Cancer Causes and Control, 3 , 4 9 3 - 494
COMMENT
Soft-tissue sarcoma The paper by Serraino et al, 1 reporting a case-control study on soft-tissue sarcoma (STS) and occupational exposures from northeast Italy, is worth several comments. First, controls were selected in such a way that 60 percent represent traumatic conditions (mainly fractures and sprains) or musculoskeletal diseases (mainly low-back pain and disc disorders). As agricultural workers have increased accident rates compared with the general population, 2,3 it is not surprising that the occupational category 'agriculture' and the related exposure category 'herbicides/pesticides' are overrepresented among the controls, yielding estimates of the relative risks (odds ratios [OR]) lower than unity (0.4 for duration of work in agriculture equal to or less than 10 years, and 0.8 for a duration of more than 10 years; 0.7 for exposure to herbicides and pesticides equal to or less than 10 years, and 0.4 for more than 10 years). These low values are likely to reflect, at least in part, the biased selection of controls (at least as far as the examination of occupational exposures is concerned). Second, ORs are presented by length of occupation or exposure but not for time since first exposure, although the latter is a key time variable when examining risks for cancers where an increase may become detectable only after several quinquennia or decades after onset of exposure. Third, subgroups of subjects for which the first exposure may go back 20 or 30 years are bound to be smaller than the total groups of cases and controls, and confidence limits for the ORs must be correspondingly larger than those shown in the paper. Taken jointly, these three considerations lend no support to the statement, "... the study was able to exclude, at the level of statistical significance, an increased STS risk of greater than 20 percent from more than 10-years' exposure to herbicides or pesticides ~ (p. 28). Which increase in risk this study may validly exclude cannot be determined from the published data. Two further aspects need to be taken into account when casting the results--as is done in the Discussion section of the paper--in the frame of the other pub@1992 Rapid Communications of Oxford Ltd
lished evidence. As the authors stress, the exposure categories (agriculture and herbicides/pesticides) are, as in many other studies, quite broad. This may dilute and make undetectable any relation between more specific exposures, e.g., to phenoxy acid herbicides (contaminated or not by TCDD), and STS. Use of validated methods of exposure assessment, such as blind evaluation of exposures with the help of an agronomist, 4,5 probably would have enabled the authors to draw firmer conclusions on specific chemicals. In any case, 'negative' conclusions drawn from evidence obtained at the level of crude and coarse categories should not be transferred directly to specific exposures. More specific exposure information is indeed available for cohort studies not cited by the authors# 7 as well as for one cohort more recently reported, 8 which indicate an excess risk of STS related to exposure to phenoxy acid herbicides and/or TCDD. Paolo Vineis
Serviziodi Epidemiologiadei Tumori, Via Santena 7, 10126Turin, Italy Rodolfo Saracci Manolis Kogevinas Paolo Boffetta Unit of AnalyticalEpidemiology, International Agencyfor Researchon Cancer, Lyon, France (Received 24 April 1992)
References 1. Serraino D, Franceschi S, La Vecchia C, Carbone C. Occupation and soft-tissue sarcoma in northeastern Italy. Cancer Causes Control 1992; 3: 25-30. 2. Coye MJ. The health effects of agricultural production: I. The health of agricultural workers. J Public Health Policy 1985; 6: 349-70. 3. Guralnick L. Mortality by Occupation Level and Cause of Death among Men 20 to 64 Years of Age: United States, 1950. Washington, DC: Department of Health, Education and Welfare, 1963; Vital Statistics--Special Reports 53, no. 5. 4, Blair A, Zahm SH. Methodologic issues in exposure assessment for case-control studies of cancer and herbicides. A m J Ind Med 1990; 18: 285-93. 5. Vineis P, Terracini B, Ciccone G, et al. Phenoxy herbiCancer Causes and Control. Vol 3. 1992
493
P. Vineis et al cides and soft-tissue sarcomas in female rice weeders. ScandJ Work Environ Health 1987; 13: 9-17. 6. Lynge E. A follow-up study of cancer incidence among workers in manufacture of phenoxy herbicides in Denmark. BrJ Cancer 1985; 52: 259-70. 7. Fingerhut MA, Halperin WE, Marlow DA, et aL Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. N EnglJ Med 1991; 324: 212-18. 8. Saracci R, Kogevinas M, Bertazzi PA, et al. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols. Lancet 1991; 338: 1027-32.
