Document NGJ3LK0dRm84xLxn7LB2g0vmE

PLAINTIFF'S EXHIBIT /- ENVIRONMENTAL FACTS/Asbestos ST0307036 Report of the Advisory Committee on Asbestos Cancers To the Director of the International Agency for Research on Cancer 'October 6,1972 ! A meeting of scientists comprising the majority of those from all over the world now I actively working in the general field of the biological effects of asbestos, was held in Lyon, | France at the International Agency for Research On Cancer (IARQ, October 5 and 6,1972. I This scientific group, established as an Advisory Committee to the Director of IARC, consisted of three panels - Epidemiology, Pathology, Physics and Chemistry. The panels ' first met in separate sessions and at the final collective session, Chairman Dr. f. C. Gilson ; prepared this report to the Director of IARC: TERMS OF REFERENCE 1. The Committee was to report on the present evidence relating exposure to asbestos dust to cancers, especially that obtained since the ' meeting of the UICC Working Group on Asbestos ; Cancers in 1964. ; 2. The Committee was to make recommenda; tions for further research and indicate priorities . for work of immediate and long-term value. CO-ORDINATION OF INTERNATIONAL i CO-OPERATION Following the meeting of the UICC Working Group on Asbestos and Cancers in 1964, a Sub committee of the UICC Commission on Geographical Pathology and Environmental Carcinogens (Chairman Dr. J. Higginson) was formed to co-ordinate work required to achieve the recommendations. In April 1970 agreements between the UICC and the IARC led to the winding up of the UICC Sub-Committee and the IARC taking on responsi bility for the Sub-Committee's work and extend ing it by supporting certain projects on asbestos cancers in several countries. The Agency has done this as part of their wider programme of in vestigating environmental carcinogens. Common memberships between the UICC Sub-Committee and the Committee advising the IARC ensured continuity of policy. In October 1972 the IARC held an international conference with 137 participants from twenty countries to review all the evidence relating asbestos with cancers. Subsequently the Advisory Committee prepared its report. This is divided into two sections. First, a general review in the form of answers to a number of important general questions about the relation of asbestos to cancers of different sites and, secondly, recommendations for further research. GENERAL REVIEW 1. Are all major commercial types of asbestos able to cause lung carcinoma? Yes. Since 1964 the evidence of a casual rela tionship has been increased by epidemiological studies showing exposure-response relations for the incidence oflungcarcinomas. The production of lung carcinomas in certain animals by all types of asbestos supports this conclusion. The epidemiological evidence in man, however, shows that there are clear differences in risk with type of fibre and nature of exposure. 2. Is there evidence of an increased risk of lung carcinoma at low levels of exposure to asbestos, such as have been encountered by the general population in urban areas? i CTfnn7fm Jofcnl-M**** ENVIRONMENTAL FACTS/Asbestos T0307037 The evidence of an exposure-response rela tionship based in part on past dust measurements and in pan on the type of job within the industry suggests that an excess lung carcinoma risk is not detectable when the occupational exposure has been low. These low occupational exposures have almost certainly been much greater than that to the public from general air pollution. 3. Since 1964 has the evidence relating past exposure to asbestos and mesotheliomas changed? The evidence has been greatly strengthened by further prospective and retrospective mortality studies in many countries of populations exposed to asbestos. There is evidence that all commercial types of asbestos except anthophyllite may be responsible. Evidence for an important difference in risk in different occupations and with the type of asbestos has increased. The risk is greatest with crocidolite, less with amosite and apparently less with chrysotile. With amosite and chrysolite there appears to be a higher risk in manufac turing than in mining and milling. There is also evidence from population studies that a propor tion of cases of mesothelioma have no known association with exposure to asbestos. 4. Is there evidence of an increased risk of mesotheiial cancers at low levels of exposure to asbestos, such as have been encountered by the general population in urban areas? There is evidence of an association of mesothe iial tumors with air pollution in the neighbor hood of crocidolite mines and of factories using mixtures of asbestos fibre types. The evidence relates to conditions many years ago. There is evidence of no excess risk of mesotheliomas from asbestos air pollution which has existed in the neighborhood of chrysotile and amosite mines. There are reported differences on incidence of mesothelioma between urban and rural areas, the causes of which have not been established. There is no evidence of a risk to the general public at present. 5. Since 1964 has the evidence changed on the importance of other factors such as cigarette smoking, waxes, oils and trace elements as con tributory factors to the cancer risk? 2 The evidence has accumu/ated indicating: a. Cigarette smoking is an important factor enhancing the lung carcinoma risk in asbestos-exposed workers, in both men and women. Asbestos workers have specially strong grounds for giving up smoking to protect their health. No association has been demonstrated between cigarette smoking and mesotheliomas. b. Animal experiments designed thus far to lest the importance of waxes and oils as contributory factors in the production of mesothelioma have shown these contami nants are unlikely to be relevant. c. From animal experiments there are no good clues suggesting that trace elements are likely to be a major factor in the production of asbestos cancers. 6. What other types of cancer are related to exposure to asbestos? Prospective surveys of occupational groups exposed to asbestos have in general shown a small excess risk of some other types of cancers (in addition to bronchial and mesotheiial), especially those of the gastro-inteslinal tract. The excess of these tumors is relatively small com pared with that for bronchial cancer. Evidence for an association with ovarian tumors has not been supported by the first large mortality survey of women previously exposed to asbestos. 7. Is there evidence of an increased risk of can cer resulting from asbestos fibres present in water, beverages, food or in the fluids used for the administration of drugs? Such evidence as there is does not indicate any risk. 8. Is there evidence of a risk of king fibrosis from low levels of exposure to asbestos such as have been encountered by the general popula tion in urban areas? There is at present no evidence of lung damage by asbestos to the general public. The amount of asbestos in the lungs of members of the general public is very small, compared to those occupa tionally exposed. It is greatest where asbestos is mined or worked and lowest in rural areas. Jolwv-tibftrtta mENVIRONMENTAL FACTS/Asbestos ST0307038 9. Has the relationship between asbestos expo sure and the development of pleural plaques been established? Pleural plaques have been associated with past exposure to all commercial types of asbestos. But additional factors, other than asbestos itself, are involved. The plaques may remain fibrous or become calcified. Not all pleural plaques are associated with asbestos. RECOMMENDATIONS FOR FURTHER RESEARCH Projects which the Panels rated high in priority are marked *; those which will require close co-operation between the Panels are marked f. EPIDEMIOLOGY The Panel agreed that asbestos related cancers occur in several sites in the body. The incidence of the different cancers varies with a number of definable factors and for other reasons, such as competing causes of death. Epidemiological studies will usually provide information on more than one type of cancer. Research directed at only a single type may, on occasions, be useful but in general the inevitable uncertainties, in some cases in the differential diagnosis of, for example, peripheral lung carcinomas and pleural mesothe liomas, and between peritoneal mesotheliomas and other intra-abdominal cancers will require that more than one type is studied at the same time. The Panel recognized that some of the epidemiological projects could only be pursued if there was close co-operation between epidemiologists, pathologists, physicists and chemists, and others, because their success will depend upon the development of improved techniques, some of which are referred to in the recommendations of the other two Panels. Projects 1. Further development of objective methods for early detection and surveillance of effects caused by asbestos. Topics for particular study include: a. Immunological techniques for screening for fibrosis and neoplasia. b. Functional tests of changes in the peripheral airways. c. Detection of pleural thickening. d. Assessment of the specificity of small irreg ular opacities in the chest radiograph as defined in ILO UIC Classification (1971 f. e. Tests of the usefulness of different tech niques of chest radiography, including the use of 100 mm. films. f. Development of statistical procedures for analysis and presentation of serial observations. 2. Evaluation of the usefulness of early detection in the prevention of progressive fibrosis and asbestos cancers, also in the identification of hazardous conditions. Routine health sur veillance of industrial populations should be designed to assist epidemiological studies, and should include measurement and recording of environmental dust levels. Surveillance of new entrants could be particularly valuable. Arrange ments should be made to register workers so that their morbidity and mortality experience can be studied even after cessation of exposure to asbestos. 3. Assessment of excess cancer risks following exposure to only one type of fibre. a. Chrysotile: The much higher cancer risk reported (or chrysotile textile workers com pared with mine and mill workers requires explanation. How much is explicable by differences in size of airborne fibres and past dustiness f There is need to make more use of past dust records for relating to in dices of disease. b. Amosite: The excess lung carcinoma and mesothelioma risk is apparently much greater in the manufacturing and applica tion sections of the industry than in the mining and milling of this type of fibre. What are the important factors in this re ported difference! c. Crocidolite: Further studies are required in occupational groups exposed only to crocidolite or amosite or chrysotile in manu facturing and application parts of the in dustry to establish more clearly differences in risks due to different fibres. 3 QTfnn'7m 8J31 ENVIRONMENTAL FACTS/Asbestos ST0307039 4. Studies of the amount and type of asbestos in the lungs of cases of mesotheliomas (if possible by cell type) in (a) national survey of mesothe liomas, (b) representative samples of cases arising in groups with a definable past exposure. 5. Studies of secular changes in incidence of pleural and peritoneal mesotheliomas nationally and internationally. 1964 UICC recommendations. It was agreed that considerable progress had been made on the majority of the recommendations. Some require further study, or modification of previous methods of investigation; these are included in the list of recommendations that follows. The recommenda tions are divided into three categories; morbidity anatomy and histology, clinical research, and experimental studies. 6. Epidemiological studies to investigate the association between past exposure to asbestos and cancer of sites other than lung, pleura, and peritoneum. 7. Studies of secular trends in the asbestos con tent of the lungs in the general population. PROJECTS Morbid Anatomy and Histology 1. Asbestosis * a. Further consideration should be given to methods for determining the amounts, types and structural features of asbestos in tissue. A Sub-Committee should be established with 8. Studies to relate amount and type of asbestos in the lung and estimates of past dust exposure and interval since last exposure. members of the Physics and Chemistry Panel, and others to accelerate work on this problem, b. The methods for assessing ihe severity of asbestosis (See Paper 9) should be tested for 9. Experimental and epidemiological studies to consistency by different observers. investigate possible differences of effect of con tinuous low and intermittent high exposure to asbestos. 2. Carcinoma *f a. An investigation of whether reduction of asbestos exposure to levels below those pro 10. Opportunities afforded by intercurrent deaths should be used to interrelate radiographic appearances, lung pathology, respiratory func tion, dust content, and type in asbestos workers. Standardized techniques and classification recommended by the Panels should be used. 11. Investigate the prognostic significance and aeliological factors in the development of ducing asbestosis also abolishes excess risk of carcinoma was considered important, b. A comparison of lung carcinomas in per sons occupationally exposed to asbestos and those not so exposed, including both cigarette smokers and non-smokers, in respect of sites of origin and cytology of tumors and presence or absence of asbestosis, would be of value. I calcified and uncalcified pleural plaques in 3. Mesotheliomas different environments. a. The International Panel of Pathologists' and 12. Investigate talc-exposed groups in mining and manufacturing to establish any differences in morbidity or mortality which might be related to the amount and shape of the fine respirable particles. National Panels established following the 1964 meeting3 have served a useful purpose. It is recommended that panels be established in other countries and membership of the Inter national Panel be extended. The main purpose of these Panels is to ensure uniformity of 13. Development of cost/benefit analyses to study the health, safety, social and economic interrelations of ihe use of asbestos. PATHOLOGY AND EXPERIMENTAL PATHOLOCY diagnostic criteria and recording of his tological types of diffuse mesotheliomas. 'The International Panel consists oI: Di. M. Kanncrstein (USAI, Prof. D. Manner ICanadal, Dr L. Meurman (Finland!, Prof- W. T. f. McCaughey (Eire). Prof. Ft. Otto (FRCl, Dr Ft. Piamevtll (Netherlands). Dr. E. Roil/sch IGDR), Prof. I Sanh fltafyl. Prof I. Webster (Sooth Africa), and Dr. 1. C. Wagner tuto as Secretary. The Panel reviewed the progress made on the 'Creai Britain, South Africa. United Stales, Canada, Netherlands. 4 CTfnmoTo Jotas-Mtnwi* ENVIRONMENTAL FACTS/Asbestos I ST0307040 Collaborative study of histology slides in National Panels is recommended. The diag nosis of mesothelioma can be made by ex foliative cytology of the pleural fluid. If the cytological diagnosis is made by a competent cylologist, biopsy may be unnecessary, b. To improve consistency of diagnosis there is an urgent need for a Comprehensive Atlas on mesotheliomas, or alternatively, for inclusion of an enlarged section on mesothe liomas in the new edition of the WHO Mono graph on Tumors of the Lung. Criteria for diagnosis by exfoliative cytology and a description of the fine structure of meso theliomas should be included. Clinical Research 1. Monitoring by immunological methods of populations exposed to asbestos should be investigated to ascertain whether it is possible to recognize those who are developing, or will develop, tumors. 2. The use of chromatographic methods for the study of mucopolysaccharides and other tumor-associated substances in pleural fluids should be explored. Sensitive methods might be developed and applied to identify secretory products of mesotheliomas in blood and urine. Further Experimental Studies * 1. Information is required about the role of fine particles, especially influence of fibre size, in the induction of tumors. These studies should be extended to include fibres other than asbestos. A Sub-Commiltee should be established to review the need for, and arrange the distribution of standard samples of asbestos and other fibres in addition to the UICC Ref erence Samples. 2. The fate of inhaled particles of various sizes, shapes and chemical compositions, should be studied to determine more precisely the quantities and sites of initial deposition, change within the body and later retention. The feasibility of increasing fibre elimination by various methods should be explored. Studies should be made of means of reducing the fibrogcnicity and carcinogenicity of fibres already retained in the lungs. 3. The use of cell and organ culture, including mesothelial tissue from man and other species, should be further investigated with a view to developing methods of screening dusts for fibrogenic and carcinogenic properties. 4. Further studies should be carried out to de termine the nature of the combined effect of tumor induction when animals are exposed to asbestos dust and cigarette smoke, metals or other chemical carcinogens, including those which act systemically such as nitrosamines. 5. Inhalation experiments should be extended to test various types of fibre; of special interest are forms of chrysotile and crocidolite in cluding the finer grade materials. 6. It was felt that studies of the pathological effects of asbestos on species other than rodents would be of value. 7. The effect of long-term ingestion of fibres of various sizes, shapes and chemical com positions should be studied. 