The authors conducted a proportional mortality study of 1 043 deaths that occurred between 1956 and 1992 among men who used mainly dichloro-diphenyl-trichloroethane (DDT) in anti-malarial campaign in Sardinia, Italy, during the late 1940s. For each cause of interest, investigators compared observed deaths with expected deaths. The estimated DDT exposure ranged from 170 to 600 mg/[m.sup.3] in indoor operations and from 24 to 86 mg/[m.sup.3] in outdoor operations. Workers directly exposed to DDT had a significant increase in risk for liver and biliary tract cancers (PMR = 228; 95% confidence interval = 143, 345) and multiple myeloma (PMR = 341; 95% confidence interval = 110, 795). However, the PMR. for liver and biliary tract cancers was also elevated among workers who did not have direct occupational contact with DDT, and the authors observed no increase in either PMR, by number of days in exposed jobs. Perhaps DDT did not increase the risk or perhaps occupational exposure, although quite high, did not further increase the risk compared with the heavy baseline exposure of the entire Sardinian population, (ie., mainly through diet and drinking water). Expansion of the cohort to include all exposed workers, and collection of information to improve exposure assessment are needed to clarify these findings.
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IMMEDIATELY following World War II, the Rockefeller Foundation promoted and supported a campaign to eradicate malaria in Sardinia, Italy, where mortality from this disease was 5-6 times higher than in the rest of Italy. Eradication operations occurred between November 1946 and September 1950, and dichloro-diphenyl-trichloroethane (DDT) was the main pesticide used. The availability of records for individuals who participated in this anti-malarial campaign provided us with the opportunity to evaluate the pattern of mortality associated with exposure to this pesticide. In this article, we have reported the results of a proportional mortality analysis conducted on 1 043 deaths among these subjects.
Researchers retrieved a list from the Archive of defunct Governmental Institutions of the State General Accounting in Rome of 5 193 subjects who participated in an anti-malarial campaign in Sardinia, Italy, from 1946 through 1950. The list included 2 908 workers who applied mainly DDT (chlordane and lead arsenate were also used for a short period in restricted areas) and who inspected areas after DDT applications. In addition, 2 285 occupationally unexposed subjects (e.g., supervisors, drivers, laboratory staff, administrative staff, directive staff) were on the list. Information abstracted for each employee included full name, date and place of birth, gender, residence, specific jobs, and dates the jobs were held.
We sought the vital status of the 5 193 subjects from the National Institute for Social Security (INPS) and from registers of the communes of residence. As of the date of this study, we identified 2 115 subjects who were deceased before December 31, 1992, and we obtained death certificates for 1 123 (53%) subjects. We identified a total of 29 women who were deceased. We obtained death certificates for 14 of the women, and they were excluded from this preliminary report. We excluded an additional 9 male subjects because dates of death were unknown. We also excluded 42 deaths that occurred in 1947-1955 to allow a minimum 8-y latency after initial employment in the anti-malarial campaign. Therefore, this preliminary proportional mortality analysis was based on 1 043 deaths among men who worked in the anti-malarial campaign and who died between January 1, 1956, and December 31, 1992.
Researchers coded the underlying causes of death according to the International Classification of Diseases, 9th revision. We derived expected numbers of events for each cause of interest from the 5-y age group-and 5-y calendar period-specific proportional mortality rates among the Italian male population for the following: total study population (n = 1 043); exposed workers (n = 590 [57%]); unexposed workers n = 453 [43%]); and categories of duration of employment in "exposed" jobs, defined as the tertiles of the distribution of the number of days worked (i.e., < 75 d, 75-149 d, and 150 d). We expressed the proportional mortality ratios (PMRs) for each cause of interest as 100 times the ratio of observed versus expected events. We calculated 95% confidence intervals (Cls) of PMRs according to the procedure reported by Liddell. No information about diet, smoking status, or alcohol consumption was available for study subjects.
