Mechanisms and shapes of causal exposure-response functions for asbestos in mesotheliomas and lung cancers.

This paper summarizes recent insights into causal biological mechanisms underlying the carcinogenicity of asbestos. It addresses their implications for the shapes of exposure-response curves and considers recent epidemiologic trends in malignant mesotheliomas (MMs) and lung fiber burden studies. Since the commercial amphiboles crocidolite and amosite pose the highest risk of MMs and contain high levels of iron, endogenous and exogenous pathways of iron injury and repair are discussed. Some practical implications of recent developments are that: (1) Asbestos-cancer exposure-response relationships should be expected to have non-zero background rates; (2) Evidence from inflammation biology and other sources suggests that there are exposure concentration thresholds below which exposures do not increase inflammasome-mediated inflammation or resulting inflammation-mediated cancer risks above background risk rates; and (3) The size of the suggested exposure concentration threshold depends on both the detailed time patterns of exposure on a time scale of hours to days and also on the composition of asbestos fibers in terms of their physiochemical properties. These conclusions are supported by complementary strands of evidence including biomathematical modeling, cell biology and biochemistry of asbestos-cell interactions in vitro and in vivo, lung fiber burden analyses and epidemiology showing trends in human exposures and MM rates.

In-vitroassessment of ß-tricalcium phosphate/bredigite-ciprofloxacin (CPFX) scaffolds for bone treatment applications.

In the present study, ß-tricalcium phosphate (ß-TCP) scaffolds with various amounts of bredigite (Bre) were fabricated by the space holder method. The effect of bredigite content on the structure, mechanical properties,in vitrobioactivity, and cell viability was investigated. The structural assessment of the composite scaffolds presented interconnected pores with diameter of 300-500 µm with around 78%-82% porosity. The results indicated that the compressive strength of the scaffolds with 20% bredigite (1.91 MPa) was improved in comparison with scaffolds with 10% bredigite (0.52 MPa), due to the reduction of the average pore and grain sizes. Also, the results showed that the bioactivity and biodegradability of ß-TCP/20Bre were better than that of ß-TCP/10Bre. Besides, in this study, the release kinetics of ciprofloxacin (CPFX) loaded ß-TCP/Bre composites as well as the ability of scaffolds to function as a sustained release drug carrier was investigated. Drug release pattern of ß-TCP/bredigite-5CPFX scaffolds exhibited the rapid burst release of 43% for 3 h along with sustained release (82%) for 32 h which is favorable for bone infection treatment. Antibacterial tests revealed that the antibacterial properties of ß-TCP/bredigite scaffolds are strongly related to the CPFX concentration, wherein the scaffold containing 5% CPFX showed the most significant zone of inhibition (33 ± 0.5 mm) againstStaphylococcus aureus. The higher specific surface areas of nanostructure ß-TCP/bredigite scaffolds containing CPFX lead to an initial rapid release followed by constant drug delivery. MTT assay showed that the cell viability of ß-TCP/bredigite scaffold loading with up to 1%-3% CPFX (95 ± 2%), is greater than for scaffolds containing 5% CPFX (84 ± 2%). In Overall, it may suggested that ß-TCP/bredigite containing 1%-3% CPFX possesses great cell viability and antibacterial activity and be employed as bactericidal biomaterials and bone infection treatment.

Lung cancer screening in patients with Libby amphibole disease: High yield despite predominantly environmental and household exposure.

BACKGROUND: Lung cancer screening with low-dose computed tomography (CT) scanning (LDCT) is accepted as a screening tool, but its application to populations exposed to recognized occupational or environmental carcinogens is limited. We apply LDCT to a population with a predominantly nonoccupational exposure to a recognized human lung carcinogen, Libby amphibole asbestos (LA). METHODS: Patients in an asbestos disease clinic in Libby, Montana who were aged 50 to 84 years, greater than or equal to 20 pack-year history of tobacco use (irrespective of quit date), and asbestos-related pleuropulmonary disease on high-resolution CT scan were offered free annual lung cancer screening over a 39-month period. RESULTS: Of 2897 clinic patients, 1149 (39.7%) met eligibility criteria, and 567 (49%) were screened with 1014 low-dose CT scans. Most screened patients had principally environmental (333 or 59%) or household exposure (145 or 25%) to LA. Seventeen primary lung cancers were identified, mostly in early stages: 10 at stage 1, two at stage 2, three at stages 3 to 4, and two at limited small-cell cancers. The screening yield was 1.9 at baseline scan and 1.5% on the first annual scan. CONCLUSIONS: Consistent with the guidelines of the National Comprehensive Cancer Network and American Association of Thoracic Surgery, LDCT for early lung cancer detection should be offered to people with significant exposure to occupational or environmental human lung carcinogens.

