Document 1ggrp0ezqpxZ6bdjmzdpyMKmo

PII: S0003-4878(01)00046-l Ama. occup. Vt 45, Mo. 7, pp. 15-518. 2001 2001 British Occupational Hygiene Society Published by Elsevier Science Ltd. All rights reserved Case-Referent Survey of Young Adults with Mesothelioma: I. Lung Fibre Analyses J. C. MCDONALD!*, B. G. ARMSTRONG!, C. W. EDWARDS!, A. R. GIBBSf, H. M. LLOYD?, F. D. POOLEY||, D. J. ROSSt and R. M. RUDD# tNational Heart and Lung Institute, Imperial College School d Medicine, London, UK; ^London School d Hygiene and Tropical Medicine, London, UK; Royal Orthopaedic Hospital, Birmingham, UK; \Uandough Hospital, Penarth, Wales, UK; ||University d Wales, Cardiff, Wales, UK; ffSt Bartholomew's Hospital, London, UK Objectives: Our study aimed to determine the lung tissue concentration of asbestos and other mineral fibres by type and length in persons with mesothelioma aged 50 yr or less at time of diagnosis, compared to controls of similar age and geographical region. In this age group it was thought that most, but not all, work-related exposures would have been since 1970, when the importation of crocidolite, but not amosite, was virtually eliminated. Methods: Eligible cases were sought from recent reports by chest physicians to the SWORD occupational disease surveillance scheme. Lung tissue samples were obtained at, autopsy from 69 male and four female cases, and mineral fibres identified, sized and counted by electron microscopy. Fibre concentrations per p-g dry tissue were compared with similar estimates from a control series of autopsies of sudden or accidental deaths. Unadjusted, and adjusted odds ratios calculated by logistic regression, assessed relative risk in relation to fibre type, length and concentration. Results: Unadjusted and adjusted odds ratios increased steadily with concentration of cro cidolite, amosite, tremolite and all amphiboles combined. There was also some increase with chrysotile, but well short of statistical significance, incremental risk examined in a linear model was as highly significant for all amphiboles together as individually. Short, medium and long amphibole fibres were all associated with increased risk in relation to length. Mullite and iron fibres were significant predictors of mesothelioma when considered without adjust ment for confounding by amphiboles, but, after adjustment, were weak and far from statisti cally significant. Conclusion: In this young age group, amosite and crocidolite fibres could account for about 80% of cases of mesothelioma, and tremolite for some 7%. The contribution of chrysotile, because of low biopersistence, cannot be reliably assessed at autopsy, but to the extent that tremolite is a valid marker, our results suggest that it was small. The steep linear trend in odds ratio shown by amphiboles combined indicates that their effects may be additive, with increased risk from the lowest detectable fibre level. Non-asbestos mineral fibres probably made no contribution to this disease. Contrary to expectation, however, some 90% of cases were in men who had started work before 1970; this was so whether or not amosite or crocidolite was found in lung tissue. 2001 British Occupational Hygiene Society. Published by Elsevier Science Ltd. All rights reserved Keywords: mesothelioma in young adults; occupation; lung fibre analysis INTRODUCTION Received 26 January 2001; in final form 14 April 2001. * Author to whom correspondence should be addressed. Tel.: 444-20-7351-8934; fax: 444-20-7351-8091; e-mail: c.mcdonald@ic.ac.uk The steady rise in mortality from mesothelioma in Britain since the 1950s, predicted to continue for some years to come, was investigated in the present study in persons, so far as possible, aged 50 yr or less at time of diagnosis. It was argued that the occu- 513 ALL-STATE LEGAL! HWBUI0010244 514 J. C. McDonald el at. pations and lung fibre content of these cases would mainly reflect exposure to asbestos since 1970, when the importation of crocidolite, but not amosite, was virtually eliminated. However, exposure to crocidolite would certainly have continued after that date, mainly as a result of asbestos removal and, as it later proved, almost all cases studied were in persons first employed before 1970. The investigation had two separate but related components. The first entailed identification