.d Angiosar Tumors Tumors comas of of the of the .Nicies liver brain lung Hepa tomas Angio Tumors of sarcomas the kidney and an- giomas Nephro- Adeno- of other blasto- card- aitee mu norm* Sebtceou* MOU* cardnomai Fore Other stomach cuta papillo neous Mam mas and epithelial mary car- acan tumors cinemas thomas Rat vrapi*I'avlev) + + +++ VC Muuse 'UTSS) ++ + (+) + f (-*-) ( + ) Hat 'i.ragueI iju'iev) VIM .Muuj* ^wiss) (+) + Rat v.rague- ! mu lev) KI*< Mouse ''W15S) 43 indifft ivnce sometimes degenerates into frank hoe* tilitv. Thr !iich costs probably represent the reason w h>. in thr field of experimental and environmental carnn'<,.vne>is, words overlap facts, opinions over lap i. and meetings and commissions reports .-uhnicivv good laboratory work. REFERENCES 1 M-ilv ri. C.. Cardnogenidty of vinyl chloride: curraM reExperimental evidence. (8th International Sympo- hj- r. the Biologkil Characterisation of Human Tumour*, t i hagen 1978). In: Advancaa in Tumour Prevention, !>. . ion and Characteriiation, ExcerpU Medic*, Amatard;, 1978. Vol I, pp. 216-237. - M- ! ni. C., Lefemine, G,, COiberti. A., Cotti, G., and Cii--itti 0. Vinyl chloride carcinogenicity bkwaaaya (ST l r v.t) aa an experimental modal for halt identification and a-'i-v-ment in environmental and occupational camnogene- In: Epidemiologic animal* et epidCmiologi* humaine: 1, ca.i du chlorure d* vinyl* monomer*. Publication* K"t ntiellea. Pari*. 1980, pp. 15-112. 3 M.:-..ni. C., Lefemine. G., COiberti, A., Cotti, G-, and (arretti. 0. Vinyl chloride carcinogenicity bioeaaey* (BT Vr .'vet) a* an experimental model for riak identification and ---^ment in environmantal and occupational carcinogen*' Otpedali Vita. Field Reaearch, Rept. 10,7:1-208 (1980). 4 Maltoni, C., Lefemine, G,, Chieco P., and Carretti, D, La i ancerogeneai ambientale profeaaionile: nuov* proapettiva October 1981 alia hice della cancerogeneai de doruro di vinile. Oapedali Vita 1 (54): 446 (1974). 5. Torkelaon, T. R., Oyen, F., and Rowe, V. K. The toxicity of vinyl chloride a* determined by repeated expoaure of laboratory animal*. Am. Ind. Hyg. Assoc. J., 22:354 (1961). 6. Viola, P. L., Bigotti, A., and Caputo, A. Oncogenic reapana* of rat akin, lung* and bone* to vinyl chloride. Cancer Rea. 31: 516-519 (1971). 7. Mahotd, C. Occupational earcinogeneeia. (2nd International Sympoaium an Cancer Detection end Prevention, Bologna 1974) In: Advance* in Tumour Prevention, Dectection and Characterisation, ExcerpU Medics. Amsterdam, Vol. 2, 1977, p. 23. 8. Mar*t*fl*r, R. J., Lelbech, W. K.; Muller. R.. Juhe, S., Lange, C. E., Rohner, H. G,, and Vehmin, G. Chronic toxic liver damage in worker* at PVC producing plants. Deut. Med. Wochachr, 98: 2511-2314 (1973). 9. Creech, J. L., and Johnson, M. N. Angioaarcoma of liver in the manufacture of polyvinyl chloride. J. Occup. Med. 16: 150-161 (1974). 10. Maltoni, C.,, and Lefemine, G. Carcinogenidty bioaaaay* of vinyl chloride: current remits. Ik Toxicity of Vinyl ChkridePoiyvinyl Chloride. New York Academy of Sciences, New York, 1975. pp. 196-218. 11. Wagoner, J. K. Statement before the Subcommittee on the Environment of the U.S. Senate Commerce Comitt**, (1974). 12. Maltoni C., COiberti, A., Gianni, L., and Chieco. P. Insorgenu di angiosarcomi in ratti in seguito a aomminiatnxione per via oral* di doruro di vinile. Oapedali Vita 2 (1): 6546 (1975). 13. Maltoni C. Vinyl chloride carcinogenicity: an experimental modal for carcinogenesis atudies. Ik Origins of Human Cancer, Cold Spring Harbor Laboratory, 1977, pp. 119-146. 29 ucc 057082 Environmental Htalth PtrtptcHvtt Vol. il, pp. 31-51, 1981 Neoplastic and Nonneoplastic Effects of Vinyl Chloride in Mouse Lung by Yasunosuke Suzuki* Neoplwtic effects at Tin?) chloride were itudied in Inngt of 77 mice expand to vinyl chloride monomer at 2500 and <000 ppm for 5 and < month* (larfe dote* and ionf-Urm exposure). Pulmonary tumon were obaerrad in 3S of 27 experimental animals. Light microecopy showed the tumors to be multiple and arranged in either tubulo-papillary or adenomatous formations. Although occasional mitotic divisions and invagination* into the bronchiolar lumen wok observed, no metastase* were found. By electron microscopy, short microvilli, tight junctions between two adjacent cells, appearance of oemiophilic lamellar bodies, large mitochondria of irregular shape, well developed Golgi complexes, continuous or discontinuous basement membranes, occasional appearance of "sequestration" and of crystalloids and lack of both cilia and mucous secretory granules were observed a* characteristic feature* of the neoplastic cells. Some of the cells werepoorIy differentiated and were equipped with poorly developed organoids, without formation of oemiophilic lamellar bodice. The pulmonary tumors corresponded to "akeologenic" tumors. It is suggested that the neoplastic ceils were transformed from type II alveolar epithelium via its hyperplastic form. Nonneopiastic effects of the chemical were also studied in the 27 mice. Major light microscopic alterations observed were proliferation and hypertrophy of the terminal bronchiolar cells, consisting of ciliated and Clara cells, hypersecretion of the epithelial mucin in the goblet cell* of both the bronchia) and the proximal bronchiolar epithelium, hyperplasia of alveolar epithelium, mobilisation of alveolar macrophages and occasional presence of peribronchial or bronchiolar chronic inflammation. Electron microscopically, Clara celts of the terminal bronchiolar epithelium showed proliferation of the rough and smooth surfaced endoplasmic reticulum and appearance of large and abnormally shaped mitochondria. Similar alterations were found in the ciliated cells. Submicroecopic changes of pulmonary alveoli were represented by focal thickening of the basement membrane, multiple foci of hyperplastic type II cell (the precondition of the alveologenic tumor), active discharge of oemiophilic lamellar bodies from the type II cell and phagocytosis of the bodies by macrophages, appearance of cholesterol crystalloids in the macrophages, degeneration of alveolar septal cells and occasional appearance of a large nucleus with swelling of the capillary endothelium. The neoplastic effect of vinyl chloride of smaller doses (IN, 10,1 and 0 [control] ppm) and shorter exposure (four weeks) was studied In lungs of 120 mice. Our preliminary observation indicated that sacrificed animals at 40 weeks after the exposure showed productions of the alveologenic tumor in Soft (100 ppm), toff (10 ppm), I off (I ppm) and Oaf 10 (control Oppm). A dote-re*pons* relation was considered in the incidence of the alveologenic tumor production of vinyl chloride. It la concluded that mourn lung is an extremely sensitive indicator of the oncogenicity of vinyl chloride. Introduction Hepatic hemangioaarcoma has been accepted as a serious health hazard associated with vinyl chloride 'Environmental Sciences Laboratory, Department of CooMedicine and Department of Pathology, Mount Sinai Scfc ol of Medicine of the City University of Now York, One Gu-.sve Levy Placo, New York, N.Y. 10029. October 1981 exposure among workers in vinyl chloride polymer ization plants (7-7). A risk of lung cancer has also been reported among the workers on the basis of epidemiological studies (8,9). Experimental studies in rats, mice, and hamsters have shown that, in addition to liver, various organs such as lung, brain, breast and ddn, includ ing sebaceous glands, were involved in induction of primary neoplasia by vinyl chloride. Although a SI number of studies have demonstrated that pulmo nary tumors can be induced by vinyl chloride in mice, the significance of such occurrence and the nature of the tumors have not yet been appropri ately explored (10-17). The occurrence of the nonneoplastic pulmonary abnormalities among vinyl chloride polymerization workers has been reported on the basis of chest x-ray US), pulmonary function (19) and smear cytology (l) of the worker's sputum. No histopathological evaluation of the abnormalities has been reported. It is believed that a relationship between lung cancer and vinyl chloride exposure exists from epidemiological studies (6,8,9,iO). A high incidence of pulmonary turnon in mice exposed to vinyl chloride has been reported by several investigators (10-15). However, the nonneoplastic pulmonary effects of the chemical have not been completely explored. We have, therefore, undertaken detailed light and electron microscopy of the mouse lung, to characterize the neoplastic and nonneoplastic pul monary effects of vinyl chloride. Materials and'Methods Frouu 1. Two pulmonary turnon induced by vinyl cklaib an aaan in th peripheral part of a mouse lung (2500 ppnit group III). Hematoxylin and eotin; 64*. Twenty-seven CDI Charles River white strain male mice, 4 to 5 weeks old st first exposure, were used. All of 27 mice used for this study were alive until they were sacrificed at three separate stages. The mice that died in the course of the experiment were excluded from the study. Group I consisted of six animals exposed to vinyl chloride at 2500 (three mice) and 6000 (three mice) ppm/hr, 5 hr/day, 5 days/week, for 5 months. They were then kept for 6 days without exposure before sacrifice. Group II included 13 mice exposed at 2500 (seven mice) and 6000 (six mice) ppm for 6 months and were kept for an additional 2 days,for recovering before sacrifice. Group III included eight animals (seven at 2500 ppm and one at 6000 ppm) which were exposed to vinyl chloride monomer for 6 months followed byi 37-day recovery period. The inhalation exposure were accomplished at the Industrial Bio-Test Libo ratory, Northbrook, Illinois. In addition to the experimental animals, 16 mice (four for group 1. four for group II, three for group III, and five which were 12 months old) were used as controls. To atudy the pulmonary effects of the chemical it smaller doses with shorter exposure, 120 mice of the same strain, sex and age were prepared. These animals were divided into four groups (30 mice in i ;u`! netJ'WT. r\J* -car enct '. no Wffl ppm U-ivt "me Table I. Pulmonary Umar production la CDI male mice eith lower doees of VC and shorter exposure (4 weeks).* VC doe*, ppm 1st sacrifice (immed Between 1st and iately after dosing) 2nd sacrifice 2nd sacrifiee (12 weeks) Between 2nd end 3rd sacrifice 3rd sacrifice (40 weeks) too (ft - ) 10 (N - 80) 1 (N - 80) 0 (V - 80) 0/10" 0/4* 0/6* otv 30* MO" (VI* (W" 0/1* 2-9 <yio* 0/10" (VI* 13* 0/10" (VI* ftV* 010" Reported as pulmonary tumor-bearinf mice/toul number of mint. "Sacrificed. Tound dead. 32 Environmental Health Perspective ucc Lu -cope ;uunu norm, <-nt. J-'oi hr, i parafl 10-6 p. co.-in, i' kIic a >>y dia u-chm -malle Octobt 057084 nary tumors and nonneoplastic pulmonary tissues and were fixed in 1% phosphate-buffered osmic acid at pH 7.2-7.4 for 2 hr or in 2% paraformaldehyde fixative followed by the osmic add. After alcohol dehydration, the blocks were embedded in epoxy resin. Ultrathin sections were obtained with an LKB microtome. The sections were stained with uranyl acetate and lead. A Siemens 101 electron micro scope was used for ultrastructural observations. Observations c* 'hloridc i Ppm in j- i 2500 : ed to | !l- 4 abothe `P I, five ok. iiat e of iese e in i Fi .i k; Neoplastic eelli stained with PAS. An arrow irH;.. . fine PAS-positive mateaal digested by diaataaa. Th.- k- . labeled M shows an abnormal mitosis (2500 ppm in p... HI/. 560*. each trc up) and were exposed to the chemical for 4 week- hr day, and 5 days/week) at 100 ppm, 10 ppm. 1 ppm and 0 ppm (control). The low dose expii.-utvs were performed at the Toxicology Re search Laboratory, Health and Environmental Sci ences. Dow Chemical U.S.A. As shown on Table 1, these ..nimals were sacrificed at three different peril kL: immediately after, 12 weeks after and 40 week- after exposure to the chemical. Six (four 100 ppm. one 10 ppm, and one control) were found dead between the first and second periods, and three (one ]"0 ppm, one 10 ppm and one 1 ppm) were found dead between the second and third periods. Luncs were examined under a dissecting micro scope after the organs were removed from sacrificed animals, to determine whether macroscopic ab normalities including tumor production were pres ent. For light microscopy, the organs were fixed in 10^ neutral buffered formalin and embedded in paraffin after dehydration in alcohol. Sections (5-6 urn) were made and stained with hematoxylineosin. Masson's trichrome, Weigert's silver, per iodic acid-Schiff's (PAS) with and without digestion by iliastase, elastin and Van Gieson's picrofuchsin technique. For electron microscopy small pieces, smaller than 1 mm8, were taken from both pulmo- October 1981 Neoplastic Effects of Vinyl Chloride at Heavy Doses and Long-Term Exposures Gross Anatomical Finding*. Pulmonary tu mors were observed in all experimental mice except one from the 6000 ppm series of group II (26 of 27). None were found in 16 controls. These tumors were round, whitish in color, multiple in number and variable in size from 1 to 5 mm in diameter. No metastases to regional lymph nodes or other organs were observed. Neither parenchymal fibrosis nor fibrotic adhesions of the pleura were detected. Light Mtcroacopg. As shown in Figure 1, the tumors were usually seen in the peripheral part of Fiouat 8. Hyperplastic pulmonary cclli are Men beneath the visceral pleura of a mouse lung (2500 ppm in group 111). Hematoxylin and eosin; 430 x. 33 iI . % y i ucc 057085 L Figure 4. Low-power electron micrograph of i well-differentiated pulmonary tumor. Arrow* indicate junctional atructuree between neoplaetic cell*. B, Baaement membrane (2500 ppm in group III), OeO,; 7900 x. lung parenchyma, although occasionally tumors were found in more proximal parts of the lung. No direct connections of the tumors with bronchi or bronchi oles were observed. The neoplastic cells were ar ranged in various ways, such as tubulopapillary and adenomatous forms. Pleomorphism and atypical structures were not striking. However, sometimes abnormal mitoses were observed, as shown in Fig ure 2 (arrow labeled M). The nuclei were round in shape and small, and chromatin was generally finely distributed. Nucleoli were generally poor in devel opment. Two different types, eosinophilic and ba sophilic, were distinguished in the neoplastic cells. Some of the cells stained with PAS, and the sub stance so stained was digested by diastase, sug gesting that it was glycogen. The neoplastic tissue was not encapsulated by connective tissue. Often, air spaces separated neoplastic tissue from normal tissue. Although malignant invasion, such as de struction of preexisting tissue, was not observed in 34 the animal lungs, invagination of the neoplastic tissue into bronchiolar air spaces was detected is instances of extremely large tumors. Collagen and reticular fibers showed little development in the neoplastic tissues. In addition to neoplastic chang es, as shown in Figure 3, focal and multiple hyper plastic changes of the alveolar lining cells wen noted in lungs exposed to vinyl chloride. In Figure 3, the hyperplastic cells are seen just beneath the visceral pleura- Since the lining cells beneath the thin connective tissue of the visceral pleura an known to be alveolar epithelium, the hyperplastic cells are assumed to be alveolar epithelial cells. Hyperplastic cells are also found in the deeper pan of lung parenchyma. Occasionally, neoplasia ud hyperplasia coexisted in the same lobe of the lung' and the distinction between neoplastic and hyper plastic cells with confidence was not always clear, as some cellular similarities were found between the two. Identification of the cell types of both Environmental Health Perspectives neoplastic was not fe Electron neoplastic trastructui included m toehondria. osmiophilic (arrows in and a base served. Fij. area of the; tubular lut than those u It. rast.ruct dria. Golgi ie>. were . arrangeme common, a: well-devdo: lum (Fig. 6 cytoplasmii -tinctures < ictober 19 UCC 057086 JL & -V.' < e'-'T^Z * steiwSfeSfe&'rA w vm. . IS? ? & * - ^-" i -#K* . /d. `L^ V -'Gf, -` r-jb'& / 9 *v*s.. f ^ -.. -. - . n>i / Ficvxt 5. Differentiated neoplasm Men in the animal lung shown in Fig. 3. Formation ofthe tubular lumen and microvilli is poor. OaO; 6600 x. elastic cted in en and in the changhyper* were Figure th the th the na are olastk cells, r part i and lung. iyperdear, ween both tives neoplit.'tic and hyperplastic cells with confidence wa~ i,..: feasible at the level of light microscopy. Eh ctron Microtcopy. Figure 4 is derived from nrnplustic tissue of the tubulo-papillary form. Ul- tra>'.ruitural characteristics of the neoplastic cell im-UxU-il microvilli, large, round, or rod-shaped mi- tovh' i/'lria, well-developed Golgi complexes, and o.-mi' 'j hilic lamellar bodies. Junctional structures (art'nus in Fit 4) between adjacent neoplastic cells and basement membrane (B) were usually ob- ser\ I'd. Figure 5 was derived from an adenomatous ari a . f the tumor. Neoplastic cells had poorly formed tubnL>r lumens and microvilli and were smaller than those shown in Figure 4. However, other ultra-tructural characteristics, such as mitochon dria. complexes, and osmiophilic lamellar bod ies. v.c-re almost identical in the two. Irregular arrangements of mitochondrial cristae were fairly comniun, and mitochondria were often wrapped by well-'!i \ eloped, smooth-surfaced endoplasmic reticu lum 1 Fig. 6). Some of the neoplastic cells contained cytoplasmic compartments formed by membrane structures (Fig. 7). The occurrence of such com October 1981 partments has been reported by Svoboda (21), who made electron microscopic observations on the neo plastic cells in mouse pulmonary tumors induced spontaneously or by urethane. Occasionally, crys talloid structures were observed in the cytoplasm of the neoplastic cells (Fig. 8). The above described neoplastic cells were quite similar in ultrastructure to type II alveolar epithelium. Capillaries in the neoplastic tissue consisted of single layers of nonfenestrated endothelium as seen in the normal alveolar capillary. In addition to well-differentiated neoplastic cells, poorly differentiated ones were also recognized (Fig. 9). As seen in Figure 9, the cells were cuboidal or cylindrical in shape and lacked formation of osmiophilic lamellar bodies. Mitochon dria were small in size, although the cells were relatively rich in rough-surfaced endoplasmic retic ulum. These cells seemed to correspond to the basophilic ones observed by light microscopy. Ex cept for the lack of a large amount of glycogen, these cells resembled immature alveolar epitheli um, as observed in fetal lung in late gestation. Neither cilia nor mucinous secretory granules were 35 ucc 057087 Figure 6. Put of the eell cytopUem of neopieetk cell. The arrow indicate* irregular mitochrandrial criatae (2500 ppm in Group III). O*04; 29, 400 x. Figure 7. Intncytoplawnic compartment* formed bv membran* atracturee (2500 ppm in group III). 004; 20, 000 x. Figure 8. CryetalWd atmeture aeen in the cytoptaam tf a neoplaatk eeB (2B00 ppm in group III). 0*04; 30,000 x. Environmental Health Perspective* Octobei UCC 057088 Figure 11. Light microscopy of bronchiok>-alvMlar int. Arrow'i indicate the it of transition between the respira tory bronchiole and the alveohia. Control mouse; Masson's trichrome staining; 420 x. Figure 12. Proliferated and hypertrophic bronchioles. Des quamated bronchiolar epithelial areas are illustrated. Muson's trichrome staining; Group 1; 2500 ppm, 420 * . observed in the neoplastic cells. Based on these findings, it was strongly suggested that the neo plastic cells were derived from the alveolar epithe lium, particularly from type II cells. A hyperplastic pulmonary alveolus is illustrated in Figure 10. Electron microscopically, aspects ofthe hyperplastic cells were evidently those of type II alveolar cells, although they showed some differences in ultrastructure from the normal type II cell. Mitochon dria were large in size and irregular in shape, and, occasionally, retention of huge osmiophilic lamellar bodies was noted in the cell cytoplasm. Cristae mitochrondriales were arranged irregularly, and well-developed endoplasmic reticulum was frequently 38 seen in the cytoplasm. Early stages of the mem brane formation responsible for Hcytoplasmic com partments" were observed in the hyperplastic cell In many respects, the hyperplastic type 11 cell is assumed to be the precursor of the neoplastic cell. An intermediate form between type 1 and II cells was frequently observed in the hyperplastic pul monary alveoli. The arrow in Figure 10 indicates a part of the cell cytoplasm which may represent a transitional form between type I and II cells. Though the secretory granules were observed in the neo plastic cells, based on these findings, it was strongly suggested that the neoplastic cells were derived from the alveolar. Environmental Health Perspectives ucc 057090 N a' L ol pi te m tr. ch di tr th re vit Ot  5. . DetMu- Fiu kf is. Hypersecretion of epithelial mudn in bronchial tpuhri.jm. Arrows indicate mucinous substance stained With i AS Group III; SOOO ppm, 420 x. Figure 14. Hyperplasia at alveolar epithelium is shown. Hematoxylin-eosin: Group III: 2500 ppm; 670 x. iem:om* cell ;11 is cell. cells pul es* nt a >ugh neo- ngly ived ' I Nonnet(plastic Effects of Vinyl Chloride at Heavy Doses with Long-Term Exposure Light Vicrofcopy. In the bronchi and bronchi oles. a- a common finding in the treated animals, proliferation and hypertrophy of the bronchiolar epithelium were noted. As shown in Figure 11, the termina! and respiratory bronchioles of the control mice \u re relatively simple in structure and the transit i. jtal point (arrows) of the respiratory bron chiole into the alveolus was easily distinguished. To differentiate the two areas, we found that Masson's tnehroine was a useful stain, since the cytoplasm of the bronchiolar cells was stained an intense brown red. The bronchioles of all the animals treated with vinyl chloride monomer showed proliferation, and October 1981 cellular hypertrophy, through the degree varied among the animals (Fig. 12). The proliferated ceils were irregular in arrangement (Fig. 12). Frequent ly, hypersecretion of epithelial mucin in goblet cells of the bronchi as well as the proximal bronchioles was observed (Fig. 13, arrows). It was noteworthy that those alterations were still found in the ani mals of group III, which had a recovery time of 37 days after vinyl chloride exposure. Chronic inflam matory changes represented by marked lympho cyte infiltration into the perivascular and peribron chiolar connective tissue were seen, particularly in group III. The most significant finding in pulmonary alveoli was a high inddence of alveologenic tumors in the treated mice, as stated before. In addition to the neoplasm, multiple foci of hyperplastic alveolar epi- 39 UCC 057091 Figche 15. Large dear microphtg** (fo*m eclU) u well u atnallbasophilic macrophage*antaaninthealveolarairapace*. Hematoxylin-Main; Group III: 2500 ppm; 420 x. Ficua* 16. Striking accumulation of a large number of tmr cella. Hematoxylin-eoain: Group III: 6000 ppm: 420 x. h kc thelium (Fig. 14), which were strongly suggestive of being preneoplastic for alveologenic tumors (it), were frequently observed. Mobilization of alveolar macrophages in the alveolar space was fairly commonly seen in the three groups of animals (Fig. IS), In several cases, foam cells were markedly acoumulated in alveolar space (Fig. 16). Two animals in group III showed bronchopneumonia-like changes, As shown in Figure 17, coexistence of the proliferated bronchioles with alveologenic tumors (arrow) was frequently observed. Electron Microtcopg, The epithelium of the terminal bronchiole consists of the Clara cell (nonribated) and ciliated ceils; it lacks mucous-producing cells in the mice. Both cell types are illustrated in Figure 40 18, obttined from s control mouse. Clara cells lick typical microvilli and their apical portion present i dome-like shape (Fig. 18). Hie smooth-surfaced endoplasmic reticulum and Golgi complex were well developed. Mitochondria were generally round is shape and their cristae were few in number (Fig 18). Two distinct granules, a beadlike structure (electron-dense; the long axis was 1.6-0.2 pm) and round phagolysosomal granule (electron-dense or opaque; 0.6 x 0.6 pm in size) were observed in tlx ceils. It is noteworthy that the ultrastructure ofthe cell is not identical among animal species and, Airther different fixation methods result in different structural appearances of the endoplasmic retkulum in the cell. Environmental Health Ferspecthw The < ch ar ai m-tae t r,,- cell u t re al un-alch n.ue ar A lov i- I'iusti fiviuen t ;, lopla a- ust I'-n ^la n.i-mbr. "h-erve October UCC 057092 ;* % .0 - *>1* >.yt i-t <4. ' tj* i 0fj *;#* * -% ' -r >. .. A ber of faun ,20 x. cells lack 'resent 1 surfaced vere well round in oer (Fig. structure jn)and a dense or edinthe ire of the and, Air different c reticu- I tiv* i # I K: t.i IT Pm of lung tiMue showing coexistence of the sht!' .1 tumor (arrow) with the prolifersted bronchiole. Mi" : ' nchrome staining; Group I: 8000 ppm; 170 x. The ( 'plasm of the ciliated cell was relatively dear and it contained rod-shaped mitochondria with cri.'tuc 1 Fig. 18). Cilia and microvilli were seen in the cell ,-urface (Fig. 18). The two diatinct granules were al>,, occasionally seen in the cell. Ultrastruetural ch.o.ces seen in those cell types of the treated mice are described below. A low-power view of the proliferated bronchiole is illustrated in Figure 19. Hypertrophic Clara cells frequently included dark cells rich in rough-surfaced endopla-tnic reticulum and free ribosomes. The cell was usually large and its shape was occasionally irregular. Deep interdigitation of the lateral cell membranes of two adjacent cells was occasionally ebsened. Golgi complexes were well developed, October 1981 and the two distinct granules described above were increased in number in the cytoplasm. The dark round granules are shown in Figure 19. Although smooth-surfaced endoplasmic reticulum of the nor mal Clara cell was generally vesicular (with a single osmic add fixation as used in this study, though this cell organoid is asternal with double fixation by glutaraldehyde and osmic add), the hypertrophic cells contained various forms of the organoid and the transformation of the rough surfaced endoplas mic reticulum into smooth-surfaced endoplasmic re ticulum was easily observed (Fig. 20). Mitochondria of abnormal shapes and large size occasionally ap peared. Cristae were rather dearly shown in such abnormal mitichondria (Fig. 21). Ciliated cells were also involved in the prolifer ated alteration. The shape of the cells was occasion ally irregular. Golgi complexes were sometimes well developed and phagolysoeomal granules as well as round dense granules frequently appeared in the cytoplasm (Fig. 22). Large round mitochondria in which cristae were fewer in number were seen. In some ciliated cells, the rough and smooth surfaced endoplasmic reticulum were markedly developed (Fig. 22). Although light microscopic observations failed to detect details of damages in the pulmonary alveo lus, various ultrastructural alterations of the alveo lar cells were revealed by electron microscopy. Mobilized alveolar macrophages were rich in phagolysosomal granules, as shown in Figure 23. Other cell organelles were also well developed. Basophilic macrophages contained a large number of free ribosomes as well as the rough-surfaced endoplasmic reticulum, while clear macrophages were represented by intracytoplasmic osmiophilic lamellar bodies (Fig. 23) which seemed to be phagocytosed from the alveolar space. Occasionally, cho lesterol crystalloids were found in the macrophages (Fig. 24, arrows). As shown in Figure 10, hyperplastic alveolar epithelium consisted of type II cells, precursors of alveolar tumor (i5). The evolutional process of the neoplastic transformation has been reported (15). Deformation of the cell shape, appearance of giant mitochondria with abnormal cristae, retention of large osmiophilic lamellar bodies, early introcytoplasmic "sequestration," and occasional huge lipid granules were observed. Microvilli of the cell sur face were frequently decreased in number. These alterations were observed in almost all mice ex posed to vinyl chloride, regardless of difference in dose and duration of recovery time. Swelling of the cytoplasm and appearance of ly sosomal granules were occasionally observed in type I cells. Transformation of the type I cells into the 41 ucc 057093 / k Ficuxc 18. Pin of the terminal bronchiole. Clara cell* and dliated cell* are Dhiitrsted. Control mouae; 0*04; 6700 type II cells was suggested, since intermediate cell types between the two were found on the alveolar lining. Focal thickening of the basement membrane was commonly seen (Fig. 25). Sometimes, the thickened basement membrane showed a fibrillar appearance ("f" in Fig. 26) and contained cell debris (arrows in Fig. 26) which seemed to be derived from alveolar septal cells. In additidh to swelling of the cytoplasm, lyso somal granules and a large nucleus (Fig. 27), seg mented or nonsegmented, were sometimes observed in the alveolar endothelium. Alveolar septal cells frequently showed hyper trophy (h in Fig. 28) and degeneration (arrows in Fig. 28). In some cases, focal reticulosis was ob served in the alveolar septum. From these light and electron microscopic stud ies, mouse lungs exposed to vinyl chloride at 2500 42 and 6000 ppm for 5 and 6 months dearly show, nonneoplastic pulmonary changes in both brondvlar and alveolar cells. Since these findings were ir detected in control mice, they are considered fl itted to vinyl chloride. Neoplastic Effects of Vinyl Chloride at Smaller Doses with a Shorter Exposure Detailed studiea on pulmonary effects of chloride at smaller doses (1,10 and 100 ppm) with* shorter exposure (4 weeks, 5 hr/day, 5 days/ week are still in a process of analyses in 90 mice. Howev er, as shown in Table 1, our preliminary study tltf involved gross anatomical and histological obsenv tiona revealed that alveologenic tumors were in duced in 5 of 9 (100 ppm), 2 of 9 (10 ppm) and 1 of(1 ppm), while the tumor was not seen in 10 comm Environmental Health Perspective ;<:n| i d.wmi-ai iiihc A Hu.<t .1 'lull i Discu K\!n-r "f VJ.V.-I v-is.-i {-a <fV- .. tji ad. '** !- . h n C'V'iK-it `i-v-ntd uber ucc 057094 M  . : ;V,viJ c i ^v:," V;yf Vv ; '*N* ^vr*'>* n--\v/-,Wv >'0 ' , r 0 p>. ' fit' V --'`.v'-.r v- ` o V:'*v> 'f JP <f * - ." ' 'f >'., rt -* -i- i . j^<u4r-r' ' -'/ii! - #f^li^i .iSi4,V.X.'45Xw- . Er* vrS fe Flaunt 19. Proliferated bronchiolar epithelium. Group 1: 6000 ppm; 3300 *. . l .' showed bronehio- : were not I iered re- [ ide at i yosure I of vinyl | n) with a i s/ week) j Howev- t udy that observawere innd 1 of 9 controls j ^ectives m ppm' .i: 40 weeks after vinyl chloride exposure. Sia- am 11 imber ofthe induced tumors were generally >mailer those of the tumors produced by the chemical <: larger doses (2900 ppm and 6,000 ppm) and lent:i r exposure (5 and 6 months). A diiM- response relation was suggested in produitiioi >: alveologenic tumor. Discussion E\;h-! imental studies (10*17) on the oncogenicity of vinyl chloride have revealed that the monomer can induce various neoplasms including hepatic humancl'>sarcoma (rat, mice, hamsters), Zymbal pland carcinoma in the external auditory meatus tratsi. breast cancer (mice), nephroblastoma (rats), "lunp adenoma" (mice), skin trichoepithelioma (ham* sters. ly mphoma (hamsters) and forestomach pap illoma ' hamsters). Evidence of the pulmonary on cogenicity of vinyl chloride in animals has been obtained.' Viola et al. (16, 17) have reported that October 1981 rats exposed to vinyl chloride exhibited lung cancer (32St). Histological features of the cancers were stated to be those of adenocarcinoma, with the exception of a single epidermoid tumor. Maltoni and Lefemine (16,11), however, reviewed the histo logical slides of Viola et al. and stated that the lung cancers reported by the latter were not primary tumors of the lungs, but metastatic cancers from Zymbal glands. Maltoni and Lefemine (16,11) also have reported on the pulmonary oncogenicity of vinyl chloride on the basis of their own data. Though they could not find bronchogenic carcinoma in rats, rare pulmonary hemangiosarcomas and fibrosarcomas were induced in these animals. Unlike the case in rats, pulmonary tumors ("adenomas") were found in mice (89 of 471). Maltoni and Lefemine (16,11) noted that some of the adenomas underwent malig nant transformation. Keplinger and associates (11) have found "alveologenic adenomas" in the lungs of mice exposed to vinyl chloride (44 of 49). Lee and associates (12) have stated that "bronchiolar ade- 43 ucc 057095 Figure 20, Part of the cytoplasm of a Clara call. Varioui profile* of the endoplasmic reticulum are aeen. Group 1:2900 ppm; 21,000 x. Figure 21. Imgular shaped mitochondria with cristM in it cytoplasm of a Clara call. Group 1:6000 ppm; 0?04; 12.600 noma" developed in mice 2 months after exposure to vinyl chloride at 50-1000 ppm. Holmberg and associates (10) found "alveologenic adenoma" in 13 of 24 mice exposed to vinyl chloride at 50 ppm for 24-52 weeks. Our present study has also confirmed that pulmonary tumors are induced by vinyl chlo ride of both the large doses (2,500 and 6,000 ppm) with long exposure (5 and 6 months) and the smaller doses (1,10 and 100 ppm) with a short exposure (4 weeks). Based on all the data available, it can be con cluded that mouse lung is an extremely sensitive organ for demonstrating the oncogenicity of vinyl chloride. Gross anatomical and histological aspects of the tumors in our investigation corresponded to the "alveologenic tumor or cancer" of Steward et al. (22-21). The alveologenic tumor has been induced by various carcinogens (22-28), such as polycyclic hydrocarbons, urethane, nitrogen mustard, methylcholanthrene, and nitrofiir derivatives and is known 44 to occur spontaneously with aging (6,29,50). Tfc cancer induced has been distinguished from tk occurring spontaneously by multiple primary fob. occasional formation of huge tumors, and occur rence without any relation to aging. It is also knott that in certain strains, such as A and DD, spout* neous tumors are quite common after 10 to 11 months ofage. Spontaneous pulmonary tumors coulc be excluded in our experimental animals; in addi tion to the above-mentioned points, neoplastic change in the lungs were absent in the controls. Electron microscopically, alveolar epithelium, par ticularly the type II cell, was assumed to be tb precursor of vinyl chloride-induced tumor in tb mouse lung. This assumption was derived n ultrastructural similarities between the normal tvp II cell and the neoplastic cell. Similar suggestion have been made by other investigators (21,28, Ji after studying pulmonary tumors induced by agent other than vinyl chloride. Environmental Health Perspective It was ;'irmatio Mi-uplast: the leve. mtermet; alveolar the linin type II imermet type II c process, patholog MR of th Kmbryol ~ame orij in-oplasti ated, we ture alv< these pe: at ion obt < >ctober UCC 057096 y 'v X' V N * *, V1' 5^ V rn tht 4, /OO. F wi'M 22. Two dUatcd call* of * terminal bronchiole. Irregular thaped mitochondria, a well developed Golgi area, round denie granule* and phagolyiome* are thown. Group I: 6000 ppm: 0a04; 9800 x. JO). The | rom the iary fod id occursoknovm , sponta10 to 12! ors could j in addif c changes > nun, par j o be the t in tht ed from mal type gestionf 28,31 j ,y agent.' j pecthe j h war noteworthy that the processes of trans formation of the normal alveolar epithelium into the m-nplastu cell could be followed morphologically on the level of ultrastructure; the appearance of an intermedia? form between type I and II cells in the aheular lining, the disappearance of type II cell in the lining due to replacement by the hyperplastic tyi* II cells, which were transformed from the intermediate form, and the neoplastic change of the type II colls were assumed to be a sequence of the process. The intermediate form appears in certain piitholopeal conditions, prior to cuboidal metapla- of the attenuated alveolar epithelium (15, 32). Embryo! pcally, both type I and II cells are of the same on^n. the entodermal epithelum. Some ofthe neoplasm cells, distinguished as poorly differenti ated. were similar in ultrastructure to the imma ture alveolar epithelium of fetal lung (15). From these [vmpectives, the process of neoplastic alter ation oi.erved in the epithelium may be interpre- October 1981 ted as a retrograde process of the normal differen tiations of the alveolar epithelium. Kaufman et al. (33) have reported that Clara cells of the mouse bronchioles developed into neoplasms which could occur in a malignant form, after transplacental ex posure to ethylnitrosurea. However, such a Clara cell tumor was not produced in our material. Waxweiler and associates reported an increased number of deaths due to lung cancer among vinyl chloride workers (9). They observed 12 cases com pered to the 7.7 cases expected. Eight of the twelve were examined histologically and were classified as undifferentiated large-cell carcinoma (five eases) and adenocarcinoma (three cases). Since these human lung cancers are of bronchogenic origin, it may be that target pulmonary cells in vinyl chloride carci nogenesis are different in human and mouse lung. Neoplastic invasion and metastases were not found in our material. However, it is known that some times both induced and spontaneous alveologenic 45 VJCC 057097 Figure 23. AlveoUr macrophage including phagolysosomes and otmiophiUc lamellar bodies. Group 1:2500 ppm; 0a04; 5800 x. tumors (22, Si-87) of mice show such changes and that the malignant transformation occurs with some delay after initiation of the tumor. In addition, transplantation of this tumor has been accomplished (23). Steward and associates (22-2i) therefore dubbed it an "alveologenic tumor" or "alveologenic cancer." Maltoni and Lafemine (13,li) have found that some vinyl chloride-induced pulmonary tumors undergo transformation, although we did not observe this in our materials. Alveologenic tumors may be considered unique in some ways, since it is possible to observe the pro cess of malignant transformation sequentially from the precursor to the malignant cell via hyperplastic and benign neoplastic states. Hepatic hemangiosarcoma is recognized as a char acteristic malignant tumor related to vinyl chloride exposure. The tumor can be induced in a variety of 46 experimental animals (mice, rats, and hamster?! (lS,li), and histological features of the tumor tit almost identical in humans and animals. In con trast, the intrapulmonary target cells of vinyl chlo ride oncogenesis may be different in humans and mice. Beyond these differences, moreover, the in duction of alveologenic tumors in mice by vinyl chloride may be predictive or a risk of human bronchogenic cancer from the chemical. Consistent with this is the fact that various carcinogens, such as polycyclic aromatic hydrocarbons, nitrogen mus tard and chromate compounds, are known to induct alveologenic tumors in mice, on one hand, and, on the other, to be associated with excess bronchogenic carcinoma among workers exposed to the carcino gens (id). It is noteworthy that a similar relation has been suggested for vinyl chloride. Nonneoplastic pulmonary effects of vinyl chloride Environmental Health Perspective* October UCC 051098 1 K 9i* 7 Ficuar 24. Put of a macrophifft. Two dwlwtiwl cryeUBoida art abown. Group III: 2500 pp; 0e0; 27,000 x. maters) Tior are In con* vl chlo* ms and the in** vinyl human sistent s, such i muainduce nd, on ogenic ircinolation ioride Ftouaz 28. Thickened basement membrane of an alveolar capillary. Group 1:4000 ppm; 0*O4; 15,000 *. October 1981 47 ucc 057099 iY * := .. ** ' :"V - .. ... .t "' > <0 ^ '<TV>`- W ' - ' V'J ^ . Figum 26. Cell debris of dtftnerated alveolar septal cells (arrow*) and flbrillar appearance ofa basement membrane (with an arrow) are illustrated. Group 1: 6000 ppm; OaO; 10,300 *. have been suggested by observations among work* er* in vinyl chloride polymerization plants. This suggestion was based on data obtained by chest x-ray examinations, pulmonary function tests, and sputum cytology studies among workers. Lilia and her associates (18) have found radiologic pulmonary changes, such as linear, reticular, and nodular opac ities, in the lower and mid lung fields in a propor tion of cases. They found that the prevalence of pulmonary changes increased with longer duration ofexposure and that there was a significant associa tion with peripheral circulatory abnormalities. How ever, pathological evaluation of these changes was not available. Miller et al. (19) have examined pul monary function of 343 workers in a vinyl chloride polymerization plant. The major finding was dimi nution of air flow in 200 workers (57.7%). Again, no physicopathological relations were established. Maltoni and Lefemine (14) reported cytological studies of sputum in vinyl chloride and poly(vinyl 48 chloride) workers. They found a significant increase in cellular changes of the bronchial epithelium; squa mous metaplasia and squamous dysplasia were com mon among workers heavily exposed to vinyl chlo ride monomer. Recently, McNamara and McLaughlin (39) have confirmed that a single 1-hr exposure to vinyl chlo ride in doses of 500 ppm or more induced pneumonitis in ICR mice and that aggravation of latent pulmo nary changes, particularly bronchopneumonia, oc curred in Fischer 344 rats. Our present (40) study has shown that CD1 Charles River male mice exposed to vinyl chloride at a heavy dose (2500 and 6000 ppm), over relatively long term (5 and 6 months), obviously showed bronchiolo-alveolar changes. These alterations wen recognized in almost all of the treated animals regardless of difference in doses (2500 and 6000 ppm), duration of exposure (5 and 6 months) and recovery time (2, 6 and 37 days). Environmental Health Perspectives Octot ucc 051100 Figure 27. Luge Buetcua in the lvolar capflhry cndothcltura. Group U: 2S00 ppm; 004; 7900x. icrease i; squa re comA chlo- ') have '] chlononius julmoia, oc- haries at a tively lowed were limaJs 6000 ) and The tyi^es of pulmonary cells which were involved in the structural alterations varied. It was interest* inp that the ultrastructural changes seen in Clara cells and to some extent in the ciliated cells were similar to those of hepatic cells of animals exposed to vinyl chloride; cellular hypertrophy and prolifer ation of the endoplasmic reticulum were common responses, seen in both the bronchiolar epithelium and the hepatic cells. Hie endoplasmic reticulum of the hepatic cells has been suggested as the site where vinyl chloride is metabolized, to be trans formed into a chemically reactive metabolite which is the Ultimate carcinogen (36, 41-45). Although it has not been shown that lung has the capacity to metabolize the chemical to produce the carcinogen; if it were so, the bronchiolar cells, particularly Clara evils, may provide this mechanism: the cells are normally equipped with well-developed smoothsurfaced endoplasmic reticula and the organelles have shown a proliferative response after mice are exposed to vinyl chloride. The fact (46) that vinyl chloride has a tendency to October 1981 be soluble in lipid substances suggests that lipidrich pulmonary cells, such as type II cells (rich in osmiophiHc lamellar bodies) and alveolar septal cells (containing lipid granules) may bind to vinyl chlo ride. If this assumption is correct, at leaat some of ultrastructural alterations seen in those cells might result from this mechanism. Both type II cells and Clara cells have been known as surfactant factorproducing cells (4 7). Hyperproduction of the surfac tant factor was suggested, since hyperplasia of those cells was commonly seen in our material. Osmiophilic lamellar bodies and cholesterol crystal loids, which were seen in alveolar macrophages, may represent lipid substances bound to vinyl chlo ride. They may be removed from lung as part of the clearance mechanism for vinyl chloride. It is well accepted that mesenchymal elements such as bone, connective tissue, and blood vessels are involved in responses to vinyl chloride in various organs (36, 48-50). Above all, malignant transformation of the blood capillary endothelium, induction of hemangio endothelioma in liver, and the subcutaneous con- 49 UCC 057101 A 5 6 S 9 10 II Figure 28. Degenerative alteration* of the alveolar septal cell* (arrows) and a hypertrophic septal cell (h with an arrow). Group I; 6000 ppm; OaO; 6300 x. 12 K 14 if) Ifi IT It! nective tissue, lung, and adipose tissue have been well documented (10,13, U, Sti lt is reasonable to assume that the alveolar capil lary endothelium and the septal cell suffered toxic effects by vinyl chloride, since these cells are part of the mesenchymal elements in lung, sites of up take and excretion of the chemical and its metabo lites (52, S3), A dose-response relationship has been suggested in the production of alveolongenic tumors by vinyl chloride. The same relationship has been seen in occurrence of alveolitis (mouse) and bronchopneu monia (rats) with the chemical (39). A delayed appearance of these inflammatory changes after periods of recovery, following exposure to the chem ical, has been postulated. A threshold dose for the induction of the nonneoplastic pulmonary lesions which are reported here has not been established. 50 This work was supported by Reseirch Grant OH-00681 ft* the National Institute for Occupational Safety and Health, t'-5 Department of Health, Education and Welfare. REFERENCES 1. Block, J. B. Angioearcoma of the liver followinf vmy: chloride exposure. J. Amer. Mad. Asa. 229: 53-54 (1ST4> 2. Creech, J. L., Jr., and Johnion, M. N. Anpossrcona & liver in the manufacture of polyvinyl chloride. J. Ocmp Mad. 16: ISO-151 (1974). 3. Falk, H., Creech,J.L., Heath, C.W.,Jr., Johnson, M.N and Key M. M. Hepatic dieeaae among worker* at a chloride polymerization plant. J. Am. Med. Assoc. Of SMS (1974). . 4. Lange, C. E,, Jflhe, S,, and Vehraan. G. Uber 4* Anftietan von Angkweikoman der Leber von nv Artntat der FVC-haretellender Industrie. Deut. Med. Wochemdf 31:1598-1S99 (1974). Environmental Health Perspective IS). 22 "4 Octo UCC 057102 I en Te 581 tram th. U.S. g vinyl 1974). om* of Occup r-- . i_ f i jnd Harry D. S. Angioaarcom*ofth* liverin thlonrfe worker. Lancet i: 1316-1819 (1974). NVhulvr.. w. J., Hammond, E. C., Seidman, H., end ^hk-.T 1 J Mortality experience of a cohort of vinyl d-jundr vorker*. Ann. N. Y. Acad. Sd. 246: 225-230 UkT'i' : TWni.- L B.. Popper, H., Berk, P. D.t Selikoff, I. J., and Falk H \ mvl chloride-induced liver diaeaae. N. Engl. J. i 17-22(1975). . Th*r-hi L. R., and Galley, W. R. Mortality atudy of morkt-r- it the manufacture of vinyl chloride and ita pulvmer ' Occup. Med. 16: 509518 (1974). j. R.J., Stringer, W.,Jonea,J., Wagoner, J. K., Falk. H . and Carter, C. Neoplaatic riak among worker* - vinyl chloride. Ann. N.Y. Acad. Sd. 271:39-48 H'.ltn)- --' B.. Tronevi, T., and Winell, M. The pathology of \ir\: , Monde expoeed mice. Acta Vet. Scand. 17: SjNWi 1976). U Krplir.ftr. M. L., Goode, J. W., Gordon, D. E,, and (alandr. J. C. Interim reaulta of expoaure of rata, ham*',t-r- ,,nd mice to vinyl chloride. Ann. N.Y. Acad. Sd. 24*1 219 22" (1975). 12 l*r. c f , Bhandtri, J. C., Hauae, W. B., Wood*, J. B., and liiv t. R. L. Inhalation toxidty of vinyl chloride (VC) or vir.;. chloride (VDC) in rata and mice. Pharmacolo- p-: 1- 24'. .1976). i t Malior.i. i . and Lefemine, G. Cerdnogenicrty bioaaaaya of vinyl vli'.rnle. current reaulta. Ann. N. Y. Acad. Sd. 246: 19V21- i'*75). * 14 Mal'.'.r.:. ( , and Lefemine, G. Cardnogenkity bioaaaaya of \mviu.: .-k1. I. Research plan and early reauha. Environ. Kt - 7 f 7-405 (1974). r> Suzuki. ) Pulmonary tumor* induced in mice by vinyl chl'.ri.l. r.'.nomer. Environ. Re*. 16: 285-301 (1978). !; Viola, r I.. Carcinogenic effect* of vinyl chloride. Ab stract- l".h International Cancer Conference, Houaton, Tttxif. ll'TU. 17 Viola. I* L., Bigotti, A., and Caputo, A. Oncogenic rt-.-poi,'. of ret akin, lung* and bone* to vinyl chloride, fanc-r fl*.*. 31: 516-522 (1971). Is. Lili*. K . Anderaon, H., Nicholaon. W. J., Daum, S., FiKhl,,-:' . A. S.. and Selikoff, I. J. Prevalence of diaeaae among. ,r.yl chloride and polyvinyl chloride worker*. Arm. N V A;ad. Sd. 246: 2244 (1976). 19 MilU-r, A . Teimein, A. S., Chuang, M., Selikoff, 1.}., and War..h.,u. R. Change* in pulmonary Amotion in worker* to vinyl chloride and polyvinyl chloride. Ann. N Y. Avad. Sd. 246: 42-62 (1975). &i. BuflVr. a.. Wood, S-, Eiller, C., Suarea, L., andKihan, D. J. M'-rality experience of worker* in a vinyl chloride monoru r production plant- J. Occup. Med. 21: 196-202 (1979i 21. Svotx-li. D. J. Uhraatructur* of pulmonary adenoma k> mice Cancer Rea. 22:1197-1201 (1962). -- Stew-:. H. L, Dunn,T. B., and Snell, K. C. Pathology of tum"r- and non-neoplaatic proliferative ledon* of the lungi of mice. In: Morphology of Experimentel Reapiratory Carni. -ecneai* (P.N. Netteaheim, M. G. Hanna, and J. W. Oeutr.vrage, Ed*., Atomic Energy Commiaaion Sympo- aiuir. -~n**, No. 21, Oak Ridge, Tenn., 1970, pp. 161-168. Stev nr., H. L. Pulmonary tumor* in mice. In: Phyaiopath- ology of Cancer, F. Homburger and W. Fiahman, Ed*., Hia-U r and Harper. New York, 2nd ed., 1959, pp. 1847. -4. Steuin. H. L., Grady, H. G., and Andenont, H. B. Dei ri- -pment of larcom* at aite of aerial tranaplantation of puln nary tumor* in inbred mice. J. Natl. Cancer Inat. 7: 207-225 (1974). October 1981 25. Heaton, W. E. Induction of pulmonary tumor* in attain A mice with methylbi*(6-eUoroethyl) amide hydrochloride. J. Natl. Cancar Inat. 10:125-130 (1949). 26. Heiton, W. E. Carcinogenic action ofthe muatarda. Cancer Rea. 10:224 (1950). 27- Laraon, C. D. Pulmonary tumor induction with alkylated urethnne*. 3. Natl. Cancer Inat. 9:35-37 (1949). 28. Mafauaki. 0. Hiatogencaia and growing pattern* of lung tumors induced by potaaaium l-methyl-l,4-dihydro-7-{2- (5-nitroAiryl)vinylH-oxo-l ,8-naphthyridin*-9cart>oxyUt* in ICR mice. Germ 66:269-267 (1975). 29. Gardner, M. B., Henderaon, B. E., Rongey, R. W., Eatea, 3. D., and Huetaer, R. J. Spontaneoua tumor* of aging wild houae mice. Incidence, pathology and C-type virui expraaaiona. J. Natl. Cancer Inat. 60: 719-784 (1973). 30. Rabctein, L. S., Peter*, R. L., and Spahn, G. J. Spontane oua turnon and pathologic ieakn* in SNRtf mice. J. NatL Cancer Inat 60:781-768 (1972). 81. Brook*. R. E. UKraetrueturt of mouie puhnonary adeno ma*. In: Morphology at Experimental Reapiratory Caranoganaaia, (P. N. Netteaheim, M. G. Hanna, and 3. W. Deatharage, Ed*. Atomic Energy Commiaakn Sympoeium Seriea, No. 21, Oak Ridge, Term., 1970, pp. 185-202. 32. Madrazo. A., Suzuki, Y., and Churg, 3. Radiation pneumanttia: UhzaatructunJ change* in th* pulmo nary alveoli following high do*** of radiation. Arch. Pathol. 96: 282-288 (1972). 33. Kauffman, S. L., Alexander, L., and Seat, L. Hiatologie and uhraatructiiral faature* of the Clara cell adenoma at the mouae lung. Lab. Inveat. 40:706-716 (1979). 34. Amaral-Mendea, J. J. Hiatopethology of primary hing turnon in th* mouae. J. PathoL 97:415427 (1968). 36. Matauyama, M., Susuld, H., and Nakamura, T. Careinogeneii* in dd/1 mk* injected during ruckling period with urethane, nitrogen muatard N-oxide and nttroaourethane. Brit. J. Cancer 22:167-171 (1969). 36. Schaffoer, F. Effect of long term vinyl chloride expoaure in mouae liver atructure. In: Primary Liver Tumour*, H Rammer, Ed., MTP Praaa Limited, Falcon Houae, Laneaater. England-1978. pp. 189199. 37. Well*, H. G., Sfye, M., and Hobnea, H. F. 17m occurrence and pathology of apontaneoua carcinoma of the hint mice. Cancer Ret. 1; 259281 (1941). 38. Hifginaoo, J. The rale of the pethologiat in environmental medicine and public health. A review. Am. J. Pathol. 86: 469484(1977). 89. McNamara, B. P. Pereonal communication 40. Suzuki. Y. Nonneoplaatic effect* ofvinyl chloride in mouae hing. Environ. Rea. 21:235-253 (i960). 41. Antweiler, H. Studie* an the metaboUam of vinyl chloride. Environ. Health Perapact. 17:217-219 (1976). 42. Barlach, H., MalaveiU*, C., BarWn, A., BreaQ, H., Toma- tit, L., and Montesano. R. Mutagenicity and metaboliam of vinyl chloride and chloride and related compound*. Envi ron. Health Perapact. 17:199196 (1976). 43. Boh, H. M., Kappua. H., Butchter, A., and Bolt, W. Diapoaitian of 1,2-C-vinyl chloride in the rut Arch. Toxicol 35:159188 (1976). 44. Bolt, H. M., L*ib, R. J., Kappua, H., and Buchter, A. Pharmacokinetic* of vinyl chloride in th* rat. Toxicology 7: 179188 (19TT). 45. Rammer, H. Mrtaboliim ofcarcinogen*: it* tigniftcanc* for the initiation of liver turnon. In: Primary Liver Tumour*, H. Remmer, Ed., MTP Praaa, Falcon Houae, Laneaater, England, 1978. 46. Wolff, M. S. Evidence for exiatenc* in human tiiau** of monomen for plattic* and rubber manufacture. Environ. Health Penpect. 17:189187 (1976). 51 ucc 057103 k 47. Smith, P., Heath, D,, and Mooaavi. H. The Clare cell. Thorax 29147-168 (1974). 48. Cook, W, A., Giever, P. 14., Dinmen, B. D., and Magnuaon, H. J. Occupational acro-osteolyiia 11: An indiutrial hygiene study. Arch. Environ. Health 22; 74*2 (1971). 49. Popper, H., and Thomaa, L. B. Altaratione on hver and apleen among workers expoeed to vinyl chloride. Ann. N.Y. Acad. Sri. 246:172-194 (1976). 50. Vettman, G., Lange, C. E,, Jobe, S-, Stein, G., and Bachner, U. Clinical manifestation and course of vuni chloride diaeaae. Toxidty of vinyl ehloride-polwinyl chii. ride. Ann. N.Y. Acad. Sri. 246:6-21 (1975) * 61. Watanabe, P. G., McGowan, G. R., Madrid. E. 0., tad Gehring, P. J. Fate of f14C] vinyl chloride fallovta inhalation exposure in tat*. Toxicol AppL PharmacoL r 49-69 (1976). 62. Watanabe, P. G,, and Gehring, P. J. Doee-dependent Ms of vinyl chloride and its possible relation to onrogenidtr z rata. Environ. Health Perspect. 17:145-162 (1976). E o b' B 4> Inti St occu; shov, crea.pentrisk > yeantop- perio than contr -Div fa-:itu 'H :Div pi-in 52 Environmental Health Perspective* Octob ucc 057104 I Jf*e of vjuy lyvinyl ctijt E nd 1* foUowu* xrmacol. j; pendent fiu **moty I 976), Envirmnuntal Htalth Ptrtptctivtt Vol. U, pp, US7, mi Effects of Aging on the Induction of Angiosarcoma by David H. Groth,* William B. Coate,* Borge M. Ulland* and Richard W. Hornung* Adult, Spra(M*I>iwlc7 albino rat* of four different apt (, 18, 32 and 52 week*) wrc expoeed to 940 ppm vinyl chloride by Inhalation for 21 week*. 5 4ay*/w**k. 7 hr/day. In each aft troop, (here were 110 to 128 mala* and the um number of female*. Hie ilmilarly houeed control troop, which wa* not expoeed to vinyl chloride, eomioted of the *am* number of male* and female* in each *f* troup. All animal* that died spontancouely, or were tacrificed moribund, or were killed *t tcheduled time* (3, 6 and 9 month* after initial esporarc) were autopeled. AU ortana won examined (roetly, and eeveral tiuue* from each animal were examined microacopicaHy. The older the rat* were when they were first expoaed, the treater the incidence of ntiourcoma*. Tlwincidenc** of anfiocarcoma* in the four ate troupe (from younteot to oldeet) in the expoaed male* In the nomeheduled *acrifle* troup* were: 0/37 (0%); 0/44 (Oft); 3/43 16.7ft); and 13/53 (24ft). Similarly, for the female*, the** incidence* were: 2/38 (5.3ft); 7/47 (15ft); 23/49 (47ft); and 11/54 (20ft). Mo*t of the an|io*arcoma* were hifhly anaplaatic, primary tumor* in the liver* that metaataaixod to the lunf*. Only one anfioearcoma wa* men in all the control rata; that occurred In cubcutaneou* tia*ue. Thi* ctudy demomtrated that older adult animal* and female* are more cuaeeptible to the antiocarcoma-inducint effect* of vinyl chloride than yount adult animal* and male*, rripecthrely. Introduction Several epidemiological ttudiet performed on occupational group* exposed to carcinogens have shown greater increased risks of cancer with in creasing exposure durations. In addition, latent periods (time between initial exposure and increased risk of cancer) in these groups are commonly 10-30 yean. These findings have been commonly attributed to greater total doses in those exposed for longer periods of time. However, there is one factor other than the total dose which could be responsible for contributing to the increased risk. That factor is Divisor, of Biomedical and Behavioral Science, National Institute f'T Occupational Safety and Health- 'HuIh ., Uboratorie* of America, Vienna, Virginia 22180. :DivL*if<r, of Technical Service*, National Inatituta for Occu pation*) cafety and Health. aging. It is equally reasonable to postulate that older adults are more susceptible to the carcino genic effect of some chemicals than young adults. That is, for the same dose of carcinogen, the incidence of cancer might be higher and the latent period shorter in older adults than in younger adults. It has been suggested that only older people should work in carcinogenic environments, since the commonly observed latent periods for cancer induction would exceed their life expectancies. If, however, the latent periods were shorter in older individuals, that approach would be counterproduc tive. The purpose of this study was to determine whether or not older adult rata were more or less susceptible to the angiosarcoma-inducing effects of vinyl chloride than young adult rats. This experi ment was not designed to test the susceptibility of sexually immature animals or to determine the lifetime effect of relatively short-term exposures. TVCf October 1981 53 ucc Materials and Methods A total of 473 male and 478 female SpragueDawley rats were exposed to 948 ppm of vinyl chloride monomer in a single 14 x 13 x 10 ft stainless steel walk-in chamber with a diffusionscreen false ceiling. Exposures were for 7 hr/day, 5 days/week for a mean duration of 24.5 weeks. An equal number of control male and female rats, kept in a similar exposure chamber, were exposed to conditioned outside air only. Air flow into the chambers was maintained at 300 ft'/min. Air tempera tures were kept at 75 3*F. The concentration of vinyl chloride in the chambers was initially moni tored by gas chromatography and later with an ultraviolet photoionization analyzer, 7 times/day on each day of exposure. The animals were individually housed in sus pended stainless steel wire-mesh cages equipped with automatic watering taps. Water was provided ad libitum, but food (Wayne Lab Blox) was re moved during exposures. Four differently aged sets of rats of both sexes were used in both the exposed and control group: Their ages at initiation of exposure were 6,17-)j 32-33 and 51-53 weeks. The numbers in each gme and their disposition appear in Tables 1 and 2. Because of the large number of animals, it unot practical to start exposures on all rats aimulfc neously. Consequently, the controls and expose rats were divided into five squads, with proportioc- ate representation of each age group and sex c each squad. Rats in each squad were assigned i the chambers over a 2-week period. Assignment;c: all rats to the chambers were completed throughoc a 10-week period. The original plan was to expose the rati for months, but because of an epidemic of pneutnom among the exposed animals during the 28th wed the exposures were terminated 29 weeks ifc initiating exposures. As the results will show, tte exposure period was adequate to demonstrate th differences in effects between groups. The experiment consisted of two subsets. An nuls scheduled for sacrifice at 3, 6 and 9 monk constituted one subset, and animals that died c Group 2 2 4 4 6 6 8 8 Totals f^le 1. Number and disposition of rati exposed to rinyl chloride. Aft at first Mean body exposure, weights st first weeks exposure, g 6 6 17.18 17-16 32-33 32-33 61-58 51-63 228 187 541 304 888 860 738 >75 Sex 11 F M F M F M F N F Initial number of rata 110 110 119 120 118 120 128 128 472 478 Number of deaths and moribund sacrificed 36 16 39 38 48 45 fiO 62 178 148 Number at final aocrificed 6 23 13 16 4 6 0 6 23 51 Number sacrificed at 8, 6 and 9 months 66 70 67 TO 68 69 67 TO 269 279 Tsui number of ntf utopuri 106 109 119 119 116 120 127 128 470 476 Group 1 1 8 3 5 6 7 7 Totals Table 2. Number and disposition of control rats. Ago at first Mean body xpoouru, weights at firm weeks exposure, g 8 8 17.18 17.18 32-38 32-88 51-58 51-63 280 172 550 304 701 358 772 385 Sex M F M F M F M F M F Initial number of rats no 110 118 120 115 120 128 127 472 477 Number of deaths and moribund sacrificed 9 6 11 9 12 10 28 27 56 52 Number at final Mcrificed 8 28 18 16 4 6 0 6 28 61 Numfaar aocrificed at 8, 6 and 9 months 80 71 TO TO TO 69 TO 69 279 279 Total number of nu autoped 84 100 94 96 86 IB 102 367 382 a t-re sac: sacrifice these tw referred latter as: the rats i remaining autopsied bi-can an number t the final r in each ol At the h anim analyses, r-unma gh ami y-glut At the a ai.'l secti' ai! renal, t: or uterus, lungs, tra lymph noi ai.y abnor neutral b JVaplast, lit. and et hologis Results N<> clini ern-e* in m me;iurem< cun' rol gro n; i rim sat The mos b'th <exes< pituitary a f*<n; rol gro tumors. A: 'if.JUp 2 2 4 4 0 $ ft s 54 Environmental Health Perspecthe October 19fr UCC 057106 al groups. i '-18, ich group Jid2. is, it was ; simulta- exposed oportiond sex in igned to -meats of oughout for 12 leumonia th week, a after ow, that rate the +.s. Animonths died or tel iber it -r ' e 9 9 9 3 )f i i w * ed were sacrificed moribund or were killed at the final sacrifice constituted the other subset. To keep these two subsets separate, the former will be referred to as the interim sacrifice group and the latter as the nonscheduled sacrifice group. When all the rats in one of the exposed groups had died, the remaining rats in all the other exposed groups were autopsied. This occurred 43 weeks after exposures began and is referred to as the final sacrifice. The number of control rats in each group autopsied at the final sacrifice were equal in number to the rats in each of their respective exposed groups. At the interim sacrifices, blood was taken from each animal for hematological and clinical chemistry analyses, including measurements for albumin, gamma globulin, alkaline phoephataae, SGOT, SGPT, and yglutamyl transpeptidase. At the autopsies all tissues were examined grossly and sections of liver, kidney, pancreas, spleen, adrenal, thyroid, pituitary, brain, gonads, prostate or uterus, urinary bladder, skin, sternum, paws, lungs, tracheobronchial lymph nodes, mesenteric lymph nodes, salivary gland, zymbal glands and any abnormal tissues from jepch rat were fixed in neutral buffered 10% formalin, embedded in Paraplu>t, slide-mounted, stained with hematoxy lin and eosin and examined microscopically by a pathologist. Results No clinically or statistically significant differ ences in mean hematological and clinical chemistry measurements were detected between exposed and control groups of the same age and sex at any ofthe interim sacrifices. The most frequently occurring tumor types in both sexes ofexposed rats were liver angiosarcomas, pituitary adenomas and mammary tumors; in the control groups, pituitary adenomas and mammary tumors. A few rats in both the exposed and control groups were found to have zymbal gland tumors or brain tumors. Although four angiosarcomas oc curred in mesenteric lymph nodes and one in the mediastinum in exposed rats, these were not con sidered to be induced by vinyl chloride since one nonhepatic angiosarcoma (subcutaneous) was also seen in control rata in this experiment and have been seen in control rats in other experiments in a low incidence (< 1%). However, one early angio sarcoma of the spleen and two metastatic angio sarcomas in the lungs (one from a primary in the mesentery) were seen in exposed rats. These were considered to be induced by vinyl chloride and are included in the angiosarcoma statistics. Since the first liver angiosarcoma did not occur until the 16th week ofthe study, only those animals alive at that time were considered to be at risk for the development of angiosarcomas. Those are the animals used in the incidence statistics. A total of 28 out of 370 males and 50 out of 387 females in all exposed groups combined were found to have angiosarcomas. Only one angiosarcoma was seen in all the controls (group 5, mile) and it was subcutaneous. The greatest percentage of angio sarcomas were found by far in the nonscheduled sacrifice groups. The exposure times, mean sur vival times, number of animals at risk, incidence of angiosarcomas and the week that the first angio sarcoma was diagnosed for each age group of males in the nonscheduled sacrifice groups are tabulated (Table 3). Although no angiosarcomas were ob served in the two youngest age groups, they were seen in 3/45 (6.7%) of the rats in group 6 and 13/55 (24%) of the rats in group 8. The first angiosarcoma occurred 7 weeks earlier in group 8 than in group 6. Histologically, the angiosarcomas were highly ana plastic and most of them had metastasized. Similar data concerning the female rats in the nonscheduled sacrifice groups are also tabulated (Table 3). Angiosarcomas were seen in all groups with increasing frequency from group 2 (youngest) Group 2 2 4 4 6 6 6 8 Table 3. Angfoearaomaa ia sxpnssS male and female rata in nonscheduled sacrifice mate. Firat Man exposure, Men survival, Rats appearance of Angiosarcoma Incidence of angiosarcomas, Sea weeks weeks at risk incidence meustasas weeks M 24.5 30.6 87 0/37 F 24.6 37.5 38 2/38 (5.3%) 2/2 80 M 24.4 31.6 44 0/44 F 24.7 38.8 47 7/47 (15%) 5/7 28 M 25.0 >0.5 46 3/45 (6.7%) 8It 38 F 24.0 80.0 49 23/49 (47%) 1023 20 M 24.5 28.9 55 13/55 (24%) 11/13 21 F 23.9 30.2 54 11/54 (20%) 6/11 18 October 1981 5$ ucc 057107 -si * v ft V ? 5 ,5 S '3 3 to group 6. The incidence in group 8, however, is lower than in group 6 and closer to that in group 4. The first angiosarcoma, however, was seen in group 8, the oldest group. In comparing the males and females, it can be seen in Table 3 that the first angiosarcoma ap peared earlier in the females in each group and that the incidence was higher in females for each age group, with the exception of group 8, the oldest age category. Since the mean survival times and expo sure durations for males and females in groups 4 and 6 were similar, the differences in incidence can be attributed to sex. The incidences of angiosarcomas in the interim sacrifice, nonscheduled sacrifice and combined groups appear in Table 4. The females sacrificed at 6 and 9 months had a much lower incidence ofangiosarcomas than those in the nonscheduled sacrifice groups, whereas, the difference in incidence between sim ilar groups of males was not as great. The incidences of angiosarcomas in the different age groups were compared using Fisher's exact test. Because of multiple comparisons, the a-level for each individuaf comparison needed to be sO.Ol for the incidences to be significantly different with an overall a - 0.06. In the nonscheduled sacrifice groups, the incidence of angiosarcomas in group 8 males was significantly different from those inci dences in group 4 and group 2 males; the incidence ofangiosarcomas in group 6 females was significantly different from those in group 4, group 2 and group 8 females. The same comparisons between the same groups in the combined nonscheduled and interim sacrifice groups were also found to be significant. The effect of age on angiosarcoma incidence in males was examined using the method of weighted least squares regression. A quadratic equation was shown to be a good model for predicting angiosarcoma incidence as a function ofage in weeks. The percent of variability in incidence rates (A*) explained by this model was: A* 99.96% for nonscheduled sacrifice groups and A* 99.85% for combined nonscheduled and interim sacrifice groups (Fig. i, Both of these models were statistically aigtiift^ (p 0.02 and p 0.001, respectively). --- The fact that most of the angiosarcomas in th females occurred in the animals that died sponte* lm' ously suggested that their deaths might be dimth * related to the angiosarcomas. A comparison i mean survival times, however, revealed that ini. mala with angiosarcomas survived as long ml frequently longer than other animals in their it spective groups (Table 6). At 4-week intervals, tfc accumulative incidence of angiosarcomas was tabu lated (Table 6) for exposed females. Although tlx incidence ofangiosarcomas at all intervals in group 2 and 6 is about the same, in group 8 the incident: decreases with time, and in group 4 it increase with time. Although a few brain tumors, mammary adeno carcinomas and zymbal gland tumors occurred exposed animals, their incidences did not appear to be significantly different from those of the controls. interim sacrifices and Anal sacrifice). Curve fitted by regno (ion mcthoda ohowrng a significant quadratic fit. R: - 99.854. Table 4. Incidence of encioiarcomae in txpoaad raU. nonacheduled (N8), interim aacriflee (IS) and combined sroupa. Group Sax NS Combined IS NS + IS 2 M 0/87 1/46 (2.2%) 1/88 (1.2%) 2 F 2/88 (6.3%) 0/50 2/88 (2.8%) 4 M 0/44 2/47 (4.3%) 201 (2.2%) 4F 7/47 (16%) 0/50 707 (7.2%) 6 M 3/46 (6.7%) 4/49 (8.2%) 704 (7.4%) 6 F 23/49 (47%) 4/49 (8.2%) 2708 (28%) 8 M 13/55 (24%) 5/47 (11%) 18/102 (18%) 8 F 11/54 (20%) 3/50 (6%) 14/104 (13%) 56 Table 5. Mean aurrtvml of exposed rata in nonachedoM i tacrillce groups. Group Mean survival, weeks Males Females RaU with Rato with AO rata tngiotarcomu All r*U angioaarconua 2 80.6 37.5 36.6 4 31.6 33.8 38.9 6 30.5 36.8 30.0 32.0 8 28.9 31.2 30.2 27.3 Environmental Health Perspective* ucc 057108 i (F:'. 1). ig. /ant as in the pontanei directly trison of that am ong and heir revals, the as tabu* ough the ngroups incidence increases y adeno:urred in ippear to controls. mCttl1 uc d deaths, iy regrea= 99.85%. rheduled . with -tarcomm i64 18.9 i2.0 n.s ve* TaW* t. Accumulative angioaareoma Incidence In exposed females, nonaeheduled sacrifice group. Interval, Group Ttelu 2 Angiosarcoms incidence Group 4 Group 6 Group 8 16-19 20-23 24-27* 28-31 32-35 36-39 40-43 0/0 0/1 0/2 0/1 0/5 3/7 (43%) 0/6 0/14 8/23 (36%) 1/18 (7.7%) 1/22 (4.5%) 12/81 (39%) 1/14 (7.1%) 2/28 (7.1%) 14/37 (88%) 1/16 (6.7%) 8/29 (10%) 18/41 (44%) 2/38 (5.3%) 7/47 (15%) 23/49 (47%) 2/5 (40%) 3/9 (33%) 622 (27%) 8/34 (24%) 10/40 (25%) 11/46 (24%) 11/54 (20%) 'Exposures terminated. Discussion The results clearly indicate that the incidence of angiosarcomas is higher and these tumors occur earlier in older rats of both sexes. In addition, the incidence of angiosarcomas is generally higher and these tumors occur earlier in female rats than in male rats. Therefore, it can be concluded that older rats are more susceptible o the angiosarcomainducing effect of vinyl chloride than are young adult rats and that female rats are more susceptible than males. The authors have been unable to find comparable studies in the scientific literature. However, Mthoni (J) reported in a summary article of his research with vinyl chloride that exposure duration was an important factor in determining angiosarcoma inci dence. In that article, he reported that rats ex posed to 10,000 ppm vinyl chloride, 4 hr/day, 5 days week for 17 weeks did not develop Ever angiosarcomas within a 155-week period, whereas, 13'60 {22%) of rats exposed to 6,000 ppm vinyl chloride 4 hr/day, 5 days/week for 52 weeks (and held for a 155-week period) developed liver angiosarcomas. In the authors' opinion, the differ ence in total dose between the two groups was not sufficient to account for the large difference in the angiosarcoma incidences, and that the major factor, therefore, was probably the difference in ages while they were being exposed. There is suggestive evidence in the literature that older adult humans might be more susceptible than young adults to the carcinogenic effects of Thorotrast. Curry et al. () stated in their article that "although the latent period between thorium injection and liver malignancy has varied from 3 years to 35 years, all of these 123 cases occurred in patients between 49 and 55 years of age." There is suggestive evidence that older beryllium workers are more susceptible to the carcinogenic effects of beryllium. The data of Mancuso's study (S) of beryllium extraction workers show an extremely high risk for lung cancer in workers between the ages of 38 and 65 who were exposed for relatively short periods of time. Studies specifically designed to test this theory in humans, as well as in animals, with other compounds are needed. If these findings can be reproduced in animals with a wide variety of classes of compounds, then it would be justifiable to modify chronic bioassay experiments by utilizing older animals at the be ginning of the studies and shortening the durations of the experiments by 6-12 months. In many cases, this should result in decreasing costs by 20-30% and, thereby, permit a greater number ofchemicals to be tested. The observation in this study that the accumula tive incidence of angiosarcomas in the 6-week-old group of rats did not increase with time after discontinuation of the exposures suggests that the carcinogen is metabolized and inhibited or excreted before most of the animals became susceptible. Whether or not these animals would have exhibited a higher incidence of angiosarcoma at some later time is not known. However, as mentioned above, Maltoni (1) was unable to induce liver angiosarcomas in young adult rats exposed to 10,000 ppm vinyl chloride 4 hr/day, 5 days/week for 17 weeks and held for a lifetime. The total dose in his experiment was 10,000 ppm x 340 hr (3,400,000 ppm-hr). The total dose in our experiment was 948 ppm x 858 hr (813,384 ppm-hr). Therefore, it is unlikely that the youngest groups in our experiment would have developed a higher incidence of angiosarcomas if they were held for a lifetime. 'Hie results of this study also suggest that older people should not be preferentially placed in carci nogenic working environments. REFERENCES 1. Mattcni, C. Recent flndlnfi on the carcinogenicity of chlori nated olefin*. Environ. Health Pertpect. 21:14 (1977). 2. Curry, J. L., Johnson, W. G., Feinberg, O. H., and UptkgTOVt, J. H. Thorium induced hepatic hemangioendo thelioma. Am. J. Roentgenol Radium Therapy Nucl. Med. 125:671-677 (1975). 8. Mancuio, T. F. Relation of duration of employment end prior respiratory illness to respiratory cancer among beryllium worken. Environ. Rea. 3: 251-275 (1970). October 1981 57 ucc 057109 Discussion In this animal model, ingested ethanol is a cocarcinogen in relation to VC induction of tumors in the liver. The incidence of angiosarcoma in VC-ethanol dosed rats (50%) was more than double that resulting from VC exposure alone (23%). VC-ethanol also induced a greater number of hepatocellular carcinomas (60%) than occurred in VC-treated animals (44%). The first deaths from angiosarcoma and carcinoma of the liver occurred earlier in VC-ethanol dosed animals indicating a shortened latent period. The Sprague-Dawley rats used by Maltoni and Lefemine in 1974 U) were more resistant to the effects of VC on the liver than the animals used in this VC-ethanol study. Following a year-long expo sure to 500 ppm VC 4 hr/dsy, 5 days/week and observation fitwn first VC exposure for 135 weeks, only 7 of 59 rats (12%) were reported to have angiosarcoma in the liver (4). Angiosarcomas de veloped in other sites such as in subcutaneous tissue, the abdominal cavity; neck, lung and uterus. Hepatocellular carcinomas were not reported. Zymbal gland carcinomas were seen in 8% of Maltoni's VC exposed animals; none were seen in this study. Ethanol has been reported to potentiate the toxicity of other halogenated hydrocarbons. In whole animals, s variety of alcohols increased the hepatotoxicity of carbon tetrachloride (CCI4) when ingested 16 to 18 hr prior to inhalation of CCl* (7). Following acute exposures, CO* toxicity was en hanced by ethanol as judged by the elevation of serum glutamic-oxaloacetic transaminase levels. In similar studies, trichloroethylene (TCE) or 1,1,1trichloroethane hepatotoxicity was potentiated by ethanol, but only at high concentrations of inhaled TCE or 1,1,1-trichloroethane (6). Ethanol potentiation of VC carcinogenesis in the liver is probably due to an effect on VC metabolism. Inhibition of VC uptake (J) and metabolism (6) by ethanol suggests there is a shared step in the oxidation of the two toxic agents. The most Hkt candidates for competition are acetaldehyde u chloroacetaldehyde. The normal substrate, ue^ dehyde, would be oxidized preferentially results; in an increased half-life of chloroacetaldehyde. Toxic manifestations of exposures were {& which were not related to the neoplastic responMany animals died because of neoplasms or mcok ary changes caused by tumors; however, dec directly attributable to toxicity was not seen. Ti toxicity of ethanol will be discussed in uwtVpublication. I wish to thank Frank Grand*. Morris Blackston* udlar Karahal* far their technical aeaiitince and Dianne Dotw fc Montana! rapport. REFERENCES 1. Craoeh, J. L., Jr., and Johnson. M. N. Angiosarcoma rfbr in the manufacture of polyvinyl chloride J. Occup. Med i` ISO (1974). 2. Detune, F., and Mark, L. Angiosarcoma* of the #vc: workere having had prolonged contact with vinyl chtava morphological description of the lesions. Union Med Cc 104:1888(1975). 5. Vida, F. I.., Bigotti, A., and Caputo, A. Oncogenicmpo ofrat akin, lungs and bone* to vinyl chloride. Casctr Set 616 (1871). 4. Maltoni, C., and Lefemine, G- Carcinogenicity bioeuiv,: vinyl chloride. 1. Research plana and early result*. Eevre Res. 7:887 (1974). 6. Hefner, R. E,, Jr., Watanabe, P. G., and Gthrinf. t Preliminary atudiea of the fate of inhaled vinyl dJcs* monomer (VCM) in rata. Ann. N.Y. Acad. Sei. 244 % (1975). 6. Hultmark. D., Sundh, K., Johansson. L.. and ArrheM t Ethanol inhibition of viny) chloride metabolism in teoteutt bepatocytaa. Chem.-Biol Interact. 25:1 (1979). 7. Coraiih, H., and Adeftrin, J. Potentiation of earboc tern chloride toxicity by aliphatic alcohols. Arch. Environ Bet: 14:447 (1987). 8. Cornish, H-, and Adehdn, J. Ethanol potentiation tfMor natad aliphatic solvent toxidty. Am. Ind. Hyg. Aaaoe.J f' 57 (1986). Cane Multi Amo by Rot Josepl Georg* Introducl lr, the las' tff-r.- by inc I'h-t/.ify carci H'iUi \er, ca tsor.ii! vxposu aJ*n u-t-d in t Tr.i-r. fore, --d to su *1 ' Consum I' -.'iing. Ri J'-'t M ' ArmyC u JdA. W "I-'eased. 62 Environmental Health PenpertW October 1981 UCC 057110 10_. util hyde ^ te* seem, resuhkhyde. 2re fount response r second, er, denseen. TV > another and fat? Douce far naofivir > Med K te livers 1 chlondt dad. Cm : respoew rn'v.31 Mfesytrf Ejivine. mg. P.J. 1 chlcridt 346: 135 lenius. E. elated m n tetnn. Health if haJep- i x. J. 37: j 2Ct1V Environmental Health Perspective* Vol. it, pp. SJ-7S, mi Cancer Induction Following Single and Multiple Exposures to a Constant Amount of Vinyl Chloride Monomer by Robert M. Hehir,* Bernard P. McNamara,1** Joseph McLaughlin, Jr.,* Donald A. Willigan,* George Bierbower* and Jerry F. Hardistyt Vinyl chloride ihSnomer (VCM), already identified aa a human animal cartinofen. was elected aa a model acent to explore an area of concern for eincle and intermittent low keel rxpoaure. In traditional cancer bioaaaay, animala are repeatedly expoaad over their Ufeapan to a dote of auapeeted chemical. In the current atudiea rata and mice were expoeed In an inhalation chamber to single one-hoar dotet of VCM ranging from SO to 50,000 ppm. A aecond group *u given 10 one.hour expoeurtf to 500 ppm or 100 one-hour cxpomrue to 50 ppm of the eeme chemical. AH animal* ware then obeerved for the remainder of their livee, generally 15-24 montha. Moribund animala were euthanized, and eurvivore were encrlfleed on chedule and thair tiaauea examined for pathological changee. Specifically, the oncogenic atudy demonatrated doac related effect* for eingle one-hour expoeure of VCM at high level*, i.e., 5,000 and 50,000 ppm. Theee concentration* increaeed the incidence at pulmonary adenoma* and carcinoma* in mica. Repeated expoeure of All mice to the earn* chemical at 500 ppm x 10 one-hour expoeure* aleo increeaed the incidence of pulmonary adenoma* and carcinoma* which are coneidcred highly Mfnifieant ip - 0.001) when compared to match control*. At the lower doe* of 50 ppm x 100 une-hour expoeure, no eignifleant increaee in tumor* waa ohaerved. Bata expoaad to identical concentration! at VCM failed to elicit a tumor!genic raiponee. Introduction In the last decade there have been conceited efforts by industry end the Federal government to identify ca: cinogenic Bubotances in the workplace. However, carcinogens are not limited to occupa tional e\| >: i.-ures. Many of these same chemicals are also used in the formulation of household products. Therefore, consumers in all walks of Ufe may be exposed to. suspect chemicals in their homes without IV S. Cor. - umer Product Safety Commieeion, Weatwood Tow ns Buildir,*:, Room 738. 5401 Weat Blvd., Waahington, O.C. MXfi. 910W^ Arm' Chemie*1 Syatema Laboratorie*, Edgewood, Md. tDonald A Willigan, Inc., Bound Brook, NJ. 08806. "Deeaa.-rd. October 1981 their knowledge. This type ofconsumer exposure is usually brief and at very low levels. The suspect chemical may be modified in the process of manu facturing the consumer product, i.e., as in the case of polymerization of vinyl chloride (VC) to polyvi nyl chloride) (PVC), or trace quantities of the unreacted monomer may be present in the product which may be leached out under normal conditions of use. There are other situations wherein a chemi cal like VC is used because it is chemically inert, for example as a propellant, and as an unreacted gaseous chemical it could become a potential health problem. While regulatory bodies try to establish safe exposure levels and industry attempts to control exposures in the production facilities, no such control measures would be of practical value in the 63 t * / i\ t ucc 057111 home environment. Another complication associat ed with making value judgements about potential risks of consumer exposure is that traditional cancer bioassays involve daily exposures to the test chemical over the animal's lifetime. There were no comparable studies on short-term exposure to a carcinogen like VC followed by a lifetime monitor ing for toxicological symptoms with complete histopathological examination at death. Therefore, our approach was to explore what happens to laboratory animals following brief or intermittent exposure to a known carcinogen like VC. Vinyl chloride appeared to be the ideal chemical to use in these experiments because of its widespread use in industrial and consumer products. Furthermore, the relationship for inducing unique pathological lesions, i.e., angiosarcoma of the liver for high exposure levels in animal and man was already established by Viola et aL (J) Maltoni (t) and Creech et al. (J). Quite apart from the need to establish a bench mark for acute short-term intermittent exposures to a carcinogen, such as vinyl chloride, was the question of "threshold effects" or "safety factor" for low level exposures. In setting up our experiments we were mindful of the many factors that could have an impact on the study design. Some of the more important factors are that (1) the substance may not reach a susceptible cell; (2) the substance may make noncarcinogenic biochemical combina tion with the cell; (3) the "initiated" lesion may not receive adequate "promotion"; (4) host factors may be unfavorable to carcinogenesis; (5) biochemical repair ofthe DNA lesion may occur; (6) morpholog ical regression of tumorigenic proliferation may occur; (7) carcinogenic ceils may be destroyed by the body's immune system. These items need to be addressed in any conventional cancer bioassay but are even more critical in searching for noncarrinogenk exposure levels. Experimental Conditions Two strains of rats, Fischer 344 (Charles River Laboratory, Wilmington, Mass.) and SpragueDawley/Wlstar (Chemical Systems Lab, Edgewood, Md.), and two strains of mice, A/J (Jackson Lab, Bar Harbor, Maine) and ICR (Charles River Labo ratory) were treated in single or multiple intermit tent inhalation exposures to VC. The chambers were Rochester type, stainless steel, 1000 liter, constructed to provide laminar air flow and insure uniform exposures to VC to test animals. Chamber concentrations were established by proportioning the amounts of VC being dispersed with the air flow through the chamber. Airflow 4 through the chamber was created by a blot? motor located in the flow pipe on the exhaust side^ the chamber. A negative pressure was in the chamber at all times when operational m the exhaust gas completely filtered (M6A1 p, particulate filter) before discharge to the envin* ment. The concentration of gas in the mtui^ chamber was monitored by using a Hevln Packard 6830A gas chromatograph with a 4% flame ionization detector. -- sw~ __ r* Exposure Procedures for VC Lifetime Cancer Studies Male and female rata and Fischer 344 and ICt mice were totally exposed for 1 hr to 50,600, Mi. and SO,000 ppm VC. Fischer rets and Ad nw equally divided by sex received ten 1 hr expomm to 500 ppm VC (1 hr/day, 5 days/wk for 2 weeks)v 100 1-hr exposures to 50 ppm (1 hr/day, 5 dsyrti for 20 weeks). Male and female parents (SprapsDiwley/Wistar) rats (obtained from Veterinary Mtd icai Division, Edgewood Arsenal, Md.) from tk reproduction study were also maintained and oh served for 24 months post exposure to 50 to SIX ppm VC 1 hr per day, 5 days per week for 10 week (49 exposures). Following exposure, all animals were air waaM until the chamber concentration was less than l ppm VC. Animals of the same sex were segregate* in stainless steel cages with a maximum number a! 5 rats in each compartment and placed in the aninu: holding area. Mice were similarly treated, but smaie cages were used and the number of mice per cos partment was limited to two. The animals wen obeerved twice daily for general health, sores, masea, alertness, activity or mortality. All animal; were weighed weekly for the first 8 weeks pee exposure and monthly thereafter. The exposure schedules for the studies described above are short in Tables 1-3. No blood chemistries or hematoloc studies were performed. Pathology Grass and Light Microtcopg. A complete pus and microscropic examination was performed oe most control and exposed animals which died or were sacrificed. Autolysis precluded such examinetion in a few cases. All rodents were to be serially sacrificed at 8,16 and 24 months post exposure. However, the lift span of the mice forced some changes in the later times of sacrifice and termination of mouse expertments. For single exposure the planned 16 and 21 month sacrifice were replaced by 18 month sacrifices Environmental Health Perspectives 1CR _ " uou --- -- Sp F"c 1 Fuel ( ___ -- *|j E ^ ucc 057112 ybin. austsi* roaintair, ational * :M6AJ ft he entire inhalati i Hewlr ak 'fetim* A and IC! 500, 50' 1 A/J mit- exposuft. weekwtr 5 daytii (Sprapif naiylltc from tlr d and oi50 to *( wed ir washK 56 than ] igregatK lumber of heanima Jt smaller per cominis wen s, maw: animal? ieks poff exposurt re showi outolqgy TtegroM uied on died or xamini- st 8,16 the hfc he later ' oeri* J 24 crifices. retire* ^por 1 wxr 4 ra: Ii R mou* K*: Mj- Table 1. Single expocure adiedule of animal* to VC. Expacuredate Sex Dole, ppm AM PM M 50 500 8/4/75 8/11/75 5000 3/18/75 50000 305/75 F 50 600 5000 50000 M 50 8/405 500 S/ll/75 6000 wwn 3/18/75 805/75 F 60 500 5000 50000 M Neg/Cont. F Neg/Cont. M Neg/Cont. F Neg/Cont 3/405 8/1105 8/1805 80605 3/405 8/1105 3/1805 80505 Exposure Age at time of group toe expoaure, week* 90 15 90 16 86 17 90 18 90 16 100 16 96 17 88 18 90 15 90 16 90 17 90 18 90 16 90 16 90 17 90 18 98 15-18 79 15-18 82 15-18 88 15-18 Table 2. Expoeur* eehadule far animal* expoeed repeatedly to VC. Expoaure period*, Sex Do**, ppm day* Expoaure date* From To Exposure group site Af*. weeks Stan End Start End ) wht-r rat A J mouse Fufhrf ret AJ mousr M 50 100 SCO 10 F so 100 500 10 M SO 100 500 10 F SO 100 500 10 M -- N*f. 100(c)* Control 10(e) F Neg. 100(c) Control 10(e) M Neg. 100(e) Control 10(e) F Neg. 100(e) Control 10(c) Vi denote? control for corresponding doec above. 8/27/75 7/7/75 smns inns inns Mins inns Mans _ -- _ __ -- 1/28/76 mans 1/26/76 7/18/76 7/18/75 1/2676 7/18/75 1/26/76 90 86 21 41 90 90 14 16 90 87 21 41 90 00 14 16 90 87 15 85 90 90 8 10 90 88 15 85 90 90 8 10 50 50 21 41 50 50 14 16 50 47 21 41 SO 50 14 16 40 89 15 86 SO 50 8 10 50 60 16 85 50 50 8 10 t >. 5 * i 4 % 6 f V i / Table 8. VC multigencration atudy. F, parent*.* Group Compound IW Number af mala* Number af female* I Air Control 25 11 VC Low doaa 26 (50 ppm) III VC High dote 25 (600 ppm) 25 25 25 Sprague-Dawley/Wiatar rata. `Exposure to 50 or 500 PPM of VC 1 hr/day, 5 dayi/week for 10 week* (49 exposure*) before mating. October 1981 65 A OCC OSI^3 This observation period was the minimum suggested by the National Cancer Institute U) for cancer bioassays in small animals. For multiple dose studies in mice the final sacrifice was at 20 months rather than 24 months. The change was made in consider ation of the risk of animal loss through death and possible cannibalism. Tissues examined were lung, trachea, heart, liver, stomach, small intestines, spleen, kidney, bladder, bone marrow (sternum), adrenals, pancreas, duodenum, brain, eye, zymbai gland, ear, nose, muscle and bone (femur). Electron Microscopic Studies. Groups of five male and five female Fisher (344) rats from each of the single 1-hr exposure studies (50, 500, 5000 and 50,000 ppm) with equal numbers of their corres ponding control groups were sacrificed at 8, 16, 24 months. Groups of five male and five female Fischer (344) rats from the multiple 1-hr exposure studies at 50 and 500 ppm VC along with equal numbers of control animals were sacrificed at 16 and 24 months. #* Results Toxicity During Exposure Rats and mice exposed for 1 hr to concentrations of VC ranging from 50 to 50,000 ppm or for repeat ed exposures, i.e., 50 ppm or 500 ppm, produced no remarkable signs of toxicity with the exception of mice at the 50,000 ppm level. At 50,000 ppm VC 50% of the male mice exhibited hyperventilation at 45 minutes together with twitching and possible ataxia. Female mice became hyperactive after 40 min exposure, and respiratory difficulty and ataxia was observed in approximately 25% of the female mice after 55 min. Upon removal from the test atmosphere, all animals recovered to normal appearance within 24 hr. After exposure there were no consistent or dose-related differences between control and exposed (single or multiple) mice or rats in death rate, toxic signs or change in body weight Gross Pathology There was a suggestion of higher frequency masses in the lungs and liven of mice exposed o* or repeatedly to VC at the higher dose levels u 500, 5000 or 50,000 ppm. Histological Examination of ICR Mice: Single Exposure Changes ascribable to vinyl chloride were app* ent primarily in the lungs with the induction t pulmonary adenomas and pneumonitis. Pnetnaona was evident in all animal groups which wen e posed to VC at 500 ppm and above. The development of bronchio-alveolar increased with exposure to higher dose levels i VC. Tables 4 and 5 summarize the significant hmir logical changes observed in ICR mice at 8 and l> months following single exposure to graded do* of VC. Mice were more susceptible than rats to pet monitis following exposure to VC. The effect hot ever was not incremental with dose level 7b incidence of pneumonitis, adenoma and cardnaa in ICR mice following single exposure is present* in Table 6. No correlation was observed better, the incidence of pneumonitis and adenoma e pneumonitis and carcinoma. However, males seemk more prone to the induction of pneumonitis, part* ulariy at 50,000 ppm, i.e., 34% M vs. 13% F. A: 5000 ppm and below, male and females were aba: equally sensitive. There was an increase in bronchio-alveolar ade nomas with exposure to higher doses of VC and the condition manifests itself more frequently in male, le., at 50,000 ppm: 51% M vs. 18% F. This trend continued at the 5000 ppm: 22% M vs. 13% F. Male and females were equally susceptible at dose level 500 ppm and below. The upper respiratory tnr. (nasal turbinates) and trachea revealed no unusu! changes specifically attributable to VC. Histologi at 8.16 a Multiple SOOppm, \Y were a< faction of mVnomas gpproximat l*. 73- f% crrtrc in in group over Table s. ovr. Ti'.-'Ji1 rt-por L:\rr r.jmbi Hrt*:ic * Hmu'.ic et ilH'iilojif Hriatio ef c* Ar.fii-ct**t Mnu-mdil Hri'i.-it c* H> |u-.it Hi-ranpo: H.-r..inpo I.jr.f i numb l*m jmoniHn-r.chio-i hnr,fhl<y; Njmbel* (ir.uriFOUf 0 mjr.'.rull Table 4. Histological examination ad ICS mica at S and 18 month* following a sinfl* (1-hr) exposure to vinyl chloride Vinyl chloride concentration, ppm Histological changes attributable to vinyl chloride Induction et pulmonary adenomas Progression to carcinoma 50,000* 6,000* 600* 60 0 (control) 46/137 (33.3%) 24148 (16.8%) 18188 (12.9%) 14138 (10.1%) 12120 (10.0%) 3137(2.2%) 1148 (0.7%) 1139 (0.7%) 0139(0%) 0120(0%) 'Pneumonitis wss evident in all animal groups which ware exposed to VCM at dost* of S00 ppm er mart. 66 Environmental Health Perspective 5ii> VJ in October ucc 057114 queney tf xwed onet ivels, it.t i in tppvJuction of leumonitif were ex- adenoma* levels of anthisto8 and 18 led doses to pneofect howvel. The arrinomi resented between i i or ! s seemed partio% F. At re about Iar adeand the n males, is trend 7. Males >ae level -y tract unusual ecthe* W, Histological Examination of A/J Mice at 8,16 and 20 Months Following Multiple Exposure SCO ppm, 19 daps, 1 hr. Changes aacribable to VC were apparent in the lung only, primarily the induction of pulmonary adenomas. Bronchio-alveolar sdenomas were induced in the test group with approximately equal frequency in males and females, i.e., 73.75 M vs. 75.6% F, respectively. The in crease in incidence as shown in Table 7 for the test group over that of the controls was substantial, by a factor of 2.2, i.e., controls, 34.4%; 500 ppm; 74.7. Progression to malignancy (carcinoma) in the test group vs. controls was also highly significant: con trols, 3/90 or 3.3%; 500 ppm, 22/166 or 13.3%. In animals scheduled for evaluation (survivors) pul monary adenomas were observed as early as 8 months post exposure in 60% of males and females; at 20 months, 75% of animals were affected. The incidence of pneumonitis, adenoma and car cinoma in A/J mice following multiple exposure to VC is presented in Table 8. Pneumonitis was ob served more frequently in the control animal than T*M* 5. Overall luminary: incident* of nonneoplaatic dune** and histologically proem neoplasms within th* Hear and lungs of ICR Swiaa mice capoaed la vinyl chloride in tingle inhalation srpoeuras. Timlie response 0 M (68)* TCJTf Incidence of response for varioua vinyl chloride eouaw 50,000 ppm 5.000 ppm 600 ppm M (74)* F (82)* M (76F F(82f M (72)* F (76)* 80 ppm M (81)* F (80)* Liver (number evaluated) 60 76 68 78 68 76 67 72 64 68 Hepitic cel) necraeit < 10 8 6 6 7 4 6 2 3 Hepatic cell vacuotetion (lipidoei*1 2 11 4 2 12 8 6 1 4 Hepatic cel! hypertrophy 1 28 8 4 18 1 Hepatic cel! hyperpteiia 44 Anpeetaei.* 14 Sinufoidal reticuloate 6 Hepatic cel! adenoma 2 1 1 2 Hepatic cell caranaoa Hemangioma 2 41619 1 2 Hemsngtosarcoma 1 Lung (number evahiatad) 60 70 61 76 66 78 68 78 71 66 Pneumonitis 1 6 21 10 18 17 19 15 4 7 Bronchio-alveolar adenoma 4 8 81 14 14 10 8 10 8 6 Bronchio-alveolar carcinoma 121 1 `Numbers in parent))**** denote animate per group. Total indude* animate from achoduted aacrifreed (8 and month period*) and spontaneous death*. Table 4. Singh inhalation exposure of ICR mice to vinyl chloride monomer. VroCneenx. D*pOpfnuire 0 (control) 30.000 3.000 300 30 Grasp Mate Feoate Combined (M+F) Mate Femate Combinod (M + F) Mate Femate Combined (M+F) Mate Female Combinod (M+F) Mate Femate Combined (M+F) Lung tiiaue: jnddenc* of response/number evaluated* Adenoma Carainoma 1)60 a*) 6/70 (9*) 7/120 (*) 21/61 (84*) KV76 (18*) 81/137 (28*) 13/86 (26*) 17/78 (22*) 80(143 (21*) 19/86 (29*) 16/73 (21) 84/139 (24ft) 4m (6ft) 7/68 (10*) 11/139 (8*) 4/60 (8ft) 8(70 (11*) 12/120 (10ft) 81/81 (51) 14/76 (18ft) 46/137 (S3*) 14/86 (22ft) 10/78 (18ft) 24/143 (17ft) 8(68 (12ft) 10(78 (14ft) 18(139 (13ft) 8/71 (lift) 6/68 (9ft) 14/189 (10ft) 0/50 (Oft) 0/70 (Oft) 0/120 (Oft) 1/61 (2ft) 2(76 (8ft) 3/137 (2ft) 1(66 (2ft) 0(78 (Oft) 1/143 (1ft) 0/66 (Oft) 1/73 (1ft) 1/139 (1ft) 0/71 (Oft) 0/68 (Oft) 0/139 (0ft) *Toul include* animate from scheduled sacrifice (8, 16, 30 month* period) and spontantou* death*. October 1981 67 ucc 057115 in either test group. No correlation was observed between the incidence of pneumonitis and adenoma or for pneumonitis and carcinoma. These results are similar to those observed in the single exposure study. 