National Academies Press: OpenBook

Veterans and Agent Orange: Update 2000 (2001)

Chapter: 7 Cancer

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Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

7
Cancer

Cancer is the second leading cause of death in the United States. Among males aged 45–64, the group that describes most Vietnam veterans, the risk of dying from cancer nearly equals the risk from heart disease, the overall leading cause of death in the United States (U.S. Census, 1999). This year about 552,200 Americans are expected to die of cancer—more than 1,500 people a day. In the United States, one of every four deaths is from cancer (ACS, 2000b).

In this chapter, the committee summarizes and reaches conclusions about the strength of the evidence in epidemiologic studies regarding associations between exposure to herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and each type of cancer under consideration in this report. The cancer types are, with minor exceptions, discussed in the order in which they are listed in the International Classification of Diseases, Ninth Edition (ICD•9). ICD•9 is a standardized means of classifying medical conditions used by physicians and researchers around the world. Appendix B lists ICD•9 codes for the major forms of cancer.

In assessing a possible relation between herbicide exposure and risk of cancer, one key issue is the level of exposure of those included in a study. As noted in Chapter 5, the detail and accuracy of exposure assessment vary widely among the studies reviewed by the committee. A small number of studies use a biomarker of exposure, for example, the presence of dioxin in serum or tissues; some develop an index of exposure from employment or activity records; and others use a surrogate measure of exposure, such as being present when herbicides were used. Inaccurate assessment of exposure can obscure the presence or absence of exposure-disease associations and thus make it less likely that a true risk will be identified.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

The outcomes reviewed in this chapter follow a common format. Each section begins by providing some background information about the cancer under discussion, including data concerning its incidence in the general U.S. population. A brief summary of the findings described in the first three Agent Orange reports—Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO; IOM, 1994), Veterans and Agent Orange: Update 1996 (hereafter, Update 1996; IOM, 1996), and Veterans and Agent Orange: Update 1998 (hereafter, Update 1998; IOM, 1999) —is then presented, followed by a discussion of the most recent scientific literature and a synthesis of the material reviewed. Where appropriate, reviews are separated by the type of exposure (occupational, environmental, Vietnam veteran) being addressed. Each section concludes with the committee’s finding regarding the strength of the evidence in epidemiologic studies, biologic plausibility, and evidence regarding Vietnam veterans.

Expected Number of Cancer Cases Among Vietnam Veterans in the Absence of Any Increase in Risk Due to Herbicide Exposure

To provide some background for the consideration of cancer risks in Vietnam veterans, this chapter also reports information on cancer incidence in the general U.S. population. Incidence rates are reported for individuals between the ages of 45 and 59 because most Vietnam era veterans are in this age group. The data, which were collected as part of the Surveillance, Epidemiology, and End Results (SEER) Program of the National Center for Health Statistics (NCHS), are categorized by sex, age, and race because these factors can have a profound effect on the estimated level of risk. Prostate cancer incidence, for example, is nearly 11 times higher in men age 55–59 than in 45–49-year-olds and more than twice as high in African Americans age 45–59 as in whites of this age group (NCI, 2000). The figures presented for each cancer are estimates for the entire U.S. population, not precise predictions for the Vietnam veteran cohort. It should be remembered that numerous factors may influence the incidence reported here—including personal behavior (e.g., smoking and diet), genetic predisposition, and other risk factors such as medical history. These factors may make a particular individual more or less likely than average to contract a given cancer. Incidence data are reported for all races and also separately for African Americans and whites. The data reported are for 1993–1997, the most recent data available at the time this report was written.

As detailed in Chapter 6, here, and in the following chapters, great uncertainties remain about the magnitude of potential risk from exposure to herbicides and dioxin in the occupational, environmental, and veteran studies reviewed by the committee. Many have inadequate controls for important confounders, and the information needed to extrapolate from the level of exposure in the studies to that of individual Vietnam veterans is lacking. The committee therefore cannot quan-

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

tify the degree of risk likely to have been experienced by Vietnam veterans due to exposure to herbicides in Vietnam. It offers qualitative observations where data permit.

GASTROINTESTINAL TRACT TUMORS

Background

As a group, this category includes some of the major cancers in the United States and the world. The committee reviewed the data on colon cancer (ICD•9 153.0–153.9), rectal cancer (ICD•9 154.0–154.1), stomach cancer (ICD•9 151.0– 151.9), and pancreatic cancer (ICD•9 157.0–157.9). According to American Cancer Society estimates, approximately 180,000 individuals will be diagnosed with these cancers in the United States in 2000 and some 97,500 individuals will die from them (ACS, 2000a). Colon cancer accounts for about half of these diagnoses and deaths. Collectively, gastrointestinal (GI) tract tumors are expected to account for 15 percent of new diagnoses and 18 percent of cancer deaths in 2000.

Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa

Selected Gastrointestinal Cancers

 

45–49 Years of Age

50–54 Years of Age

55–59 Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Stomach

Males

6.0

4.9

11.1

10.9

9.8

20.9

20.0

16.7

35.2

Females

2.6

2.0

4.7

4.4

3.5

7.3

7.8

6.6

14.1

Colon

Males

15.6

14.6

23.7

34.2

31.4

59.8

62.9

61.7

81.4

Females

14.8

13.0

24.1

27.1

23.9

49.0

49.9

48.3

72.7

Rectal

Males

7.7

6.9

10.1

14.8

13.6

17.9

24.8

24.6

27.1

Females

4.9

4.6

5.4

9.4

8.8

12.7

13.7

12.8

16.6

Pancreatic

Males

5.4

4.9

10.6

12.5

11.7

24.7

21.6

19.6

46.7

Females

3.9

3.5

6.7

8.1

7.5

13.7

13.8

13.4

22.6

aSEER nine standard registries, crude age-specific rate, 1993–1997.

The incidence of stomach, colon, rectal, and pancreatic cancers increases with age for individuals between 45 and 59. In general, incidence in males is higher than in females, and incidence in African Americans exceeds that in whites. Risk factors besides age and race vary for these cancers but always include family history of the same form of cancer, certain diseases of the affected organ, and dietary factors. Cigarette smoking is a risk factor for pancreatic cancer and may also increase the risk of stomach cancer (Miller et al., 1996).

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Infection with the bacterium Helicobacter pylori also increases the risk of stomach cancer.

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found there to be limited or suggestive evidence of no association between exposure to herbicides used in Vietnam or the contaminant dioxin and gastrointestinal tumors. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Tables 7-1, 7-2, 7-3, and 7-4 provide summaries of the results of studies underlying these findings and a list of reports that contain details of the research.

Update of the Scientific Literature

Occupational Studies

The largest industrial cohort exposed to dioxins is the group of 5,132 U.S. workers known as the NIOSH (National Institute of Occupational Safety and Health) cohort. This group was assembled from employees of 12 major chemical manufacturers that produced 2,4,5-trichlorophenol, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), Silvex, Erbon, Ronnel, and hexachlorophene. Workers engaged in production and maintenance were exposed to TCDD as a contaminant of these chemicals. The first study of mortality through 1987 among these workers (Fingerhut, 1991) found a slight excess cancer mortality for all cancers combined (standardized mortality ratio [SMR]=1.2, 95 percent confidence interval [95% CI] 1.0–1.3); however, no elevated risk was observed for cancers of the stomach, colon, rectum, or pancreas. This cohort has been updated through 1993, and an exposure-response analysis on a subcohort (approximately 69 percent of the population) has been conducted (Steenland et al., 1999).

In that study, mortality from cancer of the small intestine and colon (1.2, 0.8–1.6), rectum (0.9, 0.3–1.9), stomach (1.0, 0.6–1.8), and pancreas (1.0, 0.6– 1.6) is not different from expected. Similar results are reported for a subcohort of 608 workers whose medical records stated that they had chloracne, indicating higher TCDD exposures during their working years.

A quantitative exposure assessment was conducted on workers employed in 8 (of a total of 12) plants that had sufficient information on the level of TCDD contamination in their products and detailed work histories. For this subcohort, a job-exposure matrix was constructed, and exposure scores were calculated using three factors: (1) the concentration of TCDD in the process materials, (2) the fraction of the day each worker spent in the specific process that resulted in contact with these materials, and (3) a weighting factor for the level of contact by skin contamination or inhalation of TCDD-containing material. In the analysis of

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

this subcohort, several exposure metrics were calculated including a cumulative exposure score, the log of this score, the average exposure score (cumulative divided by duration), and cumulative exposure categorized into septiles.

Excess cancer risk was confined largely to the highest two exposure class septiles, with an all-cancer SMR of 1.5 (1.2–1.8). Site-specific GI cancers are not reported, and for all digestive cancers (ICD•9 150–159), this highest-exposure class (the two highest septiles) had a nonsignificantly elevated excess risk (1.4, 0.9–2.2).

In a study of a cohort of Danish paper mill workers, Rix et al. (1998) examined mortality from a wide range of causes. Substantial dioxin exposure among these workers is unlikely, since paper pulp was never produced at the three mills studied. Rather, they manufactured paper from imported bleached and unbleached pulp. There are no direct measures of exposure for these workers, and a qualitative assessment of chemicals used in paper manufacture by department does not include chlorinated organic compounds, although chlorine, chlorine dioxide, and hypochlorite were used. For two of the mills, the period of follow-up was January 1, 1943, to December 31, 1993, while for the third mill, follow-up started at January 1, 1965. Incident cancer cases were identified from the Danish Cancer Register, and expected numbers of cases were calculated using the rates for the total Danish population by gender, 5-year age group, and calendar time. For cancer sites of specific interest, Poisson regression models were used to analyze by duration and years since first employment and by department of employment.

For GI cancers, no statistically significant excesses were observed in men or women (standardized incidence ratios [SIRs] reported separately for esophagus, stomach, colon, rectum, and pancreas). When analyzed by department of work, men employed in maintenance and repair had a nonsignificantly elevated risk of stomach cancer (SIR=1.5, CI not reported, 15 cases), while men employed in the power station had an SIR of 1.7 (4 cases). For pancreatic cancer, men in the paper machine department had an SIR of 1.6 (6 cases), while men in the storage and transport departments had an SIR of 1.6 (8 cases).

Hooiveld et al. (1998) reported on an update of a mortality study of workers at two chemical factories in the Netherlands. This group is included in the multinational International Agency for Research on Cancer (IARC) study of cancer and exposure to organochlorine compounds. This update of the Dutch cohort added 6.5 years of follow-up to a previous study of these workers (Bueno de Mesquita et al., 1993) and included analysis by estimated maximum TCDD serum level. This value was estimated for each member of the cohort by measuring serum TCDD levels for 144 subjects, including production workers known to be exposed to dioxins, workers in herbicide production, nonexposed production workers, and workers known to be exposed as a result of an accident that occurred in 1963. By assuming first-order TCDD elimination with an estimated half-life of 7.1 years, TCDDmax was extrapolated for 47 of these workers, and a regression model was constructed to estimate the effect of exposure as a result of

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

the accident, duration of employment in the main production department, and time of first exposure before (or after) 1970 on the estimated TCDDmax for each cohort member.

For gastrointestinal cancers (esophagus, 1 case; stomach, 3 cases; intestine, 3 cases; rectum, 1 case; pancreas, 4 cases; other sites, 1 case), no excess mortality was observed among 549 exposed male workers by comparison to national (Dutch) death rates. For workers known to be exposed as a result of the 1963 accident, a nonsignificant elevation of cancer of the esophagus was reported (SMR=4.3, 0.1–24.0, 1 case); the other GI sites were not reported. Gastrointestinal cancer was not reported in the results of the comparison between exposed and unexposed male workers in the cohort or by comparison of workers with low, medium, and high levels of predicted TCDDmax.

In a meta-analysis of occupational exposures and pancreatic cancer, Ojajärvi et al. (2000) surveyed publications for the period 1969–1998, searching Medline, Toxline, and Cancerlit for studies addressing occupational exposure and pancreatic cancer. They reduced the number of studies from 1,902 to 92 studies of 161 populations after excluding studies that did not report on pancreatic cancer, did not include sufficient information for meta-analysis, were not the most recent update, or did not include verifiable information on exposure to one or more of 23 specific chemical and physical agents. This information on exposure may have been direct estimates of risk for one or more of the 23 agents or information on job title that verified exposure to one or more of these agents. Herbicides were among the 23 specific agents included; however this broad class of chemical agents was not stratified by type of herbicide. Other agents of interest included chlorinated hydrocarbon solvents, fungicides, insecticides, and polycyclic aromatic hydrocarbons, as well as several heavy metals (cadmium, chromium, iron, lead, and nickel). The set of studies included in the meta-analysis consisted of 23 studies described as administrative (linkage of administrative records or proportional mortality ratio [PMR], proportionate cancer mortality ratio, or mortality odds ratio studies); 88 studies of industrial cohorts; 7 industry-based nested case-control studies; and 43 population- or hospital-based case-control studies. Most studies included were mortality studies. Studies were analyzed using simple random effects models to calculate meta-risk ratios (MRRs). In cases where excesses were observed, population etiological fractions and etiological fractions among the exposed groups were calculated. Data were reported based on exposed populations rather than by study. For the 10 studies in which herbicide exposure was reported, the MRR was 1.0 (0.8–1.3), and the range of point estimates in these studies was 0.6–5.9. The p-value for heterogeneity by agent (herbicides) was .3. These results were virtually unchanged when stratified for gender and quality of diagnosis (MRR=1.2, 0.8–2.0 for men, not reported for women; 0.9, 0.7–1.2 when gender was unspecified or both). None of the studies included information on the histological verification of the pancreatic cancer diagnosis. When examined by study type, the MRRs for the nine SMR or SIR studies (1.1,

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

0.8–1.5) were virtually identical to the one case-control study (0.9, 0.7–1.8). Population etiological fraction and etiological fraction among the exposed groups were not calculated for herbicides. The authors concluded that the meta-analysis suggested increased risk of pancreatic cancer with exposure to chlorinated hydrocarbon solvents, nickel and its compounds, and chromium and its compounds. There was more limited evidence of increased risk for organochlorine pesticides, silica, and aliphatic and alicyclic hydrocarbon solvents. There was no evidence of increased risk with herbicide exposure.

Environmental Studies

In a review of early, mid-term, and long-term health effects, Bertazzi et al. (1998) continued the follow-up of people environmentally exposed to TCDD in the Seveso accident. The events that led to the exposure and the methods used to study this population have been fully described previously. Their 1998 report reviews the full range of indicators of exposure and effects on animal and human health. At least in the case of GI cancer mortality, the report does not appear to add any new information to Bertazzi et al. (1997), which was reviewed in Update 1998. After 15 years’ follow-up (1976–1991), death from cancer of the rectum was significantly elevated for men in zone B (relative risk [RR]=2.9, 1.3–6.2, 7 observed deaths). A statistically significant increase in stomach cancer in women in Zone B observed after 10 years (RR=2.4, 1.0–6.0, 5 deaths) was not seen in the 15-year follow-up (RR=1.0, 0.5–2.2, 7 observed deaths). Excess mortality from esophageal cancer (RR=1.6, 1.1–2.4, 30 deaths) was reported among men in zone R (considered to be the low-exposure region). No other significant elevation of death from digestive cancer overall or at any of the GI sites was observed in men or women in any exposure zone.

In another report, Bertazzi et al. (2001) extended the mortality analysis through the end of 1996. They examined mortality from GI cancer and found a pattern of mixed results, similar to those seen in their earlier studies of the Seveso population. In this study, digestive cancer overall (ICD•9 150–159) was not elevated in either zone A or zone B. When examined on a site-specific basis, cancer of the rectum (ICD•9 154) was elevated in zone B (RR=1.9, 1.1–3.5, 11 cases) but not in zone A (1.2, 0.2–8.6, 1 case). Digestive cancers classified as “other” (ICD•9 159) were nonsignificantly elevated in zones A and B, while all other digestive cancer sites had RRs of 1.0 or less. More detailed examination including stratification of the zone A and zone B populations (done both separately and combined) by 5-year intervals of latency did not reveal any significant excess risk estimates, except for an excess in stomach cancer for zone B women in the 10– 14-year latency group (2.5, 1.1–5.7, 6 cases). Cancer of the rectum was also elevated among all zone B men (2.4, 1.2–4.9, 8 cases).

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×
Vietnam Veteran Studies

In the Air Force Health Study final report (AFHS, 2000), gastrointestinal cancers as a group are not addressed; however, results for esophageal cancer and cancer of the colon and rectum are reported. Because of the absence of cases of malignant neoplasms of the esophagus in Ranch Hands, statistical analysis was not performed. A malignant neoplasm of the esophagus was observed in two members of the comparison group. For malignant neoplasms of the colon and rectum, no excess risk was seen for the Ranch Hand veterans after analyses were adjusted for covariates.

Approximately 50,000 members of the Australian Defence Force and Citizen Military Forces served in the Vietnam theater over the war years. The government of Australia conducted mail surveys of all individuals with Vietnam service, which included those involved in combat, medical teams, war correspondents, entertainers, and philanthropy workers (CDVA, 1998a, b). Questionnaires were mailed to 49,944 male veterans (80 percent response rate) and 278 female veterans (81 percent response rate). The self-reported data gathered were compared with age-matched Australian national data.

The study found that 405 male veterans and 1 female veteran indicated a doctor had told them they had colorectal cancer since their first day of service in Vietnam. For male veterans, this was higher than the expected number of 117 (96–138), while for female veterans, it corresponded to expected community rates. The authors cited possible reporting errors such as misclassification of intestinal and rectal cancers as colon cancers and reporting pre- or nonmalignant polyps as possible explanations for the high number of cases reported by male veterans.

A follow-up to the Commonwealth Department of Veterans’ Affairs (CDVA) study of male Vietnam veterans was conducted to medically confirm selected conditions reported in the survey study described above (AIHW, 1999). Sources used to validate reported conditions included clinicians, several Australian morbidity and mortality data bases, CDVA data, and documentation provided by veterans. Results from this study showed there was no significant difference in prevalence of colorectal cancer between the veterans and an Australian community standard.

Synthesis

With only rare exceptions, studies on gastrointestinal cancers and exposure to herbicide in production, from agricultural use, from environmental sources, and among veteran populations found RRs close to 1.0, providing no evidence of any increase in risk. Most of the recent studies were occupational.

The updated analysis of mortality among U.S. chemical workers did not report site-specific GI cancers, and there was a nonsignificantly elevated excess

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

risk for all GI cancers in the highest-exposed subgroups. A study of Danish paper mill workers found some nonsignificant elevations of GI cancers, but the possible link with dioxin exposure was not well established. An update of a cohort of Dutch chemical workers found no significant excess of GI cancer among the workers exposed to phenoxy herbicides or chlorophenols. A meta-analysis of studies of pancreatic cancer and occupational exposures found no evidence of associations with herbicide exposures. Updates of the Seveso cohort found some statistically significant excess risks, but these were based on relatively small numbers of cases and do not seem to occur with any consistency over the range of latency periods and exposure zones for the cohort. Among studies of Vietnam veterans, there is no significant evidence of an association between exposure and any gastrointestinal cancer.

Conclusions

Strength of Evidence in Epidemiologic Studies

VAO and the previous updates concluded that there is limited/suggestive evidence of no association between exposure to herbicides (2,4-dichlorophenoxyacetic acid [2,4-D], 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and gastrointestinal cancers (stomach, pancreatic, rectal, and colon cancers). The evidence regarding association was drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. There is no evidence found by this committee to suggest that the conclusion of limited/suggestive evidence of no association should be changed.

Biologic Plausibility

No animal studies have found an increased incidence of gastrointestinal cancer. A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

The available data on Vietnam veterans do not suggest there is an association between TCDD or herbicide exposure and any gastrointestinal cancers.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

TABLE 7-1 Selected Epidemiologic Studies—Stomach Cancer

Reference

Study Population C

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

New Studies

Steenland et al., 1999

U.S. chemical production workers

13

1.0 (0.6–1.8)

Hooiveld et al., 1998

Dutch chemical production workers

3

1.0 (0.2–2.9)

Rix et al., 1998

Danish paper mill workers

 

 

Male

48

1.1 (0.8–1.4)

Female

7

1.0 (0.4–2.1)

Studies Reviewed in Update 1998

Gambini et al., 1997

Italian rice growers

39

0.9 (0.7–1.3)

Kogevinas et al., 1997

IARC cohort

 

 

Workers exposed to TCDD (or higher-chlorinated dioxins)

42

0.9 (0.6–1.2)

Workers not exposed to TCDD (or higher-chlorinated dioxins)

30

0.9 (0.6–1.3)

Workers exposed to any phenoxy herbicide or chlorophenol

72

0.9 (0.7–1.1)

Becher et al., 1996

German chemical production workers

 

 

Plant I

12

1.3 (0.7–2.2)

Plant II

0

 

Plant III

0

 

Plant IV

2

0.6 (0.1–2.3)

Ott and Zober, 1996

BASF cleanup workers

3

1.0 (0.2–2.9)

TCDD <0. 1 µg/kg body wt

0

 

TCDD 0.1–0.99 µg/kg body wt

1

1.3 (0.0–7.0)

TCDD >1 µg/kg body wt

2

1.7 (0.2–6.2)

Ramlow et al., 1996

Pentachlorophenol production workers

 

 

0-year latency

4

1.7 (0.4–4.3)

15-year latency

3

1.8 (0.4–5.2)

Studies Reviewed in Update 1996

Blair et al., 1993

U.S. farmers in 23 states

 

 

White males

657

1.0 (1.0–1.1)

Nonwhite females

23

1.9 (1.2–2.8)

Bueno de Mesquita et al., 1993

Phenoxy herbicide workers

 

NS

Collins et al., 1993

Monsanto 2,4-D production workers

 

NS

Kogevinas et al., 1993

IARC cohort—female

 

NS

Studies Reviewed in VAO

Ronco et al., 1992

Danish male self-employed farm workers

286

0.9

Swaen et al., 1992

Dutch herbicide appliers

1

0.5 (0.0–2.7)b

Fingerhut et al., 1991

NIOSH cohort

10

1.0 (0.5–1.9)

Manz et al., 1991

German production workers

12

1.2 (0.6–2.1)

Saracci et al., 1991

IARC cohort

40

0.9 (0.6–1.2)

Wigle et al., 1990

Canadian farmers

246

0.9 (0.8–1.0)

Zober et al., 1990

BASF production workers—basic cohort

3

3.0 (0.8–11.8)

Alavanja et al., 1989

USDA forest or soil conservationists

9

0.7 (0.3–1.3)

Henneberger et al., 1989

Paper and pulp workers

5

1.2 (0.4–2.8)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Solet et al., 1989

Paper and pulp workers

1

0.5 (0.1–3.0)

Alavanja et al., 1988

USDA agricultural extension agents

10

0.7 (0.4–1.4)

Bond et al., 1988

Dow 2,4-D production workers

0

— (0.0–3.7)

Thomas, 1987

Flavor and fragrance chemical production workers

 

1.4

Coggon et al., 1986

British MCPA production workers

26

0.9 (0.6–1.3)

Robinson et al., 1986

Paper and pulp workers

17

1.2 (0.7–2.1)

Lynge, 1985

Danish male production workers

12

1.3

Blair et al., 1983

Florida pesticide appliers

4

1.2

Burmeister et al., 1983

Iowa residents

 

 

Farming exposures

 

1.3 (p < .05)

Wiklund, 1983

Swedish agricultural workers

2,599

1.1 (1.0–1.2)c

Burmeister, 1981

Farmers in Iowa

338

1.1 (p <.01)

Axelson et al., 1980

Swedish railroad workers—total exposure

3

2.2

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso residents—20-year follow-up

 

 

Zone A males

1

0.5 (0.1–3.2)

Zone A females

2

1.4 (0.3–5.5)

Zone B males

15

1.0 (0.6–1.6)

Zone B females

9

1.0 (0.5–1.9)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

 

 

Zone A females

1

0.9 (0.1–6.7)

Zone B males

10

0.8 (0.4–1.5)

Zone B females

7

1.0 (0.5–2.2)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

 

 

Zone A females

1

0.9 (0.0–5.3)

Zone B males

10

0.8 (0.4–1.5)

Zone B females

7

1.0 (0.4–2.1)

Zone R males

76

0.9 (0.7–1.1)

Zone R females

58

1.0 (0.8–1.3)

Svensson et al., 1995

Swedish fishermen, mortality

 

 

East coast

17

1.4 (0.8–2.2)

West coast

63

0.9 (0.7–1.2)

Swedish fishermen, incidence

 

 

East coast

24

1.6 (1.0–2.4)

West coast

71

0.9 (0.7–1.2)

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up, morbidity

 

 

Zone B males

7

1.0 (0.5–2.1)

Zone B females

2

0.6 (0.2–2.5)

Zone R males

45

0.9 (0.7–1.2)

Zone R females

25

1.0 (0.6–1.5)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Studies Reviewed in VAO

Pesatori et al., 1992

Seveso residents

 

 

Zones A, B males

7

0.9 (0.4–1.8)

Zones A, B females

3

0.8 (0.3–2.5)

Bertazzi et al., 1989a

Seveso residents—10-year follow-up

 

 

Zones A, B, R males

40

0.8 (0.6–1.2)

Zones A, B, R females

22

1.0 (0.6–1.5)

Bertazzi et al., 1989b

Seveso residents—10-year follow-up

 

 

Zone B males

7

1.2 (0.6–2.6)

VIETNAM VETERANS

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

32

1.1 (0.7–1.5)

Crane et al., 1997b

Australian national service Vietnam veterans

4

1.7 (0.3–>10)

Studies Reviewed in VAO

Breslin et al., 1988

Army Vietnam veterans

88

1.1 (0.9–1.5)

Marine Vietnam veterans

17

0.8 (0.4–1.6)

Anderson et al., 1986a

Wisconsin Vietnam veterans

3

Anderson et al., 1986b

Wisconsin Vietnam veterans

1

NOTE: MCPA=methyl-4-chlorophenoxyacetic acid; NS=not significant; USDA=United States Department of Agriculture.

aGiven when available.

bRisk estimate is for stomach and small intestine.

c99% CI.

