Veterans and Agent Orange Health Effects of Herbicides Used in Vietnam (1994) / Chapter Skim
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8 Cancer
8 Cancer
Pages 433-590
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From page 433... ...
Following this introduction about cancer and its epidemiology, the committee summarizes and reaches conclusions about the strength of the evidence in epidemiologic studies regarding associations between exposure to herbicides and TCDD and each type of cancer. The cancer types are discussed in the order in which they are listed in the International Classification of Diseases (U.S.
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From page 434... ...
In evaluating the epidemiologic studies, the committee noted that in many studies, insufficient time had passed since exposure for many types of tumors to develop; this is an issue of minimum latency needed for an adequate study. However, if TCDD is acting as a promoter, studies that evaluate health outcomes before the usual minimum latency period has passed may be appropriate since this function may require a shorter latency period for its hypothesized mechanism of action.
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From page 435... ...
_ A similar attempt to relate a risk factor to even a relatively common malignancy, such as lung cancer, would require a cohort of 10,000 to 20,000 individuals followed for five to ten years. For a less common cancer, such as non-Hodgkin's lymphoma, it would be even more difficult, requiring substantially more people.
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From page 436... ...
The two specific types of cancer most closely linked to herbicide exposure in the scientific literature, soft tissue sarcoma (STS) and non-lIodgkin's lymphomas, are noteworthy in that their incidence is relatively high in younger age groups even in the absence of any harmful exposures.
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From page 437... ...
Hodgkin's disease, soft tissue sarcoma, testicular cancer for men, and .,ooo 100 _ _ _ _ to to to to to a)
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From page 438... ...
For example, if the odds ratio for a particular cancer and poor exposure measure to herbicides is 1.5, this risk
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From page 439... ...
The herbicides have not been adequately tested, however, so conclusions regarding their carcinogenicity in animals must be drawn with caution. EXPECTED NUMBER OF CANCER CASES AMONG VIETNAM VETERANS To provide some background for the consideration of cancer risks in Vietnam veterans, and to evaluate the possibilities for future epidemiologic studies of cancer in this group, the committee estimated the number of cancer cases that could be expected to occur in Vietnam veterans in the absence of any increase in risk due specifically to herbicide exposure, as follows.
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From page 440... ...
However, two factors make it difficult to conduct the epidemiologic studies needed to detect any increased risk for specific cancers that herbicide exposure might cause among veterans. First, only some of those who served in Vietnam were exposed to herbicides (see Chapter 6~; therefore, any added risk for a specific cancer would best be studied in the smaller exposed population with a more limited number of cases.
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From page 441... ...
All sites: 140-208; Liver and intrahepatic bile duct: 155.0-155.2; Lung, bronchus, and larynx: 161.0-161.9, 162.2-162.9; Soft tissue sarcoma: 171.0-171.9, 164.1; Breast: 174.0-174.9 (female) , 175 (male)
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From page 442... ...
Therefore, identifying environmental and occupational carcinogenic exposures, and developing preventive measures for them, are of great public health impor tance. Epidemiologists and cancer specialists generally do not study risk factors for all cancers combined.
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From page 443... ...
A study among German production workers exposed to TCDD (Manz et al., 1991) found an SMR for total cancer mortality of 1.2 (CI 1.0-1.5)
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From page 444... ...
Vietnam Veterans Studies Many of the studies of Vietnam veterans have reported total cancer mortality. A follow-up study of 19,205 Australian Vietnam veterans found no excess of overall mortality or overall cancer mortality compared to 25,677 Vietnam era veterans who served in Australia (Fett et al., 1987a,b)
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From page 445... ...
found no excess of cancer in Vietnam veterans compared to 26,685 Vietnam era veterans who served in areas other than Southeast Asia; no excess overall cancer mortality was shown in Army I Corps veterans (Bullman et al., 1990~. A study conducted by the DVA (Watanabe et al., 1991)
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From page 446... ...
Risk factors include family history of the disease, a history of inflammatory bowel disease, and diet (Page and Asire, 1985J. High dietary intake of fats has been linked to increased risk of colon cancer, whereas high intake of dietary fiber is linked to decreased risk (Page and Asire, 1985; Prentice and Sheppard, 1990; Weisburger, 1991)
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From page 447... ...
looked at risk for colon cancer and found no excess risk for agricultural workers or others exposed to phenoxy herbicides. Likewise, a case-control study of colon cancer, following a PMR analysis (PMR = 1.5, CI 1.1-2.0)
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From page 448... ...
Bond et al., 1988 Dow 2,4-D production workers0 (0.0-3.7) Manz et al., 1991 German production workers12 1.2 (0.6-2.1)
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From page 449... ...
Saracci et al., 1991 NIOSH cohort26 1.1 (0.7- 1.6) Thomas, 1987 Flavor and fragrance chemical production workers 1.4 Burmeister, 1981 Farmers in Iowa416 1.1 Wiklund, 1983 Swedish agricultural workers777 0.8 (0.8-0.9)
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From page 450... ...
Bond et al., 1988 Dow 2,4-D production workers4 2.1 (0.6-5.4) Manz et al., 1991 German production workers8 0.9 (0.4-1.8)
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From page 451... ...