50ppm, 100 day, 1 hr. Again changes attribut able to VC were apparent in the lung only, primari ly pulmonary adenomas. However, the incidence in the induction of adenomas and progression to cardnoma are considered only marginal and not statisti cally significant. Comparatively, the potential for development of pulmonary adenomas as shown in Table 7 was great er in A/J mice following multiple exposures at 500 ppm than at 50 ppm, i.e., incidence at 500 ppm, 74.7%; at 50 ppm, 44.1%, despite an equivalent total dose of5000 ppm VC. Also, pulmonary adenomas were induced earliest (8 months) following multiple exposures at 500 ppm. It is also of interest that the Table 7. Hiftoloiicml examination of A/J raict at S, IS and SO month* feliowins multipli fl-hr) exposure* to vinyl chloride Number of exposure* and concentration ofVCM Hiitological change* attributable to vinyl chloride monomer Induction of Progr* iiian pufanonaiy adenoma* to cerdnama 0 (control*) 10 x 500 ppm* 0 (control*) 100 x 60 ppm* 31/90 (34.4%) 124/168 (74.7%) 29/84 (34.6%) 66/158 (44.1%) 3/90 (3.3%) 22/166 (18.8%) 2/84 (2.4%) 7/158 (4.4%) Highly ligniAcant difference in tha nunbar of pulmonary adenoma* (p - 0.001) observed at th* 500 ppm x 10 hr exposure lava! vtnui control by Z taat. Ho ngniScant difference for pulmonary adenoma* (p < 0.14) and carcinoma* (p - 0.19) obaarvod at the lower multiple aspoaurt levaL control groups ofAJJ mice for both multiple inh*^ studies showed s baseline incidence for pulnot? adenomas which was nearly identical, ie., a > ppm, 34.4%; at 50 ppm, 34.5%. Table 9 provides an overall summary of the ac dence of histologically proven neoplasms obur., in both strains of mice, ie., ICR and A/J, foUoir^. single and multiple exposures to VC. The mo^ tic and nonneoplastic changes observed in the b; and/or lungs of A/J mice following multiple ep sum to VC at 50 and 500 ppm are shown in Titw 10 and 11. Although other neoplasms and noo* plastic changes occurred variously in all remain organa and tissues, the response appeared me sporadically or was shared by all test group#ind. ing controls. Relationship by incidence and meto test exposure was not evident. Furtherm* morphologic deviations were not unlike thoie k mally observed in aging A/J mice maintained undestandard laboratory conditions. Reprodt One h Pawley1 a i*.h equ gained Edpewcx * hen ini were exi acre car generatu pi*t exp A coir, examina*. control ^ tws. &- Electron Microscopic Results In general, these studies indicate that expos? to vinyl chloride increased organelle turnover*-. as loss of volume control (bleb formation) and r creased lysosomal activity in the liver ofrats. Dealterations progressively decreased as recovery& exposure increased. Hepatocellular carcinoma was seen in one BiFischer rat which had received 10 exposures ofb> ppm. Lymphosarcoma was noted in one fern*-Fischer rat which had received a single exponmi 500 ppm. Since these were individual cases e since no cancers were seen at 50,000 ppm, ti lymphosarcoma and the hepatocellular cirdwc. are not likely related to vinyl chloride expomn. Inhat expobuigle Nulupli ICK n Tibi* 10. Table 1 Multiple inhalation expoamx ef A/J mice to vtoyt chloride monomer. VC Expoem* Fn^iMncy eoma, ppm droop Lung tiicue: incidence of reeponao/number evaluated* Pneumoetti* Adenoma Cnmnomi 10 X 1 10 x 1 100 x 1 100 x 1 0 Halo 0/48 (0%) 16/48 (36%) 0/43 (09) Female 2/47 (4%) 16/47 (84%) 3/47 () Combined (M+F) 3/90 (2%) 31/90 (34%) 300 (39) 600 Male <V76 (0%) 56/76 (74%) 12/76 (169) Female 000 (0%) 6800 (76%) 1000 (119) Combined (M+F) 0/166 (0%) 124/166 (76%) 22/166 (139) 0 Male 5/39 (18%) 11/38 (28%) 209 (69) Female 8/46 (7%) 18/46 (40%) 0/46 (09) Combined (M+F) 8/84 (10%) 29/84 (36%) 204 (29) 60 Male 4/77 (6%) 27/77 (36%) 3/77 (49) Female 681 (6%) 38/81 (47%) 401 (69) Combined (M+F) 9/168 (6%) 66/168 (41%) 7/168 (49) Total include* animal* from tcbadulod lacriOee (8,16, 20 month* period) and tpontanaou* daathe. 68 Environmental Health Pertpedi'*5 Kdcmi (units' f oci] h Pntunv Brunch. brunch Brunch Kttictil `Numb October UCC 057116 Itipleinh^ f for puin^. u' ^ t; sms < A/J,] The id ini mJtip wnh and Hro Reproduction Carcinogenesis Study One hundred and fifty colony rats (SpragueiffvUl<iari were divided into three groups ^iual numbers of males and females. These ,-^-v'pathopen-free, random bred animals were r^nrd from the Animal Resources Branch at f is-* nnd Arsenal. The rats were 12 weeks old vr. initially exiiosed to VC. One hundred rats ,0. exposed as described and the remaining 50 famed as unexposed controls. The parental r>r:i'>ns ofS-I) IV rats were maintained 24 months expf>sure for carcinogenic evaluation. ` A complete pross and microscopic pathological riir.mation of all tissues was performed on each r,r.:rwl and ex)>sed animal. Particular emphasis was placed on examination of brain, lung, and liver tissues and zymbal gland in the rodent ear. The livers of randomly selected rats were prepared and examined by electron microscopic techniques. Neoplastic and nonneoplastic lesions were observed in approximately equal frequency in control and F0 parent generation of Sprague-DawleyAVistar rats exposed to 50 ppm or 500 ppm of VC, 1 hr per day, five days per week for 10 weeks (49 exposures). The only lesions that occurred in higher frequen cy in the exposed animals than in control rats were eosinophilic cellular alterations presented as foci/ or areas. The appearance of these foci was related to the dosage of VC. The nature ofthese lesions are of interest but as yet are controversial, so that no inference can be drawn. exposelverast, 'j id r *6u*. The- ivetyift,- one mi ires ofS -e femiipoanvi' cases n: ppm, tiardnat DOSUtt. d* mim oT *) ) im i*) 89) V V V ) c) xtim TaM, . Summary of incidence of histologically proven neoplasms observed within tissues of mice at various interval* following (intie or multiple exposure* to vinyl chloride monomer. Ir.ulatmt: rif*ure Exposure concentration, ppm Number of neoplasms observed (scheduled sacrifice) 8 months 16 18 20 months months months Totals Total number of neoplasms observed Nrgir 11 hr(1 hr. 60,000 6,000 600 SO 0 (control) 600 x 10 0 (control) 50 x 100 0 (control) 5 8 1 0 0 12 0 4 1 24 18 2D 16 14 22 70 2 18 16 68 6 27 29 21 SO 16 14 104 40 83 38 110 78 82 62 72 170 46 137 41 ak K strain u.*rd in single (1 hr) exposure studies; and AU mice used m the multiple (1 hr) exposure studies. Table tO. Overall summary: incidence of nonneoplastic changes and hiftoioctcally proven neoplasms within the lungs of M mice exposed to vinyl chloride in multiple inhalation exposures. Tin*ur response Control (0 ppm), 100 x 1 M (39)* F (47)* Incidence of response Vinyl chloride. 60 ppm, 100 x l M (81)* F (83)* Larg inumber evaluated) 89 45 77 81 Edema 2 Congestion 4 11 Focal hemorrhage 2 2 Pneumonitis 634 6 Brondiio-aJvfoiir hyperplasii 3 3 o*eous metaplasia 1 BnjftchiO'aJveoUr ujiiwm 11 18 27 88 Bronchiatlveolsr ardnanu 2 84 Reticulum cell ssreoms J 13 18 80 48 Number? ir, parentheses denote animals per croup. Total indudes animals from scheduled sacrifice (8,16,20 month periods} and spontaneous deaths. October 1981 69 UCC 057117 Discussion The fact that the severity of carcinogenic effects of VC had been described by various investigators like Maltoni (t,S) and Lee et al. (6) to coincide with doee and length of exposure implies that the total dosage (concentration x exposure time) may be an important factor in the carcinogenicityofVC. There fore, the inhaled doee was approximated by the Haber (7) concept. In its simplest form this concept states that the dosage, Ct is the product of C (concentration in milligrams/cubic meters) and t (time in minutes). The total concentration can also be expressed in parts per million (ppm) and the time can be expressed in hours, producing Ct 1 ppm-hr. Factors for breathing rate and tion can be added. However, this simplified ( approximation of total inhaled dose is relative useful, as is, for comparative purposes. In his experiments Maltoni (5,10) exposed rc.. and mice as shown in Table 12 to a series ofdosesc VC ranging from SO to 10,000 ppm for 4 hr/djv,; days per week for 52 weeks. The results indicate! questionable carcinogenic effect at SO ppm or tou dosage of 52,000 ppm-hr after 135 weeks. In anouer experiment (BT3), Sprague-Dawley rats, tree ed in a similar fashion to BTl but for 17 weeks osK show after 86 weeks a negative carcinogenic 1* Table 11. Overall vummarr incidence of nonneoplaatk change! and Matologically proven mopUhw within the liw aad fa* a( JUS mice expoeed to vinyl chloride in multiple inhalattoa exposure*. Tteue/reipoQsc Incidence of reaponae Control (0 ppm), 10 x 1 Vinyl chloride, 600 ppm, 10 x ] M(46p F (48)* M (78)* F(*21 Liver (number evaluated)'9 Hepatic cell nacroaii Lymphoid eeO infiltrate Hepatic cell liptdoua Neutrophil infiltrate BOc duet hyperplasia Granulomatous fod Sinusoidal reticuloaia Hepatocyit Amyloidoaia Angiectaaia Hepatic cell adenoma Cholangiocaranoma 46 48 78 88 4 6 6 IS 11 22 21 1 1 1 1 1 1 1 _1 _ 11 6 18 16 Lima (number evaluated) 48 47 76 90 Edema 1 Pneumonitia 2 Broochio-alveolar hyperplaaia 2 l 2 Bronchio-tlveolar adenoma 16 16 66 68 Bi ,,->chio-alveoiar caresnoma J n 10 17 22 68 81 Nuroben in pareathaaea denote animal! per croup. Total include! inimala from acbeduled lacrifice (8,16,30 month periods) ud tpontaaeoua deatba. sponse able re genic 1 expert doses 1 5 day-' descrii at tot; suggeobtain' Spraf seems upom was U iment VC at week vitiu In t tumot to 30. mont! ppm-! In rats: days expo: ppmwere and : rabb. K< mice com) dosa mors ham Lt level days dost Teat BT1 BT8 BT6 BT7 BT4 70 Table 12. Maltoni vinyl chloride atadiea.* Specie* RATS RATS RATS RATS MICE Results (cairinagenetis), ppm-hr Quettionable at 62,000 Negative at 17,000 Quettionable at 85,000 Positive at 170,000; 860,000; 2.000,000; 8,000,000 Poahive at 24,600,000 Negative at 62,000 and 260,000 Queatknable at 620.000 Poaitive at 2,600,000; 6,200,000; 10,400,000 Poaitfve at 80.000; 160,000; 200,000; 600,000; 1,500,000; 8.600,000 Environmental Health Perspective Auth Viola Ctpu Kept. U*' Con? Com Oct UCC 057118 'Qng Cl c i detona nplified C relative. .posed ni of doses i . hr/day,: > indicate; itn or tou, . Intnotl ts, tra: veeks on); ogenie n- , } 1 > i iriodsimd jectives fmrue it a total dose of 17,000 ppm-hr, a question able response at 85,000 ppm and a positive cardno- wnic response at 170,000 ppm-hr and above. In experiment BT7, Wistar rats treated with VC at doses ranging from 50 to 10,000 ppm, for 4 hr daily, 3 days'week for 52 weeks in the same manner as described above show positive carcinogenic affects at total dosage of 2,600,000 ppm-hr. The author suggests from comparison of the experimental data obtained with two different strains ofrats (BT1/BT3), Sprague-Dawley and (BT7) Wistar, that the strain seems to be a factor in neoplastic response. Based upon neoplastic lesions observed, the Wistar strain mas less responsive than Sprague-Dawley. Exper iment BT4 with Swiss mice, involving exposure to VC at 50 to 10,000 ppm, 4 hr per day, 5 days per meek for 30 weeks produced carcinogenic effects ith a total dosage Ct of30,000 to 3,600,000 ppm-hr. In the studies of Viola, Bigotti and Caputo (2), tumors were seen in rata which had been expoeed to 30,000 ppm VC, 4 hr/day, 5 days/week, for 12 months. The total doae (Ct) of VC was 28,800,000 ppm-hr. ** In the studies of Caputo, Viola and Bigotti (8), rats and rabbits were exposed to VC for 4 hr/day, 5 days meek for 12 months at aix dose levels. The exposure to 50 ppm VC or total dose of 48,000 ppm-hr produced no tumors. Carcinogenic effects mere observed st total dosage of 320,000 ppm-hr and above for rats and at 7,800,000 ppm-hr for rabbits. Keplingvr et al. (9) exposed rats, hamsters and mice to VC. Only the data on mice were sufficiently complete for examination of total doae effect. Total dosage of j6,000 ppm-hr and above produced tu mors in mice. The final report on the rats and hamsters is still unavailable for evaluation. Lee et al. (6) exposed mice and rats to three levels of VC: 50, 250 and 1000 ppm, 5 hr/day, 5 days'week for up to 12 months. AO testa with a total dose of 4s.000 ppm-hr and below were essentially negative for mice. Positive carcinogenic effects were noted, however, in mice above 78,000 ppm-hr. The results of our study indicate that s positive carcinogenic effect in rats may not appear until the total doee (Ct) of VC exceeds 50,000 ppm-hr. The ingle exposure study with ICR mice was negative at 50 and 500 ppm-hr, borderline at 5000 ppm-hr but did produce neoplastic lesions in the lung st 50,000 ppm-hr. The A/J mice exposed to multiple doses of VC, Le., 60 ppm x 100 days x 1 hr or 500 ppm x 10 days x 1 hr fort total cumulative dose of VC of 5000 ppm-hr show a significant tumorigenic response, but only at the higher dose level - In our studies Fischer rats exposed to a total dosage of 50,500,5000, and 50,000 ppm VC for 1 hr showed no chemically induced tumor response. Nei ther did the Sprague-Dawley/Wistar rats that were exposed to 500 ppm VC 1 hr/ day, 5 days/week for 10 weeks (total dosage 24,500 ppm-hr). Table 13 summarizes various investigators' test results, including our own, on vinyl chloride. Hie tests with ICR mice, single exposure to VC, show an increased frequency of adenomas at total dosage of 5000 ppm-hr and above. For A/J mice, repeated exposures to 50 and 500 ppm VC for a total dosage of 5000 ppm-hr shows a similar dose response pat tern for adenomas. In general, in terms of total dosage Ct, carcinogenic effects are seen in the two mice strains at Ct levels of 5000 to 50,000 ppm-hr. Thus total dosage for carcinogenicity in mice is in general agreement with Lee etaL (6) (78,000 ppm-hr) and Maltoni (5) (between 30,000 and 150,000 ppm-hr) and other investigators. There is no doubt that risk is related to length of exposure and hence total dose. In our discussion much attention has been focused on the risk of cancer associated with total dosage of VC. Howev er, the multiple exposure experiment st 50 and 500 ppm dose levels with A/J mice for an equivalent total exposure to 5000 ppm-hr appears inconsistent with the thesis of total dosage. Indeed, it appears Author* ViuU. Bipi'tti and Caputo U) Caputo. V,;a and Bigotti (3) Ktplinger et aL (*) Ue) Conaumer Product Safety Conumtti' :', (19TB) Table IS. Other vinyl chloride atadlee. Spidif Results (cardnogencsiB), ppm-hr Rata Rata Rabbit* Mice (rata and hamster*) Mice ICR mice AJJ mice Fischer rax* Positive 28,800,000 Negative at 48,000 Pooitiv* at 820,000; 1,280,000; 8,200,000; 6,400,000; 12,800.000 Positive at 7,200,000 Poehive at 86,000 All testa essentially negative below 78,000 and positive above 78,000 50 and 500, negative 5000, borderline poeitive 50.000 positive 50, 500, 5000 and 50,000, negative 24,500, eosinophilic loa, no cancers October 1981 71 ucc 057119 from our own data that concentration may be the dominant factor for acute or low level intermittent exposures. This result may be explained on the basis of a number of factors, ie., metabolism, de toxication, DNA repair or a time for tumor devel opment for low level exposure beyond the animals' lifespan. As is evident from Table 13, the two strains of rats, Fischer (344) and S-D/W, were more resistant to the adverse effects of single and multiple inter mittent exposures of VC. Our studies are in agreement as to the dose-time relationship for carcinogenesis related to the VC exposure. All of the continuous exposure studies considered collectively indicate that there is a life time total dose (CO for VC. However, from our own studies with single or intermittent low level expo sures to VC we believe that concentration may be the most dominant factor in whether or not carci nogenic effects are observed. For single dose stud ies with VC in ICR mice, neoplastic lesions were produced at 5000 ppm. For multiple intermittent exposures studies with A/J mice the critical concen tration for VC was 500 ppm, total dosage 5000 ppm-hr. Approximate carcinogenic Ct levels of VC based on data for mice and rats are Ct 5,000-50,000 ppm-hr, carcinogenic tendencies; 500,000 Ct > 50,000 ppm-hr, definite carcinogenicity; Ct > 500,000 ppm-hr, high incidence of carcinogenicity. Considerations of Carcinogenicity of VC: Conclusions Cancer seems dependent on total dose of vinyl chloride, especially in life-time exposure studies, but for short-term exposure the concentration may be the most critical factor. One dose is sufficient if dose is high enough. TV carcinogenic total dose was 5000 ppm-hr for am and 50,000 ppm-hr for rats. There were apparent noncarrinogenic doe* i the study. Mice were more sensitive indicators than rat* k carcinogenic effects of vinyl chloride. REFERENCES 1. Viola, P. L., Biocottt, A, and Caputo. A. Onmfst response to rat skin, tangs tad boot* to vinyl ehlondi Cancar Rea. SI: SUMS (1971). 2. Maltoni, C. Communication amt to OSHA. Proceeds*?* the Proposed Permanent Standards for Occupational Emwon to Vinyl Chloride, Occupational Safety and Hot Adrainistratlon, U.S. Department of Labor, Wsihs*i* D.C., 1974. 8. Cratch, J. L., Jr., and Johnson, M. N. AngiaeanaHf liver in the manufacture of polyvinyl chloride. J. tec Med. 16:1S0-1&1 (1974). 4. Notional Cancer Institute. Guidelines far csrdnoftn bn* say in small rodents. NCI Caranogeneiis Technical Repr Series No. I, NCl-CC-TR-1. U.S. DHEW. February ISC* 6. Mthoni, C. The value of predictive experimental hinear; occupational and environmental carcinogenesis. An cue pie: vinyl chloride. Ambio. 4:18-28 (1978). 6. Lee, C. C., Bhandari, J. C.. Winston, J. M.. House. W.B Dixon, R. L., and Woods, J. S. Carcinogenicity of nr chloridc and vinylidene chloride. J. Toxicol. Environ. Heat 4:1540 (1978). 7. Haber, F. Die Chemie bn Kriege: Zur Geacfaiechte 6Gatkampee. In: Funf Vortrage aus den Jahrcn 192H Julius Springer, Berlin; dted in Prentiss, Chemicals m We McGraw-Hill, New York, 1987. 8. Caputo, A, Viola, P. L., and Bigotti, A. Oncogtnimr i vinyl chloride at low concentrations in rats and rabfam J Int. Res. Common. 21:1582 (1974). 9. Keplingw, M. L., Goode, J. W,, Gordon, E. E.. uc Caltndn, J. C. Interim results of exposure of rau, he aters and mice to vinyl chloride. Ann, N. Y. Acad. Set 14 219-224 (1975). 10. Makond, C-, and Lefemint, G. Carcinogenicity aaiar i vinyl chloride. Ann. N.Y. Acad. So. 246:196-218 <19751 Pn Po by l Moc D. V Introt Appr chloride in 1979. lion pro .-ton po! panicle than tht vinyl ch cly of ir i-tabilize i^-u-ral product: ufPVC and coni Mdinp. in.'Ulatio fWtile. curtain?, automot: *Dn i-ioi '! Hulih i rati. Ohio . 71 Environmental Health Perspectim October UCC 057120 u&h. Tu tor ie Environmental Health Penpeetivee Vol. 11, pp. 73-81,1981 doses r iratsfe Onwpt* chta* ^dinpcf iil Zxa, id Htah.- iShiftflK mom t 1- Ottaf enhtot- d Repor lO'lr* UNM'i n cm . W.B Of \UH Hctfer 1. .2 in Wir. ikity <f ibiti. J and ban-d.24t 3**V (f 97S). Pneumoconiosis in Animals Exposed to Poly(vinyl Chloride) Dust by David H. Groth,* Dennis W. Lynch,* William J. Moorman,* Lloyd E. Stettler,* Trent R. Lewis,* William D. Wagner* and Choudari Kommineni* Rita, guinea pip and monkey* n expo*4 by inhalation hr/day, S day*/waak) for tip to 21 muniha to a 13 mf'm' concentration of PVC duct. Automata on rati and (tiinaa pip wort performed aflor 12 month* of expoeurt and on monkaya after 22 month* of exposure. Lung function teaia were performed on monkey* after 3,14 and 22 month* of expomra. Afirefata* of aKcolar macrophage* containing PVC particle* were found in the lunp of all animal*. Theae wiTtiiln were more numerous in the monkey lung*. No flbrost* or significant cellular infiltrate* were present in or near these cellular aggregates. No significant effects on pulmonary function could be demonstrated in the monkey* expoeed to PVC. Under the condition* of this experiment, inhaled PVC produced a benign pneumoconiosis. Introduction Approximately seven billion pounds of poly(vinyl rhl-inde) (PVC) were produced in the United States in 15(79. There are two miyor types of PVC produc tion processes, suspension polymerization and emulMn polymerization. The latter process produces farticles which are respirable and much smaller than those in the former process. These polymers of vinyl chloride are usually compounded with a vari ety of ingredients (e.g., plasticizers, light mid heat stabilizers, pigments and fillers) and processed in several different ways to produce thousands of end products in common use in our society. About 40% of PVC is used to make sewage pipes, water pipes and conduits. It is also used to make construction siding, window sashes, electrical wire and cable m-ulation, packaging films (for meat, etc.), vinyl IW tile, wall coverings, phonograph records, shower curtains, bottles, fabrics for clothes, ftirniture, automotive parts and many other products. Chest x-ray abnormalities, respiratory dysfunction and pulmonary granulomas have been reported in worker* exposed to PVC dust during PVC manu facturing and fabrication (1~6). Consequently, experimental studies were initiated in 1975 to study the effects of inhaled PVC dust in animals. Materials and Methods Test Material Ten pounds of PVC (trade name Geon 121) were obtained from Goodrich Chemical Company and used in this experiment. The manufacturer's speci fications stated a particle size range of 0.5-1.5 jam. Electron microscopic examinations in this labora tory confirmed that at leaat 90% of the particles were less than 1.5 jim in diameter. The PVC was stored in its covered, fiberboard shipping container throughout the duration of the study. ^Dnujon of Biomedical and Behavioral Science, Department f . Health an! Human Service*, National ln*titut* for Occupati-ru,]>f*,y s-.d Health, Robert A. T*ft Laboratories, CindnJ'.i, Ohio U5ii6. Dust Generation and Measurements PVC powder was packed daily or every other day into a Wright dust feeder at a pressure of 3000 October 1981 73 / ucc 057121 Ib/in.*. The generated duet was fed into the main* stream of the inhalation exposure chamber intake air supply and through a static eliminator before entering the 160 ft3 chamber. Airflow through the chamber was maintained at 40 ft8/min with a nega tive chamber pressure of 0.2 in. water. Animals were exposed to PVC dust 6 hr/day, 5 days/week for up to 22Vi months. Four chamber dust samples were collected each day by drawing chamber environment air, at a rate of 10 liters/min for 20 min, through DM 5 pm pore size Metricel filters with a vacuum pump. In addi tion, simultaneous samples consisting of particles with an aerodynamic diameter * 7 pm (respirable fraction) were collected with a 10-plate, horizontal elutriator. All samples were weighed immediately after each sampling period and the chamber dust concentrations calculated. Adjustments in the dust generating system after each sampling period were made when necessary to maintain a concentration approximating 10 mg of respirable duit/m* of air. Daily and grand means (derived from averaging the daily means) for the*fbtal and respirable dust frac tions were calculated. Midway through the experiment, two 6-hr cham ber sir samples were collected on charcoal tubes while PVC dust was being generated. Those two samples and the bulk PVC were analyzed for vinyl chloride by gas chromatography. Samples of dust that were allowed to settle on Formvar-coated copper grids placed in the chamber during the PVC dust generation were examined by transmission electron microscopy. Animal* Animals used in this study were male, cesareanderived, Sprague-Dawley rata (Laboratory Supply Company, Inc., Indianapolis, Indiana); male, Hartley guinea piga (Sweetwater Farina, Hillsboro, Ohio); and imported, adult, male Cynomolgua monkeys (Primate Imparts Carp., Long Island, New York). The treatment and control groups each contained 80 rats, 40 guinea pigs and 10 mpnkeys. Because of difficulties in obtaining imported monkeys from the supplier, the control group of monkeys was re ceived several months before the exposed group of monkeys. They were not randomly assigned, be cause the control group was also used for the con trol group in another ongoing experiment Conse quently, at time of first exposure, the mean weight of the control monkeys was 4219 and that of the exposed group 3361 g. In the ensuing 22Vi months, the controls gained 552 g in weight, whereas, the exposed group gained 2116 g. The rats and guinea pigs were quarantined for 74 two weeks and the monkeys were quarantined f, one month prior to the initiation of the exposures. Stainless and galvanized steel openv* mesh cages were used is exposure caging to pr. vide adequate distribution ofthe dust aerosols vttk the exposure chambers. All of the animals in & study were individually marked by toe-clippings tattoo. All three species were individually hooiK during the 6-hr exposures, whereas the rats k guinea pigs were housed two to four animals j* cage at all other tunes. Control animals were houK in similar cages in separate animal quarters me exposed to filtered air 24 hr/day. The exposed * mils were also housed in the animal quartets a cept during the 6-hr inhalation exposure. Rsu guinea piga, and monkeys were fed standard libratory pellet diets (Rodent Laboratory Chow, Gum Pig Chow, and Monkey Chow-Jumbo from Balttz Purina, St. Louis, Missouri). Monkeys were jnc fresh fruit (oranges, bananas or apples) ten i week. Tap water was available ad libitum except during the exposure period. Food was available u the rodents at all times except during expoetn The monkeys were fed once daily at the cessation' the exposure period. Pathology Within one day after the last exposure day. a the surviving rats and guinea pigs were autopsiet Their lungs were inflated with 10% buffered form lin and sections of liver, spleen, heart, kidne;. pancreas, adrenals, thyroid, testis and urinary bWder from each animal were fixed in 10% bufient Table I. fUanlte of pulmonary ftmctioa t**t bi mk* after 14 month* txpoeur* to PVC duet* Pulmonary function taet Group* Control Eqee RL, on HfO/L/hae CL, ml/an HgO TCL, ml VC, nd 1C, ml RV, ml RV/TCL,* F*V 0.5/FVC, * PF, ml/eac FEF 50%. ml/aac FEF, 26%, ml/eac FEF 10%, mi/tec CV, ml AltylOOml Vieo V, ml 12.1 4.0 13.8: ir 22.9 $57 * 10 SO 173 s 190: 334 185 * >6 19 330: no: if 40 10 38: i; 11.3 2 2 0.0: * 87.7 5.3 - * 843 * 01 880: 13 920 64$ 262 91 173 * 114 805: <55: 1> r1 2(0: i* 21 0 21: !. 1.05 0.3 0.7: 28.7 * 19 10.8: `Data are presented u means s one standard deviate*l? each of the parsmetare. Environmental Health Pertpedh** V V'. 'it h'.i at brom formal; each It tissues micro?, all sun (>f the hronch stomac with t) lot* of lung ti. Mfsiot Pulin' Befo. <Mobei UCC 057122 antined ft- * inhalantI opens** ingtopr. olsitit nals in it dipping v illy hou e rats at nitnals ptere bou. carters ; posed u. oarten ei ure. Ru. ndard life, ow, Guini m Rabtar cere give i) twice i m excey vailablet. exposun essationc: e day, li autopsied -ed forms- kidney .iaryWi4 5 buffem Vci if ": art;;' VV'* * . i . >,. T- * ?r * . l>.-* .r * y'v .*'>- r 'r-7 . .. A.'j'.C*-*. .* . ***'* i'1* .-v ;r r*. ' *i ' '* *. n , h.-K 1 M. - phig* iggrtgitu in lung of monkey cxpoMd to PVC du*t for 22 month*. Aggregate* are primarily in rwpiratory bronrhiotrr 1 alveolar duo*. (Original magnification 40*). 2E! ElpOMC 0 13.8 = h * 17.6 = 7' 360 = 7- 338 = t 210 = if 36 = 11 9.9 = ! 3 86.8 = 1 960 = 18 906 = 18 3 636 = 1 269:15- 21 =11 , 0.67 = i '9.9 = M evrftiao fef spectho f- rmalin. Hematoxylin and eoain stained sections of each lobe of each lung and of each of the above '.;"Ues were prepared for and examined by light microscopy. Within 48 hr of the last exposure day, all eurviring monkeys were autopsied and sections "f the same aforementioned tissues plus tracheo bronchial and mesenteric lymph nodes, prostate, stomach, (iu lenum and sldn were fixed and procerred in th- >ame manner as those for the rodents with the exceptions that two sections from each l"t* of the lungs were examined, and some of the lung tissue as processed for examination by trans mission electron microscopy. Pulmonary Function Before onset of exposures and after 9,14 and 22V$ months of exposure to PVC dust, the following pulmonary function testa were performed on fast ed, anesthetized (pentobarbital anesthetic) exposed and control monkeys: total lung capacity (TLC), vital capacity (VC), inspiratory capacity (IC), re sidual volume (RV), forced expiratory volume in 0.5 sec (FeV '), peak expiratory flow (PF), maxi mum expiratory flow volume (FEF) at 50%, 25% and 10% of vital capacity, resistance (RL), compli ance (CL), closing volume (CV), N* washout (ANg/100 nU) and volume of isoflow (VisoV). These tests were performed with a variable pressure, whole-body plethysmograph. Means and standard deviations for all parameters in each group were calculated at each interval and comparisons made between groups using parametric and nonparumetric statistical analyses. October 19S1 75 ucc 057123 Fici'KE 2. Macrophage afgiegstes in htn( of monkey exposed to PVC dust far 22 months. (Magnification 385*). Figi *i the P*r Results The mean total dust concentration in the cham bers for the rodents was 13.0 mg/m* (SD - 2.34) and for the monkeys 12.9 mg/m* (SD - 4.69). The mean respirable dust concentration was 10.4 mg/m* for both the rodents and the monkeys. The mon keys were exposed on 464 days for a total of 2818 hr, while the rodents were exposed on 245 days for a total of 1426 hr. The vinyl chloride concentrations in the cham bers at the two sampling periods were 0.01 and 0.02 ppm. A small nonqualified amount of vinyl chlo ride was detected in the bulk PVC. Electron micrographs of the settled chamber dust showed individual particles ranging from 0.13 to 1.68 pm in diameter and agglomerates measuring up to 12.8 pm in diameter. Although the agglomer ates measuring greater than 7 pm in diameter 76 accounted for only 2.3* (5/222) of all the partidr counted, they were estimated to account for mo* than 20* of the mass. Pulmonary Function A summary of the extensive pulmonary funetkr evaluations indicated some signs of loss of hit; recoil pressure, probably s result of the animal' aging process. In most cases, differences were note, during the second and third testing periods (expsure months 9 and 14) and were indicative of wtr.small airway obstruction. At this time, however these differences were not statistically signifies(see Table 1). At the last evaluation (month compared with baseline (preexposure) data, then were no significant differences for any parameter tested. Because of the differences in animal sirns h- Environmental Health Perspective i\m*i the 14 he nu mean in u exist* not a this s > Ter tfpsi sross orjrar Light ofex) Octol UCC 057124 i n 3 Tr:i.' - tussion electron micrograph of macrophage from the lung of a monkey exposed to PVC dual for 22 month*. Note ` :r.r num-ri.j- r-und and oval, electron deni* particle* comprising most of the cytoplasmic space. These are the inhaled PVC articlet moh metior f lun; limai notec expcsome \-ever jfican: :h 22 there meter 'V i<>ff tu'-t-n the control and exposed groups for all except th> 14-month r ten al, meaningful comparisons could t- made onh ;>t that time period. At that time, the m* an weight <-f the controls was 4470 g and that of the e\jx>sed ar.imals was 4190 g. The results appear m Table 1. No statistically significant differences t \i.-u-d. Ini; ..irment of respiratory ftuiction does n--t apix-ar t . be indicated under the conditions of ttn.- study frnm exposure to respirable PVC dust. Pathology Ten expo-ed and ten control monkeys were aut''f>>ied 22-_ months after initiating exposures. No p-oss abnormalities were seen in the lungs or other organs that could be related to the exposures. Light micr- >copic examination of the lung sections of exposed animals revealed macrophage aggregates fh ig. 1 and 2) in the alveolar walls, alveoli, alveolar October 1981 ducts, respiratory bronchioles and around veins. The majority of the aggregates were 100-200 p.m in diameter and some were ss large as 475 pm in diameter. Their concentration varied from three to seven per microscopic field at 100 x magnification. The tightly packed, large, spherical macrophages contained colorless cytoplasm which appeared light blue under phase contrast microscopy. Only a rare aggregate contained any other type of infiltrating ceils, which usually consisted of a few polymorpho nuclear leukocytes. No other lesions that could be related to experimental treatment were present, and no metaplasia, interstitial fibrosis, nodular fibrosis or pneumonitis were present. The tracheobronchial lymph nodes contained aggregates of the same type of macrophages described above in the lungs. Trans mission electron microscopic examination of the macrophage aggregates revealed numerous round particles that do not normally occur in macrophages 77 UCC 057125 and were of the aarne size and shape as PVC particles (Fig. 3). Analysis of these particles with the microprobe revealed high concentrations ofchlo rine (Fig. 4 and 5), thus, Anther establishing their identity as PVC particles. A few aggregates of birefringent particles appeared in the lungs and high concentrations in the lymph node of both the exposed and control monkeys. These particles were identified as mica, kaolin and quartz by the use of microprobe, electron and x-ray diffraction meth ods. The bulk PVC did not contain these minerals. No macrophage aggregates were present in the control monkey lungs. No treatment related lesions were seen in sections ofthe other organs examined. The 57 exposed and 64 control rats were autop- 78 sied 12 months after initiating exposures. Micro scopic examination of the lungs of the exposed animals revealed 0-3 macrophage aggregates/mm scopic field at 100 x magnification (Fig. 6). That aggregates were smaller and much less frequen: than those seen in the monkey lungs. Chrooic pneumonitis, typical for rats, was present with equal severity and frequency in the control d exposed rats. No treatment related lesions sen seen in sections of the other organs examined. The 36 exposed and 39 control guinea pigs ;trt autopeied 12 months after initiating exposures. U*hmicroscopic examinations of the lungs of expose! guinea pigs revealed fewer collections of giant macrophages with dear foamy cytoplasm than th Environmental Health Perspective Met Ivm kv< mer seei chia trek the Qj Ti simi Oct< ucc 057126 tv / i photo (to es. Micixe exposed ite5 micre6). The* s frequent 3. Chronk ?sent with ontrol ifld -ions wen nined. pigs wen ires. Lift: jf exposed itmafn--n those rspecthw ---i-- Ml--1--- m---- _ __ ' ** S- Chinn* x-ray nap of the nine am and magnification depicted in Fig. 4. The white dot* indicate the presence of the rlrmmt chlorine. Note that the dots ere duetered in the sene area as the PVC particles, thus confirming the identification of the t*VC' Wpirrtkks m in the exposed monkeys or rata. Interrtitkd l> mphocvtic pneumonia was a constant finding in si".*! of the exposed and control animals, and the verity and incidence were not related to treat ment. Few macrophage aggregates similar to those wm m the lungs were present in the tracheobron chial lymph nudes of the exposed guinea pigs. No treatment-n.'.,;ed lesions were seen in sections of the other organs examined. Discussion The monkeys in this study developed a benign, simple pneumoconiosis resulting from the inhala* October 19>1 tion of PVC dust st s mean concentration of 13 mg/m* for 464 days (2818 hr). The cellular response visible at 22 months of exposure consisted of PVC* laden macrophages aggregated into clusters in the lungs. On the other hand, the lungs of the rats and guinea pigs contained very few macrophage aggre gates and in a much lower concentration than in the monkey lungs. This difference in degree of cellular response could possibly be explained on the basis of fewer PVC particles being deposited in the lungs of these rodents. Rodents at rest in the chambers during the day breathe exclusively through their noses. Monkeys under the same conditions do not. The rodents in this experiment had extensive bronchitis and 79 ucc 0*17127 Figuke 6. Macrophage aggngataa in the hmf of a rat expoaad to PVC duat for 12 montha. Nota vacuolated appearance o( at (Magnification 386 x I. pneumonitis, whereas the monkeys did not. Both nose breathing and bronchitis are factors which reduce the percentage deposition of inhaled parti cles in the alveolar regions of the lungs. Two studies have been published on the pathologi cal effects of inhaled PVC in rats (7, 8). In one study (7) rats and guinea pigs were placed in a PVC bagging facility. Two guinea pigs and an unstated number of rats were autopsied 2, 4 and 7 months after their continuous residence in the facility. Al though the animals developed pulmonary diseases, the small number of animals studied and the lack of adequate controls makes it impossible to assess the significance of the exposure to PVC. In the other study (8) rats exposed to high concentrations (97 gm/m3) of PVC dust in a static air chamber for 1 hr/day for up to 12 months developed bronchiecta sis, emphysema, purulent pneumonia, lung abscesses 80 and squamous metaplasia in bronchial epithelium. Although the control rats were free of these dis eases, there were only 10 controls examined. It view of the propensity for rodents (controls) u contract acute and chronic pulmonary diseases, th experimental conditions under which control anr mats are kept is extremely important, and should be stated in the protocol. No mention of this * made in that experiment. Two cases reports showing granulomas in luup of two PVC workers have been reported W. Except for the more closely packed macrophages the lesions shown by Aranaud et al. (5), the nor phology of the lesion is similar to that seen in <*.* exposed monkey lungs. Part of the compactness ti the cells in their lesion could be explained on thr basis of artifactual compression caused during thr taking of the lung biopsy. No excess collagen Environmental Health Perspective* appare pranulwey d pulmor tures < ere ' phage^they s! appear vidual fund he rel; differi: tient ' keys v expost 4' hr the in. lung v time. Ste >pecir years a grai tive ti lungs Th. tL-SUt to the a var l'YC imtia' are r PVC. It W( tnfor ronti eflec Mr on e PVC mi< Alth state unpa in a difTe deteafter Vhe have Octi ucc 057128 ;: * **-. .I ice of cdb. lithelium. hese dia* lined. In trolfi) to ages, the itrol aniid should this was in lungs d (3, 5). ihagesin the moren in our ctness of d on the ring the ' was pectives apparent in the light microscopic pictures of the panulomas they showed in their article, although [hey did refer to their case as a "case of discrete pulmonary fibrosis." Their electron microscopic pic tures of the PVC particles in in vitro cell systems were very similar to what we saw in the macro phages in the monkey lungs. The PVC particles ihev showed in s macrophage from the lung biopsy appear to be clustered in lysosomes and the indi vidual panicles are not as dense as the ones we found in the monkey lungs. That difference might be related to the different exposure durations and differing intervals since last exposure. Their pa tient was exposed to PVC for 23 years (our mon keys were exposed for 22V4 months) and had no PVC exposure for 6 years (our tissue was sampled within 4e hr of last exposure). It is possible that some of the ingredients in the PVC particles in the human lung were altered and leached out over a period of time. Szende et al. (3) reported that the lung biopsy specimen from s worker who shoveled PVC for one year sho^ ed moderate diffuse fibrosis and contained a granul' >ma with concentrically arranged connec tive tissue fibers. We did not see this in the monkey lungs. The apparent difference in response of the lung tissue from two workers exposed to PVC compared to the monkeys exposed to PVC might be related to a variety of factors, including differences in the PVC dusts. Since various types of emulsifiers and initiators are used in making PVC, and since these are not completely removed from the powdered PVC. they might explain the differences observed. It would be prudent in the future to obtain more information on PVC manufacturing processes and content of PVC dusts when studying their health effects. Mastrangelo et al. (6) published health findings on employees who were currently working in a PVC production factory. Twenty cases of pneumo coniosis were found in a population of 1216 workers. Although the data were not given, the authors stated that slight restrictive respiratory function impairments were associated with chest x-ray changes in a small percentage of cases. In our study, no differences in pulmonary function teats could be detected between exposed and control monkeys after 14 months of exposure to 13 mg PVC/m*. Whether any pulmonary function deficits would have occurred upon further exposure cannot be ascertained from this study. The lack ofany significant pulmonary function abnormality in these monkeys, however, does not mean that animals or humans exposed to other types of PVC dust or mixtures of PVC dust with vinyl chloride (or a multitude of other ingredients that might be used in fabricating PVC products) might not exhibit pulmonary func tion changes. For the first time, we have been able to show that a PVC dust generated under controlled exper imental conditions is respirable and is deposited in cell aggregates in the lungs of monkeys, that PVC particles within macrophages are fairly unique in appearance, and that their identity can be confirmed with microprobe analyse*. No pulmonary function deficits were found after 14 months of exposure to PVC concentrations of 13 mg/m, thus, confirming the pathological diagnosis of a benign pneumoconio sis. The authon with to acknowledge the aaaietanee of the follow ing people in this project: George Hadden, Brandon Barton. John Clark, David Brewer, Margrit Stoll, Myr* Spring*, Hazel Patterson, Laa Kaleja. Aidith Greta, John Holtz, Charles Gonki. Richard Nieroeier, Richard Homing and Patricia Combs. REFERENCES 1. Tribukh, S. L., et at. Work condition* and industrial hygiene measures in the manufacture and utilization of vinyl chloride plastics. Gig. Sanitar. 10: 38*44 (1949). 2. Vertkin, Yu. I., and Mamontov, Yu. R. On the state of the bronchopulmonary system in workers engaged in the manufacture of articles mad* of polyvinylchloride. Gig. Truda 14: 29*32 (1970). 3. Stand*, B., Lapis. K., Names, A., and Pinter, A. Pneumoconioeii caused by the inhalation of polyvinylchloride duet. Med. Uv. <1: 433-436 (1970). 4. Uha, R., Andenon, H., Nicholson, W. J,, Daum. S,, Fischbein, A. S., and Selikoff, 1. J. Prevalence of disease among vinyl chloride and polyvinyl chloride worker*. Ann. N.Y. Acad. Sci. 246:22-41 (1976). 6. Aranaud, A., Pommier d* Santi, P.. Garb*. L., Payan. H., and Charpin, J. Polyvinyl chloride pneumoconiosis. Thorax 38:19*26 (1978). 6. Maatnngelo, G., Manno, M., Marcer, G., et al. Polyvinyl chloride pneumoconiosis: epidemiological study of exposed workers. J. Occup. Med. 21: 540-642 (1979). 7. Frangia, N., Spinazzola, A., and Burcarelli, A. Experi mental lung damage from prolonged inhalation of PVC dust in a work environment. Med. Lav. 66:321-342 (1974). 8. Popow.J. Influence of polyvinyl chloride (PVC) dust on the respiratory system in the rat. Roczniki Akad. Mad. im. J. Marchlewtldago w Bialymatoku 24: 6-48 (1969). October 1981 81 UCC 057129 Environmental Health Penpectivet Vol. ii, pp 8SSi, 1981 Preliminary Observations of the Effect of Inhalation of PVC in Man and Experimental Animals by J. C. Wagner* and N. F. Johnson* Att> mum hu btm focuucd, both in man and exp*nmntmi animal*, on th* offoct* of inhalation of the fa* monomor, vinyl chloride. Recently, not* i* being taken of the pouibie ffc< i- nf the inhalation of the polymer in man. The particle* in question are thoo* produced rnmmi rnilly a* pa*te polymer or ditpenion polymer or having an avenge diameter of 0.IS urn, mi a. > aunting for nx** than 1W of the production in Britain. There an team ttrict regulation* for iht tunirol of the monomer ga*, but the particle* are regarded a* nuisance dust and their rmi~i'.n if not covered by specific legislation. Our -tuditt on rat*, where both inhalation and implantation method* of exposure have been uwd. and examination of tissue from human cases exposed to paste polymers, indicate that these iruII panicles can only be regarded a* evidence of exposure, and on present evidence there is no indir.iimit of causation of significant pulmonary disease. Techniques have been developed by hu h i hm particle* can be demonstrated in ordinary histological preparations and by transmisuin rlrrtron microscopy. T-.' finer panicles of PVC known in the United ' - *.- disperM >n polymer, are usually less than ' ut. in diamc'.v-r. During the last five years we o>nducted a number of preliminary investiga- - u.-ing this material, and have also observed < ..mall par.i' its in the lungs ofmen exposed to of PVC, and have recovered these parti* fnun the lun cs and livers of human cases using --.^ ration techniques. A second series of experi- ' has been -'arted but no results are available. Tr.v recognition of PVC in tissue has been greatly fii .hiatt-d by a staining method developed by n u). Normally processed histological section# it v.ained with a Sudanophilic dye, which stains particles a bright red. As the tissue has been '' x'vssed and ;.il lipid removed, only the PVC and ' Tie other reh." ed plastics will stain. The particles <v. also be n cognized under the transmission v-'x-'-ron micro-cope, and the morphological appear*:.ooj supported by the confirmation of the pres ent- of chloride when examined by x-ray microanalysis. irch Council, Pneumoconiosis Unit, Llsndough " el. Perurh. W*Je*, U-IL October 1981 Animal Experiments Experiment 1 The experimental animals were caesarean-derived, barrier-maintained rats of the I.C.I. Alderley Park Wistar strain. Six-week old rats were randomized, with equal numbers of each sex, and inoculated intnpleunSy by using a previously described tech nique (f). Forty-eight animals received 20 mg of PVC dispersion polymer into the right pleural cavi ty. The control animals were inoculated in a similar manner (Table 1). The rats were allowed to live out their lives and all are now dead. Between 12 and 18 months after inoculation, nine of the animals receiving the PVC died. Of these, five had tumors of the liver and one had a tumor originating from the site of inoculation. None of the other animals injected with PVC, nor any of the control animals, had a tumor of this type. These tumors were shown to pathologists in Britain and the United States. It was generally agreed that they were poorly differentiated sarcomas, and in three of the animals, the possibility of Kupffer cell origin was considered. As no other animals devel- 83 ucc 057130 / \I Tabic 1. Intrapleural inoculation (rat* 6 week* old). No. rats Treatment 46 rats 24 control rat* 24 control rats 24 control rats 20 mg PVC in saline 20 mg UICC eroddolite in saline 20 mg Min-U-Sil (quirts) in saline saline oped these tumors, two further experiments have been started. In the first, dispersion polymer from three British manufacturers was used, and in the second, freshly produced dispersion polymer from two sources has been inoculated, as well as similar material from which all evidence of detergent or vinyl chloride monomer has been removed. These investigations are still in progress, but in the first of these studies, the animals have passed the 18 month period without any occurrence of the tu mors. Inhalation Studiea A group of 48 rats, 24 of each sex, of the same stock as used in the previous experiments were exposed in an inhalation chamber to PVC dust, the apparatus and methods being the same as previously described (). The animals were exposed to dispel sion polymer, at a concentration of 12 mg/m3 for 7 hr/day, 5 days/week, for 5 months. There were also 48 nonexposed controls. The cumulative dose of the exposed rats was 8552 mg/m* (Table 2). Six rata from each group were killed at the end of the exposure, and a further six a year after the start of the exposure. The remaining animals were allowed Table 2. Inhalation study. No. of rata Exposura 48 rata 6 weeks old 48 control rat* 22 weeks, 12 mg/m*; cumula tive doaa 86S2 mg/m* -hr Nona to survive until they died of natural causes. The PVC particles were present in the nap. phages within the alveoli arising directly from a respiratory bronchioles immediately after the 0 posure. The distribution of these accumulate was widespread but less than a third ofthe prmaunits were involved. Occasional dust particles observed in sections from the bronchopulmotulymph glands, the Kupffer cells in the liver and: the spleen. At the end of a year, the dust was ri present in the spleen and around some fod of mT rophages there was evidence of a slight prolifer, tion ofreticulin fibers. This early dust reticuknaik: did not show evidence of progression in any of& other animals, some of which survived for nu> than two years after the initial exposure. Experience with Human Tissue We have had the opportunity of examining; limited amount of human tissue. This included Un cases of accepted angiosarcoma of the liver, a nawith severe hepatic fibrosis who underwent a a:sequent porto-cava] shunt and material from peop who had been employed in a PVC factory. The* people had either had pulmonary biopsies or k died of diseases unconnected with their occupstiott In all but one case we found small amounts ofPVt in the lung tissue. In two of three angiosarcoma, particles of PVC were found after the maceration: the liver tisaue. At this stage of the investigation, these particle can only be regarded as evidence of exposure dispersion polymer. REFERENCES 1. Wllaon, N. A method for ttaininc polyvinyl (Man* t section* (Mine Sudan IV. Stain TscfanoL 34:101-102 (IKS' 2. Wagnsr.J. C., and Barry, G. Mesothelioma* in rats fetors inoculation with aabaatoa. Brit. J. Cancer 23:567-581 (! 8. Wifner, J. C,, Bony, G., Skidmore, J. W., and Ttakret' The effects of the inhalation of asbestos in rat*. Bra Cancer 2ft 232-268 (1874). Re Wc Me by ( Intro In i: t-xamit media plastic j)lv(vi This IVder. and bj region. The un V( basis o market in mic of dost ppm (; norma! nf exp 'i'Jt-nt and at\ of a sr the among i- the lr. r.u: 84 Environmental Health Perspeetk* Octobe ucc 057131 Environmental Htalth Pertptctivtt Vol. it, pp. 85-48, tail Results of Sputum Cytology among Workers Exposed to Vinyl Chloride Monomer and to Poly(vinyl Chloride) by Cesare Maltoni* and Paola Lodi* The rwult* of systammtic eytologteal xputom examination* of 3,380 Italian VC-PVC indiutiT worker* and of 2,287 worker* in other induatria* at different potential riik and choaen a* control (roup* art repotted. The multi indicate an increaac in cellular abnomalitie* and dysplasia* in the epithelium of the respiratory tract among VC-PVC worker*. Three data arc in Une with experimental result* showing that VC produces lung tumor* in mice and with earl; epidemiological evidence among exposed worker*. Introduction In 1975. it was decided to include the cytological examination of sputum in the protocol of systematic medical surveillance of the workers in all the Italian plastic fact >ries exposed to vinyl chloride (VC) and polylvinyl chloride) (PVC). This program was co-sponsored by the Italian Federation of Unions ofChemical Workers (FULC) and by the Public Health Service of the Italian regions where the factories were located. The decision to investigate cytologieally all Ital ian VC-PVC industry workers was taken on the basis of the following facta: (1) the observation ofa marked inc rease in the incidence of lung adenoma* in mice exposed by inhalatory route, to a spectrum of doses of VC ranging from 10,000 down to 250 ppm U-3): (2) the unusual finding of cellular ab normalities in a high portion of the lung adenomas of exposed mice (1-3); (3) the observation of fre quent severe abnormalities (squamous dysplasia and atypical adenomatous hyperplasia) in the sputa of a small group of heavily exposed workers (S); the report of some increase in lung carcinomas afnong workers from two VC-PVC factories U); 'o) the finding that the majority of lung carcinomas tatitut* f Oncology and Tumor Center, Bologna, Italy. October 1981 observed among exposed workers were not of a common histotype i.e., giant cell carcinomas (5). Planning and Methods The investigation was carried out on workers from 13 Italian VC-PVC factories located in the northern, central and southern parts of Italy, namely, in ViUadossola (1), Portomarghera (3), Bollate (1), Ferrara (1), Ravenna (1), Rosignano (1), Terni (1), Brindisi (1), Ferrandina (1), Porto Torres (1) and Cagliari (1). A total of 3380 workers was examined. These workers have been and/or are exposed to the monomer and part of them also to PVC dust. For comparison 2287 workers in other industries at different potential risk were examined: namely, workers manufacturing PVC products, workers in chemical industries not dealing with plastics, metal workers, miners and workers in the chromium industry. For each sputum examination four cytological slides were prepared. The smears were stained by the Papanicolaou technique. The slides were screened and evaluated indepen dently by the pathologists of the hospitals in the area where the factories were located, then by a trained cytologist in our institute. All abnormal smears were reviewed by the senior pathologist of 85 k Tabic 1. Type, sequence and daasiflcmtion of local changes in the cental* of the various histotypes of pulmonary Stage Normal respiratory epithelium Cjoolopc Nondliated cuboid epithelium Initial nonapadfic stage Adenomatoua hyperplaaia 1 * Squamous metaplaaia 4 Intermediate specific atate Atypical adenomatoua proliferation Squamoua dyiplada 5 Tumor au*e * I In$Uu Pradmical tumor [adenocaranama | Invaaive [adenocardnoma --> Clinical tumor . In aitu squamoua carcinoma Invmarre squamoua Basal cell hyperplaaia 1 Bmlokd ptll dyaplada InattK 1 anaplastic carcinoma Invasive anaplastic carcinoma H, II-(I11) 11*111 (ID-Ill, 111. in-tv IV and V Wor rvc PV( hrtL vtor varx ml, Mrt. Mux War chn> *s Table I. Classification, characterization, diatribution by daaaea and code of (puturn eytolofy flndinp. Cell character Claaa Type* Degree Quantity Codt Not performed I Normal epithelium (LRE, URE, OCA) Histoeytee MI Normal epithelium (LRE, URE, OCA) Histoeytee II Squamoua metaplaaia LRE Hyperaecretive mucous cells Il-UII) Squamoua metaplasia LRE Adenomatoua hyperplaaia LRE IMII Mild atypical adenomatoua hyperplaaia LRE Mild squamoua dysplasia LRE Mild dysplasia URE. OCA (ID-III Mild atypical adenomatoua hyperplasia LRE Mild squamoua dysplasia LRE Mild dyaplada URE, OCA III Well defined atypical adenomatoua hyperplaaia LRE WeD defined squamoua dysplasia LRE Well defined dysplasia URE, OCA IIMV Grave atypical adenomatoua hyperplaaia LRE Grave squamoua dysplasia LRE Grave dyaplada URE. OCA IV Adenocardnoma Suspected Squamoua cardnoma Undifferentiated cardnoma V Adenocardnoma Squamous cardnoma Undifferentiated cardnocne Not evaluable + /+ + +++ *LRE " lower reapiratory epithelium; URE - upper reapiratory epithelium; OCA * oral cavity. 1. 2. 3 1. 2 1. 2, 3 3 1, 2, 3 1, 2. 3 1 1 1 2. 3 2. 3 2, 3 99 01 02 OS 01 06 06 07 09 09 10 11 86 Environmental Health Perspedi'8 *N Grw. VO: m btti Wor v*ncal, Mm. Mux Wor thru indu *0 *s Grou W'or, HVC Won Mru Muir Wort Oct* ucc 057133 . I.nrr of various type* of cytologies! change* In Pt: comparison of raeulta among VC-PVC workers and worker* T*1 of the reference (roup*. Cytological change* -V "a * -l-** of Non Hypsr- et al- ascretive uable mucous Squamoua Squamous Atypical etj-es Case* calls and meta metaplaaia Adenoma- adenoma- i in without squamous plasia with horn tou* hyper- too* hyper- Squamous --jf- epithslial metaplasia LRE peart* plaaia plaaia dytplaaia f.rient Eval- changes LRE -*/* -f + + LRE LRE LRE LRE of mate- uabl* CIpP' nil) cues No. No. No. ft No. t No. ft No. ft No. ft Dysplasia URE. OCA No. ft Sin nS 2558 799 31.2 1158 45.1 374 14.6 70 2.7 794 31.0 88 1.5 219 8.6 44 1.7 Hi 79 343 99 28.9 253 73.8 36 10.5 1 0.8 74 21.6 4 1.2 4 1.2 1 0.3 1015* 130 889 165 18.6 604 66.9 88 9.3 3 0.3 227 25.5 8 0.9 10 1.1 - - . - * i.-tru-;.* *4 54 210 78 34.8 109 51.9 30 14.3 V -r*-.' 41. 48 354 47 13.3 254 71.7 41 11.6 4 of In* 28 152 5.9 89 6B.5 69 45.4 1 0.5 1 0.3 1 0.6 5 2.4 59 16.7 7 4.6 5 1.4 6 8.9 6 2.8 4 l.l 28 18.4 1 0.3 "- ... \TJT, vorvi and chromium induetrie* and not exposed to a known risk. N n)*-ed to a M own risk. ' T*M.< Ihttnbution. by claiM* of eytological changes in sputa: comparison of results among VC-PVC worker* and worker* of the reference (roup*. Not Classes evaluable ----------- --------------- ---------------------- No cates Eval- 1,1-11 II II-(III) Il-III (IIVIII of .r,sufficient uable -- ------------ --^ --...... CfcM - material) eases No. % No. * No. ft No. ft No. ft III III-IV IV V .............. --1 . ............ No. * No. * No. ft No. * * * ?* of it'n 822 2558 799 31.2 706 27.6 780 30.4 211 8.6 21 0.8 36 1.3 7 0.2 - - - a SAT * \ i r^rutet.-vr- 422 * f K'l** 11" rhrmn Mj*tnee* )(* ..rker* 2f4 K 4rJ * ii-Tt of Hi 79 130 54 48 28 343 99 28.9 186 88.8 102 28.7 4 1.2 1 0.8 1 0.3 1 0.3 - 889 165 18.8 398 44.8 313 85.2 6 0.7 6 0.7 * 210 73 34.8 ICS 48.6 28 18.8 6 18 - 1 0.6 354 47 18.8 280 62.1 82 28.1 2 0.8 1 0.8 1 0.8 1 0.8 - - * 152 9 5.9 68 41.6 61 38.8 18 11.8 2 1.8 6 3.3 4 16 " ~ * " ' cr. r than WI'VC and chromium industries and not exposed to a known risk. 'Y `. txputtd t< ,, known risk. Table 5. Iii.tribution of classes U-4III) and over among VC-PVC workers and the workers in reference (roups. * H-r> of YC-J'VC industry it* manufacturers * -trr> of varv' j- chemical Industrie* di-Ui corkers H>r ^ in chromium industry flints IHIII). ft 30.4 29.7 36.2 13.8 23.1 33.6 Claaaea II-III, (IIVIII. % 9.4 1.6 1.4 18 0.9 13.1 Claaaea III, III-IV, ft 1.6 0.6 0.6 0.6 5.9 October 1961 87 ucc 057A34 the same institute. A joint critical reevaluation was carried out for those cases where there was not full agreement. The same criteria of classification of the lesions and their distribution by classes were adopted by all pathologists. Such criteria are based on our knowledge of the local cytological changes and of their sequence in the genesis of the various histotypes of pulmonary carcinomas (Table 1). The list of the most relevant changes correlated with environmental and occupational exposure, their distribution by classes following qualitative and quantitative parameters, and the code, are given in Table 2. This list takes into account not only cells from the pulmonary tree, but also cells from the upper respiratory tract and oral cavity. Results The number of valuable cases, the distribution of the cytological ctyqges and the distribution of the results expressed by classes in the group of work* ers in the VC-PVC industries and in the control groups, are given in Tables 3 and 4. The incidence of dysplastic changes is particularly high in the plastics industry workers when compared to the other control groups, with the exception of chro* mium workers, which can be considered a positive control. The situation is well illustrated by the distribution of classes II-(III) and above (Table 5). It may be stated that, in relation to the incidence of respiratory cell abnormalities, the workers in the VC-PVC industries can be placed halfway between chromium workers and other groups. A finding which deserves attention is the occur rence of atypical cells in the oral cavity and upper respiratory tract in 44 workers (17%) among VC-PVC workers (Table 3). The results were highly homogeneous in differ ent factories, suggesting that variations in cli^' which may affect the incidence of common pi*, mopathies, is not a determining factor. ', The difference in the distribution of the patholtf ical findings was not dependent on tobacco smu ing. Conclusions The results presented are consistent with exp* imental data and early epidemiological evidence the potential oncogenic effects of VC exposure k the lungs. Furthermore, our data suggest a possible omgenic risk for the upper respiratory tract whe should now be explored by proper epidemiologies: investigation. Much remains to be done to clarify the pr played by the monomer and by polymer dun t determining the observed cytological changes. Or data are now being re-examined, on the basis oftk complete exposure history of single workers, u better establish the role played by PVC particle REFERENCES 1. Mahoni C., and Lcfemine G. Carcinogenicity biossays i vinyl chloride. I. Research plan end early results, ta Res. 7: 387-406 (1974). 2. Mahoni. C., and Leftmine. G. Cardnogericity biosasiy; t vinyl chloride: current raaults. In: Toxicity of Vinyl Oibnr Polyvinyl Chloride, New York Academy of Sciences. Nn York, 1975, pp. 196-218. 3. Mahoni, C., Leftmine. G., Chieco. P., end Carretti, D. U cancerogeneai embientale e professional nuove prospettn, alia luce della cancerogeneai da cloruro di vinile. 0pedal! Vita, 1 (64): 446 (1974). 4. Wagoner, 1. K. Statement before the Subcommittee ft Environment of the U.S. Senate Commerce Conuwti* 1974. 6. Thomas, L- B. Personal communication. Environmental Health Penpectk* UCC 057135 5 *' wun1., imon p(r Environmental Health Penpeetivee Vol. il, pp. M-H. mi >e patta., 'acco fir. Observations of the Site-Specific A'ith esf. Carcinogenicity of Vinyl Chloride videm-c \posui> to Humans sible or. act vi h. emiolop. by Peter F. Infante* ' the pi* ?r du#:. nges. (. asis of:rkerf,: particie- WNV. laawtij. I Ch)*>, nett. i, l) L rwpr". mil* t:*v or. Vf onuwui* *r A rr\ if* of cpMcmiolotic itudtM of worken expooed to vinyl chloride (VC) woo conducted. Some of ihcie ttudie* compriiod amall cohort* and thu* wr iMMittho in the evaluation of ran inogcnic rvaponac for *ito* that do not dcmoiwtrate a hi*h relative riak. Other larger ludu- used methodology and detifn that precluded an interpretation at the rorndta. Such limiutioni were acknowledged by eome author*. t v of reetrictive jli*ea*e rubric* alio lead to the (ubmerging of *ite* that would hare demnn.trated ligniflcant race**e*. For example, *ome invaatigator* analyzed data for liver ram t r death* with the board category of digeative ayatem cancer death*. while other* combined data f'>r CVS cancer death* with the broad cateogry of "other end unapccifiad cancer," and moat tudif analyzed information for lymphatic and hematopoietic ayatem cancer death* with all data i mbined. Only four ofeight atudie* reviewed could demon*trate a tignifleant excee* of Uver ram i r among VC-expoaed worken--a ait* confirmed In human* by 1*74. In contraat, live of eight ~tudie* appear to demonatrate a ligniflcant exceaa of CVS cancer mortality. Worker* eipn-i d to VC alto demonatrate e ligniflcant exceaa of mortality for lung cancer, while the data for !> mphatic and hematopoietic ayatem cancer are auggeative. Interpretation of cancer of the latur >i*itm may have been clarified if inveetigaton had not analysed their data by broad diMa-i c'laiiiflcatione. Ir IH'Ki. shortly after vinyl chloride (VC) waa -'Ijcwl into commerce, VC toxicity was re> --'I in experimental animals (1). Over the next * i* cades, study throughout the world indicated employment in the VC induatry was associated * " wide range of toxicity in humans. Thi* ha# included nonmalignant pathologic ef- i-r symptoms, involving (but not limited to) i-nes. liver, central nervous system (CNS), and blood (.?). l--.een 19To and 1974, experimental bioaaaay ~ n.-t rated \ C-induced cancer in multiple or" ' 'wluding the liver, brain, lungs and lymphatic im u. 4), This carcinogenic response has been * > "f (zrnm.fvn Identification and Gaiaification, Health V. VT*-' Occupational Safety and Health Adminia-* ' ' s lHii,,r.,T'.ent of Labor, Waahington, D.C. 20210. . * 'V.'/V'*'""'';n thi* PP*r <*o not neceaaarily rapreaent ~ "'TM` l*ccuj.j:;,,n*i Safety and Health Adminittration. tktoher 1981 observed in several species, given a wide range of doses, by various routes of administration. Between 1973 and 1977, several epidemiologic studies were undertaken to assess the site-specific cancer risk among workers exposed to VC. For this presentation, findings of these studies will be limited to an assessment of cancer of four organs or organ systems in humans. These same sites sre known to be associated with nonmalignant VCrelated disease or symptoms in humans and cancer in experimental animals. Liver Cancer in Humans Table 1 shows a summation of data from the epidemiologic studies as related to Uver cancer. Some authors did not present site-specific analyses for Uver cancer deaths. Therefore, the most specific information available is presented. Waxweiler et si. (5) conducted s cohort study of workers who had been exposed to VC in the U.S. 89 ucc 051136 S Table 1. Epidemiologic study remits of VC-expoeed workers as related to biliary and liver or digestive system <aaeerfcm Investigation Site Observed Deaths Expected SBR ~ Wsxweiler et si. (5) Total cohort Latency > IS yr Byren et el. () Total cohort Latency > 10 yr Fox and Collier (7) Total cohort Plant #2 > 16 yr Seven other plants Monson at aL (#) Total deaths Tabershaw and Gaffcy (a) Total cohort Highest exposure. > 5 yr employment Buffler et sL UoH Biliary and liver Liver and pancreae Liver Biliary and liver Digestive organa 7 0.6 lisp 7 0.4 1606* 4 0.97 413* 4 0.68 UP - 4 1.64 244 S 0.18 2MB1 1 1.61 6 8 0.7 19 21.7 11 7.6 1LP* 94 1S1 Ott et al. Ul)* EEH ) Total cohort Latency > 20 yr Digestive organa 29 40.8 9 13.6 71 70 V < o.oi. *p < 0.06. 'Proportional mortality study risk ratio. ^No liver cancer identified among 8 cancer daatha. *No liver cancer identified among 20 cancer daatha. for at least five years and who had achieved a period of ten or more years since initial exposure (latency). On the basis of seven liver and biliary cancer deaths that fit the cohort definition, the study demonstrated an 11-fold to 16-fold excessive risk of death from cancer of this site among VC-exposed workers. These findings represent an underestimate of the riak because seven additional individuals who died from liver/biliary cancer at the plants being studied were not included in the analyses. Ofthese latter seven cases, four individu als diagnosed with liver angiosarcoma were still alive at the study cut-offdate, while two individuals who died from biliary cancer had incomplete infor mation on length of exposure to VC. A seventh individual did not fit the study cohort definition as he was exposed for only three years. He died from liver angiosarcoma 17 years after his initial expo sure to VC. Byren et a], (6) conducted a cohort study of all Swedish workers ever employed in positions where exposure to VC could have occurred. The investi gators combined deaths from cancer ofthe liver and pancreas because they believed that there waa 90 some overlap in reporting. There were four liver/pancreatic cancer deaths observed, compand to 0.77 expected (p < 0.02). An additional dot: from liver angiosarcoma was identified as having occurred after the study cut-off date and thus not included in the study. Fox and Collier (7) studied U.K. workers posed to VC. In eight factories studied, they observed a total of four liver cancer deaths compared to 1.64 expected. Three of these doth: occurred in factory 2, where only 0.13 would hivt been expected (p < 0.01). The authors stated that f. was difficult to identify angiosarcoma of the live from death certificates (the usual method of identification), since some of these deaths w* classified as primary, some as secondary liver cancer, and others were not certified as cancer deaths at alL The results from the Fox and Collier stud} probably represent an underestimate of the oh served risk of death from cancer for the foUouin? reasons: (1) 75% of the study cohort was employed for less than ten years; (2) only 8% of the cohcf was employed for more than 20 years; and (3) ever Environmental Health Persoecti'6 ucc f-rt au'.R PK** *hor Tm> *#' M talk;plan' ttud ciph\er* Ta coho indu- data drat catCi Tsbl from the 1 year cant' oft). H' jubr in th Of t note the#. KCO An: sen was beer priir und* cirri T) ent diag resu risk, that this dete exp* folk uals the stud oftl atel; be w callv B Oct* 057137 ',r those who completed 20 years of service, the wthore stated that "because their service has only fvrcntly been completed, the follow-up period is too .Sort to evaluate the carcinogenic effect of VCM." jhj.i statement obviously applies to the liver as well v to other sites. Monson et al. (8) conducted a proportional mor tality study of 161 deceased workers from two plants where VC was used. These plants were also studied by Waxweiler et al. (5). They observed ti?ht deaths from liver and bilury tract cancer itr?us 0.7 expected; the risk ratio was 11.0. Tabershaw and Gaffey reported the results of a cohort study of workers exposed to VC in 33 U.S. industrial facilities. The authors did not analyze the data separately for liver and biliary cancer. Thus, deaths for these causes are accounted for in the category' of digestive organ cancer. As noted in Table 1, for the total cohort there were 19 deaths fn>m digestive organ cancer and 21.7 expected. For the highest exposure cohort, with more than five years of exposure, there were 11 digestive organ cancer deaths observed versus 7,5 expected. None of the obsen ations are statistically significant. However, the risk of liver cancer in this cohort is ubmerged by including data for this cause of death m the analysis with digestive organ cancer deaths. Of the 19 digestive cancer deaths, the authors noted that seven were from liver cancer. Two of the* liver cancer deaths were listed as angiosarcoma according to the diagnosis on the death certificate. An additional four deaths from liver angiosarcoma were identified in this cohort by the time the study was published in 1974. Two of these deaths had been categorized by death certificate diagnosis as primary liver cancer, and two had been certified under causes of death other than cancer, i.e., cirrhosis of tve liver and hepatoma. This study again demonstrates one of the inher ent limitations of epidemiologic studies (incorrect diagnosis in relatively rare cause* of death) that result in an underestimate of the relative cancer risk. An additional factor, indicated by the authors, that may have led to an underestimate ofthe risk in this study was that the group with no vital status determination, 15% of the population, began their exposure ten years before the group for whom followup was completed. As a result, some individ uals with lunger latency periods were omitted from the study. In addition, 57% of the cohort actually studied hud less than 15 yean of latency. Because of the healthy worker effect, the authors approprittely stated that SMRs higher than expected may be w orthy of attention even if they are not statistitally significant. Buffer et al UO) and Ott et al. ill) did not October 1981 observe any liver cancer deaths among eight and twenty deaths, respectively, in their studies. An unpublished study conducted by Equitable Environmental Health (19) reported the mortality of a cohort of worken from 37 U.S. industrial facilities. This study included data for the facilities studied by Tabershaw and Gaffey (9). Data were not analyzed separately for liver cancer. However, the category of death from cancer of the digestive organs, which includes liver cancer deaths, indi cates a deficit of mortality. As shown in Table 1, even for those individuals who had achieved 20 or more yean of latency, the SMR was only 70. It is somewhat unusual to observe such a deficit of mortality among worken who had achieved such a long latency period. Brain Cancer in Humans Brain cancer also has been associated with expo sure to VC. A summary of the results of mortality studies is shown in Table 2. Although the number of cases upon which observations were based are small, Waxweiler et al. (5) and Byren et al. (6) demonstrated significant excesses of brain cancer. The relative risks were five and six, respectively. Waxweiler et al. (5) also noted an unusual distribu tion in the cell type of brain cancer. Of 10 brain cancer deaths identified among the VC-exposed workers, nine (90%) had a histologic diagnosis of glioblastoma multiforme. The tenth case had no confirmation of cell type. Hie authors contrasted this high proportion with that of the Yale autopsy series in which 33% of primary intracranial neo plasms were glioblastoma multiforme. Fox and Collier (7) observed two brain cancer deaths as compared to 3.7 expected for the entire cohort. For those cohort members categorized as having high exposure, one brain cancer death was observed versus 0.4 expected. Monson et al. (8) demonstrated a fourfold risk of brain cancer. Tabershaw and Gaffey (9) categorized brain can cer with "other and unspecified causes of cancer death;" therefore, it is not possible to determine the actual brain cancer risk identified in this study. Since the Tabershaw and Gaffey study (9) was a subset of the EEH study (19), the latter study was used to estimate the expected number of brain cancer deaths in the former study under the as sumption that the age distributions were similar. The proportion of expected brain cancer deaths from "other and unspecified cancer deaths" in the EEH study (19) was then applied to the expected from this same category in the Tabershaw and 91 ucc 057138 Table 2. Epidemiologic study multi of VC-expoeed workers ai related to central nervous system. Investigation Site Observed Deaths Expected SMR Waxweiler et al. (5) Total cohort Latency > 15 yr Byren et al. (S) Total cohort Fox and Collier (7) Total cohort Highest expoaure Monaon et al. (8) Total deatha Taberahaw and Gaffey ( Total cohort Highest exposure, > 5 yr employment All exposure levels Buffier et al. (JOY1 Ott et aL Ul) Total cohort Total cohort * EEH lit) Total cohort Brain and CNS Brim Brain Brain Other and unspecified Brain All sites other than digestive and respiratory Brain Brain and CNS 3 0.9 329 3 0.6 4981 2 0.3 612* 2 8.7 88 1 0.4 278 5 1.2 4.2I> 17 11.8 158 7 3.5 204 6 2.4' 280* 6 6.8 88 2 o.r 286 12 8.9 203* p < 0.06. "Proportional mortality study riak ratio. 'Estimated. dNo brain cancer identified among 8 cancer death*. Irvf- Wss' To- u- B'TT' To: fot l To: Hit konr To: Tster To: Hie hJ. To: Lor Sl trt et Tot. EEH Tot. Hip Mu U" "v Tn Gaffey study (9). As a result, 2.4 brain cancer deaths were estimated to have been expected and compared to six observed in the study. This difference is significant. Buffier et al. (JO) did not identify any deaths from brain cancer in their small cohort. Ott et al. (11) did not analyze their data separately for brain cancer, but rather included brain cancer deaths with cancer deaths from "all sites other than digestive and respiratory." Therefore, using an analytical tech* nique similar to that described above, the propor tion of expected brain cancer deaths among "all sites other than digestive and respiratory" from the EEH study (12) was applied to the expected in the study by Ott et al. (ll). As shown in Table 2, there was a resultant estimated 0.7 brain cancer deaths expected as compared to two observed. The excess risk is estimated to be about threefold. The EEH study (12) also demonstrates a significant excess brain cancer among workers occupationally ex posed to VC. In summary, the data for brain cancer appear to be more consistent between studies than the data for liver cancer, although the magnitude of the excessive risk is not as great for brain cancer. 98 Lung Cancer in Humans nut As shown in Table 3, Waxweiler et al. n observed 11 lung cancer deaths as compared to 5 * expected (p < 0.005) for cohort members who hac achieved 15 or more years of latency. The author also noted what appeared to be an unusual distnbt tion in the histologic types of lung cancer. Of sift histologically confirmed lung cancer cases, fc* were classified as large cell undifferentiated, ik three were categorized aa adenocarcinoma. The* ceil types are different from those usually assocated with a cigarette smoking etiology, i.e., snul cell undifferentiated and epidermoid carcinoma? With the exception of the study by Fox ik Collier (7), the remaining studies show excess r&of lung cancer ranging from 7 to 200%. However the reservation expressed by Fox and Collier (*) * mentioned earlier, about the short period offollow; limits the interpretation of their study. This cw cem is supported by the observation that the Sxt for total mortality was only 75, 75% of what wow. be expected on the barns of comparison to ux standard population. Environmental Health Perspective invw. -- Fo^ gIJWt W Hi* EHfr Ul( ___ `int- As kuffl: dose-.and 1: goriz* was u with Octob ucc 057139 329 498* 61? 33 278 4-2*1 133 204 25V 88 26 203* Table 3. Epidemiologic tudy malta of VC-*xpood worker* aa related to respiratory *y*t*m cancer death*. Death* - ion * cuhoft U*rs? > la >r T hoft Site Reepiratory Lung Obterved 12 11 S Expected 7.7 6.7 1.8 SMR 156 184* 168 ; , kA Collier l'> H.--: exposure Lung 46 610 2 3.7 90 54 V - ft tl. <#> T x death* V vj* ind Gaffey <) " x a-hurt exposure. j \t employment Lung Re*pimory IS 7.8 1.6" 25 28.9 112 12 8.6 144 * .* t`. ll. Utifl 7 *; f.hon l. Mjx*upf duration * upofurr duration Lung 5 1.7 289* 4 1.06 381* 0 0.46 " * *: uji T ** o-hort Rwpiratory t9 7 5.8 121 i ? H U* T `*1 cohort H r--. e\|io>ur<- X.'l.jm exjxtfur. 1.* r\iBur Reapintory 46 44.8 107 7 5.1 141 18 17.0 116 18 22.2 82 *, IMto. l> (,.r.ional mortality ttudy risk ratio. et si. i; ared to 3.' s who hi he author al rfistribt. r. Of eiffc: ases, fiu iated, arc ma. Thwt Uly associ i.e., smi. einoim Fox arc xcess rekHowever. Jlier (7). i* of foliowuj This conttheS-MF. . hat wouk on to the npectho Tahir 4. Epidemiologic ttudy r**uha of VC-expoaed worker* a* related to lymphatic and hematopoietic eyttem cancer death*. i--:irtxm Site* Ofaaerved Death* Expected SMR *xcileret al. 17 > U'.rnev > 1$ vr J \*r.d Collier i r X ..*! (81 i . Maw 4 Gaffey it) H.jr.nit exposure. > 5 yean rn)>lo.vmem 1.KH i 12) Latency > 2 year* (200-206) (200-805) (200-207) (200-206) (200-201,206) 000-208,206) 4 8 8 6 6 4 11 4 2.50 1.70 9.01 8.4 6.06 1.84 10.86 8.10 158 176 100 1.54 106 222 112 186 l-vmaiiona] ria^tiOtatien at DUeaaaa, 7th Reviaion. 'lr-.i-mitiona! Claaaiheation of Pimam 8th Raviaion. Ti\i|.urtional mortality ttudy risk ratio. A> shown in Table 3, data from the EEH 02) and S-fftw et al. 00) studies suggested a qualitative d ^-response relationship between VC exposure and lung cancer risk. However, retrospective catet nation of high, medium and low exposure, as **8 used in the EEH study 02), must be viewed with caution because of the subjective nature of October 1981 judgment. The study by Buffler et al. 00) is particularly noteworthy; within a small cohort of only 464 workers, a fourfold risk of lung cancer was observed. When the investigators examined the effect of smoking, under the extreme assumption that those with unknown smoking habits were smokers, the data still demonstrated a significant 93 Ucc 057140 excess of lung cancer (5 observed versus 1.98 expected.) Cancer of the Lymphatic and Hematopoietic System in Humans Table 4 summarizes data on cancer of the lym phatic and hematopoietic systems among workers exposed to VC. The relative risks for various studies ranged from 1.0 to 2.2, and none of the results demonstrated a significant excess. Although somewhat suggestive, the data need to be further analyzed by latency period and exposure levels combined. Analysis of data separately for lym phatic cancers and leukemia might also lead to meaningful observations. Summary In summary, epidemiologic evidence demonstrates that the carcinogenic effects of VC in humans extend beyond the liver. The brain and lung should also be considered target organs. Some studies indicate that the lymphatic and hematopoietic sys tems are also involved. These observations in humans are supported by studies demonstrating the induction of cancer of these same sites in experimental animals. REFERENCES 1. Patty, F. A, Yam, W. P., and Wait*, C. P. Acut* rtapona* of guinea pigi to vapor* at aom* new commercial organic . compound*, publ. Health Kept*. 46:1963-1971 ngm. . 2 Selikoff, I. J, and Hammond, E. C,, Ed*. Toxicity f*.' chloride-polyvinyl chloride. Ann. N.Y. Acad. Se 246 it (1975). 8. Viola, P. L., Biogotti. A, and Caputo, A (W, reeponae* of rat akin, lunga, and bone* to vinvi Cancer Re*. 81: 616-519 (1971). ' 4. Maltani, C., Lcfemine, G., CiHbarti, A., Cotti, G. Carretti, D. Caranofenidty bMaaaays of vinvi efelm monomer A mod*) at riak aaaaaament on enenan baaaa. Environ. Health Perapect. 41: 3-29 <1981). 5. Waxwaflar, R. J,, Stringer, W,, Wagoner, J. Falk, H., and Carter, C. Noopiaatic riak among tvtr expoaed to vinyl chloride. Ann N.Y. Acad. Sri. 271 the (1978). 6. Byren. D., Engbobn, G,, Enghmd. A., and We*tetbda) Mortality and cancer morbidity in a group of SwediAVCi and PVC production worken. Environ. Health Panv , 17:187-170 (1978). ; 7. Fox, A. J., and Collier, P. F. Mortality experimtt* worker* expoaed to vinyl chloride monomer in the turt at polyvinyl chloride in Great Britain. Brit. J. fe Mad. 84:1-10 (1977). 8. 14onion. R. R,, Patart, J. M., and Johnson. M. K. Pnw . tional mortality among vinyl-chloride worker*. Lam i 897-898 (1974). , 9. Tabarahaw, I. R., and Gaffcy, W. R. Mortality *ta4W workara in the manufacture of vinyl chloride *W b polyman. J. Occup. Mad. 18:600418 (1974). 10. BufBer, P. A, Wood, S., Eiltar, C., Suam, L. andKik D. J. Mortality experience of worker* in a vinyl dfo* monomar production plant. J. Occup. Mad. 21: 1K& (1979). 11. Ott, M. G., Langner, R. R. and Holder. B. B. Vinyl dtfam exposure in a controlled induatrial environment. A k tarn mortality experience in 694 employee*. Arch. Emm Health 30: 388-889 (1979). 12. Equitable Environmental Health. Epidemiological nk i vinyl chloride workara. Prepared for Manufacturing Cles iata Aaaodation, 1978. C k v b v di ft U *t ck tr V< i ft ik pl th iA ui ti m m tt Vt *1 th )` IT. 0) X 94 Environmental Health Per*p*ctn UCC 057141 't T' 5 ofrovl Uf, ; A 0**. wvl chk,,, C. -'U'vl chk- Mpenntr 31). A Jon**. wnf Wgfi,. d 271 *, otortote ; :*dirt Vi , 1th Penj*- xperta** :he narul 3TM- J. It, N*. Pnp- Unnt. J' udy v i* Ud r- wd Kiln- 'I ehiofn. I. 1(6-5, Ichkmi A lo study c' ig CW Environmental Health Pertpteiivu Vol. il, pp. fS-tl, liSl German Investigations on Morbidity and Mortality of Workers Exposed to Vinyl Chloride by H. Weber/ W. Reinl,* and E. Greiser* To (tudito on mortality and morbidity of worker* ttpoood to dnyl chloride monomor (VCM) hich hare been carried out on behalf of the Minietry of Labour. Health and Social Affairs on Northrhine-Weetphaiia are reported. Vinyl Chloride Mortality Study The aims of this study were to determine stan dardized mortality ratios (SMR) for male workers exposed to VCM, using the mortality rates of the German male population as reference, to study the SMRs of a cohort of worker* of the chemical industry comparable concerning age dis tribution and observation period but not exposed to VCM and to determine the SMR of a cohort of aurkers in PVC-processing plants. The study was designed as a historic cohort study, covering the period from the beginning of the VCM- and PVC-production in all ofthe German plants till the end of 1974. Table 1 shows the main characteristics of the three cohorts investigated. Only Germans and Austrians were included in data analysis because of insufficient mortality data on various foreign na tionals employed in German factories. To deter mine the mortality rates of Austrians, West Ger man rates were used. To calculate expectations of total mortality, the mortality ratea of the adequate }ear$ have been used. To calculate expectations of specific causes of death for all years before 1968, the rates of 1968 have been used; for the following years the rates of the corresponding years. Follow ing the procedure applied by Tabershaw (j), StMtlichrr Generbesnt, DUmldorf, W. Germany. _`Dubrtt-. n?Mirch Inetitute at the University of DttMtldorf, Divifion of Medical Sutiatica and Epidemiology, Dttaaeldotf, * Germany, October 1981 weighting of observed cases of specific causes of death according to unknown causes of death has been done with weighting factors calculated sepa rately for three observation periods (up to 1969, 1960-1969,1970-1974) as well as for six age groups. In all of the cohorts, follow-up rates have been near or above 90%. The percentage of causes of death that could not be investigated due to loss or deletion of death certificates varied from 7.3% to 13.1%. To calculate age-standardized mortality ratios of specific causes of death, weighting has been done according to the procedure used by Tabershaw and Gaffey (J) to compensate for unknown or unidentified causes of death. Table 2 displays total mortality as well as some of the relevant specific causes of death. It can be observed that the otherwise observed "healthy waiter effect" cannot be demonstrated in the German cohorts exposed to VCM or employed in PVC-processing plants. In the VCM cohort there are significant eleva tions of SMR of malignancies of the lymphatic and hematopoietic tissues (ICM 200-209), and of malig nancies of the GI tract (ICD 150-159). The latter is due to the paramount elevation of SMR oftumors of the liver (ICD 155). It must be noted that there is a modest elevation of SMR of tumors of the liver also in the cohort not expoeed to VCM nor employed in PVC-processing plants. No obvious explanation for this observation can be offered. In addition elevated SMRs for ischemic heart disease (ICD 410-414) can be found in all of the three cohorts. Due to methodological 95 ucc k shortcomings of the study no assessment of cardio vascular risk factors has been made. Therefore these results are of minor interest. When subdividing the VCM-exposed cohort ac cording to time of exposure there is a clear-cut increase of the SMR of liver tumors with time (Table 3). This seems to be highly suggestive of a time-response pattern. As it has been impossible: determine concentrations of VCM retrospects due to technological and methodological problem- no dose-response pattern can be established. Ho-, ever time of exposure seems to be the best avi able guess for dose. , Subclassification according to observation pence Table 1* Characteriatic* of study cohorts. Group I, VCM/PVC production Group II. reference group Population (Germans * Austrians) Mu yean Follow-up completed till 12/31/74, % deceased Ofaeerved Expected Unknown causes of death No. Total mortality (SMR) Foretgnan (excluding Austrians) Deceased * 7.021 73.734 93.2 414 435 30 7.3 96 882 4.910 78.029 89.8 417 533 47 11.3 78 711 S Gropp III. PVC processing 4.007 52.898 92.1 360 380 47 13.1 95 1.454 10 ___ ICd __ 150-: B 'B ICD Tot ICD 8 Cause of death Tabic 2. Standardised mortality ratio*. VCM/FVC production Obs. SMR Reference group Obe. SMR PVC processing Obs. SMB lift 155 191 Total mortality 414 95 417 140-209 All malignant turnon 94 112 83 140-199 Malignant tumors of organa 79 103 77 200-209 Malignancies of lymphatic and hamatopoetic tissues 15 214" 6 160-159 Malignant tumors of GI tract and peritoneum 45 149* 27 155 Malignant tumors at the liver 12 1523" 4 191 Malignant turnon of the brain 2 162 2 4*0-414 Ischemic bean disease 91 127" 115 410 Acute myocardial 66 114 88 800-949 Accidents 61 137" 44 78 360 95 83 62 85 83 60 77 2 3* 71 15 56 401* 3 431 184 5 53? 181* 96 159* 120 69 143* 99 32 110 'Beyond 9665 confidence interval (f). "Beyond 99 confidence interval (t). Table L Standardised mortality ratio* by duration of expoaura. B. c c D ICD 8 Cause of death < 1Z Obe. SMR Duration of expoeura, months__________________________ __ 13-16 61-120 > 121 Obs. SMR Obs. SMR obs. SMR Total mortality 140-199 200-209 150-159 155 191 Malignant turnon of organa Malignancies of lymphatic and hematopoetic tissues Malignant turnon of GI tract and peritoneum Malignant tumors of the liver Malignant tumors of the brain 58 6 1 3 0 0 93 138 102 98 74 20 88 22 92 4 186 5 101 12 135 13 . 2 874' 3 - 0- 1 87 130 9$ 116 31 115 287 5 249 178 17 156 1525* 7 252? 350 1 278 I } 9$ Environmental Health Perspective ucc 057143 Table 4. Standardised mortality ratios by period of observation. ICDr Cium of doth ;*-l J-3W IV) iri Malignant tumors Malignancies of lymphatic and hematopoetie tissues Malignant tumors of GI tract and peritoneum Malignant tumor* of the over Malignant tumors of the brain `Bevond 93^ confidence interval. EBr,vond 991 confidence interval. To 1958 Obs. SMR 13 160 1 147 8 370* 1 1283 1 657 Observation period 1960-69 1970-74 Obs. SMR Obs. SMR Total Obs. SMR 29 84 194 103 414 96 9 275b 6 168 16 214b 13 94 24 lTTh 46 149* 3 884* 8 2264b 12 1523b 0 1 223 2 162 Table 8. Standardised mortality ratios by age. It'De Cause of death Age group * 24 35-84 86-44 46-64 66-84 * 66 Total Obs. SUB Obs. SUB Obs. SMR Obs. SMR Obs. SMR Obs. SMR Obs. SMR T-al n-rtalitv 10 68 46 111 68 104 90 101 106 80 90 103 414 96 Malignant tumors of orgaife* 0 - 4 141 13 188* 19 141 22 76 21 100 79 103 Malignancies of lymphatic and hematopoetie tissues 0 * 2 194 4 908 4 264 8 162 2 197 15 214b r-159 Malignant tumors of Gl trset and peritoneum IV Malignant tumors of 0 - 8 397 10 366b 10 146 10 88 12 140 45 149h the liver 1M Malignant tumors of 0*0- 6 6866* 0 - S 934b 3 I664b 12 1523b the brain 0 0- 0- 1 264 1 882 0 2 162 `Beyond 95''. confidence interval. :Bryond 99'' confidence intervaL TeU* 4. Groups for subdivision of laboratory examinations. Gn>up specification A I VCMTVC production A II PVC processing BI VCMFVC production and PVC procsoaing. w ork capacity loss < 30% BII VCM/PVC production and PVC prauaang, work capacity loos * 30% f l Germans and Austrians GII Koreignen (Exd. Austrians) I*-! Plants with Ugh morbidity b II Plants with low morbidity Table A Bromsulfalein retention.* Germans and Austrians Foreigners Retention normal Retention abnormal Total 17 80 38 21 60 51 Chi square! 6.26 (p < 3.6%). Total 47 66 101 Table 7. Bromsulfalein retention.* VCM/PVC PVC Production Pmrsislng Ketention ivirmal fottmion abnormal Total 26 44 70 *Chi square, - 8 09 (p < 1%). October 1981 21 10 81 Total 47 64 101 Table I. Bromsulfalein retention.* Work capo- Work capa city lost dty loss <20% >20% Total Retention normal Retention abnormal Total 41 6 47 32 22 64 78 28 101 *CU square, 9.81 (p < 1%). 97 t I UCC 057144 (Table 4) reveals a rather inconsistent pattern: malignancies of the lymphatic tissues (ICD 200-209) are significantly elevated in the sixties only, whereas SMRs for tumors of the liver increase till the end of the study period. This might be referred to differ ent latency periods for both kinds of malignancies, but other causes might likewise have contributed to these results. However, it has to be reported that the number of angiosarcomas confirmed histologi cally in the Federal Republic of Germany in pa tients previously exposed to VCM has actually come to 17 in contrast to mere 4 at the endpoint of the mortality study (12/31/1974). The distribution of SMRs by age (Table 6) demonstrates an obvious susceptibility of males aged 35-44 for malignancies in general as well as for malignancies of the liver. The data base for the German morbidity study consists of all of the reports of suspected cases of occupational disease due to VCM or PVC produc tion or PVC processing. The reference population for these reports has to be defined as the total NORMAL la** PATHOL > UD left MG/DI NORMAL 1.0 PATHOL > 10 WORK CAPACITY LOSS WORK CAPACITY LOSS < 20* Figure 2. Vinyl chloride morbidity ttudy: oral giucow toler ance toot, 120 min after loading (naemal 120 mg/dl). *. VCM-/PVC PRODUCTION VCM-/PVC PRODUCTION AND PVC PROCESSING AND PVC PROCESSING WORK CAPACITY LOSS WORK CAPACITY LOSS cat 20* Figure 1. Vinyl chloride morbidity ttudy: total bilirubin (nor- mal 1.0). 98 VCM-/PVC PRODUCTION AN0 PVC MOCESSING WORK CAPACITY LOSS <20* VCM-/PVC PRODUCTION A PVC PR0CESINC WORK CAPACITY LOSS 20* Fiouri S. Vinyl chloride morbidity ttudy. reticulocyte! (nw- mal 15%). Environmental Health Perspective* ucc 057145 ***** K3l oouctio* assine TV LOW mnrkini population in 1974 in the above mentioned ies .Pe,, 6,500 workers in VCM or PVC production and 42,800 workers in PVC processing riven bv the German Association of Plastic Muring Industries). Till the end of 1974, 269 reports of suspected cases of occupational disease ladbeen received. As there has been no consistent of examinations performed on each of the cases, numbers of observations for various variables ana lyzed varv according to examination method per formed. Insofar as the results of this study are of much lower validity than those of the mortality rtudv. one should regard them as hints for further investigations. four attempts to subclassify observation on the aus have been undertaken (Table 6). Only those results showing significant differences when applying Mests or chi-square tests are so classified. Amazingly none of the more sensitive lab examina tions of liver functions showed s marked difference in all of the subclassifications besides bromsulfalein retention. In this instance there is a significant difference \\ hen subdividing^ VCM/PVC produc tion versus processing (Table 7), as well as by nationality (Table 8) and most pronounced when subdividing by extent of work capacity loss (Table 9). This latter result, however, must be expected when an effect of exposure on liver function is anticipated. An impaiment of the excretory liver function is suggested by elevated total bilirubin values in the subgroup with work capacity loss greater than 20% (Fig. 1). There seems to be an impaired glucose tolerance in this group, although observed in a small subeample only (Fig. 2), as well as s lower number of reticulocytes (Fig. 3). The thromocyte count in both groups was the same. These results, however, lead to no sensible inter pretation, as all results attempts failed to standard ize the methods applied far thrombocyte counts by various laboratories. REFERENCES 1. Tabenhsw, I. R., tod Gaffcy, W. R. Mortality (tody of worker* in the manufacture of vinyl chloride and iu poly mer*. J. Oecup. Mtd. 10o 609-618 (1974). 2. Baiiar, J. C. Significant* factor* for the ratio of * Poiaaon variable to ita expectation. Biometric* 20:689443 (1964). *<5 OM S 5 dives October 1981 99 ucc 057146 Environmental Htalth Ptnpteliiet Vol. i1, pp. lOl-iOS, mi Epidemiologic Study of Vinyl Chloride Workers: Mortality through December 31,1972 by W. Clark Cooper* A population of 10,173 imr, employed in 37 plant*, wo* identified a* haring workad for at least one year in jobs involving probable expoeur* to tiny! chloride monomer (VCM) prior to January 1,1073. Of the 9677 men whose vital statu* ws* determined. 