of eli gible cases, followed by detailed recording of work histories and other relevant data. The second, which is the subject of this report, required collection of lung tissue samples taken at autopsy from as many of these cases as possible, together with similar samples for comparison from accidental or sudden cardiac deaths. Procedures used in the ascertainment of cases, rec ording of work histories and occupational analyses which foim the background for the present paper are described fully elsewhere (McDonald et at., 2001, this issue). Eligible cases were sought from reports by chest physicians to the SWORD national workrelated disease surveillance scheme and were obtained for 115 men and 13 women. Yeats spent by men in each occupation were compared with expected values from census data. Of 37 industrial occupations analysed, odds ratios were significantly raised in eight: five in the construction industry and the others in shipbuilding and the manufacture of cement and non-metallic mineral products. Only four of the women had been employed in any industrial occu pation; the remainder included four in office work, two in nursing, two in sales and one in teaching. METHODS Case and control selection Cases included in the occupational study were fol lowed so far as possible until the end of 1997, by which tifne most of the 115 men and 13 women with recorded work histories had died. Inquiry indicated that in 98 of these cases there had been an autopsy. The desirability of lung burden analysis with histo logical confirmation of diagnosis was discussed with the pathologists responsible and as a result, lung tissue and tumour samples were obtained from 69 male and four female cases. Histological review made independently by our two pathologists (CWE and ARG), both considerably experienced in the diagnosis of mesothelioma (Attanoos and Gibbs, 1997), con firmed that in all cases the diagnosis of mesothelioma was at least highly probable. So far as possible, lung tissue samples were obtained as referents from the same pathologists as the cases from accidental or sud den cardiac deaths of similar age, sex and region. As such cases were uncommon, this proved difficult, so the search was extended more widely. This resulted in a much larger number of samples,,but relatively few which met the criteria of age and region com pletely. Mineralfibre analysis The methods used for the preparation and electron- microscopic analysis of fibres in lung tissue have been fully described elsewhere (Gibbs and Pooley, 1996). hi summary, small pieces of tissue were obtained from different parts of the lung from either wet fixed specimens or paraffin wax blocks, depending on availability. The samples were weighed and then digested in 40% potassium hydroxide sol ution. A similar piece of lung tissue was weighed wet and dried to constant weight, in order to determine the wet to dry ratio. Tissue embedded in wax blocks was recovered using xylene and ethanol extraction, and then dried to constant weight before preparation. The digested tissue residues were washed, centri fuged, dispersed and then collected by filtration onto cyclopore filters (pore size 0.2 pm; diameter 25 mm). These were carbon coated, the filters dissolved in chloroform, and the carbon filters mounted into gold electronmicroscope support grids for transmission electron microscopy. Random areas of the grid were examined at a magnification of x22 000. Fibres were identified, counted and sized until 100 or more had been accumulated, or a specified level of detection (0.2 fibres per pg) had been exceeded. All fibrous structures with an aspect ratio of 3:1 or greater were analysed to ascertain their elemental composition using energy dispersion X-ray analysis. Statistical analysis The analysis was confined to 69 male cases, whose ages ranged from 36 to 52 yr. Of the 74 controls, 17 were aged five or more years outside this range and were excluded from further study, leaving 57 in all. The degree of matching by age and geographical region is shown in Table 1. To allow for residual con founding, conditional logistic regression was used to estimate the odds ratios, stratifying by the five age groups and regions shown. The distribution of cases and controls by category of lung fibre concentration -- 0 (none detected), 0.10.9, 