Document Dze311pbZ0Bd2r63qr5mg6bN

t Acran tioras ftUwuivci? APR 0 5 1976 A. ROSS ADAMS pn T<fiu'N tUt*L THE TOXIC AND CARCINOGENIC RISKS OF VINYL CHLORIDE: A SERIOUS CURRENT INDUSTRIAL HYGIENE PROBLEM [Lee Rlsques Toxiques et Cancerogenea du Chlorure de Vinyl: Un Grand Probleme Actual d'Hygiene Industrie elle] by R. Truhaut and J. Berrod of Toxicological and Industrial Research Center, Department of Pharmaceutical and Biological Sciences, Rene Descartes University, Prance. from I.N.R.S., Report No. 973-80-75, (36), CDU 616-006 i(tfr PC Translation from French JNVE/jb l \ 7435 AP00007930 THE TOXIC AND CARCINOGENIC RISKS OK VINYL CHLORIDE: A SERIOUS CURRENT INDUSTRIAL HYGIENE PROBLEM by R. Truhaut* and J. Berrod** I.N.R.S. 30, rue Olivier-Noyer 75680 Paris Cedex 14 Report No. 973-80-75 (36) CDU 616-006 Abstract: Vinyl chloride or monochlorethylene CR2 *= CffCl, discovered by Eegnault in 1835 [J] by reacting potassium hydroxide in alcohol with'l,2-diehloroefhane or J, 2-dichlorethone, is one of the representatives of the class of halogenated derivatives of the aliphatic hydrocarbons most widely used in industry. After having long been considered as one of the least toxic among the substances of this series, it has recently been proven very dangerous, especia-ly due to its carcinogenic properties, which may be manifested not only in laboratory animals but also in man. ' The objective of the present article is to clarify this question* It is divided vnto several parts: 1. Presentation of the compound, indicating the ways in which it is produced and its principal physical and chemical properties, as well as its industrial uses, making it possible to define the conditions and circum stances of exposure which, along with the toxicity, determine the manifestation of the risks. 2. Information on the different forms of vinyl chloride toxicity, with particular attention to the toxic effects over a more or leas lengthy period, including the carcinogenic effects which. may result from repeated exposure to this' chlorinated hydrocarbon. S. Sisk prevention measures to be 'applied for the protection of occupationally exposed subjects. ' Director of the Toxicological and Industrial Research Center, Department of Pharmaceutical and Biological Sciences of the Rene Descartes University; Physician, Rhone-Poulenc Industries. -1\ AP0000793I 2. Presentation of Vinyl Chloride CEg * CHCl A Preparation Vs shall not discuss laboratory methods or methods abandoned by industry, such as the action o soda on dichlorethane. The phenomenal growth of the production of PVC la due in large part to the availability of cheap monomer* Direct synthesis from acetylene and hydrochloric acid has long been the main preparation method. The reaction takes place in the gaseous state between 150 and 200* C and contact with activated charcoal impregnated with mercuric chloride. The yield is 992 with a slight excess of HC1. CH - CH + HC1 - CH2 - CH Cl Another process for the preparation of vinyl chloride is the dehydro chlorination of 1,2-dichloroethane ch2ci - ce2ci"5c1 ch2 - CH Cl The choice of one method or another is guided by economic considerations (price of acetylene) and the availability of hydrochloric acid. The process involving acetylene consumes HC1 while the process with 1,2-dichloroethane produces It. Sometimes there are two laboratories to equalize the HCl balance. New processes based on oxychlorinatlon techniques have recently been applied and developed industrially. They are based on the Deacon Process, the hydrochloric add being oxidized by the air at around 500* C to produce chlorine and water. The reaction takes place in the presence of ethylene, which serves as a chlorine aaoeptor and controls the reaction. According to this principle, a procedure has been developed allowing the simultaneous synthesis of several C chlorinated compounds In variable proportions, as needed, particularly vinyl chloride, 1,2-di- \ AP00007932 chloroethane, which is subsequently transformed by thermal cracking into vinyl chloride, trichloroethylene, perchloroethylene, vinylldene chloride, etc., and tetrachloroethape which is also transformed by cracking. According to the local conditions, the process may be an HC1 consumer, an equalizer, or even an HCI producer. .C,H + Clj --*- CaHaCl + HC! ' CaH4 2 Cl, C3H3Ci, + 2 HCI CaHC!a --J. CaH,Cl + HCI CaHjCt, --> CjHaCU + HCI ! The hydrochloric acid produced in this way Is combined with ethylene and oxygen (in the form of air) at 300C using a copper catalyst. The oxychlorination reactions thus developed mainly produce diehloroethane, which is dehydrochlorinated to give vinyl chloride. !c,H7 + 2 HCI + 1/2 (Oj + 4 Na) I C*H*CIa + H.o + 2 N, ;caHacra --y c^h.ci 4 hci Two points should be emphasized: 1. The operations are conducted continuously in hermetically sealed systems and, as a consequence, without accidents (leaks in particular); exposure of the workers involved is practically nonexistent. 2. The monomer vinyl chloride produced in modem plants has a very high degree of purity. It contains less than 20 ppm by volume of organic impurities checked by gas phase chromatography (1,2-dichloroethane, methyl chloride, prppylene.. The vinyl chloride obtained in the form of a gas is liquefied and stored as a liquid under pressure. With respect to the quantities produced throughout the world, which are very high, we take the liberty of directing ouz readers to the report of a vinyl chloride study group, which met in Lyon ori June -23 and 24, 1974' under the auspices of the International Cancer Research Center [2]. -3- AP00007933 B. Phyeioal and Chemical Properties of Vinyl Chloride tinder normal temperature and pressure, vinyl chloride (molecular weight: 62.5) is a colorless gas, but It is ordinarily used after liquefaction under pressure. The physical constants are as follows: Boiling point .............................. ............................. -13.9*C Density of the liquid D2^0 ............... 0.9121 Refractive indexi.............................. .. 1.4066 Vapor density {air * 1) ......................... .....2.15 Vapor pressure .............. ............. ............................. 2660 mm of mercury at 25"C Heat of polymerization......... ............................. 23 kcal/mole (400 eal/g) It is inflammable and forms explosive mixtures with air at concentrations between 4% and 221 by volume [3]. It is slightly soluble in water (0.11% veight/weight at 25*C) [4], soluble in alcohol, and very soluble in ether, carbon tetrachloride, and benzene. It is also very soluble in lipids. On the chemical level, it is easily polymerized under the influence of solar rays and/or catalysts. This polymerization reaction has been recognized by Baumann [5] but has been'cited in particular by Ostromyslinski (6]. According to Lefaux [7), the catalysts most widely used at the present time are hydrogen peroxide, organic peroxides, ozone, and the persulfates. By combustion, it produces hydrochloric acid, carbon monoxide, and carbon dioxide gas [8]. Under the effect of strong alkalies at a high temperature, vinyl chloride is released in the form of chlorides. -4- \ AP00007934 C. Uses of Vinyl Chloride According to the Information assembled by "Chemical Information Services, Stanford Research Institute, California" and reported to the International Cancer Research Center [2], In the United States, the majority (about 97X) of the vinyl chloride produced was used for the manufacturing of polyvinyl chloride (PVC) or of copolymers in which It Is found In combination with other monomers, the principal one of which is vinyl acetate. The PVC industry came to life In Germany during the thirties, and then began its rise in the United States and Prance around 1940. It developed to a considerable extent after the war. Numerous applications of vinyl chloride have been put into practice, especially its use as a refrigerant, as an extraction solvent, and particularly as a propellant in the production of preparations for domestic use designed to be dispersed in the form of aerosols, products such as insecticides, cosmetics, or even drugs. These applications were completely eliminated in Prance a number of years ago, vinyl chloride having been replaced by non-inflammable fluorinated hydrocarbons. It still appears to be used as a raw material in the manufacturing of 1,1,1-trichloroethane or methylchloroforo, a solvent very widely used in Industry, and In the manufacturing of monochloracetaldehyde, an intermediate product in the manufacturing of certain drugs of the sulfonamide class. .The manufacture of polymers having a vinyl chloride base (PVC or copolymers), whose annual production on a world scale is about 7 million tons, (about 700,000 tons for France), is determined by the quality desired based on the specified purpose. But, from all evidence, the basic process lies in the polymerization of the vinyl chloride. This polymerization is a polyaddition reaction, the macromolecular chain elongating -5- AP00007935 by end-to-end addition of monomer molecules. It.is initiated by chemical compounds capable of decomposing under the effect of heat, producing free radicals. Generally speaking, these radicals are organic peroxides. Polymerization may take place in the presence of a dispersing medium (water) (polymerization In emulsion or in suspension)* or in a liquid monomer under pressure (bulk polymerization). In certain cases, it is carried out In _ the presence of another monomer capable of copolymerizing* for example, vinyl acetate. The temperature (generally ranging between 40 and 70*0), the pressure (6 to 10 bars), and the nature of the catalyst modify the behavior of the reaction. These different factors Influence the length of the linear macromolecular chains, and the presence and form of the lateral chains. The common industrial polymers have average molecular weights ranging between 50,000 and 100,000 [9]. They come in the form of white*powders, of low apparent density (0.40 to 0.60). The thermal degradation of PVC begins at 200C with the release of hydro chloric acid. The speed of degradation increases rapidly with the temperature. The color of the polymer turns from white to brown and then to black. The decomposition procedure is not yet perfectly understood and there are several conflicting theories. Certain authors [10] suggest the formation of free radicals followed by a molecular rearrangement with the release of HC1; other authors [11] think that the unsaturation activates the adjacent chlorine molecule. There are numerous stabilizers which prevent the degradation of PVC, regardless of the origin (thermal or under the effect of ultraviolet rays). These stabilizing agents share the property