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ENVIRONMENTAL EPIDEMIOLOGY AIR QUALITY CONTROL NIEHS SCIENCE SEMINAR h P ENVIRONMENTAL HEALTH PERSPECTIVES U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service-National Institutes of Health National Institute of Environmental Health Sciences ') VOLUME 52, OCTOBER 1983 R&S 003755 * SUBSCRIPTION INFORMATION Subscription rates are as follows: Single copies $8.00, foreign $10.00, domestic $40.00 per year, foreign $50.00 per year. The yearly subscrip tion is for 6 regular issues. Please send check or money order, in advance, to the Superinten dent of Documents, U.S. Government Printing Office, Washington, 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 ap proved by the Director of the Office of Management and Budget through August 30,1984. ENVIRONMENTAL HEALTH PERSPECTIVES is a publication of the National Institute of Environmental Health Sciences, National Institutes of Health, Depart ment of Health and Human Services. Opinions expressed herein, however, are not necessarily endorsed nor shared by any of the above agencies. DHHS publication No. (NIH) 83-218 Address communications to: Editor, ENVIRONMENTAL HEALTH PERSPECTIVES National Institute of Environmental Health Sciences Box 12233 Research Triangle Park, North Carolina 27709 Reprints of Articles Should Be Requested from the Principal Authors Unless Stated Otherwise Print Schedule: Volume 53 will present the proceedings from the Workshop on Ingested Asbestos. Volume 52, October 1983 DISCRIMINATION PROHIBITED--Under the provisions of applicable pub lic laws enacted by Congress since 1964, no person in the United States shall, on the grounds of race, color, national origin, handicap, or age, be excluded from participation in, be denied the benefits of, or be subjected to discrimina tion under any program or activity (or, on the basis of sex, with respect to any education program or activity) receiving Federal financial assistance. 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. ENVIRONMENTAL HEALTH PERSPECTIVES Volume 52, October 1983 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health R&S 003756 David P. Rail, Director, National Institute of Environmental Health Sciences EDITORS George W. Lucier Gary E. R. Hook BOARD OF EDITORS John R. Bend Colin F. Chignell Robert L. Dixon Hans L. Falk Robert A. Goyer Larry G. Hart Joseph K. Haseman David G. Hoel James E. Huff Burke Judd Heinrich V. Mailing H. B. Matthews Ernest E. McConnell James D. McKinney Clifford L. Mitchell Warren T. Piver Conrad B. Richter Raymond W. Tennant EDITORIAL REVIEW BOARD Phillip W. Albro John Bachmann J. Carl Barrett Stephen C. Bondy Gary A. Boorman Arnold R. Brody Rajendra S. Chhabra Gary Clemons Terri Damstra Jack H. Dean Richard P. DiAugustine Robert T. Drew Thomas E. Eling Richard B. Everson Lawrence Fishbein Bruce A. Fowler Donald Gardner Joe W. Grisham Frank E. Guthrie James R. Hass Victor Hasselblad Ernest Hodgson Michael Hogan David J. Holbrook David G. Kaufman Carole A. Kimmel George M. Kingman Albert C. Kolbye, Jr, Kenneth S. Korach Martin R. Krigman Donald I. McRee Tom S. Miya Robert A. Neal William C. Nelson Richard M. Philpot Herbert S. Posner Robert M. Pratt Jerry M. Rice Walter J. Rogan Seamus A. Rooney Michael D. Shelby William Sheridan Robert E. Staples Velimir B. Vouk Michael D. Waters Hanspeter Witschi Errol Zeiger EDITORIAL STAFF Dorothy L. Ritter Assistant Managing Editor Ruth Krigman, Copy Editor Linda Hein, Editorial Assistant CONTENTS Second Annual Symposium on Environmental Epidemiology E. P. Radford. Introduction.................................................................................................... Session I: General Considerations A. M. Lilienfeld. Practical limitations of epidemiologic methods...................................... F. K. Dietz, J. C. Ramsey and P. G. Wantanabe. Relevance of experimental studies to human risk.......................................................................................................... R. E. Kasperson. Acceptability of human risk.................................................................. Discussion: Session I............................................................................................................ Session II: Case Study: Ionizing Radiation A. C. Upton. Environmental standards for ionizing radiation: theoretical basis for dose-response curves.............................................................................................................. C. Denniston. Are human studies possible? Some thoughts on the mutation component and population monitoring................................................................................ E. P. Radford. Epidemiology of radiation-induced cancer................................................. Discussion: Session II:....................................................................................................... Session III: Case Studies: Occupational J. K. Wagoner. Toxicity of vinyl chloride and poly(vinyl chloride): a critical review....... C. K. Redmond. Cancer mortality among coke oven workers........................................... P. F. Infante and M. C. White. Benzene: epidemiologic observations of leukemia by cell type and adverse health effects associated with low-level exposure................................... Discussion: Session III....................................................................................................... Session IV: Case Studies: Continued P. E. Enterline, Epidemiologic basis for the asbestos standard........................................ E. J. Calabrese. Role of epidemiologic studies in deriving drinking water standards for metals.............................................................................................................. Discussion: Session IV....................................................................................................... Session V: Air Pollutants B. G. Ferris, Jr., D. W. Dockery, J. H. Ware, F. E. Speizer and R. Spiro III. The Six-City study: examples of problems in analysis of the data...................................... D. V. Bates. Epidemiologic basis for photochemical oxidant standard............................... L. H. Kuller and E, P. Radford. Epidemiological bases for the current ambient carbon monoxide standards................................................................................................... Discussion: Session V.......................................................................................................... Symposium on the Health Issues in Air Quality Control R. P. Sherwin. Preface.............................................................................................................. J. N. Pitts, Jr., A. M. Winer, G. W. Harris, W. P. L. Carter and E. C. Tuazon. Trace nitrogenous species in urban atmospheres................................................................................ J. A. Last. Biochemical alterations of lung structure as predictors of chronic lung disease ., 3J CP o 03 -U4l -4 .1 .3 .9 15 21 .31 .41 .11 .51 .61 .67 .75 .83 .93 .99 107 115 125 131 141 151 153 159 R&S 003758 A. Richters and K. Kuraitis. Air pollutants and the facilitation of cancer metastasis................... 1 F. J. Miller, J. A. Graham and D. E. Gardner. The changing role of animal toxicology in support of regulatory decisions......................................................................................................... 169 R. P. Sherwin. What is an adverse health effect?............................................................................. 177 D. V. Bates. Scientific components in standard setting...................................................................... 1S3 J. D. Hackney and W. S. Linn. Controlled clinical studies of air pollutant exposure: evaluating scientific information in relation to air quality standards............................................... 187 M. D. Lebowitz. Utilization of data from human population studies for setting air quality standards: evaluation of important issues...............................................................................193 D. Pearce, G. Mooney, R. Akehurst and P. West. Rational establishment of air quality standards...................................................................................................................................207 J. J. O'Neil and J. A. Raub. Can animal pulmonary function testing provide data for regulatory decision making?................................................................................................................. 215 A. V. Colucci and R. P. Strieter. Dose considerations in the S02 exposed exercising asthmatic............................................................................................................................. 