National Academies Press: OpenBook

Veterans and Agent Orange: Update 2004 (2005)

Chapter: 6 Cancer

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Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

6
Cancer

Cancer is the second leading cause of death in the United States. Among men aged 45–64, the group that includes most Vietnam veterans, the risk of dying from cancer nearly equals the risk of dying from heart disease, the main cause of death in the United States (US Census, 1999). In 2004, about 563,700 Americans are expected to die from cancer—more than 1,500 people per day. In the United States, one of every four deaths is from cancer (ACS, 2004a).

In this chapter, the Veterans and Agent Orange: Update 2004 committee summarizes and reaches conclusions about the strength of the evidence from epidemiologic studies regarding associations between exposure to the compounds of interest (2,4-dichlorophenoxyacetic acid [2,4-D]; 2,4,5-trichlorophenoxyacetic acid [2,4,5-T] or its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]; picloram; cacodylic acid) and each type of cancer under consideration in the report. For any new study that reports on just a single type of cancer and that does not revisit a previously studied population, its design information is summarized here with its results; design information for all other new studies can be found in Chapter 4, and tables that summarize the major studies are in Appendix A. 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 the classification used to code and classify mortality data from death certificates. ICD-9 CM (clinical modification) is used to code and classify morbidity data from medical records, hospital records, and surveillance surveys. Appendix C lists ICD-9 codes (and corresponding ICD-10 codes) for the major forms of cancer. The categories of association and the committee’s approach to categorizing the health outcomes are discussed in Chapters 1 and 2.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

In assessing a possible connection between herbicide exposure and risk of cancer, one important issue is the magnitude of exposure for the people included in a study. As noted in Chapter 5, there is a great variety in detail and accuracy of exposure assessment among the studies the committee reviewed. A small number used biologic markers of exposure, such as the presence of a compound in serum or tissues; some developed an index of exposure from employment or activity records; others used surrogate measures 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.

In this chapter, background information about each cancer, including data on its incidence in the general US population, is followed by a summary of the findings described in the previous Agent Orange reports (Veterans and Agent Orange, hereafter referred to as VAO [IOM, 1994]; Veterans and Agent Orange: Update 1996, hereafter, Update 1996 [IOM, 1996]; Veterans and Agent Orange: Update 1998, hereafter, Update 1998 [IOM, 1999]; Veterans and Agent Orange: Update 2000, hereafter, Update 2000 [IOM, 2001]; and Veterans and Agent Orange: Update 2002, hereafter, Update 2002 [IOM, 2003]), a discussion of the most recent scientific literature, and a synthesis of the material reviewed. Where appropriate, the literature is discussed by exposure type (occupational, environmental, service in Vietnam). Each section ends with the committee’s conclusion regarding the strength of the evidence from epidemiologic studies, biologic plausibility, and evidence regarding epidemiology and Vietnam veterans.

Cancer incidence data for the general US population are included in the background sections to provide a context for consideration of cancer risk in Vietnam veterans. Incidences are reported for people 50–64 years old because most Vietnam-era veterans are in this age group. The data, which were collected for the Surveillance, Epidemiology, and End Results (SEER) Program of the National Institutes of Health—National Cancer Institute, are categorized by sex, age, and race, all of which can have a profound effect on risk. Prostate cancer incidence, for example, is approximately 4.4 times higher in men between the ages of 60 and 64 than it is in men 50–54 years old; it is approximately twice as high in blacks 50–64 years old as it is in whites in the same age group (NCI, 2004). The figures presented for each cancer are estimates for the entire US population, not predictions for the Vietnam-veteran cohort. Many factors can influence incidence, among them personal behavior (tobacco use, diet), genetic predisposition, and medical history. Those factors can make someone more or less likely than average to contract a given cancer. Incidence data are reported for all races and also separately for blacks and whites. The data reported are for 1997–2001, the most recent data set available to the committee.

Incidence figures given here are not directly comparable to the figures listed in earlier Updates. Earlier reports used 1990 US Census data; this report used data from the 2000 Census, so some of the differences in incidence estimates

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

resulted from changes in demographics rather than from changes in the factors that determine cancer rates.

There is still considerable uncertainty about the magnitude of potential risk posed by exposure to the compounds of interest as shown by the occupational, environmental, and veterans’ studies reviewed by the committee. Many of those studies provided inadequate controls for important confounders, and there is not enough information to extrapolate from exposure as presented in those studies to that of individual Vietnam veterans. The committee therefore cannot measure the likely risk to Vietnam veterans that is attributable to exposure to the compounds of interest in Vietnam. Where the data permit, qualitative observations are offered.

Information about biologic mechanisms that could contribute to carcinogenic activity by any of the agents of interest is summarized in the Biologic Plausibility section at the conclusion of this chapter. It distills toxicologic information concerning how any of the chemicals of interest impact general mechanisms of carcinogenesis, which is presented in detail in Chapter 3. Such information, of course, applies to all the cancer sites discussed individually in this chapter. When biologic plausibility is addressed for a particular site, the generic information is implicit, and only toxicologic information specific to carcinogenesis at the site in question is presented.

GASTROINTESTINAL TRACT CANCERS

Gastrointestinal tract tumors are among the most common of cancers. The committee reviewed data on esophageal cancer (ICD-9 150.0–150.9), stomach cancer (ICD-9 151.0–151.9), pancreatic cancer (ICD-9 157.0–157.9), colon cancer (ICD-9 153.0–153.9), and rectal cancer (ICD-9 154.0–154.9). According to American Cancer Society (ACS) estimates, about 255,640 people will be diagnosed with those cancers in the United States in 2004, and 134,840 people will die from them (ACS, 2004a). Colon cancer accounts for about 40% of those diagnoses and deaths. Collectively, gastrointestinal tract tumors are expected to account for 19% of new diagnoses and 24% of cancer deaths in 2004. Colorectal cancer is the third most common form of cancer in men and in women, excluding basal- and squamous-cell skin cancers. The average annual incidences for gastrointestinal cancers are shown in Table 6-1.

Carcinoma of the esophagus has great geographic variation. The region of the world extending from Iran through the steps of Central Asia, Mongolia, and northern portion of China has cancer frequencies that are 10 times those of the rest of the world. In northern China, the incidence is 160 cases per 100,000, compared with 4–8 per 100,000 in North America, Europe, Southeast Asia, and Japan. In addition to a different disease incidence, there is a difference in the histopathologic type of cancer; squamous-cell carcinoma is predominant in the high-endemic areas, adenocarcinoma makes up approximately 50% of cases in the low-incidence areas of the United States, Europe, Southeast Asia, and Japan.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-1 Average Annual Incidence (per 100,000) of Selected Gastrointestinal Cancers in United Statesa

 

50–54 Years of Age

55–59 Years of Age

60–64 Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

Stomach

Males

9.7

8.7

17.3

16.4

14.9

20.9

27.1

22.7

47.4

Females

4.6

3.5

8.8

6.8

5.8

9.3

10.8

8.6

19.0

Esophagus

Males

9.7

9.0

20.6

16.8

16.1

31.2

24.8

24.7

35.5

Females

1.5

1.2

5.1

3.3

2.7

9.0

5.8

5.0

16.4

Colon (excluding the rectum)

Males

33.3

31.1

53.6

59.4

58.7

82.4

105.7

102.8

148.5

Females

27.5

25.4

41.0

44.6

41.6

74.5

78.2

77.5

111.4

Rectum and rectosigmoid junction

Males

23.3

22.2

24.1

36.9

36.8

34.7

55.1

54.2

58.7

Females

14.0

13.3

17.5

22.0

21.2

30.6

29.6

30.3

35.0

Pancreas

Males

12.7

12.1

22.5

20.3

18.8

34.7

33.7

33.4

48.4

Females

7.7

7.5

11.3

13.6

12.7

21.3

24.0

22.5

38.0

a SEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude age-specific rates, 1997–2001.

The incidences of stomach, colon, rectal, and pancreatic cancers increase with age in people 50–64 years old. In general, incidence is higher in men than it is in women, and is higher in blacks than in whites. Other risk factors for those cancers vary but always include family history of the same form of cancer, some diseases of the affected organ, and dietary factors. Tobacco use is a risk factor for pancreatic cancer that might also increase the risk of stomach cancer (Miller et al., 1996). Infection with the bacterium Helicobacter pylori increases the risk of stomach cancer. Type 2 diabetes is associated with an increased risk of cancers of the colon and pancreas (ACS, 2004a).

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the compounds of interest and gastrointestinal tumors. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Tables 6-2, 6-3, 6-4, 6-5, and 6-6 summarize the results of the relevant studies.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-2 Selected Epidemiologic Studies—Stomach Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Bodner et al., 2003

Dow chemical production workers—mortality

1.5 (0.7–2.7)

Swaen et al., 2004

Dutch licenced herbicide applicators—mortality

3

0.4 (0.1–1.3) b

Studies Reviewed in Update 2002

Burns et al., 2001

Dow 2,4-D production workers—cancer of the digestive organs—mortality

16

0.7 (0.4–1.2)

Studies Reviewed in Update 2000

Steenland et al., 1999

US 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 of body wt

0

 

TCDD 0.1–0.99 µg/kg of body wt

1

1.3 (0.0–7.0)

TCDD >1 µg/kg of 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

US 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

2

0.7 (01.–2.7)

Collins et al., 1993

Monsanto 2,4-D production workers

0

0 (0.0–1.1)

Kogevinas et al., 1993

IARC cohort—females

 

NS

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Estimated Casesa

Exposed Relative Risk (95% CI)a

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)

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

6

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

1,812

1.3 (p < 0.05)

Wiklund, 1983

Swedish agricultural workers

2,599

1.1 (1.0–1.2)c

Burmeister, 1981

Iowa Farmers

338

1.1 (p < 0.01)

Axelson et al., 1980

Swedish railroad workers—total exposure

3

2.2 (*)

ENVIRONMENTAL

New Studies

Fukuda et al., 2003

Residents of municipalities in Japan with or without waste incineration plants in males

 

 

Age-adjusted mortality (100,000)

 

38.2 ± 7.8 vs 39.0 ± 8.8 (p = 0.28)

Age-adjusted mortality (100,000) in females

20.7 ± 5.0 vs 20.7 ± 5.8 (p = 0.92)

Studies Reviewed in Update 2002

Revich et al., 2001

Residents of Chapaevsk, Russia

 

45.3 in Chapaevsk; 44.0 in Samara Regiond

 

Age-adjusted incidence (100,000) of stomach cancer in males

 

Age-adjusted incidence (100,000) of stomach cancer in females

 

33.9 in Chapaevsk; 17.6 in Samara Regiond

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

 

Mortality standardized to Samara Region

 

 

Males

59

1.7 (1.3–2.2)

Females

45

0.7 (0.5–0.9)

Studies Reviewed in Update 2000

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)

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)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

VIETNAM VETERANS

New Studies

Akhtar et al., 2004

White Air Force Ranch Hand veterans—cancer of the digestive system

 

 

All Ranch Hand veterans

Incidence (SIR)

16

0.6 (0.4–1.0)

Mortality (SMR)

6

0.4 (0.2–0.9)

Veterans, tours 1966–1970—incidence

14

0.6 ((0.4–1.1)

White Air Force comparison veterans—cancer of the digestive system

 

All comparison veterans

Incidence (SIR)

31

0.9 (0.6–1.2)

Mortality (SMR)

14

0.7 (0.4–1.1)

Veterans, tours 1966–1970—incidence

24

0.9 (0.6–1.3)

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

*

a Given when available.

b Risk estimate is for stomach and small intestine.

c 99% CI.

d Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity.

* Information not provided by study authors.

—Information denoted by a dash in the original study.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; NS, not significant; USDA, US Department of Agriculture.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-3 Selected Epidemiologic Studies—Esophageal Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 1998

Kogevinas et al., 1997

IARC cohort

 

 

Esophagus

28

1.0 (0.7–1.4)

Studies Reviewed in Update 1996

Asp et al., 1994

Finnish herbicide applicators—incidence

3

1.6 (0.3–4.6)

 

Finnish herbicide applicators—mortality

2

1.3 (0.2–4.7)

Studies Reviewed in VAO

Ronco et al., 1992

Danish male self-employed—incidence farmworkers

32

0.4 (NS)

Saracci et al., 1991

IARC cohort

8

0.6 (0.3–1.2)

Coggon et al., 1986

British MCPA production workers

8

0.9 (0.6–1.3)

Wiklund, 1983

Swedish agricultural workers

169

0.6 (0.5–0.7)

ENVIRONMENTAL

Studies Reviewed in Update 2002

Revich et al., 2001

Residents of Chapaevsk, Russia

 

 

Age-adjusted incidence (100,000) in males

 

4.1 in Chapaevsk; 4.0 in Samara Regionb

Age-adjusted incidence (100,000) in females

0.0 in Chapaevsk; 1.4 in Samara Regionb

VIETNAM VETERANS

Studies Reviewed in Update 1998

Crane et al. 1997a

Australian military Vietnam veterans

 

 

Esophagus

23

1.2 (0.7–1.8)

Crane et al. 1997b

Australian national service Vietnam veterans

 

 

Esophagus

1

1.3 (0.0–10)

a Given when available.

b Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity.