Lynge, 1985 Danish production workers men14 1.5 Saracci et al., 1991 IARC cohort24 1.1 (0.7- 1.6) Thomas, 1987 Flavor and fragrance chemical production workers 2.5 Wiklund, 1983 Swedish agricultural workers1?
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From page 452... ...
According to the committee's calculations 70 cases of cancers of the liver and the biliary passages are expected among male Vietnam veterans and 0.1 among female veterans in 1995, and 151 in male veterans and 0.1 in female veterans in 2000. In the United States, liver cancers account for only about 1.4 percent of new cancer cases and 2.4 percent of cancer deaths.
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From page 453... ...
Animal experiments have shown aflatoxin to be a potent liver carcinogen, but its role in human hepatic carcinoma with or without concurrent HBV infection remains to be defined. Epidemiologic Studies Occupational Studies Production Workers In combined data on production workers at 12 plants in the United States that produced chemicals contaminated with TODD, reported by Fingerhut and colleagues (1991)
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From page 454... ...
In a case-control study in Sweden, Hardell and colleagues (1984) observed a positive relationship between exposure to phenoxy or dichlorophenoxy herbicides and risk of liver cancer.
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From page 455... ...
One of the largest studies (Hardell et al., 1984) indicates an increased risk for liver cancer and exposure to herbicides, but another study of Swedish agricultural workers (Wiklund, 1983)
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From page 456... ...
Female residents zones A and B1 1.2 (0.2-9.1) Stehr et al., 1986 Missouri residents0 Hoffman et al., 1986 Residents of Quail Rut Mobile Home Park Vietnam veterans Cohort studies Breslin et al., 1988 Anderson et al., 1986a,b Case-control studies Army Vietnam veterans Marine Vietnam veterans Wisconsin Vietnam veterans 34 1.0 (0.8- 1.4)
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From page 457... ...
More than 120 chemicals have been identified as liver carcinogens in laboratory rodents. Increased Risk of Disease Among Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental, and veterans studies that have been reviewed, inadequate control for important confounders in these studies, and the lack of information needed to extrapolate from the level of exposure in the studies reviewed to that of individual Vietnam veterans, it is not possible for the committee to quantify the degree of risk likely to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam.
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From page 458... ...
A study in Shanghai of occupational risk factors found excess risks for workers in a variety of settings including textile weaving, baking, and metal smelting, forging, and grinding (Zheng et al., 1992a)
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From page 459... ...
Epidemiologic Studies The study by Saracci and colleagues (1991) of production workers and sprayers showed a relative risk of 2.9 for these cancers based on three cases.
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From page 460... ...
Increased Risk of Disease Among Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental, and veterans studies that have been reviewed, inadequate control for important confounders in these studies, and the lack of information needed to extrapolate from the level of exposure in the studies reviewed to that of individual Vietnam veterans, it is not possible for the committee to quantify the degree of risk likely to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam. RESPIRATORY CANCERS Background Carcinomas of the lung and bronchus (ICD-9 162.2-162.9)
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From page 461... ...
Cigarette smoking is the major risk factor for lung cancer, estimated by the American Cancer Society (1992) to be responsible for about 87 percent of lung cancer deaths in the United States.
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From page 462... ...
These subgroup SMRs were based on one, two, and five deaths, respectively; a test of the null hypothesis that there is no trend evidenced in these data has a p-value of .1. Lung cancer mortality in a cohort employed in the production and spraying of MCPA and other phenoxy herbicides (Coggon et al., 1986)
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From page 463... ...
No direct information on the smoking habits of the cohort was available, however. A review of the other occupational information for the lung cancer cases did not identify any known risk factors likely to explain the observed excess.
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From page 464... ...
Nevertheless the authors are confident that the majority of the subjects in these two plants were indeed exposed to phenoxy herbicides to some degree. An excess lung cancer mortality risk was observed (SMR = 2.2, CI 1.1-4.0, based on 11 observed cases)
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From page 465... ...
Because many of the workers smoked and were exposed to other chemicals it is not possible to rule out alternative explanations for this small excess risk. It is unlikely, however, that smoking explains the entire effect, since TABLE 8-8 Selected Epidemiologic Studies of Production Workers Lung Cancer Estimated Exposed Relative Risk Reference Study Population Cases (95% CI)
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From page 466... ...
is not elevated (Won" and Raabe, 1989~. Thus, although tobacco and asbestos cannot be ruled out, the more likely explanation for the observed elevations in risk is one or more agents associated with the production of phenoxy herbicides and related compounds.
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From page 467... ...
However, workers were exposed to a multiplicity of chemicals, some known carcinogens; individual exposure to phenoxy herbicides or to any TCDD-contaminated compound cannot be determined. It is unlikely that the elevated lung cancer risk in the entire cohort can be entirely attributable to smoking.
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From page 468... ...
TABLE 8-9 Selected Epidemiologic Studies of Herbicide/Pesticide Applicators Lung Cancer Estimated Exposed Relative Risk Reference Study Population Cases (95% CI) Axelson et al., 1980 Swedish railroad workers 3 1.4 (0.3-4-0)
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From page 469... ...
was too small to consider lung cancer risk; only one lung cancer death occurred in the comparison group of Vietnam era veterans. DVA Studies Breslin and colleagues (1988)
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From page 470... ...
