8
Cancer

Cancer is the second leading cause of death in the United States. There has been a gradual rise in the proportion of deaths from cancer in the United States during the twentieth century, due in large part to increased tobacco use. At present, more than 30 percent of Americans will develop a malignancy at some time in their lives, and approximately half of them will die from it (Seidman et al., 1985). As a result of the high incidence of cancer, the often disfiguring and uncomfortable approaches to treatment, and the general lack of success in treating many types of cancer, it has become a particularly dreaded disease.

Many types of cancers are thought to be related to herbicides and/or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but the evidence for the associations is uneven. 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. DHHS, 1991). A summary at the end of the chapter compares the cancer types for which the strength of the epidemiologic evidence is similar, and discusses the nature of the evidence that led the committee to its conclusion.

Cancer is a disease of the cell. Cancer cells are malignant: that is, they lack normal growth control, and have the ability to invade and metastasize into surrounding tissues and other organs. These properties are inherent in the cells themselves, so that, for example, a cancer cell could be transplanted



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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 8 Cancer Cancer is the second leading cause of death in the United States. There has been a gradual rise in the proportion of deaths from cancer in the United States during the twentieth century, due in large part to increased tobacco use. At present, more than 30 percent of Americans will develop a malignancy at some time in their lives, and approximately half of them will die from it (Seidman et al., 1985). As a result of the high incidence of cancer, the often disfiguring and uncomfortable approaches to treatment, and the general lack of success in treating many types of cancer, it has become a particularly dreaded disease. Many types of cancers are thought to be related to herbicides and/or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but the evidence for the associations is uneven. 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. DHHS, 1991). A summary at the end of the chapter compares the cancer types for which the strength of the epidemiologic evidence is similar, and discusses the nature of the evidence that led the committee to its conclusion. Cancer is a disease of the cell. Cancer cells are malignant: that is, they lack normal growth control, and have the ability to invade and metastasize into surrounding tissues and other organs. These properties are inherent in the cells themselves, so that, for example, a cancer cell could be transplanted

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam into a normal host and a new malignant tumor would arise. This implies that the underlying abnormality that led to the transformation of a normal cell into a malignant cell is present in the genetic material of the cell itself or in the way the genetic information is expressed. It is now well accepted that a malignant tumor develops from a single cell that has passed through a series of steps or stages of transformation. The initial stage of transformation, or "initiation," is thought to involve a mutation—that is, damage to DNA. The initiated cell and its progeny, most of which are destroyed by the body, then must pass through one or more additional stages (progression) before a clone of fully transformed malignant cells will acquire the essential properties of a malignant tumor. These generally include loss of normal specialization, faster than normal rates of cell division, and loss of normal limits on cell division. Many carcinogens that have been identified thus far are initiators and are believed to interact directly with DNA. It is also known, however, that certain substances may promote tumor formation by initiated cells, even though they are not capable of the initial cell mutation. Based on its effects in animal studies, TCDD is considered a tumor promoter, not a tumor initiator. The potential mechanisms by which TCDD can act as a tumor promoter are discussed in Chapter 4. It follows from an initiation/promotion model that tumor initiators should act early in the carcinogenic process, often decades before a cancer is diagnosed, while tumor promoters may exert their effect at any time between initiation and clinical diagnosis. The experimental evidence suggesting that TCDD acts as a tumor promoter comes from studies in laboratory animals. It is possible, though not proven, that TCDD could also promote the formation of cancer in humans after exposure to another potential carcinogen. Understanding the biological mechanism whereby TCDD interacts with the process of cancer production is critical to the committee's analysis of the plausibility of an association between human cancer and exposure to Agent Orange and other herbicides. Although direct evidence may not be available regarding the biologic plausibility of a specific tumor site, this does not preclude examination of epidemiologic data for potential association in a population. 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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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam CANCER EPIDEMIOLOGY Cancer is a popular subject for discussion in the lay press and media. Hardly a day goes by without an article trumpeting some chemical or environmental hazard as playing some role in the etiology of some malignancy. In truth, it is difficult to establish causal relationships for cancers. There are several characteristics of cancer that strongly affect and influence the ability to establish etiologic relationships. The first major characteristic in this regard is the long latency period that is thought to exist between exposure and onset of disease in most instances. Also, most etiologic agents (except cigarette smoking) probably contribute to only a relatively small fraction of cases. Furthermore, although cancer overall is relatively common, the term "cancer" actually represents a rubric of more than 100 different subtypes, categorized by anatomic site and histology, as well as by stage and other factors. Any specific subtype of cancer is a relatively rare event, and this makes its study difficult. For example, to study the impact of hypertension on the incidence of a relatively common outcome, such as coronary artery disease, an appropriately selected cohort of 1,000 to 2,000 people, followed for five to ten years, might suffice. 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. Another characteristic—cancer's relatively high case fatality rate—is an additional complication for analysis. As a consequence, many studies rely on cancer mortality rather than cancer incidence as an outcome. Depending on the specific malignancy under study and the time period being explored, this is often a reasonable approach. However, improvements in the early detection and treatment of cancer have led to improved survival rates for several types of cancer (testicular cancer, childhood leukemia, Hodgkin's disease, for example). To the degree that it is true for a given malignancy, fatality rates have declined, and conclusions derived from the use of mortality data must be viewed cautiously. Another aspect of cancer epidemiology that it is important to understand is the wide availability of tumor registries since the 1970s. For various reasons, many cities, states, countries, and other political and geographical regions have kept population-based data regarding the reporting of cancer incidence—usually by subtype, and often with survival and follow-up data—within their boundaries. These data are usually available to epidemiologists and greatly facilitate the practice of their science. Finally, an important aspect of cancer epidemiology is precision of diagnosis by pathologic criteria. Compared to diagnosis of many other