TABLE 7-2 Selected Epidemiologic Studies—Colon Cancer

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

New Studies

Steenland et al., 1999

U.S. chemical production workers

34

1.2 (0.8–1.6)

Hooiveld et al., 1998

Dutch chemical production workers

3

1.4 (0.3–4.0)

Rix et al., 1998

Danish paper mill workers

 

 

Males

58

1.0 (0.7–1.2)

Females

23

1.1 (0.7–1.7)

Studies Reviewed in Update 1998

Gambini et al., 1997

Italian rice growers

27

1.1 (0.7–1.6)

Kogevinas et al., 1997

IARC cohort

 

 

Workers exposed to TCDD (or higher-chlorinated dioxins)

52

1.0 (0.8–1.3)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

 

Workers not exposed to TCDD (or higher-chlorinated dioxins)

33

1.2 (0.8–1.6)

Workers exposed to any phenoxy herbicide or chlorophenol

86

1.1 (0.8–1.3)

Becher et al., 1996

German chemical production workers

 

 

Plant I

2

0.4 (0.0–1.4)

Plant II

0

 

Plant III

1

2.2 (0–12)

Plant IV

0

 

Ott and Zober, 1996

BASF cleanup workers

5

1.0 (0.3–2.3)b

TCDD <0.1 µg/kg body wt

2

1.1 (0.1–3.9)b

TCDD 0.1–0.99 µg/kg body wt

2

1.4 (0.2–5.1)b

TCDD >1 µg/kg body wt

1

0.5 (0.0–3.0)b

Ramlow et al., 1996

Pentachlorophenol production workers

 

 

0-year latency

4

0.8 (0.2–2.1)

15-year latency

4

1.0 (0.3–2.6)

Studies Reviewed in Update 1996

Blair et al., 1993

U.S. farmers in 23 states

 

 

White males

2,291

1.0 (0.9–1.0)

Bueno de Mesquita et al., 1993

Phenoxy herbicide workers

 

NS

Collins et al., 1993

Monsanto 2,4-D production workers

 

NS

Studies Reviewed in VAO

Ronco et al., 1992

Danish male self-employed farm workers

277

0.7 (p < .05)

Swaen et al., 1992

Dutch herbicide appliers

4

2.6 (0.7–6.5)

Fingerhut et al., 1991

NIOSH cohort

25

1.2 (0.8–1.8)

Manz et al., 1991

German production workers

8

0.9 (0.4–1.8)

Saracci et al., 1991

IARC cohort

41

1.1 (0.8–1.5)

Zober et al., 1990

BASF production workers—basic cohort

2

2.5 (0.4–14.1)b

Alavanja et al., 1989

USDA forest conservationists

 

1.4 (0.7–2.8)

USDA soil conservationists

 

1.2 (0.7–2.0)

Henneberger et al., 1989

Paper and pulp workers

9

1.0 (0.5–2.0)

Solet et al., 1989

Paper and pulp workers

7

1.5 (0.6–3.0)

Alavanja et al., 1988

USDA agricultural extension agents

 

1.0 (0.7–1.5)

Bond et al., 1988

Dow 2,4-D production workers

4

2.1 (0.6–5.4)

Thomas, 1987

Flavor and fragrance chemical production workers

 

0.6

Coggon et al., 1986

British MCPA production workers

19

1.0 (0.6–1.6)

Hoar et al., 1986

Kansas residents

 

 

No herbicide use

 

1.6 (0.8–3.6)

Herbicide use

 

1.5 (0.6–4.0)

Robinson et al., 1986

Paper and pulp workers

7

0.4 (0.2–0.9)

Lynge, 1985

Danish male production workers

10

1.0

Blair et al., 1983

Florida pesticide appliers

5

0.8

Wiklund, 1983

Swedish agricultural workers 1

1,332

0.8 (0.7–0.8)c

Thiess et al., 1982

BASF production workers

 

0.4

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Burmeister, 1981

Farmers in Iowa

1,064

1.0 (NS)

Hardell, 1981

Residents of Sweden

 

 

Exposed to phenoxy acids

11

1.3 (0.6–2.8)

Exposed to chlorophenols

6

1.8 (0.6–5.3)

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso residents—20-year follow-up

 

 

Zone A females

2

1.8 (0.4–7.0)

Zone B males

10

1.2 (0.6–2.2)

Zone B females

3

0.4 (0.1–1.3)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

 

 

Zone A females

2

2.6 (0.6–10.5)

Zone B males

5

0.8 (0.3–2.0)

Zone B females

3

0.6 (0.2–1.9)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

 

 

Zone A females

2

2.6 (0.3–9.4)

Zone B males

5

0.8 (0.3–2.0)

Zone B females

3

0.6 (0.1–1.8)

Zone R males

34

0.8 (0.6–1.1)

Zone R females

33

0.8 (0.6–1.1)

Svensson et al., 1995

Swedish fishermen, mortality

 

 

East coast

4

0.1 (0.0–0.7)

West coast

58

1.0 (0.8–1.3)

Swedish fishermen, incidence

 

 

East coast

5

0.4 (0.1–0.9)

West coast

82

0.9 (0.8–1.2)

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up, morbidity

 

 

Zone B males

2

0.5 (0.1–2.0)

Zone B females

2

0.6 (0.1–2.3)

Zone R males

32

1.1 (0.8–1.6)

Zone R females

23

0.8 (0.5–1.3)

Studies Reviewed in VAO

Lampi et al., 1992

Finnish community exposed to chlorophenol contamination

9

1.1 (0.7–1.8)

Pesatori et al., 1992

Seveso residents

 

 

Zones A, B males

3

0.6 (0.2–1.9)

Zones A, B females

3

0.7 (0.2–2.2)

Bertazzi et al., 1989a

Seveso residents—10-year follow-up

 

 

Zones A, B, R males

20

1.0 (0.6–1.5)

Zones A, B, R females

12

0.7 (0.4–2.2)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans

7

1.5(0.4–5.5)b

AIHW, 1999

Australian Vietnam veterans—male

188

221 expected (191–251)b

CDVA, 1998a

Australian Vietnam veterans—male

405d

117 expected (96–138)

CDVA, 1998b

Australian Vietnam veterans—female

1d

1 expected (0–5)

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

78

1.2 (1.0–1.5)

Crane et al., 1997b

Australian national service Vietnam veterans

6

0.6 (0.2–1.5)

Studies Reviewed in Update 1996

Dalager et al., 1995

Women Vietnam veterans

 

2.8 (0.8–10.2)

Nurses

 

5.7 (1.2–27.0)

Studies Reviewed in VAO

Breslin et al., 1988

Army Vietnam veterans

209

1.0 (0.7–1.3)e

Marine Vietnam veterans

33

1.3 (0.7–2.2)e

Anderson et al., 1986a

Wisconsin Vietnam veterans

4

Anderson et al., 1986b

Wisconsin Vietnam veterans

6

1.0 (0.4–2.2)

NOTE: MCPA=methyl-4-chlorophenoxyacetic acid; NS=not significant; USDA=United States Department of Agriculture.

aGiven when available.

bColon and rectal cancer results are combined in this study.

c99% CI.

dSelf-reported medical history. Answer to question: Since your first day of service in Vietnam, have you been told by a doctor that you have cancer of the colon?

eIntestinal and other GI cancer results are combined in this study.

TABLE 7-3 Selected Epidemiologic Studies—Rectal Cancer

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

New Studies

Steenland et al., 1999

U.S. chemical production workers

6

0.9 (0.3–1.9)

Hooiveld et al., 1998

Dutch chemical production workers

1

1.0 (0.0–5.6)

Rix et al., 1998

Danish paper mill workers

43

0.9 (0.6–1.2)

Studies Reviewed in Update 1998

Kogevinas et al., 1997

IARC cohort

 

 

Workers exposed to TCDD (or higher-chlorinated dioxins)

29

1.3 (0.9–1.9)

Workers not exposed to TCDD (or higher-chlorinated dioxins)

14

0.7 (0.4–1.2)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

 

Workers exposed to any phenoxy herbicide or chlorophenol

44

1.1 (0.8–1.4)

Becher et al., 1996

German chemical production workers

 

 

Plant I

6

1.8 (0.7–4.0)

Plant II

0

 

Plant III

0

 

Plant IV

1

0.9 (0.0–4.9)

Ramlow et al., 1996

Pentachlorophenol production workers

 

 

0-year latency

0

 

15-year latency

0

 

Studies Reviewed in Update 1996

Blair et al., 1993

U.S. farmers in 23 states

 

 

White males

367

1.0 (0.9–1.1)

Bueno de Mesquita et al., 1993

Phenoxy herbicide workers

 

NS

Studies Reviewed in VAO

Ronco et al., 1992

Danish male self-employed farmers

309

0.8 (p < .05)

Fingerhut et al., 1991

NIOSH cohort

5

0.9 (0.3–2.1)

Saracci et al., 1991

IARC cohort

24

1.1 (0.7–1.6)

Alavanja et al., 1989

USDA forest or soil conservationists

9

1.0 (0.5–1.9)

Henneberger et al., 1989

Paper and pulp workers

1

0.4 (0.0–2.1)

Alavanja et al., 1988

USDA agricultural extension agents

5

0.6 (0.2–1.3)

Bond et al., 1988

Dow 2,4-D production workers

1

1.7 (0.0–9.3)

Thomas, 1987

Flavor and fragrance chemical production workers

 

2.5

Coggon et al., 1986

British MCPA chemical workers

8

0.6 (0.3–1.2)

Lynge, 1985

Danish male production workers

14

1.5

Blair et al., 1983

Florida pesticide appliers

2

1.0

Wiklund, 1983

Swedish agricultural workers

1,083

0.9 (0.9–1.0)b

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso residents—20-year follow-up

 

 

Zone A males

1

2.2 (0.3–15.6)

Zone B males

10

1.2 (0.6–2.2)

Zone B females

3

1.3 (0.4–4.1)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

 

 

Zone B males

7

2.9 (1.3–6.2)

Zone B females

2

1.3 (0.3–5.1)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

 

 

Zone B males

7

2.9 (1.2–5.9)

Zone B females

2

1.3 (0.1–4.5)

Zone R males

19

1.1 (0.7–1.8)

Zone R females

12

0.9 (0.5–1.6)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Svensson et al., 1995

Swedish fishermen, mortality

 

 

East coast

4

0.7 (0.2–1.9)

West coast

31

1.0 (0.7–1.5)

Swedish fishermen, incidence

 

 

East coast

9

0.9 (0.4–1.6)

West coast

59

1.1 (0.8–1.4)

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up, morbidity

 

 

Zone B males

3

1.4 (0.4–4.4)

Zone B females

2

1.3 (0.3–5.4)

Zone R males

17

1.1 (0.7–1.9)

Zone R females

7

0.6 (0.3–1.3)

Studies Reviewed in VAO

Pesatori et al., 1992

Seveso residents

 

 

Zones A, B males

3

1.2 (0.4–3.8)

Zones A, B females

2

1.2 (0.3–4.7)

Bertazzi et al., 1989a

Seveso residents—10-year follow-up

 

 

Zones A, B, R males

10

1.0 (0.5–2.0)

Zones A, B, R females

7

1.2 (0.5–2.7)

Bertazzi et al., 1989b

Seveso residents—10-year follow-up

 

 

Zone B males

2

1.7 (0.4–7.0)

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans

7

1.5 (0.4–5.5)c

AIHW, 1999

Australian Vietnam veterans—male

188

221 expected (191–251)c

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

16

0.6 (0.4–1.0)

Crane et al., 1997b

Australian national service Vietnam veterans

3

0.7

Studies Reviewed in VAO

Anderson et al., 1986a

Wisconsin Vietnam veterans

1

Anderson et al., 1986b

Wisconsin Vietnam veterans

1

NOTE: MCPA=methyl-4-chlorophenoxyacetic acid; NS=not significant; USDA=United States Department of Agriculture.

aGiven when available.

b99% CI.

cColon and rectal cancer results are combined in this study.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

TABLE 7-4 Selected Epidemiologic Studies—Pancreatic Cancer

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

New Studies

Ojajärvi et al., 2000

Meta-analysis of 161 populations

 

MRR=1.0 (0.8–1.3)

Steenland et al., 1999

U.S. chemical production workers

16

1.0 (0.6–1.6)

Hooiveld et al., 1998

Dutch chemical production workers

4

2.5 (0.7–6.3)

Rix et al., 1998

Danish paper mill workers

 

 

Males

30

1.1 (0.8–1.7)

Females

2

0.3 (0.0–1.1)

Studies Reviewed in Update 1998

Gambini et al., 1997

Italian rice growers

7

0.9 (0.4–1.9)

Kogevinas et al., 1997

IARC cohort

 

 

Workers exposed to TCDD (or higher-chlorinated dioxins)

30

1.0 (0.7–1.4)

Workers not exposed to TCDD (or higher-chlorinated dioxins)

16

0.9 (0.5–1.4)

Workers exposed to any phenoxy herbicide or chlorophenol

47

0.9 (0.7–1.2)

Becher et al., 1996

German chemical production workers

 

 

Plant I

2

0.6 (0.1–2.3)

Plant II

0

 

Plant III

0

 

Plant IV

2

1.7 (0.2–6.1)

Ramlow et al., 1996

Pentachlorophenol production workers

 

 

0-year latency

2

0.7 (0.1–2.7)

15-year latency

2

0.9 (0.1–3.3)

Studies Reviewed in Update 1996

Blair et al., 1993

U.S. farmers in 23 states

 

 

White males

1,133

1.1 (1.1–1.2)

Bueno de Mesquita et al., 1993

Phenoxy herbicide workers

 

NS

Studies Reviewed in VAO

Ronco et al., 1992

Danish self-employed male farm workers

137

0.6 (p < .05)

Swaen et al., 1992

Dutch herbicide appliers

3

2.2 (0.4–6.4)

Fingerhut et al., 1991

NIOSH cohort

10

0.8 (0.4–1.6)

Saracci et al., 1991

NIOSH cohort

26

1.1 (0.7–1.6)

Alavanja et al., 1989

USDA forest conservationists

 

1.2 (0.4–3.4)

 

USDA soil conservationists

 

1.1 (0.5–2.2)

Henneberger et al., 1989

Paper and pulp workers

9

1.9 (0.9–3.6)

Solet et al., 1989

Paper and pulp workers

1

0.4 (0.0–2.1)

Alavanja et al., 1988

USDA agricultural extension agents

21

1.3 (0.8–1.9)

Thomas, 1987

Flavor and fragrance chemical production workers

 

1.4

Coggon et al., 1986

British MCPA production workers

9

0.7 (0.3–1.4)

Robinson et al., 1986

Paper and pulp workers

4

0.3 (0.1–1.1)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Lynge, 1985

Danish male production workers

3

0.6

Blair et al., 1983

Florida pesticide appliers

4

1.0

Wiklund, 1983

Swedish agricultural workers

777

0.8 (0.8–0.9)b

Burmeister, 1981

Farmers in Iowa

416

1.1

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso residents—20-year follow-up

 

 

Zone A males

1

1.3 (0.2–9.5)

Zone B males

3

0.6 (0.2–1.9)

Zone B females

1

0.3 (0.0–2.4)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

 

 

Zone A males

1

1.9 (0.3–13.5)

Zone B males

2

0.6 (0.1–2.2)

Zone B females

1

0.5 (0.1–3.9)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

 

 

Zone A males

1

1.9 (0.0–10.5)

Zone B males

2

0.6 (0.1–2.0)

Zone B females

1

0.5 (0.0–3.1)

Zone R males

20

0.8 (0.5–1.2)

Zone R females

11

0.7 (0.4–1.3)

Svensson et al., 1995

Swedish fishermen mortality

 

 

East coast

5

0.7 (0.2–1.6)

West coast

33

0.8 (0.6–1.2)

Swedish fishermen incidence

 

 

East coast

4

0.6 (0.2–1.6)

West coast

37

1.0 (0.7–1.4)

Studies Reviewed in VAO

Pesatori et al., 1992

Seveso residents

 

 

Zones A, B males

2

1.0 (0.3–4.2)

Zones A, B females

1

1.6 (0.2–12.0)

Bertazzi et al., 1989a

Seveso residents—10-year follow-up

 

 

Zones A, B, R males

9

0.6 (0.3–1.2)

Zones A, B, R females

4

1.0 (0.3–2.7)

Bertazzi et al., 1989b

Seveso residents—10-year follow-up

 

 

Zone B males

2

1.1 (0.3–4.5)

VIETNAM VETERANS

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

38

1.4 (1.0–1.9)

Crane et al., 1997b

Australian national service

 

 

Vietnam veterans

6

1.5

Studies Reviewed in Update 1996

Visintainer et al., 1995

Michigan Vietnam veterans

 

 

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Studies Reviewed in VAO

Thomas et al., 1991

U.S. Vietnam veterans—women

5

2.7 (0.9–6.2)

Breslin et al., 1988

Army Vietnam veterans

82

0.9 (0.6–1.2)

 

Marine Vietnam veterans

18

1.6 (0.5–5.8)

Anderson et al., 1986a

Wisconsin Vietnam veterans

6

5.5 (2.8–10.9)

Anderson et al., 1986b

Wisconsin Vietnam veterans

4

NOTE: MCPA=methyl-4-chlorophenoxyacetic acid; MRR=meta-risk ratio; NS=not significant; USDA=United States Department of Agriculture.

aGiven when available.

b99% CI.

HEPATOBILIARY CANCERS

Background

This category includes cancers of the liver (ICD•9 155.0, 155.2) and the hepatobiliary duct (ICD•9 155.1). According to American Cancer Society estimates, 10,000 men and 5,300 women will be diagnosed with liver cancer in the United States in 2000; 8,500 men and 5,300 women will die from the disease (ACS, 2000a).

In the United States, liver cancers account for about 1 percent of new cancer cases and 2.5 percent of cancer deaths. Misclassification of metastatic cancers as primary liver cancer can, however, lead to overreporting of deaths due to liver cancer (Percy et al., 1990). In developing countries, especially sub-Saharan Africa and Southeast Asia, liver cancers are common and are among the leading causes of death. The known risk factors for liver cancer include chronic infection with hepatitis B or C virus and exposure to the carcinogens aflatoxin and vinyl chloride. In the general population, the incidence of liver and intrahepatic bile duct cancer increases slightly with age, and remains greater for men than women and greater for African Americans than whites throughout ages 45–59 years.

Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa

Liver and Intrahepatic Bile Duct Cancers

 

45–49 Years of Age

50–54 Years of Age

55–59 Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

5.6

3.9

11.4

8.1

5.4

17.2

14.2

9.8

25.6

Females

1.5

1.0

2.0

2.6

1.8

4.5

4.1

3.5

4.0

aSEER nine standard registries, crude age-specific rate, 1993–1997.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found there to be inadequate or insufficient information to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and hepatobiliary cancers. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Table 7-5 provides summaries of the results of studies underlying these findings and a list of reports that contain details of the research.

Update of the Scientific Literature

Occupational Studies

The largest industrial cohort exposed to dioxins is the group of 5,132 U.S. workers known as the NIOSH cohort. This group was assembled from employees of 12 major chemical manufacturers that produced 2,4,5-trichlorophenol, 2,4,5-T, Silvex, Erbon, Ronnel, and hexachlorophene. Workers engaged in production and maintenance were exposed to TCDD as a contaminant in these chemicals. The first study of mortality through 1987 among these workers (Fingerhut, 1991) found excess cancer mortality for all cancers combined (SMR=1.2, 1.0–1.3); however, no elevated risk was observed for cancers of the liver or hepatobiliary duct. This cohort has been updated through 1993, and an exposure-response analysis on a subcohort (approximately 69 percent of the population) has been conducted (Steenland et al., 1999). In that update, mortality from cancer of the liver and hepatobiliary duct (ICD•9 155–156) is not different from expected (0.9, 0.4–1.6). These cancers were not examined in the subcohort of 608 workers who had medical records reporting chloracne or in the more detailed exposure assessment conducted of workers employed in 8 (of a total of 12) plants that had sufficient information on the level of TCDD contamination in their products and detailed work histories.

In a study of a cohort of Danish paper mill workers, Rix et al. (1998) examined mortality from a wide range of causes. The likelihood of substantial dioxin exposure among these workers is unclear, since the three mills in the study never produced paper pulp themselves. Rather, they manufactured paper from imported bleached and unbleached pulp. There are no direct measures of exposure for these workers, and a qualitative assessment of chemicals used in paper manufacture by department does not include chlorinated organic compounds, although chlorine, chlorine dioxide, and hypochlorite were used. For two of the mills, the period of follow-up was January 1, 1943, to December 31, 1993, while for the third mill, follow-up started at January 1, 1965. Incident cancer cases were identified from the Danish Cancer Register, and the expected numbers of cases was calculated using the rates for the total Danish population by gender, 5-year age group, and calendar time. For cancer sites of specific interest, Poisson regression models were used to analyze by duration and years since first employment and by depart-

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

ment of employment. For liver cancer, an SIR of 1.1 (0.5–2.0, 10 cases) was found for men. For women, the SIR was 0.6 (0.0–3.2, 1 case). No excess was seen when male workers were stratified by department of work.

Environmental Studies

In a review of early, mid-term, and long-term health effects, Bertazzi et al. (1998) continued the follow-up of people environmentally exposed to TCDD in the Seveso accident. The events that led to the exposure and the methods used to study this population have been fully described in Chapter 6. Their 1998 report reviews the full range of indicators of exposure and effects on animal and human health. In the case of hepatobiliary cancer mortality (ICD•9 155–156), the report does not appear to add any new information to Bertazzi et al. (1997), which was reviewed in Update 1998. After 15 years’ follow-up (1976–1991), death from hepatobiliary cancer was not reported for zone A. Zones A and B showed lower than expected mortality, except in zone B where women had a nonsignificant elevation (RR=1.1, 0.4–3.1, 4 cases).

In another report, Bertazzi et al. (2001) extended the mortality analysis through the end of 1996. They examined mortality from hepatobiliary cancer (ICD•9 155– 156) and generally found no evidence of excess risk, similar to that seen in their earlier studies of the Seveso population. In this study, there were no cases of hepatobiliary cancer mortality in zone A, and no excess was observed in zone B. No important pattern emerged when the study population was stratified by gender, latency, and zone of residence. An RR of 2.1 (0.7–6.7, 3 cases) was observed for hepatobiliary cancer for zone B women in the 10–14-year latency group.

Vietnam Veteran Studies

In the Air Force Health Study final report (AFHS, 2000), the small number of subjects with a malignant neoplasm of the liver (2 cases among 861 Ranch Hand veterans) resulted in a very limited analysis for this outcome. The percentage of Ranch Hands in the high-dioxin category with a malignant neoplasm of the liver was greater than the percentage of comparisons, resulting in a nonsignificant adjusted RR of 7.1 (0.7–71.3).

Model 4 analysis (Ranch Hand 1987 dioxin category) found a positive association between 1987 dioxin levels and a malignant neoplasm of the liver; after adjustment for covariates, the risk was 2.5-fold higher for each doubling of the 1987 measured blood dioxin level (1.0–6.2).

Synthesis

VAO and subsequent reports found that there were relatively few occupational, environmental, or veteran studies of hepatobiliary cancer (Table 7–5). The

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

updated analysis of mortality among U.S. chemical workers did not find any elevation in liver cancer mortality, nor did a study of Danish paper mill workers. Updates of the Seveso cohort mortality studies did not add any new information on hepatobiliary cancer. Among the studies of Vietnam veterans, the recent study of Air Force personnel (AFHS, 2000) provides a suggestion of an association between herbicide exposure and liver cancer; however, when considered with the overall body of evidence, this finding is not sufficient to change the conclusion that there is inadequate or insufficient evidence of an association.

Conclusions

Strength of Evidence in Epidemiologic Studies

The result of this update is no change in the conclusion of 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) and hepatobiliary cancer. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Though several of these studies involve sizable cohorts, hepatobiliary cancers are rare, and as a result, the number of expected cases is fairly small. Additionally, the NIOSH cohort study and Seveso investigations have not adjusted for life-style factors.

