Abstract  HEEP COPYRIGHT: BIOL ABS. Bilateral pleural calcifications occur endemically in regions with dispersed asbestos outcroppings which were not economically exploited. Detailed epidemiological and mineralogical studies were done. Asbestos in the form of anthophyllite and tremolite was a constant finding in the soil of the yards and fields of plaque carriers. The possible etiologic significance of sepiolite, an amphibole derivative frequently discovered in soil samples is discussed. The soil of the yard and field of a family with 3 plaque carriers (Rhodope Mountains, S.E. Bulgaria) contained the fibrous mineral sepiolite as most important amphibole variety (up to 5% of the soil samples), whereas anthophyllite and tremolite asbestos were scarce. Such mineralogic findings and published reference to the biological effects of sepiolite in vitro make the participation of the fibrous silicate sepiolite in the formation of endemic pleural plaques very probable.

Abstract  To demonstrate the relationship between non occupationally environmental exposure to crocidolite and the risk of malignant neoplasms,particularly lung cancer and mesothelioma,a mortality study was performed in the Dayao County contaminated with crocidolite from 1987 to 1995 by a retrospective cohort method.Another population of Lufeng County in the same province,where was not contaminated with crocidolite was selected as the control group.The results showed that the mortality from malignant neoplasms was 182.60 per 10 5 population per year,in which lung cancer was 53.26 per 10 5 population. RR of mortality were 1.47 and 2.14( P 0.01) from malignant neoplasms and lung cancer respectively.There were 7 deaths due to mesothelioma in the observed group.It is considered that the mortality rate from mesothelioma was very high among residents in the county contaminated with crocidolite,being 17.75 per 10 5 among people over 30 years old. No mesothelioma was observed in the control group.

Abstract  To assess the risk of lung cancer and mesothelioma after environmental exposure to crocidolite for 20-30 years, a retrospective cohort study was carried out in farmers who had been exposed to crocidolite in environment. 1610 subjects were followed up for 9 years (Jan. 1, 1987 Dec. 31, 1995). The control group consisted of 7646 farmers who resided in the noncrocidolite pollution rural area in the same province. The results showed that the annual mortality rate was 43.75 per 100,000 population for lung cancer, and 36.46 per 100,000 for mesothelioma. Significantly high risks of lung cancer (RR 5.67) and mesothelioma (RR 182.3) were noted. These results demonstrate a strong causal association between lung cancer, mesothelioma and exposure to crocidolite.

Abstract  Quantitative estimates of the risk of lung cancer or mesothelioma in humans from asbestos exposure made by the U. S. Environmental Protection Agency (EPA) make use of estimates of potency factors based on phase-contrast microscopy (PCM) and obtained from cohorts exposed to asbestos in different occupational environments. These potency factors exhibit substantial variability. The most likely reasons for this variability appear to be differences among environments in fiber size and mineralogy not accounted for by PCM.

In this article, the U. S. Environmental Protection Agency (EPA) models for asbestos-related lung cancer and mesothelioma are expanded to allow the potency of fibers to depend upon their mineralogical types and sizes. This is accomplished by positing exposure metrics composed of nonoverlapping fiber categories and assigning each category its own unique potency. These category-specific potencies are estimated in a meta-analysis that fits the expanded models to potencies for lung cancer (K(L)'s) or mesothelioma (K(M)'s) based on PCM that were calculated for multiple epidemiological studies in our previous paper (Berman and Crump, 2008). Epidemiological study-specific estimates of exposures to fibers in the different fiber size categories of an exposure metric are estimated using distributions for fiber size based on transmission electron microscopy (TEM) obtained from the literature and matched to the individual epidemiological studies. The fraction of total asbestos exposure in a given environment respectively represented by chrysotile and amphibole asbestos is also estimated from information in the literature for that environment. Adequate information was found to allow K(L)'s from 15 epidemiological studies and K(M)'s from 11 studies to be included in the meta-analysis.

Since the range of exposure metrics that could be considered was severely restricted by limitations in the published TEM fiber size distributions, it was decided to focus attention on four exposure metrics distinguished by fiber width: "all widths," widths > 0.2 mu m, widths < 0.4 mu m, and widths < 0.2 mu m, each of which has historical relevance. Each such metric defined by width was composed of four categories of fibers: chrysotile or amphibole asbestos with lengths between 5 mu m and 10 mu m or longer than 10 mu m. Using these metrics three parameters were estimated for lung cancer and, separately, for mesothelioma: K(LA), the potency of longer (length > 10 mu m) amphibole fibers; rpc, the potency of pure chrysotile (uncontaminated by amphibole) relative to amphibole asbestos; and rps, the potency of shorter fibers (5 mu m < length < 10 mu m) relative to longer fibers.