221 B. C. Jordan, H. M. Richmond and T. McCurdy. The use of scientific information in setting ambient air standards.......................................................................................................... 233 R. Frank. Health issues in the Clean Air Act................................................................................. 241 S. V. Dawson. Analysis of air pollution effects: uncertainties in proceeding to standards.............. 247 J. R. McCarroll. Health costs of a reduced energy supply.................................................................2^^ E. J. Calabrese. Expanded operational concept of high risk groups and its role in standard setting.....................................................................................................................................257 M. A. Mehlman. Current toxicological information as the basis for sulfur oxide standards............ 261 NIEHS Third Science Seminar 1982 Science Open House at the National Institute of Environmental Health Sciences....... 269 J. B. Wyngaarden. Directions and challenges in health sciences research...................................... 271 Abstracts..............................................................................................................................................277 Contributed Article D. Airey. Mercury in human hair dueto environment and diet: a review........................................303 Announcements........................................................................................................................................... 317 Errata............................................................................................................................................................318 Published Volumes of EHP....................................................................................................................... 319 Instructions to Authors.............................................................................................................................. 321 R&S 003759 IN THE NEXT ISSUE Summary Workshop on Ingested Asbestos J. R. Millette. Preface L. W. Condie. Review of published studies of orally administered asbestos E. E. McConnell. Chronic effects of dietary exposure to amosite and chrysotile asbestos in Syrian golden hamsters E. E. McConnell. Chronic effects of dietary exposure to amosite asbestos and tremolite in F344 rats J. R. Millette. Asbestos in water supplies of the United States G. M. Marsh. Critical review of epidemiologic studies related to ingested asbestos L. Polissar. Cancer risk from asbestos in drinking water: summary of a casecontrol study in western Washington E. E. SiGURDSON. Observations of cancer incidence surveillance in Duluth, Minnesota P. M. Conforti. Effect of population density on the results of the study of water supplies in five California counties M. E. Tarter. Graphical analysis of the interrelationships among waterborne asbestos, digestive system cancer and population density J, R. Millette. Epidemiology study of the use of asbestos-cement pipe for the distribution of drinking water in Escambia County, Florida L. S. Erdreich. Comparing epidemiologic studies of ingested asbestos for use in risk assessment M. S. Kanarek. The San Francisco Bay epidemiology studies on asbestos in drinking water and cancer incidence: relationship to studies in other locations and pointers for further research J. W. Meigs. Assessment of studies on cancer risks from asbestos in Connecti cut drinking water R. C. Cooper. Comments on the California studies W. J. Nicholson. Human cancer risk from ingested asbestos: a problem of uncertainty J. N. Rowe. Relative source contributions of diet and air to ingested asbestos exposure P. M. Cook. Review of published studies on gut penetration by ingested asbestos fibers E. S. Boatman. Use of quantitative analysis of urine to assess exposure to asbestos fibers in drinking water in the Puget Sound region K. Seshan. How are the physical and chemical properties of chrysotile asbestos altered by a 10-year residence in water and up to 5 days in simulated stomach acid? W, H. Hallenbeck. Asbestos penetration of the gastrointestinal tract M. E. Meek. Transmigration of ingested asbestos B. T. Mossman. In vitro approaches for determining mechanisms of toxicity and carcinogenicity by asbestos in the gastrointestinal and respiratory tracts F. B. Daniel. In vitro assessment of asbestos genotoxicity G. S. Logsdon. Engineering and operating approaches for controlling asbestos fibers in drinking water P. Toft. Asbestos in drinking water: a Canadian view J. A. Cotruvo. Asbestos in drinking water: a status report G. M. Marsh. Additional thoughts on the review of epidemiologic studies related to ingested asbestos L. Polissar. Additional notes on the case-control study in western Washington on the cancer risk from asbestos in drinking water P. M. Conforti. Additional comments on the study of the effect of population density on the results of the California Bay Area study M. E. Tarter. Answers to some questions raised by the presentation on the graphical analysis of the interrelationships between waterborne asbes tos, digestive system cancer and population density E. S. Boatman. Additional notes on the use of quantitative analysis of urine to assess exposure to asbestos fibers in drinking water in the Puget Sound region K. Patel-Mandlik. Accumulation of ingested asbestos fibers in rat tissues over time J. R. Millette. Summary of discussion sessions: workshop on ingested asbes tos R&S 003760 ii H SECOND ANNUAL SYMPOSIUM ON ENVIRONMENTAL EPIDEMIOLOGY April 27-29,1981 Pittsburgh, Pennsylvania Sponsored by the Center for Environmental Epidemiology at the University of Pittsburgh and the U.S. Environmental Protection Agency i R&S 003761 Environmental Health Perspectives Vol. 52, p.1,1983 Introduction by Edward P. Radford* 3U R (/) ooco -j 05 NS As epidemiologic studies have developed in the past twenty years, it has become apparent that results from such studies quickly become signifi cant elements in public perceptions of health ef fects from environmental agents. Most epide miology is concerned with establishing in human populations risk factors contributing to morbidity or other effects on health. Because they avoid many problems associated with interpi*etation of animal experiments, their importance in the pub lic domain is obvious. It follows, therefore, that where epidemiologic evidence exists relating an agent to human disease, there is a strong impetus to make use of that evidence in regulating condi tions leading to exposure to the agent. In this meeting, the Second Annual Symposium on Environmental Epidemiology, we have ex plored some of the limitations as well as the advantages in use of epidemiologic results for establishing standards for environmental expo sure limits. Most of the program consists of case studies of particular pollutants whose effects on various human populations have been investi gated recently, and which offer examples of the application of studies to standard-setting. In some instances these pollutants are of considerable public interest and involve highly controversial regulatory actions. Thus many parts of our soci ety need to understand the degree to which epide miologic methods are able to help define effects on human health, especially from exposure to low doses of environmental agents over long periods of time, the principal concerns of the public at large. *Center for Environmental Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15216. Environmental Health Perspectives Vol. 52, pp. 9-14,1983 Relevance of Experimental Studies to Human Risk by F. K. Dietz,*f J. C. Ramsey* and P. G. Watanabe* Confidence in the extrapolation of animal toxicity data to humans can be enhanced by the application of pharmacokinetic concepts integrated with chronic toxicity data and knowledge of a chemical's mechanism(s) of toxicity. Basic pharmacokinetic concepts (including dose-dependent or Michaelis-Menten kinetics) and their relationship to the risk estimation process are discussed using vinyl chloride and styrene as specific exam ples. Species differences in metabolic rates must be considered in order to arrive at realistic estimates of human risk to vinyl chloride-induced liver angiosarcomas utilizing 30 & V) vinyl chloride toxicity data observed in rats. Because small animal species generally metabolize chemicals more rapidly than larger species on a body surface area basis, small animals should be more sensitive to chemicals (such as vinyl chloride) that exert their oO CO 13 toxicities via the metabolic formation of toxic products. Inhaled styrene is a chemical whose clearance from the blood at low exposure levels in both rats and humans follows O"J) CO first-order kinetics. However, at higher exposure levels, the