Biologic Plausibility

Rats and mice orally administered TCDD for 2 years were evaluated for development of cancer (NTP, 1982). Neoplastic nodules in the liver of female rats were significantly increased in the high-TCDD-dose group, while a significant increase of hepatocellular carcinomas was noted in high-dose-treated male and female mice. It is interesting to note that the high dose of TCDD that increased the incidence of neoplasia in these studies also increased the incidence of toxic hepatitis in both sexes of rats and mice. A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

There are insufficient data to determine whether Vietnam veterans are at an elevated risk for liver cancer.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

TABLE 7-5 Selected Epidemiologic Studies—Hepatobiliary Cancer

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

New Studies

Steenland et al., 1999

U.S. chemical production workers

7

0.9 (0.4–1.6)

Rix et al., 1998

Danish paper mill workers

 

 

Males

10

1.1 (0.5–2.0)

Females

1

0.6 (0.0–3.2)

Studies Reviewed in Update 1998

Gambini et al., 1997

Italian rice growers

7

1.3 (0.5–2.6)

Kogevinas et al., 1997

IARC cohort

 

 

Workers exposed to TCDD (or higher-chlorinated dioxins)

12

0.9 (0.4–1.5)

Workers not exposed to TCDD (or higher-chlorinated dioxins)

3

0.4 (0.1–1.2)

Workers exposed to any phenoxy herbicide or chlorophenol

15

0.7 (0.4–1.2)

Becher et al., 1996

German chemical production workers

1

1.2 (0.0–6.9)

Ott and Zober, 1996

BASF cleanup workers

2

2.1 (0.3–8.0)

TCDD <0.1 µg/kg body wt

1

2.8 (0.1–15.5)

TCDD 0.1–0.99 µg/kg body wt

0

 

TCDD >1 µg/kg body wt

1

2.8 (0.1–15.5)

Ramlow et al., 1996

Pentachlorophenol production workers

 

 

0-year latency

0

 

15-year latency

0

 

Studies Reviewed in Update 1996

Asp et al., 1994

Finnish herbicide appliers

2

0.6 (0.1–2.2)

Blair et al., 1993

U.S. farmers in 23 states

326

1.0 (0.9–1.1)

Collins et al., 1993

Monsanto 2,4-D production workers

2

1.4 (0.2–5.2)

Studies Reviewed in VAO

Ronco et al., 1992

Danish and Italian farm workers

 

 

Danish male self-employed farmers

23

0.4

Employees of Danish farmers

9

0.8

Female family workers

5

0.5

Fingerhut et al., 1991

NIOSH cohort

6

1.2 (0.4–2.5)

20-year latency

1

0.6 (0.0–3.3)

Saracci et al., 1991

IARC cohort

4

0.4 (0.1–1.1)

Solet et al., 1989

Paper and pulp workers

2

2.0 (0.2–7.3)

Bond et al., 1988

Dow 2,4-D production workers

 

1.2

Lynge, 1985

Danish production workers

3

1.0

Hardell et al., 1984

Male residents of northern Sweden

102

1.8 (0.9–4.0)

Wiklund, 1983

Swedish agricultural workers

103

0.3 (0.3–0.4)b

Zack and Suskind, 1980

Monsanto production workers

0

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso residents—20-year follow-up

 

 

Zone B males

6

0.5 (0.2–1.2)

Zone B females

7

1.2 (0.6–2.6)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Bertazzi et al., 1998

Seveso residents—15-year follow-up

 

 

Zone B males

4

0.6 (0.2–1.5)

Zone B females

4

1.1 (0.4–3.1)

Zone R males

35

0.7 (0.5–1.0)

Zone R females

25

0.8 (0.6–1.3)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

 

 

Zone B males

4

0.6 (0.2–1.4)

Zone B females

4

1.1 (0.3–2.9)

Zone R males

35

0.7 (0.5–1.0)

Zone R females

25

0.8 (0.5–1.3)

Svensson et al., 1995

Swedish fishermen, mortality

 

 

East coast

1

0.5 (0.0–2.6)

West coast

9

0.9 (0.4–1.7)

Swedish fishermen, incidence

 

 

East coast

6

1.3 (0.5–2.8)

West coast

24

1.0 (0.6–1.5)

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up, morbidity

 

 

Zone B males

5

1.8 (0.7–4.4)

Zone B females

5

3.3 (1.3–8.1)

Zone R males

11

0.5 (0.3–1.0)

Zone R females

12

0.9 (0.5–1.7)

Cordier et al., 1993

Military service in South Vietnam for > 10 vears after 1960

11

8.8 (1.9–41.0)

Studies Reviewed in VAO

Pesatori et al., 1992

Seveso residents

 

 

Zones A, B males

4

1.5 (0.5–4.0)

Zones A, B females

1

1.2 (0.2–9.1)

Bertazzi et al., 1989b

Seveso residents—10-year follow-up

 

 

Zone B males

3

1.2 (0.4–3.8)

Zone R males

7

0.4 (0.2–0.8)

Hoffman et al., 1986

Residents of Quail Run Mobile Home Park

0

Stehr et al., 1986

Missouri residents

0

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans

2

1.6 (0.2–11.4)

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

8

0.6 (0.3–1.2)

Crane et al., 1997b

Australian national service Vietnam veterans

1

Studies Reviewed in VAO

CDC, 1990

U.S. men born between 1921 and 1953

8

1.2 (0.5–2.7)

Breslin et al., 1988

Army Vietnam veterans

34

1.0 (0.8–1.4)

 

Marine Vietnam veterans

6

1.2 (0.5–2.8)

Anderson et al., 1986a, b

Wisconsin Vietnam veterans

0

aGiven when available.

b99% CI.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

NASAL AND NASOPHARYNGEAL CANCER

Background

There are many types of nasal (ICD•9 160.0–160.9) and nasopharyngeal (ICD•9 147.0–147.9) cancers, although undifferentiated carcinoma, squamous cell carcinoma, and lymphomas account for the vast majority of malignancies. The epithelium of the nasal and nasopharyngeal cavities is partly squamous, partly columnar, and partly ciliated pseudostratified columnar. There are also serous and mucous glands and lymphoid aggregates in close association with the epithelium.

The American Cancer Society (ACS) estimates that approximately 3,900 men and 1,300 women will be diagnosed with nasal, pleural, tracheal, and other respiratory system cancers in the United States in 2000 and that some 700 men and 400 women will die from the diseases (ACS, 2000a). Roughly speaking, nasal and nasopharyngeal cancers account for between one-third and one-half of these totals. ACS (2000a) estimates suggest that approximately 6,500 men and 2,100 women will be diagnosed with cancers of the pharynx (including nasopharynx, tonsil, oropharynx, hypopharynx, and buccal cavity) and that 1,500 men and 600 women will die from them. Nasopharyngeal cancers make up approximately one in five of these cancers. The incidence rates reported below show that men are at a greater risk than women for these diseases and that incidence increases with age, although the very small number of cases indicates that care should be exercised in interpreting the numbers.

Nasopharyngeal cancer is relatively common in China and Southeast Asia. It is also more common in Chinese and Vietnamese Americans than in whites, African Americans, or other groups, suggesting that genetic factors may play a role in this disease (Miller et al., 1996). There is no similar association for nasal cancer. Reported risk factors for nasal cancer include occupational exposure to nickel and chromium compounds (Hayes, 1997), wood dust (Demers et al., 1995), and formaldehyde (Blair and Kazerouni, 1997). Studies of nasopharyngeal cancer have reported associations with the consumption of salt-preserved foods (Miller et al., 1996), cigarette smoking (Zhu et al., 1995), and Epstein-Barr virus (Mueller, 1995).

Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa

Nasal and Nasopharyngeal Cancers

 

45–49 Years of Age

50–54 Years of Age

55–59 Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Nose, Nasal Cavity, and Mid-ear

Males

0.9

0.7

1.6

1.2

1.2

1.1

1.7

1.6

2.5

Females

0.4

0.4

0.7

0.7

0.7

0.6

0.8

0.8

1.2

Nasopharynx

Males

1.5

0.4

2.3

2.1

1.0

1.9

3.5

2.2

3.5

Females

0.8

0.3

0.7

0.6

0.4

0.3

0.6

0.4

1.6

aSEER nine standard registries, crude age-specific rate, 1993–1997.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found there to be inadequate or insufficient information to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and nasal or nasopharyngeal cancer. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Table 7–6 provides summaries of the results of the studies underlying these findings and a list of reports that contain details of the research.

Update of the Scientific Literature

Occupational Studies

Caplan et al. (2000) evaluated exposures among cases with nasal cancer identified in population-based cancer registries in five metropolitan areas and three states, ensuring diversity of risk factors. The cancers were a mixed group that included mostly nasopharyngeal carcinomas (more squamous than adenocarcinomas), some sarcomas, and lymphomas. This heterogeneity makes attribution of nasopharyngeal carcinoma to particular risk factors difficult. Compared to controls, cases overall showed increased odds of 2.5 (1.1–5.3) of having smoked cigarettes and having worked in jobs that involved herbicide exposure (odds ratio [OR]=2.2, 1.2–3.7) such as lawn care, highway right-of-way maintenance, and forestry. However, subjects with nasal cancer were not more likely to have reported known exposure to herbicides or pesticides or to have worked on a farm. In this community-derived sample, cases also did not show increased odds of exposure to certain known risk factors such as wood dust. However, population-based case-control studies have low power to detect occupational risks when the exposure prevalence is low (Hu et al., 1999); therefore the lack of association with a known risk factor (wood dust) does not constitute evidence of an invalid study, relative to that study’s herbicide findings. The implication of these findings for the risk of Vietnam era veterans is unclear.

Environmental Studies

Chapter 3 of Update 1998 addressed the possibility that TCDD-induced metabolism of procarcinogens may alter cancer risk at various tissues, but there was no empirical evidence to confirm or refute this assertion. Hildesheim et al. (1997) have identified an allele of the gene expressing one form of cytochrome P450 (CYP2E1) among Chinese subjects that may be associated with a risk of nasopharyngeal cancer. This allelic form, called c2c2, was strongly associated with risk for nasopharyngeal carcinoma among nonsmoking Chinese but not Chinese who smoke. Among Chinese who smoke, the risk for nasopharyngeal

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

carcinoma was associated with the allelic form c1c1. This raises the possibility that selective induction of cytochromes by TCDD in epithelial cells of the nasal and sinus mucosa may play a role in increasing susceptibility to the effects of cancer initiators in complex ways. Studies are under way by this author and by Aparaso (2000) to resolve these and related issues.

Bertazzi et al. (2001) did not identify any nasopharyngeal carcinomas in their population of TCDD-exposed residents of Seveso.

Vietnam Veteran Studies

Ranch Hand participants do not show an excess risk of nasopharyngeal cancer or other cancers of the head and neck, nor was there an exposure-response relationship among those cancers that did occur (AFHS, 2000).

Synthesis

Nasal and nasopharyngeal cancers are relatively rare in the United States and thus difficult to study epidemiologically. Newly available studies do not change the committee’s belief that scientific evidence on the association between herbicide exposure and nasopharyngeal cancer is too sparse to draw conclusions. Information on other cancers of the respiratory tract does not affect the evaluation of nasal and nasopharyngeal cancers because they have different etiologies.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that 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) and nasopharyngeal cancer.

Biologic Plausibility

No animal studies have found an increased incidence of nasal or nasopharyngeal cancer. A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides used in Vietnam is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

The available data on Vietnam veterans do not suggest there is an association between TCDD or herbicide exposure and nasal or nasopharyngeal cancer.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

TABLE 7-6 Selected Epidemiologic Studies—Nasal and Nasopharyngeal Cancer

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

New Studies

Caplan et al., 2000

Men selected from population-based cancer registries who have nasal cancer

70

2.2 (1.2–3.7)

Studies Reviewed in Update 1998

Kogevinas et al., 1997

IARC cohort

 

 

Oral cavity and pharynx cancer (ICD•9 140–149)

26

1.1 (0.7–1.6)

Nose and nasal sinuses cancer (ICD•9 160)

3

1.6 (0.3–4.7)

Studies Reviewed in Update 1996

Asp et al., 1994

Finnish herbicide applicators

1

0.5 (0.0–2.9)

Studies Reviewed in VAO

Ronco et al., 1992

Danish and Italian farm workers

 

0.6 (NS)

Saracci et al., 1991

IARC cohort

3

2.9 (0.6–8.5)

Coggon et al., 1986

British MCPA production workers

3

4.9 (1.0–14.4)

Robinson et al., 1986

Paper and pulp workers

0

Wiklund, 1983

Swedish agricultural workers

64

0.8 (0.6–1.2)

Hardell et al., 1982

Residents of northern Sweden

 

 

Phenoxy acid exposure

8

2.1 (0.9–4.7)

Chlorophenol exposure

9

6.7 (2.8–16.2)

ENVIRONMENTAL

Studies Reviewed in VAO

Bertazzi et al., 1993

Seveso residents—10-year follow-up, morbidity

Zone R females

2

2.6 (0.5–13.3)

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans

9

1.0 (0.4–2.8)

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

 

 

Nasal cancer

2

1.2 (0.2–4.4)

Nasopharyngeal cancer

2

0.5 (0.1–1.9)

Crane et al., 1997b

Australian national service Vietnam vet erans

Nasal cancer

0

0 (0.0–>10)

Nasopharyngeal cancer

1

1.3 (0.0–>10)

Studies Reviewed in VAO

CDC, 1990

U.S. men born between 1921 and 1953

Vietnam veterans

2

0.7 (0.1–3.0)

NOTE: MCPA=methyl-4-chlorophenoxyacetic acid; NS=not significant.

aGiven when available.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

LARYNGEAL CANCER

Background

According to American Cancer Society estimates, 8,100 men and 2,000 women will be diagnosed with cancer of the larynx (ICD•9 161.0–161.9) in the United States in 2000, and 3,100 men and 800 women will die from the disease (ACS, 2000a). These numbers represent approximately 1 percent of new cancer diagnoses and deaths. Cancer of the larynx is more common in men than women, with an overall ratio in the United States of about 5:1. Incidence also increases with age in the 45–59 age group.

Risk factors include tobacco and alcohol, which act individually and synergistically. Research suggests that gastroesophageal reflux, human papillomavirus, a weakened immune system, and occupational exposure to asbestos and certain chemicals and dusts may also increase incidence (ACS, 1998).

Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa

Laryngeal Cancer

 

45–49 Years of Age

50–54 Years of Age

55–59 Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

5.0

4.5

11.6

11.3

10.5

23.2

19.7

18.7

42.2

Females

1.3

1.2

3.3

2.6

2.7

3.5

4.6

4.3

9.7

aSEER nine standard registries, crude age-specific rate, 1993–1997.

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found there to be limited or suggestive evidence of an association between exposure to herbicides used in Vietnam or the contaminant dioxin and laryngeal cancers. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Table 7–7 provides summaries of the results of the studies underlying these findings and a list of reports that contain details of the research.

Update of the Scientific Literature

Occupational Studies

The NIOSH cohort mortality study of 5,132 TCDD-exposed U.S. chemical workers at 12 plants demonstrated a relative risk of 2.2 (1.1–4.1, based on 10 deaths), confirming earlier reports from this cohort (Steenland et al., 1999) and consistent with the conclusion that a general pattern of elevated risk was observed in the studies available to previous committees. Further evidence of an

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

association arises from the demonstration of an exposure-response relationship, with a higher relative risk of 2.5 (0.3–9.1, based on 2 cases) observed in the subgroup of workers with chloracne.

Environmental Studies

Laryngeal cancer was not elevated in the one study population for which exposure to TCDD was not occupational. Bertazzi and colleagues (Bertazzi et al., 1998; Pesatori et al., 1998) reported on 15 years of follow-up of residents of Seveso, Italy, who were exposed to relatively pure TCDD in the industrial incident of 1976. They did not separate laryngeal cancer from all respiratory cancers because of the small number and found only lung cancer cases in zone A, the high-exposure area, where the population was much smaller. However, in zone B—the area of medium exposure—the number of observations allowed a more detailed examination by site. In this zone, the relative risk of 1.2 for all respiratory cancers among males (0.9–1.7, 40 deaths) was exactly the same as for lung cancer alone (N=34). This suggests a proportionate increase in risk at sites in the respiratory tract other than lung, even though statistical significance was not achieved. The relative risk for females was not elevated (RR=0.5, 0.1– 2.0, 2 cases observed). The relative risk for males in zone R, the uncontaminated area, was 0.9 (0.8–1.1, 208 cases observed), and the relative risk for females was 1.1 (0.8–1.5, 35 cases observed). These relative risks and even confidence intervals are exactly the same as those for lung cancer for males in zone R and differ by one-tenth from those for females, although lung cancer cases represented about 81 percent of all respiratory cancers. Thus, it can be concluded that the increase in risk for laryngeal cancers, which would constitute all or the great majority of the rest of the respiratory cancers, was about the same. This is weak but suggestive evidence that the findings in the Seveso study do not contradict the several positive occupational studies. Incidence rates at 20 years were essentially unchanged and showed no pattern in the incidence rate over time (Bertazzi et al., 2001).

Vietnam Veteran Studies

Ranch Hand participants have not shown an excess risk of laryngeal carcinoma or an exposure-response relationship among those cases that have occurred (AFHS, 2000).

Synthesis

Studies published since Update 1998 in general continue to support the conclusion that there is limited/suggestive evidence of an association between

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

laryngeal cancer and exposure to the herbicides of concern in this report. A conclusion that there is sufficient evidence cannot be reached at this time because the most important risk factors for cancer of the larynx are not controlled in any of these studies and may confound the relationship to the extent that they could produce the slight elevation observed in most positive studies. There are also well-designed studies of considerable statistical power that do not show such an association, although weak internal evidence suggests that there may be some effect even in the negative study from Seveso. The evidence for an association continues to rest exclusively on occupational studies.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that there is limited or suggestive evidence of an association between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and laryngeal cancer.

Biologic Plausibility

No animal studies have found an increased incidence of laryngeal cancer. A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

The AFHS did not find an excess risk of laryngeal cancer among the veterans it studied. The committee’s conclusion of limited/suggestive evidence is based on data from other groups of individuals exposed to herbicides or TCDD.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

TABLE 7-7 Selected Epidemiologic Studies—Laryngeal Cancer

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 1998

Gambini et al., 1997

Italian rice growers

7

0.9 (0.4–1.9)

Kogevinas et al., 1997

IARC cohort

21

1.6 (1.0–2.5)

Workers exposed to TCDD (or higher-chlorinated dioxins)

12

1.7 (1.0–2.8)

Ramlow et al., 1996

Pentachlorophenol production workers

2

2.9 (0.3–10.3)

Studies Reviewed in Update 1996

Blair et al., 1993

U.S. farmer in 23 states

 

 

White males

162

0.7 (0.6–0.8)

Nonwhite males

32

1.1 (0.8–1.5)

Studies Reviewed in VAO

Fingerhut et al., 1991

NIOSH cohort

1-year exposure, 20-year latency

3

2.7 (0.6–7.8)

Manz et al., 1991

German production workers

2

2.0 (0.2–7.1)

Saracci et al., 1991

IARC cohort—exposed subcohort

8

1.5 (0.6–2.9)

Bond et al., 1988

Dow 2,4-D production workers

1

3.0 (0.4–16.8)

Coggon et al., 1986

British MCPA production workers

4

2.3 (0.5–4.5)

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso residents—20-year follow-up

 

 

Zone B males

55

1.3 (1.0–1.6)b

Zone B females

5

0.8 (0.3–1.9)b

Bertazzi et al., 1998

Seveso residents—15-year follow-up

 

 

Zone B males

40

1.2 (0.9–1.7)b

Zone B females

2

0.5 (0.1–2.0)b

Zone R males

208

0.9 (0.8–1.1)b

Zone R females

35

1.1 (0.8–1.5)b

Pesatori et al., 1998

Seveso residents—15-year follow-up

 

 

Zone A males

5

2.4 (1.0–5.7)b

Zone A females

2

1.3 (0.3–5.3)b

Zone B males

13

0.7 (0.4–1.3)b

Zone B females

8

0.9 (0.4–1.7)b

Zone R males

122

1.0 (0.9–1.3)b

Zone R females

71

0.8 (0.7–1.1)b

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans

4

0.6 (0.2–2.4)

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

12

1.3 (0.7–2.3)

Crane et al., 1997b

Australian national service Vietnam veterans srans

0

0 (0 to >10)

Watanabe and Kang, 1996

Army Vietnam veterans

50

1.3

Marine Vietnam veterans

4

0.7

NOTE: MCPA=methyl-4-chlorophenoxyacetic acid.

aGiven when available.

bThis report did not separate laryngeal from lung and other respiratory cancers.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

LUNG CANCER

Background

Lung cancer (carcinomas of the lung and bronchus, ICD•9 162.2–162.9) is the leading cause of cancer death in the United States. According to American Cancer Society estimates, 89,500 men and 74,600 women will be diagnosed with this cancer in the United States in 2000, and approximately 89,300 men and 67,600 women will die from the disease (ACS, 2000a). These numbers represent roughly 13 percent of new cancer diagnoses and 28 percent of cancer deaths in 2000. The principal types of lung neoplasms are identified collectively as bronchogenic carcinoma (“bronchus” is the term used to describe either of the two main branches of the trachea) or carcinoma of the lung. The lung is also a common site for the development of metastatic cancer.

Lung cancer incidence can vary greatly in the age groups that describe most Vietnam veterans. For men and women, the incidence of lung cancer increases rapidly beginning about age 40. The incidence in 50–54-year-olds is double that of 45–49-year-olds, and it doubles again for 55–59-year-olds. The rate for African-American males is consistently higher than for females or white males.

The American Cancer Society estimates that more than 90 percent of lung cancers in males are the result of tobacco smoking (ACS, 1998). Tobacco smoke may include both tumor initiators and promoters. Among the other risk factors are occupational exposure to asbestos, chromium, nickel, aromatic hydrocarbons, and radioactive ores.

Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa

Lung and Bronchus Cancer

 

45–49 Years of Age

50–54 Years of Age

55–59 Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

33.0

30.0

66.8

79.1

72.7

163.7

154.2

145.9

298.4

Females

27.3

27.1

41.0

58.6

58.6

83.3

104.1

108.8

115.8

aSEER nine standard registries, crude age-specific rate, 1993–1997.

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found there to be limited or suggestive evidence of an association between exposure to herbicides used in Vietnam or the contaminant dioxin and lung or bronchus cancer. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Table 7-8 provides summaries of the results of the studies underlying these findings and a list of reports that contain details of the research.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Update of the Scientific Literature

Occupational Studies

The largest U.S. study of workers exposed to TCDD has provided evidence of an elevated risk among those most exposed and of an exposure-response relationship. This study has been conducted by NIOSH on U.S. chemical plant workers exposed to TCDD. Steenland et al. (1999) evaluated mortality following an interval of, or lagged by, 15 years among 5,132 chemical workers in 12 U.S. plants where TCDD exposure had been documented. The relative risk for lung cancer, alone, was 1.1 (0.9–1.3, 125 deaths observed). However, the subgroup of workers that developed chloracne, who were suspected to have high exposure, showed a relative risk of 1.5 (1.0–2.1, 30 observed). The subgroup scoring in the highest two exposure septiles (the highest two-sevenths) showed a relative risk for respiratory cancers of 1.7 (1.2–2.3, 19 observed). An exposure-response relationship was demonstrable for most of the exposure range. Higher septiles showed a higher risk compared to lower septiles of exposure, but the highest septile showed less risk than the second highest. This may be a statistical anomaly, or it could be an indication that persons who were most heavily exposed and who therefore were at the highest risk died of other TCDD-related causes before getting lung cancer. The phenomenon is known as competing mortality. Whether competing mortality is acting in the exposed population remains speculation. These findings do clearly indicate a statistically significant risk for those in the highest-exposure group, suggest a general exposure-response relationship, and also suggest that other confounders, such as cigarette smoking, do not fully account for the effect.

Environmental Studies

Bertazzi and colleagues (Bertazzi et al., 1998; Pesatori et al., 1998) reported on mortality patterns among residents of Seveso, Italy, 15 years following the 1976 industrial incident that contaminated the area with relatively pure TCDD. Lung cancer rates were not conspicuously or significantly elevated, nor were all respiratory cancers, which followed the same pattern as lung cancer. Lung cancer rates at 15 years, which follow, showed no suggestion of an exposure-response relationship or predisposition by sex. Residents in zone A, the area most heavily contaminated, showed a relative risk for males of 1.0 (0.4–2.6, 4 cases observed), but no cases were observed in females. Residents of zone B, the middle-level contaminated area, showed a relative risk for males of 1.2 (0.9–1.7, 34 cases observed) and for females of 0.6 (0.1–2.3, 2 cases observed). Residents of zone R, an area of low contamination, showed a relative risk for males of 0.9 (0.8–1.1, 176 cases observed). Incidence rates at 20 years were essentially unchanged and showed no pattern in the incidence rate over time (Bertazzi et al., 2001).

These findings are in contrast to the observation that nonmalignant respiratory disorders, which are also associated with cigarette smoking, did show a

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

statistically significant elevation in this population for some subgroups. At present, only 20 years of follow-up are available for the Seveso population. This may not be enough time to evaluate the effect on an outcome whose latency is usually measured in decades. Subsequent studies of lung cancer incidence in this cohort should provide a more complete picture.

Smoking undoubtedly plays a critical role as a risk factor for these cancers as with most lung cancers, and it is likely that almost all of the lung cancers are found in smokers in these exposed populations. The incidence of lung cancers among smokers in the exposed populations, however, may be elevated compared to other populations that include a high percentage of smokers. Comparisons of smoking prevalence among these exposed populations may reveal other explanations for the excess risk.

Vietnam Veteran Studies

In the Air Force Health Study final report (AFHS, 2000), researchers reported 10 cases of lung cancer among Ranch Hands and 3 cases among comparisons (RR=3.7, 0.8–17.1; Model 1, adjusted). Ranch Hand subjects do not show an exposure-response relationship with indicators of dioxin, exposure, or history of job assignment having an opportunity for herbicide exposure, however. Some or all of the cases may be attributable to cigarette consumption patterns in this population. The unique Ranch Hand population shows a lifetime prevalence of cigarette smoking of 72 percent, with a mean consumption among smokers of 17.3 pack-years; 46 percent of smokers have a history exceeding 10 pack-years. Confounding any association with herbicide exposure, cigarette smoking covaries with 1987 dioxin levels, as do insecticide exposure and exposure to ionizing radiation.

The government of Australia’s mail surveys of approximately 50,000 male and female nationals who served in Vietnam (CDVA, 1998a, b) reported that 120 male veterans and no female veterans indicated a doctor had told them they had lung cancer since their first day of service in Vietnam. This was in excess of the number expected for males, which was 65 (49–89). However, further analysis during the validation study (AIHW, 1999) estimated that there were 46 validated cases of lung cancer, indicating a significantly lower prevalence of lung cancer in veterans than in an Australian community standard.

Synthesis

Recent studies, extending previous observations on the NIOSH cohort, do not support a change in the conclusion that there is limited/suggestive evidence for an association between herbicides of concern in this report and risk of lung cancer. Evidence for an exposure-response relationship has been slightly strengthened since Update 1998 but still does not support a conclusion of sufficient evidence.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Although the Seveso study does not show an excess, it remains early in the follow-up of this cohort for the characterization of cancers with latencies of decades.

Conclusions

Strength of Evidence in Epidemiologic Studies

A growing body of research supports the conclusion that there is limited/ suggestive evidence of an association between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and cancer of the lung, bronchus, and trachea. Although the absence of data on smoking limits the usefulness of available studies, evidence from studies of individuals occupationally exposed to TCDD and phenoxy herbicides increasingly suggests that smoking alone is not the only factor and that these workplace chemicals are associated with an increased risk of neoplasms at these sites.

In response to a request from the Department of Veterans Affairs, the committee responsible for Update 1998 addressed cancer latency issues related to Agent Orange. A review of the literature provided some information on how long the effects of herbicide or TCDD exposures might last. The evidence reviewed by that committee suggested that if respiratory cancer does result from exposures to the herbicides used in Vietnam, the greatest relative risk might be in the first decade after exposure, but until further follow-up had been carried out for some of the cohorts it was not possible to put an upper limit on the length of time these herbicides could exert their effect. There is nothing in the most recent literature that changes this conclusion.

