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Veterans and Agent Orange: Update 2002 (2003)

Chapter: 6. Cancer

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Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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 overall leading cause of death in the United States (US Census, 1999). In 2002, about 555,500 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, 2002).

In this chapter, the committee summarizes and reaches conclusions about the strength of the evidence from epidemiologic studies regarding associations between exposure to herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and each type of cancer under consideration in this report. The cancer types are, with minor exceptions, discussed in the order in which they are listed in the International Classification of Diseases, Ninth Edition (ICD-9). ICD-9 is a standardized means of classifying medical conditions used by physicians and researchers around the world. Appendix B lists ICD-9 codes for the major forms of cancer. The categories of association and the committee's approach to categorizing the health outcomes are discussed in Chapters 1 and 2.

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

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

In this chapter, background information about each cancer, including data on its incidence in the general US population, is followed by a brief 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; and Veterans and Agent Orange: Update 2000, hereafter, Update 2000, IOM, 2001), 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, and Vietnam veteran). Each section ends with the committee's conclusion regarding the strength of the evidence from epidemiologic studies, biologic plausibility, and evidence regarding Vietnam veterans.

As mentioned above, data on cancer incidence in the general US population are included in the background sections. Those data provide context for the consideration of cancer risks in Vietnam veterans. Incidences are reported for people 45–59 years old because most Vietnam-era veterans are in this age group. The data, which were collected as part of the Surveillance, Epidemiology, and End Results (SEER) Program of the National Center for Health Statistics (NCHS), are categorized by sex, age, and race because these can have a profound effect on risk. Prostatic cancer incidence, for example, is nearly 11 times higher in men 55–59 years old than in men 45–49 years old and more than twice as high in blacks 45–59 years old as in whites in this age group (NCI, 2000). The figures presented for each cancer are estimates for the entire US population, not precise predictions for the Vietnam-veteran cohort. It should be remembered that numerous factors may influence the incidences reported here—including personal behavior (such as smoking and diet), genetic predisposition, and medical history. Those factors may make a particular person more or less likely than the average person to contract a given cancer. Incidence data are reported for all races and also separately for blacks and whites. The data reported are for 1995–1999, the most recent data available at the time this report was written.

Great uncertainties remain about the magnitude of potential risk posed by exposure to herbicides and TCDD in the occupational, environmental, and veteran studies reviewed by the committee. Many of those studies have inadequate controls for important confounders, and the information needed to extrapolate from the exposure in the studies to that of individual Vietnam veterans is lacking. The committee therefore cannot measure the risk likely to have been experienced by Vietnam veterans due to exposure to herbicides in Vietnam; it offers qualitative observations where data permit.

GASTROINTESTINAL TRACT TUMORS

Gastrointestinal tract tumors include some of the most common cancers. The committee reviewed the data on colon cancer (ICD-9 153.0–153.9), rectal cancer

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

(ICD-9 154.0–154.1), stomach cancer (ICD-9 151.0–151.9), and pancreatic cancer (ICD-9 157.0–157.9). According to American Cancer Society (ACS) estimates, about 200,200 people will be diagnosed with those cancers in the United States in 2002 and some 98,700 will die from them (ACS, 2002). Colon cancer accounts for about half those diagnoses and deaths. Collectively, gastrointestinal tract tumors are expected to account for 15% of new diagnoses and 18% of cancer deaths in 2002. The average annual incidences for gastrointestinal cancers are shown in Table 6-1.

The incidences of stomach, colon, rectal, and pancreatic cancers increase with age in people 45–59 years old. In general, incidence is higher in men than in women, and is higher in blacks than in whites. Besides age and race, 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. Cigarette-smoking is a risk factor for pancreatic cancer and may also increase the risk of stomach cancer (Miller et al., 1996). Infection with the bacterium Helicobacter pylori also increases the risk of stomach cancer.

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

The committee responsible for VAO found that there was limited or suggestive evidence of no association between exposure to the chemicals of interest (2,4-dichlorophenoxyacetic acid, 2,4-D; 2,4,5-trichlorophenoxyacetic acid, 2,4,5-

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

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

All Races

White

Black

All Races

White

Black

All Races

White

Black

Stomach

Males

5.9

4.6

11.7

10.0

9.2

16.9

18.1

15.7

24.3

Females

2.7

2.1

4.8

4.7

3.6

10.6

7.3

6.1

11.3

Colon

Males

15.3

14.6

21.3

34.2

32.0

56.8

62.5

61.0

85.0

Females

15.9

14.1

25.8

27.5

24.5

46.3

47.9

45.6

73.5

Rectal

Males

8.6

7.9

10.3

16.5

15.1

21.6

26.7

27.0

26.2

Females

6.0

5.6

6.0

9.6

9.0

12.0

15.2

14.6

16.6

Pancreatic

Males

6.1

5.8

10.3

12.8

12.0

25.7

21.6

19.8

42.5

Females

3.5

3.3

6.0

7.9

7.4

11.7

14.6

13.8

25.3

aSEER nine standard registries, crude age-specific rates, 1995–1999.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

T, or its contaminant TCDD; picloram; or cacodylic acid) and gastrointestinal tumors. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding (see Tables 6-2, 6-3, 6-4, and 6-5 for a summary of the studies).

Update of the Scientific Literature
Occupational Studies

In an occupational study, Burns et al. (2001) updated the mortality in chemical workers exposed in the production of 2,4-D. Members of that cohort are male employees of Dow Chemical Company who manufactured or formulated 2,4-D in 1945–1994. Their mortality experience is compared with national rates and with that in more than 40,000 other company employees who worked at the same location. There were 330 deaths in the 1,517 male employees who have an average follow-up of 26.2 years. Fewer deaths than expected from all malignant neoplasms and specifically cancers of the digestive organs and peritoneum (International Classification of Diseases, Eighth Revision 150–59) were found. There were 16 observed deaths compared with 21.5 expected, for a standardized mortality ratio (SMR) of 0.7 (0.4–1.2, 95% confidence interval [CI]).

Environmental Studies

An environmental study of residents of Chapaevsk, a Russian industrial community on the Volga River with documented contamination of the food and water supply by dioxins and other chemicals, demonstrated a higher incidence of colon cancer in males (22.7 per 100,000 per year) than Russia as a whole (17.9) or the Samara region of Russia (21.7), which includes Chapaevsk. Female residents of Chapaevsk did not have a higher incidence (13.3) than Russia as a whole (14.1) or Samara (15.4) (Revich et al., 2001). However, female residents of Chapaevsk did have a higher incidence of stomach cancer (33.9) than Russia (20.7) or Samara (17.6). Male residents of Chapaevsk had a lower incidence of stomach cancer (45.3) than Russia (48.1) but a higher incidence than Samara (44.0). Both male and female residents of Chapaevsk had a lower incidence of rectal cancer (15.3 and 7.0, respectively) than Russia (16.6 and 10.3) or Samara (17.1 and 11.2). Because of the lack of adjustment for confounding, the likelihood of multiple exposures, the absence of information on the completeness and accuracy of cancer diagnoses, and the ecologic study design, this study provides little evidence for associations with gastrointestinal cancers.

Vietnam-Veteran Studies

No relevant Vietnam-veteran studies have been published since Update 2000.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Synthesis

With only rare exceptions, studies on gastrointestinal cancers and exposure to herbicides in production, from agricultural use, from environmental sources, and among veteran populations found estimated relative risks close to 1.0, providing no evidence of any increase in risk. The updated analysis of mortality among US chemical workers at a Dow plant (Burns et al., 2001) did not report site-specific gastrointestinal cancers, and there was a nonsignificant increase in the SMR for all gastrointestinal cancers in the highest-exposed subgroups.

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 chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and gastrointestinal cancers (stomach, pancreatic, rectal, and colon cancers). The evidence regarding association was drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the present committee finds that there is still limited or suggestive evidence of no association between exposure to the chemicals of interest and gastrointestinal cancers.

Biologic Plausibility

No animal studies have found an increased incidence of gastrointestinal cancer after exposures to the chemicals of interest. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

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

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-2 Selected Epidemiologic Studies—Stomach Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Burns et al., 2001

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

16

SMR

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

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

0.5b (0.0–2.7)

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)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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

Farmers in Iowa

338

1.1 (p < 0.01)

Axelson et al., 1980

Swedish railroad workers—total exposure

3

2.2 (*)

ENVIRONMENTAL

New Studies

Revich et al., 2001

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

 

45.3 in Chapaevsk;

44.0 in Samara Regiond

 

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

 

33.9 in Chapaevsk;

17.6 in Samara Regiond

 

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)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

 

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)

VIETNAM VETERANS

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

32

1.1 (0.7–1.5)

Crane et al., 1997b

Australian national service Vietnam veterans

4

1.7 (0.3–>10)

Studies Reviewed in VAO

Breslin et al., 1988

Army Vietnam veterans

88

1.1 (0.9–1.5)

 

Marine Vietnam veterans

17

0.8 (0.4–1.6)

Anderson et al., 1986a

Wisconsin Vietnam veterans

3

Anderson et al., 1986b

Wisconsin Vietnam veterans

1

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.

— When information was denoted by a dash in the original study.

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

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-3 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 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

Ronco et al., 1992

Danish male self-employed farm workers

277

0.7 (p < 0.05)

Swaen et al., 1992

Dutch herbicide appliers

4

2.6 (0.7–6.5)

Fingerhut et al., 1991

NIOSH cohort

25

1.2 (0.8–1.8)

Manz et al., 1991

German production workers

8

0.9 (0.4–1.8)

Saracci et al., 1991

IARC cohort

41

1.1 (0.8–1.5)

Zober et al., 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

Paper and pulp workers

9

1.0 (0.5–2.0)

Solet et al., 1989

Paper and pulp workers

7

1.5 (0.6–3.0)

Alavanja et al., 1988

USDA agricultural extension agents

*

1.0 (0.7–1.5)

Bond et al., 1988

Dow 2,4-D production workers

4

2.1 (0.6–5.4)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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

Paper and pulp workers

7

0.4 (0.2–0.9)

Lynge, 1985

Danish male production workers

10

1.0 (*)

Blair et al., 1983

Florida pesticide appliers

5

0.8 (*)

Wiklund, 1983

Swedish agricultural workers

1,332

0.8 (0.7–0.8)c

Thiess et al., 1982

BASF production workers

1

0.4 (*)

Burmeister, 1981

Farmers in Iowa

1,064

1.0 (NS)

Hardell, 1981

Residents of Sweden

   
 

Exposed to phenoxy acids

11

1.3 (0.6–2.8)

 

Exposed to chlorophenols

6

1.8 (0.6–5.3)

ENVIRONMENTAL

New Studies

Revich et al., 2001

Residents of Chapaevsk, Russia

   
 

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

 

22.7 in Chapaevsk;

21.7 in Samara regiond

 

Age-adjusted incidence (100,000) of colon cancer 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. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

a Given when available.

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

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.

— When information was 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; 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. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-4 Selected Epidemiologic Studies—Rectal 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

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. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

ENVIRONMENTAL

New Studies

Revich et al., 2001

Residents of Chapaevsk, Russia

 

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

 

15.3 in Chapaevsk;

17.1 in Samara regionc

 

Age-adjusted incidence (100,000) of rectal cancer 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. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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.

— When information was 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; 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. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-5 Selected Epidemiologic Studies—Pancreatic Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 2000

Ojajärvi et al., 2000

Meta-analysis of 161 populations

 

MRR = 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 (*)

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 (*)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Blair et al., 1983

Florida pesticide appliers

4

1.0 (*)

Wiklund, 1983

Swedish agricultural workers

777

0.8 (0.8–0.9)b

Burmeister, 1981

Farmers in Iowa

416

1.1 (*)

ENVIRONMENTAL

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 (*)

Studies Reviewed in Update 1996

Dalager et al., 1995

Women Vietnam Veterans

7

2.8 (0.8–10.2)

 

Nurses

7

5.7 (1.2–27.0)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Visintainer et al., 1995

Michigan Vietnam veterans

14

1.0 (0.6–1.7)

Studies Reviewed in VAO

Thomas et al., 1991

US Vietnam veterans—females

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.

— When information was denoted by a dash in the original study.

ABBREVIATIONS: 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.

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, 11,000 men and 5,600 women will be diagnosed with liver or intrahepatic bile duct cancer in the United States in 2002 and 8,900 men and 5,200 women will die from them (ACS, 2002).

In the United States, liver cancers account for about 1% of new cancer cases and 2.5% of cancer deaths. Misclassification of metastatic cancers as primary liver cancer can lead to overestimating of deaths due to liver cancer (Percy et al., 1990). In developing countries, especially sub-Saharan Africa and Southeast Asia, liver cancers are common and are among the leading causes of death. The known risk factors for liver cancer include chronic infection with hepatitis B or C virus and exposure to the carcinogens aflatoxin and vinyl chloride. In the general population, the incidence of liver and intrahepatic bile duct cancer increases slightly with age; at the ages of 45– 59 years, 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 6-6.

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

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD,

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

picloram, or cacodylic acid) and hepatobiliary cancers. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding (see Table 6-7 for a summary of the studies).

Update of the Scientific Literature

An environmental study of residents of Chapaevsk, a Russian industrial community on the Volga River with documented contamination of the food and water supply by dioxins and other chemicals, demonstrated a higher incidence of liver cancer in males and females (13.5 and 5.9 per 100,000 per year, respectively) than in Russia as a whole (7.5 and 5.8) or the Samara region of Russia (6.6 and 2.7), in which the community is located. Because of the lack of adjustment for confounding by socioeconomic, lifestyle, comorbidity and other factors; and because of the likelihood of multiple exposures as well as the ecologic study design, this study cannot be taken as strong evidence for an association.

Vietnam-Veteran Studies

No relevant occupational or Vietnam-veteran studies have been published since Update 2000 (IOM, 2001).

Synthesis

The evidence from epidemiologic studies is inadequate to link herbicide exposure to hepatobiliary cancer; no new published information was found to change this opinion.

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

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

8.0

5.9

15.5

10.0

7.0

20.6

15.9

11.5

30.4

Females

1.9

1.4

3.2

3.0

2.3

4.3

4.2

3.2

7.2

aSEER nine standard registries, crude age-specific rates, 1995–1999.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-7 Selected Epidemiologic Studies—Hepatobiliary 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

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 wt

1

2.8 (0.1–15.5)

 

TCDD 0.1–0.99 µg/kg of body wt

0

 
 

TCDD >1 µg/kg of body wt

1

2.8 (0.1–15.5)

Ramlow et al., 1996

Pentachlorophenol production workers

 

0-year latency

0

 

15-year latency

0

Studies Reviewed in Update 1996

Asp et al., 1994

Finnish herbicide appliers

2

0.6 (0.1–2.2)

Blair et al., 1993

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. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

ENVIRONMENTAL

New Studies

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)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Hoffman et al., 1986

Residents of Quail Run Mobile Home Park

0

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.

— When information was 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; IARC, International Agency for Research on Cancer; NIOSH, National Institute for Occupational Safety and Health; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Conclusions
Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is still inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) 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. Although several of those studies involve sizable cohorts, hepatobiliary cancers are rare; as a result, the number of expected cases is fairly small.

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

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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. Cacodylic acid administered to laboratory animals has induced hepatic neoplasms. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

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

NASOPHARYNGEAL CANCER

There are many types of nasal (ICD-9 160.0–160.9) and nasopharyngeal (ICD-9 147.0–147.9) cancers; undifferentiated carcinoma, squamous-cell carcinoma, and lymphomas account for the vast majority of malignancies.

ACS estimates that about 3,600 men and 1,300 women will be diagnosed with nasal, pleural, tracheal, and other respiratory system cancers (this excludes cancers of the larynx, lung, and bronchus) in the United States in 2002 and that some 2,000 men and 800 women will die from them (ACS, 2002). Roughly speaking, nasopharyngeal cancers account for one-third to one-half of those totals. ACS (2002) estimates suggest that about 6,500 men and 2,100 women will be diagnosed with cancers of the pharynx (including nasopharynx, tonsil, oropharynx, hypopharynx, and buccal cavity) and 1,500 men and 600 women will die from them. Nasopharyngeal cancers make up about one-fifth of those cancers. The average annual incidences reported in Table 6-8 show that men are at a greater risk than women for these diseases and that the incidences increase with age, although the very small number of cases indicates that care should be exercised in interpreting the numbers.

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

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-8 Average Annual Incidence (per 100,000) of Nasal and Nasopharyngeal Cancers in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Nose, Nasal Cavity, and Middle Ear

Males

0.8

0.7

1.4

1.1

1.0

1.4

2.2

2.0

1.9

Females

0.2

0.3

0.2

0.7

0.7

1.4

0.9

0.9

1.1

Nasopharynx

Males

1.6

0.6

2.1

2.0

1.0

2.0

2.8

2.0

1.4

Females

0.8

0.3

0.6

0.6

0.3

0.3

0.6

0.3

0.8

aSEER nine standard registries, crude age-specific rates, 1995–1999.

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

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and nasopharyngeal cancer. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding (see Table 6-9 for a summary of the studies).

Update of the Scientific Literature

An environmental study of female residents of Chapaevsk, a Russian industrial community on the Volga River with documented contamination of the food and water supply by dioxins and other chemicals, demonstrated a higher incidence of pharyngeal cancer (2.1 per 100,000 per year) than in Russia as a whole (0.7) and the Samara region of Russia (0.6), which includes Chapaevsk. Male residents of Chapaevsk did not demonstrate an excess risk (2.2) compared with Russia as a whole (5.9) and the Samara region (2.3) (Revich et al., 2001). The usefulness of these data is restricted due to the lack of adjustment for confounding (e.g. smoking), the likelihood of multiple exposures, the ecologic study design, and the absence of information on the completeness and accuracy of cancer incidence data.

No relevant occupational or Vietnam-veteran studies have been published since Update 2000 (IOM, 2001).

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-9 Selected Epidemiologic Studies—Nasal and Nasopharyngeal Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

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

New Studies

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)

VIETNAM VETERANS

Studies Reviewed in Update 2000

AFHS, 2000

Air Force Ranch Hand veterans

9

1.0 (0.4–2.8)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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.

— When information was denoted by a dash in the original study.

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

Synthesis

Nasopharyngeal cancers are relatively rare in the United States. Newly available data do not change the committee's belief that scientific evidence of an association between herbicide exposure and nasopharyngeal cancer is too sparse to draw conclusions.

Conclusions
Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is still inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and nasopharyngeal cancer.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Biologic Plausibility

No animal studies have found an increased incidence of nasopharyngeal cancer. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides used in Vietnam is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

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

LARYNGEAL CANCER

According to ACS estimates, 6,900 men and 2,000 women will be diagnosed with cancer of the larynx (ICD-9 161.0–161.9) in the United States in 2002, and 2,900 men and 800 women will die from it (ACS, 2002). Those numbers represent about 1% of new cancer diagnoses and deaths. Cancer of the larynx is more common in men than in women, with an overall ratio in the United States of about 5:1. Incidence increases with age in the group 45–59 years old. The average annual incidence for laryngeal cancer is shown in Table 6-10.

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

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

The committee responsible for VAO found that there was limited or suggestive evidence of an association between exposure to at least one of the chemicals

TABLE 6-10 Average Annual Incidence (per 100,000) of Laryngeal Cancer in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

4.7

4.3

11.2

10.5

9.8

22.0

17.6

17.1

36.9

Females

1.4

1.1

4.0

2.7

2.4

6.3

4.2

4.1

7.5

aSEER nine standard registries, crude age-specific rates, 1995–1999.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and laryngeal cancers. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding. Table 6-11 provides summaries of the results of the studies underlying that finding.

Update of the Scientific Literature
Occupational Studies

A small study of 261 Swedish lumberjacks exposed to phenoxyacetic herbicides demonstrated no cases of laryngeal cancer, although one was seen among 241 nonexposed lumberjacks followed as a control group (Thörn et al., 2000). This study is much too small to derive stable estimates of risk.

Environmental Studies

Both male and female residents of Chapaevsk, a Russian industrial community on the Volga River with documented contamination of the food and water supply by dioxins and other chemicals, demonstrated higher incidences of laryngeal cancer (18.0 and 1.1 per 100,000 per year, respectively) than in Russia as a whole (11.3 and 0.4) (Revich et al., 2001). Because of confounding by multiple exposures, the lack of data on alcohol consumption and smoking, and because of the ecologic study design, results of this study cannot be taken as strong evidence of an association with exposure to herbicides, but they are consistent with an increased risk.

Vietnam-Veteran Studies

No relevant Vietnam-veteran studies have been published since Update 2000 (IOM, 2001).

Synthesis

No studies published since Update 2000 provide strong 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 exposures of concern is not challenged by the few data available since Update 2000.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-11 Selected Epidemiologic Studies—Laryngeal Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

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

New Studies

Revich et al., 2001

Residents of Chapaevsk, Russia

 

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

 

18.0 in Chapaevsk;

11.3 in all of Russiab

 

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

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)

Pesatori et al., 1998c

Seveso residents—15-year follow-up

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

 

Zone A males

5

2.4 (1.0–5.7)

 

Zone A females

2

1.3 (0.3–5.3)

 

Zone B males

13

0.7 (0.4–1.3)

 

Zone B females

8

0.9 (0.4–1.7)

 

Zone R males

122

1.0 (0.9–1.3)

 

Zone R females

71

0.8 (0.7–1.1)

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; 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.

Conclusions
Strength of Evidence in Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and laryngeal cancer.

Biologic Plausibility

No animal studies have found an increased incidence of laryngeal cancer associated with exposure to TCDD and the herbicides of concern. A summary of the biologic plausibility of the carcinogencity of TCDD and the herbicides in

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

The conclusion is based on data on other exposed groups. The Air Force Health Study (AFHS) did not find an excess risk of laryngeal cancer among the veterans it studied.

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, 90,200 men and 79,200 women will be diagnosed with this cancer in the United States in 2002, and about 89,200 men and 65,700 women will die from it (ACS, 2002). Those numbers represent roughly 13% of new cancer diagnoses and 28% of cancer deaths in 2002. The principal types of lung neoplasms are identified collectively as bronchogenic carcinoma (the bronchi are the two main 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 beginning at the age of about 40 years. The incidence in those 50–54 years old is double the incidence in those 45–49 years old, and it doubles again in those 55–59 years old. 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 6-12.

ACS estimates that more than 90% of lung cancers in males are the result of smoking tobacco (ACS, 1998). Among the other risk factors are occupational exposure to asbestos, chromium, nickel, aromatic hydrocarbons, radioactive ores, and inorganic arsenic. In addition to being synthesized as a herbicide, cacodylic acid, which is dimethylarsinic acid, is a metabolite of inorganic arsenic in hu-

TABLE 6-12 Average Annual Incidence (per 100,000) of Lung and Bronchial Cancer in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

31.0

27.4

67.7

72.6

66.6

149.8

147.7

129.4

285.8

Females

24.8

24.4

35.0

55.2

55.9

76.2

103.1

107.8

122.9

aSEER nine standard registries, crude age-specific rates, 1995–1999.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

mans. As discussed in Chapter 3, however, the data remain 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, and Update 2000

The committee responsible for VAO found that there was limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and lung cancer. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding. Table 6-13 provides summaries of the results of the studies underlying that finding.