pharmacokinetic fate of styrene in rats is dose-dependent, suggesting a saturation of styrene metabolism. These H data indicate that any extrapolation of observable toxicity at elevated exposure levels in rats to anticipated responses at lower levels in either rats or humans may be invalid. An integration of the foregoing concepts provides a sound scientific basis for the use of experimental animal data to predict the risk to humans from chemical exposure. If h Introduction to potentially harmful substances, interspecies j; variation in response may often preclude a simple Chemically induced carcinogenicity is one type extrapolation of animal toxicity to that antici of toxic response that has received primary atten pated in man. The purpose of this presentation is tion in recent years. The potential lethality of to review and emphasize the importance of ani cancer, combined with its generally irreversible mal pharmacokinetic studies in properly imple nature and long latent period are all characteris menting animal toxicity data to predict human tics that have placed carcinogenesis in the fore risk from chemical exposure. p front of public concern. Many chemicals shown to be mutagenic in short-term in vitro studies and/or carcinogenic in long-term animal studies have consequently been considered as potential human Pharmacokinetic Concepts and Dynamics of Toxicity carcinogens. This conclusion is typically based on Pharmacokinetics is a study of the dynamics of studies of animal models performed under tightly absorption, distribution, metabolism and excre controlled experimental conditions in which po tion of a chemical within the body. Pharmaco tentially interfering variables are kept to a mini kinetic studies of a chemical as a function of Hi mum. Although a basic toxicological goal is to administered dose often provide valuable infor 4 s evaluate the risk to man associated with exposure mation on how a chemical's overall biological fate may change in response to different amounts "Toxicology Research Laboratory, Health and Environmen within the body. Since many toxic responses to i tal Sciences, USA 1803 Bldg., Dow Chemical USA, Midland, MI 48640. chemical exposure are not only dependent on the amount of a chemical that reaches a target site :* i .1 tAuthor to whom inquiries should be addressed. Present address: Health and Environmental Sciences--Texas, Lake Jackson Research Center, Dow Chemical USA, Freeport, TX but also on how long a sensitive site might be exposed, a comparison of the pharmacokinetic 77541. fate of a chemical between different species of ft 10 DIETZ, RAMSEY AND WATANABE animals can provide data about differential sus ceptibility relating to interspecies extrapolation of toxicity data. A classical approach to pharmacokinetic analy sis depicts the body as consisting of a system of compartments. An individual compartment gen erally refers to all tissues, organs, cells and/or fluids within the body for which the rate of uptake and loss of a chemical is sufficiently similar as to preclude further kinetic resolution. Gehring et al. (I) have provided a detailed description of phar macokinetic compartments and their use in eval uating toxicity data, and consequently no de tailed discussion will be included here. While compartments do not always have direct physio logical or anatomical counterparts when ana lyzed kinetically, they constitute a basic tool by which quantitative expressions describing the fate of a chemical within the body can be derived. Dose-Independent Pharmacokinetics Over a range of selected dose levels, many chemicals exhibit first-order kinetics which can be referred to as being "linear." For these chemi cals, the rates of absorption, distribution, metabo lism and elimination from the-body are propor tional to the concentration or amount of the chemical within the body. As a consequence of this proportionality, the rate constants of all these processes are thus independent of the ad ministered dose. In a simplified fashion, firstorder kinetics may be expressed by the equation: rate = -dC/dt = kC in which C is the concentration of the chemical in the body at time t and k is the rate constant for the given process. As long as first-order kinetics apply and thus the rate constants for all processes responsible for a chemical's pharmacokinetic fate are independent of administered dose, tissue con centration and consequent toxicity should also be proportional to administered dose. Dose-Dependent Pharmacokinetics In actuality, many reactions that influence a chemical's pharmacokinetic fate are not indepen dent of administered dose, but are instead dosedependent. In this situation, saturable active transport systems or metabolic reactions that of ten play key roles in the prevention or enhance ment of chemical toxicity are not adequately de scribed by first-order kinetics. As a consequence, the administration of high dose levels, as fre quently done in long-term animal bioassays, may overwhelm these processes and result in a dispro portionate increase in blood and/or tissue concen tration and possibly elicit a toxic response. The rates of saturable processes are often de scribed by Michaelis-Menten or dose-dependent kinetics according to the equation: rate = -dC/dt = VmaxC/Km + C In this equation, - dC/dt is the rate of change in the concentration of the chemical's concentration at time t, Vmax is the maximum velocity of the process and Km is the Michaelis constant or that concentration at which the rate of the process is at a value of one-half Vmax. There are two limiting situations to this equation. When the concentra tion (C) is much greater than Km, the MichaelisMenten equation approaches a limit of: rate = - dC/dt ~ Vmilx CKm In this situation, the rate of the process is limited by the value Vm;ix, and, as C increases, the rate of the reaction remains constant. It is in this concen tration range (CKm) that the biological proc esses governed by this type of kinetic behavior have become overwhelmed and can be considered to be saturated. Conversely, if the concentration C is much les^ than Km, the rate of the processes described by the^ Michaelis-Menten equation can be approximated by: rate = - dC/dt ~ kC CKm where k = Vm.jKm. Under these conditions, the rate of the process remains proportional to the chemical's concentration and all of the previously described concepts for first-order kinetics regard ing proportionality between blood and tissue con centration and toxicity apply. Use of Animal Studies for Predicting Human Toxicity Recent authors have suggested that there are at least five potential factors responsible for spe cies variations in response to chemical exposure (2). Collectively, these factors include absorption, distribution, metabolism, site and mechanism of action and excretion of the chemical from the body. It is of interest to note that an analysts of the dynamics of many, if not all, of these factors as a function of administered dose level consti tutes what has been previously described as m pharmacokinetic study. ^ In utilizing animal studies to predict possible human toxicity, it is important to determine if the toxicity resulting from chemical exposure is due to the parent chemical itself or rather to an Fa^tuu bvd EXPERIMENTAL STUDIES AND HUMAN RISK 11 active metabolite generated via metabolic proc esses occurring within the animal. It is commonly accepted that metabolism can either lead to de toxification or activation, depending on the toxi cological potential of the parent compound and/or its possible metabolites. Consideration of this in formation is important for the extrapolation of results from animal toxicity studies to man, since there may be relative species differences in the activity of enzymes responsible for chemical me tabolism. As pointed out by Rail (3), it is often possible to estimate the relative sensitivity of different species to a chemical by using an ap proximation that the basal metabolic rate is roughly proportional to the body surface area. This suggests that if factors other than metabo lism are ignored, a large animal species is more sensitive to a directly toxic agent than a small animal species (Table 1). In contrast, a large ani mal species should then be less sensitive to toxic ity mediated by a metabolic activation than a smaller species (4). It should be emphasized, how ever, that for some types of metabolic activation the relative rates may not only be a simple func tion of body size. For example, the metabolic activation of 2-acetaminofluorene involves the formation of an active sulfate, and the species and organ sensitivity of the tumorigenicity of this agent correlates well with the level of sulfotransferase enzyme activity (5). Since the rat has a higher level of sulfotransferase than the mouse, it develops more tumors when exposed to an equiva lent