Biologic Plausibility

In a two-year study, an increased incidence of squamous cell carcinomas occurred in the lung of rats administered 0.1 µg of TCDD/kg/day (Kociba et al., 1978). That increase, however, has not been seen in other studies, including studies by the National Toxicology Program. The finding by Kociba et al. (1978), nevertheless, does suggest an association between exposure to TCDD and cancer of the lung in Sprague Dawley rats. A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

Although Ranch Hand participants show a markedly elevated risk of lung cancer, the extent to which this excess risk may be attributable to herbicide or TCDD exposure is not clear.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

TABLE 7-8 Selected Epidemiologic Studies—Lung/Bronchus Cancer

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

New Studies

Steenland et al., 1999

U.S. chemical workers who developed chloracne

30

1.5 (1.0–2.1)

Two highest cumulative exposure septiles

19

1.7 (1.2–2.3)

Studies Reviewed in Update 1998

Gambini et al., 1997

Italian rice growers

45

0.8 (0.6–1.1)

Kogevinas et al., 1997

Phenoxy herbicides: 36 cohorts

 

 

Exposed to TCDD or higher PCDD

225

1.1 (1.0–1.3)

Exposed to no or lower PCDD

148

1.0 (0.9–1.2)

Becher et al., 1996

German chemical production workers

47

1.4 (1.1–1.9)

Ott and Zober, 1996

BASF cleanup workers

6

3.1 (1.1–6.7)

Ramlow et al., 1996

Pentachlorophenol production workers

18

1.0 (0.6–1.5)

Studies Reviewed in Update 1996

Asp et al., 1994

Finnish herbicide appliers

37

1.0 (0.7–1.4)

Blair et al., 1993

U.S. farmers from 23 states

 

 

White males

6,473

0.9 (0.9–0.9)

Nonwhite males

664

1.0 (0.9–1.1)

Bloemen et al., 1993

Dow 2,4-D production workers

9

0.8 (0.4–1.5)

Kogevinas et al., 1993

Female herbicide spraying and production workers

2

1.4 (0.2–4.9)

Lynge, 1993

Danish male production workers

13

1.6 (0.9–2.8)

Studies Reviewed in VAO

Bueno de Mesquita et al., 1993

Phenoxy herbicide workers

9

1.7 (0.5–6.3)

Swaen et al., 1992

Herbicide appliers

12

1.1 (0.6–1.9)

Coggon et al., 1991

Phenoxy herbicide production workers

19

1.3 (0.8–2.1)

 

 

14

1.2 (0.7–2.1)

Fingerhut et al., 1991

TCDD-exposed workers

89

1.1 (0.9–1.4)

≥1-year exposure; ≥20 years’ latency

40

1.4 (1.0–1.9)

Green, 1991

Herbicide sprayers in Ontario

5

1.1 (0.4–2.5)

Manz et al., 1991

Phenoxy herbicide production workers

26

1.7 (1.1–2.4)

Saracci et al., 1991

Herbicide spraying and production

 

 

workers

173

1.0 (0.9–1.2)

Probably exposed subgroup

11

2.2 (1.1–4.0)

McDuffie et al., 1990

Saskatchewan farmers applying herbicides

103

0.6

Zober et al., 1990

BASF production workers

6

1.6

High exposure

4

2.0 (0.6–5.2)

Chloracne

6

1.8 (0.7–4.0)

Wiklund et al., 1989a

Pesticide appliers in Sweden

38

0.5 (0.4–0.7)

Bond et al., 1988

Dow 2,4-D production workers (15-year latency)

9

1.2 (0.6–2.3)

Low cumulative exposure

1

0.7

Medium cumulative exposure

2

1.0

High cumulative exposure

5

1.7

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Coggon et al., 1986

MCPA production workers

101

1.2 (1.0–1.4)

Background exposure

39

1.0 (0.7–1.4)

Low-grade exposure

35

1.1 (0.8–1.6)

High-grade exposure

43

1.3 (1.0–1.8)

Lynge, 1985

Danish production workers

 

 

Males

38

1.2

Females

6

2.2

Manufacture and packing only—males

11

2.1 (1.0–3.7)

Blair et al., 1983

Licensed pesticide appliers in Florida, lawn and ornamental herbicides only

7

0.9 (0.4–1.9)

Axelson et al., 1980

Herbicide sprayers in Sweden

3

1.4 (0.3–4.0)

Bender et al., 1989

Herbicide sprayers in Minnesota

54

0.7 (0.5–0.9)

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso residents—20-year follow-up

Zone A males

9

1.5 (0.8–3.0)

Zone B males

48

1.3 (0.9–1.7)

Zone B females

4

0.7 (0.3–2.0)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

Zone A males

4

1.0 (0.4–2.6)

Zone B males

34

1.2 (0.9–1.7)

Zone B females

2

0.6 (0.1–2.3)

Zone R males

176

0.9 (0.8–1.1)

Zone R females

29

1.0 (0.7–1.6)

Pesatori et al., 1998

Seveso (respiratory) —15-year follow-up

Zone A males

5

2.4 (1.0–5.7)

Zone A females

2

1.3 (0.3–5.3)

Zone B males

13

0.7 (0.4–1.3)

Zone B females

8

0.9 (0.4–1.7)

Zone R males

122

2.0 (0.9–1.3)

Zone R females

71

0.8 (0.7–1.1)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

Zone A males

4

1.0 (0.3–2.5)

Zone B males

34

1.2 (0.9–1.7)

Zone B females

2

0.6 (0.1–2.1)

Zone R males

176

0.9 (0.8–1.0)

Zone R females

29

1.0 (0.7–1.5)

Svensson et al., 1995

Swedish fishermen, mortality

East coast

16

0.8 (0.5–1.3)

West coast

77

0.9 (0.7–1.1)

Studies Reviewed in VAO

Bertazzi et al., 1993

Seveso residents—10-year follow-up, morbidity

 

 

Zone A males

2

0.8 (0.2–3.4)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

 

Zone B males

18

1.1 (0.7–1.8)

Zone R males

96

0.8 (0.7–1.0)

Zone R females

16

1.5 (0.8–2.5)

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans

10

3.7 (0.8–17.1)

AIHW, 1999

Australian Vietnam veterans—male

46

65 expected (49–81)

CDVA, 1998a

Australian Vietnam veterans—male

I20b

65 expected (49–81)

CDVA, 1998b

Australian Vietnam veterans—female

0b

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

212

1.3 (1.1–1.5)

Crane et al., 1997b

Australian national service Vietnam veterans

27

2.2 (1.1–4.3)

Dalager and Kang, 1997

Army Chemical Corps veterans

11

1.4 (0.4–5.4)

Mahan et al., 1997

Case-control

111

1.4 (1.0–1.9)

Watanabe and Kang, 1996

Vietnam service Army

1,139

1.1

Non-Vietnam

1,141

1.1

Vietnam service Marines

215

1.2

Non-Vietnam

77

0.9

Watanabe and Kang, 1995

Vietnam service Marines vs. non-Vietnam

42

1.3 (0.8–2.1)

NOTE: MCPA=methyl-4-chlorophenoxyacetic acid; PCDD=polychlorinated dioxins.

aGiven when available.

bSelf-reported medical history. Answer to question: Since your first day of service in Vietnam, have you been told by a doctor that you have lung cancer?

BONE CANCER

Background

According to the American Cancer Society, approximately 1,500 men and 1,000 women will be diagnosed with bone or joint cancer (ICD•9 170.0–170.9) in the United States in 2000, and 800 men and 600 women will die as a result of this cancer (ACS, 2000a). Primary bone cancers are among the least common malignancies. The bones are, however, frequent sites for secondary tumors of other cancers that have metastasized (i.e., have spread from another site). Only the primary cancers are considered here.

Bone cancer is more common in teenagers than adults. The incidence among individuals in the age groups that characterize most Vietnam veterans is quite low, and care should be exercised when interpreting the numbers presented below.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Among the risk factors for adults contracting bone and joint cancer are exposure to ionizing radiation from treatment for other cancers and a history of certain noncancerous bone diseases.

Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa

Bone and Joint Cancer

 

45–49 Years of Age

50–54 Years of Age

55–59 Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

0.7

0.7

0.5

0.7

0.8

0.8

1.3

1.4

1.5

Females

0.8

0.9

0.5

0.8

0.7

1.0

0.7

0.8

b

aSEER nine standard registries, crude age-specific rate, 1993–1997.

bInsufficient data to provide meaningful incidence rate.

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found there to be inadequate or insufficient information to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and bone cancer. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Table 7-9 provides summaries of the results of the studies underlying these findings and a list of reports that contain details of the research.

Update of the Scientific Literature

Occupational Studies

The update of the industrial cohort exposed to dioxins known as the NIOSH cohort (Steenland, 1999) did not report results for bone cancer.

In a study of a cohort of Danish paper mill workers, Rix et al. (1998) examined mortality from a wide range of causes. The likelihood of substantial dioxin exposure among these workers is unclear, since the three mills in the study never produced paper pulp themselves. Rather, they manufactured paper from imported bleached and unbleached pulp. There are no direct measures of exposure for these workers, and a qualitative assessment of chemicals used in paper manufacture by department does not include chlorinated organic compounds, although chlorine, chlorine dioxide, and hypochlorite were used. For two of the mills, the period of follow-up was January 1, 1943, to December 31, 1993, while for the third mill, follow-up started at January 1, 1965. Incident cancer cases were identified from the Danish Cancer Register, and expected numbers of cases were calculated using the rates for the total Danish population by gender, 5-year age group, and calendar time. For cancer sites of specific interest, Poisson regression models were used to analyze by duration and years since first employment and by depart-

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

ment of employment. For bone cancer, only one case was found, yielding an SIR of 0.5 (0.0–2.7) for men, and no cases were seen among women in the cohort.

Environmental Studies

In a review of early, mid-term, and long-term health effects, Bertazzi et al. (1998) continued the follow-up of people environmentally exposed to TCDD in the Seveso accident. The events that led to the exposure and the methods used to study this population have been fully described previously. In the case of bone cancer mortality, the report does not appear to add any new information to Bertazzi et al. (1997), which was reviewed in Update 1998. After 15 years’ follow-up (1976–1991), there were no deaths from bone cancer among residents of zone A and only one case in zone B, which occurred in a woman (RR=2.6, 0.3–19.4). Men in zone R (considered to be the low-exposure region) had an RR of 0.5 (0.1–2.0, 2 cases), while women in zone R had a significant elevation (RR=2.4, 1.0–5.7, 7 cases).

In another report, Bertazzi et al. (2001) extended the mortality analysis through the end of 1996; however mortality from bone cancer is not mentioned.

Vietnam Veteran Studies

In the Air Force Health Study final report (AFHS, 2000), bone cancer was not reported as one of the health outcomes of interest.

Synthesis

The committee found little new information to add to the sparse existing data set. There is no evidence to indicate a change from the conclusion that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides 2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram and bone cancer.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that 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) and bone cancer. The evidence regarding an association is drawn from occupational and environmental studies in which the subjects were exposed to a variety of herbicides and herbicide compounds.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×
Biologic Plausibility

No animal studies have found an increased incidence of bone cancer. A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

There are no data on which to base a conclusion concerning whether Vietnam veterans may or may not be at increased risk for bone cancer due to exposure to herbicides or TCDD.

TABLE 7-9 Selected Epidemiologic Studies—Bone Cancer

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

New Studies

Rix et al., 1998

Danish paper mill workers

Males

1

0.5 (0.0–2.7)

Females

0

 

Studies Reviewed in Update 1998

Gambini et al., 1997

Italian rice growers

1

46 (0.6–255.2)

Hertzman et al., 1997

British Columbia sawmill workers

Mortality

5

1.3 (0.5–2.7)

Incidence

4

1.1 (0.4–2.4)

Kogevinas et al., 1997

IARC cohort

5

1.2 (0.4–2.8)

Workers exposed to TCDD (or higher-chlorinated dioxins)

 

1.1

Workers not exposed to TCDD (or higher-chlorinated dioxins)

 

1.4

Ramlow et al., 1996

Pentachlorophenol production workers

0

 

Studies Reviewed in Update 1996

Blair et al., 1993

U.S. farmers in 23 states

49

1.3 (1.0–1.8)

Collins et al., 1993

Monsanto 2,4-D production workers

2

5.0 (0.6–18.1)

Studies Reviewed in VAO

Ronco et al., 1992

Danish male self-employed farm workers

9

0.9

Fingerhut et al., 1991

NIOSH cohort

2

2.3 (0.3–8.2)

Zober et al., 1990

BASF production workers

0

— (0.0–70.0)

Bond et al., 1988

Dow 2,4-D production workers

0

— (0.0–31.1)

Coggon et al., 1986

British MCPA production workers

1

0.9 (0.0–5.0)

Wiklund, 1983

Swedish agricultural workers

44

1.0 (0.6–1.4)b

Burmeister, 1981

Farmers in Iowa

56

1.1 (NS)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

ENVIRONMENTAL

New Studies

Bertazzi et al., 1998

Seveso residents—15-year follow-up

Zone B females

1

2.6 (0.3–19.4)

Zone R males

2

0.5 (0.1–2.0)

Zone R females

7

2.4 (1.0–5.7)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

Zone B females

1

2.6 (0.0–14.4)

Zone R males

2

0.5 (0.1–1.7)

Zone R females

7

2.4 (1.0–4.9)

VIETNAM VETERANS

Studies Reviewed in Update 1998

Clapp, 1997

Massachusetts Vietnam veterans

4

0.9 (0.1–11.3)

AFHS, 1996

Air Force Ranch Hand veterans

0

 

Studies Reviewed in VAO

Breslin et al., 1988

Army Vietnam veterans

27

0.8 (0.4–1.7)

Marine Vietnam veterans

11

1.4 (0.1–21.5)

Anderson et al., 1986a

Wisconsin Vietnam veterans

1

Anderson et al., 1986b

Wisconsin Vietnam veterans

1

Lawrence et al., 1985

New York Vietnam veterans

8

1.0 (0.3–3.0)

NOTE: MCPA=methyl-4-chlorophenoxyacetic acid; NS=not significant.

aGiven when available.

b99% CI.

SOFT-TISSUE SARCOMAS

Background

Soft-tissue sarcoma (STS) (ICD•9 171.0–171.9, 164.1) arises in the soft somatic tissues that occur within and between organs. Three of the most common types of STS—liposarcoma, fibrosarcoma, and rhabdomyosarcoma—occur in similar numbers in men and women. Because of the diverse characteristics of STS, accurate diagnosis and classification can be difficult. The American Cancer Society estimates that 4,300 men and 3,800 women will be diagnosed with STS, and 2,200 men and 2,400 women will die from these cancers in the United States in 2000 (ACS, 2000a).

There is no consistent pattern to the incidence of STS over the age groups that describe most Vietnam veterans.

Among the risk factors for these cancers are exposure to ionizing radiation from treatment for other cancers and certain inherited conditions including Gard-

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

ner’s syndrome, Li-Fraumeni syndrome, and neurofibromatosis. Several chemical exposures have also been identified as possible risk factors (Zahm and Fraumeni, 1997).

Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa

Soft-Tissue Sarcomas (including malignant neoplasms of the heart)

 

45–49 Years of Age

50–54 Years of Age

55–59 Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

3.2

3.0

4.1

4.1

4.1

5.2

4.4

4.3

5.5

Females

2.2

2.2

3.1

3.3

3.0

5.7

3.4

3.3

3.6

aSEER nine standard registries, crude age-specific rate, 1993–1997.

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found there to be sufficient information to determine that an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and soft-tissue sarcoma. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Table 7-10 provides summaries of the results of the studies underlying these findings and a list of reports that contain details of the research.

Update of the Scientific Literature

Occupational Studies

The largest industrial cohort exposed to dioxins is the group of 5,132 U.S. workers known as the NIOSH cohort. This group was assembled from employees of 12 major chemical manufacturers that produced 2,4,5-trichlorophenol, 2,4,5-T, Silvex, Erbon, Ronnel, and hexachlorophene. Workers engaged in production and maintenance were exposed to TCDD as a contaminant of these chemicals. The first study of mortality through 1987 among these workers (Fingerhut, 1991) found excess cancer mortality for all cancers combined (SMR=1.2, 1.0–1.3), and elevated risk was observed for STS (SMR=9.2, 1.9–27.0). This cohort has been updated through 1993, and an exposure-response analysis on a subcohort (approximately 69 percent of the population) has been conducted (Steenland et al., 1999). In that report, results for STS are not presented, and the only mention is a note in the discussion that no new soft-tissue sarcomas were observed.

In a study of a cohort of Danish paper mill workers, Rix et al. (1998) examined mortality from a wide range of causes. The likelihood of substantial dioxin exposure among these workers is unclear, since the three mills in the study never produced paper pulp themselves. Rather, they manufactured paper from imported bleached and unbleached pulp. There are no direct measures of exposure for these

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

workers, and a qualitative assessment of chemicals used in paper manufacture by department does not include chlorinated organic compounds, although chlorine, chlorine dioxide, and hypochlorite were used. For two of the mills, the period of follow-up was January 1, 1943, to December 31, 1993, while for the third mill, follow-up started at January 1, 1965. Incident cancer cases were identified from the Danish Cancer Register, and expected numbers of cases were calculated using the rates for the total Danish population by gender, 5-year age group, and calendar time. For cancer sites of specific interest, Poisson regression models were used to analyze by duration and years since first employment and by department of employment. For STS, a significant excess was observed in women in plants 1 and 2 (the two older plants) with an SIR of 2.3 (1.1–4.4, 9 cases). When the third mill (which started in 1965) was included, the SIR for women was 2.6 (1.3–4.7, 11 cases). For women employed in sorting and packing, the SIR was 4.0 (1.7–7.8, 8 cases), with no trend reported by length of employment or latency. For men, the SIR was 1.2 (0.6–2.0, 12 cases). The authors speculated that the only chemical noted to be present in the sorting and packing jobs the women held was organic glue and that exposure to chlorinated organic compounds was expected to be low among this group.

Hooiveld et al. (1998) reported on an update of a mortality study of workers at two chemical factories in the Netherlands. This group is included in the multinational I ARC study of cancer and exposure to organochlorine compounds. This update of the Dutch cohort added 6.5 years of follow-up to a previous study of these workers (Bueno de Mesquita et al., 1993) and included analysis by estimated maximum TCDD serum level. This value was estimated for each member of the cohort by measuring serum TCDD levels for 144 subjects, including production workers known to be exposed to dioxins, workers in herbicide production, nonexposed production workers, and workers known to be exposed as a result of an accident that occurred in 1963. By assuming first-order TCDD elimination with an estimated half-life of 7.1 years, TCDDmax was extrapolated for a group of 47 workers, and a regression model was constructed to estimate the effect of exposure as a result of the accident, duration of employment in the main production department, and time of first exposure before (or after) 1970 on the estimated TCDDmax for each cohort member. No STS deaths were observed among the workers exposed to phenoxy herbicides or chlorophenols in this study population.

Environmental Studies

In a review of early, mid-term, and long-term health effects, Bertazzi et al. (1998) continued the follow-up of people environmentally exposed to TCDD in the Seveso accident. The events that led to the exposure and the methods used to study this population have been fully described previously. Their 1998 report reviews the full range of indicators of exposure and effects on animal and human

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

health. For STS, the report does not appear to add any new information to Bertazzi et al. (1997), which was reviewed in Update 1998. After 15 years’ follow-up (1976–1991), death from STS was not reported for residents of zone A, and there were no cases among residents of zone B. In zone R, there were no cases among women (1.5 expected), and the RR for men was 2.1 (0.6–5.4, 4 cases).

In another report, Bertazzi et al. (2001) extended the mortality analysis through the end of 1996; however no cases of STS were observed.

Viel et al. (2000) reported on an investigation of apparent clusters of STS and non-Hodgkin’s lymphoma (NHL) cases in the vicinity of a municipal solid waste incinerator in Doubs, France. Series of incident NHL and STS cases from 1980 to 1995 were obtained from a cancer registry that included Doubs. Incident cases of Hodgkin’s disease (HD) were also obtained for the same period. The reason for including Hodgkin’s disease was to provide a check on possible selection bias by including a disease that the investigators considered to not be consistently associated with dioxin exposure. (In VAO and its updates, the committees have concluded that there is evidence of a positive association between dioxin exposure and HD.) The presumptive source of dioxin in this region is a municipal solid waste incinerator in the Besançon electoral ward in the west of Doubs. A measurement of dioxin emissions from the incinerator showed a level of 16.3 ng international toxic equivalency factor (I-TEQ)/m3, far in excess of the European Union (EU) standard of 0.1 ng I-TEQ/m3. In addition, measurements of dioxin in cow’s milk from three farms near the incinerators suggested that the dioxin content of the milk was highest at the farm closest to the incinerator. These measurements were all well below the guideline of 6 ng I-TEQ/kg of fat, however. The authors do not provide any direct evidence of human exposure.

Analysis was conducted by looking for spatial clusters around the incinerator and a focused space-time scan test. Expected numbers of cases were calculated for each canton using the incidence rates for the entire department, stratified by gender and 5-year age interval. For STS, a statistically significant spatial cluster (SIR=1.4, p=.004, 45 cases observed) was found in Besançon (where the incinerator is located) and Audeux (which borders it to the west). A similar result was obtained when the only spatial criterion was the canton, not proximity to the incinerator. In the focused space-time test, a significant excess was found for 1994–1995 in Besançon and Audeux (SIR=3.4, p=.008, 12 cases). Excess cases of NHL were also observed in these same two cantons; however, there were no spatial or space-time clusters observed for HD. Despite the strengths of the study, limitations include an unclear route of dioxin exposure and the fact that coexposures to chemicals other than dioxin from the incinerator could be responsible for the observed clusters.

Vietnam Veteran Studies

In the Air Force Health Study (AFHS, 2000), the small number of cases of

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

malignant neoplasm of the connective or other soft tissues limited the analysis. One case was identified among the 861 Ranch Hand veterans, and two cases among the comparison population of 1,249. All results from the analyses performed were nonsignificant.

The government of Australia’s mail surveys of approximately 50,000 male nationals who served in Vietnam (CDVA, 1998a) reported that 398 male veterans indicated a doctor had told them they had soft-tissue sarcoma since their first day of service in Vietnam. This was much higher than the number expected for this population, 27 (17–37). The authors report that it is likely that errors occurred in reporting this condition because STS is a rare condition that may be confused with similar sounding conditions such as Ewing’s sarcoma, lymphosarcoma, myoma, and lipoma. A follow-up to this study, conducted to medically confirm selected conditions reported in the survey (AIHW, 1999), determined there were 14 cases that could be validated, suggesting a significantly lower prevalence of soft-tissue sarcoma in veterans than in the Australian community. For female veterans, 3 cases were reported, which was within the range of 0–4 expected (CDVA, 1998b).

Synthesis

As noted in previous updates, the evidence of an association between STS and dioxin exposure is found in a small number of studies. The studies reviewed for this report continue a pattern of mixed findings. The update of the NIOSH cohort did not provide any new information on STS, since no new cases were observed. A study of Danish paper mill workers found some excess of STS among three different plants. Although the finding was quite stable among women, the link with dioxin exposure was not well established. An update of a cohort of Dutch chemical workers found no STS deaths among workers exposed to phenoxy herbicides or chlorophenols. Updates of the Seveso population did not add any new information on STS. In another study, apparent clusters of STS and NHL cases in the vicinity of a municipal solid waste incinerator found a statistically significant spatial cluster; however, concerns over poor exposure characterization lessen confidence in these findings. The study of Vietnam veterans provided no new information on STS.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that there is sufficient evidence to conclude that an association exists between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and soft-tissue sarcoma.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×
Biologic Plausibility

No animal studies have found an increased incidence of soft-tissue sarcoma. A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

The available data on Vietnam veterans do not permit a conclusion on whether they are at an elevated risk for soft-tissue sarcomas.