ABBREVIATION: CI, confidence interval; IARC, International Agency for Research on Cancer; ICD-9, International Classification of Diseases, Ninth Edition; MCPA, methyl-4-chlorophenoxyacetic acid; NS, not significant.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-4 Selected Epidemiologic Studies—Colon Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 2000

Steenland et al., 1999

US 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)

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, 1996b

BASF cleanup workers

5

1.0 (0.3–2.3)

 

TCDD <0.1 µg/kg of body wt

2

1.1 (0.1–3.9)

TCDD 0.1–0.99 µg/kg of body wt

2

1.4 (0.2–5.1)

TCDD >1 µg/kg of body wt

1

0.5 (0.0–3.0)

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

US farmers in 23 states—white males

2,291

1.0 (0.9–1.0)

Bueno de Mesquita et al., 1993

Phenoxy herbicide workers

3

1.8 (0.4–5.4)

Collins et al., 1993

Monsanto 2,4-D production workers

3

0.5 (0.1–1.3)

Studies Reviewed in VAO

Swaen et al., 1992

Dutch herbicide applicators

4

2.6 (0.7–6.5)

Ronco et al., 1992

Danish male self-employed farm workers

277

0.7 (p < 0.05)

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., 1990b

BASF production workers—basic cohort

2

2.5 (0.4–14.1)

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

Pulp and paper workers

9

1.0 (0.5–2.0)

Solet et al., 1989

Pulp and paper 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)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Thomas, 1987

Flavor and fragrance chemical production workers

4

0.6 (*)

Coggon et al., 1986

British MCPA production workers

19

1.0 (0.6–1.6)

Robinson et al., 1986

Pulp and paper workers

7

0.4 (0.2–0.9)

Lynge, 1985

Male Danish production workers

10

1.0 (*)

Blair et al., 1983

Florida pesticide applicators

5

0.8 (*)

Wiklund, 1983

Swedish agricultural workers

1,332

0.8 (0.7–0.8)c

Thiess et al., 1982

BASF production workers

1

0.4 (*)

Burmeister, 1981

Iowa farmers

1,064

1.0 (NS)

Hardell, 1981

Sweden residents

 

 

Exposed to phenoxy acids

11

1.3 (0.6–2.8)

Exposed to chlorophenols

6

1.8 (0.6–5.3)

ENVIRONMENTAL

Studies Reviewed in Update 2002

Revich et al., 2001

Residents of Chapaevsk, Russia

 

22.7 in Chapaevsk; 21.7 in Samara regiond

 

Age-adjusted incidence (100,000) in males

 

 

Age-adjusted incidence (100,000) in females

 

13.3 in Chapaevsk; 15.4 in Samara regiond

 

Mortality standardized to Samara region

 

 

Males

17

1.3 (0.8–2.2)

Females

24

1.0 (0.7–1.5)

Studies Reviewed in Update 2000

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)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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)

VIETNAM VETERANS

Studies Reviewed in Update 2000

AFHS, 2000b

Air Force Ranch Hand veterans

7

1.5 (0.4–5.5)

AIHW, 1999b

Australian Vietnam veterans—male

188

221 expected (191–251)

CDVA, 1998a

Australian Vietnam veterans—male

405e

117 expected (96–138)

CDVA, 1998b

Australian Vietnam veterans—female

1e

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

4

0.4 (0.1–1.2)

 

Nurses

4

0.5 (0.2–1.7)

Studies Reviewed in VAO

Breslin et al., 1988f

Army Vietnam veterans

209

1.0 (0.7–1.3)

 

Marine Vietnam veterans

33

1.3 (0.7–2.2)

Anderson et al., 1986a

Wisconsin Vietnam veterans

4

Anderson et al., 1986b

Wisconsin Vietnam veterans

6

1.0 (0.4–2.2)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

a Gven when available.

b Colon and rectal cancer results combined.

c 99% CI.

d Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity.

e Self-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?”

f Intestinal and other gastrointestinal cancer results are combined in this study.

* Information not provided by study authors.

—Information denoted by a dash in the original study.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; NS, not significant; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-5 Selected Epidemiologic Studies—Rectal Cancer

Reference Study Population

Estimated

Exposed Casesa

Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Swaen et al., 2004

Dutch licenced herbicide applicators—mortality

5

2.1 (0.6–4.8)

Studies Reviewed in Update 2000

Steenland et al., 1999

US 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)

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

US farmers in 23 states—white males

367

1.0 (0.9–1.1)

Bueno de Mesquita et al., 1993

Phenoxy herbicide workers

0

0 (0.0–4.3)

Studies Reviewed in VAO

Ronco et al., 1992

Danish male self-employed farmers

309

0.8 (p < 0.05)

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

6

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

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

ENVIRONMENTAL

Studies Reviewed in Update 2002

Revich et al., 2001

Residents of Chapaevsk, Russia

 

 

Age-adjusted incidence (100,000) in males

 

15.3 in Chapaevsk; 17.1 in Samara regionc

Age-adjusted incidence (100,000) in females

 

7.0 in Chapaevsk; 11.2 in Samara regionc

Mortality standardized to Samara region

 

Males

21

1.5 (1.0–2.4)

Females

24

0.9 (0.6–1.4)

Studies Reviewed in Update 2000

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)

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)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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

Studies Reviewed in Update 2000

AFHS, 2000d

Air Force Ranch Hand veterans

7

1.5 (0.4–5.5)

AIHW, 1999d

Australian Vietnam veterans—male

188

221 expected (191–251)

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

a Given when available.

b 99% CI.

c Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity.

d Colon and rectal cancer results are combined in this study.

* Information not provided by study authors.

—Information denoted by a dash in the original study.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-6 Selected Epidemiologic Studies—Pancreatic Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Swaen et al., 2004

Dutch licenced herbicide applicators—mortality

5

1.1 (0.4–2.7)

Studies Reviewed in Update 2000

Ojajärvi et al., 2000

Meta-analysis of 161 populations

 

1.0 (0.8–1.3)

Steenland et al., 1999

US 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

US farmers in 23 states—white males

1,133

1.1 (1.1–1.2)

Bueno de Mesquita et al., 1993

Phenoxy herbicide workers

3

2.2 (0.5–6.3)

Studies Reviewed in VAO

Ronco et al., 1992

Danish self-employed male farm workers

137

0.6 (p < 0.05)

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

6

1.4 (*)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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)

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

Iowa Farmers

416

1.1 (*)

ENVIRONMENTAL

Studies Reviewed in Update 2000

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 (*)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Studies Reviewed in Update 1996

Dalager et al., 1995

Female US Vietnam Veterans

7

2.8 (0.8–10.2)

 

Nurses

7

5.7 (1.2–27.0)

Visintainer et al., 1995

Michigan Vietnam veterans

14

1.0 (0.6–1.7)

Studies Reviewed in VAO

Thomas et al., 1991

Female US Vietnam veterans

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

a Given when available.

b 99% CI.

* Information not provided by study authors.

—Information denoted by a dash in the original study.

ABBREVIATIONS: CI, confidence interval; IARC; International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture.

Update of the Scientific Literature

Occupational Studies

Bodner et al. (2003) completed a 1940–1995 mortality assessment of male chemical production workers previously exposed to substantial concentrations of dioxin. No increased risk of death from gastric cancer was reported.

Swaen et al. (2004) updated the follow-up of 1,341 licensed herbicide appliers in the Netherlands. A lower-than-expected number of deaths from esophagus and stomach cancer was reported.

Environmental Studies

Fukuda et al. (2003) conducted an ecological study of 590 municipalities in Japan to examine the relationship between several indexes of dioxin emissions from incineration plants and cause-specific mortality among residents of those municipalities. Municipalities with and without incineration plants had similar age-adjusted mortality from stomach cancer (p = 0.29 and 0.92 for men and women, respectively). In analyses restricted to municipalities with incineration plants, there was a positive and statistically significant (p < 0.05) correlation in men for stomach cancer and one dioxin index (the amount of dioxins released per

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

unit of population), but a statistically significant (p < 0.05) negative correlation for three dioxin indexes (concentration of dioxins released from incinerator plants, cumulative amount of dioxins released from incinerator plants, and cumulative amount released from incinerator plants per unit of land area). There were positive and statistically significant (p < 0.05) correlations in women for stomach cancer and all dioxin indexes.

Vietnam-Veteran Studies

Akhtar et al. (2004) reported on cancer incidence and mortality in Air Force veterans of the Vietnam War. Index cases were Operation Ranch Hand veterans who sprayed dioxin-contaminated herbicides in Vietnam. Comparison subjects served in Southeast Asia during the same period but did not spray herbicides. The group reported that the incidence of cancer of the digestive system was significantly lower than expected (compared with national incidence rates) in white Ranch Hand veterans (standardized incidence ratio [SIR], 0.61; 95% confidence interval [CI], 0.36–0.96). Among the cohort’s white “comparison” veterans, digestive system cancer incidence also was lower than expected (SIR, 0.85; 95% CI, 0.59–1.19). There were insufficient numbers of other Ranch Hand veterans to make estimates.

Synthesis

With only rare exceptions, studies on exposure to the compounds of interest in production, in agricultural use, from environmental sources, and among veteran populations reported that the estimated relative risk (RR) was close to 1.0, providing evidence of no increased risk for gastrointestinal cancers. The updated analysis of the Ranch Hand cohort (Akhtar et al., 2004) showed a lower-than-expected incidence rate of digestive system cancers. The occupational studies by Bodner et al. (2003) and Swaen et al. (2004) are consistent with other reported exposure analysis and show no or decreased risk for esophageal and gastric cancer.

Conclusions

Strength of Evidence from Epidemiologic Studies

VAO and the previous updates concluded that there is limited or suggestive evidence of no association between exposure to the compounds of interest and cancer of the esophagus, stomach, pancreas, rectum, or colon. The evidence was drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

committee finds that there is still limited or suggestive evidence of no association between exposure to the compounds of interest and gastrointestinal cancers.

Biologic Plausibility

No animal studies have reported an increased incidence of gastrointestinal cancer after exposure to the compounds of interest. However, recent investigations noted an increased incidence of stomach tumors in mice expressing a constitutively active aryl hydrocarbon receptor (AhR), as might occur with constant increased exposure to TCDD.

A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

The evidence suggesting that there is no association between exposure to the chemicals of interest and gastrointestinal tumors also implies that Vietnam veterans are not at increased risk of gastrointestinal tumors as a result of any exposures they might have had to the chemicals of interest.

HEPATOBILIARY CANCERS

Hepatobiliary cancers include cancers of the liver (ICD-9 155.0, 155.2) and the intrahepatic bile duct (ICD-9 155.1). According to ACS estimates, 12,580 men and 6,340 women will be diagnosed with liver or intrahepatic bile duct cancer in the United States in 2004, and 9,450 men and 4,820 women will die from those cancers (ACS, 2004a).

In the United States, liver cancers account for about 1.4% of new cancer cases and 2.5% of cancer deaths. Misclassification of metastatic cancers as primary liver cancer can lead to overestimating the number of deaths attributable to liver cancer (Percy et al., 1990). In developing countries, especially those in 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; at the ages of 50–64, it is greater in men than in women and greater in blacks than in whites. The average annual incidence of hepatobiliary cancers is shown in Table 6-7.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D,

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-7 Average Annual Incidence (per 100,000) of Liver and Intrahepatic Bile Duct Cancers in United Statesa

 

50–54 Years of Age

55–59 Years of Age

60–64 Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

7.5

4.9

16.1

11.3

8.2

20.3

16.2

12.2

28.1

Females

2.4

1.7

3.9

3.3

2.6

5.1

5.4

4.2

6.8

aSEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude age-specific rates, 1997–2001.

2,4,5-T, TCDD, picloram, or cacodylic acid and hepatobiliary cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Table 6-8 summarizes the results of the relevant studies.

Update of the Scientific Literature

An occupational study by Swaen et al. (2004) examined cancer mortality in 1,341 licensed herbicide appliers in the Netherlands. No deaths from liver or biliary cancer were observed in the cohort.

No other relevant environmental or Vietnam-veteran studies have been published since Update 2002.

Synthesis

The evidence from epidemiologic studies is inadequate to link the compounds of interest with hepatobiliary cancer; no new published information was found to change this opinion.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the compounds of interest and hepatobiliary cancer. The evidence regarding association is drawn from previous occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Al-

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-8 Selected Epidemiologic Studies—Hepatobiliary Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Swaen et al., 2004

Dutch licenced herbicide applicators

0

Studies Reviewed in Update 2000

Steenland et al., 1999

US 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 of body weight

1

2.8 (0.1–15.5)

TCDD 0.1–0.99 µg/kg of body weight

0

 

TCDD >1 µg/kg of body weight

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

US 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)

 

Subcohort with ≥ 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

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

ENVIRONMENTAL

Studies Reviewed in Update 2002

Revich et al., 2001

Residents of Chapaevsk, Russia

 

 

 

Age-adjusted incidence (100,000) of liver cancer in males

 

13.5 in Chapaevsk; 6.6 in Samara Regionc

Age-adjusted incidence (100,000) of liver cancer in females

 

5.9 in Chapaevsk; 2.7 in Samara Regionc

Studies Reviewed in Update 2000

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)

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 years 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

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

VIETNAM VETERANS

Studies Reviewed in Update 2000

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

US men born in 1921–1953

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

a Given when available.

b 99% CI.

c Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity.

* Information not provided by study authors.

—Information denoted by a dash in the original study.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; IARC, International Agency for Research on Cancer; NIOSH, National Institute for Occupational Safety and Health; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

though several of those studies involve sizable cohorts, hepatobiliary cancers are rare, and the power of these studies to detect an increase in incidence is still likely to be low.

