Document 15OENeOqnOq27bm3NqEMRvajj

CHARLES S. MOTT PRIZE Mesothelioma and Mineral Fibers J. CHRISTOPHER WAGNER N 1952. the Chief Mining Engineer of the South African I Government wrote a memorandum to the Minister of Mines enquiring if ati types of asbestos caused the same diseases. Rather by chance. 1 was appointed Asbestosis Research Fellow at the South Africa Pneumoconiosis Re search Unit in 1954. and asked to answer the question. This investigation is still continuing. I have had several significant "lucky breaks." The first of these was in 1956. when I undertook a necropsy ex amination on a black adult male who had been the shower attendant on one of the Witwatersrand Gold Mines. He was thought to have died from tuberculosis, terminating with pleural infection which did not respond to chemo therapy. Much to my surprise I found a huge gelatinous tumor completely filling the right chest cavity, with the collapsed lung in the center. Extensive histologic and histochemical studies confirmed that the tumor was a me sothelioma or the pleura, while in the lung tissue we ob served a few asbestos bodies, but no evidence of pulmo nary fibrosis. 1 presented the case, with the full radiologic and clinical findings, at the next meeting of the local chest group. A week later, our Chief Thoracic Surgeon. Libero Fatti. was called down to the town of Kimberley, the center of the diamond mining industry, to see a patient. While he was there, he was approached by Dr. Kit Sleggs, Chief Medical Officer of the local Tuberculosis Hospital, who stated that when he had first arrived in Kimberley in 1946, tuber culosis was endemic, with a high mortality rate, particu larly when the infection had spread to the pleura. In 1952, the antitubercuiosis drugs became available which led to a rapid increase in survival from the whole region, with the exception of the cases of pleurisy from the west of Kimberley, some of whom seemed to have a secondary tumor. It was recognized by people ofthis area that anyone who developed fluid in his chest would die within the year. Dr. Sleggs took Dr. Fatti to the hospital where, to his amazement, he saw the radiographs of 14 cases that Presented at the 1985 General Motors Cancer Research Foundation Prizewinners Laureates Lectures. Jack Masur Auditorium, National In finites of Health. Belhesda. Maryland. June 12, 1985. were identical to those of the patient that I had demon strated. It was agreed that Paul Marchand, Dr. Fatti's as sistant, would biopsy the pleura of these people. Within a month, 1 had a further 12 specimens of what had pre viously been considered a very rare tumor. Fortunately, at this stage, Professor Paul Steiner from Chicago was visiting us and he confirmed my diagnosis of meso thelioma. We were puzzled as to why we were seeing so many of these tumors. 1 then recalled that we had seen asbestos bodies in the first case and that 90 miles west of Kimberley were the large mines which had been developed along the so-called blue asbestos mountains, a range of hills stretch ing for more than 400 miles from the Orange River in the south to the Botswana border in the north. We then meticulously examined every scrap oflung tissue that had accompanied the biopsy specimens, and in three more cases we found occasional asbestos bodies. I therefore suggested that we should consider an association between the blue (crocidolite) asbestos mines and development of the mesotheliomas. The next case which was submitted was ofa woman aged 55 years who gave a history ofhaving been bom in Kimberley where her father was a dentist. When she was 1 year old, the family had moved to Prieska, one of the asbestos mining villages, where she lived for 5 years before returning to Kimberley. All she remembered of it was that there was a mill in the middle of the village which produced clouds of blue dust. From further cases referred by Dr. Sleggs, we obtained histories showing that few of the patients had been em ployed by industry working as insulators with blue as bestos on steam locomotives.1-2 The majority, however, had only lived in the vicinity of the asbestos mills, some for very short periods, and, on average, their tumors de veloped 44 years after exposure. The next question was. were the tumors confined to exposure to blue asbestos or were other types of fiber in volved? South Africa was the ideal country for this study: First, it is the only region in the world in which the three major types of asbestos--crocidolite, amosite, and chrysotile--are