TABLE 7-10 Selected Epidemiologic Studies—Soft-Tissue Sarcoma

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

New Studies

Steenland et al., 1999

U.S. chemical production workers

0

Hooiveld et al., 1998

Dutch chemical production workers

0

Rix et al., 1998

Danish paper mill workers

Women in plants 1 and 2

9

2.3 (1.1–4.4)

Women in plants 1, 2, and 3

11

2.6 (1.3–4.7)

Women employed in sorting and packing

8

4.0 (1.7–7.8)

Men employed in sorting and packing

12

1.2 (0.6–2.0)

Studies Reviewed in Update 1998

Hertzman et al., 1997

Canadian sawmill workers

11

1.0 (0.6–1.7)

Kogevinas et al., 1997

IARC cohort

Workers exposed to TCDD (or higher-chlorinated dioxins)

6

2.0 (0.8–4.4)

Workers not exposed to TCDD (or higher-chlorinated dioxins)

2

1.4

Workers exposed to any phenoxy herbicide or chlorophenol

9

2.0 (0.9–3.8)

Ott and Zober, 1996

Workers exposed in 1953 accident

0

0.2 expected

Ramlow et al., 1996

Pentachlorophenol production workers

0

0.2 expected

Studies Reviewed in Update 1996

Kogevinas et al., 1995

IARC cohort

11

Mack, 1995

U.S. cancer registry data

(SEER program) review

Male

3,526

Female

2,886

Blair et al., 1993

U.S. farmers from 23 states (white males)

98

0.9 (0.8–1.1)

Lynge, 1993

Danish male production workers

5

2.0 (0.7–4.8)

Kogevinas et al., 1992

IARC cohort (10–19 years after first exposure)

4

6.1 (1.7–15.5)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Studies Reviewed in VAO

Bueno de Mesquita et al., 1993

Phenoxy herbicide workers

0

Hansen et al., 1992

Danish gardeners

3

5.3 (1.1–15.4)

Smith and Christophers, 1992

Male residents of Australia

30

1.0 (0.3–3.1)

Fingerhut et al., 1991

NIOSH cohort

4

3.4 (0.9–8.7)

Those with 20 years’ latency and 1 year of exposure

3

9.2 (1.9–27.0)

Manz et al., 1991

German production workers

0

Saracci et al., 1991

IARC cohort

4

2.0 (0.6–5.2)

Zober et al., 1990

German production workers

0

Alavanja et al., 1989

Forest or soil conservationists

2

1.0 (0.1–3.6)

Bond et al., 1988

Dow 2,4-D production workers

0

Wiklund et al., 1988, 1989b

Swedish agricultural workers

7

0.9 (0.4–1.9)

Woods et al., 1987

Male residents of Washington State

High phenoxy exposure

 

0.9 (0.4–1.9)

Those with self-reported chloracne

 

3.3 (0.8–14.0)

Coggon et al., 1986

British MCPA chemical workers

1

Hoar et al., 1986

Kansas residents

 

0.9 (0.5–1.6)

Vineis et al., 1986

Italian rice growers

66

 

 

Among all living women

5

2.4 (0.4–16.1)

Smith et al., 1983, 1984; Smith and Pearce, 1986

New Zealand workers exposed to herbicides

 

1.6 (0.7–3.8)

Lynge, 1985

Danish male production workers

5

2.7 (0.9–6.3)

Balarajan and Acheson, 1984

Agricultural workers in England

42

 

Overall

 

1.7 (1.0–2.9)

Those under age 75

 

1.4 (0.8–2.6)

Blair et al., 1983

Florida pesticide appliers

0

Hardell, 1981

Swedish workers

52

 

 

Phenoxy herbicide exposure

 

5.5 (2.2–13.8)

Eriksson et al., 1979, 1981

Swedish workers

 

5.1 matched (2.2–10.2)

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso—20-year follow-up

0

Viel et al., 2000

Residents located near a French solid waste incinerator

 

 

Spatial cluster

45

1.4 (p=.004)

1994–1995

12

3.4 (p=.008)

Bertazzi et al., 1998

Seveso—15-year follow-up

0

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

Zone R males

4

2.1 (0.6–5.4)

Gambini et al., 1997

Rice-growing farmers

1

0.3 expected

Svensson et al., 1995

Swedish fishermen, incidence West coast

3

0.5 (0.1–1.4)

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up, morbidity

Zone R males

6

2.8 (1.0–7.3)

Zone R females

2

1.6 (0.3–7.4)

Studies Reviewed in VAO

Lampi et al., 1992

Finnish town

6

1.6 (0.7–3.5)

Bertazzi et al., 1989a

Seveso residents—10-year follow-up

Zone A, B, R males

2

5.4 (0.8–38.6)

Zone A, B, R females

1

2.0 (0.2–1.9)

Bertazzi et al., 1989b

Seveso residents—10-year follow-up

Zone R males

2

6.3 (0.9–45.0)

Zone B females

1

17.0 (1.8–163.6)

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans

1

0.8 (0.1–12.8)

AIHW, 1999

Australian Vietnam veterans—male

14

27 expected (17–37)

CDVA, 1998a

Australian Vietnam veterans—male

398b

27 expected (17–37)

CDVA, 1998b

Australian Vietnam veterans—female

2b

0 expected (0–4)

Studies Reviewed in Update 1998

Clapp, 1997

Massachusetts Vietnam Veterans

18

1.6 (0.5–5.4)

Crane et al., 1997a

Australian military Vietnam veterans

0–9

<1

Crane et al., 1997b

Australian national service Vietnam veterans

4

0.7

Comparison group

2

AFHS, 1996

Ranch Hand veterans

1

Comparisons

1

Visintainer et al., 1995

Vietnam veterans

8

1.1 (0.5–2.2)

Watanabe and Kang, 1995

U.S. Marines in Vietnam

0

Studies Reviewed in Update 1996

Kogan and Clapp, 1988

Vietnam veterans in Massachusetts

9

5.2 (2.4–11.1)

Kang et al., 1986

Vietnam veterans

Comparing those who served with those who did not

 

0.8 (0.6–1.1)

Lawrence et al., 1985

Vietnam veterans in New York

2

1.1 (0.2–6.7)

Greenwald et al., 1984

New York State Vietnam veterans

 

0.5 (0.2–1.3)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Studies Reviewed in VAO

Watanabe et al., 1991

Marine Vietnam veterans

8

1.1

Bullman et al., 1990

Army veterans serving in I Corps

10

0.9 (0.4–1.6)

Michalek et al., 1990

Ranch Hand veterans

1

Comparisons

1

Breslin et al., 1988

Army Vietnam veterans

30

1.0

Fett et al., 1987

Australian Vietnam veterans

1

1.3 mortality rate, age-adjusted (0.1–20.0)

Anderson et al., 1986a, b

Wisconsin Vietnam veterans

5

1.5 (0.6–3.5)

Breslin et al., 1986

Vietnam veterans in Massachusetts

2

3.8 (0.5–13.8)

NOTE: MCPA=methyl-4-chlorophenoxyacetic acid.

aGiven when available.

bSelf-reported medical history. Answer to question: Since your first day of service in Vietnam, have you been told by a doctor that you have soft-tissue sarcoma?

SKIN CANCERS—ALL TYPES

Background

Skin cancers are generally divided into two broad categories: neoplasms that develop from melanocytes (malignant melanoma) and those that do not. The common nonmelanocytic skin cancers, which include basal and squamous cell carcinomas, have a far higher incidence than malignant melanoma but are considered less aggressive and therefore more treatable. In VAO and Update 1996, all skin cancers were assessed together. However, beginning with Update 1998, the committee chose to address studies assessing malignant melanoma separately from those assessing nonmelanocytic cancers (basal and squamous cell carcinoma). Because nonmelanocytic cancers are highly treatable, studies of these cancers have been divided further into those that discuss mortality and those that discuss incidence. Many studies report results by combining all types of skin cancers or do not specify the type of skin cancers assessed. These are also listed in Tables 7-11 and 7-12 in the interest of completeness.

According to American Cancer Society estimates, 27,300 men and 20,400 women will be diagnosed with cutaneous melanoma (ICD•9 172.0–172.9) in the United States in 2000, and 4,800 men and 2,900 women will die of this cancer (ACS, 2000a). Approximately 1,300,000 cases of nonmelanocytic skin cancers (ICD•9 173.0–173.9), primarily basal cell and squamous cell carcinomas, are

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

diagnosed in the United States each year (ACS, 2000a). Since it is not required to report these cancers to registries, the data regarding the numbers of cases are not as precise as for other cancers. The American Cancer Society estimates that approximately 1,900 individuals will die from these diseases in 2000.

Skin cancers are far more likely to occur in fair-skinned individuals; the risk for whites is roughly 20 times that for dark-skinned African Americans. Incidence also increases with age, although more strikingly for males than females. Other risk factors for melanoma include the presence of certain moles on the skin, a suppressed immune system, and excessive exposure to ultraviolet (UV) radiation, typically from the sun. A family history of the disease has been identified as a risk factor, but it is unclear whether this is due to genetic factors or to similarities in skin type and sun exposure patterns.

Excessive exposure to UV radiation is the single most important risk factor for nonmelanocytic skin cancers. Certain skin diseases and chemical exposures have also been identified as potential risk factors. SEER incidence data are not available for nonmelanocytic skin cancers.

Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa

Melanomas of the Skin

 

45–49 Years of Age

50–54 Years of Age

55–59 Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

24.6

28.0

0.8

32.8

37.0

2.2

38.6

43.4

3.0

Females

20.1

23.2

1.6

20.3

23.3

0.6

23.5

27.0

2.0

aSEER nine standard registries, crude age-specific rate, 1993–1997.

Many studies report results by combining all types of cancers or do not specify the type of skin cancer assessed. Studies such as these are listed in Tables 7-11 and 7-12 according to the VAO report in which they appeared.

TABLE 7-11 Selected Epidemiologic Studies—All (or unspecified) Skin Cancer Mortality

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in VAO

Fingerhut et al., 1991

NIOSH cohort

4

0.8 (0.2–2.1)

Saracci et al., 1991

IARC cohort

3

0.3 (0.1–0.9)

Alavanja et al., 1988

USDA agricultural extension agents

5

1.1 (0.5–2.6)

Burmeister, 1981

Farmers in Iowa

105

1.1 (NS)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

VIETNAM VETERANS

Studies Reviewed in Update 1998

Dalager and Kang, 1997

Army Chemical Corps veterans

4

1.5 (0.3–8.6)

Watanabe and Kang, 1996

Army Vietnam veterans

234

1.0

Marine Vietnam veterans

73

1.3 (1.0–1.6)

Studies Reviewed in VAO

Anderson et al., 1986a

Wisconsin Vietnam veterans

6

0.9 (0.4–2.0)

Anderson et al., 1986b

Wisconsin Vietnam veterans

5

1.3 (0.4–3.1)

NOTE: NS=not significant; USDA=United States Department of Agriculture.

aGiven when available.

TABLE 7-12 Selected Epidemiologic Studies—All (or unspecified) Skin Cancer Morbidity

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 1998

Ott and Zober, 1996

German BASF trichlorophenol production workers

5

1.2 (0.4–2.8)

Studies Reviewed in VAO

Hansen et al., 1992

Danish gardeners

32

1.1 (0.8–1.6)

Lynge, 1985

Danish male production workers

14

0.7

Suskind and Hertzberg, 1984

Monsanto production workers

8

1.6

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans

325

1.3 (1.1–1.6)

Ketchum et al., 1999

Ranch Hand (RH) veterans and comparisons through June 1997

 

 

Comparisons

158

(control group)

Background-exposure RH veterans

57

1.0 (0.7–1.5)

Low-exposure RH veterans

44

1.3 (0.8–2.0)

High-exposure RH veterans

22

0.8 (0.5–1.4)

Studies Reviewed in VAO

Wolfe et al., 1990

Air Force Ranch Hand veterans

88

1.5 (1.1–2.0)

CDC, 1988

Army enlisted Vietnam veterans

15

0.8 (0.4–1.7)

aGiven when available.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

SKIN CANCER—MELANOMA

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and skin cancer. Additional information available to the committee responsible for Update 1996 did not change this finding. The Update 1998 committee considered separately the literatures regarding malignant melanoma and nonmelanocytic skin cancers. It found that there was inadequate or insufficient information to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and melanoma. Tables 7-13 and 7-14 provide summaries of the results of the studies underlying these findings and a list of reports that contain details of the research.

Update of the Scientific Literature

Occupational Studies

Hooiveld et al. (1998) conducted a retrospective cohort study of Dutch production and contract workers exposed to phenoxy herbicides, chlorophenols, and contaminants between 1950 and 1976. Of the 1,129 workers identified in the original cohort, 549 exposed and 482 unexposed male workers were included in this study. One death was attributed to malignant melanoma, leading to an SMR of 2.9 (0.1–15.9).

Environmental Studies

Bertazzi et al. (1998) conducted a review of the effects of dioxin exposure following a 1976 industrial accident in Seveso, examining mortality in the population 15 years after the incident. Extensive monitoring of soil levels and measurements of a limited number of human blood samples allowed for classification of the exposed population into three categories: zone A—high exposure, zone B—medium exposure, and zone R—lowest level of exposure. Few deaths were attributed to melanoma. In the high-exposure (A) zone, there were no melanoma deaths observed in males; for females, 1 death was reported when 0.1 was expected (RR=9.4, 1.3–68.8). There were no deaths attributed to melanoma in zone B. Among males in zone R, 3 deaths were reported when 2.8 were expected (RR=1.1, 0.3–3.7); among females, there were 3 deaths when 5.0 were expected (RR=0.6, 0.2–2.0).

A later study (Bertazzi et al., 2001) extends the mortality analysis to 20 years following the event for zones A and B only. For zone A, there was no change in

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

melanoma mortality. The 1 reported death (0.2 expected) for females resulted in a relative risk of 6.6 (0.9–47.7). In zone B, there was 1 death among males where 0.6 was expected (RR=1.7, 0.2–12.5) and 1 death among females where 1.0 was expected (RR=1.0, 0.1–7.4).

Schreinemachers’ (2000) examination of cancer mortality over the years 1980–1989 in four northern wheat-producing states used wheat acreage per county as a surrogate for exposure to chlorophenoxy herbicides (including 2,4-D). There was an inconsistent pattern of age-standardized mortality rate ratios for malignant melanoma for white males and females. None of the values were statistically significant.

Vietnam Veteran Studies

The Air Force Health Study (AFHS) is a long-term longitudinal study of the health of veterans who participated in Operation Ranch Hand and were thus responsible for the majority of aerial spraying of herbicides in Vietnam. A matched cohort consisting of Air Force veterans who served in Southeast Asia but were not occupationally exposed to herbicides is used as the comparison group in these studies. More details on this study are contained in Chapter 6.

The latest in the series of AFHS reports describes the results of the 1997 physical examination of Ranch Hand veterans and their comparison cohort (AFHS, 2000). The authors evaluated the incidence of basal cell carcinomas (overall and at four specific sites), squamous cell carcinomas, nonmelanoma (basal cell carcinomas, squamous cell carcinomas, and malignant epithelial neoplasms not otherwise specified), and melanoma. Skin cancer analyses, except for the analyses of benign neoplasms, were limited to nonblacks because blacks have been observed to exhibit only benign skin neoplasms in all phases of the study to date. Participants with skin neoplasms that predated their service in Southeast Asia were also excluded. Factors that might influence or be correlated with the incidence of skin cancers—age, military occupation, skin color, hair color, eye color, skin reaction to sun after the first exposure, skin reaction to sun after repeated exposure, lifetime exposure to ionizing radiation and industrial chemicals (yes or no), average lifetime residential history, and measures of serum dioxin level—were statistically controlled for in some analyses.

Significantly more Ranch Hands (325 of 805) than comparisons (402 of 1,168) experienced some form of skin cancer since their service in Southeast Asia (RR=1.3, 1.1–1.6; Model 1, adjusted). However, analyses that examined dioxin concentrations in blood and/or that controlled for confounding variables yielded inconsistent results. Ranch Hand veterans in the “low” -dioxin category showed higher incidence levels than those in the “high” or “background” categories or the comparisons, and one model showed a statistically significant inverse relationship between dioxin category and skin cancer.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

There was a higher incidence of melanoma in Ranch Hands (16 of 805) than in comparisons (13 of 1,168), but the difference was not statistically significant (RR=1.8, 0.8–3.8; Model 1, adjusted) and the highest incidence of melanoma was observed in low-dioxin-category Ranch Hands. None of the models that used categories of dioxin concentration or that adjusted for confounding variables produced statistically significant results.

A 1999 paper by Ketchum and colleagues reports the results of an earlier analysis of data available through July 1997 (not including the 1997 physical examination) on the Ranch Hand and comparison cohorts. Analyses were limited to nonblack veterans and were controlled for the factors listed above. This analysis found no association between a categorical measure of serum dioxin levels and the incidence of melanoma or skin cancers in general. Ranch Hand veterans in the low-exposure category had a higher incidence of skin cancers and melanoma than those in the background- or high-exposure categories, but the difference was not statistically significant. There was also no association between dioxin category and time to onset.

The Air Force Health Studies are notable for their attempts to control for confounding factors, something absent from many studies of this health outcome. The small number of melanoma cases, however, limits the informativeness of the results.

Results from the government of Australia’s mail surveys of approximately 50,000 male and female nationals who served in Vietnam (CDVA, 1998a, b) found an excess of melanoma among both male and female veterans when comparing the number of Vietnam veterans responding yes to the question, Since your first day of service in Vietnam, have you been told by a doctor that you have melanoma? to expected national rates. Seven percent (2,689 of 40,030) of the male veterans responded yes compared to the expected 1 percent (380; 95% CI 342–418) (CDVA, 1998a). This translates to an observed-expected ratio of ~7.1. The report suggested that the indicated prevalence might be overstated because prudent physicians often remove possible melanomas and this may leave the impression that such lesions are malignant. A separate study of female veterans reported that 7 (3 percent) responded yes, while 3 (expected range 1–8) were expected, for an observed-expected ratio of 2.3 (CDVA, 1998b). One strength of these surveys is their relatively high response rates. Weaknesses include the use of self-reported cases with no validation through medical record reviews or other means, the inability to control for important confounders, and the use of a nonmilitary control group. Results for females were based on a very small number of subjects.

The follow-up validation study (AIHW, 1999) estimated that there were 483 validated cases of melanoma among respondents. This was much smaller than the reported number of cases but still in excess of the expected number, 380 (342–418).

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Synthesis

Studies reviewed for the first time in Update 2000 add to the body of knowledge by providing additional morbidity data and mortality analyses to account for factors that confound the evaluation of melanoma incidence in groups with exposure to chemical agents. The occupational and Seveso studies have too few cases to be informative. The studies of veterans in Australia and of the Ranch Hand cohort provide some important new data; however, the information is not strong enough to lead the committee to change its prior finding. The committee continues to encourage researchers to make an effort to control confounding from UV (sunlight) exposures and acknowledges the efforts of AFHS researchers in this area.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that 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) and melanoma. The evidence regarding association is drawn from occupational, environmental, and veteran studies in which subjects were exposed to herbicides and herbicide components.

Biologic Plausibility

Mice were treated topically (applied to skin surface) for 2 years with TCDD. Under the conditions of the bioassay, fibrosarcomas occurred in the integumentary system of female mice (Huff et al., 1991). Therefore, continuous dermal exposure to TCDD can induce skin tumors (fibrosarcomas, not squamous cell carcinomas) in laboratory mice. Mechanistic data from in vitro and animal studies also support a role for TCDD as a promoter in the carcinogenic process. A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

Studies of U.S. and Australian veterans have reported a higher incidence of melanoma among male, nonblack veterans than comparison groups. However, analyses controlling for factors that might influence or be correlated with the incidence of skin cancers do not show a relationship between measures of expo-

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

sure to the herbicides used in Vietnam and this health outcome. The highest melanoma incidence in the AFHS reports was observed in veterans in the low-dioxin category, which would not be expected if there was an association between exposure and the outcome. The strongest evidence to date comes from the medical validation study of Australian Vietnam veterans. The estimated expected number of cases is considerably lower than the number of reported cases that were validated. However, adjustments for potentially important confounders were not carried out. Overall, data from those who served in Vietnam are not adequate to infer an association between malignant melanoma and exposure to herbicides used in Vietnam.

TABLE 7-13 Selected Epidemiologic Studies—Melanoma Mortality

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

New Studies

Hooiveld et al., 1998

Dutch production workers

1

2.9 (0.1–15.9)

Studies Reviewed in Update 1998

Hertzman et al., 1997

Sawmill workers

17

1.4 (0.9–2.0)

Kogevinas et al., 1997

IARC cohort

Workers exposed to TCDD (or higher-chlorinated dioxins)

5

0.5 (0.2–3.2)

Workers not exposed to TCDD (or higher-chlorinated dioxins)

4

1.0 (0.3–2.4)

Svensson et al., 1995

Swedish fishermen

East coast

0

0.0 (0.0–1.7)

West coast

6

0.7 (0.2–1.5)

Studies Reviewed in Update 1996

Blair et al., 1993

U.S. farmers in 23 states (white male)

244

1.0 (0.8–1.1)

Studies Reviewed in VAO

Wigle et al., 1990

Saskatchewan farmers

24

1.1 (0.7–1.6)

Wiklund, 1983

Swedish agricultural workers

268

0.8 (0.7–1.0)b

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso residents—20-year follow-up

Zone A females

1

6.6 (0.9–47.7)

Zone B males

1

1.7 (0.2–12.5)

Zone B females

1

1.0 (0.1–7.4)

Schreinemachers, 2000

Rural or farm residents of Minnesota, Montana, and North and South Dakota

 

 

Males—counties with wheat acreage 23,000–110,999

50

0.8 (0.6–1.1)

Males—counties with wheat acreage >111,000

41

0.8 (0.6–1.1)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

 

Females—counties with wheat acreage 23,000–110,999

59

1.2 (0.9–1.8)

Females—counties with wheat acreage >111,000

29

0.7 (0.5–1.2)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

Zone A females

1

9.4 (1.3–68.8)

Zone R males

3

1.1 (0.3–3.7)

Zone R females

3

0.6 (0.2–2.0)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

Zone R males

3

1.1 (0.2–3.2)

Zone R females

3

0.6 (0.1–1.8)

Studies Reviewed in VAO

Bertazzi et al., 1989a

Seveso residents—10-year follow-up

Zones A, B, R males

3

3.3 (0.8–13.9)

VIETNAM VETERANS

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

51

1.3 (1.0–1.8)

Crane et al., 1997b

Australian national service Vietnam veterans

16

0.5 (0.2–1.3)

Studies Reviewed in VAO

Breslin et al., 1988

Army Vietnam veterans

145

1.0 (0.9–1.1)

Marine Vietnam veterans

36

0.9 (0.6–1.5)

NOTE: NS=not significant.

aGiven when available.

b99% CI.

TABLE 7-14 Selected Epidemiologic Studies—Melanoma Morbidity

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 1998

Hertzman et al., 1997

Sawmill workers

38

1.0 (0.7–1.2)

Svensson et al., 1995

Swedish fishermen

East coast

0

0 (0.0–0.7)

West coast

20

0.8 (0.5–1.2)

Studies Reviewed in Update 1996

Lynge, 1993

Danish male production workers

4

4.3 (1.2–10.9)

Studies Reviewed in VAO

Ronco et al., 1992

Danish self-employed farmers

72

0.7 (p < .05)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans

16

1.8 (0.8–3.8)

AIHW, 1999

Australian Vietnam veterans—male

483

380 expected (342–418)

Ketchum et al., 1999

Ranch Hand (RH) veterans and comparisons through June 1997

 

 

Comparisons

9

(control group)

Background-exposure RH veterans

4

1.1 (0.3–4.5)

Low-exposure RH veterans

6

2.6 (0.7–9.1)

High-exposure RH veterans

2

0.9 (0.2–5.6)

CDVA, 1998a

Australian Vietnam veterans—male

2,689b

380 expected (342–418)

CDVA, 1998b

Australian Vietnam veterans—female

7b

3 expected (1–8)

Studies Reviewed in Update 1998

Clapp, 1997

Massachusetts Vietnam veterans

21

1.4 (0.7–2.9)

Studies Reviewed in VAO

Wolfe et al., 1990

Air Force Ranch Hand veterans

4

1.3 (0.3–5.2)

NOTE: NS=not significant.

aGiven when available.

bSelf-reported medical history. Answer to question: Since your first day of service in Vietnam, have you been told by a doctor that you have melanoma?

SKIN CANCER—BASAL AND SQUAMOUS CELL (NONMELANOMA)

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and skin cancer. Additional information available to the committee responsible for Update 1996 did not change this finding. The Update 1998 committee considered separately the literatures regarding malignant melanoma and nonmelanocytic skin cancers. It found that there was inadequate or insufficient information to determine whether an association existed between exposure to the herbicides used in Vietnam or the contaminant dioxin and basal or squamous cell cancers. Tables 7–15 and 7–16 provide summaries of the results of the studies underlying these findings and a list of reports that contain details of the research.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Update of the Scientific Literature

Occupational Studies

A thorough review of the new published material did not reveal any relevant occupational studies.

Environmental Studies

A thorough review of the new published material did not reveal any relevant environmental studies.

Vietnam Veteran Studies

The AFHS is a long-term longitudinal study of the health of the group of veterans who participated in Operation Ranch Hand herbicide spray missions and a matched cohort consisting of Air Force veterans who served in Southeast Asia but were not occupationally exposed to herbicides. More details on this study series are contained in Chapter 3. The discussion of melanoma above contains more information on the methodology used in the AFHS to evaluate skin cancers.

Several analyses of nonmelanoma skin cancers were conducted: basal cell carcinomas of the ear, face, head, and neck; basal cell carcinomas of the trunk; basal cell carcinomas of the upper extremities; basal cell carcinomas of the lower extremities; all basal cell carcinoma sites combined; squamous cell carcinomas; and an all-nonmelanoma category consisting of all basal cell carcinomas, squamous cell carcinomas, and malignant epithelial neoplasms not otherwise specified.

A slightly greater proportion of Ranch Hands (15 percent; 121 of 805) than comparisons (13.3 percent; 155 of 1,168) experienced a basal cell carcinoma (BCC) after their service in Southeast Asia (RR=1.2, 0.9–1.6; Model 1, adjusted) (AFHS, 2000). An analysis that controlled for confounding variables found a statistically significant excess of BCC in Ranch Hands in the low-dioxin category (RR=1.6, 1.1–2.4), but the same analysis found no excess for Ranch Hands in the high-dioxin category (RR=1.0, 0.6–1.6). As the estimated initial serum dioxin levels in Ranch Hands increased, the percentage of participants with BCC decreased—there was a statistically significant inverse association found between initial dioxin and any basal cell carcinoma in an analysis that controlled for confounders (RR=0.7, p=.014; Model 2, adjusted). Other models yielded nonsignificant results. Analyses that separated BCC by location generated inconsistent but generally nonsignificant results, as might be expected from the small number of cases examined.

There were relatively few squamous cell carcinomas among Ranch Hands (20 of 805) and comparisons (22 of 1,168) (RR=1.5, 0.8–2.8; Model 1, adjusted). None of the analyses of this outcome yielded statistically significant

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

results. The analysis of all nonmelanomas identified 134 (out of 805) in Ranch Hands and 176 (out of 1,168) in comparisons, for a relative risk of 1.2 (0.9–1.5; Model 1, adjusted). Basal cell carcinomas make up approximately 90 percent of these, and results are similar to those reported for that outcome.

A paper by Ketchum and colleagues (1999) reports the results of an earlier analysis of data available through July 1997 (not including the 1997 physical examination) on the Ranch Hand and comparison cohorts. Analyses were limited to nonblack veterans and were controlled for the same confounding variables outlined in the melanoma section. This analysis found no association between a categorical measure of serum dioxin levels and the incidence of basal or squamous cell carcinomas. Ranch Hand veterans in the low-exposure category had a higher incidence of skin cancers and melanoma than those in the background- or high-exposure categories or the comparison group, but the differences were not statistically significant. There was also no association between dioxin category and time to onset for either cancer.