Biologic Plausibility

Rats and mice given TCDD orally for 2 years were evaluated for development of cancer (NTP, 1982). Neoplastic nodules in the livers of female rats were significantly increased in the high-TCDD-dose group, and a significant increase in hepatocellular carcinomas was noted in high-dose-treated male and female mice. The high dose of TCDD that increased the incidence of neoplasia also increased the incidence of toxic hepatitis in rats and mice of both sexes. A recent study by the National Toxicology Program (NTP, 2004) also reported an increase in hepatocellular adenoma in female rats treated orally with 100 ng TCDD/kg for 5 days/week for 104 weeks. There also were dose-related increases in cholangiocarcinoma in rats treated with 22 nanograms (ng) per kilogram (kg) of body weight or more. However, those groups also exhibited increased incidence of hepatic necrosis, oval cell hyperplasia, and bile duct hyperplasia. Cacodylic acid administered to laboratory animals has been shown to induce hepatic neoplasms.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and hepatobiliary cancers, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.

ORAL, NASAL, AND PHARYNGEAL CANCER

Oral, nasal, and pharyngeal cancers are found in many anatomic subsites, including the structures of the mouth (inside lining of the lips, cheeks, gums, tongue, and the hard and soft palate) (ICD-9 140–145), oropharynx (ICD-9 146), nasal cavity and paranasal sinuses (ICD-9 160), hypopharynx (ICD-9 148), and nasopharynx (ICD-9 147). Although those sites are anatomically diverse, cancers that occur in the nasal cavity, oral cavity, and pharynx are for the most part similar in descriptive epidemiology and risk factors. The exception is cancer of the nasopharynx, which has a different epidemiologic profile.

ACS estimates that about 30,000 men and women will be diagnosed with oral, nasal, and pharyngeal cancers in the United States in 2004 (ACS, 2004a). Almost 95% of those cancers originate in the oral cavity or oropharynx. Most of the oral, nasal, and pharyngeal cancers are squamous-cell carcinomas. Nasopharyngeal carcinoma (NPC) is the most common malignant tumor of the nasopharynx. There are three types of NPC: keratinizing squamous-cell carcinoma, non-keratinizing carcinoma, and undifferentiated carcinoma.

The average annual incidences reported in Table 6-9 show that men are at a greater risk than are women for those cancers and that the incidences increase with age, although the small number of cases indicates that care should be exercised in interpreting the numbers. Tobacco and alcohol use are established risk factors for oral and pharyngeal cancers. 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).

Nasopharyngeal cancer is relatively rare in the United States. It accounts for about 0.25% of all cancers, and generally occurs two to three times more often in men than in women. NPC is rare in most parts of the world, although incidence is higher in some parts of China, among Eskimos in the Artic region, and among some indigenous people of Southeast Asia. Studies of NPC have reported associations with the consumption of salt-preserved foods (Miller et al., 1996) and with Epstein-Barr virus (Mueller, 1995).

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-9 Average Annual Incidence (per 100,000) of Nasal, Nasopharyngeal Oral Cavity and Pharynx, and Oropharynx Cancers in United Statesa

 

50–54 Years of Age

55–59 Years of Age

60–64 Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

Nose, Nasal Cavity, and Middle Ear

Males

1.4

1.3

1.4

1.8

1.8

1.2

2.0

1.9

3.2

Females

0.6

0.6

0.9

0.9

1.0

0.7

1.0

1.1

0.9

Nasopharynx

Males

1.9

1.1

1.9

2.3

1.8

0.4

2.9

1.4

2.2

Females

0.8

0.4

0.7

0.5

0.2

0.3

0.9

0.7

b

Oral Cavity and Pharynx

Males

28.7

27.6

46.6

37.9

37.5

51.3

47.8

46.9

66.2

Females

9.4

9.1

9.9

13.3

13.7

15.3

17.3

18.2

15.6

Oropharynx

Males

0.9

0.8

2.7

1.2

1.2

2.4

1.9

1.7

5.9

Females

0.1

0.2

b

0.5

0.6

0.7

0.3

0.3

0.4

a SEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude age-specific rates, 1997–2001.

b Insufficient data to provide a meaningful incidence estimate.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and oral, nasal, and pharyngeal cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Studies evaluated previously and in this report are summarized in Table 6-10.

Update of the Scientific Literature

Occupational Studies

An occupational study by Swaen et al. (2004) examined cancer mortality in 1,341 licensed herbicide appliers in the Netherlands. No deaths from nasal, oral, or pharynx cancers were observed in that cohort.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-10 Selected Epidemiologic Studies—Oral, Nasal, and Pharyngeal Cancer

Reference

Study Population

Estimated Casesa

Exposed Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Swaen et al., 2004

Dutch licenced herbicide applicators

 

 

 

Nose

0

Mouth and pharynx

0

Studies Reviewed in Update 2000

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-sinus cancer (ICD-9 160)

3

1.6 (0.3–4.7)

Studies Reviewed in Update 1996

Asp et al., 1994

Finnish herbicide appliers

1

0.5 (0.0–2.9)

Studies Reviewed in VAO

Ronco et al., 1992

Danish and Italian farm workers

11

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 Update 2002

Revich et al., 2001

Residents of Chapaevsk, Russia

 

 

 

Age-adjusted incidence (100,000) of pharyngeal cancer in males

 

2.2 in Chapaevsk; 2.3 in Samara regionb

 

Age-adjusted incidence (100,000) of pharyngeal cancer in females

 

2.1 in Chapaevsk; 0.6 in Samara regionb

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)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

VIETNAM VETERANS

New Studies

Akhtar et al., 2004

White Air Force Ranch Hand veterans—buccal cavity cancer—incidence

 

 

 

all Ranch Hand veterans

6

0.9 (0.4–1.9)

veterans with tours 1966–1970

6

1.1 (0.5–2.3)

White Air Force comparison veterans—buccal cavity cancer—incidence

 

 

all comparison veterans

5

0.6 (0.2–1.2)

veterans with tours 1966–1970

4

0.6 (0.2–1.4)

Studies Reviewed in Update 2000

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 veterans

 

 

 

Nasal cancer

0

0 (0.0–10)

Nasopharyngeal cancer

1

1.3 (0.0–10)

Studies Reviewed in VAO

CDC, 1990

US men born in 1921–1953

 

 

 

Vietnam veterans

2

0.7 (0.1–3.0)

a Given when available.

b Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity.

* Information not provided by study authors.

—Information denoted by a dash in the original study.

ABBREVIATIONS: AFHS, Air Force Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; IARC, International Agency for Research on Cancer; ICD-9, International Classification of Diseases, Ninth Edition; MCPA, methyl-4-chlorophenoxyacetic acid; NS, not significant.

Environmental Studies

No relevant environmental studies have been published since Update 2002.

Vietnam-Veteran Studies

Akhtar et al. (2004) examined cancers of the buccal cavity—the cavity between the jaw and the cheek—as part of their investigation of health outcomes in Operation Ranch Hand veterans who were involved in the aerial spraying of herbicides. They reported no significant difference between expected and observed incidence of the cancer in either the Ranch Hand veterans or in a

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

comparison group of veterans who did not spray herbicides. No other oral, nasal, or pharyngeal cancers were examined.

Synthesis

Studies from previous Updates have not shown an association between oral, nasal, and pharyngeal cancers and the compounds of interest. The study by Akhtar et al. (2004) reviewed here also showed no increased risk of cancer of the buccal cavity. The committee affirms that there is inadequate or insufficient evidence of an association.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous Veterans and Agent Orange reports, the committee concludes that there is still inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and oral, nasal, and pharyngeal cancers.

Biologic Plausibility

A recent NTP study (2004) reported an increase in the incidence of gingival squamous-cell carcinoma in female rats treated orally (by gavage) with 100 ng TCDD/kg for 5 days/week for 104 weeks. The incidences of gingival squamous hyperplasia were significantly increased in all other groups treated with 3–46 ng/kg. This is the first time this type of tumor has been reported in animals.

A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and oral, nasal, and pharyngeal cancers, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.

LARYNGEAL CANCER

According to ACS estimates, 8,060 men and 2,210 women will be diagnosed with cancer of the larynx (ICD-9 161.0–161.9) in the United States in 2004, and 3,010 men and 820 women will die from it (ACS, 2004a). Those numbers represent a little less than 1% of new cancer diagnoses and deaths. Cancer of the larynx

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-11 Average Annual Incidence (per 100,000) of Laryngeal Cancer in United Statesa

 

50–54 Years of Age

55–59 Years of Age

60–64 Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

10.0

9.6

19.8

16.9

16.2

35.1

24.4

24.7

39.8

Females

2.5

2.3

5.5

3.5

3.4

6.3

6.5

6.7

10.8

a SEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude age-specific rates, 1997–2001.

is more common in men than in women, with a ratio in the United States of about 4:1 among persons 50–64 years old. Incidence increases with age in that group. The average annual incidence for laryngeal cancer is shown in Table 6-11.

Established risk factors for laryngeal cancer are tobacco and alcohol use, which are independent risk factors and act as synergistic risk factors. Occupational exposures—long and intense exposures to wood dust, paint fumes, and to some compounds used in the metalworking, petroleum, plastics, and textile industries—also could elevate risk (ACS, 2004b). Infection with human papilloma virus (HPV) also might raise the risk of laryngeal cancer (Hobbs and Burchall, 2004).

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to at least one of the compounds of interest and laryngeal cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Table 6-12 summarizes the results of the relevant studies.

Update of the Scientific Literature

Occupational Studies

Swaen et al. (2004) published an updated mortality study of a cohort of 1,341 licensed herbicide appliers in the Netherlands. The study was a 13-year follow-up of a mortality study of the same cohort (Swaen et al., 1992). Standardized mortality ratios (SMRs) were calculated based on the age and calendar-year cause-specific mortality rates of the general population of the Netherlands. One

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-12 Selected Epidemiologic Studies—Laryngeal Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Swaen et al., 2004

Dutch licenced herbicide applicators—mortality

1

1.0 (0.01–5.1)

Studies Reviewed in Update 2002

Thörn et al., 2000

Swedish Lumberjacks exposed to phenoxyacetic herbicides

0

(*)

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

US 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

Studies Reviewed in Update 2002

Revich et al., 2001

Residents of Chapaevsk, Russia

 

 

 

Age-adjusted incidence (100,000) in males

18.0 in Chapaevsk; 11.3 in all of Russiab

 

Age-adjusted incidence (100,000) in females

1.1 in Chapaevsk; 0.4 in all of Russiab

 

Mortality standardized to Samara region

 

 

 

Males

13

2.3 (1.2–3.8)

 

Females

1

0.1 (0.0–0.6)

Studies Reviewed in Update 2000

Bertazzi et al., 2001c

Seveso residents—20-year follow-up

 

 

 

Zone B males

55

1.3 (1.0–1.6)

 

Zone B females

 

5 0.8 (0.3–1.9)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Bertazzi et al., 1998c

Seveso residents—15-year follow-up

 

 

 

Zone B males

40

1.2 (0.9–1.7)

 

Zone B females

2

0.5 (0.1–2.0)

 

Zone R males

208

0.9 (0.8–1.1)

 

Zone R females

35

1.1 (0.8–1.5)

VIETNAM VETERANS

Studies Reviewed in Update 2000

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

0

0 (0–10)

Watanabe and Kang, 1996

Army Vietnam veterans compared with US men

50

1.3 (*)

 

Marine Vietnam veterans

4

0.7 (*)

a Given when available.

b Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity.

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

* Information not provided by study authors.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

death from cancer of the larynx was reported. Only one death was expected, leading to an SMR of 1.0 (95% CI, 0.01–5.1). The study was limited by the small number of cases and by potential confounders that could not be evaluated.

Environmental Studies

No relevant environmental studies have been published since Update 2002.

Vietnam-Veteran Studies

Akhtar et al. (2004) described cancer incidence and mortality in a prospective cohort study of Air Force Ranch Hand veterans who engaged in aerial spraying of herbicides while serving in Southeast Asia and in a comparison population of veterans who served but did not spray herbicides. Because the study does not distinguish between laryngeal and other respiratory cancers, the risk of laryngeal

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

cancer in the cohort cannot be described from the data presented. Information on respiratory cancer incidence and mortality in the cohorts is presented in the lung cancer discussion.

Synthesis

No studies published since Update 2002 provide evidence of the presence or absence of an association between the exposures of interest and laryngeal cancer. Therefore, the conclusion that there is limited or suggestive evidence of an association between laryngeal cancer and the compounds of interest is not challenged by the few data available since Update 2002.

Conclusions

Strength of Evidence in Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one compound of interest and laryngeal cancer.

Biologic Plausibility

No animal studies have identified an increased incidence of laryngeal cancer associated with exposure to the compounds of interest. A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

Although there are data to suggest an association between exposure to the chemicals of interest and laryngeal cancer, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

LUNG CANCER

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 ACS estimates, 93,110 men and 80,660 women will be diagnosed with lung cancer in the United States in 2004, and about 91,930 men and 68,510 women will die from it (ACS, 2004a). Those numbers represent roughly 14% of new cancer diagnoses and 29% of cancer deaths in 2004. The principal types of lung neoplasms are identified collectively as bronchogenic carcinoma (the bronchi are the two main

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-13 Average Annual Incidence (per 100,000) of Lung and Bronchial Cancer in United Statesa

 

50–54 Years of Age

55–59 Years of Age

60–64Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

64.2

59.0

132.1

132.6

125.0

244.0

246.7

242.0

387.0

Females

48.7

50.0

63.8

100.9

103.8

130.0

164.0

174.0

176.2

a SEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude age-specific rates, 1997–2001.

branches of the trachea) and carcinoma of the lung. The lung is also a common site of the development of metastatic cancer.

