Applying definitions of "asbestos" to environmental and "low-dose" exposure levels and health effects, particularly malignant mesothelioma.

Although asbestos research has been ongoing for decades, this increased knowledge has not led to consensus in many areas of the field. Two such areas of controversy include the specific definitions of asbestos, and limitations in understanding exposure-response relationships for various asbestos types and exposure levels and disease. This document reviews the current regulatory and mineralogical definitions and how variability in these definitions has led to difficulties in the discussion and comparison of both experimental laboratory and human epidemiological studies for asbestos. This review also examines the issues of exposure measurement in both animal and human studies, and discusses the impact of these issues on determination of cause for asbestos-related diseases. Limitations include the lack of detailed characterization and limited quantification of the fibers in most studies. Associated data gaps and research needs are also enumerated in this review.

Lung fibre burden in lung cancer cases employed in the rock and slag wool industry.

OBJECTIVES: To evaluate the relationship between estimated exposure to man-made vitreous fibres (MMVF) and to asbestos fibres and their concentration in the lung tissue of lung cancer cases amongst MMVF production workers. METHODS: Retrospective retrieval of available lung tissue specimens was conducted following a case-control study that assessed estimated occupational exposures of MMVF workers. Fibre recovery and analysis by transmission electron microscopy (TEM) were conducted to determine fibre type, fibre dimension and numbers per gram of dry lung tissue. For cases with detailed exposure data, geometric mean (GM) concentrations were compared across the exposure categories, and regression models were used to investigate the relationship between the lung fibres and the variables of estimated exposure, with and without additional variables that may affect fibre retention. RESULTS: A total of 24 samples from 17 cases of lung cancer were available for analysis: MMVF were detected in all cases. Asbestos fibres were detected in 16. No difference or trend in GM MMVF concentration was observed across the estimated exposure categories. Odds ratio (OR) for MMVF g(-1) dry lung was 0.5 (95% confidence interval: 0.1-2.4) for the second, and 3.5 (0.6-18.9) for the third quartile of index of average exposure to MMVF in industry, compared with the first (lowest exposed) quartile (no cases in the highest quartile). CONCLUSIONS: No observable relationship existed between estimated exposure and directly-measured lung fibres among this sample of cases. Retrospective specimen collection, intra-individual variability in fibre concentration, effect of unknown factors on fibre retention and small sample size militated against this study providing evidence for or against a relationship between estimated exposure and lung fibre concentrations.

Pulmonary epithelial response in the rat lung to instilled Montserrat respirable dusts and their major mineral components.

BACKGROUND: The Soufriere Hills, a stratovolcano on Montserrat, started erupting in July 1995, producing volcanic ash, both from dome collapse pyroclastic flows and phreatic explosions. The eruptions/ash resuspension result in high concentrations of suspended particulate matter in the atmosphere, which includes cristobalite, a mineral implicated in respiratory disorders. AIMS: To conduct toxicological studies on characterised samples of ash, together with major components of the dust mixture (anorthite, cristobalite), and a bioreactive mineral control (DQ12 quartz). METHODS: Rats were challenged with a single mass (1 mg) dose of particles via intratracheal instillation and groups sacrificed at one, three, and nine weeks. Acute bioreactivity of the particles was assessed by increases in lung permeability and inflammation, changes in epithelial cell markers, and increase in the size of bronchothoracic lymph nodes. RESULTS: Data indicated that respirable ash derived from pyroclastic flows (20.1% cristobalite) or phreatic explosion (8.6% cristobalite) had minimal bioreactivity in the lung. Anorthite showed low bioreactivity, in contrast to pure cristobalite, which showed progressive increases in lung damage. CONCLUSION: Results suggests that either the percentage mass of cristobalite particles present in Montserrat ash was not sufficient as a catalyst in the lung environment, or its surface reactivity was masked by the non-reactive volcanic glass components during the process of ash formation.

Case-referent survey of young adults with mesothelioma: I. Lung fibre analyses.

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 microg 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 crocidolite, 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 adjustment for confounding by amphiboles, but, after adjustment, were weak and far from statistically significant. CONCLUSIONS: 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.

Case-referent survey of young adults with mesothelioma: II. Occupational analyses.

