Pathology analysis for mesothelioma study in the United Kingdom: Current practice and historical development.

Following up on the largest case-control study of malignant mesothelioma yet performed, investigators at the London School of Hygiene and Tropical Medicine assessed 1732 male and 670 female cases as of May 2013. Epidemiological findings of a subset of these were published previously, excluding patients who died or who refused to be interviewed. Pathology reports were collected for subjects, including those both eligible and ineligible for epidemiology study based on vital status. The current investigation examined 860 cases having pathology reports available. Sixty-one cases were diagnosed using cytology only, often with equivocal diagnoses, while 799 reported at least a biopsy of the tumor. Of these, 748 had pathology sufficiently detailed for evaluation. These reports were examined for basis of diagnosis, differences between study cases and ineligible cases, pathology characteristics, and immunohistochemical and other tests used. The most prominent subtype was epithelioid (64% of study cases but only 49% of ineligible cases). Biphasic subtype was present in 10% of study cases and 16% of those ineligible. Sarcomatoid subtype was present in 7% of study cases and 19% of ineligible cases, most of whom died. Twelve percent of study cases displayed no specified subtype, versus 7% of ineligible cases. Of recorded immunohistochemical stains specific for mesothelial cell origin, calretinin (95%) and CK 5/6 or CK5 alone (84%) were by far the most common. Calretinin and CK 5/6 or CK 5 alone were also most sensitive and positive in 92% of cases presenting with surgical pathology report. Ninety percent of cases had at least one immunohistochemical marker for possible lung carcinoma applied, with BER-Ep4 and TTF-1 the most frequent at 68% and CEA at 58%. TTF-1 and CEA were positive in 1% or less of cases. Patterns of use and positive and negative results for each of these as well as other immunohistochemical stains are presented and discussed, along with a brief historical description of their development and use. Possible effects of the pathologic analysis on the results of previously published and future epidemiological studies are discussed.

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.

Asbestos Fiber Type and Length in Lungs of Chrysotile Textile and Production Workers: Fibers Longer than 18 µm.

Excess lung cancer risk for a cohort of chrysotile textile plant workers was many times the risk observed in a cohort of chrysotile miners/millers. The latter had greater exposure to chrysotile/tremolite. A previous lung burden study confirmed this excess exposure in miners/millers and showed little difference in fiber length. Selection of too short a fiber length cut-off (5 µm or more) in the previous study could have masked differences in lung-retained fiber length. In this follow-up, we counted only those intrapulmonary fibers exceeding 18 µm in length. Lung fiber concentration and dimension were assessed by transmission electron microscopy (TEM) and energy-dispersive x-ray spectrometry (EDS) for autopsy samples from 64 textile workers and 43 chrysotile miners and millers. These long fibers were significantly more concentrated in the lungs of chrysotile miners and millers, consistent with their greater exposure. However, when only these longest fibers were compared, there was a somewhat greater mean and median intrapulmonary fiber length for chrysotile textile workers (mean fiber length, all fiber types combined, 25.2 ± 10.2 µm vs. 22.9 ± 6.6 µm in miners/millers, < .001; medians 21.6 vs. 20, p < .05). Despite their lesser apparent lung cancer risk, chrysotile, tremolite, total amphibole, and total long fiber asbestos concentrations were all highest in the lungs of miners/millers. Twenty-two of 64 textile workers had lung content of crocidolite and/or amosite (32.5% of 508). These amosite/crocidolite fibers were present in the lungs of workers who ceased employment prior to the first use of such fibers recorded in this industry. The results suggest that (I) asbestos fiber length differences cannot explain the difference in lung cancer risk excess and slope between cohorts and (2) the experience of textile workers should not be used to assess risk of lung cancer in miners, cement workers, and friction product workers, regardless of fiber type.

Mesothelioma in Quebec chrysotile miners and millers: epidemiology and aetiology.