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam types of disease, which may involve only patient-described symptoms, a cancer diagnosis is usually definitive only when based on pathologic review. In addition, histologic and other subtyping can also be defined fairly accurately. In the review and critique of any study, great attention must be paid to the efforts utilized by the investigators in establishing the pathologic diagnosis. Particularly when population-based registry data are utilized, or when data are collected from less sophisticated regions or hospitals, difficulties may arise in the accuracy of the study. When death certificate diagnoses are used, accuracy may suffer as well (see Chapter 5). There are a large number of different types of cancer as defined by site and histology. In situations in which many studies have been conducted on a certain exposure, and multiple analyses conducted within each study, there is a risk of finding occasional statistical associations purely on the basis of chance. Thus, one must beware of overinterpreting an isolated finding of excess risk for a given tumor type within a single study. Consistency across studies, with consideration of dose-response relationships and use of other statistical methods that evaluate plausibility, should be assessed before reaching any conclusions regarding associations between exposures and cancer. Additionally, the confidence intervals around the estimate of association will provide guidance as to the degree of precision and study size. Wide intervals indicate that the sample size, on which the estimate was based, was relatively small, and therefore the degree of precision attributed to that estimate is more variable. These considerations are outlined more fully in Chapter 5. SPECIFIC ISSUES WITH REGARD TO HERBICIDE EXPOSURE IN VIETNAM Aside from the issues discussed above, there are also several general problems with regard to relating herbicide exposure in Vietnam to the incidence of cancer overall or to specific malignancies. As a whole, the cohort in Vietnam consisted primarily of young males and a far smaller number of females who were potentially exposed to herbicides between 1965 and 1975. A veteran who was 20 years old in 1965 is 48 years old in 1993, still very young with respect to developing cancer. Because the incidence of most malignancies is strongly age dependent, the cohort under discussion, for the most part, has not yet reached the age range of highest risk, making the incidence of cancer, and certainly of cancer subtypes, rare within most studies of veterans. The two specific types of cancer most closely linked to herbicide exposure in the scientific literature, soft tissue sarcoma (STS) and non-Hodgkin's lymphomas, are noteworthy in that their incidence is relatively high in younger age groups even in the absence of any harmful exposures. Thus, it may well be that for the most common cancer types, such as