OBJECTIVES: Our study aimed to identify occupations at increased risk of developing mesothelioma in persons aged 50 yr or less, and to relate these occupations to lung tissue concentration of asbestos fibres by type. 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. Work histories were obtained for 115 men and 13 women, usually with the help of the chest physicians or coroners. Jobs were coded by the Office of National Statistics, so that the observed years spent in each occupation could be compared with expected values from census data, 1960-90. Lung tissue samples were obtained at autopsy from 69 male and four female cases, and mineral fibres identified, sized and counted by electron microscopy. RESULTS: Of 37 industrial occupations analysed, odds ratios were significantly raised in eight: five in the construction industry and the others in shipbuilding, the manufacture of cement products and the manufacture of non-metallic mineral products (including asbestos). The concentrations in lung of crocidolite and amosite fibres, which together could account for 80-90% of cases, did not differ between occupational categories; those for amosite were appreciably higher than for crocidolite. Tremolite fibres were rarely found. CONCLUSION: Mesothelioma in this young age group is dominated by carpenters, plumbers, electricians and insulators in the construction industry, and is mainly attributable to amphibole exposure. Work in shipbuilding and manufacture of mineral products was less important than in earlier studies. Contrary to expectation, however, some 90% of cases were in men who had started work before 1970.

Asbestos lung fibre concentrations in South African chrysotile mine workers.

Mesothelioma has not been found in South African chrysotile miners and millers despite decades of producing about 100000 tons of the mineral per year. One possible explanation for the scarcity or absence of the cancer may be a relative lack of contaminating fibrous tremolite, an amphibole that variably occurs with chrysotile ores. The fibre content in the lungs of nine former chrysotile mine workers was ascertained by transmission electron microscopy. Despite fairly long service in most cases (median 9.5 yr; range 32-4 yr) the concentrations of chrysotile fibres were relatively low: only two cases exceeded 1.14 million fibres/g dried lung. Tremolite fibre levels were even lower: less than 1 million fibres/g dried lung in all but one case. Tremolite fibre concentrations exceeded those of chrysotile in only two cases. These results support the contention that South African chrysotile is not heavily contaminated by tremolite.

Malignant vascular tumours of the pleura in "asbestos" workers and endothelial differentiation in malignant mesothelioma.

BACKGROUND: Three cases of diffuse malignant vascular tumours of the pleura are described which mimicked malignant mesothelioma clinically and pathologically (so called "pseudomesothelioma"). All had occupational histories of exposure to asbestos. The relationship of these tumours to mesothelioma and asbestos exposure is discussed. METHODS: To examine the histogenetic relationship between mesothelioma and these three tumours an immunohistochemical analysis of vascular marker (CD31, CD34, and Von Willebrand factor) expression was undertaken in 92 cases of pleural mesothelioma, in addition to these three tumours. Electron microscopic fibre analysis of lung tissue was performed on each of the three cases to assess asbestos fibre content. RESULTS: Diffuse pleural epithelioid haemangioendotheliomas may closely resemble malignant mesothelioma clinically and pathologically but, of the 92 pleural mesotheliomas tested, none showed expression of CD31, CD34, and Von Willebrand factor. Although all three cases had claimed exposure to asbestos, ferruginous bodies typical of asbestos were only seen by light microscopy in case 2, and only in this subject was the asbestos fibre content raised in comparison with the range seen in a non-exposed background population. The latent period in the pleural epithelioid haemangioendotheliomas ranged from 18 to 60 years. CONCLUSIONS: Endothelial differentiation does not appear to occur in mesothelioma and therefore should be clearly separated from it. No definite association between pleural epithelioid haemangioendothelioma and exposure to asbestos can be made from this small series but further investigation is warranted.

A multi-institutional study confirms the presence and expression of simian virus 40 in human malignant mesotheliomas.

Exposure to the carcinogen asbestos is a major factor in the development of malignant mesothelioma. However, not all mesotheliomas are associated with asbestos exposure, and only a small minority of people exposed to asbestos develop mesothelioma. Therefore, the identification of the cofactors that render certain individuals more susceptible to asbestos or that cause mesothelioma in people not exposed to asbestos has been a major priority of the International Mesothelioma Interest Group. The possible association of SV40 with mesothelioma was recently discussed in a special session at the Fourth International Mesothelioma Interest Group Conference, and it was decided to conduct a multi-institutional study to independently verify the presence of this tumor virus in mesotheliomas. We report the results of this investigation: (a) DNA and protein analyses revealed SV40 sequences and SV40 large T antigen expression in 10 of 12 mesotheliomas tested (83%); and (b) electron microscopy demonstrated variable amounts of asbestos fibers in 5 (71%) of 7 corresponding lung tissues available for analysis. Our results demonstrate that SV40 DNA is frequently present and expressed in mesotheliomas in the United States. Because our data demonstrate that some patients test positive for both SV40 and asbestos, the possibility that these two carcinogens interact should be investigated in future studies.