The authors' reply Dr Vineis et al make three observations on our study on occupation and soft-tissue sarcoma (STS) in northeastern Italy) First, since 28 percent of the study controls were admitted to hospital for traumatic conditions and 32 percent for other musculoskeletal diseases, agricultural workers may have been overrepresented in the control group. The distribution of occupation in agriculture and exposure to herbicides and pesticides according to four major nosologic categories of controis (Table 1) provides some reassurance about the possibility of the aforementioned selection bias. Second, association of risk with duration of exposure is only one factor in epidemiologic inference of causality 2and other time-related variables, including time since first experience, are relevant. The only point we made in our article, however, is that the absence of any duration-risk relationship weighs against the existence of a causal link. Furthermore, duration of exposure is highly correlated with time since first exposure in our study (not shown) as well as in others? Third, obviously the confidence intervals for the Table 1. Occupation in agriculture and exposure to herbicides and pesticides among 721 controls, according to major nosologic categories. Pordenone, Italy, 1985-91 Nosologic category
Occupation or exposure (years)
Agriculture 0 1-10 > 10
74 4 22
77 4 19
74 7 19
73 4 23
Herbicides/ pesticides 0 1-10 >10
90 2 8
90 3 7
86 4 10
85 8 7
CancerCausesand Control. Vol 3.1992
Diego Serraino Silvia Franceschi Epidemiology Unit, Aviano Cancer Center, Via Pedemontana Occ., 33081 Aviano (PN), Italy Carlo La Vecchia 'Mario Negri' Institute for Pharmacological Research, Milan, Italy
(Received 5 May 1992)
Musculoskeletal Trauma Surgical Other diseases conditions (n = 227) (n = 204) (n = 124) (n = 166) % % % %
494
odds ratios of subgroups of exposure (e.g., subjects first exposed 20-30 years previously) are broader than those for the overall study group. While this is probably a minor problem in the assessment of the role of employment in agriculture (generally very prolonged, at least in the study areal), with regard to heavy exposures to herbicides and pesticides, it only points to the need for larger and, hence, more difficult studies of STS. Drs Saracci and Kogevinas are among the authors of an article, 3 based on four cases of STS, which showed no relation of risk with years since first exposure or duration of exposure. Following the subsequent correspondence, 4Saracci and Kogevinas ~commented: "Our conclusions are cautiously phrased in terms of the result for soft tissue sarcoma being compatible with a causal role of chlorophenoxy herbicides. We are all aware of the limitations of the study, especially, as Mr Peto notes, the small number of soft tissue sarcomas observed." It is surprising, therefore, that the same article is now quoted indicating "an excess risk of STS related to exposure to phenoxy acid herbicides and/or TCDD." We agree that only more precise measures of exposure will lead to firm conclusions regarding specific chemicals. In the light of the rarity of STS and the difficulties of its histologic classification, we think, however, that a case-control study of 93 cases of STS, all reviewed by one pathologist, can help identify the risk factors which matter most in the general population.
References 1. Serraino D, Franceschi S, La Vecchia C, Carbone C. Occupation and soft-tissue sarcoma in northeastern Italy. Cancer Causes Control 1992; 3: 25-30. 2. Hill AB. Principles of Medical Statistics. London: The Lancet Ltd, 1971: 309-23. 3. Saracci R, Kogevinas M, Bertazzi P-A, et al. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols. Lancet 1991; 338: 1027-32. 4. Peto R. Occupational exposure to chlorophenoxy herbicides and chlorophenols (Letter). Lancet 1991; 338: 1392. 5. Saracci R, Kogevinas M. Occupational exposure to chlorophenoxy herbicides and chlorophenols (Letter). Lancet 1991; 338: 1392-3.