of reacting with the HC1 released at the beginning of decomposition so as to prevent an autocatalysis of the reaction. Certain stabilizing agents can be used alone. These are the 6- - AP66b07936 "primary" stabilizers.. Others have a synergistic effect with the primary stabilisers but cannot be used alone. These are called "secondary"- stabilizers. The main stabilizers used for PVC are the organic metal salts (lead, tin, calcium, barium, cadmium, etc.), epoxidixed oils, or phosphites. They are generally used at levels ranging from 0.1% to 3% of the weight of the resin. Polyvinyl chloride is sometimes supplemented with plasticizers which facilitate the work of a plastic material and, in particular, give it a permanent pliability. A large number of plasticizers have been proposed.' We shall mention, in particular, the Inorganic acid esters (phosphates), the organic acid esters (phthalates, adipates, sebacates, ricinoleates...), polymers (polyesters), and high polymers (butadiene-acrylic nitrile copolymer, for example). Non-plasticized polyvinyl chloride can be worked at 170-210*C and welded at 200C in a jet of hot air. Plasticized, it can be worked at a lower temperature (160 to 160*C). The main transformation processes are extrusion, calendering, injection, and extrusion-blowing. The polymerization of vinyl chloride and the subsequent operations, unlike the manufacturing of vinyl chloride, which.takes place continuously, as we have seen, are almost always performed discontiiiuously and require human participation at various stages in the work: polymerization autoclaves, addition of adjuvants which may have a toxicity of their own, conditioning, bagging of the resins, etc. Upon stopping polymerization, a fraction of the vinyl chloride whose quantity depends on the polymerization method used (emulsion, suspension, or hulk) and which generally ranges from 3% to 20% of the total charge. Is still present in the reactor. This vinyl chloride is-eliminated from the -7- \ AP00007937 resin by degassing, either directly In the autoclave or in a special apparatus. This operation is performed, first, by connection to a condensation circuit, the vinyl chloride being recovered In liquid form to be reused at the time of another polymerization operation. When the pressure drop is total, the remaining traces of vinyl chloride are eliminated almost completely by re peated vacuum extraction separated by periods in a nitrogen atmosphere. After the last vacuum extraction, the container with the PVC Is filled with air. It may be transported either directly to screening Installations when bulk polymerization is involved, or to dryers where the water present is eliminated, in the case of emulsion or suspension processes. In the chapter dedicated to means of preventing risks which may result from exposure to vinyl chloride we shall see that, following the discovery of the occupational pathology of vinyl chloride, numerous technological Im provements vers made In the processes used, with a considerable reduction in the degree of exposure as a consequence.' 2. Toxicology of Vinyl Chloride Before going into the details, we feel that it would be useful to take an overall look at the history of the development of our knowledge on the toxicity of vinyl chloride, since this compound is a spectacular example of the constant vigilance which must be exercised by toxicologists to detect any chemical agent capable of polluting the occupational or general environment. A. Introduction to the Study of the Toxicology of Vinyl Chloride: Historical Review Vinyl chloride--undoubtedly the compound most widely used in the plastics industry for more than 20 years--has never been considered as 8- - \ AP00007938 particularly dangerous on the human toxicological level until relatively recently. Of course* It was known to be inflammable and explosive, but the precau tions taken against the risks deriving from these properties seemed to be largely sufficient. Nor vas there any lack of knowledge as to its narcotic power at high doses,, and some cases of coma had been reported during prolonged accidental a exposures in a concentrated atmosphere. There.was nothing surprising in this, since it vas known that, as with the majority of the compounds belonging to the same chemical class, its volatility--affecting pulmonary penetration-- permitted rapid access to the central nervous system, although its lipid solubility Influenced binding and retention at this level. But, even In this regard, it vas considered to be one of the least toxic chlorinated hydrocarbons, which meant the recommendation of a relatively high permissible limit In the atmosphere of working sites: 500 ppm, i.e., under normal temperature and pressure, 1275 mg/cm^. But 1963 saw the discovery for the first time of cases of bone disturbances of the osteolytic type, particularly--but not exclusively--striking .the hands, with disappearance of bone tissue from the' ungual phalanges of several fingers on both hands (acroosteolysis syndrome). The cases reported occurred # in practically all the world's producers, and especially in a particular category of workers--autoclave deemsters. These workers were responsible for manually removing, with a type of trowel, the inevitable crusty residues of polymerisation. The operation lasted about 1/4 hour in a vinyl chloride atmosphere. It sufficed to enter an autoclaye at the end of the operation to smell this weakly etheral, but characteristic odor which meant that the workers were inhaling air containing at least- 40 ppm--or often more-- ' -9- \ l AP0bb07939 of vinyl chloride, which scarcely caused a stir at the time. The proportion of subjects afflicted was in the order of 2 to 3X of the workers. Other subjects presented an abnormal prevalence of circulatory disturbances, similar to those characterising Raynaud's phenomenon. It was at the 16th International Occupational Medicine Congress* held in Tokyo in 1969* that the first three reports were presented on this subject, one by Professor Viola, occupational physician of the Solvay Company at Rossignano Solvay (Italy) I12]. The etiology was unknown due to the diversity of the ingredients used in the manufacturing of PVC, but an analysis of the data resulted in the incrimination of vinyl chloride exposure. Furthermore, Professor Viola had reproduced lesions similar to those observed in PVC workers in his experimental investigations on the rat,exposed via the pulmonary route to very high doses,of vinyl chloride it is. true (30,000 ppm), 5 days per week for 1 year. Pursuing his experimental studies, he confided to one of us who visited him about his anguish over seeing the development in exposed animals of a number of tumors (skin, lung, and bone, In particular). This was the subject of his report to the 16th International Cancer Congress in Houston (United States) in May, 1970 113). These observations, added to those concerning the effects of vinyl chloride on the bone system, had a resounding effect. They led four major European producers of PVC (Montedison, ICl, Rhone-Progil, Solvay) to join forces in consulting an eminent cencerologist. Professor Maltonl of the University of Bologna, concerning the execution of a very strict long-term experimental program. These tests were to be conducted for 2-1/2 to 3 years on several species of animals. The animals were to be' exposed by the -10- AP00007940 pulmonary route to different concentrations of vinyl chloride as purified as possible. Begun In July 19?1% these experiments* .which unfortunately confirmed the carcinogenic power of vinyl chloride* revealed--in addition to the locations reported by Viola--other specific locations, notably nephroblastomas and especially angiomas and hemangiosarcomas of the liver, which are extremely rare malignant tumors in animal species subjected to experimental tests. The production of such effects by the pulmonary route disclose a ''system pathology" resulting from exposure to vinyl chloride which proved to be a toxic agent having a vascular affinity, as demonstrated.by signs similar to Raynaud's disease (with an asphyxia of the extremities), multifocal hepatic tumors or cellular atypla, .often combined with vascular ectasia and endothelial hypertrophy. We were a long way from the microtraumatically induced local action mentioned at the beginning to explain the lesions of the hands of autoclave decrusters! However, although observations related to human bone pathology had preceded etiological confirmation in the animal as to the culpability of vinyl chloride, it could at least be hoped that the neoplastic pathology of animals would not be found in human subjects exposed to-it. Now, In January, 1974, information frorathe United States'has reduced such hops to'nothing. American organizations MdA (Manufacturing Chemists Association), NIOSH (National Institute on Occupational Safety and Health), OSHA (Occupational Safety and Health Administration) informed by the Europeans of the experimental results, had performed an epidemiological study. They were able to confirm the discovery of 13 cases of hepatic heaiangiosarcomas in workers exposed to vinyl chloride, including 7 at the -11- \ AP00007941 Goodrich Plant in Louisville (Kentucky) where--revealing coincidence--'the first cases of acroosteolysls had appeared! There is no need to stress the consequences of such observations* to vhich new ones are being progressively added--whether in the United States or in other countries--and to stress their reverberation at all levels (certain ones with passion in the vake of the first emotion) with respect to the'protective measures which it was imperative to consider* We shall only say that the discovery of'a carcinogenic effect.'of vinyl chloride in man presents toxicologists, doctors, and health specialists with a burning problem with respect to the preventive measures to be Implemented at numerous levels* first of all* according to all evidence, at the level of FVC production plants. After this general introduction, we shall now go into greater detail in examining toxicological Information concerning vinyl chloride, compiled from experimental studies on laboratory animals or epidemiological observations and surveys of exposed human subjects. We shall consider successively: 1. Data on'acute or subacute toxicity. 