707 were known to hare died. For CM, death certificate* were obtained. The standardised mortality ratio (SMR) for ail causes wa* M, that for all malignancies was 104. The only type of maiicnancy found in significant excess was in the category of malignant neoplasms of the brain and other parts of the nervous system; 12 deaths occurred where 5.0 were expected, for an adjusted SMR of 303. There were slight but inconclusive upward trend* in ail malignancies, and for malignancies of the respiratory tract, digestive tract, and central nervous system associated with reported levels of maximum exposure to VCM. When groups in whom Ism than 20 years had elapsed from the first exposure were compared with those with 20 or more elapsed yean, and 23 or more elapsed yean, no significantly different SMR's wen detected for major primary site* of malignancy. Plans for an updated study of mortality, to include deaths in the period 1073-1070 are briefly discussed The epidemiologic studies of vinyl chloride work ers summarized in this report were carried out during the period June 16,1973 through December, 1976 by Tabershaw-Cooper Associates, Inc., and Equitable Environmental Health, Inc., for the Manufacturing Chemiata Association (MCA) (now the Chemical Manufacturers Association). An initial report, dealing with 8,384 workers from 34 plants, was prepared May 3, 1974 (J). A summarized version () was published in 1974. The study population waa subsequently increased and follow-up was improved. Alter an interim report in 1976 (J), a final report based on 10,178 workers was prepared in January, 1978 U). In all ofthese studies the observation period ended December 31,1972. Participating Plants In mid-1973, the MCA identified 43 plants in the United States, belonging to 19 companies, which either produced vinyl chloride monomer (VCM) or used it in the production of po!y(vinyl chloride) *2150 Shattuck Ave., Suite 401, Berkeley, California 94704. October 1981 (PVC). Of these, 34 were included in the initial study; four were excluded because they had been in operation less than 5 years, one had stopped production in 1966, and in others information on job histories or exposures was deficient. Three plants were subsequently added to the original 34, so the 1978 report included 37 plants. Of these, 11 pro duced only VCM, 18 produced only PVC, three produced both, and five plants produced homo polymers and copolymers, with or without VCM and PVC. The geographical distribution of those in the study, as shown in Table 1, indicates a dispropor tionate number of workers from the South, particu- TaMs 1. Geographical distribution of 10,173 vinyl chlorid* workers in 1973 report. Region U.S. males (1070), Workers in study, % Northeast North Central South Wort 23.8 27.9 80.9 17.4 23.9 18.4 64.8 0.9 101 ucc 057147 larly from the East South Central and West South Central States. The South, with 30.9% of the total U.S. male population in 1970, supplied 64.8% of the study population. Of the plants participating, the one which had first begun operations with VCM had done so in 1935, the most recent was in 1968. Four plants had begun in 1942 or earlier, 13 in 1952 or earlier, and 27 in 1962 or earlier. The Study Population The objective was to include all male employees whose work had involved exposure to vinyl chloride for at least one year prior to December 31, 1972. The designation ofjobs which involved exposure to VCM was made by staff members at individual plants or by a corporate industrial hygienist. In approximately two thirds of the study population, TCA staff copied personnel records on individuals who were identified as having been in exposed jobs. In the remaining portion of the population, detailed information on exposed individuals was provided by plant personnel. The methods used in doing this are described in the complete reports cited earlier. Study Period The period of time in which the work-force of a plant was included in the study depended upon the date it began making or using VCM and also upon the earliest date when personnel records were complete for all employees, if that was later than the foregoing. This was done to eliminate periods when there was differential record retention of workers terminated, deceased, or retired. The end of the study period was December 31,1972. Estimates of Exposure In each plant, every job and location with VCM exposure was graded in terms of probable expo sure. Originally, a job history form was designed in the expectation that the exposures could be quantified in parts per million. This proved impossible in practice. However, for each plant, jobs and loca tions involving the highest exposures could be classified as "high", and other jobs classified as "medium" or "low" relative to the "high". It is recognized that this subjective classification is of questionable validity in categorizing the past and present exposure of a given worker. From the number of months spent in jobs with classifications of 3 (high), 2 (medium) and 1 Gow), a number of exposure categories were developed for use in later 102 Table 2. Baew for development of VCM cxpoatm Criterion UaB ; Duration of exposed employment Interval from beginning of expoeura to end of obeervation Estimated maximum level to which an individual was expoaed for at least 12 months, rlaaafflari as high, medium, or low. Integrated or cumulative expoeura, crediting 1 for each month at low, 2 for each month at medium and 8 far each month at high exposure to VCM Expoeura index (El) - Cumulative ecore/iverage immhas of IBOltthf Uoeuu Hitt XKhu? Lw i j j ; * ' 1 | < analyses. As shown in Table 2, individual exposure * in various papers were classified in a number if ways, including the maximum level at which c individual had been exposed for at least 12 month an integrated or cumulative exposure, and r 1 exposure index based on the cumulative mr j divided by the number of months. ! Follow-Up j As is customary in historical prospective studio ' all who had left employment were traced vhr. 1 possible. Methods included form letters sent tr. mail and use of retail credit follow-up. For the for. report, there was insufficient time to utilize Soch. Security Administration records, but for subse quent reports such follow-up was used. In the first, or 1974 report, 85% of the stud;, population was located; for the final or 1978 repor.. ' the percentage had been increased to 95%. The mortality calculations were based only oc those who were successfully traced, which is equh- . alent to assuming that mortality among those no: found was the same aa among those who wen found. This usually, but not always, results in son overestimation of mortality. | Calculation of Standardized Mortality Ratios Each worker in the study, i.e., everyone who vital status was ultimately known, was considered to have been under observation from the date which he attained a year of exposed employment from the date when his plant's records were com plete, whichever came later. Observation period.* ended December 31,1972, or on the date of dealt whichever occurred first. 1 Observed deaths were classified by cause accord; ing to the 7th (1955) revision of the Internatior* Environmental Health Perspective* j O dea esu ma! tior 197 I obt dis: obt nli T eac val Ch: mg S Ifi 1.9 at rta tin ob6c Rc fUl de. refor ua ex: 5> re! th. Tat Hi No Si S! No No To- W Or ucc 057148 I UtctOfit Months Months High Modium Low 1 2 t xposure? -imber of hich ar month; and it. e score studies. her. s. .i bt :he fur. e Soca; subse- * study report. mly on equiv)se not 5 were nsome whose idered ate on ent or ? coni* eriods death. vd,nal live* Classification of Disease#. The expected number of deaths by cause were calculated by using age and cause-specific mortality rates for United States males with the same birth years and age distribu tion for the years 1950, 1955, 1959, 1965, 1967 and 1970. Deaths for which death certificates could not be obtained were assumed to have the same cause distribution as the death certificates that were obtained. Appropriate increases were made in calculated SMR's. The statistical significance of the deviation of each SMR in the study population from an expected value of 100 was tested by a method derived from Chin Leong Chiang (5). The formula for determin ing the standard error of the SMR was 100 x SMR 5E No. expected deaths If an observed SMR differed lfrom 100 by more than 191 standard errors, it was regarded as significant at the 55 level; if it differed by more than 2.57 tandard errors, it was regarded as significant at the 15 level. SMR's based on fewer than five observed deaths were usually not tested for signi ficance. Results Table 3 summarizes the numbers of individuals, success of follow-up, person-years and deaths in successive phases of the study. The number of deaths per 1000 man-years of observation, which in general reflects the age distribution of the work force, suggests that the proportion of older individ uals increased in the study population as it was expanded and follow-up improved. Even so, the 5.n> deaths per 1000 man-yeara indicates that a relatively young population waa being observed; the U.S. male population 20 and above has about 11 TaMt 1 Numhtn of individuals, auccssi of follow-up, ponon- .'**** and doat hi analyzed in succcsaW* phases of the study. of men found v found So desth* tertilicites Toul min*yr la-Khf 1000 man-yr Report 1, Report 2, Report 3, 1974 1976 1978 8,384 7,138 85% 352 328 77.846 4.52 9,109 8,714 96% 525 511 94,221 5.57 10,173 9,677 95% 707 669 120.203 5.88 October 1981 deaths per 1000 man-years. Some published occu pational epidemiologic studies will show 20 or more. Duration of Exposure to VCM In the first report, only 15.2% of those studied had begun exposure prior to 1950 (22 yean before end of the observation period). In the third report, 33.4% had had 20 or more yean for observation since exposure began. This resulted from finding more early employees by improved follow-up, and the inclusion of an older group from one plant in the augmented population. Standardized Mortality Ratios Standardized mortality ratios (SMR's) for selected causes of death are shown in Table 4, based on the 352 deaths analyzed in Report 1 and the 707 deaths analyzed in Report 3. Results in the first report led Tabenhaw and Gaffey (1) to conclude that vinyl chloride may be associated with cancer of a number of sites, notably digestive cancer, respiratory can cer, cancer of other and unspecified sites (primarily those of the central nervous system) and lympho mas. This was based not on statistically significant excesses in each category, but upon apparent trends when different levels and durations of exposure were compared. With the enlarged study group, the SMR for malignancies in the entire population dropped slight ly, as did the SMR's for malignancies of the buccal cavity and pharynx, digestive tract and respiratory tract. However, tumors of the brain and central nervous system, when examined separately, still appeared to be in excess. A number of analyses were done in the third report in an attempt to sharpen the focus on work exposures. There appeared to be s slight but definite trend in the SMR's for all malignancies, malignancies of the digestive tract, the respiratory tract, and for other and unspecified sites with increasing levels of estimated maximum exposure (Table 5). However, the numbers ofexpected deaths were relatively few in some categories and the groups differed widely in age distribution is manifested by deaths per 1000 person-years. To reduce dilution ofthe study population by men whose exposures had begun only recently, a sepa rate analysis was carried out on those whose expo sures to VCM had begun 20 years or more prior to 1972, and on those whose exposures had begun 25 years or more prior to 1972 (Table 6). Another analysis was made of a population of men who had worked in plants producing only PVC 103 ucc 057149 ] (where VCM exposures were presumably high), whose exposures had begun 20 years or more be fore the end of the study period and who had been reported as having medium or high VCM exposures for a year or more (Table 7). This group experi enced 210 deaths where 249.7 had been expected. The pattern of mortality from malignancies was not appreciably different from that of the total stud group. In summary, increasing the study population art Table 4. Observed and expected deaths (O/E) and standardised mortality ratios for selected causes (SMR's adjusted for mw* death certificate*). Cause (ICD Mo, 7th Rev) 1974 Report O/E SMR 1978 Report O/E SMR All causes All malignancies (140-205) Buccal and pharynx (140-148) Digestive (150-159( Respiratory (160-164) Other and unspecified (180-199) Brain and CNS (193) Leukemia and aleukemia (204) Lymphomas (200-203, 20$) Major cardiovaac. renal (330-334, 400-468, 592-504) Cirrhosis liver (581) < s No. of workers Peraon-yr 352/487 79/77 5/2.84 10/21.7 45/44.3 17/11.75 3/3.77 6/6.06 155/207 3/15.6 7,128 77,846 75* 110 188 04 112 156 85 106 80* 21 707/705 139/141 5/5.19 20/40.8 25/23.9 28/20.2 12/5.0 9/6.65 11/10.36 347/385 14/26.5 9,677 120.203 89* 104 102 75 107 147 203* 143 112 96 56* `Significant at 1% leveL `Significant at 5% level. Table S. Obeerred and expected deaths (O/E) and standardised mortality ratio* for ulected caueet as related to maximum Icrtl of reported expoiur* to vinyl chloride monomer (SMR'e adjusted for milling deoth certificates). Cauae (ICD Mo, 7th Rev) Reported maximum exposure VCM Low Medium High O/E SMR O/E SMR O/E SMR All malignancies (140-205) Digestive (150-150) Respiratory (160-184) Other end unspecified (190-190) No. of worker* Person-yr Deaths/1000 persoo-yr 65/71 14/20.9 19/22.2 11/9.9 4,025 58.741 6.16 98 56/58.5 72 10/15.6 92 19/17.1 119 18/7.5 8.021 39,027 6.6 109 18/16.5 67 5/4.4 116 7/5.1 180 4/2.7 1,731 21,535 3.9 112 117 141 ISO imi ma inf fUf cer Tib or C*u ilC aT AU D R 0 Cir Table fi. Analyst! of death* based on time from beginning of exposure to end of study period (SMR's adjusted for misting death certificates). Cauae of death (ICD No. 7th reviakm) < 20 yr No. SMR > 20 yr No. SMR >25 vr No. SMR All cauae* All malignancies (140-206) Digestive (150-159) Respiratory (160-164) Other and unspecified (190-199) Leukemia (204) Cardiovaacular-renal 158 77* 549 98 3 96 81 95 108 107 73 104 8 96 21 70 16 74 8 80 37 116 22 100 6 106 22 162 13 146 3 155 6 137 4 137 68 84 279 97 211 105 "Significant at 1% level. 104 Environmental Health Perspective uoc 057ASO peeled was no: J stud. JR -proving follow-up did not strengthen the sugfr-'.ed associations between VCM exposure and rahpiancies other than those caused by hepatic tfciosareoma. as will be pointed out later, and a -crested association with tumors of the brain and n-n'.raJ nervous system. T*Me 7. !Vth- in plants producing only PVC, baaed on wfcrn show first exposure* began before 1952, and who oc medium or high VCM expoewes (SMR'i corrected for miasini death certificate*). 1.-- of death ; : No. 7th revision) K. cJn4^ rJicniwie- 1140-205) ,-'V-.:ne 11-Vi--J59) ).~; iratorv ilt>"-164) "rrand uni**cified (19(M99) -- -I, of liver iiSl) O/E 210/249.7 46/46.04 9/13.63 17/14.75 10/ 6.33 6/7.95 SMR 84* 106 70 122 167 80 `Sif.ifiriM at I', level. Angiosarcomas Nine angiosarcomas are known to have occurred in the U.S. during the study period, i.e., prior to 12/31/72. As shown in Table 8, eight of these were found in the study, but only three were coded as angiosarcoma on the death certificate. However, four others were coded as tumors of the digestive tract. Unfortunately, two were coded 230x so as to fall out of the category for malignant tumors of the GI tract, and one was coded aa cirrhosis ofthe liver. As shown in Table 8, the angiosarcoma which was not found was in a man who had died in 1981. We have not determined how he failed to be in the study population. The yean of exposure for the eight cases ranged from 4 to 23 yean, while elapsed time from beginning of exposure to death ranged from 16 to 24 yean. Tumors of the Central Nervous System The 12 turnon ofthe brain had been diagnosed on death certificates as follows: glioblastoma multiforme, 4 (1 confirmed by autopsy); astrocytoma, 2 (2 au- iii. *1 1R in No t SA-02 417 -10 -11 *12 -lfi -Or 'Nj.-nher Table 8. Angiosarcoma death* and data on VCM exposures. First expoeed Year of death Time from first exposure to death, yr Total yr exposure Eat. max. exposure Age at death 1965 1971 16 14 High 38 1949 1968 19 18 High 43 1944 1964 20 20 High 52 1944 1968 24 14 Med 45 1946 1970 24 23 Low 70 1951 1968 17 17 Med 60 1949 1969 20 20 High 50 1950 1969 19 4 High 41 -- 1961 Not in study group in registry periodically prepared by J- Stafford, Imperial Chemical Induatrie* Ltd.. Plaitic* Division. a death IR ctive* Case no. 1 2 3 4 h 6 t a 10 11 12 Table 9. Summary of brain tumor death* (ICD No. 205) and data on VCM expoeum. First expoeed Yr of death Time from lt exposure to death, yr Total yr exposure Max. exposure 1968 1967 1967 1941 1950 1956 1947 1945 1949 1947 1935 1985 1972 1972 1968 1968 1970 1971 1971 1968 1971 1971 1956 1967 14 5 11 17 20 16 24 18 22 24 21 32 5 Low 6 Low 7 Med 6 Med 8 High 3 Med 23 Low 18 High 21 Low 28 High 18 Low 22 Low * Wnber 1951 Age at death 67 43 54 61 43 54 67 44 58 49 59 57 105 cf<5-t & ucc 057151 topsies); ependymoma of the 4th ventricle (autop sy); "malignant brain tumor" or "carcinoma of the brain," 5 (with no autospies). This group is cur rently being made the subject of more rigorous review. The information obtainable from our re cords, summarized in Table 9, is insufficient to prove or disprove a cause-and-effect relationship between occupational exposure and these turnon. Conclusions A study of 707 deaths in a population of 9677 men who had worked for one year or more in jobs involving exposure to vinyl chloride and whose vital status had been determined as of December 31, 1972, did not show a significant excess ofdeaths due to malignancies. There did appear, however, to be a significant excess of tumors of the brain and central nervous system, based on 12 such deaths. There also continued to be slight but inconclusive trends toward higher SMR*s for deaths from digestive tract and respiratory tract tumors associated with maximum levels ofpast exposure. No striking changes in malignancy patterns were apparent when analy ses were directed toward individuals in whom 20 to 25 years had elapsed since first exposure. The results suggest that, except for a proven associa tion with hepatic angiosarcoma and a strongly sug gestive association with central nervous system tumors, vinyl chloride probably is not associated with significant excess cancers of other sites. It should be emphasized that the epidemiologic study summarized in this report was planned, the populations defined, and analysis under way before cases of hepatic angiosarcoma had been diagnosed in workers exposed to vinyl chloride (6). An ujxfc, is scheduled with inclusion of additional deaths: the cohort during the years 1973 through 1979. Ts study can be improved by a separate analysis t data from the plants which began operations befe 1960, and by separating, insofar as possible, en sures to vinyl chloride monomer, polyvinyl chkride, and various copolymers. It is also hoped tk criteria for defining exposure and for rating levtof exposure can be improved to permit better ink ces of integrated exposure. TVs study was begun June 15.1973 under s contract bsttce the Manufacturing Chemists Association, 1825 Connecticut & enue, N.W., Washington, D.C. (now the Chemical Manutar era Association) and Tibcnhaw/Cooper Associates. Inc. h n continued under later contracts with TCA and with EquhAi Environmental Health, Inc. REFERENCES j 1. Tabenhaw/Coopar Associates. Inc. Epidemiological Ruhr1 vinyl chloride workers, flnsl report. Submitted to the Mini* turing Chemists Association, May 3,1974. 2. Taberahaw, I.R., and Gaffcy. W. R. Mortality itndv i workers in the manufacture of vinyl chloride and iu poi;. men. J. Occup. Med. 14: 609-518 (1974). 3. Equitable Environmental Hcmhh, Inc. Supplementary tp, demiologkal study of vinyl chloride workers. Report pnpared for the Manufacturing Chemists Association, Sepucber 1974. 4. Equitable Environmental Health, Inc. Epidemiological itui of vinyl chloride workers, final report. Prepored for !b Manufacturing Chemists Association, January 1978. 5. Chling. C. L. Standard error of the tge-adusted death nu Vital Statistics Special Reports 47; 275-28511961). 6. Creech, J. L., and Johnson, M. N. Angiosarcoma of beer i the manufacture of polyvinyl chloride. J. Occup. Med. 1615 (1974). * | , I G. G in 111 . *? thi Di ha i I ar be fo: sti c* Of : Of tk of to rn Environmental Health Perspectiv ucc 057152 I death, 11979. T:anaJyuj ipnabef,.- ;ible, exp vinyl ct. hoped tL ting l*i* ^tteriK r* h*t,, intcucut A Minuiir.*- Inc. It * th Equj^:, Environmental Health Penpeetivet Vol. it, pp. 107-113, mi Epidemiology of Hepatic Angiosarcoma in the United States: 1964-1974 by Henry Falk,** John Herbert,* Steven Crowley,* Kamal G. Ishak,* Louis B. Thomas,** Hans Popper * and Glyn G. Caldwell* cal Rud> fttMznuf, Rudi Dd it y. *nt*rv r. Report r *if)pcal Ftit* t-d for -j7s. detth nu ). i of Bv*r c *d. J& li i*Liivn \ nitionwid* wmy of hepatic antioearcoma (HAS) in the United State* during the yean 1SS4 through 1974 identified 168 caae*. Of these, 42 case* (26%) were associated with known ctMogic f*, tun, such a* vinyl chloride monomer exposure during preparation of polyfvinyl chloride), use of Thorotrmst in angiography, exposure to inorganic arsenic, and treatment with androgenic* in ibolic Reroids; 126ha** (75%) are of uncertain etiology. HAS most often effects males (ratio of dpproximately 3:1), peaks in the sixth and seventh decades of life (somewhat earlier than other $un omas of the liver) and appear* to occur more often in the industrialized Northeast and M dwest (although reporting artifact may he a factor). There is an extraordinary relative risk for p. 1 ytvinyl chloride) polymerization workers; there may also be other chemical-industrial i- uciations that require further investigation. Prospective epidemiologic studies of HAS should he considered as a means of identifying other causative factors (e.g.. chemicals or drugs) related tu HAS. Introduction TnL< report is an overview of the nationwide hectic angio-arcomt (HAS) case-finding study for :hr years lf' i-1974 conducted by the Centers for IWase Control (CDC). At the stan of this study, three causative factors k*d been i<k-:.tified for HAS: vinyl chloride mono- tVCM) u. 2), Thorotmt (3), and inorganic ironic U). The recently discovered association (*'.** VCM and HAS has served as a stimulus U this inu -ligation, and multiple epidemiologic ftudies of p< :.vvinyl chloride (PVC) polymerization `t'hnmk Div-..-w Division, Contor for Environmentsl Health, ' rr.ert tar Di .;** Control, Public Health Service, U.S. Dept. ' Hulth and H ..-nan Services. Atianta, Georgia 30333. `Author to v ,m reprint requests should be addressed. :IV(artm*r- of Hepatic Pathology, Armed Forces Institute 'Pa'.hologv. W'.!,hington, D.C. 20012. "Uborstor;. of Pathology, National Cancer Institute, Ns'*! Infiituii - of Health, Bethcsda, Maryland 20014. '.wion Ln oratory for Liver Disease, Mount Sinai School Hvdicinc of the City University of New York, New York workers exposed to VCM have since demonstrated very high relative risks for the development of HAS (5, 6). Thorotmt is a colloidal suspension of thorium dioxide, a radioactive alpha-emitter with markedly prolonged radiologic and biologic halflives, which was used for carotid angiography and liver-spleen scans in the period 1930-1955. The thorium dioxide is sequestered by the reticuloendo thelial system, primarily in the Kupffer cells of the liver, radiation injury to adjacent cells is the presumed carcinogenic mechanism. Epidemiologic studies of Thorotmt recipients have shown very high relative risks for the development of HAS as well ss hepatocellular tumors (7,8). The association between arsenic and HAS is based on data from several small autopsy series in German vintners in the 1940s and 1950s U, 9), which demonstrated an increased incidence of liver disease, including HAS. These workers were exposed to inorganic arsenical pesticides during application of the pesticide and also by drinking beverages prepared from the skins of the sprayed grapes. Subsequently, HAS cases were reported following long-term ingestion of Fowler's solution (potassium arsenite) (10,11) and October 19S1 107 ucc 057153 arsenic-contaminated well water (12). Individual cases suggesting associations between HAS and hemochromatosis (13) and copper exposure (74) have also been reported. Earlier reports from this study reviewed cases associated with single causative factors (15-18), including androgenic-anabolic steroids which we feel are implicated as a fourth cause of HAS (19). In this paper, we present an overview of the case finding effort, placing the known causative factors and cases of idiopathic origin in perspective. Methods Information relating to eases of HAS occurring in the United States during the years 1964 through 1974 was solicited by CDC in a variety of ways: (1) announcements were placed in seven medical journals; (2) a mailing was sent to all pathologists in the country; (3) separate mailings were sent to all state epidemiologists, major tumor referral centers, and statewide tumor registries; (4) a death certificate review for International Classification of Diseases (ICD), Eighth Revision, Code 197.8 (liver tumors, unspecified primary or secondary) for the period 1966-1973 was conducted with the assistance ofthe National Center for Health Statistics (NCHS) and the 50 state health departments (Code 155.0, primary liver tumors, was not reviewed because it would nave been impractical to obtain the much larger number of certificates in this category and because it was felt that the majority of cases of HAS listed as such on the death certificate would have been coded as 197.8); (5) arrangements were made with the Armed Forces Institute of Pathol ogy (AFIP) to include cases in their files (1943-1975) in the review; (6) a number of cases were identified from industrial surveys of PVC polymerization workers and others potentially exposed to VCM; and (7) permission was requested to indude the previously published cases of HAS occurring in 1964-1974. The evaluation procedure for each identified case was as follows: Initially, permission was requested to review the appropriate pathologic specimens (all submitted non-AFIP case material was reviewed at the National Cancer Institute's Laboratory of Pa thology by H. P. and L. B. T.). Following confirmation of the diagnosis, the local physician was notified, and, with his permission, the nearest of kin was identified and contacted. Consent w'as obtained to review medical records, and a questionnaire was administered by telephone to obtain detailed occu pational, residential, and chemical exposure histo ries. In selected instances, friends, employers, previous physicians or others were also interviewed. 108 In all, approximately 350 submitted cases reviewed by the pathology review group, outside our requested time period of 1964-13;; Pathologic specimens were obtained for review c approximately 95% of cases, many of which *e* considered by our pathology panel not to be HAi ; Since survival after diagnosis is very brief tx many cases were only diagnosed at autopsy, i( have included all 168 confirmed cases with den ' during 1964-1974 in the study group. ( The above effort is essentially a case review > Subsequently, the 22,432 death certificates obtain* from the review of Code 197.8 were used to cam. out a case-control study of occupation as record*! , on the death certificate in the following > Death certificates were sought for all 168 confirm*! i HAS eaaea; 166 were available. Controls vm sought from among the 22,432 death certificate ii ICD Eighth Revision Code 197.8 (liver tumor, unspecified primary or secondary) that had bet : obtained in the HAS case-finding effort (see above. certificates of confirmed HAS cases were exclude 1 from the control selection process. Although death? in Code 197.8 might not represent the ideal comm : group, the rationale was that these deaths result*! from a broad variety of turnon of multiple sit* ; metastatic to the liver or represented cases whict were diagnostically uncertain; it was therefor* unlikely that any single diagnostic category would predominate or that the occupational listings would be heavily biased by any single group of cases. Up to four controls (as many as were available were matched to each case >30 years ofage on tJ basis of the following criteria: age (6 years), sex. i race, county of reaidence, and year of death (:3 yean). One hundred thirty-five cases were success' ! fully matched (79 of these had 4 matched controls. ; the overall ratio of controls to cases was approx I mately 3:1). Individuals who could not be match*! were primarily young females and residents of sparsely populated counties. A combined occupation and industry coding schen* was developed to accommodate all listings recorded ; on the certificates and to group listings on the basis of potential hazardous exposures. The dats were ; analyzed by Rothman's method for matched groups with multiple controls per case (20). ide: tin. T rer ant: me' mo the <U( cor of; 19C cer epi sea i con nor Tib __ Ur ` ^ A l F $ J* * ( ( -*1 _ . ; Result* Our study identified 168 deaths from confirmed ! HAS during the years 1964 through 1974. For this , rare tumor, the best sources of case identification were the pathologists, with the largest number o. ( cases identified through the single mailing to >1 pathologists and the second largest number ofease Environmental Health Pcnpcdb* r,. Or ucc 051154. se some 4-1974. iew in i were HAS. ef and '>' e death eview. tamed carry corded anner. irmed were ates in :umor. ' been oove); luded eaths mtrol ;nltpd sites vhich efore ;1 V)__ J s. able) n the sex. (3 cess* :rols; roxi* ched :s of ieme rded basis were oups identified through pathology referral centers (par ticularly the AFIP). Table 1 summarizes the results of the death certificate review portion of the case-finding effort and points up some of the inadequacies of using this method in epidemiologic studies of uncommon tu mors. Only 42% of the cases initially identified on the death certificate as HAS were confirmed as such on pathologic review; 50% of the cases were confirmed not to be HAS. Furthermore, only 23% of all the total cases in our study during the yean 1966-1973 would have been identified by the death certificate search alone. It can be seen that an epidemiologic study based only on a death certificate search ofCode 197.8 would have been quite inadequate. Figure 1 compares age, race and sex data for the confirmed HAS cases in our study with 131 cases of non-angio hepatic sarcoma identified in the death Table 1. HAS caaes, CDC survey: death certificate reviewcode 197.8 (8th revision 1CD), 1966-1973 Un|th of review 7.5 vesrs ' 1966-1971, 1973, 1/2 of 1971) Tots! number of death certificate* reviewed 22,482 Sitcoms* of the liver, death certificate diagnoses: Angiowrcoma (HAS) 74 (36.1*) Leiotm osarcoma 24 (11.7%) Fibrosarcoma 14 ( 6.8%) Siieoma (type unspecified) 64 (31.2%) Sarcoma (other types) J (14.1%) Toul Final ps^''logic diagnoses of 74 cases identified on death certificate as HAS Confirmed HAS Confirmed not HAS No pathology available 206 81 (42%) 37 (50%) 6 ( 8%) certificate survey (these latter cases were not confirmed by pathologic review). HAS has a strik ing male preponderance of approximately 3:1; this is not true for other hepatic sarcomas. HAS also appears to occur more often in younger age groups. The higher proportion of males than females with HAS first appears in the 40- to 49-year-old group (Fig. 2) and is associated with a younger peak age for males than females, although the mean age for female HAS cases (50.1 years) is lower than that for males (57.9 years). These findings are not solely related to the VCM-induced cases among polymer ization workers. The male preponderance is also present in the Thorotrast, arsenic, and androgenicanabolic steroid associated cases, as well as in the idiopathic cases (Table 2). Cases with known etiolo gy, however, have a younger age distribution than idiopathic casea (Table 3), with a mean age of 51.0 years compared to 57.6 years for the idiopathic casea. Table 4 presents the 168 cases of HAS by year of death and etiologic status. The VCM-, Thorotrastand androgenic-anabolic steroid-associated cases were more common during the latter part ofthe study Tabic 1. HAS emats. CDC surrey. 1964-1974: m ratio*, etioiocic categoric*. Mala Female Ratio Vinyl chloride Tharotnst Arsenic Androgenic-anabolic steroid* Subtotal Idiopathic 12 15 4 J 34 98 0 (12 ; 0) 5 (8:1) 2 (2:1) _1_ (3:1) 8 ( 4.3: 1) 33 ( 2.8: 1) med this ition er of 7 all V, Frci'RE 1. Hepatic angiosarcoma (HAS) etc** compared with nor-sngio hepatic sarcoma eaaea, by age group: U.S., 1964-1974. October 1981 Fictat 2. Hepatic angiosarcoma cases, by ag group and sax: U.S., 1964-1974 109 Ucc 057)55 Tabic 3. HAS cam, CDC surrey, 1964-1*74; af distribution for caaac of known cause ami for idiopathic caica. Age, yr Known etiology No. 45 Idiopathic No. % 0-9 10-19 30-29 30-39 40-49 60-69 60-69 70-79 80 Total 1 ( 2) 0 ( -) 0(-) 4 (10) 8 (19) 22 (52) 4 (10) 3 ( 7) 0 { -) 42 2 ( 2) 4 ( 3) 1 ( 1) 8 ( 6) 19 (15) 24 (19) 39 (31) 21 (17) 8 ( 6) 126 period. For the VCM- and androgenic-anabolic steroid-associated cases, this is due to the rela tively recent introduction of these causative agents. For the Thorotrast-induced cases, however, this pattern was an unexpected finding. Baaed on the originally calculated latent period of approximately 20 years (SI), the general impression was that such cases would be diminishing by 1975. However, the number of cases appeared to still be increasing as of 1974, apparently due to an increase in cases having relatively low-dose angiographic procedures and prolonged latent periods (16). The arsenic-associated cases (including five adults with a history of pro longed use of Fowler's solution and one child with environmental exposure) occurred primarily during the earlier years of the study and may represent the tail end of a larger problem in previous year* The number of idiopathic cases was low during the first few years of the study (perhaps related to poor recall by pathologists, and to the fact that the death certificate search started with 1966). Case num bers, however, remained steady for most of the study period except for a spurt in 1974. The latter occurred right after the original report and the attendant publicity of the first cases of VCRinduced HAS (January 1974) and may be related to improved diagnostic evaluation. Renew of the idiopathic cases occurring in 1974 demonstrated a large number of elderly cases with no evidence of clustering in s particular exposure setting. The HAS mortality rate for the entire United States during the study period was 0.75 cases per 10T population per year. Crude mortality rata by region, based on county of residence at time of diagnosis (Table 5), suggest a somewhat higher incidence in the Northeast and in the industrial portions of the Midwest. There was also an increaie in the mountain region, although this is based on a very small number of cases. The rates were low in farming states and in the South; however, since Tabic 4. HAS cam, CDC survey, 1964-1974; distribution by causative factor* and ytar of death. 1964 1966 1966 1967 1968 I960 1970 1971 1972 1973 1974 Total Idiopathic 4 10 9 13 12 18 11 12 13 11 18 IS Vinyl chloride 1 82 1 1 3 1U Arsenic 1-12 1 *_- 1 ( Tborotraat 1 2 2 S 2 4 1 5 Androgenic-anabolic (toroids 1- -1 1 14 Total 6 10 10 17 18 17 15 16 17 17 25 1 t I t * < & Region 1. New England 2. Mid-Alantic 3. E.N. Central 4. W.N. Central 5. S. Atlantic 6. E.S. Central 7. W.S. Central 3. Mountain 9. PadAe Total 110 Table 5. HAS caeca. CDC survey, 1964-1974: distribution by regien. Statas Pop. 1970 No. of cam (HASlO'/yr) ME, NH, VT, MA, RI, CT NY, NJ, PA OH, IN, IL. MI, WI MN. LA, MO. ND, SD. NB. KS DE, MD, DC, VA, WV, NC. SC, CA. FL KY, TN, AL, MS AR, LA. OK, TX MT, ID. WY, CO. NM, AZ, UT, NV WA, OR, CA, AK, HI 11,847,186 37,152,818 40,252,678 16,324,389 30,671,337 12,804,552 19,322,463 8,283,586 26.525.744 203,184,742 12 (0.92) 38 (0.98) 85 (0.79) 10 (0.S6) 23 (0.68) 7 (0.50) 12 (0.56) 10 (1.10) 21 (0.72) 168 (0.75) No. of idiopathic catai (idiopathic HAS/IOWI 9 (0.69) 28 (0.66) 30 (0.68) 9 (0.50) 15 (0.44) 1 (0.07) 10 (0.47) 7 (0.77) IT (0.58) . 126 (0.56) Environmental Health Perspective* [ . a e t 1 r f p f; d V O' ucc 057156 hi' T of fr I t child . rinutrily dur.: may reprt*.-' 3Kviotts ytik>w during related to that the dr. 5). Case nur t most of f, )74. The la;:,, spon and u, ses of VCM / be related: eview of u, jmonstr*tnj. `O evidence >: jtting. entire Vnhe ).75 cases ptclity rates t e at time r what higtwhe indujtru. o an incn-as based on, were low ir vever, sino 974 Total 18 US 1 12 --6 5 lb _4 3 168 cues are diagnosed only after referral to ' (^pital and tumor centers, it is possible that ,r-rai rates could be artifactual. T. `.'ummarue this portion of the study, it is L.,^nt that HAS has a strong male preponderc \, that it appears to occur more often in younger groups than other sarcomas of the liver, and ,.y .here may be geographic differences which are .-via'-ed simply to the distribution of VCM assoti- (^es (the largest number of which were in h,,':ucky and West Virginia). As part of the vi up effort we looked at occupation in the Vi:.- certificate case-control study. Table 6 shows v the case-control ratios were elevated only for last two occupational categories. The first of (#7) shows a highly significant difference for -.-ical workers that is entirely related to expo- ..n to VCM: all 10 cases were PVC polymerization i riw*f. The lust category (#8) combined a large -.-her of laboring groups with potential exposure a variety of chemicals; included are laborers, -j.r.imsts, maintenance workers and others. The aviation of this heterogeneous grouping of occu::i >ns with HAS is not statistically significant, nor reviewing the individual Occupational data from interview - with family members were we able identify a specific chemical, plant, or process aa a .-active factor. Nevertheless, taken together with earlier findings, this association suggests that - tie chemical exposure or industrial factors may ; related to a portion of the idiopathic cases. Such *r. a-sociation would not be unreasonable; machine.g.. art potentially exposed to trichloroethylr-,r 'an exper mental hepatocardnogen that is strucorally relatei! to vinyl chloride), inorganic arsenic and nitrosanhnes (which have been identified in rating fluid- and are a known cause of HAS in aromals) {22. 23). ptthic CMf* IAS lO'.'jT.i 0.68) 0.69) 0.68' 0.501 J.44> 0.07) 0.47) ).77> >.58) '.56) fives Discussion A particularly intriguing feature of HAS is that there are nu\v four probable causes of this tumor, and yet about 75% of the cases are of uncertain etiology. Given that the HAS cases associated with the four quite distinct etiologic factors (VCM, TnorotraM. arsenic, and androgenic-anabolic ste roids) share a common morphologic progression to HAS which is indistinguishable from that of idio pathic cases (21,), it is likely that additional causal factors arc (or will be) associated with HAS. In this .-tudy. the male preponderance, the younger age distribution, the possible geographic relationship with industrial portions of the country, and the suggestion from the death certificate case-control October 1981 study that groups with chemical exposure may be at higher risk, raise the possibility that some of the idiopathic cases may be related to presently unidentified environmental or occupational expo sures. This study and that of Baxter et al (25) confirm the limited diagnostic reliability of death certificate diagnosis of HAS and the need to assess a variety of Tabic (. Occupation aa rococdod on death certificate, casecontrol study, CDC HAS survey, 1964-1974. Occupation Casas (N -186) Control (N -421) Professional, technical. CngUMCTB Managers, administrators Sales, wholaaale/mail trade Clerical Communications Finance, insurance, real Business, store owners. proprietors Service workers Housewife, homemaker Military, government Unlisted, mired, disabled 16 6 8 9 1 2 5 8 18 2 j 40 23 29 13 5 4 11 36 G8 3 12 Agricultural (farming, stock, food, fisherman) Mining Transport Carpenters, craftsmen Manufacturing (unspecified, untitled, other) Lumber, logging, wood products Metal, steel Food, beverages, tobacco, packing Textile* Paper, printing Rubber/plastics Automobile 74 (55%) 4 (8%) 1 (1%) 4 (3%) 2 (1%) 2 0 0 2 3 1 1 0 234 (56%) 23 (5%) 8 (2%) 21 (5%) 9 (2%) 13 3 5 6 9 5 2 3 9 (7%) 46 (11%) Chemical Machinist-metal cutter 10 (7%) 1 <W>4 P * 4.29 * nrr 7 14 Machine operatora 0 8 Forgers, moldcrs, casters 1 3 Painters 14 Sanitation, water work*, poorer 3 2 Maintenance, custodians 5 9 Laborers 8 20 Construction 12 Heavy equipment operator* 2 6 Repair services 15 Mechanics 26 31 (28%) 79 (19%) p - 0.11* Statistical analysis for casa-control study with multiple mutches (SO). Ill ucc OSfl57 sources of data in order to identify cases for studies of rare tumors such as HAS. The Thorotrast data are instructive because the initial estimate of the latency period has lengthened with time; recent cases have been in individuals who had relatively low-dose procedures but pro longed latent periods (16). Hus accentuates the need to continue evaluation of VCM exposed groups for the possible appearance of a similar pattern. The time frame covered by our study is perhaps too early to detect a sizable number of cases with relatively low VCM exposure either in occupational or environmental settings. In addition, Thorotrast* induced HAS was noted approximately 10 years before Thorotrast-induced hepatocellular tumors were recognized; given the identical morphologic appearance after VCM exposure, involving mixed hyperplasia of sinusoidal cells and hepatocytes, and the occurrence of hepatocellular tumors in experi mental animals exposed to VCM (26), we need to continue to follow-up VCM-exposed cohorts for the possible appearance of hepatocellular tumors. Cases of HAS associated with various factors have previously been reported (U, 27, 28); individ ual cases associated with hemochromatosis, prior radiotherapy, chloroprene exposure and chemother apy with urethane were also noted in this study, but we have not discussed them in detail here. It would appear valuable to continue epidemiologic studies of this rare tumor. This might enable early detection of additional etiologic factors for this disease, such as the various structural analogs of vinyl chloride (e.g., vinyl bromide and vinylidene chloride) which have had industrial use. However, because of the difficulty and time involved in establishing adequate surveillance for rare tumors such as HAS or mesothelioma, it would be best to ei lablish a single framework for studying a number of rare tumors or marker illnesses at once. One would then be able, e.g., to survey pathologists or other groups at a single time to obtain information on a variety of such conditions. HAS is a rare tumor with at least four probable causes and undoubtedly others that have not yet been identified. Ascertainment of the range of causative agents for HAS, as well as for more common tumors, presents a challenge to epidemiol ogists. We acknowledge the rapport ofClark W. Heath, Jr., Matthew Zack, Joyce Cannon, Robert Albin, Alice Little end Carolyn Formter of the Center* for Dimtie Control: Paul Leaverton of the National Center for Health Statistic*; Irving J. Selikoff of the Mount Sinai School of Medicine; Norman C. Teliet of the Bureau of Radiologic Health; and Donald M. Austin of the California Tumor Regiitry. We particularly appreciate the 112 rapport of the many phyaidana, pathologists. and tumor r*. I trars who provided information and participated in the nuc I y :i REFERENCES 1* Cntd), J, L, Jr*, w) Johnson, M* N. Anfiosvtoftej I liver in the manufacture of polyvinyl chloride. J. Oer- i Mad. IS: 160-161 (1974). 2. Falk, H., Oaach, J. L., Jr, Heath, C. W,, Jr., Johns*, i ! N., and Key, M. M. Hepatic diaeaie among worker* t, vinyl choloride polymerisation plant. J. Am. Med. Aau 230; 69-68 (1974). 8. MacMaboc, H. E,, Murphy, A. S,, and Bate*. 9 i EndathaUal-cell tarcoma of liver following Thorotrast mo tion*. Am. J. Pathol. 28: S86-6S1 (1947). 4. Roth F. Arsen Lebertumaren (Hemangioendothelion, 1 Krebaforach. 61. 468-608,1967. 6. WaxwaOer, R. J., Stringer, W., Wagoner. J. K.. Jones.1 Falk, H-, and Carter, C. Neoplastic nek among eorkt- j exposed to vinyl chloride. Ann. N.Y. Acad. Sri. 271; (1976). j ' 6. Spirtas, R., and Kaminski, R. Angiosarcoma of the liter t vinyl chloride/polyvinyl chloride workers--1977 update t* the NIOSH register J. Occup. Med. 10: 427-429 (19ie 7. Da Silva Horta, J., Da Motta, L. C., and Tavam. M K Thorium dioxide effects in man--epidemiological, dm and pathological studies (experience in Portugal). Envwc Re*. 8:131-169 (1974). 8. Faber. M. Twenty-eight year* of continuous follow-up it . patient* injected with thorotrast for cerebral angwpxjr f Environ. Re*. 18; 37-48 (1979). } 9. Roth, F Delayed sequelae of chronic amnism in rinu*- ( on the Moeelle. Deut. Med. Wochenachr. 82:211-217 (1967 10. Lander, J. J., Stanley, R. J., Sumner, H. W,, Boewell. D j C., and Aach, R. D. Angiosarcoma of the liver mown ` with Fowler's solution (potassium anentte). Gastroemrtv i ogy 68:1682-1686 (1976). 11. Regelaon, W., Kim, U.f Oeptaia, J., and Holland. J. 7 . Hemangioendothelial sarcoma of liver from chronic snttc intoxication by Fowler's solution. Cancer 21:514-522 USfr 12. Rennke. H., Prat, G. A, Etcheverry, R. B,, Kata. K. I and Donoso, S. Hemangioendothelioma maligno del tugrik ; anenidamo cronico. Rev. Mad. Chile 99: 664-698 (1971; j 18. Suaaman, E. B., Nydiek, I., and Gray. G. F. Hemsnr- ' endothelial sarcoma ofthe liver and hemochromatosis Air > PathoL 97: 39-42 (1974), 1 14. Pimentel, J. C., and Menases, A. P. Liver disease in rinjwri j sprayer*. Gastroenterology 72:276-288 (1977). 1 16. Berk, P. D., Martin, J. F., Young, R. S.. Cratch. J ( Selikoff, I. J., Falk, H.. Watanabe, P.. Popper. H.. wc Thomas, L. Vinyl-chloride-associated liver disease. Arc. I Intern. Med. 84: 717-781 (1976). , 16. Falk, H., Telle*, N. C,, Ithak, K. G,, Thomas, L. B.. ik { Popper, H. Epidemiology of Thorotrast-induced hepw angiosarcoma in the United State*. Environ. Res. 18:65-7- (1979). 17. Falk, H., Herbert, J. T,, Edmonds, L., Heath, C. W . Jr Thomas, L. B., and Popper H, Review of 4 ns** ` childhood hepatic angiosarcoma-elevated environmental v ; senk exposure in one csm. Cancer 47: 3*2-391 (198U 18. Falk, H.. Caldwell, G. G., Ithak, K- G.. Thomas. L B. w : Popper H. Arsenic-related hepatic angiosarcoma- Am J Ind. Med. (in press). 19. Falk, H., Thomas. L. B., Popper. H. Ishak, K G. Hepw j angiosarcoma associated with androgemc-xnabohc iteroto.- Lancet 2; 1120-1123 (1979), Environmental Health Perspecti'*1 ucc 05715 aJH --i Study. giourt onii of d*. J. Occup , Johnson, j| workers it i Med. Aim Bites, H | irotrtM inj lotheliom). Z K., Jones. J.. long workerwa. 271:4(44* of the liver tr. 77 update u! 29 (19781. m. Y. H jical, clinical il). Environ. foDow-up of ingiogTaphv i in vintners (1937.. ell. D. r ass<united istrwmerol- Uand. J. F 'onie arsenic 4*522 ilke>. <ati. R. V.. delhigadov 36 (1971). . Heminpoitoeir. Arch emwnyird Creech. J.. er. H.. ind *aae. Ann. L. B . and ced hepatic js. 16: 65-71 C. W,, Jr.. 4 cases of nmental ar isen. .. L. B. and m_ An. J. G. Hepatic icstenwk j, Rothman. K. J. Computer analysis for case-control studies with individual matching. Int. J. Biomed. Comput. 5: 241-247 (1974). !1 Baaerga. R., Yokoo. H., and Henegar. G. C. Thorotraatinduced cancer in man. Cancer 13: 1021*1031 (1960). *> 1ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemical* to Humana. Vol. 20: Some Halogenated Hvdrocarbona. Trichloroethylene. IABC, Lyon, 1979, pp. 545-72. 23 Rappe. C., and Zingmark, P. A. Formation of AT* nitrosamlines in cutting fluids. In: Environmental As pects of .V-Nitroso Compounds. E. A. Wsheer, et el., Eds.. 1ARC Scientific Publication 19, Lyon, 1978. 24 Popper. H.. Thomas, L. B., Telles, N. C., Falk, H.. and Sehkoff. 1. J. Development of hepatic angiosarcoma in man induced by vinyl chloride, Thorotraat, and arsenic-- companion with cases of unknown etiology. Am. J. Psthol. 92: 349-376 (1978). 25. Baxter, P. J., Anthony, P. R.. MacSween. R. N. M,, and Scheuer, P. J. Angiosarcoma of the liver Annual occurrence and aetiology in Great Britain. Brit. J. Ind. Med. 37.213*221 (1980). 26. Maltoni, C. Predictive value of carcinogenesis bioassavs. Ann. N.Y. Acad. Sd. 271: 431-47 (1976). 27. Locker, G. Y., Doroahow, J. H., Zwelling, L. A., and Chabner, B. A. Hie clinical features of hepatic angiosarcoma: A report offour cues and a review of the English literature. Medicine 58: 48-64 (1979). 28. Daneahmend. T. K., Scott, G. L,, and Bradfleld. J. W. B Angiosarcoma of liver associated with Phenelzine. Brit. Hed. J. 10:1879 (1979). < October 1981 113 ucc 057159 Environmental Health Penpeetivu Vol. il, pp. HS-llS, Ml The British Hepatic Angiosarcoma Register by Peter J. Baxter* A register of British rim of primary hepatic tngiourcoma (HAS) was established in 1174 to monitor the occurrence of cases from 1963 onwards. Details of cases drinf in 1963*77 hare been obtained. Thirty-ftv* cases were Sfreed as HAS br a panel of liver petholofists, and occupational and medical information was obtained in the majority of these. Two cases were attributable to VCM exposure, and eight others had received intra-arterial Thorotrast In 1976-79, two more cases were confirmed in VCM polymerisation workers. Introduction In 1974, the Health and Safety Executive em barked upon a mortality study of all workers in Great Britain who had been exposed to vinyl chloride in the manufacture of vinyl chloride (VCM) or poh i vinyl chloride) (PVC), and a register of British cases ofprimary hepatic angiosarcoma (HAS). The na tality study embraced over 7000 people, and an analysis of deaths up to the end of 1974 has been published (l). The main finding was four certified cases of liver cancer, two of which were histologically confirmed HAS. An update of this analyst- has been postponed while, with the collab oration of the factories concerned, exposure data are being refined to take into account job changes and exposure to PVC dust. A mortality study of PVC fabricators was considered, but remains in the planning stage. The register is also the basis for a case-control study of occupation for those cases occurring from 1974 onwards (t). To determine the annual occurrence of HAS and to monitor its incidence, cases dying in 1963-73 were reviewed as well as those occurring after this period. Information on cases for the 15 years 1963-77 has now been obtained and will be outlined here. Further details may be found elsewhere (J, 4). 'Hfi' h and Safety Executive. 25 Chape) Street. London, XtV] .3; iT. England. Present addreae: Chronic Disease* Divi sion. s *cial Studies Brandi, Center for Disease Control, Atlanta. Ga. 30333. October 1981 Methods Cases were identified by s search of death certificates in seven appropriate categories of the International Classification of Diseases for a diag nosis of HAS (or one of its synonyms). Hospital pathologists and cancer registries were requested to report cases, as were the medical departments of factories manufacturing VCM or PVC. Some cases were identified from publications. When available, histological material was sought for all the reported cases and submitted to a panel of three liver pathologists (Drs. P. P. Anthony, R. N. M. MacSween and P. J. Scheuer), who reviewed the slides independently and without knowledge of the prior diagnoses. For control purposes, histological material from other liver cancers was included. For those cases agreed by the panel as HAS, the frill medical records were sought and further informa tion, for example, occupational histories and alcohol consumption, was obtained when possible by inter view with the next of kin. Results and Discussion Eighty-eight cases were reported from all sources. The panel agreed the diagnosis in 32 cases and three more were agreed from among the controls. In half of the confirmed cases the diagnosis had been recorded on the death certificate, but the remainder would have been missed if reliance had been placed upon death certificates as the sole method of ascertainment. At least some clinical and 115 ucc 057160 i necropsy details were obtained in all but two pa tients. Occupational histories were obtained in 91%, the occupation recorded on the death certificate being accepted for the remainder. The annual numbers of both reported cases and those agreed by the panel increased alter 1975, so that in 1977, 12 cases were reported, 10 of which were agreed by the panel. Between 1968 and 1977 an average eight cases per annum were reported and three per annum were agreed by the panel, the population of Britain during this period being about 50 million. The observed increase in incidence was almost entirely due to 10 cases of known etiology; eight were patients who had received intra-arterial Thorotrast (a colloidal suspension of thorium diox ide), and two others had been VCM polymerization workers. Plotting on a map the last places of residence ofall 35 agreed cases revealed a cluster of six Thorotrast cases in or around Edinburgh, where the use of Thorotrast in neurological diagno sis had been greater than at any other British center. One hundred and nine patients who had received intra-arterial Thorotrast in Edinburgh during 1933-48 have been followed up in detail (5): about three quarters of these patients have died, 13 (17%) from liver tumors. Histological material for review by the panel was available in nine of these. In those cases dying in earlier years, the tumors were predominantly cholangiocarcinomas, but later cases were all HAS, confirming that the recent emergence of Thorotrast-induced HAS in Britain is a real increase in incidence and not an artifact due to under-reporting of cases occurring in the past. Twenty-eight of the 35 cases were males; one female infant died aged 8 months. For idiopathic cases, the male-.female ratio was 4:1. Aduh cases were assigned to one of the Registrar General's five social classes according to the occupation on the death certificates- The social dasa distribution was unremarkable, except that the only cases in social classes one and two were four men, all of whom were designated as electrical engineers. In fact, six out of the 28 males had worked in the electrical industry at some time, a figure in excess of any other industry. Three other men had been em ployed in workplaces where PVC was fabricated, but the occupational histories were inadequate to confirm that these men had worked with PVC. One other male case had lived for six years before his death within a half mile of a plant manufacturing PVC. Occupational exposure to arsenic did not appear to be a factor in any of these cases. Arsenical drugs were commonly prescribed in Brit ain in the past and, in a few areas, even until the 116 early 1960's. However, one case only was suspect* to have clinical evidence of chronic arsenical irnoication, but nail and hair analyses for arsenic ttrt negative and the medical records were inadequa-., for verifying the use of arsenical drugs. None of these cases was recorded to have taken androgtr. steroids (6), but one woman had taken an estrof* preparation for several years. Alcohol did m appear to be an important factor in the majority of cases, only four men having a history of hear, consumption. In its age distribution, clinical presentation tir. prognosis, HAS resembled primary liver carcinoid U). Upper abdominal pain and a hepatic mu., were the commonest presentation, and extrahepric metastaaes were found in 23% of cases only'. Ei eluding the Thorotrast cases, and for men only, tb median interval between the onset of symptom, and death was six months for those aged under sixty years, and only six weeks for those aged sin;. I and over, a difference which was statistically highly ) significant. Hemochromatosis was not evident it any of the cases. In 1978-79, two more cases of HAS have beer confirmed in polymerization workers, and another case has led to speculation that hydrazine derive tives, such as phenelzine, may induce angiosammu in man (7). It is too early to predict the full impar of past industrial exposure to VCM in Britain an! at least until the picture becomes clearer the monitoring of HAS should continue. Ei M D( by REFERENCES 1. Fox. A- J. and Collier. P. F. Mortality experience <i i worker* expoied to vinyl chloride monomer in the hum fecture of polyvinyl chkiride in Greet Britain. Brit. J. W Med. 34: MO (1977). 2. Baxter, P. J. Epidemiological atudie* of PVC manulktw j era and fabricator*. and primary angiosarcoma ofthe j Proc. Roy. Soe. Mad. 69: 297-299 (1976). 3. Baxter, P. J,, Anthony, P. P., MacSween, R- N- M > Scheuer, P. J. Angiosarcoma of the liver in Great Bnur 1963-73. Brit. Med. J. 2: 919-921 (1977). 4. Baxter. P. J., Anthony, P. P., MacSween. R- N- R vt Scheuer, P. J. Angioearcoma of the liver inddence ini etiology in Greet Britain. Brit. J. Ind. Med. 37: 213-211 ; (1960). 5. Baxter, P. J., Anthony, P. P,, MacSween. R- N. R- Scheuer, P. J. Angioearcoma of the liver: a marker nonur for the late effect* of Thorotrast in Great Britain. Bnt. J Cancer 41: 446-433 (1960). 6. Falk, H., Thomas, L. B., Popper. H. and lahak. K. G Hepatic angiosarcoma associated with androgenic steroid*. Lancet ii:1120-1123 (1979). 7. Denethmend, T. K,, Scott, G. L., and BradfleW. J ^ Angioaarcome of liver asaociated with Phenelrint. Bn: Med. J. 1:1679 (1979). Environmental Health Perspective* Intr In have tial occu; tiorn medi varit o'.he: mary L> Ifcpa- Writ Lorn* Otto ucc 057161 M s suspects nical intoxj reenic weninadequa:*- None of androjenk Ui estroger. ol did no: majority of y Of heiv) ntation and ' carcinoma patic naff xtrahepatk 5 only. Exan only, the symptom.iged under aged si\n ally highly evident in have beer, id another ne deriva( rcoma flu. impart Jritain and learer the vperieni* of n the maiuiBnt. J. Ind minufaeturofthe liver . N. M. and rest fintam. . N. M. and ridenc* and 37: J13-211 N. M and rker turnout .ain. Brit. J shak. K. G _-nie anabolic -Id. J W. B .lzme. Bnt spectivw Environmental Health Perspectives Vol. 21, pp. 117-3X2, 19S1 Effectiveness of Federally Required Medical Laboratory Screening in the Detection of Chemical Liver Injury by Carlo H. Tamburro* and Richard Greenberg* The inertaainf concern of induetrialiied *00101100 over the potential health haxatd of aynthetk chemical* in the occupational environment ha* led to foverment requirement* for medical laboratory acreeninc of worker*. The ipeeiAe teat* for auch screening programs are moot often -elected on the bttii of medical experience which utiliaed them in aymptomatic or Hoepltallied population*. Required screening tael* for hepatic injur) includinc cancer in vinyl chloride worker* hat been ayatematically and proopectively studied-in an induatrial population worfcinc w ith aynlhetlc rubber and plaatlca. Approximately 1300 employed were atudied over a five-year period. A cohort of 069 male employee*, for the purpoeee of analytic, were divided into a "standard'* and "nonatandard" population bated upon the abaence or pretence of significant medical diieaie (including liver diaeaae). A aubcohort of 120 individual* waa further identified baaed on availabitiity of liver biopey. Evaluation of federally requited atudica included alkaline phoephataae (API, y-glutamyl tranapeptidaie (GGTP), alanine aminotranaeraec (ALT, SGPT), aspartic aminotranaferaa* (AST, SGOT) and bilirubin (BR). Alto atudied were indocyanine man clearance (ICG) and radioisotopic liver spleen scans (L-S scans). The GGTP provided the higheat positive predicted value as a screening teat for identifying "nonatandard" individuate (individual* with all type* of medical diaeaae) followed by ICG, AST. ALT. L-S scan. AP, and BR. In the identification of asymptomatic liver dieeaee the GGTP had the least ipecificity due to a high raise poaitive rat*, while the AP provided the highest specificity. The ICG clearance however, provided the beat combination of poaitive predictive value and turn of specificity and sensitivity. The AP provided additional increase in specificity as a follow-up study. There was no evidence that any of the other federally required teats added any additional benefit and did add significant increase in the fall* positive rat*. The** studies support the need for evaluating screening tests as to their sensitivity, specificity and poaitfv* predictive value, in asymptomatic individual*, before they are made established requirement*. Introduction Industrialized societies throughout the world Have become increasingly concerned over the poten tial health hazard of synthetic chemicals in the (xcupational environment. Governmental regula tions have increased the number and types of medical laboratory screening required for a large variety of halogenated hydrocarbons as well as ether potential environmental hazards. The priman- objective of these screening programs is to "Liver Ht-earth Center, Diviaion of Digestive Diaeaae*. I^-panmem of Medicine, and Department of Community Health a-' d Cancer Center. University of Louisville School of Medicine, Lj-iuviU*. Kentucky 40201. flrtober 1981 reduce disability, morbidity and mortality in work ers, especially as related to serious low-grade health hazards. In general, screening programs are instituted because of the presence in the work environment of a suspected or proven environmen tal toxin or carcinogen, which has the potential of producing low-grade injury over long periods of exposure. Moat screening studies are directed toward the detection of abnormalities in certain body systems. The specific tests are frequently selected on the basis of medical experience which utilized them in symptomatic or hospitalized populations. Prior expe riences utilizing nonspecific multiphasic health sur veillance screening and maintenance have not proven to be cost effective except under certain limited 117 ucc 057162 A conditions (J). The cost effectiveness of such tests, however, in the determination of medical screening requirements, has played a limited role due to the potential seriousness of these occupational agents. Little attention has been paid as to whether the effectiveness of federally required screening pro vides the best or, more importantly, a necessary benefit when applied to asymptomatic and other wise healthy worker populations. The discovery in 1974 of hepatic toxicity and cancer formation in vinyl chloride workers provided the opportunity to systematically and prospectively study the effectiveness of federally required and federally recommended medical screening proce dures for the detection of chemical liver injury, including cancer development (). Table 1 lists the federally required medical screening procedures since 1974 for environments utilizing vinyl chloride or polyvinyl chloride. Table 2 lists the federally recommended studies for these same environments. This paper will present a preliminary assessment of the effectiveness of these federally required studies in the accurate detection and identification of chem ically induced liver injury due to halogenated hydro carbons, especially vinyl chloride. Materials and Methods The industrial population studied consisted of approximately 1200-1400 employees of a chemical plant whose two major products were synthetic rubber and plastics. The industrial plant had been in operation for over 35 years and had a predomi nance of male employees (96%), approximately 80-37% of the work force being white, 11-12% black, less than 1% ofother racial origins. Turnover of the plant was approximately 10 to 15% per year wi' h 65-70% of the work force having worked five years or more at the plant. Employee ages ranged from 18-65, with a mean of 52 years. A cohort consisting of 969 male employees who worked continually from June 1, 1976 to May 31, 1977 was, for purposes of this analysis, divided into a "standard" and a "nonstandard" population. These designations were given on the basis of a review of Tabic 1. Federally required etudiee for vinyl chloride worker*. History and physical < 10 year* as vinyl chloride worker--(annual) > 10 years as vinyl chloride worker--(semiannual) Biochemical studies SGOT (AST) SGPT (ALT) GGTP AP TB 118 Tabic 2. Federally recommended (not required) Kudin, j Hepatic studies LDH isoenzyme Total protein Protein electrophoresis Ratlioutttopic scan Kidney dysfunction (urine examination) Albumin RBC Exfoliative abnormal cells Pulmonary system FVC FEV, Cheat x-ray (PA and lateral) j | I | | I ! ` t * all present standard medical data on each employ- s ee, including the federally required studies. Other screening studies of the medical surveillance pn- 1 grama were not utilized in the classification o' - overall medical status because, at that time, their 1 clinical usefulness was unknown or controversy j All studies were performed on an annual bast ' those individuals with ten yean or more of employ ' ment were examined and screened semiannually Compliance with medical screening studies dunr* , the five-year study period showed a continuot- participation in the history and physical examini i tions by over 75% of the work force, laboratory testa and chest x-rays by 86%, and liver-spleer. ( scans by 85%. Seventeen percent failed to under; ; at least one history and physical examination ' 9% did not have any of the radiological studies and only 4% failed to have laboratory studie- , during this period. Approximately 40-50% of these J individuals who did not undergo an examination : claimed to have been examined by their private , physician. A subcohort of120 individuals was furtheridentified ; based on the availability of a liver biopsy performed for medical reasons, both related and not related tc 1 their work. ' The term "standard" is used for those individual1 who, based upon the best medical opinion, demon strated no evidence of any significant medial disease, occupational or nonoccupational in origin The "nonstandard" population included all other not included in the standard population. The subcohort population was divided into those individuals with and without histological evident . of liver injury and ftirther subdivided into those with and without histological features charactens- - tic of chemical injury. All employees had individual work historic | These consisted of a standardized job classificatio- for all jobs within the plant since its opening nd - Environmental Health Perpti* ; ran! peccals wer exp oft: this ran emj cal ibs< mal. chei dou two Imohisb Re A wen pap* fede dea- and 3 f'Cll ri ps' pr in- hy ei Oeti ucc 057163 7 d* 4i i employ, es. Other nice procation of ne, their oversial. a1 basi>, employinnually. a during ntinuous xaminaoc-iton i een undergo Nation, studies, studies of these lination private ientified formed lated to viduals iemonnedical origin. others > those idence those eteris- tories, cation and a s nnk ordering of exposure for 22 different sus pected or potentially hazardous heptatoxic chemi cals used within the work place (3-S). The agents were rank ordered on the basis of the intensity of exposure for each of the job classifications for each of the years that the plant was in operation. From this detailed work history, a cumulative exposure ran month ration (CERM) was determined for wh employee for each of the 22 chemicals. All histologi es! material was classified as to the presence or absence of liver disease, and to whether the abnor malities were consistent with chemical or non chemical injury. This classification was conducted double blindly by three experienced physicians, two pathologists, and a hepatologist (5), without knowledge of any medical data, exposure or work history. Results Although 50 or more biochemical screening tests were performed during this study period, this paper will limit itself to .the evaluation of the federally required studies, the indocyanine green clearance (ICG) study at the 0.5 mg/kg dose (7, 8) and radioisotopic liver and spleen scan (0). The <00 C-GTP ICG SGOT G5 AST JGFT LIVER SPLEEN ALT SIZE TESTS r>Cj* fowtive predictive vahiee of screening tests in idtmif.Lation of medical disease in sn asymptomatic working popuk'.ion lN - 968). All those screening tests with positive piedu -.iv* values of greater than 70 art shown except tor uidire.: bilirubin (due to high number of congenital indirect hyper! iliruhinemia) and triglyceride determination. Above each Car in the graph are shown the sum values tor Mnri. vity and spsdfldty of each test. They generally follow the tarne ranking. October 1981 SGPT GOT AIK SGOT ICO U* OSmgSQmg PH06 RU6IN ICG Fiouaz 2. Frequency with which dinicn] biochemical tests corractly rtfUx the prsscncs of hepatic damage in chemical worker* suspected of having liver disease: (SGPT) alanine aminotransferase (ALT) (GGT) ygiutamyl transpeptidase, (SGOT) aspartic aminotransferase (AST), (Aik. Phos.) alka line phosphatase, (1CD) isodtric dehydrogenase (ICG) Indo cyanine Green clearances at 0.S and 5.0 mg/kg dote. federally required biochemical studies include alka line phosphatase (AP), y-glutamyl transpeptidase (GGPT), alanine aminotransferase (ALT/SGPT), bilirubin (ALT/SGPT), and the aspartic amino transferase (AST/SGOT). The positive predictive values of these screening tests in identifying medical disease (including liver disease) in this asymptomatic working population are shown in Figure 1. The GGTP provided the highest positive predictive value as a screening test for "nonstandard" individuals. It also provided the highest sensitivity and specificity sum shown in brackets. The predictive value of the other tests, in decreasing positivity were ICG, AST, ALT, liver and spleen scan, AP, and bilirubin. Further evaluations were conducted on the subcohort population in whom we had both histolog ical and biochemical data concerning hepatocellular damage. If one looks at only those individuals who received liver biopsies for suspected liver disease then one would find the percent of positive tests as illustrated in Figure 2. Hie ALT (SGPT), GGTP, AP and AST (SGOT) demonstrate a very high degree of sensitivity in identifying individuals with hepatic disease. As shown on the right, ICG clearances at the 0.5 mg/kg level provide a similar degree of sensitivity to SGOT and AP. The higher dose ICG clearance (5 mg/kg) appears to provide the most sensitivity for latent hepatic disease. These findings are consistent with the general medical experience with hospitalized patients. Sensitivity alone however is not an adequate indicator of a test's screening value, especially when used in asymptomatic individuals. More appro priate evaluation of these tests' value as screening instruments are shown by their sensitivity, specificity 119 ucc 057164 AVEIU6C i. i w1/1 2o Figuke 3. Sensitivity and ipedAdty of various biochemical screening test* and their aenaitivity and specificity awn valuea (S k S) baaed on 78 with biopay documentation oftheir hepatic status and all of the biochemical ocreemnf atudiea listed. All screening test* with SfrSsums less thin 110 (e.g. bilirubin and iaodtric dehydrogenase, are not illustrated. CLI t.0 aeoue *tih05 | 1 Fiouxi 4. Correlation between the histologic flndmp b,, i biopsy and each individual'! avenge total vinvl dfav exposure baaed on their averace CERM (Cumulative tip. aura Rank Month*) ratinfs. Rankings: 1 - lowest po*.:, ' expoaura; 2 - minimal axpoaura, low levels; 3 - maimexposure; 4 - worked in areas subject to occasional hr ; excursions, or frequently high and/or had intimate eonur 1 and sum values shown in Figure 3 in the biopsied subpopulation. Here again, y-giutamyl transpeptidase and ICG clearance (0.5 mg dose) show the greatest sensitivity for identifying individuals with liver disease. However, GGPT had the least specificity, reflecting its high incidence of false positives. Specificity increased with the use of AST, ALT, and ICG clearance. The alkaline phosphatase pro vided the highest specificity, suggesting that mild or low grade chronic hepatic injury due to environ mental agents may be activating hepatic AP syn thesis in the absence of biliary tract obstruction or cholestasis. The ICG clearances, even at the low dose (0.5 mg/kg),, clearly remains the test with the best combined sensitive and specific screening study for detection of individuals with subdinical hepatic disease. This subcohort biopsied group was further exam ined on the basis ofthe histological interpretation of their liver biopsies and their work exposure to vinyl chloride. All biopsied individuals were subdivided into three groups; 19 with histological evidence consistent with chemical liver ii\jury; 30 with histo logical evidence of liver disease, nonchemical liver injury; and 29 with normal liver biopsies. Each of the histological subgroups were farther subdivided based on their vinyl chloride exposure, on a scale of 1 to 4 (Fig. 4). The chemical liver injury group contained the highest percentage of individuals with the highest average rating (CERM) for vinyl chloride expo sure. In contrast, with those with liver disease, nonchemical, and those with normal livers have a 120 more even distribution of individuals relative u their degrees of vinyl chloride exposure. In our previous studies we noted that almost individuals with histologically specific lesion o' vinyl chloride injury or angiosarcoma had a tou. average CERM rating of 3.5 or greater. Tot asterisk in Figure 3 indicates the percentage o.' , individuals in each of the three histological groupwith exposure ratings of 3.5 or greater. Again, the chemical liver injury group have the highest per centage of individuals with the high exposure ratings. This further supports previous work U. l(/ identifying focal hepatocellular hyperplasia as the earliest histological characteristics ofchemical injury in liver disease. A study of the frequency with which these teste are positive among those individuals with liver ; disease, based on their histological findings (chem- ical versus nonchemical), provides additional data supporting the clinical observation that an increased AF has s greater specificity for chronic liver injury Figure 5 shows the ratio of the proportion of > positive screening tests in those with histological chemical liver disease divided by the proportion of positive tests in those whose disease is not of chemical origin. All tests, independent of their sensitivity and specificity for liver injury, were more frequently abnormal in the presence of nonchemical, subdinical liver injury, except for AP. In contrast, AP was far more frequently abnormal in those individuals with chemical liver injury, which tended to be more chronic than scute and generally less severe. Environmental Health Perspectives , Fi-;i / m, a* IK' Ois T) live spec reqt first ofm tion use* exp SYTT din: abil fror tom falsGG' fica and pro inci the em: sen asy rec me Oct ucc 057165 *6' MCiI 4 <*'>>) ' on liver yl chlondt ative Expo-*t possibit 1 modwitt yonii hijt e conun itive to Host a]] sion of a total r. The - of groups on, the st perposure U. 10) as the injury j test* liver ehem1 data eased ijury. ion of ogical ion of ot of their were :e of t for ently liver )cute (SOOT) (SOFT) TESTS 03 Fiores 5. Frequency with which biochemical tests were tbnormil m those with different tvpe^of hepatic injury expresses is s ratio: (CLI) chemical liver injury. (LD) liver disease, nonchemicaL Discussion This preliminary systematic review of the posi tive predictive values and the sensitivity and specificity of federally and some non-federally required tests for chemical workers provides the first scientific and biological basis for the selection of medical screening tests for liver iryury in occupa tional environments. Although these commonly used medical tests have been found by clinical experience to be effective as diagnostic tools in the symptomatically ill or hospitalized population, little clinical work has been done to determine their ability to accurately separate biological variations from early latent or undertying disease in asymp tomatic individuals. Tests which provide very high false-positive rates (decreased specificity) such as GGTP, interfere with the screening process identi fication of the high risk worker by the extra time and cost required for repeat testing, the decreased productivity for the employer, the employees' increased anxiety, and by the loss of confidence in the effectiveness of the testing program by both employees and employer. Determination of the sensitivity and specificity of screening studies for asymptomatic individuals is essential if effective recommendations are to be made a federal require ment. This evaluation process also provided the October 1981 best means of developing effective triage protocols for the screening program. For example, in this particular population of industrial workers, we have shown that the assessment of hepatic function is best accomplished by low dose ICG clearance (0.5 mg/kg). The ICG clearance is somewhat s more complicated technique (i.e., injection of substance and repeated blood sampling) but requires only 10 min to perform, and needs only one needle stick. In exchange it provides the best singular screening test for latent hepatic injury. If adequate medical facilities are not easily accessible, then ALT Bhould be substituted. If either ICG clearance and/or ALT studies are found to be abnormal, an AP should be done and a diagnostic work-up instituted to deter mine the etiology (11). The rationale for these recommendations is based on the actual study of chronic subacute chemical injury in an asymptomatic population, not preselected because of signs or symptoms. Therefore the test's ability to correctly differentiate disease from nondisease or one type of injury from another is more accurately determined. Chemical and envi ronmental agents of low toxicity tend to produce repeated or persistent injury which accumulates over time. Tests which measure overall functional capacity quantitatively or semiquantitatively, rather than measuring acute low-grade injury over time are more likely to detect changes. For this reason, clearance or tolerance studies provide the best means for identifying latent hepatic disease, while enzyme studies like ALT, GGPT, and SGOT usu ally reflect acute cellular injury of higher grade or degree and cannot accurately reflex accumulative damage until very late in the disease process. Tests which provide information concerning the progres sion or nonprogression of injury will be far more helpful to the practicing occupational physician. They provide him/her with a better capability to discern between nonoccupational and occupational disease, and the best available reassurance for the worker of his or her safety while allowing the greatest possibility for continued productivity and employment. Finally, these data provide a sound scientific basis upon which to modify federal requirements. The removal of specific testing requirements which, with field experience, prove not to have any significant positive predictive value, or effective sensitivity and specificity will aid in reducing overall cost and help maintain continued compliance by industry and workers. There may be theoretical reasons to maintain or continue some of the present federally required screening studies, but these reasons should be separately identified and not be confiised with the purposes of the more effective test in the 121 ucc 057166 detection of occupationally related liver injury. The capabilities and limitations of any new tests or old tests for new screening purposes in detection of other potential occupational hazards, should be validated before making them a required screening procedure. This would lay the foundation for sys tematic determination of effectiveness of screening procedure against a proven standard. Unvalidated federal requirements provide the worker and employer with a false sense of security and safety by what is believed to be effective monitoring. More importantly, such a situation can lead to delay in effective correction of cause and disease preven tion. Conclusions Biochemical screening for hepatic injury in asymp tomatic chemical workers can be done most effec tively by the use of liver specific clearance studies. ICG clearance provides the best combination of positive predictive value and sensitivity and specificity for functional hepatic testing at the present time. None of the presfeftt federally required studies provide any significant degree of sensitivity with out marked reduction in specificity in asymptomatic individuals. The ALT (SGOT) is the most useful among those Federal tests presently required and the alkaline phosphatase may provide additional specificity as a follow-up study in those individuals with positive ICG or ALT screening studies. There is no evidence that any ofthe other federal studies add any benefit and strong evidence that they significantly increase the false-positive results in well individuals. All screening studies should undergo evaluation as to their positive predictive value and sensitivity and specificity in asymptomatic individuals before becoming permanent or established requirements. Portion! of this work wore supported b\ National cn~ Institute Contract No-l-CN-SS212 and Manufacturing Chr ists Aaaodation Grant. The authori wiah to acknowledge the help and coopentw Hynaon, Weatcott A Dunning and 8. F. Goodrich Chenn Company. REFERENCES 1. Collen, M. F. Coat effectiveness of multiphasir Wv ! testing services. In: Multiphasic Health Testing Serve* M. F. CoUen, Ed., Wiley, New York, 1978, Chapter i: I Seethe F, pp. 487-580. j 2. Creed), J. L., Makk, L., Whelan, J. G., Jr., and Tsmbw | C. H. Hepstotoxicity among polyvinyl chloride prahr>- ; workers miring Am year of surveillance program. Gov ! anterology 87:786 (1974). I 8. Greenberg, R. A., Tamburro, C. H.. and Kupchella. E c f Prospective medical turvetllance program for dettcuae iv { prevention at industrial related cancer. In: Prevention 1 Detection of Cancer Fart 1, Vd. 2; H. Niebum, Ed | Marcel Dekker, New York, 1878, pp. 1921-28. 4. Tambum, C. H,, Greenberg, R. A., Newby, L. G., t > Turns, D. M. Implementation and assessment of o tow > oration cancer control detection and prevention pmgmt: | n cohort of industrial workers. Program Contract #St>: CN-SS212 Final Report, Division of Cancer Control tx Rehabilitation, National Cancer Institute. Bethesda, Sir. land. 1978. 6. Greenberg, R. A., and Tamburro. C. H Exposure Me* ' for epidemiological surveillance of carcinogenic agent* r. i industrial chemical environment. J. Occup. Med., in pt*M 1 6. Tamburro, C. H., Makk, L., and Popper. H. Early ht)au histological aiterationa among chemical (vinyl mornnr ' worker*. Gastroenterology 77: ASS (November 1979). 7. Fortwengier, P., and Tamburro, C. H. Use ofdye damn in the detection of hepatocellular injury among vinyl ! ride workers. Clin. Res. 23:284A (1875). 8. Tamburro, C. H,, Creech, J. L, Dtvii. A., end Greater R. A. Indocyanine green clearance as a prospective mho tor of hepatocellular chemical toxicity. Gastroenterology 3 ( 988 (1878). j 9. Whelan, J. G., Jr., Greenberg, R., and Tambum, C H Radioisotopic scans and gray scale ultrasonography r detection of liver damage. Gastroenterology 79:1129 ilte 10. Peeper, H. and Thomas, L. B. Alterations of lh-*r w. . spleen among workers exposed to vinyl chloride. Ann. S \ Acad. Sd. 248; 172 (1976). j 11. Tamburro, C. H. Chemical hepatitis, pathogenesis, tot . tion and management. Med. Clin. N. Amer. 81:545 (UP> 1 P ai by p. envi uphi ere, varit tion unde steir. term (vint polyi film; ated ua ride, becoi wear medi, nelat< of th< evalu have of tht Ma ride : mono *nce< rases UlU Wt\ 122 Environmental Health Perspecti'* Octob ucc 057167 Cincv " Thus operation t,' A C hernia Environmental Health Perspective* Vol. il, pp. liS-ltS, list i**ic heih; g S*nm> Chapter 17 i Tambumi producttof am. Gutrv :h*Ilk. E. f 'tectum w. vention me burgs, Ed L G., md of i demon prognm tr. reel #.\ui ontrol end mde. Uni-. ure indict* gents m tr in presriy hepeui monomer 197**>. f rents \ . ehiuJreenberg. jvt inditeerology 75 rro. C. H gnphv m liver and Ann. NY sis, detec545 (JT9i vet Poly(vinyl Chloride) Processes and Products by R. N. Wheeler, Jr.* Polytrinyl chloride) reeint are produced by four basic processes: suspension, emulsion, bulk and solution polymerisation. PVC suipeniion raaina are usually relatively dust-free and granular with varying degree* of particle poroeity. PVC emulsion resins are small particle powders containing very little free monomer. Bulk PVC resins are similar to suspension PVC resins, though the particles tend to be more porous. Solution PVC resins are smaller in particle sis* than suspension PVC with high porosity particles containing essentially no free monomer. The variety of PVC resin products does not lend itselfto broad generalizations concerning health hatardt. In studying occupational hazards the particular PVC process and the product must be considered and identified in the study. 11 Pohlvinyl chloride) is a ubiquitous part of our environment today, in that it appears in clothing, upholstery, flooring, wire insulation, food contain ers. phonograph records and an almost infinite variety of other items. Despite this wide applica tion and the size of the industry there is little public understanding of the term. A part of this confusion .-terns from the human inclination to abbreviate terms--thus, we say PVC when discussing poly vinyl chloride) resins, poly(vinyl chloride) latexes, poly/vinyl chloride) compounds, poly(vinyl chloride) film and so forth. This confusion has been accentu ated by governmental regulators, who define PVC as a pol.. n.er containing any amount of vinyl chlo ride. On taking these two factors into account it has become almost impossible to distinguish what is meant when the term PVC is used in the various media. In order to study possible PVC industryrelated health problems one must know something of the various processes and products to properly evaluate study results. Many study results can have significance only if the source and composition of the PVC is stated. Manufacture of synthetic resins from vinyl chlo ride and other monomers involves reacting these monomers in agitated pressure vessels in the pres ence ofcat alysts and converting these liquids and/or ***** to solid resins. A considerable amount of heat fatal Carbide Corporation, P. 0. Box 8361, South Charleston, Virgin* 25308. is generated by the reaction. This is removed by cooling the vessel. As the monomer is converted to polymer during the reaction, the rate of reaction slows down; thus, after some optimum reaction time, the unconverted remaining monomer is re moved from the reacting mass by heat and vacuum and the resin (PVC) is recovered as a dried white powder or as a liquid latex or solution. This polymerization reaction may take place in pure monomer, in a solution, in a water-monomer emul sion or in a water suspension of monomer. The nature of the polymerization process determines the nature of the subsequent recovery process, and the nature ofthe resin particles produced. Current ly there are four basic vinyl chloride polymerization techniques which give use to the following four processes: (1) suspension polymerization, (2) emul sion polymerization, (3) bulk polymerization, and (4) solution polymerization. Suspension polymerization is the major process used for the manufacture of PVC resins and is used for about 82-85% of U.S. production (Fig. 1). It involves the charging of one or two parts water and one part vinyl chloride monomer or comonomer mixture to an agitated reactor along with initiator and suspending agents such as poly(vinyl alcohol). The mass is reacted at 50-65C until about 85-90% of the contained monomer is converted to resin. The resin-water mixture is heated, sometimes under vacuum, until the unconverted monomer is substantially removed. The resin is then removed October 1981 123 ucc 057168 from the water and dried in rotary, flash or fluid bed dryers by exposure to heated air. The dried resin is transferred to storage silos, whence it is shipped to fabricating plants in bulk containers or in paper bags. If only vinyl chloride monomer is reacted, the product is PVC homopolymer. If a monomer such as vinyl acetate is mixed with the vinyl chloride then a PVC copolymer is produced. The advantages of the suspension resin process are its high productivity per unit reactor volume, its flexibility with regard to polymer composition and resin particle characteristics and the granular nature of its product. The relatively large resin particles (50 to 150 pm) cause problems in removing unconverted vinyl chloride monomer. The mono mer tends to diffuse slowly from the center of the resin particle to the surface, where it is removed by the monomer recovery operation; thus removal often is incomplete. In the past, residual vinyl chloride monomer concentrations in suspension PVC resins ranged as high as 2000 ppm by weight until improved methods were developed in response to recognized need for lower residual levels. The process produces a wide variety of products, each of which presents different monomer release characteristics as well as differing suitability for particular fabricating operations. As a general rule, small particle size resins have lower residual mo nomer than large particle size; porous particle resins have lower residual monomer than nonporous particle resins; and resins containing little or no comonomer have lower residual monomer than resins with significant amounts of comonomer. The relatively large suspension resin particle, whil* retaining monomer from the manufacturing ptv , cess, results in a product that has excellent han- ; dling properties such as bulk flow. Recent ' improvements in monomer stripping technology, : have resulted in most PVC suspension homopolyme- resins containing about 10 ppm residual Vim': chloride monomer at the time of shipment while the residual vinyl chloride monomer in most copolv- ! men ranges from 25 to 200 ppm at the time of j shipment. ) The stress on residual monomer content at the > time of shipment in the preceding paragraph h purposeful. Vinyl chloride monomer is not soluble in the PVC nor is it absorbed or adsorbed in the resin particle. It is entrapped, and, given an opportunity, it escapes to the ambient air. Heating tends to accelerate this escape. PVC resin in a : bulk-container loses its residual monomer at a rate of 25 to 50% per month. PVC resin in a paper bag loses its residual vinyl chloride monomer at an 1 approximate rate of 75% per week. Once the j residual monomer is gone, there is no source of ! monomer from the PVC resin, i.e., the resin doc? I not decompose to yield significant amounts of monomer. If heated, the resin gives off hydrogen chloride and turns black. Thus a year-old PVC resin contains almost no residual monomer; on heating until it blackens it will always give off hydrogen chloride. PVC resin fabricating operations drive off the free residual monomer in the first heating step: thus the probability of a toxic response from vinyl chloride monomer contained in the vinyl film or mol<: A! syst' liqui poly: so f< solid ing : peri' this shut exp< ride with that Cret fouli wasl nate Ei Iv u.' and* of th sion but spec tern the (ami syst' In part surf, syst WATER Ftcuat 1. Suspension polymerisation process. 124 Environmental Health Perspectives Octc ucc 051169 t moldings produced is remote. AU PVC processes have a problem with reactor a stern fouling to some degree. The conversion of a iquid monomer to a high molecular weight solid polymer while contacting reactor walls, baffles and w forth results in the deposition of some of that solid polymer on surfaces. This deposition or foul ing interferes with the reactor operation so that periodically it has to be removed. In earlier times, this was removed manually by a man working in a shutdown reactor. These reactor cleaners were exposed to very high concentrations of vinyl chlo ride monomer (several thousand ppm). It was within the group of men in this cleaning operation that the excess of angiosarcoma was observed by Creech U). More recently, techniques to minimize fouling and techniques for cleaning such as solvent washing and hydroblasting have reduced or elimi nated the need for reactor entry and cleaning. Emulsion i>olymemation is the second moat wide ly used process for the manufacture of PVC resins and comprises 10-12% oftotal U.S. production. One of the important things to understand about emul sion polymerization is that it is not a single process but a large family of processes, each producing specialized products that are defined or specified in terms of performance in a particular application. In the interest of brevity, the two nuyor process families will be discussed: the water-soluble initiator system and the oil-soluble initiator system (Fig. 2). In the water-soluble initiator system, one to two pans water, one part monomer, 0.01 to 0.03 parts surfactant and water-soluble initiator (a redox s> stem or a persulfate salt) are charged or fed to an agitated reactor and reacted at 30-60C to form a synthetic latex. The reactor imitation must be sufficiently vigorous to emulsify the monomerwater mixture but not so vigorous that the latex is coagulated. When 80-95% of the monomer is con verted to polymer, the latex may be gently stripped of the unconverted monomer with heat and vacu um, or it may be subjected to a second initiator treatment and reacted to essentially 100% mono mer conversion. The product of this polymerization may be simply filtered and shipped to consumers as a latex for coatings, mastics, and the like, or the polymer may be recovered as a dry resin. Recovery techniques vary. The most commonly used is sim ply spray-drying of the latex, though some resins are recovered by coagulating the latex and dewa tering with subsequent drying of the coagulum (resin). In the oil-soluble initiator system, one part monomer containing an organic peroxide is emulsified in one to two parts water containing 0.01 to 0.03 parts surfactant. The resulting emulsion is reacted at 30-60*C to form a synthetic latex. Approximate ly 80-90% of the monomer is converted to polymer. After reaction, the latex is gently heated and vacuum-treated to remove the unconverted mono mer. After stripping, the latex may be shipped as s product though most of it is converted to a dry powder by spray-drying. The basic difference be tween the oil-soluble initiator process and the water-soluble initiator is that the size ofthe emulsified monomer particle determines the resin particle size in the oil-soluble initiator process, while polymer ization technique determines the resin particle size October 1981 PVC latex Fiouac 2. Emulsion polymerization proeooo. 125 in the water initiator process. The resin particles formed during emulsion polymerization range in size from 0.05 to 2 urn. In the course of recovery and drying these may be agglomerated to particles as large as 30 pm. For some uses the agglomerates may be ground to a median particle size of about 2 pm. The small particle size results in rapid lose of residual vinyl chloride so that the resin contains about 1 ppm free monomer as produced. Because of handling problems, nearly all the resin is bagged, letting the small amount of monomer retained escape easily before it arrives at a fabricating plant. Nearly all dried emulsion process PVC resin is utilized by paste or dispersion fabrication tech* niques. The resin, pigments and other additives are stiiTed into plasticizer, yielding a thick viscous liquid piastisol. This plastisol is spread on a cloth or a paper or poured into molds. The coated mold or cloth is heated, causing the resin and plasticizer to fuse into a solid forming the finished plastic article. In this fashion, the small manufacturer or the producer of elaborate shapes or highly styled items can make a product.Math a minimum capital invest* ment. The emulsion polymerization process, in addition to the reactor fouling problem noted for suspension polymerization, has less flexibility with regard to changes in process conditions. Each change in reaction, stripping or drying has an identifiable effect on product properties and quality. Some of these properties are well known, and quality tests keep them under control. Others are not well known and are recognized when customers com plain. Emulsion process resins cost more to pn, i cess duce, and plant operators tend to be ven conservator | bulk in the approach to process changes. Because ofthif I th e difficulty, emulsion process plants tend to emr. i Ti more vinyl chloride monomer to the ambient airper 150. pound of resin produced. In Europe particularly 1 ofn there have been reports of worker dermatitis froit 0f h surfactants and possible pneumoconiosis from resir , for dust inhalation in the emulsion process plants (2-; i. \ pin Bulk polymerization is the third major process in i resi> terms of volume for the manufacture of PVC resitir I this but supplies only about 5% of U.S. production (Fig i pnx 3). The process involves the chiu*ging of vinyl i thar chloride monomer and initiator to a first-stags i & polymerizer, where about 10% of the monomer v 1 Uni- converted to polymer. This batch is then transfer- 1 29 red to a second-stage polymerizer where additional chlo monomer, and sometimes initiator, are added. The ' tor polymerization is continued until about 80-859 of ' poly the container monomer is converted to polymer. 1 that The unreacted vinyl chloride is removed by heat : Thi.- and vacuum and the finished resin product tram- tiny ferred to storage bins for later shipment to fabricat- | rec< ing plants. The absence ofwater in the polymerization : and stage eliminates the need for the drying step and ' pon provides some economy in capital and operating ! sus| costa. tint The advantages of the bulk process are iu . Mar simplicity, the uniformity of the resin particle siu. find the high porosity of the resin particles and the j purity of the polymer (no soaps or suspending aids'. ; The disadvantages are: less flexibility in product 1 mix (homopolymers only) than the suspension pro- PVC RESIN Figure 3. Bulk polymerisation proem. 128 Environmental Health Perspecthto Oet ucc 057171 I ft atn, -e of thito emi: U air pr ticularl;. itis fror om resir. 'ts(i-i) rocessir C resin.ion (Fig of vinvi -st-stajc nomer i# ransferdditional ied.Tl* '-85`J of jolvmer. by hea: :t trans-abricatenzation -tep and aerating are its "ize. i. the igaidsi product ion pro- ^ and poorer removal of residual VCM. These Jdk process resins are generally directly competiwith suspension process PVC homopolymers. " jh( relatively large porous resin particles (SO to 130 am) tend not to retain monomer, thus removal /residual VCM is theoretically easy. The transfer ,f heat from the reactor wall to the resin particle f0r stripping is poor thus offsetting the advantages tuned by the high particle porosity in removing residual VCM. In the early 1970s, residual VCM in yjs type of resin was of the order of 1000 ppm when r reduced, but more recently these resins have less than SO ppm in residual VCM when produced. Solution polymerization is a process unique to Cruon Carbide Corporation and accounts for about of the total resin produced (Fig. 4). Vinyl chloride monomer, comonomer, solvent and initia tor are fed to a continuous reactor system. The ;<ilymer formed is soluble in the reacting mass so that the reactor product is a viscous resin solution. This solution is distilled to remove the unconverted -myl chloride monomer, and the resin product is recovered by treating the resin solution with water and drying the product. The r|sin particle is very ;*jrous, is always a copolymef, is free of soaps and spending agents, has a median particle size of 75 u:n and contains less than 0.2 ppm residual VCM. Manufacturing investment is high, and the product finds its greatest use as a coating material, i.e., paints and lacquers, that utilize its good dissolving qualities. It is used in relatively small quantities, and is nearly always shipped in bags rather than bulk. In addition to the basic PVC resins described earlier, there is a wide variety of resin powders, pellets, liquids and latexes in commerce that fall under the general designation of PVC. These are chemically or mechanically converted PVC resins such as post-chlorinated resins and compounded resins containing plasticizers, stabilizers and the like. As a general rule, the additional processing has removed essentially all ofthe residual VCM and agglomerated the dusts. Converted PVC resins have no involvement with problems related to vinyl chloride monomer exposure. Conclusions Poly(vinyl chloride) resins are produced by four basic techniques: suspension, emulsion, bulk and solution polymerization. The variety of PVC resin products does not lend itself to broad generalizations concerning hazards to worker health. In evaluating occupational hazards, the PVC process, the PVC product and other materials present must be considered before valid conclusions can be reached. WATER vent <va October 1981 haste HATER Figure 4. Solvent vinyl resin proccM. 