For mesothelioma, the hypothesis that chrysotile and amphibole asbestos are equally potent (rpc = 1) was strongly rejected by every metric and the hypothesis that (pure) chrysotile is nonpotent for mesothelioma was not rejected by any metric. Best estimates for the relative potency of chrysotile ranged from zero to about 1/200th that of amphibole asbestos (depending on metric). For lung cancer, the hypothesis that chrysotile and amphibole asbestos are equally potent (rpc = 1) was rejected (p <= .05) by the two metrics based on thin fibers (length < 0.4 mu m and < 0.2 mu m) but not by the metrics based on thicker fibers.

The "all widths" and widths < 0.4 mu m metrics provide the best fits to both the lung cancer and mesothelioma data over the other metrics evaluated, although the improvements are only marginal for lung cancer. That these two metrics provide equivalent (for mesothelioma) and nearly equivalent (for lung cancer) fits to the data suggests that the available data sets may not be sufficiently rich (in variation of exposure characteristics) to fully evaluate the effects of fiber width on potency. Compared to the metric with widths > 0.2 mu m with both rps and rpc fixed at 1 (which is nominally equivalent to the traditional PCM metric), the "all widths" and widths < 0.4 mu m metrics provide substantially better fits for both lung cancer and, especially, mesothelioma.

Although the best estimates of the potency of shorter fibers (5 < length < 10 mu m) is zero for the "all widths" and widths < 0.4 mu m metrics (or a small fraction of that of longer fibers for the widths > 0.2 mu m metric for mesothelioma), the hypothesis that these shorter fibers were nonpotent could not be rejected for any of these metrics. Expansion of these metrics to include a category for fibers with lengths < 5 mu m did not find any consistent evidence for any potency of these shortest fibers for either lung cancer or mesothelioma.

Despite the substantial improvements in fit over that provided by the traditional use of PCM, neither the "all widths" nor the widths < 0.4 mu m metrics (or any of the other metrics evaluated) completely resolve the differences in potency factors estimated in different occupational studies. Unresolved in particular is the discrepancy in potency factors for lung cancer from Quebec chrysotile miners and workers at the Charleston, SC, textile mill, which mainly processed chrysotile from Quebec. A leading hypothesis for this discrepancy is limitations in the fiber size distributions available for this analysis. Dement et al. (2007) recently analyzed by TEM archived air samples from the South Carolina plant to determine a detailed distribution of fiber lengths up to lengths of 40 mu m and greater. If similar data become available for Quebec, perhaps these two size distributions can be used to eliminate the discrepancy between these two studies.

Abstract  The most recent update of the U.S. Environmental Protection Agency (EPA) health assessment document for asbestos (Nicholson, 1986, referred to as “the EPA 1986 update”) is now 20 years old. That document contains estimates of “potency factors” for asbestos in causing lung cancer (KL’s) and mesothelioma (KM’s) derived by fitting mathematical models to data from studies of occupational cohorts. The present paper provides a parallel analysis that incorporates data from studies published since the EPA 1986 update. The EPA lung cancer model assumes that the relative risk varies linearly with cumulative exposure lagged 10 years. This implies that the relative risk remains constant after 10 years from last exposure. The EPA mesothelioma model predicts that the mortality rate from mesothelioma increases linearly with the intensity of exposure and, for a given intensity, increases indefinitely after exposure ceases, approximately as the square of time since first exposure lagged 10 years. These assumptions were evaluated using raw data from cohorts where exposures were principally to chrysotile (South Carolina textile workers, Hein et al., 2007; mesothelioma only data from Quebec miners and millers, Liddell et al., 1997) and crocidolite (Wittenoom Gorge, Australia miners and millers, Berry et al., 2004) and using published data from a cohort exposed to amosite (Paterson, NJ, insulation manufacturers, Seidman et al., 1986). Although the linear EPA model generally provided a good description of exposure response for lung cancer, in some cases it did so only by estimating a large background risk relative to the comparison population. Some of these relative risks seem too large to be due to differences in smoking rates and are probably due at least in part to errors in exposure estimates. There was some equivocal evidence that the relative risk decreased with increasing time since last exposure in theWittenoom cohort, but none either in the South Carolina cohort up to 50 years from last exposure or in the New Jersey cohort up to 35 years from last exposure. The mesothelioma model provided good descriptions of the observed patterns of mortality after exposure ends, with no evidence that risk increases with long times since last exposure at rates that vary from that predicted by the model (i.e., with the square of time). In particular, the model adequately described the mortality rate in Quebec chrysotile miners and millers up through >50 years from last exposure. There was statistically significant evidence in both the Wittenoom and Quebec cohorts that the exposure intensity-response is supralinear1 rather than linear. The best-fitting models predicted that the mortality rate varies as [intensity]0.47 for Wittenoom and as [intensity]0.19 for Quebec and, in both cases, the exponent was significantly less than 1 (p < .0001). Using the EPA models, KL’s and KM’s were estimated from the three sets of raw data and also frompublished data covering a broader range of environments than those originally addressed in the EPA 1986 update. Uncertainty in these estimates was quantified using “uncertainty bounds” that reflect both statistical and nonstatistical uncertainties. Lung cancer potency factors (KL’s) were developed from 20 studies from 18 locations, compared to 13 locations covered in the EPA 1986 update. Mesothelioma potency factors (KM’s) were developed for 12 locations compared to four locations in the EPA 1986 update. Although the 4 locations used to calculate KM in the EPA 1986 update include one location with exposures to amosite and three with exposures to mixed fiber types, the 14 KM’s derived in the present analysis also include 6 locations in which exposures were predominantly to chrysotile and 1 where exposures were only to crocidolite. The KM’s showed evidence of a trend, with lowest KM’s obtained fromcohorts exposed predominantly to chrysotile and highest KM’s from cohorts exposed only to amphibole asbestos, with KM’s from cohorts exposed to mixed fiber types being intermediate between the KM’s obtained from chrysotile and amphibole environments. Despite the considerable uncertainty in the KM estimates, the KM from the Quebec mines and mills was clearly smaller than those from several cohorts exposed to amphibole asbestos or a mixture of amphibole asbestos and chrysotile. For lung cancer, although there is some evidence of larger KL’s fromamphibole asbestos exposure, there is a good deal of dispersion in the data, and one of the largest KL‘s is from the South Carolina textile mill where exposures were almost exclusively to chrysotile. This KL is clearly inconsistent with the KL obtained from the cohort of Quebec chrysotile miners and millers. The KL’s and KM’s derived herein are defined in terms of concentrations of airborne fibers measured by phase-contrast microscopy (PCM), which only counts all structures longer than 5 μm, thicker than about 0.25 μm, and with an aspect ratio ≥3:1. Moreover, PCM does not distinguish between asbestos and nonasbestos particles. One possible reason for the discrepancies between the KL’s and KM’s from different studies is that the category of structures included in PCM counts does not correspond closely to biological activity. In the accompanying article (Berman and Crump, 2008) the KL’s and KM’s and related uncertainty bounds obtained in this article are paired with fiber size distributions from the literature obtained using transmission electron microscopy (TEM). The resulting database is used to define KL’s and KM’s that depend on both the size (e.g., length and width) and mineralogical type (e.g., chrysotile or crocidolite) of an asbestos structure. An analysis is conducted to determine how well different KL and KM definitions are able to reconcile the discrepancies observed herein among values obtained from different environments.