Australian Vietnam Veterans Among Australian Vietnam veterans compared to Vietnam era veterans serving in Australia, the relative risk was 2.7 (CI 0.2-30.0) for lung cancer (Fett et al., 1987b)
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From page 471... ...
, positive associations were found consistently only in those studies in which TCDD or herbicide exposures were probably high and prolonged, especially the largest, most heavily exposed cohorts of chemical production workers exposed to TODD (Zober et al., 1990; Fingerhut et al., 1991; Manz et al., 1991; Saracci et al., 1991) (see Table 8-8)
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From page 472... ...
Increased Risk of Disease Among Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental, and veterans studies that have been reviewed, inadequate control for important confounders in these studies, and the lack of information needed to extrapolate from the level of exposure in the studies reviewed to that of individual Vietnam veterans, it is not possible for the committee to quantify the degree of risk likely to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam. BONE CANCER Background According to the American Cancer Society, 2,000 new cases of bone and joint cancer (ICD-9 170.0-170.9)
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From page 473... ...
The principal known risk factors for osteosarcoma are exposure to radiation and, at older ages, Paget's disease. Epidemiologic Studies Bone and joint cancers are relatively uncommon.
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From page 474... ...
Wiklund, 1983 Swedish agricultural workers 44 1.0 (0.6-1.4) b Ronco et al., 1992 Danish male self-employed farm workers 9 0.9 Vietnam veterans Breslin et al., 1988 Army Vietnam veterans 27 0.8 (0.4-1.7)
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From page 475... ...
. Most occur de novo rather than from transformation of the much more common benign tumors of the soft tissues.
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From page 476... ...
Because of the diversity and rarity of STSs, the average pathologist may not have detailed knowledge of the differential criteria, and even specialists in STS pathology disagree on some types. Overall, there is no clear histogenetic basis for registry classification of soft tissue sarcomas.
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From page 477... ...
Although there is no direct evidence of a similar response in humans, it is well established that human exposure to polyvinyl chloride is associated with the development of hepatic angiosarcoma. Epidemiologic Studies Occupational Studies Production Workers A cohort of German production workers (Zober et al., 1990)
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From page 478... ...
When an analysis was performed by years since first exposure, all 4 deaths occurred between 10 and 19 years, while the number expected was 0.7 (SMR = 6.1, CI 1.7-15.53. The finding of an increased risk of soft tissue sarcoma in the IARC analysis is in accord with that of the NIOSH cohort (Fingerhut et al., 1991)
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From page 479... ...
A substantial body of evidence, however, points toward an association of STS with exposure to phenoxy herbicides and related compounds, whereas the possibility of a link to 4-aminobiphenyl has not previously been reported. Summary of Production Worker Studies The production workers studied in pesticide and related industries have exposures that are likely to have been fairly high and sustained for long periods.
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From page 480... ...
No cases of STS were observed among female gardeners. It is difficult to link the elevated risk in men to phenoxy herbicides with any confidence because of the diversity of exposures in gardeners, but the finding is nevertheless suggestive of an association.
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From page 481... ...
Of histologically confirmed but not typed soft tissue sarcomas, 21 living and 31 deceased male cases were included in the matched-pairs analysis, and an odds ratio of 6.2 was observed for soft tissue sarcoma and exposure to either phenoxy herbicides or chlorophenols. When the analysis was conducted without regard to match status of the matched pairs, the OR was similar, 5.7 (CI 2.9-11.3)
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From page 482... ...
for exposure to all other types of phenoxy herbicides. Chlorophenol exposure excluding phenoxy herbicide exposure yielded an odds ratio of 3.3 (CI 1.3-8.11.
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From page 483... ...
. The odds ratio for STS and exposure to phenoxy herbicides for at least one day more than five years before diagnosis was 3.3 (CI 1.4-8.1)
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From page 484... ...
Viewed as a group, the four case-control studies of Hardell and colleagues on STS provide strong evidence for an association with phenoxy herbicide exposure and chlorophenol exposure (Figure 8-3~. The pooled odds ratio for phenoxy herbicide exposure is 2.7 (CI 1.8-4.1~.
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From page 485... ...
A fifth case-control study was conducted in southern Sweden by an essentially different group of investigators, with methods that seem to differ somewhat from those of the Hardell studies (Wingren et al., 19901. For cases of STS reported to the regional cancer registry, no separate histologic confirmation of the diagnoses was done, nor were the histologic types listed in the paper.
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From page 486... ...
However, this estimate is based on six exposed cases and one exposed control, and so yields an exact CI of 0.8-334. The authors do not report a combined odds ratio for either chlorophenol or herbicide exposure, nor can one be estimated from the separate tables because of the possibility that some subjects may have reported both types of exposure.
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From page 487... ...
Among all living women, the odds ratio for certain or possible exposure was 2.4 (CI 0.4-16.1) , but was based on five cases and seven controls so that confidence intervals are quite wide and do not exclude the null.
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From page 488... ...
, and for "lumber grader" the odds ratio was 2.7 (CI 1.1-6.4~. No such elevated risks of STS were found among jobs identified as being exposed to phenoxy herbicides.
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From page 489... ...
The odds ratio for STS following at least one day of exposure to phenoxy herbicides or chlorophenols more than five years before diagnosis was 1.0 (CI 0.3-3.1~. For more than 30 days of exposure, the risk estimate was 2.0, but based on very small numbers, yielding a CI from 0.5 to 8.0.
