50
L
TT E R
E
S to the
EDIT OR
Mesothelioma and non-occupational environmental exposure to asbestos SiR,—The largest Italian plant producing asbestos-cement operated during 1907-85 at Casale Monferrato, in north-west Italy, a town with about 40 000 people. We studied mortality in 1964-86 among workers at the plant and found 864 deaths (710 expected); 117, 43, and 89 of those deaths were certified as being due to lung cancer, pleural cancer, and asbestosis, respectively.’ Wives of male employees were also identified and their mortality experience is now being analysed. We report here an estimate of the incidence of pleural mesothelioma among residents in the administrative area corresponding to the local health unit of Casale Monferrato, divided into three zones (Casale Monferrato itself, towns adjacent to Casale, and other towns and villages). Histological diagnoses of pleural mesotheliomas have been looked for in the records of the local hospital and of four other large hospitals whose catchment areas include the local health unit. This survey identified 89 residents with a histological diagnosis of mesothelioma during 1980-89; cytological diagnoses on pleural fluid are not considered here. Occupational exposure in the asbestos-cement factory was ascertained by linkage with the rosters of employees, and women married to an asbestos-cement worker were also identified. 26 patients had worked at the plant at some time after 1907, and 3 others were wives of 1 of them. The other 60 cases were used in the computation of the rates shown in the table, which includes corresponding rates estimated by the Varese Province cancer registry for 1976-87. For men and women there is an impressive excess of pleural mesothelioma not attributable to occupational exposure in the plant. The numbers are small but there does seem to be a downward gradient with distance from Casale Monferrato. Overascertainment of cases or underestimation of occupational exposure are potential biases favouring an excess of pleural mesothelioma associated to non-occupational exposure to asbestos. However, the diagnoses were made in large hospitals by people experienced in the diagnosis of malignant mesothelioma. In the mesothelioma registry for Tuscany 87-5% of the cases were confirmed after re-evaluation by a panel of pathologists and histochemical studies (E. Chellini, personal communication).
RATES OF PLEURAL MESOTHELIOMA
*On Italian
population, 1981
Comparison with the data for Varese province implies, if anything, underestimation of rate ratios. The Varese and other cancer often include pleural mesothelioma that has not been confirmed histologically (50% in Varese vs 0% in Casale Monferrato) and histologically confirmed cases with diagnoses other than mesothelioma, which in Varese accounted for 4/22 registered cases in 1978-81.3 Bias due to inadequate criteria for excluding prevalent cases in Casale is unlikely, given the poor prognosis for pleural mesothelioma.4 Although no other asbestosrelated activity in the local health unit of Casale Monferrato is known, occupational exposure to asbestos in activities other than asbestos cement work cannot be excluded. Had such exposure occurred the bias in the computation of rate ratios should be small since rates reported from the Varese cancer registry include an
registries
asbestos-exposed cases. Our findings suggest that a risk of cancer from exposure to asbestos may arise in the general (non-occupational) environment, a subject which has hitherto been controversial.5 The International Agency for Research on cancer and the administrations of Piemonte and of USL76 (Casale Monferrato) provided financial contributions to the study. We thank Prof A. Donna and Dr L. Gubetta, of the pathology departments at the General Hospital of Alessandria and of the Pneumologic Hospital of Orbassano (Turin) for permission to examine their files. Cancer
Epidemiology Unit, Department of Biomedical Sciences, and Human Oncology, University of Turin, 10126 Turin, Italy, Departments of Pathology and Internal Medicine, General Hospital, Casale Monferrato, and Departments of Pathology, Universities of Turin and Pavia 1.
