Weinig verbetering overlevingskansen longkanker en mesothelioom

23-08-2005

De overlevingskansen van kankerpatiënten in Noord-Holland/Flevoland zijn sinds 1988 duidelijk gestegen.Bij sommige vormen van kanker is echter weinig verbetering opgetreden. Dit geldt bijvoorbeeld voor longkanker en mesothelioom (longvlies-/buikvlieskanker). Bron: IKCnet.nl, 1 augustus 2005. Meer http://www.ikcnet.nl/nieuws/index.php?id=1220

Noors onderzoek: verhoogd risico op maag-darmkanker

23-08-2005

Een cohort van 726 vuurtorenwachters dat in de periode vanaf 1917 tot 1967 werkzaam was geweest werd onderzocht op kankerincidentie in de periode 1960 tot 2002. Bij de subgroep die asbest via drinkwater had binnengekregen werd een relatief hoge incidentie van maag-darmkanker gevonden. Bron: Kjaerheim, K. et al. (2005).Cancer of the gastrointestinal tract and exposure to asbestos in drinking water among lighthouse keepers (Norway). Cancer causes and control. vol. 16 (2005), afl. 5, pag. 593-598 (6).

Kjaerheim, Kristina. Ulvestad, Bente. Martinsen, Jan Ivar. Andersen, Aage / In: Cancer causes and control. vol. 16 (2005), afl. 5, pag. 593-598 (6) / 2005

Abstract

Objective Previous studies of predominantly ecological design have indicated a possible elevation of gastrointestinal cancer risk in population groups exposed to drinking water contaminated with asbestos from natural sources or asbestos’ cement containing water pipes. In the present study the possible effect of ingested asbestos fibers on gastrointestinal cancer risk was investigated in an occupational group where a proportion of the employees was exposed to asbestos in their drinking water.

Method A cohort of 726 lighthouse keepers first employed between 1917 and 1967 were followed up for cancer incidence from 1960 to 2002. The standardized incidence ratio (SIR) was calculated as the number of new cancer cases divided by the expected number based on five-year age and sex specific incidence rates in the general rural population of Norway. A 95% confidence interval (CI) was calculated for all SIR values assuming a Poisson distribution of the cancer cases.

Results Risk of stomach cancer was elevated in the whole cohort (SIR: 1.6, CI: 1.0-2.3), in the subgroup with definite asbestos exposure (SIR: 2.5, CI: 0.9-5.5), and when the group was followed for 20&#8201.years and more after first possible exposure (SIR: 1.7, CI: 1.1-2.7). Less consistent results were found for colon cancer. SIR was 1.5 (CI: 0.9-2.2) overall, 0.8 (CI: 0.1-2.9) among the exposed, and 1.6 (CI: 1.0-2.5) twenty years and more after first possible exposure.

Conclusion The results support the hypothesis of an association between ingested asbestos and gastrointestinal cancer risk in general and stomach cancer risk specifically.

Australië: dierexperimenteel onderzoek naar vitamine E bij mesothelioom

14-07-2005

Alpha-TOS, een soort vitamine E, heeft in experimenten met muizen mesothelioomkankercellen gedood en de groei van tumoren tegengehouden, zegt de Australische celbioloog Dr. Neuzil. Hij hoopt dat het middel over ongeveer 2 jaar bij mensen kan worden getest.

Bron: The Courier Mail, Daily Telegraph, 23 mei 2005.

The Courier Mail (Queensland, Australia)

May 23, 2005 Monday

HEADLINE: Vitamin cancer treatment hope

BODY:

A VITAMIN E-related compound may kill deadly cancer cells caused by asbestos exposure, says an Australian cell biologist who has already established its success in trials using mice.

Gold Coast-based Griffith University researcher Jiri Neuzil said alpha-TOS, which is closely related to vitamin E, killed mesothelioma cancer cells in experiments with mice.

Most victims of mesothelioma, an aggressive cancer that destroys a protective membrane covering internal organs including the lungs, have inhaled asbestos particles.

Dr Neuzil said alpha-TOS also halted growth of mesothelioma tumours, for which there is currently no cure, under a five-year study involving researchers from Australia, Italy and the Czech Republic.

He said the compound had also showed hints of suppressing breast cancer, melanoma, lung cancer and colon cancer tumours in animal experiments. Dr Neuzil said alpha-TOS would ultimately be put to the test in human trials, which he hoped to begin within two years.