Abstract  Objective: In order to examine the associations between sinonasal cancer and occupational exposures other than wood dust and leather dust, the data from 12 case–control studies conducted in seven countries were pooled and reanalyzed. Methods: The pooled data set included 195 adenocarcinoma cases (169 men and 26 women), 432 squamous cell carcinomas (330 men and 102 women), and 3136 controls (2349 men and 787 women). Occupational exposures to formaldehyde, silica dust, textile dust, coal dust, flour dust, asbestos, and man-made vitreous fibers were assessed with a job-exposure matrix. Odds ratios (ORs) were adjusted for age, study, wood dust, and leather dust, or other occupational exposures when relevant. 95% confidence intervals (CIs) were estimated by unconditional logistic regression. Results: A significantly increased risk of adenocarcinoma was associated with exposure to formaldehyde. The ORs for the highest level of exposure were 3.0 (CI = 1.5–5.7) among men and 6.2 (CI = 2.0–19.7) among women. An elevated risk of squamous cell carcinoma was observed among men (OR = 2.5, CI = 0.6–10.1) and women (OR = 3.5, CI = 1.2–10.5) with a high probability of exposure to formaldehyde. Exposure to textile dust was associated with non-significantly elevated risk of adenocarcinoma, among women only: the OR for the high level of cumulative exposure was 2.5 (CI = 0.7–9.0). High level of asbestos exposure was associated with a significantly increased risk of squamous cell carcinoma among men (OR = 1.6, CI = 1.1–2.3). Conclusions: The results of this pooled analysis support the hypothesis that occupational exposure to formaldehyde increases the risk of sinonasal cancer, particularly of adenocarcinoma. They also indicate an elevated risk of adenocarcinoma among women exposed to textile dust, and suggest that exposure to asbestos may increase the risk of squamous cell carcinoma.

Abstract  Exposures to an amphibole fiber in Libby, Montana cause increases in malignant mesothelioma (MM), a tumor of the pleural and peritoneal cavities with a poor prognosis. Affymetrix microarray/GeneSifter analysis was used to determine alterations in gene expression of a human mesothelial cell line (LP9/TERT-1) by a non-toxic concentration (15×10(6) μm2/cm2) of unprocessed Libby six-mix and negative (glass beads) and positive (crocidolite asbestos) controls. Because manganese superoxide dismutase (MnSOD; SOD2) was the only gene upregulated significantly (p < 0.05) at both 8 and 24 h, we measured SOD protein and activity, oxidative stress and glutathione (GSH) levels to better understand oxidative events after exposure to non-toxic (15×10(6) μm2/cm2) and toxic concentrations (75×10(6) μm2/cm2) of Libby six-mix.