C. MAGNANI G. BORGO G. P. BETTA M. BOTTA C. IVALDI F. MOLLO M. SCELZI B. TERRACINI
Magnani C, Terracini B, Bertolone GP, et al. Mortalità per tumori ed altre malattie del sistema respiratono tra i lavaratori del cemento amianto a Casale Monferrato: uno
studio di coorte storico. Med Lav 1987; 78: 441-53. 2. Berrino F. Registro tumon della Lombardia: incidenza e mortalità per tumore nella Provincia di Varese, anni 1976-87, rapporto preliminare. 3. Berrino F, Crosignani P, Gatta G, et al. Registro Tumon della Lombardia: incidenza e mortalità in Provincia di Varese negli anni 1976-81. Notiz Samtà 1985; 10: 47. 4. Ruffie P, Feld R, Minkin S, et al. Diffuse malignant mesothelioma of the pleura m Ontario and Quebec: a retrospective study of 332 patients. J Clin Oncol 1989; 7: 1157-68. 5. Bignon J, Peto J, Saracci R, eds. Non-occupational exposure to mineral fibres. ( IARC Sci Publ 90). Lyon: IARC, 1989.
Tacrine in Alzheimer’s disease SIR,-Dr Jones (June 15, p 1475), commenting on our April 27 paper, notes limitations with the mini mental state examination (MMSE). The lack of parallel forms for this test is an unfortunate deficiency that many are trying to remedy. This makes the MMSE, especially when the test is repeated with short intervals, subject to practice effects in the placebo group which may disguise a true drug effect. We avoided this difficulty by allowing three months between tests. Dr Whalley (p 1476) cites the criticism of the MMSE by one of us (R. L.) out of context: those comments referred to frequent use with short intervals in a crossover trial without a wash-out period. Jones rightly points out that some patients may have shown improvements of 25% or more. There was considerable variability in response, which was illustrated in the matrix. This is not, as Dr Lindesay (p 1476) suggests, an indication that the drug "does not act on the dementia process" but a reflection of the heterogeneity of the condition. His suggestion that tacrine is acting upon associated conditions, such as disturbed mood, is not borne out by the Rosen Alzheimer’s disease assessment scale, non-cognitive subscale,l which shows no significant difference between tacrine and placebo in measures of mood. Lindesay is also mistaken in raising the spectre of a drug that might prolong the distress of patients and carers and increase the economic cost of the disorder. We have stressed that we do not believe that a neurotransmitter-based approach is likely to affect the structural basis of the disease, but we do think that even a temporary improvement in cognitive function is worthwhile both socially and, possibly, economically. Although these results may cast doubt on a cholinergic hypothesis of memory
L
TT E R
E
S to the
EDIT OR
Mesothelioma and non-occupational environmental exposure to asbestos SiR,—The largest Italian plant producing asbestos-cement operated during 1907-85 at Casale Monferrato, in north-west Italy, a town with about 40 000 people. We studied mortality in 1964-86 among workers at the plant and found 864 deaths (710 expected); 117, 43, and 89 of those deaths were certified as being due to lung cancer, pleural cancer, and asbestosis, respectively.’ Wives of male employees were also identified and their mortality experience is now being analysed. We report here an estimate of the incidence of pleural mesothelioma among residents in the administrative area corresponding to the local health unit of Casale Monferrato, divided into three zones (Casale Monferrato itself, towns adjacent to Casale, and other towns and villages). Histological diagnoses of pleural mesotheliomas have been looked for in the records of the local hospital and of four other large hospitals whose catchment areas include the local health unit. This survey identified 89 residents with a histological diagnosis of mesothelioma during 1980-89; cytological diagnoses on pleural fluid are not considered here. Occupational exposure in the asbestos-cement factory was ascertained by linkage with the rosters of employees, and women married to an asbestos-cement worker were also identified. 26 patients had worked at the plant at some time after 1907, and 3 others were wives of 1 of them. The other 60 cases were used in the computation of the rates shown in the table, which includes corresponding rates estimated by the Varese Province cancer registry for 1976-87. For men and women there is an impressive excess of pleural mesothelioma not attributable to occupational exposure in the plant. The numbers are small but there does seem to be a downward gradient with distance from Casale Monferrato. Overascertainment of cases or underestimation of occupational exposure are potential biases favouring an excess of pleural mesothelioma associated to non-occupational exposure to asbestos. However, the diagnoses were made in large hospitals by people experienced in the diagnosis of malignant mesothelioma. In the mesothelioma registry for Tuscany 87-5% of the cases were confirmed after re-evaluation by a panel of pathologists and histochemical studies (E. Chellini, personal communication).