Mechanical and cytotoxicity evaluation of nanostructured hydroxyapatite-bredigite scaffolds for bone regeneration.

Despite the attractive characteristics of three-dimensional pure hydroxyapatite (HA) scaffolds, due to their weak mechanical properties, researches have focused on the development of composite scaffolds via introducing suitable secondary components. The aim of this study was to develop, for the first time, three-dimensional HA-bredigite (Ca7MgSi4O16) scaffolds containing various amounts of bredigite nanopowder (0, 5, 10 and 15wt.%) using space holder technique. Transmission electron microscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy and X-ray diffraction spectroscopy were applied in order to study the morphology, fracture surface and phase compositions of nanopowders and scaffolds. Furthermore, the effects of scaffold composition on the mechanical properties, bioactivity, biodegradability, and cytotoxicity were also evaluated. Results showed that the composite scaffolds with average pore size in the range of 220-310µm, appearance porosity of 63.1-75.9% and appearance density of 1.1±0.04g/cm(3) were successfully developed, depending on bredigite content. Indeed, the micropore size of the scaffolds reduced with increasing bredigite content confirming that the sinterability of the scaffolds was improved. Furthermore, the compression strength and modulus of the scaffolds significantly enhanced via incorporation of bredigite content from 0 to 15wt.%. The composite scaffolds revealed superior bioactivity and biodegradability with increasing bredigite content. Moreover, MTT assay confirmed that HA-15wt.% bredigite scaffold significantly promoted cell proliferation compared to tissue culture plate (control) and HA scaffold. Based on these results, three-dimensional HA-bredigite scaffolds could be promising replacements for HA scaffolds in bone regeneration.

Long-term toxicity of naturally occurring asbestos in male Fischer 344 rats.

Naturally occurring asbestos (NOA) fibers are found in geologic deposits that may be disturbed by mining, earthworks, or natural processes, resulting in adverse health risks to exposed individuals. The toxicities of Libby amphibole and NOA samples including Sumas Mountain chrysotile (SM), El Dorado tremolite (ED), and Ontario ferroactinolite cleavage fragments (ON) were compared in male Fischer 344 (F344) rats 15 mo after exposure. Rat-respirable fractions of LA and SM displayed greater mean lengths and aspect ratios than ED and ON. After a single intratracheal (IT) instillation (0.5 or 1.5 mg/rat), persistent changes in ventilatory parameters and a significant increase in lung resistance at baseline and after methacholine aerosol dosing were found only in rats exposed to 1.5 mg SM. High-dose ED significantly elevated bronchoalveolar lavage lactate dehydrogenase (LDH) activity and protein levels, while high-dose SM increased γ-glutamyl transferase and LDH activities. A moderate degree of lung interstitial fibrosis after exposure to 1.5 mg SM persisted 15 mo after exposure, unchanged from previous findings at 3 mo. LA induced mild fibrosis, while ED and ON produced minimal and no apparent fibrosis, respectively. Bronchioloalveolar carcinoma was observed 15 mo after exposure to LA or ED. Data demonstrated that SM, given by bolus IT dosing on an equivalent mass basis, induced greater pulmonary function deficits, airway hyperresponsiveness, and interstitial fibrosis than other NOA, although unlike LA and ED, no apparent evidence for carcinogenicity was found. All NOA samples except ON cleavage fragments produced some degree of long-term toxicity.

Comparative long-term toxicity of Libby amphibole and amosite asbestos in rats after single or multiple intratracheal exposures.