Exposure to 15×10(6) μm2/cm2 Libby six-mix elicited significant (p < 0.05) upregulation of one gene (SOD2; 4-fold) at 8 h and 111 gene changes at 24 h, including a 5-fold increase in SOD2. Increased levels of SOD2 mRNA at 24 h were also confirmed in HKNM-2 normal human pleural mesothelial cells by qRT-PCR. SOD2 protein levels were increased at toxic concentrations (75×10(6) μm2/cm2) of Libby six-mix at 24 h. In addition, levels of copper-zinc superoxide dismutase (Cu/ZnSOD; SOD1) protein were increased at 24 h in all mineral groups. A dose-related increase in SOD2 activity was observed, although total SOD activity remained unchanged. Dichlorodihydrofluorescein diacetate (DCFDA) fluorescence staining and flow cytometry revealed a dose- and time-dependent increase in reactive oxygen species (ROS) production by LP9/TERT-1 cells exposed to Libby six-mix. Both Libby six-mix and crocidolite asbestos at 75×10(6) μm2/cm2 caused transient decreases (p < 0.05) in GSH for up to 24 h and increases in gene expression of heme oxygenase 1 (HO-1) in LP9/TERT-1 and HKNM-2 cells.

Libby six-mix causes multiple gene expression changes in LP9/TERT-1 human mesothelial cells, as well as increases in SOD2, increased production of oxidants, and transient decreases in intracellular GSH. These events are not observed at equal surface area concentrations of nontoxic glass beads. Results support a mechanistic basis for the importance of SOD2 in proliferation and apoptosis of mesothelial cells and its potential use as a biomarker of early responses to mesotheliomagenic minerals.

Abstract  Asbestos induces DNA and chromosomal damage, but the DNA repair pathways protecting human cells against its genotoxicity are largely unknown. Polymorphisms in XRCC1 have been associated with altered susceptibility to asbestos-related diseases. However, it is unclear whether oxidative DNA damage repaired by XRCC1 contributes to asbestos-induced chromosomal damage.

We sought to examine the importance of XRCC1 in protection against genotoxic effects of crocidolite and Libby amphibole asbestos.

We developed a genetic model of XRCC1 deficiency in human lung epithelial H460 cells and evaluated genotoxic responses to carcinogenic fibers (crocidolite asbestos, Libby amphibole) and nongenotoxic materials (wollastonite, titanium dioxide).

XRCC1 knockdown sensitized cells to the clastogenic and cytotoxic effects of oxidants [hydrogen peroxide (H₂O₂), bleomycin] but not to the nonoxidant paclitaxel. XRCC1 knockdown strongly enhanced genotoxicity of amphibole fibers as evidenced by elevated formation of clastogenic micronuclei. Crocidolite induced primarily clastogenic micronuclei, whereas Libby amphibole induced both clastogenic and aneugenic micronuclei. Crocidolite and bleomycin were potent inducers of nuclear buds, which were enhanced by XRCC1 deficiency. Libby amphibole and H₂O₂ did not induce nuclear buds, irrespective of XRCC1 status. Crocidolite and Libby amphibole similarly activated the p53 pathway.

Oxidative DNA damage repaired by XRCC1 (oxidized bases, single-strand breaks) is a major cause of chromosomal breaks induced by crocidolite and Libby amphibole. Nuclear buds are a novel biomarker of genetic damage induced by exposure to crocidolite asbestos, which we suggest are associated with clustered DNA damage. These results provide mechanistic evidence for the epidemiological association between XRCC1 polymorphisms and susceptibility to asbestos-related disease.

Abstract  Knowledge of mortality patterns following exposure to asbestos has been determined mostly from cohort studies of men who were exposed to asbestos in their workplace. Women are more likely to have obtained their asbestos exposure domestically or from their environment.

2552 women and girls are documented to have lived in the blue asbestos mining and milling township of Wittenoom between 1943 and 1992 and were not involved in asbestos mining or milling. Quantitative asbestos exposure measurements were derived from periodic dust surveys undertaken in the industry and around the township. Death records were obtained for the period 1950-2004. Standardised mortality ratios (SMRs) were calculated to compare the Wittenoom women's mortality with that of the Western Australian female population.

There were 425 deaths, including 30 from malignant mesothelioma. There was excess mortality for all causes of death (SMR = 1.13), all neoplasms (SMR = 1.42), symptoms, signs and ill defined conditions (SMR = 6.35), lung cancer (SMR = 2.15) and pneumoconiosis (SMR = 11.8). Mortality from cancer of the ovary (SMR = 1.52), upper aerodigestive cancers (SMR = 2.70) and tuberculosis (SMR = 5.38) was increased but not significantly. The risk of death from mesothelioma was increased, but not significantly, in residents known to have lived with or washed the clothes of an Australian Blue Asbestos Company asbestos worker (HR = 2.67, 95% CI 0.77 to 9.21; HR = 2.61, 95% CI 0.85 to 7.99, respectively).