RATES OF PLEURAL MESOTHELIOMA
*On Italian
population, 1981
Comparison with the data for Varese province implies, if anything, underestimation of rate ratios. The Varese and other cancer often include pleural mesothelioma that has not been confirmed histologically (50% in Varese vs 0% in Casale Monferrato) and histologically confirmed cases with diagnoses other than mesothelioma, which in Varese accounted for 4/22 registered cases in 1978-81.3 Bias due to inadequate criteria for excluding prevalent cases in Casale is unlikely, given the poor prognosis for pleural mesothelioma.4 Although no other asbestosrelated activity in the local health unit of Casale Monferrato is known, occupational exposure to asbestos in activities other than asbestos cement work cannot be excluded. Had such exposure occurred the bias in the computation of rate ratios should be small since rates reported from the Varese cancer registry include an
registries
asbestos-exposed cases. Our findings suggest that a risk of cancer from exposure to asbestos may arise in the general (non-occupational) environment, a subject which has hitherto been controversial.5 The International Agency for Research on cancer and the administrations of Piemonte and of USL76 (Casale Monferrato) provided financial contributions to the study. We thank Prof A. Donna and Dr L. Gubetta, of the pathology departments at the General Hospital of Alessandria and of the Pneumologic Hospital of Orbassano (Turin) for permission to examine their files. Cancer
Epidemiology Unit, Department of Biomedical Sciences, and Human Oncology, University of Turin, 10126 Turin, Italy, Departments of Pathology and Internal Medicine, General Hospital, Casale Monferrato, and Departments of Pathology, Universities of Turin and Pavia 1.
C. MAGNANI G. BORGO G. P. BETTA M. BOTTA C. IVALDI F. MOLLO M. SCELZI B. TERRACINI
Magnani C, Terracini B, Bertolone GP, et al. Mortalità per tumori ed altre malattie del sistema respiratono tra i lavaratori del cemento amianto a Casale Monferrato: uno
studio di coorte storico. Med Lav 1987; 78: 441-53. 2. Berrino F. Registro tumon della Lombardia: incidenza e mortalità per tumore nella Provincia di Varese, anni 1976-87, rapporto preliminare. 3. Berrino F, Crosignani P, Gatta G, et al. Registro Tumon della Lombardia: incidenza e mortalità in Provincia di Varese negli anni 1976-81. Notiz Samtà 1985; 10: 47. 4. Ruffie P, Feld R, Minkin S, et al. Diffuse malignant mesothelioma of the pleura m Ontario and Quebec: a retrospective study of 332 patients. J Clin Oncol 1989; 7: 1157-68. 5. Bignon J, Peto J, Saracci R, eds. Non-occupational exposure to mineral fibres. ( IARC Sci Publ 90). Lyon: IARC, 1989.
Tacrine in Alzheimer’s disease SIR,-Dr Jones (June 15, p 1475), commenting on our April 27 paper, notes limitations with the mini mental state examination (MMSE). The lack of parallel forms for this test is an unfortunate deficiency that many are trying to remedy. This makes the MMSE, especially when the test is repeated with short intervals, subject to practice effects in the placebo group which may disguise a true drug effect. We avoided this difficulty by allowing three months between tests. Dr Whalley (p 1476) cites the criticism of the MMSE by one of us (R. L.) out of context: those comments referred to frequent use with short intervals in a crossover trial without a wash-out period. Jones rightly points out that some patients may have shown improvements of 25% or more. There was considerable variability in response, which was illustrated in the matrix. This is not, as Dr Lindesay (p 1476) suggests, an indication that the drug "does not act on the dementia process" but a reflection of the heterogeneity of the condition. His suggestion that tacrine is acting upon associated conditions, such as disturbed mood, is not borne out by the Rosen Alzheimer’s disease assessment scale, non-cognitive subscale,l which shows no significant difference between tacrine and placebo in measures of mood. Lindesay is also mistaken in raising the spectre of a drug that might prolong the distress of patients and carers and increase the economic cost of the disorder. We have stressed that we do not believe that a neurotransmitter-based approach is likely to affect the structural basis of the disease, but we do think that even a temporary improvement in cognitive function is worthwhile both socially and, possibly, economically. Although these results may cast doubt on a cholinergic hypothesis of memory