COMMENT
Soft-tissue sarcoma The paper by Serraino et al, 1 reporting a case-control study on soft-tissue sarcoma (STS) and occupational exposures from northeast Italy, is worth several comments. First, controls were selected in such a way that 60 percent represent traumatic conditions (mainly fractures and sprains) or musculoskeletal diseases (mainly low-back pain and disc disorders). As agricultural workers have increased accident rates compared with the general population, 2,3 it is not surprising that the occupational category 'agriculture' and the related exposure category 'herbicides/pesticides' are overrepresented among the controls, yielding estimates of the relative risks (odds ratios [OR]) lower than unity (0.4 for duration of work in agriculture equal to or less than 10 years, and 0.8 for a duration of more than 10 years; 0.7 for exposure to herbicides and pesticides equal to or less than 10 years, and 0.4 for more than 10 years). These low values are likely to reflect, at least in part, the biased selection of controls (at least as far as the examination of occupational exposures is concerned). Second, ORs are presented by length of occupation or exposure but not for time since first exposure, although the latter is a key time variable when examining risks for cancers where an increase may become detectable only after several quinquennia or decades after onset of exposure. Third, subgroups of subjects for which the first exposure may go back 20 or 30 years are bound to be smaller than the total groups of cases and controls, and confidence limits for the ORs must be correspondingly larger than those shown in the paper. Taken jointly, these three considerations lend no support to the statement, "... the study was able to exclude, at the level of statistical significance, an increased STS risk of greater than 20 percent from more than 10-years' exposure to herbicides or pesticides ~ (p. 28). Which increase in risk this study may validly exclude cannot be determined from the published data. Two further aspects need to be taken into account when casting the results--as is done in the Discussion section of the paper--in the frame of the other pub@1992 Rapid Communications of Oxford Ltd
lished evidence. As the authors stress, the exposure categories (agriculture and herbicides/pesticides) are, as in many other studies, quite broad. This may dilute and make undetectable any relation between more specific exposures, e.g., to phenoxy acid herbicides (contaminated or not by TCDD), and STS. Use of validated methods of exposure assessment, such as blind evaluation of exposures with the help of an agronomist, 4,5 probably would have enabled the authors to draw firmer conclusions on specific chemicals. In any case, 'negative' conclusions drawn from evidence obtained at the level of crude and coarse categories should not be transferred directly to specific exposures. More specific exposure information is indeed available for cohort studies not cited by the authors# 7 as well as for one cohort more recently reported, 8 which indicate an excess risk of STS related to exposure to phenoxy acid herbicides and/or TCDD. Paolo Vineis
Serviziodi Epidemiologiadei Tumori, Via Santena 7, 10126Turin, Italy Rodolfo Saracci Manolis Kogevinas Paolo Boffetta Unit of AnalyticalEpidemiology, International Agencyfor Researchon Cancer, Lyon, France (Received 24 April 1992)
References 1. Serraino D, Franceschi S, La Vecchia C, Carbone C. Occupation and soft-tissue sarcoma in northeastern Italy. Cancer Causes Control 1992; 3: 25-30. 2. Coye MJ. The health effects of agricultural production: I. The health of agricultural workers. J Public Health Policy 1985; 6: 349-70. 3. Guralnick L. Mortality by Occupation Level and Cause of Death among Men 20 to 64 Years of Age: United States, 1950. Washington, DC: Department of Health, Education and Welfare, 1963; Vital Statistics--Special Reports 53, no. 5. 4, Blair A, Zahm SH. Methodologic issues in exposure assessment for case-control studies of cancer and herbicides. A m J Ind Med 1990; 18: 285-93. 5. Vineis P, Terracini B, Ciccone G, et al. Phenoxy herbiCancer Causes and Control. Vol 3. 1992
493
P. Vineis et al cides and soft-tissue sarcomas in female rice weeders. ScandJ Work Environ Health 1987; 13: 9-17. 6. Lynge E. A follow-up study of cancer incidence among workers in manufacture of phenoxy herbicides in Denmark. BrJ Cancer 1985; 52: 259-70. 7. Fingerhut MA, Halperin WE, Marlow DA, et aL Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. N EnglJ Med 1991; 324: 212-18. 8. Saracci R, Kogevinas M, Bertazzi PA, et al. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols. Lancet 1991; 338: 1027-32.