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From page 490... ...
The overall odds ratio for high phenoxy herbicide use and risk
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From page 491... ...
Individual exposure estimates were not available, but data from two surveys suggest that 72 percent of applicators used phenoxy herbicides for at least one day compared to 16 percent of forestry and agricultural workers. Summary of Pesticide Applicator Studies Most of the pesticide applicator studies are too small to individually have power to detect STS, although presumably the degree of exposure for the average study subject was much higher in these studies than in, for example, the agricultural worker studies.
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From page 492... ...
Despite uncertainties about the magnitude of the increased risk, which stem from differences among comparison populations, the increase cannot be ignored. Vietnam Veterans Studies Ranch Hand Study The Ranch Hand study is described in Chapter 7.
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From page 493... ...
, and a higher proportion also reported work in a meat-packing or processing plant, where chlorophenol exposure sometimes occurs (p ~ .05~. Odds ratios for these associations are not provided, but it is possible to calculate crude (i.e., without adjustment for age or other factors)
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From page 494... ...
, but it is likely that cases from the two studies overlapped. The first used data from DVA hospitals and found an odds ratio for STS comparing those serving in Vietnam to those without such service of 0.8 (CI 0.6-1.1)
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From page 495... ...
compared to nonveterans. The adjusted mortality odds ratio for STS comparing Vietnam veterans to other veterans of the Vietnam era was 1.1 (CI 0.2-6.71.
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From page 496... ...
The authors calculated an odds ratio as an estimate of the relative risk of STS among these two groups, using all other subjects in the Massachusetts Cancer Registry with cancers other than STS, non-Hodgkin's lymphoma (NHL) , or kidney cancer as the comparison population.
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From page 497... ...
In contrast, the comparison population mortality experience was drawn from published national statistics relying solely on the standard death certificate. There was one death from STS found among Vietnam veterans and one among the Vietnam era group, yielding an age-adjusted relative mortality rate of 1.3 (CI 0.1-20.01.
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From page 498... ...
Summary There are at least three fundamental problems that make the interpretation of epidemiologic studies on soft tissue sarcoma and exposure to phenoxy herbicides and related compounds especially difficult. First, if there are several potential causative agents present in a particular environment, it may be difficult to determine which is associated with STS.
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From page 499... ...
The problems of the existing classification schemes have been discussed above, without clear conclusions about what may be the "correct" classification system. Additional refinement of the clinical and pathological definitions of soft tissue sarcomas in epidemiologic studies would also help to determine which of the specific cancers in this class are associated with herbicides and/or TCDD.
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From page 500... ...
(2,4-D; 2,4,5-T and its contaminant TCDD; cacodylic acid; and picloram) and soft tissue sarcoma.
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From page 501... ...
According to the committee's calculations, 486 cases of melanoma are expected among male Vietnam veterans and 1.1 among female veterans in the year 1995. In the year 2000, the expected numbers are 632 cases in male veterans and 1.3 in female veterans.
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From page 502... ...
These included studies of chemical production workers in the United States and other countries (Suskind and Hertzberg, 1984; Lynge, 1985; Coggon et al., 1986; Bond et al., 1988; Zober et al., 1990; Fingerhut et al., 1991; Manz et al., 1991; Saracci et al., 1991) , agricultural workers (Burmeister, 1981; Alavanja et al., 1988; Wigle et al., 1990; Hansen et al., 1992; Ronco et al., 1992', pesticide applicators (Blair et al., 1983;
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From page 503... ...
Conclusions Strength of Evidence in Epidemiologic Studies There is limited/suggestive evidence of no association between exposure to herbicides* (2,4-D; 2,4,5-T and its contaminant TCDD; cacodylic acid; and picloram)
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From page 504... ...
Bond et al., 1988 Dow 2,4-D production workers0 0.0 (0-6.8) Suskind and Hertzberg, 1984 Monsanto production workers8 1.6 Coggon et al., 1986 British MCPA chemical workers other skin cancers3 3.1 (0.6-9.0)
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From page 505... ...
. According to the committee's calculations, 13.2 cases of breast cancer and 1.6 cases of uterine cancer are expected among female Vietnam veterans in 1995.
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From page 506... ...
Early age at menarche and late age at menopause are associated with increased risk as are late or no childbearing. Breast Cancer Among U.S.
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From page 507... ...
Risk factors for breast cancer include early age at menarche, late age at first birth and low parity (or nulliparity) , late age at menopause, and in addition, family history of breast cancer and personal history of benign cystic breast disease (Henney and DeVita, 1987~.
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From page 508... ...
Occupational Studies Production Workers Many studies have excluded women from analysis because of their small numbers in the groups under study. For example, Fingerhut and colleagues (1991)
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From page 509... ...
In a study focusing on all persons employed in the manufacture of phenoxy herbicides in Denmark before 1982, Lynge (1985) linked employment records for 1,069 women with the National Cancer Register contributing 17,624 person-years of follow-up: 13 cases of breast cancer were diagnosed, giving an SMR of 0.9; 9 cases of cervical cancer, SMR = 1.3; and 2 cases of cancer of the endometrium, SMR = 0.7.
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From page 510... ...