2. Data on more or less long-term toxicity. S. Acute and Subacute Toxicity of Vinyl Chloride The acute toxicity of vinyl chloride, i.e. the series of harmful effects vhich may result from a single exposure, has been studied by inhalation for different periods of air containing various concentrations of the product in several species of animals: -- in the mouse> by Peoples and Leake (1933) [14] and by the researchers from the Pharmacology and Toxicology Division of the National Institute of Public Health of the Netherlands [15]; -12- AP60007942 -- In the rat, by H. Baneiger (I960) [16] and by Lester et al. (1963) 17]; -- in the guinea pig, ratj and other laboratory animal species by Mastro- Matteo et al. (1960) El8]. The following table (Table I) summarizes the data obtained on the guinea pig. We must also add Co this table the data Supplied by Patty [3], according to which the maximum concentrations capable of being survived by the guinea pig for varying exposure periods are the following: 50 to 70,000 ppm for 1 hour; 25,000 ppm for 8 hours, although exposure to concentrations of 15,000 ppm for 1 hour and 5,000 ppm for 8 hours, respectively, did not'cause serious problems... Patty described pulmonary edema and hyperemia of the kidney and the liver in animals dying of an acute exposure. In summary, observations in laboratory animal? showed an affinity,, for the central nervous system, ..with narcotic effects which can represent true anesthesia*and, at sufficient doses, cause death from respiratory and cardiac collapse. The rapid reversibility of the narcotic effects after stopping the exposure should also be noted. We must point out that, according, to the figures shown in the table, exposure of the guinea pig to a concentration of 10,000 ppm did not cause any apparent disorder; but it is not without Interest to recall that Viola's experiments 12], rats exposed to concentrations of 30,000 ppm 4 hours per day and 5 days per week for a period of 1 year, did not present disturbances immediately. Although we are talking about longer exposure times, to be sure, We would el'so like to mention Torkelson who, in*1961, exposing rats to vinyl chloride doses of 500, 200, and -13- AP00007943 Table 2. tfxperimental data related. to the acute toxicity of vinyl chloride in the guinea pig. ____ _ ______ _________________________________: Concentrations Parts Per Million by Volume (p.p.m.) 400,000 mg/llter 1024 n ii Duration of Exposure 15 seconds 10 to 20 minutes Observations animal lying on its side dead 150,000 to 200,000 n ti 384 to 640 i if 1 minute 16 to 20 minutes 18 to 35 minutes animal lying on Its side deep narcosis dead 100,000 M II 256 n n 2 minutes 60 minutes 120 to 340 minutes animal lying on its side deep narcosis greatly retarded respiration * but not dead 50,000 it 123 ti 50 minutes 360 minutes deep narcosis greatly retarded respiration, but not dead 10,000 25.6 480 minutes no signs of narcosis 100 ppm for 4 to 5 months, observed lesions of the liver and kidneys without tumorous manifestation on anatomo-pathological examination 1193... 0 The narcotic effect of vinyl chloride is found Inman* Two'accidental deaths have been reported 1161. They occurred, during work performed in a local vineyard (fermenting chamber) where the vinyl chloride content must have been high and the surveillance nonexistent. One member of our group succeeded in obtaining information from a large chemical product company, concerning observations made in two workers who had gone Into the Initial stage of anesthesia In decru'stlng vats that -14- AP00007944 they had entered before degassing and who owed their health only to the prompt intervention of the supervisors* The doses must have been greater than 10,000 ppm* At lesser doses, vinyl chloride has an irritating effect on the eye (conjunctivitis, keratitis) and skin (erythema and even phlyctenae in the case of spurting of liquid vinyl chloride), in these cases justifying immediate,heavy and prolonged washing--an emergency procedure Imperative for any chemical bum. As a supplement to the observations concerning the acute toxicity of vinyl chloride, we thought that it would be a good idea to indicate the few data unearthed In the specialized scientific literature on subacute toxicity, i.e. on the toxic effects which may eventually be produced by repeated exposure to vinyl chloride during a short period and at very short Intervals. Indications on this subject have been given in a monograph from the National Institute of Public Health of the Netherlands [15]. Rats and mice, exposed for 4 hours per day for 5 to 8 consecutive days to a concentration of vinyl chloride sufficient to Induce signs of mild narcosis, did not present any signs of liver or kidney pathology. .In their study of the effects of vinyl chloride on the rat, Lester et al. 0* [17] exposed the animals to concentrations of 50,000 ppm for 8 hours per day during a period of 19 days and 20,000 ppm for 8 hours per day during a period of 92 days. They did not observe any effect on growth, hemoglobin level, hematocrit, prothrombin level, or on the macroscopic and microscopic characteristics of the principal organs. However, at two concentrations, they observed an increase in the liver weight/body weight ratio and a decrease in the white blood cell count and, at a concentration of -15- AP0bb07945 50,000 ppm, an Increase in the red blood cell count. In nan, Lester et al* 117] observed 3 men and 3 women exposed for 5 minutes 2 times per day at 6-hour Intervals' for a period of 3 consecutive days,.at concentrations of 4,000, 8,000, 16,000, and 20,000 ppm, respectively. They observed that only levels above 6,000 ppm caused mild symptoms of in* toxlcation? vertigo, nausea, and decreases in visual and auditory acuity. Baretta, Stewart et al. (1869) [20] followed the behavior and reactions of human subjects exposed for 7*1/2 hours to vinyl chloride concentrations of 50, 250, and 500 ppm, respectively. It was only at the highest concentra tion of 500 ppm that 2 of the exposed subjects developed dryness of the mucous membranes of the eyes and nose. Two of the 6 subjects exposed to 50 ppm were exposed 2 days later to 500 ppm for a period of 3-1/2 hours, without manifesting any harmful effects. C. More or Less Long-Term Toxicity of Vinyl Chloride As ve indicated in our general look at the history and evolution of knowledge on the danger of vinyl chloride---which we included in the introduction to the study of the toxicology of this chlorinated hydrocarbon--two prominent facts have been disclosed during the past 12 years. 1. The production of bone and angioneurotic lesions in workers exposed to vinyl chloride during the manufacturing of PVC. 2. The demonstration--first by experiment on laboratory animals and then by epidemiological investigations of occupationally exposed groups-- of the carcinogenic power of vinyl chloride. Ve will examine these two points In turn: 2. Bone and angioneurotic lesions caused by occupational exposure to vinyl chloride. The first cases of bone-lesions were discovered in 1963, -16- AP00007946 occurring simultaneously is different countries* all in autoclave decrusters. A Russian publication 121] dating from 1968, reported these problems, which had been observed for several years in personnel working with PVC in sus pension. Some workers complained of subjective disturbances, similar to those characterizing Raynaud's phenomenon: asphyxia of the extremities followed by intense vasodilatation, sometimes followed by- distrubances having an affinity for the skin. Sometimes, at most, a condition was observed resembling scleroderma, a collagen (connective tissue) disease consisting of a thinning of the skin which, atrophied and sometimes ulcerated, "sticks" to the underlying bones, sometimes considerably inter fering with movement 122-33]. Other vascular disorders have been reported, in particular myocardial infarction and arteritis of different sites. One case of type was reported by a member of our group at the International Occupational Medicine Congress held at Buenos Aires in 1972 134] . Other workers, not having any subjective symptoms or any apparent disturbances, nevertheless presented bone lesions which could only Be re vealed by systematic radio logical surveys after the discovery of other affected subjects working at the same occupation. The typical lesions found which will always be pathognomonic for the disorder, involve the hands (one or both) and consist of lysis of the ungual phalanges, first of all of the index and middle fingers, but often of all the fingers on th.e hand. These cases of bandlike osteolysis have been and remain the principal symptom of the disease. The terminal phalanges definitely look fractured, but the characteristic would be very large in such an event. This is not the only bone lesion. Notches resembling "halberds" -17- AP00007947 have frequently been found on the edge of the phalanx* resembling the bony lesions of gout* also amputations of the distal phalanx C'barley-sugar" images). Microgeodes have also Been observed elsewhere on the skeleton: the ribs* the pelvis* the iliac crest* the hones of the tarsus* and the phalanges of the toes As a result* incrimination of a local action Is not very plausible* all the more so since subjective manifestations were nonexistent in certain cases. It vas not really possible under these conditions to state that a bone disorder of this magnitude* if it was induced by a local trauma* vas not always accompanied by significant skin disturbances. Moreover, studies on the absorption of vinyl chloride have since shown the very cutaneous skin absorption of this compound. The currently reported cases of acroosteolysis, do not make it possible to suggest any predisposing factor, because of their disparity* such as age* sex* race* duration of exposure (cases appearing rapidly within a few months)* or the beneficial effect of certain individual protective measures* in particular*the wearing of gloves. The polymerization process is no longer an intervening factor. Cases have been reported with all types of processes. It is therefore definitely Inevitable to consider a systemic disorder^ predominantly caused by penetration through the lungs. Furthermore, American researchers have made a careful study* in particular of workers suffering from bone disturbances* and the biological tests performed on these subjects have not proved to be very conclusive. Phosphorus and calcium levels* in particular, were not disturbed. According to Lefevre [35]* toxicologists at the Solvay Company, who studied the chronology of the lesions in detail, everything begins with distal AP00007948 amputation of the phalanx. The classical band of osteolysis Is, according to him, a false sign* since repair by recalcification begins at the end and continues proximally, thinning the band.until it disappears upon. '.'restitutio ad integrum". v- . Thus, whether or not the bone lesions are accompanied by aephyxic vascular disturbances (the most frequent cases), generalized disorders are very definitely involved. Zt can be stated that -these problems are linked to peripheral vascular disorders, with or without subjective disturbances, end sometimes to dermal sclerosis recalling scleroderma. It should also be remarked that reported cases of acroosteolysls have diminished very significantly in recent years, certainly due to the preventive measures which have been taken, in particular the application of hydraulic decrustlng apparatus. , In any case, this indisputable occupational pathology has been recognized by French law, which has set up a new table of occupational diseases subject to compensation (Table 52) which we have reproduced here: No. 52. Disorders attributed to vinyl chloride polymerization operations. (Decree No. 73-215 of 23 February 1973). Exposure time : 6 months. Designation of the Diseases Time Taken ** by the Disorder 0 Angioneurotic disturbances of 2 months fingers. Osteolysis of the ungual phalanges of the hands confirmed radlologlcally. 