In men and women, the incidence of lung cancer increases greatly beginning about the age of 40. The incidence in people 50–54 years old is double that in people 45–49 years old, and it doubles again in those between the ages of 55 and 59. The rate in black males is consistently higher than that in females or white males. The average annual incidence of lung cancer is shown in Table 6-13.

ACS estimates that more than 90% of lung cancers in males are attributable to tobacco use (ACS, 1998), but there are other risk factors: occupational exposure to asbestos, uranium, vinyl chloride, nickel chromates, coal products, mustard gas, chloromethyl ethers, gasoline, diesel exhaust, and inorganic arsenic. Important environmental risk factors include exposure to tobacco smoke and radon (ACS, 2004c).

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to at least one compound of interest and lung cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Table 6-14 summarizes the results of the relevant studies.

Update of the Scientific Literature

Occupational Studies

Bodner et al. (2003) provide an update of cancer mortality among 2,187 male Dow Chemical Company employees who worked in production areas where there was a potential for dioxin exposure. There were 168 cancer deaths reported in that cohort over the years 1940–1994. RR and SMR were not elevated for lung

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-14 Selected Epidemiologic Studies—Lung and Bronchus Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Bodner et al., 2003

Dow chemical production workers—mortality

54

0.8 (0.6–1.1)

Swaen et al., 2004

Dutch licenced herbicide applicators—mortality

27

0.7 (0.5–1.0)

Studies Reviewed in Update 2002

Burns et al., 2001

Dow 2,4–D production workers—mortality

31

 

0.9

(0.6–1.3)

Thörn et al., 2000

Swedish lumberjack workers exposed to phenoxyacetic herbicides

 

 

 

Foremen—incidence

1

4.2 (0.1–23.2)

Studies Reviewed in Update 2000

Steenland et al., 1999

US 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

US 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)

 

Workers with exposure above “background” levels

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-year 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)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

McDuffie et al., 1990

Saskatchewan farmers applying herbicides

103

0.6 NS

Zober et al., 1990

TCDD reactor accident 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)

 

 

 

Respiratory cancer

9

1.2 (0.6–2.3)

 

Low cumulative exposure

1

0.7 (NS)

 

Medium cumulative exposure

2

1.0 (NS)

 

High cumulative exposure

5

1.7 (NS)

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

Fukuda et al., 2003

Residents of municipalities in Japan with vs without waste incineration plants

 

 

 

Age-adjusted mortality (100,000), lung cancer in males

 

39.0 ± 6.7 vs 41.6 ± 9.1 (p = 0.001)

 

Age-adjusted mortality (100,000), lung cancer in females

13.7 ± 3.8 vs 14.3 ± 4.6 (p = 0.11)

Studies Reviewed in Update 2002

Revich et al., 2001

Residents of Chapaevsk, Russia

 

 

 

Age-adjusted incidence (100,000) of lung cancer in males

 

164.5 in Chapaevsk; 102.4 in Samara regionb

 

Age-adjusted incidence (100,000) of lung cancer in females

19.6 in Chapaevsk; 11.1 in Samara regionb

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

 

Mortality standardized to Samara region

 

 

 

Males

168

3.1 (2.6–3.5)

 

Females

40

0.4 (0.3–0.6)

Studies Reviewed in Update 2000

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)

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)

 

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

Akhtar et al., 2004

White Air Force Ranch Hand veterans, respiratory-system cancer

 

 

 

All Ranch Hand veterans

 

 

 

Incidence (SIR)

33

1.1 (0.8–1.6)

 

Mortality (SMR)

21

0.9 (0.6–1.3)

 

Veterans, tours, 1966–1970—incidence

26

1.1 (0.7–1.6)

 

White Air Force comparison veterans, respiratory-system cancer

 

 

 

All comparison veterans

 

 

 

Incidence (SIR)

48

1.2 (0.9–1.6)

 

Mortality (SMR)

38

1.1 (0.8–1.5)

 

Veterans, tours 1966–1970—incidence

37

1.2 (0.9–1.6)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Studies Reviewed in Update 2000

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

120c

65 expected (49–81)

CDVA, 1998b

Australian Vietnam veterans—female

0c

(*)

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 (1.0–1.3)

 

Non-Vietnam

77

0.9 (*)

Watanabe and Kang, 1995

Marines Vietnam service vs non-Vietnam

42

1.3 (0.8–2.1)

a Given when available.

b Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity.

c Self-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?”

* Information not provided by study authors.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; MCPA, methyl-4-chlorophenoxyacetic acid; NS, not signficant; PCDD, polychlorinated dibenzodioxin; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

cancer among all exposure categories (54 observed; 62.5 expected), and the risk did not increase with higher exposure potential (as estimated by job title). There was not an excess number of lung cancers among workers who were diagnosed with chloracne (SMR, 0.3; 95% CI, 0.0–1.1), which is a crude marker for dioxin exposure.

Swaen et al. (2004) published an updated mortality study of a cohort of 1,341 licensed herbicide applicators in the Netherlands. That study is a follow-up of an earlier mortality study of the same cohort (Swaen et al., 1992), extending the period for 13 years. SMRs were calculated based on the Netherlands’ cause-specific mortality rates. Swaen et al. (2004) reported no significant increase in cancer of the trachea and lung (SMR, 0.71; 95% CI, 0.47–1.04), but the study was limited because it did not evaluate potential confounders, such as tobacco use.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×
Environmental Studies

Fukuda et al. (2003) conducted an ecological study examining the association between mortality and dioxin emissions from incinerators in 590 Japanese municipalities. The researchers developed dioxin-related municipal index for the concentration of dioxins, the amount of dioxins per unit of population, the cumulative amount of dioxins, and the cumulative amount of dioxins per unit area of land. Sex-specific and age-adjusted mortality rates were calculated for specific health outcomes, including lung cancer. There was significantly lower mortality from lung cancer in male residents of municipalities with incinerators than among male residents of municipalities without incinerators (39.0 cases/100,000 vs 41.6 cases/100,000; p = 0.001). Regression analysis showed no significant association between lung cancer and the dioxin-related municipal indexes after controlling for socioeconomic factors.

The study was limited by its ecological design: Because there were no individual measures of dioxin exposure, only group averages, it would be difficult to determine whether those who developed lung cancer also had higher exposures to dioxins. The authors did not report on migration patterns in the municipalities or on the period in which the incinerators operated. Thus it is unclear whether there would be sufficient latency for lung cancer to develop. The study also was limited because the authors did not control for important potential confounders, such as tobacco use.

Vietnam-Veteran Studies

Akhtar et al. (2004) describe cancer incidence and mortality in a prospective cohort study of Operation Ranch Hand veterans who participated in aerial herbicide spraying during the Vietnam War. There was no difference in the incidence of cancer of the respiratory tract in all Ranch Hand veterans (SIR, 1.13; 95% CI, 0.79–1.57) from that in others who served during the time of heaviest use of Agent Orange (1966–1970) (SIR, 1.08; 95% CI, 0.72–1.55) when compared with national incidence rates. No difference in mortality attributable to respiratory tract cancer was noted (SMR, 0.87; 95% CI, 0.55–1.31). Cancer of the lung was not differentiated from other cancers of the respiratory tract.

Synthesis

Evidence remains inconclusive but suggestive of an association between exposure to at least one compound of interest and lung cancer. The best evidence comes from studies of heavily exposed occupational cohorts. Bodner et al. (2003) did not identify an increased risk of lung cancer among chemical company employees, which is consistent with results of previous studies of that cohort. But the results must be weighed against results for previously reviewed occupational cohorts that did show evidence of an association (Becher et al., 1996; Otto and

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Zober, 1996; Steenland et al., 1999). Also supportive of an association are the numerous lines of mechanistic evidence, discussed in the section on biologic plausibility, that provide further support for the conclusion of limited or suggestive evidence.

The evidence of an association is less conclusive from environmental exposures and studies of Vietnam veterans. Many studies lack sufficient information on potential confounders, such as history of tobacco use; adjusting for those factors cannot be done, and thus interpretation of the results is limited.

Conclusions

Strength of Evidence in Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one compound of interest and carcinomas of the lung and bronchus.

Biologic Plausibility

As noted in Update 2002, there is evidence of increased incidence of squamous-cell carcinoma of the lung in rats exposed to high concentrations of TCDD. A more recent study reported a significant increase in cystic keratinizing epitheliomas in rats exposed to TCDD for 2 years. Rats administrated cacodylic acid showed an increased frequency of carcinoma of the lung. The relevance of those studies to human exposure is not clear. Mechanistic data from in vitro and animal studies, however, also provide evidence that TCDD promotes the carcinogenic process. Lung tissue has been found to have high concentrations of the AhR, which mediates the effects of TCDD, and recent data have shown that CYP1A1 and CYP1A2 are expressed in lung biopsy specimens from human subjects. Those enzymes are responsible, in part, for the activation of procarcinogens, such as found in tobacco smoke (which also contains AhR ligands), to genotoxic intermediates. Thus, it is biologically plausible that exposure to TCDD synergizes the carcinogenic effects of a variety of other compounds to which human lung tissue is exposed.

A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

Although there are data to suggest an association between exposure to the chemicals of interest and lung cancer, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

BONE AND JOINT CANCER

ACS (2004a) reports that about 1,230 men and 1,210 women will be diagnosed with bone or joint cancer (ICD-9 170.0–170.9) in the United States in 2004 and that 720 men and 580 women will die from bone or joint cancers this year. Primary bone cancers are among the least common malignancies. The bones are, however, frequent sites of secondary tumors of other cancers that have metastasized. Only primary bone cancer is considered here. The average annual incidence of bone and joint cancer is shown in Table 6-15.

Bone cancer is more common in teenagers than it is in adults. Bone cancer is quite rare among people in the age groups of most Vietnam veterans (50–64 years of age). Among the risk factors for adults’ contracting bone or joint cancer are exposure to ionizing radiation in treatment for other cancers and a history of some non-cancer bone diseases, including Paget’s disease.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and bone and joint cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Table 6-16 summarizes the results of the relevant studies.

Update of the Scientific Literature

An occupational study by Swaen et al. (2004) examined cancer mortality in 1,341 licensed herbicide appliers in the Netherlands. No deaths from bone cancers were observed in the cohort.

TABLE 6-15 Average Annual Incidence (per 100,000) of Bone and Joint Cancer in United Statesa

 

50–54 Years of Age

55–59 Years of Age

60–64 Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

0.9

1.0

1.1

1.4

1.5

1.2

1.7

1.9

b

Females

0.9

1.1

0.5

1.0

1.1

0.3

0.9

0.9

b

a SEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude age-specific rates, 1997–2001.

b Insufficient data to provide meaningful incidence.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-16 Selected Epidemiologic Studies—Bone and Joint Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Swaen et al., 2004

Dutch licenced herbicide applicators

0

Studies Reviewed in Update 2000

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)

3

1.1 (0.2–3.1)

 

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

2

1.4 (0.2–5.2)

Ramlow et al., 1996

Pentachlorophenol production workers

0

Studies Reviewed in Update 1996

Blair et al., 1993

US 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

Iowa Farmers

56

1.1 (NS)

ENVIRONMENTAL

Studies Reviewed in Update 2002

Revich et al., 2001

Residents of Chapaevsk, Russia Mortality standardized to Samara region (bone, soft tissue cancer)

 

 

 

Males

7

2.1 (0.9–4.4)

 

Females

7

1.4 (0.6–3.0)

Studies Reviewed in Update 2000

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)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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)

a Given when available.

b 99% CI.

* Information not provided by study authors.

—Information denoted by a dash in the original study.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; NS, not significant; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

No other relevant environmental or Vietnam-veteran studies have been published since Update 2002.

Synthesis

There are no new data in the one new study (Swaen et al., 2004) to indicate an increase in bone cancer. Therefore, there is no evidence to support a change from the earlier conclusion that there is inadequate or insufficient evidence to determine an association between bone cancer and exposure to the compounds of interest.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the compounds of interest and bone cancer. The conclusion is based on

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

occupational and environmental studies in which the subjects were exposed to a variety of herbicides and herbicide compounds.

Biologic Plausibility

No animal studies reported an increased incidence of bone cancer after exposure to the compounds of interest. A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and bone and joint cancer, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.

SOFT-TISSUE SARCOMAS

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. ACS estimates that about 4,760 men and 3,920 women will be diagnosed with STS in the United States in 2004 and that about 2,020 men and 1,640 women will die from it (ACS, 2004a). The incidence of STS in the age groups of most Vietnam veterans has no consistent pattern. The average annual incidence of STS is shown in Table 6-17.

Among the risk factors for STS are exposure to ionizing radiation during

TABLE 6-17 Average Annual Incidence (per 100,000) of Soft-Tissue Sarcoma (Including Malignant Neoplasms of Heart) in United Statesa

 

50–54 Years of Age

55–59 Years of Age

60–64 Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

4.1

4.2

4.3

4.4

4.2

5.9

6.3

6.7

4.3

Females

2.8

3.0

2.8

4.3

4.1

6.7

5.0

4.7

7.3

a SEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude age-specific rates, 1997–2001.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

treatment for other cancers and some inherited conditions, including Gardner’s syndrome, Li-Fraumeni syndrome, and neurofibromatosis. Several chemical exposures have been identified as possible risk factors (Zahm and Fraumeni, 1997).