Mesothelioma in a community in the north of England.

OBJECTIVES: To find the numbers of mesotheliomas in Calderdale over the period 1966-94 and determine their relation to asbestos exposure, pathology, and mineral fibre burden within the lungs of affected subjects. METHODS: Cases were entered into the study if the subject has been diagnosed with mesothelioma after postmortem and histopathological examinations. Occupational data were obtained mainly from the case records of the Cape Asbestos medical officer, hospital, and medical practitioner and from death certificates. Analyses of the mineral fibres were performed with transmission electron microscopy and energy dispersive x ray spectrometry. RESULTS: 73 mesotheliomas were diagnosed from 1966 to 1994. Forty four were associated with exposure at the Acre Mill factory, which manufactured asbestos products. Concentrations of amphibole asbestos fibres were found to be raised above controls in 31 out of 32 cases associated with Acre Mill exposure, in 10 out of 12 other cases exposed to asbestos and eight out of 17 cases not exposed to asbestos. CONCLUSIONS: There was a high number of mesotheliomas in Calderdale. More than half of the cases were associated with occupation at the Acre Mill factory and were associated with exposure to amphibole asbestos, predominantly crocidolite. No cases associated with neighbourhood exposure to asbestos were identified.

Fiber levels and disease in workers from a factory predominantly using amosite.

The Cape Boards Plant at Uxbridge produced insulation board containing amosite asbestos between 1947 and 1973 with only small amounts of chrysotile. After 1973 only amosite was used. In this study we examined lung samples from 48 workers who had been employed at the plant and who had come to autopsy. The study investigated the fiber levels against the lung pathology including amount of interstitial fibrosis and numbers of ferruginous bodies. The degree of interstitial fibrosis and number of asbestos bodies were graded and the tissues were analyzed by transmission electron microscopy and energy dispersive X-ray analysis and the fibers counted and typed. The 48 cases included 5 mesotheliomas and 14 lung cancers. The mineral analysis results were dominated by the amosite fiber levels. The amounts of chrysotile were relatively small. There were higher levels in lung cancer cases than mesotheliomas and higher levels in mesothelioma cases than those who had died from nonasbestos related diseases. Analysis of the lung tissues showed a consistent pattern of high amosite levels, which confirms the impression that amosite was the predominant form of asbestos used and also indicates that the factory had been a very dusty one.

Retention patterns of asbestos fibres in lung tissue among asbestos cement workers.

Retention patterns in lung tissue (determined by transmission electron microscopy and energy dispersive spectrometry) of chrysotile, tremolite, and crocidolite fibres were analysed in 69 dead asbestos cement workers and 96 referents. There was an accumulation of tremolite with time of employment. Among workers who died within three years of the end of exposure, the 13 with high tremolite concentrations had a significantly longer duration of exposure than seven in a low to intermediate category (medians 32 v 20 years; p = 0.018, one sided). Crocidolite showed similar patterns of accumulation. In workers who died more than three years after the end of exposure, there were no correlations between concentrations of amphibole fibres and time between the end of exposure and death. Chrysotile concentrations among workers who died shortly after the end of exposure were higher than among the referents (median difference in concentrations 13 million fibres (f)/g dry weight; p = 0.033, one sided). No quantitative differences in exposure (duration or intensity) could be shown between workers with high and low to intermediate concentrations. Interestingly, all seven workers who had had a high intensity at the end of exposure (> 2.5 f/ml), had low to intermediate chrysotile concentrations at death, whereas those with low exposure were evenly distributed (31 subjects in both concentration categories); hence, there was a dependence between last intensity of exposure and chrysotile concentration (p = 0.014). Among 14 workers with a high average intensity of exposure, both those (n = 5) with high tissue concentrations of chrysotile and those (n = 10) with high tissue concentrations of tremolite fibres had more pronounced fibrosis than those with low to intermediate concentrations (median fibrosis grades for chrysotile: 2 v 1, p = 0.021; for tremolite: 2 v 0.5, p = 0.012). Additionally, workers who died shortly after the end of exposure with high concentrations of chrysotile and crocidolite had smoked more than those with low intermediate concentrations (medians for chrysotile 35 v 15 pack-years, p = 0.030; for crocidolite 37 v 15 pack-years, p = 0.012). The present data indicate that chrysotile has a relatively rapid turnover in human lungs, whereas the amphiboles, tremolite and crocidolite, have a slower turnover. Further, chrysotile retention may be dependent on dose rate. Chrysotile and crocidolite deposition and retention may be increased by tobacco smoking; chrysotile and tremolite by fibrosis.