3 years List of the Main Occupations Capable of Provoking these " Diseases Work performed in vinyl chloride polymerization shops. especially: manual decrustlng of autoclaves and polymerization. The course of the reported cases of acroosteolysls has always been favorable when the stricken subjects were removed from the risk as soon as the diagnosis was made. Recalcification (which, as we have seen, begins in the distal part of AP00007949 the phalanx) continues smoothly, but "restitutio sd integrum" always taV.es fairly long and rarely requires less than 10 months, sometimes clearly more. Few radiological scars remain. Sometimes, small "collar-stud" phalanges accompany cicatricial deformities, (shortening of the previously afflicted ungual phalanges) end curved nails. e . When they exist (alone or in combination), circulatory disturbances require-a rather long period to disappear. Kath.tr often, they produce a particularly annoying sensitivity to cold, occasionally during the winter. Treatment consists of administering calcium (intravenously) and vitamin C. Several cases have given one member of our group the impression that the oral administration of hydroxyprollne was capable of accelerating the healing process. As far as Raynaud's syndrome is concerned, its existence justifies the implementation of a classical vascular therapy. 2. Carcinogenic: power of vinyl chloride. Tn the case of this toxic potential* the experimental facts have, preceded the revelations of epidemiological Studies in exposed human subjects. We shall examine presently available information in that order. .. a) The experimental facts* The first observations of a carcinogenic activity of vinyl chloride in laboratory animals were made by Viola (13, 36]. This author exposed Wistar rats, 4 hours per day and 5 days per week for 1 year* to air containing 30,000 ppm of vinyl chloride. Seventeen animals out of 26 survived or were sacrificed during the period extending between the 40th and the 54th week after the initiation of treatment. They all presented skin tumors (14 epidermoid carcinomas, 2 mucoepidermoid carcinomas, 1 papilloma) which were subsequently identified by Maltoni and Lefemlne (1974) as tumors of. Zyrabal's gland, -20- i j AP00007950 corresponding in the rat to"the parotid gland in wan and particularly rich in fatty tissue* In addition, 7 animals shoved pulmonary tumors (5 adeno carcinomas, 1 adenocanthoma, 1 spinocellular carcinoma) subsequently identified by Maltoni and Lefemine [37] as being metastases of the shin tumors although in 5 animals had osteochondromas. y Tha skin tumors were exclusively located in the region of the suboaxillary glands and Zymbal's glands, although the bone tumors had developed in the metacarpal and metatarsal regions of the 4 limbs. No tumors appeared in the 25 control animals sacrificed at tha same time as the treated animals. Table II summarizes the results obtained. We previously emphasized the concern evoked by these results, which were the subject of a preliminary report at the International Cancer Congress held in Houston (May, 1970), and we indicated that they led a group of European PVC producers to entrust Professor Maltoni with carrying out a program of experiments on a large scale. The investigations of the Italian caneerologist and his team were conducted in 3 animal species: the mouse, the rat, and the hamster.. The animals were exposed for A hours per day, 5 days per week, for periods ranging from 30 weeks to 52 weeks, to the inhalation of air containing vinyl chloride concentrations ranging from 50 to 10,000 ppm. Tables III, IV, and V summarize the results obtained. * They show that the carcinogenic potentiality of vinyl chloride begins to be manifested, although to a slight degree, starting at a concentration of - 50 ppm under these experimental conditions. These results (which, in the case of the mouse and the hamster, represent those obtained in experiments which had not yet been completed when ve last heard about them) have been discussed in several recent articles by Maltoni et al. [38, 39, 40). Interested readers will find here, in addition to references of previous -21- \ AP00007951 Table XT. Experiments of Maltoni et at. (1971)* Protocol similar to that of P.L, Viola. Sprague-Pawley rats exposed 4 hours per .day, S days per week for 43 weeks to a concentration in the air of 30,000 ppm of vinyl chloride. Pesults after 68 weeks (end of experiment). Rats * ........ Animals with Tumors- . '` . * j Groups 1 Number of Number of and Animals- Survivors Treatmeht at the upon Beginning Appear % of the ance 'of ' -1* , p . .Experi the First Survivors ment ' Tumor and at the ' a * 24th Week .Carcinomas-of Zymbal* s Gland Number Latencv Z Time (Weeks), Nephro- blastemas Angiosarcomas * Liver ; Other .Locations Other Types Animals vl(tt - or 2 or More locations Tumors *1 . ...c* h'. ' Number . 'Number;- Number t . Number * 30,000 . p.p.m.' of ; vinyl. ' chlorj.de ' . 60; $ , .60 1. * _..;*.V ' i ' a f} i1 . * ! i * N. \ r1* ! */ . *,rf(, # 31 S2 ` - 43.'. , 7 * . : 3* * i .*'* :** .' r.;-v / ; * .. I ` I'-. *.. " ,; *. ' ** 9 :;rt: z y% AP00007952 Table 111. First stags experiments of C. Maltpni et at. on Sprague-Dcamtey rate* ,Animats exposed 4 hours per day, 5 days per week for 52 weeks. Beginning of experiment; July, 1971+ Results after `35 weeks tend `of experiment). * Animals with Tumors ; Groups and Treatment (Concentra tions in' p.p.ro. of . Vinyl Chloride) '* IQOOO' Number o f Anim als Latency T ine Number Sprague-Dai/ley Rats Carcinomas 4. Z' of Zymbal*s '.Gland. . Nephro blastomas . Number of " V- Survivors Upon Appearance of the First Tumor1 3 K and at the Week 26th K' oav>Uv -ert &vn0J |4 1 N 55 CO , 81 . 10 20 50 5 8 59 Angiosarcomas Subcti- Cutan- taneous ;>.eoii3 Angio Card-. Liver - Others mas nomas Hepa tomas Y H a s.s. J3H 9 15 ; an . 4%)* i- ' s I' 3 i4 u l u I 3 . 1' Neuro Other blasto Types mas or Loca tions Ani mals **4th or More Tumors u . 7 u` ii g ' !K ma. 7 28 . oooo. 72 ; V. 60 7 ;V 7 12 02 4 7 65 13 22 70 3 . "3V ,1' *. 1 . 3 * a. 31 asoo. 74 .y bo 2 3 * 33 6 10 74 13 22 76 3 v3 ' 1 :2 6 '4 32 ' 500 ... aco 67 " 07 .59 -V. 4 7. . 79 . A 7 03 - 7 12 V 81 - ` 69 ; 'if - - M 0 10 60 4 7 79 >2 ;2 y'.-1 v -r ' *4 3. T .4 ; Tt V 3 . .. .6 00 64 59 . ;; ' - - em 1 2 135 . 1 2 ,`135 . . } VA2DOO** * Controls. 06 ; .. 49 . C3 ' 58 mm sm . - - *' a* -- - . *" * -- : * * *v 1 Total 577 404 ` '*' 7i ~ 20 - 0m 47 - ; ; 14 . -12 .i /* . ' . - ':***: , mm 1 ir- . 7 MV .. 15 9 19 * * 10 6 45 | 155 AP00007953 *Zynbal's gland. **VA-Vinyl acetate "as a control" Table IV. Experiments of C. Maltoni et at. in Swiss mice. Exposure: 4 hours per day, 5 days per week for SO weeks. Results after 70 weeks (January 1975). Grouns and Treatment (Concentra tions in n.n.n. of Vinyl Chloride) 10000 * Animal's Animals with Tumors Number of Angio Vascular Animals at sarco .Tumors. Other Animal; the Begin ning of the Experiment Number* Survivors Pulmonary Tumors ' . Mammary Carcinomas mas of the Liver* (Other Types ot Locations) Skin Tumors Types or with 2 Locations' or man Tumors o' o $ 9c1 *r o cf I- cf 9 cf Latency 0 -f Number % Time (Weeks) dumber % Latency Time-. 'itinihfir Humber Number Number Number 2230 30 CO 26 'co - - - 30 70 30 . 1.3 47 31 B a - 3 2 ' ` 38 'coco 30 30' CO 20 20 54 - - " 3B 70 30- 8 28 33 5, 9 0 4 39 . . 2000 . .** - 500 ' ' . 7.50 ; ' , ' 50 Controls ,Total -30 30 GO 23 30 53 - - 30 30 00 29 29 58 - ** 20 57 38. 8G 6 G3.0 30 60 29 29 58 2 - 2 30 30 GO 27 30 07 ms 33 57 23 tBl -CO 70 150 74 07 141 15 30 45 2GQ 2G0 510 230 241 471 17 30 03 .5 3 43 9 30 35 11 41 7 24 37 11 > n45 .11 32 . 3D tso; 11 37 40 - -53 . 09 -- 47 12 .3 2 . 31 17 . 1 43 - a .415,. 2 11 3 * 40 - * , aft73, 15 1 . .5 15 *Animals alive after 16 weeks when the first tumor was reported (carcinoma of the mammary gland) (the percentage is . indicated). oo: *o! T o ta l j S urvivors* A n g io s a rc o m a s o f the Liver Melanomas Lymphomas (Other Types 'or L o ca tio n s' Anim als w ith 2 o r More Tumors - Table V. Experiments of C. Maltoni et aZ^ on.hamsters. Exposure: .4.hours per day, days per week for 3Q weeks* Results after 67 weeks (January, 1875}* Animals (Golden Hamsters) Groups and Treatment (Concentra tions in p.p.m. of Vinyl Chloride) 'lumber Animals with Tumors JWHO4SJ) r.fUO*-l8)l Jfr4lS->fJ>f xCeHO jJfovri.-Bne Ktue~ U iwo M rt s e) h Sh B Number Number Number. T? *w mo saw h *J: l! *&.) A. <o JZJ Number Number Number .10030 35 G . -- 4 -- --* 1 --S 6000 32 5 -- .2 1 .2 3 1 6' 2.500. '33 ' 9 1 -- -- * ' 1 4 2. * 6 . 500 33 11 2 1 - 1 - 1 !' '1 *: `G . 250 ' 32 6 _ * 2 ' 1 M - 3 50 33 11 3 1 1 *. -- -- - 5 . Controls 70 30 Tola! 258 78 -- 2 2 . 15 --1 2 .6 '' 9 _. 3 . 