As stated in the discussion of melanoma, the Air Force Health Studies are notable for their attempts to control for confounding factors, something absent from many studies of this health outcome. The small number of cases, however, limits the informativeness of the results.

The government of Australia conducted mail surveys of all individuals with Vietnam service, which included those involved in combat, medical teams, war correspondents, entertainers, and philanthropy workers (CDVA, 1998a, b). Questionnaires were mailed to 49,944 male veterans (80 percent response rate) and 278 female veterans (81 percent response rate).

Seventeen percent of both male (6,936) and female (37) respondents reported having been told by a doctor that they had a basal cell or squamous cell carcinoma since their first day of service in Vietnam (CDVA, 1998a, b). There was no estimate made of the expected number of cases or the range of expected numbers. The authors state that such skin lesions are often removed without pathological confirmation and their prevalence is not monitored by cancer registries, so proper comparisons are not calculable. The strengths of these surveys include their relatively high response rates. Weaknesses include the use of self-reported cases and the inability to control for important confounders. Results for females were based on a very small number of subjects.

Synthesis

There are relatively few studies that examine nonmelanomas and fewer that separate basal and squamous cell carcinomas, even though there are differences in the etiologies of these outcomes. Studies of U.S. and Australian Vietnam veterans reviewed for the first time in this report provide new morbidity data for these outcomes, with AFHS studies accounting for factors that confound the

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

evaluation of nonmelanoma incidence in groups with exposure to chemical agents. As was true for the evaluation of melanomas, these studies do not provide information that would lead the committee to change its prior findings. The committee continues to encourage researchers to make an effort to control confounding from UV (sunlight) exposures and acknowledges the efforts of AFHS researchers in this area.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that 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) and basal or squamous cell cancers.

Biologic Plausibility

Mice were treated topically (applied to skin surface) for 2 years with TCDD (Huff et al., 1991). Under the conditions of the bioassay, fibrosarcomas occurred in the integumentary system of female mice. Therefore, continuous, dermal exposure to TCDD can induce skin tumors (fibrosarcomas, not squamous cell carcinomas) in laboratory mice. Mechanistic data from in vitro and animal studies also support a role for TCDD as a promoter in the carcinogenic process. A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

The AFHS report a higher incidence of nonmelanomas among male, nonblack veterans than in the comparison group. However, analyses controlling for factors that might influence or be correlated with the incidence of skin cancers do not show a relationship between measures of exposure to the herbicides used in Vietnam and these health outcomes.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

TABLE 7-15 Selected Epidemiologic Studies—Other Nonmelanoma (basal and squamous cell) Skin Cancer Mortality

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 1998

Hertzman et al., 1997

Sawmill workers

38

1.0 (0.7–1.2)

Kogevinas et al., 1997

IARC cohort

Workers exposed to TCDD (or higher-chlorinated dioxins)

4

1.2 (0.3–3.2)

Workers not exposed to TCDD (or higher-chlorinated dioxins)

0

Svensson et al., 1995

Swedish fishermen

East coast

0

0.0 (0.0–15.4)

West coast

5

3.0 (1.0–7.1)

Studies Reviewed in Update 1996

Blair et al., 1993

U.S. farmers in 23 states (white male)

425

1.1 (1.0–1.2)

Studies Reviewed in VAO

Coggon et al., 1986

British MCPA chemical workers

3

3.1 (0.6–9.0)

Wiklund, 1983

Swedish agricultural workers

708

1.1 (1.0–1.2)b

NOTE: MCPA=methyl-4-chlorophenoxyacetic acid.

aGiven when available.

b99% CI.

TABLE 7-16 Selected Epidemiologic Studies—Other Nonmelanoma (basal and squamous cell) Skin Cancer Morbidity

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 1998

Zhong and Rafnsson, 1996

Icelandic pesticide users

5

2.8 (0.9–6.6)

Svensson et al., 1995

Swedish fishermen

East coast

22

2.3 (1.4–3.5)

West coast

69

1.1 (0.9–1.4)

Studies Reviewed in VAO

Ronco et al., 1992

Danish self-employed farmers

493

0.7 (p < .05)

ENVIRONMENTAL

Studies Reviewed in Update 1998

Gallagher et al., 1996

Alberta, Canada, residents—squamous cell carcinoma

All herbicide exposure

79

1.5 (1.0–2.3)

Low herbicide exposure

33

1.9 (1.0–3.6)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

 

High herbicide exposure

46

3.9 (2.2–6.9)

All fungicide exposure

96

1.4 (0.9–2.1)

Low fungicide exposure

40

0.8 (0.4–1.4)

High fungicide exposure

56

2.4 (1.4–4.0)

Alberta, Canada, residents—basal cell carcinoma

 

 

All herbicide exposure

70

1.1 (0.8–1.7)

All fungicide exposure

76

0.9 (0.6–1.3)

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up, morbidity

Zone A males

1

2.4 (0.3–17.2)

Zone B males

2

0.7 (0.2–2.9)

Zone R males

20

1.0 (0.6–1.6)

Studies Reviewed in VAO

Pesatori et al., 1992

Seveso residents

Zones A, B males

3

1.0 (0.3–3.0)

Zones A, B females

3

1.5 (0.5–4.9)

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans

Basal cell carcinoma (BCC)

121

1.2 (0.9–1.6)

Squamous cell carcinoma (SCC)

20

1.5 (0.8–2.8)

CDVA, 1998a

Australian Vietnam veterans—male

6,936b

CDVA, 1998b

Australian Vietnam veterans—female

37b

Studies Reviewed in VAO

Wolfe et al., 1990

Air Force Ranch Hand veterans

Basal cell carcinoma

78

1.5 (1.0–2.1)

Squamous cell carcinoma

6

1.6 (0.5–5.1)

aGiven when available.

bSelf-reported medical history. Answer to question: Since your first day of service in Vietnam, have you been told by a doctor that you have other skin cancers (BCC and SCC)?

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

BREAST CANCER

Background

Breast cancer (ICD•9 174.0–174.9 for females) is the single most common cancer among women in the United States, excluding nonmelanocytic skin cancers. The American Cancer Society estimates that 182,800 women will be diagnosed with breast cancer in the United States in 2000 and that 40,800 will die from the disease (ACS, 2000a). Overall, these numbers represent approximately 30 percent of the incidence of new cancers and 15 percent of cancer deaths among women. Among women aged 40–55, breast cancer is the leading cause of cancer death.

Breast cancer incidence generally increases with age. In the age groups that characterize most Vietnam veterans, the incidence for whites is slightly higher than that for African Americans. Risk factors other than aging include a personal or family history of breast cancer and certain characteristics of one’s reproductive history (specifically, early onset of menarche, late onset of menopause, and either no pregnancies or first full-term pregnancy after 30 years of age). A pooled analysis of six large-scale prospective studies of invasive breast cancer found that alcohol consumption was associated with a linear increase in incidence in women over the range of consumption reported by most women (Smith-Warner et al., 1998). The potential role of other personal behavioral and environmental factors in breast cancer incidence is being studied extensively.

The majority of women Vietnam veterans who were exposed to Agent Orange are now approaching or have reached menopause and will experience an increasing risk of breast cancer. It is therefore predictable on the basis of demographics alone that breast cancer will be a conspicuous and significant cause of death.

Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa

Breast Cancer in Females

45–49 Years of Age

50–54 Years of Age

55–59 Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

198.5

201.0

199.3

263.7

272.4

243.5

305.0

312.9

290.2

aSEER nine standard registries, crude age-specific rate, 1993–1997.

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found there to be inadequate or insufficient information to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and breast cancer. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Table 7–17 provides summaries of the

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

results of the studies underlying these findings and a list of reports that contain details of the research.

Update of the Scientific Literature

Occupational Studies

A thorough review of the new published material did not reveal any relevant occupational studies.

Environmental Studies

Since Update 1998, there has been elaboration on the experience of a nonoccupationally exposed population that, unlike most extant occupational studies, has included sufficient numbers of women to report statistically stable risk estimates.

Since Update 1998, Bertazzi and colleagues have reported on 15 years (Bertazzi et al., 1998) and 20 years (Bertazzi et al., 2001) of observation of residents of Seveso, Italy, who experienced relatively pure TCDD exposure in the 1976 industrial incident. No elevations in mortality from breast cancer were found. Among residents of zone A, the area of highest contamination, the relative risk for females was 0.6 (0.1–3.9, 1 death observed), and there were no deaths from this cause among males. Among residents of zone B, the medium-exposure area, the relative risk for females was 0.8 (0.4–1.5, 9 deaths observed), and there were no deaths from this cause among males. As reported in Bertazzi et al. (1998), among residents of zone R, the area of low contamination, the relative risk for females was 0.8 (0.6–1.0, 67 deaths observed), and there were no deaths from this cause among males.

Several studies conducted in the late 1990s examined exposure to organochlorine compounds. The largest and most complete of these was conducted by Bagga et al. (2000), who examined cumulative exposure to organochlorines as reflected by levels of DDT and its metabolites in breast adipose tissue and found no difference in levels of women with breast cancer compared to women undergoing reduction mammoplasty. Age, body mass index, menopausal status at the time of diagnosis, and family history of breast cancer were taken into account in this study.

Similarly, Demers et al. (2000) reported on a large study from hospitals in Quebec in which total and 25 specific organochlorine levels did not differ between women with and without breast cancer. This study did report that among women with breast cancer, those with lymph node involvement, indicating spread of the tumor, and those with larger tumors had higher tissue organochlorine levels than those with more limited disease, after adjusting for age and other factors.

Høyer et al. (2000) studied 195 women in Copenhagen in a community survey who had provided blood samples in 1976–1978, and again in 1981–1983,

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

and who subsequently developed breast cancer. The blood was analyzed for organochlorine compounds. Higher dieldrin levels, but not levels of other organochlorines tested such as total polychlorinated biphenyls (PCBs), were associated with markedly reduced survival times after diagnosis, demonstrating a dose-response relationship. The increased risk of dying from breast cancer in women with higher dieldrin levels was associated with more aggressive tumor behavior, such as high-grade malignancies, earlier metastases, and advanced disease at the time of diagnosis. Among the organochlorines, dieldrin is strongly estrogenic, meaning that it binds to estrogen receptors and duplicates the effects of hormones. This hormonal mimicry may have an effect on tumor promotion and cancer cell growth, or even on the aggressiveness of the cancer, which is suggested by the evidence. The phenoxyacetic herbicides, dioxins, furans, and PCBs may act differently.

Organochlorine herbicides were not specifically and separately examined in these studies, however. Duell et al. (2000) studied women who were exposed to organochlorine pesticides, including but not limited to herbicides, while living and working on farms in North Carolina. Consistent with earlier, similar studies, no excess risk of breast cancer was found overall, and the results were compatible with a reduced risk in proportion to duration of farming. However, investigators could not rule out an increased risk in a subgroup of farming women who directly handled pesticides on farms.

Vietnam Veteran Studies

The government of Australia’s mail survey of approximately 278 female veterans yielded 223 responses. When asked if a doctor had told them they had breast cancer since their first day of service in Vietnam, 17 females responded in the affirmative. This is in excess of the 5 cases that were expected and beyond the expected range of 2–11 cases. Although there is a statistically significant excess of breast cancer in this study population, there are non-war-related risk factors that may be confounding the findings. Such factors include low number of pregnancies, childlessness, or mothers giving birth to their first children at an older age. Based on these data, it is difficult to interpret whether environmental exposures in Vietnam contributed to the excess of breast cancer reported.

Synthesis

Much available evidence suggests that exposure to TCDD, and probably the herbicides of concern in this report, exerts a protective effect for women against the risk of developing breast cancer. This finding is supported by the known antiestrogenic activity of TCDD, which may be expected to antagonize endogenous estrogen effects and does reduce the incidence of mammary tumors in

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

treated animals. Animal studies also suggest a reduction in the frequency of breast cancer following exposure to TCDD. It is thus biologically plausible that exposure to TCDD, whatever its other effects, may reduce the risk of breast cancer experienced by women with comparable reproductive history.

Contradicting this interpretation of the literature are earlier studies of Australian Vietnam veterans (Crane et al., 1997a) and one very large occupational cohort (Kogevinas et al., 1997) that do show an excess risk among males; the occupational cohort also demonstrated a significant elevation among women. Overall, the data are not conclusive in supporting a protective effect or an association between exposure to the herbicides of concern in this report and the risk of breast cancer. The significance of these findings for Vietnam era veterans who may have experienced different patterns of organochlorine exposure, reflecting the herbicides of concern, is not known.

Although there appears to be limited evidence to suggest that there is an epidemiologically defined protective effect of exposure to TCDD in reducing the overall incidence of breast cancer, this should be understood as limited to the narrow context of frequency of new disease. The term “protective” is used here in a narrow technical sense of exposure being associated with a reduction in risk. The effect is not necessarily a benefit, because it remains possible that exposure to TCDD and Agent Orange may affect lethality, distribution of tissue type, rate of progression, and invasiveness. There is limited evidence that this may be the case for organochlorine exposure in general (Demers et al., 2000), but the data of Høyer et al. (2000) suggest that the effect is very specific in terms of compound. It is not known whether compounds relevant to Agent Orange exposure have this effect.

The possibility that TCDD may exert a significant biological effect means that there is a possibility that exposure could adversely affect the natural history of tumors that do arise. Limited evidence, as yet unconfirmed, suggests that there may be adverse effects from organochlorine exposure on the natural history of the cancers that occur. Of concern is the finding from Quebec (Demers et al., 2000) that markers for higher organochlorine exposure are associated with more invasive and progressive disease at the time of diagnosis, once a cancer does develop. In Danish women studied by Høyer et al. (2000), higher levels of one organochlorine were associated with poorer prognosis of breast cancer, but the relevance to women exposed to Agent Orange is uncertain.

Importantly, there is no evidence from which to evaluate the possibility that exposure to organochlorines may modify the natural history if exposure takes place at certain sensitive periods during the development of breast tissue, such as puberty and pregnancy.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that 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) and risk of breast cancer. Some current evidence suggests that there may be an inverse correlation with incidence of tumors, but the evidence is limited and unconfirmed.

Biologic Plausibility

No animal studies have found an increased incidence of breast cancer. A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

There are no data on which to base a conclusion concerning whether Vietnam veterans may or may not be at increased risk for breast cancer due to exposure to herbicides or TCDD.

TABLE 7-17 Selected Epidemiologic Studies—Breast Cancer

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

New Studies

Duell et al., 2000

Used pesticides in the garden

228

2.3 (1.7–3.1)

Laundry for pesticide user

119

4.1 (2.8–5.9)

Studies Reviewed in Update 1998

Kogevinas et al., 1997

IARC cohort, female; identical to Manz et al. (1991)

9

2.2 (1.0–4.1)

IARC cohort, male

2

2.6 (0.3–9.3)

Studies Reviewed in Update 1996

Blair et al., 1993

Female U.S. farmers from 23 states

White

71

1.0 (0.8–1.3)

Nonwhite

30

0.7 (0.5–1.0)

Kogevinas et al., 1993

Female herbicide spraying and production workers

7

0.9 (0.4–1.9)

Probably exposed to TCDD

1

0.9 (0.0–4.8)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Studies Reviewed in VAO

Ronco et al., 1992

Danish family farm workers

429

0.8 (p < .05)

Manz et al., 1991

German production workers

9

2.2 (1.0–4.1)

Saracci et al., 1991

IARC cohort

1

0.3 (0.0–1.7)

Lynge, 1985

Danish production workers

13

0.9

Wiklund, 1983

Swedish agricultural workers

444

0.8 (0.7–0.9)b

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso residents—20-year follow-up

Zone A females

2

0.8 (0.2–3.1)

Zone B females

12

0.7 (0.4–1.3)

Bagga et al., 2000

Women receiving medical care in Woodland Hills, California

73

NS

Demers et al., 2000

Women in Quebec City newly diagnosed

315

NS

Høyer et al., 2000

Female participants of Copenhagen City Heart Study

195

Overall survival RR 2.8 (1.4–5.6)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

Zone A females

1

0.6 (0.1–3.9)

Zone B females

9

0.8 (0.4–1.5)

Zone R females

67

0.8 (0.6–1.0)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

Zone A females

1

0.6 (0.0–3.1)

Zone B females

9

0.8 (0.4–1.5)

Zone R females

67

0.8 (0.6–1.0)

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up, morbidity

Zone A females

1

0.5 (0.1–3.3)

Zone B females

10

0.7 (0.4–1.4)

Zone R females

106

1.1 (0.9–1.3)

Studies Reviewed in VAO

Bertazzi et al., 1989b

Seveso residents—10-year follow-up

Zone B females

5

0.9 (0.4–2.1)

Zone R females

28

0.6 (0.4–0.9)

VIETNAM VETERANS

New Studies

CDVA, 1998b

Australian Vietnam veterans—female

17c

5 expected (2–11)

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

3

5.5 (1.1–16.1)

Studies Reviewed in Update 1996

Dalager et al., 1995

Women Vietnam veterans

26

1.0 (0.6–1.8)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Studies Reviewed in VAO

Thomas et al., 1991

Women Vietnam veterans

17

1.2 (0.6–2.5)

NOTE: NS=not significant.

aGiven when available.

b99% CI.

cSelf-reported medical history. Answer to question: Since your first day of service in Vietnam, have you been told by a doctor that you have breast cancer?

CANCERS OF THE FEMALE REPRODUCTIVE SYSTEM

Background

This section addresses cancers of the cervix (ICD•9 180.0–180.9), endometrium (also referred to as the corpus uteri, ICD•9 182.0–182.1, 182.8), and ovaries (ICD•9 183.0). Statistics for other cancers of the female reproductive system are presented as well. The American Cancer Society estimated the following numbers of new female reproductive system cancers in the United States for 2000 (ACS, 2000a):

Site

New Cases

Deaths

Cervix

12,800

4,600

Endometrium

36,100

6,500

Ovary

23,100

14,000

Other female genital

5,500

1,400

Taken together, these numbers represent roughly 6 percent of new cancer diagnoses and 5 percent of cancer deaths in women.

Incidence patterns and risk factors vary for these diseases. Cervical cancers occur more often in African-American women than in whites, whereas whites are more likely to develop endometrial and ovarian cancers. The incidence of endometrial and ovarian cancer also depends on age, with older women at greater risk. Other risk factors for these cancers vary. Human papillomavirus infection is the most important risk factor for cervical cancer. Diet, a family history of the disease, and breast cancer are among the risk factors for endometrial and ovarian cancers.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa

Female Genital System Cancers

 

45–49 Years of Age

50–54 Years of Age

55–59 Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Cervix

16.7

15.1

21.9

15.8

13.9

22.9

15.6

12.7

28.3

Endometrium

24.7

24.9

12.0

45.8

47.4

27.0

66.0

69.6

39.6

Ovary

22.8

24.2

12.9

29.8

30.9

20.7

35.6

38.4

21.4

Other genital

3.1

3.1

3.8

4.9

5.0

3.8

5.4

5.4

6.0

Overall

67.3

67.3

50.6

96.3

97.2

74.4

122.6

126.1

95.3

aSEER nine standard registries, crude age-specific rate, 1993–1997.

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found there to be inadequate or insufficient information to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and female reproductive cancers. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Tables 7-18, 7-19, and 7-20 provide summaries of the results of the studies underlying these findings and a list of reports that contain details of the research.

Update of the Scientific Literature

Occupational Studies

Very few new data have appeared in the literature that relate exposures to 2,3,7,8-TCDD to uterine, ovarian, or cervical cancers. In a study of herbicides and adjuvants (i.e., additives to herbicides), levels of FSH (follicle-stimulating hormone) and free testosterone were elevated postapplication compared to pre-application in male appliers (Sweeney et al., 1997/98). Whether these findings (e.g., the associations with FSH) generalize to females is unknown.

Environmental Studies

A publication by Bertazzi et al. (1998) on the Seveso population indicates no increases in female reproductive cancers among those exposed in any of the three zones. In zone A, which had the highest exposures, no uterine cancer deaths are reported; 1 ovarian cancer death occurred where 0.4 was expected (RR=2.3, 0.3–16.5). In zone B, with the second-highest exposures, the numbers of deaths from uterine and ovarian cancers were both less than expected. In zone R, where exposures were lower, but still above those not exposed to the accident, there were 27 uterine cancer deaths, with 23.7 expected, for a relative risk of 1.1 (0.8– 1.7) and 21 ovarian cancer deaths, with 20.7 expected (RR=1.0, 0.6–1.6).

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

The latest follow-up on cancer incidence in Seveso, which includes diagnoses made between 1976 and 1996 (20-year follow-up), shows 1 case of ovarian cancer in zone A and 2 in zone B (Bertazzi et al., 2001). When combined, these three represent a relative risk of 0.7 (0.2–2.0). An earlier paper (Pesatori et al., 1993) had shown 2 cases among young women (<19 years of age) during the period 1977–1986, where 0.0 were expected, both from zone R. The latest update also indicates 2 cases of uterine cancer in zone B, where 3.8 were expected, for a relative risk of 0.5 (0.1–2.1).

A case-control study of endometrial cancer was conducted in Sweden (Weiderpass et al., 2000). There were 154 cases and 205 eligible controls frequency-matched on age; women who had had a hysterectomy or had ever taken hormone replacement therapy were excluded. The authors measured 10 organochlorine pesticides and 10 PCB congeners. TCDD was not measured, although it can be assumed to have been present as a contaminant. Statistical analyses were conducted for individual compounds and for groups based on estrogenic or anti-androgenic activity. Cases had higher mean concentrations of p,p′-DDT, p,p′-DDE (dichlorodiphenyldichloroethylene), hexachlorobenzene, and p-HCH (hexachlorocyclohexane). However, after adjustment for age and body mass index, no pesticides were associated with endometrial cancer case status.

The biologic plausibility that TCDD may interact with endometrial tissue was investigated by Kuchenhoff et al. (1999). Endometrial tissue was collected from 86 premenopausal women, and expression of the aryl hydrocarbon receptor (AhR) mRNA and protein were measured. In 43 percent of the women, the endometria showed AhR expression; receptor protein was exclusively in the apical part of the cytoplasm of epithelial cells in the endometrial glands. AhR mRNA was expressed in the cytoplasm of endometrial epithelial cells. AhR expression was maximal at the time of ovulation.

Vietnam Veterans Studies

A study of female Vietnam veterans from Australia used a mail survey to obtain information on health conditions, reproductive histories, and conditions of their children (CDVA, 1998b). Out of 484 veterans, only 278 were successfully traced, and 223 responded. Tracing is more difficult for women who marry and change their name. As a result, the respondents were far less likely to be married, and they reported only half as many children as a comparable community group. There appeared to be an excess of all cancers combined. There were 4 cases of uterine cancer (1 expected) and 8 cases of cervical cancer (1 expected). One case of ovarian cancer (zero expected) and no cases of vaginal cancer (zero expected) were observed. The numbers are small, and since the authors did not stratify or adjust for marital status, these comparisons may be confounded. Because the health status of unmarried adults is generally worse than that of married adults of the same age, results may be biased toward

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

greater differences between the veterans and the comparison group. Stratification or adjustment in multivariate models for marital status could be used to eliminate this confounding bias. Nevertheless, the findings can be viewed as indicating a possibility that service in Vietnam may have an association with some reproductive cancers in females.

Synthesis

The epidemiologic studies regarding female reproductive tract cancers are summarized in Tables 7-18, 7-19, and 7-20. The evidence from these studies remains inconclusive, in spite of some strong associations with ovarian and uterine cancers, largely because most of the published studies include a small number of cases and/or have poor exposure characterization or too short a follow-up period. The committee concludes that more research is needed on populations of women with documented exposure to herbicides and TCDD.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that 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) and uterine, ovarian, or cervical cancers. The evidence regarding association is drawn from occupational and environmental studies in which subjects were exposed to a variety of herbicides and herbicide components and from a study of Australian female Vietnam veterans.

Biologic Plausibility

No animal studies have found an increased incidence of female reproductive cancer; however, recent work has demonstrated that TCDD interacts with the AhR in endometrial tissue. A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

The limited data on increased risk for female reproductive cancers in Vietnam veterans come from an Australian study. Although the proportion of women

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

with uterine and cervical cancers was higher than expected, the small number of cases and the possibility of confounding from marital status preclude drawing definitive conclusions. An ongoing study in female U.S. veterans of the Vietnam era may shed further light on this issue.

TABLE 7-18 Selected Epidemiologic Studies—Cancers of the Cervix

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 1998

Kogevinas et al., 1997

IARC cohort

0

Studies Reviewed in Update 1996

Blair et al., 1993

U.S. farmers in 23 states

Whites

6

0.9 (0.3–2.0)

Non whites

21

2.0 (0.3–3.1)

Studies Reviewed in VAO

Ronco et al., 1992

Danish farmers

Self-employed farmers

7

0.5

Family workers

100

0.5

Employees

12

0.8

Wiklund, 1983

Swedish agricultural workers

82

0.6

VIETNAM VETERANS

New Studies

CDVA, 1998b

Australian Vietnam veterans—female

8b

1 expected (0–5)

aGiven when available.

bSelf-reported medical history. Answer to question: Since your first day of service in Vietnam, have you been told by a doctor that you have cancer of the cervix?

TABLE 7-19 Selected Epidemiologic Studies—Cancers of the Uterus

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 1998

Kogevinas et al., 1997

IARC cohort (includes cancers of the endometrium)

3

3.4 (0.7–10.0)

Studies Reviewed in VAO

Blair et al., 1993

U.S. farmers in 23 states

Whites

15

1.2

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

 

Nonwhites

17

1.4

Ronco et al., 1992

Danish farmers

Self-employed farmers

8

0.6

Family workers

103

0.8

Employees

9

0.9

Wiklund, 1983

Swedish agricultural workers

135

0.9

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso residents—20-year follow-up

Zone B females

2

0.5 (0.1–2.1)

Weiderpass et al., 2000

Swedish females

154

1.0 (0.6–2.0)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

Zone B females

1

0.3 (0.0–2.4)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

Zone B females

1

0.3 (0.0–1.9)

Zone R females

27

1.1 (0.8–1.7)

VIETNAM VETERANS

New Studies

CDVA, 1998b

Australian Vietnam veterans—female

4b

1 expected (0–5)

Studies Reviewed in Update 1996

Dalager et al., 1995

Women Vietnam veterans

4

2.1 (0.6–5.4)

aGiven when available.

bSelf-reported medical history. Answer to question: Since your first day of service in Vietnam, have you been told by a doctor that you have uterine cancer?