In former mine workers of Libby, MT, exposure to amphibole-containing vermiculite was linked to increased rates of asbestosis, lung cancer, and mesothelioma. Although many studies showed adverse effects following exposure to Libby amphibole (LA; a mixture of winchite, richterite, and tremolite), little is known regarding the relative toxicity of LA compared to regulated asbestos, or regarding the risks associated with acute high-dose exposures relative to repeated low-dose exposures. In this study, pulmonary function, inflammation, and pathology were assessed after single or multiple intratracheal (IT) exposures of LA or a well-characterized amosite (AM) control fiber with equivalent fiber characteristics. Male F344 rats were exposed to an equivalent total mass dose (0.15, 0.5, 1.5, or 5 mg/rat) of LA or AM administered either as a single IT instillation, or as multiple IT instillations given every other week over a 13-wk period, and necropsied up to 20 mo after the initial IT. When comparing the two fiber types, in both studies LA resulted in greater acute neutrophilic inflammation and cellular toxicity than equal doses of AM, but long-term histopathological changes were approximately equivalent between fibers, suggesting that LA is at least as toxic as AM. In addition, although no dose-response relationship was discerned, mesothelioma or lung carcinomas were found after exposure to low and high dose levels of LA or AM in both studies. Conversely, when comparing studies, an equal mass dose given over multiple exposures instead of a single bolus resulted in greater chronic pathological changes in lung at lower doses, despite the initially weaker acute inflammatory response. Overall, these results suggest that there is a possibility of greater long-term pathological changes with repeated lower LA dose exposures, which more accurately simulates chronic environmental exposures.

[Study on identification of traditional Chinese medicine Yangqishi and Yinqishi by X-ray diffraction].

The aim of this paper is to clarify the mineral origin of traditional Chinese medicine (TCM) Yangqishi and Yinqishi and guide identification of the both, by X-ray diffraction (XRD) Fourier patterns. Morphological identification and conventional physical and chemical analysis wee used to identify 22 batches of Yangqishi and Yinqishi. It used XRD Fourier patterns which has been collected from sample powders to analyze phase composition. It has been found experimentally that the mineral origin of Yinqishi is Talc schist and the mineral origin of Yangqishi is tremolite and actinolite. The results also showed that the method using XRD can get not only an accurate but also rapid identification of Yangqishi and Yinqishi. There are many differences in medicinal properties, efficacy, indications and composition of Yangqishi and Yinqishi, so be careful not to mix them up.

Study on identification of traditional Chinese medicine Yangqishi and Yinqishi by X-ray diffraction / 中国中药杂志

The aim of this paper is to clarify the mineral origin of traditional Chinese medicine (TCM) Yangqishi and Yinqishi and guide identification of the both, by X-ray diffraction (XRD) Fourier patterns. Morphological identification and conventional physical and chemical analysis wee used to identify 22 batches of Yangqishi and Yinqishi. It used XRD Fourier patterns which has been collected from sample powders to analyze phase composition. It has been found experimentally that the mineral origin of Yinqishi is Talc schist and the mineral origin of Yangqishi is tremolite and actinolite. The results also showed that the method using XRD can get not only an accurate but also rapid identification of Yangqishi and Yinqishi. There are many differences in medicinal properties, efficacy, indications and composition of Yangqishi and Yinqishi, so be careful not to mix them up.

The relationship between various exposure metrics for elongate mineral particles (EMP) in the taconite mining and processing industry.

Different dimensions of elongate mineral particles (EMP) have been proposed as being relevant to respiratory health end-points such as mesothelioma and lung cancer. In this article, a methodology for converting personal EMP exposures measured using the National Institute for Occupational Safety and Health (NIOSH) 7400/7402 methods to exposures based on other size-based definitions has been proposed and illustrated. Area monitoring for EMP in the taconite mines in Minnesota's Mesabi Iron Range was conducted using a Micro Orifice Uniform Deposit Impactor (MOUDI) size-fractionating sampler. EMP on stages of the MOUDI were counted and sized according to each EMP definition using an indirect-transfer transmission electron microscopy (ISO Method 13794). EMP were identified using energy-dispersive x-ray and electron diffraction analysis. Conversion factors between the EMP counts based on different definitions were estimated using (1) a linear regression model across all locations and (2) a location-specific ratio of the count based on each EMP definition to the NIOSH 7400/7402 count. The highest fractions of EMP concentrations were found for EMP that were 1-3 µm in length and 0.2-0.5 µm in width. Therefore, the current standard NIOSH Method 7400, which only counts EMP >5 µm in length and ≥ 3 in aspect ratio, may underestimate amphibole EMP exposures. At the same time, there was a high degree of correlation between the exposures estimated according to the different size-based metrics. Therefore, the various dimensional definitions probably do not result in different dose-response relationships in epidemiological analyses. Given the high degree of correlation between the various metrics, a result consistent with prior research, a more reasonable metric might be the measurement of all EMP irrespective of size. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: figures detailing EMP concentration.].