Women who were former residents of Wittenoom, exposed to asbestos in their environment or in their home, have excess cancer mortality, including mesothelioma, compared with the Western Australian female population.

Abstract  A cohort of 1,154 employees, mainly women, who had worked 1940-1945 on the manufacture of military gas masks using filter pads containing 20% crocidolite, was traced through 2003, by which time 65 were known to have died from mesothelioma. The last known death with mesothelioma was in 1994, whereas a further 5 cases would have been expected in those with known duration of exposure. Lung tissue samples, from 50 deaths from mesothelioma and 20 other causes, had been analyzed for mineral fiber content. For ten of the mesothelioma cases data on fiber size were collected. Crocidolite fiber concentrations were analyzed in relation to exposure by time and duration. Fiber concentrations overall fell fairly steadily by decade of death, and increased with length of exposure up to 36 months and then fell sharply. The annual rate of elimination estimated by regression was 7.5% corresponding to a half life of 9.2 years. The proportion of fibers longer than 6 mum increased over time implying that the shorter fibers were eliminated more rapidly than the longer ones. The decline in concentrations with time confirms the hypothesis that crocidolite and, by inference, other amphibole fibers are slowly removed from the lung, but since the longer more carcinogenic fibers were cleared more slowly it is unclear to what extent this clearance explains the slowing down of the increase in mesothelioma mortality from about 40 years from the most recent exposure. The exact biostatistical models which most closely conform with the data remain open to question.

Abstract  BACKGROUND:Several papers have reported state-wide projections of mesothelioma deaths, but few have computed these predictions in selected exposed groups. OBJECTIVE: To predict the future deaths attributable to asbestos in a cohort of railway rolling stock workers. METHODS: The future mortality of the 1,146 living workers has been computed in term of individual probability of dying for three different risks: baseline mortality, lung cancer excess, mesothelioma mortality. Lung cancer mortality attributable to asbestos was calculated assuming the excess risk as stable or with a decrease after a period of time since first exposure. Mesothelioma mortality was based on cumulative exposure and time since first exposure, with the inclusion of a term for clearance of asbestos fibres from the lung. RESULTS: The most likely range of the number of deaths attributable to asbestos in the period 2005-2050 was 15-30 for excess of lung cancer, and 23-35 for mesothelioma. CONCLUSION: This study provides predictions of asbestos-related mortality even in a selected cohort of exposed subjects, using previous knowledge about exposure-response relationship. The inclusion of individual information in the projection model helps reduce misclassification and improves the results. The method could be extended in other selected cohorts.

Abstract  Libby, Montana is the site of a large vermiculite deposit that was mined between 1920 and 1990 to extract vermiculite for commercial applications such as insulation, gardening products, and construction materials. The Libby vermiculite deposit also contains amphibole minerals including tremolite, actinolite, richterite, and winchite. Historically, Libby mine workers experienced high exposures to amphibole structures, and, as a group, have experienced the health consequences of those occupational exposures. It has been suggested that Libby residents also have been and continue to be exposed to amphibole structures released during the vermiculite mining operations and therefore are at increased risk for disease. The Agency for Toxic Substance and Disease Registry (ATSDR) conducted two epidemiological-type studies of residents living in Libby and the surrounding areas to assess these risks. The Environmental Protection Agency (EPA) collected and analyzed exposure data in Libby and used those data to project risks of asbestos-associated disease for Libby residents. The EPA has placed the Libby Asbestos Site, which includes the mine and the town of Libby, on its National Priority List of hazardous waste sites in need of clean up. This article presents a review of the exposure studies conducted in Libby and an analysis of health risks based on the data collected in those studies. Libby mine workers have experienced elevated levels of asbestos-associated disease as a consequence of their occupational exposures to amphibole structures. Libby residents' exposures typically are substantially lower than mine workers' historical exposures, and the health risk projections for residents are, accordingly, substantially lower.

Abstract  Research was conducted in order to assess potential exposure to asbestos while harvesting firewood from amphibole-contaminated trees near Libby, MT, USA. Three firewood-harvesting simulations took place in the summer and fall of 2006 in the Kootenai Forest inside the US Environmental Protection Agency (EPA) restricted zone surrounding the former W.R. Grace vermiculite mine. Another simulation was conducted near Missoula, MT, USA, which served as the control. The work practices following each simulation were consistent throughout each trial. Personal breathing zone (PBZ) asbestos concentrations were measured by phase contrast microscopy (PCM) and transmission electron microscopy (TEM). Surface wipe samples of personal protective clothing were measured by TEM. The mean (n = 12) PBZ PCM sample time-weighted average (TWA) concentration was 0.29 fibers per milliliter, standard deviation (SD = 0.54). A substantial portion (more than five fibers per sample) of non-asbestos fibers (cellulose) was reported on all PBZ samples (excluding field blanks) when analyzed by TEM. The mean (n = 12) PBZ TEM sample TWA concentration for amphibole fibers <5-microm long was 0.15 fibers per milliliter (SD = 0.21) and the mean (n = 12) PBZ TEM concentration for amphibole fibers >5-microm long was 0.07 fibers per milliliter (SD = 0.08). Substantial amphibole fiber concentrations were revealed on Tyvek clothing wipe samples. The mean concentration (n = 12) was 29 826 fibers per square centimeter (SD = 37 555), with 91% (27 192 fibers per square centimeter) comprised fibers <5-microm long. There were no significant differences in PBZ and wipe sample concentrations among the tasks performed by four investigators. Each of these three simulations were consistent in demonstrating that amphibole fibers are released from tree reservoirs during firewood-harvesting activities in asbestos-contaminated areas and that the potential for exposure exists during such activities.