The mean age at hire was 37.4 y (standard deviation [SD] = 10.4 y, median = 37 y). Twenty-five percent of the study population started work at age 30 y or younger, and 12% began employment at age 51 y or older. The mean age at death was 68.3 y (SD = 11.7 y, median = 69 y, range = 30-99 y). Twenty-three percent of the study population died at age 59 y or younger, and 15% died at age 80 y or older. None of the 14 women for whom death certificates were available had worked in exposed jobs: 3 died from malignant neoplasms (1 stomach cancer, 1 cancer of the gall bladder, 1 cancer of the uterus); 2 from diabetes; 5 from cardiovascular diseases; 2 from respiratory diseases; and 1 each from digestive disease and ill-defined death.
Based on information on the annual use of DDT, its concentration in the pesticide mix, and the concentrations applied to surfaces, we estimated that exposure ranged from 170 to 600 mg/[m.sup.3] in outdoor operations. On average, for a man working 6 h/d in pesticide application, the minimum indoor exposure would have been 254 g/d -- a figure almost twice that reported by the World Health Organization for similar operations.
Proportional mortality ratios for selected causes of death are shown separately for the unexposed and exposed groups in Table 1. Among the unexposed group, deaths from nonmalignant respiratory diseases were excessive. However, the excess was smaller and was not significant statistically among workers exposed to DDT. We noted significant deficits in proportional mortality for cardiovascular diseases and liver cirrhosis in both groups. Accidental deaths were elevated a nonsignificant 16% among exposed workers.
Table 1. -- Proportional Mortality Ratios (PMRs) among Unexposed Employees and Among Workers Exposed to DDT During the 1946-1950 Anti-Malarial Campaign in Sardinia, Italy
Cause of death Obs. PMR 95% Cl
Infectious diseases 8 106 45,208
Pulmonary tuberculosis 4 78 21,201
All cancers 134 110 92,130
Oral cavity and pharynx 2 51 6,182
Cancer of the digestive system 39 88 63,121
Esophagealcancer 2 65 7,233
Stomach cancer 8 46 20,91
Colon cancer 6 93 30,203
Rectal cancer 4 101 27,260
Liver and biliary tract cancer 15 210 117,346
Pancreatic cancer 1 24 0,135
Cancer of the respiratory system 52 131 98,171
Laryngeal cancer 4 90 24,230
Lung cancer 44 127 92,170
Pleural cancer 1 180 2,999
Prostate cancer 9 126 57,238
Bladder cancer 6 107 39,234
Kidney cancer 6 303 111,659
Brain and CNS cancer 3 139 28,406
Hemolymphatic system cancer 6 80 29,174
Non-Hodgkin lymphomas 1 53 1,295
Multiple myeloma 1 94 1,522
All leukemias 4 111 30,285
Myeloid leukemia 2 170 19,614
Diabetes 12 137 71,240
Dieseases of the nervous system 7 128 51,264
Cardiovascular diseases 143 80 68,94
Respiratory diseases 52 141 105,185
Digestive diseases 28 79 52,114
Liver cirrhosis 13 59 31,101
Genitourinary diseases 8 102 44,201
Accidental deaths 22 91 57,137
Cause of death Obs. PMR 95% Cl
Infectious diseases 9 101 46,191
Pulmonary tuberculosis 5 86 28,201
All cancers 158 99 84,115
Oral cavity and pharynx 6 121 44,263
Cancer of the digestive system 57 99 75,128
Esophageal cancer 6 153 56,332
Stomach cancer 14 63 35,106
Colon cancer 2 23 3,84
Rectal cancer 2 38 4,137
Liver and biliary tract cancer 22 228 143,345
Pancreatic cancer 3 55 11,160
Cancer of the respiratory system 41 78 56,106
Laryngeal cancer 1 18 0,99
Lung cancer 40 87 62,119
Pleural cancer 0 -- --
Prostate cancer 7 68 27,140
Bladder cancer 8 103 44,203
Kidney cancer 4 151 41,387
Brain and CNS cancer 2 73 8,263
Hemolymphatic system cancer 12 123 63,215
Non-Hodgkin lymphomas 2 81 9,294
Multiple myeloma 5 341 110,795
All leukemias 5 107 34,249
Myeloid leukemia 3 189 38,552
Diabetes 6 50 18,108
Diseases of the nervous system 5 67 22,157
Cardiovascular diseases 179 74 64,86
Respiratory diseases 53 108 81,142
Digestive diseases 39 88 63,120
Liver cirrhosis 16 59 34,96
Genitourinary diseases 9 89 41,169
Accidental deaths 35 119 83,165
Risk for all cancers was not increased significantly among exposed employees. We observed significant increases in the PMR for liver and biliary tract cancer among both groups (exposed: PMR = 228; unexposed: PMR = 210); for multiple myeloma (PMR = 341) among the exposed; and for kidney cancer among the unexposed (PMR = 303). Myeloid leukemia risk was elevated among the exposed (PMR = 184) and unexposed (PMR = 170), but neither risk was significant statistically.