Alpha-TOS was selective because it pursued mesothelioma cancer cells but caused only minor damage, if any, to normal cells in mice, he said.

Dr Neuzil said he stumbled on the compound’s promising qualities “by mistake five years ago.

Australië: onderzoek naar vitamines en asbestose

14-07-2005

In de West-australische plaats Wittenoom werd van 1943 tot 1966 het gevaarlijke blauwe asbest gewonnen (crocidoliet). In 2002 werden 1885 inwoners, waarvan 1042 (ex-)werknemers onderzocht op asbestose (stoflongen) en bepaalde vitamine-niveaus in het bloed (retinol, caroteen en vitamine E). De onderzoekers vonden een relatie tussen chronisch lagere vitamine-niveaus en een grotere kans om aan asbestose te overlijden. Van de onderzoeksgroep overleden 76 personen aan asbestose, een te kleine groep om causaliteit te kunnen bepalen. Meer onderzoek is nodig.

Bron: Alfonso, H.S. et al. (2005). Plasma Concentrations of Retinol, Carotene, and Vitamin E and Mortality in Subjects With Asbestosis in a Cohort Exposed to Crocidolite in Wittenoom, Western Australia. Journal of occupational and environmental medicine. vol. 47, afl. 6, pag. 573-579 (7)

Alfonso, Helman S.. Fritschi, Lin. de Klerk, Nicholas H.. Ambrosini, Gina. Beilby, John. Olsen, Nola. Musk, A William (2005). Plasma Concentrations of Retinol, Carotene, and Vitamin E and Mortality in Subjects With Asbestosis in a Cohort Exposed to Crocidolite in Wittenoom, Western Australia. Journal of occupational and environmental medicine. vol. 47, afl. 6, pag. 573-579 (7).

Abstract

Objective:We sought to examine the relationships between plasma concentrations of retinol, carotene, and vitamin E and mortality associated with asbestosis in people previously exposed to crocidolite.

Methods:Cox regression modeling was applied to examine these relationships at the first measurement of each vitamin, at the measurement at each visit, and with the rate of change of each vitamin during the follow-up.

Results:There were 76 deaths of people with asbestosis during the follow-up period and 1885 subjects censored. Mortality in subjects with asbestosis was inversely related to plasma levels of retinol and Vitamin E concentrations and to their rate of increase during the follow-up. Carotene concentrations at first visit were associated with lower mortality but not during the follow up period.

Conclusions:Chronically low levels of these vitamins are associated with an increased risk of dying with asbestosis.

Experimenteel onderzoek bij ratten naar reactie op amfibool- en serpentijn-asbestvezels

14-07-2005

Asbest bestaat uit microscopisch kleine vezels. Er zijn verschillende soorten, onderverdeeld in serpentijnen en amfibolen. Serpentijnen hebben gekrulde vezels, de vezels van amfibolen hebben de vorm van staafjes en zijn gevaarlijker. Een groep ratten werd gedurende 5 dagen herhaaldelijk blootgesteld aan een groot aanta calidria chrysotiel vezels (serpentijn), een andere groep aan een aantal tremolietvezels (amfibool). Tot één jaar na de proef werd bij de ratten die aan chrysotiel waren blootgesteld geen ontstekingsreactie gezien. Dit in tegenstelling tot de aan tremoliet blootgestelde ratten die sterk reageerden, ondanks blootstelling aan 16 x minder vezels dan de aan chrysotiel blootgestelde ratten. Bernstein, D. et. al., (2005). Comparison of Calidria Chrysotile Asbestos to Pure Tremolite : Final Results of the Inhalation Biopersistence and Histopathology Examination Following Short-Term Exposure. Inhalation toxicology. vol. 17, afl. 9, pag. 427-450 (24).
Bernstein, David. Chevalier, Jörg. Smith, Paul (2005). Comparison of Calidria Chrysotile Asbestos to Pure Tremolite : Final Results of the Inhalation Biopersistence and Histopathology Examination Following Short-Term Exposure. Inhalation toxicology. vol. 17, afl. 9, pag. 427-450 (24).