Abstract  This report provides an update of the mortality experience of a cohort of South Carolina asbestos textile workers.

A cohort of 3072 workers exposed to chrysotile in a South Carolina asbestos textile plant (1916-77) was followed up for mortality through 2001. Standardised mortality ratios (SMRs) were computed using US and South Carolina mortality rates. A job exposure matrix provided calendar time dependent estimates of chrysotile exposure concentrations. Poisson regression models were fitted for lung cancer and asbestosis. Covariates considered included sex, race, age, calendar time, birth cohort and time since first exposure. Cumulative exposure lags of 5 and 10 years were considered by disregarding exposure in the most recent 5 and 10 years, respectively.

A majority of the cohort was deceased (64%) and 702 of the 1961 deaths occurred since the previous update. Mortality was elevated based on US referent rates for a priori causes of interest including all causes combined (SMR 1.33, 95% CI 1.28 to 1.39); all cancers (SMR 1.27, 95% CI 1.16 to 1.39); oesophageal cancer (SMR 1.87, 95% CI 1.09 to 2.99); lung cancer (SMR 1.95, 95% CI 1.68 to 2.24); ischaemic heart disease (SMR 1.20, 95% CI 1.10 to 1.32); and pneumoconiosis and other respiratory diseases (SMR 4.81, 95% CI 3.84 to 5.94). Mortality remained elevated for these causes when South Carolina referent rates were used. Three cases of mesothelioma were observed among cohort members. Exposure-response modelling for lung cancer, using a linear relative risk model, produced a slope coefficient of 0.0198 (fibre-years/ml) (standard error 0.00496), when cumulative exposure was lagged 10 years. Poisson regression modelling confirmed significant positive relations between estimated chrysotile exposure and lung cancer and asbestosis mortality observed in previous updates of this cohort.

This study confirms the findings from previous investigations of excess mortality from lung cancer and asbestosis and a strong exposure-response relation between estimated exposure to chrysotile and mortality from lung cancer and asbestosis.

Abstract  The case history is presented of a lung transplant recipient who developed malignant mesothelioma. This is thought to be the first such report. Mesothelioma should be suspected in lung transplant recipients with a haemorrhagic pleural effusion in the native lung when there is no convincing evidence for bronchogenic carcinoma or post transplant lymphoproliferative disease, even in the absence of exposure to asbestos.

Abstract  SV40 is a DNA tumor virus thrust upon human populations primarily as a contaminant in various vaccine preparations. Some estimates suggest that millions of people are currently infected with the virus. The virus causes primary brain tumors, bone tumors, lymphomas, and mesotheliomas when injected into some rodent models. It has also been detected in a similar spectrum of human tumors. However, epidemiological studies have failed to conclusively demonstrate a higher incidence of disease in affected populations. To date, over 60 reports from 49 different laboratories have shown SV40 sequences in tissues from human cancer patients. Six studies, however, have failed to detect evidence of virus in similar tissues. Some have suggested that SV40 may act as a cocarcinogen with asbestos to cause mesothelioma formation, or that it may be responsible for the 10-20% of mesotheliomas with no reported history of asbestos exposure. This report briefly covers the historical evidence for SV40 carcinogenesis and then covers experiments now underway to better understand the role of SV40 in human mesotheliomas.

Abstract  ICD-9 code 163 (malignant neoplasm of pleura) listed as underlying cause of death detected only 40% of Scottish mesothelioma cases (all body sites) from the cancer registry in 1981-1999. This is lower than both the previously published 55% figure, derived from UK mesothelioma register data 1986-1991, which is based on any mention of mesothelioma on death certificates, cross-referenced to cancer registry data, and the 44% figure derived from Scottish mortality data 1981-1999, which captured any mention of mesothelioma on the death certificate. Detection from cancer registry data increased to 75% under ICD-10 in Scotland, confirming earlier predictions of the benefit of ICD-10's more specific mesothelioma codes. Including the accidental poisoning codes E866.4 (ICD-9) and X49 (ICD-10), covering poisoning by 'unspecified' and 'other' causes, which appear to have been used as coding surrogates for mesothelioma when asbestos exposure was explicitly mentioned in deaths suggestive of a mesothelioma, and which are recorded as the underlying cause of death in 4-7% of mesotheliomas, may improve the mesothelioma detection rate in future epidemiological studies.

Abstract  In occupational epidemiology, it is often possible to obtain repeated measurements of exposure from a sample of subjects (workers) who belong to exposure groups associated with different levels of exposure. Average exposures from a sample of workers can be assigned to all members of that group including those who are not sampled, leading to a group-based exposure assessment. We discuss how this group-based exposure assessment leads to approximate Berkson error model when the number of subjects with exposure measurements in each group is large, and how the error variance approximates the between-worker variability. Under the normality assumption of exposures and with moderately large number of workers in each group, there is attenuation in the estimate of the association parameter, the magnitude of which depends on the sizes of the between-worker variability and the true association parameter. Approximate equations for attenuation have been derived in logistic and Cox proportional-hazards models. These equations show that the attenuation in Cox proportional-hazards models is generally more severe than in logistic regression. Furthermore, when the between-worker variability is large, our simulation study found that the approximation by equation is poor for the Cox proportional-hazards model. If the number of subjects is small, the approximation does not hold for either model.

Abstract  This epidemiological study was conducted to determine whether high-resolution computed tomography (HRCT) is useful to screen for pulmonary abnormalities in people exposed to vermiculite containing asbestos. During June-September 2001, we evaluated HRCT of 353 people in Libby, MT, who had been exposed to asbestiform minerals associated with vermiculite. Of these, 334 participants of the summer 2000 medical testing program underwent HRCT of the chest at St. John's Lutheran Hospital and 19 eligible people who recently had undergone an HRCT scan at the same facility and under the same testing protocol allowed the study reviewers to use that scan. All 353 study participants were former vermiculite mine/mill workers (n = 55), their household contacts (n = 99), and people exposed to vermiculite through recreational or other activities (n = 199). Participants' 2000 medical testing results indicated only one of the three B-reader chest radiograph reviewers had reported a pleural abnormality (indeterminate chest radiograph). Three expert computer tomography (CT) scan evaluators reviewed the HRCT scans and identified pleural abnormalities in 98 (27.8%) of the 353 participants whose previous chest radiographs were classified indeterminate. Of these 98 people, 69 (70.4%) were either former vermiculite mine/mill workers or household contacts, and 40 (40.8%) showed pleural calcification on HRCT. Thirty out of the 40 people with pleural calcification reported having no occupational exposure to either Libby vermiculite or asbestos. Our findings indicate that low-dose HRCT can be considered for screening certain former vermiculite mine/mill workers and their household contacts who have indeterminate chest radiographs and may be useful for diagnosing a suspicious finding on a chest radiograph, particularly in a high-risk person.

Abstract  We conducted a case-control study on asbestos exposure and presence of SV40 in tumor samples of malignant mesotheliomas (MMs) and bladder urotheliomas (BUs). PCR analysis revealed the presence of SV40 DNA (SV40+) in eight (42.1%) MMs and 6 (33.3%) BUs. The odds ratio for MM Asb- and SV40+ was 0.4 [95% confidence interval (95% CI), 0.03-4.0], for Asb+ and SV40- was 3.6 (95% CI, 0.6-21.0), and for Asb+ and SV40+ was 12.6 (95% CI, 1.2-133.9). Our results suggest that SV40 increases the risk of MM among individuals exposed to asbestos.

Abstract  A cohort of 889 men and 1077 women employed for at least 1 month between 1946 and 1984 by a former Italian leading asbestos (mainly textile) company, characterised by extremely heavy exposures often for short durations, was followed up to 1996, for a total of 53,024 person-years of observation. Employment data were obtained from factory personnel records, while vital status and causes of death were ascertained through municipality registers and local health units. We observed 222 cancer deaths compared with 116.4 expected (standardized mortality ratio, SMR=191). The highest ratios were found for pleural (SMR=4105), peritoneal (SMR=1817) and lung (SMR=282) cancers. We observed direct relationships with duration of employment for lung and peritoneal cancer, and with time since first employment for lung cancer and mesothelioma. Pleural cancer risk was independent from duration (SMR=3428 for employment <1 year, 7659 for 1-4 years, 2979 for 5-9 years and 2130 for > or =10 years). Corresponding SMRs for lung cancer were 139, 251, 233 and 531. Nonsignificantly increased ratios were found for ovarian (SMR=261), laryngeal (SMR=238) and oro-pharyngeal (SMR=226) cancers. This study confirms and further quantifies the central role of latency in pleural mesothelioma and of cumulative exposure in lung cancer.