127 UCC 057172 ! REFERENCES 1. Creech, J. L. and Makk, L. Liver disease among polyvinyl chloride production worker*. Ann. N.Y. Acad. Sri. 246: 80-87 (1875). 2. Suriu, I., Prodan. L., Ilea, Elena, Paudurarn, A., and Paacu, Livia. Clinical manifeatationi in vinyl chloride poiaoning. Ann. N.Y. Acad. Sri. 246: S3-69 (1975). 8. Popow, J, Effect of polyvinyl chloride dust on the man- ry system of the rat. Rocmiki Akad. Med. im tawakiego w Bialymstokur (Suppl. 24) 48. 5 (1969) 4. Vertlan, Yu. I,, and Mamontov, Yu. R. The state of u, bronchi and lung* in worker* employed in the manuka chloride articles. Gig. Truda Prof. Zabol *< 29-82 (1970). 11 W P. by Int T and <VC inci exp reti piei Als Lai. hyp ind; Lor wei occ; moi and add thn pro prit lot ind: Coi pol; I Stuc 467C 128 EnvironmenUI Health Perspectives Oct ucc 057173 Environmental Health Pertpeetixes Vol. il, pp. 129-186, 1981 Worker Exposure to Vinyl Chloride and Poly(vinyl Chloride) by James H. Jones* Th* National Institute for Occupational Safety and Health (NIOSH) in tarty 1974 began industrial hygitne itudiea of rtnyl chloride expoted worker*. Three VC monomer plants, three VC polymerisation plants, and seven PVC fabrication plants werf surveyed. VC polymerisation plant worker* and worker* in one job category in VC monomer plant* were exposed to average let cl- above 1 ppm. The highest average exposure was 22 ppm. NIOSH health hazard evaluation studies since these initial survey* have primarily shown nondetectable levels of vinyl chloride. A Nit control technology study in 1977 showed that exposure levels in VC polymerisation plants had been drastically reduced but exposure levels above 1 ppm were still found in several cess*. Introduction 4 ** Industry-Wide Study Tr.r National Institute for Occupational Safety : Health (NIOSH) began studies of vinyl chloride Yt early in 1074 following a report of increased .' lence of anriosarcoma of the liver among VC workers. A part of this work included V'.spective cohort mortality and industrial hyr< r,r studies of the VC polymerization industry. V-.. NIOSH contracted with Bendix Corporation, .'j-neh Support Division, to conduct industrial v-'.rne studies in the VC monomer production .: Lstry and the polyvinyl chloride (PVC) fabrics- industry. These industrial hygiene itudiea re done to document the levels of VC exposure tvjrring in industry at that time. Three VC * numer plants, three VC polymerization plants a'. i seven PVC fabrication plants were studied. In addition to the VC industry-wide study, NIOSH, '''"Ugh their health hazard evaluation (HHE) :r jCTam has sampled for PVC at 34 other plants, jr.marily VC fabrication operations. Also a study document c ontrol methods utilized in the plastics rdustry was performed under contract by Enviro C-mrol. This study included work at live VC t-lymerization plants (J-J4). 'IbvuiiMi of Surveillance, Hazard Evaluations ind Field Nitior.^1 Institute for Occupational Safety and Health, * 5 Columbia Parkway, Cincinnati, Ohio 4S22B. VC Monomer Plants One of the VC monomer plants sampled used the acetylene-hydrogen chloride process, the older pro cess for making VC, and the other two used the ethylene dichloride pyrolysis process. It was not possible to assess the difference in worker exposure between the two processes because the plant using the acetylene-hydrogen chloride process was oper ating at only 10% capacity during the surveys in December 1974. As can be seen in Figure 1, only the job of loader shows exposure substantially above 1 ppm. VC exposure for this job was being reduced, at the time of the surveys, by the redesign of tank car hookup systems and the use of sir-supplied breathing apparatus while the tanks ears were connected or disconnected. VC Polymerization Planti Three VC polymerization plants were sampled. Located at these plants were three suspension resin operations, three dispersion resin operations, one mass resin operation and one solvent resin operation. As can be seen in Figure 2, suspension and dispersion resin operations had the highest exposure levels. Within plants the reactor area operators and helpers had the highest exposures. fktober 1981 129 ucc 057174 i VT ro n c rn trn tin n D5 m sf m J/TU\/p x i _ if ^ *^u**#n*ion ''olvwerti.v .on 2 ni*W*i*n Plveri:aT,oP *%i* "olvTteri nation 0 Solvent Polyotrimiftf J nan** o' I Hr. tr**j ?\ 1 we sio1 ?UT ha' th< P* fUr Cl \ an< me alt 1 tio 1 we ob* inf jar fir^ eei frt Hi ita in t* &R Reactor oAperer*ator it ftc.ictnr Aren llelner A___ am DAryreenr An"j!erjfa_ 'ipernipr MaiM3eLfwjsmae _ Figure 2. Mean* and ran(M of VC expoaurta in VC polymerization pi-"*- 130 Environmental Health Perspectives Oc ucc 057175 pVC Fabrication Plants In the seven PVC fabrication plants samples ere collected in calendering, compounding, extrumn, molding, and plastisol operations. All expomres were quite low with calender operators having the only exposures above 1 ppm. Figure 3 fhows the relationship of VC exposure between the segments of the PVC industry. As would be ex pected, VC polymerization had the highest expo sures and PVC fabrication the lowest. Changes in Exposure Since 1974 We have no information generated by NIOSH and know of none in the literature on how VC monomer plant exposures have changed since 1974, although it would be expected that the single "high" exposure category, loader, has had exposure reduc tions. Informat ion on how well VC polymerization plants were able to reduce exposures since 1974 was obtained during the control technology study. This information is in the form of company personnel .sampling data for VC over a period of time. At the fot plant, a mass polymerization plant, the per centage of personnel samples below 1 ppm has gone from in 1974 to 73% in 1976 (Fig. 4). At the second plant, a suspension and dispersion polymercation plant, the percentage of personnel samples below 1 ppm has gone from 0% in 1974 to 65% in 1977 (Fig. 5). At the third plant, a mass polymer ization plant, VC exposures are given by job for the period October 1974 to May 1975 and then for January 1977. In Figure 6, it can be seen that exposures dropped substantially, in most cases by a factor of almost 10. VC exposures at the fourth plant, a suspension polymerization plant, are given for both 1975 and 1976. As seen in Figure 7, in most cases a two-fold drop in exposure levels occurred. Although the percentage drop is lower than the third plant, the final exposures are about the same. At the fifth plant, a dispersion polymerization plant (Fig. 8), VC exposures are given by job for the period May 1975 to December 1975 and then for January 1976 to September 1976. Again reductions were sufficient to bring exposure averages to the same approximate level (less than 1 ppm) as the preceding two plants. PVC fabrication plants had exposures predomi nantly below 1 ppm in early 1975 when the industry wide study was done. In addition to this work, HHE's have been conducted at 26 PVC fabrication plants beginning May 1974 and ending in April 1978. Detectable levels of VC were found in only 10 plants with only 1 plant of the 15 sampled since April, 1975 having detectable levels. At that plant sampled in March, 1976, the highest level found was 0.38 ppm. PVC dust exposures were also briefly examined October 1981 Figure 3. Mtana and range* at VC expoaurea in VC related induitna*. 131 ucc 057176 i Freuai 4. Distribution of VC oponm at a man polymerization plant. Ficuu S. Distribution of VC exposures at a suspension and dispcrakm polymerization plant. Environmental Health Penpecthn Octol ucc 057177 Optrator #* Picum 6. Chang* in VC expoaura* at a max* polymerization plant. IT rVifi* c u t r .tl lm '*rtober 1981 Operator Charfinj Operator Di^lnf Rtactor Cleaner Operator Mechanic Figum 7. Chang* in VC expoaun* at a tutperuion polymerization plant. 133 ucc 057178  s/'s . i:/?s n - 0/-ft 0(_ Forman OX fttactor Operator Charging factor Operator ItoVing i>rvar rXHTttoT *aoer StartrCleaner Fiouxc 8. Change in VC axpoaurea at a diapcriian polymerization plant. Fiouat 9. PVC duat axpoaum at VC polymerization planta. Environmental Health Penpeetnw ucc 057179 7S ft erspective* during the industry-wide study. Total dust concentntions were determined. Because it was felt that p\'C would be the primary constituent of the dust, po analysis for PVC was performed. Respirable samples were not collected because it was felt that the static charge on PVC particles would cause malfunctioning of the normally used sampling equip ment, such as nylon cyclones. A few samples were examined by optical microscopy. In these samples all particles had diameters less than 7 pm, and 90% ofthe particles had diameters less than 2.5 urn. Hie samples examined were from dispersion resin oper ations. This result was expected, since dispersion resins generally are in the range of 2-10 pan in diameter, ^.-pension resins, the major resins in terms of production, are generally much larger, about 100 itm in diameter. The sampling results displayed in Figure 9 show that dispersion resin bagging had by f*r the highest exposure, averaging 8.6 mg/m8. We we no information on whether PVC dust expo!>ures have been reduced since 1974. It appears, baaed on the information that we currently have that the PvC fabrication industry has achieved good control of VC exposures. The VC ;>il>tnerization industry was making big strides in controlling exposures, but we have no information tu tell if they have continued to lower exposures -mce 1977. We have no information on exposure reductions in the VC monomer production indus try. but it appeared that only one job category was Mgnificantly above the standard in 1974. references 1 Burroughs G. E. Health Hazard Evaluation Determination Report No. 77-13-414, Tee Printing, Lancaster, Pennsylva nia. DHEW, PHS. CDC, NIOSH. 1979. 2 Butler. G. J. Health Hazard Evaluation Determination Report No. 74-149-189, Protecto Wrap Company, Denver, Colorado DHEW, PHS. CDC, NIOSH, 197*. 3 Butler. G. J. Health Hazard Evaluate Determination Report No. 74-151-181, Western Forge Corporate, Colondo Spring*, Colorado. DHEW, PHS, CDC. NIOSH, 1975, 1 Butler. G. J., and Bodnar, A. H. Health Hazard Evaluation Determination Report No. 74-29-161, Ethyl Viaqueen Divi sion of E'.hyl Ccrp., Terra Haute, Indiana, DHEW, PHS, CDC, NIOSH, 1974. i Chroetek. W. J., and Thoburn, T. W. Health Hazard Evilua-.^n Determination Report No. 74-107-279, General Electnt Company, Silicone Products Department, Water ford; NVv York. DHEW, PHS, CDC, NIOSH. 1976. Enviro Control, Inc. Engineering control technology aefeeemer.- for the plaatic* and retina induttiy. DHEW, PHS, . CDC. NIOSH, 1978. * Hewh. J P., and Roetand, R. A. Health Hazard Evaluation Determination Report No. 74-94-253, Armctrong Cork ComP"y- Jackson, Mississippi. DHEW, PHS, CDC, NIOSH, 1975. e Geiuert. J. O. Health Hazard Evaluation Determination October 1981 Report No. 75-90-236, Ruaaell Corporation, Alexander City, Alabama, DHEW, PHS, CDC, NIOSH, 1975. 9. Geieeert, J. O., and Herbert, J. Health Hazard Evaluation Determination Report No. 76-28-332, Welch Plastics and Manufacturing Company, Cohimbua, Ohio. DHEW, PHS, CDC, NIOSH, 1976. 10. Geiaaert, J. 0,, and Herbert, J. Health Hazard Evaluation Determination Report No. 76-29-322, Columbue Products Corporate, Cohnnbua, Ohio. DHEW, PHS, CDC, NIOSH. 1976. 11. Gillee, D. Health Hazard Evaluate Determination Report No. 74-184-193, PHC Industries, Inc., Camden, New Jersey 06108. DHEW, PHS, CDC, NIOSH, 1975. 12. Gillee, D,, and Lybiuger, J. Health Hazard Evaluation Determination Report No. T7-U1-501, Allied Chemical Corporation, Danvffle, lUnrie. DHEW, PHS, CDC, NIOSH, 1978. 13. Gunter, B. J., Butler, G. J,, and Lucas, J. B. Health Hazard Evaluation Determinate Report No. 74-125-215, Monoghan Company, Denver, Colorado. DHEW, PHS, CDC, NIOSH, 1975. 14. Gunter, B. J., and Hatch, L. Heath Hazard Evaluation Determinate Report No. 75-135-328. A ft S Tribal Indus tries, Poplar. Montana. DHEW, PHS, CDC, NIOSH, 1976. 15. Gunter, B. J., and Lucas, J. B. Health Hazard Evaluation Determination Report No. 74-61-232, Gates Rubber Com pany, Denver, Colorado. DHEW, PHS, CDC, NIOSH, 1975. 16. Gunter, B. J., and Nelson. B. Health Hazard Evaluation Determination Report No. 77-4-402, A ft S Tribal Indus trie, Poplar, Montana. DHEW, PHS, CDC. NIOSH. 1977. 17. Herrin, R. L. Health Hazard Evaluation Determination Report No. 75-81-252, Artex Manufacturing Company. Inc., Overland Park, Kanaaa. DHEW, PHS, CDC. NIOSH. 1975. 18. Jones. J. H. Worker exposure to vinyl chloride during production and fabrication of vinyl chloride and polyvinyl chloride. DHEW, PHS, CDC, NIOSH, I960. 19. Kominsky, J. R., and Wisaeman, C. L. Health Hazard Evaluate Determination Report No. 77-35-423. Ford Motor Company, Vinyl Operations Plant, Mt. Clemens. Michigan. DHEW. PHS, CDC, NIOSH, 1977. 20. Okawa, M. T. Health Hazard Evaluation Determination Report No. 74-71-142, Deko Remy Division, Anaheim. California 92801. DHEW, PHS, CDC, NIOSH. 1974. 21. Okawa, M. T. Health Hazard Evaluation Determination Report No. 74-98-173, Richdel Corporate, Canon City, Nevada. DHEW. PHS, CDC, NIOSH, 1975. 22. Okawa, M. T. Health Hazard Evaluate Determinate Report No. 75-20-209, Richdel Corporate, Canon City, Nevada. DHEW, PHS, CDC, NIOSH, 1975. 23. Okawa, M. T. Health Hazard Evaluation Determination Report No. 75-1-194, Storm Products Company, Palo Alto, California. DHEW, PHS, CDC, NIOSH, 1975. 24. Okawa, M. T- Health Hazard Evaluate Determination Report No. 76-120-220, Storm Products Company, Palo AJto, California. DHEW, PHS, CDC, NIOSH. 1975. 25. Price, J. H. Hazard Evaluation and Technical Assistance Report No. TA 74-45, Appalachian Laboratory and Occupa tional Safety and Health. Morgantown, West Virginia. DHEW, PHS. CDC, NIOSH, 1977. 26. Price, J. H. Health Hazard Evaluation Determination Report No. 77-92-541, Packard Electric, Division of General Motors Corporation, Warren, Ohio. DHEW, PHS, CDC. NIOSH, 1978. Z7. Roper, C. P,, Jr. Health Hazard Evaluation Determination Report No. 74-120-260, Goodyear Tire and Rubber Compa ny, Gadiden, Alabama. DHEW, PHS, CDC. NIOSH. 1976. 28. Roper, C. P., Jr., and Cromer, J. W., Jr. Health Hazard 135 ucc 057180 i Evaluation Determination Report No. 74-118-218, General lire and Rubber Company, Marion, Indiana. DHEW, PHS, CDC, NIOSH, 1975. 29. Rube, R. L. Health Hazard Evaluation Determination Report No. 75-94-219, Proto Production Plaatka, Inc., Boulder. Colorado. DHEW, PHS, CDC, NIOSH, 1975. 80. Rube, R. L. Health Heard Evaluation Determination Report No. 78-70-528, Hoepal Medical Corporation, Little ton, Colorado. DHEW, PHS, CDC. NIOSH, 1978. 31. Rube. R. L., and Anderaen, L. Health Heard Evaluation Determination Report No. 76-17-396, The Hayea k Albion Company, Speneerville, Ohio. DHEW, PHS, CDC, NIOSH, 1977. 32. Saliabury, S. A. Health Heard Evaluation Determination Report No. 7646-348, Sbeller-Globe Corporation, Hardy Diviaion, Union City, Indiana. DHEW, PHS, CDC, KICK1976. " Straub, W. E. Health Heard Evaluation Detwmi-Report No. 74-8&185. M. H. Gal] Company, Lanou Pennaylvania. DHEW. PHS, CDC, NIOSH, 1973L 34. Straub, W. E. Health Heard Evaluation Detenu**Report No, 74-89-189, New York Telephone 4 Trim-. Company, 42nd Street and 7th Avenue. New York. York. DHEW, PHS, CDC, NIOSH, 1975. 85. Thobum, T. W. Health Heard Evaluation Determmnr Report No. 73-123-296, Campbell Platics, Inc., Schewu dy, New York. DHEW, PHSTCDC, NIOSH, 1W6 86. Vandervort, R. Health Haard Evaluation Detcrmncjc Report No. 74-58-217, Goodyear Tire and Rubber CorukSt. Marya, Ohio45885. DHEW. PHS, CDC, NIOSRlT: ! M El by a 136 Int it ' sell PY< pat. car or con it v 5tU` infc ing act' bet 1 rat: ! Gui dis* . the cur Ma 1 ofl 1 sip art bat i nr ! *a Environmental Health Perspective occ 051181 HS.CDC.Mo-, Jon Dettniurj.j "W. Lancw> SH. I9T5. ion Dstjpnu^.^. "one i New Hrk. \t, on Determine' >SH, J9S76.eW4 on Determine,Rubber Compi le, NIOSH. J!rr. Environmental Health PenpeeUvee Vol. 41, pp, 137-143, mi Mortality Among PVC-Fabricating Employees by Leonard Chiazze, Jr.,* and Lorraine D. Ference* The results of cross-sectional mortality study of 3647 deaths occurring among current and funner (white) employee* of 17 PVC fabricator* during 1964-1*73 art presented. Sex-race-caute- specific proportionate mortality ratio* (PMR'i) were computed by uiing two teparate standards; one, the U.S. mortality in 1968; the second, U.S. mortality for the individual yean 1964-1973. In addition, a cate-control analyti*. bated upon 44 breast cancer deaths among white female tinpioyeet, it pretented. PMR's are significantly different from unity for all cancers, and for ranccrs of the digestive system among both white male* and whit* females. Although observed deaths tignifleahfly exceeded expectations for cancer of the breast, a subsequent cat* control analyti* reveals no statistically significant relative risks for breast cancer. rspectivgf Introduction In March. 1974, Organization Resources Coun-t l-irs (ORCi was requested by representatives of i'VC prodwers who are members of ORC's Occu* ;v.ional Safety and Health Standards Group, to .any out a study of health risks to employees * rking in the PVC fabricating industry. After ordering a number of alternative study designs, was decided that a cross-sectional mortality i-.udy would best meet the need for providing .'.formation as rapidly as possible. Details regard'[ reason;- for selecting this type of study, the actual stud\ design and results of the inquiry have h*n reported previously (J). In the original report, proportionate mortality ratios were calculated according to the method of Ouralnick O and by using the sex-cause-age specific dL-iribution of deaths among U.S. whites in 1968 as the basis for determining expectation (3). For the current report, we have analyzed the data using the Mintel-Haenszel procedure both for determination of PMR's and in order to test whether PMR's differ significant :y from unity (4, 5). In addition, PMR's are presented using two separate standards as the basis for expectation. `Division of Biostatittics and Epidemiology, Georgetown University School of Medicine, 3750 Reservoir Rotd, N. W., Washington, D.C. 20007. A follow-up to the cross-sectional mortality in vestigation, utilizing deaths among white women for whom the underlying cause of death was cancer of the breast, was undertaken (6), and results of the case-control analysis will be presented. Materials and Methods Although alternative study designs were consid ered, several factors led to the decision to carry out a cross-sectional mortality study. First, the pri mary study objective was to determine relatively quickly whether any angiosarcoma deaths could be identified among the study group and this was best accomplished by examining causes of death among relatively recent decedents. Second, it would not have been possible to identify clearly and com pletely (if at all) the cohort of workers necessary for a historical cohort mortality study within a reason ably short period oftime. As a result, the study was baaed upon 4336 deaths which occurred during the years 1964-1973 among active or retired employees of 17 companies engaged in PVC fabrication (Table 1). This report will be restricted to the 3847 deaths among whites, since the number of deaths for most causes among nonwhites was quite small, making interpretation of cause specific mortality difficult at best. Since the population at risk could not be deter- October 1981 137 UCC 057182 I Table 1. Distribution of deaths among employees of 17 PVC fabricators by face and sex, 1964-1973. Sex Race Total Male Female Unknown Total 4336 3676 White 3847 3252 Nonwhite IBS 174 Unknown 291 251 658 596 24 39 2 0 0 2 mined, mortality rates as measures ofrisk could not be calculated. Rather, results are summarized in terms of proportionate mortality ratios (PUR) calculated according to the method of MantelHaenszel (5). Two separate standards have been employed. The first is the sex-cause-age specific distribution of deaths among U.S. whites in 1968 (1968 Standard). A second standard employs the sex-cause-age specific distribution of deaths among U.S. whites in each ofthe years 1964-1973 (1964-1973 standard). Cause-specific PMR's based upon the 1968 standard are<adjusted for age, race and sex. Cause-specific PMR's based upon the 1964-1973 standard are adjusted for year of death as well as for age, race and sex. The Mantel-Haenszel procedure for assessing the statistical significance of a difference between the observed and expected numbers of deaths for a specific cause requires the construction of a series of 2 x 2 contingency tables as shown in Table 2. Separate tables are constructed for each level of the factorts) to be adjusted for. If, for example, we wish to compute a PMR for all decedents for cause X, adjusted for age (five age groups) and year of death (10 years: 1964-1973), i.e., 1964-1973 stan dard, we would have 60 2 x 2 tables: age < 36, year of death 1964; age < 35, year of death 1966;.. . ; age < 65, year of death 1973. Observed deaths and expected deaths are summed over the 50 separate 2x2 tables to produce a PMR for cause X, adjusted for age and year ofdeath. The resulting age-year of death-adjusted PMR compares the number ofdeaths from cause X observed in the study group to the number of deaths from cause X expected in the study group, if the proportion of total deaths Tabic 2. Conatniction of 2x2 contingency tabiae. Number of death* in group 1, attributed to Specified cause Other causes Total deaths Study croup A. C, N,, Standard B, A Np Total M,, V* T, 138 ascribed to cause X was the same, age group by a^group and year by year, as for the company group. The statistical significance of the PMR (a test u'. the hypothesis that the PMR is 1.0 against tic alternative that the PMR is different from 1.0) t evaluated by using the Mantel-Haenszel continuiv, corrected chi-square with one degree of freedom, Lt. d i: li e T* Xmh* (11Aj - IE(Aj) 1 - Vjf 1 VarA, where Var Ai ltMa T*ATi - 1) (1 ELAi) " Expected value of A, * (Af,, NhV T, The case-control analysis is based on 44 death.among white females in the study with cancer oftie breast as the underlying cause of death. Controlwere drawn from deaths due to diseases of tie circulatory system and accidents, and matched b> age plus or minus five yean and company, if possible. Forty of the cases were matched on both criteria and four on the basis of age alone. The baafor the case-control analysis, then, is the 44 breac cancer deaths and 134 matched controls distribute among eight of the 17 companies. c A) Results Proportionate Mortality Ratios Cause specific PMR's adjusted for age are pre sented for white male and white female employe* in Tables 3 and 4. For Table 3, expected numbers of deaths are based on the cause-sex-age specific dis tribution of deaths among U.S. whites applied to the study group. For Table 4, PMR's are adjusted for year of death as well as race, sex and age Statistically significant departures from unity (i.r.. PMR * 1) are evaluated by using the MantelHaenszel continuity corrected chi-square with one . degree of freedom. Causes of death for which the j calculated chi-square indicated a statistically sig nificant excess or deficit at the a - 0.05 level of significance are indicated in the table. It is impor tant to remember that when carrying out a large number of significance testa, some number will turn out to be significant on the basis of chance alone t When dealing with a large number of tests for PMR's, it may be more appropriate to consider tie j Mantel-Haenszel test as a screening device rath* j Environmental Health Perspective , Oir I I t ( A. A Oct UCC 057183 group b. ^ compiX. IKW; again.-; from 11, el contir,-. "erdom, if A'i.)/ T 4-I death. nceroftf, Contn,'. ** of th. atched t. npany, i; d on bo:.-W *. jfea-* stribute.; are preiployee# nbrnof :ific difolied to djusted nd age. ty (i.e.. Mantelith one ich the Jy sigeve! of impora large ill turn alone, -ts for j**" the -er ctive* living it a strict probabiliatic interpretation. -n these caveats, we see that based upon the . - f-andard. among white males there are statis- . Significant PME's for all cancers, digestive ^ respiratory cancer and other and unspecified cancers (Table 3). Among white females, PMR's are significantly different from one for all cancers, di gestive cancers, breast cancer, urinary cancer and other and unspecified cancers. In contrast to white males, the PMR for urinary cancer among white ,, (Mured death* and cauaa ipeeifie proportionate mortaltty ratio* (PMR) for employees of 17 PVC fabricator! by i ' (whit* only). 1964-1973 (expectation* baaed on U.8. mortality, 1SSS). of death l nncvr fjorjJ cavttv and pharynx {''ip*iivt organs and peritoneum Stomach Large intestine Rectum Liver Pancrear Other and jntpacified digwtiv* Itopintorv Linux a Trachea, bronchu* and hmf Other Breart Female genital organ* Cervix Corput Ovary ICDASth Reviaion 000-099 140-909 140-149 160-189 161 158 154 155 157 152. 156,156, 159 160-163 161 162 160,163 174 180-184 180 181,182 188 Male genital organ* Prattate Other Vnnarv organa Bladder Kidnev Brain and nervou* ayatem Lvmphoma; Leukemia.- Other and unapedfied cancer* irherouaee IhabetH Dteeate* of circuittery eyetem Heart di.-eaa* Rheumatic heart diaeaat Hypertensive "-----Ischemic heart diiaaa* Myocardial infarction Cerebrr t abular diiaaa* Other circulatory Diwaaee , f respiratory ayatem Cirrhoji* >f liver Cholelhhi .-ia, cholecyatiti* nd ch< langiti* Accident.-. poiioningf and violence Accident* Suicide All other cauaa* 186-187 186 186,187 188-189 188 189 191-191 200-208, 208, 209 204-207 170-173, 190. 190-199 250 890-188 (390-388), 402, 404, (410-429) 398-898 400-404 410-419 410 480-488 460-458 460-519 571 574-675 800-999 800-949 950-969 Reaidual Male Obaerved death* PMR 3262 1.0000 670 1.1905? 16 0.8882 212 1.8068* 41 1.3000 72 1.8688* 26 1.8230 6 1.4806 87 1.1807 30 1.3861 206 1.1647* 9 1.0695 194 1.1704* 8-- 0-- ---- -a- -- ---- ---- 42 0.7986 41 0.8223 1* 87 1.1158 20 1.0068 17 1.2800 16 1.1499 44 1.8560 19 0.8117 79 1.6132? 48 0.8655 1980 1.051* 1496 1.0625* 15 0.6878 86 1.0675 1381 1.0599* 898 1.1040* 290 0.9918 40 1.5294* 144 0.6344* 42 0.6675* 7 1.1018 187 0.7007* 134 0.7048* 39 0.7427 229 1.0410 Female Obaerved death* PMR 595 1.0000 181 1.8286* 3-- 58 1.5184* 8 1.6226 24 1.5785* 8 2.0822 0* 7 1.1612 6 1.8680 12 1.0119 0-- 12 1.0788 0 44 1.8710* 19 0.8232 5 0.6827 6 1.2911 7 0.6714 ---- ---- ---- 11 2.9296* 4-- 7 3.4685* 4-- 9 1.1900 1-- 25 1.9684* 10 0.5540 278 0.9067* 188 0.9009 7 0.7502 8-- 158 0.8644* 98 0.9688 66 0.9138 8 1.2396 17 0.5604* 8 --** 3-- 46 1.1864 87 1.3869 2-- 57 1.1500 4FMR ,i tTulleantly different from one et o 0.06. October 1981 139 ucc 057184 I females is high and, although baaed upon only 11 deaths, is statistically significant. On the other hand, in contrast to the observation in white men, the PMR for respiratory cancer among white women is very close to unity. Similar to the observation in white men, mortality from cirrhosis of the liver is low, but the corresponding number of obwn ] deaths is quite small. | Among both white male and female employee I diseases of the circulatory system account for i large percentage of total deaths. In each a* > observed numbers of deaths are close to expend | Table 4. Observed death* and cause (pacific proportional* mortality ratUa (PMR) far amployaa* of 17 PVC fabricator! L _ (whit* only), 1984-1973 (expectation* based on U.8. a*octa)ity, 1*64-1973). ti: V lr. f.< IV If Cause of dtath 1CDA 8th Revision All cau*e* All cancer Buccal cavity and pharynx Digestive organ* and peritoneum Stomach Large intestine Rectum Liver Fincreaa <* Other and umpedAad digestive Respiratory system Lirynx Trachea, bronchus and lung Other Breast female genital organs Cervix Corpus Ovsry Other Vale genital organs Prostate Other Urinary organs Bladder Kidney Brain and nervous system Lymphomas Leukemia* Other and unspecified emoeers Other causes Diabetes Diseases of circulatory system Heart diseaee Rheumatic heart disease Hypertensive disease Ischemic heart disease Myocardial infarction Cerebrovascular disease Other circulatory Diseases of respiratory system Cirrhosis of liver Cholelithiasis, cholecystitis and cholangitis Accidents, poisonings and violence Accidents Suicide All other cause* 000-999 140-200 140-149 160-159 161 168 164 166 167 162, 156, 168, 159 160-168 181 162 160, 168 174 180-184 180 181, 182 188 184 186-187 186 186,187 188-189 188 189 191-198 200-208, 206. 209 204-107 170-178,190, 108-199 280 390-468 (890-386). 402, 404, (410-429) 898-398 400-404 410-413 410 430-438 450-458 460-619 671 574-675 800-999 800-949 950-969 Residual *PMR significantly different from one at a * 0.06. HO Malt Observed deaths PMR 3252 670 15 212 41 72 26 6 87 30 206 ~ 9 194 3 0 --* * * 1.0000 1,1667* 0.8840 1.2667* 1.8084 1.3289* 1.3184 0.9801 1.1202 1.3189 1.1166 1.0663 1.1266 --* -- -a. -- 42 0.7687 41 0.7964 1 87 1.0942 20 0-9884 17 1.2517 16 1.1267 44 1.3525 19 0.8019 79 1.5976* 48 0.8998 1980 1.0688* 1495 1.0600* 16 0.7080 86 1.1541 1381 1.0612* 888 1.1148* 290 1.0011 40 1.5062* 144 0.6888* 42 0.6438* 7 I-1S36 187 0.6991* 134 0.7084* 39 0.7084* 229 1.0246 Female Observed deaths PMR 596 1.0000 181 1.29 8 S3 1.4813* 6 1.85(1 24 1.5410* 8 2.1185 0 7 1.1481 6 1.4548 12 0.9100 0* 12 0.9787 0 44 1.3448* 19 0.8161 5 0.6869 6 1.2738 7 0.6597 1-- --* -a __ _ 11 2.8365* 4w 7 3.4206* 4-- 9 1.1944 1-- 25 1.9564* 10 0-6743 278 0.9132* 188 0.9085 7 0.8009 3-- 158 0.8522* 93 0.9962 65 0.9184 6 1.2256 17 0.6546 3-- 3-- 46 1.1173 37 1.3266 2 -** 57 1.1197 Environmental Health Perspective* ucc til 1 Ifl . da' rv up ntut 1< p> If ft. Ci va inv nr no be ab co fr> a* st te pr ca fo) cb vi V! ib ex sc in 5). se* 44 se' j 0. 057185 ob*n-: mploy^, Junt fw, -ach ca* e*Pt Confer, Table 5. Diltribution of 44 breact cancer deathi and 134 matched control* by expoiure category- .t^jrr exteRorv v fipwure --table exporuTM ; ...Me expwure ;**"e exposure ' rx-yiao exposure Breast cancer, cases Number 1 27 61.4 6 13.6 00 2 4.5 _9 20.5 44 100 Matched control Number % 97 72.4 17 12.6 4 3.0 6 4.5 JO 7.5 184 100 P.MR 1~mT 1.2856* 1 4813* 1 6541 1.54S0* 2.1163 1.1161 1.1546 1.8100 >.8767 .3446* r.2738 '.6)97 6365* 42n6* .1944 9564* 6743 9132* 9035 8008 85T* 9962 9184 2256 6546 1173 3266 J7 ectivec though statistically significant. Results based upon the 1964-1973 standard are, i- general, consistent with those on the 1968 stan di (Table 4i. There are, however, some notable .options. In general, the PMR's based upon the 1h>4-1973 standard are lower than those based .:.,n the 1968 standard. Further, the PMR for respiratory cancer among white males is not sig* runcantly different from one when based on the l4-19(3 standard. Among white women, the PMR for other (noncancefj respiratory deaths t. significantly below unity based on the 1964-1973 standard. Case-Control Analysis Comparison of cases and controls on a variety of variables where information was available, includ ing length of employment, ever married versus never manned, and child-bearing history, reveals no statistically significant differences (p > 0.05) between cases and controls for any of these vari ables. Review of employment histories for cases and controls revealed a wide variety of jobs ranging from office and clerical work to production jobs such is bench inspector, press operator, trimmer, as sembler and sweeper. The wide range of job con tent and location made it impossible to determine precisely whether there was PVC exposure in every case, or the precise length of that exposure. There fore. a subjective ranking system was developed to classify exposures. Work histories were reviewed with plant personnel and PVC exposure potential was categorized into five classes--no exposure, improbable exposure, possible exposure, definite exposure and unknown exposure. This classification scheme enabled some definitive exposure statement in 80$ of the cases and 92% of the controls (Table 5). After matching by age and company, 38 matched sets of cases and controls were developed from the 44 cases and 134 controls. There are fewer matched sets than cases because, in six instances, it was October 1981 necessary to combine cases of similar age within the same set in order to have at least one control per matched set The Mantel-Haenszel procedure was used to derive a summary estimate of relative risk and to test for significant departures from unity U, 7). In this procedure, each of the 38 sets can be viewed as a 2 x 2 contingency table. Thus, the ith set can be represented as in Table 6. Relative risk is defined as the ratio of the proba bility of dying from cancer of the breast among women exposed to PVC to the probability for women not exposed. Estimates of these individual proba bilities are not available from a case-control study. However, a measure ofestimated relative risk from case-control studies as suggested by Mantel and Haenszel has been calculated as in Eq. (2). To assess whether the departure from unity of an observed relative risk is too great to have occurred by chance alone, a summary chi-square test cor rected for continuity was performed using the Mantel-Haenszel procedure. The calculated chisquare must be 3.84 or larger in order to conclude with 95% assurance that the observed relative risk did not differ from unity by chance alone. R - It (B/C{/Ti) (2) Combining the five exposure categories into two may be accomplished in a variety of ways, resulting in several possible relative risk measures as shown in Table 7. None of the calculated relative risks, including the second shown which treats anything other than no exposure as definitely exposed, are statistically Tabic 4. Representation of fth act. PVC exposure Ye* No Total A, B, S,, C, D, a* Mi. T, 141 ucc 057186 k significant; i.e., they may have occurred by chance alone. Similar analyses were carried out on a company-by-company basis. None of the relative risks so calculated is significantly different from unity. Discussion and Summary The cross-sectional mortality study was designed with two objectives. The first was to determine if any angiosarcoma deaths had occurred among em ployees of the PVC fabricators under study. Since no angiosarcoma deaths were found among the employees studied, the first question has an un equivocal answer. A secondary objective was that of examining the distribution of deaths by cause among the employees under study. Implicit in that objective is the question of whether or not that distribution is, in some sense, unusual. There is no unequivocal answer to the latter question. Whether or not an observed distribution of causes of death is unusual clearly relates to the standard or compari son population as wett*as the analytic methodology (6). This is illustrated by the observation that there are PMR's which are significantly different from unity on the 1968 standard and not on the 1964-1973 standard. However, it seems much more important to focus on the large area of agreement between the two standards rather than on the few areas of disagreement. On the basis of the PMR analyses, there are statistically significant excesses in total cancer mor tality among both white males and white females when compared to the distribution of deaths for the total United States specific for color and sex and adjusted for age. Excesses in cancer mortality ap pear concentrated in cancers of the digestive sys tem and, in particular, in cancers of the intestine for both men and women. In addition, there is a suggestion that mortality from cancer of the breast and urinary organs among white women employ* .urt is higher than that for the total U.S. There * i 0n!v however, several reasons why definitive inteqr- j tation is difficult. Factors meant to suggest IL : iarpe proportionate mortality analyses must be interpry i fvi#t ted cautiously have been reviewed previously ($./, , <*tei However, while these results must be interpret.*: in risi with caution, they appear to be consistent wrj , previously studied workers and suggest the n*: t for some continuing investigation u). 'i One such follow-up investigation has been p* I sented here in the form of a case-control stud, / *rf 'r i f*>O> involving the 44 breast cancer deaths. On the btv of a case-control analysis, estimates of relative n i t were derived but none of these relative risk tsv ' mates is significantly different from one, althoup ( such results must be interpreted with caution. s. Absence of a statistically significant relative rw ; tt does not demonstrate that there is not an exc* ! v risk of death from breast cancer among worn*- ; 4 [j employees with PVC exposure. In fact, when s . , statistically significant relative risks are found, it t* * N pertinent to ask what the chances are of detects ; & L an increase of a given magnitude from the avaiiaK- 4 data. Using the method described by Walter u. we have subjected each of the relative risk mates (Table 7) to a least significant relative an ; analysis under the conditions that we desire 95''- 1 assurance that a risk of such magnitude, if ot* served, did not occur by chance alone and } probability of detecting the least significant relative risk if it exists. Even in the case where all but no exposure an counted as exposed, the smallest relative risk whid , could be detected from these data is nearly 31 < Nearly 200 cases and 200 controls would have beer, j necessary to detect a true doubling of the rei. under the specified conditions. Given the sample size in this study and the percentage of control* i exposed (a percentage which was unknown at the I Table 7. Relative risk (RR) and least *l*nlflcant relative risk (LSRR) estimated for contrast* of various exposure csltfoo , combinations. Contrast Definite exposure vs. no exposure Definite + improbable + possible + unknown exposure vs. do exposure Definite + possible exposure vs. no + improbable exposure Definite + possible + unknown exposure vs. no improbable exposure Number of eases 29 44 36 44 RR (Relative risk) estimate1 1.81 1.94 0.6Z4 2.73 LSRR (Least sigmftcv*. relative risk) tttmttt' 6.77 2.92 6.02 3.41 *None of the relative risk estimates ire statistically significantly different from unity (p > 0.06). . The true relative risk would have to be at least this large to have an 80* assurance of detection (i.e., power 0.80) with s typ* error of 0.06 (i.e., a * 0.06). 142 Environmental Health Penpecti'ri ucc 057187 1^'"Ployt*. There ar> 'e mterprc J8?est tlu- * interprv >Us]y (J.;, interprets stent u1L. t the net*; ken prttroi stud-. n the ba.^. -lative rtl ` risk est). < fl)though *ution. iative hik an exce*> g "omen " hen no >und, it i, detecting available dter (m risk estiitive risk s' 95^ e, oband 80G relative sure are sk which 'riy 3:1. *ve been '-he risk sample controls i at the of the study), it would be possible to detect -verv large increases in risk. There seems viinnabie assurance, therefore, that such very * increases in the risk for breast cancer do not ,u-* among these PVC fabricators, but no such raiment can be made for possibly smaller increases z ask- references 1 Chiaw. 1-.. Jr., Nichols, W. E., and Won*. 0. Mortality mo* employ*#* of PVC febrieators. J. Occup. M*d. 19; 623-628 (1977). Gunlnick. L. Mortality by Occupation and Caua* of Death ~ Among Men 20-64 Year* of A**: United Stataa, I960 (Vital Statistics-Special Raporta, VoL SS, No. 3). U.S. Govt. Printing Office, Washington, D.C., 1963. 3 National Center for Health Statistics. Vital Statiitka of the United States. 1968, Volume II, Mortality, Part A. Waahmgton, D.C.. U.S. Govt. Printing OfBca, 1972. pp. 140-203 4 Martel. X. end Heenaxel, W. Statistical aspects of the tnaiv;i< of data from retrospective studies of disease. J. Nati. Cancer Init. 22: 719-748 (I960). 3. U. F. P . Friumeni, J. F., Jr.. Mantel. N., end Miller, R. W. Csrn.tr mortality among eUfemiata. J. Natl. Cancer Inst. 43:1139-1164 (1969). 6. Chiaae. L., Jr., Wong, 0., Nichols, W. E., and Ference, L. Breast cancer mortality among PVC fabricator*, J. Occup. Med. 22: 677-679 (I960). 7. Pike, M. D., and Marrow, R. H. Statistical analysis of patient-control studies in epidemiology: factor under inves tigation an all-or-Done variable. Brit. J. Prev. Soc. Med. 24: 42-44 (1970). 8. Chiaae, L,, Jr. Problems of study design and interpreta tion of industrial mortality experience. J. Occup. Med. 18: 169-170 (1976). 9. Redmond, C. K., and Breshn, P. P. Comparison of methods for seesuing occupational haards. J. Occup. Mad. 17:313-317 (1975). 10. Monaon, R. R., Patart, J. M., and Johnson, M. N. Proportional mortality among vtayi-chlcride worker*. Lan- eet ih 397-396 (1974). 11. Lloyd, J. W,, and Cioecn. A. Long term mortality study of aeehrorkea: 1. Methodology. J. Occup. Med. 11:299-310 (I960)* 12. Redmond, C. K., Ciocco, A., Lloyd, J. W., end Rush, H. W. Long term mortality study of steelworkers: IV. Mortal ity from malignant neoplasms among coke oven worker*. J Occup. Med. 14: 621-629 (1972). 18. Tabenhaw, I. R., and Gaffey, W. R. Mortality etudy of workers in the manufacture of vinyl chloride and it* polymer*. J. Occup. Med. 16; 509-318 (1974). 14. Walter, S. D. Determination of significant relative risks and optimal sampling procedures in prospective end retro spective comparative studiea of various sue*. Am. J. Epidemiol 106: 887-397 (1977). lificsnt mate11 t*7Xl 'lives October 1981 143 ucc 057188 Environmental Health Pertpectivet Vol. 41, pp. US-151,1981 Mortality and Cancer Rates among Workers in the Swedish PVC Processing Industry by Gustavo Molina*, Bo Holmberg*, Stig Elofsson*, Lars Holmlund,* Rein Moosing,* and Peter Westerholm** Pcnonntl tltte frwm four PVC-proc**inf induitri** were collctd on production oftmploypoi with at least three months at employment at the beginning of IMS and the last day of employment December 31.1974. Of 2073 persons, 103 could not be followed up, because they had moved abroad. The remaining persons comprise the cohort of 1970 individuals who were analysed and compared with the national population with respect to mortality from various diseases and cancer morbidity. The death risk from myocardial infarction is elevated in the cohort. This elevation is moot dearly apparent in the subcohort which had at least two years of exposure time and where the analysis was directed at circumstances chronoloficalty close to the time of exposure. The myocardial infarction risk related to vinyl chloride exposure is discussed in relation to earlier studies on the vascular effects of vinyl chloride. An indication of an elevated risk of morbidity and mortality from tumors in the digestive organs is also present. However, this is not statistically continued. A few future follow-ups of the present study are necessary in order to clarify any possible elevated risk of tumors in the PVC-processing industry. Vinyl chloride has been shown to cause sclero derma. Raynaud's phenomenon, acroosterolysis, liver damage and liver cancer (hemangiosarcoma) it) in workers exposed to vinyl chloride monomer (VCM). This has been shown in studies (9, S) performed at companies which fabricate polyfvinyl chloride) (PVC). In animal experimental studies it has been reported that inhalation of VCM causes malignant tumors in different organs in rodents U-). In Sweden, in 1974, two cases of liver heman- Occupa-.ional Toxicology Unit, Department for Occupational Medicine, labor Medicine Division, Department of Occupational Safety, Bt x 100. 26 Stockholm, Sweden. `Sutirt.cai Institution, Stockholm University, Box 6701,118 & Stockh lm, Sweden. tGroup for Applied Ststistki, Rarlbergtvsgen 82, 113 36 Stockholm. Sweden. "Bureau of Statistics, Department of Welfare, 106 30 Stock holm. Sueden. giosarcoma were diagnosed in employees at a company engaged in the processing of VCM and PVC (7). Later another two cases occurred at the same factory. Studies on other forms of cancer (8, 9) suggest that VCM-exposed workers in the PVC fabricating industries may possibly run an elevated risk of contracting forms of cancer other than hemangio sarcoma in the liver. Earlier, an excess mortal ity from cardiovascular diseases was also observed (10) in employees in the PVC manufacturing indus try. The present retrospective cohort study was per formed for the purpose of determining the pattern of morbidity and mortality in the PVC processing industry. The PVC processing industry, generally speaking, has had a lower level of exposure to VCM than the fabrication industry. In the Swedish PVC processing industry, at present, about 5000 persons are employed in production. October 1981 145 ucc 057189 I Material and Methods Information for the study was collected from four PVC processing companies. The four companies all used PVC which, after additions of various chemi cals, is heat-treated for fabrication into floor cover ing, lace, pipes, and food packaging. Data Collection The following data were collected from the per sonnel lists at the companies: personal number, name, beginning and end of exposure (year and month) and class of exposure. In order for a person to be included in the original cohort, at least three months of employment was required in the period beginning in 1945 and the ending December 13, 1974. The exposure was classified as follows: class 3 (high), work in the mixing department; class 2 (medium), heat treat ment machines; and class 1 (low), other production departments. , The collected data were transferred to punched cards and magnetic tape for statistical processing. The magnetic tape was coordinated with the na tional total population and the so-called death tapes for the 1961-1976 period and checked against the cancer registry by the Central Bureau of Statistics (SCB). The personnel numbers which could not be recovered at this time were checked by the national taxation office. The original cohort included a total of2,073 persons. Ofthese, 103 persons (5%) dropped out, 70 or whom had moved abroad, 5 were found in the missing persons register of the tax office, and 28 could not be traced. Study Cohortr For the statistical processing, the results of the cohort of 1970 persons were divided into a number ofsubcohorts (study cohorts): (1) all persons with at least three months of exposure (follow-up time from the beginning ofexposure and through 1976); (2) all persons with at least six months of exposure ex cluding those who stopped before 1961 (follow-up time from beginning of exposure but no earlier than 1961 and through 1976); (3) all persons with at least six months of exposure and where the exposure began no earlier than 1961 (follow-up time from beginning of exposure and through 1976); (4) all persons with at least two years exposure (follow-up time from two years after beginning of exposure but no earlier than 1961 and through 1976 but no more than ten years after exposure stopped); (5) ail persons with at least two years exposure (follow-up time from ten years after exposure began but no 146 earlier than 1961 and through 1976). The two latter named study cohorts were cho- in order to study whether any differences existed the death cause pattern with respect to when deaths occurred after the beginning of expose iThe first of the study cohorts was intended to shr- light on possible causes of death which occur rtii tively early, e.g., accidents caused by the job. Tt* 1 second was intended to shed light on such dtac j causes as occurred after a longer time had pas*,; j Tumors caused by occupational exposure, for n I ample, often have a long latency period, 5-10 yr * ! longer. , i i Results j The original cohort was relatively young at t) i beginning of exposure. The age distribution in thr ' different exposure classes is given in Table 1. Or* j finds various dissimilarities between the exptm j classes. In class 1 (low), 41.7% were younger the J 35 years at the beginning of exposure; in dawif (average), 47.7%; and in class 3 (high), 50.69. Then ; i Table 1. Ace diatributton in orifinal cohort at befiiuiint 4 i cxpocure Ac* < IS 20-24 26-29 30-64 36-39 jft || 46-49 50-64 68-89 60-64 >66 No. tt pfnont % in each exposure class 1 2 3 1-3 1.6 7.5 13.5 19.1 17.0 18.7 11.1 8.0 5.1 2.8 0.7 100% (1601) 2.0 14.6 15.7 15.4 13.2 12.6 12.6 7.8 8.9 2.0 0.8 100% (867) 8.9 2.1 14.3 9.2 21.4 144 17.0 193 J0.7 15.9 9.8 133 8.9 113 5.4 7.f 1.8 4.T 1.6 2.4 0.0 0.4 100% 1W. (112) (1970 i; da (; fli Lip d* TtWe I certain' kut !' Sk.CiW i t-diov, tmdrii: Ri,k a 1ST ere a with r> it shot hich entran which: times i has lor The merea.tional < the su' Stud least si :he ris a hat r> deaths Table 2. Distribution of exposure time in the orifinel eetott Mentha <5 6-18 24-69 60-119 > 120 % in each exposure dam 1 2 3 14 18.1 0.3 0.0 10.1 38.4 8.4 8.9 31.3 25.0 17.4 10.7 219 15.3 45.7 15.2 20* 8.2 28.3 65.2 15.1 100% <M - 1510) 100% <M - 367) 100% 1007 lit - 112) (V - 190' Environmental Health Per*P*rti'w Tiblt S 1 ehort i.jp di cl* Lip cli Lip cl* Octob* ucc 057190 rere chop 's existed u ? " hen thr ' e*POSUTt to sh*; occur rel*. * job. The such dea*.: -ad passed re, for ex5-JO yr or -wg at the ion in the de 1. One exposure ngcr than in class 2 >*. Theie ^ginning ti 1-3 2.1 9.2 It 4 Is 3 15.9 13.3 11.3 7.8 47 2.4 06 10', 1 (1970) *1 cohort. 1-3 If: 31 3 22.S 20. S 15.1 100% 970) ctive# claw 1 dart2 n: daw 3 t; dart 1-3 Table 3. Obaerved and anticipated number of death* a* of December 31,1976. No. of death* Number Obaerved Expected Ratio O/E 1303 53 55.5 0.95 356 14 21.9 0.84 112 6 10.3 0.70 1171 73 87.8 0.84 Approx. 95% confidence interval - 0.26 x 0.34 0.47 x 0.19 TiMt 4. Obtened and anticipated number of death* from nftiin ceuaea durin* the 1969-1976 period in tho*e with at wt iii month' of expoaure indudinc thooe who itoppad before 1961.* Ob Ex Ratio aerved pected O/E Vi.rrjm tumor: 140-209 17 14.0 1.21 .'.-.live organ turnon 150-159 i.->,vascular disease* Vll 8 4.9 1.83 22 24.3 0.91 2 cirdAJ infarction 410.90 15 20.0 1.49 i-rdrnts. Mucide. etc. XVII 13 9.2 1.42 * `Ki-k nlculatrd from the beginning of expoaure but no earlier -a- Ml. Study cohort 2 (1771 penon*). eere also di'Similarities in the length of exposure *r,h respect to exposure class (Table 2). However, r. should be noted that the table includes cases ihich were 'till under exposure at the final date for entrance into the cohort (December 31, 1974), for which reason, a certain bias toward short exposure times is found. Regardless of this, exposure class 3 .us longer exposure times on the average. The cohort as a whole reveala no noteworthy increase in the total risk compared with the na tional average, nor is there any indication of this in the subgroups making uy the study cohort. Study cohort 1, which includes everyone with at least six m> nths of exposure and with calculation of the risk from the beginning of exposure, is some what rental kable in that the anticipated number of deaths is si^mificantly higher than that observed up Figure 1. Cumulative death* (in percent): (?) obterved: (V) anticipated. Expected value calculated from beginning of expoaure. Study cohort 1 (1970 penon*). The percentage for a given year wa* calculated aa 100 (number of paraon* dying through year in question divided by the number of penon* beguiling expoaure up to and including the year in question). to 1964 (Fig. 1). This is commented on fiirther in the discussion. Study cohort 2 (Tables 3 and 4; Fig. 2) includes persons with at least six months of exposure, excluding those who stopped before 1961. The risk calculation is made from the beginning of the exposure, but no earlier than 1961 and up to the end of the follow-up time (1976). The observed number of deaths is somewhat lower than expect ed, much lower in exposure class 2. Classes 2 and 3 are relatively small and are sensitive to random deviations in this type of analysis. In order for random deviations not to influence the results, the classes were combined. This is true of all study cohorts. This distribution with respect to the vari- Tiblt 3. Ob-erved and anticipated number of death* aa of December 31, 1971 in thoee with at leaat lix month* of expoaure beginning no earlier than 19S1.* Cohort Exp. clau 1 Exp. data 2 Exp. daaa 3 Exp. daaa 1-8 Number 1139 247 42 1428 No. of deatha Obaerved Expected 43 41.2 4 11.7 1 1.8 48 54.7 Ratio O/E 1.04 0.34 0.88 Approx. 96% confidence interval x 0.31 x 0.34 x 0.35 *Ruk calculation from beginning of expoaure. Study cohort 3 (1423 penon*). October 1981 147 ucc 057191 I T*f nr < tees n test Figure 2. Cumulative deatha (in percent). Expected vahie calculated through 1961. study cohort 2 (1771 penoni). Percentage for a given year calculated aa in Fig. 1. Figure 4. Obwrvcd death risk per year at different p**,time after beginning of expoeure expressed in perwir.; corresponding anticipated risk in those who begin tip*.in 1961 or tiler. Study cohort 3 (1428 persona). Ms Du C* M> Ac S- T*i Table 6. Obeerved and anticipated number of deatha certain cause* during the 1969-1976 among thorn with at Wot aix months of expoeure beginning in 1961 or later1 Ms D., Ob Ex tax served pected OE 9 Uu. Figure 3. Cumulative deatha (in percent) of thoec who began expoeure in 1960 or later. Study cohort 3 (1428 pereone). Percentage for a given year calculated aa in Fig. 1. ous death causes is shown in Table 4. The observed and anticipated number ofdeatha duringthe 1961-1968 period is relatively small, only a few cases, and the death cause classification was modified as mentioned earlier in 1969, for which reason 1961-1968 period is not discussed separately. By and large, the picture is the same there as for the 1969-1976 period re ported on. From Table 4, one sees that the ob served number of deaths, especially those from tumors of the digestive tract, myocardial infarction and accidents, is somewhat higher than anticipated. However, the differences are not significant. Study Malignant turnon 140-209 Digeetive organ turnon 150-159 Cardiovascular diseases VII Myocardial infarction 410.90 Accident*, suidde. etc. XVII 9 9.7 o. 4 3.3 1.8' 16 162 0.# 14 11.2 1.25 11 7.3 l.il `Risk calculated from the beginning ofexposure. Study b_3 (1428 persons). cohort 3 (Tables 5 and 6; Figs. 3-5) which pertain? to those who began working in 1961 or later btr. which otherwise satisfy the same criteria as study cohort 2, displays a similar picture. An analysis of study cohort 3 according to for mula B (Figs. 4 and 5) indicates that the annual risk during the first year ofexposure is somewhat lover than the anticipated one, but that after about tc years, an increased risk occurs so that the observed risk becomes higher than the anticipated. Tabic 7. Obaarvad and anticipated number of deatha from certain cause* during the 1969-1974 among those with at least tvs yean of expoeure.1 Obeerved Expected Ratio 0/E Malignant turnon 140-209 Digettive organ turnon 150-169 Cardiovascular diseases VII Myocardial infarction 410.90 Accident*, auidde, etc. XVII 5 (9) 2 (4) 15 (16) 11 (12) 4 (6) 7.4 (8.9) 2.6 (3.2) 12.7 (15.8) 5.4 (6.6) 4.6 (6.1) 0.86b (1.01) 0.7Sb (1.27) 1.186 <1.01)L 2,03b u.str1 0.b7b (0.97) `Risk calculated from two yean after beginning of exposure snd no more than 8ve yean (10 yean) after end of exposure. Stud;cohort 4 (1155 persona). "p < 0.05. 148 Environmental Health Per*p*cth ucc di if *r m lo in tu m at m 01 ot d. af* n a e fr k Ct 6 g o 0 057192 tp V T*bk 8. Observed and anticipated number of daatha from (iruin cause* during the 1969-1976 in thoaa with at itait two yean of exposure.* Ob Ex Ratio served pected O/E Vilignam turnon 140-209 DifHtive organ turnon 150-159 Ctidiovsscular diacaae* VII Mvoardui infarction 410.90 Accident*. suicide, etc. XVII 9 6.0 1.51 4 2.2 1.85 12 11.1 1.08 8 4.5 1.77 2 2.5 0.79 'Risk calculated from 10 yean after beginning of exposure. Study cohort 6 (680 penone). % observed anticipated e a Fiouax S. Cumulative eurvival probability (in percent) ofthoae who began expoaure in 1961 or later and have at leaat aix month* of expoaure. Study cohort 3 (1428 penona). Table I. Observed and anticipate number of death* from cancer during 1961-1976 in thoae with at leaat aix month* of expoaure excluding thoae who (topped before 1961.* Ob- Ex- Ratio served pected O/E lUiignsnt turnon (total) 51 44.6 1.14 Digestive organ tuition (150-159) 11 8.5 1.29 'Risk calculated from beginning of expoaure but no earlier than 1961 Study cohort 2 (1771 penona). In study cohort 4 (Table 7) which concerns time during ongoing exposure or s relatively short time after the end of exposure, i.e., "short-term per spective." one sees an increased death risk from myocardial infarction. Other causes are somewhat lower here than expected. In study cohort 5 (Table 8), finally, one finds an indication of an increase in the death risk as regards tumors, but also for myocardial infarction. The differences between the observed and anticipated numbers are not, however, statistically confirmed at the S'? level. The result with respect (b mortality can be sum marized as follows. In the study cohorts, overall, one finds no noticeable increase in mortality. On the other hand, there are indications of a shift in the death cause pattern compared with the national average. This shift is expressed primarily in the fact that the number of myocardial infarctions is noticeably higher during ongoing exposure or within a relatively short period of time after the end of exposure. There are also indications that the death from tumors can be elevated among persons with a long latency period (Tables 7 and 8). In the question of cancer morbidity, there is no certain increase in study cohort 2 (Table 9 and Fig. 6). In the question of tumors of the digestive or gans. in the same study cohort, 11 cases were observed as opposed to an anticipated 8.5. Hie Fioust 6. Cumulative rata* of eaaaa of all cancer (in percent). Study cohort 2 (1771 penona). The pareamage for a given year waa calculated a* 100 (number of penon* diagnosed through year in question divided by the number of penona beginning expoaure through year in question). difference is not statistically verified. One of these eleven tumors was liver cancer (ICD 155.0). Discussion A noteworthy finding which arises in the analysis of the total cohort mortality (Fig. 1) is that the number of deaths at the beginning of the observa tion period (1947-1964) is significantly lower than one would expect in relation to the national aver age. This difference is so great that one cannot directly consider it to be randomly conditioned, nor can it be entirely ascribed to the so-called healthy worker effect. Theoretically, of course, the possibil ity exists that the selected cohort, in the question of mortality and the factors which influence said mor tality, deviates from the general population. A more credible possibility is, however, that the personnel register that was available at the company involved at the time of this study was incomplete in the matter of hirings during this early period. A per sonnel register which, in the mid-1960's, was purged October 1981 149 ucc 051^3 1 of persons who began employment before I960, could lead to the difference mentioned above. The companies involved reported that such a purging did not occur, so far as they knew. If such a purging (thinning out) nevertheless occurred, this would have resulted in the elimina tion of persons with a long observation time at the time of follow-up. In the present study, the risk calculations were limited to beginning no earlier than 1961. This means a limitation of the analysis to pertain to the group of employees who were living at the beginning of 1961 and where the risk of an elimination is positively eliminated. This limitation, however, signifies a weakening of the analysis, since parts of the cohort with long follow-up times are excluded. Basically, this weakening signifies a poorer possibility of discovering an elevated inci dence of cancer if one exists. The myocardial infarction mortality (ICD 410.90) is elevated in the cohort. This elevation occurs most clearly in the category of the total cohort which has at least two years of employment time and where the analysis was directed at the period of time following two years after the beginning of employ ment and extending to no more than five years after the beginning of employment. Therefore, this in volves that fraction of the mortality from myocar dial infarction which chronologically is relatively closely connected to the time of employment. It is impossible on the basis of such observations to draw conclusions that the elevation was caused by exposure to vinyl chloride. The observed increase in myocardial infarction mortality is, however, so striking that it, in combination with the known facts about the toxic properties of vinyl chloride, must be given consideration. There are no reasons to assume that varying diagnostics, standards or practices in filling out the death certificates alone could provide an explanation. A natural conclusion is, therefore, that if one disregards the possibility of a random local phenomenon, the increased fre quency is to be ascribed either to selection of indi viduals susceptible to the risk or an outbreak of risk factors in the close environment of employees. A combination ofthese two circumstances is, ofcourse, also possible theoretically. In this connection, it should be noted that many risk factors for myocardial infarction are environ mentally conditioned in the fact that they constitute part of the lifestyle of the modem social environ ment in an industrialized country. Cigarette smok ing, physical inactivity, overweight and high blood lipids constitute environmental factors which are related to social behavior. It is a well known fact that the risk of coronary vascular disease in the heart varies, inter alia, with the total load of risk ISO factors. Among other risk factors, one can name hereditary characteristics and high blood w*. sure. In this connection, there is reason to recoils indit not - that the causal network of coronary disease is m tifactorial and that the disease has' an environnr tal relationship in the broad sense. There is a*, reason to recall the aspect that the total risk ?- creases when several risk factors, known or ur, known, are allowed to collaborate (ii, isy It has not been possible to establish the distrih. ova- nor i long rnclu until folio1 tion of such already known riak factors for corotw disease in the cohorts studied with respect to iv (olio' five-, national population in general. Therefore, no tor tinued analysis of the matter of the causal relatior. this. In ship between close environment and heart dim., m morbidity can be made within the limits of tL study. dust1 Exposure classes 2 and 3 constitute subcohor.. that are too small, in the present study, to aUo * PP*unal meaningful discussion of the myocardial infuwii- risks relative to the various exposure levels in ibt processing industry. In this connection, one shoul; also consider the circumstance that the exposun classes in this study are based on interviews vt: 11 the employees directed at the work environment t the time in question some 10 to 15 years ap I. Therefore, this involves an environment which hi.- subsequently undergone changes. Objective class, fication criteria in the matter of exposure, e.g.. r i. : the form of environmental measurements, do nr exist. The distribution into exposure classes is. for 4. this reason, fraught with uncertainty. In animal experiments, it has been found that 0* i toxicity picture in rodents chronically exposed u VCM involves the blood vessels. Besides henan- (. giosarcoma in the liver and the other organs U. i tite inhalation of VCM ia also believed to an* development oftelangiectasis (4) in the liver ofmi* which can lead to death from hemocoele. Chang* in the sinus cells have been observed in liver bu sies in VCM-exposed workers (13). Capillary dung* in the skin of the fingers have also been observe (U-16), both in VCM-exposed workers with other vascular-involved diseases, such as acroosteolysL- , Raynaud's phenomenon, and sclerodermia, and ir j VCM-exposed workers without such diseases. V j over-representation of deaths from cardiovascular j diseases has also been observed in s study on th* PVC-fabricating industries (10). Animal experiiwr ; tal and previous medical studies of VCM-expos** populations therefore support the assumption that the increased risk ofmyocardial infarction observe in the present study could possibly be ascribed VCM exposure. As regards the mortality and morbidity fro' tumors, the results are uncertain. There are certaz ; Environmental Health Perspedh* . Oct. UCC 057194 I *u Utr TIL > ir. ur. ibu nr. tt or, or. 9* 'hi- rif 'i or. the uM Jtv nfc a: a. 9 Si- m 10! or he to n- 5) SC ec es ow i*d er i, m .n i ie > d it d o --rations of an elevation, but the differences are statistically confirmed. One can think of two wibilities here: (1) in reality, there is no increase - the risk of tumors; (2) there is indeed an in-vi.4d risk of tumors. The results neither confirm r refute this. Tumors do not occur until after a r.p latency period. The majority of the persons Juried in the study did not begin their exposure '*:il the 60's and 70's and therefore could not be >ued for a sufficiently long time. An accurate ; :i<w-up of the present cohort during the coming -.e-year period should bring greater clarity into ::js In the present connection, it is of interest that in t recently published mortality study (17) on almost ;i.ai deaths in the American PVC-processing ini.itry. an overrepresentation in cancer mortality ;*ars to exist (all cancer), especially gastrointea'rj] cancer in both sexes. REFERENCES ls 1 Hohnberg. B., and Molina, G.: The industrial toxicology of vinyl chloride. A review. Work-Environ, Health 11:138-144 (1974). 2 Creech, J L., and Johnaaon, M. N. Angiosarcoma of the liver m the- manufacture of polyvinyl chloride. J. Occup. Med.. 16 150-151 (1874). Lloyd. W J. Angiosarcoma of the liver in vinyl chloride/ polwmvl chloride worfcera. J. Occup. Med., 17: 333-334 (1975). 4 Hotaberc B., Kronevi, T., and Winell, M. The pathology of vinyl ciloride exposed mice. Scand., 17:328-342 (1878). 5 Mihoni. <' The value of predictive experimental bioassay in ocnipr.onal and environmental carcinogenesis. An ex ample: vu.yl chloride. Ambio, 4: 18-23 (18761. 6 Viols. P L., Bigotti, A., and Caputo. A. Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Rea., 31: 516-522 (1971). 7. Byren, D., and Holmberg, B. Two possible cases of angiosarcoma of the liver in a group of Swedish vinyl chloride-polyvinyl chloride workers. Ann. N. Y. Acad. Sd., 246: 249-250 (1975). 8. Monson, R. R., Peters. J. M., and Johnaaon, M. N. Proportional mortality among vinyl chloride workers. Lan cet ii, 397-398 (1974). 9. Tabershaw, J. R., and GafTey, W. R. Mortality study of workers in the manufacture of vinyl chloride and its gdymers. J. Occup. Med., 18: 509-518 (1974). yren. D., Enghotm, G., Enghind, A., and Westerhoim, P. Mortality and cancer morbidity in a group of Swedish VCM and PVC production workers. Environ. Health Perspact. 17:167-170 (1976). 11. RCP and BCS. Prevention of coronary heart disease. Report of joint working party of the Royal College of Physicians of London and the British Cardiac Society. J. Roy. CoU. Physicians, 10: 218-275 (1978). 12. TibbUn, G., Wilhelmsen, L., and Warka, L. Risk factors for myocardial infarction and death due to ischemic heart dtaeaaa and other causes. Am. J. Cardiol. 35: 514-522 (1975). 13. Popper, H., and Thomas, L. B. Alteration of liver and spleen among worker* exposed to vinyl chloride. Ann. N.Y. Acad. Sri., 246:172-198 (1975). 14. Marks, H., Johnaaon, M. N., Whetstone, C. L,, and Le Roy, E. C. Capillary abnomiahtiaa in polyvinyl chloride production workers. J. Am. Mad. Assoc., 236: 1368-1371 (1976). 15. Maries, H., Johnaaon, M. N., Whetstone, C. L., and Le Roy, E. D. In vivo capillary abnormalities in vinyl chloride workers. In: Microcirculation, Val. 2. J. Grayson and W. Zingg, Ed*.. Plenum Press, New York, 1976. 16. Maries, H., Darke, C. S., Archibald. R. M., and Le Roy, E. C. in vivo observations of skin capillaries in workers exposed to vinyl chloride. An English-American compari son. Brit. J. lnd. Mad., 36:1-7 (1978). 17. Chiazae, L., Nichola, W. E., and Wong, 0. Mortality among employees of PVC fabricator*. J. Occup. Mad.. 19: 628-628 (1977). 18. Chiang, C. L. Stochastk Processes in Bkstatiaties. An Introduction. Wiley, New York, 1871, v October 1981 151 occ 0S1A95 Enviroonwntal Htoltk Perrpectivti Vol. il, pp 153-157, mi Epidemiological Study of Pneumoconiosis in the Italian Poly(vlnyl chloride) Industry by G. Mastrangelo,* B. Saia,* G. Marcer* and G. Piazza* Among HI* worker* employed in polylvinyl chloride) production factory. 10 mw of pneumoconioeie *w found. Non* of thee* worken had had previoue txpocur* to organic or inorganic duatc; 731 had been expoeed to PVC duet (employed in drying, tacking and Mending at polymer) and 485 had been expoeed to monomer alone. Cheat x-ray (lime were read by two independent phyiician* utilizing the ILO/UC Pneumoconfoeii Claerification, ItTl. X-ray abnormalitiea wery characterized by limited profution. irregular type and low gravity; in a email percentage of eaeee theee were aaeociated with (light reetrictive rnpiratory function impair ment!. All 20 workerx with PVC-induced pneumoconioeie had been expoeed to high PVC duet pollution for at leaet fire year*. Mild nonepeeiilc alteratione (profution of 0/1 elate) were found both in the group expoeed to PVC duet and in the group expoeed to VCM alone. Such change! (obeerved in 388 caeca, 31.9% of the whole population), at* related mainly to age and (looking habit*, and the rule of expoeurt ie minor. We examined the working population of plants producing poly(vinyl chloride) (PVC) in Porto Merghera, Italy; 1216 workers had no previous dust exposure. Of these 731 were exposed to PVC dust polymer alone while 485 were exposed to vinyl chloride m momer (VCM). In the dicing, sacking uid blending departments, PVC dust eoncentrations were over 10 mg/m* of total dust in about 60% of the samples, whereas in the polymerization departments no concentration over 10 mg/m3 was f und. In the samples taken, particles with diameterc of 1 jim to 6 pun constituted 4.6 to 30.9% of total dust weight. All the worker* had chest x-rays according to HO standards and a spirographic examination. Chest x-ray films were read by two independent physicians utilizing the ILO/UC pneumoconiosis classification. For statistical analysis, a consensus reading was used. 'Htituto rti Medicine del Lavoro, UnivenitA degk Stud! love, \is Faccioleti 71, Padua, Italy. Utitutu ih Radiologia (I Cattedra) UnivenitA degli Stud! ' * Vie Giuetinian 3, Padua, Italy. October 1981 Table 1 shows that there are no significant differences in age and smoking habits, but the exposure duration is higher in the workers not exposed to dust. Table 1. Group No. of % of Age, yr Expoeurt, yr eubjeete imoken (mean a SD) (mein a SD) Expoeed to PVC duet Not expoeed to PVC duet 7*1 485 73.9 37.7 a 8.8 *8.7 85.7 a 8.5 6.1 a 4.0 8.8 a 4.5 Table 2. PVCdnft cxpoAirt, yr Age diitribution of eaeee* 30 yr 31-40 yr 41-50 yr > 50 yr <5 6-10 > 10 _ __ - 2(2.4) 5(8.3) 1(5.9) - 2(3.8) 8(9.0) 2(9.5) *Values in perentheeee are percentage* of eutdeeta with PVC pneumoconioeie in etch elate of age and expoaure. 153 ucc 057196 In 20 subjects we found chest x-ray changes of at least class 1 according to the ILO/UC classification. The mean age of this group was 44.9 5.2 years and the mean length of exposure was 11.6 5.4 yean. Sixteen subjects (80%) were either smokers or ex-smokers. Table 2 summarizes the distribution of cases in relation to age and length of exposure. In all age groups there is an increase of disease prevalence associated with the increasing length of exposure. In the case of the x-ray changes, 16 subjects had class 1/0 profusion, 2 cases class 1/1,1 case class 2/1, and 1 case class 2/2. Irregular opacities were prevalent: 10 were type s, three were type t, six were type p and one was type r. They were diffused, mainly over median lobe areas. A chest x-ray of a worker exposed to PVC dust (Fig. 1) for 15 years shows a gross reticular pattern: profusion is class 2/2, type t. In the right hemithorax of the same subject (Fig. 2) there is a mottled reticular patten. Figure 3 is an enhanced view of the right hemithorax showing the mottled reticular patten more clearly. Another case it PVC induced pneumoconiosis can be seen in Figure 4. The worker was exposed to PVC dust for 20 years. A fine, dense mio* micronodulation is evidenced. Profusion is class l- type p-s. Figure 5 shows the right hemithom'i the same subject; pin-point opacities can be ml In spite ofage and the considerable exposure, majority of cases were in a low profusion categor, indicating the slow evolution of the disease. All h* worked in high air-bone dust level environn*-. (mostly drying and sacking) for at least five vtar None of the 20 subjects was in s group unexpo* to dust and none had experienced previous ou> tional exposure to organic or inorganic dusts. . considered the alterations to be PVC pneumoeov sis. In 388 subjects (31.9%) we found slight d*r x-ray alterations consisting of linear or irrepuvanishing opacities or both, classified as class ir. the remaining 808 subjects were class 0/0. Table 3 reports the total population distribute excluding 20 subjects with PVC pneumoconk*;- Results are presented in a two-way table: etc entry reports the number of observations. Sampltare classified according to age and PVC exposure: PVC + represents presence, and PVC absence of PVC; x-ray + indicates the group *tj das.risk vari; T; sign The for ( degr able vaii Figum l. Cheat x-ray of a worker txpoaed to PVC dual for 15 yean. Protoaion elaaa 2<2; type t Environmental Health Perspecthn t ucc 057197 PVC X-T X-r PVC X-r X-r 1 ( i !%** f cbn^ iee*P*un.. Tismn cat**. disease. cnvjfojy^. "st five v*. 0UP uneib* ^'ious ocn,;, wit dust* i' ; Pneumw_ d s%ht ch. . or in**.. <3 as da**. (, -s 0 0. n distribute "Umoeonii, table,* ea1 )ns. Samp; PVC dL. , and PVf group f * r.iitl Rv'ht hemithorax of the am cubjeet M in Fig. 1. Figuki S. Enhanced view of the right hemithorax of Fig. 2, showing the mottled reticular pattern. 01 profusion. To assess the influence of both r.<k indicators we performed a two-way analysis of variance for proportions. Table 4 shows that both age and exposure were ;gnificant factors influencing x-ray abnormalities. The square of a multiple partial association coefficient f r qualitative data waa calculated to measure the degree of a.-sociation between the dependent vari able (x-ray changes) and each of the two predictor variables (age and exposure). Age and exposure are alternately held constant. Age is s most important factor. When exposure is held constant, 33.2% of the x-ray changes are shown to depend upon age, when age is held constant, 6.5% are shown to depend upon exposure. Table 5 summarizes the distribution of the cases according to smoking habits in workers exposed and not exposed to PVC dust. Table 6 shows that chest abnormalities are significantly influenced by both risk indicators. Tables. Table 4. PVC * X-ray - X-nv PVC- X-ray - X-ray - Age distribution of subject* 30 yr 31-40 yr 41-60 yr > 80 yr 20 78 128 36 133 107 108 17 n1o7 46 168 65 87 16 9 Source of variation Age PVC do* exposure Interaction Error *p < 0.01. V < 0.06. Degreet of Sum of Ussn freedom squares squares 3 30.9718 10.3238 1 0.7843 0.7843 8 0.9882 0.3294 1188 227.9403 0.1919 F 63.81* 4.09" 1.72 October 1981 155 UCC 057198 PVL * -<V V-'- Figure 4. Cheat x-y of a worker expoaad to PVC duat for 20 yean. Profusion dan 2/1; type p-a. PVC + X-rty + X-ray - PVCX-ray + X-ray - TaUeS. Nonamokers 40 147 2S 1X7 Smokers 216 SOB 107 226 Source of Variation Age PVC dual exporart Interaction Error *p < 0.01. 156 Table*. Degrees of Sum of freedom aquam 1 7.8860 1 1.7847 1 0.1028 1182 251.9125 Mean aquaraa 7.8850 1.7847 0.1028 0.2113 F 37.31* 8.44* 1.0 Figure 5. Right hemithorax of the aame subject as in Fig < Environmental Health Perspectfct ucc 051199 When exposure is held constant, habitual smoking * responsible for 17.1% of the changes. When poking habits are held constant, exposure to PVC dust is shown to be responsible for 8.9% of the i-rv abnormalities. Our epidemiological study confirms experimental md pathological data already reported regarding j* effects of PVC dust. Lung changes are directly related to PVC dust exposure, whereas VCM ttposure alone fails to cause these changes. There* fore, we believe that pulmonary changes are not W.hogenically similar to other vinyl chloride in* duced abnormalities, that is fibrosis of the liver, scleroderma-like skin changes, and peripheral vas cular damage. In our study there was only a 1.6% prevalence of pneumoconiosis in the total population, but in the workers exposed to effective risk of pneumoconio sis (731 subjects) the prevalence rose to 2.7%. Apart from 20 cases of pneumoconiosis, mild nonspecific alterations (profusion of 0/1 class) were found in the group exposed to PVC dust and in the group exposed to VCM alone. Such changes are related mainly to age and smoking habits, and the role of exposure is minor. 4 u in Fig, 4. .'lives October 1981 157 UCC 057200 Excess Lung Cancer Risk in a Synthetic Chemicals Plant by Richard J. Waxweiler,* Allan H. Smith,t Henry Falk* and Herman A. Tyroler" A fUndardized mortality ratio of 1.4* for rwpiratory lyctcm cancer (42 obaervad deaths ranua > 2 expactad, p < 0.01) was observed amonf a cohort of 4806 males employed at a synthetic t hemitali plant since its startup in 1042. Upon review of pathologic material, the excess was found to be limited to adenocarcinoma and large cell undifferentiated lung cancer. Many of the workers had been exposed to vinyl chloride, as well as to chlorinated solvents, poly<vinyl chloride) (PVC) dust, scrylates and acrylonitrile. To evaluate the association between lung cancer and occupational chemical exposures, detailed work histories for each cohort member ere combined with exposure ratings for each of 1> chemicals for each Job for each calendar year >ince 1642. A serially additive expected dose model was then constructed which compared the doses of the chemicals observed for the lung cancer cases to the doses expected based on 'iibcohorti without lung cancer individually matched to the cases. PVC dust appeared to be the most likely etiologk agent (P * 0.037). Time trends of PVC dust exposure indicated a potential latent period of 5-16 years before death. Introduction Our previ.>usly published (2) retrospective cohort mortality study of workers exposed to vinyl chlo ride monomer (VCM) st a synthetic chemicals plant demonstrated an excess risk of death from respira tory system cancer in addition to the already recognized association between VCM exposure and angiosarcoma of the liver (-20). Preliminary re view of the lung cancer case* indicated they were all adenocarcinomas or large cell undifferentiated tumors--an unusual histologic distribution. Although lung tumors have been induced exper imentally by exposure to VCM (), the epidemiologic 'Industry-wide Studies Branch, Division of Surveillence. Hiurd E\*lustions and Field Studies, Nstional Institute for Omjpttior.il Sifety and Health, 4676 Columbia Parkway, Cin cinnati, Oho 45226. 'Depart'-lent of Community Health. Wellington Clinical School of Medicine . Wellington Hoepital, Wellington 2, New Zealand. tDivision of Chronic Diaeaaoa, Center for Environmental Health. Center* for Diseaie Control. Atlanta, Georgia 30333. "Deportment of Epidemiology, School of Public Health, Vnivenity of North Carolina, Chapel Hill, North Carolina 27514. data are suggestive but equivocal. Two cohort studies found no excess lung cancer risk U-6). In six other studies, elevated lung cancer risks were found overall or among subcohorts; however, few of these excesses were statistically significant due to moderate excess risks and/or small numbers of cases (7-9,11-13). Because of the uncertainty in the literature regarding the association between VCM exposure and lung cancer and because of the diversity of occupational chemical exposures experienced by the lung cancer cases in our previous study (2), we decided to evaluate our cohort further to determine whether or not lung cancer was associated with VCM or with other chemical exposures. Thus, the following research had three objectives: (1) by using a retrospective cohort design, to determine if our previously published excess lung cancer risk tmong employees exposed to VCM at this synthetic plastics plant also existed for the total plant popula tion (2) by using a case-comparand study, to de termine whether an excess lung cancer risk of s particular histologic type was in force at the plant and (3) by using a serially additive expected dose model, to test whether one or more particular October 1981 159 ucc 057201 I chemicals used at the plant were associated with either the excess risk of all or of a specific histologic type of lung cancer. Methods and Results Retrospective Cohort Study The population at risk for the retrospective co hort study consisted of the 4806 males ever em ployed at this plant from its opening in 1942 until December 31, 1973. In the absence of individual data on race, everyone was assumed to be white because the company indicated that less than 2% of the population had been nonwhite. Date of birth and detailed work histories at this plant of all jobs and dates worked by each individual were coded. By follow-up of all study members from the first date hired at the plant through December 31,1973, it was determined that 4174 were alive and 559 had died. The 73 (1.5%) persons lost to follow-up were considered alive throughout the study. The 16 (3%) deceased persons for whom no death certificates could be located were assumed dead, cause of death unknown. A modified life table analysis (NIOSH) was used to obtain person years at risk of dying by five year age and calendar time periods. United States white male death rates specific for five year age and calendar intervals were used to calculate the expected deaths and standardised mortality ratios (SMR's). SMR's were tested for statistical significance using the Poisson distribution (one sided). The cohort was young; by December 31, 1973, only 30% of the cohort, if alive, would have been over 54 years of age. However, 63% of the cohort had been hired before 1954 and thus had the oppor tunity to achieve 20 years' latency. Two separate analyses of the cohort were made. Initially, all members were considered at risk from their first date of employment at the plant. This analysis yielded 556 observed and 550 expected deaths (Table 1). Risk of death due to malignant neoplasms of the central nervous system (SMR * 209) and respiratory system (SMR 149) were both significantly elevated. A second "over tenyear latency" analysis was carried out by beginning person-years at risk only after an individual had achieved the tenth anniversary of his first date of employment at the plant. Results similar to those in the first cohort analysis were found but with slightly higher SMR's. Respiratory system cancer had an SMR of 156 based on 39 observed cases. Because our previously published analysis (l) of just the presumably VCM-exposed workers at this plant 160 Table 1. Obeervad and expected death* amon* chemical tim worker cohort. Cauee (1CDA-7 Code) Observed Expected SKK All caute* Ail malignant naopiasma 566* 350.2 10] (140-206) 109 92.5 lit Digestive *y*t*ra (150-159) 24 25.6 to Rwpiratory system (160-164) Central nervous syatem (193) 42 9 28.2 uy 4.3 2W Lymphatic and hematologic (200-206) 9 11.4 Other cancer* 26 23.0 io `Five penaoa, including throe ofthe original 359 death*. r> not included in the cohort analytic because of miaaing m histone*. S < 0.01. pc 0.06. also found an SMR of 156 after 10 years latency, these results indicate an excess lung cancer risk not solely due to VCM exposure. v a o, si. at ar R of ot )u: St: to. 27 ab ea: ap an ris 14 wt un Case-Comparand Study The second objective of this study was to determine whether an excess risk existed for a particular histologic type of lung cancer. Because no historical data exist on histology-specific lung cancer inci dence or mortality rates and because histologic classification is somewhat variable between pathol ogists and over time, a case-comparand design as chosen to accomplish the second objective. Medical records and pathology reports were ob tained on all deceased members ofthe cohort whose death certificates mentioned cancer or respiratory disease. For 45 cohort members, primary or un specified lung cancer was reported on at least one of these three records. A few persons who died after December 31, 1973, the cohort ending date, wen included. Ofthe 45 cases, 42 were bom in Kentucky or an adjacent state. Histologic material was re quested. The worker case group consisted of the 27 of the 45 deceased individuals for whom histologic specimens were available. As a comparison group, the lung cancer cases (comparands) most closely preceding and succeeding the chemical plant worker case in the chronolog- ically ordered hospital pathology logs were selected that matched in age at diagnosis, sex, race, and county ofresidence. For four cases, only one matched comparand could be found. Histologic material was reviewed by a panel of pathologists unaware of the employment histone (case versus comparand status) of the deceased The histologic type distributions, according to the Environmental Health Perspectiw* ucc j I i j j - an Tat Hit Epi Sm. Mt Ur Oth Tot. Tot* Epic Sm* Ado: Ur* l S Oct- 051202 II* w ( 9* A M Ti Iff. 9,|*h.. ,, m`-'sul* >,, 5 latenn *r n5)( r;.: to deter- >articuJar > rici cer ind- w.'tolopr n patholsign u-a,. vene ob it whose piratory ' or unst one of ed after e, were .ntuckv was ref the 27 stologic r cases icceedunologsleeted e, and atched tnel of tones 'd. . .M tivet ,<ran#' Administration classification scheme iU), compared between the cases and comparand*. ` results of the majority opinion of the pathol* . ^nei are listed in Table 2. The panel found a .1* f.cantly (p < 0.05, chi-square) higher percent* bt Urge cell undifferentiated (type 4) cancers r - the worker cases than among the community - **;brands (30vs. 10%). p ! using the SMR for respiratory system cancer its in the retrospective cohort study and the *rr\ed and expected histologic distribution of cancer deaths based on the case-comparand . Table 3 demonstrates the calculation of his specific lung cancer SMR's (column C). Ifthe .'cu-es for which histologic specimens were avail* i-.< are consuiered representative of all 45 lung r cases, it appears the excess lung cancer risk i. -.ars limited to types 3 and 4, adenocarcinoma i large cell undifferentiated, with the greater vr. due to the latter. Approximately 13.5 of the ;; * excess lung cancers among the plant workers -dd be due to adenocarcinoma and large cell . iifferentiated carcinoma. *a I: appears that there is a histology-specific exlung cancer risk among workers at this plant i.- l that this differential distribution of cell types is Table 2. Cut and matched comparand hietologie diatribe* tiona. Htfolofie type Veteran* Ad- Freaucncy minietretkn Community claaaification Worker comparand code casee Epdernwid 5-nD cell undifferentiated Adeflocaranoma Urge ceD undifferentiated Older Total 1 2 -8 4 6 (22ft) 16 (80ft) < (22ft) It (80ft) 7 (26ft) 14 (28ft) 8 (80ft) 6 (10ft) 0 1 ( 2ft) XT (100ft> 50 (100*) not an artifact of the geographic region nor of the pathologist's techniques. The fact that this risk occurs for adenocarcinomas and for large cell undif ferentiated lung cancers makes it very unlikely that it is due to cigarette smoking. Serially Additive Expected Dose Model The third objective waa to test whether any presumed occupational chemical exposures were associated with the excess lung cancer risk at the plant. It was decided to analyze the previously mentioned cohort data in a serially additive ex pected dose (SAED) model (10), obtaining for each lung cancer case the observed and expected doses of each chemical, conditional on certain characteris tics. The purpose of the SAED model is to compare the observed exposure of each case in a study with the exposures of fellow workers close to the case in year of birth, and in age at commencement of work at the company. If the total work force in the plant under study is referred to as the cohort, then each case can be thought of as belonging to s subcohort of workers with approximately the same year of birth and age at commencement of work in the plant. In each year that a case worked at the plant, his exposure can be compared with that ofthe other members of his subcohort who were working in that year. Company personnel compiled estimated exposures on a scale of0 to 5 (5 being the highest exposure) for each of 19 chemicals (Table 4). Each job was as signed an exposure rank for each calendar year of the study (Table 5). These exposure data were then linked with work histories identifying the jobs each worker had in the plant and the calendar time involved. The analytical method is based on esti mating exposure dose by multiplying the exposure level by the number of days worked at that level. These "doses" are accumulated over a calendar year for a case to yield the observed dose and for Table 8. Hietologie epeclflc lung cancer ri*k among plant pereowiel. Hietoloeic dietribntion Obaarvad (A) Expacted (B) Hietologie Exceea caaci among apedflc SMR thoae pathologically C - 149IAJB) reviewed (X))* Total Epidermoid Small cell Adenocarcinoma Loifecell 100ft 22.2ft 22.2ft 25.9ft 29.0ft 96ft' 80ft 80ft 28ft 10ft 149 no 110 188 441 8.9* 0.0 0.0 1.9 6.2 *D - (27 A) - (27 B x 100/149). "E - <45 A) - (45 B x 100/149). 'Specific cell type* do not add up to total became of "other' type lung cancer among comparand*. October 1981 Total exceaa caaealE)6 u.r 0.9 0.9 3.2 10.8 161 ucc 057203 I his subcohort to yield an expected dose for each year that a case works. The methodology has pre viously been described in detail elsewhere (10). In addition to testing the total-dose hypothesis, the SAED analysis facilitates examination of the observed and expected doses for each year of exposure before death. Exposures to 19 chemicals Table 4. Expoeure rating* Mad to classify job*. Rating Exposure 0 No exposure 1 Minimal expoeure to low level* (chemical in building-- not handled, low vapor prewure and duat leval, probably work* on different Boor) 2 Moderate expoeure (work* ground the chemical, but exposure i minimal) 5 Work* in are** where subject to occasional high excursions (normally exposure i* minimal but occasional qrflla. laaka, or dust expoeure may occur) 4 Works in areas where level is high (exposure levels in the area are frequently high; might consider that some risk is invotvefrif chemical is very toxic) 6 Intimate contact, akin or high inhalation (auch a* poly cleaner* in writer year* handling slurry) Table 5. Chemical expoeure rating* ipeclftc forjob identification number and calendar year for a given chemical. Chemical #1, Exposure rating* job identifi cation number 1942 1948 1944 1946 1946 1973 1 000222 2 S68666 8 221 100 84 "4 4 4 1 1 1 were assessed; seven ofthe chemicals were, however excluded from the formal analysis because so fet persons were exposed to them at levels 3, 4 and 5 (Table 6). The SAED model analysis resulted in the ob served minus expected cumulative dose difference per case in Table 7. The differences for PVC dun are striking in comparison with the other expo sures. For the large cell undifferentiated caiwr and adenocarcinomas combined and for large cell undifferentiated cancer by itself, the differences in exposure to PVC dust are three to four times as large as thoae estimated for vinylidene chloride, tlx Table S. Frequency ofJob categories having at Itact om jw of exposure greater than tpadlte exposure* levels.* No. at each exposure level 1 2 3 44 Acrylic add Acrylamides Acryiomhrik Acetylene Acrylate* Biephenol A Butadiene Ceprylyl chloride Chlorinated solvents Chloroethyi vinyl ether Diethyl mateato Mercuric chloride Methanol Phenol Tduene Vinyl chloride Vinylidene chloride Vinyl acetate PVC duet 13 4 3 0 0 14 4 4 0 0 36 25 13 6 1 20 17 10 3 1 89 30 21 8 2 7 2 0 00 23 16 9 S 1 25 3 6 6 3 30 13 7 4 4 22 6 4 1 0 14 6 0 0 0 16 7 S 3 1 30 21 14 2 2 2 1 0 00 2 0 0 00 66 40 29 21 4 20 14 8 5 2 26 18 10 0 0 66 32 19 9 6 *E.g., for aayUc add. employee* could have worked in ll differentjob categoric* that hid exposure leval* of one or higher in at least on* calendar year between 1942 and 1973. Table 7. Observed minue expected cumulative doe* difference* per lung cancer Chemical AH lung cancer* Pathologically reviewed eaeee Adenocarcinoma and large cell Acrylonitrile Acetylene Acrylate* Butadiene Caprylyl chloride Chlorinated idvento Mercuric chloride Methanol Vinyl chloride monomer Vinylidene chloride Vinyl acetate PVC duat -662 -363 -322 -330 -647 -863 -607 -430 -1428 -341 -707 763 -402 -283 -261 -207 -258 -672 -426 -618 -796 210 -480 2448 -446 291 -88 -406 -270 -160 -211 -466 26 804 -217 3226 Large cell -128 -167 -339 -622 -1139 749 -62 -1078 907 1625 328 4626 162 Environmental Health Perspectives ucc 057204 , however, se so few 4 and 5 n the ob> ifferenoe* VC dust ier exposd cancer large cell .Tences in times as bride, the tat on* rtr levels.* -re lv*i 45 O0 00 c1 81 62 00 51 f3 44 10 00 33 22 00 00 .1 4 52 00 96 "iced ir 13 ? or higher ell >ectives next most evident chemical. The significance levels ofthe larger of these differences are found in Table gfor the total cumulative doses and also for cumula tive doses until 10 years before death. Statistical significance was observed only for exposure to PVC dust. Latency analysis for PVC dust (Fig. 1) shows a peak for the difference between observed minus expected dose during the period 5 to 16 years before death. As the diagnosis of the disease of interest becomes more narrowly defined as a patho logically homogeneous entity, the dose difference per case increases, yet the implied latent period stays constant. Discussion The first objective of this study was to determine if the excess lung cancer risk among employees exposed to VCM also existed for the total plant population, including those persons not exposed to VCM. The retrospective cohort mortality study showed that respiratory system cancers occurred ipproxiriately 50% more frequently among the em ployees of the entire plant than would have been expected based on age, sex, race, and calendar year specific United States death rates. A similar excess had been previously shown to exist among the subcohort of employees exposed to VCM (1). Thus, the excels iung cancer risk at the plant appeared to be independent of VCM exposure unleu one hy pothesized that it was due to extremely low levels of VCM that could have permeated throughout the plant. Potentially confounding variables are age, sex, calendar year, race/ethnidty, migration, urban res idence, cigarette smoking and socioeconomic status (SES). In the retrospective cohort study, age and calendar year cannot confound because they are adjusted in the results. All persons in the study are male and 98% are presumed white. White male specific rates were used for comparison to control tnose potential confounders by subject category re striction. Ethnicity and migration (both inter- and intmountry) effect# are considered minimal for all three study designs because 42 of the 45 cases were bom in Kentucky or an adjacent state. Urban resi dence is mainly associated with an excess of epidermoid and small cell undifferentiated lung can cer (15) rather than the histologic types of lung cancer found in excess in this study. Excess lung cancer risk is associated with low socioeconomic status (16, IT), measured either by education (rela tive risk of 1.2 for persons with fewer than eight yean ofschool) or by occupation (relative risk of 1.8 for laborers). Since the cohort consists of a mixture of socioeconomic status levels, there is probably insignificant confounding due to SES at the plant considered as a whole. Furthermore, recent infor- TiMt 8. Probability vain* of paired t-tosta of cumulative efftrvncr. between obeerved and expected doses for Inns cantor cane. 10 or mare Total years before (aD yesup death All caaee (.V - 46) PVC duet All pathologically reviewed cue* t-V 27) PVC dust Adenocarcinoma and large cell tV - 15) PVC dust Vinyl:dene chloride Large cell (N - 8) PVC duet Chlorinated aolventa Vinyhdene chloride 0.186 0.023* 0.087* 0.267 0.066 0.360 0.201 0.268 0.047* 0.061 0.336 0.177 0.436 0.322 Twelve chemicals were tested for each hinc cancer group, thus, under in assumption of independence of tests, one would tipect one teat to bo significant at the 0.06 level. *P < 0.05. October 1981 Fionas 1. Obeerved minus expeetad dose difference* per case among lung cancer caaee tor PVC dust. 163 UCC 057205 i mation indicates that these risk gradients may be partially due to smoking patterns (18, 19), which would affect epidermoid and small cell undifferenti ated lung cancers. The second objective of this research was to determine whether an excess lung cancer risk of a particular histologic type existed. The case-comparand study showed that there was an excess of adenocar cinomas and large cell undifferentiated lung cancers among the cases occurring among plant employees compared to other lung cancer cases from the same community. Because the pathologists reviewed both sets of slides without knowing which were those of plant employees, it is unlikely diagnostic biases occurred. Histologic specimens were more difficult to find among the cases which died earlier and which were older on the date of death. However, community comparands were matched with the cases on age and date of diagnosis and had to have specimens available themselvesphence a biased ascertainment by histology between cases and comparands would be unlikely. The choice of community comparands makes it unlikely that a community wide pollutant was responsible for the excess risk at the plant for types 3 and 4 lung cancer. Consequently, it can be inferred from Table 3 that the excess lung cancer risk in the cohort was limited to adenocarcinoma and large cell undifferentiated cancer. Adenocarci nomas, accounting for a minor proportion of this excess risk, have been shown to be weakly, if at all, related to cigarette smoking (U, 20-22) Large cell undifferentiated carcinoma of the lung is the only major histologic type that has appeared to be unrelated to cigarette smoking. Thus, ciga rette smoking was probably not a major confound ing variable. However, the role of smoking as a promoter or cocarcinogen cannot be ruled out. Nev ertheless, the conclusion of this phase of the inves tigation was that an excess risk occurred among plant employees for types 3 and 4 lung cancer, especially type 4. The third objective was to test whether one or more particular chemicals used at the plant were responsible for either the excess risk of all lung cancer or of the types 3 and 4 or just type 4 lung cancer. The SAED model was specifically devel oped for this objective. The major hypothesis was tested for each chemi cal in the SAED model by using the one-sided t-test of the observed minus expected cumulative doses over all years before death and ten or more years before death (Table 8). PVC dust was the only chemical that was statistically significant. These results suggest that an excess of types 3 and 4 lung cancer exists at this plant and is related to PY( dust exposure. The suggestion of PVC dust being a lung cam:, ogen is biologically plausible. Almost all PVC par cles produced by the emulsion system, one of tb systems at this plant, are in the respirable tanc(23). These particles could settle in the lungs ik conceivably by themselves cause lung cancer. 