mined, the latter accounting for more than 96% of the world's production. Secondly, these deposits had been exploited for more than 40 years by larayajjjjj EXHIBIT 1905 HWBUI0010757 1906 Cancer May 15 1986 Vol. 57 forces. Through the South African Pneumoconiosis Bu reau, we were able to examine the lungs of the majority ofasbestos miners who died, revealing that mesotheliomas of pleura, and occasionally of peritoneum, were only ob served in the workers from the Cape asbestos mines and those living in the vicinity. In recent years, a few cases have been reported from the amosite mining areas, but detailed analysis is required to see ifthese men had worked on the associated crocidolite deposit. No cases have been recorded among chrysotile miners or from the mines of the neighboring countries of Swaziland and Zimbabwe. On (his evidence, we considered that we were justified in implicating crocidolite asbestos in the development of these tumors.3 Ifwe were correct, there were three obvious worrying aspects: first, the exposure could be for as short as 3 months in some cases; secondly, there was a long time between first exposure and development of the tu mors; and thirdly, the majority of the cases had paraoccupalional exposures. A further question arose as to whether a similar situ ation existed with the manufacturers of asbestos products. In 1962, we began to investigate the problem in the United Kingdom where, in that year, the Inspectorate of Factories had records of over 100 carcinomas occurring in asbestos workers, but only 4 mesotheliomas. This was because there had been surveillance of the employed asbestos workers, but not of the people who had only worked for a short period, particularly those employed in the factories during the two World Wars; in addition, there had not been an intensive surveillance of the laggers (insulators). By going through hospital records and material in the pathology departments, we discovered more than 100 cases during the next 2 years, and in association with various colleagues (Dr. Muriel Newhouse deserves special mention),4 we were able to establish the association with exposure to asbestos dust.5 In Britain, however, as we found later in other in dustrial countries, the actual fiber implicated was much more, difficult to assess, as the majority of workers had been exposed to most varieties of asbestos dust. An un accountable feature was the high incidence of peritoneal tumors, which has also been found in New York.6 A sig nificant proportion of the mesothelioma cases was from people who had lived in the vicinity of the asbestos fac tories, or had been exposed to the clothing of relatives who had brought dust home on their clothes. By 1964, cases were being reported from several other countries, and an international meeting was organized in New York by Dr. Harold Stewart to correlate the studies, under the aegis of the International Union Against Cancer (UICC).7 From this meeting, plans were formulated to establish whether crocidolite was the main cause of the tumors and whether the general population was at risk. A major problem was the need for a method for estab lishing the type of fiber to which a case of mesothelioma had been exposed when the only remaining evidence was a small block of lung tissue or histologic sections. This was eventually solved by Dr. F.D. Pooley, from Depart ment of Mineral Exploitation, University College, Cardiff, who over the last 20 years has been developing more and more sophisticated methods for identifying, quantifying, and measuring fibers in tissue.8 The current method de pends upon the use of EDAX (energy dispersive analysis of x-rays) on a transmission electron microscope with di rect computer read-out studying fibers extracted from known amounts of lung tissue.* These methods have shown a predominance ofamphibole fibers, mainly amo site and crocidolite, but occasionally tremolite, in the lungs of cases of mesothelioma when compared to tissue from age-matched control cases.10 Cases of pure crocidolite ex posure have occurred among women who inserted the crocidolite pads into the cannisters of the respirators pre pared for the Ministry of Defense during the last World War; in contrast, so far no cases have been recorded from the people involved in packing the civilian respirators, which contained chrysotile. The epidemiologic studies started under the UICC and HWBUI0010758 No. 10 Mesothelioma and Mineral Fibers Wagner 1907 later continued under the International