The authors' reply Dr Vineis et al make three observations on our study on occupation and soft-tissue sarcoma (STS) in northeastern Italy) First, since 28 percent of the study controls were admitted to hospital for traumatic conditions and 32 percent for other musculoskeletal diseases, agricultural workers may have been overrepresented in the control group. The distribution of occupation in agriculture and exposure to herbicides and pesticides according to four major nosologic categories of controis (Table 1) provides some reassurance about the possibility of the aforementioned selection bias. Second, association of risk with duration of exposure is only one factor in epidemiologic inference of causality 2and other time-related variables, including time since first experience, are relevant. The only point we made in our article, however, is that the absence of any duration-risk relationship weighs against the existence of a causal link. Furthermore, duration of exposure is highly correlated with time since first exposure in our study (not shown) as well as in others? Third, obviously the confidence intervals for the Table 1. Occupation in agriculture and exposure to herbicides and pesticides among 721 controls, according to major nosologic categories. Pordenone, Italy, 1985-91 Nosologic category
Occupation or exposure (years)
Agriculture 0 1-10 > 10
74 4 22
77 4 19
74 7 19
73 4 23
Herbicides/ pesticides 0 1-10 >10
90 2 8
90 3 7
86 4 10
85 8 7
CancerCausesand Control. Vol 3.1992
Diego Serraino Silvia Franceschi Epidemiology Unit, Aviano Cancer Center, Via Pedemontana Occ., 33081 Aviano (PN), Italy Carlo La Vecchia 'Mario Negri' Institute for Pharmacological Research, Milan, Italy
(Received 5 May 1992)
Musculoskeletal Trauma Surgical Other diseases conditions (n = 227) (n = 204) (n = 124) (n = 166) % % % %
494
odds ratios of subgroups of exposure (e.g., subjects first exposed 20-30 years previously) are broader than those for the overall study group. While this is probably a minor problem in the assessment of the role of employment in agriculture (generally very prolonged, at least in the study areal), with regard to heavy exposures to herbicides and pesticides, it only points to the need for larger and, hence, more difficult studies of STS. Drs Saracci and Kogevinas are among the authors of an article, 3 based on four cases of STS, which showed no relation of risk with years since first exposure or duration of exposure. Following the subsequent correspondence, 4Saracci and Kogevinas ~commented: "Our conclusions are cautiously phrased in terms of the result for soft tissue sarcoma being compatible with a causal role of chlorophenoxy herbicides. We are all aware of the limitations of the study, especially, as Mr Peto notes, the small number of soft tissue sarcomas observed." It is surprising, therefore, that the same article is now quoted indicating "an excess risk of STS related to exposure to phenoxy acid herbicides and/or TCDD." We agree that only more precise measures of exposure will lead to firm conclusions regarding specific chemicals. In the light of the rarity of STS and the difficulties of its histologic classification, we think, however, that a case-control study of 93 cases of STS, all reviewed by one pathologist, can help identify the risk factors which matter most in the general population.
References 1. Serraino D, Franceschi S, La Vecchia C, Carbone C. Occupation and soft-tissue sarcoma in northeastern Italy. Cancer Causes Control 1992; 3: 25-30. 2. Hill AB. Principles of Medical Statistics. London: The Lancet Ltd, 1971: 309-23. 3. Saracci R, Kogevinas M, Bertazzi P-A, et al. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols. Lancet 1991; 338: 1027-32. 4. Peto R. Occupational exposure to chlorophenoxy herbicides and chlorophenols (Letter). Lancet 1991; 338: 1392. 5. Saracci R, Kogevinas M. Occupational exposure to chlorophenoxy herbicides and chlorophenols (Letter). Lancet 1991; 338: 1392-3.