4 2 . publications of the Maltoni team* more precise comments on the results obtained, as well as supplementary- information, especially data concerning the positive results obtained during the experiments conducted op the Wistar rat which proved to be more resistant than the Sprague-Davley rat. However, we must emphasize the negative results obtained with vinyl acetate. We think it is important to point out that positive results, roughly confirming those of the Maltoni team, were obtained in experiments conducted -25\ AP00007955 by "Biotest Laboratory" in the United States, notably on mice subjected for 7 hours per day and 5 days per week to vinyl chloride concentrations of 50, 200, and 2,500 ppm. We were not able to obtain sufficiently precise informa tion on this subject to be in a position to analyze the results in the present article* We shall limit ourselves to indicating that: after 8 months of exposure, although no tumor had beep observed in the controls, the following were noted: * in the group erased to 2,500 ppm, 28 angiosarcomas of the liver, 28 pulmonary adenomas, and 6 mammary adenocarcinomas,, including-1 with pulmonary matastases; * in the group exposed to 200 ppm, 11 angiosarcomas of the liver, 12 pulmonary adenomas, and 3 mammary adenocarcinomas, including 1 tilth pulmonary matastases; * in the group exposed to SO ppm, 2 angiosarcomas of the liver, 2 pulmonary adenomas, and 2 mammary adenocarcinomas with pulmonary matastases. Each group included 50 animals. The experiments will be finished at the end of 1975. Although the title of this article clearly Indicates that our objective in writing it was to stress the dangers involved in occupational exposure to vinyl chloride, we feel that it Is appropriate to mention in Table VI the preliminary results obtained by Professor Maltonl et al. from his experiments on the oral administration of vinyl chloride to the Sprague-Dawley rats. These experiments are of prime Interest for food toxicology, because of the possible existence of vinyl chloride residues in polyvinyl chloride food wrappers and the possibility'of its migrating into the food. This particular problem will be the subject of an article by -26- AP00007956 one member of our group* when we have learned the results, of .the long-term experiments in rats currently underway in various European or American laboratories. Table VI. Preliminary results of an experiment by C. Maltoni et at. involving administration by stomach catheter (S days per week) of vinyl chloride in solution in olive oil to Sprague-Dawley rate* (Duration of the experiment at the end of April 29?&: 58 weeks). Number of Animals Experimental Conditions (Doses of VC in mg/kg of Body Weight) Angiosarcomas of the Liver Other Angiosarcomas Other Locations 80 (half male and half female) 80 80 50 16.65 3.33 3 '1 (thymus) 1 (Zymbal'e gland) 1 -- ---- Remark: The first positive results (1 angiosarcoma of the thymus in a female animal of the group exposed to a dose of 50 mg/kg; 1 angiosarcoma of the liver in a male animal of the group exposed to a dose of 16.65 mg/kg) were announced by Maltoni et al< at the end of February 1975 [41]. It is a veil-known fact that numerous carcinogenic chemicals have mutagenic properties. The joint use of microorganisms or mammalian cells, and of in vitro and in vivo metabolic activation systems has made It possible to demonstrate this. In this context, it was natural to investigate whether vinyl chloride had a mutagenic potential. In this regardj positive results Have been obtained by various authors, among others by Rannug et al. [42] and by the researchers of the International Cancer Research Center pf Lyon [43, 44, 45]. Without going into a detailed critical examination of the results, it Is Interesting to note that viny.l chloride manifests mutagenic activity only after metabolic activation. In thi9 regard, according to the indications of Malaveille, the strong mutagenic capacity of monochloroethylene oxide and -27- 0 x AP6b607957 Country Date of Diagnosis Age at Diagnosis Number of Years Be tween the First Ex posure and the Diagnosis Total Number of Years of Exposure Occupation USA USA USA USA USA USA USA USA USA USA USA USA USA USA USA USA USA England England England Sweden Sweden Norway V. Germany V. Germany W. Germany W. Germany V. Germany U. Germany France France Italy Italy Romania Czecho slovakia Canada June 1952 43 years Aug. 1961 41 years April 1964 52 years 1968 45 years May 1968 55 years March 1969 41 years May 1969 50 years March 1970 61 years May 1960 36 years July 1972 47 years 15 15 20 24 17 19 20 23 14 10 15 15 18 18 17 4 15 23 13 10 March 1973 49 years June 1973 60 years 22 36 16 Dec. 1973 58 years Feb. 1974 45 years March 1974 43 years May 1974 53 years Oct. 1974 43 years Feb. 1970 55 years 28 12 19 30 19 24 28 12 17 30 19 11 Dec. 1972 71 years 1974 36 years Feb. 1970 43 years May 1972 61 years Dec. 1971 56 years Sept. 1968 38 years 1971 40 years March 1973 43 years 26 9 19 27 22 12 14 21 20 3-1/2 18 23 21 12 12 21 1974 44 years 17 17 July 1974 49 years 17 11 . 1975 43 years 13 12 Feb. 1967 43 years .19 19 Jan. 1975* 63 years 16 13 April 1971 36 years 6 3 Dec. 1972 43 years 15 6 1970** 27 years 11 5-1/2 No date currently available. Polymerizer Bookkeeper in a plant manu facturing PVC Polymerizer Insulation of electric wires containing PVC Polymerizer Pourer of oil mixtures with PVC on raw materials Polymerizer Production of vinyl chloride Polymerizer Filler of pesticide cans with vinyl chloride as a propellant Polymerizer it Production of PVC bags Polymerizer 7 cases confirmed quite recently but ve have not received any details so far. Ravler. J.-N. Diter, and J. Pialat: A case of hepatic angiosarcoma in a worker ex posed to monomer vinyl chloride. Report presented to the Society of Occupational Medicine and Biotechnology of Lyon on 12/13/1974. Arch. AfeZ. Prof. 1975, 36 No. 3, pp. 171-179. **It was diagnosed as a mixed hepatocarclnoma and angiosarcoma. Notes It may perhaps appear surprising to the reader that cases of angiosarcoma of the liver are reported for the years preceding 1974. But this is explained by the fact that it Is only when the carcinogenic power of VC was disclosed in animals that retrospective epidemiological studies were conducted throughout the world, which made It possible to find these cases (diagnosis always operative). These epidemiological studies are much harder to carry out in our country, where death certificates are not kept and where there ia no cancer registry, in contrast to the US, for example. -28- AP00007958 monocbloracetate make them good candidates for the last carcinogenic form of vinyl chloride. Nevertheless, additional studies are necessary to permit conclusions which can clarify the mechanism of action-of .vinyl - chloride. It Is not without Interest to note at this point that various structural analogues of vinyl chloride or its metabolites have manifested carcinogenic properties in certain experiments. This is the ease with epichlorohydrin or 1,2-epoxy 3-butene. Monochloracetic acid, the terminal metabolite of vinyl chloridej was shown to be inactive in this regard, in the experiments of Van Duuren (cited by Malavellle). Recently, Viola and Caputo showed that vinylidene chloride (VDC) or 1,1-dichloroethylene (CC^ * Cl^) carcinogenic in the rat. This compound has been recognised experimentally as having mutagenic properties (cf. among others Malavellle [46)) while vinyl acetate'lacks these properties. A very recent item of information is also very disturbing: researchers at the chemical carcinogenisis division of the National Cancer Institute in the United States have demonstrated the carcinogenic potential of trichloroethylene after repeated oral administration to mice, at doses' which were actually relatively .high. The rat is apparently not sensitive, * which would confirm the'negative results obtained about 10 years ago 0 in-investigations conducted independently by 6. Rudali and by our own group 147]. Of course, interpreting results of this type requires a proper- perspective. It is nonetheless true that they must lead to epidemiological investigations in workers exposed to these various chlorinated hydrocarbons and to a reinforcement of preventive measuresaimed at reducing the degree of exposure. -29- AP6OOO7959 b) Results of epidaaiologiaal investigations in subjects occupationally exposed to vinyl chloride. As ve have pointed out In our introduction to the study of the toxicology of vinyl chloride, the disclosure of the carcinogenic potential of vinyl chloride in experimental animals prompted investigations, starting at the beginning of 1974, into whether this potential could he manifested In man, especially workers Involved In cleaning autoclaves In PVC manufacturing plants who could have been exposed repeatedly to inhalations of relatively high doses of the chlorinated hydrocarbon. To the firet cases of angiosarcoma of the liver, rapidly discovered In the United States in such subjects, other cases are progressively being added, not only in the United States but also in Canada and in various European countries. To our knowledge, there are currently 41 cases. He have compiled them in Table VII indicating, among other items, the age of the subjects at the time of diagnosis, the number of years between the first exposure and diagnosis, the total number of exposure years, and the occupation of the subjects exposed; notice that the vast majority had jobs in polymerization shops. Unfortunately, this list is likely to be lengthened as epidemiological investigations are continued, causing certain deaths in occupationally ex posed subjects to be attributed, to angiosarcoma of the liver. A certain latency period is known to be required before this disease appears, as in the case of many ocher occupational cancers. 3. Preventive Measures to be Implemented for the Protection of Exposed Subjects The Information acquired in recent years makes it evident that, in addition to its other toxic properties, vinyl chloride has carcinogenic potency in man. Because of the resulting formidable risk, if it is desired to continue using this compound as a raw material in the chemical industry, it becomes -30- AP00007960 imperative to set up very strict methods of technical prevention and to have truly adequate methods available to enforce their implementation as veil as the effectiveness of their application. In addition. Individual protective measures must be clearly recommended, taking care--by providing adequate information and a true health education-- to draw the workers' attention to the major Importance of compliance with the instructions given with respect to the precautions to be taken for the pro tection of their health. Finally, technical preventive measures and individual protective measures must be completed by a strict medical surveillance. We shall take up these various points one by one, in a necessarily verygeneral manner. A. Technical Preventive Measures These concern, first of all, the industrial conditions under which, vinyl chloride is used, and constitute the decisive factor as to the degree of exposure. Next, they are concerned with surveillance over the work environment. In this respect, there is the very important problem of establishing per missible limits and controlling them by adequate methods of analysis. 