In a cohort of some 11,000 men born 1891-1920 and employed in the Quebec chrysotile production industry, including a small asbestos products factory, of 9780 men who survived into 1936, 8009 are known to have died before 1993, 38 probably from mesothelioma--33 in miners and millers and five in factory workers. Among the 5041 miners and millers at Thetford Mines, there had been 4125 deaths from all causes, including 25 (0.61%) from mesothelioma, a rate of 33.7 per 100,000 subject-years; the corresponding figures for the 4031 men at Asbestos were eight out of 3331 (0.24%, or 13.2 per 100,000 subject-years). At the factory in Asbestos, where all 708 employees were potentially exposed to crocidolite and/or amosite, there were 553 deaths, of which five (0.90%) were due to mesothelioma; the rate of 46.2 per 100,000 subject-years was 3.5 times higher than among the local miners and millers. Six of the 33 cases in miners and millers were in men employed from 2 to 5 years and who might have been exposed to asbestos elsewhere; otherwise, the 22 cases at Thetford were in men employed 20 years or more and the five at Asbestos for at least 30 years. The cases at Thetford were more common in miners than in millers, whereas those at. Asbestos were all in millers. Within Thetford Mines, case-referent analyses showed a substantially increased risk associated with years of employment in a circumscribed group of five mines (Area A), but not in a peripherally distributed group of ten mines (Area B); nor was the risk related to years employed at Asbestos, either at the mine and mill or at the factory. There was no indication that risks were affected by the level of dust exposure. A similar pattern in the prevalence of pleural calcification had been observed at Thetford Mines in the 1970s. These geographical differences, both within the Thetford region and between it and Asbestos, suggest that the explanation is mineralogical. Lung tissue analyses showed that the concentration of tremolite fibres was much higher in Area A than in Area B, a finding compatible with geological knowledge of the region. These findings, probably related to the far greater biopersistence of amphibole fibres than chrysotile, have important implications in the control of asbestos related disease and for wider aspects of fibre toxicology.

Asbestos, asbestosis, and lung cancer: observations in Quebec chrysotile workers.

One prospective epidemiologic study of asbestos cement workers with radiological small opacities has been cited as a rationale for attributing excess lung cancer to asbestosis. This approach could have considerable practical value for disease attribution in an era of decreasing exposure. However, a recent International Agency for Research on Cancer review concludes that the mechanism of production of asbestos-related lung cancer are unknown. Asbestosis, therefore, cannot be a biologically effective dose marker of lung cancer susceptibility. Asbestosis nonetheless would be useful in identifying asbestos-attributable lung cancer cases if it could be proven an infallible exposure indicator. In this study, we tested this hypothesis in the chrysotile miners and millers of Quebec, Canada. We examined exposure histories, autopsy records, and lung fiber content for 111 Quebec chrysotile miners and millers. If the hypothesis of an asbestosis requirement for lung cancer attribution were accurate, we would expect as asbestosis diagnosis to separate those with lung cancer and high levels of exposure from those with lower levels of exposure in a specific and sensitive manner. This is the first such study in which historical job-based individual estimates based on environmental measurements, lung fiber content, exposure timing, and complete pathology records including autopsies were available for review. We found significant excesses of lung tremolite and chrysotile and estimated cumulative exposure in those with lung cancer and asbestosis compared to those with lung cancer without asbestosis. However, when the latter were directly compared on a case-by-case basis, there was a marked overlap between lung cancer cases with and without asbestosis regardless of the measure of exposure. Smoking habits did not differ between lung cancer cases with and without asbestosis. In regression models, smoking pack-years discriminated between those with the without lung cancer, regardless of asbestosis status. Most seriously, the pathologic diagnosis of asbestosis itself seemed arbitrary in many cases. We conclude that although the presence of pathologically diagnosed asbestosis is a useful marker of exposure, the absence of this disease must be regarded as one of many factors in determining individual exposure status and disease causation.

Evaluation of neurotoxicity in pediatric renal transplant recipients treated with tacrolimus (FK506).