amount of 2-acetaminofluorene. In this in stance, the larger animal species is more sensi tive to the effects of the metabolically activated agent than the smaller species. Thus, the reliabil ity of interspecies extrapolation depends to a large degree upon how much is known of the details of metabolism and how metabolism affects toxicity in the species of interest. Pharmacokinetic Concepts and Risk Estimation Many mathematical models are commonly used in extrapolating an observed carcinogenic re sponse in animal bioassays at relatively high dose levels (6). While these models differ from each other by the rapidity in which a zero response is approached as the dose level approaches zero, they are similar in that they usually assume that a zero response occurs only when the dose level equals zero. Another feature common to these models is their assumption that the concentration of the carcinogenic entity is directly proportional to the dose level of the administered chemical. Table 1. Predicted relative cancer risk from equivalent doses (mg/kg) calculated on the basis of (body weight).a Species Man (70 kg) Dog (20 kg) Rabbit (3 kg) Rat (0.5 kg) Mouse (0.03 kg) aAfter Rail (3). Predicted relative cancer risk Directly toxic Metabolically activated agents agents 1.00 1.00 0.66 1.52 0.35 2.85 0.18 5.58 0.08 13.20 This assumption applies whether the carcino genic entity is produced via a metabolic activa tion of the parent chemical or whether the parent chemical itself is the primary toxicant. An impor tant consequence of this assumption is that toxic ity or carcinogenicity is also expected to be pro portional to administered dose level. Recent studies of several chemicals, including vinyl chlo ride and styrene, illustrate how an understanding of the pharmacokinetic fate of these compounds as influenced by the magnitude of administered dose can be used to evaluate animal toxicity data in order to predict the hazard to man from expo sure to these agents. Vinyl Chloride An example of dose-dependent pharmaco kinetics that directly relates to carcinogenic risk estimation in man is that of inhaled vinyl chlo ride (7, 8). Vinyl chloride has been demonstrated to induce hepatic angiosarcomas in rats at expo sure levels ranging from 10 to 10,000 ppm, with an essentially flat dose-response curve at expo sure levels from 1,000 to 10,000 ppm (9). Numer ous studies have indicated that a reactive metab olite of vinyl chloride is likely to be the carcinogenic entity for this halogenated ethylene rather than the parent compound itself (10-15). Other studies have shown that the bioactivation of vinyl chloride in rats is a saturable process that follows Michaelis-Menten kinetics becoming overwhelmed at high exposure levels, thereby limiting the in vivo production of the toxic metab olite (7, 16-19). As a consequence of this satura ble metabolic activation, Gehring et al. (7) have shown that the toxicity or carcinogenicity in rats resulting from vinyl chloride exposure is not di rectly proportional to all exposure concentra tions. Alternatively, these authors found it was possible to relate the observed carcinogenicity in rats to the amount of vinyl chloride metabolized after pharmacokinetic parameters describing the r&S 003766 12 DIETZ, RAMSEY AND WATANABE saturable bioactivation of vinyl chloride were de termined. In accordance with these observations of the kinetic behavior of vinyl chloride in rats, Gehring et al. (7, 8) utilized similar pharmacokinetic con cepts to estimate the amount of vinyl chloride metabolized in man. Their prediction incorporat ed the concepts that vinyl chloride bioactivation in man was a saturable process as observed in laboratory animals and that the metabolic proc ess responsible for vinyl chloride metabolism in mammals was related to differences in body sur face area. Using this methodology, these authors predicted that man's rate of vinyl chloride bioac tivation would be much less than that observed in rats, resulting in a decreased sensitivity of man to the tumorigenic effects of vinyl chloride (7, 8). Recent data from other laboratories on the rate of vinyl chloride metabolism have provided addi tional support for this conclusion. In studies of the pharmacokinetics of vinyl chloride in differ ent species (including man), Buchter et al. (20, 21) and Filser and Bolt (22) have confirmed that a marked species variation in vinyl chloride metab olism does indeed exist (Table 2). These investiga tors found that mice and rats metabolized vinyl chloride at a rate approximately 5-12 times that for man. In contrast to the results observed in these rodent species, rhesus monkeys were found to metabolize vinyl chloride at a rate that closely paralleled that seen in man. Collectively, these results are significant in that they confirm the predictions reached by Gehring et al. (7, 8), who used pharmacokinetic concepts to predict differ ences in the relative rates of vinyl chloride me tabolism in rats versus man. 1200 ppm the maximum blood concentration reached a value of 64 (xg/mL. Thus, as exposure concentration increased by 15-fold, the maximum blood concentration increased over 80-fold, indi cating a dose dependency in the pharmacokinetic profile of styrene. As reviewed by the original authors (23), these and other data indicated that the capability of laboratory animals to metabolize styrene becomes overwhelmed at exposure con centrations somewhere between 200 and 600 ppm. These results indicate that any extrapola tion of animal toxicity data observed at exposure levels of 600 ppm and above to anticipated re sponses in animals at lower levels may be invalid. How do these results relate to the extrapolation of styrene toxicity data in laboratory animals to that in man? Such an extrapolation can be greatly facilitated by a direct pharmacokinetic comparison of the chemical in question between both species. Accordingly, Ramsey and Young Table 2. First-order metabolic clearance rates for vinyl chloride in man versus other species.* Species Clearances, L/hr/kg body weight Man Monkey Rat Mouse 2.02 3.55 11.00 25.60 "Data from Buchter et al. (20,21) and Filser and Bolt (22). pg Styrene/ ml Blood Styrene Styrene is another example of a chemical whose metabolic elimination in experimental animals is dose-dependent. In an analysis of the pharmaco kinetic fate of styrene in rats following a 6-hr inhalation exposure to 80, 200, 600 or 1200 ppm, Ramsey and Young (23) observed that there was a marked dose dependency in the elimination of styrene from the blood. Figure 1 depicts a plot of the blood styrene concentration versus time data in animals exposed to 80 or 1200 ppm for 6 hr. Other animals were left in the exposure chambers for periods of up to 24 hr in order to establish whether plateau blood levels were achieved. Note that a disproportionality exists between maxi mum blood concentration and exposure level. At an exposure level of 80 ppm, the maximum styrene concentration was 0.8 p.g/mL, while at Figure 1. Blood styrene concentration in rats exposed to 80 or 1,200 ppm. Data from Ramsey and Young (23). HQ Styrene/ ml Blood EXPERIMENTAL STUDIES AND HUMAN RISK 13 ity data obtained at high levels to predict possible risks to humans at lower exposure levels. Conclusions In summary, it should be noted that animal studies of pharmacokinetic behavior only repre sent one segment of the total data base of interre lated information required to make a rational extrapolation of toxicity data observed in labora tory animals to anticipated responses in man. Other authors have demonstrated that the risk estimation process is greatly enhanced when ani mal studies of pharmacokinetic behavior are inte grated with observations of chronic toxicity and a knowledge of mechanisms of toxicity such as the production of active metabolites that interact with critical macromolecular sites. Collectively, an evaluation of the relationships between these parameters and toxicity in experimental animals will improve the estimation of relative degrees of risk to man associated with chemical exposure. FIGURE 2. Blood styrene concentration in humans exposed to 80 ppm for 6 hr. Data from Ramsey and Young (23). (23) conducted a pharmacokinetic study of in haled styrene in human volunteers exposed to 80 ppm for 6 hr. Figure 2 depicts the blood styrene concentration during and after exposure in the four volunteers. Note that the blood styrene con centration rose to a maximum of 0.9 ug/mL at 6 hr and declined in a linear fashion. A comparison of these results with those of Figure 1 indicates a marked similarity between the pharmacokinetic fate of styrene in man and rats following exposure to 80 ppm. These authors concluded that this type of similarity lends confidence to the extrapolation of toxicity data observed in laboratory animals at levels below 80 ppm to that anticipated in man. In contrast, the demonstration of a saturable elimi nation of styrene from laboratory animals at higher exposure levels precludes the use of toxic REFERENCES 1. Gehring, P. J., Watanabe, P. G., and Blau, G. E. In: New Concepts in Safety Evaluation, Vol. 1, Part 1 (M. A. Mehltnan, R. E. Shapiro and H. Blumenthal, Eds.), Hemi sphere Publishing Corp., New York, 1979, pp. 195-270. 