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was sufficient information to determine an association between exposure to at least one of the compounds of interest and STS. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. (Table 6-18 summarizes the relevant studies.)

Update of the Scientific Literature

Occupational Studies

Bodner et al. (2003) completed a mortality assessment (1940–1994) of male chemical production workers who worked in areas in which there was a potential for dioxin exposure. Although not statistically significant, the incidence of STS in that cohort was considerably greater than expected (SMR, 2.4; 95% CI, 0.3–8.6; 2 cases); the broad confidence interval resulting from the small number of cases makes it difficult to draw a conclusion from the data. Both cases were in workers whose job titles were associated with a “very high” potential for exposure.

Environmental Studies

Comba et al. (2003) performed a case–control study of STS in a population living near an industrial-waste incinerator in Mantua, Italy. A paper by Costani et al. (2000), reviewed in Update 2002, assesses the same population. Dioxins are among the contaminants produced by the combustion of such wastes. Cases (17 male; 20 female) were identified from pathology registries in 4 adjoining municipalities; control subjects were age- and gender-matched from population registries for the region. There was a significant increase in risk of STS associated with residence within 2 km of the incinerator (odds ratio [OR] 31.4; 95% CI, 5.6–176.1; 5 cases); no association was found for STS in residents outside that area. The study was considerably weakened by lack of data on TCDD concentrations in the environment or in tissue samples and by the absence of pathologic review of cases.

Tuomisto et al. (2004) performed a case–control study of STS in a population in Southern Finland. Cases (110) were location- and age-matched with control subjects (227) who had had appendectomies. Fish consumption—the putative source of dioxin exposure—was similar among both groups. TCDD concentrations were measured in subcutaneous fat samples taken from the subjects. The

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-18 Selected Epidemiologic Studies—Soft-Tissue Sarcoma

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Bodner et al., 2003

Dow chemical production workers—Mortality

2

2.4 (0.3–8.6)

Studies Reviewed in Update 2000

Steenland et al., 1999

US 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 (0.2–4.9)

 

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

US cancer registry data (SEER program) review

 

 

 

Male

3,526

(*)

 

Female

2,886

(*)

Blair et al., 1993

US farmers in 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)

Studies Reviewed in VAO

Bueno de Mesquita et al., 1993

Phenoxy herbicide workers

0

0 (0.0–23.1)

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)

 

Latency 20 years, exposure 1 year

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)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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)

 

Self-reported chloracne

*

3.3 (0.8–14.0)

Coggon et al., 1986

British MCPA chemical workers

1

1.1 (0.03–5.9)

Hoar et al., 1986

Kansas residents

 

 

 

All farmers

95

1.0 (0.7–1.6)

 

Farm use of herbicides

22

0.9 (0.5–1.6)

Vineis et al., 1986

Italian rice growers

 

 

 

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

17

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

 

 

Overall

42

1.7 (1.0–2.9)

 

Those under 75 years old

33

1.4 (0.8–2.6)

Blair et al., 1983

Florida pesticide appliers

0

(*)

Hardell, 1981

Swedish workers

 

 

 

Phenoxy herbicide exposure

13

5.5 (2.2–13.8)

Eriksson et al., 1979, 1981

Swedish workers

25

(2.2–10.2) 5.1 matched

ENVIRONMENTAL

New Studies

Comba et al., 2003

Residents near an industrial-waste incinerator in Mantua, Italy

 

 

 

Residence within 2 km of incinerator

5

31.4 (5.6–176.1)

Tuomisto et al., 2004

STS patients and controls—southern Finland

110

 

 

Quintile 2 (median tissue concentration 20 ng/kg WHO-TEQ)

*

0.4 (0.2–1.1)

Quintile 5 (median tissue concentration

 

~60 ng/kg WHO-TEQ)

*

0.7 (0.2–2.0)

 

Studies Reviewed in Update 2002

Costani et al., 2000

Residents near a chemical plant in

20

2.3 (1.3–3.5)

 

Mantua, Italy—mortality

 

 

Studies Reviewed in Update 2000

Bertazzi et al., 2001

Seveso—20-year follow-up

0

(*)

Viel et al., 2000

Residents near French solid-waste incinerator

 

 

 

Spatial cluster

45

1.4 (p = 0.004)

 

1994–1995

12

3.4 (p = 0.008)

Bertazzi et al., 1998

Seveso—15-year follow-up

0

(*)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative 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

Studies Reviewed in Update 2000

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., 1997ac

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

 

Comparison group

1

Visintainer et al., 1995

Vietnam veterans

8

1.1 (0.5–2.2)

Watanabe and Kang, 1995

US 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

86

0.8 (0.6–1.1)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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

10

0.5 (0.2–1.3)

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

(*)

 

Comparison group

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)

 

Comparison group

1

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)

a Given when available.

b Self-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?”

c Data for different military branches presented separately. Number of exposed cases range from 0–9; all CIs include 1.

* Information not provided by study authors.

—Information denoted by a dash in the original study.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; SEER, Surveillance, Epidemiology, and End Results (SEER) Program; STS, soft-tissue sarcoma; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; WHO TEQ, Toxicity Equivalent as defined by the World Health Organization.

researchers did not observe an association between STS and either 2,3,7,8-TCDD or World Health Organization (WHO) toxicity equivalent (TEQ) dioxin concentrations in the human tissue. The OR for the highest quartile of WHO TEQ was 0.7 (95% CI, 0.2–2.0); for 2,3,7,8-TCDD it was 0.5 (95% CI, 0.2–1.4).

No relevant Vietnam-veteran studies have been published since Update 2002.

Synthesis

The environmental-exposure report from Mantua, Italy (Comba et al., 2003) lacks exposure data, tissue concentrations for dioxin, and independent pathologic review of diagnosed cases. The case report study from Finland (Tuomisto et al., 2004) was a carefully conducted study in men and women who have a low but

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

life-long exposure to dioxin in the food chain (Baltic fish). Individual biologic samples were used to estimate dioxin exposure in STS cases and controls; there was no positive association between STS risk and dioxin concentrations. In fact, there was a suggestion for increased risk of STS at the lowest dioxin exposure.

Findings from occupational, environmental, and Vietnam-veteran studies show sufficient evidence to link herbicide exposure to STS. That evidence is supported by long-term follow-up studies of dioxin-exposed chemical workers. The reports by Bodner et al. (2003), Comba et al. (2003), and Tuomisto et al. (2004) do not change the conclusions from those of previous committees.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an association between exposure to at least one of the compounds of interest and STS.

Biologic Plausibility

No increased incidence of STS has been reported from animal studies. A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

Although there are data to suggest an association between exposure to the chemicals of interest and STS, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

SKIN CANCER—MELANOMA

Skin cancers are generally divided into two broad categories: neoplasms that develop from melanocytes (malignant melanoma [MM]) and neoplasms that do not. Non-melanocytic skin cancers (primarily basal-cell and squamous-cell carcinomas) have a far higher incidence than malignant melanoma but are considered less aggressive and therefore more treatable. The average annual incidence of melanoma is shown in Table 6-19. Beginning with Update 1998, the committee chose to address MM studies separately from those of non-melanocytic cancers. Because non-melanocytic cancers are highly treatable, their discussion is divided further into studies on mortality and studies on incidence. Many researchers report results by combining all types of skin cancer; often, they do not specify the

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-19 Average Annual Cancer Incidence (per 100,000) of Skin Cancers (Excluding Basal and Squamous-Cell Cancers) in United Statesa

 

50–54 Years of Age

55–59 Years of Age

60–64 Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

Melanomas of the Skin

Males

33.0

38.8

0.8

43.1

49.6

1.6

54.1

63.9

4.3

Females

23.7

28.3

0.5

27.0

32.0

2.7

27.9

33.9

1.3

Other Non-Epithelial Skin Cancers

Males

3.3

3.3

4.3

2.7

2.9

1.6

4.2

4.3

4.8

Females

1.8

1.7

3.0

1.8

1.8

2.0

2.5

2.8

1.3

a SEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude age-specific rates, 1997–2001. SEER incidence data are not available for nonmelanocytic skin cancer.

types assessed. In the interest of completeness, mortality and morbidity studies are listed in Tables 6-20 and 6-21.

According to ACS estimates, about 29,900 men and 25,200 women will be diagnosed with cutaneous melanoma (ICD-9 172.0–172.9) in the United States in 2004, and 5,050 men and 2,860 women will die from it (ACS, 2004a). More than 1 million cases of non-melanocytic skin cancer (ICD-9 173.0–173.9), primarily basal-cell and squamous-cell carcinomas, are diagnosed in the United States each year (ACS, 2004a). Because it is not required to report those cancers to registries, the numbers of cases are not as precise as for other cancers. ACS reports that although melanoma accounts for only about 4% of skin cancer cases it is responsible for about 79% of skin cancer deaths (2004a). ACS estimates that 1,000–2,000 people die each year from non-melanocytic skin cancer.

Melanomas occur more frequently in fair-skinned people; the risk for whites is roughly 20 times that for dark-skinned blacks. Incidence also increases with age, although more strikingly in males than in females. Other risk factors include the presence of some moles on the skin, 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 that is the result of genetic factors or attributable to similarities in skin type and sun exposure patterns.

Excessive exposure to UV radiation is the most important risk factor for non-melanocytic skin cancer, although some skin diseases and chemical exposures also have been identified as potential risk factors. Exposure to inorganic arsenic

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-20 Selected Epidemiologic Studies—All (or Unspecified) Skin- Cancer Mortality

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Swaen et al., 2004

Dutch licenced herbicide applicators—mortality

5

3.6 (1.2–8.3)

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

Iowa Farmers

105

1.1 (NS)

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)

a Given when available.

* Information not provided by study authors.

ABBREVIATIONS: CI, Confidence Interval; IARC, International Agency for Research on Cancer; NIOSH, National Institute for Occupational Safety and Health; NS, not significant; USDA, US Department of Agriculture.

is a risk factor for skin cancer, and cacodylic acid is a metabolite of inorganic-arsenic.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and skin cancer. Additional information available to the committee responsible for Update 1996 did not change that finding. The Update 1998 committee considered the literature on MM separately from that of non-melanocytic skin cancers. It found that there was inadequate or insufficient information to determine association between the compounds of interest and MM. The Update 2000 and Update 2002 committees concurred with the findings of the Update 1998 committee. (Tables 6-22 and 6-23, respectively, summarize the relevant melanoma mortality and morbidity studies.)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-21 Selected Epidemiologic Studies—All (or Unspecified) Skin- Cancer Morbidity

Reference

Study Population

Exposed Casesa

Estimated Relative 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

Studies Reviewed in Update 2000

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 RH veterans

88

1.5 (1.1–2.0)

CDC, 1988

Army enlisted Vietnam veterans

15

0.8 (0.4–1.7)

a Given when available.

* Information not provided by study authors.

ABBREVIATIONS: AFHS, Air Force Health Study; CDC, Centers for Disease Control and Prevention.

Update of the Scientific Literature

Occupational Studies

Swaen et al. (2004) presented results for a 21 year follow-up—from January 1980 to January 2001—of mortality in a cohort of 1,341 licensed herbicide applicators working for government agencies in the Netherlands. Information was available on the types and amounts of herbicides used in all municipal spraying projects in 1980, but those data could not be linked to the work of any individual applicators. No data were available on any potential risk factors other than age. SMRs were calculated based on age and calendar-year, cause-specific mortality rates of the general population of the Netherlands. Five deaths from skin cancer were recorded for the cohort (one melanoma, two squamous-cell carcinoma, two

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-22 Selected Epidemiologic Studies—Melanoma Mortality

Reference

Study Population

Exposed Casesa

Relative Risk Estimated (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 2002

Burns et al., 2001

Dow 2,4-D production workers

0

Studies Reviewed in Update 2000

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

US 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

Studies Reviewed in Update 2000

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)

 

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)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Relative Risk Estimated (95% CI)a

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)

a Given when available.

b 99% CI.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; CI, confidence interval; IARC, International Agency for Research on Cancer; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

unknown). Only 1.4 deaths would have been expected, leading to an SMR of 3.6 for deaths attributable to all skin cancers (95% CI, 1.2–8.3).

Environmental Studies

No environmental studies of melanoma have been published since those reviewed in Update 2002.

Vietnam-Veteran Studies

Akhtar et al. (2004) reported on the incidence of cancer in veterans of Operation Ranch Hand and a comparison cohort of other Air Force veterans who served in Southeast Asia during the same period but who were not involved in herbicide spraying. The cancer occurrence was ascertained for the period between each veteran’s departure from Southeast Asia and December 31, 1999. Information on cancer was derived from study examinations (1982, 1985, 1987, 1992, 1997), medical records, and death certificates. SIRs were calculated to compare the observed number of cancers with the number expected based on sex, race, age, and calendar-year-specific incidence rates from SEER data. In all, 1,189 Ranch Hand veterans and 1,776 comparison Air Force veterans were included in the analyses.