Update of the Scientific Literature
Occupational Studies

A cohort of 1,517 male employees of the Dow Chemical Company who were involved in the manufacture or formulation of 2,4-D at some time in 1945–1994 demonstrated no excess mortality from cancer of the lung (SMR = 94) (Burns et al., 2001)

A small study of 261 Swedish lumberjacks exposed to phenoxyacetic herbicides suggested a possible excess of lung cancer by demonstrating single cases in the subgroup of foremen (only 15 persons, with a nominal standardized incidence ratio, SIR, of 417) and female lumberjacks (103 persons, with a nominal SIR of 217), although five such cases were seen among 241 nonexposed lumberjacks followed as a control group (SIR 115, not significant) (Thörn et al., 2000). This study is much too small to derive stable estimates of risk that are generalizable to other populations.

Environmental Studies

Residents of Chapaevsk, a Russian industrial community on the Volga River with documented contamination of the food and water supply by dioxins and other chemicals, demonstrated increased incidences of lung cancer (164.5 per 100,000 per year among men, 19.6 among women) compared with Russia as a whole (89.4 and 9.8, respectively) and the Samara region of Russia (102.4 and 11.1), which includes Chapaevsk (Revich et al., 2001). Data on cigarette-smoking patterns and other exposures were not reported, but arsenic was among the other chemicals to which some residents of Chapaevsk may have been exposed. Because of confounding by multiple exposures and because of the ecologic-study

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-13 Selected Epidemiologic Studies—Lung and Bronchial Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Burns et al., 2001

Dow 2,4–D production workers

31

SMR = 94 (0.6–1.3)

Thörn et al., 2000

Swedish lumberjack workers exposed to phenoxyacetic herbicides

   
 

Foremen

1

SIR = 417

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)

McDuffie et al., 1990

Saskatchewan farmers applying herbicides

103

0.6 NS

Zober et al., 1990

BASF production workers

6

1.6 (*)

 

High exposure

4

2.0 (0.6–5.2)

 

Chloracne

6

1.8 (0.7–4.0)

Wiklund et al., 1989a

Pesticide appliers in Sweden

38

0.5 (0.4–0.7)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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

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

 

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)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

 

Zone R females

29

1.0 (0.7–1.6)

Pesatori et al., 1998

Seveso (respiratory)—15-year follow-up

 

Zone A males

5

2.4 (1.0–5.7)

 

Zone A females

2

1.3 (0.3–5.3)

 

Zone B males

13

0.7 (0.4–1.3)

 

Zone B females

8

0.9 (0.4–1.7)

 

Zone R males

122

2.0 (0.9–1.3)

 

Zone R females

71

0.8 (0.7–1.1)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

 

Zone A males

4

1.0 (0.3–2.5)

 

Zone B males

34

1.2 (0.9–1.7)

 

Zone B females

2

0.6 (0.1–2.1)

 

Zone R males

176

0.9 (0.8–1.0)

 

Zone R females

29

1.0 (0.7–1.5)

Svensson et al., 1995

Swedish fishermen—mortality

 

East coast

16

0.8 (0.5–1.3)

 

West coast

77

0.9 (0.7–1.1)

Studies Reviewed in VAO

Bertazzi et al., 1993

Seveso residents—10-year follow-up— morbidity

   
 

Zone A males

2

0.8 (0.2–3.4)

 

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

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)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

 

Non-Vietnam

77

0.9 (*)

Watanabe and Kang, 1995

Vietnam service Marines 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; MCPA, methyl-4-chlorophenoxyacetic acid; PCDD, polychlorinated dibenzodioxin; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

design, results of this study cannot be taken as strong evidence of an association with herbicide or TCDD exposure.

Vietnam-Veteran Studies

No relevant Vietnam-veteran studies have been published since Update 2000 (IOM, 2001).

Synthesis

Evidence remains inconclusive but suggestive regarding an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and lung cancer. Absence of data on smoking and other confounding factors, such as other occupational exposures, limits the usefulness of the results of available studies. The most prominent and convincing evidence came from the National Institute for Occupational Safety and Health (NIOSH) cohort, which experienced some of the highest TCDD exposures of any population studied. Lung was the only individual cancer site that showed an excess among these workers. In addition, numerous lines of mechanistic evidence, discussed below under “Biologic Plausibility,” provide further support for the conclusion of limited/suggestive evidence.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Conclusions
Strength of Evidence in Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and cancer of the lung (carcinomas of the lung and bronchus).

Biologic Plausibility

As noted in Update 2000, there is evidence of increased incidence of squamous-cell carcinoma of the lung in rats exposed to high concentrations of TCDD. Cacodylic acid administered to rats has resulted in 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 support a role of TCDD as a promoter in the carcinogenic process. Lung tissue has been found to have high concentrations of the aryl hydrocarbon receptor (AhR) that mediates the effects of TCDD, and recent data have shown both CYP1A1 and CYP1A2 to be 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 may synergize the carcinogenic effects of a variety of other chemicals to which human lung tissue is exposed. A summary of the biologic plausibility of the carcinogencity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

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

BONE AND JOINT CANCER

According to the ACS, about 1,300 men and 1,100 women will be diagnosed with bone or joint cancer (ICD-9 170.0–170.9) in the United States in 2002, and 700 men and 600 women will die from it (ACS, 2002). 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

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-14 Average Annual Incidence (per 100,000) of Bone and Joint Cancer in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

0.6

0.6

0.9

1.0

1.1

0.7

1.2

1.3

1.9

Females

0.7

0.8

0.8

0.9

0.9

0.9

0.8

0.9

b

aSEER nine standard registries, crude age-specific rates, 1995–1999.

bInsufficient data to provide meaningful incidence.

cancer is considered here. The average annual incidence of bone and joint cancer is shown in Table 6-14.

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

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

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and bone cancer. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding (see Table 6-15 for summaries of the studies).

Update of the Scientific Literature

An environmental study of residents of Chapaevsk, a Russian industrial community on the Volga River with documented contamination of the food and water supply by dioxins and other chemicals, reported seven deaths in male residents due to cancer of the bones or soft tissues (SMR = 2.1 [0.9–4.4]) and seven deaths in female residents (SMR = 1.4 [0.6–3.0]). Because cancers of the bone and soft tissue are combined in this analysis, the results cannot be taken as evidence for an association with bone cancer alone.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-15 Selected Epidemiologic Studies—Bone Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

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

Farmers in Iowa

56

1.1 (NS)

ENVIRONMENTAL

New Studies

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. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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.

— When information was denoted by a dash in the original study.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; 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.

Vietnam-Veteran Studies

No relevant occupational or Vietnam-veteran studies have been published since Update 2000.

Synthesis

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

Conclusions
Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence to determine whether an association exists

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and bone cancer. The evidence regarding an association is drawn from occupational and environmental studies in which the subjects were exposed to a variety of herbicides and herbicide compounds.

Biologic Plausibility

No animal studies have found an increased incidence of bone cancer after exposure to the chemicals of interest. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

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

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 4,400 men and 3,900 women will be diagnosed with STS in the United States in 2002 and that about 2,000 men and 1,900 women will die from it (ACS, 2002). 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 6-16.

TABLE 6-16 Average Annual Incidence (per 100,000) of Soft-Tissue Sarcoma (Including Malignant Neoplasms of Heart) in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

3.0

2.8

4.2

4.0

4.0

5.8

4.3

4.4

3.7

Females

2.3

2.3

3.0

3.0

3.0

3.4

3.7

3.6

4.5

aSEER nine standard registries, crude age-specific rates, 1995–1999.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Among the risk factors for those cancers are exposure to ionizing radiation from 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, and Update 2000

The committee responsible for VAO found that there was sufficient information to determine that an association existed between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and STS. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding (see Table 6-17 for a summary of the studies).

Update of the Scientific Literature

In an environmental study, Costani et al. (2000) report on an unusually high frequency of STS among the general population living near a chemical plant in the northern Italian city of Mantua, a city of about 50,000 people in a county that is mainly agricultural. A number of industrial activities were developed in the last 20 years, including a paper mill, a petroleum refinery, a petrochemical plant, three thermoelectric plants, three toxic-waste deposits, and a toxic-waste and medical-waste incinerator. A general practitioner's noting five cases of STS over an 8-year period prompted a call to all general practitioners in the area to report cases of STS and to verify the histologic diagnosis. Complete information was obtained on 20 cases diagnosed in 1984–1996. The corresponding number of expected cases based on the provincial cancer registry was 8.9, for an SMR of 2.3 (95% CI 1.3–3.5). The malignancies were classified according to the ICD-10 codes of 8800–9044. The most frequent types were leiomyosarcoma, dermatofibrosarcoma, and fibrosarcoma. The authors hypothesized that the cause of the geographically confined excess was soil contamination, but there were no soil or air samples or exposure data to support the hypothesis.

No relevant occupational or Vietnam-veteran studies have been published since Update 2000.

Synthesis

Findings from prior occupational, environmental, and veteran studies show sufficient evidence to link herbicide exposure to STS. An additional environmental-exposure report from Mantua, Italy, adds to this evidence.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-17 Selected Epidemiologic Studies—Soft-Tissue Sarcoma

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

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)

 

Those with 20 years of latency and 1 year of exposure

3

9.2 (1.9–27.0)

Manz et al., 1991

German production workers

0

(*)

Saracci et al., 1991

IARC cohort

4

2.0 (0.6–5.2)

Zober et al., 1990

German production workers

0

(*)

Alavanja et al., 1989

Forest or soil conservationists

2

1.0 (0.1–3.6)

Bond et al., 1988

Dow 2,4-D production workers

0

(*)

Wiklund et al., 1988, 1989b

Swedish agricultural workers

7

0.9 (0.4–1.9)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Woods et al., 1987

Male residents of Washington State

 

High phenoxy exposure

*

0.9 (0.4–1.9)

 

Those with self-reported chloracne

*

3.3 (0.8–14.0)

Coggon et al., 1986

British MCPA chemical workers

1

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

66

 
 

Among all living women

5

2.4 (0.4–16.1)

Smith et al., 1983, 1984;

Smith and Pearce, 1986

New Zealand workers exposed to herbicides

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

52

5.5 (2.2–13.8)

Eriksson et al., 1979, 1981

Swedish workers

25

(2.2–10.2) 5.1 matched

ENVIRONMENTAL

New Studies

Costani et al., 2000

Residents near a chemical plant in Mantua, Italy

20

SMR = 2.25 (1.3–3.5)

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

(*)

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)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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

Crane et al., 1997b

Australian national service Vietnam veterans

4

0.7

 

Comparison group

2

AFHS, 1996

Ranch Hand veterans

1

 

Comparisons

1

Visintainer et al., 1995

Vietnam veterans

8

1.1 (0.5–2.2)

Watanabe and Kang, 1995

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)

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

(*)

 

Comparisons

1

(*)

Breslin et al., 1988

Army Vietnam veterans

30

1.0

Fett et al., 1987

Australian Vietnam veterans

1

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

Anderson et al., 1986a,b

Wisconsin Vietnam veterans

5

1.5 (0.6–3.5)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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 CI's include 1.

* Information not provided by study authors.

— When information was 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; 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; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Conclusions
Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is sufficient evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and STS.

Biologic Plausibility

No animal studies have found an increased incidence of STS. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

The available data on Vietnam veterans do not permit a conclusion on whether they are at increased risk for STS.

SKIN CANCER—MELANOMA

Skin cancers are generally divided into two broad categories: neoplasms that develop from melanocytes (malignant melanoma) and neoplasms that do not.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-18 Average Annual Cancer Incidence (per 100,000) of Melanoma of the Skin in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

24.8

28.9

0.9

34.0

38.8

1.7

41.3

46.7

2.3

Females

21.6

25.4

1.8

23.7

27.4

0.9

25.3

29.6

3.0

aSEER nine standard registries, crude age-specific rates, 1995–1999.

Nonmelanocytic skin cancers (primarily basal-cell and squamous-cellcarcinomas) 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 6-18. In VAO and Update 1996, all skin cancers were assessed together. However, beginning with Update 1998, the committee chose to address studies assessing malignant melanoma separately from those

TABLE 6-19 Selected Epidemiologic Studies—All (or Unspecified) Skin-Cancer Mortality

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in VAO

Fingerhut et al., 1991

NIOSH cohort

4

0.8 (0.2–2.1)

Saracci et al., 1991

IARC cohort

3

0.3 (0.1–0.9)

Alavanja et al., 1988

USDA agricultural extension agents

5

1.1 (0.5–2.6)

Burmeister, 1981

Farmers in Iowa

105

1.1 (NS)

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

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-20 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 Ranch Hand 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.

assessing nonmelanocytic cancers. Because nonmelanocytic cancers are highly treatable, studies of them have been divided further into studies that discuss mortality and studies that discuss incidence. Many studies report results by combining all types of skin cancers or do not specify the type of skin cancers assessed. In the interest of completeness, studies of skin-cancer mortality and morbidity are listed in Tables 6-19 and 6-20.

According to ACS estimates, about 29,000 men and 22,400 women will be diagnosed with cutaneous melanoma (ICD-9 172.0–172.9) in the United States in 2002, and 5,000 men and 2,800 women will die from it (ACS, 2002). About 1,300,000 cases of nonmelanocytic skin cancer (ICD-9 173.0–173.9), primarily basal-cell and squamous-cell carcinomas, are diagnosed in the United States each year (ACS, 2000). Because it is not required to report those cancers to registries, the numbers of cases are not as precise as for other cancers. The ACS estimates that about 1,900 people will die from nonmelanocytic skin cancer in 2002.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Skin cancer is far more likely to occur 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 for melanoma include the presence of some moles on the skin, a suppressed immune system, and excessive exposure to ultraviolet (UV) radiation, typically from the sun. A family history of the disease has been identified as a risk factor, but it is unclear whether this is due to genetic factors or to similarities in skin type and sun-exposure patterns.

Excessive exposure to UV radiation is the most important risk factor for nonmelanocytic skin cancer. Some skin diseases and chemical exposures have also been identified as potential risk factors. Exposure to inorganic arsenic is a risk factor for skin cancer, and cacodylic acid is a metabolite of inorganic arsenic. As discussed in Chapter 3, however, the data remain 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 the sections on skin cancer.

SEER incidence data are not available for nonmelanocytic skin cancer.

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

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant TCDD 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 malignant melanoma separately from that of nonmelanocytic skin cancers. It found that there was inadequate or insufficient information to determine whether an association existed between exposure to herbicides used in Vietnam or the contaminant TCDD and malignant melanoma. The Update 2000 committee concurred with the findings of the Update 1998 committee (see Tables 6-21 and 6-22 for summaries of the melanoma mortality and morbidity studies, respectively).

Update of the Scientific Literature
Occupational Studies

Burns et al. (2001) conducted a study of mortality in a cohort of 1,517 male Dow Chemical Company workers involved in the production of 2,4-D in 1945– 1994. Information regarding the measurement of exposure and the collection and analysis of data is provided in Chapter 5. No deaths due to melanoma were reported in the study.

Cancer incidence and mortality were analyzed in a cohort of 504 forestry

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-21 Selected Epidemiologic Studies—Melanoma Mortality

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Burns et al., 2001

Dow 2,4-D production workers

 

Melanoma

0

0.0

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. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (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; IARC, International Agency for Research on Cancer; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

workers in Sweden (Thörn et al., 2000). The cohort included 261 workers exposed to phenoxy herbicides and 243 nonexposed workers. Follow-up data were collected in 1954–1994 on cancer mortality and in 1958–1992 on cancer incidence. The observed frequency of cancer was compared with expected values on the basis of data on the population of Sweden. The only case of melanoma in the cohort was recorded in an exposed female worker (SIR = 95% CI 3.5, 0.1–19.2).

Environmental Studies

An analysis of cancer incidence and mortality was conducted in the city of Chapaevsk in the Samara region of Russia (Revich et al., 2001). Studies of the air, soil, and water in Chapaevsk revealed general dioxin contamination in the environment. Mortality data were not reported for melanoma. The age-adjusted incidence of melanoma in Chapaevsk relative to the Samara region during 1998 was somewhat lower in men (4.2 vs 5.1 per 100,000) but notably higher in women (8.9 vs 3.5). The numbers of cases in Chapaevsk and the Samara region were not given, hypothesis-testing and interval estimation were not performed, and no confounding factors were considered besides age.

Vietnam-Veteran Studies

No relevant Vietnam-veteran studies have been published since Update 2000.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-22 Selected Epidemiologic Studies—Melanoma Morbidity

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Thörn et al., 2000

Swedish lumberjack workers exposed to phenoxyacetic herbicides

   
 

Female

1

3.5 (0.1–19.2)

 

Male

0

0.0

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)

New Studies

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

Studies Reviewed in Update 2000

AFHS, 2000

Air Force Ranch Hand veterans

16

1.8 (0.8–3.8)

AIHW, 1999

Australian Vietnam veterans—male

483

380 expected (342–418)

Ketchum et al., 1999

Ranch Hand (RH) veterans and comparisons through June 1997

   
 

Comparisons

9

(control group)

 

Background-exposure RH veterans

4

1.1 (0.3–4.5)

 

Low-exposure RH veterans

6

2.6 (0.7–9.1)

 

High-exposure RH veterans

2

0.9 (0.2–5.6)

CDVA, 1998a

Australian Vietnam veterans—male

2,689c

380 expected (342–418)

CDVA, 1998b

Australian Vietnam veterans—female

7c

3 expected (1–8)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Studies Reviewed in Update 1998

Clapp, 1997

Massachusetts Vietnam veterans

21

1.4 (0.7–2.9)

Studies Reviewed in VAO

Wolfe et al., 1990

Air Force Ranch Hand veterans

4

1.3 (0.3–5.2)

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.

Synthesis

The new epidemiologic studies add little information on the association between exposure to herbicides and the incidence of melanoma. Despite the extended period of follow-up (30–40 years), the occupational studies of chemical workers and lumberjacks do not include enough workers to be informative for this outcome. The data on the increased incidence of melanoma in women of Chapaevsk relative to the Samara region and Russia at large are intriguing, but more information is needed about the completeness of surveillance of the incidence of melanoma and the number of cases included in these measures of incidence.

Conclusions
Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and melanoma. The evidence regarding association is drawn from occupational, environmental, and veteran studies in which subjects were exposed to herbicides and herbicide components.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Biologic Plausibility

Mice were treated topically (on 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 support a role of TCDD as a promoter in the carcinogenic process. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

Although previously reviewed studies of US and Australian veterans have reported a higher incidence of melanoma among male, nonblack 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 was observed in veterans in the low-TCDD category; this would not be expected if there were an association between exposure and melanoma. 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. Overall, data on those who served in Vietnam are not adequate to infer an association between malignant melanoma and exposure to herbicides used in Vietnam.

SKIN CANCER—BASAL-CELL AND SQUAMOUS-CELL (NONMELANOMA)

See the preceeding section for background information on skin cancer.

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

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant 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 nonmelanocytic skin cancers separately from that of malignant melanoma. It found that there was inadequate

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-23 Selected Epidemiologic Studies—Other Nonmelanoma (Basal-Cell and Squamous-Cell) Skin Cancer—Mortality

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Burns et al., 2001

Dow 2,4-D production workers

 

Non-melanoma skin cancer

0

0.0

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.

— When information was denoted by a dash in the original study.

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

or insufficient information to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and basal-cell or squamous-cell cancers. The Update 2000 committee concurred with that finding (see Tables 6-23 and 6-24 for summaries of the studies).

Update of the Scientific Literature
Occupational Studies

Burns et al. (2001) conducted a study of mortality from multiple causes in a cohort of 1,517 male workers involved in the production of 2,4-D in 1945–1994. The study is a continuation and extension of previously reported research on

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-24 Selected Epidemiologic Studies—Other Nonmelanoma (Basal-Cell and Squamous Cell) Skin Cancer—Morbidity

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

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

New Studies

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. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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.

workers at the Dow Chemical Company; additional information on study design is presented in Chapter 4. No deaths due to skin cancer (melanoma or other forms) were recorded in the cohort.

The incidence of fatal and non-fatal cancer was assessed in a cohort of 504 forestry workers in Sweden employed in 1954–1967 (Thörn et al., 2000). The cohort included 261 workers exposed to phenoxy herbicides and 243 nonexposed workers. Follow-up data on the occurrence of cancer were collected in 1954–1994 on mortality and in 1958–1992 on incidence. The frequency of cancer in the cohort was compared with that in the population of Sweden at large. Nonmelano-

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

cytic skin cancer was diagnosed in one exposed foreman in the cohort (SIR = 16.7, 95% CI 0.2–92.7) and three nonexposed workers (SIR = 2.0, 95% CI 0.4–5.8).

Environmental Studies

Revich et al. (2001) assessed cancer incidence and mortality in Chapaevsk, a city in the Samara region of Russia. Studies of the air, water, and soil in Chapaevsk indicated widespread dioxin contamination from a major chemical plant that has produced hexachlorane and chemicals used in herbicides and pesticides. The age-adjusted incidence of skin cancers other than melanoma during 1998 was reported separately for Chapaevsk and for the entire Samara region. The incidence of these cancers was similar in men (55.9 vs 55.7 per 100,000, respectively) and somewhat higher in women (64.0 vs 47.6). No information was provided on the number of cases used to compute those rates, no p values or confidence intervals were reported for the comparison of the rates, and no confounding factors besides age were considered.

Vietnam-Veteran Studies

No relevant Vietnam-veteran studies have been published since Update 2000.

Synthesis

There is little new information in the epidemiologic literature on the relationship between herbicide exposure and the occurrence of nonmelanoma skin cancer. Analyses of mortality, such as that of Burns et al. (2001), are not useful in the study of these cancers, because they rarely lead to death. Only four cases have occurred in the small cohort (N = 504) of lumberjacks, and three in the nonexposed group (Thörn et al., 2000). The data on Chapaevsk compared with the Samara region at large suggest a 34% increase in incidence that is limited to women. The precision of that estimated difference and its consistency over time are unknown. Completeness of reporting is particularly problematic for nonmelanocytic skin cancers, and information on this issue would need to be obtained for the interpretation of the report by Revich et al. (2001).

Conclusions
Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence to determine whether an association exists

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and basal-cell or squamous-cell cancers.

Biologic Plausibility

In mice treated with TCDD topically (on skin surface) for 2 years (Huff et al., 1991), under the conditions of the bioassay, fibrosarcomas occurred in the integumentary system of females. The data indicate 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 support a role for TCDD as a promoter in the carcinogenic process. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

The AFHS report reviewed in Update 2000 indicates a higher incidence of nonmelanoma skin cancers among male, nonblack veterans than in the comparison group. However, analyses controlling for factors that might influence or be correlated with the incidence of skin cancers do not show a relationship between measures of exposure to the herbicides used in Vietnam and these cancers.