Agency for Re search on Cancer, have now been in progress for 20 years. It has been established that mesotheliomas are rare in the Quebec mining area and have never occurred in people living in the vicinity of these mines, nor have any been recorded among the Russian chrysotile miners, working in the Urals, nor from the south African chrysotile mines or the Italian mines in the Alps. The one exception was the chrysotile mine in Cyprus, and the fact that mesothe liomas were occurring at this most ancient of asbestos mines started a new concept in our studies. Before coming to this, however, it is necessary to discuss the fibrous min erals, which will be considered under the following head ings: (1) asbestos minerals of commercial value; (2) as bestos minerals as potential environmental contaminants; (3) synthetic mineral fibers; (4) naturally occurring fibrous minerals ofcommercial value; and (5) naturally occurring fibrous minerals as potential environmental contami nants.11 ? Asbestos Minerals Asbestos ofCommercial Value Practically all the present knowledge about the hazards associated with inhalation of fibrous mineral dusts has been obtained in studies of asbestos. Asbestos is now con sidered to consist of six naturally occurring minerals: chrysotile, crocidolite, amositc, anthophyllite, trcmolite, and actinolite. Chrysotile is a member of a group of min erals referred to as the serpentines and it is composed almost exclusively of magnesium in combination with silica, while its sheet structure is curled to produce hollow tube-like fibers. The other five minerals, members of the mineralogic group referred to as the amphiboles, are very similar in crystal structure, being chain silicates, but they vary in chemical composition. Crocidolite and amosite are iron-rich varieties, anthophyllite is a magnesium-rich i mineral, and tremolite and actinolite contain a large amount of calcium together with magnesium. The world ! production of asbestos in 1976 was 5 X 109 kg, 97% of this being chrysotile, white the remainder was crocidolite and amosite. The commercial production of the other three amphiboles had been minimal in the past, but they are important as contaminants of other minerals and agricultural soil, as will be discussed later. Chrysotile is widely distributed, with the largest commercial production from the Ural mountains in Russia, Quebec Province in i Canada, Zimbabwe and Swaziland in Southern Africa, i the Italian Alps, and Cyprus. Until recently, crocidolite was mined in Western Australia, but is now mined almost exclusively in the Cape Province in South Africa. Amosite i is exploited only in the Transvaal, but deposits have been discovered in Southern India. Asbestos has over a thousand uses, so that the number f occupations in which exposure may have occurred is large. Crocidolite, because of its resistance to acids and sea water, was extensively used in naval insulation and fireproofing, as insulation for steam locomotive boilers, and later for soundproofing in passenger coaches. A sig nificant amount was used in the insulation of buildings, but in Britain the use of crocidolite and its importation has been severely limited since 1969. Amosite has been used for thermal insulation, in floor tiles, and in the su perstructure ofships. Chrysotile has been used for all other purposes, but particularly in asbestos cement products, insulation, fireproofing, and in the manufacture of friction materials such as brake linings and clutch plates. Chry solite is still the main fiber used in textiles, but this is no longer a major section of the industry. The destruction by demolition of buildings, ships, and railway rolling stock is a source of environmental pollution. Asbestos Minerals as Potential Environmental Contaminants Asbestiform minerals contaminating banded ironstone: Although banded ironstone deposits frequently contain small seams of fibrous silicates, occasionally large deposits occur, which are the source of the amphibole asbestos fibers that are exploited in the southern hemisphere. Other deposits are of no commercial value, such as the taconite fibers in the Mesabi Range on the shores of Lake Superior. Although iron-ore mining in this region is causing con tamination of the atmosphere and the water of the lake, no evidence of a hazard to humans has been established. Tremolite as a contaminant of other mineral deposits: Tremolite is friable and of little economic importance, but has been used as an industrial talc. It is a