The analyses of melanoma were restricted to white veterans (89% of the study population). Melanoma was more common among Ranch Hand veterans

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-23 Selected Epidemiologic Studies—Melanoma Morbidity

Reference

Study Population

Exposed Casesa

Relative Risk Estimated (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 2002

Thörn et al., 2000

Swedish lumberjack workers exposed to phenoxyacetic herbicides

 

 

 

Female

1

3.5 (0.1–19.2)

 

Male

0

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 < 0.05)

ENVIRONMENTAL

Studies Reviewed in Update 2002

Revich et al., 2001

Residents of Chapaevsk, Russia

 

 

 

Age-adjusted incidence (100,000) of melanoma in males

 

4.2 in Chapaevsk; 5.1 in Samara regionb

 

Age-adjusted incidence (100,000) of melanoma in females

8.9 in Chapaevsk; 3.5 in Samara regionb

VIETNAM VETERANS

New Studies

Akhtar et al., 2004

White Air Force Ranch Hand (RH) veterans—incidence

 

 

 

All RH veterans

17

2.3 (1.4–3.7)

 

RH veterans w/ tours between 1966–1970

15

2.6 (1.5–4.1)

 

White Air Force comparison veterans—incidence

 

 

 

All comparison veterans

15

1.5 (0.9–2.4)

 

Comparison veterans w/ tours between 1966–1970

12

1.5 (0.8–2.6)

Studies Reviewed in Update 2000

AFHS, 2000

Air Force RH veterans

16

1.8 (0.8–3.8)

AIHW, 1999

Australian Vietnam veterans—male

483

380 expected (342–418)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Ketchum et al., 1999

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

2,689c

380 expected (342–418)

CDVA, 1998b

Australian Vietnam veterans—female

7c

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 RH veterans

4

1.3 (0.3–5.2)

a Given when available.

b Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity.

c Self-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?”

ABBREVIATION: AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval.

than would have been predicted from the general population (17 observed, 7.33 expected; SIR, 2.3; 95% CI, 1.4–3.7). The comparison cohort of Air Force veterans had a more modest excess of melanoma (15 observed, 10.24 expected; SIR, 1.46; 95% CI, 0.85–2.36). The probability value for the statistical test of difference between the SIRs (2.33 and 1.46) was 0.19. The SIR for Ranch Hand veterans was fairly constant when the analyses with SEER data were repeated with restriction to veterans whose tours ended between 1966 and 1970 (SIR, 2.57), veterans who spent no more than 2 years in Southeast Asia (SIR, 2.36), and veterans who were in Vietnam for 100% of their service in Southeast Asia (SIR, 3.05).

The incidence of melanoma also was analyzed by a categorical measure of dioxin concentration. The comparison Air Force veterans served as the referent group; the Ranch Hand veterans were divided into background (≤10 parts per trillion [ppt]); low exposure (>10 ppt, dioxin at end of service in Vietnam estimated at ≤118.5 ppt); and high exposure (>10 ppt; dioxin at end of service in Vietnam estimated at >118.5 ppt). The analyses used proportional hazards models to adjust for age at tour, military occupation, skin reaction to sun exposure, and eye color. When the analyses were restricted to veterans who had served no more than 2 years in Southeast Asia, elevated incidence rates were observed for each

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Ranch Hand category: background, RR, 2.99; 95% CI, 0.53–16.8; low, RR, 7.42; 95% CI, 1.34–41.04; high, RR, 7.51; 95% CI, 1.12–50.21. There was no statistically significant association between exposure and incidence of melanoma among veterans with more than 2 years of service in Southeast Asia (data not shown). Similar rate ratios were observed when Ranch Hand veterans with 100% of their service in Vietnam were contrasted with comparison veterans who had served elsewhere in Southeast Asia. There was no difference in the incidence of melanoma in the analysis of the remaining veterans (Ranch Hand veterans with some service outside of Vietnam and comparison veterans with some service in Vietnam).

Synthesis

The study by Swaen et al. (2004) reported that mortality from all skin cancers combined is greater among herbicide applicators than would have been expected in the general population of the Netherlands during the same 21-year study period. The authors recognize that herbicide applicators are likely to have significant exposure to UV radiation, a well-established, important risk factor for skin cancer. Because of the study design (comparison based on the general population), it is impossible to separate the effect of the two occupationally related exposures (sunlight and herbicides).

Akhtar et al. (2004) assessed the incidence of melanoma in Ranch Hand veterans relative to a sample of the general population (studied by the SEER Program) and to a comparison cohort of Air Force veterans. Melanoma was more common in both groups of veterans than in the general population, particularly in the Ranch Hand veterans. The authors acknowledge an important limitation in this contrast—detection of melanoma in study participants could be elevated compared with that in the general population because of the better detection made possible by the study’s schedule of periodic physical examinations. In addition, comparisons with the SEER data cannot be adjusted for such confounders as sun exposure. For those reasons, the “internal” comparison (between groups of veterans) assumes added importance.

In the analyses limited to Ranch Hand and comparison Air Force veterans, the associations with melanoma are restricted to the stratum of veterans with no more than 2 years of service in Southeast Asia and to a stratum created by the subset of Ranch Hand veterans who served only in Vietnam and comparison veterans who served elsewhere in Southeast Asia. If those categories somehow capture a confounding factor, the appropriate analysis would combine information from each stratum (more than 2 years of service and 2 years or less) to produce an adjusted RR. No satisfactory rationale is given to support the notion that a valid analysis of melanoma must be limited to veterans with less than 2 years of service or to a definition that completely confounds Ranch Hand status with service in Vietnam. In the absence of such a rationale, the overall associa-

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

tion between exposure to herbicides and the incidence of melanoma in this study is not definitive.

Although previously reviewed studies of US and Australian veterans have reported a higher incidence of melanoma among male, non-black veterans than among comparison groups, 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 melanoma. The highest melanoma incidence in the AFHS reports (Ketcham et al., 1999) was observed in veterans in the low-TCDD category; that would not be expected if there were an association between exposure and melanoma. Comparison of the results with those from the report by Akhtar et al. (2004) is not possible because Akhtar et al. (2004) limited analysis to a subset of their study population. 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. Adjustments for potentially important confounders, however, were not carried out.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and melanoma. The evidence regarding association is drawn from occupational, environmental, and veterans’ studies in which subjects were exposed to herbicides and herbicide components.

Biologic Plausibility

Mice were treated topically (on the 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); this indicates that 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 provide evidence that TCDD promotes the carcinogenic process. Furthermore, recent data have shown the ability of TCDD to repress the expression of several tumor suppressor genes and immortalize human keratinocytes.

A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×
Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and melanoma, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.

SKIN CANCER—BASAL-CELL AND SQUAMOUS-CELL (NON-MELANOMA)

The preceding section presents background information on skin cancer.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and skin cancer. Additional information available to the committee responsible for Update 1996 did not change that finding. The Update 1998 committee considered the literature on non-melanocytic skin cancers separately from that for malignant melanoma. It found that there was inadequate or insufficient information to determine an association between exposure to the compounds of interest and basal-cell or squamous-cell cancers. The Update 2000 and Update 2002 committees concurred with that finding. (Tables 6-24 and 6-25 summarize the relevant studies.)

Update of the Scientific Literature

The only new study is an occupational cohort study with data on non-melanoma skin cancer (Swaen et al., 2004) summarized in the previous section of this chapter. In that study of cancer mortality in a cohort of herbicide applicators, the analysis of skin cancer is based on five deaths (one melanoma, two squamous-cell carcinoma, two unknown type), and the SMR is computed for all skin cancers combined. The results and interpretation of the study are stated in the update of the scientific literature on melanoma.

No relevant environmental or Vietnam-veteran studies have been published since Update 2002.

Synthesis

In the study by Swaen et al. (2004), the mortality from all skin cancers combined is greater among herbicide applicators than would have been expected from the general population of the Netherlands during the same 21-year period. The authors recognize that herbicide applicators are also more likely than are those in the general population to be exposed to sunlight, a well-established,

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-24 Selected Epidemiologic Studies—Other Non-melanoma (Basal-Cell and Squamous-Cell) Skin Cancer—Mortality

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Swaen et al., 2004

Dutch licensed herbicide appliers Melanoma, squamous cell carcinoma, and unknown skin cancer

5

3.6 (1.2–8.3)

Studies Reviewed in Update 2002

Burns et al., 2001

Dow 2,4-D production workers

 

 

 

Non-melanoma skin cancer

0

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

US 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

a Given when available.

b 99% CI.

* Information not provided by study authors.

—Information denoted by a dash in the original study.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

important risk factor for skin cancer. The study design (with comparison based on the general population) makes it impossible to distinguish the effects of the two occupationally related exposures (sunlight and herbicides).

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-25 Selected Epidemiologic Studies—Other Non-melanoma (Basal-Cell and Squamous-Cell) Skin Cancer—Morbidity

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 2002

Thörn et al., 2000

Swedish lumberjacks exposed to phenoxyacetic herbicides

 

 

 

Foremen

1

16.7 (0.2–92.7)

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 < 0.05)

ENVIRONMENTAL

Studies Reviewed in Update 2002

Revich et al., 2001

Residents of Chapaevsk, Russia

 

 

 

Age-adjusted incidence (100,000) of skin cancer in males (non-melanoma)

 

55.9 in Chapaevsk; 55.7 in Samara regionb

 

Age-adjusted incidence (100,000) of skin cancer in females (non-melanoma)

64.0 in Chapaevsk; 47.6 in Samara regionb

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)

 

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)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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

Studies Reviewed in Update 2000

AFHS, 2000

Air Force Ranch Hand veterans

 

 

 

Basal-cell carcinoma

121

1.2 (0.9–1.6)

 

Squamous-cell carcinoma

20

1.5 (0.8–2.8)

CDVA, 1998a

Australian Vietnam veterans—male

6,936c

(*)

CDVA, 1998b

Australian Vietnam veterans—female

37c

(*)

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)

a Given when available.

b Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity.

c Self-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?”

* Information not provided by study authors.

ABBREVIATIONS: AFHS, Air Force Health Study; CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval.

insufficient evidence to determine an association between exposure to the compounds of interest and basal-cell or squamous-cell cancers.

Biologic Plausibility

Fibrosarcomas occurred in the integumentary system of female mice treated with TCDD topically (on the skin surface) for 2 years (Huff et al., 1991). The data indicate that continuous dermal exposure to TCDD can induce skin tumors (fibrosarcomas, not squamous-cell carcinomas) in laboratory mice. Mechanistic

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

data from in vitro and animal studies also provide evidence that TCDD promotes the carcinogenic process. Furthermore, recent data have shown the ability of TCDD to repress the expression of several tumor suppressor genes and immortalize human keratinocytes.

A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and non-melanoma skin cancers, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.

BREAST CANCER

Breast cancer (ICD-9 174.0–174.9 for females) is the second most common type of cancer (after nomelanocytic skin cancer) among women in the United States. ACS estimates that 215,990 women will be diagnosed with breast cancer in the United States in 2004 and that 40,110 will die from it (ACS, 2004a). Overall, those numbers represent about 33% of the incidence of new cancers and 15% of cancer deaths among women. Incidence data on breast cancer are presented in Table 6-26.

Breast cancer incidence generally increases with age. In the age groups of most Vietnam veterans, the incidence in whites is higher than is that in blacks. Risk factors other than age include personal or family history of breast cancer and some characteristics of reproductive history—specifically, early menarche, late onset of menopause, and either no pregnancies or first full-term pregnancy after the age of 30. A pooled analysis of six large-scale prospective studies of invasive breast cancer showed that alcohol consumption was associated with a linear increase in incidence in women over the range of consumption reported by most

TABLE 6-26 Average Annual Incidence (per 100,000) of Breast Cancer in Females in United Statesa

50–54 Years of Age

55–59 Years of Age

60–64 Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

258.3

268.7

226.5

334.1

349.3

273.3

389.0

407.9

326.1

a SEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude age-specific rates, 1997–2001.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

women (Smith-Warner et al., 1998). The potential of other personal behavioral and environmental factors (including exogenous hormones) to affect breast cancer incidence is being studied extensively.

Most female Vietnam veterans who were potentially exposed to herbicides in Vietnam are approaching or have recently reached menopause. Given the high incidence of breast cancer among older and post-menopausal women in general, based on demographics alone it is expected that the breast cancer burden among female Vietnam veterans will increase in the near future.

Breast cancer occurs primarily in women, but occasionally does occur in men (ACS, 2004a). The vast majority of breast cancer epidemiology studies, however, involve women. The committee, therefore, makes its conclusions based on the studies in women.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and breast cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Table 6-27 summarizes the relevant research.

Update of the Scientific Literature

No relevant occupational, environmental, or Vietnam-veteran studies have been published since Update 2002.

Synthesis

No studies published since Update 2002 have investigated breast cancer. Previously-published studies support the conclusion that the evidence is inadequate or insufficient to determine an association between exposure to the compounds of interest and breast cancer.