1: fact, one case of supposedly PVC dust-induced pntv moconioeis has been found in a worker (21), w: pulmonary granulomas (25, 26) have been induck in animals exposed to PVC dust. In a large propor tional mortality study of 4341 deaths that occunk among PVC fabricators, persons expected to b exposed to VCM and PVC dust demonstrated! slight (PMR " 117) excess lung cancer risk (ifi. VCM gas is easily inhaled, and possibly would b in contact with tissue only a short time before beiit* either exhaled or absorbed into the bloodstream However, VCM becomes entrapped in the PVC dust and can be released slowly over time. Thu.-. PVC dust particles in the lung may slowly relea* VCM to small adjacent areas of the tissue, proton; mg the contact time of that chemical to tissue. If this latter hypothesis is true, then it begs tb question of why almost all ofthe liver angiosanm cases occurred among polymer reactor cleaners wlv received extremely high VCM doses while the tun; cancer cases occurred frequently among the le& heavily exposed workers. In fact, there was nc relationship between VCM and lung cancer in thianalysis; yet, one would expect the lung to be tb major route of entry for VCM regardless of tb cancer site. REFERENCES 1. Waxwefler, R. J,, Stringer, W,, Wagoner, J. K., Jodh.J.. Falk, H., and Carter, C. Neoplastic risk among wortm expoaed to vinyl ebbtide. Ann. N.Y. Acad. Sd. 271: to-v (1974). 2. Maltoni, C. Vinyl chloride carcinogenicity: an experiment model for caranogeneaia studies. In: Origins of Humor Cancer. H. H. Hiatt, J. D. Watson, and J. A. Winatt Eds., Cold Spring Harbor Labs., Cold Spring Hsrtw N.Y,, 1977. 3. Thomas, L. B., Popper, H,, Berk, P. D., Selikoff, I., and Falk, H. Vinyl chloride induced liver disease--from d* pathic portal hypertension (Banti's syndrome) to inf* sarcomas. N. Engl. J. Med. 292; 17-22 (1975). 4. Nicholson, W. J., Hammond. E. D., Seidmsn, H.. and Selikoff, I. i. Mortality experience of a cohort of nry chloride-polyvinyl chloride worker*. Ann. N.Y. Acad. So 246: 225-230 (1975). 6. Duck, B. W,, Carter, J. T,, and Coombet, E. J. Mon**) study of worker* in polyvinyl chloride production pls`. Lancet 2:1197-1199 (1975). 6, Berry, G., and Roaaitcr, C. E. Vinyl chloride and mortitoy Lancet ii: 416-417 (1974). 164 Environmental Health Perspecth** UCC 057206 :. o c: A i. t o' y *F a t V . S F u 1 11. F ii r ii r i c 1 111y a 1 15. 1 IS. 1 Oc ;<* P\ ,ng carr.- one of tr, ible rv,-. Jungs t :ancer. ] Jcedpn,.. n induce e pro^,. OCCUJTk ted to b 'strata i fk u:h ould U :"ore beir.tdstrean, be PV( e. Thu.releajr prolong- ssue. If es th'arconu ers whhe lung h Igfn< ' in thi be th* of the . n,t U G.. Langner, R. R., end Holder, B. B. Vinyl Monde exposure in controlled industrial environment. SrtEnrtwn. Health 333439 (1375). . testable Environmental Health, Inc.: Epidemiologic study df vinyl chloride workers. Final report submitted to the Manufacturing Chemists Association, 1978. Fo*. A. J., and Collier, P. F. Mortality experience of corien exposed to vinyl chloride monomer in the manufkc- an of polwinyl chloride in Greet Britain. Brit J. Ind. M(d 34:1-10 (1977). South. A. H.. Waxweiler, R. J., and Tyroier, H. A. EndemioiogK investi|ition of occupational carrinogeneais serisllv additive expected doee modeL Am. J. Epid. 112: 737-797 (1980). Fox. A. J.. and Collier, P. F. Low mortality rate* in industrial cohort ttudias due to selection far work and survival in the industry. Brit J. Preven. Soe. Med. 30: 25-230 (1976). j Baffler, P. A.. Wood, S., Clayton, E., Snares, L., and viinn D. J- Mortality experience of workera in a vinyl chi-ride monomer production plant. J. Oocup. Med. 21: 195-203 (1979). .1 Byren. D.. Engholm, G., Enghind, A., end Weaterhobn, P. Mortality and cancer morbidity in a group of Swedish VCM and PVC production workers. Environ. Health Perspact 17. 167-170 (1976). 14 Yesner, R.. Geifman. N. A., and Fcinstein, A. R. A rtappraisal of hiatopathology in lung cancer and correlation of cell type - with antecedent cigarette smoking. Am. Rev. Retp. Du 107: 790-797 (1973). . > ; Hieiuiel. W., Loveland, D. B., and Sirken, M. G. Lung cincer mortality as related to residence and smoking histories. 1. White make. J. Natl. Cancer Inst 28:947-1001 (1962). it Kitagawa. E. M., and Hauaer, P. M. Differential Mortality in the United States: A Study in Socioeconomic Epidemiolo gy. Harvard Univcnity Preas, Cambridge. Mast., 1973. 17. Gurainick, L. Mortality in I960 by occupation and industry. Vital StatistkeBpedal Reports 53, 1-5, U.S. Dept. HEW, 1961-1968. 18. Sterling, T. D., and Weinkam, J. J. Smoking characteristic* by type at employment J. Occup. Med. 18: 743-754 (1976). 19. Winkelatein, W,, Jr. Contemporary perspectives on preven tion. Bull N.Y. Acad. Med., 51: 27-28 (1975). 20. Doll, R., and Hill, B. Mortality in relation to smoking: ten years' observations at British doctors. Brit Med. J. 5395: 1399-1410 (1964); ibid. 5396: 1460-1467 (1964). 21. Weiss, W., Boucot K. R., and Sekhnan, H. Risk at hing cancer according to histologic type and dgarette dosage. J. Am. Med. Assoc 222; 799-901 (1972). 22. Auerbach, 0., Garfinkel, L, and Parka, V. Histologic type at lung cancer in relation to Booking habits, year at diagnosis and sites of metastasis. Chest 67:382-387 (1975). 23. Janas, J. H. Worker exposure to vinyl chloride in vinyl chloride end polyvinyl chloride production and fabrication. NIOSH Technical Report Draft, January, 1978. 24. Saonde, B., Lapis, K., Names, A., and Pinter, A. Pneumo coniosis earned by the inhalation of polyvinyl chloride dust. Med. Lavoro 61: 438-486 (1970). 25. Frongia, N., Spinanoia, A., and Bucarelh, A. Experimental lung damage from prolonged inhalation of airborne PVC dust Med. Lavoro 66: 321-842 (1974). 26. Agirwal, D. K., Raw, J. L., Srivaatava, S. P., and Seth, P. K. Some biochemical and histopathologieel changes induced by polyvinyl chloride dust in rat lungs. Ind. Tax. Res. Center Report, Lucknow, India, 1978. 27. Chians, J., Jr., Nichols, W. E., and Wong, O. Mortality among employees of PVC fabricator!. J. Occup. Med. 19: 623-628 (1977). me, J. * orkrr> 1. 4(Mo imental Hum** instfn. lirbor. I . and n idioangM- .. and vinyl d Sct rtaiity piint. jlitv! October 1981 165 ucc 057207 Review of Pulmonary Effects of Poly(vinyl Chloride) and Vinyl Chloride Exposure by Ruth Lilis* The contribution! of mwiI nemt report* to the definition of pulmonary offocta of PVC duat inhalation art reviewed. Granulomatous reaction, with inclusion of PVC partklaa In macro* phacca and hiatocytaa, and aaaociatad interstitial pulmonary ftbrosi* have bean found to load to exertional dyspnoea, difTuae micronodular chest radiocraphic opacitioa and restrictive pulmo nary dyifunction. Th effects of vinyl chloride (VC) monomer (gas) on proteins and the immunologic mechanisms triggered by the altered protein are possible mechanisms for the development in some cases of interstitial pulmonary fibrosis secondary to VC exposure. Vinyl chloride, a confirmed carcinogen, has been associated with, among other malignant tumors, a significant increase in the incidence of lung cancer. The magnitude of this effect has not yet been completely evaluated. Several recent reports (1-3) have contributed new observations on pulmonary disease in vinyl chloride (VC)* and poly(vinyl chloride) (PVC)exposed patients. Earlier reports, a few even preceding the identific ation in 1974 of vinyl chloride aa a human carcinogen (with hemangiosarcoma of the liver the marker tumor, but most probably not the only tumor), had centered on the rather unexpected occurrence of pulmonary radiologic abnormalities U-) or pulmonary function impairment (i, 9-12) or had indicated dyspnea as a prominent symptom ill, is) in VC and/or PVC exposed workers. The radiologic pattern first described in 1975 (5) was essentially that of reticular-linear and/or nodu lar (small rounded) opacities, involving both lungs, predominantly in the lower zones. Pulmonary function abnormalities reported have been both restrictive and obstructive dysfunction with diffusion defects and arterial desaturation in some cases. Three recent reports, one a case report (I), the other two epidemiologic surveys (2, 3), seem to identify PVC dust as the etiologic agent in s *Err. ironmenul Sciences Laboratory, Department of Com munity Medicine, Mount Sinai School of Median* of the City Cniver.-ity of New York, One Gustave Levy Place, New York, N'.Y. 10029. October 1981 peculiar type of pulmonary fibrosis associated with a granulomatous reaction. Exertional dyspnea, difiUse micronodular chest radiographic abnormalities and restrictive pulmo nary dysfunction, were the main characteristics in the case of PVC pulmonary fibroaia associated with granulomatous lesions (1). Electron microscopic examination of lung tissue showed giant muhinucleated cells containing a nonhomogeneous material in their cytoplasm, which was identified to be PVC (2). A similar pattern was reproduced by incubation of human macrophages obtained by bronchial lavage, with PVC powder absorption of PVC particles in the cytoplasm was rapid, with thinly granular lysosomal material de posited against the PVC particles. Similar histologic lesions had been previously described in a human case U) and in an experimen tal study in guinea pigs and rata (U). In another experimental study, intratracheal administration of PVC dust in rata (15) has been shown to result in an increase in the activity of lysosomal enzymes, interstitial fibrosis and granulomatous lesions sur rounded by fibroblasts, reticulin and collagen fibers. An epidemiologic study of a large group of workers exposed to PVC and VC (2) detected 20 cases of "typical pneumoconiosis," i.e., chest x-ray changes consisting in irregular opacities or micronodular shadows of at least class 1 profusion, 167 ucc 057208 i according to the ILO U/C Classification. All these cases were found among PVC exposed employees. The pattern of radiologic abnormalities described is very similar to that reported in the case in which the lung biopsy revealed fibrosis and granuloma* tous reaction, with inclusion of PVC particles. The same study reported the presence of less marked radiologic abnormalities, of the linearreticular type, in a much larger proportion (32%) of the population examined; these changes were pres ent both in VC monomer exposed and in PVC exposed employees. While the prevalence was higher in smokers than nonsmokers, 65 of the 388 x-rays with linear-reticular opacities were found in persons who had never smoked. In another large epidemiologic study (3), expo sure to respirable PVC dust was found to be associated in a proportion of exposed workers with the presence of small rounded opacities on the cheat radiograph and a decline in mean ventilatory capac ity. '* The question of pulmonary effects due to vinyl chloride monomer continues to be of great interest. The multi-organ effects of vinyl chloride include the peculiar syndrome of acroosteolysis, sclerodermalike skin changes, vascular changes affecting the arteries, arterioles and capillaries of hands and fingers, liver and spleen capsular fibrosis, liver fibrosis, abnormalities of the sinusoidal vessels in the liver, and portal hypertension. Ward (16) inves tigated the immunologic status of 58 workers from a VC polymerization plant. The findings included hyperimmunoglobulinemia, cryoglobulinemia, cryofibrinogenemia, in vivo complement activation via the classic pathway, with C4 and C* conversion and an increase in the B cell lymphocyte population. Immunofluorcscent examination of skin, muscle and lung biopsy specimens revealed the presence of circulating immune complexes, with deposition on the vascular endothelium and occlusion of small vessels. Immunoglobulin, complement and fibrinogen deposition in the subintimal regions of the vessel were found in areas with subintimal fibrosis and luminal occlusion. Grainger et al. (17) have accumulated evidence suggesting the following mechanism: the vinyl chloride metabolite cyclic chlorethylene epoxide, an alkylating agent with high biological activity binds to IgG producing structural conformational changes that promote aggregation of IgG molecules. The modified IgG may also become antigenic. The IgG aggregates are cryoprecipitable and may initiate complement activation. Precipitation of IgG aggre gates by cold leads to complement activation, platelet aggregation and conversion of fibrinogen u fibrin with polymerization. Occlusion of small V(*. sets results, and ischemia stimulates new collage? biosynthesis. similar abnormalities of the immunologic statu., were found in another study of 22 workers exposeto vinyl chloride, with Raynaud's syndrome and. K some eases, acroosteolysis. Latent cryoglobulincmii was detected in 18 cases, with increases ofimmununoglobulins, IgA and IgG (18). Circulating cryoimmunoglobulins are a promi nent feature of idiopathic pulmonary fibrosis (i and increased IgG levels have been shown to bt characteristic for bronchoalveolar lavage fluid o.' such patients. Interstitial pulmonary fibrosis is a possible efftr. of vinyl chloride exposure. The occurrence of mort dramatic and specific abnormalities in other orgir. systems--liver, spleen and peripheral drculatkmhas probably prevented more focused attention or. pulmonary effects of vinyl chloride in the past. ) Long-term effects of vinyl chloride include well documented carcinogenicity. Lung cancer has be*found to occur with an increased incidence ii. several mortality studies (20-8$). Abnormalities ir. sputum cytology tests have been found to be mort frequent in VC/PVC-exposed workers than in other ! chemical industry employees and in smokers Uf' In experiments on mice, Suzuki (1) has describee 1 hyperplastic changes of the alveolar lining cells im! > pulmonary tumors in the majority of exposed animals. The ultrastructure was thought to indicate that the tumors originated in type II alveolar cell' Alveologenic tumors were also described in several other experimental studies (2S-27). Interestingly, other known carcinogens, such as polycyclic aro matic hydrocarbons, nitrogen mustard and chro mates, produce pulmonary tumors in experimental animals similarly, originating in the type 11 alveolar cell The efTects of vinyl chloride-poly(vinyl chloride exposure on the respiratory system of exposed workers seem to indicate two patterns of nonmihgnant effects: a granulomatous reaction to PVC dust, with inclusion of PVC particles in macro phages and histocytes and associated interstitial fibrosis, and an interstitial pulmonary fibrosis due to vinyl chloride monomer effects on protein mole cules and the immunologic mechanisms triggered by the altered protein. The long-term carcinogenic effect, with a agmfican: increase in the incidence of lung cancer, also i* concern, although the magnitude of this effect ha* not yet been completely evaluated. t Amau and Cl St: 19* 2. Maatr, Omip nyl ch poaed 3 N>uU! y.. w> d>as Paper of Vi/) tural. public 4 Siend n-eai Lavot a Lilia. Fiacht amon, NY. S. Lilia. Pulm- orki 7 Lilia, Modii P-lye h Wegr G . aprodu Milk Char chlor 42S2 IV. Berk of vi txpo 11 Linp mgei Svati 12. Walkabnor ture 22-23 13 Walkakin. 168 Environmental Health Perspecth** . Octob ucc 057209 inogtnt, mall i-h. collage* nc statupos; >e and, u, ulinenui ljwnunu i promjosis in, vn to be fluid o' 'le effect of mote ef organ iationw ition on ast. de wefl as be-mce iii lilies in * more n other r '). H-.^ed Us and xposed ulicate r ceiiN -everal dngly. >c arochronental veoiar iride) posed nalifPVC iacrostitiai s due .nole* jered Scant is of t has references a.. Ponunier d Santi, P. Garbe, L., Payan, H.t tfd Chsrprn. J. Polyvinyl chloride piwumoeoniosia. Thorix B IMS (1978). . Minnrgelo. G,, Manno, M,, Marcer, G., Bartohicd, G,, ' Onumani, C., Saladino, G,, Simonalo, L., Saia. B. Polyvi- r. i chloride pneumoeonioaia: epidemiological study of uworkers. J. Oecup. Med. 21: 540345 (1979). jMtar. c. A.. Copland, L. H., Thomley, P. E., Hurley, 4. r and Otterv, J. An epidemiological study of respiratory duwaae in workers exposed to poly(vinyl chloride) dust. Paper presented at Conference to Reevaluate the Toxicity of Vinyl Chloride Monomer, Poly(vinyl Chloride) and Struc tural Analog*. Betheada, Md., March I960; not received for publication. , iande. B.. Lapid, K., Nemaa, A., Pinter, A. Pneumoeotno- fir caused bv the inhalation of polyvinyl chloride dust. Med. Uvoro #1: 433-436 (1970). LjIi*. R.. Anderson, H. A., Nicholson, W. 4., Daum, S., Fmchbein. A., and Seltkoff, 1. J- Prevalence of disease imong vinv! chloride and polyvinyl chloride workers. Aim. N Y. Acad. Sd. 24: 22-41 (1975). Liu, R., Anderson, H., Miller, A. and Setikoff, I. J. Puhnonan change* among vinyl chloride polymeriaation worker*. Chest 69:2, Supplement. 296-608 (1976). : Lilia, R.. Anderson, H. A., Miller, A., SeBkoff, 1. J. Modification* pulmonaires et exjibsmon au chlorate et polychlorure de vmyle. Med. Hyg. 35: 1542-1546 (1977). Wegmen. D. Discussion in: Lange, C.-E., Jube, S,, Stain. G.. and Veltman, G. Further results in polyvinyl chloride production workers. Ann. N.Y. Acad. Sd. 246:18-21 (197$). * Miller. A Tciratein, A. S., Chuang, M. and SeUkoff, 1.4. Change* in pulmonary function in workers exposed to vinyl chloride and polyvinyl chloride. Ann. N.Y. Acad. Sd. 246: 42-52 (1975). 1" Berk. P D.. Martin, 4. F. and Waggoner, 4. G. Perristenee of vinyl chloride induced liver injury after conation of exposure. Ann. N.Y. Acad. Sd. 246: 70-77 (1975). 11 Lange. C.-E., 4uhe, S., Stein. G., Veitman. G. Die aogenanme Vlnyl-chlorid-Krankheit--Eine berufsbedingte System*kleroae? Inter. Arch. Arbeitsmed. 82:1-82 (1974). L' Walker. A. E. A preliminary repeat et a vascular abnormality occurring in men engaged in tha manufactur* of polyvinyl chloride. Brit. 4. Dermatol, 96 (Sllh 22-23 (1975). II Walker. A. E. Clinical aspects of vinyl chloride < *knL Proc. Roy. Soe. Med. 69:286-290 (1978X 14. Fnmgia, N., Spinazzola, A., and BucareUi, A. Lesioni pohnonari sperimemali da inaladonc prohingate di PVC in ambiente di lavoro. Med. Lavoto 65:321-342 (1974). 16. Agarwal, D. K., Kaw, 4. L., SrivasUve, S. P., Seth, P. K. Some biochemical and histopathologic*! changes induced by polyvinyl chloride in dust in rat hmg. Environ. Res. It: 388341 (1978). 16. Ward, A. M., Udnoon, S,, Watkins, 4., Walker, A. E., Darke, C, S. Immunological mechanisms in the pathogens- sis of vinyl chloride disease. Brit Mad. 4.1:936-938 (1976). 17. Grainger, R. G., Walker, A. E., Ward, A. M. Vinyl chloride monomer-induced disease: clinical, radiological and immuno logical aspect*. In: Induced Diet***, Drug, Irradiation, Occupation. L. Prefer (ad.), Grune and Stratton, New York. I960, p. 191-814. 18. Langauer-Lewowicka, H,, Dodziak, Z., Bymkowaka, Z., and Marita, 4. Cryoglobulinemia in Raynaud's phenomenon due to vinyl chloride. Int, Arch. Oecup. Environ. Health 36: 197-297 (1976), 19. Crystal, R. G., Fulmer, 4. D., Roberta, W. C., Mosa. M,, Line, B. R,, and Reynold*, H. Y. Idiopathic pulmonary fibroaia: clinical, hiatolofic. radiographic, physiologic. sdntigraphic, cytologic and biocbomical aspect*. Ann. Intern. Med. 85: 768-788 (1976). 20. Tabenhaw, I. R. and Galley, W. R. Mortality study of workers in the manufacture of vinyi chloride and its polymer*. 4. Oecup. Med. 16:509-518 (1974). 21. Ott, M. G., Lengner, R. R,, end Holder, B. B. Vinyl chloride exposure in e controlled industrial environment. Arch. Environ. Health 30: 338389 (1975). 22. WaxweOer, R. 4., Stringer, W., Wagoner.4. JL, ud4<m*a. 4. Neoplastic risk among workera exposed to vinyl chloride. Amt. N.Y. Acad. Sd. 271: 40-48 (1978). 23. Mahotii, C. Preeuraor lesion* in exposed population* as indicators of occupational oncer risk. Ann. N.Y. Acad. Sd. 271:444-447 (1976). 24. Suzuki, Y. Pulmonary tumors induced in mice by vinyl chloride monomer. Environ. Re*. 16:286301 (1978). 25. Keplinger, M., Goode, J. W., Gordon, D. E., Csisndr*.J. E. Interim results of exposure of rats, hamsters, and mice to vinyl chloride. Ann. N. Y. Acad. Sd. 246:219-224 (1975). 26. Lee, C. C., Bhandari, 4. C,, Hauae, W. B., Peters, P. 4., Woods, 4., Dixon, R. L. Inhalation toxidty of vinyl chloride (VC) or vinybdine chloride (VDC) in rats and mice. Pharma cologist 18:246 (Ahetr. 718) (1976). 27. Hoimberg, B., Tronrvi. T., and Wlndl, M. The pathology of vinyl chloride expomd mice. Acta Vet Scand. 17: 328342 (1976). w October 1981 169 ucc 057210 1970 through 1978. The annual incidence rate for this period was also 0.25, almost double the expect ed rate of 0.14 per million in the United States (8), There are several possible explanations for these observations. New York is more industrialized than many other states, and it is possible that the exposed cohort might be larger. Increased recogni tion and reporting of this entity might also be a factor. Finally, relatively few workers have been exposed for a long time to high levels of vinyl chloride monomer. As Fox and Collier (i 7) point out, more than half of the people who have ever been exposed to VCM in the manufacture of PVC in Great Britain are currently employed in the industry; approximately 75% of men who have been employed in the industry have been employed for less than 10 years; only 8% have been employed for 20 years or longer, approximately half the persons who have been exposed to VCM have been intermittently exposed; and only 10% of those who have been constantly exposed have been exposed to high concentrations. Thus it is possible that we are only beginning to see the full impact of industrial exposure to VCM. This suggestion is supported by the observation of Monson et al. (18) that the relative frequency ofall cancers appears to be increasing with time in vinyl chloride workers. Other factors must also be considered in examin- ing the frequency of ASL in our society. Working conditions in the manufacture of PVC have un doubtedly been influenced since the early 1940s. This was largely due to the recognition after 1957 that exposure to high concentrations of VCM an cause acro-osteolysis (19) and Raynaud-like phe nomena, and in the early 1970s that high concentntions ofthis chemical increase the risk of dying from ASL (5). A reasonable assumption is that earlier workers were probably exposed to higher concen trations of VCM than those who entered this industry during the last decade. Interestingly, it has recently been suggested that the age at diagno sis and latency period for ASL might be increasing (75). If verified, these preliminary observations Tabic 1. Angiosarcoma of tho Hrar (ASL) in raaidefitt of Now York State (excluding New York City), 1970-1971 Year of ASL Exposure Caao Age Race* Sex diagnoaif hiltory* Metaetatk lite Other tumor* Type Year of Site diagram 1 60 W M 1870 Diraet, VC Adrenal, omentum 2 46 W F 1970 Poaaibk, VC Kidney, acaip, dura -- 3 46 w M 1970 Bona, adrenal -- 4 18 B F 1970 -- Spleen, lymph node* -- 5 66 W F 1971 Spleen, omentum, adrenal*, lymph nodaa --* 6 88 w M 1971 -- Lymphoetreom* Ileum 1955 7 4)12 w F 1971 -- Lung*, adrenal*, akin -- 8 81 0 F 197* Poecibk, VC Heart, brain, tungi, adrenal* ___ S 10 77 84 - w w M F 1972 -- 1972 Diraet, AS Spleen, marrow, lymph node* -- -- Fibromyxolipo- Knee 1969 ureotn* 11 47 w M 1972 Direct. ThO, Brain, lymph node* Metenchyuoma Liver 1973 -- 12 12 81 82 w w F M 1972 Poaaibk, VC Spleen 1972 -- Spleen, panere**, adrenak, -- Traditional Bladder 1973 14 SO w M 1972 brain, bona, lung*, lymph node* cell carcinoma _ ___ IS 21 w F 1974 Poaaibk, VC ___ -- IS 42 w M 1974 -- 17 82 w F 1974 _ ___ 18 66 w U 1975 Diraet. VC -- ___ IB 72 w M 1975 ___ -- 20 42 w M 1977 -- Spleen, brain, lung*, duodenum 21 64 w F 1977 ___ 22 82 w M 1977 ___ 22 82 w F 1978 * ___ -- 24 46 w M 1978 -- -- -- *W White; B * black, O oriental. "VC vinyl chloride, PVC - poiy(vinyl chloride), Aa anenk, ThO, thorium dioxide; posiible lived within one mile of VC or PVC factory. 208 Environmental Health Perspectives ucc 057211 OM* Thir n of of all vinyl unin`kin; * un- 940,. 1957 I can phentrafrom arlier ncenthis Iv, it <*gnoasing itions ? 1955 1969 1973 1973 iCtivM -jrht be of great importance in evaluating the possibility that lower doses of VCM might be ttMciated with ASL after a prolonged latency wriod. Apart from the risk of ASL associated with industrial exposure to VCM, the possibility exists jut nonoccupational exposure might also be asso rted with ASL. Block (20) has suggested that this disorder might result from chronic low level expo sure to this chemical. Landrigan and Heath (21) found cases of ASL among workers at two polyfvinvl chloride) fabrication plants and in residents living nearby. A study in New York State (16) found that five individuals with ASL (but no apparent occupational exposure to VCM) lived in closer proximity to polymerization and fabrication plants than their matched controls. In a study of 10 patients with ASL in Wisconsin (22), one patient lived near a chemical company that made plastics and resins. These observations might be fortuitous and must be tempered by the preliminary evidence suggesting that no excess of ASL is found among PVC fabricators (11). At present there is no conclu sive evidence associating this tumor with nonoccu pational exposure to VCM. However, this issue and a closely related one--that chronic low dose expo sure might be associated with an increased risk of ASL--require further evaluation. To fully appreci ate the potential magnitude of this issue, one must consider both residential proximity to plants and other potential sources of public exposure. Esti mates have been made that 4.6 million people live within five miles of United States monomer and polymer production facilities (23). During the yean of uncontrolled emissions, it was calculated that the average exposure level to this population was approximately 17 PPB (23). Household use of aerosol products in enclosed spaces, even in short 30-sec bursts, could result in sir concentrations of VCM as high as 400 ppm which can persist several hours after spraying (9,10). The Biologic Spectrum of Vinyl Chloride Reference has already been made to the associa tion between VCM and acro-osteolysia, Raynaudlike disorders and ASL. It is also clear that this agent can induce nonmalignant liver disease. In Russia a form of chronic hepatitis was found in approximately 25% of VCM workers (24). In addi tion, Thomas et al. (25) documented the occurrence ofport*] hypertension associated with hepatic fibrosis fBanti s syndrome) in s study of the hepatic tissues obtained from 20 workers with industrial exposure. October 1981 Of great concern is the growing evidence sug gesting that the spectrum of disorders associated with VCM might include certain other neoplastic diseases, pneumoconiosis and possibly excess fetal loss. Several mortality studies have been conducted in recent years. Monson et al. (18) found an apparent excess of lung and brain cancers. A slight excess of digestive tract, lymphatic and hematopoi etic tumors was also observed. A historical pro spective mortality study of 8384 men who had at least one year of occupational exposure to vinyl chloride demonstrated that cancers of the digestive system (primarily ASL), respiratory system and brain and lymphomaa occurred more often than expected in those members with the greatest estimated exposure (26). Similar results were ob served by Waxweiler et al. (27) in a retrospective cohort study of workers from four plants engaged in the polymerization of vinyl chloride for at least 15 years. Although observed numbers in each of these studies are quite small, the strength of these observations he in their consistency. In addition inhalation studies by Viola et al. (28), Maltoni (29) and Neplinger et al. (60) have demonstrated that this chemical induces adenomas and adenocarcino mas of the lung, neuroblastoma of the brain, lymphoma and various other tumors in a variety of animal species. Two other studies are notable for the different results obtained. A mortality study of over 4000 deaths among current and former em ployees of 17 PVC fabricators from 1964 through 1973 found an excess of cancers of the breast and urinary organs among white females (31). Fox and Collier (17) studied 7000 men who were at some time between 1940 and 1974 exposed to VCM and found no evidence to support the hypothesis that cancers other than those of the liver are associated with this agent. Vinyl chloride inhalation or PVC might cause abnormalities of pulmonary function and chest x-rays (32, S3). Szende et si. (34) was the first to describe pneumoconiosis due to PVC. Although PVC dust appears to be the major offender, Lilia et al. (32) showed that inhalation of this agent induced less severe respiratory function abnormalities than simultaneous inhalation of VCM and PVC. In a more recent study of 1216 PVC production work ers, 20 cases of pneumoconiosis were found. Dura tion of exposure was about 12 years, on the average, and never less than five years (35), This study also suggests that pulmonary changes are directly related to PVC dust, while VCM exposure alone fails to cause these changes (65). Available evidence also suggests that VCM is mutagenic (36), and workers appear to have an excess of chromosomal aberrations in lymphocytes 209 UCC 057212 when compared to nonexposed controls (ST). Selikoff (S8) found that fetal death rates among wives of VCM workers ranged from seven to 14 per 100 pregnancies. Infante et al. (39) conducted a casecontrol study of the pregnancy outcome among wives of workers exposed to VCM and found a significant excess of fetal loss in the exposed group. While suggestive, these observations require verification, particularly in view of the many fac tors known to influence pregnancy outcome. REFERENCES 1. Airtnga. D. Primary Angiosarcoma* of the llvr, lnt Surf. 60: 196-203 (1975). 2. McMahon, H. E., Murphy, A. S., Bate*, M. Endothelial-call sarcoma of the liver following Thorotraat injections. Am. J. Pathol. 23: 585-695, (1947). 3. DaSilva Horta. J. Lata laaions in man caused by colloidal thorium dioxide (Thorotraat). Arch. Pathol. 62; 403-418, (1966). 4. Roth, F. Chronic arsenic poiaoninf in vinayird worker* of the Moselle with apodal reference to arsenic cancer. Z. Krebaforch, 61: 287-319, (1956). 5. Lander, J. J., Stanley, R. J., Sumner, H. W,, Boswell, D. C., and AACH, R. D. Angiosarcoma at the liver associated with Fowler'* solution (potassium arsenite). Gastroenterol ogy, 68: 1582-1586 (1975). 6. Creech. J. L., Jr., and Johnson. M. N. Angiosarcoma of the liver in the manufacture at polyvinyl chloride. J. Occttp. Med., 16: 150-151 (1974). 7. Lee, F. I., and Harry, D. S. Angiosarcoma of the liver in a vinyl chloride worker. Lancet i: 1816-1318 (1974). 8. Heath, C. W., Falk. H., and Craach, J. L., Jr. Characteris tic* of cats* of angiosarcoma of the liver among vinyl chloride workers in the United States. Ann. NY Acad. Sd. 246: 231-236 (1975). 9. 1ARC Monographs on the Evaluation at Carcinogenic Risk of Chemical* to Man, VoL 7. International Agency for Research on Cancer, Lyon, 1974, pp. 291-806, 10. Key. M. M., Henachel, A. F,, Butler, J., Ligo. R. N,, and Taberahaw, 1. R. Occupational Disease* A Guide to Their Recognition. U.S. Deportment at Health, Education and Welfare, Washington, D.C., 1977, pp. 219-221. 11. Baxter, P. J., and Fox, A J. Angiosarcoma of the liver as the certified cause of death 1968-1973. Lancet tt: 27-28 (1975). 12. Falk, H. and Waxwsilsr, R. J. Epidemiological studies at vinyl chloride health effect* in the United Stats*. Proc. Roy. Soc. Mod., 69: 303-806 (1976). 13. Anon. Editorial: vinyl chloride end oncer. Brit. Med. J. 1; 590-591 (1974). 14. Hammond. E. C. and Stttkcff, 1. J. Two death* of a rare esneer. Occup. Heshh Nursing 22. 17-19 (1974). 15. Spirtas, R. and Kaminski, R. Angiosarcoma at the liver in vinyl chloride/polyvinyl chloride worker*. J. Occup. Med. 20: 427-429 (1978). 16. Brady, J., Liberator*, F., Harper, P.. Greenwald, P., Burnett, W., Device, J. N. P., Bishop, M., Folan, A., and Vienna, N. Angiosarcoma of the liver, an epidemiologic survey. J. Natl. Cancer Inst., 59: 1383-1385 (1977). 17. Fox, A. J. and Collier, P. F. Mortality experience of workers exposed to vinyl chloride monomer in the manufac ture of polyvinyl chloride in Great Britain. Brit. J. Ind. Med. 34:1-10 (1977). 18. Monson, R. R., Peter*, J. M., and Johnson, M. N. Propor- 210 tional mortality among vinyl-chloride workers. Lam 397-398 (1974). 19. Lester, D., Graenburg, L. A., and Adam;. W. R. Effu0' single repeated exposure at humans and rats to rav chloride. Am. Ind. Hyg. Assoc. J. 24:265-275 (1983). 20. Block, J. B. Angiosarcoma of the liver following chloride exposure. J. Am. Med. Aaaoc. 229: 53-54 (lift/ 21. Landrigan, P. J. and Haath, C. W., Jr., in preparation. 22. Fiechtner, J. J. and Reyes, C. N., Jr. Angioaarcom* of th liver in a rural population: four rases diagnosed in a month period. J. Am. Med. Aaaoc. 236:1704-1706 (1976). 23. Nicholson, W. J. Cancer following occupational exposure u asbestos and vinyl chloride. Cancer (suppl.) 39:1792-iaoi (1977). 24. Puadhin, G. A Affection at the liver and bile duct; x worker* engaged in the production ofsome type* ofpiattxt Sov. Med. 28:132-136 (1966). 25. Thomas, L. B,, Popper, H., Berk, P. D.. SeUkoff, I.. uS Falk, H. Vinyl-chloride induced liver disease. New EhU Med., 292:17-22 (1975). 26. Taberahaw, J. R., and Gaffey, W. R. Mortality attriy f workan in the manufacture of vinyl chloride sad *i monomer*. J. Occup. Med., 16: 509-618 (1974). 27. WaxweQer, R. J., Stainger, W., Wagoner, J. K., Jonaa J. Neoplastic risk among workers exposed to vinyl chloride Ann. N.Y. Arad. Sd. 271: 40-48 (1976). 28. Viola, P. L., Biogotti, A., and Caputo. A Oncogen reaponae of rat akin, lung* and bone to vinyl chteidt. Cancer Res. 31: 518-619 (1971). 29. Maltonl, C. Preliminary report on the carcinogenicity bnw says of vinyl chloride. U.S. Dept, at Labor. Informal Fan Finding Hearing of Possible Hazards at Vinyl Chloride Manufacture and Use, Washington D.C.. Feb. 1974. 30. Keplinger, M. L., Goode, J. W., Gordon, D. E., nd Caiandra, J. C. Interim results of exposure of rats, him sten, and mice to vinyl chloride. Ann. N.Y. Acad. Sd 244. 219-220 (1975). 31. Chaim*. L., Nichols, W. E., and Wong, O. Mortality among employees of FVC fabricators. J. Occup. Med., 19:623-Sb (1977). 32. LJUs, R., Anderson, H., Nicholson, W. J., Damn. S. Fiscfabein, A. S., and Selikoff, I. J. Prevalence of dbewc among vinyl chloride and polyvinyl chloride worker*. Am N.Y. Arad. Sd. 246:22-41 (1975). 33. Miller, A, Tirstein, A S,, Chuang, M.. Selikoff. I. J.. ad Warahaw, 1. Changes in pulmonary ftinction in werktn exposed to vinyl and polyvinyl chloride. Ann. N.Y. Acad. Sd. 246: 42-52 (1976). 84. Sxende, B., Lapis, K., Nernes, A., and Pinter, A. Pnetom eonioais caused by inhalation of polyvinyl chloride dud Med. Uv. 61: 488-486 (1970). 36. Mastrangelo, G., Manno, M., Marcer, G., Bartolucd. G. B.. Gemignani, C., Saladino, G., Simonato, L,. and Spia. B Polyvinyl chloride pneumoconiosis: epidemiological study tf exposed workers. J. Occup. Med. 21: 540-542 (1979). 36. Baruch, H., MalaveiHe, C., and Montesano. R. Human, nt and mouse liver-mediated mutagenidty of vinyl chlonde is 5. typkimurium strains. Inst. J. Cancer, 15.429-137 (19751 37. Funea-Cravioto, F., Lambert. B., Lindtten. J., Ehrenbnt L., Natarajan, A T., and Osterman-Golkar, S. Chrcme am* abbentions in worker* exposed to vinyl chlonde Lancet, 1: 459 (1976). 38. Selikoff. I. J. Paper presented at N1EHS Conference oe Public Health Implications of Component of Plastic; Mum- facturt, Pinehum, N.C., July 1974. 39. Infante, P. F., Wagoner, J., McMiehael, A.. Waxweiler. B. J., and Falk, H. Genetic risk* of vinyl chlonde. Lancet, t 734-736 (1976). Environmental Health Perspective* ucc 057213 Enuironmtntal Health Pertpectivtt Vol. U, pp. 211-2*0,1981 * of y! Iht a* >. *j ' tr, K* wd LJ. ' of iu fc, ?TUf de. art Hie a a,. it: Oftf & s., Iff von. and cid motut, B.. B. yaf rst m 75). erg. pIDOide. - on wu, R. ves Review of Experimental Carcinogenesis by Compounds Related to Vinyl Chloride by Kenneth C. Chu* and Harry A. Milman* Th* experimental esrrinogenwif multi on ix compound* related to rtajl chloride are reported. Vinyliden* chloride, riven by inhalation, was careinocenic in male CD-I mice, male CD rat*. Sprague-Daiy rat* and male Swim mice. Trichloroethylene, riven by carafe and inhalation, wai carcinogenic in the B6C3F1 mice. When given by ravage, perehloroethylene waa carcinogenic in the B6C3F1 mice, and dichloroethane wae carcinogenic in Ofborne-Mendel rata and B4C3F1 mice. Dibromoethane. given by gavage and inhalation, wai carcinogenic in BSC3F1 mice. F344 rata and Oehorne-Mendel rata. Finally, epichlorohydrfn waa carcinogenic in male Sprague-Dawley rata agtBSCSFl mke. Introduction Since the carcinogenicity of vinyl chloride (VC) was demonstrated in experimental (1) and epid emiologic studies (2), data on the potential carcino genicity of vinyl chloride structural analogs and related compounds have been increasing. This paper will attempt to review the experimental carcinoge nicity data on a number of these compounds, while another paper iS) will discuss the epidemiologic results. Hs /C' ,C=Cs HH Vinyl chloride VC Hv ,CI H Cl Vinylidene chloride VDC Cl C = CN H Cl Trichlorotfhyitn* TCI Cl Cl II AH-C-C-H H 1,2-Olchloroelhan# DCE Sr Sr II H-C-C-H II HH 1,2 -Oibromoothane DBE 'National Cancer Institute, Bcthcada, Md. 30206. 'Environmental Protection Agency, Washington D.C. 20460. October 1981 V/ v Cl Cl Tetrochloroelhyleno PCE H HH I II H-C-C-C-CI N/ I OH Epichlorohydrin EFC 211 ucc 057214 Results Vinylidene Chloride (VDC) A summary of some of the carcinogen bioassays of vinylidene chloride is given in Table 1. The strongest evidence of a carcinogenic effect was in a bioassay involving Swiss mice performed by Maltoni et al. U, 5). In this study, 24/150 dosed male mice had kidney turnon as compand to 0/190 in the controls. In the study by Lee et al. (6, 7), dosed CD-I mice and CD rats had two or three liver angiosarcomas. Since this type of tumor was in duced by vinyl chloride in humans and rodents and the study was terminated after only one year, the results an viewed as biologically significant. In an inhalation study in Sprague-Dawley rats by Maltoni et al. U, 5), increases in mammary gland tumors in the dosed animals wen reported. However, these incidences did not follow a dose-response relation ship. In contrast to these positive studies, a number of nonpositive two-year carcinogen bioassay studies have been nported (6-9). Most notable is this initial report that preliminary evaluations of vinylidene chloride in a two-year National Toxicology Pro gram (NTP)/NCI bioassay of Fischer 344 rats, given at 2-10 mg/kg of body weight and of B6C3F1 mice, given at 1-5 mg/kg of body weight, did not indicate any significant increased incidences of tumors in the dosed animals as compared to controls. Trichloroethylene (TCE) A summary of some of the carcinogen bioasssu oftrichloroethylene is reported in Table 2. In B6C3F] mice, this compound, given by gavage, was found to be carcinogenic, inducing hepatocellular turnon (10). In confirmation of this finding, an inhaivmr study in B6C3F1 mice, performed by Biotest Uboratories, gave similar results (ll). Bioassays of TCE were nonpositive in two strain* of rats, the Sprague-Dawley and Osbome-Mende! (10-lt). Additional NTP/NCI carcinogen bioassiv; are under way in five strains of rat and the B6C3F1 mice to examine species and strain differences. Tetrachloroethylene (Perchloroethylene) PCE The carcinogen bioassay results of testing PCE are given in Table 3. In B6C3F1 mice, this conpound, given by gavage, was carcinogenic inducing hepatocellular tumors. Studies in two strains of rats, Osbome-Mendel and Sprague-Dawley, produced no carcinogenic ef fects (1S-H). Additional carcinogen bioassays in four strains ofrats and the female B6C3F1 mice are currently underway at NTP/NCI. 1,2-Dichloroethane (DCE) The experimental carcinogenicity results of test ing DCE are given in Table 4. In B6C3F1 mice, the Spadec/Sti* Moum, CD-I Rat, CD Rat, Spr-Daw 212 Rout* (vehicle)* Inhal Inll lwK] Table 1. Bloacaayc of vinylidene chorid* (VDC). Doee Dosing period Group Taifet site (tuner Sea ppm (duration), wk tilt incidences)^ or mg'fcg* 11 SB 52D(52) 36 Liver, hemangjourcomi 0 * 36 (2/36 0/26) F 56 52D(S2) 36 Liver, hemangSccarroma 0 36 (1/36 0/86) M SB 521X52) 36 Hemangioearcwna 0 m 36 (2/36 0/36) F 56 0 521X5*2) 36 NSC 36 M 150 100 SZDa CU fe) 00 NSC 30 50 25 * #* 30 80 10 a 30 0 a 100 F 150 52D0Jfe) SO Mammary gland 100 a a 30 (nondoec response) 50 a 30 25 a a 30 10 aa 30 0 a 100 Refertim <,n (C.T) u# Environmental Health Perspective! ucc 057215 bioassa;. n BfiCjf'i ' as founii *J* tumor, nhalatior Labo- o strain, s-Mendf] 'ioassav, B6C3f] nees. ylene) npPCE lis comnducing Mendel emc efays in lice are ) .tce. the ;rence .ynnSU* Table 1 (emit.) Route Dose Dosing period Group Target site (tumor (vehicled Sex ppm (duration), wk Aizc incidences)* or mg/kg' Si X. Spr-Dw Hiaasr, Chin M jft B6C3F1 NCli Inhal Gav (Olive oil) M F 11 F Inhal Gav (Corn aU) M F M 25 10 0 25 10 0 20 10 5 0 20 10 5 0 25 0 25 0 10 2 Pj:*. F344 NCI) Pji. Spr-Dsw Pot. Spr-Dsw Ra. Viftar Rat, Spr-Drw F Gav '* (Com oil) U F Inhal M F Water M F Inhal Inhal M F U F 10 2 0 5 1 0 5 1 0 75 25 0 75 25 0 200 100 60 0 200 100 00 0 200-100 0 200-100 0 100 75 0 100 75 0 Chin - Chinese hamster, FS44 - Fischer 344 rat; Spr-Dsw Gsv = gavtgs; Inhal inhalation. Tnit,. ppm for inhalation; mg/kg for other routes. NSC * Not shown to be carcinogenic. Preliminary results. 52EKlife) m ma 52D(life) a4 *a 52D(life) 44 >4 m S2D0ife) aa * ** 52D(lif) ** 52D(life) 44 (103) * (108) * (108) * * (103) " 781X104) 781X104) " (104) 4 4 m (104) P 52D(104) 52D(104) 62DU04) aa a S2aD(1a04) aa 150 Kidney 30 (24/150 0/190) 190 150 NSC 30 190 50 NSC 50 50 50 50 NSC 50 50 50 30 NSC 30 30 NSC 30 50 NSC* 50 50 50 NSC* 50 50 50 NSC* 50 50 50 NSC* 50 50 86 NSC 85 86 86 NSC 84 88 47 NSC 48 48 80 47 NSC 48 48 80 51 NSC 80 28 NSC 30 30 NSC 16 30 SO NSC 21 80 Sprague-Dswley rat October 1981 Reference U. 5) U. J) U, 5) () () () () 213 ucc 057216 1 compound, given by gavage, was carcinogenic, in ducing lung tumors in both sexes and mammary gland and uterus tumors in dosed female animals (25). The chemical was also carcinogenic in Os borne-Mendel rats, giving forestomach tumors and extrahepatic hemangiosarcomas in both sexes, sub cutaneous fibromas in the males and manunan gland tumors in the females (25). In contrast, a preliminary report by Maltoni (n indicated that DCE was not shown to be carcino genic in an inhalation study with Swiss mice and Sprague-Dawley rats. Since there were strain and Sp Ri i S' Spedee/Str* Mouse B6C3F1" Route (vehidaF Gav (Corn oil) Mouee B6C3Fld Inhal d Rat, Oeb-Mdl" Gav (Con oil) Rat, Spr-Dmw Gav (Olive ofl) Rat, Chariet River* Inhal Rat, Marshall (NCI) Rat, ACT (NCI) Rat, F344 (NCI) Gav (Cam ofl) Gav (Conoil) Gav (Con oil) 214 Table 2. Bloaaaaya of trichloroethylene (TCE). Dote, Doaing period Group Target aite (tumor Sex mg/kg (duration), wk HZ* inddenccaF Rcfcrmn M 233V nev 0 78a0(9m0) a 50 Liver, hepatocellular so (31/48 26/50 1/20) 20 (10) F 1739 869 0 781X90) "* * 50 Liver, hepatocellular 50 11/47 4/50 0/20) 20 M 600 ppm (104) 300 ppm 100 ppm 0 " a a 100 Liver, hepatocellular 100 (43/97 31/100 28/95 18 99) 100 100 (11) F 600 ppm (104) 300 ppm * 100 ppm 0 100 Liver, hepatocellular 100 (13/99 9/94 4/100 6/99) 100 100 M 1097 549 0 78Da (1m10) * 50 NSC 50 20 (10) F 1097 549 0 781aX1a10) ** 50 NSC 50 20 M 250 50 0 521X140) ** 30 NSC 30 30 Hi) F 250 50 0 521X140) * ** 30 NSC 30 30 M 600 ppm (104) 300 ppm " 100 NSC 100 (11) 100 ppm 0 * 100 100 F 600 ppm 300 ppm (104) * 100 NSC 100 100 ppm 100 0 100 M 1000 500 0 (110) 50 Aaaay atm in program 50 St- 2/79 50 F 1000 500 (11a 0) 50 Aaaay etfllin program 60 0 50 M 1000 500 (11a 0) 50 Aaaay (till in program 50 St. 209 0 50 F 1000 500 0 (110) 50 Aaaay (till in prograai 50 * 50 M 1000 (110) 50 Aaaay (till in progreaa 500 50 St- 678 0 50 F 1000 (110) 50 Aaaay (tin in prograaa 500 0 a 50 50 Environmental Health Perspectfrn ucc 057217 (M Ri (S' b t r C do dif ie> tal 1,: ar> sp. inf tu: I*Dr he tu- tic canm im mi tuk. Ej in <k Table 2 (eont.) (Jj;, Osh-Md) NCI) Pit. August SCI) Pi:. B6C3F) NCI) Route (vehicle)11 Sex Doee, mg/kg Dosing period Group Target site (tumor (duration), wk uze incidences)* Gev M 1000 (Com oil) 500 0 F 1000 500 0 Gev M 1000 (Corn oQ) 500 0 F 1000 500 0 Gev M 1000 (Coro oil) 0 F 1000 0 (110) # (110) " (110) * (110) * * (110) (110) so Assay still in progress 50 St. 12(79 50 50 Assay still in progress 50 50 50 Assay still in progress 50 St. 10/79 so 50 Assay ttiU in progress 50 50 50 Assay still in progress 50 SC&78 50 Assay still in progress 50 FM - FiKhcr 344 rat; Osb-Mdl Osbome-Mendel rat; Spr-Daw - Sprague-Dawley rat. "Giv > gavage, Inhal " inhalation. 'NSC " Not shown to be carcinogenic. "With 0.09% epichlorohydrin. Reference ia dose differences s well as route of administration differences between the NTP/NCI and Maltoni stud ies. the causes of the differences in the experimen ts] results are not readily apparent. 1,2-Dibromoethane (DBE) The results of some carcinogen bioassays on DBE an given in Table 5. In bioassays on B6C3F1 mice and Osborne-Mendel rats, DBE given by gavage was carcinogenic, inducing multiple tumors in each species and sex. There were not only chemically induced turnon at the site ofapplication (farestomach tumors) Ljt also tumors distant from the site of application (lung turnon in mice and extrahepatic hemangiosarcomaa in male rats and hepatocellular tumors in female rats) (19). In addition, a preliminary analysis of an inhala tion study of DBE performed by NTP/NCI indi cates that nasal cavity tumors were found in dosed rats and dosed female mice. Furthermore, elevated incidences of lung turnon were found in the dosed mice as well as elevated incidences ofmammary gland tumors in dosed females of each test species. Meso theliomas were also induced by DBE in male rats. Epichlorohydrin (EPC) The bioassay results on epichlorohydrin are given in Table 6. Recently, this compound, given by October 1981 inhalation, was found to be carcinogenic inducing nasal cavity turnon in male rats (17). In addition, experiments by Van Duuren (18-19) indicated that EPC was an initiator in a two-stage study and induced local sarcomas by subcutaneous injection, addition more comprehensive epidemiological stud ies involving the manufacture, production and use of these compounds should be undertaken. A summary of some of the bioassay results for each compound by species/strain is given in Table 7. Discussion The data on these compounds can generate some interesting points for discussions, such as the prob able mechanism of some of these compounds, the controversy over TCE results and suggestions for future action. In the first case, studying the summary table indicates that the compounds (DBE, DCE, and EPC) which are proposed to alkylate directly, gave forestomach tumors when given by gavage or nasal cavity tumors when given by inhalation while the compounds which are proposed to require meta bolic activation did not produce these types of tu mors. One can envision that these compounds, due to their alkylating ability and their ability to induce site of application tumors, are direct-acting carcin ogens. Two of these former compounds, DBE and 215 ucc 057218 Tabic 3. Bioaaaayi of perchlorocthylene (PCE). Spedea/Str* Route (vehicle)* Sex Dose, mg/kg Dosing period Group Target site (tumor (duration), wk tise incidence*)' Moum B6C3F1 Gav M 1072 (Corn oil) 536 0 780D(90) m 50 Liver, hepatocellular 50 (27/48 32/49 220) 20 F 772 386 0 78D(90) 0 50 Liver, hepatocellular 50 (19/48 19/48 0/20) 20 Rat, Osb-Mdl Gav (Corn oil) M 941 471 0 71D(110) ** *' 50 NSC 50 20 F 949 474 0 7110X1010) 0m 50 NSC 50 30 Rat, Spr-Daw Inhal (Corn oil) M 600 ppm 300 ppm 0 521*X1*85) * 96 NSC 96 96 F 600 ppm 300 ppm 0 521PX1m35) 0m 96 NSC 96 96 Rat, Sherman Gav M 750 (103) 50 Aaaay (till in progress (NCI) (Com oil) 375 50 St 2/78 0 50 F 750 (108) 50 Assay still in progress 375 50 0 SO Rat. Wistar Gav M 750 (103) 50 Aaaay still in progress (NCI) (Com oil) 375 50 St. 11/78 0 50 F 750 (103) 50 Assay still in progress 375 50 0 50 Rat, Long-Evans Gav M 750 (103) SO Aaaay atdl in progress (NCI) (Com ail) 375 50 St. 7/78 0 so F 750 (103) 50 Assay still in progress 375 50 0 50 Rat, F344 Gav M 750 (108) 50 Assay still in progress (NCI) (Com ad) 375 50 St 9/78 0 50 F 750 (108) 50 Assay still in progress .. 375 50 0 50 Rat. B6C3F1 Gav F 300 (108) 100 Assay still in progress (NCI) (Com ad) 100 100 50 100 25 100 0 100 *F344 m Fischer 344 rat; Oab-Mdl Osbome-Mendel nt; Spr-Dsw Sprague-Dawley rat *Gav m savage; Inhal - inhalation. 'NSC " Not shown to be carcinogenic. Reference US) US) (Ji) DCE, also induced tumors distant from the site of application. This fact may be an important point in the controversy over TCE. This controversy stems from the fact that the results on TCE indicated that the mice studies were positive while the rat studies showed the chemical did not produce a carcinogenic effect. Then have been several explanations. It has been postu lated that epichlorohydrin, used as a stabilizer in the TCE tested, is responsible for the positive effect, not TCE (21). The NCI Technical report on TCE (JO) indicated that there was 0.09ft EPC in Environmental Health Perspective* ucc 057219 Tabic 4. Bieaaaay* of 1,2-dkhlomcthaiie (DCE). I I.fl Sptoti'Str* Mouse. B6C3F1 Rat, Osb-Mdl House, SwiM JUt, Spr-Otw Gav (Com oil) Gav (Com oil) Inhal Inhal Doae, Doting period Group Target aite (tumor Sex mg/kg (dilution), wk eiie mrideneeaF Ref erence M 195 97 781X9#1) 0 F 299 149 781X91) 0 M 96 691X110) 47 m 0 F 96 891X93) 47 (110) 0 M 250-150 ppm SO ppm (life) 0 10 ppm 0 5 ppm 0 00 F 260-150 ppm (life) SO ppm * 10 ppm 0 5 ppm 0 00 M 250-150 ppm 50 ppm 10 ppm 6 ppm (life) " m m 0* F 250-150 ppm 50 ppm (life) " 10 ppm 5 ppm " 0 50 Lung 50 (15/48 1/47 0/19) 20 so Lung (15(48 7(60 1(20) 50 Mammary gland (7/48 9(50 0/20) 20 Uterus (5(47 5(49 0/20) 50 Foewatomach (9/50 8(60 0(10) 60 Hemangjoaareoma (7/60 9/80 0(20) 20 SQ Fibroma (6/50 5(60 020) 50 Mammary gland 50 (18(60 1/60 040) 20 90 NSC* 90 90 90 180 90 NSC* 90 90 90 180 90 NSC* 90 90 90 90/180 90 NSC* 90 90 90 90/180 (15) (15) at) at) *0ib-Mdl Otbome-Mendel rat; Spr-Daw Sprague-Dawley rat. Giv > Ravage; Inhal inhalation. *NSC Not shown to be carcinogenic. ^Preliminary rtaulta. the TCE. The doses of TCE were about 2000-1000 mgftg of body weight, corresponding to less than 2 ragkg of body weight of epichlorohydrin. If epich lorohydrin is the active agent, one might expect forestomach tumors from a gavage study because of its alkylating ability. However, the target site in the mice is the liver. In addition, if epichlorohydrin is the carcinogen, then why are the results negative in the rat? Direct-acting carcinogens, like epich lorohydrin, are less likely to show such a species difference than compounds which would require metabolic activation, such as TCE itself. Thus, an alternative explanation is that there is a species difference reflecting some type of metabolic or tar get site sensitivity difference between the species. The answer may be forthcoming. NTP/NCI is testing TCE without EPC in the B6C3F1 mice and five strains of rat. If EPC is the active compound, the mice study should not show a carcinogenic effect. However, if TCE is the active agent then the B6C3F1 mouse study should be positive. The results in the rats will also give insight into whether there is a species or a spedes/strain difference for TCE. Similar types of studies are also underway with PCE. In addition, Maltoni has indicated that he has started bioassays on TCE with B6C3F1 mice and Swiss mice. With the possible resolution of the TCE issue, there still remains the differences in experimental results involving vinylidine chloride (VDC). The results in VDC may indicate that there are impor tant species and strain differences. As a conse quence, this compound may be an ideal candidate for studying species/strain differences systematical- October 1981 217 UCC 057220 4 Table 5. PIitimiji of 1,2-dibromethane (DBE). Spedes/Str* Route (vehicled Sex Daee, mg/kg Dosing period (duration), wk Group Target site (tumor sue incidences) Mouse B6C3F1 Gav (Com oQ) M F Rat, OsbJidl Gav (Com oil) M F Mouse B6C3F1 (NCI) Inhal M F Rat, F344 (NCI) Inhal M F 107 82 0 107 82 0 41 38 0 89 87 0 40 ppm 10 ppm 0 40 ppm 10 ppm 0 40 ppm 10 ppm 0 40 ppm 10 ppm 0 53D(78) ' 531X9# 0) (80) 341X49) 47IT (88) 440(61) 571r (88) (108) m w (108) (108) m (10ft8) 50 Forestomach (29/4945/500/20) 50 Lung (10/47 4/45 0/20) 20 60 Forestomoch (28/5046/490/20) 60 Lung (8/46 11/48 020) 20 60 Fomtomach (33/6045/500/20) 80 Hemangicsarcama 20 (4/60 11/60 020) 60 Forastomach(29/5040/50020) 60 Liver, hepatocellular 20 (6/481/47 020) 60 Lung (19/46 3/48 0/41)* 60 60 60 Natal cavity (6/50 0/50 020)* 50 Mammary gland (8/80 14/80 2/50)' 50 Lung (37/60 6/49 1/491* 60 Natal cavity (28/6020/500/30)* 80 Mesothelioma 50 (26/60 7/60 1/80)* 50 Nasal cavity (29/5020/500/S0F 60 Mammary gland 60 (24/60 29/60 4/60)* *F344 * Fischer 344 rat; Oib-Mdl - Otborne-Mendel nt *Gav * gavage; Inhal - inhalation. *Prelirain*ry result*. (10 Table I. Bloomy* of epichlorohydrin (EPC). Spedes/Str* Route (vehicle)* Sex Doee Doting period Group Tenet site (tumor (duration), wk its* incideneeef Reference Rat, Spr-Dsw Mouse, ICR/Ha Swiss Mouse, ICR/Ha Swisa Mouat Mouse. C3H Mouse, ICR/Ha Mouse, 1CR/Ha yh*i SC SC Skin SMw SUa IP M 100 ppm 30 ppm 0 6D(life> (Hfc) F 1 mg in 0.1 ml (life) tricatvyUn wkiy F 1 mg in 0.06 ml (Ufa) tricapryUn wkiy 1 mg in 0.1 ml 1 doee acetone than 2.5 g pborbot 56D myrtstste* me IBr (lift) F 2 mg in 0.1 ml 571X57) acetone 8/wk F 1 mg in 0.06 ml (64) tricaprylin wkiy 140 Nasal cavity 100 (15/140 2/100 0/100 0/60) 100 60 60 Local sarcomas (2/50 0/50) 60 Local sarcomas (7/60 1/60) 30 Initiator (10/30 320) 40 NSC SO NSC 30 NSC a 7) un (10 US) m US) US) Spr-Daw - Sprsgue-Dawley rat. bIP m intr*peritoneal injection; SC * tubcutanoou* injection; Skin - akin pointing. 'NSC " Not shown to be carcinogenic. 218 Environmental Health Perspective! ucc 057221 Table 7. Summary of Moaaaay muiU on vinyl chloride analon and related compound* for come tumor rite*. -- VC VDC TCE PCE DCE DBE ECH HcmingioUJWltl* Lunf tumor* summary (Und tumor* female)) Kidney turnon Hrptocellular turnon forenomach tumor* Nittl ctvity tumors Local urcoma SDRat-G Mouae-I* Rat-I* Mouae-I* Rat-I* Mouae-I* m-CD-1 Mouae-I m-CD Rat-I SD Rat-I m-Sw Mouao-I B6C3F1-G B6C3F1-I NSC F344 Rat-G1 OMRat-G B6C3F1-G" SD Rat-G Wit Rat-I CR Rat-I Ch Ham-1 SD Rat-W SD Rat-I SDRat-G B6C3F1-G OMRat-G SDRat-G m-OM Rat-G m-OM Rat-G B6C3P1-G OMRat-G B6C3F1-G B6C3F1-G B6C3F1-Gb F344 Rat-Ib B6C3F-Ifc f-OM Rat-G m-OM Rat-G OMRat-G B6C8F1-G F344 Rat-Ib f-B6C3Fl-Ib SD Rat-I Sw Mouae-I m-SD Rat-I f-ICR/H* Sw Mouae-SP 'Effect seen in at leaat two atnina. 'Preliminary mult* on NTP/NCI atudiea. ly. In addition, the differences in the NCI and .Malton: studies on DCE could be the source for additional research. Front an examination of Table 7, the compounds with positive results in multiple species yielding multiple tumor sites are the direct acting carcino gens, DBE and DCE. (EPC has not been tested extensively yet.) This strong evidence in experi mental carcinogenesis should, at least, trigger mea sures to decrease exposure to these compounds. In addition more comprehensive epidemiological stud ies involving the manufacture, production and use of these compounds should be undertaken. REFERENCES 1. Viola, P. L,, Bigott, A., and Capoto, A. Oncogenic maponao of rat akin, lung*, and bonaa to vinyl chloride, Cancer Rea. 31; 316-522 (1871). 2 Infante, P. Multiple rite risk analyria of vinyl chloride reh .ed cancer in workan-review. Environ. Health PenpacL 41: '100 (1961). 1. Apfeldorf, R. and Infknte, P. Review of epidemiological ituiiy reauha of vinyl chloride related compound*. Environ. Health Penpect. 41: 000 (1961). 4. Haltoni, C., Cotti, G., Moriai, L,, andChieco, P. Carcinoge nicity bioaaiayi of vinylidene chloride: Reaearch plan and early result*. Med. Lav. 68: 241-262 (1977). 5. MaJtoni, C. Recent finding* cm the carcinogenicity of chlori nated olefin*. Environ. Health Perapect. 21:1-6 (1977). 1 Lee, C. C., Bhandrai, J, C., Winaton, J. M., Houae, W. B., Dixon, R. L., and Wooda, J. S. Carcinogenicity of vinyl October 1981 chloride and vinylidene chloride. J. Toxicol. Environ. Health 4:15-30(1978). 7. Lae, C. C,, Bhartari. J. C., Winaton, J. M., Home, W. B,, Peter*, P. J., Dixon, R. L. and Wooda, J. S. Inhalation toxicity of vinyl chloride and vinylidene chloride. Environ. Health Panpect. 21: 2532 (1977). 8. Rampy, L. W., Quaat. J. F., Humiaton, C. G., Babner, M. F., and Schweu, B. A. Interim reaulta of two-year toxico logical atudiea in rata of vinylidene chloride incorporated in the drinking water or administered by repeated inhalation. Environ. Health Penpect. 21: 33-43 (1977). 9. Viola, P. L., and Caputo, A. Carcinogenicity atudiea on vinylidene chloride. Environ. Health Penpact. 21: 45-47 (1977). 10. National Cancer Inatitute (NCI). Carcinogeneai* baoaaaay of trichloroethylene. NC1-CG-TR-1 DHEW/Pub/NIH-76302, 1976. 11. Bell, Z. G., Oiaon, K. J. and Benya, T. J. Final report of 219 ucc 057222 1 I audit findingi of Manufacturing Chemists Association (MCA) administered trichloroethylene chronic inhalation study at Industrial Bio-Test Laboratories, Nov. 1978. 12. Maltoni, C. Carcinogenicity bioassays of vinyl chloride monomer. A model of risk assessment on experimental basis. Environ. Health Perspsct. 41:000 (1961). 13. NCI. Bioassay of tetrachloroethylene for possible carcino genicity. NCI-CG-TR-13 DHEW/Pub/NIH-77-813 (1977), 14. Rtunpy, L. W., Quaat, J. F., Leong, B. K. J. and Gehring, P. J. Results of long term inhalation toxicity studies on rats of 1,1,1-triehloroethane and perchloroethytene formulations. Paper presented at International Congress on Toxicology, Toronto, Canada: Abstracts, p. 27 (1977). 15. NCI. Bioassay of 1,2-djchloroethane for possible carcinoge nicity, NCI-CG-TR-44 DHEW/Pub/NIH-78-1361.1978). 16. NCI. Bioassay of 1,2-dibromoethane for possible carcinoge nicity, NC1-CG-TR-86 DHEW/Pub/NIH-78-1338, 1978. 17. Laekin, S., Sellakumor, A. R., Kuschner, M., Nelson, N., La Mendola, S., Ruach. G. M., Katz, G. V.. Dulak. N. f and Albert, R. E. Inhalation esrdnogenidty ofepkhlorohYdnn. In pres*. 18. Van Ouuren, B. L., Goldschmidt, B. M., Katz, c. Seidmann, I., and Paul, J. S. Carcinogenic activity tf alkylating agents. J. Natl. Cancer Inst. 53: 695 (1974). 19. Van Duuren, B. L., Katz, C., Goldschmidt, B. M.. Frenkel, K., and Sivak, A. Carcinogenicity of halo-ethers II. Structure-activity relationships of analogs of biMchloromtthvii ether. J. Natl. Cancer Inst. 48:1431-1439 (1972). 20. Weil, C. S., Condra. N., Haun, C,, and Striegel. J. A. Experimental cardnogenicity and acute toxicity of reptvsentative epoxides. Am. Ind. Hyg. Assoc. J. 24: 305-32s (1963). 21. Henschler. D., Eder, E., Neudecker, T., and Metzler. V. Cardnogenicity of trichbroethylene: fact or artifact? Arch. Toxicol. 37: 233-286 (1977). t* 220 Environmental Health Perspective* ucc 057223 Environmental Health Perepectivte Vo/. 11, pp. til-tie, ItSl Review of Epidemiologic Study Results of Vinyl Chloride-Related Compounds by Rosanne Apfeldorf* and Peter F. Infante* Epidemiologic study rtralte addressing the carcinogenicity of six compound! related to vinyl chloride (rinyliden* chloride, trichloroethylene, perchloroethylene, carbon tetrachloride, ethyl* ene dibromide and epichlorohydrin) are reviewed. Thestudy result* suggest an increased carcinogenic risk among workers exposed to epfchlorohytbin and to dry cleaning and degreasing solvent*. Although ecverai etudiee report no significant cxceaa of cancer mortality, an evaluation of the design of theee inveeticatione demonetratee that theae nerative cohort etudiee coneieted of population* of insufficient earnpie eixe and latency to permit any meaningful contusions regarding carcinogenic riek. Therefore, experimental etudiee muat be relied upon to determine whether ecverai of thee* eubetancee poee a potential carcinogenic riek to humane. Available evidence indicate* that all of theee eubetancee have demonetrated a carcinogenic reeponae in experimental animate and moct are mutagenic in experimental text eyetoma. Introduction In the early 1970's, bioassays demonstrated the induction of cancer at multiple sites in experimental animal? exposed to vinyl chloride (VC) by several routes ofadministration. Subsequently, epidemiologic studies confirmed an excess cancer risk of multiple sites among individuals employed in operations using VC (1). As s result of these observations, attention was focused on the toxicity of structural analog? of vinyl chloride. This review will present information on the potential for human exposure and the carcinogenic risks associated with exposure to these substances. Magnitude of Exposure Studies of occupational groups exposed to six VC-related substances have been conducted. Esti mates of the annual production, number of worker exposures derived from 1972-74 National Occupa- 'Office of Carcinogen Identification and Classification, Health Standard* Programs, Occupational Safety and Health Adminiatrttion. U.S. Department of Labor, Washington, D.C. 20210. The opinion* expressed in this paper reflect those of the authors ind are not necessarily those of the Occupational Safety and Health Administration. tional Hazard Survey data and current OSHA permissible exposure limits expressed aa 8-hr timeweighted averages (TWA), for levels of occupa tional exposure to these substances are presented in Table 1. These substances are produced in high volume, and exposures involve large numbers of workers. As some of theee substances were not produced in relatively high volume until the 1950's (), the latency period required for the statistically sensitive evaluation of any potential cancer risk in the exposed individuals has not yet been achieved for a large proportion of exposed individuals. Table 2 presents occupations and industrial uses for six substances structurally or industrially re lated to VC. Epichlorohydrin (ECH) is used in the manufacture of epoxy resins and has been used as a chemical stabilizer in trichloroethylene (TCE) and in plastics. Vinylidene chloride (VDC) is used in the manufacture of copolymers and fibers. Ethylene dibromide (EDB) is used in the manufacture of petroleum products and as a pesticide. TCE, per chloroethylene (PCE) and carbon tetrachloride (CCU) are used in metal degreasing operations. Although TCE and CCU hove been used as dry cleaning solvents in the past, PCE is the major dry cleaning solvent in use today. Experimental evidence now demonstrates that many of the compounds structurally and industri- October 1981 221 ucc 057224 ally related to vinyl chloride are carcinogenic (3). Many of these substances are also mutagenic U, 5). Bioassay study results have demonstrated the induction of tumors at multiple sites as a result of exposure to EDB and CCI4. Cancers of the respira tory tract have been induced in experimental ani mals exposed to EDB and ECH. Liver cancers have been induced in animals exposed to VDC and EDB as well as to the industrial solvents TCE, PCE and CCl* While these experimental studies were being conducted, the Interagency Regulatory Liaison Group (IRLG) was drafting documentation guide lines for epidemiologic studies (). Also during this time, hearings on OSHA's cancer policy were proceeding, with much emphasis given to the role of nonpositive epidemiologic studies in qualitative risk assessment. The epidemiologic considerations, expressed in the IRLG guidelines and discussed in the OSHA cancer policy (7) will be used in this paper to assess the methodology and results of several epidemiologic studies of populations poten tially exposed to one or more of the structural analogs of vinyl chloride. Epidemiologic Study Results A study of workers exposed to ECH was reported by Enterline in 1978 (8). These data were analyzed by using the NIOSH life table program (9) and are presented in the summary data table (Table 3). Members of the cohort were employed for more than one quarter ofa year any time between I9t8 to 1986, and followed through the end of 1977. Ex pected numbers of deaths were based on U.S. age, sex, race and calendar tune-period specific rates Ninety-four percent of the employees had achieved a minimum of IS years of latency. Fifty-one deaths from all causes were observed, and 82 were expect ed. Thirteen deaths due to cancer were observed compared to 14.2 expected. Though not statistically significant, a doubling of the lung cancer risk was observed among individuals who had achieved 1 latency period of at least 15 years since fint exposure to ECH. For the entire cohort, eight lung cancers were observed when 4.9 were expected These data suggest that workers exposed to ECH may be at an increased risk of lung cancer, but further follow-up ia necessary to in order to achieve Tablt 1. Eatimete* of U.S. annual production, number of worker expoeurea, and OSHA time-weighted averages for VC aid structural analof*. Carcinogenic substance Annual U.S. Estimated number of production, lb x 10* worker exposure* OSHA TWA. ppm' Epichlorohydrin (ECH) Vinyiidene chloride (VDC) Trichloroethylene (TCE) Perchloroethylene (PCE) Carbon tetrachloride (CCU) Ethylene dibromide (EDB) Vinyl chloride (VC) 2vr 200* 800' 770* 70S* Off 7544* 86,000 6,600-68.000 282,000 600,000 160,000-2,000.000 9,000-660,000 27,000-2,200,000 6 None 100 100 10 20 1 'International Tnde Commission aatimate*. TWA - 8-hr tima-wtigbtad averagt. '1978 estimate*. *Yar not available. *1978 ttimate*. Table L Industrial uaca and potential occupation* with exposure to ala carcinogenic aubatanco*. Substance* Manama** Major occupational exposure induatrie* ECH VDC TCE PCE ca EDB Manufacture of epoxy reain*, surface active agent*, and other chemical* Manufacture of copolymer* and modacrytic Abort Metal degreasing, organic aolvent Drv cleaning and textile*, metal cleaning, chemical manufacturing Chemical manufacturing, grain fumigation, organic aolvent Fumigant, fUet additive, organic aolvent Aaaembicn, machiniata, painter*, chemical worker* Chemical workera, plaatic* worker* Chemical workers, mete! workers, textile processing Dry cleaners, chemical workers, textile w orkers, metal workers Chemical workers, grain ftunigatora Chemical workers, petroleum products, exterminators and ftunigstors See Table l. 222 Environmental Health Perspectives ucc 057225 a more sensitive estimate of the carcinogenic risk in humans. Several factors should be considered in evaluating these data. Some cohort members had been employed in the manufacture of isopropyl iJcohol (IPA). This process has been associated ith nasal sinus cancer, but the data to date have not demonstrated an excess of lung cancer among workers employed in the manufacture of IPA. In addition, the size of the cohort was small, and the iverage age of the cohort members during the followup period was only 48 years. The young age of the cohort is reflected in the low SMR of & for the entire cohort. Nevertheless, the data appear to be consistent with results of experimental bioassay which demonstrate ECH-induced cancers of the respiratory system. Shellenberger et al. (10) reported on the mortal* itv experience of 553 white male employees poten tially exposed to ECH for at least one month between October 1957 and November 1976. Ex pected numbers of deaths were based on death rates for the Texas white male population for 1960 and 1970. Cause-specific observed and expected deaths and standardized mortality ratios for the entire cohort and for a subcohdrt employed in at least one job with a TWA of greater than 1 ppm were calculated. Twelve deaths were observed among cohort members, compared to 20.7 expect ed. No specific cause of death was in excess. Only two cancer deaths were observed compared to 3.5 expected. This cohort has not been observed for a long enough time period, as only 13% of the cohort had a latency of 15 or more yean since employment. Ott et al. (11) reported on the mortality experi ence of 138 employees exposed to VDC at any time between 1942 and 1968 and followed through 1973. Mortality among the exposed group was compared to the expected based on U.S. white male mortality rates. Five deaths were observed, compared to 7.5 expected. Only one cancer death was observed, compared to 1.1 expected. Clearly, the sample size is too small to allow any meaningful conclusion. Axelson et al. (IS) reported on the mortality experience of 518 male workers exposed to TCE in the 1950's and 1960's and followed through 1975. Eleven deaths from cancer occurred in the total cohort when 14.5 were expected. Among the subcohort who had achieved at least 10 years since first exposure, 9 deaths from all cancers were observed compared to 9.5 expected. The number of deaths from tumors are too small to analyze by site specific risk. Table 3. Observed and expected death* from rtudte* of worker* exposed to selected haiocenatad hydrocarbon*. Suboiace ECH Study Total daatha Ob*. Exp. SMR Enterline (S) 51 81.7 68 Brown and Rinsky (S) Total cancer death* Ob*. Exp. SMR 13 14.2 92 Subcohort * IS yr as 44.6 74 latency ECH Shellenberyer (10) 12 20.7 58 VDC Ott (ID 5 7.B 67 Subcohort, * IB yr 2 2.6 77 latency TCE AxelsenUf) 49 62.0 79 Subcohort 10 yr 8 7.6 106 litcncy, high xporar8 EDB Ott(J5) as 616 111 Subeohort * 15 yr 26 21.8 119 latency TCE Blair UJ)* 330 660 * PCE CO, 12 8.9 135 2 S.5 57 1 1.1 91 1 0.6 200 11 14.5 76 6 1.8 167 7 6.8 121 6 4.8 140 67 67.9 1.28 TCE Blair CU)* 1292 1292 - 244 223.7 1.09 Site-tpecffle cancer death* Site Ob*. Exp. Retpirxtory Lung Digestive Lymphatic Luiif 8 5.2 8 4.9 2 3.4 2 1.9 7 3.5 SMR 154 163 58 108 200 Reepfrataey Respiratory 1 0.8 333 1 0.2 500 Lung bronchus Cervix uteri Kidney Skin Leukemia Digestive Esophagus Liver Lung Digestive 17 10.0 10 4.8 2 1.0 3 0.7 5 2.2 26 18.0 10 5.4 10 6.1 62 58.7 86 72.6 1.7 2.1 2.0 4.3 2.3 1.4 1.9 1.6 1.1 1.2 'Relative nek. October 1981 223 ucc 057226 I Mortality patterns among dry cleaning and laun dry workers, potentially exposed to CC14, TCE, PCE and petroleum solvents, were studied by Blair et al. (13) and analyzed by the proportionate mortality method. The age-, race- and sex-specific cause of deaths for persons in the U.S. between 1957 and 1970 served as the comparison. A significant excess of cancer mortality was observed, with 87 cancer deaths observed and 67.9 expected. Malig nancies of the respiratory system, skin and uterine cervix were significantly elevated. Because these workers were exposed to multiple substances known to be carcinogenic, it is difficult to attribute this excess to one substance. Blair (14) recently reported the results of a proportionate mortality study of workers in the metal polishing and plating industry. These work ers were potentially exposed to various metals, corrosive and caustic alkaline solutions, and sol vents such as TCE and PCE. Mortality patterns among white male metal platers who died between 1951 and 1969 wgje compared with expected num bers based on cause-specific proportionate mortal ity for U.S. white males. Excess cancers of the esophagus and liver were present in the study population. Excess cancers of other organs, such as lung and digestive system, were not statistically significant. As with the dry cleaner population, exposures to more than one substance known to induce cancer experimentally do not allow the determination of any specific etiologic factor. Ott et al. (15) reported on the mortality experi ence of 161 men exposed to EDB. Expected deaths were calculated from the U.S. white male general population. No excess of total deaths or total malignancies occurred. Of the total cohort, 86*1 achieved a latency of at least 15 years since first exposure. The number of cancer deaths in this study is too small to permit any valid inferences regarding the carcinogenic risk of the EDB exposed workers. Of the substances reviewed, only the studies of workers exposed to ECH and to dry cleaning and degreasing solvents suggest an elevated risk of cancer. The excess liver cancer in the studies by Blair et al. (IS, 14) is noteworthy in view of experimental study results demonstrating the in duction of liver cancer with the same industrial solvents to which these workers were exposed. The remaining studies report no significant excess of cancer mortality. However, it is apparent that each of these "negative" cohort studies did not consist of a sufficient sample size and latency period to permit any meaningful conclusion regarding carcinogenic risk. The probability of identifying an excess cancer risk in the study population, if in fact it is present, is referred to as the power of the study. The power for the cohort studies reviewed was calculated based on the methods of Cutler et al. (16) and Beaumont and Breslow (27). Table 4 shows the Table 4. Observed and expected numbers of cancer death latency, minimum number of cancer deaths needed to insure statistical significance at the 0.05 level (one tailed-test) and the statistical power to detect a 1.5 relative risk. Substance Investigators Ska of cancer Expected no. of it Observed comparison population deaths ntt Minimum no. of deaths required to conclude that study population rate exceeds comparison population rate* Probability of concluding that study population rate exceeds companion population rate when i is actually 1.5 timet as high (power)* ECH Enterline (d). All cancer 13 14.15 22 0.52 Brown and Rinaky Lung cancer 8 4.92 10 0.26 ( Greater than All cancer 12 8.92 15 0.38 16 yr latency Lung cancer 7 3.48 8 0.21 ECH SheDenberger (10) All cancer 2 3.50 8 0.21 VDC 0UUl) AH cancer 1 1.1 4 0.12 Greater than All cancer 1 0.6 3 0.09 15 yr latency TCE Axelaon (It) AD cancer 11 14.5 22 0.53 Greater than AD cancer 9 9.5 16 O 40 10 yr latency EDB Ott (IS) Greater than AD cancer AD cancer 7 6 5.8 4.3 11 0.29 9 0.24 15 yr lataney If the minimum number of cases is observed, the probability of incorrectly concluding that the study population rat* exceeds the comparison population rate, when in fact it does not, is less than 0.05. "Calculated as: Z'1 " *' - 2n* CRV* - 1) - Z\ where R - relative risk, Z* - upper 100a percentile of unit normal distribution, Z"~*> - upper 100 (1 - 0) percentile of unit normal distribution, and n expected number of cases. 224 Environment*! Health Perspectives ucc 057227 to.. }' c*peri*d deaths e genera) or total ort, 86^ inee first s in this defences ! exposed tudies of wing and d risk of 'udies by view of g the inindustrial "sed. The xeess of hat each onsist of o permit inogenic * cancer present, e power debated and 3ws the tatwtical ty of that '.ion rote pamon * when H 5 time; wer)6 eed* the jutien, .'Ctives obsen ed and expected number of total cancer of lung cancer deaths, the minimum number of deaths needed to observe the respective significant ex*ses and the resultant power to identify a 50% mcrease in the risk. The data are calculated for the total cohorts and the subcohorta with 10 or more or 15 or more years since initial exposure, as indicated in the studies. In order to conclude that the rate of oncer in the study population is greater than the nte ofcancer in the control population, the number ofobserved cancer deaths must equal or exceed the minimum number of deaths required, as calculated using the Poisson distribution. The power calcula tions were based on the ability to detect an increase of 50% in the overall cancer risk of the study population, i.e., a relative risk of 1.5. [Criteria established by OSHA (70 for adequate sensitivity md specificity ofan epidemiologic study require the ability to detect a relative risk of 1.5 in site-specific cancer risk.] The power of each study was deter mined by using the expected number of cancer deaths generated by the respective comparison population rate. The power to detect a 50% increase in total cancer mortality `for the entire cohort ranges from 0.12, as shown for the VDC study of Ott et al., (ll) to 0.52 for the Enterline study of ECH (S) and 0.53 for the Axelson study of TCE ill). These calculations clearly illustrate that the probability of detecting a 50% increase in total cancer mortality was rather low. For the cohorts with 10 or more or 15 or more years of latency, the power to detect a difference is even less. If the more appropriate site-specific cancer risk is consid ered, the statistical power to detect a difference is still lower. These latter data are not presented. Further calculations from data in Table 3 illus trate the site-specific insensitivity of these studies. Given the expectation of 0.2 respiratory cancer deaths as reported in-the VDC analysis (11), an observ ed risk of tenfold would be required to achieve statistical significance. However, this would still be based on only two deaths from a common malignancy. Axelson et al. (10) outlined several Imitations of their analysis of workers exposed to TCE. A twofold risk oftotal cancer mortality would have been required to demonstrate a statistically significant excess in their study population, the magnitude of which is rarely observed in cohort mortality studies. The authors concluded that "the cancer risk to man from TCE can by no means be ruled out from this study, particularly with regard to uncommon malignancies such as liver cancer." The authors further stated that had one case of liver cancer been observed, the relative risk for cancer at this site would have been 3.4 for the total cohort and 25.0 for the high exposure subcohort. As October 1981 stated by OSHA (7), the group of exposed subjects must be large enough to permit detection at least a 50% increase in site-specific cancer incidence in comparison to the control population. Cohort mor tality studies Buch as these do not meet these criteria and therefore lack the sensitivity and specificity to detect an excessive cancer risk. Conclusion Although experimental studies have now demon strated the carcinogenicity and mutagenicity of VC related compounds, in general, epidemiologic stud ies available for review do not allow for the assessment of carcinogenic risk among humans exposed to these substances. This conclusion is baaed on the observation that all of the cohort studies reviewed lacked sufficient statistical power because of the small sample sizes. Furthermore, individuals were not followed over an adequate period of time to allow cancers to become clinically manifest Although information presented indicates that all of the substances studied are high production volume chemicals with large estimated numbers of exposed workers, the number of workers available for study who have achieved an adequate latency period is small. The retention of personnel records containingthe information necessary for epidemiologic study of health hazards is not s requirement in the United States and adds to the problem ofinsufficient sample sizes available for study. On the basis of these observations, it is apparent that qualitative carcinogenic risk of a specific chemical substance to humans must be estimated through the conduct of experimental studies. REFERENCES 1. Infante, P. F. Observation; of the iite-*p*cii5c carcinoffenidty of vinyl chloride to human*.Environ. Health Penpect. 41M (1981). 2. Davia. D. L., and Magee, B. H. Cancer and induatrial chemical production. Science 206:13S6 (1979). >. Chu, K. C., and Milman, H. A. Review of experimental caranogenesia of vinyl chloride related compound*. Envi ron. Health Peropect. 41:211 (1981). 4. Bartach, H., Malaveflle, C., Barfain. A., and Planche. G. Mutagenic and alkylating metabolite* of halo-ethylene*, chlorobutadiene* and dichlorobutenet produced by rodent or human liver tiaauea. Arch. Toxicol 41: 249 (1979). 5. Fabricant, J. D., and Chalmers. J. C. Evidence of the mutagenicity of 1,2 dkhloroethane and itructunlly related compound*. In: Ethylene Dichloride: A Potential Health Riak? B. Amaa, P. F. Infant* and R. Reltt. Ed*.. Cold Spring Harbor Laboratory, Cold Spring Harbor, N Y., 1980. 6. Interagency Regulatory Liaison Group (U.S.). Draft I.R.L.G. Guideline for DoeumenUtion of Epidemio- 225 UCC 057228 i logical Studies, Epidemiology Work Group, Novem ber 1979. 7. U.S. Occupational Safety and Health Administration. Identification, Classification, and Regulation of Po tential Occupational Carcinogens. U.S. Department of Labor, 45 FR 5001, January 22, 1960. 8. Enterline, P. E. Updated mortality in workers exposed to epiohlorohydrin. Submission to OSHA Docket No. H-100, File 4, 1978. 9. Brown, D. P,, and Rinaky, R. A. Reanalysis of the Shell epichlorohydrin study. NIOSH Unpublished report, 1979. 10. SheUenbeiger, R. J.. HcClimans, C. D., Ott, M. G., Flake, R. E., and Daniel, R. L. An evaluation of the mortality experience of employees with potential for exposure to epichlorohydrin. Submission to OSHA Docket No. H-100, File 8, 1979. 11. Ott, M. G., Fishbeck. W. A.. Townsend, J. C., and Schneider, E. J. A health study of employees exposed to vinylidene chloride. J. Oceup. Med. 18: 735 (1976). 12. Axelson, 0., Anderson. K., Hogstedt, C.. Holmberg, B., Molina, G., and de Verdier, A. A cohort study on trichloro ethylene exposure and cancer mortality. J. Occup Med 194(1978). ** 13. Blair, A., Decoufie, P., and Grauman. D. Causes of dest) among laundry and dry cleaning workers. Am J Puhi Health 69: 508 (1979). 14. Blair, A. Mortality among workers in the metal polishur and plating industry, 1951-1969. J. Occup. Med. 22- lie (I960). 15. Ott, M. G., Scharnweber, H. C., and Langner, R. R. tv mortality experience of 161 employees exposed to ethylen dibromidc in two production units. Brit. J. Ind. Med r 163 (I960). 16. Cutler, S. J., Schneidcrman, M. A., and Greenhouse, S. W Some statistical consideration! in the study of cancer e industry. Am. J. PubL Health 44:1159 (1964). 17. Beaumont, J. J., and Bresiow, N. E. Power conaideritm in epidemiologic studies at vinyl chloride workers. Pn*r presented at Conference to Reevaluate Toxidty of Vinyl Chloride, Po!y<vinyl Chloride) and Structural Analop Betbesda, Md.. March I960 (not rac'd for publication). <a 226 Environmental Health Perspective* UCC 057229 i Environmental Health Prrrp*cUvtt Voi. u, pp. m-m, mi Needs for Public Health Intervention and Needs for New Research on Vinyl Halides and Their Polymers: A Public Policy Perspective by Dale Hattis* Comid*rtion of need* for public health intervention* and now rtmrch require* comparative HfunMAU of the health benefit* that are likely to mult from alternative u*m of limited rerulatorj- and technical reeource*. Thia paper briefly examine* regulatory and reaearch prioritic* in the liihtef recent information on the carcinogenic hazard* of vinyl chloride and alkyl and vinyl halide* related to vinyl chloride, the r**piratory-y*t*m hazard* of poly (vinyl chloride), and the reproducttv* hazard* of vinyl chloride. Specific auggeetione are made far relatively promising type* of efforts in three areas. Introduction The papers presented in this conference repre sent a considerable expansion of available informa tion on the hazards of vinyl chloride, poly(vinyl chloride), and vinyl bromide. There are also useful renews of previously available literature on a broad range ofother alkyl and vinyl halides. In this session, the focus shifts from the often slow and deliberate process of expanding what we ``know'* about oareftilly circumscribed questions in VC/PVC toxicology/epidemiology to whit at first glance will seem a much more speculative process. Judge ments must be made about appropriate priorities for regulation ("public health intervention") and for new research--and for purposes of making such judgements it is important not only to understand what we can be said to know today about a restricted set of well-researched hazards, but what is ultimately likely to be true and worth knowing about the whole range of alternative hazards which could be the targets of research and regulatory efforts. For purposes of setting regulatory policies, we `Ct-ntcr for Policy Alternative*, Mu**chu*ett* Inctitutc of Technology, Cambridge, MumchuMtU, 02139- need to ask, "Where is there likely to be a relatively large amount ofham occurring which is likely to be relatively easily preventable by using the intervention tools at hand?" Some of the modes of intervention available either to OSHA or EPA for addressing different kinds of problems include: conventional OSHA time-weighted-average exposure limits for specific air contaminants, enforced by industrial hygiene inspections (best adapted to hazardous exposures which are concentrated in a few estab lishments with relatively large numbers of workers exposed per establishment, for most productive use of limited industrial hygiene inspection manpower); limitations on the manufacture or sale in interstate commerce of specific chemicals or formulations for specific high-hazard uses, under the Toxic Sub stances Control Act (best adapted to hazardous exposures which occur in dispersed locations in industry si a result of the use of specific industrial chemical products, e.g., degreasing and dry-cleaning solvents); efforts to redirect dosage away from unusually sensitive subgroups of workers or pre vent effects by preventive medical surveillance, mandated in OSHA standards; and "generic policy" standards (e.g., the recent generic OSHA carcino gen policy) designed to facilitate standard-setting and stimulate "voluntary" corporate action in ad* October 1981 227 ucc 057230 vance of standard-setting for a range of hazards deemed to pose similar types of issues for public policy. For purposes of assessing priorities for research relevant to public health, we need to ask, "Where is there an opportunity to significantly reduce uncer tainties in the benefits of candidate public health intervention measures, using the research tools at hand?" The relevant research tools here include not only toxicological and epidemiological research into likely health effects, but also technological research on control methods and innovative development of safer industrial processes. The present paper will attempt to address these questions of regulatory and research needs in the light of recent information on three topic areas that are the subjects of this conference: the carcinogenic hazard of vinyl chloride, and alkyl and vinyl halides related to vinyl chloride, the respiratory-system hazards of poly(vinyl) chloride and the reproductive hazards of vinyl chloride. Through the details of these separate subjects, there is one theme that will emerge--both scientists in considering research opportunities and policy makers in considering public health interventions need to structure their efforts to have the widest possible application. Policy makers must seek sensitive points of lever age in the world, where a limited intervention may be expected to produce substantial health benefits for a large number of people. Scientists must seek the critical experiments which contribute to the establishment of generalized rules or principles, with application to the widest possible set of questions of public health significance. Carcinogenic Hazards of Vinyl Chloride and Related Compounds Does the information that has become available over the last few years suggest that a new round of public health initiatives to fturther reduce the even tual incidence of vinyl chloride cancers is likely to achieve greater health protection benefits than alternative uses of the same technical, standard setting and enforcement resources? In order to give an affirmative answer to this question, it would be necessary (though not necessarily sufficient) for us to draw two conclusions from available information about vinyl chloride: (a) that there is a substantial chance that long-term exposure to vinyl chloride at the current standard level of 1 ppm poses an appreciable risk, and (b) that a new round of OSHA standard setting and enforcement would 228 lead to substantial reductions in current average worker exposures to vinyl chloride. With respect to the first question, I think there i* substantial basis for concern that the current 1 ppm vinyl chloride standard may pose an appreciable carcinogenic risk to workers. As part of a 1976 retrospective assessment of the benefits and costs of the original OSHA 1 ppm standard (1), my colleagues and I made projections of likely human risk based on the available data from Dr. Maltoni's BT1 (rat) and BT4 (mouse) results (2), an assump tion of linear dose-response kinetics at low doses, and four alternative sets of rules for translating the rodent vinyl chloride dosages to equivalents for human workers. (Basically, the four alternative rodent/human extrapolation rules arose from the four permutations of the choice between expressing dosage as milligrams/body weight vs. milligrams/body surface area and the choice of whether or not to divide the rodent dosage by 35 to adjust for the 35-fold difference between rodent and human lifespans.) These projections suggested that a year of worker exposure to vinyl chloride at the current OSHA 8-hr limit of 1 ppm might be expected to lead to an additional cancer risk from all tumors of between] x l(r* and 3 x 10"* for the four different extrapolation rules. Even the lower of these figures implies that some tenths of a percent of workers exposed over an appreciable portion of a working lifetime at the standard level may expect to develop an occupationally related cancer, if one of the more pessimistic (higher) extrapolation rules should prove more nearly correct, the ultimate toll might well be in the tens of percent for long-exposed workers. On examination of the more complete animal carcinogenesis data presented by Dr. Maltoni, it appears that projections of roughly the same order of magnitude would be made baaed on the more recently available information. The one possible exception is the appreciable excess of mammary cancer which appears to persist at relatively low exposure levels. Data from studies in humans modify this picture slightly. The preliminary epidemiological informa tion which is available to date does not seem to be indicating as large a risk among workers exposed to vinyl chloride in the past as might be expected under the more pessimistic extrapolation rules from the animal data. For example, the best guess one might make from the data of Dr. Weber for German chemical industry workers with and with out exposure to past high levels of vinyl chloride is that the vinyl chloride workers appear to show m excess of deaths from all malignancies amounting to something like 6% of the total deaths which have occurred so far in that cohort. It should be stressed, Environmental Health Perspectives ucc 05723) rei> ppm a bit1976 'OSU mv man oni'f imp oses. ?the s for ativ . th* >sinfr body ot to the man vear Tent lead s of rent ure* kers P more irove ?11 be rs. umal ni, h order more jsible mary y low cture ormato be sedto ected rule* ^ues* er for uith-idei* o\v an ingto have a* of course, that because of the decades-long latency period for most occupational cancers, it is likely hat the final percentage of past vinyl chloride- ixposed workers who develop occupational cancers rill be higher than that observable among the deaths which have occurred to date. In sum, prudent people in both government and industry must consider that a real chance re mains that chronic worker exposure at the level of the current 1-ppm standard may carry an appre ciable cancer risk. As new production and control technology become available over the coming years there should be a regular, continuing program to implement superior processes and reduce worker exposure as far below 1 ppm aa is technically feasible. Available data suggest that the Swedish PV polymerization industry is now operating with average worker exposures in the range of 0.2 to 0.3 ppm (J). My impression from talking with OSHA industrial hygienists and from the observa tion that as of 1976-77 over 90% of vinyl chloride samples from OSHA inspections were in compli ance with the 1 ppm standard 4), is that this kind of performance may also be being achieved in the U.S. 1 think it is doubtful, however, that a new round of formal OSHA standard-setting on vinyl chloride ould represent the most productive use of the agency's limited resources at this time. Even with in the family of alkyl and vinyl halides which have been discussed at this conference, there are mate rials which,even if they prove to be some orders of magnitude less potent as carcinogens than vinyl chloride, are likely to yield greater public health benefits from intervention. The PVC polymeriza tion industry has several thousand workers, ex posed to vinyl chloride on average in the range of tenths of a ppm. Because of the mqjor pressures placed on the vinyl chloride/poly(vinyl chloride) production industries over the past several years, it seems unlikely that there are still many available but unexploited techniques far making further order-of-magnitude reductions in exposure. On the other hand, the number of workers in the dry cleaning industry is in the hundreds of thousands (o). and available data indicate exposures to perchloroethylene in the high tens and low hundreds of ppm ($). Meta] degreasing operations may offer another similar picture with respect to exposure to trichloroethylene. Solvent and chemical intermedi ate use* of ethylene dichloride and peatiddal and fuel additive uses of ethylene dibromide may also place substantial numbers of people at risk in situations where many of the relatively easy tech nical measures to reduce exposures have not yet been implemented. Even though the available data October 1981 on the carcinogenicity of some of these materials is not as conclusive as for vinyl chloride, and relative potencies are highly uncertain, the dangers of widespread cancer and related risks and likely untapped opportunities to control exposures sug gest that they should be placed relatively higher on OSHA and EPA priority lists for public health interventions than vinyl chloride. After this extended discussion of intervention priorities it will perhaps not be surprising that I see the importance of further scientific work on vinyl chloride primarily in terms of its potential to produce generalizeable lessons for quantitative animal-to-human extrapolations, to advance under standing of the dynamics of metabolism of precur sor substances to active carcinogenic intermediates, and to provide a set of reasonable technical expec tations relevant to future risk assessments for chemicals related to vinyl chloride. The epidemiological observations an worker groups with previous exposure to vinyl chloride dearly need to be pursued in future years. However, in the future, much more disaggregated data should be made widely available for analysis using different approaches for separately assessing the effects of duration of exposure, calendar year of exposure, age at which exposure occurred, relative level of exposure and years of follow-up relative to the yean of exposure. Because of the observed "satu ration" of some vinyl chloride tumor responses observed in animals (2), it is important not simply to assume in analyzing the epidemiological data that high-level short-term exposures will have the same effects ss low-level long-term exposures that deliver the same total dose. Epidemiological observations on the large work er groups exposed to dry cleaning solvents have already yielded tentative indications of excess can cer incidence in some cases (7). Further ongoing epidemiological work on these populations is clearly of major importance. In preparation for possible positive findings in these efforts, I think it would be prudent now to foster creative technological devel opment work to understand the options for alterna tive dry deaning/degreasing solvent systems and equipment to make large reductions in worker exposures, should that be eventually called for. Finally, further observations in animal systems should seek biochemical explanations for the ways in which the quantitative vinyl chloride carcinogen ic response changes with dosage, animal strain snd bodily tissue. Given such knowledge, comparative studies with other alkyl and vinyl halides may provide better quantitative guidance on likely car cinogenic dose response curves for this whole family of related chemical agents. 