The presence of severe and mild neurotoxicity in our pediatric renal transplant recipients treated with tacrolimus was determined by chart review (severe neurotoxicity) and patient survey (mild neurotoxicity). 14 patients were studied (mean age 15 yr, 5 month, +/- 4.4 yr). 1 patient experienced seizures, felt to be related to malignant hypertension. No other episode of severe neurotoxicity was documented. Most patients (12/14) reported at least one mild neurologic symptom, and half stated their symptoms were present at least 'most of the time'. The most frequent complaints were myalgias (7/14, 50%) and tremors (7/14, 50%) followed by fatigue (5/14, 38%). Severe neurotoxicity may be relatively infrequent in pediatric renal transplant patients treated with tacrolimus. Milder neurologic complaints may be commonly seen in this population, but in general are not severe enough to cause discontinuation of tacrolimus.

IgG subclass levels in pediatric patients on chronic peritoneal dialysis.

Patients maintained on chronic peritoneal dialysis (CPD) have been reported to have a variety of abnormalities of humoral immunity, including hypogammaglobulinemia, altered response to vaccination, and selective absence of IgG2. We measured serum immunoglobulin and IgG subclass levels in 22 pediatric CPD patients followed at our institution; 8 patients had low total IgG; 4 of these had low levels of IgG2 and 3 also had low IgG1, but IgG2 levels were detected in all patients. Thus, many pediatric CPD patients may have low IgG, and some may have low IgG1 and IgG2 as a reflection of low total IgG. However, we did not demonstrate a selective absence of IgG2 in these patients.

Biological indicators of chrysotile exposure.

Chrysotile asbestos is retained in lung tissue, where it may be used as a marker of exposure. Studies include analysis of sputum and bronchoalveolar lavage fluid, but principally lung parenchyma from autopsy or surgically resected specimens. Asbestos bodies form on chrysotile fibres but are generally not a good indicator of human exposure to chrysotile because of their greater probability of formation on amphiboles. Chrysotile fibre analyses in lung have advantages and limitations. Chrysotile concentration is related to the level of environmental and occupational exposure, but in the latter situation owing to deposition, fibre alteration and clearance cumulative exposure and interval between end-exposure and death clearly affect results. Autopsy case series are biased toward increased proportions of asbestos-related diseases as compared to epidemiological cohort data. Analytical problems include potential contamination by chrysotile at autopsy, from fixatives, from post-fixative processing and in the analytical laboratory itself. These may have greatest effect in studies of individuals with low exposure, for tissue other than lung, and for short chrysotile fibres. Selection of control subjects should be contemporaneous with that of cases, and control subjects should fully reflect the hospital population at the time of case death. Limited data are available on fibre analysis in pleural tissue. More are needed. Issues requiring attention include avoidance of contamination, selection of controls, and sample site selection (parietal pleura, or tumour or plaque). For mesothelioma, two case-control studies of lung fibre burden show the principal relationship to be with long amphiboles, but some methodological problems exist. Lung cancer shows no such fibre-type differences. Asbestosis seems to be associated with long-fibre chrysotile and tremolite in one study and short fibres in others. Overall, lung retained dose is a useful indicator of chrysotile exposure if used cautiously in inference, and is very useful in the evaluation of historical exposures and industrial hygiene data in epidemiological studies.

Relation between lung asbestos fibre burden and exposure indices based on job history.