contaminant in chrysotile and talc deposits and is released when the materials are milled. It has been used as material for stuc coing of domestic dwellings in certain villages in Turkey, Cyprus, and elsewhere in the Eastern Mediterranean. In Turkey, the villagers collect it from quarries that have been used for generations, and it is sometimes removed from the tailing dumps in the vicinity of the chrysotile asbestos mine in Cyprus. In Korea, there are mines pro ducing tremolite for which a market is being sought. Possible contamination in agriculture: Fibrous mineral contamination in agriculture has only been appreciated during the last few years, and may yet be shown to be of consequence, as evidence to date is still fragmentary. The first confirmed situation as far as asbestos is concerned is in Bulgaria, where the finding ofpleural plaques in workere in the tobacco fields containing tremolite and antho phyllite in the soil has been reported. Synthetic Mineral Fibers Synthetic mineral fibers can be divided into four groups: Slag wools, rockwools, glass and ceramic wools, and fil * HWBUI0010759 1908 Cancer May 15 1986 Vol. 57 aments. The materials of each group consist of glassy mineral fibers. AH man-made mineral fibers are formed from a liquid melt at temperatures of 1000 to 1500oC, but the methods of producing the fibers vary. All the man-made mineral fibers produced have glassy structures, and thus are not crystalline. Their length and diameter distribution differ considerably and are depen dent on the method of production and the chemical com position. Usually, commercially produced fibers of man made minerals are considerably coarser than asbestos fi bers, although specialized samples have been produced with dimensions very similar to those of asbestos. These synthetic fibers fall into three broad categories of fiber size. The first is the continuous filament glass fibers that are used in textiles and as a reinforcement for plastics and other materials, with fiber diameters greater than 8 ptn. In the second category are insulation wools with fibers nominally 1-6 pm in diameter, however, there are ends that are as small as 0.2 pm. The third category contains fibers smaller than 1.0 pm in diameter, which are used for specialized purposes such as scientific filter papers. Man-made mineral fibers are usually coated with bind ing compounds to produce fabricated shapes and forms. In the past, insulation wool binders have included bitu men, urea, and phenol-formaldehyde resin compounds. Today, innovations in binding agents based on resin sys tems are continuously being made. Naturally Occurring Fibrous Minerals The naturally occurring fibrous minerals are a miscel laneous collection. The majority are silicates, but one metal--rutile (the fibrous form of titanium)--is proving of interest because it has been recovered from the lungs of various industrial workers, including slate miners and processors. The two groups of fibrous silicates of particular current interest are the clays and the zeolites. Zeolites are a complex group of silicates formed by metamorphosis in deposits of volcanic ash. They are characterized by an open lattice structure useful for infiltration catalysis and absorption in the chemical industryand agriculture. Most of the commercially used zeolites are now synthesized and nonfibrous. Few of the natural materials are fibrous, but there are at least three that are: mordenite, clinoptilite, and erionite. These fibrous zeolites form hexagonal glassy rods that may occur singly or in strands and'vary in di ameter from deposit to deposit. Extremely fine erionite fibers have been found in a few deposits in Oregon in the United States, and in centra! Turkey. The implications of erionite fiber exposure will be explained later. The absorbent days have been used for various indus trial purposes for many years, and recently there has been an increasing demand for these materials as cat litter. A chance discovery was that some of the material used for cat litter was fibrous in nature. Although these minerals appeared visually to consist ofsolid minerals, when finely ground samples were examined under the transmission electron microscope, they were found to contain numer ous short fine fibers. The fibers were particularly noticeable in minerals of the meerschaum group, including attapulgite, palygorskite, and sepiolite. Sequelae ofExposure to Asbestos Dust There have been numerous descriptions of the lesions resulting from exposure to