Abstract:

Calidria chrysotile asbestos, which is a serpentine mineral, has been shown to be considerably less biopersistent than the durable amphibole mineral tremolite asbestos, which persists once deposited in the lung. The initial results of this inhalation biopersistence study in rats that demonstrates this difference were reported in Bernstein et al. (2003). This article presents the full results through 1 yr after cessation of the 5-day exposure. This study was based upon the recommendations of the European Commission (EC) Interim Protocol for the Inhalation Biopersistence of synthetic mineral fibers (Bernstein & Riego-Sintes, 1999). In addition, the histopathological response in the lung was evaluated following exposure. In order to quantify the dynamics and rate by which these fibers are removed from the lung, the biopersistence of a sample of commercial-grade chrysotile from the Coalinga mine in New Idria, CA, of the type Calidria RG144 and that of a long-fiber tremolite were studied. For synthetic vitreous fibers, the biopersistence of the fibers longer than 20 µm has been found to be directly related to their potential to cause disease. This study was designed to determine lung clearance (biopersistence) and the histopathological response. As the long fibers have been shown to have the greatest potential for pathogenicity, the aerosol generation technique was designed to maximize the number of long respirable fibers. The chrysotile samples were specifically chosen to have 200 fibers/cm 3 longer than 20 µm in length present in the exposure aerosol. These longer fibers were found to be largely composed of multiple shorter fibrils. The tremolite samples were chosen to have 100 fibers/cm 3 longer than 20 µm in length present in the exposure aerosol. Calidria chrysotile has been found to be one of the most rapidly cleared mineral fibers from the lung. The fibers longer than 20 µm in length are cleared with a half-time of 7 h. By 2 days postexposure all long fibers have dissolved/disintegrated into shorter pieces. The fibers between 5 and 20µm in length were cleared with a half-time of 7 days. This length range represents a transition zone between those fibers that can be fully phagocytosed and cleared as particles and the longer fibers that cannot be fully engulfed by the macrophage. The fibers/objects shorter than 5 µm in length were cleared with a half-time of 64 days, which is faster than that reported for insoluble nuisance dusts such as TiO 2 . By 12 months postexposure, 99.92% of all the remaining chrysotile was less than 5 µm in length. Following the 5 days of repeated exposure to more than 48,000 chrysotile fibers/cm 3 (190 fibers L > 20 µm), histopathological examination revealed no evidence of any inflammatory reaction either after the cessation of the last exposure or at any time during the subsequent 12-mo period. This is in marked contrast to the amphibole tremolite, which was also investigated using the same inhalation biopersistence protocol. The long tremolite fibers, once deposited in the lung, remain over the rat’s lifetime with essentially an infinite half-time. Even the shorter fibers, following early clearance, also remain with no dissolution or further removal. At 365 days postexposure, there was a mean lung burden was of 0.5 million fibers L > 20 µm and 7 million fibers 5-20 µm in length with a total mean lung burden of 19.6 million fibers. The tremolite exposed rats, even with exposure to 16 times fewer total fibers than chrysotile, showed a pronounced inflammatory response with the rapid development of granulomas as seen at day 1 postexposure, followed by the development of fibrosis characterized by collagen deposition within these granulomas and by 90 days even mild interstitial fibrosis. With the short exposure, this study was not designed specifically to evaluate pathological response. however, it is quite interesting that even so there was such a marked response with tremolite. These findings provide an important basis for substantiating both kinetically and pathologically the differences between chrysotile and the amphibole tremolite. As Calidria chrysotile has been certified to have no tremolite fiber, the results of the current study together with the results from toxicological and epidemiological studies indicate that this fiber is not associated with lung disease.

Onderzoek naar de schadelijke werking van ijzer in asbest

14-07-2005

Nog steeds is niet helemaal duidelijk hoe asbest kanker veroorzaakt. Men denkt dat ijzer daarbij een rol speelt. De meest gevaarlijke asbestsoorten hebben een relatief hoog ijzergehalte. Baldys en Aust onderzochten de werking van asbestvezels en ijzer op de Epidermale Groei Factor Receptor (EGFR) in menselijke epitheel en mesotheelcellen uit long en longvlies. Zij gebruikten drie soorten asbest, t.w. crocidoliet, amosiet en chrysotiel met respectievelijk 27, 27 en 2% ijzer. Zij vonden dat ingekapselde crocidoliet asbestvezels de EGFR receptor inactiveerden en daarmee indirect de celdeling kunnen ontregelen. IJzer lijkt daarbij een mediërende werking te hebben. Baldys, A. & Aust, A.E. (2005). Role of Iron in Inactivation of Epidermal Growth Factor Receptor after Asbestos Treatment of Human Lung and Pleural Target Cells. American journal of respiratory cell and molecular biology. vol. 32, afl. 5, pag. 436-442 (7).
American Journal of Respiratory Cell and Molecular Biology. Vol. 32, pp. 436-442, 2005