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. The ACS estimates that about 203,500 women will be diagnosed with breast cancer in the United States in 2002 and that 39,600 will die from it (ACS, 2002). Overall, those numbers represent about 30% of the incidence of new cancers and 15% of cancer deaths among women. Among women 40–55 years old, breast cancer is the leading cause of cancer death. Incidence data on breast cancer are presented in Table 6-25.

Breast-cancer incidence generally increases with age. In the age groups of most Vietnam veterans, the incidence in whites is slightly higher than 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 years. A pooled analysis of six large-scale prospective studies of invasive breast cancer found that alcohol consumption was associated with a linear increase in incidence in women over the range of consumption reported by most women (Smith-Warner et al., 1998). The potential role of other

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-25 Average Annual Incidence (per 100,000) of Breast Cancer in Females in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

 

200.0

202.5

194.5

273.0

280.8

261.8

328.1

338.0

297.4

aSEER nine standard registries, crude age-specific rates, 1995–1999.

personal behavioral and environmental factors in breast-cancer incidence is being studied extensively.

Most female Vietnam veterans who were potentially exposed to herbicides in Vietnam are approaching or have reached menopause and will experience an increasing risk of breast cancer. It is expected on the basis of demographics alone, therefore, that breast cancer will be a conspicuous and significant cause of death.

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

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and breast cancer. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding. Table 6-26 provides summaries of the results of the studies underlying the finding.

Update of the Scientific Literature
Occupational Studies

Since Update 2000, Duell and colleagues (2001) have published results on the reproducibility of self-reported data on farm exposures to potentially hazardous agents, such as pesticides. Using a 10% sample (comprising 30 cases and 31 controls) of the original case–control study (Duell et al., 2000), they show that farming-exposure information obtained from rural women by using detailed farm-by-farm exposure assessment is generally reproducible with an ever–never method. However, in some subgroups of cases (such as older women and low-educated women), they reported lower proportions of exact agreement. The overall pattern in reproducibility across questions was different between cases and

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-26 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

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

New Studies

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. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

VIETNAM VETERANS

New Studies

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; IARC, International Agency for Research on Cancer; PCB, polychlorinated biphenyls; RR, relative risk; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

controls. But overall case–control differences in the kappa statistic, a statistical measure of agreement beyond chance, were small. The new results provide some assurance that the conclusion of “no overall excess risk of breast cancer” reported in Duell et al. (2000) is not due to measurement error in the exposure assessment.

Environmental Studies

Holford et al. (2000) studied the joint effects of all congeners of polychlorinated biphenyls (PCBs) with analytic methods that properly account for the high colinearity in the multiple components. On the basis of data on 490 patients with breast-related surgery at Yale-New Haven Hospital (304 cases and 186 controls), they showed that total PCB was not significantly associated with breast-cancer risk (OR = 1.0; 95% CI 0.9–1.1). However, significant protective effects were detected for potential antiestrogens and a dioxin-like congener, 156 (OR = 0.9; 95% CI 0.8–1.0). Although a higher risk of breast cancer was detected for congeners 180 and 183, the study underlined the need to analyze components of PCB

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

properly if biologically meaningful but potentially different effects of the multiple components of PCB were to be examined properly. This study used breast adipose tissue and hence required the use of female controls without breast cancer who had undergone breast surgery. That prevented the use of general-population controls and hence limited the external validity of the results.

Revich et al. (2001) studied the relationship between the relatively high dioxin concentrations in Chapaevsk, Russia (in air, soil, drinking water, and cows' milk because of pollution from a chemical plant in the area), and breast-cancer incidence and related mortality. The incidence rate of female breast cancer, age-adjusted to the Russian standard population, was higher in Chapaevsk in all age groups (69.6) than in Russia (46.2) and the Samara region (50.7) in 1998. The Chapaevsk women also had higher breast-cancer mortality (SMR = 2.1, 95% CI 1.6–2.7). One of the main weaknesses of this study is the lack of adjustment for such risk factors as family size (parity), breastfeeding, alcohol use, body-mass index (BMI), and fat consumption.

Aronson et al. (2000) reported results of a hospital-based case–control study in Ontario, Canada (Toronto and Kingston). The study used data on 217 breast-cancer cases and 213 benign controls that were frequency-matched by age (5-year age groups) and site to test whether breast-cancer risk is associated with breast adipose-tissue concentrations of several organochlorines. Questionnaire information was collected via mail or telephone interview on demographics, menopausal status, weight (at the age of 25 years and 2 years before interview), height, reproductive history, use of exogenous hormones, physical activity, diet, and family history of breast cancer. Using unconditional logistic-regression models with adjustments for age, study site, menopausal status, and other congener-specific additional confounders, the authors found statistically significant associations between risk of breast cancer and some PCB congeners with dioxin-like activity, albeit at much lower concentrations than dioxins or coplanar PCBs. Specifically, there was an increase in breast cancer in, for instance, the groups with the highest exposure (over 85th percentile) to PCB 105 (OR = 3.2, 95% CI 1.5–6.7) or PCB 118 (OR = 2.3, 95% CI 1.1–4.8) but not PCB 156 (OR = 1.4, 95% CI 0.7–2.7). Those associations showed a dose-response relationship and a stronger effect in premenopausal women. The study used breast adipose tissue and hence required as controls women who had biopsies that were negative for malignancy. That prevented the use of general-population controls and so limits the external validity of the results. It was also reported that the subjects excluded because of lack of information on organochlorine concentrations differed from subjects included in the study. The cases were older (by about 4 years), they had a higher BMI, a lower proportion of them were premenopausal, and more came from Kingston than the controls. Similar differences were also reported for controls. Those differences may further limit the external validity of the study.

Demers et al. (2002) conducted a case–control study on 314 breast-cancer cases and 523 hospital and population controls to test whether exposure to spe-

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

cific PCB congeners was associated with risk of breast cancer. The study focused on mono-ortho PCB congeners that are known to display dioxin-like activity. Cases and controls were matched with respect to age (within 5-year groups) and region of residence (rural vs urban). Risk of breast cancer was examined in all study subjects and separately by menopausal status. A telephone interview was conducted to collect information on lifestyle, dietary habits, and reproductive history. All study subjects were required to be 30–70 years old and to be residing in the Quebec City area. The association between risk of breast cancer and specific PCB congeners was examined with unconditional logistic-regression models. The results indicate that there was a significantly increased risk of breast cancer with increased plasma concentrations of PCB 118 (OR = 1.6, 95% CI 1.0– 2.5) and PCB 156 (OR = 1.8, 95% CI 1.1 –2.9) for the highest quartile compared with the first quartile. The associations were stronger for premenopausal women, with ORs of 2.9 (95% CI 1.1–7.3) and 2.9 (95% CI 1.2–7.2) for PCB 118 and 156, respectively. Effect modification by menopausal status, however, was not statistically significant. The risk of breast cancer was found to be statistically associated with the mean total concentration of mono-ortho congeners (PCB 105, PCB 118, and PCB 156), with ORs of 2.0 (95% CI 1.2–3.3), comparing the fourth with the first quartile. Again, the association was found to be stronger in premenopausal women (OR = 2.6, 95% CI 1.0–6.6). All the models were adjusted for age, region of residence, BMI, history of benign breast cancer, and duration of breastfeeding. The study was well conducted and appears to have used appropriate statistical methods. Its laboratory methods have smaller error rates than those used in other studies, such as the study by Aronson et al. (2000).

Warner et al. (2002) reported results from the Seveso Women's Health Study to test whether serum TCDD concentrations were associated with risk of breast cancer. As described in previous reports and elsewhere in this update, the Seveso cohort is a unique resource for studying the effect of TCDD because of an industrial explosion that occurred in the area in July 1976 and resulted in the highest TCDD concentrations known in human residential populations. The new historical cohort study differs from previous studies on the Seveso cohort in using individual TCDD concentrations as opposed to zones as indicators of exposure. The study involved 981 women (recruited from March 1996 to July 1998) who were infants to 40 years old in 1976, had resided in one of the most contaminated zones (zone A or B), and had adequate stored serum collected soon after the explosion. The 15 breast-cancer cases were diagnosed an average of 15.2 years after the explosion. On the basis of proportional-hazards models, there was a significant association between TCDD concentrations (treated as a continuous variable) and risk of breast cancer (crude hazard ratio = 2.1, 95% CI 1.0–4.6) over a 10-fold range of TCDD concentration. There was also a suggestion of a dose-response relationship, although not statistically significant, when TCDD concentrations were categorized into four groups. The associations did not appear to be confounded by gravidity, parity, age at first pregnancy, age at last pregnancy,

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

lactation, family history of breast cancer, age at menarche, current BMI, use of oral contraceptives, menarchial status at explosion, menopause status at diagnosis, weight, height, smoking, or alcohol consumption. Those potential confounders were entered into the model one by one because of the relatively small number of breast-cancer cases, a limitation of the study. The study has several strengths; it avoided potential biases associated with disease survival by examining the relationship between serum TCDD and breast-cancer incidence, it adjusted for risk factors (with information collected at the time of interview), and it used individual serum TCDD-concentration data.

Vietnam-Veteran Studies

In a study that included 4,140 female Vietnam veterans and 4,140 veteran controls that did not serve in Vietnam, Kang et al. (2000) concluded that Vietnam veterans had not experienced a significantly higher prevalence of breast cancer (OR = 1.2, 95% CI 0.9–1.5) or gynecologic cancer in the 3 decades since the conflict. Subjects were asked to complete a structured telephone interview to provide information on demographics, pregnancy history, pregnancy outcomes, menstrual history, military experience, smoking and drinking history, and general health. Information on history of gynecologic cancer was followed up with reviews of medical and hospital records. The prevalence of breast cancer was higher in female Vietnam veterans than in non-Vietnam veterans, but the difference was not statistically significant even after adjustment for demographic factors, lifestyle-related characteristics, and military experience. In a cancer-mortality study of the same 8,280 female veterans (based on a vital-status follow-up to December 31, 1991), there were 26 breast-cancer-related deaths, but differences from non-Vietnam veterans were not statistically significant (relative risk [RR] = 1.0, 95% CI 0.6–1.8). There were age differences between cases and controls. The study was well designed and appears to have adequate power. Given the paucity of data on Vietnam veterans, the study is highly relevant for the assessment of the effect of Agent Orange and other herbicides on breast-cancer risk in Vietnam veterans. But its usefulness may be limited because questions on exposure focused on the Vietnam experience as a whole instead of on exposures to Agent Orange, other herbicides, or their contaminants. Reanalysis of the dataset once the modeled exposures from the current study, which is being overseen by the NAS, become available could yield valuable information of the effects of Agent Orange on breast-cancer risk.

Synthesis

The studies published since Update 2000 continue to support the conclusion that the evidence is inadequate or insufficient to determine whether there is an association between exposure to herbicides used in Vietnam or their contami-

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

nants and breast cancer. In a study that is perhaps the most relevant to the charge of the committee, Kang et al. (2000) have shown that there is no statistically significant increase in breast-cancer risk in Vietnam veterans. However, their study suffers from the use of nonspecific exposure information. The protective effect of some dioxin-like congeners reported in Holford et al. (2000) is consistent with results of previously reported studies. Results from Duell et al. (2001) rule out measurement error as a potential explanation of the previously reported lack of association between breast-cancer risk and farm exposures to potentially hazardous agents, such as pesticides. Recall bias is an important issue in the study. The results from Revich et al. (2001) give some evidence of increased risk of breast cancer and related mortality, but inadequate control for potential confounders and the use of the ecologic-study design limit the usefulness of the results. However, the study population promises to yield valuable information if better-designed studies are conducted with it. Results from Aronson et al. (2000) and Demers et al. (2002) yielded evidence of a relationship between development of breast cancer and increased concentrations of PCB congeners that have dioxin-like activity. The results from Warner et al. (2002) yielded further evidence of increased breast-cancer risk associated with increased serum TCDD. The Aronson et al. (2000), Demers et al. (2002), and Warner et al. (2002) studies were well conducted and free of major weaknesses in study design and potential biases. Therefore, they provide evidence of association between breast-cancer risk and exposures to TCDD and PCB congeners with dioxin-like activity.

Conclusions
Strength of Evidence from Epidemiologic Studies

There is some evidence of a protective effect of some dioxin-like congeners. The suggestive evidence of increased risk of breast cancer in Revich et al. (2001) probably needs to be followed up with better-designed studies. There is new evidence of increased risk of breast cancer associated with increased concentrations of PCB congeners with dioxin-like activity (Aronson et al., 2000; Demers et al., 2002) and with increased TCDD concentrations in the Seveso cohort (Warner et al., 2002). But PCB congeners 105, 118, and 156 also have non-dioxin-like components, and the observed effects may be attributable to those components. Moreover, the results of Warner et al., (2002) are based on only 15 cases. Therefore, on the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is still inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and risk of breast cancer.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Biologic Plausibility

All experimental evidence indicates that 2,4-D, 2,4,5-T, and TCDD are not genotoxic or at most are weakly genotoxic. However, TCDD has been demonstrated to be a carcinogen in animals and is classified as a human carcinogen because of its ability to act as a strong tumor promoter. The promoting activity may take place by a number of 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 said tissue. One study observed 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 this chemical. 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 of TGF-α, and these may 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 may have antiestrogenic properties. However, some studies suggest that TCDD exposure may facilitate the transition of breast-cancer cells from estrogen dependence to estrogen independence; this has been demonstrated to be one key step in the progression of breast cancer. In addition, studies have shown that prenatal exposure to TCDD increases the number of mammary tumors induced by other chemicals. Thus, experimental data indicate biologic plausibility of an association between exposure to TCDD and TCDD-containing herbicides and breast cancer. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

There are no data on which to base a conclusion concerning whether Vietnam veterans are at increased risk for breast cancer because of exposure to herbicides or TCDD.

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 ovaries (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 2002 are presented in Table 6-27 (ACS,

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-27 Estimates of the Numbers of New Cancers of Female Reproductive System in United Statesa

Site

New Cases

Deaths

Cervix

13,000

4,100

Endometrium

39,300

6,600

Ovary

23,300

13,900

Other genital organs

2,000

800

aACS, 2002.

2002). Taken together, the numbers represent roughly 6% of new cancer diagnoses and 5% of cancer deaths in women.

Incidence patterns of and risk factors for these diseases vary (see Table 6-28). 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, with older women at greater risk. Human papillomavirus infection is the most important risk factor for cervical cancer. Diet, a family history of the disease, and breast cancer are among the risk factors for endometrial and ovarian cancer.

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

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and female reproductive cancers. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding (see Tables 6-29, 6-30, and 6-31 for summaries of the studies).

TABLE 6-28 Average Annual Incidence (per 100,000) of Female Genital System Cancers in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Cervix

16.5

14.8

24.6

14.7

12.8

18.0

14.3

11.7

25.6

Endometrium

23.9

24.1

10.3

50.6

53.4

26.3

69.7

74.5

41.1

Ovary

21.8

22.9

14.3

30.8

33.0

17.1

35.8

38.4

22.6

Other genital organs

3.7

3.6

3.6

4.9

5.2

3.4

5.9

6.0

6.0

Overall

65.8

65.4

52.8

101.0

104.3

64.8

125.6

130.6

95.4

aSEER nine standard registries, crude age-specific rates, 1995–1999.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-29 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

New Studies

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

New Studies

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

8b

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; IARC, International Agency for Research on Cancer.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-30 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

New Studies

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; IARC, International Agency for Research on Cancer.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-31 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

New Studies

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; IARC, International Agency for Research on Cancer.

Update of the Scientific Literature
Occupational Studies

No relevant occupational studies have been published since Update 2000.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Environmental Studies

An investigation of female reproductive cancers and dioxin exposure was conducted in Chapaevsk, a town in Russia where dioxin contamination of air, water, cow's milk, and human serum and breast milk has been documented, with clear declines in exposure with increasing distance from the factory. Cancer mortality in Chapaevsk in 1995–1998 was compared with that in the surrounding Samara region. The SMR for cervical cancer was 1.8 (95% CI 1.0–3.1) on the basis of 13 cases. Age-standardized cervical-cancer incidences in Chapaevsk were 1.6 times higher than those in Russia at large and 1.8 times higher than those in Samara at large. To the extent that Russian mortality and morbidity data are complete and valid, the risk of cervical cancer appears to be increased, but the number of cases on which the rates were calculated was not provided and may have been small. Incidence and mortality data for a longer period would be more informative. Moreover, a comparison of demographic and socioeconomic descriptors of the Chapaevsk residents and those in surrounding Samara or in Russia at large would aid in the interpretation of health and mortality differences.

Vietnam-Veteran Studies

Kang et al. (2000) report on gynecologic cancers among female Vietnam veterans. Army veterans were identified from a list obtained by the US Army and Joint Services Environmental Support group. The Air Force, Navy, and Marine Corps provided computerized lists. Military-service data were abstracted from personnel records. After record review, 4,643 women met the eligibility criteria of having had a permanent tour of duty from July 4, 1965, through March 28, 1973, a period of substantial US military involvement in Vietnam. Of those, 4,390 were found to be alive as of January 1, 1992. A comparison group of female veterans whose tour of duty did not include service in Vietnam but who were assigned to a military unit in the United States during the Vietnam War was identified, and 4,390 people were randomly selected from among those still alive on January 1, 1992. After exclusion of 250 from each group who participated in a pilot study, an attempt was made to locate the remaining 4,140 in each group, for a total eligible cohort of 8,280. Various location strategies were used, and fewer than 5% (370) were not located; another 339 were deceased. A full telephone interview was conducted on 6,430, after 775 refused (13% of Vietnam veterans and 17% of non-Vietnam veterans) and another 336 completed only a short written questionnaire. The questionnaire collected information on demographic background, lifestyle factors, reproductive history, military experience, use of oral contraceptives and hormone replacement therapies, and health status. A self-reported history of gynecologic cancers (defined by the authors as cancers of the breast, ovary, uterus, and cervix) was collected. The authors attempted to “retrieve hospital records on all reported cancers as far back as 30 years.” Of

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

records successfully found, 99% of the breast cancers were confirmed and overall 90% of cancers were confirmed. The authors did not provide data on validation of the three sites other than breast, but stated that Vietnam status was not associated with verification of outcome.

A description of the two cohorts shows that the age distribution of the Vietnam veteran group has more older women than the non-Vietnam veteran group. The racial distribution was similar in the two, but the branch and duration of military service differed. Logistic-regression models indicated no significant excess of the four cancer sites combined (OR = 1.1, 95% CI 0.9–1.4) or for any single site: breast cancer OR = 1.2 (95% CI 0.9–1.5); ovarian cancer OR = 1.8 (95% CI 0.7–4.6); uterine cancer OR = 1.0 (95% CI 0.6–1.6); and cervical cancer OR = 1.1 (95% CI 0.7 –1.7). Those ORs were adjusted for age, race, branch of service, pay grade, marital status, nursing occupation, smoking, drinking, family history of cancer, use of birth-control pills, and postmenopausal estrogen and progestin use. However, given that the two groups differed in their age distribution, standard adjustment might be inadequate to control for confounding. A survival analysis with age as the time scale and with age at diagnosis, rather than at interview, would be the most appropriate way to analyze these cohorts. The direction of bias induced by the analytic strategy used by the authors could be toward the null.

The study has several strengths, including the success in locating over 95% of the cohort about 25 years since the Vietnam War and the high response rate. The grouping of breast cancer with cervical, uterine, and ovarian cancer is not justified, inasmuch as some risk factors have opposite effects in the breast from those in the other organs, but the analysis by organ site remains valid. Although it is not a large study, the numbers are adequate for most of the outcomes. Assuming that there is no residual confounding by age, this investigation provides evidence that service in Vietnam does not substantially increase the risk of uterine or cervical cancer. The increased risk of ovarian cancer, although not significant, may be of concern in that it could be downwardly biased because of deficiencies in the statistical analysis. It should also be noted that the report made no attempt to examine exposures to herbicides or TCDD in Vietnam. An analysis linking the locations of military service of these Vietnam veterans to spraying missions may make it possible to evaluate Agent Orange exposure in relation to the outcomes.

Synthesis

The study of female Vietnam veterans provides some evidence that female reproductive cancers—namely, neoplasms of the cervix, uterus, and ovary—are not increased in this cohort. Because service in Vietnam may not be a good surrogate for exposures to herbicides or their contaminants, however, the results cannot be interpreted as evidence of no effect of these chemicals on gynecologic

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

cancers. Interpretation of the Russian study, in which TCDD exposures were clearly increased, is difficult because the potential for confounding by socioeconomic factors was not addressed, temporal patterns were not presented, and the number of cases of cervical cancer appeared to have been small. Overall, no strong studies addressing female reproductive cancers in relation to herbicides or their contaminants have been conducted since Update 2000.

Conclusions
Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and uterine, ovarian, or cervical cancer.

Biologic Plausibility

No animal studies have found an increased incidence of female reproductive cancer after exposure to the chemicals of interest. One study (Kociba et al., 1978), however, has found 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 TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

The sparse data on increased risk of female reproductive cancers in Vietnam veterans come from an Australian study. Although the proportion of women with uterine and cervical cancers was higher than expected, the small number of cases and the possibility of confounding by marital status preclude drawing definitive conclusions. Furthermore, a study in female US Vietnam veterans did not indicate any such increased risk.

PROSTATE CANCER

According to ACS estimates, 189,000 new cases of prostate cancer (ICD-9 185) will be diagnosed in the United States in 2000, and 30,200 men will die from the disease (ACS, 2002). That makes prostate cancer the second-most common cancer among men (after nonmelanocytic skin cancers). Among men, it is expected to account for about 29% of new cancer diagnoses and 11% of cancer

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-32 Average Annual Incidence (per 100,000) of Prostate Cancer in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

 

32.0

28.3

79.2

127.5

120.9

254.3

310.2

299.9

573.4

aSEER nine standard registries, crude age-specific rates, 1995–1999.

deaths in 2002. The average annual incidence of prostate cancer is shown in Table 6-32.

The incidence of prostate cancer varies dramatically with age and race. The risk increases by a factor of 4 between the ages of 45 –49 years and 50–54 years, and nearly doubles between the ages of 50–54 years and 55–59 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 2 times that of whites in the United States, 5 times that of Alaskan 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.

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 purposes have led to increased reports of incidence in the United States because of improved detection. The long-term impact of screening on incidence and mortality, however, is difficult to predict for any country or population and will depend on the rapidity with which the screening tool is adopted, its differential use in men of various ages, and the aggressiveness of tumors detected early with this test (Gann, 1997). Differences among countries in the rate of use of PSA could cause more variability in the results of studies in different countries.

Prostate cancer tends not to be fatal in the overwhelming majority of cases, so studies of mortality may be unable to detect 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 treatments that would decrease the likelihood of death.

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

The committee responsible for VAO found that there was limited or suggestive evidence to determine whether an association exists between exposure to the

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and prostate cancer. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding. Table 6-33 provides summaries of the results of the studies underlying the finding. It is important to note that the table contains both morbidity and mortality studies. As discussed previously, the type of study must be taken into consideration when interpreting and weighing the evidence and, therefore, simply examining all the estimated risks in the table together will not provide a good assessment of the risks.