In 1948 and 1949, workers used, in addition to DDT, small amounts of chlordane and lead arsenate. To determine whether risks for liver and biliary tract cancers, multiple myeloma, and myeloid leukemia varied in accordance with possible exposure to other pesticides, we calculated PMRs according to whether subjects worked only before 1948 or only from 1948 forward. No changes were observed (data not shown).
Researchers conducted a search in the archive of the regional agency, which continued pest-control operations after the anti-malarial campaign was completed to identify individuals who continued working in this agency and who may have experienced further exposure to DDT and other pesticides. Forty-nine (9%) deaths among exposed workers occurred in subjects who continued working in the regional pest-control agency. The proportional mortality analysis restricted to this subgroup was limited by the small sample size, but the observed versus expected ratios were similar to those observed for the rest of exposed workers for all cancers, lung cancers, and liver and biliary tract cancer (data not shown).
In this analysis, we used the number of days of work in exposed jobs as a surrogate of the cumulative exposure to DDT. We calculated PMRs for specific causes for unexposed subjects and by categories of duration of employment, defined by the tertiles of the distribution of number of days of work among exposed subjects (Table 2). The pattern of liver cancer mortality was inconsistent. It increased from 2.3-fold among exposed subjects employed less than 75 d, to 2.8-fold among subjects employed 75-149 d, and then decreased to 1.9-fold among exposed subjects employed 150 d or more. We determined the largest PMR for multiple myeloma among exposed subjects who had the shortest duration of employment. Myeloid leukemia risk increased as number of days in exposed jobs increased, but the number of deaths was very low, and we observed an increase in PMR for unexposed subjects also.
Table 2. -- Proportional Mortality Ratios (PMRs) for Selected Cancer Sites Among Subjects Exposed to DDT During the 1946-1950 Anti-Malarial Campaign in Sardinia, Italy, by Tertiles of Duration of Employment in Exposed Jobs
Exposed [is less
than] 75 d
(No. deaths = 186)
Cause of death Obs. PMR 95% Cl
All cancers 51 102 76,134
Cancer of the digestive system 17 94 55,151
Liver and biliary tract cancer 7 234 94,481
Lung cancer 10 70 33,129
Kidney cancer 1 122 2,677
Cancer of the
lymphohemopoietic system 4 136 36,347
Multiple myeloma 3 642 129,1875
Myeloid leukemia 0 -- --
Exposed 75-149 d
(No. deaths = 204)
Cause of death Obs. PMR 95% Cl
All cancers 52 91 68,119
Cancer of the digestive system 17 83 48,133
Liver and biliary tract cancer 10 281 134,516
Lung cancer 13 78 42,134
Kidney cancer 2 207 23,748
Cancer of the
lymphohemopoietic system 4 109 29,279
Multiple myeloma 1 191 2,1064
Myeloid leukemia 1 173 2,961
Exposed [is greater than
or equal to] 150 d
(No. deaths = 172)
Cause of death Obs. PMR 95% Cl
All cancers 50 109 81,144
Cancer of the digestive system 21 127 78,194
Liver and biliary tract cancer 5 188 61,439
Lung cancer 16 124 71,201
Kidney cancer 0 -- --
Cancer of the
lymphohemopoietic system 4 146 39,375
Multiple myeloma 1 240 3,1333
Myeloid leukemia 2 446 50,1609
Risk for liver and biliary tract cancer increased with age at first exposure -- from 2.2-fold at age 30 y to 3.3-fold at age 41-50 y -- but no death from this cause occurred among subjects who were first exposed to DDT at age 51 y or older. Deaths from multiple myeloma and myeloid leukemia were not concentrated in specific groups of age at first exposure (data not shown).