Role of Iron in Inactivation of Epidermal Growth Factor Receptor after Asbestos Treatment of Human Lung and Pleural Target Cells. Aleksander Baldys and Ann E. Aust

Department of Chemistry and Biochemistry, Utah State University, Logan, Utah

Abstract

Although the mechanism by which asbestos causes cancer remains unknown, iron associated with asbestos is thought to play a role in the pathogenic effects of fibers. Here, we examined the effects of asbestos on the epidermal growth factor receptor (EGFR) in human lung epithelial (A549) cells, human pleural mesothelial (MET5A) cells, and normal human small airway epithelial (SAEC) cells. Treatment of A549, MET5A, and SAEC cells with asbestos caused a significant reduction of EGFR tyrosine phosphorylation. This was both time- (15 min to 24 h) and concentration-dependent (1.5, 3, and 6 µg/cm2) in A549 cells. Also, treatment with 6 µg/cm2 crocidolite for 24 h diminished the phosphorylation levels of human EGFR 2 (HER2). Exposure of A549 cells to 6 µg/cm2 crocidolite for 3–24 h resulted in no detectable Y1045 phosphorylation and no apparent degradation of the EGFR. Inhibition of fiber endocytosis resulted in a considerable inhibition of EGFR dephosphorylation. Removal of iron from asbestos by desferrioxamine B or phytic acid inhibited asbestos-induced decreases in EGFR phosphorylation. The effects of crocidolite, amosite, and chrysotile on the EGFR phosphorylation state appeared to be directly related to the amount of iron mobilized from these fibers. These results strongly suggest that iron plays an important role in asbestos-induced inactivation of EGFR.

VK: gaat asbestgerelateerde longkanker altijd samen met asbestose?

14-07-2005

De vraag of longkanker door asbest is veroorzaakt terwijl er geen sprake is van asbestose, blijft controversieel. Dit concluderen Engelse onderzoekers na analyse van 9 epidemiologische artikelen. De momenteel beschikbare technische middelen bieden niet voldoende mogelijkheden om dit te onderzoeken. Waarschijnlijk is het type asbestvezel van belang, concluderen Engelse en Amerikaanse onderzoekers.

Bron: Thorax. vol. 60 (2005), afl. 5, pag. 433-436 (4)

Asbestos, asbestosis, and lung cancer : a critical assessment of the epidemiological evidence

Hessel, P.A.. Gamble, J.F.. Mcdonald, J.C. / In: Thorax. vol. 60 (2005), afl. 5, pag. 433-436 (4)

The question of whether lung cancer can be attributed to asbestos exposure in the absence of asbestosis remains controversial. Nine key epidemiological papers are reviewed in a point/counterpoint format, giving the main strengths and limitations of the evidence presented. Of the nine papers, two concluded that asbestosis was necessary and seven that it was not. However, the study design, nature and circumstances of exposure and method of analysis of the studies differed considerably, and none was considered definitive. It is concluded that, because of the relative insensitivity of chest radiography and the uncertain specificity of findings from histological examinations or computed tomography, it is unlikely that epidemiology alone can put either the strict scientific or practical medicolegal questions beyond doubt. It is probable that the issue may depend critically on asbestos fibre type, an aspect not so far addressed.

VS: geen aanwijzing voor kanker door asbest in drinkwater

14-07-2005

In Woodstock werd in 1985 asbestvervuiling ontdekt in het drinkwater. Dit kwam door asbestcementpijpen die half jaren 50 waren geïnstalleerd. De kankerstatistieken van Woodstock werden over de periode 1980-1998 vergeleken met nationale gegevens. Er werd geen relatie met asbest gevonden.