Update of the Scientific Literature

In an occupational study, Burns et al. (2001) updated data on mortality in the Dow Chemical Company cohort, extending follow-up to 1994. Further details about methods of data collection and exposure assignment are provided in Chapter 5. During the entire follow-up of 1,517 men, seven deaths due to prostate cancer occurred; 5.2 were expected. The SMR of 1.3 had a wide confidence interval (0.5–2.8). Studies of mortality are problematic when a disease is not necessarily fatal and multiple factors related to diagnosis and treatment may influence survival. Often, those factors include socioeconomic status, education, and access to health care (including health-insurance status and coverage), distance to medical facilities, and individual health-care seeking behavior. As discussed above, those issues are especially problematic when studying prostate cancer.

A cohort of lumberjacks in Sweden was examined for mortality and for incidence of various cancers. The cohort consisted of males and females employed by a forestry company at any time from 1954 to 1967. The pay slips of the company included information about the number of working hours or days in different work tasks and were used to construct a measure of exposure to phenoxy herbicides. The cohort was divided into two exposure groups, one with more than 5 working days of phenoxy-herbicide exposure and the other with 5 days or less. The authors excluded those exposed to pesticides other than phenoxy herbicides or DDT. They excluded nonexposed women because there were few in this group; exposed women were included. Data for foremen were analyzed separately. The cohort consisted of 261 exposed and 243 nonexposed persons. The mean exposure time among exposed workers was 30 days (range, 6–114 days); foremen had a mean exposure time of 176 days. Follow-up was from 1954 through 1994 for mortality and from 1958 through 1992 for incidence. The number of person-years of follow-up was not provided. SMRs and SIRs were calculated from death and cancer registration information to derive expected rates. Two cases of prostate cancer occurred among 15 foremen, whereas 0.4 was expected (for a highly unstable SIR of 4.7). Among the 139 other exposed workers, three cases occurred, whereas 3.5 were expected. Given the small sample,

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-33 Selected Epidemiologic Studies—Prostate Cancer Morbidity and Mortality

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Burns et al., 2001

Dow 2,4-D production workers

7

SMR = 1.3 (0.5–2.8)

Thörn et al., 2000

Swedish lumberjacks exposed to phenoxyacetic herbicides

   
 

Foremen

2

SIR = 4.7 (*)

 

Male lumberjacks

3

SIR = 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)

 

Morbidity from male genital tract cancers

116

1.2 (1.0–1.4)

Kogevinas et al., 1997

IARC cohort

43

1.1 (0.8–1.5)

Becher et al., 1996

German chemical production workers

9

1.3 (*)

Ott and Zober, 1996

BASF cleanup workers

4

1.1 (0.3–2.8)

Zhong and Rafnsson, 1996

Icelandic pesticide users

10

0.7 (0.3–1.2)

Studies Reviewed in Update 1996

Asp et al., 1994

Finnish herbicide appliers

5

0.8 (0.3–1.8)

Blair et al., 1993

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)

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)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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

New Studies

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)

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up— morbidity

   
 

Zone R males

16

0.9 (0.5–1.5)

Studies Reviewed in VAO

Pesatori et al., 1992

Seveso residents

 

Zones A, B males

4

1.4 (0.5–3.9)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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

Studies Reviewed in Update 2000

AFHS, 2000

Air Force Ranch Hand veterans

26

0.7 (0.4–1.3)

AIHW, 1999

Australian Vietnam veterans—male

212

147 expected (123–171)

CDVA, 1998a

Australian Vietnam veterans—male

428c

147 expected (123–171)

Studies Reviewed in Update 1998

Clapp, 1997

Massachusetts Vietnam veterans

 

Exposed cancers

15

0.8 (0.4–1.6)

Crane et al., 1997a

Australian military Vietnam veterans

36

1.5 (1.1–2.1)

 

Army

26

1.6 (1.1–2.4)

 

Navy

8

2.2 (0.9–4.3)

 

Air Force

2

0.5 (0.1–1.9)

AFHS, 1996

Air Force Ranch Hand veterans

2

4.0 (*)

Watanabe and Kang, 1996

Army Vietnam veterans

58

0.9 (*)

 

16+ years after discharge

*

1.1 (*)

Studies Reviewed in Update 1996

Visintainer et al., 1995

Michigan Vietnam veterans

19

1.1 (0.6–1.7)

Studies Reviewed in VAO

Breslin et al., 1988

Army Vietnam veterans

30

0.9 (0.6–1.2)

 

Marine Vietnam veterans

5

1.3 (0.2–10.3)

Anderson et al., 1986b

Wisconsin Vietnam veterans

2

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.

— When information was 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; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; USDA, US Department of Agriculture.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

one might wish to combine the two exposed groups (foreman and other workers); in this case, the SIR would be 1.3. In contrast, the nonexposed lumberjacks experienced a deficit of cases: 4, whereas 9.4 were expected, for a SIR of 0.4 (0.1–1.1).

Environmental Studies

Revich et al. (2001) have reported on the incidence of cancer and other health conditions in Chapaevsk, a city in the Samara region of Russia. A variety of industries are located in Chapaevsk, and one major chemical plant appears to be responsible for dioxin contamination that has been measured in the air, water, and soil of the city. Incidence rates have been generated for Chapaevsk, the Samara region, and Russia during 1998. The age-adjusted incidence of prostate cancer for this year was markedly lower in Chapaevsk (7.0 per 100,000) than in the Samara region and Russia (22.0 and 19.6 per 100,000, respectively). No information was provided on the number of cases in the calculations of indicence or whether geographic differences in incidence were also observed in previous years. There was no discussion of the differences between Chapaevsk, the Samara region, and Russia in potential confounders or the completeness of cancer registration.

Vietnam-Veteran Studies

No relevant Vietnam-veteran studies have been published since Update 2000 (IOM, 2001).

Synthesis

As for previous updates, the new data are somewhat equivocal. The two recent occupational studies have rather small numbers of cases. The Dow Chemical Company cohort results show a small increase in risk of prostate cancer. Given the size of the study, the finding does not attain statistical significance, although it is quite consistent with results from many previous studies of exposure to TCDD. Inasmuch as the cohort included herbicide exposure, any observed association could be related to 2,4-D rather than to TCDD. Whether the exposed population had better access to care than the general population, which might reduce their mortality, should also be considered. Furthermore, factors that increase incidence might differ from those related to mortality among those with the disease. Screening with PSA results in earlier detection and may therefore reduce mortality. Differences across populations in the rate of use of PSA could alter the relationship between exposure and mortality from prostate cancer.

In contrast, the study of Swedish lumberjacks does address incidence but, given the study size, yields only weak evidence that those with the highest expo-

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

sures to phenoxy herbicides may have an increased risk of prostate cancer. No interpretaion of the data on Chapaevsk is possible without additional information on the precision of the differences in incidence rates, the stability of these differences over time, and the possible role of confounding and incomplete ascertainment of cases. Conclusions with regard to exposures to herbicides or their contaminants rely primarily on earlier studies of incidence.

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

Although the data are generally mixed, it should be kept in mind that most Vietnam veterans have not yet reached the age when prostate cancer tends to appear and that morbidity is likely to represent a more sensitive outcome than mortality for this site of cancer.

Conclusions
Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and prostate cancer. Although the associations are not large, a number of studies provide evidence suggestive of a small increase in morbidity or mortality from prostate cancer. The evidence regarding association is drawn from occupational studies in which subjects were exposed to a variety of pesticides, herbicides, and herbicide components and from studies of Vietnam veterans.

Biologic Plausibility

No animal studies have found an increased incidence of prostate cancer after exposure to the chemicals 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, a chemical that alters the production or metabolism of hormones. Data on the effect of TCDD on

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

hormone concentrations in occupationally exposed men are therefore relevant. Sweeney et al. (1997/98) examined 281 workers at two production facilities from the National Institute for Occupational Safety and Health (NIOSH) study and found a trend toward higher serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and a trend toward lower testosterone according to the serum concentration of lipid-adjusted 2,3,7,8-TCDD. Those results were seen in models adjusted for age, alcohol, smoking, and diabetes mellitus; the models for LH and testosterone were also adjusted for BMI. The data suggest that exposures of workers to TCDD, particularly above 20 picograms/gram (pg/g) serum lipids, are associated with alterations in male reproductive hormone concentrations. That the prostate may be a target organ for hormonally active xenobiotics lends biologic plausibility to an association with TCDD exposure. In addition, several studies have shown human prostate cell to be directly responsive to TCDD in terms of enzyme induction.

A summary of the biologic plausibility for the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

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

TESTICULAR CANCER

ACS estimates that 7,500 men will be diagnosed with testicular cancer (ICD-9 186.0–186.9) in the United States in 2002 and that 400 men will die from it (ACS, 2002). The average annual incidence of testicular cancer is shown in Table 6-34.

Testicular cancer is far more likely in men younger than 40 than in those who are older. On a lifetime basis, the risk for white men is about 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 play a role. Several other hereditary and environmental factors have been suggested, but results of research regarding them are inconsistent (Bosl and Motzer, 1997).

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-34 Average Annual Incidence (per 100,000) of Testicular Cancer in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

 

6.1

7.0

1.6

3.6

4.0

1.0

2.1

2.4

0.9

aSEER nine standard registries, crude age-specific rates, 1995–1999.

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

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and testicular cancer. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding (see Table 6-35 for a summary of studies).

Update of the Scientific Literature

In an update of a study of mortality in chemical workers potentially exposed to 2,4-D at Dow Chemical Company in 1945–1994, Burns et al. (2001) identified one death from testicular cancer among 1,517 male Dow employees, for a relative risk of 2.2 (0.0–12.5). They conclude that there is no significant risk of testicular cancer in this cohort.

No relevant environmental or Vietnam-veteran studies have been published since Update 2000 (IOM, 2001).

Synthesis

The updated occupational-study analysis at Dow Chemical Company provides no evidence to suggest that chronic herbicide exposure increases the risk of testicular carcinoma.

Conclusions
Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-35 Selected Epidemiologic Studies—Testicular Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

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)

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)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

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

 

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.

— When information was 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; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; NS, not significant.

is inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and testicular cancer.

Biologic Plausibility

No animal studies have found an increased incidence of testicular cancer after exposure to the chemicals of interest. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Increased Risk of Disease Among Vietnam Veterans

There are insufficient data on testicular cancer in Vietnam veterans to draw a specific conclusion as to whether they are at increased risk.

URINARY BLADDER CANCER

Urinary bladder cancer (ICD-9 188.0–188.9) is the most common of the genitourinary tract cancers. According to ACS estimates, 41,500 men and 15,000 women will be diagnosed with this cancer in the United States in 2002, and 8,600 men and 4,000 women will die from it (ACS, 2002). In males, in whom this cancer is about 3 times as likely in females, those numbers represent about 6% of new cancer diagnoses and 3% of deaths. Overall, bladder cancer is the fifth most common cancer and the fifth leading cause of cancer death in the United States. The average annual incidence of urinary bladder cancer is shown in Table 6-36.

Among men in the age groups that characterize most Vietnam veterans, bladder-cancer incidence is about twice as high in whites as in blacks. Bladder-cancer incidence increases greatly with age over 40 years. For men in the age groups shown in Table 6-36, the incidence in each 5-year group is roughly double that in the age group before it.

The most important known risk factor for bladder cancer is smoking; about half of bladder cancers in men and one-third in women are thought to be due to smoking (Miller et al., 1996). Occupational exposure to aromatic amines (also called arylamines), polycyclic aromatic hydrocarbons (PAHs), and some other organic chemicals 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 haematobium have been implicated as risk factors. Exposure to inorganic arsenic is also a risk factor for bladder cancer, and cacodylic acid is a metabolite of inorganic arsenic. As discussed in Chapter 3, however, the data remain insufficient to conclude that studies of inorganic arsenic exposure are

TABLE 6-36 Average Annual Incidence (per 100,000) of Urinary Bladder Cancer in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

13.5

14.7

10.1

26.4

28.9

14.5

51.0

55.4

29.0

Females

3.7

4.2

2.4

9.1

10.4

5.4

14.9

16.3

11.3

aSEER nine standard registries, crude age-specific rates, 1995–1999.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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, and Update 2000

The committees responsible for VAO and Update 1996 found that there was limited or suggestive evidence of no association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant 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. Update 2000 did not change the 1998 conclusion (see Table 6-37 for a summary of the studies).

Update of Scientific Literature
Occupational Studies

Burns et al. (2001) updated a study of mortality in Dow chemical workers potentially exposed to 2,4-D in 1945–1994. Among 1,517 male employees, there was one death from bladder cancer (SMR = 0.5, 95% CI 0.1–2.8) for the entire follow-up period compared with an expected of two. The authors conclude that there is no evidence of causal association between exposure to 2,4-D and mortality due to bladder cancer.

Environmental Studies

Revich et al. (2001) report on suspected dioxin exposure and resulting cancer risk in Chapaevsk, which is located in the Samara region of Russia. This region is the site of large petrochemical plants that produce crop-protection chemicals and chemical fertilizers. Dioxins were detected in the air (0.116 pg/m3), in the soil (8.9–298 ng/kg), in the town's drinking water (28.4–74.1 pg/L), and in cow's milk and human milk. Overall male cancer mortality in Chapaevsk is 1.2 times as high as in the Samara region and 1.3 times as high as in Russia. Thirty-one deaths due to cancers of the urinary organs were observed in men of Chapaevsk, for an SMR of 2.6 (1.7–3.6). The age-adjusted bladder-cancer incidence in men is about twice that of the Samara region in general. Age-adjusted incidence of bladder cancer was also elevated in women of Chapaevsk relative to women of the Samara region (3.9 vs 2.3/100,000), but there was no excess in mortality from cancer of the urinary organs in women (SMR = 0.8). No data were available to assess and correct for confounding by smoking and occupation.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-37 Selected Epidemiologic Studies—Urinary Bladder Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

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

Farmers in Iowa

274

0.9 (NS)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

ENVIRONMENTAL

New Studies

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. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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

10

1.6 (0.9–3.1)

 

Zones A, B females

1

0.9 (0.1–6.8)

Lampi et al., 1992

Finnish community exposed to chlorophenols

14

1.0 (0.6–1.9)

VIETNAM VETERANS

Studies Reviewed in Update 2000

AFHS, 2000

Air Force Ranch Hand veterans

11

3.1 (0.9–11.0)

Studies Reviewed in Update 1998

Clapp, 1997

Massachusetts Vietnam veterans

80

0.6 (0.2–1.3)

Crane et al., 1997a

Australian military Vietnam veterans

11

1.1 (0.6–2.0)

Crane et al., 1997b

Australian national service Vietnam veterans

1

0.6 (*)

Studies Reviewed in VAO

Breslin et al., 1988

Army Vietnam veterans

9

0.6 (0.3–1.2)

 

Marine Vietnam veterans

4

2.4 (0.1–66.4)

Anderson et al., 1986a

Wisconsin Vietnam veterans

0

Anderson et al., 1986b

Wisconsin Vietnam veterans

1

a Given when available.

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

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

* Information not provided by study authors.

— When information was denoted by a dash in the original study.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; 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.

Vietnam-Veteran Studies

No relevant Vietnam veteran studies have been published since Update 2000 (IOM, 2001).

Synthesis

A new study of occupational exposure to herbicide production shows no relationship of chronic herbicide exposure to bladder-cancer mortality. An environmental study in Russia reported an increase in age-adjusted bladder-cancer incidence for men and women; however, the study does not control for occupation and smoking history, and there was no information on the number of cases

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

included in the analysis or the completeness of surveillance for cancer in Chapaevsk and the Samara region. The committee concludes that there is no evidence to support changing the “inadequate or insufficient” categorization for bladder cancer.

Conclusions
Strength of Evidence in Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and urinary bladder cancer.

Biologic Plausibility

No studies have found an increased incidence of urinary bladder cancer in TCDD-treated animals. Cacodylic acid administered to laboratory animals has induced neoplasms of the urinary bladder. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

Although the sparse data available on Vietnam veterans suggest that they may be at an increased risk for urinary bladder cancer, the estimated risk ratios are unstable. Further studies of Ranch Hand Air Force veterans may clarify whether exposure incurred in Vietnam, or exposure to TCDD in particular, is associated with altered risks of bladder cancer.

RENAL CANCER

Cancers of the kidney (ICD-9 189.0) and renal pelvis (ICD-9 189.1) are often grouped in epidemiologic studies; cancer of the ureter (ICD-9 189.2) is also sometimes included. Although diseases of those organs have different characteristics and may have different risk factors, there is logic to grouping them: the structures are all exposed to filterable compounds, such as PAHs, that appear in urine. ACS estimates that 19,100 men and 12,700 women will be diagnosed with renal cancers (ICD-9 189.0, 189.1) in the United States in 2002 and that 7,200 men and 4,400 women will die from them (ACS, 2002). These figures represent

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-38 Average Annual Incidence (per 100,000) of Kidney and Renal Pelvis Cancer in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

13.4

13.2

17.1

21.7

21.2

33.5

34.9

35.1

43.4

Females

6.0

5.8

8.1

9.8

9.6

15.1

16.1

16.5

22.6

aSEER nine standard registries, crude age-specific rates, 1995–1999.

2–3% of all new cancer diagnoses and deaths. The average annual incidence of renal cancer is shown in Table 6-38.

Renal cancer is twice as common in men as in women. In the age groups that represent most Vietnam veterans, black men have a higher incidence than white men. With the exception of Wilms' tumor (which is more likely to occur in children), renal cancer is more common in people over 50 years old.

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

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

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and renal cancer. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that conclusion (see Table 6-39 for a summary of the studies).

Update of the Scientific Literature
Occupational Studies

In an occupational study, Burns et al. (2001) updated the mortality of chemical workers potentially exposed to 2,4-D who worked at Dow Chemical Company in 1945–1994. In 1,517 male employees, there were two renal-cancer deaths

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-39 Selected Epidemiologic Studies—Renal Cancer

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Burns et al., 2001

Dow 2,4-D production workers

2

2.2 (0.1–3.3)

Studies Reviewed in Update 2000

Steenland et al., 1999

US chemical production workers

13

1.6 (0.8–2.7)

Hooiveld et al., 1998

Male Dutch production and contract workers

 

Total cohort—kidney cancer

4

4.1 (1.1–10.4)

 

Total cohort—“urinary organs”

8

3.9 (1.7–7.6)

 

Accidentally exposed subcohort

0

Studies Reviewed in Update 1998

Kogevinas et al., 1997

IARC cohort

Workers exposed to TCDD (or higher-chlorinated dioxins)

26

1.6 (1.1–2.4)

Workers exposed to any phenoxy herbicide or chlorophenol

29

1.1 (0.7–1.6)

Studies Reviewed in Update 1996

Mellemgaard et al., 1994

Danish Cancer Registry patients

 

Occupational herbicide exposure among males

13

1.7 (0.7–4.3)

 

Occupational herbicide exposure among females

3

5.7 (0.6–5.8)

Blair et al., 1993

US farmers in 23 states

 

White males

522

1.1 (1.0–1.2)

 

Nonwhite males

30

 

White females

6

 

Nonwhite females

6

Studies Reviewed in VAO

Ronco et al., 1992

Danish male self-employed farm workers

141

0.6 (p < 0.05)

Fingerhut et al., 1991

NIOSH cohort

8

1.4 (0.6–2.8)

Manz et al., 1991

German production workers

3

1.6 (0.3–4.6)

Saracci et al., 1991

IARC cohort

11

1.0 (0.5–1.7)

Alavanja et al., 1989

USDA forest conservationists

*

1.7 (0.5–5.5)

 

Soil conservationists

*

2.4 (1.0–5.9)

Henneberger et al., 1989

Paper and pulp workers

3

1.5 (0.3–4.4)

Alavanja et al., 1988

USDA agricultural extension agents

*

1.7 (0.9–3.3)

Bond et al., 1988

Dow 2,4-D production workers

0

* (0.0–6.2)

Robinson et al., 1986

Paper and pulp workers

6

1.2 (0.5–3.0)

Coggon et al., 1986

British MCPA production workers

5

1.0 (0.3–2.3)

Lynge, 1985

Danish male production workers

3

0.6 (*)

Wiklund, 1983

Swedish agricultural workers

775

0.8 (0.7–0.9)b

Blair et al., 1983

Florida pesticide appliers

1

0.5 (*)

Burmeister, 1981

Farmers in Iowa

178

1.1 (NS)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

ENVIRONMENTAL

New Studies

Revich et al., 2001

Residents of Chapaevsk, Russia

 

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

 

12.3 in Chapaevsk;

12.8 in Samara regionc

 

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

 

6.1 in Chapaevsk;

7.3 in Samara regionc

Studies Reviewed in Update 2000

Bertazzi et al., 2001

Seveso residents—20-year follow-up

 

Zone B males

3

0.9 (0.3–3.0)

 

Zone B females

3

2.1 (0.7–6.7)

Schreinemachers, 2000

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

   
 

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

147

1.0 (0.8–1.2)

 

Males—counties with wheat acreage ≥111,000

129

1.0 (0.8–1.3)

 

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

85

0.9 (0.7–1.2)

 

Females—counties with wheat acreage ≥111,000

90

1.1 (0.8–1.4)

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up— morbidity

   
 

Zone R males

10

0.9 (0.4–1.7)

 

Zone R females

7

1.2 (0.5–2.7)

Studies Reviewed in VAO

Pesatori et al., 1992

Seveso residents

 

Zones A, B males

0

 

Zones A, B females

1

1.1 (0.2–8.1)

VIETNAM VETERANS

Studies Reviewed in Update 2000

AFHS, 2000

Air Force Ranch Hand veterans

11

3.1 (0.9–11.0)

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

22

1.2 (0.8–1.9)

Crane et al., 1997b

Australian national service Vietnam veterans

3

3.9 (*)

Studies Reviewed in Update 1996

Visintainer et al., 1995

Michigan Vietnam veterans

21

1.4 (0.9–2.2)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Studies Reviewed in VAO

Breslin et al., 1988

Army Vietnam veterans

55

0.9 (0.5–1.5)

 

Marine Vietnam veterans

13

0.9 (0.5–1.5)

Kogan and Clapp, 1988

Massachusetts Vietnam veterans

9

1.8 (1.0–3.5)

Anderson et al., 1986a

Wisconsin Vietnam veterans

1

Anderson et al., 1986b

Wisconsin Vietnam veterans

2

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.

— When information was denoted by a dash in the original study.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; 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.

(RR = 0.9) and 2.2 expected (95% CI 0.1–3.3). The authors conclude that there is no evidence of an association between exposure to 2,4-D and mortality due to renal cancer.

Environmental Studies

Revich et al. (2001) have evaluated the occurrence of cancer and other health outcomes in Chapaevsk, a city in the Samara region of Russia with documented levels of dioxin contamination in the air, soil, and water. The assessment of cancer in this study is based on comparisons with the Samara region and Russia; additional information on the design of this study and measurement of exposure can be found in Chapters 4 and 5 of this report. Age-adjusted incidence of renal cancer is reported for 1998; the levels of cancer in Chapaevsk and the Samara region are similar for men (12.3 vs 12.8 per 100,000) and for women (6.1 vs 7.3 per 100,000). The incidence rates of renal cancer in all of Russia for 1998 are slightly lower (11.8 per 100,000 for men, 5.8 per 100,000 for women). No information is given on the number of cases in the calculation of these incidence rates or the stability of these rates in previous years.