Cumulative Retrospective Exposure Assessment (REA) as a predictor of amphibole asbestos lung burden: validation procedures and results for industrial hygiene and pathology estimates.

CONTEXT: A detailed evaluation of the correlation and linearity of industrial hygiene retrospective exposure assessment (REA) for cumulative asbestos exposure with asbestos lung burden analysis (LBA) has not been previously performed, but both methods are utilized for case-control and cohort studies and other applications such as setting occupational exposure limits. OBJECTIVE: (a) To correlate REA with asbestos LBA for a large number of cases from varied industries and exposure scenarios; (b) to evaluate the linearity, precision, and applicability of both industrial hygiene exposure reconstruction and LBA; and (c) to demonstrate validation methods for REA. METHODS: A panel of four experienced industrial hygiene raters independently estimated the cumulative asbestos exposure for 363 cases with limited exposure details in which asbestos LBA had been independently determined. LBA for asbestos bodies was performed by a pathologist by both light microscopy and scanning electron microscopy (SEM) and free asbestos fibers by SEM. Precision, reliability, correlation and linearity were evaluated via intraclass correlation, regression analysis and analysis of covariance. Plaintiff's answers to interrogatories, work history sheets, work summaries or plaintiff's discovery depositions that were obtained in court cases involving asbestos were utilized by the pathologist to provide a summarized brief asbestos exposure and work history for each of the 363 cases. RESULTS: Linear relationships between REA and LBA were found when adjustment was made for asbestos fiber-type exposure differences. Significant correlation between REA and LBA was found with amphibole asbestos lung burden and mixed fiber-types, but not with chrysotile. The intraclass correlation coefficients (ICC) for the precision of the industrial hygiene rater cumulative asbestos exposure estimates and the precision of repeated laboratory analysis were found to be in the excellent range. The ICC estimates were performed independent of specific asbestos fiber-type. CONCLUSIONS: Both REA and pathology assessment are reliable and complementary predictive methods to characterize asbestos exposures. Correlation analysis between the two methods effectively validates both REA methodology and LBA procedures within the determined precision, particularly for cumulative amphibole asbestos exposures since chrysotile fibers, for the most part, are not retained in the lung for an extended period of time.

More than 97% of human papilloma virus type 16 (HPV-16) was found with chrysotile asbestos & relatively smooth round tumor outline, and less than 3% was found with HPV-18 and tremolite asbestos & irregular sawtooth-like zigzag outline in breast cancer tissues in over 500 mammograms of female patients: their implications in diagnosis, treatment, and prevention of breast cancer.

In the past, Human Papillomavirus Type 16 (HPV-16) was considered to be the main cause of cancer in the oropharynx and genital organs. Cervical cancer of the uterus is the most well-known cancer associated with HPV-16. Among the oncogenic HPVs, types 16 and 18 are most responsible for the majority of the HPV-caused cancers. Recently, using EMF Resonance Phenomenon between 2 identical substances, we non-invasively measured HPV-16 and HPV-18 among 25 physicians and 25 dentists and found that all 50 have HPV-16 in oral cavities and oropharynx but not HPV-18. However most dentists have a stronger infection than physicians. Among them were 2 female dentists with breast cancer containing HPV-16 and strong infections of HPV-16 in the oral cavities and oropharynx. When the author checked their breast cancer positive areas as well as the mammograms of cancer positive areas, Chrysotile Asbestos co-existed with an infection of HPV-16. We then examined over 500 published mammograms of women with malignant breast cancer published by other institutes, and we found HPV-16 in more than 97% and HPV-18 in less than 3% of the breast cancer mammograms examined. Less than 0.4% of cases were found as a variety of combination of HPV-16 & HPV-18. We also discovered that breast cancer with HPV-16 always co-exists with increased Chrysotile Asbestos deposits, and the outline of the breast cancer positive area is a relatively smooth and round or oval shape, and breast cancer with HPV-18 always co-exists with increased Tremolite Asbestos, where the tumor outline is an irregular saw-tooth like zigzag pattern. Based on these findings, better methods of diagnosis, treatment and prevention with a vaccine can be developed.

Sumas Mountain chrysotile induces greater lung fibrosis in Fischer344 rats than Libby amphibole, El Dorado tremolite, and Ontario ferroactinolite.