Bron: Browne, M. L. et al. (2005). Environmental research. vol. 98 (2005), afl. 2, pag. 224-232 (9)

Cancer incidence and asbestos in drinking water, Town of Woodstock, New York, 1980#x0201.1998

Browne, Marilyn L.. Varadarajulu, Deepa. Lewis-Michl, Elizabeth L.. Fitzgerald, Edward F. / In: Environmental research. vol. 98 (2005), afl. 2, pag. 224-232 (9) / 2005

Abstract

Late in 1985, asbestos contamination was discovered in the public water supply of the Town of Woodstock, Ulster County, New York. Contamination resulted from asbestos’cement pipes installed in the town water system in the mid to late 1950s and the corrosiveness of the local water. The New York State (NYS) Department of Health established the Woodstock Asbestos Exposure Registry (WAER) in 1986 to monitor rates of cancer among individuals who lived on the water supply between 1960 and 1985. Demographic, health, and residential information were collected on 2936 registrants. The follow-up period for observation of cancer was 1980-1998, consistent with the expected lag of 20-30+ years for development of asbestos-related cancers. The NYS Cancer Registry was used to ascertain cancer diagnoses. Standardized incidence ratios (SIRs) for gastrointestinal, respiratory, and total cancers were all approximately 1.00 or less and all 95% confidence intervals (CIs) included 1.00. For individual types of the gastrointestinal cancers, only the SIR for pancreatic cancer was marginally statistically significant at 2.19 (95% CI=1.00-4.16), based on a total of nine observed cases. The excess in pancreatic cancer occurred primarily among men (SIR=3.08. 95% CI=1.13-6.70) and was only slightly elevated among women (SIR=1.39. 95% CI=0.29-4.06). This association may be related to factors other than asbestos exposure such as occupation and lifestyle or to chance. No cases of mesothelioma were observed among WAER participants. There was no increase in incidence by latency or duration of residence on the water supply, but the ability to detect these trends is limited by small numbers and unknown dates of initial exposure. The general pattern of results did not demonstrate a likely link between exposure to asbestos in drinking water and cancer occurrence among participants in the WAER.

Australië: doorbraak in screening van mesothelioom

25-03-2005

Australische onderzoekers hebben een bloedtest ontwikkeld die kan helpen bij het opsporen van mesothelioom. De niet invasieve test, Mesomark genaamd, werd ontwikkeld door onderzoekers van de Universiteit van West Australië. In Australië krijgen ongeveer 700 mensen per jaar deze ziekte.

Bron: The Advertiser, 20 april / The West Australian, 19 april.

The Advertiser

April 20, 2005 Wednesday

HEADLINE: Breakthrough

AUSTRALIAN researchers have developed a world-first blood test which could help people worldwide in the early detection of mesothelioma, a deadly asbestos-related cancer of the lung lining. The non-invasive blood test developed by University of Western Australia Professor Bruce Robinson and researchers is a breakthrough in the early detection of the disease. About 700 people each year are diagnosed with the disease in Australia, which has the highest reported incidence in the world.

The West Australian (Perth)

April 19, 2005 Tuesday

HEADLINE: Test offers hope on mesothelioma

Rockingham man David Saw believes a new blood test for mesothelioma, which is being launched today, could have saved him a three-day hospital visit and a lot of trauma.

Mr Saw went to his doctor last year believing he had pulled a muscle.

He was suffering chest pain and shortness of breath.

After a CAT scan and biopsy, it was revealed the 49-year-old had contracted the deadly lung cancer from working with asbestos as a young man.

“A test would have been a lot easier, I ended up in hospital and they had to cut me open,” he said.

The test, called MESOMARK, will be available from general practitioners or specialists who can order it from a pathology provider.

The head of the mesothelioma research team at Sir Charles Gairdner Hospital which developed the test, Professor Bruce Robinson, said it would not only help in diagnoses of the disease, but also in treatment.

“Until now you could only gauge whether treatment was working effectively by doing a CAT scan, and they’re difficult to do. With this test, we can gauge treatment and also diagnose it at an earlier stage,” Professor Robinson said. Biopsy would be needed to confirm diagnosis.

The blood test measures levels of a substance called soluble mesothelin-related peptide, a distinctive biomarker released by mesothelioma cells.

About 700 Australians are diagnosed with the disease every year and WA has the highest rate of mesothelioma in the world.

Asbestos Diseases Society of Australia president Robert Vojakovic said the test could help the possible 6000 people who were children in Wittenoom when the town still had an active blue asbestos mine.