Among the 37 deaths from cancer of the liver and biliary tract observed in the present study, 22 (59%) resulted from primary liver cancer; this number exceeded the 16.9 expected deaths from liver cancer and cancer of the biliary tract combined. Thirteen of the 37 (35%) deaths resulted from cancer of the liver (unspecified primary or secondary), 1 of 3 resulted from a malignant neoplasm of the gall bladder, and 1 of 37 resulted from a neoplasia of the Vater's ampulla.
Although most industrialized countries have restricted or prohibited production and use of DDT for almost three decades, the investigation of long-term effects of human exposure to DDT is relevant to public and occupational health because DDT is still used in some developing countries. Residues continue to be found in various foodstuffs. Nonetheless, surveys of DDT concentrations and DDT's most persistent metabolite, dichloro-diphenyl-dichloroethylene (DDE), in the adipose tissue and serum of general population samples reveal a worldwide decline that began in the 1970s, and continues to the present.[7-10] Researchers have observed an elevated correlation between body burden of organochlorine compounds and fish[11-13] and fatty food consumption. In addition, researchers recently reported an association between DDE level in serum and cancer of the breast and other sites.[15-21]
Our results showed significant excesses of liver cancer and multiple myeloma among DDT-exposed workers. Liver cancer, however, was also elevated significantly among unexposed workers, and it did not increase with duration of exposure. Multiple myeloma was elevated significantly only among exposed workers, but the highest risk we observed was among workers who had been employed for the least amount of time. It should also be noted that the 4.5-fold increase in the PMR for myeloid leukemia among exposed subjects in the longest duration category (150 d) was based on only 2 deaths.
We used deaths among the Italian male population during 1956-1992 as the reference because regional mortality figures, by age groups and gender, were available only since 1970. Standardized mortality rates from all cancers, lung cancer, stomach cancer, and kidney cancer were 16%, 12%, 41%, and 33%, respectively, lower among the Sardinian male population than among the total Italian male population, whereas liver cancer and leukemia mortality were 14% and 11%, respectively, higher among the Sardinian male population. To date, no one has published figures that show the results of comparing multiple myeloma and single leukemia types. Geographic factors may therefore account for part of the observed increase in the PMR for liver and biliary tract cancer.
Any conclusion based on these preliminary results is weakened by the study limitations and by incomplete tracking of death certificates. The lack of a clear dose-response effect, as well as the finding of excesses among subjects whose job titles did not imply direct contact with the pesticide, may indicate that DDT is not responsible for the increased risk. Conversely, given that environmental exposure to DDT was presumably high for the entire Sardinian population (i.e., mainly through diet and drinking water), it is plausible that occupational exposure -- although quite high -- did not further increase risk, compared with baseline exposure. Also, the number of days of work in exposed jobs may not have been a good surrogate for dose in this study. Availability of data for the complete cohort and a more detailed exposure estimate at an individual level, together with the aid of additional questionnaire information from survivors, may help clarify the results presented herein.
The work of Dr. Pierluigi Cocco at the National Cancer Institute was supported with funds from the International Union Against Cancer (Geneva, Switzerland) and the NCI/EORTC Exchange Program (Brussels, Belgium).
Submitted for publication March 22, 1996; revised; accepted for publication September 26, 1996.
Requests for reprints should be sent to Pierluigi Cocco, M.D., Istituto di Medicina del Lavoro, Universita di Cagliari, via San Giorgio 12, 09124 Cagliari, Italy.
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Source Citation:Cocco, Pierluigi, Aaron Blair, Patrizia Congia, Giovanna Saba, Costantino Flore, Maria R. Ecca, and Costantino Palmas. "Proportional mortality of dichloro-diphenyl-trichloroethane (DDT) workers: a preliminary report." Archives of Environmental Health 52.n4 (July-August 1997): 299(5). General OneFile. Gale. BROWARD COUNTY LIBRARY. 25 Oct. 2009
Gale Document Number:A19575801
Disclaimer:This information is not a tool for self-diagnosis or a substitute for professional care.
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