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam lung, colon, and prostate cancers, the length of follow-up since the Vietnam conflict remains too short to adequately evaluate possible associations with exposure. The age-specific incidence rates for the cancer types of special significance for the Vietnam veteran population are shown in Figure 8-1 for men and in Figure 8-2 for women. For most cancers (illustrated as a ''typical cancer"), the incidence rates increase with age (note that the vertical axis of the graph uses a logarithmic scale), but for some cancers, such as brain cancer, acute lymphocytic and all leukemias, and non-Hodgkin's lymphoma, the rate of increase with age is more gradual than the rest; thus the incidence rates under age 40 (compared to those over age 40) are relatively high. Hodgkin's disease, soft tissue sarcoma, testicular cancer for men, and FIGURE 8-1 Average age-specific incidence rates for selected cancers in men for the period 1985-1989. The "typical" cancer illustrates a common pattern of age-specific rates seen in cancers not included in the figure; age-specific rates for all cancers combined have been rescaled (1:100) to construct the typical cancer. Rates are for 5 year age groups and are presented on a logarithmic scale. SOURCE: Miller et al., 1992.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam FIGURE 8-2 Average age-specific incidence rates for selected cancers in women for the period 1985-1989. The "typical" cancer illustrates a common pattern of age-specific rates seen in cancers not included in the figure; age-specific rates for all cancers combined have been rescaled (1:100) to construct the typical cancer. Rates are for 5 year age groups and are presented on a logarithmic scale. SOURCE: Miller et al., 1992. cancer of the cervix for women are unique among the cancers under study in that their age-specific incidence rates peak below age 40. EXPOSURE It should be emphasized that for most of the studies reviewed for association between cancer outcomes and herbicide exposure, the actual exposure of each individual is in fact unknown. Some studies develop an index to approximate a scale of degrees of exposure; some studies use a surrogate measure of exposure, such as veterans service in Vietnam. The effect of this inadequate exposure measurement is a dilution of the statistical measure of the magnitude of the association. 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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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam estimate is lower than what would be expected if good individual exposure data were available. The effects of misclassification of those who are exposed and unexposed are discussed in Chapter 6. Thus, studies with weak or no association should be considered in conjunction with the way in which exposure was measured. PLAUSIBILITY DATA Cancers of a variety of types have been identified in studies of animals exposed to TCDD, as described in detail in Chapter 4. These include liver, lung, and skin tumors in rats and mice. TCDD is not considered a genotoxic carcinogen, and in multistage models of carcinogenesis, TCDD acts as a tumor promoter and has little, if any, tumor-initiating activity. TCDD mediates carcinogenesis through a variety of biochemical effects that are dependent on the presence of a cellular receptor protein referred to as the Ah receptor. This receptor has been identified in both laboratory animals and humans, and appears to play a role in regulating cell proliferation and differentiation. The multiple site specificity of TCDD is likely to reflect its multiple mechanisms of action. In contrast to TCDD, the experimental data supporting the carcinogenic activity of the herbicides used in Vietnam are considerably weaker. Only 2,4-D (2,4-dichlorophenoxyacetic acid) has produced positive results in an animal bioassay, and these are of controversial validity. 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. First, all Vietnam veterans were assumed to be born between 1946 and 1950, which corresponds to the largest five year age cohort. Second, the committee assumed that the most recent available national annual cancer incidence rates, those for 1985-1989 estimated by the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program (Miller et al., 1992) would apply to Vietnam veterans. Further, if one assumes that 2,600,000 men and 7,000 women served in Vietnam (see Chapter 3), the expected number of specific cancers among Vietnam veterans in 1995 was estimated by applying the sex-specific SEER rates for ages 45-49