Conclusions

Strength of Evidence from Epidemiologic Studies

The committee maintained the conclusion that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and risk of breast cancer.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-27 Selected Epidemiologic Studies—Breast Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 2000

Duell et al., 2000

Female farm workers and residents in North Carolina

 

 

 

Used pesticides in the garden

228

2.3 (1.7–3.1)

 

Laundered clothes for pesticide user

119

4.1 (2.8–5.9)

Studies Reviewed in Update 1998

Kogevinas et al., 1997

IARC cohort, female; identical with 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 US farmers in 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)

Studies Reviewed in VAO

Ronco et al., 1992

Danish family farm workers

429

0.8 (p < 0.05)

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

Studies Reviewed in Update 2002

Aronson et al., 2000

Female patients from Ontario, Canada—highest exposures to dioxin-like congeners

 

 

 

PCB 105

44

3.2 (1.5–6.7)

 

PCB 118

49

2.3 (1.1–4.8)

Demers et al., 2002

Female patients from Quebec, Canada—analyzed for specific

 

 

 

PCB congeners

PCB 118

 

 

 

All women

104

1.6 (1.0–2.5)

 

Premenopausal women

11

2.9 (1.1–7.3)

 

PCB 156

 

 

 

All women

101

1.8 (1.1–2.9)

 

Premenopausal women

17

2.9 (1.2–7.2)

Holford et al., 2000

Patients at Yale-New Haven hospital with breast-related surgery; dioxin-like congener 156

*

0.9 (0.8–1.0)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Revich et al., 2001

Residents of Chapaevsk, Russia

 

 

 

Age-adjusted incidence (100,000) of breast cancer in females

 

69.6 in Chapaevsk; 50.7 in Samara regionc

 

Mortality standardized to Samara region

 

 

 

Females

58

2.1 (1.6–2.7)

Warner et al., 2002

Seveso women

981

 

 

Seveso women with breast cancer who had a 10-fold increase in TCDD level

15

2.1 (1.0–4.6)

Studies Reviewed in Update 2000

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)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

VIETNAM VETERANS

Studies Reviewed in Update 2002

Kang et al., 2000

Female Vietnam veterans

170

1.2 (0.9–1.5)

Studies Reviewed in Update 2000

CDVA, 1998b

Australian Vietnam veterans—female

17d

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)

Studies Reviewed in VAO

Thomas et al., 1991

Women Vietnam veterans

17

1.2 (0.6–2.5)

a Given when available.

b 99% CI.

c Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity.

d Self-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?”

* Information not provided by study authors.

ABBREVIATIONS: CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; IARC, International Agency for Research on Cancer; NS, not significant; PCB, polychlorinated biphenyl; RR, relative risk; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Biologic Plausibility

All experimental evidence indicates that 2,4-D, 2,4,5-T, and TCDD are weakly genotoxic if anything. However, TCDD is a demonstrated carcinogen in animals and is classified as a human carcinogen because of its ability to act as a strong tumor promoter. The promoting activity could occur by several biochemical mechanisms, including the altered expression of genes involved in tissue differentiation and the increase in enzymes responsible for the metabolic activation of procarcinogens to metabolites that are themselves genotoxic. The AhR, which mediates the actions of TCDD, is present in animal and human breast tissue, and some evidence suggests that it is necessary for the normal development of that tissue. One study showed that activation of the AhR pathway and metabolism of benzo[a]pyrene, a constituent of tobacco smoke, are necessary for the repression of the BRCA-1 gene by that compound. Repression of the gene is thought to be a predisposing event in the onset of sporadic breast cancer. Other studies have shown that TCDD includes the c-myc promoter and the production

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

of TGF-α, which could modulate the proliferation and tumorigenesis of mammary cells. Lifetime exposure to estrogen is a risk factor for human breast cancer, and, under some conditions, TCDD could have antiestrogenic properties. TCDD also can induce the expression of a cytochrome P450, CYP1B1, that metabolizes estradiol to 4-hydroxyestradiol. That metabolite is directly genotoxic and can undergo redox cycling to form genotoxic reactive oxygen species; it could be involved in carcinogenesis in the breast (Jefcoate et al., 2000). Some studies suggest that TCDD exposure facilitates the transition of breast cancer cells from estrogen dependence to estrogen independence; that has been demonstrated to be one important step in the progression of breast cancer. Some studies also have shown that prenatal exposure to TCDD increases the number of mammary tumors induced by other chemicals. Thus, experimental data indicate biologic plausibility for an association between exposure to TCDD and TCDD-containing herbicides and breast cancer.

A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and breast cancer, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.

CANCERS OF THE FEMALE REPRODUCTIVE SYSTEM

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 ovary (ICD-9 183.0). It also presents statistics on other cancers of the female reproductive system. ACS estimates of the numbers of new female reproductive system cancers in the United States in 2004 are presented in Table 6-28 (ACS, 2004a). Genital system cancers represent roughly 12% of new cancer cases and 11% of cancer deaths in women.

TABLE 6-28 Estimates of New Cases and Deaths in 2004 in United States for Selected Cancers of the Female Reproductive Systema

Site

New Cases

Deaths

Cervix

10,520

3,900

Endometrium

40,320

7,090

Ovary

25,580

16,090

Other female genital

6,130

1,640

a ACS (American Cancer Society), 2004.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-29 Average Annual Incidence (per 100,000) of Female Genital System Cancers in United Statesa

 

50–54 Years of Age

55–59 Years of Age

60–64 Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

All genital sites

91.0

95.4

58.5

120.6

127.1

86.1

150.9

156.2

139.9

Cervix

12.9

11.5

15.2

13.4

12.2

21.9

15.5

13.3

26.4

Endometrium

47.9

51.4

24.0

68.3

73.1

37.2

88.0

93.7

71.7

Ovary

25.5

27.5

15.0

33.3

35.7

21.3

38.9

40.5

31.5

Other genital organs

1.1

1.1

0.5

1.4

1.6

0.3

1.8

2.1

1.3

a SEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude age-specific rates, 1997–2001.

Incidence patterns of and risk factors for those diseases vary (Table 6-29). Cervical cancer occurs more often in black 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; older women are at greater risk. Obesity increases the risk of endometrial cancer by 2–5 times, depending on how obese the subject is. HPV infection is the most important risk factor for cervical cancer; HPV types 16 and 18 account for about half of those cancers. Diet, a family history of the disease, and breast cancer are among the risk factors for endometrial and ovarian cancer.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to the compounds of interest and female reproductive cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Tables 6-30, 6-31, and 6-32 summarize the results of the relevant studies.

Update of the Scientific Literature

No occupational, environmental, or Vietnam-veteran studies of cancer of the female reproductive system have been published since Update 2002.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-30 Selected Epidemiologic Studies—Cervical Cancers

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 1998

Kogevinas et al., 1997

IARC cohort

0

0 (0.0–3.8)

Studies Reviewed in Update 1996

Blair et al., 1993

US farmers in 23 states

 

 

 

Whites

6

0.9 (0.3–2.0)

 

Nonwhites

21

2.0 (0.3–3.1)

Lynge, 1993

Danish female production workers

7

3.2 (1.3–6.6)

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 (0.4–0.8)b

ENVIRONMENTAL

Studies Reviewed in Update 2002

Revich et al., 2001

Residents of Chapaevsk, Russia

 

 

 

Age-adjusted incidence (100,000) of cancers of the cervix

 

20.7 in Chapaevsk; 11.7 in Samara regionc

 

Mortality standardized to Samara region

13

1.8 (1.0–3.1)

VIETNAM VETERANS

Studies Reviewed in Update 2002

Kang et al., 2000

Female Vietnam veterans

57

1.1 (0.7–1.7)

Studies Reviewed in Update 2000

CDVA, 1998b

Australian Vietnam veterans—female

8d

1 expected (0–5)

a Given when available.

b 99% CI.

c Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity.

d Self-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?”

* Information not provided by study authors.

ABBREVIATIONS: CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; IARC, International Agency for Research on Cancer.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-31 Selected Epidemiologic Studies—Uterine Cancers

Reference

Study Population

Exposed Casesa

Estimated Relative 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

US farmers in 23 states

 

 

 

Whites

15

1.2 (*)

 

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 (0.4–0.8)b

ENVIRONMENTAL

Studies Reviewed in Update 2000

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

Studies Reviewed in Update 2002

Kang et al., 2000

Female Vietnam veterans

41

1.0 (0.6–1.6)

Studies Reviewed in Update 2000

CDVA, 1998b

Australian Vietnam veterans—female

4c

1 expected (0–5)

Studies Reviewed in Update 1996

Dalager et al., 1995

Women Vietnam veterans

4

2.1 (0.6–5.4)

a Given when available.

b 99% CI.

c Self-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?”

* Information not provided by study authors.

ABBREVIATIONS: CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; IARC, International Agency for Research on Cancer.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-32 Selected Epidemiologic Studies—Ovarian Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 1998

Kogevinas et al., 1997

IARC cohort

0

0 (0.0–2.6)

Studies Reviewed in Update 1996

Kogevinas et al., 1993

IARC cohort

1

0.7 (*)

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)

ENVIRONMENTAL

Studies Reviewed in Update 2000

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

Studies Reviewed in Update 2002

Kang et al., 2000

Female Vietnam veterans

16

1.8 (0.7–4.6)

Studies Reviewed in Update 2000

CDVA, 1998b

Australian Vietnam veterans—female

1b

0 expected (0–4)

a Given when available.

b Self-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?”

* Information not provided by study authors.

ABBREVIATIONS: CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; IARC, International Agency for Research on Cancer.

Synthesis

No studies published since Update 2002 have investigated female reproductive cancers. Previously-published studies support the conclusion that the evidence is inadequate or insufficient to determine an association between exposure to the compounds of interest and female reproductive cancers.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and uterine, ovarian, or cervical cancer.

Biologic Plausibility

No animal studies have reported an increased incidence of female reproductive cancer after exposure to the compounds of interest. One study (Kociba et al., 1978), however, showed a reduced incidence of uterine tumors in rats fed TCDD at 0.1 mg/kg diet for 2 years.

A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and female reproductive cancer, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.

PROSTATE CANCER

According to ACS estimates, 230,110 new cases of prostate cancer (ICD-9 185) will be diagnosed in the United States in 2004, and 29,900 men will die from the disease (ACS, 2004a). That makes prostate cancer the second most common cancer among men (after non-melanocytic skin cancers); it is expected to account for about 33% of new cancer diagnoses and 10% of cancer deaths in 2004. The average annual incidence of prostate cancer is shown in Table 6-33.

Incidence varies dramatically with age and race. The risk more than doubles between the ages of 50–54 years and 55–59 years, and it nearly doubles again between the ages of 55–59 years and 60–64 years. As a group, American black 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, 5 times that of Alaska natives, and nearly 8.5 times that of 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:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-33 Average Annual Incidence (per 100,000) of Prostate Cancer in United Statesa

50–54 Years of Age

55–59 Years of Age

60–64 Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

137.6

132.6

259.4

331.8

321.5

580.0

600.6

587.3

1,009.6

a SEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude age-specific rates, 1997–2001.

The study of the incidence of and mortality from prostate cancer is complicated by trends in screening for the disease. The recent introduction and widespread adoption of prostate-specific antigen (PSA) for screening have led to improved detection and thus to reports of increased incidence in the United States. The long-term influence of better screening on incidence and mortality, however, is difficult to predict for any country or population, and it will depend on the rapidity with which the screening tool is adopted, its differential use in men of various ages, and the aggressiveness of tumors detected early with this test (Gann, 1997). Differences among countries in PSA use could cause more variability in the results.

Prostate cancer tends not to be fatal, so mortality studies might miss an increased incidence of the disease. Findings showing an association between an exposure and prostate cancer mortality should be examined closely to determine whether the exposed group might have had poorer access to treatment that would increase the likelihood of death.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was limited or suggestive evidence to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and prostatic cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Table 6-34 summarizes results of the relevant studies, and it includes morbidity and mortality studies. The type of study must be considered in the interpretation and weighing of evidence. Simply examining all the estimated risks in the table together will not provide a good assessment of the risks.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-34 Selected Epidemiologic Studies—Prostate Cancer Morbidity and Mortality

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Alavanja et al., 2003

Pesticide appliers from Iowa and North Carolina—Incidence

566

1.14 (1.05–1.24)

Bodner et al., 2003

Dow chemical production workers—Mortality

1.7 (1.0–2.6)

Swaen et al., 2004

Dutch licenced herbicide applicators—Mortality

6

1.0 (0.4–2.2)

Studies Reviewed in Update 2002

Burns et al., 2001

Dow 2,4-D production workers—Mortality

7

1.3 (0.5–2.8)

Thörn et al., 2000

Swedish lumberjacks exposed to phenoxyacetic herbicides

 

 

 

Foremen—Incidence

2

4.7 (*)

 

Male lumberjacks—Incidence

3

0.9 (*)

Studies Reviewed in Update 2000

Sharma-Wagner et al., 2000

Swedish citizens

 

 

 

Agriculture and stock raising

6,080

1.1 (1.0–1.1)

 

Farmers, foresters, and gardeners

5,219

1.1 (1.0–1.1)

 

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)

 

Incidence (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

US farmers in 23 states

 

 

 

Whites

3,765

1.2 (1.1–1.2)

 

Nonwhites

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)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Studies Reviewed in VAO

Morrison et al., 1993

Canadian farmers, 45–69 years old, 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 < 0.05)

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)

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

4,827

1.2 (p < 0.05)

Wiklund, 1983

Swedish agricultural workers

3,890

1.0 (0.9–1.0)b

Burmeister, 1981

Iowa farmers

1,138

1.1 (p < 0.01)

ENVIRONMENTAL

Studies Reviewed in Update 2002

Revich et al., 2001

Residents of Chapaevsk, Russia

 

 

 

Age-adjusted incidence (100,000) of prostate cancer

 

7.0 in Chapaevsk; 22.0 in Samara regionc

Studies Reviewed in Update 2000

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)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up—Incidence

 

 

 

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

Akhtar et al., 2004

White Air Force Ranch Hand veterans

 

 

 

All Ranch Hand veterans

 

 

 

Incidence (SIR)

36

1.5 (1.0–2.0)

 

Mortality (SMR)

2

0.7 (0.1–2.3)

 

Veterans, tours 1966–1970—Incidence

34

1.7 (1.2–2.3)

 

White Air Force comparison veterans

 

 

 

All comparison veterans

 

 

 

Incidence (SIR)

54

1.6 (1.2–2.1)

 

Mortality

3

0.8 (0.2–2.1)

 

Veterans, tours 1966–1970—Incidence

42

1.6 (1.2–2.2)

Giri et al., 2004

Veterans using the DVA Medical Center in Ann Arbor, MI

 

 

 

All cases

11

OR 2.1 (0.8–5.2)

 

Cases in white veterans only

*

OR 2.7 (0.9–8.2)

Studies Reviewed in Update 2000

AFHS, 2000

Air Force Ranch Hand veterans

26

0.7 (0.4–1.3)

AIHW, 1999

Australian Vietnam veterans

212

147 expected (123–171)

CDVA, 1998a

Australian Vietnam veterans

428d

147 expected (123–171)

Studies Reviewed in Update 1998

Clapp, 1997

Massachusetts Vietnam veterans

 

 

 

Exposed cancers

15

0.8 (0.4–1.6)

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 (*)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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

a Given when available.

b 99% CI.

c Incidence rates provided in absence of information on exposed cases or estimated relative risk for morbidity.

d Self-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?”