8. The effects of fibres and associated metals on the metabolism of target organs should be investigated. PHYSICS AND CHEMISTRY The Panel reviewed the progress made on the 1964 UICC Recommendations. The proposals for the preparation and characterization of the UICC Reference Samples of asbestos had been satis factorily implemented, and the Panel re commended that a list of references to papers featuring the samples should be distributed to investigators in this field. Considerable progress had been made on methods of identifying the type of fibre in tissues but a quantitative method when several types of fibres were present had yet to be developed. The Panel discussed the further contribution that physical and chemical studies can make to research on the biological effects of asbestos and other fibrous materials. Of especial interest are the effects of fibre size and shape on the retention of material in the lungs, the site of deposition, the migration of fibres within the body, and their carcinogenic or other biological activity. The following recommendations were made: 5 ' ST030704I U3I ENVIRONMENTAL FACTS/Asbestos PROJECTS 1. Materials for experimental work a. Supplies of asbestos from relevant sources should be obtained where there is evidence of variation in geological form, trace element content or significant biological findings. b. Small samples of various fibrous materials should be prepared for studies on the influence of fibre size and shape on carcinogenicity. For ihis purpose the samples should be milled to different degrees of fineness. c. For investigations on the influence of particle shape and size, on the inhalation and subsequent fate of asbestos fibres a chrysotile and an amphibole of fibre length greater than the UICC samples should be prepared. *12. Methods a. There is an urgent need for the quantitative assessment, size analysis and characterization of particles and fibres in the lungs and other organs. Details of available methods should be circulated, international comparisons under taken, methods standardized and new tech niques developed. b. No methods are at present available for the preparation of fibres in narrow ranges of diameter and length in sufficient quantities for inoculation experiments. Techniques for these purposes are urgently required, especially in view of the advantages such graded samples could provide for investigating the influence of these physical factors on the carcinogenicity of fibres of different materials. c. Since the degree of dispersion of fibres (especially chrysotile) used in inoculation studies may have a marked influence on their carcinogenicity, methods are required for quantifying dispersion. d. Inhalation studies require precise control of the characteristics of the dust clouds. Improved methods of dispensing fibrous dusts in such investigations need to be developed. e. Methods are available for collecting the important size fractions of dust clouds in in halation studies when the particles are of com pact shape. Similar methods must be de veloped for fibrous particles. f. The present membrane filter methods of measuring the levels of airborne asbestos dust require standardization. This should be done by inter-laboratory trials on a continuing basis. Particle counting by electron microscopy should also be developed. Gravimetric assess ment methods and the automation of particle counting should be explored. 3. Inhalation Studies Considerable information is now available on the deposition, retention and migration of parti cles of compact shape. Recently developed methods, especially radio-active tracer tech niques, should be used to obtain similar knowledge for fibrous particles. This information is needed to identify the biologically important size fraction and to help interpretation of epidemiological and pathological studies. 4. Occupational and Environmental Studies The use of both fibre counts and gravimetric methods for assessing asbestos dust concentra tions should be encouraged. Data collected over an extended period will be particularly valuable in identifying the parameters of the dust which can be correlated with epidemiological evidence on the health hazard. 