Overall, 18 women with ovarian cancer were classified as definitely and probably exposed compared to 14 controls, giving an odds ratio of 4.4 (CI
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From page 511... ...
Slightly more than one-fourth of the cancer deaths were due to breast cancer among the Vietnam veterans; compared to the other Vietnam era veterans, the relative risk was not significantly elevated (RR = 1.2, CI 0.6-2.5~. The small numbers of deaths within the cohort of women who served in Vietnam preclude conclusions at this time regarding Vietnam experience and cause-specific mortality; additional follow-up is essential to determine whether
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From page 512... ...
While animal data suggest TCDD may act as an antiestrogen, and it has been shown to inhibit growth of breast cancer cell lines in tissue culture, the extrapolation to prevention of reproductive cancers is plausible but has not been demonstrated. Increased Risk of Disease Among Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental, and veterans studies that have been reviewed, inadequate control for important confounders in these studies, and the lack of information needed to extrapolate from the level of exposure in the studies reviewed to that of individual Vietnam veterans, it is not possible for the committee to quantify the degree of risk likely to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam.
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From page 513... ...
In 2000, the expected numbers are 777 bladder cancers and 497 renal cancers in male veterans and 0.7 and 0.6, respectively, in female veterans. The American Cancer Society figures for 1992 also showed 132,000 new cases of prostate cancer (ICD-9 185)
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From page 514... ...
Leather tanners, shoe workers, and those occupationally exposed to asbestos appear to have an increased risk for cancer of the kidney. Exposure to cadmium, thorosate, and petroleum products is also associated with increased mortality from kidney cancer (Linehan et al., 19891.
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From page 515... ...
These include studies of chemical production workers in the United States and other countries (Lynge, 1985; Coggon et al., 1986; Bond et al., 1988; Fingerhut et al., 1991; Manz et al., 1991; Saracci et al., 1991) , agricultural workers (Burmeister, 1981; Wiklund, 1983; Ronco et al., 1992)
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From page 516... ...
Occupational studies include studies of chemical production workers in the United States and other countries (Lynge, 1985; Coggon et al., 1986; Bond et al., 1988; Zober et al., 1990; Saracci et al., 1991) , agricultural and forestry workers (Burmeister, 1981; Alavanja et al., 1988, 1989; Green, 1991; Ronco et al., 1992)
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From page 517... ...
Bond et al., 1988 Dow 2,4-D production workers 0 -(0-7.2) Lynge, 1985 Danish production workers men 11 0.8 Coggon et al., 1986 British MCPA production workers 8 0.9 (0.4-1.7)
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From page 518... ...
Other occupational and environmental studies of prostate cancer generally have been consistent. These include studies of chemical production workers in the United States and other countries (Bond et al., 1988; Lynge, 1985; Coggon et al., 1986; Zober et al., 1990)
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From page 519... ...
found an odds ratio of 2.3 (CI 1.0-5.5) for service in Vietnam.
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From page 520... ...
Coggon et al., 1986 British MCPA production workers18 1.3 (0.8-2.1) Lynge, 1985 Danish production workers9 0.8 Manz et al., 1991 German production workers7 1.4 (0.6-2.9)
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From page 521... ...
Coggon et al., 1986 British MCPA production workers 4 2.2 (0.6-5.7) Saracci et al., 1991 IARC cohort 7 2.3 (0.9-4.6)
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From page 522... ...
In contrast to TCDD, there is no convincing evidence of, or mechanistic basis for, the carcinogenicity in animals of any of the herbicides, although they have not been studied as extensively as TCDD. Increased Risk of Disease Among Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental, and veterans studies that have been reviewed, inadequate control for important confounders in these studies, and the lack of information needed to extrapolate from the level of exposure in the studies reviewed to that of individual Vietnam veterans, it is not possible for the committee to quantify the degree of risk likely to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam.
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From page 523... ...
i The studies that had inconsistent findings with regard to brain cancers ncluded studies of chemical production workers in the United States and other countries (Lynge, 1985; Coggon et al., 1986; Bond et al., 1988; Fingerhut et al., 1 99 1; Saracci et al., 1 99 1 ) , agricultural workers (Burmeister, 1 98 1; Wigle et al., 1990; Morrison et al., 1992; Ronco et al., 1992)
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From page 524... ...
Bond et al., 1988 Dow 2,4-D production workers 0 (0-4.1) Coggon et al., 1986 British MCPA production workers 11 1.2 (0.6-2.2)
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From page 525... ...
In contrast to TCDD, there is no convincing evidence of, or mechanistic basis for, the carcinogenicity in animals of any of the herbicides, although they have not been studied as extensively as TCDD. Increased Risk of Disease Among Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental, and veterans studies that have been reviewed, inadequate control for important confounders in these studies, and the lack of information needed to extrapolate from the level of exposure in the studies reviewed to that of individual Vietnam veterans, it is not possible for the committee to quantify the degree of risk likely to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam.
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From page 526... ...
. In 1992, the annual incidence and deaths for each cancer were as fol lows: Males Females Cancer New CasesDeaths New Cases Deaths Hodgkin's disease 4,200900 3,200 600 Non-Hodgkin's lymphomas 23,O0010,000 18,000 9,400 Multiple myeloma 6,3004,700 6,200 4,500 According to the committee's calculations, 94 new cases of Hodgkin's disease, 380 new cases of non-Hodgkin's lymphoma, and 57 new cases of multiple myeloma are expected among male Vietnam veterans and a total of 0.8 of all of these cancers among female veterans in 1995.