* Information not provided by study authors.

—Information denoted by a dash in the original study.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; OR, odds ratio; USDA, US Department of Agriculture.

Update of the Scientific Literature

Occupational Studies

Alavanja et al. (2003) conducted a prospective cohort study of 55,332 male agricultural pesticide applicators from Iowa and North Carolina. 2,4-D and 2,4,5-T were among the herbicides for which data were collected; no data on dioxin were reported. Exposure, health, and demographic information were collected via questionnaire, with matching to state cancer registries for cases. The overall prostate cancer SIR was 1.14 (95% CI, 1.05–1.24) in an analysis that controlled for age, race, state of residence, years of education, type of applicator license, tobacco use, and family history of prostate cancer. In the factor analysis, use of chlorinated pesticides, ever having used chlorinated phenoxy-herbicides 2,4,5-T and 2,4,5-TP, and farmer–applicator over age 50 were correlated with prostate cancer risk. However, the incidence ratios for 2,4-D and 2,4,5-T use were not reported “because they did not demonstrate a significant exposure–response association with prostate cancer.”

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×
Environmental Studies

No relevant environmental studies have been published since Update 2002.

Vietnam-Veteran Studies

Akhtar et al. (2004) analyzed cancer incidence and mortality in Air Force veterans of the Vietnam War. Statistically significant SIRs for prostate cancer were noted for Operation Ranch Hand (1.46; 95% CI, 1.04–2.00) and comparison (1.62; 95% CI, 1.23–2.10) veterans. When the analysis was restricted to veterans whose tours ended in 1966–1970, the period of heaviest herbicide spraying, the estimate increased in the Ranch Hand cohort (SIR, 1.68; 95% CI, 1.19–2.33) but did not materially change in the comparison cohort (SIR, 1.64; 95% CI, 1.20–2.20).

In a pilot case–control study of veterans using a Department of Veterans Affairs medical center in Ann Arbor, Michigan, Giri et al. (2004) identified cases by searching computerized pathology records for a diagnosis of prostate cancer, and limited cases to those in the same age groups that characterize service in Vietnam. Controls were randomly selected from males within the medical center who were born in the appropriate years and who had not had a diagnosis of prostate cancer. Exposure to Agent Orange was determined by reviewing administrative records within the veterans’ medical records. Veterans were asked about exposure to Agent Orange. Of the 47 case subjects and 142 control subjects questioned, 7 cases (14.9%) and 19 controls (13.3%) said they did not know whether they had been exposed; they were excluded from the analyses. After adjusting for age and race, men with prostate cancer were shown to be twice as likely to report previous exposure to Agent Orange, but the 95% CI included 1 (OR, 2.1; 95% CI, 0.8–5.2). In a smaller analysis, of white veterans only, the OR was 2.7 (95% CI, 0.8–8.2).

Synthesis

The occupational study (Alavanja et al., 2003) does not contain an adequate breakdown of the farmer–applicators’ exposure to herbicides, so a statement about prostate cancer risk in that population is not possible. The pilot study by Giri et al. (2004) produced results that are consistent with other studies’, indicating an increased risk of prostate cancer after exposure to the compounds of interest. Because of its limitations, however, that study does not provide much weight of evidence. Although the ORs are elevated, the confidence intervals include 1—a possible result of the small sample size. The use of self-reported exposure assessments also could have biased the results. The study of Air Force veterans (Akhtar et al., 2004) reports an increased risk of prostate cancer in Ranch Hand men compared with national incidence rates (SIR, 1.46; 95% CI,

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

1.04–2.0; p = 0.03). The investigators also compared prostate cancer incidence in Ranch Hands with Air Force veterans who were stationed in Southeast Asia but not in Vietnam; there was no significant increase in prostate cancer (SIR, 1.68 vs SIR, 1.64; p = 0.92). The RR of prostate cancer in Ranch Hands correlated with putative exposure to Agent Orange (high 6.04 vs low 2.17 vs background 1.5; p = 0.01). Those data support the committee’s prior conclusion that there is limited or suggestive evidence of an association between exposure to Agent Orange and prostatic cancer.

Prostatic cancer is a common condition in older men, so it is likely that multiple factors are responsible and unlikely that herbicide exposure is a major cause. Still, even a small relative risk can mean a large number of cases. Therefore, an observed increase of 13% in incidence among Swedish pesticide appliers attributable solely to exposure to the pesticides or TCDD could translate into many cases. Generally speaking, for common conditions, such as prostatic cancer incidence and cardiovascular disease, RRs are not expected to be high for any particular causative factor because the background rates are already high; that situation is in contrast with rare diseases, which tend to exhibit higher relative ratios.

Conclusions
Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one of the compounds of interest and prostatic cancer. Although the associations are not large, several studies provide evidence that suggests a small increase in morbidity or mortality. The evidence regarding association is drawn from occupational studies in which subjects were exposed to a variety of pesticides, herbicides, and herbicide components and from studies of Vietnam veterans.

Biologic Plausibility

No animal studies have reported an increased incidence of prostatic cancer after exposure to the compounds of interest. The plausibility of a causal relationship could be argued on the basis that the prostate is hormonally responsive and that TCDD has been shown to be an endocrine disruptor—that is, that it alters the production or metabolism of hormones. Data on the effect of TCDD on hormone concentrations in occupationally exposed men are therefore relevant. Sweeney et al. (1997/1998) examined 281 workers at two production facilities included in the National Institute for Occupational Safety and Health (NIOSH) cohort and reported a trend toward higher serum follicle-stimulating hormone and luteiniz-

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

ing hormone (LH) and a trend toward lower testosterone, according to the serum concentration of lipid-adjusted TCDD. Those results were seen in models adjusted for age, alcohol and tobacco use, and diabetes mellitus; the models for LH and testosterone also were adjusted for body mass index. The data suggest that exposures of workers to TCDD, particularly above 20 pg/g serum lipids, are associated with alterations in male reproductive hormone concentrations. That the prostate could be a target organ for hormonally active xenobiotics lends biologic plausibility to an association with TCDD exposure. In addition, several studies have shown enzyme induction in human prostate cells to be directly responsive to TCDD.

A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

Although there are data to suggest an association between exposure to the chemicals of interest and prostate cancer, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

TESTICULAR CANCER

ACS estimates that 8,980 men will be diagnosed with testicular cancer (ICD-9 186.0–186.9) in the United States in 2004 and that 360 men will die from it (ACS, 2004a). The average annual incidence of testicular cancer is shown in Table 6-35.

Testicular cancer occurs more often in men younger than 40 than it does in those who are older. On a lifetime basis, the risk for white men is about 4 times that for black men. Cryptorchidism, or undescended testes, is a major risk factor for testicular cancer. Family history of the disease also appears to be a risk factor. Several other hereditary and environmental factors have been suggested, but the results of research are inconsistent (Bosl and Motzer, 1997).

TABLE 6-35 Average Annual Incidence (per 100,000) of Testicular Cancer in United Statesa

50–54 Years of Age

55–59 Years of Age

60–64 Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

4.1

4.7

1.4

2.1

2.3

1.2

1.6

1.8

0.5

a SEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude age-specific rates, 1997–2001.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and testicular cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Table 6-36 summarizes the results of the relevant studies.

Update of the Scientific Literature

No relevant occupational, environmental, or Vietnam-veteran studies have been published since Update 2002.

Synthesis

The evidence from epidemiologic studies is inadequate to link herbicide exposure and testicular carcinoma; no new published information was found to change that determination.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and testicular cancer.

Biologic Plausibility

No animal studies have reported an increased incidence of testicular cancer after exposure to the compounds of interest. A summary of the biologic plausibility of the carcinogenicity of the chemicals of interest in general is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and testicular cancer, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-36 Selected Epidemiologic Studies—Testicular Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 2002

Burns et al., 2001

Dow 2,4-D production workers

1

2.2 (0.0–12.5)

Studies Reviewed in Update 2000

Fleming et al., 1999b

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

US 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

Studies Reviewed in Update 2000

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:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

VIETNAM VETERANS

Studies Reviewed in Update 2000

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

114

1.1 (*)

 

Vietnam service, Marines

28

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, DC, area hospitals

31

2.3 (1.0–5.5)

Watanabe et al., 1991

Army Vietnam veterans

109

1.2 (NS)

 

Marine Vietnam veterans

28

0.8 (NS)

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)

a Given when available.

b “Male genital cancers.”

c 99% CI.

d Self-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?”

* Information not provided by study authors.

—Information denoted by a dash in the original study.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; NS, not significant.

URINARY BLADDER CANCER

Urinary bladder cancer (ICD-9 188.0–188.9) is the most common of the urinary tract cancers. According to ACS estimates, 44,640 men and 15,600 women will be diagnosed with this cancer in the United States in 2004, and 8,780 men and 3,930 women will die from it (ACS, 2004a). In males, in whom this cancer is about 3 times as likely as it is in females, those numbers represent about 6% of new cancer diagnoses and 3% of deaths. Overall, bladder cancer is sixth on

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-37 Average Annual Incidence (per 100,000) of Urinary Bladder Cancer in United Statesa

 

50–54 Years of Age

55–59 Years of Age

60–64 Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

25.3

27.8

14.1

48.6

53.8

23.3

84.7

93.4

43.6

Females

8.3

9.3

5.1

13.9

15.5

9.6

24.2

27.3

16.4

a SEER (Surveillance, Epidemiology, and End Results Program) nine standard registries, crude age-specific rates, 1997–2001.

the cancer list in the United States. The average annual incidence of urinary bladder cancer is shown in Table 6-37.

Among men in the age groups that characterize most Vietnam veterans, bladder cancer incidence is about twice as high in whites as in blacks, and almost three times as high in males as in females. Bladder cancer incidence increases greatly after the age of 40. For men in the age groups shown in Table 6-37, the incidence in each 5-year group is almost double that in the age group before it.

The most important known risk factor for bladder cancer is tobacco use, which accounts for about half of bladder cancers in men and one-third in women (Miller et al., 1996). Occupational exposure to aromatic amines (also called arylamines); polycyclic aromatic hydrocarbons (PAHs); and some other organic compounds used in the rubber, leather, textile, paint products, and printing industries is associated with higher incidence. High-fat diets and exposure to the parasite Schistosoma hæmatobium have been implicated as risk factors. Exposure to inorganic arsenic is also a risk factor for bladder cancer; cacodylic acid is a metabolite of inorganic arsenic. As discussed in Chapter 3, however, the data are insufficient to conclude that studies of inorganic arsenic exposure are directly relevant to exposure to cacodylic acid. Therefore, the literature on inorganic arsenic is not considered in this section.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committees responsible for VAO and Update 1996 concluded that there was limited or suggestive evidence of no association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and urinary bladder cancer. Additional information available to the committee responsible for Update 1998 led it to change that conclusion to one of inadequate or insufficient information regarding an association. The Update 2000 and Update 2002 committees did not change that finding. Table 6-38 summarizes the results of the relevant studies.

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 6-38 Selected Epidemiologic Studies—Urinary Bladder Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Bodner et al., 2003

Dow chemical production workers—mortality

0.7 (0.1–2.0)

Swaen et al., 2004

Dutch licenced herbicide applicators—mortality

2

0.7 (0.1–2.4)

Studies Reviewed in Update 2002

Burns et al., 2001

Dow 2,4-D production workers

1

0.5 (0.1–2.8)

Studies Reviewed in Update 2000

Steenland et al., 1999

US 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

Dutch male 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 < 0.05)

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)

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

Iowa Farmers

274

0.9 (NS)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

ENVIRONMENTAL

Studies Reviewed in Update 2002

Revich et al., 2001

Residents of Chapaevsk, Russia

 

 

 

Age-adjusted incidence (100,000) of bladder cancer in males

 

40.2 in Chapaevsk; 19.8 in Samara regionc

 

Age-adjusted incidence (100,000) of bladder cancer in females

 

3.9 in Chapaevsk; 2.3 in Samara regionc

 

Mortality standardized to Samara region (Urinary organs)

 

 

 

Males

31

2.6 (1.7–3.6)

 

Females

17

0.8 (0.5–1.3)

Studies Reviewed in Update 2000

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, 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

5

1.3 (0.4–3.1)

 

West coast

20

1.0 (0.6–1.6)

 

Swedish fishermen—incidence

 

 

 

East coast

10

0.7 (0.4–1.3)

 

West coast

55

0.9 (0.7–1.1)

Suggested Citation:"6 Cancer." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa