Non-asbestiform elongate mineral particles and mesothelioma risk: Human and experimental evidence.

The presentations in this session of the Monticello II conference were aimed at summarizing what is known about asbestiform and non-asbestiform elongate mineral particles (EMPs) and mesothelioma risks based on evidence from experimental and epidemiology studies. Dr. Case discussed case reports of mesothelioma over the last several decades. Dr. Taioli indicated that the epidemiology evidence concerning non-asbestiform EMPs is weak or lacking, and that progress would be limited unless mesothelioma registries are established. One exception discussed is that of taconite miners, who are exposed to grunerite. Drs. Mandel and Odo noted that studies of taconite miners in Minnesota have revealed an excess rate of mesothelioma, but the role of non-asbestiform EMPs in this excess incidence of mesothelioma is unclear. Dr. Becich discussed the National Mesothelioma Virtual Bank (NMVB), a virtual mesothelioma patient registry that includes mesothelioma patients' lifetime work histories, exposure histories, biospecimens, proteogenomic information, and imaging data that can be used in epidemiology research on mesothelioma. Dr. Bernstein indicated that there is a strong consensus that long, highly durable respirable asbestiform EMPs have the potential to cause mesothelioma, but there is continued debate concerning the biodurability required, and the dimensions (both length and diameter), the shape, and the dose associated with mesothelioma risk. Finally, Dr. Nel discussed how experimental studies of High Aspect Ratio Engineered Nanomaterials have clarified dimensional and durability features that impact disease risk, the impact of inflammation and oxidative stress on the epigenetic regulation of tumor suppressor genes, and the generation of immune suppressive effects in the mesothelioma tumor microenvironment. The session ended with a discussion of future research needs.

A case study of the translocation, bioprocessing and tissue interactions of EMP following inhalation exposure.

Human autopsied lung sections from a resident in the Quebec asbestos region were examined. The study utilized high resolution transmission electron microscopy, scanning transmission electron microscopy (HRTEM/STEM) with the analytical capabilities of electron energy loss spectroscopy (EELS) and energy dispersive spectroscopy (EDS) detectors. We report the first analytical ultrastructural characteristics of EMPs, detailing chemical concentration gradients inside the iron-protein coatings and lateral elemental gradients in the local tissue regions. It is shown that the EMPs are subjected to bioprocessing which involves physicochemical transformations and also an elemental transport mechanism that alters the inhaled EMP as well as the surrounding cellular matrix. At high resolution imaging the iron-rich coating around the EMP was observed to have a distinct channel-like nanostructure with some parallel aligned nanofibrils that are reminiscent of tooth enamel which consists of biomineralized nanocomposites with alternating organic/inorganic matrices.

Overreliance on a single study: there is no real evidence that applying quality criteria to exposure in asbestos epidemiology affects the estimated risk.

A critical need exists for reliable risk management policies and practices that can effectively mitigate asbestos-related health threats, and such policies and practices need to be based on sound science that adequately distinguishes hazardous situations from those that are not. Toward that end, the disparate means by which study quality has been addressed in recent meta-analyses used to establish potency factors (K ( L ) and K ( M ) values) for asbestos cancer risks were compared by conducting additional sensitivity analyses. Results suggest that, other than placing undue emphasis on the influence of the K ( L ) and K ( M ) values reported from a single study, there appears to be little to no evidence of a systematic effect of study quality on K ( L ) or K ( M ) values; none of the findings warrant excluding studies from current or future meta-analyses. Thus, we argue that it is better to include as much of the available data as possible in these analyses while formally addressing uncertainty as part of the analysis itself, rather than sequentially excluding studies based on one type of limitation or another. Throwing out data without clearly proving some type of bias is never a good idea because it will limit both the power to test various hypotheses and the confidence that can be placed in any findings that are derived from the resulting, truncated data set. We also believe that it is better to identify the factors that contribute to variation between studies included in a meta-analysis and, by adjusting for such factors as part of a model, showing that the disparate values from individual studies can be reconciled. If such factors are biologically reasonable (based on other evidence) and, if such a model can be shown to fit the data from all studies in the meta-analysis, the model is likely to be predictive of the parameters being evaluated and can then be applied to new (unstudied) environments.

Pleural mesothelioma surveillance: validity of cases from a tumour registry.

BACKGROUND: Pleural mesothelioma is a rare tumour associated with exposure to asbestos fibres. Fewer than than one-quarter of cases registered in the Quebec Tumour Registry (QTR) have been compensated as work-related. While establishing a surveillance system, this led to questioning as to whether there has been over-registration of cases that are not authentic pleural mesotheliomas in the QTR. OBJECTIVE: To assess whether registered cases of pleural mesothelioma could be confirmed. METHODS: A medical chart review was designed to assess the proportion of mesothelioma cases newly registered in the QTR in 2001/2002 that could be confirmed. For each registered case, clinical, medical imaging and pathology information were sought and, occasionally, additional immunohistochemistry staining was obtained. Three specialists - a chest physician, a radiologist and a pathologist - reviewed the available information and material, coding each mesothelioma case as to degree of certainty of the mesothelioma diagnosis. RESULTS: The QTR reported 190 incident cases of mesothelioma (81% males) for the period. The specialists classified 81% of charts as 'certain/probable' or 'possible' mesotheliomas, 8% as 'unlikely to be a mesothelioma' and 11% as 'not a mesothelioma'. After excluding chart summaries of unsatisfactory quality, 87% to 88% of the charts were classified as 'certain/probable' or 'possible' mesotheliomas, and 9% to 11% were still considered 'not a mesothelioma'. CONCLUSION: Tumour registry data are a valid source of information for mesothelioma surveillance. While there is some over-registration of mesothelioma cases in the QTR, a significant majority of registered cases appeared to be authentic. Over-registration cannot explain the greater proportion of cases that were not compensated.

Accuracy of urine cytology and the significance of an atypical category.

The "atypical urothelial cell" cytologic category is nonstandardized. We subclassify atypical cases to "atypical, favor a reactive process" or "atypical, unclear if reactive or neoplastic." We evaluated the predictive significance of atypical cases by looking at their histologic follow-up. Among the 1,114 patients and 3,261 specimens included, 282 specimens had histologic follow-up. An atypical diagnosis did not carry a significant increased risk of urothelial neoplasia compared with the benign category. Although an "atypical unclear" diagnosis carried a higher rate of detection of high-grade cancer on follow-up biopsy in comparison with "atypical reactive" or "negative" diagnoses (26/58 [45%] vs 15/52 [29%] and 16/103 [15.5%], respectively), this difference was not statistically significant. These results suggest that dividing atypical cases into 2 categories based on the level of cytologic suspicion of cancer does not add clinically relevant information within the atypical category. They also raise the question of the significance of the atypical category altogether.

Risk of mesothelioma and occupational exposure to asbestos and man-made vitreous fibers: evidence from two case-control studies in Montreal, Canada.

OBJECTIVE: To examine the effects of exposure to occupational asbestos and man-made vitreous fibers (MMVF) across a wide range of occupations on risk of mesothelioma. METHODOLOGY: Two population-based case-control studies (1979-1986 and 1996-2001) provided 35 histologically confirmed mesothelioma cases and 1965 controls. A detailed job history was obtained to evaluate occupational exposure to many agents, including asbestos and MMVF. RESULTS: The mesothelioma odds ratio for exposure to any asbestos type was 3.7 (95% confidence interval = 1.7 to 7.8). The subset exposed to amphibole fibers experienced an odds ratio = 7.0 (95% confidence interval = 2.7 to 18.5). Effects of MMVF could not be disentangled from those of asbestos. DISCUSSION: In workers with exposure levels lower than in most historical cohort studies and across a wide range of industries, a strong association was found between asbestos, especially when it was amphibole, and mesothelioma.

Occupational exposure to asbestos and man-made vitreous fibers, and risk of lung cancer: evidence from two case-control studies in Montreal, Canada.

OBJECTIVE: To examine the effects of occupational asbestos and man-made vitreous fibers (MMVF) on the risk of lung cancer in two population-based case-control studies entailing exposure at lower levels than in historic cohort studies. METHODOLOGY: Study I (1979 to 1986) comprised 857 cases and 1066 population and cancer controls. Study II (1996 to 2001) comprised 858 cases and 1295 population controls. A detailed job history was obtained to evaluate lifetime occupational exposure to 294 agents, including asbestos and MMVF. RESULTS: We found increased risks for substantial exposure to asbestos (odds ratio = 1.78; 95% confidence interval: 0.94 to 3.36). The corresponding odds ratio for substantial exposure to MMVF was 1.10 (95% confidence interval: 0.37 to 3.22). DISCUSSION: Low and moderate levels of exposure to asbestos, as encountered in this population, were associated with some excess risk of lung cancer. Results for MMVF were inconclusive.

Correlation of cytotechnologists' parameters with their performance in rapid prescreening of papanicolaou smears.

BACKGROUND: Efficient quality control is essential to ensure high sensitivity of Papanicolaou (Pap) smears. For this purpose, rescreening of 10% random negative smears is increasingly felt to be ineffective. Rapid rescreening (RR) of all negative Pap smears is more practical and has received widespread acceptance, especially in Europe, although its sensitivity is difficult to monitor and its retrospective nature may influence the vigilance of the screeners. The method of rapid prescreening (RPS) overcomes these drawbacks because rapid review of Pap smears precedes full screening. METHODS: All routine conventional Pap smears (n = 8364) over 2 months underwent RPS by 12 cytotechnologists, followed by full screening. Data were analyzed to determine correlation between the RPS sensitivity of individual cytotechnologists and both their sensitivity in full screening and their years of experience as cytotechnologists. RESULTS: There was a striking variability in sensitivity (15.4%-72.7%) among the 12 screeners with an atypical squamous cells of undetermined significance (ASCUS) threshold. There was no correlation between RPS sensitivity of individual cytotechnologists with either their sensitivity in full screening or their years of experience as cytotechnologists. CONCLUSIONS: The skills required of a cytotechnologist for achieving a high sensitivity in RPS are apparently different from those of full screening and are independent of the sensitivity of the screeners at full screening or of the years of experience as cytotechnologists.

Mineralogical and exposure determinants of pulmonary fibrosis among Québec chrysotile miners and millers.

OBJECTIVES: Lung fibre content was determined for 86 former chrysotile miners and millers in two Québec mining regions: Thetford mines (TM) and the Asbestos region (AR). METHODS: Fibres were assessed using transmission electron microscopy (TEM) and energy dispersive X-ray spectrometry (EDS). Asbestos body (AB) concentrations were assessed by microscopy of tissue digests. Corresponding histological lung tissue sections were quantitatively graded for the severity of interstitial fibrosis on a 12-point scale. Fibrosis score and its associations with (1) fibre concentrations and fibre dimensions within three fibre length intervals (less than 5 microm, 5-10 microm, and over 10 microm), and (2) several exposure variables were evaluated using correlation coefficients and regression techniques. RESULTS: Concentration of short (<5 microm) tremolite fibres was the best predictor of fibrosis grade in both mining groups (r=0.44, P<0.01 and r=0.39, P<0.01 for TM and AR, respectively). Chrysotile fibre concentration showed a lower correlation with the fibrosis grade for subjects from TM only. Long (>10 microm) amosite fibre concentration showed a linear relationship with the fibrosis score in miners and millers from AR. Exposure variables, including smoking, had no predictive value for fibrosis grade. Within fibre length categories, fibre dimension was not related to the fibrosis score. CONCLUSION: Lung fibre concentration as measured by TEM/EDS, especially that of short (<5 microm) tremolite fibres, is a better predictor of fibrosis grade in these two groups of chrysotile miners than either the concentration of ABs or the duration of exposure. Due to the limitation of our counting method, almost all fibres longer than 10 microm observed in this study were shorter than 14 microm. Thus, if length plays a role in fibrogenesis, it may be related to fibres of greater length than those covered in this study.