Lung asbestos burden was compared with exposure indices derived from job history interviews in 42 male subjects originating from the Montréal Case-Control Study project, 12 of whom had documented asbestos exposed job histories. Job interview data consisting of a chronological timetable of job histories were translated into detailed exposure indices by an expert group of hygienists and chemists. Total and individual asbestos fibre type concentrations were quantified by transmission electron microscopy with fibre identification by energy dispersive chi ray spectrometry after deparaffinisation of tissue blocks and low temperature plasma ashing. Geometric mean or median asbestos content was higher in subjects with an asbestos exposed job history than those without for retained dose of amosite, total commercial amphiboles, and total asbestos fibre. Except for crocidolite fibre diameter, which was significantly less in the lungs of exposed workers, no consistent differences were found in measurements of fibre dimension for any fibre type. Subgroups of subjects exposed to silica, metals, or smokers and non-smokers without significant occupational exposure showed varying patterns of lung asbestos fibre type deficit compared with the asbestos exposed subgroup. There was an overall trend for higher lung asbestos content proportional to higher exposure indices for asbestos representing concentration, frequency, and reliability. These exposure indices as well as duration of exposure (in years) were independent predictors of total asbestos content in regression analyses when combined in a model with age. Stepwise regression indicated that exposure concentration was the most important variable, explaining 32% of the total variation in total asbestos content. Smoking, whether expressed in ever or never smoked dichotomy or in smoked-years, had no relation to lung asbestos content in this model.

Trends in cancer mortality in Kanawha County, West Virginia, 1950-1984.

There has been much concern recently about possible adverse health effects related to exposure to toxic chemicals among residents of Kanawha County in southern West Virginia. An epidemiological study of trends in cancer mortality from 1950-1984 among the general population of Kanawha County in southern West Virginia was mounted. Cabell County, West Virginia was chosen to be a comparison county for Kanawha in addition to West Virginia and the total United States. The cancer mortality rates for white males and females were calculated using NCHS mortality data and Census Bureau population data available on the Mortality and Population Data System (MPDS) at the University of Pittsburgh. Mortality rates for cancer in Kanawha and Cabell Counties were evaluated over the time period 1950-1984 with an age-period-cohort (APC) analysis. In this analysis, poisson regression models were fit using the statistical program GLIM (Generalized Linear Models) to determine the separate effects of age, period of death, and birth cohort on the specific cancers of interest (lung, liver, bladder, CNS, leukemia, lympho-reticulosarcoma, all cancers). There were no significant county differences for cancer death rates between Kanawha and Cabell Counties except for leukemia among white males [O.R. = 1.27, 95% (C.I. = 1.03-1.6)], and for lympho-reticulosarcoma [O.R. = 1.66(1.24-2.07)], suggesting a possible occupational exposure. For leukemia, aleukemia, the effect observed seems to have declined. In contrast, the elevation of lympho-reticulosarcoma rates has remained in recent years (1970-1984).

Malignant melanoma of the skin among workers in a telecommunications industry: mortality study 1976-83.

An incidence study of malignant melanoma of the skin (MMS), conducted previously among the workers of four plants of a large telecommunications industry located in Montreal, Canada, showed a standardised incidence ratio of 2.7 (95% confidence interval (95% CI) 1.3-5.02) for the years 1976 to 1983. To describe more precisely the magnitude of the problem a mortality study was started among the same population (n = 9590) for the same period (1976-83). At the end of 1983, 9180 workers were alive, 261 were dead, and 149 (1.5%) were not traced. Standardised mortality ratios (SMRs) for all causes of death were surprisingly low for men (SMR = 0.57; 95% CI 0.50-0.64) and women (SMR = 0.56; 95% CI 0.37-0.82). The SMRs for major causes of death were also less than expected. These results may be explained by a pronounced selection bias (healthy worker effect) and by the short duration of follow up (eight years). For MMS, two deaths occurred among men (SMR = 2.00; 95% CI 0.24-7.22) and one among women (SMR = 4.81; 95% CI 0.12-26.78). A third man who died of MMS was miscoded as having a primary pulmonary melanoma. Including this case increased the SMR for MMS to 3.00 (95% CI 0.62-8.77; p = 0.08). Polyvinyl chloride and polychlorinated biphenyls were used in the plants and some of the workers did soldering. A planned case-control study will investigate other possible exposures at work.

A comparative ecological study of selected cancers in Kanawha County, West Virginia.