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam to male and female populations of the size given. SEER incidence rates for ages 50-54 were used to construct similar estimates for the year 2000. The incidence rates of most cancers increase with age, and some Vietnam veterans are older than the assumptions in this calculation, so the numbers given are perhaps underestimated. Also, 2.6 million is the minimum estimate of the number of Vietnam veterans. Furthermore, these calculations make no assumption of any higher risk among veterans because of exposure to herbicides in Vietnam or other aspects of the Vietnam experience. Because of these biases, the figures presented in the following section of this report should be interpreted as providing only order-of-magnitude estimates, not precise predictions for the Vietnam veteran cohort. The results of the committee's calculations of the number of expected cancer cases in the Vietnam cohort are shown in Table 8-1. Based on rates in the general U.S. population, the expected numbers of new cancer cases per year in male veterans are relatively small. Overall, about 0.3 percent of male veterans and 0.4 percent of female veterans are expected to be diagnosed with cancer in 1995. In 2000, new cancers are expected in 0.5 percent of male and 0.6 percent of female veterans. The estimates range from as few as 21 cases for acute lymphocytic leukemia in 1995 to as many as 494 for non-Hodgkin's lymphoma. The exceptions to this pattern are cancers of the prostate, colon, and lung, for which the expected numbers of new cases among male veterans in 2000 are 855, 931, and 2,860, respectively. The number of cancers of each type expected among female veterans is very much smaller, owing to the smaller number of women (compared to men) who served in Vietnam; only for breast cancer is the expected number higher than ten new cases per year, and for many of the cancers under study, the expected number of new cases is less than one. The estimates in Table 8-1, which are based on cancer incidence rates in the general population, show that each year, regardless of the effect that herbicides might have on cancer incidence, many veterans can be expected to be diagnosed with cancer. 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. Second, some cancers are sufficiently rare that even among all Vietnam veterans there will be too few cases for reliable epidemiologic studies. This problem of inadequate numbers of cancer cases was also seen in the Centers for Disease Control's (CDC) Selected Cancers Study; even with a network of cancer registries that covered 10 percent of the U.S. male population, born between 1921 and 1953, the statistical power to detect an association between some of the cancers under study and Vietnam service was low.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam TABLE 8-1 Number of Cancer Cases Expected Among Vietnam Veterans in 1995 and in 2000   Males   Females   Cancer Site 1995 2000 1995 2000 All Sites 6,689.8 12,126.4 28.6 39.6 Colon 460.2 930.8 1.1 2.4 Rectum 293.8 587.6 0.6 1.0 Pancreas 163.8 325.0 0.3 0.5 Stomach 192.4 340.6 0.3 0.4 Liver and intrahepatic bile duct 70.2 150.8 0.1 0.1 Lung, bronchus, and larynx 1,432.6 3,224.0 2.5 5.0 Bone 10.4 20.8 0.1 0.0 Soft tissue 65.0 85.8 0.1 0.2 Melanoma 486.2 631.8 1.1 1.3 Breast 23.4 26.0 13.2 15.5 Uterus — — 1.6 2.8 Cervix — — 1.2 1.2 Ovary — — 1.5 1.9 Kidney and renal pelvis 306.8 496.6 0.4 0.7 Bladder (invasive and in situ) 374.4 777.4 0.3 0.6 Prostate 179.4 855.4 — — Testis 117.0 85.8 — — Brain and other nervous system 226.2 267.8 0.4 0.4 Hodgkin's disease 93.6 109.2 0.1 0.1 Non-Hodgkin's lymphoma 379.6 494.0 0.5 0.7 Multiple myeloma 57.2 132.6 0.2 0.3 Leukemia 205.4 358.8 0.4 0.5 Acute lymphocytic 20.8 20.8 0.0 0.0 Chronic lymphocytic 44.2 122.2 0.1 0.1 Acute myeloid 41.6 83.2 0.1 0.2 Chronic myeloid 41.6 62.4 0.1 0.1 NOTES: Not applicable is designated as—. Estimates for breast cancer, cervical cancer, and melanoma do not include carcinoma in situ. Specific categories of cancer correspond to the following ICD-9 codes. 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); Uterus (corpus and not otherwise specified): 179, 182.0-182.1, 182.8; Cervix: 180.0-180.9; Ovary: 183.0; Hodgkin's disease: 201.0-201.9; Non-Hodgkin's lymphoma: 200.0-200.8, 202.0-202.2, 202.8-202.9; Multiple myeloma: 203.0, 203.2-203.8; Melanoma: 172.0-172.9; Bone and joint: 170.0-170.9; Colon: 153.0-153.9, 159.0; Rectum: 154.0-154.1; Pancreas: 157.0-157.9; Stomach: 151.0-151.9; Brain and other nervous system: 191.0-191.9, 192.0-192.3, 192.8-192.9; Kidney and renal pelvis: 189.0, 189.1; Bladder: 188.0-188.9; Prostate: 185; Testis: 186.0-186.9; Leukemia: 202.4, 203.1, 204.0-204.9, 205.0-205.9, 206.0-206.9, 207.0-207.2, 207.8, 208.0-208.9; Acute lymphocytic leukemia: 204.0; Chronic lymphocytic leukemia: 204.1; Acute myeloid leukemia: 205.0; Chronic myeloid leukemia: 205.1. SOURCE: Calculated using data in Miller et al., 1992.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam OVERALL CANCER Background The American Cancer Society estimated that 1,130,000 Americans were diagnosed with cancer in 1992, and approximately 520,000 people died from it (ACS, 1992). Overall, cancer mortality increased from 162 per 100,000 in 1973 to 173 per 100,000 in 1989 (Miller et al., 1992) (these rates are age-adjusted to the 1970 population). According to the committee's calculations, approximately 6,690 new cases of cancers of all types are expected among male Vietnam veterans in 1995 and approximately 29 among female veterans. In 2000, the expected numbers are approximately 12,126 new cases in male veterans and 40 in female veterans. Doll and Peto (1981), in their now classic monograph, studied attributable risks for cancer (the proportion of all cancer cases that can be attributed to a particular cause). The most important overall risk factor was tobacco exposure, which was estimated to account for about 30 percent of all cancer incidence. This reflects the strong carcinogenic effect of tobacco smoke, the numerous anatomic sites that are affected, and the prevalence of smoking in the population. Diet, which represents a large number of different types of exposure, was found to have an impact of similar magnitude, although the confidence intervals on this risk estimate were extremely wide. Occupational and environmental exposures to carcinogens, the closest analogues to Agent Orange exposure, were found by Doll and Peto to have a smaller attributable risk for cancer overall (i.e., only a small proportion of cancer of all sites combined could be attributed to these exposures). Nevertheless, these environmental agents may be highly carcinogenic. For instance, only a fraction of the overall population is exposed to asbestos, and only a fraction of the work force is exposed to a particular carcinogen such as benzene or polycyclic hydrocarbons. Nonetheless, individuals exposed to these chemicals may have a high risk of developing cancer. Therefore, identifying environmental and occupational carcinogenic exposures, and developing preventive measures for them, are of great public health importance. Epidemiologists and cancer specialists generally do not study risk factors for all cancers combined. The causal associations and other characteristics for anatomically and histologically defined subtypes of cancer are so variable that general statements regarding "cancer" are of little use. The usefulness of studying overall cancer would be evident if a slight increase in risk occurred for many different cancers. The small relative increase for a given site might, however, not be detectable because of low statistical power resulting from the small number of cases. An apparent increase in risk of "all cancers" in a given study might actually stem from an increase