1-9.9, 10-99.9,100+ fibres per jig --was tabu lated for each specific fibre type, for all amphiboles, all asbestos fibres and for seven other types of mineral fibre. Relative risks were estimated relative to the zero fibre concentration group. In order to allow for the effect of one fibre type when considering another, relative risks were also estimated, adjusting for other fibre types by including them simultaneously in the model. Models were also fitted which allowed for risk to vary continuously with exposure. Linear relative risk models were found to fit much better than the more commonly used log-linear models. For models including more than one fibre type, linear-additive 1 t HWBUI0010245 Controls Cases Controls Cases Lung fibre analyses of mesothelioma Table 1, Cases and controls included in analysis, by age group and region 36-39 2 2 40-44 13 16 Age 45-49 19 33 50-56 23 18 Total 57 69 Scot and N IS 13 NW and HE 16 14 Region Mid (E and N) 11 17 Wales and SW London, SE and Total E Anglia 10 5 57 9 16 69 515 models fitted much better than the more usual exponential-multiplicative. In these analyses, confi dence intervals were calculated using the likelihood profile method of Prentice and Mason (Prentice and Mason, 1986).The proportion of cases attributable to each fibre type was calculated from the linear model slope estimates according to the method described by Bruzzi (Bruzzi et a!., 1985). RESULTS Asbestos fibres The distribution in cases and controls (Table 2) shows substantially higher concentrations in cases of all asbestos fibres, all amphibotes, crocidolite, amosite and, although rarer, tremolite; cases also bad more chrysotile. Unadjusted odds ratios reflect these differ ences, with large values for all groups with concen trations of crocidolite, amosite and all amphiboles, increasing with concentration. The odds ratios for tremolite were also elevated, but imprecisely esti mated and of limited statistical significance. There were moderately elevated risks with chrysotile fibres, but the association fell well short of statistical sig nificance. The estimated increment in relative risk in the linear model was highest for crocidolite and, among amphiboles, lowest for tremolite, but with overlapping confidence intervals. Allowing for the effect of other fibre types on risk by entering ail four in the model proved difficult, as odds ratios became very unstable. Therefore Table 2 shows the estimates for each specific amphibole allowing for the effect of the other two, and for all amphiboles and chrysotile adjusting for each other. Mutually adjusted patterns remain broadly the same, but with differences between the three amphiboles Fibre type Table 2. Distribution of lung fibre concentrations with grouped and continuous odds ratios Concentration (per pg) Cases Controls Unadjusted OR Adjusted OR* Crocidolite Amosite Tremolite All amphiboles Chrysotile 0 0.1-0.9 I.0-9.9 10.0Linear model1' 0 0.1-0.9 i.0-9.9 10.0Linear model" 0 0.1-0.9 L0-9.9 10.0Linear model* 0 0.1-0.9 1.0-9.9 10.0Linear model*1 0 0.1-0.9 1.0-9.9 10.0- Linear model*' 28 27 U 3 13 23 26 7 55 13 1 0 6 26 28 9 14 28 26 1 48 1.0 1.0 8 5.3 (2.0-14.3) 4.6 (1.3-15.5) 1 17.5(2.0-155) 3.9 (0.3-40.4) 0 CO W 13.2 (3.3--44.5) 40.0 (2.6-388) 34 1.0 1.0 18 5.6 (1.6-18.8) 5.1 (1.4-18.6) 5 24.9 (5.7-108) 17.9(3.5-91.4) 0W W 11.4(2.8-49.2) 14.3 (2J2-! 13) 51 1.0 i.0 6 2.2 (0.9-6.6) 2.3 (0.7-8.0) 0- - 0- - 6.9 (0.2-30.9) 29.6 (CO-340) 28 1.0 L0 24 9.2 (1.9-44.5) 8.8 (1.8-43.5) 4 64.7 (9.8-425) 59.9 (9.0-400) 1 55.8 (3.9-792) - 19.4 (4.2-137) 47.6 (6.0->999) 19 1.0 1.0 21 1.5 (0.6-3.9) 1.9 (0.5-6.7) 16 2.2 (0.8-6.2) 2.2 (0.6-8.4) 1" " 0.1 .(<0--1.2) 2.2 (<0->999) "Crocidolite,amosite and tremolite are adjusted for each other. Total amphiboles and chrysotile are adjusted for each other. "Average increment in odds ratio per fibre/pg. HWBUI0010246 516 J. C. McDonald el al. Table 3. Estimates of fractions of cases attributable to each fibre type Fibre type Attributable fraction Unadjusted 95%CS Adjusted* CrocidoUte Amosite Tremolite Ah amphiboles Chrysotile 51% 70% 12% 86% 11% `Adjustments as for Table 2. (38-56) (57-77) (1-18) <74-91) ((M3) 33% 46% 7% 84% 11% well within the bounds of chance. The model with the three amphiboles included separately Fitted the data no better than the model combining amphiboles. Table 