"Pleurale plaques" voorspelt asbestgerelateerde longkanker

15-03-2005

Bij mannen die geen asbestose (“stoflongen” door asbest) hebben komt asbestgerelateerde longkanker vaker voor dan was verwacht. “Pleurale plaques” (een goedaardige verdikking van het borstvlies) is een belangrijke voorspeller van asbestgerelateerde longkanker. Deze nieuwe inzichten komen uit een onderzoek van meer dan 10 jaar onder 4000 Amerikaanse mannen die aan asbest blootgesteld zijn geweest.
Increased lung cancer among asbestos workers with no evidence of asbestosis

Below, details of a new paper on asbestos and lung cancer, forwarded by Frank Mirer, director of health and safety at the US autoworkers’ union UAW.

The paper looks important for two reasons – firstly because of the lung cancer without asbestosis finding – in some jurisdictions official workers’ compensation schemes only pay benefits to lung cancer sufferers who also have asbestosis.

Secondly, the paper is valuable because it establishes the importance of pleural plaques as a predicator of lung cancer. Insurers and employers in the UK, USA and elsewhere are at this moment trying to play down the significance of the association between pleural plaques and asbestos.

Their motive is to reduce their compensation liabilities. One consequence of this might be a lower likelihood of diagnosis of pleural plaques (many of the health checks are the result of compensation inquiries), so we could lose our early warning system or “sentinel health event” for an enormous lung cancer risk. In the UK at the moment there are several thousand asbestos related lung cancers ever year – the combined annual death toll for asbestos related lung cancers and mesothelioma is expect to reach 10,000 within 20 years.

Yours, Rory

Rory O’Neill

International Federation of Journalists

Increased lung cancer among asbestos workers with no evidence of asbestosis

A very important study giving quantitative measures of risks of asbestos exposure was just published. The study is an important data source for evaluating medical criteria for compensation of asbestos exposed workers, now being discussed in Congress.

The project was a chemoprevention test whether Vitamin A – an antioxidant – protected against future effects of past asbestos exposure. The investigators had enrolled over 4,000 asbestos workers and followed them for over a decade. Recruitment must have been a huge task The chemoprevention study was terminated because Vitamin A increased the risk of lung cancer.

The study confirmed excessive rates of lung cancer among men with radiographic asbestosis, but also among workers with no evidence of asbestosis. Among workers with no evidence of asbestosis at baseline, men with more than 40 years’ exposure in high-risk trades had a risk approximately fivefold higher than men with 5-10 years. Pleural plaques on the baseline x-ray and abnormal baseline flow rate were strong independent predictors of subsequent lung cancer.

Hopefully, people with access to the full text of this study will comment further.

American Journal of Epidemiology 2005 161(3):260-270.

Predictors of Lung Cancer among Asbestos-exposed Men in the µ-Carotene and

Retinol Efficacy Trial

Mark R. Cullen1 , Matt J. Barnett2, John R. Balmes3, Brenda Cartmel1, Carrie

A. Redlich1, Carl A. Brodkin4, Scott Barnhart4, Linda Rosenstock5, Gary E.

Goodman2,6, Sam P. Hammar7, Mark D. Thornquist2 and Gilbert S. Omenn8,9

Despite numerous published studies, debate continues regarding the risk of developing lung cancer among men exposed occupationally to asbestos, particularly those without radiographic or functional evidence of asbestosis. The µ-Carotene and Retinol Efficacy Trial (CARET), a study of vitamin supplementation for chemoprevention of lung cancer, has followed 4,060 heavily exposed US men for 9-17 years. Lung cancer incidence for 1989-2002 was analyzed using a stratified proportional hazards model. The study confirmed excessive rates of lung cancer among men with radiographic asbestosis. Comparison of study arms revealed a strong, unanticipated synergy between radiographic profusion category and the active intervention. In the large subgroup of men with normal lung parenchyma on chest radiograph at baseline, there was evidence of exposure-related lung cancer risk: Men with more than 40 years’ exposure in high-risk trades had a risk approximately fivefold higher than men with 5-10 years, after adjustment for covariates. The effect in these men was independent of study intervention arm, but pleural plaques on the baseline radiograph and abnormal baseline flow rate were strong independent predictors of subsequent lung cancer. Residual confounding by subclinical asbestosis, exposure to unmeasured lung carcinogens, or differences in smoking are unlikely to explain these observations better than a carcinogenic effect of asbestos per se.