The physical properties of different types of asbestos may strongly affect health outcomes in exposed individuals. This study was designed to provide understanding of the comparative toxicity of naturally occurring asbestos (NOA) fibers including Libby amphibole (LA), Sumas Mountain chrysotile (SM), El Dorado tremolite (ED), and Ontario ferroactinolite (ON) cleavage fragments. Rat-respirable fractions (PM2.5) were prepared by water elutriation. Surface area was greater for SM (64.1 m²/g) than all other samples (range: 14.1-16.2 m²/g), whereas mean lengths and aspect ratios (ARs) for LA and SM were comparable and greater than ED and ON. Samples were delivered via a single intratracheal (IT) instillation at doses of 0.5 and 1.5mg/rat. One day post-IT instillation, low-dose NOA exposure resulted in a 3- to 4-fold increase in bronchoalveolar lavage fluid (BALF) cellularity compared with dispersion media (DM) controls, whereas high-dose exposure had a more severe effect on lung inflammation which varied by source. Although inducing less neutrophilic inflammation than ON and ED, exposure to either LA or SM resulted in a greater degree of acute lung injury. Three months post-IT instillation, most BALF parameters had returned to control levels, whereas the development of fibrosis persisted and was greatest in SM-exposed rats (SM > LA > ON > ED). These data demonstrate that fiber length and higher AR are directly correlated with the severity of fibrosis and that, in the rat, exposure to SM is more fibrogenic than LA which suggests that there may be cause for concern for people at risk of being exposed to NOA from the Sumas Mountain landslide.

Effects of Libby amphibole asbestos exposure on two models of arthritis in the Lewis rat.

Epidemiological data suggest that occupational exposure to the amphibole-containing vermiculite in Libby, MT, was associated with increased risk for developing autoimmune diseases and had an odds ratio of 3.23 for developing rheumatoid arthritis (RA). The collagen-induced arthritis (CIA) and the peptidoglycan-polysaccharide (PG-PS) models of RA were employed to determine whether exposure to Libby amphibole (LA) induced a more rapid onset, increased expression, or prolonged course of RA. Female Lewis rats were intratracheally instilled with total doses of 0.15, 0.5, 1.5, or 5 mg LA or 0.5 or 1.5 mg amosite asbestos, and arthritis was induced with either the PG-PS or CIA model. Neither LA nor amosite exposure affected the disease course in the CIA model, or the production of rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP) antibodies. LA exposure reduced swelling in the PG-PS model and decreased anti-PG-PS and total immunoglobulin M (IgM) antibody titers. Both amosite and LA exposure increased the number of rats with circulating anti-nuclear antibodies (ANA), the majority of which presented a speckled staining pattern. However, this ANA enhancement was not dose responsive. These results failed to show a positive correlation between LA exposure and RA disease in two animal models, although upregulated ANA suggest an altered immunological profile consistent with other systemic autoimmune diseases.

Pulmonary inflammatory and fibrotic responses in Fischer 344 rats after intratracheal instillation exposure to Libby amphibole.

Increased incidences of asbestosis have been reported in workers from Libby, MT, associated with exposures to amphibole-contaminated vermiculite. In this study pulmonary and histopathological changes were investigated following Libby amphibole (LA) exposure in a rat model. Rat respirable fractions of LA and amosite (aerodynamic diameter <2.5 µm) were prepared by water elutriation. Male F344 rats were exposed to single doses of either saline (SAL), amosite (0.65 mg/rat), or LA (0.65 or 6.5 mg/rat) by intratracheal instillation. At times from 1 d to 3 mo after exposure, bronchoalveolar lavage (BAL) was performed and right and left lungs were removed for reverse-transcription polymerase chain reaction (RT-PCR) and histopathological analysis, respectively. Data indicated that 0.65 mg amosite resulted in a higher degree of pulmonary injury, inflammation, and fibrotic events than LA at the same mass dose. Exposure to either amosite or high dose LA resulted in higher levels of cellular permeability and injury, inflammatory enzymes, and iron binding proteins in both BAL fluid and lung tissue at most time points when compared to SAL controls. However, mRNA expression for some growth factors (e.g., platelet-derived growth factor [PDGF]-A and transforming growth factor [TGF]-1ß), which contribute to fibrosis, were downregulated at several time points. Furthermore, histopathological examination showed notable thickening of interstitial areas surrounding the alveolar ducts and terminal bronchioles. On a mass dose basis, amosite produced a greater acute and persistent lung injury for at least 3 mo after exposure. However, further testing and analysis of LA are needed with regard to the dose metric to fully evaluate its potential fibrogenicity and carcinogenicity.