Abstract  Inhalation of asbestos fibers leads to interstitial lung disease (asbestosis) characterized by inflammation and fibrosis. The pathogenesis of asbestosis is not fully understood, but reactive oxygen species are thought to play a central role. Extracellular superoxide dismutase (EC-SOD) is an antioxidant enzyme that protects the lung in a bleomycin-induced pulmonary fibrosis model, but its role has not been studied in asbestos-mediated disease. EC-SOD is found in high levels in the extracellular matrix of lung alveoli because of its positively charged heparin-binding domain. Proteolytic removal of this domain results in clearance of EC-SOD from the matrix of tissues. We treated wild-type C57BL/6 mice with 0.1 mg of crocidolite asbestos by intratracheal instillation and euthanized them 24 h later. Compared with saline- or titanium dioxide-treated control mice, bronchoalveolar lavage fluid (BALF) from asbestos-treated mice contained significantly higher total protein levels and increased numbers of inflammatory cells, predominantly neutrophils, indicating acute lung injury in response to asbestos. Decreased EC-SOD protein and activity were found in the lungs of asbestos-treated mice, whereas more EC-SOD was found in the BALF of these mice. The EC-SOD in the BALF was predominantly in the proteolyzed form, which lacks the heparin-binding domain. This redistribution of EC-SOD correlated with development of fibrosis 14 days after asbestos exposure. These data suggest that asbestos injury leads to enhanced proteolysis and clearance of EC-SOD from lung parenchyma into the air spaces. The depletion of EC-SOD from the extracellular matrix may increase susceptibility of the lung to oxidative stress during asbestos-mediated lung injury.

Abstract  Fibrous tremolite is a widespread amphibole asbestiform mineral, airborne fibres of which constitute an environmental hazard in Libby, Montana, northern California, and elsewhere.

To determine excess risk from lung cancer, mesothelioma, and all-cause mortality in a cohort of men exposed to tremolite, but no other form of asbestos.

Mortality by certified cause and various measures of exposure to tremolite and related amphibole fibres was assessed in a cohort of 406 vermiculite mineworkers in Libby, Montana, employed before 1963 and followed until 1999.

Total deaths were: lung cancer 44 (SMR 2.40), non-malignant respiratory disease (NMRD) 51 (SMR 3.09), all causes 285 (SMR 1.27); included among the total were 12 deaths ascribed to mesothelioma (4.21% of all deaths). Adjusted linear increments in relative risks (per 100 f/ml.y), estimated by Poisson regression, were: lung cancer (0.36, 95% CI 0.03 to 1.20), NMRD (0.38, 95% CI 0.12 to 0.96), and all deaths (0.14, 95% CI 0.05 to 0.26).

The all-cause linear model would imply a 14% increase in mortality for mine workers exposed occupationally to 100 f/ml.y or about 3.2% for a general population exposed for 50 years to an ambient concentration of 0.1 f/ml. Amphibole fibres, tremolite in particular, are likely to be disproportionately responsible for cancer mortality in persons exposed to commercial chrysotile, but to what extent cannot be readily assessed.

Abstract  Mining, handling, processing, and personal or commercial use of asbestos-contaminated vermiculite have led to widespread contamination of the Libby, Montana, area. We initiated a medical testing program in response to reports of respiratory illness in the community. The purpose of this analysis was to identify and quantify asbestos-related radiographic abnormalities among persons exposed to vermiculite in Libby and to examine associations between these outcomes and participants' self-reported exposures. A cross-sectional interview and medical testing were conducted in Libby from July through November 2000 and from July through September 2001. A total of 7,307 persons who had lived, worked, or played in Libby for at least 6 months before 31 December 1990 completed the interview. Of those, 6,668 participants > or = 18 years of age received chest radiographs to assess the prevalence of pleural and interstitial abnormalities. We observed pleural abnormalities in 17.8% of participants and interstitial abnormalities in < 1% of participants undergoing chest radiography. We examined 29 occupational, recreational, household, and other exposure pathways in the analysis. The prevalence of pleural abnormalities increased with increasing number of exposure pathways, ranging from 6.7% for those who reported no apparent exposures to 34.6% for those who reported > or = 12 pathways. The factors most strongly associated with pleural abnormalities were being a former W.R. Grace worker, being older, having been a household contact of a W.R. Grace worker, and being a male. In addition to being a former W.R. Grace worker, environmental exposures and other nonoccupational risk factors were also important predictors of asbestos-related radiographic abnormalities.

Abstract  Background: Asbestos inhalation is recognized as an exposure that increases the risk for the development of lung disease. It is unique among dusts in that it is both a carcinogen and capable of inducing extrapulmonary responses such as pleural thickening and fibrosis as well as malignancy. One feature of asbestos suggested as crucial in its pathological activity is its fibrous morphology. Long fibers that have been inhaled are cleared less readily and are thus more persistent in the body. Furthermore certain experimental models link fiber length to levels of risks for development of certain diseases. The present review will survey the data on this subject. Methods: The review considers experimental models that have been used to assess the response to various lengths of fibers in animal models in addition to data obtained from studies of human materials. The review also emphasizes the importance in defining the method by which a sample is categorized. Results: Data are offered which support the potential for longer fibers as well as shorter fibers to contribute to pathological responses. Conclusions: The data presented argue that asbestos fibers of all lengths induce pathological responses and that caution should be exerted when attempting to exclude any population of inhaled fibers, based on their length, from being contributors to the potential for development of asbestos-related diseases.