2. Reichsman, F. P., and Calabrese, E. J. Animal extrapola tion in environmental health: its theoretical basis and practical applications. Rev. Environ. Health 3: 59-78 (19791. 3. Rail, D. P. Difficulties in extrapolating the results of toxicity studies in laboratory animals to man. Environ. Res. 2: 360-367 (1969). 4. Reitz, R. H., Gehring, P. J., and Park, C. N. Carcinogenic risk estimation for chloroform: An alternative to EPA's procedures. Food Cosmet. Tbxicol. 16: 511-514 (1978). 5. Miller, E. C. Carcinogenesis by aromatic amines and amides. Reported at the symposium on environmental carcinogenesis. Michigan State University, East Lansing, MI. 1978. 6. Gaylor, D. W., and Shapiro, R. E. In: New Concepts in Safety Evaluation, Volume 1, Part 2 (M. A. Mehlman, R. E. Shapiro and H. Blumenthal, Eds.), Hemisphere Publishing Corp., New York, 1979, pp. 65-87. 7. Gehring, P. J., Watanabe, P. G., and Park, C. N. Resolu tion of dose-response toxicity data for chemicals requiring metabolic activation: example--vinyl chloride. Tbxicol. Appl. Pharmacol. 44: 581-591 (1978). 8. Gehring, P. J., Watanabe, P. G., and Park, C. N. Risk of angiosarcoma in workers exposed to vinyl chloride as predicted from studies in rats. Toxicol. Appl. Pharmacol. 49: 15-21 (1979). 9. Malloni, C.. and Lefemine, G. Carcinogenicity assays of vinyl chloride: current results. Ann. N.Y. Acad. Sci. 246: 195-224 (1975). 10. Barbin, A., Bresil, H., Croisy, A., Jacquignon. P,, Malaveille, C., Montesano, R., and Bartsch. H. Liver-microsome-mediated formation of alkylating agents from vinyl bromide and vinyl chloride. Biochem. Biophys. Res. Comraun. 67:596-603(1975). 14 DIETZ, RAMSEY AND WATANABE 11. Bartsch, H., Malaveille, C., and Montesano, R. Human rat and mouse liver mediated mutagenicity of vinyl chloride in salmonella typhimurium strains. Int. J. Cancer 15: 429-437 (1975). 12. Bolt, H. M., Kappus, H., Kaufmann, R,, Appel, K. E., Buchter, A., and Bolt, W. Metabolism of 14C-vinyl chlo ride in vitro and in vivo. Inserm 52: 151-164 (1975). 13. Malaveille, C,, Bartsch, H., Barbin, A., Camus, A. M., and Montesano, R. Mutagenicity of vinyl chloride, chloroethylene-oxide, chloroacetaldehyde and ohloroethanol. Biochem. Biophys. Res. Commun. 63: 363-370 (1975). 14. Kappus, H,, Bolt, H. M., Buchter, A., and Bolt, W. Liver microsomal uptake of (140 vinyl chloride and transfor mation to protein alkylating metabolites in vitro. Tbxicol. Appl. Pharmacol. 37: 461^71 (1976). 15. Watanabe, P. G., Zempel, J. H., Pegg, D. G., and Gehring, P. J. Hepatic Macromolecular binding following exposure to vinyl chloride. Tbxicol. Appl. Pharmacol. 44: 571-579 (1978). 16. Bolt, H. M., Kappus, H., Buchter, A., and Bolt, W. Disposi tion of (1,2-140 vinyl chloride in the rat. Arch. Tbxicol. 35: 153-162 (1976). 17. Watanabe, P. G., Hefner, R. E., Jr., and Gehring, P. J. Vinyl chloride induced depression of hepatic non-protein sulfhydryl content and effects on bromosulphthalein (BSP) clearance in rats. Toxicology 6:1-8 (1976). 18. Watanabe, P. G., McGowan, G. R,, and Gehring, P. J. Fate of 14C-vinyl chloride after single oral administration in rats. Tbxicol. Appl. Pharmacol. 36:339-352 (1976). 19. Watanabe, P. G., McGowan, G. R., Madrid, E. 0,, and Gehring, P. J. Fate of i4C-vinyl chloride following inhala tion exposure in rats. Toxicol. Appl. Pharmacol. 37: 49-59 (1976). 20. Buchter, A,, Bolt, H. M., Filser, J. G., Goergens, H. W,, Laib, R, J., and Bolt, W. Pharmkokinetik und Karzinogenese von Vinylchlorid arbeitsmedizinische Risikobeurteilung. Verhandl. Deut. Gesell. Arbeitsmed. 18: 111-124 (1978). 21. Buchter, A., Filser, J. G., Peter, H., and Bolt, H. M. Pharmacokinetics of vinyl chloride in the rhesus monkey. Tbxicology Letters 6: 33-36 (1980). 22. Filser, J. G., and Bolt, H. M. Pharmacokinetics of halogenated ethylenes in rats. Arch. Tbxicol. 42: 123-136 (1979). 23. Ramsey, J. C., and Young, J. D. Pharmacokinetics of inhaled styrene in rats and humans. Scand. J. Work. Environ. Health 4: 84--91 (1978). R&S 003768 Environmental Health Perspectives Vol. 52, pp. 61-66,1983 Toxicity of Vinyl Chloride and Poly(vinyl Chloride): A Critical Review by Joseph K. Wagoner* ? < In 1974, vinyl chloride (VC) was first reported in the open scientific literature to induce angiosarcoma of the liver both in humans and in animals. Additional research has now demonstrated the carcinogenicity of VC to other organs and at lower concentrations. The target organs for VC now clearly include the liver, brain and the lung, and probably the lymphohematopoietic system. The evidence for a carcinogenic risk has been extended to jobs associated with poly(vinyl chloride) exposure. Cases of liver angiosarcoma have been reported among individuals employed in PVC fabrication facilities and an epidemiological study has demonstrated a significant association between exposure to PVC dust and the risk of lung cancer mortality. Cases of angiosarcoma of the liver also have been reported among individuals living in near proximity to vinyl chloride-poly(vinyl chloride) plants. An association between PVC dust and pneumoconiosis also has been demonstrated. On the basis of findings, prudent control of PVC dust in the industrial setting is indicated. aboratory Bioassay In 1971, 44 years after vinyl chloride was intro duced into American commerce (1), 24 years after vinyl chloride was shown to cause cardiac arrhythmia in experimental animals (2), 22 years after vinyl chloride was reported to be associated with hepatic abnormalities in workers in a Rus sian plastic factory (3), 14 years after toxic angioneuropathy was noted among workers exposed to vinyl chloride below the then Russian maxi mum allowable concentration of 390 ppm (4), 11 years after the vinyl chloride production process was associated with a severe neurologic disorder in Minamata, Japan (5), 10 years after vinyl :hloride at concentrations down to 200 ppm were reported to cause centrilobular granular de generation of the liver (6) and 5 years after vinyl chloride was shown to induce acro-osteolysis in workers cleaning reactor vessels (7), Viola et al. (8) reported the induction of tumors of the skin, lung and bone in rats exposed by inhalation to 30,000 ppm of vinyl chloride. These oncogenic findings have been interpreted by some to have elicited little response because *ConsuIting Epidemiologist, 8310 Carrleigh Parkway, Springfield. VA 22152. the testing was conducted only at unrealistically high dosages bordering on the lower explosive limit of vinyl chloride (9). In reality, however, such was not the case. In May of 1971, Viola had presented to several U.S. companies unpublished findings of an increased incidence of tumors in rats exposed to vinyl chloride concentrations down to and including 500 ppm (10). Additional ongoing studies involving vinyl chloride expo sures of 20,000, 10,000, 5,000, 2,000, 500 and less than 500 ppm were also described to those same companies. In like manner, Maltoni, in 1972, upon noting angiosarcoma of the liver and cancer of other sites in rats exposed by inhalation to vinyl chloride at lower concentrations, also had transmitted his findings to the Manufacturing Chemists Association in the United States and to several chemical companies in Europe (11). Gov ernment, labor and the independent research community were first informed of the expanding carcinogenic properties of vinyl chloride in Janu ary of 1974, when representatives of industry announced having found liver angiosarcoma in three workers who had cleaned reactor vessels as part of their employment at a single vinyl chlo ride polymerization facility in the United States. Almost simultaneously, findings of the induction of liver angiosarcoma in rats exposed to vinyl chloride were made public. 