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam in a single type of cancer. Nonetheless, a variety of attempts at defining cancer risk among veterans exposed to Agent Orange, other herbicides, and TCDD have been reported and deserve description and analysis. Epidemiologic Studies Occupational Studies Many studies have examined cancer mortality among a number of different occupational groups. One occupational group of interest for the association between cancer and exposures to herbicides is agricultural workers and farmers. A study of agricultural extension agents in the cooperative extension service of the U.S. Department of Agriculture (USDA) found no excess of overall cancer mortality (Alavanja et al., 1988). No excess overall cancer was observed in a study conducted among Danish gardeners (Hansen et al., 1992) or among herbicide applicators in Finland (Riihimaki et al., 1982, 1983). The overall proportionate mortality ratio (PMR) was decreased among Iowa farmers (Burmeister, 1981) and Swedish agricultural workers (Wiklund, 1983). A study among licensed herbicide applicators in the Netherlands (Swaen et al., 1992) found no significant increase in cancer mortality. A possible decrease in overall cancer mortality among farmers might be due to healthier life-styles overall, with decreased tobacco usage (Sterling and Weinkam, 1976), or to increased physical activity. Other occupational groups potentially exposed to herbicides and dioxins are forestry and paper workers. No excess cancer mortality has been found in several studies of these workers conducted in Canada (Green, 1991), Finland (Jappinen and Pukkala, 1991), or the United States (Robinson et al., 1986; Henneberger et al., 1989). One study of 201 deceased white men who had been employed in pulp and paper production did find a statistically significant PMR of 1.3 [confidence interval (CI) 1.0-1.7] for all malignant neoplasms (Solet et al., 1989), which reflected an excess risk of lung cancer. The National Institute for Occupational Safety and Health (NIOSH) study (Fingerhut et al., 1991) of workers in 12 plants in the United States that produced chemicals contaminated with TCDD found a standardized mortality ratio (SMR) of 1.2 for all cancers (CI 1.0-1.3). The SMR was higher in the subcohort with more than one year of exposure and more than 20 years latency (SMR = 1.5, CI 1.2-1.8). 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) compared to the total population, with increased cancer mortality among men having 20 or more years of employment. Saracci and coworkers (1991) found no overall increase in cancer mortality in their international study of workers exposed to phenoxy herbicides

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