Vietnam-Veteran Studies

No relevant Vietnam-veteran studies have been published since Update 2000 (IOM, 2001).

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Synthesis

There are no data to support changing the “insufficient or inadequate” categorization for renal cancer. The study of Dow Chemical workers has low precision due to the small number of deaths from renal cancer. The study of Chapaevsk does not report the number of cases included in the analysis or the completeness and accuracy of cancer surveillance, and does not consider confounders besides age. Accordingly, these studies offer very little evidence for the absence of an association.

Conclusions
Strength of Evidence in Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and renal cancer.

Biologic Plausibility

No studies have found an increased incidence of renal cancer in TCDD-treated animals. Cacodylic acid administered to laboratory animals has induced neoplasms in the kidney. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

The sparse data available on Vietnam veterans do not suggest that they are at an increased risk for renal cancer.

BRAIN TUMORS

According to ACS, about 9,600 men and 7,400 women will be diagnosed with new cases of brain and other nervous system cancers (ICD-9 191.0 –191.9, 192.0–192.3, and 192.8–192.9) in the United States in 2002, and 7,200 men and 5,900 women will die from them (ACS, 2002). Those numbers represent about 1.4% of new cancer diagnoses and 2.4% of all cancer deaths. The average annual incidence of brain and other nervous system cancers is shown in Table 6-40.

Among people in the United States who are 45–59 years old, brain cancer is more common in men than in women and more common in whites than in blacks.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-40 Average Annual Incidence (per 100,000) of Brain and Other Nervous System Cancers in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

6.6

7.1

4.9

11.0

12.1

6.1

13.4

14.7

10.3

Females

4.6

5.2

2.0

6.4

7.0

4.9

9.5

10.2

8.7

aSEER nine standard registries, crude age-specific rates, 1995–1999.

Exposure to ionizing radiation is an established risk factor for brain cancer. Several other potential factors have been examined, but ACS notes that most brain cancers are not associated with any known risk factors.

Cancers of and affecting the brain fall into numerous histologic types and subtypes. Meningiomas, which are cancers of the tissue surrounding the brain and spinal cord, do not arise from nerve tissue and do not share a similar risk profile with cancers that do. Metastases from cancers elsewhere in the body may be found in the brain and may be difficult to distinguish from primary brain cancers. Because of that diversity, the potential for misclassification, and the relative infrequency of brain cancers, this group of cancers has been difficult to study epidemiologically and to attribute to specific exposures.

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

The committee responsible for VAO found that there was limited or suggestive evidence of no association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and brain cancer. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that conclusion (see Table 6-41 for a summary of the studies).

Update of Scientific Literature

Two occupational studies published since Update 2000 were located. A cohort of 1,517 male employees of the Dow Chemical Company who were involved in the manufacture or formulation of 2,4-D at some time in 1945–1994 demonstrated no excess mortality from brain cancer (SMR = 109) (Burns et al., 2001). However, the numbers in that study were small, and the study had limited power to detect an increase in an uncommon outcome.

A small study of 261 Swedish lumberjacks exposed to phenoxyacetic herbicides demonstrated no cases of brain cancer although one was seen among 241

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-41 Selected Epidemiologic Studies—Brain Tumors

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Burns et al., 2001

Dow 2,4-D production workers

3

SMR = 109 (22–319)

Thörn et al., 2000

Swedish lumberjacks exposed to phenoxyacetic herbicides

0

(*)

Studies Reviewed in Update 2000

Steenland et al., 1999

US chemical production workers

8

0.8 (0.4–1.6)

Studies Reviewed in Update 1998

Gambini et al., 1997

Italian rice growers

4

0.9 (0.2–2.3)

Kogevinas et al., 1997

IARC cohort

 

Workers exposed to TCDD (or higher-chlorinated dioxins)

12

0.6 (0.3–1.1)

 

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

10

0.8 (0.4–1.5)

 

Workers exposed to any phenoxy herbicide or chlorophenol

22

0.7 (0.4–1.0)

Becher et al., 1996

German chemical production workers— subcohort I

3

2.3 (0.5–6.8)

Ramlow et al., 1996

Pentachlorophenol production workers

 

0-year latency

1

 

15-year latency

1

Studies Reviewed in Update 1996

Asp et al., 1994

Finnish herbicide appliers

3

1.2 (0.3–3.6)

Dean, 1994

Irish farmers and farm workers

 

Males

195

 

Females

72

Blair et al., 1993

US farmers in 23 states

 

White males

447

1.2 (1.1–1.3)

 

Nonwhite males

16

1.0 (0.6–1.6)

 

White females

9

1.1 (0.5–2.1)

 

Nonwhite females

1

0.4 (0.0–2.1)

Studies Reviewed in VAO

Morrison et al., 1992

Farmers in Canadian prairie province— 250+ acres sprayed with herbicides

24

0.8 (0.5–1.2)

Ronco et al., 1992

Danish male self-employed farm workers

194

1.1 (*)

Swaen et al., 1992

Dutch herbicide appliers

3

3.2 (0.6–9.3)

Fingerhut et al., 1991

NIOSH cohort

5

0.7 (0.2–1.6)

Saracci et al., 1991

IARC cohort

6

0.4 (0.1–0.8)

Wigle et al., 1990

Saskatchewan farmers

96

1.0 (0.8–1.3)

Alavanja et al., 1989

USDA forest or soil conservationists

6

1.7 (0.6–3.7)

Henneberger et al., 1989

Paper and pulp workers

2

1.2 (0.1–4.2)

Alavanja et al., 1988

USDA agricultural extension agents

*

1.0 (0.4–2.4)

Bond et al., 1988

Dow 2,4-D production workers

0

* (0.0–4.1)

Musicco et al., 1988

Men and women in the Milan, Italy, area

61

1.6 (1.1–2.4)

Coggon et al., 1986

British MCPA production workers

11

1.2 (0.6–2.2)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Robinson et al., 1986

Paper and pulp workers

4

0.6 (0.2–2.1)

Lynge, 1985

Danish male production workers

4

0.7 (*)

Blair et al., 1983

Florida pesticide appliers

5

2.0 (*)

Burmeister, 1981

Farmers in Iowa

111

1.1 (NS)

ENVIRONMENTAL

Studies Reviewed in Update 2000

Bertazzi et al., 2001

Seveso residents—20-year follow-up

 

Zone B males

1

0.5 (0.1–3.5)

 

Zone B females

3

2.2 (0.7–7.0)

Schreinemachers, 2000

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

   
 

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

131

0.9 (0.8–1.2)

 

Males—counties with wheat acreage ≥111,000

130

1.1 (0.9–1.4)

 

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

94

1.0 (0.7–1.2)

 

Females—counties with wheat acreage ≥111,000

95

1.2 (0.9–1.5)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

 

Zone B males

1

0.8 (0.1–5.5)

 

Zone B females

3

3.2 (1.0–10.3)

 

Zone R males

12

1.3 (0.7–2.5)

 

Zone R females

8

1.1 (0.5–2.4)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

 

Zone B males

1

0.8 (0.0–4.2)

 

Zone B females

3

3.2 (0.6–9.4)

 

Zone R males

12

1.3 (0.7–2.3)

 

Zone R females

8

1.1 (0.5–2.2)

Svensson et al., 1995

Swedish fishermen—mortality

 

East coast

2

0.6 (0.1–2.1)

 

West coast

15

1.0 (0.6–1.7)

 

Swedish fishermen—incidence

 

East coast

3

0.5 (0.1–1.4)

 

West coast

24

0.9 (0.6–1.4)

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up— morbidity

   
 

Zone R males

6

0.6 (0.3–1.4)

 

Zone R females

6

1.4 (0.6–3.4)

Studies Reviewed in VAO

Pesatori et al., 1992

Seveso residents

 

Zones A, B females

1

1.5 (0.2–11.3)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Bertazzi et al., 1989a

Seveso residents—10-year follow-up

 

Zones A, B, R males

5

1.2 (0.4–3.1)

 

Zones A, B, R females

5

2.1 (0.8–5.9)

VIETNAM VETERANS

Studies Reviewed in Update 2000

AFHS, 2000

Air Force Ranch Hand veterans

1

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

39

1.1 (0.8–1.5)

Crane et al., 1997b

Australian national service Vietnam veterans

13

1.4

Dalager and Kang, 1997

Army Chemical Corps veterans

2

1.9b (—)

Studies Reviewed in Update 1996

Dalager et al., 1995

Female Vietnam veterans

4

1.4 (0.4–3.7)

Visintainer et al., 1995

Michigan Vietnam veterans

36

1.1 (0.8–1.5)

Boyle et al., 1987

Vietnam Experience Study

3

Studies Reviewed in VAO

Thomas and Kang, 1990

Army Chemical Corps Vietnam veterans

2

5.0 (NS)

Breslin et al., 1988

Army Vietnam veterans

116

1.0 (0.3–3.2)

 

Marine Vietnam veterans

25

1.1 (0.2–7.1)

Anderson et al., 1986a

Wisconsin Vietnam veterans

13

1.6 (0.9–2.7)

Anderson et al., 1986b

Wisconsin Vietnam veterans

8

0.8 (0.3–1.5)

Lawrence et al., 1985

New York Vietnam veterans

4

0.5 (0.2–1.5)

a Given when available.

b Crude rate ratio of Vietnam to non-Vietnam veterans.

* Information not provided by study authors.

— When information was denoted by a dash in the original study.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; 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.

nonexposed lumberjacks followed as a control group (Thörn et al., 2000). That study is much too small to derive stable estimates of risk that are generalizable to other populations.

No relevant environmental or Vietnam-veteran studies have been published since Update 2000 (IOM, 2001).

Synthesis

Data from epidemiologic studies are inadequate or insufficient to link herbicide exposure to brain cancer; no new published information was found to change this opinion.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Conclusions
Strength of Evidence in Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is limited or suggestive evidence of no association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and brain cancer.

Biologic Plausibility

No new studies suggest that TCDD induces cancers of the brain. The evidence that exposure to 2,4-D in animals causes brain tumors remains questionable. In one study (Hazleton Laboratories America, 1986) in which Fischer 344 rats received 2,4-D at 45 mg/kg of body weight, six of 60 male rats developed brain tumors compared to one control rat. However, that study has been criticized for several reasons, and brain tumors have not occurred in other studies. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

The sparse data available on Vietnam veterans do not suggest that they are at an increased risk for brain tumors.

NON-HODGKIN'S LYMPHOMA

Non-Hodgkin's lymphoma (ICD-9 200.0–200.8, 202.0–202.2, and 202.8– 202.9) is the more common of the two primary types of cancer of the lymphatic system. ACS estimates that 28,200 men and 25,700 women will be diagnosed with this disease in the United States in 2002 and that 12,700 men and 11,700 women will die from it (ACS, 2002). Collectively, lymphomas (which also include Hodgkin's disease) are the fifth-most common form of cancer in the United States and the sixth leading cause of cancer death. The average annual incidence of non-Hodgkin's lymphoma (NHL) is shown in Table 6-42.

NHL incidence is uniformly higher in males than in females and, in most age groups, higher in whites than in blacks. In the cohorts that characterize most Vietnam veterans, rates increase with age in whites and vary inconsistently in blacks.

The causes of NHL are poorly understood. People with suppressed or compromised immune systems are known to be at higher risk, and some studies show

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-42 Average Annual Incidence (per 100,000) of Non-Hodgkin's Lymphoma in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

20.2

20.1

26.2

28.8

29.1

33.8

37.4

39.3

33.6

Females

12.4

12.8

12.5

18.8

19.3

17.7

28.5

30.7

19.2

aSEER nine standard registries, crude age-specific rates, 1995–1999.

increased incidence in people with HIV, human T-cell lymphotropic virus, Epstein-Barr virus, and gastric Helicobacter pylori infections. A number of behavioral, occupational, and environmental risk factors have also been proposed (Blair et al., 1997).

Although chronic lymphocytic leukemia shares many traits with NHL (immunohistochemical traits, B-cell origin, and progression to an acute aggressive form of NHL), it is discussed separately after the general section on leukemia.

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

The committee responsible for VAO found that there was sufficient information to determine that an association exists between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and NHL. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that conclusion (see Table 6-43 for a summary of the studies).

Update of the Scientific Literature
Occupational Studies

Thörn et al. (2000) conducted an occupational cohort study of male and female lumberjacks employed in Sweden by a forestry company in 1954 –1967. The company's pay slips included information about the number of working hours or days in different work tasks and were used to construct a measure of exposure to phenoxy herbicides. The cohort was divided into two exposure groups, one with more than 5 working days of phenoxy herbicide exposure and the other with 5 days or fewer. The authors excluded those exposed to pesticides other than phenoxy herbicides or DDT. They also excluded nonexposed women,

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-43 Selected Epidemiologic Studies—Non-Hodgkin's Lymphoma

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Burns et al., 2001

Dow 2,4-D production workers

3

SMR = 1.0

Thörn et al., 2000

Swedish lumberjacks exposed to phenoxyacetic herbicides

2

2.3 (0.3–8.5)

Studies Reviewed in Update 2000

Steenland et al., 1999

US chemical production workers

12

1.1 (0.6–1.9)

Hooiveld et al., 1998

Dutch male production and contract workers

3

3.8 (0.8–11.0)

Studies Reviewed in Update 1998

Gambini et al., 1997

Italian rice growers

 

1.3 (0.3–3.3)

Keller-Byrne et al., 1997

Farmers in central United States

 

1.3 (1.2–1.6)

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

1.3 (0.9–1.8)

Becher et al., 1996

German chemical production workers

6

3.3 (1.2–7.1)

Nanni et al., 1996

Italian farming and animal-breeding workers

23b

1.8 (1.2–2.6)

Ramlow et al., 1996

Pentachlorophenol production workers

5c

1.3 (0.4–3.1)

Amadori et al., 1995

Italian farming and animal-breeding workers

164

1.8 (1.2–2.6)

Studies Reviewed in Update 1996

Kogevinas et al., 1995

IARC cohort diagnosed with NHL

 

Exposed to 2,4,5-T

10

1.9 (0.7–4.8)

 

Exposed to TCDD

11

1.9 (0.7–5.1)

Asp et al., 1994

Finnish herbicide appliers

1

0.4 (0.0–2.0)

Dean, 1994

Irish farmers and farm workers

 

Males

244b

 

Females

84b

Hardell et al., 1994

Male residents of northern Sweden

 

Exposure to phenoxy herbicides

25

5.5 (2.7–11.0)

 

Exposure to chlorophenols

35

4.8 (2.7–8.8)

Morrison et al., 1994

Farm operators in three Canadian provinces

 

All farm operators

*

0.8 (0.7–0.9)

 

Highest quartile of herbicides sprayed

19

2.1 (1.1–3.9)

 

Highest quartile of herbicides sprayed relative to no spraying

6

3.0 (1.1–8.1)

Blair et al., 1993

US farmers from 23 states (white males)

843

1.2 (1.1–1.3)

Bloemen et al., 1993

Dow 2,4-D production workers

2

2.0 (0.2–7.1)

Bueno de Mesquita et al., 1993

Dutch production workers

Workers exposed to phenoxy herbicides

2

3.0 (0.4–10.8)

Lynge, 1993

Danish male production workers

10

1.7 (0.5–4.5)

Persson et al., 1993

Swedish NHL patients

 

Exposure to phenoxy herbicides

10

2.3 (0.7–7.2)

 

Occupation as lumberjack

9

6.0 (1.1–31.0)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Zahm et al., 1993

Females in eastern Nebraska farms

119

1.0 (0.7–1.4)

Kogevinas et al., 1992

IARC cohort

 

Workers exposed to any phenoxy herbicide or chlorophenol

11

1.0 (0.5–1.7)

Studies Reviewed in VAO

Hansen et al., 1992

Danish gardeners—men and women

8

2.0 (0.9–3.9)

Ronco et al., 1992

Danish farm workers—self-employed and employees

147

1.0 (*)

 

Italian farm workers—self-employed and employees

14

1.3 (*)

Smith and Christophers, 1992

Male residents of Australia

 

Exposure >1 day

15

1.5 (0.6–3.7)

 

Exposure >30 days

7

2.7 (0.7–9.6)

Swaen et al., 1992

Dutch herbicide appliers

0

Vineis et al., 1991

Residents of selected Italian provinces— male residents of contaminated areas

*

2.2 (1.4–3.5)

Wigle et al., 1990

Canadian farmers

 

All farmers

103

0.9 (0.8–1.1)

 

Farmers spraying herbicides on 250+ acres

10

2.2 (1.0–4.6)

Zahm et al., 1990

White male residents of Nebraska

 

Ever done farm work

147

0.9 (0.6–1.4)

 

Ever mixed or applied 2,4-D

43

1.5 (0.9–2.5)

Alavanja et al., 1989

USDA soil conservationists

12

1.8 (0.7–4.1)

 

USDA forest conservationists

10

2.5 (1.0–6.3)

Corrao et al., 1989

Italian farmers licensed to apply pesticides

 

Licensed pesticide users and nonusers

45d

1.4 (1.0–1.9)

 

Farmers in arable land areas

31

1.8 (1.2–2.5)

LaVecchia et al., 1989

Residents of the Milan, Italy, area— agricultural occupations

*

2.1 (1.3–3.4)

Persson et al., 1989

Orebro Hospital—exposed to phenoxy acids

6

4.9 (1.0–27.0)

Wiklund et al., 1989b

Swedish pesticide appliers

27

1.1 (0.7–1.6)

Alavanja et al., 1988

USDA extension agents

*

1.2 (0.7–2.3)

Dubrow et al., 1988

Ohio residents

15

1.6 (0.8–3.4)

Olsson and Brandt, 1988

Lund Hospital patients

 

Exposed to herbicides

*

1.3 (0.8–2.1)

 

Exposed to chlorophenols

*

1.2 (0.7–2.0)

Wiklund et al., 1988

Swedish agricultural and forestry workers

 

Workers in land or animal husbandry

 

1.0 (0.9–1.1)

 

Timber cutters

 

0.9 (0.7–1.1)

Pearce et al., 1987

Male residents of New Zealand

 

Farming occupations

33

1.0 (0.7–1.5)

 

Fencing work

68

1.4 (1.0–2.0)

Woods et al., 1987

Male residents of Washington state

 

Phenoxy herbicide use

*

1.1 (0.8–1.4)

 

Chlorophenol use

*

1.0 (0.8–1.2)

 

Farming occupations

*

1.3 (1.0–1.7)

 

Forestry herbicide appliers

*

4.8 (1.2–19.4)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Hoar et al., 1986

Kansas residents

 

Farmers compared with nonfarmers

133

1.4 (0.9–2.1)

 

Farmers using herbicides >20 days/year

7

6.0 (1.9–19.5)

Pearce et al., 1986

Male residents of New Zealand— agricultural sprayers

19e

1.5 (0.7–3.3)

Pearce et al., 1985

Male residents of New Zealand— agricultural occupations, 20–64 years old

224

1.4 (0.9–2.0)

Burmeister et al., 1983

Iowa residents

 

Farmers

1,101

1.3 (*)

 

Farmers in 33 counties with highest herbicide use

   
 

Born before 1890

*

3.4 (*)

 

Born 1890–1900

*

2.2 (*)

 

Born after 1900

*

1.3 (*)

Riihimiki et al., 1982

Finnish herbicide appliers

0

Wiklund, 1983

Swedish agricultural workers

476

1.1 (0.9–1.2)

Cantor, 1982

Wisconsin residents

175

1.2 (1.0–1.5)

Hardell et al., 1980

Umea Hospital patients

 

Exposed to phenoxy acids

41

4.8 (2.9–8.1)d

 

Exposed to chlorophenols

50

4.3 (2.7–6.9)d

ENVIRONMENTAL

New Studies

Hardell et al., 2001

Case control study of NHL—TEQ >27.8 and EA >80

8

2.8 (0.5–1.8)

McDuffie et al., 2000

Case control study of NHL in Canada

 

Exposed to phenoxyherbicides

131

1.4 (1.1–1.8)

 

2,4-D

111

1.3 (*)

 

Mecoprop

53

2.3 (*)

Studies Reviewed in Update 2000

Bertazzi et al., 2001

Seveso residents—20-year follow-up

 

Zone A males

1

3.2 (0.4–23.0)

 

Zone A females

1

3.3 (0.5–23.7)

 

Zone B males

2

0.9 (0.2–3.8)

 

Zone B females

3

1.6 (0.5–4.9)

Schreinemachers, 2000

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

   
 

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

186

0.8 (0.7–1.0)

 

Males—counties with wheat acreage ≥111,000

176

0.9 (0.8–1.1)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

 

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

202

1.0 (0.8–1.2)

 

Females—counties with wheat acreage ≥111,000

162

1.0 (0.8–1.2)

Viel et al., 2000

Residents near a French municipal solid-waste incinerator

286

1.3 (p = 0.00003)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

 

Zone B males

2

1.5 (0.4–6.0)

 

Zone R males

10

1.1 (0.5–2.1)

 

Zone R females

8

0.9 (0.4–1.8)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

 

Zone B males

2

1.5 (0.2–5.3)

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up—morbidity

 

Zone B males

3

2.3 (0.7–7.4)

 

Zone B females

1

0.9 (0.1–6.4)

 

Zone R males

12

1.3 (0.7–2.5)

 

Zone R females

10

1.2 (0.6–2.3)

Studies Reviewed in VAO

Lampi et al., 1992

Finnish community exposed to chlorophenols

   
 

Compared with two uncontaminated municipalities

16

2.8 (1.4–5.6)

 

Compared with cancer-control region

16

2.1 (1.3–3.4)

Pesatori et al., 1992

Seveso residents

 

Zones A, B males

3

1.9 (0.6–6.1)

 

Zones A, B females

1

0.8 (0.1–5.5)

 

Zone R males

13

1.4 (0.7–2.5)

 

Zone R females

10

1.1 (0.6–2.2)

Bertazzi et al., 1989b

Seveso residents—10-year follow-up

 

Zone B females

2

1.0 (0.3–4.2)

 

Zone R males

3

1.0 (0.3–3.4)

 

Zone R females

4

1.6 (0.5–4.7)

VIETNAM VETERANS

Studies Reviewed in Update 2000

AFHS, 2000

Air Force Ranch Hand veterans

1

0.2 (0.0–2.6)

AIHW, 1999

Australian Vietnam veterans

62

48 expected (34–62)

CDVA, 1998a

Australian Vietnam veterans—male

137f

48 expected (34–62)

CDVA, 1998b

Australian Vietnam veterans—female

2f

0 expected (0–4)

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

 

1.3 (0.5–3.5)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Watanabe and Kang, 1996

Marine Vietnam veterans

46

1.7 (1.2–2.2)

Studies Reviewed in Update 1996

Visintainer et al., 1995

Michigan Vietnam veterans

32

1.5 (1.0–2.1)

Studies Reviewed in VAO

Clapp et al., 1991

Massachusetts Vietnam veterans

 

1.2 (0.6–2.4)

Dalager et al., 1991

Vietnam veterans diagnosed with NHL

100

1.0 (0.7–1.8)

O'Brien et al., 1991

Army enlisted Vietnam veterans

7g

1.8 (*)

Thomas et al., 1991

Women Vietnam veterans

3

1.3 (0.3–1.8)

Watanabe et al., 1991

Army Vietnam veterans compared with Army non-Vietnam veterans

140

0.8 (*)

 

Army Vietnam veterans compared with combined Army and Marine Vietnam-era veterans

140

0.9 (*)

 

Marine Vietnam veterans compared with Marine non-Vietnam veterans

42

1.8 (1.3–2.4)

 

Marine Vietnam veterans compared with combined Army and Marine Vietnam-era veterans

42

1.2 (*)

CDC, 1990

US men born 1921–1953

 

Vietnam veterans

99

1.5 (1.1–2.0)

 

Army Vietnam veterans

45

1.2 (0.8–1.8)

 

Marine Vietnam veterans

10

1.8 (0.8–4.3)

 

Air Force Vietnam veterans

12

1.0 (0.5–2.2)

 

Navy Vietnam veterans

32

1.9 (1.1–3.2)

 

Blue-water Navy Vietnam veterans

28

2.2 (1.2–3.9)

Michalek et al., 1990

Air Force Ranch Hand veteran mortality

0

(*)

Wolfe et al., 1990

Air Force Ranch Hand veteran morbidity

1

(*)

Breslin et al., 1988

Army Vietnam veterans

108

0.8 (0.6–1.0)

 

Marine Vietnam veterans

35

2.1 (1.2–3.8)

Garland et al., 1988

Navy enlisted personnel 1974–1983

68

0.7 (0.5–0.9)

Burt et al., 1987

Army combat Vietnam veterans

39

1.1 (0.7–1.5)

 

Marine combat Vietnam veterans

17

3.2 (1.4–7.4)

 

Army Vietnam veterans (service 1967–1969)

64

0.9 (0.7–1.3)

 

Marine Vietnam veterans (service 1967–1969)

17

2.5 (1.1–5.8)

Fett et al., 1987

Australian Vietnam veterans

4

1.8 (0.4–8.0)

Anderson et al., 1986a

Wisconsin Vietnam veterans

 

Wisconsin Vietnam veterans compared with Wisconsin nonveterans

13

0.7 (—)

 

Wisconsin Vietnam veterans compared with non-Vietnam-era veterans

13

0.6 (—)

 

Wisconsin Vietnam veterans compared with Vietnam-era veterans

13

1.0 (—)

Anderson et al., 1986b

Wisconsin Vietnam veterans compared with general population

24

0.7 (—)

 

Wisconsin Vietnam veterans compared with Wisconsin veterans

24

1.1 (—)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Holmes et al., 1986

West Virginia Vietnam veterans compared with West Virginia Vietnam-era veterans

2

1.1 (*)

Lawrence et al., 1985

New York Vietnam veterans

10d

1.0 (0.4–2.2)

a Given when available.

b Includes NHL and chronic lymphocytic leukemia combined.

c Includes all lymphomas combined.

d Includes NHL and Hodgkin's disease.

e Only NHL other than lymphosarcoma and reticulosarcoma (ICD-9 202).

f 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 NHL?”

g NHL, four living cases and three deaths originally listed in the CDC Vietnam Experience Study (Boyle et al., 1987).

* Information not provided by study authors.

— When information was denoted by a dash in the original study.

ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid, 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CDC, Centers for Disease Control and Prevention; CDVA, Commonwealth Department of Veterans ' Affairs; EA, Epstein-barr virus early antigen; IARC, International Agency for Research on Cancer; NHL, Non-Hodgkin's Lymphoma; SIR, standard incidence ratio; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, toxin equivalents; USDA, US Department of Agriculture.

because there were few in this group, but they included exposed women. The cohort consisted of 261 exposed and 243 nonexposed persons; the mean exposure time was 30 days (range, 6–114 days) among exposed workers and 176 days among foremen. Follow-up was from 1954 through 1994 for mortality and from 1958 through 1992 for incidence. The number of person-years of follow-up was not provided. SMRs and SIRs were calculated from death and cancer registration information to derive expected rates.

Of the three cases of NHL found, two were in the exposed group, for which the expected number of incident cases was 0.9, yielding an SIR of 2.3 (95% CI 0.3–8.5); and the third was among the nonexposed group, for which the expected number of cases was 1.2. The authors also noted rather high cancer incidence in the small group of highly exposed foremen (six of 15 persons). The strengths of this study were the detailed information on exposure to phenoxy herbicides, the nearly complete follow-up (98%) and the quality of the cancer registry in Sweden. Nevertheless, the sample size of this study was too small or the follow-up insufficient for evaluation of increased risks for such rare cancers as NHL. As in most occupational cohorts, data on nonworkplace confounders were not available.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

An update on mortality in a cohort of 1,517 Dow Chemical Company employees was recently published (Burns et al., 2001), extending the follow-up to 1994. A job–exposure matrix assessing potential phenoxy herbicide exposure for 1945–1982 had been created by an industrial hygienist, with categories for time-weighted average concentrations of greater than 1.0 mg/m3, 0.1–1.0 mg/m3, and less than 0.1 mg/m3. For follow-up from 1983 to 1994, a new category of “very low” was added for jobs that had nondetectable exposure-monitoring concentrations or in which less than 50% of time was spent in a low-exposure area. The limit of detection for that monitoring was not specified by the authors. A total of 495 workers worked for any period in either high-exposure or moderate-exposure jobs.

SMRs were calculated to compare the total male cohort with the US population. To control for the healthy-worker effect, comparisons were also made with an internal reference cohort of all other Dow employees at the Midland plant. For the exposed cohort, the total number of person-years of follow-up was 39,799, for an average of 26.2 years. For all sites of cancer, there were 83 deaths compared with 86.9 expected, for an SMR of 1.0 (95% CI 0.8–1.2). Three deaths due to NHL were observed, compared with the same number expected, for an SMR of 1.0. The internal comparisons yielded an adjusted RR of 2.6 (95% CI 0.9–8.3), reflecting a lower than expected mortality from NHL in the nonexposed cohort. The authors did note that two of the three deaths from NHL occurred in workers with moderate exposure; this suggested a dose-response relationship.

The finding of an increased RR from internal comparisons is interesting and raises several questions: Is there a healthy-worker effect for NHL? Why were the NHL deaths fewer than expected among those in the referent group at Dow Chemical Company? What exposures were prevalent in this referent group but not in the phenoxy-herbicide-exposed men? In any case, despite industrial-hygiene monitoring data that covered several decades, the study provides little information regarding phenoxy herbicides and their contaminants in relation to the risk of NHL. First, although larger than that in the study of Swedish lumberjacks, the cohort is small for detecting such rare outcomes as NHL. Second, as in most occupational mortality studies, lifestyle confounder information was lacking. Third, it is unclear whether exposure assignments were validated or even replicated by multiple hygienists. Fourth, mortality studies are problematic in that their outcome is influenced not just by the incidence of a disease but also by the stage at diagnosis and the treatment received.

Environmental Studies

In a small clinic-based case–control study of NHL, Hardell et al. (2001) collected adipose tissue for determination of TCDD and dibenzofuran exposure. The authors enrolled 33 cases of NHL and 39 patients undergoing surgery for benign lesions, from whom an adipose tissue sample was taken from the abdomi-

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

nal wall. One underlying concern in this study was whether Epstein-Barr virus (EBV), a risk factor for some subgroups of NHL, might predispose those with TCDD exposure to a higher risk, potentially resulting in a synergistic effect. EBV is a ubiquitous infection throughout the world, usually occurs initially during childhood, and is often subclinical. Growth transformation of B cells is induced by latent EBV infection. Antibodies to EBV nuclear antigens can be used to assess infection or the host's immunologic control of the infection. EBV titers were obtained for 23 cases and 32 controls. Organochlorines were measured with high-resolution gas chromatography and mass spectrometry, and lipids were measured gravimetrically. Body burdens were then expressed in picograms per gram of lipid, or parts per billion (ppb). Dioxin-like toxic equivalence was calculated to obtain the person 's body burden of compounds operating through mechanisms similar to those of 2,3,7,8-TCDD.

The authors stated that “no significant differences were found between cases and controls. ” Although that statement is true for dioxins, controls actually had significantly higher concentrations of 1,2,3,7,8-pentachlorodibenzofuran and two other furans also were substantially higher in controls. All three of those congeners, however, were present at rather low concentrations, particularly relative to all polychlorinated dibenzo-p-dioxin (PCDD) concentrations, and possibly were in the range where laboratory quantitation may be unreliable (Willman et al., 2001). Cases and controls also differed little with respect to antibodies to EBV antigens. The interaction between higher TCDD or furan exposure and high titers for EBV early antigen (EA) IgG was analyzed. The study was too small to yield any definitive findings. Nevertheless, after stratification on NHL subtype, there is a clear association of EA titers greater than 80 with a higher risk for low-grade B-cell NHL, which is expressed at all levels of TCDD and furan exposure and is sometimes magnified at higher TCDD and furan exposure. Confidence intervals are extremely large (usually covering a factor of 80–100) because of the small numbers of cases and controls in all exposure groups. Furthermore, weight loss in people with NHL is a possible concern, in that it could result in at least a transient rise in concentrations of organochlorine compounds in circulating lipids. The authors attempted to address that concern by adjusting for BMI at the time of the adipose sampling and a year earlier. They do not indicate, however, whether BMI was measured or self-reported, particularly for the value a year earlier, and self-reported weight can be quite inaccurate (Villanueva, 2001). Although the hypothesis and findings are intriguing, this study is too small to shed much light on the risks of NHL posed by TCDD exposure.

A large population-based cross-Canada case–control study of NHL in relation to pesticides was recently reported (McDuffie et al., 2001). The report included the results of a multicenter study of incidence of NHL, soft-tissue sarcoma, Hodgkin's disease, and multiple myeloma among men 19 years old or older in six provinces. A pilot study was used to generate an efficient definition of pesticide exposure that distinguished incidental or bystander environmental

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

exposure from more intensive exposure and cases from controls. The cases and controls who participated in the pilot study were not included in the analysis reported from the full investigation. A validation study of the questionnaire for farmers was also conducted to evaluate concordance of self-reported agrochemical purchases with vendor and supplier records. Using an initial postal questionnaire, the authors obtained confounder data and some exposure history. A list of pesticides was mailed to those with pesticide exposure of 10 h/year or more, according to the screening questions, and for a 15% random sample of the remainder, and a telephone interview was conducted later to collect detailed exposure information. HIV-positive subjects and persons with Kaposi's sarcoma were excluded. A pathologist reviewed slides from cases to validate NHL; 84% (N = 436) were validated; tumor blocks could not be obtained for the others, for financial reasons. Controls were selected with age stratification from health-insurance records, computerized telephone listings, or voter lists. The final sample size was 517 cases of NHL and 1,506 controls.

On the basis of the postal questionnaire screening questions, the authors observed an OR, adjusted for age and province, of 1.2 for those with 10 h/year or more of exposure. Analysis of the detailed exposure data with unconditional logistic regression showed an adjusted OR of 1.4 (95% CI 1.1–1.8) for phenoxy herbicides, with 131 exposed cases. Two of four phenoxy herbicides (including any with 1% or more prevalence of exposure) also showed increased risks: OR = 1.3 for 2,4-D and 2.33 for mecoprop, with 111 and 53 exposed cases, respectively. The only other individual herbicides associated with NHL were the dicamba compounds (Banvel and Target), which showed an OR of 1.7 (95% CI 1.0–2.8) based on 26 cases exposed to one or the other. Those models were adjusted for age, province of residence, and several medical variables that significantly predicted either a reduced or increased NHL risk: history of measles, mumps, cancer, and allergy desensitization shots and a positive family history of NHL in a first-degree relative. Several classes of insecticides and fungicides also were associated with an increased NHL risk. In a model that contained multiple pesticides, mecoprop and aldrin were both associated with higher risk. When data on frequency of exposure were analyzed, individuals exposed more frequently to 2,4-D, or mecoprop did not show the highest risks for NHL.

That study provides fairly strong data supporting an association between NHL and pesticides. First, it is a large study—over 500 cases. Second, investigation of pesticides was the primary focus of the study; for this reason, the exposure data were obtained from detailed exposure histories and covered a wide array of occupational and environmental exposures. The authors seem to have paid meticulous attention to the development of the questionnaire, including modification of questionnaires used by others, pilot validation, a strategy of mailing a list of pesticides in advance of the interview, and a sequential approach from broad categories to major pesticide classes to chemical groups and finally to individual compounds. Third, cases were systematically validated. Nevertheless, the study

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

has several important weaknesses: low response rates (among those contacted, 67% of cases and 48% of controls); the lack of a clear dose–response relationship in connection with exposure days per year (this may be explained by the modest range of frequency of exposure and the lack of information on exposure magnitude or body burdens); the possibility of recall bias; the lack of examination of cell lines or histologic subtypes of NHL; and the inability to determine independent effects of individual herbicides or classes of herbicides in NHL etiology. As the authors warn, few men were exposed to only one pesticide or one class of pesticides. Still, the authors did show that the association of NHL with mecoprop is independent of that with aldrin. It is also possible that combinations of compounds, perhaps in multiple chemical classes, play a role. Despite those limitations, the study adds weight to previous findings in the scientific literature and suggests specific chemical compounds that might be responsible.

Veitnam-Veteran Studies

No relevant Vietnam-veteran studies have been published since Update 2000 (IOM, 2001).

Synthesis

In previous reports, the evidence was found to be sufficient to support a conclusion of an association between NHL and exposures to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid). Most of the evidence suggests that 2,4-D or 2,4,5-T, rather than TCDD, is responsible for the associations observed in occupational cohorts. For instance, the main cohorts with TCDD exposure do not have increased rates of NHL. None of the five studies reviewed for this report provide strong evidence contradicting the previous finding of IOM committees. The two occupational studies are too small to be useful for evaluating the hypothesis of interest, and the same applies to the clinic-based case–control study of the interaction with Epstein-Barr virus. The exposure data from the childhood NHL study were inadequate. Finally, the large Canadian case–control study, despite some limitations, provided supportive evidence of an association between phenoxy herbicides and NHL.

Conclusions
Strength of Evidence in Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is sufficient evidence to conclude that an association exists between exposure to

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and NHL. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components.

Biologic Plausibility

Increased rates of lymphoma have been reported to occur in female B6C3F mice exposed to TCDD at 1 mg/kg of body weight via gavage twice a week for 2 years (NTP, 1982). Other animal studies have not noted an increase in lymphoma in TCDD-exposed animals. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

Analysis in the Ranch Hand study was limited by the small numbers of veterans with NHL, and no conclusions could be drawn. However, data from a survey study of male Vietnam veterans from Australia indicated a possibly increased risk of NHL.

HODGKIN'S DISEASE

Hodgkin's disease (HD) (ICD-9 201.0–201.9) is distinct from NHL in its cell of origin, demographics, and genetics. According to ACS estimates, 3,700 men and 3,300 women will be diagnosed with the disease in the United States in 2002, and 800 men and 600 women will die from it (ACS, 2002). The average annual incidence of Hodgkin's disease is shown in Table 6-44.

TABLE 6-44 Average Annual Incidence (per 100,000) of Hodgkin's Disease in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

3.1

3.2

3.8

2.7

2.9

2.0

3.7

4.1

4.2

Females

1.9

2.0

2.0

2.2

2.3

3.4

2.1

2.2

1.8

aSEER nine standard registries, crude age-specific rates, 1995–1999.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

HD is less common in people in the age groups that characterize most Vietnam veterans than in younger or older people. Among people over 40 years old, the incidence in males generally exceeds that in females, and the incidence in whites exceeds that in blacks. However, the very small numbers of cases indicate that care should be exercised in interpreting the figures.

The potential infectiousness of HD has been a topic of discussion since its earliest description. An increased incidence in people with a history of infectious mononucleosis has been observed in some studies, and a link with Epstein-Barr virus has been proposed. In addition to the occupational associations discussed below, higher rates of the disease have been observed in people with suppressed or compromised immune systems.

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

The committee responsible for VAO found that there was sufficient information to conclude that an association exists between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and HD. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding (see Table 6-45 for summary of studies).

Update of the Scientific Literature

The update of the Dow Chemical Company cohort (Burns et al., 2001), which extended follow-up to 1994 for 1,517 workers, reported one case of HD; 0.6 case was expected (SMR = 1.5, 95% CI 0.04–8.6). No other studies of this outcome were found.

Synthesis

The relatively low incidence of HD complicates the evaluation of epidemiologic studies addressing this lymphoreticular tumor. Newly published studies report small numbers of cases and are imprecise although the pattern is one of excess risk in nearly all exposed study populations. However, earlier studies carried out in Sweden (for example, the work of Hardell and colleagues) were well conducted, were based on good exposure characterization, and have not been contradicted by later work. The committee believes that data available for review in this report, when combined with information available to previous Veterans and Agent Orange committees, demonstrate a pattern of increased mortality and morbidity risk. Although it has not been demonstrated as clearly as that related to NHL, a positive association between TCDD and the development of HD is biologically plausible because of their common lymphoreticular origin and common risk factors.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-45 Selected Epidemiologic Studies—Hodgkin's Disease

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Burns et al., 2001

Dow 2,4-D production workers

1

SMR = 1.5 (0.04–8.6)

Studies Reviewed in Update 2000

Steenland et al., 1999

US chemical production workers

3

1.1 (0.2–3.2)

Hooiveld et al., 1998

Dutch chemical production workers

1

3.2 (0.1–17.6)

Rix et al., 1998

Danish paper mill workers

 

Men

18

2.0 (1.2–3.2)

 

Women

2

1.1 (0.1–3.8)

Studies Reviewed in Update 1998

Gambini et al., 1997

Italian rice growers

1

0.7 (0.1–3.6)

Kogevinas et al., 1997

IARC cohort

10

1.0 (0.5–1.8)

Becher et al., 1996

German chemical production workers

0

Ramlow et al., 1996

Pentachlorophenol production workers

0

Waterhouse et al., 1996

Residents of Tecumseh, Michigan

 

2.9 (1.1–3.4)

Studies Reviewed in Update 1996

Asp et al., 1994

Finnish herbicide appliers

2

1.7 (0.2–6.0)

Blair et al., 1993

US farmers in 23 states—white males

56

1.0 (0.8–1.3)

Kogevinas et al., 1993

IARC cohort—females

1

(*)

Persson et al., 1993

Swedish NHL patients—exposure to phenoxy herbicides

5

7.4 (1.4–40.0)b

Kogevinas et al., 1992

IARC cohort

3

0.6 (0.1–1.7)

Studies Reviewed in VAO

Eriksson et al., 1992

Swedish Cancer Registry patients

 

Male sawmill workers

10

2.2 (*)

 

Male farmers

97

1.2 (*)

 

Male forestry workers

35

1.2 (*)

 

Male horticulture workers

11

1.2 (*)

Ronco et al., 1992

Danish and Italian farm workers

 

Male Danish farmers—self-employed

27

0.6 (*)

 

Male Italian farmers—self-employed

10

2.9 (*)

 

Male Italian farmers—employees

1

0.4 (*)

 

Male Italian farmers—self-employed and employees

11

1.9 (*)

 

Female Italian farmers—self-employed

1

1.9 (*)

Swaen et al., 1992

Dutch herbicide appliers

1

3.3 (0.04–18.6)

Fingerhut et al., 1991

NIOSH cohort

3

1.2 (0.3–3.5)

 

20-year latency, 1+ years of exposure

1

2.8 (0.1–15.3)

Green, 1991

Ontario herbicide sprayers

0

(*)

Saracci et al., 1991

IARC cohort

2

0.4 (0.1–1.4)

Zober et al., 1990

BASF production workers

0

Alavanja et al., 1989

USDA forest or soil conservationists

4

2.2 (0.6–5.6)

LaVecchia et al., 1989

Residents of the Milan, Italy, area

 

Agricultural occupations

*

2.1(1.0–3.8)

 

Chemical industry occupations

*

4.3 (1.4–10.2)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Persson et al., 1989

Orebro Hospital patients

 

Farming

6

1.2 (0.4–3.5)

 

Exposed to phenoxy acids

4

3.8 (0.5–35.2)

Wiklund et al., 1989b

Swedish pesticide appliers

15

1.5 (0.8–2.4)

Alavanja et al., 1988

USDA agricultural extension agents

 

PMR analysis

6

2.7 (1.2–6.3)

 

Case–control analysis

6

1.1 (0.3–3.5)

Bond et al., 1988

Dow workers

1

2.7 (0.03–14.2)

Dubrow et al., 1988

Ohio farmers

3

2.7 (*)

Wiklund et al., 1988

Swedish agricultural and forestry workers

 

Workers in land or animal husbandry

242

1.0 (0.9–1.2)

 

Workers in silviculture

15

2.3 (1.3–3.7)

Hoar et al., 1986

Kansas residents

 

All farmers

71

0.8 (0.5–1.2)

 

Farm use of herbicides (phenoxy acids and others)

28

0.9 (0.5–1.5)

 

Farmers using herbicides >20 days/year

3

1.0 (0.2–4.1)

 

Farmers using herbicides >15 years

10

1.2 (0.5–2.6)

Pearce et al., 1985

Male residents of New Zealand— agricultural occupations, 20–64 years old

107

1.0 (0.6–2.0)

Hardell and Bengtsson, 1983

Umea Hospital patients

 

Exposed to phenoxy acids

6

5.0 (2.4–10.2)

 

Exposed to high-grade chlorophenols

9

6.5 (2.7–19.0)

 

Exposed to low-grade chlorophenols

5

2.4 (0.9–6.5)

Riihimaki et al., 1982

Finnish herbicide appliers

0

(*)

Wiklund, 1983

Swedish agricultural workers

226

1.0 (0.9–1.2)c

Burmeister, 1981

Farmers in Iowa

47

1.2 (NS)

Hardell et al., 1980

Umea Hospital patients

 

Exposed to phenoxy acids

41

4.8 (2.9–8.1)d

 

Exposed to chlorophenols

50

4.3 (2.7–6.9)d

ENVIRONMENTAL

Studies Reviewed in Update 2000

Bertazzi et al., 2001

Seveso residents—20-year follow-up

 

Zone B males

2

3.0 (0.7–12.4)

 

Zone B females

2

4.3 (1.0–18.3)

Schreinemachers, 2000

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

   
 

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

32

1.8 (1.1–2.9)

 

Males—counties with wheat acreage ≥111,000

14

0.8 (0.4–1.5)

 

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

19

1.0 (0.6–1.9)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

 

Females—counties with wheat acreage ≥111,000

14

0.9 (0.4–1.7)

Viel et al., 2000

Residents around a French municipal solid-waste incinerator

9

1.5 (NS)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

 

Zone B males

2

3.3 (0.8–14.0)

 

Zone B females

2

6.5 (1.5–29.0)

 

Zone R females

4

1.9 (0.6–5.8)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

 

Zone B males

2

3.3 (0.4–11.9)

 

Zone B females

2

6.5 (0.7–23.5)

 

Zone R females

4

1.9 (0.5–4.9)

Studies Reviewed in Update 1996

Bertazzi et al., 1993

Seveso residents—10-year follow-up—morbidity

 

Zone B males

1

1.7 (0.2–12.8)

 

Zone B females

1

2.1 (0.3–15.7)

 

Zone R males

4

1.1 (0.4–3.1)

 

Zone R females

3

1.0 (0.3–3.2)

VIETNAM VETERANS

Studies Reviewed in Update 2000

AFHS, 2000

Air Force Ranch Hand veterans

1

0.3 (0.0–3.2)

Studies Reviewed in Update 1998

Watanabe and Kang, 1996

Marine Vietnam veterans

25

1.9 (1.2–2.7)

Studies Reviewed in Update 1996

Visintainer et al., 1995

Michigan Vietnam veterans

20

1.1 (0.7–1.8)

Studies Reviewed in VAO

Watanabe et al., 1991

Army Vietnam veterans compared with Army non-Vietnam veterans

116

1.0 (*)

 

Marine Vietnam veterans compared with Marine non-Vietnam veterans

25

1.9 (*)

 

Army Vietnam veterans compared with non-Vietnam veterans

116

1.1 (*)

 

Marine Vietnam veterans compared with non-Vietnam veterans

25

1.0 (*)

CDC, 1990

US men born 1921–1953

 

Vietnam veterans

28

1.2 (0.7–2.4)

 

Army Vietnam veterans

12

1.0 (0.5–2.0)

 

Marine Vietnam veterans

4

1.7 (0.5–5.9)

 

Air Force Vietnam veterans

5

1.7 (0.6–4.9)

 

Navy Vietnam veterans

7

1.1 (0.4–2.6)

Michalek et al., 1990;

Wolfe et al., 1990

Air Force Ranch Hand veteran mortality

0

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Breslin et al., 1988

Army Vietnam veterans compared with Vietnam-era Army veterans

92

1.2 (0.7–1.9)

 

Marine Vietnam veterans compared with Marine Vietnam-era veterans

22

1.3 (0.7–2.6)

Boyle et al., 1987

Vietnam Experience Study

0

Fett et al., 1987

Australian Vietnam veterans

0

Anderson et al., 1986a

Wisconsin Vietnam veterans compared with Wisconsin nonveterans

6

0.5 (0.2–1.2)

 

Wisconsin Vietnam veterans compared with non-Vietnam-era veterans

6

1.0 (0.4–2.2)

 

Wisconsin Vietnam veterans compared with Vietnam-era veterans

6

1.0 (0.4–2.1)

Anderson et al., 1986b

Wisconsin Vietnam veterans

4

Holmes et al., 1986

West Virginia Vietnam veterans compared to West Virginia Vietnam-era veterans

5

8.3 (2.7–19.5)

Lawrence et al., 1985

New York Vietnam veterans compared to New York Vietnam-era veterans

10c

1.0 (0.4–2.2)

a Given when available.

b 90% CI.

c 99% CI.

d Includes both NHL and HD.

* Information not provided by study authors.

— When information was 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; IARC, International Agency for Research on Cancer; NHL, non-Hodgkin's lymphoma; NIOSH, National Institute for Occupational Safety and Health; PMR, proportionate-mortality ratio; USDA, US Department of Agriculture.

Conclusions
Strength of Evidence in Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is sufficient evidence to conclude that an association exists between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and HD.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Biologic Plausibility

No animal studies have found an increased incidence of HD after exposure to the chemicals of interest. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility. As mentioned previously, the common lymphoreticular origin and common risk factors between NHL and HD add to its biological plausibility.

Increased Risk of Disease Among Vietnam Veterans

The available data on HD in Vietnam veterans are too limited to form the basis of a conclusion regarding increased risk.

MULTIPLE MYELOMA

Multiple myeloma (MM) (ICD-9 203.0, 203.2–203.8) is characterized by the proliferation of bone marrow stem cells that results in an excess of neoplastic plasma cells and the production of excess abnormal proteins, usually fragments of immunoglobulins. ACS estimates that 7,800 men and 6,800 women in the United States will be diagnosed with this disease in 2002 and that 5,500 men and 5,300 women will die from it (ACS, 2002). The average annual incidence of MM is shown in Table 6-46.

MM incidence is highly age-dependent, with a relatively low rate in people under 40 years old and most cases occurring at the ages 55–70 years. Rates in blacks are at least twice those in whites. Incidence in males is slightly higher than in females, with the difference becoming much more pronounced with age.

An increased incidence of MM has been observed in several occupational groups, including farmers and agricultural workers and those with workplace exposure to rubber, leather, paint, and petroleum (Riedel et al., 1991). People

TABLE 6-46 Average Annual Incidence (per 100,000) of Multiple Myeloma in United Statesa

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

Males

3.3

2.8

8.2

7.5

6.9

13.9

12.5

10.5

36.9

Females

2.8

2.4

6.4

4.7

4.0

13.4

7.6

6.5

18.5

aSEER nine standard registries, crude age-specific rates, 1995–1999.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

with high exposure to ionizing radiation are also at greater risk. The evidence regarding other risk factors is mixed.

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

The committee responsible for VAO found that there was limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and MM. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding (see Table 6-47 for summary of studies).

Update of the Scientific Literature

In an occupational study, mortality from multiple causes was analyzed in a cohort of 1,517 male workers involved in the manufacture or formulation of 2,4-D in 1945–1994 (Burns et al., 2001). Mortality in the cohort was compared with mortality for all white US males. (Further information about the design of the study, including the measurement of exposure and the collection and analysis of data, is provided in Chapter 4.) Only one death due to myeloma was observed in the cohort (SMR = 0.8, 95% CI 0.0–4.5). The value for the SMR was unchanged in an additional analysis that assumed an induction period of 20 years (SMR = 0.8).

Cancer incidence and mortality were assessed in a cohort of 504 forestry workers in Sweden employed in 1954–1967 (Thörn et al., 2000). The cohort included 261 workers exposed to phenoxy herbicides and 243 nonexposed workers. Data on cause-specific mortality were collected for the period 1954 –1994, and cancer incidence was identified from the Swedish Cancer Register for the period 1958–1992. Expected rates of cancer were based on population data from Sweden (additional information about study design is summarized in Chapter 4). No cases of MM occurred in exposed workers, and one case occurred among the nonexposed (SIR = 1.5, 95% CI 0.0–8.6).

No relevant environmental or Vietnam-veteran studies have been published since Update 2000 (IOM, 2001).

Synthesis

The new information on exposure to herbicides and the incidence of MM comes from two relatively small occupational cohort studies (Burns et al. 2001; Thörn et al. 2000). These studies have very limited power for the assessment of an association with MM. Accordingly, they yielded no suggestion of an increased risk of MM from exposure to herbicides—but also no evidence to dismiss the possibility of such a risk.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-47 Selected Epidemiologic Studies—Multiple Myeloma

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Burns et al., 2001

Dow 2,4-D production workers

1

SMR = 80 (2–446)

Thörn et al., 2000

Swedish lumberjacks exposed to phenoxyacetic herbicides

0

Studies Reviewed in Update 2000

Steenland et al., 1999

US chemical production workers

10

2.1 (1.0–3.8)

Hooiveld et al., 1998

Dutch chemical production workers

0

0.0 (*)

Studies Reviewed in Update 1998

Gambini et al., 1997

Italian rice growers

0

Kogevinas et al., 1997

IARC cohort

 

Workers exposed to TCDD (or higher-chlorinated dioxins)

9

1.2 (0.6–2.3)

 

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

8

1.6 (0.7–3.1)

 

Workers exposed to any phenoxy herbicide or chlorophenol

17

1.3 (0.8–2.1)

Becher et al., 1996

German chemical production workers—Plant I

3

5.4 (1.1–15.9)

Studies Reviewed in Update 1996

Asp et al., 1994

Finnish herbicide appliers

3

2.6 (0.5–7.7)

Dean, 1994

Irish farmers and farm workers

170

1.0 (*)

Semenciw et al., 1994

Farmers in Canadian prairie provinces

160

0.8 (0.7–1.0)

Blair et al., 1993

US farmers in 23 states

 

White males

413

1.2 (1.0–1.3)

 

White females

14

1.8 (1.0–3.0)

 

Nonwhite males

51

0.9 (0.7–1.2)

 

Nonwhite females

11

1.1 (0.6–2.0)

 

Farmers in central US states

 

White males

233

1.2 (*)

 

White females

12

2.6 (*)

Brown et al., 1993

Iowa male users of pesticides or herbicides

111

1.2 (0.8–1.7)

Lynge, 1993

Danish production workers

 

Male

0

0

 

Female

2

12.5 (1.5–45.1)

Zahm et al., 1992

Eastern Nebraska users of herbicides

 

Male

8

0.6 (0.2–1.7)

 

Female

10

2.3 (0.8–7.0)

 

Eastern Nebraska users of insecticides

 

Male

11

0.6 (0.2–1.4)

 

Female

21

2.8 (1.1–7.3)

Studies Reviewed in VAO

Eriksson and Karlsson, 1992

Residents of northern Sweden

20

2.2 (1.0–5.7)

Swaen et al., 1992

Dutch herbicide appliers

3

8.2 (1.6–23.8)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Fingerhut et al., 1991

NIOSH cohort

5

1.6 (0.5–3.9)

 

20-year latency, 1+ years of exposure

3

2.6 (0.5–7.7)

Saracci et al., 1991

IARC cohort

4

0.7 (0.2–1.8)

Alavanja et al., 1989

USDA forest or soil conservationists

6

1.3 (0.5–2.8)

Boffetta et al., 1989

ACS Prevention Study II subjects

12

2.1 (1.0–4.2)

 

Farmers using herbicides or pesticides

8

4.3 (1.7–10.9)

LaVecchia et al., 1989

Residents of the Milan, Italy, area

 

Agricultural employment

*

2.0 (1.1–3.5)

Morris et al., 1986

Residents of four SEER areas

*

2.9 (1.5–5.5)

Pearce et al., 1986

Male residents of New Zealand

 

Use of agricultural spray

16

1.3 (0.7–2.5)

 

Likely sprayed 2,4,5-T

14

1.6 (0.8–3.1)

Cantor and Blair, 1984

Wisconsin residents—farmers in counties with highest herbicide use

*

1.4 (0.8–2.3)

Burmeister et al., 1983

Iowa residents (farmers in counties with highest herbicide use)

   
 

Born 1890–1900

*

2.7 (p < 0.05)

 

Born after 1900

*

2.4 (p < 0.05)

Riihimaki et al., 1982

Finnish herbicide appliers

1

2.5 (0.3–14.0)

ENVIRONMENTAL

Studies Reviewed in Update 2000

Bertazzi et al., 2001

Seveso residents—20-year follow-up

 

Zone B males

1

0.7 (0.1–5.0)

 

Zone B females

4

3.7 (1.3–10.2)

Schreinemachers, 2000

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

   
 

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

108

1.0 (0.8–1.3)

 

Males—counties with wheat acreage ≥111,000

75

0.8 (0.6–1.0)

 

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

91

1.0 (0.8–1.3)

 

Females—counties with wheat acreage ≥111,000

77

1.0 (0.7–1.3)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

 

Zone B males

1

1.1 (0.2–8.2)

 

Zone B females

4

6.6 (2.3–18.5)

 

Zone R males

5

0.8 (0.3–2.0)

 

Zone R females

5

1.0 (0.4–2.5)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

Zone B females

4

6.6 (1.8–16.8)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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 B males

2

3.2 (0.8–13.3)

 

Zone B females

2

5.3 (1.2–22.6)

 

Zone R males

1

0.2 (0.0–1.6)

 

Zone R females

2

0.6 (0.2–2.8)

Studies Reviewed in VAO

Pesatori et al., 1992

Seveso residents

 

Zones A, B males

2

2.7 (0.6–11.3)

 

Zones A, B females

2

4.4 (1.0–18.7)

 

Zone R males

1

0.2 (0.0–1.5)

 

Zone R females

3

0.9 (0.3–3.1)

VIETNAM VETERANS

Studies Reviewed in Update 2000

AFHS, 2000

Air Force Ranch Hand veterans

2

0.7 (0.1–5.0)

Studies Reviewed in Update 1998

Crane et al., 1997a

Australian military Vietnam veterans

6

0.6 (0.2–1.4)

Crane et al., 1997b

Australian military Vietnam veterans

0

(*)

Watanabe and Kang, 1996

Army Vietnam veterans

36

0.9 (*)

 

Marine Vietnam veterans

4

0.6 (*)

Studies Reviewed in VAO

Breslin et al., 1988

Army Vietnam veterans

18

0.8 (0.2–2.5)

 

Marine Vietnam veterans

2

0.5 (0.0–17.1)

a Given when available.

* Information not provided by study authors.

— When information was denoted by a dash in the original study.

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; ACS, American Cancer Society; AFHS, Air Force Health Study; IARC, International Agency for Research on Cancer; NIOSH, National Institute for Occupational Safety and Health; SEER, Surveillance, Epidemiology, and End Results (SEER) Program; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture.

Conclusions
Strength of Evidence in Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and MM. The evidence regarding association is drawn from earlier occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Biologic Plausibility

No animal studies have found an increased incidence of MM after exposure to the chemicals of interest. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

There are insufficient data on MM in Vietnam veterans to draw a specific conclusion as to whether they are at increased risk.

LEUKEMIA

There are four primary types of leukemia (ICD-9 202.4, 203.1, 204.0 –204.9, 205.0–205.9, 206.0–206.9, 207.0–207.2, 207.8, 208.0–208.9): the acute and chronic forms of lymphocytic leukemia and the acute and chronic forms of myeloid (or granulocytic) leukemia. According to ACS estimates, 17,600 men and 13,200 women will be diagnosed with some form of the disease in the United States in 2002, and 12,100 men and 9,600 women will die from it (ACS, 2002). Collectively, leukemias were expected to account for 2.5% of all new cancer diagnoses and nearly 4% of cancer deaths in 2002. The different forms of leukemia have different patterns of incidence and in some cases different risk factors. The incidences of the various forms of leukemia are presented in Table 6-48.

Acute lymphocytic leukemia (ALL) is a disease of the young and of people over 70 years old, and it plays a rather small role in the age groups that characterize most Vietnam veterans. The lifetime incidence of ALL is slightly higher in whites than blacks and in males than females. Exposure to high doses of ionizing radiation is a known risk factor for this form of leukemia; the evidence on other factors is inconsistent.

Acute myeloid leukemia (AML) is the most common acute leukemia among adults; its incidence increases steadily with age in people over 40 years old. In the Vietnam-veteran age groups, AML accounts for roughly one-fourth of cases of leukemia in men and one-third in women. Overall, AML is slightly more common in males than in females. White males have a higher incidence than white females; the lifetime incidence in black males and females is roughly equal. Risk factors associated with an increased risk of AML include high doses of ionizing radiation, occupational exposure to benzene, and some medications used in cancer chemotherapy (such as melphalan). Fanconi's anemia and Down syndrome are associated with an increased risk of AML, and tobacco-smoking has been suggested as a risk factor.

Chronic lymphocytic leukemia (CLL) is the most common of the four primary types of leukemia in men. Because CLL shares many traits with lymphomas

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-48 Average Annual Incidence (per 100,000) of Leukemias in United States a

 

45–49

Years of Age

50–54

Years of Age

55–59

Years of Age

 

All Races

White

Black

All Races

White

Black

All Races

White

Black

All Leukemias

Males

8.0

8.1

7.5

14.1

14.7

12.5

19.4

19.9

14.9

Females

6.1

5.9

7.5

9.8

10.0

8.6

12.5

13.3

9.8

Acute Lymphocytic Leukemia

Males

0.6

0.5

1.2

1.0

1.1

0.3

0.8

0.8

0.5

Females

0.4

0.4

0.4

0.7

0.4

0.3

0.7

0.7

0.8

Chronic Lymphocytic Leukemia

Males

2.2

2.4

1.6

5.2

5.4

5.1

8.2

8.7

7.0

Females

1.2

1.2

1.2

2.7

2.8

2.9

3.9

4.4

1.9

Acute Myeloid Leukemia

Males

2.2

2.1

2.1

3.8

4.0

3.0

4.7

4.9

2.3

Females

2.5

2.3

3.2

3.2

3.3

1.7

4.5

4.6

4.2

Chronic Myeloid Leukemia

Males

1.3

1.3

1.4

1.8

1.8

3.4

2.7

2.6

2.8

Females

1.2

1.2

1.2

1.9

1.9

2.6

1.9

1.8

1.5

All Other Leukemiab

Males

1.2

1.3

0.9

1.8

2.0

0.7

2.0

2.1

1.4

Females

0.7

0.7

1.0

0.7

0.7

0.9

1.0

1.1

1.1

aSEER nine standard registries, crude age-specific rate, 1995–1999.

bIncludes leukemic reticuloendotheliosis (hairy-cell leukemia), plasma-cell leukemia, monocytic leukemia, and acute and chronic erythremia and erythroleukemia.

(immunohistochemical, B cell origin, progression to an acute aggressive form of non-Hodgkin's lymphoma), the committee has reviewed CLL separately from the other leukemias; the committee's review of CLL is presented in the next section.

The incidence of chronic myeloid leukemia (CML) increases steadily with age in people over 30 years old. Its lifetime incidence is roughly equal in whites and blacks and is slightly higher in males than in females. Among people in the age groups that characterize most Vietnam veterans, CML accounts for about one-fifth of cases of leukemia. It is associated with an acquired chromosomal abnormality known as the Philadelphia chromosome; exposure to high doses of ionizing radiation is a known risk factor for this abnormality.

Little is known about the risk factors associated with other forms of leukemia. However, two human retroviruses have been linked to human leukemias: HTLV-1 appears to cause adult T-cell leukemia or lymphoma, whereas the data linking HTLV-2 to hairy-cell leukemia are less definitive.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Summary of VAO, Update 1996, Update 1998, and Update 2000

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and leukemia. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding (see Table 6-49).

Update of the Scientific Literature
Occupational Studies

Burns et al. (2001) reported data on a cohort of 1,517 male workers involved in the manufacture or formulation of 2,4-D in 1945–1994. A job–exposure matrix was developed to assign workers to exposure categories based on measurements of time-weighted average exposure. Mortality in the study cohort was compared with mortality for all white US males and for an internal reference population of nonexposed manufacturing workers in the same company (see Chapter 4 for study details). Mortality from leukemia in the entire cohort was similar to rates in all US males (four deaths; SMR = 1.3, 0.4 –3.3). Similar results were obtained in an analysis based on a 20-year induction period. In the comparison with nonexposed workers, an excess in lymphopoietic mortality was noted in workers with high-cumulative-dose exposure to 2,4-D (four deaths; RR = 2.1 for 0-year induction and 2.7 for 20-year induction). That subgroup of exposed workers did not experience deaths from non-Hodgkin's lymphoma but may have included deaths from Hodgkin's disease and MM in addition to leukemia.

Cancer incidence and mortality were assessed in a cohort of 504 forestry workers in Sweden who were characterized by presence or absence of exposure to phenoxy herbicides in 1954–1967 (Thörn et al., 2000; see Chapter 4 for study details). Follow-up for mortality was completed through 1994, and data on cancer incidence were available from 1958–1992. No cases of leukemia occurred in the exposed members of this cohort.

Environmental Studies

Revich et al. (2001) analyzed data on cancer incidence and mortality in Chapaevsk, a city of 83,000 residents in the Samara region of Russia. A number of industries are in Chapaevsk, and production at one major chemical plant appeared to be responsible for dioxin contamination that was documented in the air, soil, and water of the city. Mortality due to leukemia during the years 1995–1998 was compared with mortality in the Samara region as a whole; the SMR was 1.5 for both men and women (0.8–2.7 in men; 0.8–2.4 in women), on the basis of 11

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 6-49 Selected Epidemiologic Studies—Leukemia

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Burns et al., 2001

Dow 2,4-D production workers— lymphopoietic mortality in workers with high 2,4-D exposure

4

2.1 (0-yr induction) 2.7 (20-yr induction)

Thörn et al., 2000

Swedish lumberjack workers exposed to phenoxyacetic herbicides

0

Studies Reviewed in Update 2000

Steenland et al., 1999

US chemical production workers

10

0.8 (0.4–1.5)

Hooiveld et al., 1998

Dutch chemical production workers

1

1.0 (0.0–5.7)

Rix et al., 1998

Danish paper mill workers

 

Males

20

0.8 (0.5–1.2)

 

Females

7

1.3 (0.5–2.7)

Studies Reviewed in Update 1998

Gambini et al., 1997

Italian rice growers

 

0.6 (0.2–1.7)

Kogevinas et al., 1997

IARC cohort

34

1.0 (0.7–1.4)

Becher et al., 1996

German chemical production workers— cohort 1

4

1.8 (0.5–4.7)

Ramlow et al., 1996

Pentachlorophenol production workers

2

1.0 (0.1–3.6)

Waterhouse et al., 1996

Residents of Tecumseh, Michigan

 

1.4 (1.0–1.9)

Studies Reviewed in Update 1996

Asp et al., 1994

Finnish herbicide appliers

2

(*)

Semenciw et al., 1994

Farmers in Canadian prairie provinces

357

0.9 (0.8–1.0)

Blair et al., 1993

US farmers in 23 states

1,072

1.3 (1.2–1.4)

Kogevinas et al., 1993

Female herbicide-spraying and production workers

1

Studies Reviewed in VAO

Bueno de Mesquita et al., 1993

Dutch production workers

 

Workers exposed to phenoxy herbicides

2

2.2 (0.3–7.9)

Hansen et al., 1992

Danish gardeners

 

All gardeners—all other types of leukemia

3

1.2 (0.3–3.6)

 

Male gardeners—all other types of leukemia

3

1.4 (0.3–4.2)

Ronco et al., 1992

Danish and Italian farm workers

 

Danish self-employed farmers

145

0.9 (*)

 

Danish male employees

33

1.0 (*)

 

Italian self-employed farmers

12

0.7 (*)

 

Italian male employees

8

0.9 (*)

Fingerhut et al., 1991

US chemical workers

6

0.7 (0.2–1.5)

Saracci et al., 1991

Chemical workers

 

Exposed

18

1.2 (0.7–1.9)

 

Probably exposed

0

0 (0.0 –11.2)

 

Nonexposed

3

0.9 (0.2–2.6)

 

Unknown exposure

0

0 (0.0–10.3)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Brown et al., 1990

Residents of Iowa and Minnesota

 

All types of leukemia, ever farmed

 

1.2 (1.0–1.5)

 

All types of leukemia, any herbicide use

 

1.2 (0.9–1.6)

 

Herbicide users, phenoxy acid use

 

1.2 (0.9–1.6)

 

All types of leukemia, 2,4-D use

 

1.2 (0.9–1.6)

 

All types of leukemia, 2,4,5-T use

 

1.3 (0.7–2.2)

Wigle et al., 1990

Saskatchewan farmers

138

0.9 (0.7–1.0)

Zober et al., 1990

BASF production workers—second additional cohort

1

5.2 (0.4–63.1)

Alavanja et al., 1988

USDA agricultural extension agents

*

1.9 (1.0–3.5)

Bond et al., 1988

Dow workers with chloracne

2

3.6 (0.4–13.0)

Blair and White, 1985

Residents of Nebraska—all cases, all leukemia—farming

 

1.3

ENVIRONMENTAL

New Studies

Revich et al., 2001

Residents of Chapaevsk, Russia

 

Mortality standardized to Samara region

 

Males

11

1.5 (0.8–2.7)

 

Females

15

1.5 (0.8–2.4)

Studies Reviewed in Update 2000

Bertazzi et al., 2001

Seveso residents—20-year follow-up

 

Zone B males

9

2.4 (1.2–4.7)

 

Zone B females

3

1.1 (0.4–3.5)

Schreinemachers, 2000

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

   
 

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

246

1.0 (0.8–1.1)

 

Males—counties with wheat acreage ≥111,000

248

1.1 (1.0–1.3)

 

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

183

1.0 (0.8–1.2)

 

Females—counties with wheat acreage ≥111,000

146

0.9 (0.8–1.2)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

 

Zone B males

7

3.1 (1.4–6.7)

 

Zone B females

1

0.6 (0.1–4.0)

 

Zone R males

12

0.8 (0.4–1.5)

 

Zone R females

12

0.9 (0.5–1.6)

Studies Reviewed in Update 1998

Bertazzi et al., 1997

Seveso residents—15-year follow-up

 

Zone B males

7

3.1 (1.3–6.4)

 

Zone B females

1

0.6 (0.0–3.1)

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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 B males

2

1.6 (0.4–6.5)

 

Zone B females

2

1.8 (0.4–7.3)

Studies Reviewed in VAO

Bertazzi et al., 1992

Seveso residents—10-year follow-up

 

Zones A, B, R males

4

2.1 (0.7–6.9)

 

Zones A, B, R females

1

2.5 (0.2–27.0)

VIETNAM VETERANS

Studies Reviewed in Update 2000

AFHS, 2000

Air Force Ranch Hand veterans

2

0.7 (0.1–5.0)

AIHW, 1999

Australian Vietnam veterans

27

26 expected (16–36)

CDVA, 1998a

Australian Vietnam veterans—male

64b

26 expected (16–36)

CDVA, 1998b

Australian Vietnam veterans—female

1b

0 expected (0–4)

Studies Reviewed in Update 1998

Dalager and Kang, 1997

Army Chemical Corps veterans

 

1.0 (0.1–3.8)

Crane et al., 1997b

Australian military Vietnam veterans

 

0.5 (0.1–3.0)

Studies Reviewed in Update 1996

Visintainer et al., 1995

Michigan Vietnam veterans

30

1.0 (0.7–1.5)

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 leukemia?”

* Information not provided by study authors.

— When information was denoted by a dash in the original study.

ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid, 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; IARC, International Agency for Research on Cancer; USDA, US Department of Agriculture.

deaths in men and 15 deaths in women. Age-adjusted incidences during 1998 were reported for leukemia and lymphoma combined. The rates in Chapaevsk were lower than in the Samara region in men (2.4 vs 14.6 per 100,000) but higher in women (19.0 vs 13.9). The actual number of cases was not given, p values and confidence intervals were not calculated, and there was no adjustment for factors other than age.

Vietnam-Veteran Studies

No relevant Vietnam-veteran studies have been published since Update 2000 (IOM, 2001).

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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Synthesis

Studies of leukemia reviewed for the first time in this report offer no compelling or consistent evidence of an association with exposure to herbicides. No cases occurred among exposed workers in the cohort of lumberjacks in Sweden. Four workers from the Dow Chemical Company with high cumulative exposure to 2,4-D did die from lymphopoietic cancer, but at least some of the deaths may have been due to HD or MM, forms of cancer that have already been causally linked with a history of exposure to herbicides. The relationship between mortality from leukemia and residence in Chapaevsk is suggestive but somewhat imprecise. The possible excess incidence of leukemia in Chapaevsk is difficult to interpret, in that only 1 year of data are presented, the incidences of leukemia and lymphoma are reported together, and the incidence in Chapaevsk is higher than that in the Samara region and Russia in women but substantially lower in men. Further information on the quality of cancer registration in Chapaevsk, the Samara region, and Russia is needed to understand fully the meaning of these data.

Conclusions
Strength of Evidence in Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and leukemias other than CLL.

Biologic Plausibility

No animal studies have found an increased incidence of leukemia after exposure to the chemicals of interest. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

The limited data available on Vietnam veterans do not suggest that they are at increased risk for leukemias other than CLL.

CHRONIC LYMPHOCYTIC LEUKEMIA

In the proposed World Health Organization classification of non-Hodgkin 's lymphoid neoplasms, CLL and its lymphomatous form, small lymphocytic lym-

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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phoma, are mature B-cell neoplasms (IARC, 2001). About 7,000 new cases (4,100 in men, 2,900 in women) of CLL will be diagnosed in the United States in 2002 (ACS, 2002). Nearly all cases occur after the age of 50. The rate per 100,000 in persons 50-74 years old is 18.7 and in persons 75 years old and older 38.8. For average annual incidence information, see the previous section on leukemia.

The requirements for diagnosis of CLL include an absolute peripheral-blood lymphocyte count of more than 10 × 109 per liter, a predominant population of mature-looking lymphocytes, and a hypercellular or normal cellular bone marrow containing more than 30% lymphocytes. The malignant cells in CLL exhibit a characteristic membrane phenotype with coexpression of pan-B-cell antigens, including CD19, CD20, and CD23 along with CD5. However, the cell-surface membranes express only weak surface membrane immunoglobulin.

Patients with CLL are staged according to the Rai classification: Stage 0, clinical features of lymphocytes in the blood and marrow only; Stage I or II (intermediate risk), lymphocytosis, lymphadenopathy, and splenomegaly with or without hepatomegaly; and Stage III or IV (high risk), lymphocytosis and anemia and/or thrombocytopenia. The most consistent abnormal finding at initial diagnosis is lymphadenopathy —from small lymph nodes to nodes as large as an orange. Patients with large lymphadenopathy, white-cell counts over 100 × 109 per liter, or thrombocytopenia require therapy. The disease is complicated by autoimmune anemias and recurrent infection because of hypogammaglobulinemia.

Diffuse small-cell lymphocytic lymphoma is the term for the condition of patients with lymphomatous presentation of CLL. Patients seek medical attention for painless generalized lymphadenopathy that in many cases has lasted for several years. Unlike the situation in CLL, the peripheral blood may be normal or reveal only mild lymphocytosis. However, the bone marrow is positive in 75– 95% of cases. Both small-cell lymphocytic lymphoma and CLL can transform into aggressive NHL known as Richter's syndrome. Richter's syndrome is characterized by diffuse large-cell lymphoma or its immunoblastic variant. It is resistant to current therapies, and the median survival is about 6 months.

Summary of Studies on CLL

In response to a request from the Department of Veterans Affairs and because CLL shares more traits (immunohistochemical characteristics, B-cell origin, and progression to an acute aggressive form of NHL) with NHL than with other types of leukemia, the committee reassessed the available epidemiologic data to determine whether CLL merited reclassification regarding association with exposure to herbicides. The relevant data are summarized in Table 6-50.

Six studies reported in previous updates in which CLL was specifically investigated were reviewed. Waterhouse et al. (1996) performed a prospective study of site-specific cancer incidence in 7,016 males and females in a rural farming community in Michigan in 1959–1987. There was a significant increase

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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TABLE 6-50 Selected Epidemiologic Studies—Chronic Lymphocytic Leukemia

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 1998

Waterhouse et al., 1996

Residents of Tecumseh, Michigan— CLL

10

SIR = 1.8 (0.8–3.2)

Amadori et al., 1995

CLL in Italian workers

 

Farming or animal-breeding workers

15

2.3 (0.9–5.8)

 

Farming

5

1.6 (0.5–5.2)

 

Animal-breeding

10

3.1 (1.1–8.3)

Studies Reviewed in VAO

Hansen et al., 1992

Danish gardeners

 

All gardeners—CLL

6

2.5 (0.9–5.5)

 

Male gardeners—CLL

6

2.8 (1.0–6.0)

Brown et al., 1990

Residents of Iowa and Minnesota

 

CLL, ever farmed

156

1.4 (1.1–1.9)

 

CLL, any herbicide use

74

1.4 (1.0–2.0)

Blair and White, 1985

Residents of Nebraska

 

All cases, all leukemia—farming

1,084

1.3

 

CLL

248

1.7 (CI did not include 1.0)

Burmeister et al., 1982

Residents of Iowa

 

CLL in white male farmers using herbicides

 

1.9 (1.2–3.1)

ENVIRONMENTAL

Studies Reviewed in Update 2000

Bertazzi et al., 2001

Seveso residents—20-year follow-up— lymphatic leukemia

   
 

Zone A

0

 

Zone B

2

1.1 (0.3–4.4)

 

Total

2

1.0 (0.2–3.9)

aGiven when available.

— When information was denoted by a dash in the original study.

Abbreviations: USDA, United States Department of Agriculture.

in the lymphopoietic neoplasms, NHL, Hodgkin's disease, and CLL (combined SIR = 1.40, 95% CI 1.0–1.9, p = 0.03). Waterhouse et al. (1996) also conducted a case–control study of risk factors in 74 patients with lymphoma and leukemiamatched with four controls each. Family history was the only covariant significantly associated with disease; there was a correlation with pesticide use but the

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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database did not distinguish herbicides from insecticides and fungicides. Amadori et al. (1995) conducted a population-based case–control study in an agricultural area of Italy. Subjects working in agriculture denoted as farmers or farmers with animal breeding had a high risk of CLL (OR = 1.6, 95% CI 0.5–5.2, and 3.1, 95% CI 1.1–8.3, respectively). If both groups were combined the OR was 2.3 (95% CI 0.9–5.8). There was no information on herbicide exposure. The study of cancer risk in Danish male gardeners highly exposed to pesticides (Hansen et al., 1992) showed a significant increase in CLL (standardized morbidity ratio, SMbR = 2.8, 95% CI 1.0–6.0) on the basis of 6 exposed cases. The paper states that gardeners holding outdoor jobs were exposed primarily to herbicides through the growing season but also to insecticides and fungicides; however, data on exposure were not presented for CLL cases. Blair and White (1985) reported that CLL mortality among farmers in Nebraska in 1957 –1974 was significantly increased (OR = 1.7). The higher risk occurred among farmers residing in counties associated with cattle and dairy products; however no information was provided on herbicide exposure of the CLL group.

Two of the epidemiologic studies reported on herbicide exposure and CLL. In a study of 1,675 white Iowa males who died of leukemia (Blair and White, 1985). CLL and nonspecific nonacute lymphocytic leukemia were significantly increased in farmers (OR = 1.7). Further analysis showed a strong relationship of CLL deaths in counties with acres producing soybeans and acres treated with herbicides. Brown et al. (1990) carried out a population-based case–control interview study of 578 white men with leukemia and 1,245 controls living in Iowa and Minnesota. CLL mortality (244 cases) was higher in farmers than in nonfarmers (OR = 1.4). When risk was calculated for CLL subtype, ORs were significantly increased for use of any herbicide (OR = 1.4), any insecticide (OR = 1.3), and any animal insecticide (OR = 1.3). The risk of CLL in farmers who ever handled 2,4-D was 1.3. The risk of CLL in men who first handled 2,4,5-T at least 20 years before interview was significantly increased (OR = 3.3, 95% CI 1.2–8.9).

Bertazzi et al. (2001) evaluated lymphocytic leukemia in the 20-year follow-up of Seveso residents. No increased risk was seen, with relative risks of 1.1 (95% CI, 0.3–4.4) and 1.0 (95% CI, 0.2–3.9) for Zone B residents and the total of Zone A and B residents, respectively.

No relevant Vietnam-veteran studies that specifically investigate CLL have been published since Update 2000 (IOM, 2001).

Synthesis

A reanalysis of the epidemiologic studies indicates that farming occupation, especially where there is exposure to the herbicides 2,4-D and 2 4,5-T, is associated with significant risk of CLL mortality. Many more studies support the hypothesis that herbicide exposure can contribute to NHL risk. Most cases of CLL

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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and NHL reflect malignant transformation of B-lymphocyte progenitor cells, so these diseases could have a common etiology.

Conclusions
Strength of the Evidence

On the basis of its evaluation, the committee concludes that there is sufficient evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and CLL.

Biologic Plausibility

No animal studies have found an increased incidence of CLL after exposure to the chemicals of interest. A summary of the biologic plausibility of the carcinogenicity of TCDD and the herbicides in general is presented at the end of this chapter. Chapter 3 discusses recent toxicologic studies that concern biologic plausibility.

Increased Risk of Disease Among Vietnam Veterans

The limited data available on Vietnam veterans do not suggest that they are at increased risk for CLL.

SUMMARY

On the basis of the occupational, environmental, and veteran studies reviewed, the committee has reached one of four standard conclusions about the strength of the evidence regarding an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and each of the kinds of cancer studied. As explained in Chapter 2, the distinctions reflect the committee's judgment that if an association between exposure and a given outcome is “real,” it would have been found in a large, well-designed epidemiologic study in which exposure to herbicides or TCDD was sufficiently high, well characterized, and appropriately measured. For consistency with the charge to the committee by the secretary of veterans affairs in Public Law 102-4 and with accepted standards for scientific reviews, the distinctions between the four conclusions are based on statistical association, not on causality. The committee used the same criteria to categorize diseases according to the strength of the evidence as were used in VAO, Update 1996, Update 1998, and Update 2000.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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Health Outcomes with Sufficient Evidence of an Association

For outcomes in this category, a positive association with one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) must be observed in studies in which chance, bias, and confounding can be ruled out with reasonable confidence. The committee also regarded evidence from several small studies that were free of bias and confounding and that showed an association that is consistent in magnitude and direction as sufficient evidence of an association.

In previous reports, the committees found sufficient evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and three cancers: soft-tissue sarcoma, non-Hodgkin 's lymphoma, and Hodgkin's disease. The scientific literature continues to support the classification of those three cancers in the category of sufficient evidence. In this update the committee considers the available data on CLL separate from other leukemias. On the basis of those data, the committee classifies CLL in this category.

Health Outcomes with Limited or Suggestive Evidence of Association

For outcomes in this category, the evidence must be suggestive of an association with at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid), but may be limited because chance, bias, or confounding could not be ruled out with confidence. Typically, at least one high-quality study indicates a positive association; often several studies provide positive results, but the results of other studies are inconsistent.

In previous reports, the committees found limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and: laryngeal cancer, lung cancer, bronchial (tracheal) cancer, prostatic cancer, and multiple myeloma. The scientific literature continues to support the classification of those diseases in the category of limited or suggestive evidence. On the basis of the literature, no additional cancers satisfy the criteria for inclusion in this category.

Health Outcomes with Inadequate or Insufficient Evidence to Determine Whether an Association Exists

The scientific data on many of the kinds of cancer reviewed by the committee were inadequate or insufficient to determine whether an association exists. For those cancers, the available studies are of insufficient quality, consistency, or statistical power to support a conclusion of the presence or absence of an association. For example, some studies fail to control for confounding or have inadequate exposure assessment. This category includes hepatobiliary cancers (can-

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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cers of the liver and intrahepatic bile duct), nasopharyngeal cancer, bone cancer, skin cancer (including basal-cell carcinoma, squamous-cell carcinoma, and nonmelanocytic skin cancer), breast cancer, cancers of the female reproductive system (including cancer of the cervix, endometrium, and ovaries), testicular cancer, urinary bladder cancer, renal cancer (cancers of the kidney and renal pelvis), and the various forms of leukemia other than CLL.

Health Outcomes with Limited or Suggestive Evidence of No Association

For outcomes in this category, several adequate studies covering the full range of exposure that human beings are known to encounter are consistent in not showing a positive association with exposure to one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid). The studies have relatively narrow confidence intervals. A conclusion of “no association” is inevitably limited to the conditions, magnitude of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small increase in risk associated with the exposure studied can never be excluded.

In previous reports, the committees found a sufficient number and variety of well-designed studies to conclude that there is limited or suggestive evidence of no association between a small group of cancer types and exposure to herbicides or TCDD: gastrointestinal tumors (of the colon, rectum, stomach, and pancreas) and brain tumors. The most recent scientific evidence continues to support the classification of such kinds of cancers in this category. On the basis of evaluation of the scientific literature, no additional cancers satisfy the criteria for inclusion in this category.

Biologic Plausibility

Chapter 3 presents details of the committee's evaluation of recent toxicologic studies relevant to the biologic plausibility of a connection between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and various forms of cancer. Some of the preceding discussions of cancer outcomes include references to papers relevant to specific types of cancer.

Although evidence suggests that TCDD is not genotoxic, data on animals indicate that TCDD has carcinogenic activity. A number of animal species—such as rats, mice, and hamsters—have been exposed to TCDD and examined for increases in tumor incidence and cancer. They have included studies in which TCDD was fed to animals, applied to their skin, injected under their skin, or injected into their abdominal cavity. The research indicates that TCDD can both cause cancers or tumors and act as a promoter (that is, enhance the incidence of some cancers or tumors in the presence of known carcinogens). Increased cancer rates have been observed at several sites in the body, notably the thyroid gland,

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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skin, and lungs. Studies have demonstrated an increased incidence of liver cancer after TCDD exposure but only after other adverse changes in the liver were observed. TCDD is also an extremely potent promoter of neoplasia in laboratory rats. Decreased rates of some cancers—including those of the uterus, pancreas, and pituitary and mammary glands—have also been reported. The sites at which effects were observed and the exposure needed to induce them varied considerably from species to species.

The mechanism by which TCDD exerts its carcinogenic effects is not established. TCDD has a wide array of effects on growth regulation, hormone systems, and other factors associated with the regulation of cellular processes involving growth, maturation, and differentiation; those effects could influence tumor formation. Data on female rats suggest that complex hormonal interactions are involved in TCDD-induced carcinogenesis.

Studies are consistent with the hypothesis that the effects of TCDD are mediated by the aryl hydrocarbon receptor (AhR), a protein in animal and human cells to which TCDD can bind. After the binding of TCDD, the TCDD–AhR complex has been shown to bind DNA and lead to changes in transcription (that is, genes are differentially regulated). In many cases, the differential gene regulation leads to transformation of a normal cell into an abnormal cell. Furthermore, data on animals genetically modified not to express the AhR suggest that the AhR plays a role in normal growth, and this supports the hypothesis that TCDD could affect cell growth.

The transcriptional alterations induced by TCDD result in alterations in some forms of cellular regulation and metabolism at a very basic level. For example, TCDD has been shown to induce cytochrome P4501A1 (CYP1A1) and other metabolizing enzymes. Those changes result in altered cell metabolism and could be involved in TCDD's carcinogenic activity, especially as this may involve the metabolic activation of other chemicals to carcinogenic intermediates. An accumulation of data also indicates that genes and pathways modulating cell cycle, altering the pattern of cell death, involved in the production and activity of hormones and growth factors, and involved in cellular oxidative stress appear to be predominantly affected. Those data are consistent with findings that TCDD alters cell pathways involving growth, maturation and differentiation, all of which could modulate processes involved in the tissue-specific formation of tumors. On the other hand, tissue-specific protective cellular mechanisms can affect the response to TCDD, further complicating the carcinogenic effects of this chemical.

There are differences among various experimental animals in susceptibility to TCDD-induced effects; the sites at which tumors are induced also vary from species to species. Modulated gene expression by TCDD is also highly specific for species and cell type. Differences in the induction or repression of responsive genes likely play a role in the different responses seen in different cell types and species.

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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Although structural differences in the AhR have been identified among different species, this receptor operates in a similar manner in animals and humans. Therefore, a common mechanism is likely to underlie the carcinogenic effects of TCDD in humans and animals, and data on animals support a biologic basis of the carcinogenic effects of TCDD in humans. Because of the many species and strain differences in TCDD responses, however, controversy remains regarding the magnitude of TCDD exposure that is carcinogenic.

Fewer studies have been conducted on the carcinogenicity of the herbicides. Several studies of the carcinogenicity of 2,4-D, 2,4,5-T, and picloram have been performed in laboratory animals. In general, the results were negative. However, some studies do not meet present-day standards for cancer bioassays, and others produced equivocal results. Thus, it is not currently possible to have confidence in the conclusions regarding the carcinogenicity of these compounds. With respect to genotoxicity, however, most of the evidence indicates that 2,4-D is genotoxic only at very high concentrations. Although 2,4,5-T increased the formation of DNA adducts by cytochrome P450-derived metabolites of benzo[a]pyrene, most available evidence indicates that 2,4,5-T is genotoxic only at high concentrations.

There is some evidence that cacodylic acid (also known as dimethylarsinic acid, DMA) is carcinogenic. DMA may induce DNA modifications that sensitize it to free-radical injury. Other studies concluded that it is a promoter of urinary bladder, kidney, liver, and thyroid gland carcinogenesis in rats; causes pulmonary neoplasms in mice; and causes bladder hyperplasia and tumors in rats. Another exposure study in mice, however, produced negative results.

The evidence suggests that a connection between TCDD and cancer in humans is, in general, biologically plausible. However, differences in sensitivity and susceptibility among individual animals, strains, and species; the lack of strong evidence of organ-specific effects among species; and differences in route, dose, duration, and timing of exposure complicate any more definitive conclusions about the presence or absence of a mechanism of induction of site-specific cancers by TCDD. Experiments on 2,4-D, 2,4,5-T, and picloram in animals and cells do not provide a strong biologic basis for the presence or absence of carcinogenic effects of these compounds. Some animal data might support a carcinogenic effect of DMA, but these data alone are not sufficient to draw conclusions on the carcinogenicity of this compound in humans.

Considerable uncertainty remains about how to apply this information to the evaluation of potential health effects of herbicide or TCDD exposure in Vietnam veterans. Scientists disagree about the extent to which information derived from animals and cellular studies predicts human health outcomes and about the comparability of health effects resulting from high-dose and low-dose exposure. Investigating the biologic mechanisms underlying TCDD's carcinogenic effects continues to be an active field of research, and future updates of this report might

Suggested Citation:"6. Cancer." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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have more and better information on which to base conclusions, at least for that compound.

Increased Risk of Disease Among Vietnam Veterans

Under the Agent Orange Act of 1991, the committee was asked to determine (to the extent that available scientific data permit meaningful determinations) the increased risk of various diseases it studies among those exposed to herbicides during their service in Vietnam. As discussed under the specific cancers, for most cancer outcomes there is insufficient data to quantitate the increased risk to Vietnam veterans.

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This book updates and evaluates the available scientific evidence regarding statistical associations between diseases and exposure to dioxin and other chemical compounds in herbicides used in Vietnam, focusing on new scientific studies and literature.

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