62 J. K, WAGONER 003770 The carcinogenic properties of vinyl chloride mortality analysis of 161 deceased workers ha\ were further clarified in 1974, when Caputo et al. ing been employed at one of two plants in the (12) reported an increasing incidence of liver an United States producing and polymerizing vinyl giosarcoma with an increasing dosage of vinyl chloride. The specific sites of cancer with the chloride. Among rats exposed to vinyl chloride by greatest excess were the liver and biliary tract, inhalation, the incidence of liver angiosarcoma with an 11-fold excess; the brain, with a 4-fold was 3% at 500, 5% at 1,000, 6% at 5,000, 8% at excess; the digestive tract and the lung. a 10,000 and 12% at 20,000 ppm. Among controls In 1975, Nicholson et al. (20) published a study 19 A not exposed to vinyl chloride, liver angiosarcoma was not found. In that same year Maltoni and of cancer mortality among 257 individuals occu pationally exposed to vinyl chloride for at least 5 Lefemine (13) also reported the induction of tu years, with the initial exposure having occurred mors in mice, hamsters and rats exposed to vinyl more than 10 years in the past during employ chloride by inhalation. The spectrum of induced ment in a U.S. plant polymerizing vinyl chloride. tumors included angiosarcomas of the liver, ade A 2.3-fold excess in deaths from cancer of all sites nomas and adenocarcinomas of the lung, neuro combined was demonstrated with three deaths blastomas of the brain, lymphomas and carcino due to hemangiosarcoma of the liver. In that same mas of other sites. Vinyl chloride in that study year, Ott et al. (21) reported the mortality experi was shown to induce liver angiosarcoma in rats at ence of 549 individuals occupationally exposed to 50 ppm of exposure. Keplinger et al. (14) in that vinyl chloride-poly(vinyl chloride). Whereas no same year also reported the induction of liver angiosarcomas of the liver were found, an excess angiosarcoma in mice exposed to 50 ppm of vinyl of all malignancies combined was reported among chloride by inhalation. Subsequently, Holmberg those workers classified as having been highly et al. (15) reported the induction of hepatic and exposed when contrasted with workers of all extrahepatic angiosarcoma in mice following in other exposure intensities. Among the nine can halation exposure to vinyl chloride at 50 ppm. cer deaths in the highly exposed group of workers^ Shortly thereafter Maltoni (16) extended the car four were due to lung cancer. In a discussion ofl cinogenicity of vinyl'chloride to lower levels of the limitations of the study, the investigator? exposure. Vinyl chloride administered by inhala noted that the majority of workers in the category tion was shown to induce tumors at a variety of "other than highly exposed" had less than one sites, including liver angiosarcoma at 25 ppm and year of work experience in departments with ex mammary carcinomas at 25, 10, 5 and 1 ppm. posure to vinyl chloride-polyvinyl chloride. Recently Maltoni (17) reported the induction of Duck et al. (22) in 1975 reported that a study of hepatic and extrahepatic angiosarcoma at 10 ppm 2100 employees of a vinyl chloride polymerization of vinyl chloride. plant in the United Kingdom revealed no excess Epidemiology of total or cause-specific mortality. In addition to reporting no excess of cancer mortality. The in Occupational Exposure: Vinyl Chloride Production or Polymerization vestigators reported an inverse relation between vinyl chloride exposure and cancer mortality, i.e., as the duration of exposure to vinyl chloridepoly* vinyl chloride) increased, the risk of cancel- In 1974, the same year that the public was first decreased. The results and conclusions of that informed that vinyl chloride induced liver an study were adjudged by Wagoner et al. (23) to be giosarcoma and cancers of other sites by way of spurious and due to the use of faculty analytical experimental bioassay, epidemiological studies methodology. Upon reanalysis of the data in that also were reported demonstrating an excess of study, Duck and Carter (241 reported an in cancer of multiple organs among workers occupa creased risk of cancer of the digestive system tionally exposed to vinyl chloride. Tabershaw and among workers observed 15 years or more after Gafiey (IS) reported that cancers of the buccal onset of exposure to vinyl chloride-polv(vinyl cavity and pharynx, digestive tract (primarily chloride). liver angiosarcoma), respiratory tract, central Subsequently, Waxweiler et al. (25) reported nervous system (primarily brain) and the lym the results of a retrospective study of mortalitjT phatic system were excessive among workers in among a cohort of 1294 workers occupationally the United States having been employed for at exposed to vinyl chloride in the United States. least one year in plants producing and/or polym Since occupationally induced cancers often take erizing vinyl chloride. Monson et al. (19) in that years to become clinically manifest following ex same year reported the results of a proportionate posure to carcinogens, the studv was restricted to t' TOXICITY OF VINYL CHLORIDE AND PVC 63 those individuals with 5 years or more of employ ment in departments and jobs directly involving vinyl chloride exposure and with 10 years or more elapsed time since onset of initial exposure. Spe cific jobs and departments with vinyl chloride exposure were determined following a walk through survey and review of the manufacturing process, engineering controls and air-sampling data for the plants studied. When analyses were based on the total study cohort, only two major causes of death were in excess: nonneoplastic respiratory disease (6 observed vs. 3.4 expected) and all malignant neoplasms combined (35 ob served vs. 23.4 expected). The latter excess was statistically significant at p - 0.05. When analy ses were made according to site of malignancy and latency (interval since onset of exposure), an excess cancer mortality was found for four organ systems, i.e., central nervous system, respiratory system, hepatic system and lymphatic and hema topoietic system. The excessive mortality was sta tistically significant for three of the four organ systems, i.e., cancer of the central nervous, the respiratory and the hepatic systems, among workers who had been observed 15 years or more since onset of exposure. During the course of the study by Waxweiler et al., an evaluation was made of the pathologic data underlying each neo plasm identified. Of the 14 cases of liver cancer identified, 11 were diagnosed as angiosarcoma. Of ten cases of brain cancer identified, nine were shown to be glioblastoma multiforme in type. Furthermore, of eight lung cancer cases histologi cally confirmed, all were large cell undifferenti ated or adenocarcinoma in type. Byren et al. (26) in 1976 also reported a statisti cally significant excess of liver-pancreatic and brain cancer deaths among 771 workers employed in a Swedish vinyl chloride/poly(vinyl chloride) production plant. These investigators reported that this excess appeared within the first 5 years after onset of exposure to vinyl chloride. In 1977, von Reinl et al. (27) reported the results of a study of cancer mortality among 7021 males employed in the production and polymeri zation of vinyl chloride. When compared to the mortality experience of the West German male population, vinyl chloride-polyfvinyl chloride) exposed workers experienced an excess of cancer of multiple organs, i.e., liver, lung, brain and the lympatic and hematopoietic system. Fox and Col lier (28) in 1977 also reported the results of the study of cancer mortality patterns among 7561 males who, at some time between 1940 and 1974, were employed at one of four plants producing poly(vinyl chloride). An excess mortality from liver cancer was shown for each group of workers whether exposure to vinyl chloride was judged to have been high, medium or low. The authors commented that, although there were no data from the study to support an excess mortality from cancers other than of the liver, the period of follow-up of the workers was too short to permit a clear evaluation of those carcinogenic effects at that time. Epidemiological investigations have now clearly demonstrated that laboratory bioassay findings were predictive not only for the carcino genicity of vinyl chloride, but also for several of the target organs. On the basis of these results, the IARC (29) in 1979 concluded "Vinyl chloride is a human carcinogen. Its target organs are the liver, brain, lung and haemo-lymphopoietic system." Occupational Exposure: Poly(vinyl Chloride) Packing and Fabricating Christine et al. in 1974 reported (30) two histopathologically confirmed cases of hepatic an giosarcoma in Connecticut among individuals who had been employed in industrial facilities that used poly( vinyl chloride). One of these indi viduals, a 47-year-old man, had worked for the previous 10 years as an accountant in a factory producing vinyl sheets and processing poly(vinyl chloride) resins. This individual had frequently visited the plant's production area. The second individual, a 61-year-old man, had spent 25 years in an electrical plant operating a machine that applied poly(vinyl chloride)-containing plastic to wires. In 1977, Baxter et al. (31), in a review of 14 cases of hepatic angiosarcoma diagnosed in Great Britain during 1963-73, noted one case who had worked on a process which used polyfvinyl chlo ride) as a raw material. In 1975, Selikoff wrote to NIOSH suggesting that appropriate precautions be taken to avoid the inhalation of poly(vinyl