9 2. Conditions of the industrial use of vinyl chloride. We have mentioned the basic concepts In this regard in the first part of this article, dedicated to the presentation of vinyl chloride. We have emphasised that these concepts are essential for defining the conditions and exposure circumstances which, together with the qualitative and quantitative aspects of toxicity, determine the manifestation of the risks. The capacity of VC to polymerise and the production of PVC or copolymers constitute T-y far the principal use of this chlorinated hydrocarbon. But we now wish to stress -31- AP00007961 that* with the progressive disclosure of the health risks that nay result from the exposure of workers Involved in this production* especially during recent years* a very large number of chemical and technological refinements have been made in the processes used* A better knowledge of the kinetics of the reactions involved* both in the production of vinyl chloride and - particularly In Its polymerization, combined with considerable progress made In the field of chemical engineering, have made it possible to reduce the degree of exposure to vinyl chloride considerably, while improving the output. An Increase In the size of the autoclaves (from 1 cubic meter to 50 -cubic meters and even 200 cubic meters), combined with execution of the decrusting process under hydraulic.pressure and prolonged degassing, as well as-progress in the area of automation, have made it possible to work continuously with closed systems. For these reasons, the technology of modem polymerization shops has considerably reduced the possibilities of the workers' being exposed to vinyl chloride, particularly eliminating the possibility, which was frequent 10 or 15 years ago, of inhaling.toxic puffs of air while manually decrusting the polymerization autoclaves. Of course, the situation has been improved much more in the recent, modern installations than In those that are already old. 2, SurveiVUmae of the working environment. In this regard, in the case of toxic substances that may be found in the air of working areas, the very important problem of determining the permissible limits comes up as always [48]. In the case of vinyl chloride, about 30 years ago, the major concern was the risk of explosion at concentrations greater than 30,000 ppm. Following a study on the dose-response relationship with respect to the manifestation of such an effect In laboratory animals and Inman, the-disclosure of the -32- i AP00007962 I neurotoxic potential of vinyl chloride led to the recommendation of a per missible limit of 500 ppm, which is essentially equivalent to 1.275 ag/cm^ under normal temperature and pressure conditions. This value was much greater than the value for the perception threshold of the slightly ethereal odor of chlorinated hydrocarbon--a threshold which* moreover* varies according to the individual. It was notably less than the concentrations (1*000 ppm and more) to which workers Involved in cleaning autoclaves might have been exposed before 1960. We would like to emphasize that it was a question of a mean value integrated with respect to timet valid for repeated exposures day after day under industrial working conditions* 8 hours per day and S days per week. The discovery chat repeated.exposure to vinyl chloride can Induce vascular effects and the acroosteolysis syndrome which ve ... described above, led to a lowering of the permissible limit* defined as previously, to 200 ppm, which is equivalent to 5 mg/cm^ under normal tempera ture and pressure conditions. This value had been especially recommended .by the American Conferences of Government Industrial Hygienists in the list of Threshold Limit Values adopted in 1973 [49]. The revelation of the fact that vinyl chloride has a carcinogenic potential in various laboratory animal species and the recognition of its carcinogenic potency' in man led the same organization, in May 1974, to revise its position drastically and to postpone the establishment of a permissible limit for this human carcinogen. This a ticklish problem since there is a very widespread concept that __ there is no threshold for carcinogens, either physical or chemical, and ' * that, under these conditions, it is not possible to establish permissible limits for them other than on the basis of the concept-of socially -33Vv ------------- AP0bd07965 permiseible riska. However, certain objections of s scientific nature have formulated In recent years against such a rigid theory. Since It Is not possible for us to expand on this subject here, we take the liberty of referring the reader to the report of a scientific group of the World Health Organization 150} and to an article by one member of our group 151]. We would only like to point out that, even if the experimental data used by H. Druckrey, the German specialist on chemical carcinogenesis, as the basis of his proposed theory on the formation of totally irreversible reactions to carcinogenic substances were recognized as being exact, a certain number of theoretical considerations or experimental facts would lead us to consider the possibility of establishing thresholds at least for certain carcinogens. The present problem is that, for such a de termination, it is necessary to have recourse to adequate quantitative data on the minimal doses of carcinogens, so as to establish doses without effect. In the vast majority of cases, these data are completely lacking at the present time. ,* Whatever may be the case, a certain number of national or international organizations have focused on the problem. This has been especially true of the O.S.H.A. (Occupational Safety and Health Administration) of the Depart ment of Labor of the United States of America which, following the guidelines of its committee of expert consultants (H.X.O.S.E.), published In "U.S. Federal Register" (issue of 5 April 1974, 39, 12342) a regulation establishing, for a period of 6 months, a preliminary ceiling value (a value not to be ex ceeded even for short durations of exposure to a vinyl chloride concentration in the atmosphere of working areas) of 50 ppm. It was specified in this regulation, in all operations where the vinyl chloride concentrations -34- AP00007964 exceeded this figure, respiratory equipment was lndisensable for the exposed subjects and that everything has to be done to reduce these concentrations to the limit provisionally considered permissible. At the same time, the Chemical Industries Association of the United Kingdom recommended 50 ppm as a celling value and 25 ppm as an average value. At the beginning of October 1974, In a regulation appearing in "U.S. Federal Register** for October 1974 (39, 194, pp. 35890-97), O.S.H.A. adopted a much more restrictive attitude. Thia regulation vent Into effect starting on January 1, 1975. It Is stipulated, in effect, that no worker should be exposed to an average concentration In a given period Cone 8-hour work day) greater than 1 ppm of vinyl chloride, i.e., 3 mg/cm^ at 25*C. A ceiling value of 5 ppm for a duration of exposure not exceeding 15 minutes was simul taneously selected. Up to December 31, 1975, provided that the vinyl chloride concentra tions never exceed 25 ppm, the regulation allows manufacturers the possibility to provide the exposed subjects with respiratory masks, whose type Is defined according to the concentrations present in the air of the shops. But this Is only a temporary measure until the concentrations have been reduced to the limits previously mentioned. Many other points are found in a long text published in the "Federal Register". We shall limit ourselves here to mentioning that no worker should be exposed to direct contact with liquid vinyl chloride and, furthermore, areas affected by this regulation should have signs indicating that vinyl chloride Is an agent capable of producting cancer. -35- AP00007965 These provisions vere discussed at an international symposium held in Milan on October 2B and 29, 1974, under the auspices of a subcommittee of the International Association for Occupational Medicine (MEDICHEM). Representatives of industry have become aware of the fact that it is not realistic to schedule their application without allowing a sufficient period t6 alter their Installations. One member of our group, who presided over this meeting, at the end of the discussion gave his own opinion>shared by the cosigner of this article. It is summarized as follows: if vinyl chloride Is considered to be a carcinogen for man, all efforts must be taken to eliminate the exposure of workers to this compound In practice. As far as the average limit of 1 ppm and the celling value of 5 ppm for brief durations of exposure are concerned, these are reasonable on theoretical grounds. Actually, even if the possibility is acknowledged of considering a threshold for carcinogenic chemical agents of the vinyl chloride type whose mechanism of action, after metabolic activation, may well be alkylation of certain sites on the nucleic acid macromol^cule, it is indispensable to establish. In.long-term investigations`on laboratory animals, an ineffective concentration, to which a sufficiently high safety factor should then be applied for extrapolation to man. However, as we have seen, in experiments conducted until tills time, the lowest tested concentrations of vinyl chloride in the air (50 ppm) caus'ed the appearance of tumors and especially angiosarcomas of the liver. From all'evidence. It is vise to recommend to Industry that`they'do everything to meet the.standards adopted by the American authorities. But, fully conscious of our responsibilities, we think that to be realistic, 'industry.should be permitted sufficient time to attain -36- AP00007966 this objective. This Is why we have pragmatically proposed the following permissible limits on a temporary basis, for 2 years starting'on 1 January 1976. pairing this recommendation with the need for strict individual protective measures: Average value for a given period (8 hours par day-- 5 days per week): 5 ppm. Ceiling value for an exposure duration not exceeding 15 minutes: 15 *ppm. Meanwhile, industry can prepare itself to confront stricter requirements| if the experiments currently being conducted on laboratory animals subjected to concentrations in the air less than 50 ppa reveal the appearance of tumors and, in particular, of angiosarcomas of the liver. An important problem arises with respect to these permissible limits: the necessity of controlling their observance. Towards this objective, it is indispensable to provide analytical methods of adequate specificity. Sensitivity, and.accuracy. .. .. In this regard, up to 1973, the methods generally used to estimate vinyl chloride concentrations in working areas relied on the use of exposure meters equipped with tubes having a reagent producing a color with vinyl chloride. But the sensitivity of these methods did not go beyond 100 ppm under normal conditions of usage. With the need for considerably reducing the value of the permissible limits, it becomes necessary to establish much more sensitive methods. Without