229 UCC 057232 Respiratory-System Hazards of Poly(vinyl Chloride) The elegant study presented by Dr. Seaton, supported by the studies and case reports of other workers, indicates quite clearly that long-term exposures to fine PVC dust (less than 5-10 pin in size) can lead to chronic declines in standard measures of lung function. In considering public health interventions based on these results, 1 would suggest again that two questions be asked: (a) do the present data give us reason to suspect that fine PVC dust is much more hazardous per unit of exposure than other miscellaneous organic and inorganic dusts with comparable parties! size rang es that are not regulated under OSHA's "nuisance dust" exposure standard, and (b) how extensive is the PVC dust problem likely to be relative to the problem posed by other particulates. Taking the latter question first, it appears from the presentation of Dr. Wheeler on poly(vinyl chloride) processeb*and products that PVC prepa rations with predominantly small particle sizes are mainly produced by a relatively small sector of the industry that uses the "emulsion" polymerization process. Given this, and the possibility that even for this sector of the industry in the fiiture, much of the material could be marketed in wet form now that the dust hazard is becoming recognized, it seems likely that a coercive intervention aimed specifically at fine PVC resin producers and con sumers might yield relatively small benefits. On the other hand, the problem of exposure to miscellaneous "nuisance" dusts in general is clearly common in many different industries. I think it is likely that a general reappraisal of policies and standards with regard to miscellaneous particulates in respirable size ranges might well lead to significant long term benefits in the prevention of chronic pulmonary impairment To build an appropriate database for such a reappraisal, I would suggest that in conjunction with the next round of NIOSH's National Occupational Hazard Survey, there should be a cross-sectional survey of lung function among workers exposed for many years to various kinds of respirable particulates (controlling, of course, for past smoking habits and other relevant factors). Based on the results of such a survey and other relevant data, policy-makers could determine what regulatory distinctions should be made between different kinds of fine particulate matter. At the very least, it seems likely that the term "nuisance" as applied to miscellaneous dusts should be done away with if, as I suspect, there is a general observation that long term exposures to fine par ticulates is associated with an increased risk of impaired lung fiinction. Before leaving this subject I would like to one additional plea to researchers doing epidemio logical work on potential chronic respiratory haz ards. For purposes of policy analyses on possible standards, it is vital that data be presented not only in terms of average losses in lung function among populations as related to exposure and age charac teristics, but also in terms which allow the full reconstruction ofthe population distribution oflung function values ss related to exposure and age. Potentially important changes at the tails of popu lation distributions of lung fiinction may be ob scured unless the basic regression analyses which determine average effects are supplemented by presentations which reveal what is happening to subgroups which for other reasons have better or worse lung function than average. Reproductive Hazards of Vinyl Chloride For this area too, it seems to me that an effort to resolve the general issues posed by reproductive hazards in the workplace and set a "generic policy" standard will be likely to have greater long term public health benefits than an attempt to promul gate a standard which is narrowly focussed on the reproductive hazards of vinyl chloride. There are some very important general issues which need resolution, and the educational effects of the policy making process alone could have substantial aidespread beneficial effects through changes in current practices in industry. Beyond the reduction of exposures--which should be pursued to the maximum extent feasibledesigning appropriate medical surveillance and com pensated removal programs for workers exposed to reproductive hazards is a very delicate and contro versial subject. Many women, in particular, an justifiably fearful that newly won employment opportunities may be eroded and that attempts to eliminate women with child-bearing potential from employment in specific jobs have the effect of reinforcing the old notion that women's primary function in society is to make babies. Cases of real abuse in company medical removal policies have been alleged in the lead industry in w hich some women have apparently felt forced to choose be tween their jobs and undergoing sterilization oper ations. Adding to the concern of women over unequal treatment has been the fact that male mutagenic 230 Envir nmental Health Perspective* ucc 057233 reks have not received the same level of attention rith respect to medical removal as have female teratogenic risks. Exposure of reproductively ac| Uve males to mutagens is thought to generally pose greater mutagenic risks than exposure of females, I because male reproductive cells divide continuously throughout life, whereas female reproductive cells do not usually divide after birth until fertilization. In epidemiological studies of mutation rates for point mutations, mutagenic risks generally show a stronger positive correlation with paternal age than with maternal age (A). I believe that with care and sensitivity to these issues, it is possible to design medical removal protection programs which reduce teratogenic and mutagenic risks while not infringing on individual rights or other social values. A reasonable general approach could include a frill and frank disclosure to all exposed workers of the known and suspected mutagenic and teratogenic risks of the substances with which they are working. Removal, with eco nomic protection, at the worker's option, should be triggered by the intention of the darker to have children, sufficiently in advance of conception to allow the substances) of concern to be eliminated from the body before the critical events which occur in each sex. For prevention of mutagenesis in males, reduction of the body burden of the sub stance of concern to the desired protective level should occur some months before conception, to allow sensitive postspermatagonial stages in the development of sperm to be purged from the system. Return to the previous job can be safely permitted after conception is confirmed, provided that precautions are taken against transport of the hazardous substance home on the worker's cloth ing. For prevention of teratogenesis in pregnant women, reduction ofthe substance ofconcern to the desired protective level should occur prior to con ception. Return to the previous job should probably wait either until the completion of the pregnancy or the completion of lactation, depending on an as sessment ss to whether the substance poses haz ards to the child by way of the mother's milk. In conclusion, I would like to reiterate, that in considering priorities both for public heslth inter ventions and for research, it is often helpful to step back a few paces from the immediate problems at hand. With careful consideration of the generic issues posed by specific problems related to vinyl chloride, I think both scientists and policy makers alike can direct their efforts toward projects with greater payoff than would be realized by straight forward extensions of previous efforts. REFERENCES 1. Hadrima, J., Hattii, D., MesroMan, A., Haacn, S., Katz, J., and Ashford, N. A Casa Study on the Regulation of Vinyl Chlorida Emission* in the Workplace. Cantor for Policy Alternatives, Massachusetts Institute of Technolo gy. Cambridge. 1976. 2. Maltoni, C. "ne value of predictive experimental bioasaayi in occupational and environmental carcinogenesis: an ex ample: vinyl chloride. Ambio 4:18 (1975). 3. Hobnberg, B., and WestUn, A Considerations in the decision of the Swedish occupational health standard for VCM Ann. N.Y. Acad. Sd. 329: 201 (1979). 4. Doniger, D. 0. Federal regulation of vinyl chlorida: A short course in the law and policy of toxic substances control. Ecology Law Quart 7: 497 (1978). 5. Anon. Employment and Earnings. U.S. Bureau of Labor Statistics. Washington, March 1980. 6. National Institute for Occupational Safety and Health. Criteria for a Recommended Standard . . . Occupational Exposure to Tetnchloroethylene (Perchloroethylene). U.S. Department of Heslth, Education, and WeHhrt Publication No. (N10SH) 78-185, Washington, D.C., 1976, pp. 140-146. 7. Blair, A., Dacoufle, P. and Grauman, D. Causes of death among laundry and dry darning workers. Am. J. PubL Health 6fc 506 (1979). 8. Vogel, F., aid Motulaky, A. G. Human Genetics-- Problems and Approaches. Springer Veriag, New York. 1979, pp. 301-307. October 1981 231 ucc 057234 Contributed Articles ucc 057235 Environmental Health Penpeetivee Vol. U, pp. tss-tss, mi Process-Dependent Risk of Delayed Health Effects for Welders by Richard M. Stern* In most industrialized countries Lari* numbcn of worker* arc exposed to welding Aims*. Althoufh the feneral pattern of welders' health may not eignlllcantly differ from that ofworker* in other duety induttriai occupation* which demonstrate derated Incid*nc* of respiratory tract dictate* with lone latency period*, the extremely wide range of cubetanee* at potentially high concentration* produced by various welding technologic* may five rite to undetected proeeee tpecifle high-risk working condition*: ("hot spot*")- The origin, prevalence and range at magnitude of such hot spot*, especially for cancer of the respiratory tract, is discussed, with emphasis placed on the assessment of risk resulting from exposure to CriVI) and Ni accompany ing the use of various technologies for the welding of stainless and high alloy steels. The wide variation of health effects found within the Industry, however, indicates the need for a standard protocol for future epidemiological studies, as wall as for the development of suitaMe methodologies for experimental risk assessment. Introduction The use of welding as a technology for the joining of materials occurs worldwide, engaging of the order of 0.2-2% of the working population in typical industrialized countries. The major processes have been in universal use for of the order of SO yean, and materials and hence exposures have been shown to be, under similar circumstances, compa rable throughout the world. The technology is extremely labor-intensive, labor accounting for eO-90% of production costs for all but the most modem automatic processes. However, new pro cesses with higher productivity having an increased range of applicability are continuously being intro duced. Since these demonstrate typical doubling times (in terms of their absolute use) of 7-10 years, depending on the details of the economic growth in the individual country, some processes which cur rently account for significant worker exposure were relatively rare 20 years ago. The nature of the technology is such that, when ever an arc is struck, the resulting high tempera ture which melts both work piece and consumable *The Danish Welding Institute, 2800 Glostrup, Denmark. October 1981 wire or rod produces significant amounts of vapor ized metal and (where present) slag formers and flux, which condense in the rising plume of heated air to form a high local concentration (upwards of 100 mg/m3) of a complex mixture of gases, oxides and other compounds, whose chemistry is deter mined by the technology, materials and welding parameters used in each case. The possibility of high, localized concentrations of a wide variety of biologically active substances which in turn have a wide range of toxicity [e.g., O,, NO*, Cr(VI), V, As, Mn, Ni, Be, Cu, Na, K, Si, F, Pb] represents a potential source of health risk to significant numbers of workers throughout the world. The magnitude of actual risks which occupa tional exposures represent are however largely unknown and uninvestigated. Since the fume con centrations of various substances vary a millionfold from process to process, and since individual expo sure can depend to a large extent on job situation, one can anticipate that the average risk arising from welding, for a given welder, or any given welding population, and therefore for the welding industry as a whole, is not homogeneous but is made up of a range of process and job-specific risks whose order of magnitude could be estimated by a proper risk assessment (i, t), based on knowledge 235 ucc 057236 of the nnge of process and job specific exposures involved. The observation ofa wide range in the nature and degree of health effects among welders using sim ilar technologies in different localities, and between local users of different technologies indicates that a number of variables determine exposure and hence actual risk, even within a given welding process. Any attempt to reduce occupational health risk must therefore be based on an understanding of these parameters, and the way in which they might affect the nature of the material produced (e.g., the chemistry of the consumables), the rate at which fume is generated (e.g., the values of the welding variables; voltage, polarity, current, arcing time), the local fume concentration (e.g., type of ventila tion) or the background exposure (e.g., workshop mix of technologies and applications). Welders could be used as suitable model popula tions for studies of process or occupation dependent risk provided one has a knowledge of; (a) the magnitude of available populations and their distri bution among various technologies, (b) the types of exposures appropriate to these subcohorts and (c) the techniques necessary to estimate the origin and magnitude of risk accompanying each class of exposure. One useftil approach to establishing the necessary methodology is to attempt to identify specific job situations which might be associated with high degrees of excess risk, i.e., processdependent "hot spots." Distribution of Welding Populations Types of Processes There exist approximately 20 major technologies within the welding industry which are used on ten major classes of materials providing the possibility for of the order of 5000-10,000 different working environments due to the possible variations in com position of workpiece, consumables and welding variables. Manual metal arc welding (MMA) uses short lengths of electrode coated with a complex material which provides for flux, slag and protection from oxidation through its melting and decomposition. Ten major electrode producers, each offering 100 different electrodes, which can be welded with three types of polarity (AC, DC), on several types of joints, account for 3000-5000 separate exposures which differ from each other by a factor of two or more in the absolute concentration of at least one of the 14 major chemical constituants ofwelding fume. 236 Metal inert gas welding (MIG) uses a continuous wire electrode and an inert gas (e.g., argon) which provides a shield against oxidation. For some classes of materials, an active gas <e.g., C02, 02) is mixed with the inert gas to provide better surface proper ties (MAG process). Tungsten inert gas welding (TIG) uses a nonmelting electrode and occasionally extra filler material. Gas welding uses an oxy-acetylene or similir flame to melt the work piece. Submerged arc welding (SA) uses a fully automated process where the arc is maintained under a covering of powdered flux. In spot welding, material is joined by local reststive heating (provided by a transformed current pulse) under electrode pressure. Cutting, burning and air (arc) gouging are pro cesses involving the preparation of work pieces and are frequently performed by welders, their assis tants, or special workers within the same trade. The mgjor classes of materials are: mild steel (MS), an alloy of iron, carbon, silicon, and occasion ally molybdenum or manganese; stainless and high alloy steel (SS), containing iron, nickel, and chro mium, and occasionally cobalt, vanadium, manginese, and molybdenum; aluminum (AL), either pure, or as an alloy with magnesium, silicon and/or occa sionally chromium. Distribution of Welders Worldwide distribution of welders among the different technologies and their applications is difficult to determine directly because the average number of welders per firm is small (ofthe order often), and a large fraction (30-50%) of individuals exposed to welding fumes are not full-time welders but are also employed in allied trades. The best indirect method of estimating national welding populations is to determine the local use of welding consumables snd assume 500 kg of electrodes and 2500 kg of wire per man-year for MMA and MIG welding, respectively. Unfortunately the competitiveness of the market for electrodes tends to make such information s trade secret, but from unpublished trade figures it is possible to estimate the distribution in more common categories, as is shown in Table 1. Two countries, Sweden and Germany, have re cently conducted detailed surveys of their welding industries. The results presented in Table 2 show that there exist wide international variations in the relative distribution of weld ing activity by technol ogy and material. In general, however, the five combinations, MIG/MS, MIG/SS, MIG Al, MMA'MS. and MMA/SS account for between 60-70% of *11 welders. Environmental Health Perspectives ucc 051231 iOUf 'V which ie classes is mixed s proper- nmelting erial. similar Uy autoi under a cal resis1 current are proiecesand eir assistrade. ild steel iccasionind high nd chro mangaicrpure, or occa- ong the difficult number en), and **ed to are also method is is to oles and wire per ctively. market lation a gures it n more ave revelding 2 show sin the echnoP he five 1A/MS, i of all ,, ..ves Tibi* 1. Diftributio<i of wcMen by country to rarioui proc--c* Country Holland. 1978" juan. 1978' iTa.. 1976- Germany, 1970* \onr*v. 1978" Great Britain, 1978*' ^gjn, I97&b Franco, 1978 l-.SS.R-. 1980* taden Holland Japan L.S.A. Germany L.S.SR. Saodtn Holland Japan I.S.A. Germany Sndtn Holland Japan C.S.A. Gormanv Proeeaa MMA MIG+MAG+TIG Stainleu ttMl 5,400 3,500 80,000 13.000 1,200 (7) 10,000 (?) 1,600 9,000 3,100 1,900 No. of welders Other 18.600 31,300 350,000 10,000 57,000 Sub. Arc Other (bad. gu) `Data of Ulfranon (3). *Data of van der Sluis (4). 'Data of Masumoto ot al. (S). Data of Jefferson (6). *Data of Flemming and Soaaenheimer (7). `Eatimated. Total 24.000 34,800 430,000 500,000 97,000 21.000 87,000 57,000 81,000 1,500,000 13,200 1,460 30,000 58,900 66,000 200,000 780 15,000 10,000 1,000 106,000 Process-Specific Welders* Exposure Each technology produces a unique type of aero sol, of which 80-90% of the chemistry is determined by the composition of the consumable material, which is chosen to be metallurgically compatible with that of the work piece. To a first approxima tion, five combinations of the processes described above with various materials provide upwards of 70% of the total expoaure, listed in order of complexity of fame composition as follows: (a) MIG/AL: aluminum oxide, ozone; (b) MIG/MS (MAG MS): ferric oxide, manganese, silicon, cop per, nitrogen dioxide; (c) MIG/SS: same as MIG/MS plus nickel, chromium, ozone; (d) MMA/MS: same as MIG/MS plus sodium, potassium, molybdenum, fluorine, titanium, calcium, aluminum; (e) MMA/SS: same as MMA/MS plus chromium, nickel, vanadi um. (Approximately 40% of MMA/MS welding is performed on plates coated with shop primer, pro- October 1981 during in such cases an additional 1-5% organic gas due to the pyrolytic decomposition of the epoxy or other polymer binder: welding fames are otherwise usually free of organic material Cutting and goug ing provide high exposure! to the oxides of iron, carbon and nitrogen and occasionally to zinc, tin, lead, and/or barium). The amount of fume produced per unit time de pends on the choice of welding parameters (cur rent, voltage, wire dimensions, etc.) and the weld ers' exposure is additionally influenced by the actual job situation and degree of ventilation and/or fume exhaust provided. The approximate cumulative dis tribution of workplace exposures to total fame for the major technologies is shown in Figure 1. Shop background levels (BG) are also given. The curves shown are only valid between 15 and 85% and appear to be representative for the trades indicated, data from Sweden, Denmark and the U.K. agreeing to within about a factor of 2. The use 237 UCC 057238 Tabic 2. Distributions of Swedish welders by process and material.1 Process Total Mild stsel No. of welders Stainless steel A1 Other MMA MIG + MAG TIG Gss Sub. Arc Total 25,585 9,143 4,216 3,823 783 43,550 16,854 6,232 1.541 2,762 540 27,929 5,896 1,594 1,529 479 210 9,708 1,496 1,141 913 325 32 3,907 1.339 176 233 257 1 2,006 `Adapted from Ulfvsrson (J). The German data, although unavailable for publication in detail 18), indicate that, while in i960 the total number of welders has remained essentially unchanged from 1970 (see Table 1). there has been a reduction of about 259 in the number of MMA/MS welders and a corresponding increase in the number of welders using semiautomatic metal-gas techniques in this decade. Note that in Sweden the ratio of MMA to M1G/MAG/TIG welders is aproximately 2:1, while in Germany it is currently l.i. Similarly 9% of the Swedish welding population works on aluminum alloys while only 3-4% of German welders are engaged in these processes. The data generally agree with estimates made based on consumable sales in the individual countries, sssunwif approximately 500 kg electrodes and 2500 kg wire per man year of MMA and MIG/MAG welding, respectively. Fioube 1. Cumulative distribution ofworking place exposures (%) vs. fume concentration (8 hr average) (mg/m*) Car stainless steal and aluminium welding (in Sweden) and shipyard welding (in Denmark), including background levels (BG), HberaUy Interprated from Ulfvarson 13) and Beck Hansen (f). of point extraction will reduce the average levels by approximately a factor of two to three (S). Note that for some applications a significant fraction of welders is exposed above 5-10 mg/ms: levels above 100 mg/m3 have been occasionally reported. Because of local variations in consumable compo sition and distillation effects in the arc which can cause enrichment of the fume by as much as a factor of 100 for volatile components, it would be ex 238 tremely difficult to make an a priori prediction of exposure to the individual elemental components of the fume baaed only on a knowledge of the process technology and work piece composition. Fortunate ly, however, a great deal is known about the amount and chemistry of welding fumes produced from individual electrodes and processes, and the varia tions thereof. A comparative study of MMA/MS fumes produced under standardized conditions by Danish, Dutch, British and Swedish welders (JO) shows that locally, a welder or group of welders produce an amount of fume per unit time for a given electrode which varies by less than 3% within 959 confidence limits, when well supervised, and which varies by less than 18% (95% limits) when unsuper vised. National average fume production rates van by 3% from each other, when corrected for differ ences in the welding parameters actually used. Variations arise because a given electrode can be welded over a range of currents and voltages. Use ful welds can be produced over a range ofcurrent of a factor of two, resulting in factor of two variation in burning rate and hence in specific fume produc tion rate. Similarly, ftune production per unit elec trode length is proportional to arc length (and there fore voltage) which also can vary by a factor oftwo. Hence absolute ftune production rates (and thenfore concentrations and exposures) at maximum currents and voltages are approximately four times those at minimum values of the welding parame ters. In addition, extreme variations in welding parameters can result in a variation of about 409 in the relative concentration of the major fume components: Trace elements 1% concentration) can show much larger variations. The results of laboratory measurement (JO) f total fume and elemental concentrations resulting from the welding of a series of representative teeh- Environmental Health Perspectives ucc 057239 * in ilv ' in iht ntl> 1 | in ihr^, *unur.g ion of nts of rocess -inateTiourn from vansAMS ns bv s (JO) elders given i~ w. .Jj uper vary lifferused. an be U se em of ation oduceleehere* two. neremum imes ame* lding :40<* "urne tion) 0) of lting :ech* ive* TtU* 3- Average concentration, of important toxic wbeUneee for a representative (election of welding praceeiea. Steady-amt* concn in 10 m*, 3-6 kW, 25 aec per air exchange, t 1 aec Ozone COM!) (20 cm from ire, t - 1 mc), Ozone, ppm* ppmb Fume, ii*/m* NO,, CrtVI), Ni ppm ng/m* iig/m* A4. Wm* Cu. pg/m* Pb, pg/m* Mn, pg/m* T.V Ciinc limit *31, A, MIG/MS liSl.A+CO,, HAG/MS 51. C02. MAG/MS FT11. COj. MAG/MSf 3RS17, MIG/SS 16.15, A. AIMIG 16.04. A. AllfIG 16.01. A. ATMIG OK 48.15. MMA/MS* P 316. MMA/SS* PK 46.16. MMA/MS" 0.1 0.1 5000 0.3 * 1.0" 15* 2 0.3 0.3 1.0 200 150 800* 0.22 0.8 x W* 15000 0.12 1.5 15 1.5 30 1.5 470 0.16 0.8 x W 17000 0.015 0.5 1.5 0.5 50 3.0 1700 0.56 2.8 x 1(T* 12000 0.048 0.5 1.5 1.2 48 4.0 840. 0.88 4.2 x MT* 2S000 0.23 1.0 5.0 2.0 75 8.0 4000 0.31 6.8 x ur* 6000 0.28 36 250 0.G SO 5 350 0.39 7.i x nr* 22000 0.14 20 0.5 14 -- 0.72 3.8 X ur* 22000 0.11 0 0 -------- 0.88 -- 23000 0.08 4 1 -------- -- 10000 0.02 2-- 5 10 3 350 ___ ___ 10000 0.02 800 50 -- so 8 270 -- -- 10000 0.02 3 13 30 3 500 Removal of fome will mault is a longer tim# constant t and an inciwaat m theae value* by a factor of 2-10; t - haifiife in itandard (tiding fome. `Calculated from near com (r < SO cm) only; practical level* will be higher by a factor of 2-5. TropoMd. NIOSH. (pwpoaed NIOSH limit* for carcinogen*. 'Change in 1980 from 9000. (Low hydrogen. `Kutile-baak. ,a nolopes produced under comparable, standard con ditions (3-5 kW) are presented in Table 3. The values are the estimated steady-state concentra tions to be found in a 10 ms volume with an air exchange every 25 sec. Ozone concentrations de pend on the half-life for this reactive substance, which is in turn determined by the amount and nature of the fume present. For the sake of simplic ity, it will be assumed that theae few processes are representative for the industry, and theae fumes can be considered as surrogates for those compris ing the major exposures of welders. By combining the data of Figure 1 with those of Table 3. it is possible to estimate the relative fric tion of welders engaged in a particular trade whose exposure will exceed a given Threshold Limiting Value (TLV), and who by definition can be consid ered to be at "administrative risk." The fraction of populations at administrative risk for different sub stances, as a function of technology and material are shown in Table 4. In general, the majority of exposures to other elements do not exceed the respective TLV values provided the TLV for total fume is not exceeded. The estimates of Table 4 are baaed on the aver age elemental concentrations ofthe surrogate weld October 1981 ing fumes listed in Table 3. If one considers all the common consumable types within each major cate gory, which are available industry wide, then a given elemental concentration for a class of fume can vary by a factor of three from these "average" values. In spite of such variations, examination of available data CM, li) such as presented in Table 3 permits separation of welders into cohorts having average exposures which can be expected to be distinct with respect to the presence or absence of certain characteristic substances, and hence which might result in unique health risks. The Health of Welders Pneumoconiosis and Siderosis The extremely rich literature of case histories, health surveys, and hygienic measurements in the welding industry has recently been catalogued (). The generalized risks of welding are indicated by reports of cases of accidental death due to electric shock, and occasional acute and sometimes fatal intoxification due to inhalation of high concentra tions of Cd, ozone and oxides of nitrogen, and manganese; metal fume fever due to exposure to 239 ucc 057240 Table 4. Estimated fraction of weldera at administrative risk, defined as that* exceeding the TLV for various *ubetencts u function of the proem*.* Substance TLV Source Process Welder, st risk. % Mild Stainless iteel steel Aluminum Total fume, (ig/m* Ni, tig/tn1 Cr (VI), pgfm* Mn, |ig/m* NO,, ppm Total Aim*, ug/m* Ni, iig/m1 Cr (VI), iig/m1 Mn, ug/m* NO,, ppm O,, ppm Total fume, i*g/ma Cr (VI), i*g/nr Mn, iig/m* NO,, ppm O,, ppm a 6000 IS 10 800 o. 5000 15 10 800 0.6 0.1 5000 10 800 0.6 0.1 NIOSH accepted NIOSH proposed, I860 (carcinogenic) NIOSH, probable, 1980 (carcinogenic) NIOSH. in effect, I960 NIOSH propoeed, 1981 NIOSH accepted NIOSH propoeed, 1980 (cardnogemc) NIOSH, probable, 1980 (carcinogenic) NIOSH, in effect. 1980 NIOSH propoeed. 1981 Accepted NIOSH accepted NIOSH, probable, 1980 (eweinogenie) NIOSH. in effect, 1980 NIOSH propoeed, 1981 Accepted MMAb MIG TIG 75 10 10 (?) 60 2 2 45 75 98 5 20 8 30 75 5 20 20 8 5 20 __ 90 40 40 1 8 5 1 Derived from Table 3 and Figure 1. The fractional population* ahown to exceed TLV* can only be estimated; the relative friction* given are therefore uncertain to about 20% (with an abaolute uncertainty of no lea* than 5% for the imall value*). Approximately 40% of all MMA.'MS welder* work on primed plate* and are therby expoaed to organic gaaes of unknown TLV having concentration* ranging from l to 5% of thoae found for inorganic Zn, Cd, Pb, Sn, and/or Cu appears to be common. Some risks are, however, obviously processdependent: e.g., exposure during the welding of stainless steel in confined spaces to high concentra tions of fume containing water soluble Cr(VI) has been reported to lead to acute and chronic chrome intoxification, dermatitis and asthma US-18). It is difficult at present to estimate the absolute incidence rates of these acute effects, since case reports are isolated and must be interpreted in terms of the $-4 million man-years of welders' expo sure accumulated annually in the countries whose literature is commonly cited. One might therefore examine epidemiological studies of welders in the hope of determining the absolute level of health effects. Several recent cross-sectional studies would appear to be based on sufficiently large local popu lations of welders to permit some quantitative de termination of the effects of chronic exposure to welding fumes in several different localities and job situations. A survey of the occurrence of (legally defined) pneumoconiosis (silicosis, asbestosis and silicoasbestosis) during the decade 1966-1975 has been conducted for the maritime-construction complex 240 La Spezia which has a total work force of approxi mately 12,000 individuals, among whom are an undetermined number of welders (19). The relative cumulative incidence (in percent of all 951 cases) vs. exposure (in years) for the entire work force is shown in Figure 2. Approximately 50** of the total cases occur within 26 years exposure. The relative cumulative incidence for those 143 individuals identified as electric and gas welders is shown for comparison. The median response for this subcohort was at 23 years exposure. Since welders perform their activities throughout the maritime complex, they are exposed (as bystanders) to the same gen eral atmosphere as the average work force, and therefore should have the same general pattern of disease, superimposed upon which is the effect, if any, of their speafic welding activity. Since how ever neither asbestos nor crystalline silica appear in welding fumes, this incidence of asbestosis and silicosis among welders can only be due to bystander exposure. From Figure 2 it can be seen that the effect of welding would appear to be to accelerate by approximately IVk (i.e., 2-3 years) the onset of the pneumoconiosis characteristic for La Spezia, as detected among the welding population. Since the Environmental Health Perspective* ucc 057241 > ununi <0 4" 4U 1 S 1 n TLV e an ative s) vs. ce is total ative duals n for ohort -form plex, gen. and m of *ct, if howspear s and mder .t the erate set of ia, as e the tives Ficntr 2. Fraction oftotal incidence ofpneumoconiosis (SI) vs. length ofexposure (years) for the total workforce in La Speda as well v for the welding subpopulation. Also shown ia the fraction of total incidence of small round opacities (1 nun or greater) vs. length of exposure (years) for British shipyard welders. relative size of the welding population appears to be unknown, the absolute incidence rate for their pneu moconiosis cannot be compared with that of the general shipyard population. It is however difficult to imagine that the numbers of welders with silicosis asbestosis compared to the entire group (143/951 - 15%) could be different from the ratio of elders to total exposed employees, without there being a significant variation in the respective inci dence patterns. This conclusion it justified by the observations of a contemporaneous clinical study of randomly selected shipyard workers in Trieste which shows that welders exhibit a lower incidence of pleural changes (lesions and calcification: 10/37 * 7.3%, 2 137 1.5%) than the average ofall shipyard employees (63/556 - 11%, 26/556 - 4.4%) who in general exhibit a 10-20 fold excess incidence of bronchopneumopathies compared to the general popu lation (20). In a second article (21), diagnostic chest x-rays from 661 British shipyard welders were examined by a panel of three readers to determine the abso lute incidence of small round opacities of class 0/1 or October 1981 higher (i.e., larger than 1 mm: "siderosis") as a function of welding exposure. The relative cumula tive incidence for the 51 positive cases is plotted on Figure 2 as well. It can be seen the data follows a lognormal distribution, with approximately a 10 year median delay in detection of siderosis for British welders compared to the detection of pneu moconiosis in Italian welders, and that the lowexposure tail appears to be missing. The British welders also worked in all sections of the shipyard, using a wide variety of processes, mostly MMA, but including MIG and TIG techniques (apparently absent in the La Spezia work experience). The absolute cumulative incidence for siderosis vs. length of exposure among the British welders is shown in Figure 3: Data for a cohort of 220 (East) Goman welders (22) is shown for comparison. After the average length of employment of 17 years, approximately 1.6% of the British welders exhibit detectable x-ray mottling (caused by the local ac cumulation of welding fumes (mostly Fe304) having a high x-ray opacity). Doubling the exposure time results in a tenfold increase in incidence. The inci- 241 ucc 057242  9*9 iU/Jt ^ 99 ft IW 90 * i - so g 2V (EAST) GERMAN WEIDI RS SMALL opacit IES BRITISH WELDERS SMALL OPACITIES 0/1 + OTHER (-TB) A GRADE IS ------ 9------- T i| __ m _ 4 * i, 7y\~rr7r A <v V// EXPOSURE (YEARS) Figure 3. Frictional incidence of mull round opiatic* (* of total cohort) vi. length of expoiurc (yean) for British ihjpvirf welder*, and for lideroei* for (East) German shipyard welder*. dence of other anomalies, and of grade III siderotis (opacities of 3 mm or greater) is also shown for the total population. The (East) German welders show a considerably different pattern of incidence of siderosis, with approximately 45% demonstrating de tectable x-ray mottling after an average exposition of approximately 14 yean: the incidence of grade III siderosis after this exposure is 1%. Since the British welden are estimated to have exposure of approximately 5 tng/m*, one can con vert the length-of-exposure data to cumulative ex posure (mg/m* yean), as is shown in Figure 4. For comparison an shown the cumulative incidence data for silicosis for gold and for coal miners (fcj), since they represent the classic case of a lognormal dependence of cumulative incidence on total expo sure. Average exposure levels in the East German shipyard would nave to be 25-35 mg/m* for the incidence vs. cumulative exposure data to be com parable in the two cases. The absolute incidence ntes for siderosis for the British and (East) German shipyard populations were 400/100,000 and 1500/100,000 cases/man-year< 242 respectively. The two studies are comparable how ever only if similar age distributions exist in both shipyards. British welders form a homogeneous group, having started work at age 17 with a univer sal apprenticeship, while the (East) German weld ers, who have an average age of 36 (compared to 34 for their British colleagues) commenced their work ing exposure at the average age of 23, some 6 yean later, and presumably have some other type of early working experience. (The Italian working experience is very similar to that of the East Ger man group.) The striking variation in siderosis inci dence between the groups may have a number of origins: there is most likely a significant difference in exposure in the shipyards studied, but there might be significant differences in lung retention in the two cohorts due to age or genetic factors. It is also possible that criteria for reading thoracic x-nys may vary from country to country. The siderosis discussed above, as found in ship yard and other welders is usually described as "benign", the x-ray mottling regressing after cessa tion of exposure in most cases (2i). Some smaller Environmental Health Perspective* ucc 057243 le howin both reneous univeri weldid to 34 r work6 yean ype of orking st Gersis inci* fiber of Terence . there ition in s. It is x-rays n shipbed as cessa;maller dives fraction of welders exhibits complex welder's pneu moconiosis characterized by irreversible changes including fibrosis (17, 25) which may be due to specific welding exposure, particular individual sen sitivity, or may be an expression of a bystander effect similar to that seen for the La Spezia welding population. Most shipyard welding is done on primed plates of mild steel. Stainless steel welding is usually performed in shops dedicated to such activity. In one clinical study of 95 welders employed in an Italian metalworking shop using a wide range of technologies on both mild and Ni- and Cr-rich alloy steels, for those welders with more than 10 years experience only 8% show normal thoracic x-rays, 251* have normal respiratory function, and only 8% do not exhibit chronic bronchitis: all demonstrate squamous metaplasia of varying degrees (26). Examination ofthe cross-sectional studies described above and others published in the literature of the past decade indicates that each subcohort appar ently exhibits a health pattern characteristic for its own local working environment, to which a number of factors contribute. The fact that the welding October 1981 cohort in one English shipyard exhibits approxi mately 8% abnormal thoracic x-rays (2% siderosis, 0.5% cancer, 3% tuberculosis, 4% other) while the cohort of a German shipyard exhibits 50% siderosis after the same length of employment is most prob ably an expression of different degrees of exposure to similar materials: productivity, arcing time, and electrode dimensions are probably higher, and ven tilation poorer, in the East German yard, although this supposition can only be verified by direct mea surement. On the other hand, the fact that 92% of welders in a workshop with mixed exposures to mild and stainless steels have abnormal thoracic x-rays, together with a high incidence of squamous metaplasia is more likely a reflection of the pres ence of metals such as Cr and Ni in the fumes from alloy steels, usually absent from the mild steels used in shipyard construction. Pulmonary Function Cross-sectional studies of pulmonary ftmction, which should be more sensitive than clinical x-ray surveys for the detection of the effects of exposure 243 ucc 057244 i to welding fumes, are also difficult to interpret because of two major confounding effects: smoking and population dynamics (e.g., worker self selec tion). The effects of smoking and age on ventilatory function of the general population have been stud ied in detail (27). In studies on welders (28), no statistically significant differences between welders who smoked and controls who smoked could be detected: for nonsmoking welders and controls, only closing volume, closing capacity, total lung capacity and Nz-cardiogenic oscillations were significantly different, presumably due to the deposition ofweld ing fume particles in peripheral small airways. Stud ies of respiratory effects in other populations in the metal industry can show more pronounced effects (29), although they may not become apparent until after 30 years exposure or longer (SO) for some occupations. The role of population dynamics through worker self selection among the welding population has been demonstrated (SI). Of 100 welders first exam ined in 1963, only 19 could be identified and reexam ined in 1978 in an effort to determine the effects of 15 years of exposure to welding fumes. For the two cohorts the average values of forced vital capacity (FVC), maximum expiratory flow volume at 50% vital capacity (MEFVM) and forced expiratory vol ume over the first second (FEVt) were found to be higher in 1978 by approximately 4%, 0.6% and 4%, respectively. This apparent slight increase in the respiratory function of these welders is however due to the fact that while the initial cohort had values of FVC, MEFVm and FEVj ofapproximately 108, 107 and 105% of normal, respectively, those welders with more nearly average respiratory char acteristics left the occupation and could not be reexamined. Those welders who remained, howev er, were the individuals whose respiratory charac teristics were the highest, having in 1963 values of FVC, MEFVgo and FEV, of 115, 119 and 113% of normal, which in fact had been reduced on the average by 4, 13 and 6% after further 15 years exposure, with various differences in degree and statistical significance due to smoking habits. The opportunity to change jobs is a function of the regional economic situation which has strong varia tions with time and locality. Thus cross-sectional studies which only examine the age distribution e.g. (28) may underestimate the real effects of exposure on a constant population, and variations in population dynamics (i.e., job mobility) may be strongly reflected in differences in cross-sectional studies from widely disparate societies. The literature discussed above demonstrates the existence of statistically significant exposure related incidence of chronic respiratory tract disease in 244 welders also documented elsewhere (32, 33), and hence there appears to be convincing evidence fora finite risk of delayed health effects for the welding occupation in general. On the other hand, a aipHUnt fraction of welders is employed in shipyards, and shipyard workers in general exhibit a statistical overincidence of chronic respiratory tract riisMtf (Si, SS), including cancer (35, 36). Thus there is a strong possibility that shipyard welders are par tially at risk because of bystander effects related to their place of employment but unrelated to weld ing. Possible Cancer Risk for Welders A number of epidemiological surveys of general welding populations have shown statistically significant overincidence of lung or respiratory tract cancer for this occupation (32, S3,36-39) the data of five of these studies (32, S3, 37-39) is reviewed in Table 5. The five studies encompass some 150,000 welders, represent approximately 420,000 man years at risk, and show an accumulated observed inci dence of 415 cases with 308 cases expected, assum ing an observed/expected (O/E) ratio of unity for unexposed populations. Although there are slightly different approaches taken in each of the studies, the range ofO/E incidence ratios lies between 1.0-2.8 (95% confidence limits) (0.85-3.2 within 99% confidence limits), to be compared with an O/E ratio for unex posed but equivalent populations of the order of 0.6-1.0 (95% confidence limits) (uncorrected for smok ing) (A0). Thus there is sufficient evidence to reject the null hypothesis that welding or being a welder does not contribute to occupationally related cancer incidence. If the statistically significant overincidence of respiratory tract cancer among welders is due to their occupation, is not a bystander effect (56) and is not due to some systematic confounding effect such as smoking habit (welders exhibit an over prevalence of smoking by 22%) (32) or other life style effect, then it may have its origin partially in the general working place exposure of all welders, and partially in specific, high risk exposures. A general occupational risk might arise from the lung burden of dust [approximately 2 g in older welders (14)] which, if it resulted in an increase of the order of five years in "lung age" over chronological age. could account for the observed overincidence in age specific cancer rate. Technology or job specific risk would be associated with processes which produce welding flames possessing high carcinogenic potency (i.e. "hot spots"). Environmental Health Perspective* ucc 057245 Tibi* 5- Summary of epidemtoiocical studies of welders which demonstrate e statistically significant tutw incidence of respiratory tract cancer. Author Locality Reference population* O* Eu 0/E 0/E Study dcaign and 96%* population Uilhim {39) Wash, state, U.S. age- 67 49 137 0.05 1.2-1.7 White males; deaths from U.S. adjusted (PMR) cancer of trachea, bronchus, lung (1951-70); 2000-3000 welders Mtnck 137) Lot Angeles LA Co. age- 21(d) 34 137 0.06 l.O-l.8 White males; lung deaths (d) Co. specific 27(i) (d t- i) (1966-70) plus 2 yr incidence (i) (SMR) (1972-73); 15,300 welders Dtc. SuppL Great National 246 192 127 0.01 1.3-1.8 All males; lungdeaths (1968-69); m Britain age-adjusted (PMR/ 1S1 0.01 128,000 welders (SMR) 116 (SMR* Bstumont and Seattle, U.S. age- 53 40 1.31 NS 0.96-1.6 White males; respiratory cancer Weiss <JJ) Wash. adjusted (SMR) deaths (1964^-76): 3200 welders 40 23.7 1.69 0.01 1.1-2.3 and burners (base rate (SMR) 38/100,000) Bresk>w California Noncancer me*1 9/16" 1.5 0.06 1.1-1.9 Males, lung cancer patients et si. (J) patients in (1949-52); 493 caaea; 493 same hoapitala controls matched for smoking habits; 5 yr employment as welders and sheet metal workers doing welding * The number expected for any given cohort is extremely dependent on the reference population choaen and hence the obter\>d'cxpected ratio will exhibit the aame sensitivity. `Observed. Expected. `Significance. 'Limits to 0/C within 95% confidence interval. 'PMF. social class adjusted. SMF, adjusted for smoking [excess incidence - 122% SMR (expected) 110-160 " 135 smoking adjustment: 151-136 116). kProi'ortion of caeca among welders (14 cases, 2 controls). Individuals who occupationally perform welding fall into several distinct categories. In countries, like Great Britain, with a well defined apprentice ship system, workers enter the welding trade at the age of 17 and remain for the mgjor fraction of their working life (21). Approximately one half of this population is itinerant within the trade, being occupied with a wide range of technologies both daily and within a working lifetime. Perhaps in equal number of individuals are engaged in rather well defined and limited range of welding situa tions, and are exposed over relatively long periods to a narrow range of type* of welding Aimes (e.g. stainless steel welders). In addition to these fulltime welders there exists a large population of individu als in other jobs who weld occasionally and who contribute of the order of 30% talltime equivalents to the populations listed in Table 3. Since the nominal composition of the fumes from most welding processes is known (IS, 10), it is instructive to examine the technologies most repre October 1981 sentative for the industry in order to determine if there exist well defined cohorts who might suffer excessive exposure to suspected carcinogens, and conversely, to identify unexposed cohorts who might serve as control groups. If the welding population can be shown to have a sufficiently inhomogeneous exposure to carcinogens, one could then address the problem of identifying, quantifying, and elimi nating the "hot spots" thereby defined. Of the five metals which have been identified or strongly suspected as being human carcinogens (in some frequently unknown form) [As, Be(?), Cd, Ni, Cr) Ul-i7), nickel and chromium appear in significant concentrations only in the Aimes from stainless and alloy steels, arsenic is a ubiquitous trace impurity in most welding fluxes, cadmium is absent from welding consumables but occurs in many brazing alloys (an allied but separate trade), and beryllium is most probably present only in certain highly unique situations. Approximately 40% of all MMA welders (on mild steel), mostly those employed in 245 ucc 057246 Tab)* s. Typical exposure* (8 hr). % of welding popula tion Process 36 = 5 MMA/MS unprimed* 34 = 5 MMA/MS shop primed turfictf* 10 = 5 MMA/MS 3= 1 MIG/SS 3 = 3 AL/M1G Total fume 5000 10000' Fe,0 3000 4000 Benzo (a) pyrene 0.06 Exposure, iLgtm1 Total organic (gaseous) CrfVI) (waterTotal soluble/ Total Cr insoluble) Ni As 15 0.5 0.35/0.25 - 3.5 300td 1.0 0.541.5 5 Cut As ting bestos oa NO, *4 * 4 0, * 5000 500 _ 3500 1350 10000 300 - * 300 140/10 50 - . 4 4 _ * 350 20/5 125 - - * 4 8 4/4 " " - - 4 MIG/MS and MAG/MS values art expected to be similar to corresponding MMA/MS exposure but depend to such a gnat extern or, consumables etc. that MIG/MS and MAG/MS welders cannot be assumed to form a homogeneous exposure group. Shipbuilding and structural steel trades. `Assuming a tine-based primer. 11Assuming a formation rate of 8 = 2* of that of total fume. shipyards, utilize laps* material coated with shop primer, an antirust compound, usually a polyvinyl butyral or phenolic or epoxy resin, containing iron oxide and/or zinc tetraoxychromate. Welding on this material produces a fume containing 1-3% or ganic gases from the pyrolytic decomposition of the primer. In addition to aldehydes, alcohols and ke tones, this organic "soup" has been shown to con tain a vast variety of compounds such as naphtha lene, methylbenzofurene, phenol, cresol, dioxane, pyridine, 2,4-dexadienal, 2-hexanone, and benzene and other saturated and unsaturated alphatic and aromatic hydrocarbons (C-C14) US, *9) and there fore must be suspected of possessing some carcino genic potency of unknown but nonzero magnitude. Most other welding fumes are free of organic mate rial (a notable exception being that from cellulose electrodes used on pipelines). In addition to welding Aimes, bystander expo sure to carcinogens might be significant: at least 40% ofall welders have some historical contact with asbestos (1, 39), while those working in machine shops have occasional exposure to cutting oil mist, a suspected sinonaeal carcinogen (50,51). Moat weld ers are exposed to iron oxide particulates, which alone are probably inactive, but which appear to be a cocarcinogen for benzo(a)pyrene (.52) which has been identified in some workshop backgrounds (3). The magnitude of possibly carcinogenic exposures which are expected to accompany the use of some representative welding technologies is summarized in Table 6, derived from nominal concentrations and compositions shown in Figure 1 and Table 3, respectively. 246 Semiquantitative Risk Assessment The ubiquitous exposure of most welders to pos sible work place carcinogens as illustrated in Table 6 might well explain the observed excess incidence of respiratory tract cancer summarized in Table 5. The demonstrated 5:1 excess incidence of meso thelioma among dockyard welders in Plymouth. England (36), giving an absolute rate of 80/100,000 cases/man year could contribute only of the order of 10% to the average overinddence of welders respi ratory tract cancer if this "signal'' cancer due to asbestos exposure is induded, although no specific mention of this tumor is found in the studies listed in Table 5. Naval dockyards in general, and Plym outh in particular, may represent a mesothelioma "hot spot.** On the other hand, it is tempting to try to estimate what fraction of actual risk is repre sented by the exposure of stainless steel welders to Cr(VI) and Ni since, because of their skills, they represent a coherent cohort with reasonably well defined exposures with a minimum of confounding effects (no asbestos), and the health effects of occu pational exposure to Ni and Cr have been studied to a great extent in the respective (nonwelding) Ni and Cr industries UJ-47). Although a linear dose-response model is probtbly inappropriate for human cancer (53), and the available and relevant information is fragmentary and frequently inaccurate, one can attempt a sur vey of exposure-response data found in the litera ture of epidemiological studies carried out in the chromium and nickel industry. A tentative sum mary of relevant data is presented in Table 7. Here Environmental Health Perspectives ucc 057247 NO, 0, *t extent or, Table 7. Approximate carcinogenic doae-reaponae relationahlp. Total metal (cumulative Absolute lung cancer exposure), mg/m* yr* incidence rate/100,000 Latency, yr (avenge) Chromium industry Cr plating (54) Ferrochromc (55) Chromate (55) Chrome pigment (57) Chrome pigment (55) Average CriVI) Vicfcel refining industry (Clydach) (55. 50) Total CKVI) 0.5 0.44 2-25 (4) 2.0 S2 Total NI 11-110' < 360* 100 600 760 500x250 64 (lung) (16) 5-42 (21) 8-80 (22-32) 5-21 (15) (21W15) 15-40 Average' 33 21 (naael) 20-84 'Estimated geometric*] avenge. Maximum eonaiatent with observed nonsignificant overinddence. `Exposure is to Ni(C0)4 + Ni + NiO + Ni*S. Age group at riak (avenge) (58) 54-70 45-64 (50) 45-70 44-70 (68) sment stoposI in Table incidence Table 5. of me$o> ymouth, vino.ooo ;rof rs respir due to > specific es listed id Plym.helioma ig to try s repre elders to Us, they bly well 'ounding of occuudied to ding) Ni s probaand the nentary >t a sure literst in the ve Bum7. Here actives estimated geometrical-average cumulative exposures to Cr(VI) and average lung cancer rates are listed together with the relevant age group and range in latency period for the four industries: chromium plating and ferrochrome, chromate and chrome pig ment production (54-60). Exposure in the case of chromium plating is principidly to water-soluble Cr(VI), while in the other three industries it is to a varying mixture of Cr(VI) and Cr(III) of different solubilities. The values shown must be considered highly uncertain and the tentative conclusion that these industrial exposures can be considered to result in an approximately similar risk per dose in the range shown must be considered extremely speculative, since an additive model of carcinoge nicity with a single causitive agent is implicitly used. Note that if the distributions of exposure shown in Figure 1 are typical in other industries, there is approximately a range of a factor of 16 for the exoosure levels of 90% of the cohorts studied. Historical exposures are extremely difficult to estimate since even in those cases where reliable concentration measurements have been made, they show such a wide interindividual range that one can question the statistical use of a geometrical (or any other) average: compositions can frequently only be arrived at by an educated guess, leading to an order of magnitude uncertainty in estimates for total exposures. Furthermore, for the case of Ni and Cr, the actual causative agents are unknown and there is emerging evidence that at least for Ni, there is an extremely wide variation of carcinogenic potency for different substances. In spite of the obvious speculative nature of the October 1981 data of Table 7 one could attempt to use the doseincidence data to predict order of magnitude effects for stainless steel welders. A 20-year exposure to the average Cr(VI) concentration of 0.15 mg/m3 found for MMA/SS welders would give an average total Cr(VI) exposure of 3(mg/ms) (years), similar to that found in Table 7 in the chromium industry, and hence might be expected to lead to the same magnitude of cancer incidence. Obviously the expo sure, and hence on this simple model the expected incidence rates, for MIG/SS welders are of the order of a factor of six lower than for MMA/ SS welders. The risk for Ni for these trades, although non-zero, is negligible compared to that for Cr(Vl), with the exception of the relatively few MIG weld ers using pure Ni filler wire. Such interindustrial comparisons, if appropriate, can also be used as an aid in the proper design of epidemiological studies by indicating those exposure levels, latency peri ods, and cohort sizes consistent with detection of an effect at an acceptable level of significance. For example, a cohort of some 200 MMA/SS welders exposed at high total ftime concentrations (10 mg/m3) for the period 1950-1955 and followed to 1980 should provide statistical material just sufficient to verify or reject the model presented above. One unavoidable conclusion to be made based on the proceeding discussion is that unless water solu ble Cr(VI) is not a carcinogen of potency compara ble to that of other industrial Cr(VI) exposures, the manual metal arc welding of stainless steel with conventional electrodes represents a "hot spot" for risk of occupationally related respiratory tract can cer. Should this exposure represent a potential 247 UCC 057248 overincidence of a factor of three (SMR * 300), then the 10% subcohort of MMAVSS welders could contribute to approximately a 30% overinddence for the entire industry (SMR * 130). It is not clear in which direction systematic errors and bias in the selection of data will effect such a zeroth order risk assessment. Certainly the probable nonlinearity of the dose-inddence relationship will provide for a disproportionately large effect among those indi viduals with significantly higher than average ex posures. Since there is as yet little epidemiological data (on selected subcohorts of welders with restricted exposures) on which to attempt an evaluation ofthe type of risk assessment proposed above, justification for the supposition of process-dependent "hot spots" (especially of genetic risk) must be sought on the basis of indirect (i.e., nonhuman) experiments on the (geno)toxic properties of welding fumes. Screening Tests for Mutagenesis and Carcinogenesis Utility of Screening Tests Because of the existence of an extraordinarily wide variety of welding atmospheres, a direct de termination of toxic risk for welding fume by tradi tional in vivo methods is impractical: such studies would only provide information concerning a single process or group ofprocesses and only with difficulty could be extrapolated to a larger segment of the industry. Similarly evaluation of most single pro cesses by means of human epidemiology is imprac tical. On the other hand, short-term screening tests for mutagenesis and carcinogenesis would appear to be ideally suited for use in evaluating the relative genetic risk entailed by exposure to various weld ing fumes assuming that the obvious problems con cerning exposure-related dose for such complex aerosol systems can be resolved. The fumes have an aerodynamic mass median diameter (MMD) of the order of 0.2 p-m (51) (MMA fiimes have an addi tional component with MMD - 1 pm) and a demon strated elemental deposition in the human respira tory tract of the order of 30-40% (Si). Despite the uncertainty in the relationship be tween mutagenicity and carcinogenicity of metals (41, 42, 47, 6S-66), semiquantitative fast in vitro screening methods could be used to assess relative risks of welding fumes of similar composition by studying the origin of variations of genotoxicity and hence by implication their possible carcinogenic 248 potency (67-69). Such conclusions can be based or the expectation that a number of steps which de termine specific (i.e., molar) genotoxicity in vitn, (solubility, species formation rate and activity of intermediate metalorganic metabolites, membrane diffusion, the nature and efficiency of detoxification pathways and repair mechanisms, and particle cell interactions (such as phagocytosis)) can be expected to exist in vivo as well (70-75). Although at present there is not sufficient infor mation to be able to interpret the significance of the general observation of mutagenicity of a large num ber of the metals many of which can be found to some degree in various welding fumes, there would appear to be strong incentive to examine the possi bility for the in vitro risk assessment of nickel and chromium, not only because of their importance in welding, but because of the widespread worker exposure in other industries. The development of specific screening techniques for Ni and Cr welding aerosols, and the subsequent demonstration of their general applicability would be a significant step in industrial hygiene. Mutagenicity of Ni and Cr The present state of understanding of the muta genicity of Ni and Cr has recently been reviewed (42,47,66, 76). Nickel induces base-pairing aberra tions of nuclear acids, infidelity of DNA replication, chromosome aberrations in cultured mammalian ceils, sister chromatid exchange in cultured human lym phocytes in vitro and aberrant DNA synthesis and or repair and binding to nuclear macromolecules in vivo. Neoplastic cell transformation can be induced by particulates of crystalline Ni3S2 (a potent exper imental animal carcinogen) which excite phagocyto sis but not by amorphous NiS (a concarcinogen). Hexavalent chromium, Cr(VI), induces infidelity of DNA replication, is mutagenic in bacterial test systems (B. subtillit, S. typhimnrium), and in duces chromosomal aberrations and aberrant DNA synthesis or repair in -tissue culture cells in ritn. The cytotoxic activity of Cr(VI) is eliminated by the extracellular reduction to Cr(III), an oxidation state for which there is little membrane permeability. On the other hand Cr(III) is highly effective in induc ing infidelity of DNA synthesis, indicating that (MUD may be the ultimate carcinogen and that reduction of Cr(VI) at a target molecule may be the critical carcinogenic step (77). Only CaCrO< hi? been established as an experimental animal carcin ogen, and there is considerable uncertainty about the exact role played by solubility of Cr(VI)com' pounds in the determination of their carcinogenic potency (42,43, 47). Environmental Health Perspectives ucc 057249 ed on ty o{ brai* ation le e%U ected infor- v>f thf numnd to *ould possi;1 and 'ce in orker nt of Idinp their ep in outl awed erration. i \ modor ?S IN uced iper-yto- n). ielit.v test d in3.VA ilro. j the state On iducthat that ethe has rein* bout com* renic ives Tibit 8- Ranf* of distribution in oxidation state and solubility fraction for Cr and Ni in stainless steel weMinf Ames. MM1 option Kite Witer-ioluble, % Serum-soluble, % pH - 8.8 pH - 7.0 Insoluble, % Total, % mass Cl-(HI) + Cr Cr (VI) Ton) Cr Ni NIG SS Cr (III) + Cr Cr (VI) TetilCr Ni WG Ni* Ni N'i.S'iO 1:1 Ni.XiO - 1:10 0 2.2--4.3 2.2-4.3 0.01-0.3 0 0.005-1.5* 0.005-1.5 0.05-0.25 0.2-0.4 0.2-0.35 0.5-1.2 0.5-0.6 13-43 7-8 `Drays rapidly (is reduced to 0.5% after 24 hr at room temperature) (71, 71). 'Data of Nieburh et al. (SO). 0.2-2.1 0.03-0.42 0.2-2.5 0.27-1.6 3.56-13.78 0.01-0.42 3.80-13.8 S.5-6.3 0.2-2.1 2.2-4.3 2.4-64 0.38-1.9 3.56-13.78 0.02-2.0 4.06-15.8 3,5-6.5 60-72 56.3-68.3 Mutagenicity Studies of Welding fumes A number of pilot studies *fcve recently been undertaken to determine the extent and origin of penotoxkity of welding fumes. Such a study is necessary in any attempt to rank Aimes from van* ouf processes in terms of relative genetic risk. The need for rapid screening methods can be inferred from Table 8, which shows the range of Cr and Ni in various solubilities and oxidation states in some typical MIG/SS and MMA/SS welding fumes. It can be seen that relative concentrations of individual components vary by an order of magnitude even in the limited sample shown here, and presumably some rapid method must be developed to determine the risk associated with each of the various combi nations of metals produced. Stainless steel welding Aimes are positive in the Salmonella histidine revertant plate incorporation test (81. 82), where the active mutagen has now been shown to be Cr(VI) (83, Si). Fumes from MIG/SS show a specific (molar) revertant rate equal to that for their water soluble Cr(VI) content while those from MMA/SS show a reduced rate indicative of an antisynergistic effect. The addition of microsomes results in a (occasionally complete) reduction of the effect. The test system is negative for Aimes which contain only Ni, and for others in which CrtVI) is absent (including those from mild steel welding processes). A slight but statistically significant increase in mutagenicity is observed for stainless steel welding Aunes in the N-thioguanine resistance of V79 chi* October 1981 nese hamster cells which survive exposure to the highly toxic material (82). The recessive lethal test in drosophila is negative for exposure in the larval stage to MIG/Ni Aimes (a mixture of Ni:NiO) and to MIG/SS particles, and to fresh MIG/SS fume in the adult stage. No significant enhancement for adult sensitivity to DES was found to result from fresh MIG/SS exposure (83). Aqueous solutions of NiS04 and aqueous and (fetal calf) serum-soluble fractions prepared from a Ni rich welding fume (MIG/Ni) demonstrate equal specific activity in inducing sister chromatid ex change in human peripheral lymphocytes in cul ture. The serum solubility of both Ni and NiO is extremely high at physiological pH (7.2), as shown in Table 8 (80). Water-soluble Cr<VI) and fumes from an MMA/SS welding process representing an equivalent Cr(VI) dose show similar transplacental genotoxic potency in interperitoneal administration in the mouse spot test (Fleckentest) (83, 88). Stainless steel fume particles are cytotoxic and genotoxic in cultured mammalian cells (87, 88). From these pilot studies it can be seen that Cr(VI) and Ni as contained in welding fumes ap parently exhibit the same types of genotoxidty as is expected for these metals in general (60, 73, 89, 90). Since there is no evidence to the contrary, one should assume that the actual risk for genetic dam age and other delayed health effects to welders can be expected to be similar to that found in other industries with exposure to these substances. The presence ofsome unique combinations, such ss ozaneCr<VI), Ni-Mn, however, might result in local 249 ucc 057250 synergistic or antisynergistic effects, which should be studied in detail. Summary and Conclusions Throughout the industrialized world the welding industry is found to provide a relatively large popu lation with a potential exposure to high concentra tions of a wide range of toxic and biologically active material, occupational exposure to some of which, albeit in other forms and in other industries, is suspected of inducing human respiratory tract can cer. In vitro and in vivo studies of some representa tive welding fumes demonstrate mutagenic, embryotoxic, cytotoxic and genotoxic potential. Epidemi ological studies show that welders exhibit a statistically significant excess incidence of respira tory tract disease, including cancer, which appears to depend on cumulative exposure. Further evi dence implies that specific occupational risk, espe cially of delayed health effects, may be extremely process-dependent. There is also strong evidence that the local workshop environment significantly influences the degree of such risk. The factors which can effect the absolute health risks experi enced by different welding cohorts should in princi ple be controllable if they can be identified. A demonstration that inhomogeneous risks are pri marily restricted to "hot spots" would have major implications for the assignment of priorities for the use of limited resources for risk reduction within the industry. The first indication of a significantly enhanced lung cancer risk (i.e., a "hot spot") for a cohort of stainless steel welders which satisfies the necessary criteria of length and magnitude of exposure, and latency period has recently been published (91). For the cohort studied (234), mostly MMA/SS weld ers with a minimum of 5 yean experience; average exposure of 16 yean (3735 man-years) to Cr(VI) concentrations of approximately 216 |ig/m3) three cases of respiratory tract cancer were found vs. 0.68 expected. The average cumulative exposures of3.4 (mg/m3 years) result in a risk rate of82/100,000 cases/man-yearwith a local background of18/100,000: a risk ntio of 4.4:1. These observations lie within a factor or two for the risk ntio and within a factor of six for the absolute excess incidence nte predicted for this exposure to Cr(Vl) by the crude semiquantitative risk assessment model presented. Al though it is obvious that there is not as yet sufficient evidence on which to test any health risk model for welden, it is clear that the combination of risk assessment methodologies and good epidemiologi 250 cal data will be a powerful tool for the future. The international welding industry would appear capable of providing a large number of model popu lations on which to base the development of tech niques of multifocal epidemiological studies to de termine the origin and extent of process-specific risk. Great care must, however, be taken in design of the study protocols to cope with the observed differences between various welding populations. Recent discussions concerning the variation in age adjusted lung cancer incidence with occupation found for local populations (55), and the strong urbanrural gradient (92) which they exhibit, point to a possible uncertainty in expected incidence rates of a factor offrom two to four the results of multifocal epidemiological studies carried out on essentially similarly exposed populations would be extremely useful in helping to establish guidelines for the choice of appropriate reference populations, with out which it may be extremely difficult to prove the existence of occupationally related excess cancer risks. The parallel development of in vitro fast screening tests for mutagenesis and/or carcinogen esis appropriate for use with metallic participate aerosols might provide a unique opportunity for the establishment of practical risk assessment proto cols for use in the metal industry in general. The resulting protection against exposure to carcino gens should reduce the risk for genetic effects in general (93). Without the development of risk assessment meth odologies, protective legislation (i.e., TLVs) based on the concept of homogeneous risk, if set at the lowest feasible level, will penalize industries with low risk exposures, while elevated compromise lev els might permit dangerous exposures to unidentified high risk material. Finally, it should be pointed out that the wealth of technologies available to this important, populous industry ensures that if "hot spots" of risk can be identified, the means of reduc ing risk at the source are at hand, provided appro priate alternate low risk procedures can be identified. Added in proof: Analysis of the citations of a recent literature search (2) has uncovered over 100 cases of welders who exhibit abnormal epithelial proliferation ("fibrosis"). For the more than 70 cases for which welding history is known and diagnosis is verified by pathology, the observed incidence is uniformly distributed over starting age (13-52 years) and length of exposure (3-40 years), and does not appear to indicate any specific process-dependent risk (e.g., stainless steel welders account for 5-10% ofthe welding population), although in vitro studies show that fumes from stainless steel welding have t high fibrogenic potential compared to those from other processes (94). Environmental Health Perspectives ucc 057251 ure, d appear lei oopu- ech^ to de'-specific n design 'bserved jlations. n in age on found ` urbanlint to a rates of uhifocal -entiaJly tremely for the withove the cancer 'ro fast inogenticulate for the protoL The arcinoects in tmeth' ^sed the s with se levmtified ed out :o this if "hot reducapproitified. is of a erlOO thelial icases osis is nee is years) as not ndent >10<* .udies lave a from lives The generous support of The Danish National Fund For Twhiucsl-Scientiftc Rosesrth (STVF), Danish Council of Tech*tofv (TK), and The National Medical Research Council (SLF) , ruefully acknowledged. This manuscript ia a summary of and ,r extension to work partially financed by The Health and jtltty Directorate, Directorate-General For Employment and jj.i Affairs, CEC, Luxembourg. 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Prolonged exposure to a stressful stimulus (noise) as a cause of raised blood pressure in man. Lancet, i: 86-87 (1977). 112. Psrvizpoor, D. Noiae exposure and prevalance of high blood pressure among weavers in Iran. J. Occup. Med. 18: 780-731 (1976). 113. Petereon, E. A., Tanis, D. C,, Augenstein. J. S-. Seifert, R., Bromley, H. R. Long term noise exposure and cardio vascular fiinction in monkeys. Paper presented at the Model Noise Symposium. National Information Center for Quiet, Washington, D.C. 1979. 114. Borg, E., and MoOtr, A. R. Noise end blood pressure: effect of lifelong expoeure in the tat. Acta Physiol. Scand. 108: 340-442 (1978). 115. Sontag, L. W. Effect of noiae during pregnancy upon fetal and subsequent adult behavior. In: Physiological Effects of Noiae, B. L. Welch, and A. M. S. Welch, Eds., Plenum Press, New York, 1970, p. 131-141. 116. Kimmel, C. A., Cook, R. O., and Staples, R. E. Teratogenic potential of noise in mica and rats. Toxicol. Appl. Pharmacol. 36:289-245 (1976). 117. Jones, F. N. and Tauacher, J. Residence under airport landing pattern a* a factor in teratism. Arch. Environ. Health 33:10-12 (1978). 118. Edmonds, L. D., Layde, P. M., and Erickson. J. D. Airport noise and teratoganesis. Arch. Environ. Health, 34: 243-247 (1979). 119. Bortky, P. N. Review of community response to noise. Proceedings, 3rd International Congress on Noise as s Public Health Problem, American Speech and Hearing Association. Washington, D.C., 1980. 120. Wood, S. G. Traffic noise regulation: t comparative study. Brigham Young Univ. Law Rev. 1979: 461-807. 121. Environmental Protection Agency. The Urban Noise Sur vey. Office of Noise Abatement and Control. EPA No. 550/9-77-100, 1977. 122. Environmental Protaction Agency. General provisions for product noise labeling and noise labeling requirements for hearing protactort. Part 111. Fed. Reg. 56120-56147, September 28,1979. 123. Environmental Protection Agency. Noise and environ ment. EPA Journal 5 (No. 9): October 1979. sa-s ^ 8 October 1981 309 UCO 057255 Erratum C. Jelinek (Food and Drug Administration) Environmental Health Perspectives 39:143-151 (1981) The author has discovered that two data entries in the table on p. 147 are incorrect. Under the column headed "Current", the value "0.25" should be "0.025", and the value "0.15b" should be "0.015b". October 1981 311 ucc 057256 Volume no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 83 34 35 36 37 38 39 40 Previous Volumes of EHP Subject Conference on Polychlorinated Biphenyl Review--Perspective Article* Conference on Phthalate Esters Review--Perspective Articles Conference on Chlorinated Dibenzodioxins and Dibenzofurans Workshop on the Evaluation of Chemical Mutagenicity Data in Relation to Population Risk Low Level Lead Toxicity and the Environmental Impact of Cadmium Review--Perspective Articles Conference on Asbestos Conference on Mobile Air Emission. 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Mutagenidty of fume particle* from ^Inlets steel welding. Sand. J. Work Environ. Health ;.,m R M A chemical, physical and biological aaaay of .fklme fume In: The / Vitro Effect* Of Mineral Duata, R. - Bnwn. I. P Gormley, M. Chamberlain, and R. Daviaa, d*. Academic Prea*. London, 1980, pp. 203-209. _ R. M.. Thomien, E., and Laraen, H. Origin of itldmf fume mutagenicity in S. typkimunum. In prepan- JOfl. , Madsen. 1. The mammalian spot test and Ha use for the (sun* of potential carcinogenicity of welding fume particles and hexavalent chromium. Acta Pharmacol. Toxicol. 47:66-70 * .1*0). Kmidien, I.. and Stern, R. M. Assaying potential cardno- pmcity of welding fume and hexavalent chromium with the majiunalian spot test. In: Colloquium on Welding and Health, Instituto de Soldadura, International Institute of Welding. Commission VIII, Lisbon, I960; SUC Report (D.28. ' Ko*hi. K. Effects of fume particles from stainless steel melding in lister chromatid exchanges and chromosome iberrations in cultured Chinese hamster cells. Ind. Health, 17.3SM9 (1979). 88. White, L. R.. Richards, R. J., Jakobsen, K., and 0stgaard, K. Biological effects of different type* of welding fume particulates. In: The In Vitro Effects of Mineral Duata, R. C. Brown, I. P. Gormley, M. Chamberlain, and R. Davie*, Eds., Academic Press, London, 1980, pp. 211-218. 89. Newbold, R. F., Amos, J., and Connell, J. R. The cytotoxic, mutagenic and dastogenic effects of chromium-containing compounds on mammalian cells in culture. Mutat. Res. 67:56-64 (1979). 90. Levis, A. G., and Majone, F. Cytotoxic and dastogenic effects of soluble chromium compounds on mammalian cell cultures. Brit. J. Cancer 40:523-833 (1979). 91. Sjdgren, B. A retrospective cohort study of mortality among stainless steel welders. Sand. J. Work Environ. Health 6:197-200 (1980). 92. Doll, R. Atmospheric pollution and lung cancer. Environ. Health Penpect. 22:23-31 (1978). 98. Hemminki. K., Saloniemi, I., Luoma. K., Salonen, T., Partanen, T., Vainio, H., and Hemminki, E. Transplacental carcinogens and mutagens: childhood cancer, malformations and abortions a riak indiestors. J. Toxicol. Environ. Health, in press. 94. Stem, R. M., Pigott, G. H., and Abraham, J. L. Fibrogenk potential of welding fUrae. Report 81.29, Danish Welding Institute, to be published. ' # il. October 19S1 253 ucc 057259 Environmental Health Perspectives Vol. H. pp. iSi-176. I9S1 Assessment of the Health Effects of Atmospheric Sulfur Oxides and Particulate Matter: Evidence from Observational Studies by James H. Ware,* Lawrence A. Thibodeau,* Frank E. Speizer,*4 Steven Colome* and Benjamin G. Ferris, Jr.* Steadily risine energy cocti have increased the need for reliable information on the health effect* of atmospheric sulfur oxide* and particulate matter. Because ethical and practical consider ation* limit (tudiea of this question under controlled condition*, observational studies provide an important part of the relevant information. This paper examine* the currently available epidemiologic evidence from population studies of the health effects of these pollutant*. Nonexperimental studies also have important limitations, including the inability to measure accurately the exposure burden of free living individuals, and the potential for carious confounding by other factors affecting health. We begin with a discussion of some of these methodologic issue*. The evidence is then reviewed, first in association a-ith fluctuations in 24 hr mean concentration of sulfur oxides and particulate matter, and then in association with differences in mean annual concentration. In the last section, this evidence is summarised and used to approximate the exposure-response relationship linking pollutant concentrations with mortality and morbidity level*. Introduction In view of the potential for adverse health effects of air pollution, and the expense of control mea sures, reliable assessment of the health effects of different air pollutants is an important public health This work was supported in pan by contracts funded by tha Eli' ironmcntal Protaction Agency in conjunction with prepara tion of the Air Quality Criteria Document for Particulate Matter and Sulfur Oxide* and by grant ES01I06 from the National Institute of Environmental Health Science* and Electric Power Re.-earch Institute Contract No. RP 1001 EPRI. The opinions expressed are thoss of the author* and may not reflect the position of the Environmental Protection Agency. `Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115. TCh*nning Laboratory, Harvard Medical School and Brigham and Woman's Hospital October 1981 problem. Lowrance (1) has defined four tasks in this assessment: identifying the health effects; quantifying these effects at various ambient concentrations; estimating how many people are exposed st these levels; and calculating the overall health risk associated with a given degree of air quality. This paper addresses the quantification of the health effects of sulfur oxides and particulate matter, especially at ambient concentrations near the present air quality standards. The health effects of these air pollutants can be studied to some extent in controlled conditions. Laboratory studies of animals allow careful control of the concentration of individual pollutants and conditions of exposure, as well as detailed study of the effects on study animals. These studies have been useful for identifying possible mechanisms of action and potential health effects. However, it is 255 ucc OS7260 difficult to use animal studies to quantify these effects in human populations, primarily because the basis for extrapolating from animal to man is uncertain. The uncertainty of such extrapolation is increased by significant interspecies variability in the response to pollutants. Laboratory studies with human subjects avoid extrapolation from animal to man but raise other concerns, such as ethical considerations and practi cal difficulties in studying long-term exposures. In addition, laboratory studies cannot duplicate the activity patterns and pollutant mixture experienced by free living populations. Within these constraints, studies involving human subjects can be used to establish the response to short-term exposure. Studies of occupational groups have been sug gested as another source of information. Although these studies may provide good estimates of expo sure, the mix of pollutants and concentrations is usually different from ambient air. Exposures are for 8 hr or less rather than on a more continuous basis. Temperature and humidity conditions are also likely to differ from those experienced by the general population. Furthermore, the working popu lation differs froimthe general population in impor tant ways. The very young, elaerly and ill persons are not included. There is considerable selection by the employer and self-selection by the worker, so that those with current disease or who are more sensitive or susceptible are not as well represented as in the general population. As a result, one cannot conclude from a negative study in an occupational group that the same exposure is safe for the general population. If an association between an air pollu tant and a health effect is found in an occupational setting, there may be a greater association in general populations. Because of the limitations of each of these types of investigation, epidemiologic studies in general population groups provide much of the relevant information about the health effects of sulfur oxides and particulate matter at levels of exposure near present ambient standards. Here, too, there are limitations with respect to estimating exposure and measuring effects. Other risk factors, such as cigarette smoking and occupational expo sures, must be considered, and confounding fac tors, such as socioeconomic status, race and weather must also be evaluated. In these studies, exposures are not subject to manipulation, though ambient levels can change during the course of a study. This makes it difficult to determine whether mean con centration, peak concentration, variability, or some other aspect of air pollution concentration is the most important determinant of health effects. Observational studies cannot demonstrate cause 256 and effect, rather we infer causalitv based on the precepts proposed by the Surgeon General's Advisory Committee on Smoking and Health (2) and bv Hill ($): the strength of the association, the consis tency of the data, the specificity of the results, the temporality of the observations, the demonstration of a biological gradient and the plausibility and coherence of the results. Ideally, findings will be replicable by specific experimentation, and conclu sions will be further strengthened when different approaches or methods yield similar results. The next section of this paper briefly sum marizes the methodological issues which should be considered in evaluating nonexperimental studies of the efTects on health of exposure to atmospheric sulfur oxides and particulate matter. We then review the evidence from selected studies of the association between mortality and morbidity level* and 24-hr mean concentration of sulfur oxides and particulate matter the evidence linking mortality and morbidity levels to annual mean concentra tions. The evidence is summarized in the final section. Methodological Issues In Observational Studies Observational (nonexperimental) studies of the association between health and air pollution an sometimes viewed as natural experiments in which the exposure to pollutants varies over groups or time. However, this view ignores several special characteristics of observational studies of air pollu tion. One of the most important is inaccurate measurement of the exposure burden of individu als. Pollution data are usually obtained from one or several outdoor monitoring stations, but the expo sure burden can vary greatly between individuals living in the same neighborhood because of special features of the outdoor micrometeorology and the indoor environment 4*6). The effects of errors in the independent variable on the estimated associa tions between air pollution and health effects de pends on both the size and expectation of the errors. Many health endpoints, including lung func tion, hospital admission and frequency of symp toms, also are measured with substantial variabili ty. When an association between air pollution and health is found, collinearity (high correlation) of sulfur oxide and particulate concentrations (D and the possibility of complex chemical interaction* reported from laboratory studies (8. 9) frequently make it difficult to associate the effect with either pollutant alone (10). Observational studies of respiratory disease or Environmental Health Perspectives ucc 057261 the tong function must consider a host of confounding particularly extreme temperatures, could influence variables (11), many of which have greater health mortality and morbidity rates. 1 by effects than air pollution. When these variables are A substantial reduction in ambient sulfur oxide sis- ignored or inadequately measured, resulting bias and particulate concentrations, achieved in most the can easily be greater than the association of inter English and American cities by the 1970's, pro tion est. In addition, many observational studies use duced a gradual decline in severity and eventual and linear or other simple models to summarize com disappearance of episodes in which either sulfur I be plex data sets without assessing the adequacy of dioxide or particulate matter exceeded 1000 p,g/m3 elu the model. Unless data displays, simple groupings (measuring particulate matter either by the British ent or other analyses are used to show that these Black Smoke method or as Total Suspended Particu models are properly summarizing the data, one can lates). Episode studies were gradually supplanted um- only have limited confidence in the results. by studies of fluctuations in daily mortality over i be These factors, taken together, create additional extended periods, and investigations of potentially dies uncertainty in interpreting observational studies in more sensitive indices of health effects, including eric comparison with laboratory experiments. The most lung function and respiratory disorders. Sensitive hen difficult problem in interpreting the evidence from population subgroups, such as asthmatics and chil the a group of observational studies is determining how dren, have also been studied. The pollution concen v'els effectively these potential problems have been trations in studies of acute exposure have typically and addressed in each study. been measured by 24-hr mean concentrations, though tlity There is an unavoidable element of subjectivity high level exposures for shorter periods might be tra- in the assessment of evidence. In an effort to important. inal reduce that subjectivity we have included in the Counts of total daily mortality show a seasonal assessment those studies which satisfy five criteria. pattern with a peak in winter, and rates on succes (1) They have been reported in the open litera sive days are interdependent. Early studies used ture. the deviation of daily mortality from the 15-day (2) Concentrations of both *sulfiir dioxide and moving average to eliminate seasonal effects. More particulate matter were reported. recently, investigators have used sophisticated (3) Major confounding factors were controlled, time-series-analysis techniques in an effort to elim the particularly temperature in studies of acute expo inate seasonal effects and other long-term trends ar" sure. and smoking, race and socioeconomic status in affecting daily mortality. Elimination of seasonal .1 studies of chronic exposure. effects by these methods may be incomplete, and or d) The findings pertain to concentrations less this becomes especially important when investiga rial than 1000 |im/m3 for both sulfur dioxide and particu tors attempt to identify pollution effects that are Uu- late matter. small relative to effects of temperature, season and ate (5) The data collection, analysis and interpreta even day ofthe week. We will return to this issue in du- tion were free of error or potential bias which could the discussion of individual studies. 1 or be reasonably expected to substantially affect the Morbidity data are more difficult to gather than po- results. daily mortality figures. For that reason, investiga lals Studies failing to meet one or more of these tions of morbidity effects of acute exposure to rial criteria were also included, when discussion of their sulfur oxides and particulate matter have usually the validity and significance was seen as an important been small, permitting relatively simple analysis. s in part of assessing the evidence from observational These studies would be unlikely to detect small ria- studies. increases in morbidity at relatively low air pollution de- concentrations. the Studies reported in this section used three sepa ine- Health Effects of Acute Exposure rate measures of particulate pollution. The British upjili- to Sulfur Oxides and Particulates studies used the British Black Smoke method and reported particulate levels in ng/m3 (BS). Some and The earliest studies of the acute health effects of American studies used the filter soiling method and i of air pollution focused on dramatic episodes of severe reported particulate concentrations in units of and air pollution (12-18). The sudden increases in mor Coefficient of Haze (CoHs). Other American studies ons tality and morbidity that accompanied these epi measured Total Suspended Particulates (TSP) by ltly sodes and the frequency and severity of respiratory the high-volume sampler method. Results are re her complaints left little doubt that air pollution was, at ported for each study in the original units, and the least in part, the cause of the adverse health relationship between the different measures is or effects. Investigators also recognized that weather, considered when summarizing the evidence. October 1981 257 L ucc 057262 A Mortality Effects of Acute Exposure to Sulfur Oxides and Particulate Matter In this section, we examine studies of the associ ation between daily mortality rate, as measured by the recorded number of deaths, and 24-hr average concentration of sulfur dioxide and particulate mat ter. The clearest evidence comes from studies of relatively high pollution concentrations, while stud ies of lower concentrations have been equivocal, primarily because collinearity of temperature and other weather variables with pollution concentra tions have made it difficult to interpret associations between daily mortality and air pollutant concen trations. Studies of Daily Mortality in London. Two important British studies bearing on mortality effects ofacute exposure to SOj and particulate matter at concentrations near present 24-hr air quality stan dards were reported by Martin and Bradley (19) and Martin (20). Martin and Bradley related daily mortality from all causes (and from bronchitis and pneumonia) to the concentrations of S02 and black smoke (BS) in London during the winter of 1958-59. The authors found a considerable number of coinci dent peaks in pollution concentration and daily mortality. The correlation of mortality from all causes with air pollutant concentration, measured on the log scale, was 0.61 for BS and 0.52 for S02. The correlation between mortality and mean daily temperature was -0.03 (not significant), while the correlation of mortality with humidity was 0.19 (significant at the 0.05 level). The authors noted that about two-thirds of the air pollution episodes were accompanied by thick fog, and the correlation between mortality and visibility was found to be -0.55. Visibility is influenced both by fog and particulate pollution. Although the authors emphasized the relation- Table 1. Average deviation at daily mortality from 15-day moving average, by concentration of imoke (London, Nov. 1, IMS, to Jan. SI, IMS).* Smoke concentration, t*g/m*(BS) Number of day* Mean deviation 100-1M 200-299 300-399 400-499 500-599 600-699 700-799 800-1199 1900-v 6 -20.83 12 -13.66 18 -10.80 19 -7.15 9 10.89 19.72 7 4.17 10 21.49 ( 38.36 `Data of Martin and Bradley (if). 258 ship between differences in pollution concentration and differences in death rate on successive days, their paper provided total deaths, smoke concen tration and SOj concentration from November 1, 1958 to February 28, 1959. We have re-examined their data after excluding the month of February, as an epidemic of Type A influenza had a significant influence on daily mortality in that month. For the remaining 92 days, the deviation of each day's total mortality from the 15-day moving aver age (truncated at each end of the series) was computed. The avenge deviation is given for intervals of BS concentration in Table 1 and S0Z concentration in Table 2. Although Lawther (21) has suggested that the number of deaths increased significantly when BS rose above 750 p.g/m3 and S02 concentrations exceeded 710 pg/m , these tables do not suggest those values. If one begins with a threshold hy pothesis, that mortality is not affected until air pollution concentrations exceed threshold levels, one might choose threshold values of 500 pg/m3 of BS and 300 pg/m3 ofSO* from these data. However, the data are also consistent with a monotonic exposure-response hypothesis, that mortality level increases with air pollution concentration over a broad range of values, including those just dted. A similar analysis was carried out by Martin for the winter of 1959-60 (20). That winter had fewer incidents of high pollution. The significant positive correlation between mortality and pollution was still present, although the author reported that the correlation coefficients were somewhat lower than in the previous year. Tables 3 and 4 show Martin's results combining high pollution days from 1958-59 and 1959-60, excluding days with pollution concen trations lower than the previous day. The mean deviation is positive in every group reported. Bronchitis mortality was also found to be significantly, though less strongly, correlated with pollution level. Pneumonia mortality was not found to be correlated with pollution. Table 2. Averse* deviation of daily mortality from 15-day moving average, by concentration of SO, (London. Nov. 1. IMS, to Jan. 31, IMS).