3 shows the estimated proportion of cases attributable to each fibre type. The confidence inter vals for these estimates reflect uncertainty in the rela tive risks, but not uncertainty in the selection of the cases. Confidence intervals for adjusted proportions are not shown, as they could not be calculated reliably. Although it is clear that a large majority of cases could be explained by the amphiboles including tremolite, as pure chrysotile fibres do not persist in lung tissue, their contribution is uncertain. The effect of amphibole fibre length is examined in Table 4 with odds ratios calculated for three ranges: <6, 6-10 and >10 pm. Shorter fibres were more abundantthan longer fibres, and as high concen trations of all fibre lengths tended to occur together (correlations from 0.6 to 0.9), discrimination was dif ficult Short, medium and long fibres were all associa ted with mesothelioma risk; those longer than 10pm had the greatest increment in risk per fibre, followed by medium (6-10 pm) and then by short (<6 pm), with coefficients of 417, 116 and 9, mutually adjusted. The difference between the coefficients was on the borderlines of conventional levels of statistical significance (likelihood ratio test =5.9 on 2 df, P - 0.05). Otherfibres Seven types of non-asbestos mineral fibres were identified in all but three of the 69 cases, and in all 57 controls. The detailed distributions are shown in Table 5. Muliite and iron were significant predictors of mesothelioma when considered without adjustment for the confounding effect of amphiboles, with which they were appreciably correlated (Spearman's rank correlation 0.28-0.43). After allowing for this con founding, the associations were weak and far from statistically significant. The remaining five fibre types showed little evidence of association with mesotheli oma, with or without adjustment for amphiboles. DISCUSSION The results of this study suggest that in the UK, a high proportion of deaths from mesothelioma in young men whose working lives began in the 1960s, and were predominantly in the 1910s or later, resulted from crocidolite or amosite exposure. Although risk per fibre was as high for tremolite as for other amphi boles, it was found less frequently, and so made little contribution to explaining the cases. As tremolite deposits often occur in proximity to chrysotile it can be considered a more biopersistentmarker for it Thus the low proportion of cases attributable to tremolite would also imply a low proportion attributable to chrysotile, though appreciably less than the 20% esti mated in a survey of predominantly much older cases across Canada some 20 years ago (McDonald et al., 1989). As had been observed in two previous studies (McDonald et al., 1989; Rogers et al., 1991), long fibres were associated with greater risk than shorter fibres, hut as all sizes were usually found together. Table 4. Distribution of amphibole fibre concentrations by length, ws'tii grouped and continuous odds ratios Kbre length Concentration (per pg) Cases Controls Unadjusted OR Adjusted OR* <6 pm 0 7 28 1.0 1.0 0.1-0.9 26 24 5.7 {IS--22-3) 4.1 (1.0-17.1) 1.0-9.9 29 4 41.9 (7.7-229) 13.4(2.2-82.9) 10.0- 7 1 33.6 (2.7-419) 3.6 (0.1-91.4) Linear model 13.4 (33-67.0) 9.3 (1.1-77.9) 6-10 pm 0 34 51 1.0 1.0 0.1-0.9 27 6 7.2 (2.4-21.1) 2.9 (0.8-10.4) 1.0-9.9 60 m m 10.0- 20 m m finear model 28.2 (7.1-106) 116(7.1->999) >10 pm 0 40 55 1.0 1.0 0.1-0.9 24 2 17.1 (3.6-81.9) 4.8 (0.8-27.6) 1.0-9.9 40 m m 10.0- 10 00 m linear model 70.9 (14.1-517) 417 (15.&-999) "One size traction adjusted far the other two. i HWBUI0010247 Mullite Controls Cases Iron Controls Cases Rutile Controls Cases Muscovite Controls Cases Silica Controls Cases Kaolin Controls Cases Alumina Controls Cases Lung fibre analyses of mesothelioma Table 5. Distribution of other fibres in cases and controls: details Concentration (per pg) 0 0.1-0.9 10-9.9 10.0- 1 8 37 u 1 7 24 34 20 29 7 1 8 37 21 0 12 34 11 _ U 39 16 20 30 7 - 26 24 16 - 20 29 8 _ 30 22 14 - 53 4 - 60 6 - - 51 2 4 0 58 7 O 1 S17 Total 57 66 57 66 57 66 57 66 57 66 57 66 57 66 the discriminationwas difficult. Risk; associated with amphibole concentration were close to linear and per haps independent of fibre type. Mineral fibres, other than asbestos, showed little or no evidence of a causal