Malignant mesothelioma in women.

BACKGROUND: Malignant mesothelioma reportedly shows different epidemiology and pathology in females, and a proportion are believed to arise spontaneously. METHODS: One hundred and seventy seven cases of malignant mesothelioma in females were reviewed, examined by histochemistry and immunohistochemistry, assessed for asbestosis and lung fibre burden by transmission electron microscopy with energy dispersive x ray analysis, and compared with 31 female controls. RESULTS: Two of one hundred and three cases tested for carcinoembryonic antigen were positive and were excluded from further analysis. Tumour cases showed increased amphibole burdens; in those in whom exposure information was known, 74 (80%) of 93 patients had a history of exposure to asbestos. Seventy two (47%) of 152 patients had lung fibrosis. Tumour site and histological type were little different from those reported in adult males. Mixed type histological pattern, lung fibrosis, and peritoneal site were associated with heavier lung asbestos burdens, but not exclusively. Thirty five (30%) of 117 patients had amphibole burdens of less than 2 x 10(6) fibres/g; the sites affected and the histological pattern of tumours in this group were similar to those in cases with amphibole fibre counts of > or = 2 x 10(6)/g lung. A higher lung amphibole burden than the mean burden in control females was found in 115 (98%) of 117 patients tested. CONCLUSIONS: The pathology of malignant mesothelioma appears to be similar in women and in men, and in cases associated and unassociated with asbestos.

Talc pneumoconiosis: a pathologic and mineralogic study.

Seventeen cases of "talc pneumoconiosis" were examined pathologically and mineralogically to ascertain whether a true talc pneumoconiosis existed and also to compare these results in primary, secondary, and tertiary exposures. Mineralogic analyses were performed on wet tissue or tissue blocks by a variety of techniques, including analytical transmission electron microscopy and x-ray diffraction. Overall, the pathologic appearance of the tissues was similar in primary, secondary, and tertiary exposures, although ferruginous bodies and foreign body giant cells were not always present in cases caused by secondary exposures. Mixed dust fibrotic lesions were found in two cases in which there were substantial quantities of quartz present. There was great variation in the minerals found within the lung tissues. Several cases showed significant quantities of mica and kaolin in addition to talc. One case consisted predominantly of mica and in fact could be regarded as "mica pneumoconiosis"; this diagnosis was correctly attributed because of the mineralogic findings. Tremolite fibers were found in only two cases. Substantial quantities of crocidolite and amosite fibers were found in one case. This study shows that "talcosis" frequently represents disease associated with a variety of minerals and that talc is a common denominator. It shows also the usefulness of lung dust mineral analysis, particularly in secondary industries, for evaluating the cause of a pathologic reaction when exposures are especially complex.

Fibre distribution in the lungs and pleura of subjects with asbestos related diffuse pleural fibrosis.

The lungs from 13 cases of diffuse pleural fibrosis associated with a history of exposure to asbestos were examined. Samples were taken from the visceral pleura and central and subpleural zones of the lungs for histopathological and mineralogical studies. The fibre type, size, and number were estimated for each of these regions by transmission electron microscopy and energy dispersive x ray analysis. Amphibole fibre counts were raised when compared with a non-occupationally exposed group and matched those seen in cases of pleural plaques, mild asbestosis, and mesothelioma. A wide case to case variation of distribution was seen. No significant difference was apparent between central and subpleural zones, whereas low asbestos counts were found in the pleura; these were mainly short chrysotile fibres. Within the lungs more (45%) of the longer (greater than 4 microns) and thinner (less than 0.25 micron) amphibole fibres were retained in keeping with other studies implicating such fibre profiles in the pathogenesis of asbestos related disease.

Mineral fibres, fibrosis, and asbestos bodies in lung tissue from deceased asbestos cement workers.