* Smoke concentration, ng/m* Number of day* Mean deviation 100-199 200-299 300-399 400-499 600-v 17 -13.01 29 -12.16 22 6.87 11 9.32 13 27.21 `Data of Martin and Bradley US). Environmental Health Perspective* ucc 057263 Table S. Average deviation of daily mortality from 15-day erinf average, by concentration of (moke (BS) (London, 195M0).* Smoke concentration, Mg/m3 (BS) Number of daya Mean deviation 500-599 600-699 700-799 800-1099 1100 + 9 5.2 6 13.0 9 9.2 8 15.6 7 40.0 *Dau of Martin (0). Table 4. Average deviation of daily mortality from 154ay marine overact, by concentration of SO] (London. 195840).* SO, concentration, pg/m3 Number of daya Mean deviation 400-499 500-599 600-799 800-896 900+ . 9 9.0 6 11.6 9 16.0 6 19.2 5 39.6 `Data of Martin (SO). These two studies represent an important part of the evidence for mortality effects of short-term elevations in S02 and particulate pollution. Al though temperature was not an important con founding factor in the two winters studied, fog was an important factor in many air pollution episodes, especially in the winter of 1958-59. Reported analy ses have not adequately controlled for the effects of fog on mortality. During this period, daily mean concentrations of SO2 and BS were highly corre lated (r - 0.89 for the winter pf 1958-59). Conse quently, these associations cannot be attributed to either pollutant individually. Additional evidence for acute effects of short term elevations in sulfur dioxide and particulate matter concentrations was provided by the analysis of a pollution episode in London in December, 1975 (&, J3). Maximum 24-hr concentrations of994 fig/m3 (S02i and 546 M-g'm3 (BS) were reported, and an increase of 100 to 200 deaths above expected totals was observed during the week in which the episode occurred. A doctors' strike in the period immedi ately prior to this episode had an unknown impact on the mortality data. Siudiet ofDailyMortality in \etc York City. The other principal source of information on variation in daily mortality comes from a series of studies in New York City. This information includes reports Table 5. Average deviation ofdally mortality from normal, by level of amoke ahade (CoHs) (New York. 1M0-S4, October through March).* Smoke (hade level (CoH) Number of daya Mean deviation (SE) <1.0 1.0-1.9 2.0-2.9 3.04.9 4.0-4.9 S.0-S.9 6.0+ 26 -2.8 (8.S) 160 -1.6 (1.4) 318 -2.4 (1.0) 239 1.5 (1.2) 88 2.5 (2.3) 19 18.8 (4.8) 9 17.2 (7.8) 'Data of Giaucr and Greenberg (7). October 1981 (4-26) of several air pollution epiaodes not dis cussed here, since pollutant concentrations were too high to contribute significantly to our assess ment. However, Glasser and Greenburg (27) car ried out an analysis of daily mortality in New York City during the five-year period 1960-64, using only data from the months October through March. The 24-hr average pollution concentrations were based on hourly SOj and bihourly smoke shade (CoHs) readings from a single monitoring station. Death rates were analyzed both as deviations from a 15-day moving average and as deviations from the five-year average for that day. The two analyses were said to have qualitatively similar results. In cross-tabulation of daily mortality by S02 and smoke shade level, S02 appeared to be more strongly related to mortality and was used as an index of pollution in some analyses. Multiple re gression analysis showed a stronger association of mortality with SO* than with either temperature or rainfall. Tables 5 and 6 summarize the analysis by Glasser and Greenburg. These results have been inter preted as showing a mortality effect for smoke shade above 5 CoHs and S02 above 786 pg/m3, though they are again supportive of a monotonic exposure response relationship. Although the ob servations of daily mortality are correlated, Glasser and Greenburg computed standard errors for the mean deviations by assuming independence. Most TabU S. Avorafc deviation of daily mortality from normal, by level of SO, (New York, 196044. October through March).* SO, concentration, t*f(m* Number of daya Mean deviation (SE) <262 112 -3.5 (1.6) 525-786 811 -8.1 (1.0) in 1.8 (1.4) 787-1048 66 9.4 (2.0) >1048 80 11.9 (2.5) `Data of Glaaaer and Greenberg (7). 259 ucc 057264 of these standard errors were near 2.0, though the entry 18.8 in Table 5 had a quoted standard error of 4.3. The authors also stratified days by tempera ture into three groups: those more than five de grees below normal, within five degrees of normal, and more than five degrees above normal. The result of the stratified analysis differed little from the unadjusted analysis. However, this simplified approach to covariance adjustment may not elimi nate the confounding effects due to temperature. Multivariate analyses of the New York data de scribed below suggest that more careful control for temperature and other meteorologic factors has a substantial effect on the results. To analyze possible mortality effects of even lower levels of pollution, the 15-day moving aver age method is not sufficiently sensitive. Further more, some authors have argued that more sophis ticated adjustment techniques are necessary to ensure that seasonal and temperature effects are eliminated in the adjusted analysis. To achieve that objective, Schimmel and coworkers (28-30) have reported three analyses of mortality data from New York City in whiolrthe adjustment methodology was refined over time. Buechley et al. (31) and Buechley (32) have also analyzed some of the same data. Schimmel and Murawski (29) emphasized the common seasonal trends in mortality, pollution and temperature in New York City, and the possibility that nonlinear relationships would make linear regression unsatisfactory as an adjustment tech nique. They eliminated periods associated with heat waves and analyzed the remaining data in three time periods, 1963-66, 1967-69 and 1970-72. While smoke shade level varied little over the three periods, the average SO* level declined dramatical ly, as shown in Table 7. Schimmel and- Murawski estimated the percent age of premature deaths due to air pollution to be 2.78, 2.48 and 3.20, based on regression analysis of the three periods using a model with no lag effects. The percentage attributed to SO2 was 0.58, 1.22 and 0.62, values not significantly different from zero. Since the percentage of excess deaths attributed to air pollution differed little in periods with three-fold differences in S02 concentration, they concluded that S02 concentration is merely an index variable for other unmeasured extraneous variables and not a cause of adverse health effects at these levels. Schimmel (30) continued his analysis of these data by utilizing time series techniques to eliminate any seasonal or other cyclical effects contributing to associations between pollution and mortality. In this analysis, the regression of mortality on SO; was not significant and negative coefficients were obtained in some regressions. Buechley (31, 32) also sought to identify major nonpollutant variables influencing daily mortality and found that mortality was affected by the annual cycle, summer heat waves, influenza epidemics and a temperature variable. These four variables ex plained 78% of the variation in daily mortality during the U-year period 1962-72 in New York City. Although SO* concentration and particulate level also entered significantly into the regression uation, Buechley found that the coefficient for S>2 concentration in regression analysis of daily mortality during the winter of 1971-72 was slightly higher than the corresponding coefficient for the winter of 1967-68, even though the mean S0i concentration in the second winter was only 10% of that in the earlier period. Both Schimmel (30) and Buechley (32) concluded that the associations they found between mortality and air pollution could be explained by joint associ ation with temperature and other weather vari ables. Their work highlights the limitations of observational studies when the study objective is accurate estimation of small primary relationships when other independent variables are more strong!}' associated with mortality. These other variables influence the estimate of the primary relationship, and the proper method of adjustment is unknown. Thus, it will be difficult to reliably quantify small mortality effects offluctuations in ambient pollution concentrations by analyzing observational data. Tabic 7. Avcrafc pollution Irrtli during three time period* analyzed by Schimmel and Murawiki.* Time parted SQrkval, tif/m* CoHi Wval 1963-66 1967-69 1970-72 112 2.07 369 2.27 15S 2.13 `Data of Schimmel end Murawtld (If). 260 Morbidity Effects of Acute Exposure to Sulfur Oxides and Particulate Matter Levels of air pollution which acutely affect mor tality rates should affect other health indices, including incidence and prevalence of respirator}' disease as measured by emergency room visits or hospital admissions, prevalence and severity of respiratory symptoms as measured by question- Environmental Health Perspective! ucc 057265  an ous iCtS esc late gto In SO; ere sjor ality inual and i exalitv York ilate sion for lailv htlv the SO. %of i ality soci* vari* s of e is >hips ngly ibles ship, own. ;mall jtion i. to r mor* ices, itorv ts or y of tion- naire during regular contact with a panel of partici pants, or changes in various aspects of lung func tion. Unlike mortality rates, these health data must often be specially obtained by the investigator. This has limited the size of morbidity studies. Many studies have used the diary or panel method, in which a group of participants regularly record or report symptoms. Substantial nonparticipation rates have been a problem in many of these studies, and make it difficult to interpret the symptom reports by those from whom observations are obtained. Illness data were obtained in many of the early severe pollution episodes (13, 15,33). This informa tion did little more than confirm the mortality results, though there was some evidence that the increase in illness was not as large in percentage terms as the increase in deaths, and the effects were not so sudden. Martin (20) examined hospital admissions for the winters of 1958-59 and 1959-60 and found, alter adjustment for day of the week and correction for 15-day moving average, significant correlations for both cardiovascular and respiratory conditions with BS and sulfur dioxide. The average deviations by pollution concentration, given in Tables 8 and 9, show more irregularity than the mortality data. ** Table 8. Average deviation of reipirmtory and cardiac morbid ity from 15-day movinf average, by amok* concentration (BS) (London, 1S58-80).* Smoke concentration, ng/m* (BS) 500-599 600499 700-799 800-1099 1100+ Data of Martin (fO). Number of day* 9 6 9 8 7 Mein deviation 8.2 -0.7 2.4 4.9 12.9 Tabic I. Average deviation of reapiratoey and cardiac morbid ity from 15-day moving average, by SO* concentration (Lon don, 195840).* SO, concentration, tig/m* 400-499 500-599 600-799 800-899 900+ `Data of Martin (to). October 1981 Number of day* 9 6 9 6 5 Mean deviation 2.2 5.1 6.9 12.8 12.8 In a second important British study, Lawther et al. (3i, 35) collected daily self-reported health status from 194 persons with chronic respiratory disease during the winters of 1959-60 and 1964-65. Health status was reported relative to the previous day, and worsening of health status by self-evaluation was clearly associated with increases in air pollu tion. The authors reported that this effect could be seen on days when the 24-hr average level of SOj exceeded 500 ng/m* and smoke exceeded 250 iig/m3 (BS). The strength of this response declined as the winter progressed and there was some evidence for an adaptation or desensitization effect or even loss of interest by participants. Lawther et al. commented that these responses could have resulted from brief exposure to maximum concen trations several times the 24-hr average. Studiet ofBronchial Asthma. Some studies of pollution and asthma have reported negative or equivocal results (36, 37). However, Cohen et al. (38) found a weak association between air pollution and the frequency of asthma attacks in a study of patients living near a coal-fueled power plant in West Virginia. Temperature was most strongly correlated with frequency of attacks among 20 patients having at least one attack during the study. In a multiple regression analysis, either S02 or TSP concentration was significantly correlated with attack rate after adjustment for temperature (p < 0.01). When days were classified as high and low particulate concentration (above or below 150 yxg/m3 TSP), or as high and low SO* concentration (above or below 200 |xg/m3), symptom prevalence was significantly higher on the high pollution days. These values should not be interpreted as thresh old values, since the dividing line seems arbitrary and the table comparing the two groups of days does not seem to be temperature adjusted. The authors provide little information about changes in panel membership over time, and also give insufficient information about their data analysis methods. In particular, they combined data from children and adults participating in the study. The sensitivity of asthmatics to exogenous allergens, respiratory in fections, dust, animals, smoking, cold weather and psychological factors also suggests caution in attributing changes in symptom prevalence to changes in air pollution concentration. Studiet of Acute Respiratory Diteate. Few studies relating acute exposure to moderate levels of air pollution to increased incidence of acute respiratory disease have been published. Although early studies by Dohan and Taylor (39) and Dohan U0) found an association between the level of suspended sulfates and work absences for respiratory disease among outdoor telephone workers, ipsen et 261 ucc 057266 A al. Ui) conducted a near replication of their study and found that apparent associations between ab senteeism and air pollution were eliminated by adjustment for temperature, humidity and wind velocity. StudiesofPulmonaryFunction. Van der Lende et al. US) obtained results in a study of respiratory symptoms and lung function in the Netherlands which could represent an acute effect of air pollu tion. Examination of a large general population group in 1969 and again in 1972 failed to show the expected small decrease in levels of Forced Vital Capacity (FVC) and Forced Expiratory Volume in one second (FEV,), but rather small significant increases. The authors suggested that this could be attributed to improvement in air quality, from reported maximum 24-hr smoke level of 160 \t.g/m3 (BS) and SO2 concentration of 300 |xg/m3 in 1969 to 40 Mg/m3 (BS) and 100 ixg/m3 (S03) in 1972. [This and some other continental European studies used OECD calibration curves to express Black Smoke in p-g/m3. Some reviewers have suggested that the reported values should be increased, perhaps by a factor of 2, to be pomparable with the British Black Smoke method US).] Expected decreases in pulmonary function were seen in a rural area measured at the same times. The authors explored possible sources of bias in the study but were unable to explain their results on that basis. If real, these changes are most reasona bly interpreted as an acute, reversible response to elevated concentrations of air pollution. Stebbings et al. (44) studied pulmonary function in 272 children during and after an air pollution alert in Pittsburgh in 1975. The 24-hr average S02 concentration reached.350 p-g/m3 and the 24-hr TSP level reached 770 pghn3. The mean FEV0.rs and FVC values, instead of increasing as hypothesised, declined throughout the six-day period. Because the investigators did not have a pre-alert lung function measurement, the values obtained during the alert days could not be compared to "normal'' lung function values. Since the children were fol lowed for only the week, the possibility of a later increaseinlungfunction valuescould not beexcluded. In a later report, Stebbings et al. (45) identified a group of children whose lung functions showed large increases after the alert. Since the proportion of such children was significantly greater in the alert than in a control area, they concluded that the alert had been associated with reduced lung function. Since the analysis was selected in re sponse to the data, was based on unvalidated methodology, and failed to explain the anomalous finding of an excess of children in the alert area whose lung function declined during the study, 262 these results do not provide sound evidence for health effects of air pollution at the levels reported. Health Effects of Chronic Exposure to Sulfur Oxides and Particulate Matter Studies of health effects of chronic exposure to air pollutants are typically cross-sectional, compar ing mortality or morbidity rates within or among a number of communities. The possibility that the estimates of air pollution effects will be biased by other community differences related to health is particularly great in these studies. Concentrations of air pollutants are usually higher in urban than in rural areas, and many authors have noted that smoking patterns, family size, age distribution, occupation, domestic crowding, nutrition, physical activity and other characteristics of the population can differ between rural and urban areas. Although some studies have sought to match communities on important characteristics or use multivariate ad justment techniques to control for the effects of these factors, their effectiveness is typically un known. This is especially true when complex re gression models are used for adjustment, for the adjustment is limited by the degree to which the model correctly specifies the relation between these factors and the outcome under study. Mortality Effects of Chronic Exposure to Sulfur Oxides and Particulate Matter The study of Buck and Brown (46) was one of the first to show an association between annual avenge concentration ofSO2 and Black Smoke and mortality rate across communities in Great Britain. Howev er, mortality data were obtained in 1955-59 and pollution was measured in 1962. Pollution levels were falling during this period. Although it has been argued that mortality effects were seen in boroughs where Black Smoke and SOj levels exceeded 200 pg/m3, it is likely that exposures prior to and during 1955-59 were somewhat higher than in 1962. Wicken and Buck (47) also found differences in lung cancer and bronchitis mortality rates between areas of high and low pollution after adjusting for age. smoking habits and social class. However, this study was also limited by unavailability of concur rent air pollution measurements in most of the communities studied. More recently, several investigators have used multivariate regression techniques to analyze mor tality data obtained from vital statistics sourcesThe following sections discuss these investigations. Environmental Health Perspectives ucc 057267 re to nparwg t the ;d bv lth it itions >anin 1 that ition, lysical ilation hough ieson e ad its of y unx revr the h the these lire tter of the erage tality owev9 and levels it has jen in needed ' and 11962. n lung i areas r age. \ this oncuryf the e used e mor>urces. itions. -ettves Analyses of Total Mortality Rates As noted above, there are many reasons why ntortality rates vary among communities. There fore. study units should be selected to minimize variation due to factors other than air pollution. On ihe other hand, study units must be selected to conform with the available data. For mortality studies. Standard Metropolitan Statistical Areas iSMSA's) and cities meet this condition but present several difficulties. Investigators, recogniz ing that the study units differ with respect to factors other than air pollution, attempt to adjust for these differences by including socioeconomic and demographic variables in their analysis. Nev ertheless, it is likely that the effects of variables such as personal habits, occupational exposure, and medical care cannot be fully quantified and elimi nated in this way. If any of these factors covaries with air pollution levels, a spuriously large effect will be attributed to air pollution. The evidence in a multiple regression analysis relating mortality to pollution can be expressed through the coefficients of the pollutants and their standard errors. Comparison of the results of regression analyses from njpjor studies relating mortality rates to pollutionlevels across communi ties illustrates the problems that arise in inter preting these studies. The four regression equations summarized in Table 10 are taken from the work of Lave and Seskin US). TSP represents the average of 26 biweekly measurements of24-hr TSP in each SMSA, while S04 is the lowest sulfate determination from these 26 observations. Regressions LSI and LS2 were both obtained from the analysis of 1960 mortality data for 117 SMSA'g. The two regression equations differ only in that the second contains one additional adjustment variable, home heating fuel. Adding this variable reduces the coefficients of the air pollutants by a factor of three and they are not significant in LS2. Lave and Seskin argue that this occurs because home heating fuels are a major pollution source, home heating fuels and pollutants are highly correlated. This contrast illustrates one effect of collinearity on the regression coefficients. Regression LS3 results from fitting the model from regression LSI to 1961 data. Mortality and pollu tion values were about the same in the two years, and the coefficients are quite similar also. When the same model is fitted to the 1969 data (regression LS4), the estimated effects are larger even though mean TSP level declined from 118 jig/m to 96 ug/m3 and the average S04 level declined from 4.72 ixg/m3 to 3.46 mf/m3. These comparisons show how sensi tive these multiple regression analyses are to variable selection, and also raise questions of con sistency. Table 10. Coefficient* of TSP and SO, in four represaion* reported by Lave and Setkin.* Rerreeakm Source Coefficient (SE) TSP so. Other variables* LSI Data from 117 U.S. SMSA's in 1960 LS2 Data from 117 U.S. SMSA'i in 1960 LS3 Data from 117 U.S. SMSA's in 1961 LS4 Data from 117 U.S. SMSA's in 1909 0.452 (0.109) 0.171 (0.158) 0.516 (0.178) 0.818 (0.241) 6.31 (2.33) 1.84 (2.16) 4.56 (2.49) 7.74 (8.67) D. A, R, 1. P D. A. R. 1, P, HHF D. A. R. 1. P D. A, R. I. P Data of Lave and Seskin US). Symbol* uaed in thia column are defined in Table 12. Table 11. Coefficients of T8P and 90, in repressions analysis by Lipfcrt and Crocker et al. HegretiMm Souret Coefficient TSP so. Other variables* LI Data from 60 U.S. SMSA's in 1909b L2 Data from 60 U.S. cities in 1969* LS Data from 136 U.S. cities in 1969* L4 Data from 181 U.S. cities in I960* Cl Data from 60 U.S. cities in I960' 0.78 5.4 D, A, R. 1 0.78 8.2 D. A. R, 1 1.00 -2.0 A, R. I, H, B 0.72 -4 3 A. R, I, H. B. C. lop D 0.11 -0.31d MD. MI. E. CH, C, CT, R. MA. DF `Symbol* used in this column are defined in Table 12. bData of Lipfen US. SO). Data of Crocker et aL (Si). ``Coefficient of SO*. October 1981 263 UCC 057268 i Results of four regression analyses reported by Lipfert U9, 50) are shown in Table 11. The first (LI) is based on analysis of 1969 mortality data from 60 U.S. SMSA's, using a model much like regression LS4 in Table 10. Very similar coefficients are obtained. The first two models in Table 11 differ only in that the first uses mortality data from 60 SMSA's while the second uses mortality data from 60 U.S. cities. The coefficient of S04 is larger in the second regression using smaller geographic areas. Model L3 differs from L2 in that more cities are included and age of housing and birth rate are added as independent variables, while cigarette consumption is added in L4. Though the coefficient of TSP changes very little, the coefficient of S04 is negative in these regressions. The final regression in Table 11 is taken from an analysis of 60 U.S. cities in 1970 by Crocker et al. (51). In addition to variables used by other investi gators, this model includes variables for climate, education, availability ofmedical care and nutritional habits. Although Crocker uses S02 and not S04 as a pollution variable, neither pollutant contributes significantly to the regression. Crocker et al. report a correlation between S02 and S04 of 0.74. The association between air pollutant concentra tion and mortality rates in different analyses can be summarized by the elasticity. An elasticity is a dimensionless number that represents the expected percent change in the dependent variable, mortali ty, associated with a lOtfo increase from the mean value in each of the pollutant variables in the regression. Elasticity is computed by multiplying each air pollutant regression coeffinent by the Table 12. Definition* of other independent variable* need la multiple refreeskma in Table* 10 and 11. Variable Definition D A R I P HHF H B MD MI E CH C CT MA Population denaity in penon/mfle* Percentage of population 6S or older Percentage of population nonwhit* Percentage of population with income below SSOOO/year Log erithm of SMSA population Percentage of borne* tiling ead) of several home haating tack Percentage! of homing unit* built before I960 Birthe/1000 popuiation/year No. ot phyeiciine per capita Median income Percentage of penon* 2E or older with high tchooi diploma Percentage of penon* living in home* with more than 1.5 penon* per room No. of cigarette pack* purchaeed per capita No. of days with temperature below (PC Median age average value of that pollutant in the data set, adding these quantities for all pollutants, and dividing by the average mortality over study units. So long as the set of pollution variables chosen contains variables capturing the total association between all air pollutants and mortality, the elastic ity will be relatively insensitive to the choice of a subset of these highly coilinear pollutant variables. Thus, the elasticities can be viewed, at least approximately, as measuring the total mortality effect of all pollutants included. Table 13 gives elasticities for the nine regression analyses summarized in Tables 10 and 11. Regres sions LSI, LS3, and LS4 were the simplest models used by Lave and Seskin and had the largest elasticity. In regressions using more variables, such as home heating fuel in regression LS2, smaller elasticities were obtained. (When occupa tion was added to the model for regression LSI, elasticity declined to 0.05). Regressions LI and L2 included population density, percentage above 65, percentage nonwhite and percentage with income below S3,000 as independent variables. When birth rate and age of homes were added (L3) or cigarette smoking (L4), elasticity declined to 0.06 and 0.04, respectively. The effect of cigarette smoking should especially be noted. Finally, in the analysis by Crocker et al. (51) using several other added independent variables (Cl), the elasticity was nearly zero. These variables included measures of medical care, diet, climate and cigarette consumption and could easily be defended as critically important in any analysis controlling for other factors expected to influence mortality. Though it has sometimes been argued that smok ing is not associated with air pollution concentra tion, Crocker et al. report a correlation of 0.23 between cigarette consumption and sulfur dioxide in the 60 cities in their study. Certainly the two variables are not causally related, but both may reflect other characteristics of the population. Schwing and McDonald (52) report on a study of ; Table 13. Elaetkitie* far air pollutant* in nine r*rm*ioa analyeee of mortality. Regretakn Elasticity LSI 0.09 L82 0.03 LSS 0.09 LS4 0.12 LI 0.10 U 0.09 L3 0.06 L4 0.04 Cl 0.004 264 Environmental Health Perspectives ucc 057269 > ~fa ''-rch - Out not increasing at ages 6. 3 and SO., adient of cross the Jtant con' with m- and 130 js cohort t again at ssociation vious air ie pre\ aly higher on areas ion areas nd at age s assocj- Vinter 96546 249 101 SE 3.9 5.5 4.4 5.5 5.5 9J ectives ged with cigarette smoking at these ages. Because ution concentrations in 1962 were presumably ,i lower than those in earlier years, the concen ts cited probably understate the exposure of , participants. We note that exposure during ihood to air pollution concentrations in excess ji 130 M-gin3 (BS) and 130 p-g/m3 (S02) resulted in no significant increase in respiratory illness by adult hood compared to those exposed to lower air pollu tion concentrations. Lambert and Reid (61) mailed self-administered questionnaires to 18,379 men and women in Britain to assess the relationship of smoking and air pollu tion to bronchitis symptoms. The reply rate tvas TW from the 35-69 year-old age group studied. From the 9,975 replies analyzed, the authors con clude that the prevalence of respiratory symptoms increased with pollution levels independently of cigarette smoking. Air pollution was found to have i greater effect on the symptoms of smokers than nonsmokers, in terms of the absolute difference in symptom prevalence rates. The exposure levels in this study are approxi mate. since only 30# of the population surveyed uas covered by actual air pollution measurements. The pollutants measured, BS and S02, were taken from 1965 data of the British National Air Pollution Survey. The balance of the population was assigned to exposure categories based on the DouglasWaller (58) index which was developed from 1952 domestic coal consumption. A comparison of symp tom-prevalence ratios from measurements of BS, S02. and index values shows similar ratios and simi'ar gradients for symptoms with increasing pol lution. The lack of complete air pollution data adds uncertainty to the exposure estimates, but in those areas where BS and S02 measurements were avail able, increased prevalence of symptoms was found in association with BS and S02 levels between 100 and 150 M-g m3, as an annual average. Polish Studies. A study of two areas of con trasting air quality in Cracow, Poland, was con ducted by Sawicki. The study began with a cross sectional survey in 1968 and continued with a pro spective study until 1973 (62). Annual average par ticulate values in 1968 were 90 and 170 p.gin. In 1968, chronic bronchitis prevalence was greater in the more polluted area for men, but not for women. The difference was statistically significant for men who were nonsmokers or present smokers. These data are given in Table 16. Asthmatic disease prev alence w as also greater among smokers living in the more polluted area and FEV, as a percentage of FVC was lower for most age-sex-smoking-history groups. Between 1968 and 1973, the annual mean concen tration of S02 and BS declined slightly for Cracow as a whole but increased slightly at the sites close to the homes of most study participants. In 1973, respiratory disease was again more prevalent among those living in the areas of high pollution for many, but not all of the age, race, and sex groups studied. Mean FEV, level was not significantly different in the two areas. The prevalence of obstructive dis ease was higher in the more polluted area only for present smokers. The authors concluded that smok ing and, to a lesser extent, occupational exposure and age had the greatest effect on respiratory illness prevalence, while air pollution at the place of residence was listed as one of several factors haring a smaller effect on respiratory illness. Rudnik et al. (63) reported extensively on the early phase (1970-1976) of a long-term study of the factors which influence development of childhood Table 16. Prevalence of chronic bronchitis hr m and imokinf statu* in 1968.* Smoking status Total Xontmokers Ex-Smokers Present smokers Period of smoking 1-10 years 11-20 years >21 years Low uollution area Man Woman N" 1* SE4 N P SE 323 11* 1.7 362 4 1.0 56 4 2.6 266 2 0.9 46 4 2.9 18 11 7.4 2*1 14* 2.3 78 10 3.4 56 5 1* 41 7 4.0 m 3.0 21 14 7.6 76 26 5.2 16 IS 8.4 High pollution tret Men Women N P SE N P 262 19* 2.4 396 5 58 7 3.4 254 3 40 5 3.4 34 6 164 27* 3.5 96 10 42 7 3.9 38 29* 7.4 84 38 5.2 42 5 18 6 38 18 `Data of Sawidti <6t). 1 Number of persona studied. 'Prevalence of chronic bronchitis. ''Standard error of the observed rate. `Rate* which arc significantly different at the 0.06 levaL October 1981 SE 1.1 1.0 4.1 3.0 3.4 5,6 6.2 ucc 057270 prevalence and on potentially confounding factors such as cigarette smoking and occupation. Never theless, when only a few observations have been made at different air pollution levels, it is difficult to construct generalizable quantitative dose-response relationships. The major studies suggesting morbidity effects of exposure to elevated concentrations of particu late matter and/or sulfur oxides have been reported from three countries; Great Britain, Poland and the Unites States. British Studies. Lunn et al. (56, 57) studied schoolchildren living in four areas of Sheffield, En gland with different air pollution concentrations. These concentrations are shown in Table 14 for the two winters studied. Questionnaires were answered by parents and the investigators found substan tially higher prevalence of symptoms of respiratory disease in the three more polluted areas than in the less polluted area (Table 15). These children were followed up in 1967-69 when they were nine years old (57). As a result of the institution of smoke control, smoke levels were reduced to about half their former levels. When children from the three dirtier areas weiy pooled and compared to children from the clean area in the second study, there were no differences in symptom prevalence rates. Pollu tion concentrations in the later period were 48 (Ag/m3 (BS) and 123 ug/m3 (S02) in the clean area and averaged about 140 pg/m3 (BS) and 200 tig/m3 (S02) in the dirty areas. Douglas and Waller (5$) reported on a study of a sample of children born during one week in March 1946. Air pollution was assessed by creating an index based on coal consumption. The authors cre ated four pollution categories, and found that the prevalence of lower respiratory disease, but not upper respiratory disease increased with increasing pollution when the children were studied at ages 6, 7, 11 and 15. Comparison ofthe index to measured BS and S02 concentrations in 1962 established a gradient of mean annual pollutant concentrations across the four pollution categories. The lowest pollutant con centrations in 1962 among the categories with in creased morbidity were 130 jig/nr (BS) and 130 Mg/m3 (S02). Colley et al. (59) followed this cohort at age 20, and Kieman et al. (60) followed it again at age 25. Neither investigation found an association of respiratory disease symptom with previous air pollution exposure, although at age 20 the preva lence of respiratory symptoms was slightly higher among those who had lived in high pollution areas (11.5%) than among those from low pollution areas (10.2%), and a similar relationship was found at age 25. Respiratory symptom prevalence was associ- Table 14. Air pollution concentration* in communities studied by Lunn t al.* Grtenhill Winter 1964 1965-66 Concentration (24-hr average), ue/m* Longlev Park Winter Winter 1964 1966-66 1964 1966-66 Atterclilfe Winter 1964 1965-66 BS 97 (70-78) 280 177 262 220 301 249 SO, 123 (109-134) 181 194 219 241 275 301 `Data of Lunn et aL (58). Table IS. Symptom* by area in tha study of Lunn at al.* Symptom GraanhiD N* P* SE4 Lontley N P SE Park Attercliffe N P SE N P SE Nasal discharge 406 6.4 1.2 192 5.2 1.6 130 1S.4 3.2 82 14.6 3.9 3 colds 413 34.4 2.3 194 43.8 3.4 130 48.5 4.4 82 46.3 5.5 Eardrum finding 361 9.4 1.5 178 10.7 2.3 12S 14.4 3.1 75 17.2 4.4 Frequent cough 411 22.9 2.1 194 36.1 3.4 130 34.6 4.2 82 50.0 5.5 Cold going to chaat 412 34.7 2.4 194 42.8 3.6 130 40.0 4.3 82 53.7 6.5 Lower respiratory 413 23.0 4.3 192 36.0 S.8 127 35.0 7.1 82 30.0 9.2 infection 'Data of Lunn et al. {58). bThe number of response* obtained. The percentage of positive responses. '`The estimated standard error of the observed percentage. 266 Environmental Health Perspectives uco 057271 46 SMSA's (1959-61) in which 23 explanatory varijfaies are used, including climate, socioeconomic, occupational and smoking variables and eight air pollutants. This study differs from those summa rized in Tables 10 and 11 in that the investigators included all 23 variables in their models. To counter revere collinearity, the authors used two methods of analysis, ridge regression and constrained least squares, rather than ordinary least squares. (The previously reported studies all used ordinary least squares.) Ridge regression is a numerical method for stabi lizing estimates of regression coefficients from a data set that has coilinear explanatory variables. While the method does achieve stability, it does so by selecting an arbitrary constant that has the effect of shrinking each estimated coefficient to ward zero. Though ridge regression leads to smaller standard errors for the estimated coefficients, these coefficients are no longer interpretable as partial regression coefficients, that is, measures of the effects of changes in a single variable while the other \ ariables are held fixed. As emphasized throughout this presentation, coilinear data sets are fundamentally insufficient to allow assignment of mortality effects to individual members of a group i -f coilinear explanatory Variables. Schv ing and McDonald also use constrained least squares, constraining the air pollution coefficients to positive values. This may be unreasonable when eight air pollutants are studied simultaneously. Thur ston et al. (5J) report that respirable sulfate as a fraction of total sulfate is not constant over differ ent let els of air quality. They note that in "dirty" cities the fraction is 0.6 to 0.7 while in "clean" cities the fraction is 0.8 to 0.9. Thus, if the respirable sulfate affects mortality, an indicator of overall air quality such as TSP could take a negative sign, when noth TSP and respirable sulfates are included in the model, to account for the difference in the respirable sulfate fraction between cities. Schu ing and McDonald report an elasticity of 0.22 from ridge regression and an elasticity of 0.045 from constrained least squares. These values are still an order of magnitude larger than that re ported bv Crocker et al. (0.004). This discussion has been provided to illustrate the limitations of multiple regression analyses of vital statistics data, using explanatory variables defined by data availability rather than intrinsic interest, and complicated by severe collinearity of poilu: ant and other explanatory variables. The model can -inly be approximately correct, the surrogate explanatory variables can never lead to an ade quate adjusted analysis, and it is impossible to separate associations of mortality rate with pollu October 1981 tant and confounding variables. This group of stud ies, in our opinion, provides no reliable evidence for assessing the health effects of sulfur dioxide and particuiate matter. Morbidity Effects of Chronic Exposure to Sulfur Oxides and Particulate Matter This section focuses on those studies that provide the air pollution and health-status data necessary to assess the morbidity effects of chronic exposure to sulfur oxides or particulates. These studies most commonly represent the cumulative exposure to air pollutants as an arithmetic average concentration of sulfur compounds and particulates during an interval including the study period. Since chronic exposure may refer to the lifetime of an individual, this measure of exposure may be misleading when pollution concentrations have changed substantially during the years preceding the study. Morbidity outcomes are generally limited to respiratory symp toms and measured lung function. Respiratory symp toms are most commonly assessed with seif- or interviewer-administered questionnaires. The stan dard questionnaire developed by the British Medi cal Research Council (54) has been used typically, with modifications or additions. (A standard ques tionnaire has recently been developed under the joint sponsorship of the American Thoracic Society and the Division of Lung Diseases, National Heart, Lung and Blood Institute, and is recommended for all U.S. population studies (55).] Lung function is generally measured by spirometry from which both forced expiratory volume and flow rates can be determined. Relationships between air pollution and nonrespiratory or systemic morbidity are usu ally not explored. Most of the studies reviewed are cross-sectional investigations of morbidity prevalence. Many of the difficulties of inferring a cause-effect relationship between air pollution and health outcome in such studies have been discussed above. Typically, a few cities or areas with different air pollution concen trations are compared. The study populations are either matched on, or analyses standardized for, differences in variables such as age distribution, race, socioeconomic characteristics, occupational cate gories, and smoking habits. Often only two cities or areas with contrasting air quality are compared. Rarely are more than half a dozen areas compared. The effect of limited observations at differing air pollution levels is partially mitigated by the ability to gather extensive information on outcome vari ables such as ventilatory function and symptom 265 UCC 057272 4 chronic nonspecific respiratory disease (CNSRD). The authors discussed an early pilot study that was used to test and develop the design and instru ments for the main study. The main study, sched uled for completion in 1962, compares 3805 eight to ten year olds, on respiratory symptoms, illness, and lung function (PEFR), in the Polish communi ties of Cracow (two areas), Nowy Targ, and Limanowa. The arithmetic mean air pollution val ues for each of two years in these communities are shown in Table 17. The authors provide detailed information on the distribution and seasonal pat tern of the air pollution observations. Most of the symptoms analyzed and past respira tory illness were less prevalent in the cleaner com munities of Nowy Targ and Limanowa than in the two areas in Cracow. There was some indication that symptom rates were lower in the cleanest city of Limanowa than in Nowy Targ. Peak expiratory flow rate (PEFR) was lower in Cracow. In fact, PEFR of children without symptoms in Cracow was lower than in symptom-positive children in the cleaner areas. The authors concluded that living in the more polluted .community had a deleterious effect on respiratory symptoms, illness, and lung flmction. The effect of living in Cracow was greater than the other social, economic and environmental factors investigated by the authors. Unfortunately, PEFR as measured with Wright peak flow meters is subject to considerable variation due to variabil ity between machines. It is not clear from these reports how this phenomenon was controlled. U.S. Studiet. A series of studies conducted in a New Hampshire pulp mill town, beginning in 1961, Table IT. Two-year mu air pollution value*.* SO, uf/m1 1974 1975 BS. ua/M1 1974 1975 Cracow-1 Cracow-2 Nowy Tars Limanowa 111.4 138.2 57.1 41.5 108.1 148.5 88.8 64.3 189.7 204.9 82.0 58.4 150.9 227.4 79.8 49.2 'Data of Rudnick at *L <M). represent some of the earliest work on the health effects of chronic exposure to sulfur oxides and particulates in this country. In the initial study, Ferris and his colleagues (Si, 65) compared symp tom prevalence and lung function in three areas with different pollution levels within Berlin, New Hampshire and found no associations after control for cigarette smoking. In a subsequent study (66), a random survey was carried out in the relatively clean city of Chilliwack, British Columbia. Though the pollution levels were considerably lower than those in Berlin, the prevalence of chronic respira tory disease was not significantly different in the two towns after adjustment for age and smoking habits. The average values of FEV, and peak expiratory flow rate (PEFR) were higher in Chilliwack than in Berlin for 30 of 32 subgroups defined by sex and smoking history after controlling for age and height. The authors suggested that differences in ethnicity, weather, medical facilities and other factors may have confounded the examination of the effect ofair pollution. The Berlin, New Hampshire population was fol lowed up in 1967 and again in 1973 (67-69). During the period between 1961 and 1967, all measured indicators of air pollution fell. In the 1973 follow-up. sulfation rates nearly doubled from the 1967 level (0.469 to 0.901 mg SO3/IOO cm2/day) while TSP values fell from 131 to 80 pg/m3 (Table 18). Concen trations of SO2 were estimated by assuming that all atmospheric sulfur was in the form of S02. For all three periods, concentrations of S02 at these sites were below the present annual ambient air stan dard. During the 1961 to 1967 period, standardized respiratory symptom rates decreased and there was an indication that lung ftinction also improved. Thus, the higher pollution concentrations seen in 1961 were judged to be associated with increased incidence of respiratory symptoms and impairment of lung ftinction. Between 1967 and 1973, age-sex standardized respiratory symptom rates and agesex-height standardized pulmonary function level* were unchanged. The authors concluded that either Table IS. Pollution levels, Berlin, New Hampshire, during three study period*. Year (a) Total dustftU, g/m*/30 days TSP. ug/m* Sulfation (lead peroxide). mg SOj/100 cm'/cUy Sulfauon converted to SOj. ugni" 1961 1966-67 1973 18.4 14.3 -- 180 -131 80 0.731 0.469 0.901 55 37 66 `Assuming all sulfur in the form of SO). 268 Environmental Health Perspectives ", UCC 057273 the change in air pollution concentration during the latter period was not associated with a change in respiratory health or that the study was too small to detect an effect. The comparison of health status between 1961 and 1967 suggests morbidity effects at 180 p.g/m3 (TSP) and 55 tig''TM3 (S02). These effects could represent a combination of transient (acute) and irreversible (chronic) effects of air pol lution exposure. The TSP value of 180 (ig/m3 was based on sampling during the summer months and probably underestimated the annual average con centration. The comparison of 1967 to 1973 is unin formative because of offsetting changes in pollution concentrations, although S02 concentrations were below present ambient standards in both periods. Mostardi and Leonard (70) compared the results of pulmonary function testing in 42 high school students from an urban area with pollution concen trations of 100 fig/m3 (S02) and 109 p-g/m3 (TSP) and 50 students from a rural area with pollution concen trations of 72 pg/m3 (S02) and 83 pg/m3 (TSP) (maximum annual average over five years). This study was flawed by failure to consider smoking effects. Subsequently, Mostardi and Martell (71) reported on 173 and 161 students respectively from the same urban and rural areas. They tested FVC and FEV0 75 on subjects residing for 4 years or more in the area-. The groups were analyzed separately by sex and nonsmoking males were separately considered. The two groups had similar anthropometric charac teristics. Approximately 20% lower values of FEV0 7B and 10% lower values of FVC were reported in the more polluted area for the total group, for males, females, and for non-smoking males. While a higher proportion of smokers was found in the urban area (123 vs. 6% in the rural area) the authors claim this did not influence their results. They did not men tion race in this study. In the first report (70) the authors found that the lung function differences persisted after exclusion of the three black students in the urban area. The observed differences of 20% for FEVo.-n and 103 for FVC in two communities with relatively small differences in ambient concentrations of SOz and TSP are striking. Other studies discussed here suggest that air pollution at these levels would not have this large an impact on lung function. This implies that other community differences such as racial composition or socioeconomic status may have contributed to the intercommunity differences. The observed differences cannot be reliably attributed to differences in air pollution concentrations. The remainder of the evidence for health effects of sulfur oxides and particulate matter comes from the Community Health and Environment Surveil October 1981 lance System (CHESS) program, sponsored by the Environmental Protection Agency during the late 1960's and early 1970's. Much of this work was published in a monograph (72) and subsequently summarized in three brief papers (73-75). These studies have been severely criticized. The most important criticism is that methodology and quality control for aerometric measurements was seriously flawed. In particular, spills of reagent and other errors in handling measuring equipment led to un derreporting of S02 values by 50 to 100%, while smaller biases were identified in the procedures for particulate measurement, resulting in underreport ing by an estimated 10 to 30%. A number of other problems of study design, participant follow-up and data quality control were detected, raising doubts about the accuracy and proper interpretation of reported results. Ultimately, the CHESS studies were the subject of a special Congressional hearing (76) and an investigation by an expert panel con vened by a Committee of the U.S. House of Repre sentatives (77). The principal criticism ofthe CHESS report arising from this review was that the data had been overinterpreted in the CHESS monograph. As we have indicated, observational studies of the health effects of air pollution are particularly difficult to conduct because individual exposure is poorly measured and populations may not be com parable in ways related to respiratory health. In view of the special problems occurring in the stud ies published in the CHESS monograph and the failure of subsequent publications to meet these criticisms, we believe that these studies cannot be used to assess the exposure response relationship between sulfur oxide and particulate concentrations and morbidity. This decision substantially reduces the evidence for morbidity effects of chronic expo sure to particulates and S02 at levels near present air quality standards, in that most of these studies reported health effects in association with pollutant concentrations near these standards. A more ex tensive discussion of this controversy can be found in the above cited congressional reports and a re cent review article (79). Two studies which were part of the CHESS program were published separately (79, 80). Infor mation in these articles addresses some of the criti cisms of the CHESS program. Hammer et al. (79) surveyed children in four metropolitan New York communities chosen for socioeconomic similarity. Some of the aerometric data used in Hammer's analysis are shown in Table 19. The TSP values for 1968-70 were obtained by extrapolating from the TSP values at the Manhattan station using dustfall values in each borough and the ratio of dustfall to TSP at the Manhattan station. Values of S02 in 269 UCC 057274 i Table It. Approximate air pollution concentration*/ Pollutant Air oollution concentration, uv'm3 1968-1970 1971 1972 SO, Riverhead Queen* Bronx TSP Riverhead Queen* Bronx N/Ab 175 150 N/Ab 85 no 23 51 51 34 63 86 22 50 38 36 89 60 'Data of Hammer et al. (79). bNot available. Queens and Bronx were obtained from stations in the boroughs. Data for Riverhead were provided by Suffolk County (New York). The fourth conununity, Sheepshead, was geographically contiguous to the area studied in Queens, and was assumed to have similar pollution values. All data for 1971 and 1972 were obtained from the CHESS monitoring network. Although Riverhead unquestionably had substantially less air pollution than the other three communities,'Doth historically and during the study, the values cited can be regarded only as approxima tions to the ambient concentrations in the study communities. Questions on respiratory disease were answered retrospectively by parents. Significant differences were found in rates of lower respiratory disease in the low pollution community compared to the three high pollution communities for all ages from 1 to 12. Sex and education of head of house hold were considered in the analysis. Although smoking may have been a factor in older children, this study suggests morbidity effects at pollution concentrations of about 17& pg/ms (S02) and 85 p.g/ms (TSP), using the average of the annual expo sures over the years 1968 to 1970. Interpretation of this study is complicated by a 10-fold decline in SOj and 3-fold decline in TSP over the 12 year period and by the lack of direct local measurement of air pollution concentration. More detailed information might improve exposure esti mation for each child by age and period ofexposure. Hammer (80) also conducted a retrospective study, using parent-answered questionnaires covering four years recall of acute lower respiratory disease in 10,000 children aged 1 to 12 years. The two com munities chosen for comparison differed in particu late air pollution concentration but had low SO* concentrations (Table 20). The values for 1968-1970 cited in Table 20 were obtained by fitting trend lines to a few data points. As with the New York study, we can be confident that the cleaner community (Charlotte) had lower TSP concentrations, while in this study both corn- 270 munities had very low S02 concentrations. Howev er, the TSP concentrations cited are approximate. Hammer found that lower respiratory disease morbidity was less prevalent for children in the cleaner community (Table 21). A separate analysis of children with bronchial asthma produced more equivocal findings. Among asthmatics, morbidity rates in the more polluted community were greater for only about half of the comparisons made. In the case of asth matic blacks, bronchitis rates were greater in the cleaner community. On the whole, this study showed an association between TSP concentration and mor bidity level. Among the remaining studies in the CHESS program, the study of chronic respiratory' disease prevalence in the Salt Lake Basin (8i) is deserving of fiirther attention. Although large and statisti cally significant differences were found in disease prevalence between communities with high and low levels of S02 and sulfates, these pollutants wen among those found to be especially inaccurately measured by the CHESS aerometric network, and Utah State Aerometric was incomplete for the rel evant years. Nevertheless, the health data have not been convincingly criticized, and an air pollu tion gradient was recognized to exist across the study communities, despite problems of precise measurement. Further work with these data may increase the acceptance of this study. At the August 1980 meeting of the Clean Air Scientific Advisory Committee, EPA officials re ported that unacceptably high data entry error rates had been detected in some CHESS data sets, and that data sets for the major CHESS studies would be reentered and reanalyzed to establish the validity of earlier results reported from the CHESS program. Unfortunately, this report further weak ens the credibility of CHESS results. Although we cite results from tw'o CHESS studies, continued use of these findings is contingent upon successful validation of the data sets by the staff of the EPA. The studies that have been reviewed in this section provide the observational evidence for mor- Table 10. Approximate air pollution value* for Birminfha* and Charlotte, 1908-71 vtra*t/ Pollutant City AirpoMutii.n value*, mm1 1968-70 1971 TSP Charlotte Birmingham SO, Charlotte Birmingham <25 <25 <25 <25 81 74 141 133 `Data of Hammer (80). Environmental Health Perspectives ucc 057275 owevmaf ist in tile alysis more more about asth'n the nowed 1 mor- HESS isease erving itistiisease nd low were rately k, and 'le rel* have politi cs the redfe a may ils error i sets, tudies sh the HESS veakgh we -inued essful EPA. n this *mor- nshsie <71 a 25 74 3S lives Table 21. Age-adjusted ratet (11 of one or more episode* of lower respiratory disease, by race and are interval-* Race White Black Data of Hammer ISO). Age, yr 1-4 5-8 9-12 1-4 5-8 9-12 Any lower respiratory Disease, (t Charlotte Birmingham 35.0 38.9 29.9 36.3 22.0 26.4 27.8 24.0 16.4 20.6 12.7 15.9 Bronchitis. (4 Charlotte Birmingham 23.1 27.7 20.4 26.2 14.9 18.6 13.7 10.6 7.8 7.9 6.3 6.9 bidity effects of chronic exposure to S02 and partic ulate matter. In the next section, we summarize and interpret all of the evidence for health effects of acute and chronic exposure. Summary and Conclusions Individual studies providing evidence on the as sociation between health effects and the ambient concentration of sulfur oxides and particulate mat ter have been described in preceding pages. This section is devoted to a summary of that evidence in an effort to present a perspective on using the available data to establish concentrations for both acute and chronic exposure associated with increased morbidity or mortality. The analysis in this section has been influenced by the many thoughtful re views published in recent years (78, 82-89). For the purposes of this discussion, acute expo sure is measured by the 24-hr average concentra tion of each pollutant. Current National Ambient Air Quality Standards for maximum 24-hr average concentration are 260 jig/m3 for TSP and 365 jig/m3 for S02. Exposures over shorter periods may be important, perhaps as measured by the peak hourly concentration in each 24-hr period. Exposures cal culated from different short term averaging periods arc highly correlated in most situations. The choice of method for measuring chronic ex posure is less straightforward, and can have a significant influence on the determination of con centrations associated with health effects. Most studies reported arithmetic average concentrations of each pollutant over some sampling period includ ing the study period. Although the sampling period did not cover an entire year in every instance, we express the values reported in the various studies as an annual mean concentration. Current National Ambient Air Quality Standards for annual mean concentration are 75 tig/m3 for TSP (computed as the geometric mean of 24-hr samples) and 80 (ig'nr for S02 (arithmetic mean). Since arithmetic October 1981 means were used almost exclusively for reporting particulate and sulfur oxide concentrations in the studies ofchronic exposure, these values have been used in summarizing the evidence. Differences be tween geometric and arithmetic means are usually unimportant compared to other sources of uncer tainty in measuring exposure. Many of the studies cited failed to obtain concur rent aerometric data. When available, those data were collected at one or a few sites distant from the homes of study participants. The air monitoring techniques were often primitive by current stan dards, with a resulting potential for substantial bias or variability in measuring concentration. Even when ambient concentrations are optimally mea sured, the implications for individual exposure are uncertain. Consequently, very great uncertainties about the actual air pollution exposures of study participants in most ofthe studies discussed w eaken analyses of the relationship between exposure and health effect response. For studies using Black Smoke (BS) to measure particulate concentrations, the conversion to TSP values is highly uncertain and depends upon condi tions in the study environment. We convert BS to TSP values using the results of Commins and Wal ler (89). Since their study was conducted in London between 1955 and 1963, the applicability to other sites or times is unknown. Although we use their conversion to unify the discussion, this introduces additional uncertainty. For the one New York study using Coefficient of Haze (CoHs), we use the con version developed in New York by Ingram and Golden (90). They equate 5 CoHs to 580 ug/m3 (TSP). Some studies have reported sulfate concentra tions, and there has been considerable interest in the fine particulate fraction (91). However, the correlation between TSP concentrations and its components has been consistently high in observa tional studies. Thus, these studies provide no basis for separately assessing the health effects of differ ent fractions by size or chemistry of ambient par- 271 UCC 057276 ticulate matter. Further understanding ofthe proper measure of particulate concentration in terms of health significance will come from advances in un derstanding of lung physiology and from exposure studies with animals. Assessing causal relationships from studies of association is a familiar problem for epidemiolo gists, and the problem is especially difficult in air pollution research. When exposures are near pres ent air quality standards, the health effects of air pollution exposure are likely to be small. Many other individual characteristics influence lung func tion and the risk of respiratory disease. Some of these, like smoking, occupational differences, and socioeconomic status, are well known but difficult to measure, others like passive smoking have been recognized only recently. The association of lung function and respiratory disease with these charac teristics is often much greater than the likely ef fects of air pollution. The possibility in any observa tional study that these factors have been inadequately controlled adds additional uncertainty to the inter pretation of the nonexperimental studies. Thus, the determination ofconcentrations associated with ad verse effects is tempered by recognition of these potential nonsampling errors. For all of these reasons, the epidemiologic data base is extremely weak In particular, it is insufficient to distinguish between a threshold hypothesis, that health effects are seen only above certain concen trations, and a monotonic exposure-response hy pothesis, that health effects increase (perhaps very slightly) with air pollution concentration over a very wide range. Although we favor the latter hypothesis as more physiologically plausible, we have chosen to interpret the evidence in terms of concentrations at which health effects have been detected. These values should not be interpreted as threshold values. Finally, SO* and particulate con centrations were highly correlated in many of the studies cited. Thus we cite concentrations jointly of SO* and TSP at which health effects have been detected, and then discuss the evidence for health effects of the individual pollutants. Health Effects of Acute Exposure to S02 and Particulate Matter The studies providing evidence for health effects resulting from acute exposure to SOz and particu late matter are summarized in Table 22. The selec tion criteria excluded studies of S02 or TSP expo sures above 1000 pg/m3, and the list is strikingly short. The two mortality studies cited (from the same group) found increased mortality associated with TSP concentrations of 500-600 tig m3 in con junction with S02 concentrations of 300-400 (ig/m3. These studies summarize a relatively small body of data from two winters in London. The individual studies do not suggest a threshold phenomenon. Although there is some suggestion of an association at lower concentrations, the evidence is very scanty. For all of the reasons discussed above, this inter pretation is subject to considerable uncertainty, and this explains in part the divergent views ex pressed by different reviewers. Time series analy ses of daily mortality records over several years have sometimes suggested small mortality effects of air pollution concentrations at much lower con centrations, particularly in association with particu late concentration in the New York studies, but the results have been highly dependent on model selec tion and are internally inconsistent. Only two reports of associations between morbid ity and 24 hour average pollutant concentrations are cited in Table 22, and one of these is again the study by Martin. Thus, the acceptable epidemiologic evidence for health effects in association with acute elevations of S02 or TSP concentrations below 1000 M-g/m3 consists of only two studies. Other reports, including those of Cohen (38), Van der Lende US), and Glasser and Greenberg (27) are suggestive but subject to numerous ambiguities related to meth- Table 22. Summary of evidence for health effect* of acute exposure to SO and particulate matter. Type of study Reference Effect* observed 24-hr average pollutant levels at which effects were detected. ta*'m TSP SOt Mortality Morbidity Martin and Bradley (It) Martin (SO) Martin (fO) Lawther et al. (Si, SS) Increase* in daily total mortality above the 15-day moving avenge Increase* in daily total mortality above the 15-day moving avenge Increases in hospital admission* for cardisc or respiratory illness Worsening of heslth status among 195 bronchitic* GOO 600 600 350 300 400 400 oOO 272 Environmental Health Perspectives ucc 057277 alth ects .icu- ;lec- po ngly the ated con- m3. iv of -ual non. -tion nty. iternty. exlalyears ects con:icu.!- bidions th ogic 'Ute JOO rts, W), but etb- ell ed. odology and interpretation. Although severe air pollution episodes have frequently been associated with excess mortality and morbidity, there is only a small body of evidence to document such effects at concentrations below 1000 ptg/m3. Health Effects Associated with Chronic Exposure to SO2 and Particulate Matter As noted above, the evidence for mortality ef fects of chronic exposure to SOz or particulate matter is inconclusive. Though several studies have found associations, the methodological uncertain ties are so great as to make these studies essen tially valueless for quantifying the exposure-response relationship. The morbidity studies that have found differences in levels of health effects in association ith differences in pollutant concentrations are summaiized in Table 23, and displayed in Figure 1. In these studies, upper and lower respiratory symp toms, chronic bronchitis and reduced pulmonary function were observed in association with TSP concentrations in excess of about 180 u-g/m3. In one study, acute respiratory disease was increased in association with reported TSP concentration of 135 ng m3 though these values were estimated from relatively weak aerometric data. As with the stud ies of acute effects, most of these studies could be interpreted as demonstrating that the prevalence of adverse health effects increases monotonically with exposure over the entire range of exposure studied. These studies provide little evidence to assess the health effects associated with elevated S02 concentrations along with moderate particulate concentrations. Although Hammer (T9) and the Salt Lake Studies (72) did report such associations, the problems with methodology and aerometric mea surement in those studies limit their value in this assessment. Though exposure to these pollutants at concentrations below those cited may imply some increase in risks, it will be difficult to resolve this question in an observational setting, because health effects of pollutants at these concentrations are likely to be small relative to effects of other factors which vary over communities. WCPtf** 4<4/aJt 1)0 SI so B 11 ; 1 1 M U> U* MS 1W < MO IBHHntM I */') Figum 1. Plot of studio* in which increased levels of adverse health effects were associated with chronic exposure to higher concentrations of TSP and SO,. Studies are plotted at the lowest concentrations at which increases wen seen and by the reference numbers in the bibliography. The dashed tinea correspond to the current National Ambient Air Quality Standards for annual mean concentration. BO Table 23. Summary of evidence for health effect! of chronic expooure to SO, and particulate matter. T\-p* of study Reference Effects observed Annual average pollutant levela at which effects noted, ue'm* TSP SO, Cross-sectional (four areas) Cross-sectional study serosa Britain Cross-sectional (two areas) Cross aactiotia) (four areas) Longitudinal and cross-sectional Cross sectional (two areas) Lumet eL (M, S7) Lambert and Reid (dl) Sawidti (ft) RudnfltetaL (#) Ferris etaL Hammer ito) Increased frequency of respiratory symptoms; decreased hing function in live-year-olds Increased prevalence at respiratory symptom* More chronic bronchitis, asthmatic disease in smokers; reduced FEV* Increased history snd symptoms of respiratory illness Higher rat* of respiratory symptoms; snd decreased lung function Increased frequency of scut* lower respiratory disease 360 200 270 2SS 180 136 225 100 12$ 125 55 <25 October 1981 273 ucc 057278 i Summary The studies summarized in Table 22 indicate that increased mortality and morbidity are associated with exposure to 24-hr average TSP concentrations of 500-600 pg/m3 and SO2 concentrations of 300-400 Mg/m3 and a temporary decrease in lung function has been associated with a TSP concentration of250 M-g/m3 and a S02 concentration of 300 pg/m3. This conclusion is based on only two independent stud ies. There is little evidence concerning health ef fects of short term exposure to only one of these pollutants. Various studies not accepted in this assessment have reported health effects at lower pollutant concentrations, but we believe that the evidence from these studies is inconclusive. The studies summarized in Table 23 indicate that increased morbidity is associated with chronic ex posure to TSP concentrations exceeding 180 pg/m3 (annual average). Though effects were found both with and without parallel increases in S02 concen tration, there is no basis in these studies for evalu ating the effects of elevated S02 concentrations without increased particulate pollution. Once again, one cited study (SO) and several studies not ac cepted for this assessment have reported health effects at lower concentrations and with elevated S02 concentrations, particularly the studies in the CHESS program. In our opinion, the evidence for health effects at these lower concentrations is in conclusive, but should be the subject of continuing investigation. Though we have focused on the evi dence from observational studies, the evidence from animal studies and controlled studies of human exposure must also be considered, particularly in relation to the less severe effects of short-term high exposures. These studies will also play an impor tant role in future efforts to link health effects with chemical or size fractions of the SOs-TSP pollution complex. Nonexperimental studies provide little information on this issue because of the collinearity of the components of interest. This will be espe cially important in studying line particulates. Although we have given single numbers as con centrations above which various health effects occur, these numbers are based on very sparse data from studies not designed to establish such values. Thus, the numbers are subject to uncertainty which is difficult to quantify. In view of the limitations of studies based on multivariate analysis of data obtained from sources not oriented to air pollution research, future stud ies will be most informative if they involve thor ough and detailed investigation of well defined pop ulations. Direct measurement and careful control of poten- 274 tial confounding factors will be especially impor tant, as will improved measurement of the air pol lution exposure of individuals. The need for such research may grow as energy usage patterns shift in response to limited availability of oil and natural gas. The public health significance of this question is sufficient to justify the commitment of additional resources to improving the data base on health effects of sulfur oxides and particulate matter. Many colleagues and aaaodatet have made helpful suggestions and constructive criticisms of earlier drafts of this paper. 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Health Effecta of Air Pollution. American Lung Assoc., New York, 1978. 88. Ferris. B. G., Jr. Health effect* of exposure to low level* of regulated air pollutants. A critical review. J. Air Pol Control Assoc. 28: 482 (1978). 89. Commins, B. T., and Waller, R. E. Observations from a 10-year study of pollution at a site in the city of London, Atm. Environ. 9: 44 (1967). 90. Ingram, W. T., and Golden, J. Smoke curve calibration. J. Air Poll. Control Assoc. 23:110 (1973). 91. Miller, F. J., Gardner, D. E.. Graham. J. A., Lee. R. E,, Jr., Wilson, W. ., and Bachman, J. D. Size considerations for establishing s standard for inhalable particles. J. Air Poll. Control Assoc. 29: 610 (1979). 276 Environmental Health Perspective* ucc 057281  rwninton*>' Inn. Finld**, j. Air dioiud* Me. Arch. the conduct "iity Health 3) Studies, 'overnment * Agency-| '* Commu> (CHESS); `tative*. is Mhinjton, < Holland, A. V., and Jn. Reap, 79). iy*a, C. G. ii*ea*e. I. it in New lotion RePubliahlnf iaeaae in Oiaacna- ocool, G. on, D. 0. k* Basin 0/1-74-04, sA^non. la-v. Air n Control enanent fan. AdPollution S. Gov- pended S. World Vaahing- denty of Dution. level* of ir Poll. from a -london. *ion. J. R. E.. ration* 4. Air ea Environmental Htalth Penptctivts Vol. il. pp S?7-i89, 1981 Mathematical Models of the Uptake of Carbon Monoxide on Hemoglobin at Low Carbon Monoxide Levels by Robert Joumard,* Mireille Chiron,* Robert Vidon,* Michel Maurin* and Jean-Marc Rouzioux* Coburn'* differential equation for the uptake of carbon monoxide by hemoglobin and two particular type* of tolution of thi* equation were contidered and the Mlution* verified for a (roup of healthy adult* contittinf of 73 non*mokin( pedestrian* or car patsenfert exposed to low level* of carbon monoxide as experienced in the city of Lyon. The CO level* at the breathing level and the walkinf speed of the subjects was continually measured, and the carboxyhemoclobin levels determined sttlie beginning and the end of each test journey. The values of ell the other relevant parameters were also determined. The half-life of carboxyhemoglobin was studied a* a function of the degree of activity, the age, the sex and the height of the subjects. Finally a mathematical model was set up to represent a periodic uptake of CO which made it poesible to estimate the variations in the carboxyhemoglobin level for any subject during a period of a day or a week without any need to know the initial level. There is normally a very small concentration of CO in the air as a result of natural phenomena, its level being between 0.01 and 1 ppm. Measurements carried out on the Isle of Sark (1), where motor vehicle traffic is prohibited, confirmed that the CO levels were always less than 1 ppm. Measurements made in urban areas in various places in the world over many years have resulted in a considerable quantity of information on CO levels. The exact location where the measurements are made is important, since the highest concentrations are found in the midst of a stream motor vehicles and also inside such vehicles, as confirmed by this investigation. Pedestrians walking along the side walks are exposed to a lesser concentration of CO than are motorists. People who are obliged to remain at certain critical locations such as toll "Intthut de Recherche d* Transport*, Conti* devaluation et d Recherche de* Nuisances at da I'Enargia, BP 75, 89672 Bi on Cddex, Franc*. `Faculty de Mddcdne Alexis Carrel, Laborxtoire de IMdedne Legale et Toxicologic' Rue Guillaume Pandin, 69006 Lyon, France, October 1981 booths, garages or in traffic jam in enclosed and poorly ventilated streets are exposed to high CO levels due to road traffic (2,3). In order to obtain some idea ofthe conditions, a person moving within a city will experience CO levels having an average level for the hour in excess of 30 ppm U). American standards for permissible levels to which the public may be exposed are in fact sometimes exceeded Dangerous HbCO Level and Particularly Vulnerable Subjects The effect of carbon monoxide is to reduce oxygenation of the tissues and this effect may be experienced immediately or after a longer period of time. Any increase above the endogenous level can in theory be harmful for a person having an extreme requirement for oxygen, and who cannot compensate a reduced supply of oxygen by physio logical means. Such subjects consist mainly of people suffering from coronary atheromatic ischaemia or from cerebral vascular deficiencies. Also at risk 277 ucc 057282 here are people suffering from pernicious anaemia or from respiratory deficiencies, patients recovering from major surgery or premature babies. Aronow and Isbell (7) refers to a "critical" carboxyhemoglobin level of between 0.025 and 0.030 for angina pectoris sufferers, such a level giving rise to an appreciable reduction in the time elapsing before the onset of a painful attack following a given physical ef fort. The World Health Organization (S) estimates that the level for the population exposed to atmo spheric pollution should not exceed these limits. In the case of our sample, the 0.025 level was exceeded for 19 out of the 73 subjects (pedestrians or car passengers) as a result of their displacement in the city. However this level can in theory easily be exceeded for subjects remaining in heavily polluted localities. The 0.025 carboxyhemoglobin level would result from an exposure to a 13 ppm CO concentra tion for more than 24 hr. Kinetics of the Uptake and Elimination of Carbon Monoxide Symbols and uriits used are summarized in Table 1. We used SI units, but for CO concentration used ppm because it is independent of the temperature. Differential Equation Cobum et al. (8) have proposed the following differential equation (1) for carboxyhemoglobin level as s function of time: Vb AflOj/Pc^ (1/Dl + Pb- Ph^a) dtCOVdt + [CO] - Pico WtVPc^ + Vo, AflOtJ/Pe^ (VDl + Pb_- Ph^a) < 13.3 kPa (100 mm Hg) and 6.3 kPa (47.5 mm Hg), respectively. The value of P<0 is directly related to that of C by the equation: P<0 * PB x HrC. We also assumed that y - HbCO * 17 [CO]/[Hb], (or 1000 [COJ/1.316 [Hb], if (CO] and [Hb] are in ml/100 ml and g/100 ml of blood, respectively), and similarly that HbX * 17 [X]/[Hb], The value of Dh is related to the height and body surface of the subject and the value decreases with age. A number of relation ships have been proposed, and the resulting calcu lated values may difFer 20 to 30% for the same subject. We used the following relationships (9): For a man aged 18 or more: Di. - 0.329# - 0.000135Y - 0.318 For a woman aged 18 or more: Dl - 0.119#-0.000087F-0.015 For a child: Dl - 0.117A - 0.022 The value of Vb for adults depends on the sex of the subject and we assumed values of to 13 and m/15 for male and female subjects, respectively. For children we assumed values of 0.071m, 0.075m and 0.080m for 15, 10 and 1-6 year old subjects respec tively (10). The value of VCo for a standard male subject has been given as 5.2 x 10"6 mmole/sec (0.007 ml/min) (8). We assumed that the value varied with the total hemoglobin level VJHb] (for a standard male subject, Vb - 5 liters and [Hb] - 155 g/L blood), giving Vco - 5.2 x lfr* VhtHbJ/Sdoo) The degree of alveolar ventilation is proportions! (11) to the oxygen consumption V'A - 19.63Voa, and this consumption depends in turn on the power expended by the subject (12). Thus we have: VK - 4.33 x 10-* P Numerical Value* of the Different Parameters The values given below are statistical average* for subjects in good health and very different values can apply in individual cases, particularly in the case of subjects suffering from certain diseases. The value of M can vary from 185 to more than 250, and we assumed a value ofM - 250. [Og] was givens value such that: [O*] + (CO] + [X] * 8.92 mmole/ liter of blood (200 ml/L) PB was assumed to have a value of 99.3 kPa (745 mm Hg) for the town of Lyon, which is at an altitude of 120 m above sea level. Pcot and Phjo were assumed to have value* of 278 Power Expended The power expended is the sum of the basal metabolism, the muscular power and the specific dynamic action ofthe foods: P MB + PM + SDA. The basal metabolism is proportional to the surface area of the body: MB * Ax. Pandolf et al- (IS) have established an equation giving the rate of energy expenditure for a subject when standing or when walking at different speeds and when carrying or not carrying a load. P (SDA - 0) - 1.5m + 2(m + m') (m'/mf + (m + m') (1.5V* + 0.35oV) Environmental Health Perspectives ucc 057283 Hg>. o also '.000 Oml larly lated and tionalcu- ame : x of n, 15 For and pec- has min) the nale ing: inal and -ver .sal Sc )Jl ace ion ect >da + 7 * Symbol .4 ttti Hu C ICO] d hI ft) in H [Hb] HbCO HbOi HbX HEL k K & K, K, m m' Jf MB I0J fc. ;s vfi *d* 5DA V Vvco IT*t t (XI Y 1 t fi fe to a & Unit m* ppm mmole/1. of blood romole/sec/kPa m g/1, of blood fraction fraction fraction fraction fraction/ppm fractionippm/iac fraction ftaction/iac fr*ction*/sec kg kg W mmole/1, of blood kPa kPa kPa kPa kPa W W w ml* mmole/aac liter* mmoie/iec mmole U/kf W/n? mmole/L of blood yean fraction fraction fraction fraction fraction per cont sac October 1981 Table 1. Symbols and unit* used. Definition Body surface area Other form of the coefficient in Cobum's equation Other form of the coefficient in Cobum's equation Carbon monoxide concentration in air CO level in blood A coefficient depending on the type of meal Pulmonary CO diffusion capacity A coefficient depending on the condition of ground surface Function used for resolving Cobum's equation Function used for resolving Cobum's equation Height of subject Hemoglobin level Carboxyhemoglobin level with respect to the total hemoglobin Oxyhemoglobin level with respect to the total hemoglobin X hemoglobin level with respect to the total hemoglobin (e.g., nitroeylhemoglobin) Limit cndogeneou* carboxyhemoglobin level with respect to the total haemoglobin A constant for carboxyhemoglobin level Rate constant for carboxyhemoglobin formation A coefficient employed in step-by-step calculation: carboxyhemoglobin and oxyhemoglo bin levels Coefficient employed in step-by-step calculation: partial rat* constant for CO uptake Coefficient employed in step-by-step calculation: partial rate constant for CO uptake Weight of subject Load carried by subject Haldane's constant Basal metabolism Oxygen level in the pulmonary capillaries Fraction of the daily energy allowance for one meal Total power expended by the subject Barometric pressure Average partial CO pressure in the pulmonary capillaries Average partial oxygen pressure in the pulmonary capillaries Vapor pressure of water Partial CO pressure in inspired air Muscular power (expended) Instantaneous specific dynamic action per 1 U of food ingested at last meal Specific dynamic action of foods Walking speed Alveolar ventilation rate Blood volume Rate of cndogeneou* CO production Volume of oxygen consumed Heat production to food/kg of body weight Basal metabolism per unit body surface area Possible gas level other than 0, and CO in the pulmonary capillaries (e.g. nitric derivatives) Age of subject ( HbCO): proportion of carboxyhemoglobin with respect to total hemoglobin particular periodic solution of Cobum's equation value of y at time to Initial measured value of HbCO Final calculated value of HbCO Final measured value of HbCO Inclination Kronecker symbol (1 - standing, 0 - other cases) Time constant Half-lifc 279 ucc 057284 A The validity of this equation has been verified for young male subjects of average height and weight (1.75 m, 78.2 kg). The equation gives the value of the total power expended, including the basal metabolism, but for a zero SDA value. We also considered Scherrer's findings US); he stated that the power expenditure amounts to 1.2 times the basal metabolism for a standing subject and to 1.1 times the same basal metabolism when the subject is sitting and at rest (and 0.9 times when the subject is asleep). We made use of a coefficient d to allow for these factors. Certain authors have shown that a female or an overweight subject expends less energy when at rest as a result of a smaller proportion of muscular tissue which accounts for the difference in metabolism with effort. The additional expenditure of energy as a result of performing work PM is the same (LA). If we wish to apply the above equation for a subject of either sex then the first term (1.5m) in the expres sion must be a function of the sex. We accordingly replaced the first term by Adx, where x is a function of both age and sex (15) and the second term appears only for a stationary, standing sub ject. We then have: P(SDA * 0) - Adx + 25(m + m') (m'/mf + e (m + m') (1.5V + 0.35aV) (1) The SDA or additional postprandial heat is de fined as the increase in the rate of energy ex penditure resulting from the ingestion of a meal, the other conditions being basal. This specific dynamic action varies with time and it rises to a maximum value some 2 hr after the ingestion of a meal (15). Furthermore it should be noted that the SDA value depends on the type of food consumed and it can be assumed, as a first approximation, that it is a function of the energy value of the meal, this latter being a function of the age and sex of the subject. It is also proportional to the weight of the individual and we can accordingly refer to w,, the heat allowance per kilo of weight of the subject. We therefore have: SDA - mw, (Y, sex)p, sda where sda is the SDA for 1 kJ of food and pr is the fraction of the daily energy allowance for each meal. What is the relative importance of MB, PM and SDA? With our mixed group of subjects made up half of pedestrians and half of car passengers we had values of MB 91, PM m 80 and SDA 23. On considering a theoretical subject over a period of one week we obtained average values of MB, PM 280 and SDA of 78, 13 and 17, respectively. Thus the SDA is approximately 20. It represents nearly a quarter of the basal metabolism to which we need to add the muscular work rate which can be greater than the basal metabolism. Thus the SDA is not negligible. Solving the Differential Equation Three methods of solving Coburn's equation are considered. Fint Method: Step-by-Step Solution. Let y, and y2 be the carboxyhemoglobin levels at times t, and tx, respectively; if C remains unchanged from time to time we can write: Vs * Vi + (** " fi) { Aj - [Ki/(K0 - y,)] } where Ao 17(8.92 - fXl) IHbJ 17 A, VJlHb] [Pc0 + MP. x 10-*C M { (1/Dl) + [(PB-PV)/VJ (1) ,1 (2) * ` & [ ](8.92 - [X])PeQ MVbi(l/DL) + I(P.-PHi0)^J (3) The advantage of this method of solving the equation in comparison with the other two methods considered below is that no assumptions need to be made. The disadvantage is that an error is intro duced, since no distinction is made between the tangent to the curve and the curve itself at each point. Second Method: Analytical Solution. If we ignore [CO] (and [X] but it is not strictly necessary) with regard to [OJ, then the basic equation can be put into the form of a linear first order differential equation: (k/K)dyldt + y - JkC + HEL > This is also the form of equation proposed by Chovin and Richalet (17) except for the inclusion of Environmental Health Perspective* UOv 057285 Y Tius the near'v a m d greater is not :ion are Let yi times tj id from 1} (1) <Z) g the ithods itobe intron the - each If we jsary) an be ential (4) id by ion of tivea the HEL term, which was based on the results of the experimental investigation by Hanks and Farquhar (15). Peterson and Steward (19) have verified it for constant concentrations (50 to 200 ppm) in industrial conditions on the whole. If, in addition, C can be regarded as a linear function of time (C " at + CO then the analytical solution to the equation becomes: y - HEL + + Ci} + {y, - k [a (Jfc/JO - C,] - HEL} r*" where 17 x 8.92MP, x l(H Ffo/Hb] 17F, x 10* ^Hb] [(1 DI O + KPh- level. This well-established disadvantage can dis appear if we ignore [CO] with regard to [02] and if the parameters K, C and HEL are periodic func tions of time (k being constant for a given subject). It is possible to find a periodic solution by using some analytical properties. For convenience, we use a more mathematical language in this section. If we rewrite the equation dyidt + a(t)y * 6(f) with ait) K(t)/k bit) - K(t) C(t) + K(t) HEL(t)/k this is a linear differential equation of the first order, whose general solution is yiO - yofit) + g(D with the new functions (SO) HEL 17 x 8.92flf^co Pc0j[Hb] [(l/b[) + [<Pb - AO exp {- f a(u)du) A0) * 1 and The time constant k/K is then given by: 8.92M /l , - -- n (_ + \dl -/> \ v. / g(t) - AOJ b(u)/fiu) du g(0) 0 If a(t) and bit) are periodic functions of period T and if aft) a* 0, it may be easily shown that The constant k is such that the HbCO level follow ing an infinite time of exposure to a concentration C will be kC + HEL. In particular, the value of* is a function of the hemoglobin level and is independent of the level of activity.. The value of the factor K, which defines the rate of uptake of CO by the hemoglobin, increases with the degree of alveolar ventilation and hence with physical activity. Stan dard values of k and K are listed in Table 3 below. The limit endogenous carboxyhemoglobin level HEL al-o increases with the amount of physical activity, but the level remains very low (< 0.002). This analytical method of solving the equation er ables us to determine any HbCO level, if the initial level is known, provided the variation of C is linear and K remains constant during the interval concerned, which are not unreasonable assumptions. Third Method: Periodic Solution. The two methods of solving the differential equation described above depend on a knowledge of the initial HbCO October 1981 m - g(t)AO/U ~AO) + git) is a particular solution which is periodic (of period T), and every general solution y0 fit) + g(t) con verges towards ytt) as f is increasing (t * 3 or AT) (21). Then the yit) function is a convenient analyti cal tool to describe the actual variations of the carboxyhemoglobin level yit) if the data used X.C.HEL are periodic ftinctions of time. So we make the realistic assumption that these data rep resentative of the activity and CO exposure of a person are periodic over a period of 24 hr, or, better, over 7 days; moreover, since these varia tions are known, it is no longer necessary to mea sure or to choose arbitrarily the initial HbCO level to describe the variations of the HbCO level in any time interval. In practice, we obtain the values of K, HEL and C every 15 min (during 24 hr or 7 days) and calculate the basal integrals fit), git) at the same moments by numerical methods on a comput er. 281 UCC 057286 i For the second and third methods, we ignore [CO] with regard to [O2]: the greater the value for HbCO, the more k and HEL are overestimated. We can give [Os] its initial value [8.92 - (Hb/17) 3/1] or its mean value. Besides, if we do not ignore [X] when we can estimate it, we must replace 8.92 by 8.92 - [X], Experimental Verification In order to validate the theoretical analysis, we carried out tests with a total of 73 subjects whose ages varied from 18 to 60 years and who all stated that they were nonsmokers. This sample was divided into two groups of subjects: one group consisting of car passengers who remained seated in each case for the duration of a test journey within and around the town, and a second group consisting of pedestrians who walked at a nearly constant speed in each case in the actual polluted atmos phere existing in certain streets of the city of Lyon. The pedestrians were accompanied by a technician who ensured that the walking speed was main tained throughdifr each test journey on making measurements at intervals of 3 to 4 min (the mean speed is 1.09 m/sec). Samples of blood were taken at the beginning and end of each journey and these samples analyzed in order to obtain values of [Hb], yim and y^. The analysis of the blood samples was based on the method developed by Boudene, Godin and Roussel (.22), where the proportions of hemoglobin and CO in the blood were determined by means of infrared spectroscopy. The carbon monoxide levels in the atmosphere were measured on a continuous basis by means of a polarography technique by using a portable Ecolyser and a paper recorder. For each ofthe subjects we had in addition to our knowledge of the values of [Hb], y},,, y2m and C, information concerning the sex, weight, height and age of the subject, the load carried by the subject, the time of day when the subject undertook the test journey and continuous information on the walking , , , J | , , Table 1 Average valuee of the different parameter! for the ample eubjeeti. Parameter Men Women n As* m, kg t\ kg H.m C, ppm V, nvtec Duration, min D,, mmole'iec/kPa A, m* K.Btm x Mr*, mmoie/eec ?