5. Physics and Chemistry Panel It is recommended that an international Panel be established to assist in implementing these recommendations. The Panel would periodically review requirements for materials for experi mental work; provide guidance on physical and chemical problems; and arrange national and international standardization trials. b <5Tfnn7nii ST0307042 ENVIRONMENTAL FACTS/Asbestos I ADVISORY COMMITTEE Epidemiology Panel Dr. M. Becklako, McGill University, Department of | Epidemiology and Health, 3775 University Street, Montreal \ 110, Quebec, Canada. Dr. H. Bohllg, Municipal Hospital Ludenscbeid, 588 Ludcnscheid, Germany. Dr. N. Day, International Agency for Research on Cancer, ; Unit of Epidemiology and Biostatistics, 150 Cours Albert I Thomas, 69008 lyon. Trance. Prof. P. C. Elmet, Queen's University of Belfast, Depart ment of Therapeutics and Pharmacology, InstituteofClinical Science, Grosvenor Road, Belfast BTI2 68/, N. Ireland, UK. Dr. J. C. Gilson, Medical Research Council, Pneumoconio sis Unit, Llandough Hospital, Penarth, Glamorgan, Wales, UK. (Chairman). Dr. J. Lepoutre, S. A. Eternit, Medical Department, 2920 Kapelle-op-den-Bos, Belgium. Prof. |. C. McDonald, McGill University, Department of Epidemiology and Health, 3775 University Street, Montreal HO, Quebec, Canada. Mr. C. E. Rosslter, Medical Research Council, Pncumoco| niosisUnit, Llandough Hospital, Penarth, Glamorgan, Wales, UK. Dr. H. Sakabe, Ministry of Labor, Department of Industrial Physiology, National Institute of Industrial Health, 2051 Kizukisumiyoshicho, Kawasaki, lapan. Dr. 1.1. Selikoff, Mount Sinai School of Medicine, Environ mental Sciences Laboratory, 100th Street and Fifth Avenue, New York, N Y. 10029, USA. Dr. C. K. Sluis-Cremer, South African Medical Research Council, National Research Institute of Occupational Diseases, P.O Box 4788, lohannesburg. South Africa. Dr. W. Smither, British Asbestos Research Council, 114 Park Street, London W1Y 4AB, England. Dr. G. Wright, Head, Department of Medical Research, St. Luke's Hosp. 11311 Shaker Blvd., Cleveland, Ohio 44101, USA. unable to attend ; Pathology Panel Dr. A. C. Allison, Medical Research Council, Clinical Re search Centre, Watford Road, Harrow, Middlesex HA1 3UI, England, UK. Mr. G. Berry, Medical Research Council, Pneumoconiosis Unit, Llandough Hospital, Penarth, Glamorgan, Wales, UK. Dr. P. Bogovski, International Agency for Research on Cancer, Unit of Environmental Carcinogens. ISO Cours Albert Thomas, l yon 69008, France. Dr. M. Kannerslein, Barnert Memorial Hospital Centre, Pathology Dept., 680 Broadway, Paterson, N.l. 07514, USA. Prof. W. T. E. McCaughey, Trinity College School of Path ology, University of Dublin, Dublin 2, Eire. Prof. D. Magner, Canadian Tumor Reference Centre, De partment of Pathology, University of Ottawa, Ottawa. Ontario, KIN 6N5, Canada. Prof. H. Otto, Direktor des Pathologischen Instituts der 5tadt Krankenanstalten, Beurhausstrasse 40, 46 Dortmund, W. Germany. Dr. H. T. Planteydt, Stichting Streeklaboratorium "Zeeland," Noorpoortplein 2, Middelburg, The Netherlands. Dr. M. Stanton, National Institute of Health, Department of Health, Education and Welfare, Belhesda, Md. 20014, USA. Dr. J. C. Wagner, Medical Research Council, Pneumo coniosis Unit, Llandough Hospital, Penarth, Glamorgan, Wales, UK (Chairman). Prof. S. Watanabe, National Cancer Centre, Department of Pathology, Research Institute, Tsukiji, 5-1-1, Chome Chu-ku, Tokyo, lapan. Prof, I. Webster, Medical Research Council South Africa, National Research Institute for Occupational Diseases, P.O. Box 4788. lohannesburg. South Africa. Physics and Chemistry Panel Dr. L. Le Bouffant, Centre d'Etudes et de Recherches des Charbonnagcs de France, Verneuil-en-Hallatte, B.P. No 27, 60550 Creil, France. Mr. G. W. Gibbs, McGill University, Department of Epidemiology and Health, 3775 University Street, Montreal HO, Quebec, Canada. Dr. S. Holmes, Asbestos's Research Council, do Turner Bros. Asbestos Co. Ltd., P.O. Box 40, Rochdale, England, UK. Mr. A. Morgan, Atomic Energy Research Establishment, Health Physics and Medical Division, Building 364, Harwell, Didcol, Berkshire, England, UK. Dr. F. D. Pooley, University College of S. Wales and Monmouthshire, Department of Mineral Exploitation, New port Road, Cardiff, Wales, UK. Dr. S. Spell, lohns-Manville Research and Engineering Centre, Greenwood Plaza, Denver, Colorado, USA. Dr. V. Timbrell, Medical Research Council, Pneumoconio sis Unit, Llandough Hospital, Penarth, Glamorgan, Wales, UK. Dr. R. S. du Toit, Government Mining Engineer's Divi sion, Department of Mines, P.O. Box 1132, lohannesburg, South Africa. Mr. W. H. Walton, Institute of Occupational Medicine, Roxburgh Place, Edinburgh EH8 9SU, Scotland, UK. (Chairman). 7 Reprinted by permission of IARC. For further information on this subject please contact: Environmental Affairs Department Johns-Manville Greenwood Plara t Denver, CO R0217 f* le-v* Prrtw n USA <5T0^ft70d^ ST0301043