Lung tissue from 76 deceased asbestos cement workers (seven with mesothelioma) exposed to chrysotile asbestos and small amounts of amphiboles, has been studied by transmission electron microscopy, together with lung tissue from 96 controls. The exposed workers with mesothelioma had a significantly higher total content of asbestos fibre in the lungs than those without mesothelioma, who in turn, had higher concentrations than the controls (medians 189, 50, and 29 x 10(6) fibres/g (f/g]. Chrysotile was the major type of fibre. The differences were most pronounced for the amphibole fibres (62, 4.7, and 0.15 f/g), especially crocidolite (54, 1.8 and less than 0.001 f/g), but were evident also for tremolite (2.9, less than 0.001, and less than 0.001 f/g) and anthophyllite (1.7, less than 0.001, and less than 0.001 f/g). For amosite, there was no statistically significant difference between lungs from workers with and without mesothelioma; the lungs of workers had, however, higher concentrations than the controls. Strong correlations were found between duration of exposure and content of amphibole fibres in the lungs. Asbestos bodies, counted by light microscopy, were significantly correlated with the amphibole but not with the chrysotile contents. Fibrosis was correlated with the tremolite but not the chrysotile content in lungs from both exposed workers and controls. Overall, similar results were obtained using fibre counts and estimates of mass.

Comparison of fibre types and size distributions in lung tissues of paraoccupational and occupational cases of malignant mesothelioma.

The results of analysis of mineral fibres in lung tissues from 10 paraoccupational cases of malignant mesothelioma were compared with analysis obtained from seven cases of malignant mesotheliomas that had developed in gas mask workers. Nine of the paraoccupational cases were considered to have developed their tumours because of exposure to asbestos on their husbands' working clothes and one cancer developed in the daughter of a man who had died of asbestosis. The gas mask workers had direct exposure to asbestos while working in a factory that produced military gas masks. The results of mineral fibre analysis in the paraoccupational cases were variable; six showed high crocidolite concentrations, seven raised amosite concentrations and two normal concentrations of all types of asbestos fibre measured. Chrysotile was raised in one case but crocidolite and amosite were also increased. The gas mask workers showed a consistent pattern with high crocidolite concentrations and normal or low concentrations of chrysotile and amosite. Fibre lengths for chrysotile were similar in both groups and predominantly less than 5 microns. Crocidolite fibres tended to be longer in the gas mask workers than in the paraoccupational group and longer than chrysotile in both groups. Amosite fibres tended to be more variable in width than those of chrysotile or crocidolite.

Non-occupational malignant mesotheliomas.

The mineral content of the lungs from 84 cases of malignant pleural mesothelioma was estimated by electron microscopy and energy-dispersive X-ray analysis. These cases were chosen because the history of asbestos exposure was absent, indirect or ill-defined. The occupational exposures were classified according to the method of Zielhuis, and the results indicated that this classification is unnecessarily complicated. The chrysotile counts in the lungs from these mesothelioma cases were similar to those in controls and in a previous series of mesotheliomas in which the majority had had direct exposure to asbestos. Amphibole counts were intermediate between those in controls and in the previous series of mesotheliomas with direct asbestos exposure. These findings confirm those of previous studies indicating that amphiboles are more important than chrysotile in the causation of malignant mesothelioma. The results confirm that some mesotheliomas develop in the absence of asbestos exposure.

Mesotheliomas--asbestos exposure and lung burden.

The assessment of asbestos fibres in the lungs at post mortem in groups of mesotheliomas, groups occupationally exposed to asbestos, and controls has shown that all these groups contain significant levels of asbestos as a lung burden. The amounts in each group are dependent on the degree of past exposure, being highest in those cases with a known or extrapolated occupational exposure, less in those cases with recorded neighbourhood or environmental exposure, and less again in those cases with no evidence of exposure to asbestos and in controls. Relative risk estimates and the use of models developed for occupational situations do not provide good estimates of the relevance of environmental fibres in producing mesotheliomas in the general population. This may be the result of differences between the groups in their time periods of exposure and long-term elimination of asbestos from the lungs. The number of mesotheliomas that might be due to low-level environmental exposure to asbestos cannot be determined from lung contents alone, but an assessment based on detailed occupational histories from the Australian Mesothelioma Surveillance Program show that the problem is not one of great importance when compared with other public health issues.