going into detail, we wish to`mention that the specialists then turned toward infrared spectrometry and gas phase chromatography. The results of infrared spectrometry are influenced by external parameters (humidity of the -37- AP00007967 air). therefore, gas phase chromatography, generally with a flame ionization detector, was selected. Analytical methods based on the application of this technique make it possible to achieve a sensitivity on the order of 0.1 ppm with an accuracy of 62. An entire series of techniques has been proposed. The .establishment of a standarized method is currently being studied in the "Air Ouelity" section of the applied chemistry department of the International Union of Pure and Applied Chemistry (IUPAC). Two types of control may be implemented: On the one hand, permanent surveillance by means of a fixed apparatus sampling the atmosphere at several characteristic points in the shop [6-10]. On the other handt determination of individual exposure at each working site by means of a portable micropump apparatus accompanying the worker in all his movements. This apparatus is equipped with an appropriate adsorbent (silica gel> activated charcoal, etc.) for capturing the vinyl chlorid^ which is then absorbed by a suitably chosen solvent (carbon disulfide, ethyl acetate). The analysis is then performed by gas phase chromatography and makes it possible to determine the vinyl chloride level present In the volume of air sampled during the course of the workday by the micropump. B. Individual Protective Measures Ko matter how effective, collective protective measures could not permit us to dispense with the classical hygienic and .individual protective measures of the chemical industry (washing of bends, special .soaps, double cloakroom for separating work clothes) on which we cannot elaborate in this article. Nevertheless, we must stress that the use of an Independent open-circuit respiratory unit is indespensible when checking and repairing polymerization installations. It is quite obvious that educating tlve workers as to the nature . -38- AP00007968 and degree of the risks to which the? are exposed constitutes, in the case of vinyl chloride, as generally speaking in the case of toxic substances responsible for occupational exposure, an essential factor in prevention, permitting them to play an active role in this control* Thus, a great deal of significance Is attached to their health education** which oust be extended to the foremen, engineers, chemists, and administrative personnel, it is '* very important "to display* in full.view in the shops* a set of instructions, written in simple and clear terms, specifying the preventive measures to be observed against the risks of vinyl chloride exposure. C. Medical Surveillance Today, thanks to the progressive use of absolutely indispensable technical prevention measures, bone pathology due to vinyl chloride exposure is In the process of disappearing. We are Justified In hoping that the same will be true as far as the carcinogenic risk Is concerned. Of course, an explosion of hepatic angiosarcoma cases in the future may be feared, since it cannot be forgotten that they may occur in workers who have been subjected to exposures at levels known to be high, 10 to 15 years . ago and even more. The present atmospheric concentrations in PVC manufacturing shops are fortunately considerably lower, .and we must continue to make an effort in this area. Nevertheless, can the physician responsible for monitoring the workers at such a plant rely only on these measurements? .It may be difficult for all levels of the hierarchy to understand this, even at a time when the whole importance of preventive medicine is justifiably recognized. As a consequence, it Is a good idea to define the basis for the medical surveillance of workers exposed to vinyl chloride. Everything we know concerning the pathology linked to exposure to this -39- AP00007969 compound must direct the attention of the occupational physician: '-- towards the vascular system and bones; -- towards the liver; towards the-nervous system; **" towards the skin. Employment medicals. This attention must first of all be given at the time of the employment medical. In our opinion, candidates with the following histories should not be assigned to jobs possibly involving exposure to VC: -- confirmed hepatic insufficiency (recent history of viral hepatitis, in particular, within the past year); -- a hematological disorder or blood coagulation disturbance (acrocyanosis , anglohemophilia, hemoglobinopathy, leukopenia, etc.); -- vascular disturbances suggesting--even mildly--RaynaudTs syndrome; -- history of bone disease; -- diabetes, chronic nephropathy; -- history of epilepsy; -- atopic eczema (this is also valid for any exposure to industrial chemicals). Thus, .an accurate Interview of the subject* Is necessary, as well as a thorough clinical examination (but isn't this true of any serious hiring test?). The data obtained in this clinical examination should be supplemented by biological tests of such a nature as to define the health profile of the candidate. Which tests? We feel that it is reasonable to require the following: -- blood count; -40- I AP00007970 -- blood picture; -- platelet count; -- determination of the blood transaminases (SGOT and SGPT) (to identify a possible viral'hepatitis); -- urine test (reactive Btrips) and, naturally, -- a lung X-ray; -- X-rays of both hands (placed quite flat on the plate). These will subsequently be very useful as a reference source, since'the number of small traumatic sequelar lesions which may cause the change willbeknovn if their existence had not'previously been demonstrated. Of course, as always, there will be subjects representing borderline cases. After they have been assigned to jobs, they should be followed up subsequently. Furthermore, there should be no question of limiting the occupational physician to a fixed list of examinations. This clinical examination, which remains the medical act par excellence, will sometimes prompt him to request additional tests. We feel that It is useful to remind the reader here that it is well worth while to be strict during the hiring test--this test being the responsibility #* of the occupational physician and influencing the subsequent fitness of the worker. Follow-up examinations of workers admitted at the time of the hiring examination. Interval: twice a year. Clinical and radiographic examination of the hands (in certain cases, the speed with which the bone lesions appear is known). The appearance of these lesions will be cause for a change of job and, -41- APOOO6797I as we know, will bring about a remission of the lesions. The problem here Is relatively simple. On the other hand, in the area of preventions carcinogenic risks, in the present state of knowledge we. do not have any biological test furnishing a sufficiently early warning. Many biological teats have been proposed, -and the number of blood parameters which have been the subject of discussions between physicians definitely proves the problem of establishing a typical list. However, we cannot abstain from discussing this. Of course, if the clinical examination shows a palpable liver (a large liver is always pathological), the worker should be 'sent to his physician or to a specialized department. In the contrary case, as far as we are concerned, we think it is reasonable to require the following biological tests: -- blood count; ~ blood picture; -- platelet count; -- two liver function tests (cholestasis tests): - * determination of alkaline phosphatases; determination of the blood fibrin; -- once a year* a thoracic-abdominal X-ray, a pulmonary checkup and examination for possible splenomegaly, which Is undoubtedly the best sign of portal fibrosis syndrome, which we know to be frequent. -- a determination of the blood sedimentation rate:, definitely not a specific test but one which, if the result reveals a significant .`elevation (on the order of 70 mm and higher during the first hour), con firmed by a second-Test, practically always indicates`a serious active disorder and justifies interruption of work and strict medical surveillance; -42- AP00007972 -- finally, two tests merit particular attention: examination of the `ocutap fundic, of a certain usefulness; eulfohromophthalein test (BSP). We feel that determination of the level of dye retention in the serum after 45 minutes is the best test of hepatic cholestasis; it could even be the only one to be performed In monitoring workers who may possibly have been exposed to vinyl chloride. Unfortunately, it is difficult to apply and takes a good deal of time. The testing of a number of other biological parameters is advised in the list of Items to be monitored by certain foreign occupational physicians (Americans, in particular). As far as ve are concerned, it seems impossible to recommend these tests routinely, since certain ones would require highly specialized laboratories beyond the reach of the occupational medical de partments of many plants. In particular, we wish to mention enzymatic determinations which, when positive, Indicate an established tumor which has already reached an advanced stage. In this case, moreover, the clinical examination would very probably have outstripped these positive findings due to the observation of a large liver. One exception may be the determination of blood ornithine carbemyltrensferase--relatively easy to do--which Is considered as one of the most sensitive hepatic function tests. As far as we are concerned, ve would not insist on the abovementioned tests. Ve finish by pointing out that angiosarcoma of the liver will soon be added to Table Ho. 52 of occupational diseases reproduced in this article. 4. Conclusions Concluding this article, in which we attempted to analyze the information AP00007973 currently available on the risks that may result from occupational exposure to vinyl chloride, mainly during the manufacturing of vinyl polychlorides and subsequent operations, we feel that a certain number of points should be strongly emphasized: 1. About 10 years ago, the danger for workers exposed.to vinyl chloride appeared to result only from its inflammability combined with its explosive nature between certain concentration limits, its mixing with the air, as veil as its narcotic effects. The disclosure that it is capable of causing an acroosteolysls syndrome and especially, more recently, is carcinogenic effects in man, are a spectacular example of the vigilance that must constantly be exerted by toxicologists, occupational physicians, and epidemiologists with respect to the possible toxic potential of chemical agents that may be found in working environments. 