chloride) dust, both in the packaging and transport and in its handling during the manufacture of poly(vinyl chloride) products. Selikoff based his suggestion on the results of studies by Lilis et al. (32) and Miller et al. (33) showing radiographic and pulmonary function changes among vinyl chlorides-poly(vi nyl chloride) workers and on the findings of a poly(vinyl chloride) inhalation toxicologic study by Frongia et al. (34). This latter investigation showed that rats and guinea pigs, exposed in the same occupational setting as workers who were employed in filling sacks with poly( vinyl chloride) powder, subsequently developed alveolar reac tions and septal thickening. This investigation R&S 003771 64 J. K. WAGONER R&S 003772 also showed that 7 months after their initial exposure, both species exhibited granulomatous changes, with fine granules observed intracellularly. Agarwal et al. (35) in 1978 demonstrated that intratracheal administration of polyfvinyl chloride) dust in rats resulted in an increase in the activity of lysomal enzymes, interstitial fibro sis and granulomatous lesions surrounded by fi broblasts, reticulin and collagen fibers. Pulmo nary disorders possibly associated with exposure to poly(vinyl chloride) resins produced by the emission process might by expected, as dust sam ples taken by NIOSH during the bagging of poly fvinyl chloride) resin have shown concentrations ranging from less than 1 up to 19 mg/m3, with about 90# of the particles being smaller than 2.5 pm and 100# smaller than 7 pm in diameter. In 1978, Arnaud et al. (36) reported a case of pneumoconiosis in a 53-year-old man who had been exposed to poly(vinyl chloride) in the bag ging area of a VC polymerization plant. This patient presented with exertional dyspnea, pul monary function changes, and chest radiographic abnormalities. Electron microscopy of lung tissue obtained by drill biopsy showed foreign particles in the macrophages that were identical to poIy( vi nyl chloride) powder viewed under the electron microscope. In vitro incubation of poly(vinyl chlo ride) powder with human lung macrophages showed that the macrophages engulfed the pow der to give an appearance similar to that seen in vivo. The authors noted that the histological le sions in this patient were identical to those re corded by Szende et al. (37), who diagnosed ad vanced pneumoconiosis in a 31-year-old man secondary to the inhalation of polyfvinyl chloride) dust. Szende et al. also reported that microscopic examination of poly(vinyl chloride) dust particles showed them to be morphologically similar to particles found in the patient's lungs. Results of epidemiologic studies by Vertkin and Hamontov (38) and by Mastrangelo et al. (39) further support the role of polyfvinyl chloride) in the etiology of pneumoconiosis. A total of 1216 employees of a polyfvinyl chloride) production factory in Italy underwent chest X-ray examina tions. Of 731 examined individuals with exposure to polyfvinyl chloride) dust, 20 were diagnosed as having pneumoconiosis. All of these individuals had worked 5 years or more in departments clas sified as having polyfvinyl chloride) dust pollu tion. No cases of pneumoconiosis were observed among the 485 examined individuals who worked in areas free of polyfvinyl chloride) dust. The effects of vinyl chloride-polyfvinyl chlo ride) exposure on the respiratory system of ex posed workers seem to indicate a pattern of neoplastic effects, a granulomatous reaction to polyfvinyl chloride) dust, with inclusion of poly fvinyl chloride) particles in macrophages and histocytes, and associated interstitial fibrosis. The long-term carcinogenic effect, with a sig nificant increase in lung cancer also is of concern. In 1978, Waxweiler et al. (40) reported the results of a study of lung cancer at a single vinyl chlo ride-polyfvinyl chloride) facility. One objective of this study was to determine whether there was an excess risk of lung cancer of a particular histolog ical type at the plant. A case control study showed a clear excess of type 3 (adenocarcinoma) and type 4 (large-cell undifferentiated) lung cancers in cases occurring among plant employees as com pared to other lung cancer cases from the same hospital of diagnosis, matched for age and calen dar period of diagnosis. The authors noted that adenocarcinomas of the lung, accounting for a minor proportion of this excess risk, have been shown to be at most only weakly related to ciga rette smoking; some studies have shown no asso ciation at all. The authors also noted that large cell differentiated carcinoma of the luj^^ accounting for the vast majority of the exc^f lung cancer risk, is the only major histological type that has never been related to cigarette smoking by epidemiologic study. Thus, they con cluded that cigarette smoking was not a major confounding variable in the study. A further study was made by Waxweiler et al. to test whether one or more chemicals used at the plant were responsible for the excess of lung can cer of types 3 and 4 or for the excess of only type 4. A model was specifically developed for this pur pose. The sensitivity and specificity of the model was demonstrated by its confirmation of the rela tionship between angiosarcoma of the liver and direct vinyl chloride exposure. The authors re ported that of all 19 chemicals used at the plant, polyfvinyl chloride) dust was the only chemical for which they found a statistically significant association with lung cancer mortality and specifi cally with large-cell undifferentiated lung cancer. The studies mentioned above suggest that the excess lung cancer risk in the vinyl chloridepolyfvinyl chloride) industry is related to expo sure to polyfvinyl chloride) dust. That the dust itself or as a carrier of residual vinyl chlor monomer is a factor in the etiology of lung can seems biologically plausible. Poly<vinyl chlori dust particles are known to be often in the respi rable range--that is, less than 10 pm in diame ter. Almost all polyfvinyl chloride) particles pro duced by the emulsion system, one of the systems TOXICITY OF VINYL CHLORIDE AND PVC 65 at the facility studied by Waxweiler et al., are in the respirable range. These particles could easily settle in the lung and conceivably by themselves cause lung cancer. However, it is known that vinyl chloride monomer becomes entrapped in polyCvinyl chloride) dust and can be released slowly over time. Thus it is also possible that poly(vinyl chloride) dust particles in the lung could slowly release vinyl chloride monomer to small adjacent areas of the tissue, prolonging the contact time of that chemical with tissue. On the basis of these findings, one must seri ously question the safety of the current OSHA standard for poly(vinyl chloride) dust, i.e., a stan dard which treats poly(vinyl chloride) as a nui sance dust. Community Exposure to Vinyl Chloride Christine et al. (30) reported two cases of he patic angiosarcoma in Connecticut having a prob able residential exposure to vinyl chloride. One individual with hepatic angiosarcoma lived within 2 miles of the plant producing poly( vinyl chloride)-coated wire, while the second individual lived within 0.5 miles of a plant producing vinyl sheets. Each of these two plants also had a case of hepatic angiosarcoma among its labor force. Nei ther of these residential cases was known to have had occupational exposure to vinyl chloride or arsenic or diagnostic exposure to thorium dioside, the only three agents known to cause hepatic angiosarcoma in humans. Baxter et al. (31), in 1977 reported another case of liver angiosarcoma in Great Britain who had lived for 6 years within half a mile of a plant manufacturing polylvinyl chloride). On the basis of these observations, Brady et al. (41) in 1977 undertook a study in New York State of 26 confirmed cases of hepatic angiosarcoma. Controls comprised of individuals who had an internal malignant tumor other than primary liver cancer were matched with index cases on the basis of age at diagnosis, race, sex, place of residence and vital status. This study showed a statistically significant association be tween angiosarcoma of the liver and direct occu pational or therapeutic exposure to arsenic (two cases), vinyl chloride (three cases) and thorium dioxide (two cases). In addition, this study demon strated that of ten female cases of liver angiosar coma (no direct occupational or therapeutic expo sure to vinyl chloride, arsenic or thorium dioxide) one lived within 1700 ft of a vinyl chloride polymerizarion plant and four lived from 500 to 4500 ft of a polyfvinyl chloride) fabrication plant. In contrast, none of their matched controls lived within 1 mile of any facility polymerizing vinyl chloride or fabricating polyfvinyl chloride). These study findings are supportive of the role of in direct modes of vinyl chloride exposure in the etiology of