asbestos dusts. The sequelae are as follows: (I) the presence of asbestos bodies in the sputum; (2) pleural plaques and diffuse pleural fibrosis; (3) interstitial pulmonary fibrosis (asbestosts); (4) carci noma ofthe lungs; (5) diffuse mesothelioma ofpleura and peritoneum: and (6) an increased incidence of gastroin testinal tumors and possible increase in incidence of car cinoma of the larynx. On detailed investigation, each of these findings has provided problems that not only apply to asbestos exposure, but also have to be considered in the wider assessment of other mineral fibers. The comparison between the fibers in the lungs of the mesothelioma cases collected in Britain with those in the United States and Canada has shown that, in both coun tries, chrysotile fibers are found equally in cases and con trols. In Britain, it is crocidolite that is associated with mesotheliomas: whereas in the United States, it is usually amosite and. less frequently, crocidolite.12 The Advisory Committee to the British Secretary of State for Employ ment concluded that in the causation of mesotheliomas, crocidolite was more dangerous than chrysotile, and amosite may be intermediate between the two.11 Significance ofFiber Size The importance of fiber size in the inhalation and re tention of fibrous mineral dusts was first emphasized in a study that showed that The fiber diameter is the most important factor in the deposition, and the length is only of minor significance. Later, in a study of the ultimate diameters of crocidolite and amosite fibers, the diameter was identified as a vital factor in assessing the probability of a fiber being associated with the development of a me sothelioma. Similar results were recorded from animal experiments in which asbestos and other mineral fibers were implanted into the pleural and peritoneal cavities of rats. At this stage of the investigations. Dr. Harold Stewart introduced me to Mearl Stanton. Dr. Stanton and 1 planned a series of collaborative investigations in which we compared the results of our initial implantation stud ies.14 Then Dr. Stanton undertook a detailed program on intrapleural implantations of a large variety of fibrous dusts in different size ranges. It was from these outstanding experiments that the concept of the importance ofspecific <9 i HWBUI0010760 No. 10 Mesothelioma and Mineral Fibers - Wagner 1909 fiber size was recognized.15 From these and other inves tigations, it now appears that the size of the fiber respon sible for mesotheliomas has a diameter or less than 0.25 #tm and probably a length greater than 5.0 pm. Fibers up to 3.0 pm in diameter inKaled and retained in the pe ripheral airways are associated with pulmonary fibrosis, and the effective length of at least 10 pm suggested by Timbrell and Skidmore in 1968 has not been challenged.14 There is no agreement on the maximum length of fibers that would be hazardous. The most important finding in all these experiments was that mineral fibers other than asbestos having these diameters and lengths are capable of causing mesotheliomas. Whether this finding also ap plies to the development of pulmonary fibrosis is still Un der investigation. Studies on the Other Fibers Our experiences with the other fibers will be described in chronological order from the time when we first became involved with a particular material. Tremolite and Aclinolile as Contaminants ofOther Mineral Deposits As mentioned previously, we received our first meso thelioma case from Cyprus in 1968 of a woman who had lived all her life in the vicinity of the 3000-year-old Amiandos Chrysolite Asbestos Mine. On microscopic ex amination of the biopsy specimen, a small fragment of lung tissue was attached to the tumor in which a few as bestos bodies were seen. Pooley8 had demonstrated that asbestos bodies are rarely seen in the lungs of workers exposed to chrysotile dust, but on examination of the tis sue he confirmed that amphibole fiber was present which was either tremolite or actinolite (as these two minerals are very similar, no differentiation has been made in this and in further studies). To date, we have confirmed the diagnosis of seven cases of mesothelioma from Cyprus and have been notified of an additional five cases. We have only obtained lung tissue from one further case of mesothelioma and a miner with early asbestosis, both of which also contained tremolite/actinolite fibers. We were fortunate to obtain the lungs of six mature sheep.which were being prepared for a wedding