[Pulmonary concentration of asbestos fibers in steel workers with pleural mesothelioma]. / Concentrazione polmonare di fibre di amianto in lavoratori siderurgici affetti da mesotelioma pleurico.

The asbestos fibre burden of the lung has been used in the past as a biological indicator of cumulative exposure to the mineral so much so that in 1997 reference limits even for non-occupationally exposed people have been proposed. This kind of analysis was performed on groups of workers of different type of industries and allowed to achieve a qualitative-quantitative estimate of past exposure to asbestos, even in absence of exposure estimates by environmental monitoring. An important example is the steel industry where asbestos was widely used in the past, but for which there are not available exposure estimates of workers. Among the mesothelioma cases collected by the Mesothelioma Registry of the Province of Brescia from 1980 to present there are 55 workers who spent at least 5 years in steel industry, on a total of 289 cases classified as asbestos exposed (19%). For 8 subjects who worked in steel mills and production of electrical steel pipes, of which 4 in the same plant, lung tissue samples were available for the asbestos fibres burden analysis (7 samples coming from autopsies and 1 from extra-pleural pneumonectomy). In all cases the diagnosis was given with histological analyses supplemented with immunohistochemistry. In 7 cases autopsied the diagnosis was confirmed. The work histories have been reconstructed in detail through the interview process, inclusive of details of duties performed. The asbestos fibre burden analyses showed a range of concentrations between 260,000 and 11,000,000 ff per grams of dry tissue; the concentration of amphiboles was much higher than that of chrysotile. The highest body burden was detected in the maintenance workers of the same plant in witch a cluster of malignant mesothelioma was observed. In conclusion, this study illustrates the results of asbestos fibres burden analyses in subjects where exposure to asbestos is sure but not quantifiable. The results showed also that these concentrations can reach values that overlap with those found in asbestos-cement workers and in asbestos-textile workers. These data suggest to consider the cases of mesothelioma occurred in the steel workers at least as "possible" exposure, even in the absence of adequate information on the circumstances of contact with asbestos. This study, although based on a small number of cases, is the only one ever held in Italy on workers in this sector.

Asbestos bodies in bronchoalveolar lavage fluid and sputum.

The aim of the study was to determine the concordance of asbestos body (AB) detection in sputum and bronchoalveolar lavage fluid (BALF). AB were detected in the BALF of 110 former or current asbestos workers with medium weak exposure level and, for 65 subjects, in sputum. Several spontaneous sputum samples were taken from each subject. AB prevalence in BALF was rather low (48.2%) especially in subjects with former chrysotile exposure (32.5%). AB prevalence was lower in smokers (40.9%) and ex-smokers (40.7%) than in non-smokers (68.7%). In the sub-group, who underwent both sputum and BALF examination, the concordance of AB detection was observed only in 56.8% of the cases. Neither of the two methods had significant prevalence over the other but were complementary, as both are useful in increasing the probability of AB detection.

The epidemiology of mesothelioma in historical context.

Primary malignant mesothelial tumours were recognized by pathologists before asbestiform minerals (chrysotile, crocidolite and amosite) were mined commercially. The discovery, 40 yrs ago, of a causal link with crocidolite and the wide-ranging epidemiological studies which followed are the subject of this review. Early case-control and descriptive surveys, supplemented by cohort studies in insulation workers and chrysotile miners, quickly demonstrated major occupational and geographical differences, with high risk in naval dockyard areas and in the heating trades. In the 1980s, reliable cohort surveys showed that in mining and in the manufacture of asbestos products the mesothelioma risk was much higher when exposure included crocidolite or amosite than chrysotile alone. However, qualitative and quantitative information on exposure was too often inadequate for this evidence to be conclusive. Well-controlled lung fibre analyses have reduced these deficiencies and demonstrated the probable implications of the greater biopersistence of amphibole fibres. Chrysotile for industrial use often contains low concentrations of fibrous tremolite, which may well explain the few cases of mesothelioma associated with this type of asbestos. Progress in this field has been much retarded by controversy, for which the 20 year gap between the availability of reliable estimates of risk for the mining of chrysotile and that for crocidolite or amosite may have been largely responsible.