liver angiosarcoma. Summary Adenomas and adenocarcinomas of the lung, angiosarcomas of the liver and of other sites, lymphomas, mammary carcinomas, neuroblasto mas of the brain, in addition to various other tumors have been induced in mice, rats and ham sters exposed by inhalation to vinyl chloride. In addition vinyl chloride when administered by in halation has been found to induce hepatic and extrahepatic angiosarcomas at concentrations as low as 10 ppm and mammary carcinomas at even lower concentrations, i.e., 5 and 1 ppm. Several mutually confirmatory studies, using the retrospective cohort method, have shown an increased risk of liver angiosarcoma and cancer of other sites among employees of vinyl chloride polymerization facilities. The full magnitude of this site-specific cancer risk among employees of vinyl chloride polymerization plants will only be determined following full lifetime observation. Nevertheless, studies already have shown that for liver angiosarcoma the excess risk is approxi mately 11 to 16 times that of the general popula tion. For brain cancer the excess risk is 4-fold. The role of indirect modes of exposure to vinyl chloride has now been shown to be associated with an excess risk of cancer. Several cases of liver angiosarcoma have been reported among individuals living in close proximity (less than 2 miles) to facilities polymerizing vinyl chloride or fabricating poly(vinyl chloride). A recent epide miological study has demonstrated that 50% of females with liver angiosarcoma (5/10) lived within 1 mile of such industrial facilities, whereas none of their matched control did so. Experimental bioassay and epidemiological studies have shown a high concordance for the carcinogenicity of vinyl chloride, specifically for liver angiosarcoma. This excess of liver angiosar coma has been shown to persist from the polymer ization of vinyl chloride to the residence in near proximity to such facilities. Both experimental and epidemiological data indicate that PVC dust is probably associated with respiratory effects, both neoplastic and non neoplastic in nature. REFERENCES 1. U.S. TarifT Commission. Census of Dyes and of Other Synthetic Organic Chemicals, 19`27. Tariff Information R&S 003774 66 J. K. WAGONER Series No. 37, U.S. Government Printing Office, Washing ton, DC, 1928, p. 139. 2. Oster, R. H., Carr, C. J., and Krantz. J. C. Anesthesia. Narcosis with vinyl chloride. Anesthesiology 8: 359 f 1947), 3. TVibukh, S. R., Tikhomirova, V. A., and Koslov, L. A. Working conditions and measures for their sanitation in the production and utilization of vinyl chloride plastics. Gigiena Sanit. 10: 38 (1949). 4. Filatova, V, S., Balahonova, L. I., and Gronsberg, E. S. Hygienic characteristics of vinyl chloride. Gigiena Truda Prof. Zabolevaniya 2: 6 (1958). 5. Kurland, L. T., Faro, S. N., and Siedler, H. Minamata disease. World Neurology 1: 370 (1960). 6. Torkelson, T. R., Oyen, R. F., and Rowe, V. K. The toxicity of vinyl chloride as determined by repeated exposure of laboratory animals. Am. Ind. Hyg. Assoc. J. 22: 354 (1961). 7. Cordier, J. M., Fievez, C.. Lefevre, M. J., and Sevrin, A. Acroosteolysis combined with skin lesions in 2 workers exposed in cleaning autoclaves. Cahiers Med. Travail. 4: 14 (1966). 8. Viola. P. L., Bigotti, A., and Caputo, A. Oncogenic re sponse or rat skin, lungs and bones to vinyl chloride. Cancer Res. 31: 516-522 11971). 9. Heckman, J. H. Symposium presentation, 1980. 10. Wheeler, R. N., Jr. Personal communication, 1971. 11. Maltoni, C. Predictive value of carcinogenesis bioassavs. Ann. N.Y. Acad. Sci. 271: 431-443 < 1976). 12. Caputo, A., Viola, P. L, and Bigotti. A. Oncogenicity of vinyl chloride at low concentrations in rats and rabbits. Int. Res. Communs. 2: 1582 (1974). 13. Maltoni, C., and Lefemine, G. Carcinogenicity bioassay of vinyl chloride: current results. Ann. N.Y. Acad. Sci. 2-16: 195-218 (1975i. 14. Keplinger, M. L., Goode, J. W., Gordon. D. E., and Calandra, J. C. Interim results of exposure of rats, ham.-Aers, and mice to vinvl chloride. Ann. N.Y. Acad. Sci. 246: 219- 224 G975). 15. Holmberg. B., Kronevi. T.. and Winell, M. The pathology of vinyl chloride exposed mice. Acta Vet. Scand. 17: .328- 342 (1976). 16. Maltoni, C. Vinyl chloride carcinogenicity: an experimen tal model for carcinogenesis studies. In: Origins of Human Cancer, Book A (H. H. Hiatt. J. D. Watson, and J. A. Winsten, Eds.i, Cold Spring Harbor Laboratory. 1977 p. 119. 17. Maltoni. C. Carcinogenicity bioassays of vinyl chloride monomer: a model of risk assessment on experimental basis. NIEHS HIOSH OSHA conference to Re-evaluate Toxicity of Vinyl Chloride. Polyvinyl Chloride and Struc tural Analogues. Bethesda. Maryland 11980). IS. Tabershaw, I. R., and Galley. W. R. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J. Occup. Med. 16: 509-518 (19741. 19. Monson. R. R., Peters, J, M.. and Johnson, M. N. Propor tional mortality among vinyl-chloride workers. Lancet 2: 397-39S (1974 'T 20. Nicholson, W. J.. Hammond, E. (_'., Seidman. H.. and Selikoll', I. J, Mortality experience of a cohort of vinyl chloride-polyvinyl chloride workers. Ann. N.Y. Acad. Sci. 246: 225-230 (19751. 21. Ott, M. G.. Langner. R. R.. and Holder, B. B. Vinyl chloride exposure in a controlled industrial environment, a long-term mortalitv experience in 594 employees. Arch, Environ. Health 30 333-339'1975>. 22. Duck. B. W.. Carter. J. T., and Coomhes. E. J. Mortality studv of workers in a polvvinyl-ehloride production plant. Lancet 2: 1197-1199(1975'. 23. Wagoner, J. K., Infante, P. F., and Saracci, R. chloride and mortality. Lancet 1: 194-195 (1976). 24. Duck, B. W., and Carter, J. T. Vinyl chloride and mortal ity? Lancet 2: 195 (1976). 25. Waxweiler, R. J,, Stringer, W., Wagoner, J. K., Jones, J., Falk, H., and Carter, C. Neoplastic risk among workers exposed to vinyl chloride. Ann. N.Y. Acad. Sci. 271: 40-48 (1976). 26. Byren, D., Engholm, G., Englund, A., and Westerholm, P. Mortality and cancer morbidity in a group of Swedish VCM and PVC production workers. Environ. Health Perspect. 17: 167-170(1976). 27. Reinl, W., Weber, H., and Greiser, E. Epidemiological study on mortality of VC-exposed workers in the Federal Republic of Germany. Medichem. 2 (Sept. 1977). 28. Fox, A. J,, and Collier, P. F., Mortality experience of workers exposed to vinyl chloride monomer in the manu facture of polyvinyl chloride in Great Britain. Brit. J. Ind Med. 34: 1-10(1977). 29. IARC. Evaluation of Carcinogenic Risk of Chemicals to Humans. 19. Some Monomers. Plastics, and Synthetic Elastomers, and Acrolein, (ARC, Lyon, 1979, pp. 37S-438. 30. Christine, B. W., Barrett, H. S., and Lloyd. D. S. Angiosar coma of the liver--Connecticut. Morbidity and Mortality Weekly Report 23: 210 (1974). 31. Baxter, P, J., Anthony, P. P., MacSween. R. N. M.. and Scheuer, P. J. Angiosarcoma of the liver in Great Britain, 1963-73. Brit. Med. J. 2: 919-921 (1977). 32. Lilis, R., Anderson, H., Nicholson, W. J., Daum, S. Kishbein, A. S., and Selikoff. I. J. Prevalence of disesase among vinyl chloride and polyvinvi chloride wo Ann. N.Y. Acad. Sci. 246: 22-41 (1975). 33. Miller, A., Teirstein, A. S., Chuang, M., Selikoff. I. J., and Warshaw, R. Changes in pulmonary function in workers exposed to vinyl chloride and polyvinyl chloride. Ann N.Y. Acad. Sci. 246: 42-52 (1975). 34. Fmngia, N., Spinaz/.ola, A., and Bucarelli, A. Experimen tal lung damage from prolonged inhalation of airborne PVC dust. Med. Lav. 65: 321-342 (1974). 35. Agarwal, D. K., Kaw, J. L., Srivastava, S. P., and Seth, P. K. Some biochemical and histopathological changes in duced by polyvinvi chloride dust in rat lung. Environ. Res. 16: 333-341 (1978). 36. Arnaud. A., Pommier de Santi, P., Garbe, L., Payan. H., and Charpin. J. Polyvinyl chloride pneumoconiosis. Tho rax 33: 19-25 < 1978). 37. Szende, B., Lapis, K., Nemes, A., and Pinter, A. Pneumo coniosis caused by the inhalation of polyvinyl chloride dust. Med. Lav. 61: 433-436 (1970). 38. Vertkin, Y. I., and Mamontov, Y. R. On the state of the bronchopulmonary system in workers engaged in the manufacture of articles made of polyvinyl chloride. GigienzTVuda Prof. Zabolevaniya, 19: 29 (1970). 39. Mastroangelo. G., Manno, M., Marier, G. Bartolucci, G. B., Gemignani, C., Saladine, G., Simonato, L., and Saia, B. Polyvinyl chloride pneumoconiosis: epidemiological study of exposed workers. J. Occup. Med. 21: 540-542 (1979). 40. Waxweiler, R. J.. Smith. A. H.. Tyroler, H. A., and Falk. H. An epidemiologic investigation of an excess lung can cer risk in a synthetic chemicals plant. Paper pr esented at International Congress on Occupational Health. D nik. Yugoslavia, 1978. 41. Brady, J. S.. Likeratore. F.. Harper. P.. Greenwuld. p., Burnett. W.. Davies, J. N. P., Bishop, M.. Polan, A., and Vianna, N. Angiosarcoma of tae liver: an epidemiologic survey. J. Natl. Cancer Inst. 59: 1383-1385 (19771.