feast, which also con tained tremolite/actinolite fibers. Previously, in 1969, Dr. Pooley had visited the mine and had found fine tremolite in the ore body and in the surrounding area with a di ameter.of less than 0.5 pm. A similar situation occurs in Eastern Turkey, although the finest tremolite that we have obtained is mined in South Korea, which, when inocu lated intrapleurally into rats, resulted in a high incidence of mesotheliomas. In contrast, a coarser flake-like tremolite occurs in the talc mine in California, but no evidence of disease has been observed among the miners and millers from this site, nor were lesions produced when this material was used in our experimental studies.'7 A coarse fibrous trem olite is found as a contaminant of the Quebec chrysotile deposits, which is found in the lungs of the miners and millers who develop pleural plaques and asbestosis.18 This contaminant is incorporated with the commercial chry sotile, particularly with the fiber produced from the tail ings, and has been found in the lungs of United States factory workers, especially where the plants had used the Canadian crude fiber in the past. A similar tremolite is quarried in Central Turkey, where it is used for stuccoing houses, causing huge calcified pleural plaques in both workers and house-dwellers, some of the houses even being "white-washed" inside as well as out. Tremolite contamination of the soil is widespread, and evidence of pleural plaqueing in agricultural workers has been found in Turkey,19 Greece,20 Bulgaria,21 Yugoslavia and Czechoslavakia, and more recently in Austria. Erionite In 1974, Professor Izzet Baris came to visit us to dem onstrate the radiographs of the case with large calcified pleural plaques which he had found in Central Turkey." I had previously written a paper for the Abbot Pharma ceutical firm on blue asbestos and mesotheliomas; pro duced in Ahhotlempo, with excellent illustrations, which had been translated into numerous languages including Turkish. I discussed the asbestos story with Baris and gave him the Turkish copy of the Abbottempo journal,22 after which he wrote a short article for a Turkish Medical Jour nal, which was taken up by several Turkish newspapers. Much to his surprise, Baris received a letter from the head man of the village of Karain in the Urgup region of Cap padocia, stating that he thought a similar tumor was oc curring in his villagers as had been described in South Africa. As is now well known,22 Baris went to investigate and discovered a horrifying situation with several villages in the area, including the town ofTuskoy, having the highest incidence of mesothelioma in the world. In Karain, with a population of 327 people older than age 20 years, during the last 5 years, 50 deaths have been recorded, 21 ofwhich were due to mesotheliomas, with a slightly lower rate in Tuskoy. There has been a great deal of controversy con cerning the origin of the tumors. One of my colleagues, J.W. Skidmore, joined the epidemiologic team in the val ley and collected dust samples which were analyzed by Fred Pooley, who found the presence of very fine fibers ofa zeolite fiber known as erionite, while Patrick Sebastien found this material in the sputum of people from the af flicted population' of one of the villages. Baris has obtained numerous biopsy specimens from these villages, but very I HWBUI0010761 1910 Cancer May 15 1986 Vo!. 57 few of these have associated lung tissue, although in two specimens, Pooley has found these fine erionite fibers which do not present in lung biopsy specimens from else where in Turkey. We were able.to collect the lungs of 40 sheep from various regions ofTurkey, and these fine fibers were only found in the animals which had come from the suspect villages, while coarse zeolite fibers were found in the lungs of Sheep from other sites in the Urgup Valley. In experimental studies of40 animals that we inoculated with the dust that Skidmore had obtained from the village of Karain,24 38 animals developed mesotheliomas. In many of the volcanic areas of the world, tuff containing zeolite fibers including erionite occur, but only in a few situations does the very fine erionite fiber occur, such as western states of Oregon, Nevada, and Utah. We obtained some of the Oregon erionite from Professor F. H. Mumpton of New York, which produced a 100% rate of me sotheliomas in the animals after inoculation. A similar rate of tumors was produced following inhalation, which is unique in our