association. There is evidence, however, that there probably always has been a low background inci dence of mesothelioma in both men and women unre lated to asbestos (McDonald and McDonald, 1993). The adjusted fractions attributable to amphiboles (84%) and chrysotile (11%) do not take this into account, but still leave 5% unexplained (see Table 3). The clear-cut findings from this study, with their considerable implications for fibre carcinogenesis and the public health, although strongly supported by a large body of epidemiological data (McDonald and McDonald, 1996) and by a recent comprehensivestat istical analysis (Hodgson and Damton, 2000), must be examined nevertheless for the possibility of errors or bias. First there are questions of case and control selection. Probably not more than 70% of mesotheli-' oma cases in the UK are reported to SWORD and lung tissue was obtained for analysis from only some 60% of the eligible cases reported. Although conceiv able, we think it improbable that a chest physician's knowledge of a patient's exposure history might affect whether or not a case were reported, but not whether lung tissue at autopsy was later available for analysis. The selection of controls was certainly less than ideal, but without obvious bias in relation to the questions under investigation. More important is the fact that the electronmicroscopicanalyses were made, and results recorded, for tissue specimens, identified only by serial numbers unrelated to case/control status. The most serious and fundamental source of poten tial bias is the fact that mineral fibres vary in their biopersistence, and in particular that chrysotile is far less durable in lung tissue than crocidolite, amosite or tremolite. As a result, findings for chrysotile at autopsy will reflect recent exposures of little etiolog ical importance rather than those many years ago, whereas those for amphiboles will do the reverse. From animal studies it seems likely that carcinogenic ity results mainly from biopersistence (Sear! el ai,, 1999; Miller et al,, 1999a,b), and if this is the case the clearance of chrysotile does not invalidate the conclusions from fibre analysis. In humans the evi dence that durable agents are more carcinogenic is strong although indirect, consisting of extensive epid emiological evidence that exposure to suchbiopersistent agents as crocidolite, amosite, tremolite and erionite is followed by a far higher incidence of mesothelioma than occurs after chrysotile exposure (Hodgson and Damton, 2000). The farther indications that chrysotile as mined and milled and used commer cially is often contaminated with fibrous tremolite help to complete the picture. Tremolite fibres alone have been shown to carry a high risk of mesothelioma (McDonald et al., 1986) and that their level of con centration in the various chiysotile mines of Quebec is correlated with the incidence of this disease (McDonald and McDonald, 1997). Acknowledgements--This research was conducted with the help of chest physicians, pathologists and coronets throughout the United Kingdom, and was supported by grants from the Health and Safety Executive and die Wellcome Trust. HWBUI0010248 518 J. C. McDonald a of. REFERENCES Attanoos RL, Gibbs A*. Pathology of malignant mesotheli oma. Histopathology 1997;30:403-18. Bruzzi P, Green SB, Byar DP, Brinton LA, Schairer C. Esti mating the population attributable risk for multiple risk fac tors using case-control data. Am J Epidemiol 1985;122:904-14. Gibbs a1, Pooley FD. Analysis and interpretation of inorganic mineral particles in `lung'tissues. Thorax 1996;51:327-34. Hodgson JT, Damton A. The quantitative risks of mesotheli oma and lung cancer in relation to asbestos exposure. Ann Occup Hyg 2000;44(8):565-601. McDonald JC, Armstrong B, Case B, Doell D, McCaughey WTE, McDonald AD, Sibasticn P. Mesothelioma and asbes tos fibre type: evidence from lung tissue analysis. Cancer 1989;63:1544-7. McDonald JC, Edwards CW, Gibbs AR, Lloyd HM, Pooley FD, Ross DJ, Rudd RM Case-reSerent survey of young adults with mesothelioma: 1L occupational analyses. Ann Occ Hyg, 2001 ;45(7):5t9-23. McDonald JC, McDonald AD. Mesothelioma: is there a back ground? Eur Respir Rev 1993;3(l 1};71--3. McDonald JC, McDonaldAD. The epidemiology of mesotheli oma in historical context EurResp J 1996;9:1932-42. McDonald JC, McDonald AD. Chsysotile, tremofite and car cinogenicity. Ann Occup Hyg 1997;41:699-705. McDonald' JC, McDonald AD, Armstrong B, S&astien P. Cohort study of modality in vermiculite miners exposed to tremolite. Brit J hid Med 1986;43:436-44. Miller BG, Searl A Davis JMG, Donaldson K, Cullen RT, Bolton RE, Buchanan D, Soutar CA. Influence of fibre length, dissolution and biopersistence on the production of mesothelioma in the rat peritoneal cavity. Ann Occ Hyg 1999;43(3):153-66. Miller BG, Jones AD, Searl A, Buchanan D, Cullen RT, Soutar CA, Davis JMG, Donaldson K, Influence of characteristics of inhaled fibres on development of tumours in the rat lung. Ann Occ Hyg 1999;43(3): 167-79. Prentice RL, Mason MW. On the application of linear relative risk regression models. Biometrics 1986;42:109-20. Rogers AJ, Leigh J, Berry G, Ferguson DA, Mulder HB, Ackad M. Relationship between lung asbestos fibre type and con- . ? 7, centration and relative risk of mesothelioma: a case-control study. Cancer 1991;67:1912-20. j Searl A, Buchanan D, Cullen RT, Jones AD, Millet BG, Soutar 7' CA. Biopersistence and durability of nine mineral fibre types in rat lungs over 12 months. Ann Occ Hyg ' * M 1999;43(3):143--53. HWBUI0010249 IARC MONOGRAPHS PROGRAMME RE-EVALUATES CARCINOGENIC RISKS FROM AIRBORNE MAN MADE VITREOUS FIBRES A scientific working group of 19 experts from 11 countries convened by the Monographs Programme of the International Agency for Research on Cancer (IARC) has concluded its re-evaluation of the carcinogenic risk of airborne man-made vitreous fibres. Man-made vitreous fibres in the form of wools are widely used in thermal and acoustical insulation and in other manufactured products in Europe and North America. These products, including glass wool, rock (stone) wool, and slag wool, have been in use for decades and have been extensively studied to establish whether fibres that are released during manufacture, use, or removal of these products present a risk of cancer when inhaled. Epidemiologic studies published during the 15 years since the previous IARC Monographs review of these fibres in 1988 provide no evidence of increased risks of fung cancer or of mesothelioma (cancer of the lining of the body cavities) from occupational exposures during manufacture of these materials, and inadequate evidence overall of any cancer risk. Beside this, much industrial effort has gone into development of newer materials that have similar insulation properties to the older products, but which disappear from body tissues much more rapidly. The reason for this effort is that asbestos, a known human carcinogen which causes both mesothelioma and lung cancer and had been used as insulating material for several decades, is extremely slow to decompose and disappear from body tissues In which it has been deposited. This characteristic, known as high biopersistence, is correlated with the high carcinogenic potency of asbestos fibres. Some of these newer materials have now been tested for carcinogenicity and most are found to be non-carcinogenic, or to cause tumours in experimental animals only under very restricted conditions of exposure. The Monographs working group concluded that only the more biopersistent materials remain classified by IARC as possible human carcinogens (Group 2B). These include refractory ceramic fibres, which are used industrially as Insulation in hightemperature environments such as blast furnaces, and certain special-purpose glass wools not used as insulating materials. In contrast, the more commonly used vitreous fibre wools including insulation glass wool, rock (stone) wool and slag wool are now considered not classifiable as to carcinogenicity to humans (Group 3). Continuous glass filaments, which are used principally to reinforce plastics, are also considered not classifiable as to carcinogenicity to humans. For further details of the Monographs evaluation, consult http://monoqraohs.iarc.fr. under "Agents most recently evaluated," or Inquire by e-mail to grosseffiiarc.fr. For further details of current research at IARC on man-made vitreous fibres, inquire by e-mail to boffettaigiarc.fr. For more general information, contact Dr Nicolas Gaudin, Chief, Communications (qaudin@iarc.fr). http://www.iarc.fr/pagcroot/PRELEASES/prl37a.litiTil 25/10/2001