TABLE 7-20 Selected Epidemiologic Studies—Ovarian Cancer

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 1998

Kogevinas et al., 1997

IARC cohort

0

Studies Reviewed in Update 1996

Kogevinas et al., 1993

IARC cohort

1

0.7

Lynge, 1993

Danish female production workers

7

3.2

Studies Reviewed in VAO

Ronco et al., 1992

Danish farmers

Self-employed farmers

12

0.9

Family workers

104

0.8

Employees

5

0.5

Donna et al., 1984

Female residents near Alessandria, Italy

18

4.4 (1.9–16.1)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso residents—20-year follow-up

Zone A females

1

1.6 (0.2–11.2)

Zone B females

2

0.5 (0.1–2.0)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

Zone A females

1

2.3 (0.3–16.5)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

Zone A females

1

2.3 (0.0–12.8)

Zone R females

21

1.0 (0.6–1.6)

VIETNAM VETERANS

New Studies

CDVA, 1998b

Australian Vietnam veterans—female

1b

0 expected (0–4)

aGiven when available.

bSelf-reported medical history. Answer to question: Since your first day of service in Vietnam, have you been told by a doctor that you have ovarian cancer?

PROSTATE CANCER

Background

According to American Cancer Society estimates, 180,400 new cases of prostate cancer (ICD•9 185) will be diagnosed in the United States in 2000, and 31,900 men will die from the disease (ACS, 2000a). This makes prostate cancer the most common cancer among men, excluding nonmelanocytic skin cancers. Among men it is expected to account for approximately 29 percent of new diagnoses and 11 percent of cancer deaths in 2000.

Prostate cancer incidence varies dramatically as a function of age and race. The risk increases fivefold between 45–49 and 50–54 years of age, and nearly triples between 50–54 and 55–59 years of age. As a group, African-American men have the highest recorded incidence of prostate cancer in the world (Miller et al., 1996). Their risk is roughly twice that of whites in the United States, 4 times higher than Alaskan natives, and nearly 7.5 times higher than Korean Americans.

Little is known about the causes of prostate cancer. Other than race and age, risk factors include a family history of the disease and a diet high in fats.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa

Prostate Cancer

45–49 Years of Age

50–54 Years of Age

55–59 Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

26.6

23.8

61.2

111.4

104.4

224.6

284.4

273.0

522.0

aSEER nine standard registries, crude age-specific rate, 1993–1997

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found there to be limited or suggestive evidence to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and prostate cancer. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Table 7–21 provides summaries of the results of the studies underlying these findings and a list of reports that contain details of the research.

Update of the Scientific Literature

Since Update 1998, a few new published papers have reported data on prostate cancer mortality or incidence in populations with possible or documented exposures to TCDD. Several of these involved occupational exposures (Dich and Wiklund, 1998; Fleming et al., 1999a, b; Steenland et al., 1999; Sharma-Wagner et al., 2000), two reports concern the Seveso cohort (Bertazzi et al., 1998, 2001), and data are reported from the Ranch Hand study (AFHS, 2000) and the Australian Vietnam veterans Validation Study (AIHW, 1999).

Occupational Studies

Three occupational studies provide data on mortality from prostate cancer. In the NIOSH study of 5,132 production workers with known exposure to 2,3,7,8-TCDD, Steenland et al. (1999) examined mortality from prostate cancer. A total of 28 such deaths were observed, yielding an SMR of 1.2 (0.8–1.7). No further analyses by dose or using internal comparisons were reported for this outcome.

A study of cancer mortality in pesticide appliers was conducted in Florida. Fleming et al. (1999a) followed 33,658 appliers age 20 or more, licensed by the Florida Department of Agriculture and Consumer Services between January 1, 1975, and December 31, 1993. Ninety percent were male (N=30,155), and the total number of person-years of follow-up was 290,791 (an average of just less than 10 years per person). The mean age at first license, among men, was 39.5 (standard deviation [SD]=13.3), and the mean years licensed was 7.1 (SD=4.4). There were 64 deaths from prostate cancer, for an SMR of 2.4 (1.8–3.0). The

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

authors state that there was a decreasing trend with later years of license (data not shown). There is reference to, but no documentation of, similar findings for incidence. The authors also note a current theory that postulates vitamin D exposure to be protective for prostate cancer; if true, those working outdoors might be at lower risk than the general population, which spends a considerable portion of time indoors, even in Florida.

A second study focused on pesticide appliers, but examined prostate cancer incidence. Dich and Wiklund (1998) carried out a cohort study for incident cases of prostate cancer among 20,025 pesticide appliers in agriculture, licensed between 1965 (when licensing was begun) and 1976 in Sweden. The most commonly used pesticides were phenoxyacetic acid herbicides, organochlorine compounds, mercury, and organophosphorous compounds. Cases were identified through the Swedish Cancer Registry. The follow-up period was through December 31, 1991, and the mean follow-up for this cohort was 21.3 years. In this cohort, there were 401 cases compared with 355 expected, for a standardized incidence ratio of 1.1 (1.0–1.2). Among those born later than 1935, the SIR was 2.0 (0.8–4.2), while for those born earlier, it was 1.1 (1.0–1.2). The authors noted that besides pesticides, the environment of farmers and pesticide appliers includes other potential carcinogens, such as exhaust fumes, solvents, fuel oils, and exposure to animals and consequently zoonotic viruses. The authors speculate about cadmium and cadmium compounds, which are present in pesticides and also occur as impurities in fertilizers; however, it should be noted that an early finding of an excess of prostate cancer among workers exposed to cadmium (Lemen et al., 1976) was not confirmed in the numerous later studies conducted with improved exposure assessment (e.g., Armstrong and Kazantzis, 1983; Sorahan and Waterhouse, 1983). The small excess incidence of prostate cancer in pesticide appliers found by Dich and Wiklund is particularly interesting given an earlier follow-up of this same cohort to 1982 (Wiklund et al., 1989a), which found no increased risk: the SIR was 1.0 (0.8–1.2). In other words, all of the excess occurred in the last 9 or 10 years of follow-up.

In an exploratory study, Sharma-Wagner et al. (2000) linked the National Swedish Cancer Registry to the 1960 National Census using the 10-digit personal ID codes assigned to every Swedish citizen to examine prostate cancer incidence rates by industry and occupation. The authors included cases diagnosed from 1961 through 1979 and derived the expected numbers of cases from national rates for 5-year birth cohorts. Slightly elevated SIRs were found for farmers, fishermen, and hunters, who had an SIR of 1.0 (1.0–1.1), while employment in agriculture had an SIR of 1.1 (1.0–1.1). Slight excesses were again seen when these broad groups were divided into specific categories: the SIR for actual agriculture and stock raising was 1.1; similarly, farmers, foresters, and gardeners showed a 10 percent excess. This study lacked data on smoking or duration of employment and had no exposure information for the specific industries or occupations examined. Also, prostate cancer incidence was reduced

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

among paper mill workers (SIR=0.9, 0.8–1.0), but elevated for pulp grinding (SIR=1.4, 1.0–1.9). The magnitude of dioxin exposures in these occupations or industries is unknown.

Environmental Studies

The Seveso cohort had been followed through 1991, and its mortality compared with people living in the surrounding areas of Lombardy (Bertazzi et al., 1998). In this 15-year period, among males, there were no cases in 5,541 personyears for the small group having the highest exposure (i.e., those in zone A), with 0.7 expected; 6 observed in 42,219 person-years for those in the medium-exposure zone B, with 4.8 expected for a relative risk of 1.2 (0.6–2.8); and 39 observed during 265,408 person-years for those in the low-exposure zone R, with 33 expected for an RR of 1.2 (0.8–1.7).

A further follow-up of the Seveso cohort evaluated the latency between the chemical accident that led to widespread TCDD exposure and the occurrence of various cancers from 1976 to 1996. In these 20 years of follow-up, 8 cases of prostate cancer occurred in zone B, with 3 of these in the first 4 years after exposure. Although the RR in the first 4 years is 2.2, the 95% CI is quite wide (0.7–7.1) (Bertazzi et al., 2001).

Vietnam Veterans Studies

Two studies of men who served in Vietnam examined prostate cancer incidence. The Air Force Health Study 1997 follow-up of Ranch Hand personnel did not reveal any excess of prostate cancer cases (AFHS, 2000). Ranch Hand personnel did not have higher risks than the comparison cohort, nor was the risk of prostate cancer seen to rise with increasing blood dioxin levels. Analyses of PSA (prostate-specific antigen), a biological marker of increased risk for prostate cancer, were also reported for this cohort. Most of the analyses showed no significant differences. The only analysis that showed a significant finding was one in which higher initial dioxin levels were associated with a lower prevalence of abnormally high PSA levels (AFHS, 2000).

In contrast, Australia’s Vietnam veterans did show an excess risk of prostate cancer compared to the number expected based on an Australian community standard: 212 observed versus 147 expected cases (AIHW, 1999).

Synthesis

As with previous updates, the new data are not entirely consistent, and studies focusing on mortality may have insufficient power or suffer from biases related to health care access and utilization. Among the three mortality studies, the two cohorts showing nonsignificant excesses of prostate cancer of about 20

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

percent (Bertazzi et al., 1998; Steenland et al., 1999) had the highest-quality exposure information; however, when observed associations are this weak, biases could have induced artifactually elevated risks. It is unclear what these biases may be in such varied populations involving quite different types of exposure scenarios. Generally, in studies using mortality as an outcome, detection bias is unlikely to explain any elevated risks.

On the other hand, factors that increase incidence might not be the same as those related to subsequent mortality among those with the disease. The recent introduction and widespread adoption of PS A for screening purposes has led to increased incidence rates in the United States; the long-term impact of screening on incidence or mortality rates is difficult to predict for any country or population and will depend on the rapidity with which the screening tool is adopted, its differential use across various ages of men, and the aggressiveness of tumors detected early by this test (Gann, 1997). Differences among countries in the rate of use of PSA could produce more variable, less consistent results in studies of exogenous exposures and prostate cancer.

Since prostate cancer tends not to be fatal in the overwhelming majority of cases, studies of mortality may be unable to detect an increased incidence of this disease. For this reason, a positive finding in a mortality study should be examined closely to determine whether the exposed group might have had poorer access to treatments that would decrease the likelihood of death. For example, is it possible that pesticide appliers in Florida would have had less access to medical care than their counterparts of the same ages in the general population? The finding of an excess of prostate cancer incidence would tend to weigh against this explanation, but further details on the incidence data are not available.

Similarly, weak findings in mortality studies should be viewed skeptically since these studies provide little information about the incidence of the disease. One might consider whether the exposed population had better access to care, hence reducing its risk of mortality. Is it possible that in Seveso, for example, those in the exposed zones receive more close surveillance or more aggressive medical care than those in the unexposed region? Similarly, although we do not have information on TCDD production workers, those with employment in manufacturing are more likely to have health insurance than the general U.S. population, potentially reducing the likelihood of death from an incident case of prostate cancer. The true association would then be stronger than that observed.

The excess prostate cancer incidence in the study from Sweden, the strong association in the study of Florida’s pesticide appliers, and the reference of Fleming et al. (1999b) to positive findings for incidence in the Florida cohort are all suggestive of a positive association, but unfortunately, the exposure in these cohorts is not well defined. Therefore, these studies provide some evidence that pesticide application is a risk factor for prostate cancer; they do not provide direct evidence that 2,3,7,8-TCDD or the herbicides used in Vietnam are carcinogenic to the prostate. The clear excess observed in Australia’s Vietnam veterans sup-

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

ports an association between prostate cancer and exposures incurred in Vietnam, under the assumption that the veterans are not receiving better health surveillance than the general population of the same age in that country. In contrast, the null findings among Ranch Hand personnel run counter to this conclusion. Since the Ranch Hand and comparison cohorts receive similar surveillance within the AFHS, diagnostic issues would not be expected to bias the results.

The plausibility of a causal relationship could be argued on the basis that this organ is hormonally responsive, and TCDD has been shown to be an endocrine disrupter (i.e., a chemical that alters the production or metabolism of hormones). Data concerning the effect of TCDD on hormone levels in occupationally exposed men are therefore relevant. Sweeney et al. (1997/98) examined 281 workers at two production facilities from the NIOSH study and found a trend toward elevated serum levels of follicle-stimulating hormone and luteinizing hormone (LH), and a trend for lower testosterone levels, according to the serum concentration of lipid-adjusted TCDD. These findings were from models adjusted for age, alcohol, smoking, and diabetes mellitus, and the models for LH and testosterone were also adjusted for body mass index. They suggest that exposures of workers, particularly to greater than 20 pg/g, are associated with alterations in male reproductive hormone concentrations. The prostate may be a target organ for hormonally active xenobiotics, lending biologic plausibility to an association with TCDD exposure.

Prostate cancer is a very common condition in older men. For this reason, it is likely that there are multiple factors responsible for its development. Still, even a small relative risk can mean a large number of cases. Thus, if the observed 13 percent increased incidence among Swedish pesticide appliers was due solely to exposure to dioxin, it could translate into a large number of cases. Generally speaking, for common conditions such as prostate cancer and cardiovascular disease, relative risks are not expected to be high for any particular causative factor since the background rates are already high. This situation is in contrast to that for rare diseases, where one tends to observe higher RRs.

Although the data are generally mixed, it should also be kept in mind that most Vietnam veterans have not yet reached the age at which this cancer tends to appear and that morbidity is likely to represent a more sensitive outcome than mortality for this site of cancer. Further follow-up of the Ranch Hand cohort will be particularly valuable for the assessment of this outcome.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is limited/suggestive evidence of an association between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and prostate cancer. Although the associations are not large, there are a

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

number of studies providing evidence suggestive of a small increase in either morbidity or mortality from prostate cancer. The evidence regarding association is drawn from occupational studies in which subjects were exposed to a variety of pesticides, herbicides, and herbicide components and is also based on data from studies of Vietnam veterans. A major consideration is the fact that prostate cancer tends not to be fatal; thus, mortality studies have lower statistical power to detect a comparable effect than a similar-sized morbidity (incidence) study would have. In incidence and mortality studies, comparisons of exposed and unexposed populations may be biased by differences in health care seeking behavior, access to care, and quality of care received. The high incidence of this disease in older men suggests that multiple factors are responsible for its occurrence and therefore that relative risks will not be expected to be high, even if the absolute numbers of cases are substantial.

Biologic Plausibility

No animal studies have found an increased incidence of prostate cancer. A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

Studies that have been conducted in Vietnam veterans have had a low likelihood of detecting an increased risk of prostate cancer, if service in Vietnam is actually associated with this cancer, because of weak study design and the relatively young age of Vietnam veterans. Continued follow-up of the Ranch Hand cohort for both biologic monitoring of PSA levels and verification of prostate cancer incidence will be important for determining prostate cancer risk. The statistically significant elevated prostate cancer SMRs for Australian male Vietnam veterans is suggestive that U.S. Vietnam veterans may be at increased risk. Further follow-up that includes, in particular, studies of morbidity among living veterans would help to define the risk.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

TABLE 7-21 Selected Epidemiologic Studies—Prostate Cancer

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

New Studies

Sharma-Wagner et al., 2000

Swedish citizens

Agriculture and stock raising

6,080

1.1

Farmers, foresters, and gardeners

5,219

1.1

Paper mill workers

304

0.9 (0.8–1.0)

Pulp grinding

39

1.4 (1.0–1.9)

Fleming et al., 1999a

Florida pesticide appliers

353

1.9 (1.7–2.1)

Fleming et al., 1999b

Florida pesticide appliers

64

2.4 (1.8–3.0)

Steenland et al., 1999

NIOSH cohort

28

1.2 (0.8–1.7)

Dich and Wiklund, 1998

Swedish pesticide appliers

401

1.1 (1.0–1.2)

Born 1935 or later

7

2.0 (0.8–4.2)

Born before 1935

394

1.1 (1.0–1.2)

Studies Reviewed in Update 1998

Gambini et al., 1997

Italian rice growers

19

1.0 (0.6–1.5)

Hertzman et al., 1997

Canadian sawmill workers

Mortality

282

1.0 (0.9–1.1)

Morbidity for male genital tract cancers

116

1.2 (1.0–1.4)

Kogevinas et al., 1997

IARC cohort

43

1.1 (0.8–1.5)

Becher et al., 1996

German chemical production workers

9

1.3

Ott and Zober, 1996

BASF cleanup workers

4

1.1 (0.3–2.8)

Zhong and Rafnsson, 1996

Icelandic pesticide users

10

0.7 (0.3–1.2)

Studies Reviewed in Update 1996

Asp et al., 1994

Finnish herbicide appliers

5

0.8 (0.3–1.8)

Blair et al., 1993

U.S. farmers in 23 states

Whites

3,765

1.2 (1.1–1.2)

Non whites

564

1.1 (1.1–1.2)

Bueno de Mesquita et al., 1993

Dutch production workers

3

2.6 (0.5–7.7)

Collins et al., 1993

Monsanto 2,4-D production workers

9

1.6 (0.7–3.0)

Studies Reviewed in VAO

Morrison et al., 1993

Canadian farmers, age 45–69 years, no employees, or custom workers, sprayed ≥250 acres

20

2.2 (1.3–3.8)

Ronco et al., 1992

Danish self-employed farm workers

399

0.9 (p < .05)

Swaen et al., 1992

Dutch herbicide appliers

1

1.3 (0.0–7.3)

Fingerhut et al., 1991

NIOSH cohort

17

1.2 (0.7–2.0)

20-year latency, 1-year exposure

9

1.5 (0.7–2.9)

Manz et al., 1991

German production workers

7

1.4 (0.6–2.9)

Saracci et al., 1991

IARC cohort

30

1.1 (0.8–1.6)

Zober et al., 1990

BASF production workers

0

— (0.0–7.5)

Alavanja et al., 1989

USDA forest conservationists

 

1.6 (0.9–3.0)

Soil conservationists

 

1.0 (0.6–1.8)

Henneberger et al., 1989

Paper and pulp workers

9

1.0 (0.7–2.0)

Solet et al., 1989

Paper and pulp workers

4

1.1 (0.3–2.9)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Alavanja et al., 1988

USDA agricultural extension agents

 

1.0 (0.7–1.5)

Bond et al., 1988

Dow 2,4-D production workers

1

1.0 (0.0–5.8)

Coggon et al., 1986

British MCPA production workers

18

1.3 (0.8–2.1)

Robinson et al., 1986

Paper and pulp workers

17

1.2 (0.7–2.0)

Lynge, 1985

Danish production workers

9

0.8

Blair et al., 1983

Florida pesticide appliers

2

0.5

Burmeister et al., 1983

Iowa residents

 

1.2 (p < .05)

Wiklund, 1983

Swedish agricultural workers

3,890

1.0 (0.9–1.0)b

Burmeister, 1981

Iowa farmers

1,138

1.1 (p< .01)

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso residents—20-year follow-up

Zone B males

8

1.2 (0.6–2.4)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

Zone B males

6

1.2 (0.6–2.8)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

Zone B males

6

1.2 (0.5–2.7)

Zone R males

39

1.2 (0.8–1.6)

Svensson et al., 1995

Swedish fishermen, mortality

12

1.0 (0.5–1.8)

Swedish fishermen, incidence

38

1.1 (0.8–1.5)

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up, morbidity

 

 

Zone R males

16

0.9 (0.5–1.5)

Studies Reviewed in VAO

Pesatori et al., 1992

Seveso residents

Zones A, B males

4

1.4 (0.5–3.9)

Bertazzi et al., 1989a

Seveso residents—10-year follow-up

Zones A, B, R males

19

1.6 (1.0–2.7)

Bertazzi et al., 1989b

Seveso residents—10-year follow-up

Zone B males

3

2.2 (0.7–6.9)

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans

26

0.7 (0.4–1.3)

AIHW, 1999

Australian Vietnam veterans—male

212

147 expected (123–171)

CDVA, 1998a

Australian Vietnam veterans—male

428c

147 expected (123–171)

Studies Reviewed in Update 1998

Clapp, 1997

Massachusetts Vietnam veterans Exposed cancers

15

0.8 (0.4–1.6)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Crane et al., 1997a

Australian military Vietnam veterans

36

1.5 (1.1–2.1)

Army

26

1.6 (1.1–2.4)

Navy

8

2.2 (0.9–4.3)

Air Force

2

0.5 (0.1–1.9)

AFHS, 1996

Air Force Ranch Hand veterans

2

4.0

Watanabe and Kang, 1996

Army Vietnam veterans

58

0.9

16+ years after discharge

 

1.1

Studies Reviewed in Update 1996

Visintainer et al., 1995

Michigan Vietnam veterans

19

1.1 (0.6–1.7)

Studies Reviewed in VAO

Breslin et al., 1988

Army Vietnam veterans

30

0.9 (0.6–1.2)

Marine Vietnam veterans

5

1.3 (0.2–10.3)

Anderson et al., 1986b

Wisconsin Vietnam veterans

2

NOTE: MCPA=methyl-4-chlorophenoxyacetic acid; USDA=United States Department of Agriculture.

aGiven when available.

b99% CI.

cSelf-reported medical history. Answer to question: Since your first day of service in Vietnam, have you been told by a doctor that you have prostate cancer?

TESTICULAR CANCER

Background

The American Cancer Society estimates that 6,900 men will be diagnosed with testicular cancer (ICD•9 186.0–186.9) in the United States in 2000 and that 300 will die from the disease (ACS, 2000a).

Testicular cancer is far more likely in men younger than 40 than in those who are older. On a lifetime basis, the risk for white men is about four times greater than for African Americans. Cryptorchidism, or undescended testicles, is a major risk factor for testicular cancer. Family history of the disease also appears to play a role. Several other hereditary and environmental factors have been suggested, but research regarding them is inconsistent (Bosl and Motzer, 1997).

Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa

Testicular Cancer

45–49 Years of Age

50–54 Years of Age

55–59 Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

5.6

6.3

1.3

3.6

4.1

0.4

2.1

2.3

1.0

aSEER nine standard registries, crude age-specific rate, 1993–1997.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and testicular cancer. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Table 7-22 provides summaries of the results of the studies underlying these findings and a list of reports that contain details of the research.

Update of the Scientific Literature

Occupational Studies

A case-control study of occupational risk factors for testicular cancer was conducted by Hardell et al. (1998). The researchers identified cases between 30 and 75 years of age from the Swedish Cancer Registry over the period 1989– 1992. Controls were age matched, with two identified for each case. There were 4 cases of testicular cancer among cases with self-reported occupational exposure to herbicides and 24 cases among controls, leading to an OR of 0.3 (0.1–1.0).

Fleming et al. (1999b) examined cancer incidence over the years 1975–1993 in a cohort of licensed pesticide appliers in Florida. Phenoxy herbicides were among the exposures for this cohort. Age-matched incidence data for the Florida general population were used for comparison. The researchers found a statistically significant elevation in testicular cancer (SIR=2.5, 1.6–3.7; based on 23 cases) in the pesticide appliers.

Environmental Studies

The 15-year follow-up of people environmentally exposed to TCDD in a 1976 industrial accident in Seveso, Italy (Bertazzi et al., 1998), did not report testicular cancer separately, but instead subsumed it into a category called “genitourinary cancers” (ICD•9 179–189). No deaths among males were recorded in this category in zone A, the high-exposure area. In zone B, the medium-exposure area, 10 deaths were observed where 10.5 were expected (RR=1.0, 0.5–1.8); in the low-exposure zone, R, 73 deaths were observed where 72.3 were expected (1.0, 0.8–1.3). A later study (Bertazzi et al., 2001) extending the mortality analysis to 20 years following the event reported 1 genitourinary cancer death in zone A (0.5, 0.1–3.7) and 16 in zone B (1.1, 0.7–1.8).

Vietnam Veteran Studies

The 15-year update of the Ranch Hand study (AFHS, 2000) reported 3 cases of testicular neoplasms: 1 in the low initial dioxin category and 2 in the medium.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

No cases were found among the comparison population. The small number of cases did not permit meaningful statistical analysis of this outcome.

The government of Australia conducted mail surveys of 49,944 male veterans (80 percent response rate) who served in Vietnam, including those involved in combat, medical teams, war correspondents, entertainers, and philanthropy workers (CDVA, 1998a). The self-report data that were gathered were compared with age-matched Australian national data. Of the veterans, 151 indicated that they been told by a doctor that they had cancer of the testis since their first day of service in Vietnam. This was significantly in excess of the expected number of cases, 110 (expected range=89–131). However, it was noted that there was a potential for benign tumors of the testis, scrotum, and epididymis to have been misreported as testicular cancer. A follow-up to this study was conducted to medically confirm selected conditions reported in the survey (AIHW, 1999). Sources used to validate reported conditions included clinicians, several Australian morbidity and mortality data bases, DVA data, and documentation provided by the veterans. Based on these data, the authors estimated that there were 59 validated cases of cancer of the testis among respondents, fewer than the expected number.

Synthesis

The relatively low incidence of testicular cancer reported in the studies reviewed by the committee complicates their evaluation. Among the studies reviewed in this report, only Fleming et al. (1999b) reported a statistically significant difference between the observed and expected number of cases. However, the pesticide appliers studied by these researchers were likely exposed to a wide variety of chemicals, making it difficult to ascribe any effect to a particular compound. Studies with either large numbers of cases or known TCDD exposures do not show an increased risk among males exposed to the herbicides used in Vietnam or dioxin.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that 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) and testicular cancer.

Biologic Plausibility

No animal studies have found an increased incidence of testicular cancer. A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×
Increased Risk of Disease Among Vietnam Veterans

There are insufficient data on testicular cancer in Vietnam veterans to draw a specific conclusion as to whether or not they are at increased risk.