This study compares mortality rates for selected causes of death in Kanawha County, West Virginia, to rates reported in a number of geographically defined populations for 1950-1984. Specific conditions selected for study included cancers of the biliary passages and liver, the bladder and other urinary organs, and the central nervous system (CNS), as well as leukemia and aleukemia, lymphosarcoma and reticulosarcoma, Hodgkin's disease, and cancer of all other lymphopoietic tissue. The analysis made use of several techniques for the investigation of ecological data, including the modeling of rates using Poission regression. The primary findings of this study concern two subgroups of cancers of the lymphatic and hematopoietic tissue: (1) leukemia and aleukemia, and (2) lymphosarcoma and reticulosarcoma. For both subgroups of cancers, white male residents of Kanawha County show evidence of significantly elevated mortality rates over the 35-year period of this study.

Health effects of tremolite. Now and in the future.

Although tremolite asbestos has been well characterized since 1916, appreciation of its role in disease induction is relatively recent. It has always been understood that the morphology of tremolite is complex, and part of the slowness in recognizing it as a hazard has been definitional in nature. Reduced to simple terms the questions are, when is tremolite "asbestos-like," when is it an innocuous amorphous particle, do these forms occur together, with what confidence can they be separated for regulatory purposes, and what is the spectrum of disease potential for varying exposure? A brake on regulation is partially due to a convergence of opinion of unlikely and unintentional allies: industries producing tremolite-containing materials and some epidemiologists resisting attribution of risk to tremolite on the grounds that its known effects--pleural plaques, asbestosis, lung cancer and mesothelioma--are principally due to chrysotile, which is often contaminated with fibrous tremolite. The latter group concentrate their skepticism on internal-dose biomarker studies associating lung tremolite content with mesothelioma (but not so clearly with lung cancer or asbestosis). They ignore the basic carcinogenic quality of fibrous tremolite, shown in both animal and epidemiological studies. Evidence from the Quebec chrysotile/tremolite mining districts suggests that very low concentrations of tremolite in ambient air can be translated into high concentrations in lung, even in those without occupational exposure. Disease incidence, especially for mesothelioma, seems also to be associated with tremolite air and lung content. The risk associated with tremolite has been demonstrated in Corsica, Cyprus, the United States, and Canada. Of particular importance is an apparent increase in the proportion of mesothelioma risk attributable to tremolite, since the fibers heretofore most responsible for that disease--commercial amphiboles--have been or are being severely regulated or completely eliminated in production and use. Further, amosite and crocidolite, while still a concern, form a small fraction of "asbestos-in-place": most of this material is chrysotile and we do not really know to what degree it is contaminated with tremolite. The available evidence suggests that bulk analysis or airborne fiber analysis will not answer this question, and perhaps only animal bioaccumulation assay is sufficient. Until we know more, it seems prudent for public health to avoid dispersing chrysotile/tremolite into the environment, and, where we can, to regulate all tremolite "fibers" conservatively.

Lung dust analysis in the assessment of past exposure of man-made mineral fibre workers.

In the cohort of American MMMF workers reported by ENTERLINE et al. [Ann. occup. Hyg. 31, 625-656 (1987)] autopsies were recorded in 652 (13.5%) of 4840 deaths. Lung tissue samples were sought from all pathologists and obtained in 145 (22.2%), together with similar samples from 124 matched referents. Lung fibre counts by phase contrast microscopy were 60% higher (P less than 0.05) in workers than referents. Electron microscopy (ATEM) also showed more fibres of all kinds--MMMF, asbestos and other--but no convincing excess of any one type. Lung samples of only 26% of workers contained any MMMF, almost all siliceous in nature and in low concentration. There were too few cases of lung cancer (19) for any useful conclusion; however, in the plant with the highest lung cancer SMR (200), and a probable mesothelioma, amosite at greater than 1.0 fibres per micrograms (f micrograms-1) was found in four of six workers but in none of their matched referents. Although our findings contribute little to the interpretation of the results obtained by ENTERLINE et al. they indicate the potential value of tissue analyses in monitoring epidemiological studies of MMMF exposure.