>* *. V*m . rnn Activity A Activity B 37 32 147 71 3 1.75 13.9 0.70 126 0.190 1.85 5.46 5.55 0.019 0.007 0.023 0.008 236 140 36 32 133 57 3 1.62 13.7 0.64 123 0.175 1.59 3.78 3.49 0.018 0.006 0.021 0.006 208 117 282 Environmental Health Perspective* ucc 057287 j our -d C, >r the 2 i**s speed of the pedestrians. Knowing the initial level in each case we calculated the successive carboxyhemoglobin levels throughout the duration of the test and the final level for each subject. An example of the results obtained as a result of mak ing these calculations is given in Figure 1. The calculations were made on using the analytical method without approximate rectification of [02] to solve the differential equation and also on using the step by step method on estimating HbX O or HbX 0.010. In Table 2 we list with respect to the sex of the subjects, average values of the different pa rameters for the sample subjects: age, [Hb], m, m', H, CO concentration, V, duration of the tests, Z>L, A, Vb, VcO, ylm, y2m and the half-life for the subjects when at rest (A) and when walking at a speed of 4 km/hr (B). As a verification of the validity of the theoretical calculations we compared the final measured levels with the different calculated values. We applied statistical tests to the pairs of values (yim, y2m), (yzm, yii) and ty2Jylm, y^yim) in order to ascer tain if there were any significant differences be tween them (at 5%) for different subsamples as regards the sex and the type of activity. As a result of this it was found that the*initial and final mea sured levels ylm and y2m were significantly differ ent (p * KT7). The method of calculation employed did not have any effect on the results; the differ ences in the levels determined by each method were not significantly different from one another. There was no significant difference between the calculated and measured levels either for the whole sample of subjects or, except for the case of male pedestrians, for any subsample. This was found for both the (y2m, yfc) and the (y2Jylm, y^Vim) Pw ofvalues. We calculated also A - [sign of(y2m - ylm)] (Kj* * ysmVVim. which is positive when the calcu lated change is too great. Mean A showed that the calculated changes were generally lightly too small and in the case of nude pedestrians clearly too small The calculated results as a whole were very satisfactory for all subjects and particularly so in the case of female pedestrians, thus we can con clude that the two method (analytical or step-bystep solutions) were equally valid, at least when the level of HbX + HbCO is low. The analytical solu tion is therefore to be preferred for environmental pollution since it is easier to use; we can give if necessary to [OJ its initial or mean value. The differential equation for the uptake-elimination of carbon monoxide by hemoglobin and the use of the selected parameter values to model the phenomena is generally valid, although it would appear that the changes in the HbCO levels are underestimated for October 1981 male pedestrians (the degree of alveolar ventilation is no doubt insufficient in the model). Applications Effects on a Particular Subject The procedure employed to verify the validity of the theoretical approach can also be applied to real life cases. This requires measuring or estimating the CO concentrations throughout the period of time being considered and assuming an initial HbCO level. We can then determine the effects of the changing environment on a real or imaginary subject. However, it is often difficult, ifnot impossible, to obtain information on the CO concentration in the air and on the level of activity of the subject at each instant. We must therefore ask what error would be introduced on using average values of CO con centration and/or of the level of activity of the subject? To answer this question let us consider a female subject exposed to an average CO concen tration of 15 ppm and walking along at an average speed of 1 m/sec, with both these values varying from zero to twice the average level. The initial level of HbCO is assumed to amount to either 0.010 or 0.050. When calculating the results for this case it was found that no errors are introduced when assuming these average values despite the random variations in the instantaneous values of CO con centration and the level of the subject's activity. In general it was found that only a small error is introduced by assuming an average value for the level of activity but that a significant error can result when assuming an average value for the CO concentration and the period of integration involved is greater than the half-life (see below). The error, however, becomes negligible for periods of integra tion which are less than the half-life by an order of magnitude or more. Graphs for Determining the Uptake and Elimination of CO Under Different Conditions A desk calculator has to be employed to obtain analytical solutions of the differential equation, and we have therefore produced a aeries of graphs resulting from theoretical calculations which show the way in which CO is taken up or eliminated from hemoglobin for CO concentrations of 0, 10, 30, 50 283 ucc 057288 and 100 ppm for an average (French) women (1.60 m high, 55 kg in weight): . Level of activity A: Subject seated and at rest. VA * 4.06 mmole/ sec * 5460 ml/min Level of activity B: Subject walking along at a speed of4 km/hr. VA * 8.87 mmole/sec (11930 ml/ min) Level of activity C: Subject involved in some strenuous physical or sporting activity such as cy cling (at a speed of 15 to 20 km/hr), football or swimming, resulting in a doubling in the value of VA compared to the value for activity B: VA 17.74 mmole/sec - 23860 ml/min Two sets of curves are shown on each of these graphs for the different CO concentrations and levels of activity, one set originating from a aero and the other set from a 0.100 HbCO level. Reference can be made to this graph in determin ing the approximate fixation-elimination of CO for a subject for a given initial level of HbCO and for continuously varying concentrations of CO in the atmosphere and of levels of activity of the subject. The graphs include curves for each of the three levels of activity for each of the CO concentrations. As an example of the use of these graphs we can consider (see Fig. 2) the case of an average female subject having an initial HbCO level of 0.020 who is successively exposed to different CO concentra tions as follows: 30 ppm for 1 hr while at rest, HbCO 0.028; 50 ppmforlhrwhilewalkingalongat a speed of 4 km/hr, HbCO 0.049; 0 ppm for 1.5 hr while at rest, HbCO 0.037; 100 ppm for 1 hr while at rest. On referring to the appropriate graphs for these exposures it will be found that the final HbCO level for the subject amounts to 0.067. Model of Periodic Conditions Ott and Mage (3) used a simplified point-by point determination of the HbCO level, CO eoncen- 284 Environmental Health Perspective* ucc 057289 the tration being known hour by hour and the physical total time (corresponding to 14% of the working ec* activity being constant. For a more precise calcula time) and the average CO concentration (working "lPt tion, a point-by-point determination is only possible and rest periods combined) amounted to 3.7 ppm. ons. in the case of relatively short periods of time. For Second Case. A saleswoman lived on the can longer periods of time and in cases where the CO outskirts of a large town and worked in a shop nale concentrations and the levels of activity of the located in the main street and in the vicinity of road no is subject vary in a periodic manner it is better if we traffic from Tuesday to Saturday. She travelled to ltra- make use of the periodic method of solving the work by bus and spent a part of the weekend in the est, differential equation. We employed this method for country. The CO concentrations taken into account igat solving the differential equation for two different were those actually measured at the side-walk of 5hr cases, the time base being a quarter of an hour and the main street. The CO concentrations in the other hile the most significant period for the calculations locations and the levels of activity taken into 5 for being 1 week. The details of these two cases and the account were as estimated. On assuming the sub bCO results of the calculations were as follows. ject to be a nonsmoker, it was found that the HbCO Firtt Coat. A customs officer whose place of level oscillated between values of 0.002 and 0.022. work was at the side of the road near the French- The average CO concentration amounted to 4.7 Swiss frontier lived in the surrounding countryside. ppm (Fig. 3). The CO concentration at the place of work was In order to have some idea of the effects of measured during the winter of 1978. It was found pollution due to motor vehicle traffic in comparison that the carboxyhemoglobin level varied from 0.002 with the effects of smoking cigarettes (assuming 10 to 0.033. The level exceeded 0.025 for 3.3% of the inhalations of 30 ml at 4% CO concentration per im m u - i* i Ficuss 3. Simulation of tho periodic variation in HbCO level for a nonsmoking saleswoman and for a subject smoking a total of 103 cigarettes per week. October 1981 285 ucc 0S7290 cigarette) we also considered the case of the same saleswoman smoking at the rate of one cigarette per hour (103 cigarettes per week). The results of the calculations for this case are also shown on Figure 3. The HbCO level oscillated between values of 0.017 and 0.087, while the average CO concentration due to both the motor vehicle traffic and the smoking amounted to 18.3 ppm. The HbCO level exceeded 0.025 for 97% and 0.040 for 79% of the time. The levels were in general some four times greater for the cigarette smoking than for the nonsmoking subject. The simulation of periodic variations in carboxyhemoglobin levels would appear to be a very useful technique in assessing the effects of carbon monox ide pollution of the atmosphere and of the varia tions in the actual CO concentration. The calculated HbCO levels given in the examples above are quite consistent with the HbCO levels quoted in the literature (n~28). It is necessary, however, to have information on the behavior of the subject on a quarter of an hour to quarter of an hour basis, but there are no problems in making assumptions concerning the bdftavior of a subject over certain very long periods of time (nighttime and rest periods). It is accordingly possible to determine the effects of any particular variations in CO concentra tions during specific periods of time (e.g., during working hours or when travelling). Thus this tech nique has many potential applications. Half-life of the Carboxyhemoglobin Given a constant CO concentration in the air, the time involved for the HbCO level to change from level y] to level y2 is given by: At -- t log HZ*Skz* y2 - HEL - IcC If the atmosphere is unpolluted (C - 0) then At is the period of time during which the HbCO level decreases from y, to y2. Thus we can determine, for example, the time needed for the HbCO level to fall from 0.200 to 0.010 and from 0.50 to 0.10 for the three standard subjects (male, female and child) and for the previously defined levels of activity A, B and C (Table 3). If we neglect HEL in the equation for the value of At (HEL is always small and is a function of the level of activity of the subject), it then becomes a simple matter to determine the periods of time for the initial HbCO levels to be halved. The times At are then independent of the initial and final HbCO levels, and they depend only on the levels of activity ofthe subjects and the physiological factors involved. Thus we can determine the half-life (t^ * t log 2) in each ease, this being the period of tune for the HbCO level to fall to half of any given value in an unpolluted atmosphere (Table 3). The real half-life is a little lower because we ignore [CO] with regard to [OJ. The lower the value of th, the faster will any HbCO level be reduced to one half in an unpolluted atmosphere, and conversely the faster will the new level be doubled in the case of a constant concentra tion of CO, given that At is proportional to t for such changes in level. The time taken for the HbCO level to double will in fact be proportional to t (or to t^) the value ofthis time constant in turn depending essentially on the value of y2 with respect to the absolute maximum level kC, Thus it would be important to have a good knowledge of half-life. It is interesting to consider what are the population groups (healthy subjects) that are most sensitive to CO pollution in terms of half-life values. The results of the calculations for our sample subjects showed that the standard deviation for the half-life values for either sex amounted to 8%. Thus calculated individual half-life values will deviate appreciable Tabla 3. "Standard" veluee, for 30 year-old men and women and for f ytars-old children, of the constant k, the alvtolv ventilation rat* V,, the rate constant for HbCO formation K, th* half-life, the time need for the HbCO level to fall from 0.200 to 0.010 and from O.OsO to 0.010 in unpolluted air, for th* levels of physical activity A (at rest-sitting). B (walking 4 km/hour) and C (strenuous or sporting activity). Men, k 0.00183/ppm Activity Activity Activity level A level B level C Women, k 0.00202'ppm Activity Activity Activity level A level B level C Children, k * 0.00223 ppm Activity Activity Activity level A level B level C V., nunole/sec K* 10-7. fraction/ppm/sec Half-life Tl.. min T<0.20-*<x01),min t(0.06- 0.01), min S.17 0.96 223 1030 676 10.88 1.S1 131 687 321 21.77 2.86 90 402 220 4.06 1.11 210 973 643 8.87 1.91 122 646 299 17.74 2.75 85 379 207 3.23 1.89 162 706 494 6.12 2.16 120 535 293 10.26 2.81 92 410 Environmental Health Per- ves ucc 057291 n At is > level ne, for V' or ie ;hild) ity A, value of the mes a ne for .es At 4bCO ;ls of iCtors " f tune value ? real [CO] !1 any lluted 3 new itrar for fbCO (or to nding o the d '* it. 4 ation ve to suits owed alues ated iable oo t* ndC ity C JS 31 ivts HbCO half-life. from the average and the actual deviation will be even greater in the case of the actual population. The half-life increases with age, the increase being rapid up to the age of 20 years, after which the increase with age slows down (Fig. 4). Age has a greater effect on the half-life than does the sex of the subject. Thus it may be seen from Figure 4 that the half-life for subjects at rest doubles as the age increases from 2 to 70 years, whereas the difference in half-life between male and female subjects does not exceed 6%. The half-life decreases with physical activity, the effect here being about the same for both male and female subjects but less pronounced for children where the muscular power expended is a small proportion ofthe total power expended. The degree of variation in the half-life with age or the sex of the subject decreases as the level of activity increases. We also studied the effect of the height on the half-life in the case ofhealthy subjects whose weight was an optimum with respect to height according to the relationship: m " 75H + 0.25F 67.5 for a male subject, the weight being assumed to be 5 to 10% less for a female {29). Height had only a slight effect on half-life in the case of female subjects involved in a low level ofactivity, when rVfe was found to increase with height. October 1981 C nclusions The uptake-elimination of carbon monoxide by hemoglobin, i.e., the variation in the level of carboxyhemoglobin (HbCO) of a subject, can be defined by a fairly complex differential equation which involves a number of physiological parame ters. We verified the validity of this equation on a sample of 73 subjects made up of persons of both sexes, and for different levels of physical activity and low carbon monoxide levels. As a result of our tests on these sample subjects we established the validity of two methods of simulating the uptakeelimination of carbon monoxide which take account of the nonpathologic variations for individual sub jects. Thus the HbCO levels at each instant of a given period of time (day, week, etc.) can be predicted with reference to initial level and on taking account of the applicable conditions as a result of an analytical method of solving the differ ential equation (actual calculations in each case or use of an existing set of graphs based on previous calculations). This can be done better by a mathematically based simulation of the periodic variations in HbCO levels without reference to initial level. The HbCO levels depend first of all on the CO concentration in the atmosphere and then on the level of physical activity, the age (the half-life increasing with age) and finally on the sex (the half-life is a little shorter for the female sex) of the subject. It would appear that the HbCO levels predicted by the periodic simulation are a function of the HbCO half-life (as determined by a fairly simple calculation) but this matter should be the subject of a more systematic statistically based study. Although we did not study the matter in any detail, it appears that subjects suffering from certain ailments and in particular from respiratory deficiencies for whom certain physiological vari ables deviate appreciable from the normal values can have carboxyhemoglobin levels that are signi ficantly different from those encountered in the course of this investigation. We need more detailed information for such eases. It is difficult to reach any conclusion with regard to the short-term and long-term effects of the low carboxyhemoglobin levels that have been observed in a nonsmoking population. With the exception of people who are exposed to the atmospheric pollu tion due to road vehicle traffic, in particular be cause of their occupation, it appears however that there are no effects on either the alertness or sensory perception of pedestrians or car passengers making journeys of short duration in the city of Lyon. For the car passengers in our sample, who 287 UCC 057292 k were the subjects exposed to the highest level of atmospheric pollution, the HbCO level amounted to 0. 027. on the average, at the end of their test journey. The levels of atmospheric pollution nor mally encountered can however have effects on advent of arteriosclerotic lesions. Thus such levels are sufficient to result in the occurrence or an increase in the seriousness of acute ischaemic incidents in subjects who already suffer from artery deficiencies. Apart from being useful in establishing carbon monoxide atmospheric pollution indices, the results of this study may also contribute to the establish ment ofthe standards for acceptable carbon monox ide concentrations on the basis of the following approach: establish the carboxyhemoglobin levels that must not be exceeded for both healthy and pathological subjects; determine the CO concentra tions that are in agreement with these carboxy hemoglobin levels by simulating the cyclic varia tions as well as employing other techniques. In making this approach, it must be understood that there is no such thing as a population of average subjects^ Jiut the physiological characteris tics and hence tne sensitivity to the effects of carbon monoxide vary in accordance with a Gaussian distribution about the mean values that we have considered here for healthy subjects. There is also the fact that there are pathological variations of physiological data for a significant proportion of the population. More generally, the results ofthe study can be of use whenever it appears to be necessary to give proper attention to certain periods of time that are being studied out of their normal context (e.g., in the case of industrial medicine studies periods of time, other than the concerned with work high carbon monoxide concentration considered periods, could affect carboxyhemoglobin levels), first for low pollution, because the precision of certain methods is a good as low is HbCO level. This study has been the subject of an internal report (JO). REFERENCES 1. Calc, F. V. Comparative effect* of atmospheric pollution and cigarette smoking on carboxyhaemoglobin levels in man. Nature 255: 699-701 (1975). 2. Borgeat, W. M. A., Oiberardinia, L.. and Speixer F. E. Health effect* of exposure to automobile exhaust. 5. Expo sure of toll booth operator* to automobile exhauat. Am. lnd. Hyg. Ataoc J. 38: 184-191 (1977). 3. Kohl, U., and Lob. M. Risque* d'oxycarbonisme chroniqu* dana let geragea. Schweia Had- Wocbanachr. 106: 50-56 (1975). 4. Deliey, J., Joumard, R., and Vidon R. Pollution par ie monoxyde de Carbone i l'inttriew d'une voiture en circula 288 tion. Poll. Atm. 72: 313-319 (1976). 5. World Health Organization. Environmental Health Criteria. 13. Carbon monoxide, WHO, Geneva, 1979. 6. Joumard R., and Vidon R. Diaperaon dans une rue en U. 3. rtaulut* statistiques de$ teneura et trafics. IRT-CERNE report, Bron, France, 1980. 7. Aronow, W. S., and Isbell, M. W. Carbon monoxide effect on exerciie induced angina pectoris. Ann. Int. Med.. 79. 392-396 (1973). 8. Cobum, R. F,, Forater, R. E. and Kane P, B. Considera tion* of the physiological variables that determine the blood carboxyhemoglobin concentration in man. J. Clin. Invest 44: 1899-1910 (1966). 9. Giammona, S. T. J., and Daly, W. J. Pulmonary diffusing capacity in normal children ages 4 to 13. Am. J. bis. Child. 110: 144-151 (1965). 10. Osgood E. E. Pediatric* 15: 000 (1955). 11. Gaktti, P. U Lee Ochange* reapiratoire* pendant l'exerdce muaeulaire. (Respiratory exchanges during muscular effort). Helv. Physiol. Acta 17: 34-61 (1959). 12. Scherrer, J. Physiologic du Travail (Physiology of work). Vol. 1. Masson. Paris, 1967. 18. Pandolf, K. B-. Givoni, B., and Goldman, R. F. Predicting energy expenditure with load* while standing or walking very slowly. J. Appl. Phyaiol., 43: 577-581 (19T7i 14. Gehlsen, G. M., and Dill D. B. Comparative performance of men and women in grade walking. Human Biol. 49:381-386 (1977). 15. Keele and Neil. Sampson Wright's Applied Physiology, 12th Ed., Oxford University Press. 1971. 16. Apfelbaum, M., Bostsairon, J., and Duret F. Physiologic, Vol 2. Vigot Frtres, Paris, 1972. 17. Chovin, P., and Rkhalet, J. Etude thtonque de Is anetique de la fixation du monoxyde de carbone sur rhemogtobine du tang. (Theoretical study of the kinet ics of the fixation of carbon monoxide on the haemoglobin of the blood.) Ann. Fals. Exp. Chim.. 710: 177-194 (1973). 18. Hanks, T. G.. and Farquhar, R. D. Final report PH 22-68-31. National Air Control Administration. Durham, N.C., 1969. 19. Peterson, J. E., and Steward, R. D. Predicting the carboxyhemoglobin level* resulting from carbon monox ide exposure*. Report CRC APRAC CAPM-3-6B MC0W-ENVM-CO73-1, 1973. 20. Goursat, E. Cours d'Analyae, Vol. 2. Gauthiers. Villart, Paris, 1926. 21. Maurin M. Impact du monoxyde de carbone sur Ie* individut. IKT-CERNE report, Bron, France. 1978. 22. Boudene C., Godin, J., ana Roussel, A. Method* de dotage de Foxyde de carbone dan* Ie sang sans extraction separte prealable par absorption selective dana 1'intrarouge. Arch. Maiad. Prof. Med. Ttav, Sec. Soe. (Pari*) 34:449-156 (1973). 23. Ott, W. R,, and Msge D. T. Interpreting urban carbon monoxide concentration* by means of a computerized blood COHb model. J. Air PoU. Control Aaeoc. 28:11-916 (1978). 24. Grialer, R., Gobbi. A., Giavardi, C., Gainuni. G.. Sovenm. R,, and Botta, A. Vslori di HbCO rilevati in 1>"*0 ibitanti di Milano non eaposti sU'aaaorbiroento professional* di CO. Med. Lav. 66: 34-47 (1975). 25. Kahn, A., Rutledge, R. B., Davis, G. L.. Altes. J. A., Garter. G. E., Thornton, C. A., and Wallace, N. p. Carboxyhemoglobin source* in the metropolitan St. Louis Population. Arch. Environ. Health, 29:127-135 (1974). 26. Seppanen, A., Klkkinen, V., and Tenkku, M. Effect of gradually increasing carboxyhaemoglobin saturation on '1sual perception and paychomotor performance of smoking and non-smoking subjects. Ann. Clin. Re*. 9:314-319 (1977), Environmental Health Perspective* V* ucc 057293 T toil. U RNE ffect . 79: ierailood vest. ing hild. dant iring irk), -'ting king ce of 12th ** ; la sur netatan -164 1 the nox1-66 lea age tree reh. 7). bon ood m rmi, tidi CO. A., D. ouia t of i ei- ting m 27. Toibati, I. D., Har-Kedar, I., and Ben-David. A. Carboxyhaemogiobin level* in blood donors in relation to cigarette smoking and to occupational exposure to carbon monoxide. Israel J. Med. Sci.. 10: 241-244 (1974). 26. Billiet, L., Baisier, N., and Naedts, J. P. Effet de la taille, du sexe et de l'tge *ur la capacity de diffusion pulmonaire de 1'sdulte normal. (Effect* of the height, sex and age on the pulmonary diffusion capacity of a normal adult.) J. Physiol. (Paris), 55:199 (1963). 29. Lecoq R. Manuel d'Analyses Medicales et de Biologie Clinique. (Manual of Medical and Clinical Biology- Analyses ) Besancon. France, 1967. 30. Joumard, R., Chiron, M., and Vidon, R. La fixation du monoxyde de carbon* sur l'hemoglobine et ses effets sur l'homxne. (Uptake of carbon monoxide on haemoglobin and the effects on man.) IRT-CERNE report, Bron, France, 1979. October 1981 289 UCC 0S7294 Environmental Health Perspectives Vol. il, pp. $91-309. 1981 Noise and Stress: A Comprehensive Approach by Jack C. Westman* and James R. Walters1 The fundamental purpoee* of healing are to alert and to warn. As a result sound directly evokes emotions and actions. The processing of sound by the brain is outlined to provide a biological and psychological basis for understanding the way in which sound can become a human stressor. The auditory orienting response, startle reflex and defensive response translate sound stimuli into action and sometimes into stress induced bodily changes through "flght or flight" neural mechanisms. The literature on the health and mental health effects of noise then is reviewed in the context of an integrated model that often a holistic approach to noise research and public policy formulation. The thesis of this paper is that research upon, and efforts to prevent or minimise the harmful effects of noise have suffered from the lack of a full appreciation of the ways in which humans process and react to sound. <a Introduction The damaging effects of noise usually are re garded as limited to the structures of the ear through impairing one's ability to hear sounds such as speech and music. Often unappreciated is the fact that noise has more pervasive physiological effects (1, 2). In the course of evolution, certain fishes devel oped organs of hearing to orient themselves in space. In amphibians, vision provided the ability to locate prey but was not sufficient in terrestial environments to warn of other predators. Hearing accordingly developed as an organ for perceiving and responding to danger M). Hearing also has played a role in sexual mating behaviors in mam mals and even insects. These primitive functions exist in humans as well. From the outset sound has evoked emotions and actions through the inner ear's direct connections to ` fight or flight" neural mechanisms via the auto nomic nervous system. Because of this defensive 'Department of Payehiatiy, University of Wisconsin, Clinical Science Center, 600 Highland Avenue, Madison, Wisconsin 58792. tOffice of Noise Abatement, Environmental Protection Agen cy, Washington, D. C. 20460. October 1981 purpose, hearing also cannot be turned off, and sound registers in the brain even during sleep. Only later in primate evolution did the auditory system include higher cerebral centers permitting the appearance of spoken language. The current usage of the terms "nonauditory" or "extraauditory" is unfortunate. This distinction designates as nonauditory the auditory system's original, primitive influence upon wakefiilness and body activity. The auditory system and physiologi cal responses to sound are inseparably connected. Therefore, all of the effects of noise on the body mediated by the ears are "auditory" effects. More precisely, the effects of sound on the body through vibration of structures other than those of the auditory system are "non-auditory" or "extra- auditory." Another basic consideration in understanding the Ainctioning of the auditory system merits empha sis. The human auditory system was designed to process the frequencies and intensities relevant to survival in the sound environments of nature. The evolutionary process has not allowed humans enough time to adapt hearing to sounds generated by loud modem noise sources. This means that the auditory apparatus is not prepared to cope with commonly encountered urban and industrial noise. Conse quently, we find ourselves exposed to sound envi- 291 UCC 057295 ronments that overload the auditory system. An analogous situation would occur in the visual sys tem if we were forced to look at the sun and thereby damage the retina. The fundamental relationships of hearing to emo tion and action and the auditory system's vulnera bility to modern sounds are not appreciated sufficiently by the public. Research also has suf fered from a lack of breadth and depth in conception resulting in contradictory findings. For example, laboratory studies of healthy young people have concluded that noise has no harmful psychophysiological effects on humans. At the other extreme are reports that jet aircraft noise increases psychiatric hospital admissions. We lack a comprehensive model to ensure that research on sound includes the critical variables that make it a significant source of human stress. Much of the research cited in this paper suffers from methodological inadequacies because noise is but one of a number of variables affecting complex human beings. Before delineating the system levels involved in bodily responses to sound, we first will outline the neuroanatomy and physiology of the central processing mebfianism of sound. Neuroanatomy of the Auditory System An appreciation of the structural basis for physio logical and behavioral responses to sound can be gained from knowledge of the neuroanatomy of the auditory system (Fig. 1). The auditory pathways of the central nervous system consist of direct path ways from the inner ear to the auditory cortex and indirect pathways to the reticular activating sys tem which connect to the limbic system and other parts of the brain, the autonomic nervous system and the neuroendocrine system U). The direct auditory connections consist of ascend ing pathways which carry impulses excited by sounds from the receptor'cells in the organ of Corti to the auditory centers in the cerebral cortex. These pathways end in the temporal lobe where the sum of incoming impulses are consciously perceived and interpreted. The ascending auditory pathways travel along the auditory nerve via the cochlear nucleus, superior olivary complex, inferior colliculus, nuclei of the lateral lemniscus and geniculate body to a number of areas in the auditory cortex which in turn are connected to other cortical areas that Figure 1. Processing of sound by the brain. 292 Environmental Health Perspectives ucc 057296 receive inputs from the other sensory organs as improve performance on tasks which are inherently well. underarousing, repetitive, and monotonous. Con There also are descending pathways from the versely, sound can impair performance on tasks sii, temporal cerebral cortex to the dorsal cochlear demanding concentration and complicated responses 1 be nucleus via the inferior colliculus and to the organ (8). Sound contributes to the homeostasis of the the of Corti via the medial geniculate body, inferior central nervous system and consequently influences s of colliculus and lateral lemniscus through the olivo the physiological homeostasis of the body through ath- cochlear bundle. These descending pathways have the autonomic and neuroendocrine centers of the and inhibitory and, to a minor degree, excitatory hypothalamus. sys- influences. The arousal level of the central nervous system *.her In addition to these direct pathways to and from depends upon the intensity, complexity, variabili 'em cerebral cortex, there are a variety of indirect ty, predictability and meaning of sound stimuli. The connections from the inner ear to the brain centers auditory system responds most to changes in the end- that control basic physiological, emotional and be timing of sound stimuli. Therefore, a transient by orti havioral responses of the body. Nerve fibers branch increase in the firing of auditory neurons may be out from the various synaptic junctions along the produced by the termination of a sound as well as tex. direct auditory pathways to motor cell nuclei by its inception. Some neurons in the auditory the subserving reflexes within the brainstem and to the system respond to stimulus onset with a high rate ed reticular activating system in the midbrain. of impulse discharge, quickly cease firing, remain ays Impulses reaching the reticular activating sys silent while the stimulus is continued, and dis lear tem excite still other impulses that spread to higher charge a second burst of impulses when the stimu ilus, cerebral centers that control alertness, cognition lus stops. However, in a much larger number of 'ody and motor performance. At the same time the neurons, the rate of firing declines to a lower level h in reticular activating system conveys impulses to of activity shortly after the initial high frequency 'hat hypothalamic autonomic nervous system centers discharge and then is tonically maintained during which are linked to the sympathetic-adrenal neuro long periods of continued stimulation. These sound endocrine system and the^by regulate the secre stimulus-induced alterations persist after the stim tion ofthe catecholamines, adrenaline (epinephrine) ulation ceases (9). and noradrenaline (norepinephrine). Impulses con The direct effects of certain sounds on emotions veyed by the reticular activating system also are and attitudes is illustrated by the fact that chalk transmitted to the pituitary-adrenal neuroendocrine scraping on a blackboard can cause chill sensations system which secretes corticosteroids (cortisol). in a listener. Musical rhythm, tempo and melody The catecholamines play an important role in mobi can evoke moods ranging from calmness to excita lizing immediate adaptive resources of the body, tion or elation. Music also can promote positive and the corticosteroids provide for more enduring attitudes toward work. The further influence of adaptation to prolonged stress (5). Thus, the audi higher cerebral cortical centers on the emotional tory apparatus is connected to the entire central reaction to sound stimuli is illustrated by a study of nervous system and the neuroendocrine system as sound in hospitals in which one source of annoyance well was staff conversations in the halls, not because of undue loudness but because of the discussion of Physiology of Sound patients (10). Sound stimuli also influence the other sensory In conjunction with the other special senses, the systems. For example, sound input overload can auditory system serves to maintain the arousal of induce visual changes in color perception, cause the brain projections to the temporal cortex and the nystagmus and vertigo and even act as an analgesic reticular activating system via the limbic system <IJ). and the hypothalamus. In this way cognitive pro In summary, sound stimuli play a vital role in cesses and emotions interplay with sound stimuli in maintaining arousal ofthe brain and thereby influence influencing the state of consciousness. the basic physiological functioning of the body. The cerebral cortex requires a certain level of Sound may influence the body after cessation of the arousal to make optimum use of incoming sensory stimulus through reverberating neural circuits within information upon which efficient behavior and phys lower and higher brain centers. In this way sound iological functioning depend (6). Neither underarbusal can produce physiological reactions that develop a nor ovenrousa! is conducive to effective perfor momentum of their own independent of the original mance of physiological functioning (7). Sound can stimulus. October 1981 293 k Fundamental Auditory Responses Orienting Response (Novelty Reflex) The basic behavioral response to all sound stimuli is the orientation reflex, which involves ascending and descending auditory cortical pathways and is reflected by an arousal pattern in the electroen cephalogram. The response orients the head and eyes toward the source of a sound in order to ready the organism to receive and respond to the sound stimulus situation. There is an associated decrease in auditory threshold and increased attention to the sound stimulus. The orienting response occurs to sounds of low or moderate intensity and significance. The person's cognitive appraisal of the sound stimulus deter* mines the intensity and duration of the orienting response. It extinguishes, or habituates, after var ying repetitions so that the individual can accom modate to familiar and insignificant sounds with relative ease and concentrate on a preferred activi ty. If an appreciable amount of time passes be tween repetitions of ^specific sound, habituation disappears and repetition of the same sound again evokes an orientation response. Habituation usu ally does not occur if attention to a sound is volun tarily sustained or ifa sound has special significance, either positive or negative. Sounds of close to hear ing threshold intensity do not easily habituate, probably because of the auditory system's difficulty in assessing their significance. Even after behavioral habituation has occurred, sound stimuli continue to activate both cortical and subcortical areas of the brain (9). This is in part because excitation transmitted by the reticular ac tivating system continues to arrive in the cerebral cortex after that transmission directly ceases. When the decision is made not to orient to a sound, descending cortical excitation actively restrains, but does not eliminate, the reticular activating sys tem's excitation from spreading to higher areas of the brain. After the orienting response to sound habituates, there may be no change or an increase in the amplitude of the electrical responses evoked in the cerebral cortex and the medial geniculate body. The reticular activating system and the struc tures that it influences continue to be affected by sound even after behavioral habituation has occurred. This is not surprising because the organism's sur vival would be threatened by decreased altertness to danger if unattended stimuli were excluded from cognitive appraisal. 294 Startle Reflex The second basic auditory response is the startle reflex which is evoked by sounds of sudden, in tense, or frightening significance. The reflex has a series of components. First, the middle ear muscle reflexes via the superior olive to the tensor tympani through the fifth cranial nerve and to the stapedius muscle through the seventh cranial nerve provide a small degree of protection against sounds of ex tremely high intensity. The auropalpebral reflex via the superior olive and the sixth cranial nerve produces eye blinking. There also is opening of the mouth and flexion of the neck via the seventh and eleventh cranial nerves. More generally, there is flexion of most muscle groups in a "freezing" pos ture with raising of the shoulders, abduction of the arms, flexion of the fingers, contraction of the ab domen, and bending of the knees mediated by the ascending auditory and descending cerebral cortical motor pathways. The typical reflex is completed in less than one second. Those components of the startle reflex that reflect cerebral cortex activity are subject to habituation or enhancement, however, those involving lower centers in the brainstem are not. The startle reflex accordingly can be decreased by anticipation, in creased by background sound levels and exaggerated by emotional states such as fear. The Defensive Response ("N" Response) Although usually an extension of the orienting or startle responses, the defensive response merits separate consideration because it can occur inde pendently of them and does not require Bounds of high intensity. This response is produced by sounds of sufficient intensity, significance or duration to be perceived as threatening and to mobilize a "fight or flight" reaction. The response includes alerting of the cerebral cortex, emotional arousal, and prepa ration of the body for action ill). Sounds in the range of 70 to 120 dB can produce the defensive response which appears first in the form of skeletal muscle tension that quickly reaches its peak and decays within s few seconds. Next there is a decrease in skin electrogalvanic resis tance which changes more gradually than the skele tal muscle tension. Pupillary dilation occurs as well. A variety of circulatory responses are next in order first an acceleration of pulse rate and decrease in pulse pressure, then a constriction of the finger and dilation of the chin blood vessels, followed by a slowing of pulse rate and an increase in pulse pres sure. Finally in the series comes a shift to slower, Environmental Health Perspectives t i ucc 057298 e . * SD > W 3 - rp ar , h.- ua uscle ipani idius idea f exeflex _-rve fthe and re is posf the abthe tical ;d in Sect tion ver -flex inated ? or rite lde3 of ids >be tor ?of P* uce bhe hes ext siseleelL 'en m and y* eser. deeper breathing. The defensive response also in cludes a reduction in salivary and gastric secretions and slowing of digestive processes U). The defensive response largely involves the sym pathetic nervous system but has some parasympa thetic aspects. This response is not limited to a single organ system or structural division of the nervous system. It occurs independent ofemotional response on the part of the subject. It is altered by sound intensity and band width in a dose-dependent fashion. It does not completely habituate (IS), al though under laboratory experimental conditions, substantial apparent physiological habituation has been reported (U). It also may be elicited by low levels of sound with special significance (IS). Under actual working conditions, the physiological effects of the defensive response were found in sawyers exposed to bandsaw noise (16). Another laboratory study noted a decrease in blood eoeinophile level reflecting a stress response after 25 min exposure to 85 dB level noise (17). The defensive response can become the stress that leads to the General Adaptation Syndrome that will be described more fully later with its alarm, resistance, and exhaustion stages if the sound stressor is of sufficient duration, quantity, and qual ity (18). When this takes place the hypothalamicpituitary-adrenal axis is mobilized with resulting increase in adrenal cortisol and epinephrine output. During prolonged exposure to intense sounds, these endocrine effects may produce gastroduodenal ul cers and renal changes in laboratory animals (l). Next we will enumerate the critical variables that determine w-hether or not sound stimuli be come stressors that produce human stress. Sound as a Stressor Modern urbanization, crowding, the mass media, information technology, conditions ofwork and noise are overloading the human sensory environment (19). Of these stimuli our interest is in sound, particularly noise, although sound with meaning, such as speech, also can contribute to overloading an individual's processing capabilities. The progres sive increase in noise from industrial, traffic and home sources, both machine and human generated, has reached offensive proportions in the United States (SO, SI). Noise essentially is unwanted sound. As such, subjectively experienced noise is any sound that produces annoyance or communication or task per formance interference. The same sound stimulus may be perceived subjectively as noise by some and not by others. For this reason it is useful to define objectively experienced noise as sound that pro October 1981 duces harmful bodily effects, which may or may not be subjectively perceived. This point is important because noise can be subjectively or objectively stressful, or both. In information processing terms, noise is sound that overloads the central nervous system's prothis state can be detected by changes in the electro encephalogram (ST). The reception of a stimulus is influenced by two kinds of cognitive state charac teristics, current transient influences and enduring qualities of the individual. The first characteristics are transient influences that are more evident and easily measured than the second type. They include level of mental arousal, from sleep through alertness to anxiety; the con text of sensory stimuli arriving through the other special senses; the motor context which includes ongoing task performance, the activities of the in dividual; the meaning of the stimulus evoked by associations from cerebral cortical memory areas; the degree of perceived control of the stimulus, whether one is able to control the situation is help less or expects failures (SS) and social values and attitudes toward the stimulus sources. The level of mental arousal is influenced whether or not a sound stimulus is consciously perceived as a stressor. During the stage of early sleep, for exam ple, sound can produce orienting and defensive responses and alter the quality of sleep without causing awakening. At the other extreme, an anx ious individual can experience heightened sensitiv ity to a sound stimulus. For example, a study of college age males rated on an anxiety scale dis closed that for subjects rated high on anxiety, household noise levels were stressors as manifested by impaired task performance and subjective frus tration (8). The interaction of sound stimuli with other sen sory stimuli may be significant. For example, re lated visual stimuli enhance the effect of sound. Clinically, sound can have an analgesic effect when certain intensities and frequencies occur in the pres ence ofpain as is known in the practice ofdentistry. The ongoing motor activity of an individual influences cognitive state with higher levels of arousal by sound stimuli occurring while complex tasks are being performed and lower levels of arousal occur ring when routine, monotonous activities are taking place. For obvious reasons related to survival at a prim itive level the meaning of sound is one of the most important factors that determines an organism's response. Threatening sounds of any kind portend potential danger, however, certain sounds acquire particular significance because of their symbolic meaning to the individual. Conversely, familiar, 295 ucc 057299 i repetitive sounds of moderate intensity cease to attract attention. Meaning connoting potential dan ger, then is related to unfamiliarity, rapid changes in intensity, or learned associations. For example, a study of evoked auditory potentials in the brain demonstrated that quickly changing acoustical events produce prominent cerebral excitation. The study also showed that sounds with symbolic meaning were perceived as more annoying than meaningless Bounds of the same intensity and also produced larger evoked cerebral potentials (29). Of particular importance is the fact that habitua tion does not occur to repeated novel laboratory stimuli that imply conflict or are coupled with an instruction to pay attention to that stimulus. Even covert associations with sound stimuli, such as a subject's attitude toward the experimenter, may decrease habituation (8). In addition, the symbolic meaning of a sound stimulus can evoke irrational responses, adding unconscious determinants of mean ing (30, 31). In addition to the meaning of the sound stimulus, a sound's predictability is an important determi nant of response. In one study, unpredictable noise resulted in lower tolerance for frustration and greater impairment of performance efficiency than predict able noise (32). Furthermore, those investigators found that an individual's ability to control the noise source, and even the belief that one could, reduced the adverse impact of unpredictable noise (8). They postulated that the deleterious effects ofnoise were a function of unpredictability and the belief that one cessing capacity because it Is too great in quantity, appears too rapidly or is dissonant in meaning or pattern. Noise is a commonly used standardized stressor in laboratory testing designed to evaluate human responses to stress (5, 22). In laboratory animals, for example, it is used as a stressor to produce lesions in the renal, reproductive and car diovascular systems (23). Another illustration of the use of sound is in stress studies such as the one by Cantrell, who exposed healthy young male volunteers to intermit tent noise for several weeks (4). He found significant increases in plasma cortisol and blood cholesterol levels in addition to associated annoyance and sleep disturbance effects during prolonged exposure to bursts of 85 to 90 decibel noise. We can use current approaches in stress research to facilitate our understanding ofsound as a stressor (22,25), In stress research the environmental condi tions and the intervening bodily structures and processes that determine when and in what forms stress reactions occur are taken into account (26). The work of Rahe, although encompassing life change in addition to sensory stressors, is particu larly useful in identifying specific variables that should be taken into account in research on the human effects of noise. Rahe developed a life stress and illness model which identifies the key steps along a pathway extending from a person's expo sure to a stressor to the eventual reporting of an illness (25). Rahe's model (Fig. 2) utilizes the anal ogy of a series of optical lenses and filters in which stressors are depicted by a series of "light rays" of different stimulus characteristics. The influence of a person's perceptual state in altering the experience of a stressor is represented by a "polarizing filter" shown in step 1. Possible sensitization, or desensitization, of a person to a stressor is indicated by changes in the "light rays" as they pass through the filter. The psychological defense mechanisms which appear to be capable of "diffracting away" a stressor's impact are depicted SOUND STIMULI Figure 2. DISFUNCTIONlUNtsa (HAVION whmi ILLNttS NEASUMNSNT Rahe model of life stress and illness (tS). 298 Environmental Health Perspectives b; di ic; St ce im J* flit co; re; if i tu; tor pei inti ste pei wh rep 1 per res to i ject the the exp fest Ral exp CO; B chai first cogi this eleclus char endi T1 that seco from text spec ongc indi\ assoi the whet helpl and ; Th Octot ucc 057300 I to by the negative lens in step 2. Stimuli not so or not a sound stimulus is consciously perceived as a :a; diffracted pass on to produce a variety of physiolog stressor. During the stage of early sleep, for ical reactions represented by the ``black box" in example, sound can produce orienting and defen m Step 3. The wavy lines emerging from the black box sive responses and alter the quality of sleep without '.'ho cease to represent specific stressors and begin to causing awakening. At the other extreme, an nit- indicate various psychophysiological responses to anxious individual can experience heightened ant perceived and "undefended" stressors. Next a "color sensitivity to a sound stimulus. For example, a ;rol filter" shown in step 4 depicts how a person may study of college age males rated on an anxiety scale eep cope with or absorb certain of these physiological disclosed that for subjects rated high on anxiety, to reactions. Prolonged psychophysiological activations, household noise levels were stressors as manifested if unabsorbed, lead to organ dysfimction and even by impaired task performance and subjective frus rch tually to psychological and bodily symptoms. Symp tration (28). sor tomatic individuals may then seek medical care. A The interaction of sound stimuli with other sen idi- person's "focusing" of attention on symptoms is sory stimuli may be significant. For example, ind indicated by the illness behavior "positive lens" in related visual stimuli enhance the effect of sound. m step 5. If these symptoms are reported to health Clinically, sound can have an analgesic effect when ). personnel, the person receives a medical diagnosis certain intensities and frequencies occur in the life which then can be used as a measure of illness as presence of pain as is known in the practice of cu- represented in Step 6. dentistry. hat The value of Rahe's model is that it incorporates The ongoing motor activity of an individual the pertinent system levels in conceptualizing human influences cognitive state with higher levels of ess responses to stressors, ranging from organ system arousal by sound stimuli occurring while complex ?ps to societal levels. It permits inclusion of both sub tasks are being performed and lower levels of .jo- jective and objective data as well. Furthermore, arousal occurring when routine, monotonous activi an the model reflects clinical ^realities by recognizing ties are taking place. ial- the social factors that influence whether or not For obvious reasons related to survival at a ich experienced dysfunctions become labeled as mani primitive level the meaning of sound is one of the 'of festations of illness. For these reasons, we will use most important factors that determines an organ Rahe's model to elucidate key variables in the human ism's response. Threatening sounds of any kind r experience of sound as a stressor. portend potential danger, however, certain sounds e. acquire particular significance because of their ble >a Cognitive State symbolic meaning to the individual. Conversely, familiar, repetitive sounds of moderate intensity Bearing in mind the preceding discussion of the cease to attract attention. Meaning connoting po cal characteristics of sound experienced as noise, the tential danger, then is related to unfamiliarity, of first step in processing a sound stimulus is the rapid changes in intensity, or learned associations. ed cognitive state of the individual. Some variations in For example, a study of evoked auditory potentials this state can be detected by changes in the in the brain demonstrated that quickly changing electroencephalogram (27). The reception ofa stimu acoustical events produce prominent cerebral exci lus is influenced by two kinds of cognitive state tation. The study also showed that sounds with characteristics, current transient influences and symbolic meaning were perceived as more annoy enduring qualities of the individual. ing than meaningless sounds of the same intensity The first characteristics are transient influences and also produced larger evoked cerebral potentials that are more evident and easily measured than the (29). second type. They include level of mental arousal, Of particular importance is the fact that habitua from sleep through alertness to anxiety; the con tion does not occur to repeated novel laboratory text of sensory stimuli arriving through the other stimuli that imply conflict or are coupled with an special senses; the motor context which includes instruction to pay attention to that stimulus. Even ongoing task performance, the activities of the covert associations with sound stimuli, such as a individual; the meaning of the stimulus evoked by subject's attitude toward the experimenter, may associations from cerebral cortical memory areas; decrease habituation (8). In addition, the symbolic the degree of perceived control of the stimulus, meaning of a sound stimulus can evoke irrational whether one is able to control the situation is responses, adding unconscious determinants of mean helpless or expects failures (23) and social values ing (30, 31). and attitudes tow ard the stimulus sources. In addition to the meaning of the sound stimulus, The level of mental arousal is influenced whether a sound's predictability is an important determi- October 1981 297 UCC 057301 nant of response. In one study, unpredictable noise resulted in lower tolerance for frustration and greater impairment of performance efficiency than predictable noise (32). Furthermore, those investi gators found that an individual's ability to control the noise source, and even the belief that one could, reduced the adverse impact of unpredictable noise (8). They postulated that the deleterious effects of noise were a function of unpredictability and the belief that one had little or no control over the noise source. A laboratory study of rhesus monkeys exposed to noise disclosed that plasma cortisol levels were significantly higher in animals with no control over the noise source than in those with control (S3). Similar findings resulted from an experimental study of humans performing mental arithmetic problems under noise exposure (Si). The importance of attitude toward the noise source is illustrated by another study in which a positive or negative attitude toward all aspects of one's com munity consistently influenced the reporting of per ceived annoyance by noise positively or negatively (35). In the same vein, a Swedish study disclosed that propaganda promoting the importance of the air force diminished the reported annoyance levels in a community exposed to military aircraft noise (36). The second kind of variables that influence the cognitive state of an individual are enduring back ground characteristics in the form of individual differences in temperament and cognitive styles, organic disease processes and mental illness. Individual variations have been demonstrated in the ways that sensory stimuli are processed. Some individuals reduce and some augment the intensity of stimuli, leading to low or high sensitivity to a particular stimulus (19). Sensitivity to noise also is correlated with empathic, creative, intellectually oriented personality traits, confirmingSchopenhauer's comment that "noise is a torture to people of great intellect" (37). Extraverted children may have a higher level of noise tolerance than introverted children (38). Moreover, individuals who express criticism tend to report annoyance by noise ($5). Further evidence of individual differences in sensi tivity to noise is reflected by the finding that some people thrive on noise which tends to synchronize their electroencephalograms while most people show electroencephalographic desynchronization (39, iO). At the other extreme, it is likely that 4 to 6 % ofthe normal population is "noise sensitive," in the sense that they do not adapt to noise at all (8). For all of these types of individuals, noise has implications detrimental to their mental health. As an illustration of other background illness characteristics, one study showed that cardiac in farction and schizophrenic patients showed greater stress responses to noise as measured by cortisol and urinary catecholamine levels than did normal subjects Ul). Similarly, persons with cerebral vas cular disease were found to be more susceptible to the detrimental effects of noise than normal sub jects US). Another unique group of patients harmed by sound are those susceptible to audiogenic sei zures. Some are affected by sounds that produce the startle response and others by sounds such as music U3). The role of psychiatric status in sensitivity to sound was suggested in a study in which normal subjects and patients with specific phobias showed habituation of physiological responses to noise while hysterica] patients did not. Moreover, patients with diffuse phobias, anxiety neuroses and agitated de pressions all habituated more slowly than normals (U). In a general sense, another survey found that psychiatric patients were more annoyed by noise than normal subjects US). Defense Mechanisms The next cluster of variables that influence an individual's response to sound stressors are inter nal defense mechanisms noted in step 2 of Rahe's model. In contrast with coping techniques which are directed toward changing the stimulus envi ronment, the defense mechanisms are devoted to maintaining homeostasis or internal equilibria, within the person. The defense mechanisms operate automatically and unconsciously. The most primitive is the acous tic reflect which offers a small degree of protection from high intensity sounds. Another example of a physiological defense is cerebral cortical inhibition such as was demonstrated in a study of laboratory animals exposed to extreme sound which ultimately produced convulsive seizures and lethal cerebral hemorrhages. This study found that a seizure pro ducing epileptogenic focus of excitation arising in the medulla was actively inhibited by the cerebral cortex. When this inhibitory process was exhaust ed, seizures occurred U6). In addition to these physiological defenses, psy chological defenses shield the individual from phys iological arousal and also play a significant role in reducing sensitivity to sound. For example, the psychological defenses of repression and denial can minimize physiological responses as was found in a study of patients in a coronary intensive care unit (25). 298 Environmental Health Perspectives ucc 051302 ati :50l mal vase to subrned seiice i as to mal wed hile >ith demis .hat oise an ter m's Tiru 1 to `Jiin ally >US- `'on of a lion tory tely bral pro in bral UStr asyiyse in die can in a unit vea Psychophysiological Responses The next level, step 3 in the model, comprises psychophysiological responses to sound stressors. The psychophysiological responses can be divided into two categories. First are responses within the awareness of the individual, such as sweating, change in heart rate and muscle tension. Second are those responses which occur outside of one's direct aware ness, such as changes in serum lipids, cortisol, blood pressure and blood sugar levels. The psychophysiological responses are manifes tations of the defensive response to sound, can be immediate or delayed, and occur in interactional patterns. Thus, studies of single physiological re sponses oversimplify the mixture of responses. An example of an immediate psychophysiological re sponse to noise is the finding of elevated diastolic and systolic blood pressures and urinary excretion of norepinephrine metabolites in brewery workers on days in which they deliberately did not wear hearing protective devices U8). Genetic and constitutional individual differences may increase the likelihood that a particular organ system will respond to stressors more than others and over time lead to disease. There also may be a critical period during infancy in which visceral learn ing takes place, adding conditioning of an individu al's disposition to the physiological responsiveness through a specific "target" organ system U9). For example, in certain predisposed individuals, the target organ is the cardiovascular system, and sound stimuli produce intermittent increases in blood pres sure which may eventually cause structural changes in blood vessels leading to permanent hypertension m. Stimulus and Response Regulation The next cluster of variables are stimulus and response reduction mechanisms. These coping tech niques may deal with the stressor itself or with the physiological and emotional responses to it (51,52). Using ear protective devices is an example of deal ing with the stressor itself by reducing the recep tion of the sound stimulus. If one becomes aware of the psychophysiological responses, particularly if they are seen as threats to health, deliberate response management tech niques can be employed. For example, muscle re laxation may "absorb" the muscle tension that con tributes to elevation in blood pressure. In a broader social sense, stimulus regulation can be achieved through an individual's participation in community, industrial and consumer efforts to acoua- tically condition home and working environments and manufactured products. Dysfunction: Illness Behavior In step 5 in the model, the lack or failure of defense mechanisms and regulation techniques play important roles in producing dysfunction. The con cept of sensory and information input overload is useful in understanding how the central nervous system responds when defense mechanisms and regulation techniques fail to adequately screen in coming stimuli. In this conception sensory inputs are the sound stimuli and information inputs are sounds with symbolic, message containing mean ing. Overload results from an excess of the number or rate of sensory or symbolic stimuli or both. Human experiments have shown the disorganiz ing and psychotogenic effects of sensory overload. Experimental exposure to intense visual and audi tory sensory overload produces dramatic effects in the form of heightened and sustained arousal, mood changes, illusions, hallucinations, and body image distortions (19). Sensory and informational sound overload also are commonplace in modern, urban living (53). Jets, air compressors, sirens, rock and roll music and road traffic are generally unpredictable and often uncontrollable sources of stimulation that contrib ute to making the sound of our environment inimi cal to mental well being. Low frequency noises have effects similar to the more familiar piercing high frequency sounds (Si, 55). A typical household vignette illustrates the un recognized importance of sound sensory and infor mational overload in our lives. The washing ma chine provides a steady hum, the clothes dryer suddenly begins to vibrate; then the telephone jan gles while the delivery boy rings the doorbell; a jet aircraft rumbles overhead and automobile horns are heard, a television set blares in the background; and amidst this conftuion, children begin to fight, cry and scream. The overall noise level is not high by hearing damage risk criteria, but a homemaker can attest to the resulting frustration, irritability and even anger. Over time, one manages to adapt to this noise routine. However, one makes errors in balancing the checkbooks, screams at the children for minor transgressions, is irritable with one's spouse, and generally shows symptoms of stress by the end of the day. Furthermore, when one be comes resigned to a lack of control over one's envi ronment, the resulting "learned helplessness" itself may become a stressor and contribute to additional symptoms of depression (10, 56). October 1981 299 ucc 057303 J Selye's classic work on stress provides a frame work for understanding the body's responses to sensory and information input overload (18), His terms stressor and stress are comparable to stress and strain in physics. In his view stressors produce two types of changes in the body. The first is a primary nonspecific change in an organ system called the "Local Adaptation Syndrome." This local adaptation occurs repeatedly in normal living. For example, running produces stress in the musculo skeletal and cardiovascular systems. The resulting exhaustion is reversible through rest. The second change is the "General Adaptation Syndrome" which is activated by intense and per sistent stressors that produce a specific effect on the adrenal glands, thymus and stomach. The fully developed general adaptation syndrome consists of three stages: an alarm reaction, a stage of resis tance and an ultimate stage of exhaustion. Extremely severe stress can lead rapidly to exhaustion and death. Stressors, then, set in motion adaptive responses which maintain biological and psychological homeo stasis. In addition to specific organ system respons es, a relatively stereotyped set of neuroendocrine reactions contribute to the development of the gen eral adaptation syndrome. Most prominent are in creased secretion of the adrenal cortical hormone, cortisol, and increased activity of the sympathetic nervous system, including increased secretion of epinephrine by the adrenal medulla. The increase in sympathetic nervous system activity prepares the individual for "fight or flight." The net effect of these responses is to mobilize nutrients, such as glucose from the liver and fatty adds from fat tissue, to "arouse" the central nervous system, to provide more oxygen and nutrients to skeletal mus cles, to increase contractibility of skeletal muscles and to increase coagulability of the blood. When these responses are persistent, the sustained ef fects of cortisol may appear in the form of gastric ulceration, inhibition of immune responses, hyper tension, atherosclerosis, sterility and personality changes (57). Most stressors act for a limited time and produce changes corresponding to the first and second stages of Selye's syndrome. The complete general adaptation syndrome results in a specific set of physical changes: enlargement of the adre nals, shrinkage of the thymus and lymph nodes and ulceration of the stomach. Selye's conception helps to explain that subjec tive experience and physiological responses to stressors can appear to have returned to normal or pre-stressor levels during the second stage of resis tance. This point is essential in understanding the phenomenon of habituation which has been repeat 300 edly observed in experimental studies of human responses to sound as a stressor (5, 14). Habitua tion may reflect the completion of a local adaptation syndrome cycle with restoration of normal bodily functioning. On the other hand, it may reflect a stage of resistance during which the body is moving into the full general adaptation syndrome which gains a momentum of its own and exacts a physio logical cost through the development of dysfunction of the various organ systems. A stimulus appraised as threatening gradually loses its capacity to arouse an emotional response if it is reappraised on repetition as less harmful and results in adaptation (26). This surface adaptation may be deceptive, however, and continued expo sure to the stressor may produce cumulative effects that appear after stimulation is terminated. This may be in the form of strain induced by the adap tive responses themselves. In spite of adaptation, then, stressors may cause biological and behavioral aftereffects Mowing cessation of the stimulus (8). Laboratory studies of the physiological and be havioral reactions to noise indicate that adaptation (habituation) generally takes place in healthy sub jects. There is laboratory evidence, however, which suggests that some components of physiological responses to noise do not habituate completely (58), although this work has been questioned (15). It is important to distinguish between the tension re sponse of an organism to stressors and stress which is a dangerous condition resulting from failure to manage tension effectively (59). Another factor should be taken into account. More than lower animals, human reactions to stressors not only depend upon the direct impact of stimuli themselves but also on associated cues that signify the meaning and consequences of the stimu li. Human stress, therefore, must be defined in terms of transactions between a stimulus and an individual's reaction to the situation. The fact that sound stimuli are processed cogni tively, therefore, introduces the important concep tion that psychological stressors, such as the antici pation of harm, can strongly influence human responses to sound stressors (52). Activation of the neuroendocrine system usually depends upon the individual's recognition of a stressor as a threat. The auditory system, however, like heat or cold stressors, automatically activate the reticular acti vating system and thence can evoke autonomicneuroendocrine responses. Dysfunction resulting from sound stressors, then, may be the direct result of the sound stressor situation or may indirectly result from the activa tion and progress of the general adaptation syn drome- Dysfunction may be subjectively experienced Environmental Health Perspectives ucc 057304 man tuaiti' >dii, "t a ring hich siotion as symptoms, for example, annoyance and tinnitus, or be objectively demonstrable as physical signs, for example, elevated blood pressure and hearing loss. At the same time subjective reports of inter ference with task performance and speech commu nication also can be accompanied by objective changes in cerebral responses on the electroencephalogram (27), Human dysfunction can be categorized according finger vasoconstriction as during waking without its voluntary motor component (31). The evidence also is clear that noise exposure during sleep lightens the level of sleep, especially for subjects of an anxiety-introversion personality type (27, 70, 74). Sleep disturbances have been reported in response to low frequency noise in the 20-1000 Hz range (55). Intermittent noise above the mean background level has a greater effect than >ally e if and tion \poects This lapion, oral (8). be-ion ub!ch ical 58), t is ra nch * t" to the influence of noise on five basic, interrelated functions that influence the well being, or mental health, of an individual: (1) hearing, (2) sleep, (3) task performance, (4) speech communication and (5) emotional state. Hearing, The effects of noise on hearing in the form of temporary and permanent threshold shifts and progressive deafhess are well documented (60-62). There are three levels of hearing at which loss of acuity can occur the primitive, warning, and sym bolic (62). The primitive level includes the familiar back ground sounds of one's every day environment. Loss at this level constitutes a form of sensory deprivation and may lead to a sense of isolation. Loss of hearing at the warning level contributes to a sense of insecurity and physical vulnerability in the environment. Loss at the symbolic level inter feres with interpersonal communication and may result in social isolation, withdrawal and depres sion. Overlap between levels of hearing loss magnifies the psychological impact on the affected individual. louder, more continuous noise on vegetative func tions (75). Age and sex in addition to sleep stage are critical factors in determining the physiological responses of noise sensitive individuals. Older sub jects and women are more sensitive than younger subjects and men. Moreover, sounds with meaning tend to awaken subjects at lower intensities than those without meaning (75). A study devoted to the next day effects of noise-exposed interrupted sleep showed impaired performance of tasks affected by the lack of sleep. Thera also is suggestive evidence that noise experi enced during the waking hours may reduce the duration of sleep of susceptible persons (77). All of these findings suggest that susceptible persons may be affected by noise occurring during sleep as well as during the waking state. For night workers, mothers with babies and elderly persons, day and nighttime noise can be a significant prob lem (31). Task Performance, There is little evidence that significant performance impairment on simple tasks mt. to t of hat nu* in an In addition-the need to wear a hearing aid in itself may cause self-consciousness and undermine self esteem. The emotional and psychological reactions to hearing loss accordingly are threats to an indi vidual's mental health (13, 64, 65). In a more general vein, the loss of hearing with aging (prebycusis) has been related in part to noise exposure in urbanized societies (66, 67). occurs under continuous noise below 80 to 90 dB (77). Unpredictable or intermittent noise, however, does affect performance at even lower levels (73). It is well established that noise has a negative effect on work tasks that involve listening or conversing (79). Adverse effects occur with complex, multicomponent tasks that require prolonged vigilence or continuous performance and those in which miepicilan ie :he at. old :tilic- Sleep. Chronic sleep disorders detrimentally af fect health and well-being. A major portion of com plaints about noise arise from disturbance of rest and sleep (31). The Environmental Protection Agency Urban Noise survey found that 28% of the sampled population experienced sleep disturbance which also was rated as the most annoying effect of noise (20). Similar findings have been reported by other sur veys (68-71). The electrophysiological response to noise tends to decrease during exposure to noise during sleep, information content is high- Under these circum stances, impairment oftask performance persisting after exposure to noisy environments has been reported (80, 81). Evidence has accumulated regarding noise inter ference in the school performance of children When children are involved in complex activities requir ing precise movements and intense concentration, noise produces inattention and impaired task per formance (82, 83). A study of the effects of noise generated by however, autonomic responses do not (31, 72). This expressway traffic in homes showed higher reading ior va- vn,-ed has been shown in a study in which cardiovascular responses did not habituate to traffic noise experi enced by sleeping subjects (73). In sleep, noise evokes the same orienting response in the form of EEG arousal and changes in heart rate, GSR and achievement for children exposed to lower ambient noise levels (84). Another study suggests poorer task performance by young children from noisy than quiet homes (85). A study compared children from schools and >- October 1981 301 ucc 057305 1 homes with noise levels of 87-99 dBA with those of 48-65 dBA levels. The children in the noisy envi ronments showed increased distractibility and im paired achievement in school. Over a period of four years they became more distractible, indicating increased sensitivity to noise with the passage of time (86, 87). Children exposed to high noise levels in schools also attain lower reading achievement than those with low noise levels (88-90). One study of preschool children found that reflex motor reactions to sound and light stimuli were delayed in those exposed to moderate background levels. The children with the higher noise level required more time in task performance as well (91). All of these performance effects influence an individual's attitude toward work and may consti tute additional stressors in themselves, contribut ing to frustration and stress reactions. Speech Communication. Interference with com munication through speech not only creates per sonal frustration but has consequences in social interaction. Individuals react to noise levels that do not completely interfere with intelligibility. Noise accordingly may reduce efforts to converse, lead to repeated speech, and ultimately to withdrawal (99). The hearing impaired are particularly susceptible to these reactions (98). Interference with communi cation between teachers and children in air traffic exposed schools also has been found (94). Children's speech acquisition and language de velopment may be impaired since the repetition of speech needed to develop these skills is reduced as background noise level increases. Noise accord ingly may interfere with the perception of speech by young children and affect the acquisition of language. More than adults, children depend upon the clear perception and repetition ofspeech sounds during early learning periods (61). Emotional State. The most prominent subjec tive emotional response to noise is annoyance, a commonly reported but difficult to describe and quantify emotional state. Research on annoyance is hampered by the ambiguity ofthe term and the fact that one can be annoyed by noise itself or by its symptomatic and behavioral consequences. Arhlin relates annoyance to the direct effects, such as hearing loss, sleep, task performance and speech interference, and the indirect effects of noise, such as blood pressure elevation, headaches, fatigabili ty, anxiety, depression and accident risk (95). A standardized definition of annoyance is needed because each study tends to report annoyance in a different way. In its moat specific sense annoyance is an emotion with a protective fiinction. It moti vates an individual to try to avoid or influence the 302 sound stressor. Like discomforts such as pain, chill and warmth, annoyance serves to warn an individ ual of unpleasant or harmful environmental condi tions. Annoyance also can be produced by interfer ence with task performance sleep and somatic symptoms. The direct experience of annoyance by noise itself differs from indirect annoyance because of a headache. Annoyance directly related to noise, then, is an unpleasant emotion experienced as irritability and iB a form of anger or hostility related to the state of the individual in a particular social and environ mental context. For example, the sound of the barking of one's own dog may be less annoying than the barking of a neighbor's dog. In another vein, some experimental subjects refused to continue in a noise study because they perceived it as unpleasant (8). There also is a tendency to regard sound as noise at work more than at home (96). Because of this relationship to the peculiarities of the context, annoyance can be expected to vary in its occurrence and reporting. Annoyance is heightened when noise is perceived as unnecessary; when those responsible for the noise are perceived as unconcerned about the exposed population's welfare; when other aspects of the environment are disliked; when noise is be lieved to be harmful to health, and when noise is associated with fear (10). Although defined differently from study to study, annoyance is a commonly used concept in surveys of community responses to noise. The tendency is to define annoyance of the respondents in terms of physiological responses, although a scale has been develops! that excludes somatic symptoms (45). It can be inferred then that the more annoyed a respondent the greater the physiological reactions the person is experiencing. Direct physiological measurements would be preferable to subjective reports, however, the stage of this research is not sufficiently advanced to permit the specific mea surement of noise induced stress isolated from other environmental stressors. The evaluation of annoyance is further compli cated. Not only is it an ambiguous concept, but respondents are influenced by the questions they are asked. For example, more positive responses were obtained when people were asked if aircraft noise produced specific symptoms than if asked about symptoms without suggesting a connection to aircraft noise (97, 98). When annoyance was ana lyzed according to attitude, activity interference and symptoms, McKennel found that 65ft of his sample reported feeling annoyed, 35ft reported interference with activities and 5% reported symp toms (99). Environmental Health Perspectives ucc 057306 chill livid- OT rfe*istic e by ause is an and teof ronthe than ein, in a sant 4 ag -e of ext, ?nce ived the the :sof bee is idy. 'of een . It 1a ons al ive not earom dKout ney set -aft -ted ito na nce his led np- Although methodological problems are important in assessing studies of reported annoyance due to noise, a number of surveys suggest that between 30% and 40% of urban dwellers are regularly annoyed by noise (20, SI, 31, 96,100). In the flight pattern of Heathrow airport in London, 65% re ported annoyance (.99). Noise in industrial situations also may induce what has been described as an "astheno-vegetative syndrome" in the form of increased fatigability, decreased capacity for focusing attention and slow ing of motor reactions (101). Disease: Illness Measurement In step 6 of the model, whether or not people define themselves as ill depends upon individual and cultural attitudes toward assuming the patient role. These personal and social factors influence whether or not an individual minimizes or exagger ates symptoms and adopts "sick" behaviors such as missing work and seeking health care. The critical step for defining illness, then, occurs when health care is sought and a diagnosis is established. This point is the entree for measuring illness resulting from sound induced streak There is an inevitable gap between laboratory studies of the immediate and delayed effects of noise on health. Still, some investigators regard noise pollution in densely populated areas as a social danger comparable to that of known ingested carcinogens and air pollutants (102). Imposing prob lems, however, stand in the way of proving this thesis as illustrated by methodological criticisms of a study which found that people residing near the Los Angeles International Airport had a higher death rate from stress related diseases than a con trol population (103). More specifically, European research on indus trial noise has identified a cluster of symptoms encountered by physicians and referred to as "noise sickness" (31, lOi). This syndrome is manifested by tinnitus, increased sensitivity to noise, fatigability, lowering of general resistance to illness, headaches, irritability, sleep interference, "heart pains," weight loss, tremors, digestive disorders and ultimately hearing loss. These symptoms are based upon the stress responses of the auditory, autonomic, car diovascular, endocrine, and gastrointestinal systems and precede the actual loss of hearing. Although short-term studies show that work per formance can be maintained under noisy conditions, the more important consideration is the long-range effect of noise on health. The European data appear to show that complete physiological and psychologi cal adaptation to prolonged noise exposure does not October 1981 occur. The person reacts unfavorably to noise from the beginning, and adverse reactions progressively increase with the passage of time. This is most evident in work requiring complex task performance. Because of the cumulative negative effect on one's state of health, the adaptation of many individuals working in noisy environments exacts a health cost (101). For convenience we will briefly summarize the relationship between noise exposure and (1) men tal illness, (2) cardiovascular disorders, (3) gastro intestinal disorders, (4) neurological disorders and (5) fetal abnormalities. Noise and Mental lllneu. The role of noise in mental illness is most difficult to assess. Several studies ofmental hospitals in the vicinity of Heathrow Airport in London disclosed a small but significantly higher admission rate than those in less noisy areas (105-107). Another piece of evidence relating a form of mental illness to noise is through an indirect rela tionship between noise induced hearing loss and mental illness. Acquired deafness forces a change in life style toward greater social isolation and leads to an over-representation of mental illness in deaf people of ail ages. One study found that 46% of a group of elderly deaf persons were paranoid and 21% had affective disorders (65). On the other hand, noise-related annoyance in itself probably is not a cause of mental illness, although psychiatric patients do constitute a vul nerable group to the adverse effects of noise. So matic and emotional symptoms associated with an noyance by noise are significant, however (15). The consumption of tranquilizers and sedatives has been used as an index of these symptoms resulting from noise exposure. Greater usage of these medications have been found in air and road traffic areas ex posed to high levels of noise (69, 99, 108,109). Noise and Cardiovascular Disorders. There is a consistent correlation between prolonged expo sure to high intensity industrial noise and an in creased prevalance of hypertension, as demonstrated by over 40 studies (110). The risk increases with advancing age and increasing years of employment for both men and women. The risk also is greater under circumstances of intermittent impulse or im pact sound than continuous or relatively steady sound. There is significant confirmation under actual living and laboratory conditions of the association between high intensity sound and cardiovascular disorders in children and adults (10, 69, ill, US. More specifically, prolonged noise exposure pro duced sustained elevations in blood pressure in a controlled experimental study of Rhesus monkeys. A carefully designed and monitored study of mon- 303 ucc 057307 saAiloadsjaj MM>H iBiuauiuoJtAuj 3utpBaistui Atntnotind uaaq ssq ..Ajoiipnsuou,, 9B punos jo spajja iBDt3o|oisAqd [BJaua3 aqi jo uotjeu -3isap aqj, 'HJlwq piuaui pus fsotsAqd joj astou jo 33UB0tJtu2lS 3q) aiBjaSSBXS iO dZtUIlUIW IBqi suotsnpuoo Suiptyuoa oj pa[ say suia[qojd paiBjaj -asiou jo spadsB .itoanu uo qonasaj tBautaoay -ssaJis usuinq pus A3o[ouuoopuaojnau `A3o[otsXqd -ojnau ` auiojBUBOjnau jo aSpaj.itouq luajjno uodn pasBq punos jo 3uissaoojd Ajoitpns aqi jo [apoui paisjJaiut ub paquosap dABq a.it `saqosojddB bais -uaqajdutoo ajout ajB[nunjs oi pojja ub uj -punos oi jdbsj pus ssaoojd susuinq qotq.n ui sAb.yv aqi jo uouBtoajddB ynj b jo qoai aqi uiojj pajajjns a.vsq asiou jo sioajja jnjuimq aqi `aztuitutui io luaAaad o; suojja puB `uo qojBasaj jsqj st stsaqi jno uoueo||dui| q^TBaq usuinq 01 isajqi lusoytuSis b si asiou isqi aAOjd 01 iou inq soytoads aiBununqt oi qonasaj jaqimj paau a ^ -aABq 01 Aja^q an a.vt aouapua qonasaj jo spupj ajuo aqi an asaqi suossaj [Botqia joj Apms [buiiub 8upuuuoo isoui aqi ubas ui pajaptsuoo aq isnui pus isixa sAb.iv[b saouajajjip saioadg -uoti Biajjoa b sutBUiaj uotiBjajjoo b `Aa.uns [BatSoionii -aptda paisoiisiqdos isoui aqi uaAa uj -saouatos pot -sXqd aqi jo isqi uiojj AfjBiuauiBpunj sjajjtp saouaps qiptaq aqi ui qonasaj sa[qBUBA Sutua.uaiutjo apni fipuu aqi jo asnsoaq asuas jsiuauiuadxa isapuis aqi ut paqsqqsisa aq joabu ubo assastp usuxnq pus sntnuttis b uaaMiaq joajja pus asnso jo joojd saji tsod iBqi aztu3oosj isnui a.it `asiou jo suotiBoqdun qipaq aqi uotisanb oi asooqo oq.tA asoqi joj (or) ajq J81BJ joj suotiBoqduii aSuBj-Suo] aABq qotq.n luauuredun 3ui -uiBaj puB (BiuauidopAap paonpui-astou oi ajqtidaosrts A'(jB(no(UBd aq Abiu uajpjtqo isqi st aouapUa aqj, siuauiuojLtua jtaqi aouanyut AtiUBoytu3ts iouubo pus aouBoytuSts Jiaqijo ssauamts apiq a/isq `utaqi podau XpnoauBiuods iou op uaopnqo asnsoaq uotjuajiB [Btoads a.uasap uajpjtqo uo asiou jo spajja aqj, 'SBO( SUI -jsaq paonpui asiou jo uopuaAajd aqi aousqua qa.ii Abui astou jo sooajja (B3io[otsXqd aqi oi uopuans isqi SupsaSSns snadds Sutisaq oi aSsuisp aaojaq aoBjjns asiou jo sjoajja ptotSojots^qd asuaAps aqi `ajouuaqtmj -qsu qqsaq passanui qipn paisioossB si V8P 06 1 VHP 98 P 8I*Al ^tsuaiu? qipn subsa* g oi g uBqi ajout jo ajnsodxa punos isqi aisotput asiou jo spajja qipiaq aqi uo siBp aqi `XiBuniuns uj (811 `ill) paqsqqBisa iou inq a.ttisaSSns st sniaj UBUinq aqi uo astou jo pajja asja.tpB aqi jo aouapua aqi `jaAaMoq `auiti stqi iv (9il) asiou oi paquq uaaq a.tsq satiqBUuou -qs (Bisj puB [BoiaiBui `sfBiuiuB [Biuauiuadxa uj MS (Sit) siuauiBjadutai otutqUqjs^p aABq puB BAtpBjadXq an oq.vt siubjui aq pjnoo ajns -odxa astou q paonput Xisixub {bujoibui jo pajja (Bisuajd ajiqns aiqtssod y Xiiaipb jBiaj pasaajo -ui aonpojd ubo asiou oi paitjaj Ajatxus pujaisj^ -qnuiiis punos {BUjaixa Xq pauotitpuoo aq ubo sniaj aqi `/CouBuSaad jo jaisauiui isb[ aqi uj -aSusqo aiBJ maq pus ^iiaiiob joioui ut papayaa sb ojain ui punos [BiuatuuojiAua oi spuodsaj pus saAtaojad sniaj UBUinq aqj, `titfjouuouqY 1B)*J PUD spunos UTBwao Xq paiBitdoajd an sajnztas japjostp stqi qipit sjsnpiAtpui uj -(ff) auiojpuXs anizias otuaS -otpnB aqi st uo;iB{nunis Xjoitpns Aq pajoajys A[ioaj -tp si isqi japjostp (it8o(ojnau uouxutooun uy -uibj8o( -Bqdaouaojpap aqi ut XitAtp* (BUOt3aajo 8uunosqo put .`qnunis (snsu oi Aiutiasaj passajoap b iaunj uorpsaj snjnunis panajoap :;aaj puB spusq aqi jo AiiAptsuas appBi passajoap taouBjBq jo asuas pajai -jb ub tsjouiaji pqaAa pus pusq puB `stsojpAqjad -Aq `sixayajjadXq `utsiqdBjSoiBUiap sb qons aous IBqun oituouoinB tapnput suSts psdtouud aqj (oil) ajnsodxa asiou [suoiisdnooo uuai-Suo[ qipn paiB lOossB saJuBqo (BotSo(ojnau podaj sjoibSiissaui jo jaqumu y uapjotiQ p&iBopunax puv ok>v (toi `oi) dtqsuotiBiaj b qons sisaS -8ns A(8uojis `jaABMoq `asiou [Buisnpui uo ajniBja -iq usadojnj aqj, `(oil) siapjostp {BuiisaiuioJissS ut ajnsodxa astou uuai 3uo( jo a(OJ aqi inoqB siuaui -3pnr Xjtisnf oj luatotynsui an aiqBjiBAB Xpuasajd BIBp aqj `BJJUO$fQ lttUff99fUtOJ1tOQ pUB 9ttO\ (01) ajnsodxa astou uiojy suotiosaj asjaAps .noqs oi A(aqq AqBioadsa an uaippqo pus uotiBonpd'jo sjaAB] mo( pus sauioout .wo{ qiLB `suotjnitisui ut a(doad `snqj, -uiaqi [ojiuoo oi a(qsun an oq.B a{doad pajjB oj Aiaqq isoui an sjossaiis (BiuauiuojiAua `ajouuaqunj Aiisuap uotiapidod pus amssajd qjo.M sb qons `sjossajis jaqio qipn pautquioo uaq.it sjsnpiAtpui ajqpdao -sns jo qi[Baq aqi sioajys asiou isqi pooqqaqti aqi qjut luaistsuoo st sjapjostp XBpiosBAOtpno i*oqs iou op astou oi pasodxa suosjad qs isqi psj aqj, uotiBnits uBumq aqi oi dtqsuotiBjaa jasop b snaq it asntb -aq lUBiJodun st saisuiud jo Apms stqi `(tit) sibj ui uoisuayadAq aonpojd iou ptp s(aAa( astou qStq oi ajnsodxa Suotajq isqi pasofosip Apms s^iog aoutg -susuinq ui uiajsAs JBpiosBAOtpjso aqi uo spajja astou tiuai-3uo[ joj stssq b 3utiw23ns `luauiuojuua asiou aqi oi ajnsodxa Sutniniuoosip jays paists -jad saSusqo asaqj '(tt) suiqiAqj amssajd poo(q [BUjntp ui suoiiBjai(B puB S(3Aaj amssatd poojq ut subtiB.\a(a pautsisns `lUBoytuSts paso(ostp sja -qjOM Ajopbj uBqjn jo iBqi ButiBpiuns luauiuoJtAua astou snonutiuoo b oj sqiuoui atmi joj pasodxa sAaq UCC 057308 tal ab\t this fer- Jt . cts of m 3 to BA is more, irface : that may hear- >ecial ouslv tance ents. arly iamtions alth >osiUus the ultialth iysideela- dy. of ;ed to tan to se of 0 it 'd d > Am .6 e Tm d 1 s to the general public. Because of this fragmentation and ambiguity, definitive action has been stymied by misunderstanding of the economic, social, and personal costs of noise control efforts. Underlying the confusion is the failure to appreciate that, beyond human communication, sound plays a vital role in the physiological functioning of the body. As is true with other human problems, additional inevitable resistances to facing and remediating the untoward effects of noise have been encountered. This is particularly because the root causes of noise pollution are the imposition of modern technology and population pressures on natural human living conditions. Solutions accordingly require adjustments in styles of behavior and living. Even though short range inconveniences may lead to long range be nefits, the human tendency is to resist change and maintain the status quo. Workers fail to wear prot ective hearing devices, manufacturers do not acous tically condition products and government does not adequately enforce standards. Moreover, the human capacity to adapt to noisy environments masks the magnitude of the problem. Hearing loss in itself further may reduce awareness of noxious sounds. These resistances are important determinants of ambiguities in the measurement of community re sponses to noise (119). We believe that the paralysis of effective action is not a result of lack of knowledge but of a failure to integrate and articulate existing knowledge so that compelling reasons can stimulate the motivation needed to implement changes. For this reason, education of the public and workers in the field is the most important need today. The compelling reasons for action are the facts that substantia] groups of the population are vul nerable to adverse health effects from noise, that the quality of life is generally eroded by annoyance from noise, that sleep is disrupted, that productiv ity is reduced, and that the education of children is affected by noisy environments. Without question noise can be a stressor and consequently an important underestimated pollu tant ofmodern society as are chemicals and particu late matter that pollute the air, water, and food. Moreover, noise significantly affects the human ner vous and endocrine systems. Because these sys tems are capable of sophisticated short range adap tive maneuvers, the harmful effects of noise, like other pollutants, usually become evident at later points in time. Noise is one of the main sources of sensory overload for city dwellers and industrial workers (19). More than other pollutants noise interacts with other sensory stressors, population density, life change and life circumstances. Thus, noise plays an October 1981 aggravating role in addition to stress generated by environmental conditions and attitudes toward them. These complex interactions have led to despair in ferreting out the exact role of noise in stress in duced dysfunctions. When seen in the context of all of these factors, however, noise often emerges as the one most accessible to preventive and remedial action. This is reflected in the already existing federal, state, and local noise control measures. Actually, there is little more that needs to be known. The problem lies in the lack of coordination between acoustical engineering, urban planning, health, architecture, audiology, and other related professional disciplines. There are essentially three points of intervention in noise control: reducing sound emission from the source, blocking sound transmission from the source to the ear, and protecting the ear itself from receiv ing the sound. Practical considerations limit the reduction of sound emission from industrial, traffic and aircraft sources. Still, acoustical conditioning of working and living environments can effectively reduce transmitted sound. Finally, sound can be effectively blocked at the level of the ear through protective hearing devices. By intervening at any or all of these levels there are few noise problems that cannot be effectively managed today. Thus, the problem is not that remedies are unavailable or too costly, but that the least expensive ones are not being used. The multifaceted nature of solutions to the noise problem involves the cooperation of those who gen erate and those who are affected by noise. We cannot realistically expect dramatic reductions in the sources of noise pollution (120). Unlike other forms of environmental pollution, however, indi viduals can minimize the adverse effects of noise upon them. To the extent of economic feasibility industry should more actively reduce noise emis sion at the source by machines, vehicles, and appli ances. Beyond that point, individuals can and should protect themselves from harmful sounds through acoustical conditioning and sound occluding ear de vices. The fundamental problem is one of attitude at the levels of government, industry, consumers, and health care workers. Noise already has been identified as a national hazard by Congress in the form of the Noise Control Act of 1972 and the Quiet Communi ties Act of 1978. Federal standards for new product noise emission, labeling requirements, and state and local regulations are being promulgated (121122). Yet unachieved, however, is public awareness of the significance of noise pollution. An attitude of helplessness prevails leading to either resignation to the existence of noise or escape from it by 305 ucc 057309 moving out the urban areas or changing jobs. Un appreciated is the fact that citizen initiatives, com munity organization, labor union bargaining, con sumer demand, and personal efforts can create a climate in which an attitude of mastery over noise rather than helplessness can be achieved. The basis now exists for public, consumer and labor expectations that acoustical conditioning be given priority equivalent to air conditioning in hous ing and industrial construction and in machine and appliance manufacturing. The problem lies simply in a lack of awareness of the importance of these factors. People have become accustomed to accom modating to noise through bodily defense mecha nisms and lack an understanding of the personal and governmental resources available to them. Cit izens do not fully appreciate that, negative research findings and preoccupation with the details of meas uring community annoyance notwithstanding, they have the right to determine the quality of their lives and to be free from the harrassment of noise generated by industrial, vehicular, office, airport, and household appliance souirces. Summary The fundamental purposes of hearing are to alert and to warn. The auditory orienting response, star tle reflex and defensive response translate sound stimuli into action and sometimes into stress in duced bodily changes. In the course of human evo lution the additional purposes of communication and entertainment developed as sound assumed symbolic meaning. The brain's processing of sound has been outlined as the biological and psychological basis for the effects of sound on the body. An integrated model then was presented for analyzing the impact of sound as a stressor on the body and for identifying key variables for research on the health effects of noise. In addition to the characteristics ofthe sound stimulus, a variety of personal and social factors determine whether or not noise becomes a stressor. The cognitive state, defense mechanisms, psychophysiological responses and stimulus and response regulation techniques of the individual person play vital roles. When the tension induced by sound persistently alters the homeostasis of the neuroen docrine system, a state of stress results with ac companying dysfunction in hearing, sleep, task per formance, speech communication, and emotional state. When dysfiinction leads to the assumption of the patient role, stress induced illness can be identified in the form of the suggested syndrome of "noise sickness;" cardiovascular, neurological, and gastro- 30 intestinal disorders; and possibly aggravated men tal illness and feta] abnormalities. Noise is a stressor and an important, largely unrecognized, pollutant of our environment. Our quality of life generally is eroded by annoyance from noise, and substantial segments of the popula tion are vulnerable to its adverse health effects. More specifically, sleep is disrupted, productivity is reduced and the education and development of children is affected by noisy environments. The prevention and reduction of noise pollution need not await further knowledge. The technology for reducing noise emission, acoustically condition ing environments and protecting hearing now ex ists. The problem is the lack of public awareness of the significance ofnoise pollution and solutions to it. 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