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From page 527... ...
Epidemiology Both viral infections and chemical exposures have been postulated as risk factors for this group of diseases, but the causers) remain unknown.
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From page 528... ...
Of 17 cases identified over a ninemonth period, 14 had occupations compatible with possible exposure to phenoxy herbicides or chlorophenols, and 11 cases reported such exposures.
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From page 529... ...
These Swedish findings prompted further studies in Sweden and many studies of the health effects of herbicide use in other countries, including the United States. Occupational Studies Production Workers Two studies dominate the evidence relating exposure to TCDD and a risk of NHL, in that their results include virtually all studies providing exposure information in plants producing phenoxy herbicides or chemicals potentially contaminated with TCDD.
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From page 530... ...
The odds ratios were 4.8 (CI 2.98.1) for any exposure to phenoxy acids and 4.3 (CI 2.7-6.9)
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From page 531... ...
, which suggests that interview data introduced little bias. Analyses within forestry or agricultural worker groups, according to continuous or limited employment since 1950, showed, respectively, odds ratios of 0.8 and 1.0 for workers unexposed to phenoxy acids versus 5.1 and 2.4, respectively, for continuous and limited forestry/agriculture employment with exposure to phenoxy acids.
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From page 532... ...
Despite the high odds ratio for herbicide exposure, the study showed a significantly reduced OR = 0.3 (CI 0.1-1.0) for farming, based on seven cases.
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From page 533... ...
Some studies provide information on NHL odds ratios only in relation to farm employment but had hypothesized that herbicide exposure was a risk factor of interest. A case-control study for NHL deaths in relation to farming for 1958-1983 in Hancock County, Ohio, found an overall odds TABLE 8-22 Non-Hodgkin's Lymphoma Results from U.S.
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From page 534... ...
Elevated odds ratios, especially for reticulum cell sarcoma, were found for herbicide use according to acres treated (OR = 2.9, CI 1.0-8.2) , insecticide use (OR = 4.6, CI 1.6-13.1)
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From page 535... ...
The overall odds ratios for any past occupational exposure to phenoxy herbicides were 1.1 (CI 0.8-1.4)
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From page 536... ...
resulted in odds ratios, based on cancer controls, of 1.5 (CI 0.7-3.3)
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From page 537... ...
showed no significant association for NHL and exposures to phenoxy herbicides or chlorophenols. The odds ratios increased from 1.5 (CI 0.6-3.7)
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From page 538... ...
tailed multivariate analysis of the risk of death from non-Hodgkin's lymphoma; results showed an increasing relative risk according to acres sprayed with herbicides and dollars spent on herbicides. The increase in non-Hodgkin's lymphoma was found to be largely confined to farms of less than 1,000 acres.
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From page 539... ...
Increasing odds ratios were usually found in analyses where there was likelihood of herbicide exposure. In studies that controlled for other possible NHL risk factors the herbicide-related risk generally remained.
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From page 540... ...
Studies other than in the United States and Sweden are more limited, but significantly increased risks for NHL in relation to herbicide use are seen, adding strong support to the conclusions of the Swedish and U.S. studies.
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From page 541... ...
The adjusted odds ratio for NHL compared to male veterans who did not serve in Vietnam was 1.5 (CI 1.1-2.01; compared to Vietnam era veterans with no service in Vietnam, the odds ratio was also 1.5 (CI 1.02.3~. Various confounders were considered in regression analyses, including registry, age, race, ethnicity, education and potential exposure to herbicides, pesticides, or chlorophenols outside Vietnam.
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From page 542... ...
Further, it is unlikely that bias is an explanation of the elevated risks since six other cancers considered showed no elevated odds ratios. The authors conclude that Vietnam veterans have approximately a 50 percent increased risk of developing NHL, but state that Agent Orange or dioxin would appear not to be responsible for the increase, based on the above negative associations of service in sprayed areas and the low levels of TCDD found among 646 Vietnam veterans with service in III Corps (CDC, 1989~.
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From page 543... ...
, which analyzed the causes of death of 24,235 Vietnam veterans compared with 26,685 Vietnam era veterans who served between 1965 and 1974. Summary data from these studies are presented in Table 8-26.
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From page 544... ...
Marine Vietnam veterans compared to Marine Vietnam era veterans 35 2.1 (1.2-3.8) Watanabe et al., 1991 Army Vietnam veterans compared to Army Vietnam era veterans 140 0.8 Army Vietnam veterans compared to combined Army and Marine Vietnam era veterans 140 0.9 Marine Vietnam veterans compared to Vietnam era veterans 42 1.8 Marine Vietnam veterans compared to combined Army and Marine Vietnam era veterans 42 1.2 Case-control mortality studies Burt et al., 1987 Army combat Vietnam veterans compared to Army Vietnam era veterans Marine combat Vietnam veterans compared to Marine Vietnam era veterans Army Vietnam veterans (service 1967-1969)
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From page 545... ...
Case-control analyses according to combat status by Burt and colleagues (1987) showed that men with combat specialties had higher mortality odds ratios (MORs)
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From page 546... ...