TABLE 7-22 Selected Epidemiologic Studies—Testicular Cancer

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

New Studies

Fleming et al., 1999

Florida pesticide appliers

23

2.5 (1.6–3.7)

Hardell et al., 1998

Workers exposed to herbicides

4

0.3 (0.1–1.0)

Studies Reviewed in Update 1998

Hertzman et al., 1997

British Columbia sawmill workers

Mortality

116b

1.0 (0.8–1.1)

Incidence

18

1.0 (0.6–1.4)

Kogevinas et al., 1997

IARC cohort

7

1.3 (0.5–2.7)

Ramlow et al., 1996

Pentachlorophenol production workers

0

Studies Reviewed in Update 1996

Blair et al., 1993

U.S. farmers in 23 states

White males

32

0.8 (0.6–1.2)

Nonwhite males

6

1.3 (0.5–2.9)

Studies Reviewed in VAO

Ronco et al., 1992

Danish self-employed farm workers

74

0.9

Saracci et al., 1991

IARC cohort

7

2.3 (0.9–4.6)

Bond et al., 1988

Dow 2,4-D production workers

1

4.6 (0.0–25.7)

Coggon et al., 1986

British MCPA production workers

4

2.2 (0.6–5.7)

Wiklund, 1983

Swedish agricultural workers

101

1.0 (0.7–1.2)c

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso residents—20-year follow-up

Zone A males

1

0.5 (0.1–3.7)

Zone B males

16

1.1 (0.7–1.8)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

Zone B males

10

1.0 (0.5–1.8)

Zone R males

73

1.0 (0.8–1.3)

Studies Reviewed in Update 1998

Zhong and Rafnsson, 1996

 

 

Icelandic pesticide users

2

1.2 (0.1–4.3)

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up, morbidity

Zone B males

1

1.0 (0.1–7.5)

Zone R males

9

1.4 (0.7–3.0)

Studies Reviewed in VAO

Pesatori et al., 1992

Seveso residents

Zones A, B males

1

0.9 (0.1–6.7)

Zone R males

9

1.5 (0.7–3.0)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans

3

AIHW, 1999

Australian Vietnam veterans—male

59

110 expected (89–131)

CDVA, 1998a

Australian Vietnam veterans—male

151d

110 expected (89–131)

Studies Reviewed in Update 1998

Clapp, 1997

Massachusetts Vietnam veterans—incidence

30

1.2 (0.4–3.3)

Crane et al., 1997a

Australian military Vietnam veterans

4

NS

Crane et al., 1997b

Australian national service Vietnam veterans

4

1.3

Dalager and Kang, 1997

Army Chemical Corps veterans

2

4.0 (0.5–14.5)

Watanabe and Kang, 1996

Vietnam service, Army

 

1.1

Vietnam service, Marines

 

1.0

Studies Reviewed in Update 1996

Bullman et al., 1994

Navy veterans

12

2.6 (1.1–6.2)

Studies Reviewed in VAO

Tarone et al., 1991

Patients at three Washington, D.C., area hospitals

 

2.3 (1.0–5.5)

Watanabe et al., 1991

Army Vietnam veterans

109

1.2

Marine Vietnam veterans

28

0.8

Breslin et al., 1988

Army Vietnam veterans

90

1.1 (0.8–1.5)

Marine Vietnam veterans

26

1.3 (0.5–3.6)

Anderson et al., 1986a

Wisconsin Vietnam veterans

11

1.0 (0.5–1.7)

Anderson et al., 1986b

Wisconsin Vietnam veterans

9

1.0 (0.5–1.9)

NOTE: MCPA=methyl-4-chlorophenoxyacetic acid; NS=not significant.

aGiven when available.

b“Male genital cancers.”

c99% CI.

dSelf-reported medical history. Answer to question: Since your first day of service in Vietnam, have you been told by a doctor that you have cancer of the testis?

URINARY BLADDER CANCER

Background

Urinary bladder cancer (ICD•9 188.0–188.9) is the most common of the genitourinary tract cancers. According to American Cancer Society estimates, 38,300 men and 14,900 women will be diagnosed with this cancer in the United States in 2000, and 8,100 men and 4,100 women will die from the disease (ACS, 2000a). In males, where this cancer is about three times more likely to occur than

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

in females, these numbers represent approximately 6 percent of new cancer diagnoses and 3 percent of deaths. Overall, bladder cancer is the fifth most common cancer and the fifth leading cause of cancer death in the United States.

Among males in the age groups that characterize most Vietnam veterans, bladder cancer incidence is about twice as high in whites as in African Americans. Rates are slightly higher in white women than in African-American women. Bladder cancer incidence increases greatly with age for individuals older than 40. For the age groups shown below, the incidence rate in each 5-year grouping is roughly double that of the age group before it.

The most important known risk factor for bladder cancer is smoking. About half of bladder cancers in men and one-third in women are thought to be due to smoking (Miller et al., 1996). Occupational exposures to aromatic amines (also called arylamines), poly cyclic aromatic hydrocarbons (PAHs), and certain other organic chemicals used in the rubber, leather, textile, paint products, and printing industries are also associated with higher incidence. High-fat diets have been implicated as risk factors, along with exposure to the parasite Schistosoma haematobium.

Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa

Urinary Bladder Cancer

 

45–49 Years of Age

50–54 Years of Age

55–59 Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

13.8

15.1

8.3

27.1

29.1

16.5

49.9

53.7

30.1

Females

4.1

4.7

2.9

9.1

10.2

5.1

14.7

16.3

8.5

aSEER nine standard registries, crude age-specific rate, 1993–1997.

Summary of VAO, Update 1996, and Update 1998

The committees responsible for VAO and Update 1996 found that there was limited or suggestive evidence of no association between exposure to herbicides used in Vietnam or the contaminant dioxin and urinary bladder cancer. Additional information available to the committee responsible for Update 1998 led it to change this conclusion to that of inadequate or insufficient information regarding an association. Table 7-23 provides summaries of the results of the studies underlying these findings and a list of reports that contain details of the research.

Update of Scientific Literature

Occupational Studies

Hooiveld et al. (1998) conducted a retrospective cohort study of 549 exposed and 482 unexposed male Dutch production and contract workers exposed to

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

phenoxy herbicides, chlorophenols, and contaminants between 1950 and 1976. Four deaths attributed to bladder cancer were identified, leading to a marginally significant standardized mortality ratio of 3.7 (1.0–9.5). A separate analysis of 140 male workers exposed to TCDD as a result of an accident recorded one death due to bladder cancer (SMR=2.8, 0.1–15.5).

In an updated analysis of cohorts involved in the NIOSH study, Steenland et al. (1999) performed mortality analyses involving 5,132 chemical workers at 12 U.S. plants by use of life table techniques (U.S. population referent) and Cox regression (internal referent). The SMR for bladder cancer was based on 16 deaths (6 in the high-exposure group) and was 2.0 (1.1–3.2) for the total cohort and 3.0 (1.4–8.5) for the chloracne cohort. Although the case numbers among the high-exposure cohort were relatively few and the authors did not comment specifically on this organ site, the SMR associated with bladder cancer in individuals with high exposure was the second highest among all diagnostic categories. However, the authors point out that this association is complicated by the fact that the observed elevation in bladder cancer cases was largely due to an excess at only a single plant (which accounted for 10 of the 16 deaths) where there was also exposure to 4-aminobiphenyl, an arylamine that is a well-established human bladder carcinogen (IARC, 1987).

Environmental Studies

The follow-up of people environmentally exposed to TCDD in a 1976 industrial accident in Seveso, Italy, continues. The events that led to the exposure and the methods used to study this population are described in earlier reports and in Chapter 6. Bertazzi et al. (1998) updated the analysis after 15 years’ follow-up. There were no deaths from bladder cancers among females in zones A (high-exposure area) or B (medium-exposure area). The numbers of deaths observed among females in zone R (low-exposure area) and among males in all three zones were not statistically different from the numbers expected. A later study (Bertazzi et al., 2001) extends the mortality analysis to 20 years following the event for zones A and B. Two additional deaths were observed in zone B, but the overall results were again statistically indistinguishable from expected numbers.

Schreinemachers’ (2000) examination of cancer mortality over the years 1980–1989 in four northern wheat-producing states combined the analysis of bladder cancer with other cancers of the urinary organs (ICD•9 189.3). This analysis, which used wheat acreage per county as a surrogate for exposure to chlorophenoxy herbicides (including 2,4-D), found slightly lower than expected age-standardized mortality rate ratios (SRRs) for these cancers for white males and slightly higher than expected SRRs for white females. None of the values were statistically significant.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×
Vietnam Veteran Studies

In their 15-year update of the Ranch Hand study, AFHS (2000) researchers reported a relatively sparse number of malignant neoplasms of the kidney or bladder combined among Ranch Hands (11 of 861) and comparisons (6 of 1,249) (RR=3.1, 0.9–11.0; Model 1, adjusted). After adjustment for covariates, the incidence in Ranch Hands in the low-dioxin category (5 cases) was higher than in comparisons, but the confidence interval is quite wide (RR=4.4, 1.0–19.0; Model 3, adjusted). All other comparisons based on occupation, rank, and dioxin category did not show significant elevated risk for Ranch Hands.

Synthesis

Various factors complicate the interpretation of the newest studies of urinary bladder cancer. Coexposure to TCDD and the known bladder carcinogen 4-aminobiphenyl in one plant examined in the Steenland et al. (1999) study makes it very difficult to discern whether dioxin exposure affected the observed incidence. Bladder and kidney cancers—data which were combined for analysis in AFHS (2000) —have a common association with smoking but are otherwise etiologically distinct diseases, weakening the informativeness of the AFHS results. Other studies are hampered by the small number of bladder cancer cases identified.

Nonetheless, the recent research on urinary bladder and kidney cancer raises questions about the possibility of an association with herbicide or dioxin exposure. The committee encourages further follow-up on the AFHS and occupational cohorts and urges researchers to separate kidney and bladder cancers in their analyses and to fully control for exposure to other potential or known bladder carcinogens in the occupational setting.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that 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) and urinary bladder cancer.

Biologic Plausibility

No animal studies have found an increased incidence of urinary bladder cancer. A summary of the biologic plausibility for the carcinogenicity of TCDD

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

Although limited data available on Vietnam veterans do suggest they may be at an elevated risk for urinary bladder cancer, the estimated risk ratios are very unstable. Further studies of Ranch Hand Air Force veterans may clarify whether exposures incurred in Vietnam, or dioxin in particular, are associated with altered risks for bladder cancer.

TABLE 7-23 Selected Epidemiologic Studies—Urinary Bladder Cancer

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

New Studies

Steenland et al., 1999

U.S. chemical production workers

Total cohort

16

2.0 (1.1–3.2)

High-exposure cohort

6

3.0 (1.4–8.5)

Hooiveld et al., 1998

Male Dutch production and contract workers

Total cohort

4

3.7 (1.0–9.5)

Accidentally exposed subcohort

1

2.8 (0.1–15.5)

Studies Reviewed in Update 1998

Hertzman et al., 1997

British Columbia sawmill workers

Mortality

33

0.9 (0.7–1.2)

Incidence

94

1.0 (0.8–1.2)

Kogevinas et al., 1997

IARC cohort

Workers exposed to TCDD (or higher-chlorinated dioxins)

24

1.4 (0.9–2.1)

Workers exposed to any phenoxy herbicide or chlorophenol

34

1.0 (0.7–1.5)

Studies Reviewed in Update 1996

Asp et al., 1994

Finnish herbicide appliers—incidence

12

1.6 (0.8–2.8)

Bueno de Mesquita et al., 1993

Dutch production workers

1

1.2 (0.0–6.7)

Collins et al., 1993

Monsanto 2,4-D production workers

16b

6.8 (3.9–11.1)

Studies Reviewed in VAO

Ronco et al., 1992

Danish male self-employed farmers

300

0.6 (p < .05)

Fingerhut et al., 1991

NIOSH cohort

9

1.6 (0.7–3.0)

20-year latency

4

1.9 (0.5–4.8)

Green, 1991

Herbicide sprayers in Ontario

1

1.0 (0.0–5.6)

Saracci et al., 1991

IARC cohort

13

0.8 (0.2–1.4)

Zober et al., 1990

BASF production workers

0

— (0.0–15.0)

Alavanja et al., 1989

USDA forest or soil conservationists

8

0.8 (0.3–1.6)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Henneberger et al., 1989

Mortality among paper and pulp workers

4

1.2 (0.3–3.2)

Alavanja et al., 1988

USDA agricultural extension agents

8

0.7 (0.4–1.4)

Bond et al., 1988

Dow 2,4-D production workers

0

— (0.0–7.2)

Coggon et al., 1986

British MCPA production workers

8

0.9 (0.4–1.7)

Robinson et al., 1986

Paper and pulp workers

8

1.2 (0.6–2.6)

Lynge, 1985

Danish male production workers

11

0.8

Blair et al., 1983

Florida pesticide appliers

3

1.6

Burmeister, 1981

Farmers in Iowa

274

0.9 (NS)

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso residents—20-year follow-up

Zone A males

1

1.7 (0.2–12.0)

Zone B males

5

1.1 (0.5–2.8)

Schreinemachers, 2000

Rural or farm residents of Minnesota, Montana, North Dakota, and South Dakota

 

 

Males—counties with wheat acreage 23,000–110,999

147

0.8 (0.7–1.0)

Males—counties with wheat acreage >111,000

129

0.9 (0.7–1.1)

Females—counties with wheat acreage 23,000–110,999

67

1.1 (0.8–1.5)

Females—counties with wheat acreage >111,000

59

1.1 (0.8–1.6)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

Zone A males

1

2.4 (0.3–16.8)

Zone B males

3

0.9 (0.3–3.0)

Zone R males

21

0.9 (0.6–1.5)

Zone R females

4

0.6 (0.2–1.8)

Studies Reviewed in Update 1998

Gambini et al., 1997

Italian rice growers

12

1.0 (0.5–1.8)

Ott and Zober, 1996

BASF cleanup workers

2

1.4 (0.4–3.2)

Svensson et al., 1995

Swedish fishermen, mortality

East coast

1.3 (0.4–3.1)

West coast

1.0 (0.6–1.6)

Swedish fishermen, incidence

East coast

0.7 (0.4–1.3)

West coast

0.9 (0.7–1.1)

Studies Reviewed in VAO

Pesatori et al., 1992

Seveso residents

Zones A, B males

10

1.6 (0.9–3.1)

Zones A, B females

1

0.9 (0.1–6.8)

Lampi et al., 1992

Finnish community exposed to chlorophenols

 

1.0 (0.6–1.9)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans

11

3.1 (0.9–11.0)

Studies Reviewed in Update 1998

Clapp, 1997

Massachusetts Vietnam veterans

80

0.6 (0.2–1.3)

Crane et al., 1997a

Australian military Vietnam veterans

11

1.1 (0.6–2.0)

Crane et al., 1997b

Australian national service Vietnam veterans

1

0.6

Studies Reviewed in VAO

Breslin et al., 1988

Army Vietnam veterans

9

0.6 (0.3–1.2)

Marine Vietnam veterans

4

2.4 (0.1–66.4)

Anderson et al., 1986a

Wisconsin Vietnam veterans

0

Anderson et al., 1986b

Wisconsin Vietnam veterans

1

NOTE: MCPA=methyl-4-chlorophenoxyacetic acid; NS=not significant; USDA=United States Department of Agriculture.

aGiven when available.

bMany of the employees studied were also exposed to 4-aminobiphenyl, a known bladder carcinogen.

RENAL CANCER

Background

Cancers of the kidney (ICD•9 189.0) and renal pelvis (ICD•9 189.1) are often grouped together in epidemiologic studies; cancer of the ureter (ICD•9 189.2) may also be aggregated with these. Although the diseases of these organs have different characteristics and may have different risk factors, there is logic to this aggregation because these structures are all exposed to filterable compounds, such as poly cyclic aromatic hydrocarbons, that appear in urine. The American Cancer Society estimates that 18,800 men and 12,400 women will be diagnosed with renal cancers (ICD•9 189.0, 189.1) in the United States in 2000 and that 7,300 men and 4,600 women will die from the disease (ACS, 2000a). These figures represent between 2 and 3 percent of all new cancer diagnoses and deaths.

Renal cancer is twice as common in men as in women. In the age groups that represent most Vietnam veterans, African-American men have a slightly higher incidence than white men; African-American and white women have roughly the same rate of the disease. With the exception of Wilm’s tumor (which is more likely to occur in children), renal cancer is more common in individuals older than 50 years of age.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Smoking is a well-established risk factor for renal cancer. Phenacetin-containing analgesic abuse has also been implicated. Individuals with certain rare syndromes—notably, von Hippel-Lindau syndrome and tuberous sclerosis—are at higher risk. Other potential factors include diet, weight, and occupational exposure to asbestos and cadmium. Firefighters, who are routinely exposed to numerous pyrolysis products, are a known higher-risk group.

Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa

Kidney and Renal Pelvis Cancer

 

45–49 Years of Age

50–54 Years of Age

55–59 Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

12.9

12.2

21.2

23.0

22.5

37.4

32.8

32.7

41.7

Females

5.7

5.6

8.0

10.6

10.5

13.7

15.6

16.0

19.4

aSEER nine standard registries, crude age-specific rate, 1993–1997.

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and renal cancer. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Table 7-24 provides summaries of the results of the studies underlying these findings and a list of reports that contain details of the research.

Update of the Scientific Literature

Occupational Studies

Hooiveld et al. (1998) conducted a retrospective cohort study of 549 exposed and 482 unexposed male Dutch production and contract workers exposed to phenoxy herbicides, chlorophenols, and contaminants between 1950 and 1976. Four deaths attributed to kidney cancer were identified, leading to a statistically significant standardized mortality ratio of 4.1 (1.1–10.4). A “urinary organs” category combining bladder and kidney cancer produced an SMR of 3.9 (1.7– 7.6), based on 8 deaths. No kidney cancer deaths were recorded in a separate analysis of 140 male workers exposed to TCDD as a result of an accident.

In the update of the industrial cohort exposed to dioxins known as the NIOSH cohort, Steenland et al. (1999) performed mortality analyses involving 5,132 chemical workers at 12 U.S. plants by use of life table techniques (U.S. population referent) and Cox regression (internal referent). The SMR for kidney cancer

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

was 1.6 (0.8–2.7), based on 13 deaths. No Cox regression analysis was conducted for renal cancer.

Environmental Studies

Bertazzi and colleagues’ (2001) most recent follow-up of people environmentally exposed to TCDD in a 1976 industrial accident in Seveso, Italy, extends the mortality analysis to 20 years following the event. Details of this ongoing study are given in Chapter 6. There were no deaths from kidney cancers among individuals in zone A, the high-exposure area. Three deaths each were reported for males (RR=0.9, 0.3–3.0) and females (RR=2.1, 0.7–6.7) in zone B, the medium-exposure area. These figures were not distinguishable from the expected numbers of deaths.

Schreinemachers’ (2000) examination of cancer mortality over the years 1980–1989 in four northern wheat-producing states combined kidney and ureter cancer for analysis (ICD•9 189 excluding 189.3). This analysis, which used wheat acreage per county as a surrogate for exposure to chlorophenoxy herbicides (including 2,4-D), reported age-standardized mortality rate ratios near unity for white males and females. A trend of increasing SMR as a function of acreage per county was noted for males.

Vietnam Veteran Studies

In their 15-year update of the Ranch Hand study, AFHS (2000) researchers reported a relatively sparse number of malignant neoplasms of the kidney or bladder combined among Ranch Hands (11 of 861) and comparisons (6 of 1,249) (RR=3.1, 0.9–11.0; Model 1, adjusted). After adjustment for covariates, there was a marginally significant difference in incidence between Ranch Hands in the low-dioxin category (5 cases) and comparisons (RR=4.4, 1.0–19.0; Model 3, adjusted). All other comparisons based on occupation, rank, and dioxin category did not achieve statistical significance.

Synthesis

Studies of renal cancer published since Update 1998 continue the pattern of equivocal results seen previously. The informativeness of the Hooiveld et al. (1998) results is limited by the lack of control for smoking—a known confounder. Cigarette smoking also covaried with the indicators of herbicide exposure used by AFHS researchers, confounding their analyses. The elevated incidence observed in the AFHS cohort was seen in Ranch Hands in the low-dioxin category but not the high-dioxin category, which would not be expected if an association existed between exposure and the outcome.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that 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) and renal cancer.

Biologic Plausibility

No animal studies have found an increased incidence of renal cancer. A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides in general is presented in the conclusion to this chapter. A discussion of toxicological studies that concern biologic plausibility is contained in Chapter 3.

Increased Risk of Disease Among Vietnam Veterans

The limited data available on Vietnam veterans do not suggest they are at an elevated risk for renal cancer.

TABLE 7-24 Selected Epidemiologic Studies—Renal Cancer

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

OCCUPATIONAL

New Studies

Steenland et al., 1999

U.S. chemical production workers

13

1.6 (0.8–2.7)

Hooiveld et al., 1998

Male Dutch production and contract workers

Total cohort—kidney cancer

4

4.1 (1.1–10.4)

Total cohort—“urinary organs”

8

3.9 (1.7–7.6)

Accidentally exposed subcohort

0

Studies Reviewed in Update 1998

Kogevinas et al., 1997

IARC cohort

Workers exposed to TCDD (or higher-chlorinated dioxins)

26

1.6 (1.1–2.4)

Workers exposed to any phenoxy herbicide or chlorophenol

 

1.1 (0.7–1.6)

Studies Reviewed in Update 1996

Mellemgaard et al., 1994

Danish Cancer Registry patients

Occupational herbicide exposure among males

13

1.7 (0.7–4.3)

Occupational herbicide exposure among females

3

5.7 (0.6–5.8)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

Blair et al., 1993

U.S. farmers in 23 states

White males

522

1.1 (1.0–1.2)

Nonwhite males

30

White females

6

Nonwhite females

6

Studies Reviewed in VAO

Ronco et al., 1992

Danish male self-employed farm workers

141

0.6 (p < .05)

Fingerhut et al., 1991

NIOSH cohort

8

1.4 (0.6–2.8)

Manz et al., 1991

German production workers

3

1.6 (0.3–4.6)

Saracci et al., 1991

IARC cohort

11

1.0 (0.5–1.7)

Alavanja et al., 1989

USDA forest conservationists

 

1.7 (0.5–5.5)

Soil conservationists

 

2.4 (1.0–5.9)

Henneberger et al., 1989

Paper and pulp workers

3

1.5 (0.3–4.4)

Alavanja et al., 1988

USDA agricultural extension agents

 

1.7 (0.9–3.3)

Bond et al., 1988

Dow 2,4-D production workers

0

— (0.0–6.2)

Robinson et al., 1986

Paper and pulp workers

6

1.2 (0.5–3.0)

Coggon et al., 1986

British MCPA production workers

5

1.0 (0.3–2.3)

Lynge, 1985

Danish male production workers

3

0.6

Wiklund, 1983

Swedish agricultural workers

775

0.8 (0.7–0.9)b

Blair et al., 1983

Florida pesticide appliers

1

0.5

Burmeister, 1981

Farmers in Iowa

178

1.1 (NS)

ENVIRONMENTAL

New Studies

Bertazzi et al., 2001

Seveso residents—20-year follow-up

Zone B males

3

0.9 (0.3–3.0)

Zone B females

3

2.1 (0.7–6.7)

Schreinemachers, 2000

Rural or farm residents of Minnesota, Montana, North Dakota, and South Dakota

 

Males—counties with wheat acreage 23,000–110,999

147

1.0 (0.8–1.2)

Males—counties with wheat acreage >111,000

129

1.0 (0.8–1.3)

Females—counties with wheat acreage 23,000–110,999

85

0.9 (0.7–1.2)

Females—counties with wheat acreage >111,000

90

1.1 (0.8–1.4)

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up, morbidity

 

Zone R males

10

0.9 (0.4–1.7)

Zone R females

7

1.2 (0.5–2.7)

Studies Reviewed in VAO

Pesatori et al., 1992

Seveso residents

Zones A, B males

0

Zones A, B females

1

1.1 (0.2–8.1)

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population

Exposed Casesa

Estimated Risk (95% CI)a

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans

11

3.1 (0.9–11.0)

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

22

1.2 (0.8–1.9)

Crane et al., 1997b

Australian national service Vietnam veterans

3

3.9

Studies Reviewed in Update 1996

Visintainer et al., 1995

Michigan Vietnam veterans

21

1.4 (0.9–2.2)

Studies Reviewed in VAO

Breslin et al., 1988

Army Vietnam veterans

55

0.9 (0.5–1.5)

Marine Vietnam veterans

13

0.9 (0.5–1.5)

Kogan and Clapp, 1988

Massachusetts Vietnam veterans

9

1.8 (1.0–3.5)

Anderson et al., 1986a

Wisconsin Vietnam veterans

1

Anderson et al., 1986b

Wisconsin Vietnam veterans

2

NOTE: MCPA=methyl-4-chlorophenoxyacetic acid; NS=not significant; USDA=United States Department of Agriculture.

aGiven when available.

b99% CI.

BRAIN TUMORS

Background

According to the American Cancer Society, approximately 9,500 men and 7,000 women will be diagnosed with new cases of brain and other nervous system cancers (ICD•9 191.0–191.9, 192.0–192.3, 192.8–192.9) in the United States in 2000, and 7,100 men and 5,900 women will die from these cancers (ACS, 2000a). These numbers represent approximately 1.4 percent of new cancer diagnoses and 2.4 percent of all cancer deaths.

For individuals in the United States age 45–59, brain cancer is slightly more common in males than females and slightly more common in whites than African Americans.

Exposure to ionizing radiation is an established risk factor for brain cancer. Several other potential factors have been examined, but the American Cancer Society notes that the majority of brain cancers are not associated with any known risk factors.

Suggested Citation:"7 Cancer." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Average Annual Cancer Incidence (per 100,000 individuals) in the United Statesa

Brain and Other Nervous System Cancers

 

45–49 Years of Age

50–54 Years of Age

55–59 Years of Age

 

All Races

White

Black

All Races

White