2. The disclosure of the carcinogenic potential of vinyl chloride by experiments on animals, followed by its recognition as a human carcinogen epi demiological investigations in occupationally exposed groups, show the major 'importance of conducting adequate experimental investigations on laboratory Animals for any chemical compound manufactured industrially, for which practical applications are planned, and paying thg greatest attention to. the results thus obtained with respect to technical prevention and individual protective measures, as well as the medical surveillance of'the workers exposed. 3* Many investigations still remain-to be done, in. an attempt to clarify the mechanisms of toxic action and especially carcinogenic action of vinyl chloride. In this regard, we feel that it is appropriate to emphasise that many facts already known suggest that the initial attack point lies in the vascular system, and that this affinity must be affected by biochemical factors -44- AP00007974 which are still unknown. 4. On the practical level of prevention, the determination of permissible limits of vinyl chloride in the air of working environments constitutes a burning current problem whose study, in our opinion, requires experiments involving the exposure of various species of laboratory animals to a range of concentrations sufficiently low to enable us to establish concentrations without effect. In this regard, the thorny and controversial problem of the existence of thresholds for carcinogenic agents should not be forgotten, especially for compounds recognized as being carcinogenic in man. 5. While awaiting the accumulation of the scientific information indispensable to an objective discussion of the decisions to be made, it becomes necessary to require industry (which has, moreover, already extended considerable effort in this direction, leading to the practical disappearance of bone pathology) immediately to implement.preventive measures and especially technical preventive measures, making It.possible to reduce the degree of exposure of the workers to the lowest possible level. It is In such a spirit that In the present article, while taking into account certain pragmatic aspects which we feel affect the entire community, we recommended the Immediate application, for a limited period of time, of permissible limits which would represent a considerable advance over the current situation. REFERENCES (13 Regnault: Ann, chim, phy,, 1835, 58, p. 308. (2] I.A.R.C.: Intern, technical report No. 74/005. Report of a working group on vinyl chloride, 1974. [3] Patty, F.A.: Industrial hygiene and toxicology, Tntersclence publishers. New York/London, 1963, Vol. 2, pp. 1303-1305. [43 Hardie, D.W.F., int Kirk, R.E. and Othmer, D.F.: Encyclopedia of Chemical Technology, 2nd ed., 1964, 5, New York, John Wiley & Sons, pp. 171-178. -45- AP00007975 [51 Baumann: Aftnal, % 1872, 163, p* 37. [61 Oatromyslinski: J. Soe. Physico. Chimique fiusse, 1916, 48, p. 32, cited by F. Swartz In Grlgnard, V., Treatises on Organic Chmistvy* 3, p. 361. [7] Lefaux, R.: Plastic 'Materials in the Food Industry. Associated Technical Publications Edition-Group of the French Editions Company, 1972, p. 44. [8] O'Hara, M.M., Crider, L.B., Daniel, R.L.: Combustion Product from Vinyl Chloride Monomer, Amer. Indus tr. Eyg. Assoc, T., 1971, 32, p. 153. [9] Faroes, R.M. end Mead, D.J.: Journal Phys. Chem., 1953, pp. 47-59. [10] Stroraberg, R.P. et al.: Thermal Decomposition of PVC, J. Polym. Sai., March 1959, 35, No. 129, p. 355. [11] Boyer, R.P.: A Statistical Theory of Dlscloration of Halogen Containing Polymers., J. Phys. and Colloid, Chemistry, January 1947, 51, No. 1, p. 80. [12] Viola, P.L.: Pathology of Vinyl Chloride, Communication of the XVIth International Congress of Occupational Health, Tokyo, September 1969, Proceed, pp. 296-297. [13] Viola, P.L.: Carcinogenic Effect of Vinyl Chloride, Xth International Cancer Congress, Houston, [illegible] session 3, Chemical carcinogenesis various [illegible] Proceed, 29, 4 p. [14] Peoples, A.S., Leake, C.D.: The Anesthetic Action of Vinyl Chloride, J, Pharmacol. Experim. Therap., 1933, 48, p. 284. [15] Monograph. National Institute of Public Health, The Netherlands, 6 April 1964, p. 2. [16] Danziger, H.: Accidental Poisoning by Vinyl Chloride, Report of two cases, Canada Med. Assoc. J.t 1970, 82, p. 828. [17] Lester, D., Greenberg, L.A. et al.: Amer, 2nd. Eyg. Assoc. , 1963, 24, pp. 165-275. [18] Mastromatteo, E., Fisher, A.M. et al.: Am. 2nd, Eyg. Assocl. <7., 1960, 21, pp. 394-398. [19] Torkelson, T.R., Oyen, P. and Rowe, V.K.: The Toxicity of Vinyl Chloride as Determined by Repeated Exposure of Laboratory Animals, Amer. Industr. Eyg. Assoc. J. , 1961, 22, pp. 354-361. [20] Baretta, E.D., Stewart, R.D. et al.: Amer. 2nd, Eyg. Assoc. 30, pp. 536-544. 1969, [21] Antonjuzkenko, V.A.: Occupational Poisoning by. Vinyl Chloride, Gigiena truda i prof. Zabolev., 1968, 13, pp. 50-52. -46- AP00007976 [221 Cordier, J.M., Fierez, C., Lefevre, M.J., Sevrin, A.: Acroosteolysls and Associated Skin Lesions in Two Workers Affected during Autoclave Cleaning, Cahiere de medecine du travail* 1966, 4. p. 3. [23] Harris, D.K., Adams, W.G.F.: Acrooateolysis Occurring in Men Engaged in the Polymerization of Vinyl Chloride, Bfit> Med* J.j 1967, pp 712- 714. [24] Chatelain, A., Kotillon, P.: A Syndrome of Acroosteolysls of Occupational Origin Newly Observed in France, J. radiol. eleotrol, 1967, 49, pp 277-- 280. [25] Marin, A., Strauss, J. Michiels, K., Benoit, J.P., Baltie, R. and Pierre, C.: Acroosteolysls of Occupational Origin, Revue rhumztisme, 1967, 6, pp. 340-351. [26] Sclu, I., Drejman, I. and Valaskai, M.: Studies of Diseases Due to Vinyl Chloride, Med* lav., 1967, 58, pp. 261-271. [27] Wilson, R.H., McCormick, W.E., Tatum, C.F. and Creech, J.L.: Occupational Acroosteolysls, Report of 31 cases, Joum, Amer. Med. Abboo. , 1967, 201, pp. 577-581. [28] Benoit, J.P.: Acroosteolysls: A New Pathological Manifestation in Industry of Plastic Materials, Cahiers de notes documentairee t 1969, 54. [29] Dinman, B.D., Cook, W.A., Whitehouse, W.M., Kagxiuson, H.J. and Ditcheck, T.: Occupational Acroosteolysls. I. An Epidemiological Study, Arch. Environm. Healthy 1971, 22, pp. 61-73. [30] Cook, W.A., Giever, P.M., Dinznan, B.D. and Magnuson, H.J.: Occupational Acroosteolysls. II. An Industrial Hygiene Study, Ardh. Environm. Health, 1971, 22, pp. 74-82. [31] Mszella Di Bosco, M. Faccinl, E.: The Occupational Pathology of Vinyl Chloride with Particular Reference to Acroosteolysls in Operated Subjects Employed in the Cleaning of Polymerization Autoclaves, Riv. di din. tossi, 1973, 3, fasc. 1-2. [32] Lange, C.E., Juhe, S., Stein, G. and Veltman, G.: The So-called Vinyl Chloride Sickness--an Occupationally Induced Systemic Sclerosis? Internationales Arohiv. fur Arbeitsmed., 1974, 32, No. 1-2, pp. 1-32. [33] Moulin, G., Rety, J., Pallard, P., Vouillon, G. and Guttln, G.: Sclerodermel Aspects of Occupational Acroosteolysls (Polymerization of Vinyl Chloride), Arm. dermatol., 1974, 101, No. 1, pp. 33-44. [34] Berrod, J., Bourichon, J., Lazard, ?. and Rety, J.: Acroosteolysls and Vascular Disturbances Related to Vinyl Chloride. With Respect to a Clinical Observation. XVIII International Work Congress, Buenos Aires, September 1972, Summary p. 43. [35] Lefevre, M.J.: Radiological and Evolutional Diagnosis of Cases of Acroosteolysls. mMEDICAMm. First International Symposium of Occupational Physicians in the Chemical Industry, Ludvigshafan, 27-29 April 1972, Report pp. 260-266. -47- AP00007977 [36] Viola, P.L., Bigotti, A. and Caputo, A.: Oncogenic Responses of Rat Skin, Lungs and Bones to Vinyl Chloride, Cancer Research, 1971, 31, pp. 516-522. [37] Maltonl, C. and Lefemlne, G.: Carcinogenicity Bloassays of Vinyl Chloride. I. Research Plan and Early Results, Environmental Res.* 1974, 7, Ho. 3, pp. 337-405. , [38] Maltonl, C. Lefemlne, G, Chieeo, P. and CaTretti, D.: Environmental and Occupational Carcinogenesis in the Light of the Carcinogenesis of Vinyl Chloride, Gli oepedali delle vite, 1974, 1, Ho. 5-6* [39] Maltonl, C. and Lefemlne, G.i The Potentiality of Experimental Tests in the Prediction of Oncogenic Environmental Risks* An Example! Vinyl Chloride, Rend. Sci. Fis. Mat. Rat. (uncei), 1974, fasc. 3, aerie VII, vol. 56. [40] Maltonl, C. Lefemlne, G., Chieeo, P. and Carrettl, D.: Vinyl Chloride Carcinogenesis: Current Results and Perspectives. Med. del lea)., 1974, 65, No. 11-12, pp. 421-444. [41] Maltoni, C., Cilibertl, A., Braunl, L. and Chieeo, P.: Insurgence of Angiosarcoma in Rats Polloving Oral Administration of Vinyl Chloride., Gli oepedale della vita, 1975, 2, Ho. 1, pp. 65-66. [42] Rannug, U., Johansson, A., Ramel, C. end Machtmeister, C,A* The Mutagenicity of Vinyl Chloride after Metabolic Activation. Second International Symposium on Chromosomlc Abberations Caused by Chemical Substances Used in Industry, Milan, 28-29 October 1974, cf. also No. 3, 1974. [43] Malavellle, C-t Communication Presented to the Ninth Session of the French Association of Chemical Carcinogenesis, Paris, Curie Institute (24 May 1975) and Bartsch, H., Malavellle, C. and Montesano, R.: Tissue Mediated. Int. Cancer J. , 1975, 15, p. 429. [44] Bartsch, H. Malavellle, C. and Montesano, R. \ Mutagenic and Carcino genic Effects of Vinyl Chloride (to appear in Autumn 1975) Mutation Research (Review in genetic toxicology). [45] Malavellle, C., Bartsch, H.p Montesano, R., Barbin, A., Camus, A.M., Crolzy, A. and Jacqulgnon, P.: Biochem. biophys. ree. comnon. 1975, 63, p. 363. [46] Malavellle, C.: Tissue Mediated Mutagenicity of Vinyl Chloride and Chloro 2-Butadiene, Nature^ 1975, (at press). [47] Truhaut, R.: Carcinogenic Hazards from Drugs. Account from a symposium of the International Union Against Cancer, Paris, November 1965, Ed. Springer Verlag, 1967. [48] Truhaut, R-: Present State of the Problem of Allowable or Tolerable Limits for Potentially Toxic Chemical Agents in Occupational Environments, Arch. ml. prof., 1971, t. 32, No. 4-5, pp. 353-370. -48- AP00007978 {49] Threshold Limit Values for Chemical Substances and Physical Agents in the Working Environment with Intended Changes for 1973* Booklet published by the American Conference of Governmental Industrial Hygienists. {50] Report of a Scientific Group of theW.H.O. on the Carcinogenicity and Mutagenicity of Chemical Agents* Geneva, 13-17 August 1973, series of reports of the W.H.O., 1974, No. 346. [51] Truhaut, R.: Can Permissible Levels of Carcinogenic Compounds in the Environment be Established? Account of the International Congress on Cancer, Florence, October 1974, ed. Excerpta medica, Amsterdam, 1974. -49- AP6b007979