In the cohort mortality study (Anderson et al., 1986b) , which extended through 1984, the SMRs from NHL were 1.1 and 0.8 when using comparison rates derived, respectively, from Wisconsin Vietnam era veterans and Wisconsin general population data.
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From page 547... ...
Further, in CDC studies, a high risk was also found for a different population of Marines and using a general population control. Both the DVA and the CDC studies generally found only small nonsignificant increases in odds ratios for Army personnel.
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From page 548... ...
indicate no increased risk. Thus, unlike most of the other cancers studied by the committee for which the data do not distinguish between the effects of herbicides and TCDD, the available epidemiologic data suggest that the phenoxy herbicides, including 2,4-D, rather than TCDD may be associated with non-Hodgkin's lymphomas.
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From page 549... ...
Increased Risk of Disease Among Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental, and veterans studies that have been reviewed, inadequate control for important confounders in these studies, and the lack of information needed to extrapolate from the level of exposure in the studies reviewed to that of individual Vietnam veterans, it is not possible for the committee to quantify the degree of risk likely to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam. Epidemiologic Studies of Hodgkin's Disease Occupational Studies Production Workers In the study of Fingerhut and colleagues (1991)
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From page 550... ...
No HD cases occurred, approximately 0.1 was expected over the follow-up period, 1954-1987 (Zober et al., 19901. Agricultural/Forestry Workers Table 8-28 summarizes the principal results of the studies undertaken to assess the association between HD and actual or potential agricultural exposures to phenoxy herbicides in the United States.
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From page 551... ...
was found for any farm use of herbicides (phenoxy acids and others) and an odds ratio of 1.2 (CI 0.5-2.6)
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From page 552... ...
Despite the high odds ratio for herbicide exposure, the study showed only a slightly increased odds ratio of 1.2 (CI 0.4-3.5) for farming, based on six cases.
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From page 553... ...
These studies must be given strong weight in the consideration of whether an association exists between the development of HD and phenoxy acid exposure. The study of Persson and colleagues (1989' also showed a large positive odds ratio for herbicide exposures, although not statistically significant.
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From page 554... ...
The odds ratios for association with HD and service during Vietnam were 1.2 (CI 0.7-2.4) compared to Vietnam era
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From page 555... ...
Marine Vietnam veterans compared to Marine Vietnam era veterans 22 1.3 (0.7-2.6) Watanabe et al., 1991 Army Vietnam veterans compared to Army Vietnam era veterans 116 1.0 Marine Vietnam veterans compared to Vietnam era veterans 25 1.9 Army Vietnam veterans compared to Vietnam era veterans 116 1.1 Marine Vietnam veterans compared to Vietnam era veterans 25 1.0 CDC case-control mortality studies CDC, l990c U.S.
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From page 556... ...
The odds ratios for HD according to service branch, compared to men with no military service, are 1.0 (CI 0.5-2.0)
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From page 557... ...
In contrast to TCDD, there is no convincing evidence of, or mechanistic basis for, the carcinogenicity in animals of any of the herbicides, although they have not been studied as extensively as TCDD. Increased Risk of Disease Among Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental, and veterans studies that have been reviewed, inadequate control for important confounders in these studies, and the lack of information needed to extrapolate from the level of exposure in the studies reviewed to that of individual Vietnam veterans, it is not possible for the committee to quantify the degree of risk likely to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam.
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From page 558... ...
cohorts of workers engaged in the production and spraying of phenoxy herbicides or of compounds contaminated with TCDD.
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From page 559... ...
Among studies of farming populations with information on potential herbicide use was a nested case-control analysis of MM among subjects enrolled in the prospective, nationwide Cancer Prevention Study of the American Cancer Society (Boffetta et al., 19891. From an analysis of 282 MM cases and 1,128 controls, an odds ratio of 2.1 (CI 1.0-4.2)
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From page 560... ...
for cases identified over age 64 and compared with correspondingly aged cases of other cancer in the New Zealand cancer registry during the period 1977- 1981. These odds ratios were the highest found in this study, which also considered NHL and HD, but no individual
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From page 561... ...
for exposure to phenoxy herbicides. An analysis by days of phenoxyacetic acid use showed no clear trend with exposure; the odds ratio for each of three exposure categories was 2.0 or greater.
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From page 562... ...
Ten studies of agricultural and forestry workers provide information on MM risk in relation to herbicide or pesticide exposure. All demonstrated an odds ratio or SMR greater than 1.0; seven did so at a statistically significant level.
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From page 563... ...
The finding of an association between exposure to phenoxy acids or TCDD and Hodgkin's disease and non-Hodgkin's lymphoma in humans strengthens the suggestive evidence for an association between multiple myeloma and exposure to phenoxy acids. Increased Risk of Disease Among Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental.
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From page 564... ...
Epidemiologic Studies Occupational Studies Production Workers The NIOSH cohort study (Fingerhut et al., 1991) found no increase in leukemia deaths (N= 6)
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From page 565... ...
Nonsignificantly elevated relative risks of 2.1 were found for all female employees with no latency (two cases) and 4.0 for females involved in the manufacturing or packaging of phenoxy herbicides.
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From page 566... ...