experience, for the highest rate we had previously produced by this technique was 10% with crocidolite. Dr. Allen Poole undertook in vitro studies with the Oregon erionite and showed it to be "the only fibrous dust we have so far examined which gives reproducible and unequivocal results in in vitro assays designed to detect genoioxicity,"55 Fortunately, the region where this fiber is found in Oregon is sparsely populated ranching country. Absorbent Clays Absorbent clays which are fibrous are used as oil ab sorbents in factories and garages, cat litter, and a "gelling" agent in drilling muds for the oil industry. During this last year, major industrial groups are considering further use for these materials. Our studies of the absorbent clays have led to detailed mineralogic-environmental-radiologic studies in Spain, together with experimental inves tigation at this Unit. Our human and animal investigations have been confined to the production of Sepiolite and Attapulgite in Spain. We have, however, carried out fiber sizing of attapulgite fibers from the United States, West Africa, and France. The main study with the Spanish fibers did not produce mesotheliomas following implantation, with the exception of one particular attapulgite fiber from a small mine in a village called Torrejon near Placentsia in the far western region of Spain. According to the pro ducers, this fiber has been used as a substitute for chrysotile, since it has an excellent gelling effect and has been used for "drilling muds" by several major oil companies, who have confirmed that they are mixed dry in enclosed chambers on the rigs, producing a very dusty atmosphere. Experimentally, when this material is implanted intrapleurally, it has produced nearly as many mesotheliomas as the contaminated chrysotile it is replacing. The Significance ofthe Selective Retention ofFibers At present, we are endeavoring to assess the significance of the selective retention offibers. We are convinced that the diseases associated with exposure to mineral fibers are due to the fibers that are retained in the lungs. If this hypothesis is correct, then the lungs are the. most impor tant dust samplers that are available for the recording of lifetime exposure of an individual. In the investigations that have been described, there are a number ofsituations in which the significant mineral or minerals retained in the lungs have either not been recorded or are a minimal fraction ofthe total dust sampling of the appropriate en vironmental or occupational atmosphere. This is partic ularly important in the chrysotile millers, who were found to have significant amounts of tremolite in their lungs, and again in the discovery of erionite fiber in lungs ofthe population in the Turkish villages. In view ofthe findings, it would appear that the analysis of the lung mineral con tent is essential when searching for a potential occupa tional hazard. By relying on environmental dust studies, it is possible to obtain results that may be misleading. The Chrysotile Factor Our view that chrysotile, ifuncontaminated, is probably a material causing little disease, is not accepted by many workers, although the number of converts is increasing. We have provided the major evidence for the innocence of chrysotile to humans, but our experiments suggested that chrysotile is both fibrogenetic26 and carcinogenitic.27'28 Dr. Pooley is now undertaking a major study into both original samples that we used in our studies and those fibers retained in the lungs, and preliminary results suggest that we were using contaminated fiber. It is obvious that the whole fate of chrysotile after in halation requires further study. We know ofcertain com mercial treatments which will straighten out the fiber, and that if chrysotile has been subjected to heat for long pe riods, it loses the coiled-woven configuration, while a search is being made to see ifthere is a source ofchrysotile that is free of contamination by other mineral fibers. The other possibility is for the industry to develop economic methods for the removal of these contaminants. Conclusions It is now established that the inhalation of all mineral fibers ofa specific diameter and length size range may be associated with the development of diffuse pleural and peritoneal mesotheliomas. Pulmonary fibrosis is asso ciated with the inhalation of mineral fibers which can be coarser than those involved in the development of me sotheliomas. In these situations, the importance of the selective retention offibers must be stressed. It is the fiber HWBUI0010762 No. 10 Mesothelioma and Mineral Fibers Wagner 1911 that is retained in the lung tissue that is responsible for the disease. Finally. I have not answered the question of the relative toxicity of the various asbestos fibers, but evidence points to exposure to the amphibolesTbr material containing amphibote, as being more hazardous than exposure to uncontaminated chrysolile fibers. REFERENCES 1. Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesotheliomas and asbestos exposure in the Northwestern Cape Province. BrJlndMed I960; 17, 260-271. 2. Sleggs CA, Marchand P, Wagner JC. Diffuse pleural mesotheliomas in South Africa. SAMJ 1961; 35:28-34. 3. Wagner JC. Asbestos dust and malignancy. Proceedings ofthe XIV International Congress of Occupational Health, Madrid. Amsterdam: Excerpta Medica. 1963; 3, 1066-1067. 4. Newhouse ML, Thompson H. Mesothelioma of pleural and peri toneum following exposure to asbestos in the London area. Br J Ind Med 1965: 22:261. 5. Wagner JC. Epidemiology ofdiffuse mesothclial tumours: Evidence ofan association from studies in South Africa and the United Kingdom. Ann NY Acad Sci 1965; 132:575, 578. 6. Selikoff IJ. Lung cancer and mesothelioma during prospective sur veillance of 1249 asbestos insulation workers. 1963-74. Ann NY Acad Sci 1976a: 271:448-456. 7. Report and Recommendations of the Working Group on Asbestos and Cancer, Appendix I. Ann NY Acad Sci 1965; 132:706-721. 8. Pooley FD. The identification or asbestos dust with an electron microscope Microprobe Analyser. Ann Occup H)g 1975; 18:181-186. 9. Pooley FD. The use of an analytical electron microscope in the analysis or mineral dusts. Pltil Trans R Soc (London) 1977; A286:625658. 10. Pooley FD. Wagner JC. The significance of the selective retention of mineral dusts. B.O.H.S. Sixth International Symposium on inhaled Particles. /Inn Hygiene (in press, 1986). 11. Wagner JC. Mineral fiber carcinogenesis. Chemical Carcinogens, vol. I. ACS Monograph 1984: 182:631-641. 12. McDonald AD. Biological effects of mineral fibres. In: Wagner JC. ed. Mineral Fiber Content of Lungs in Mesothelial Tumors: Prelim inary Report. Lyon: IARC 1980; 30:681-685. 13. Acheson ED, Gardner MJ. Asbestos, vol. 2. Papers prepared for the Advisory Committee. London: Health & Safety Commission, 1979; Her Majesty's Stationery Office. 14. Stanton MF. Wrench C. Mechanism of mesothelioma induction with asbestos and fibrous glass. J Natl Cancer Insi 1972;48:797-821. 15. Stamen MF, Layard M. Definitions and Measurements Methods. In: National Bureau of Standards Special Publication 506: Proceedings of the Workshop on Asbestos, July 18-20, 1977. Gaithersburg, MD: NBS, 1978. 16. Timbrel! V, Skidmore JW. Internationale Konfercnzc der Biologische Wirkungen des Asbestes Dresden. Holstein E, ed. Ouch Zentralinsl Abeiumed (Berlin) 1968; 52-56. 17. Wagner JC, Chamberlain M, Brown RC el at. Biological effects of tremolite. Br J Cancer 1981; 45:352. IS. Pooley FD. An examination of the fibrous mineral content of asbestos lung tissue from the Canadian Chrysotile Mining Industry. En viron Res 1976; 12:281. 19. Baris YI el al. An outbreak of pleural mesothelioma and chronic fibrosing pleurisy in the village of Karain/Urgup in Anatolia. Thorax 1978; 33:181. 20. Bazas T, Bazas B, Kitas D, Gilson JC, McDonald JC. Pleural calcification in North West Greece (Letter). Lancet 1981; 1:245. 21. Burilkov T, Michaelova L. Asbestos content of the soil and en demic pleural asbestosis. Environ Res 1970; 3:443-451. 22. Wagner JC. Asbestos and cancer. In: Richardson RG, ed. Abbotlempo, Book 3. Abbot Universal Ltd, 1968; 26-29. 23. Baris YI. Pleural mesotheliomas and asbestos pleurisies due to environmental asbestos exposure in Turkey: An analysis of 120 cases. Hacenepe Bulletin ofMedicine/Surgery. 1975; 8:165-185. 24. Wagner JC, Skidmore JW, Hill RJ, Griffiths DM. Erionite ex posure and mesotheliomas in rats. Br J Cancer 1985; 51:727-750. 25. Poole A, Brown RC, Turner CJ, Skidmore JW, Griffiths DM. In vitro gerotoxic activities of fibrous erionite. BrJ Cancer 1983; 47:697. 26. Wagner JC, Berry G, Skidmore JW, Timbrell V. The effects of the inhalation of asbestos in rats. BrJ Cancer 1974; 29:252-269. 27. Wagner JC, Berry G. Mesotheliomas in rats following inoculation with asbestos. BrJ Cancer 1969; 23:567-581. 28. Wagner JC. Berry G, Timbrell V. Mesolheliomata in rats after inoculation with asbestos and other materials. Br J Cancer 1973; 28: 173-185. i HWBUI0010763