They further classified exposure based on type of herbicide used. For those who used phenoxy herbicides, the odds ratio for all types of leukemia combined was 1.2 (CI 0.9-1.6~; for those who used 2,4-D the odds ratio for all leukemias was 1.2 (CI 0.9-1.63; and for those who used 2,4,5-T the odds ratio for all leukemias was 1.3 (CI 0.7
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From page 567... ...
Ronco and colleagues (1992) calculated the standardized incidence ratio for male and female owners and employees at farms in Denmark and mortality odds ratios in Italy.
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From page 568... ...
compared death from leukemia as reported on death certificates with the number of years employed as a forestry worker. These workers were presumably exposed to phenoxy herbicides for more than six months.
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From page 569... ...
Again, a nonsignificant but elevated relative risk was calculated for lymphatic leukemia for males (RR = 9.6, CI 0.9-106.01. The relative risk for overall leukemia among males was 2.1 (CI 0.7-6.9)
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From page 570... ...
Vietnam Veterans Studies Epidemiologic studies of Vietnam veterans have been conducted by several states, the DVA, the CDC, the Australian government, the Air Force, and others. None of these studies found an elevated risk for leukemia among Vietnam veterans (Anderson et al., 1986a,b; Boyle et al., 1987; Felt et al., 1987b; Breslin et al., 1988~.
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From page 571... ...
Conclusions Strength of Evidence in Epidemiologic Studies There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides* (2,4-D; 2,4,5-T and its contaminant TCDD; cacodylic acid; and picloram)
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From page 572... ...
Soft tissue sarcomas are a rare but diverse group of tumors that share a common International Classification of Diseases code but have a wide variety of forms and causes. The strongest evidence for an association between STS and exposure to phenoxy herbicides comes from a series of case-control studies involving a total of 506 cases conducted by Hardell and colleagues in Sweden (Hardell and Sandstrom, 1979; Eriksson et al., 1981;
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From page 573... ...
examined NHL and Hodgkin's disease together and found an odds ratio of 6.0 (CI 3.79.7) based on 105 cases for exposure to phenoxy acids or chlorophenols, and these results held up under further investigation of the validity of exposure assessment and other potential biases (Hardell, 1981J.
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From page 574... ...
are considered as a whole, it is noteworthy that the strongest evidence for an association with exposure to phenoxy herbicides is the series of case-control studies conducted by Hardell and colleagues and the cohort studies of herbicide applicators and agricultural workers. Studies in other countries are sometimes positive, but not as consistently.
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From page 575... ...
Among the many epidemiologic studies of respiratory cancers (specifically cancers of the lung, larynx, and trachea) , positive associations were found consistently only in those studies in which TODD or herbicide exposures were probably high and prolonged, especially the largest, most heavily exposed cohorts of chemical production workers exposed to TCDD (Zober et al., 1990; Fingerhut et al., 1991; Manz et al., 1991; Saracci et al., 1991)
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From page 576... ...
Ten studies of agricultural and forestry workers provide information on MM risk in relation to herbicide or pesticide exposure. All demonstrated an odds ratio or SMR greater than 1.0; seven did so at a statistically significant level.
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From page 577... ...
indicates an increased risk for liver cancer and exposure to herbicides, but another study of Swedish agricultural workers (Wiklund, 1983) estimates a relative risk that is significantly less than 1.0.
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From page 578... ...
To estimate the magnitude of risk for a particular health outcome among herbicide-exposed Vietnam veterans, quantitative information about the dose-time-response relationship for each health outcome in humans, information on the extent of herbicide exposure among Vietnam veterans, and estimates of individual exposure are needed. Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the studies that have been reviewed, the inadequate control for important confounders, and the uncertainty about the nature and magnitude of exposure to herbicides in Vietnam (as discussed in Chapter 6)
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From page 579... ...
1981. Increased risk of lung cancer in pesticide-exposed male agricultural workers.
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From page 580... ...
1993. Occupational exposure to phenoxy herbicides and chlorophenols and cancer mortality in the Netherlands.
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From page 581... ...
1991. Mortality and incidence of cancer at four factories making phenoxy herbicides.
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From page 582... ...
1990. Exposure to dioxins as a risk factor for soft tissue sarcoma: a population-based case-control study.
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From page 583... ...
1986. Final Report: A Case-Control Mortality Study on the Association of Soft Tissue Sarcomas, Non-Hodgkin's Lymphomas, and Other Selected Cancers and Vietnam Military Service in Pennsylvania Males.
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From page 584... ...
1986. West Virginia Department of Health Vietnam-Era Veterans Mortality Study, Preliminary Report.
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From page 585... ...
1985. A follow-up study of cancer incidence among workers in manufacture of phenoxy herbicides in Denmark.
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From page 586... ...
1993. Farming and prostate cancer mortality.
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From page 587... ...
1993. Risk factors for prostate cancer.
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From page 588... ...
1992. Phenoxy herbicides and chlorophenols: a case control study on soft tissue sarcoma and malignant lymphoma.
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From page 589... ...
1991. Incidence rates of lymphomas and softtissue sarcomas and environmental measurements of phenoxy herbicides.
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From page 590... ...
1987. Soft tissue sarcoma and non-Hodgkin's lymphoma in relation to phenoxy herbicide and chlorinated phenol exposure in western Washington.
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Key Terms
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