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Veterans and Agent Orange: Update 2002 (2003)

Chapter: 9. Other Health Effects

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Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

9

Other Health Effects

This chapter discusses data on the possible association of the herbicides used in Vietnam (2,4-dichlorophenoxyacetic acid, 2,4-D; 2,4,5-trichlorophenoxyacetic acid, 2,4,5-T; picloram; and cacodylic acid) and the contaminant of 2,4,5-T, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with the following noncancer health outcomes: chloracne, porphyria cutanea tarda, respiratory disorders, immune system disorders, diabetes, lipid and lipoprotein disorders, gastrointestinal and digestive disease (including liver toxicity), circulatory disorders, amyloidosis, endometriosis, and adverse effects on thyroid homeostasis. Background information about each outcome is followed by a brief summary of the findings described in earlier Veterans and Agent Orange reports, a discussion of the most recent scientific literature, and a synthesis of the material reviewed. When appropriate, the literature is discussed by exposure type (occupational, environmental, or 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. The categories of association and the committee's approach to categorizing the health outcomes are discussed in Chapters 1 and 2.

CHLORACNE

The skin disease chloracne is characteristic of exposure to TCDD and other cyclic organochlorine compounds. It shares some pathologic processes (for example, the occlusion of the orifice of the sebaceous follicle) with more common forms of acne (such as acne vulgaris), but it can be differentiated by the presence

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

of epidermoid inclusion cysts, which are caused by proliferation and hyperkeratinization (horn-like cornification) of the epidermis. Although chloracne is typically distributed over the eyes, ears, and neck, patterns of chloracne among chemical-industry workers exposed to TCDD have also included the trunk, genitalia, and buttocks (Neuberger et al., 1998).

Chloracne has been extensively studied and is used as a marker of exposure in studies of populations exposed to TCDD and other organochlorine compounds, such as polychlorinated biphenyls (PCBs) and pentachlorophenol. It is one of the few findings consistently associated with such exposure and is a well-validated indicator of high exposure to those compounds, particularly TCDD (Sweeney et al., 1997/98). If chloracne occurs, however, it appears shortly after the chemical exposure, not after a long latency. Although it is refractory to acne treatments, it usually regresses over time. Therefore, new cases of chloracne would not be the result of exposures during Vietnam and are not a concern for this report.

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

The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO; IOM, 1994) found there to be sufficient information 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 chloracne. Additional information available to the committees responsible for Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), and Update 2000 (IOM, 2001) did not change that finding. Reviews of the studies underlying the finding may be found in the earlier reports.

Update of the Scientific Literature

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

Synthesis

Chloracne is clearly associated with high exposure to cyclic organochlorine compounds, but it appears shortly after exposure, not after a long latency.

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:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

is sufficient evidence 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 chloracne.

Biologic Plausibility

As noted in previous reports, chloracne has been reported in response to exposure to TCDD but not to purified phenoxyacetic herbicides.

Increased Risk of Disease Among Vietnam Veterans

There is sufficient evidence that chloracne is associated with TCDD exposure. However, given the lack of ability to extrapolate from exposure in studies of TCDD and chloracne to individual Vietnam veterans, it is not possible to quantify the risk of chloracne in Vietnam veterans. Furthermore, because TCDD-associated chloracne is evident shortly after exposure, there is no risk of new cases long after service in Vietnam.

PORPHYRIA CUTANEA TARDA

Porphyria cutanea tarda (PCT) is an uncommon disorder of porphyrin metabolism which causes thinning and blistering of the skin in sun-exposed areas, hyperpigmentation (excess pigment in skin), and hypertrichosis (excess hair growth) (Muhlbauer and Pathak, 1979; Grossman and Poh-Fitzpatrick, 1986). The condition is not completely understood, but evidence indicates that people with particular mutations associated with hemochromatosis and people with an iron-overload condition are predisposed to PCT. Known risk factors are high alcohol intake, estrogen intake (as in oral contraceptives), liver disease, hemodialysis, HIV infection, and diabetes. In addition, data suggest poor diet might be a risk factor.

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

The committee responsible for VAO found there to be 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 PCT in genetically susceptible people. The available data, however, indicated that PCT manifests shortly after exposure to TCDD. Therefore, new cases of PCT due to exposures during the Vietnam war will not occur. Additional information available to the committee responsible for Update 1996 led it to conclude that there was only limited or suggestive evidence of an association, and Update 1998 and Update 2000 did not change that conclusion. Reviews of the studies underlying those findings may be found in the earlier reports.

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Update of the Scientific Literature

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

Synthesis

If PCT was caused by exposure to TCDD, it would appear soon after the exposure and recovery would occur after the exposure ceased. In any case, manifestation of PCT following exposure to TCDD would have been rare. Although it has been seen after exposure to TCDD in industrial settings, Vietnam veterans enrolled in the Ranch Hand study have not been found to have symptoms suggestive of the disorder.

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 PCT.

Biologic Plausibility

PCT has not been replicated in animal studies in response to TCDD, although other porphyrin abnormalities have been reported after exposure to TCDD.

Increased Risk of Disease Among Vietnam Veterans

Given the available data on individual exposures in both Vietnam veterans and study subjects, it is not possible to estimate the risk of PCT in individual Vietnam veterans. However, because PCT is an early response to TCDD, no new cases of PCT due to wartime exposures are expected among Vietnam veterans.

RESPIRATORY DISORDERS

Nonmalignant respiratory disorders comprise acute and chronic lung diseases other than cancer. Acute lung diseases include pneumonia and other lung infections and could be increased in frequency and severity when the normal defense mechanisms of the lower respiratory tract are compromised. Chronic nonmalignant respiratory disorders generally take two forms: airways disease

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

and parenchymal disease. Airways disease is a general term for disorders characterized by obstruction of the flow of air out of the lungs and includes chronic obstructive pulmonary disease (COPD), emphysema, asthma, and chronic bronchitis. Parenchymal disease, or interstitial disease, is a general term for numerous disorders that cause inflammation and scarring of the deep lung tissue, including air sacs and supporting structures. Those disorders are less common than airways disease and are characterized by reductions in lung capacity, but they often include a component of airways obstruction. In addition, some severe chronic lung disorders, such as cystic fibrosis, are hereditary. Because Vietnam veterans underwent health screenings, no severe hereditary chronic lung disorders are expected in this population.

The major risk factor for both acute and chronic respiratory disorders is cigarette-smoking. Although cigarette-smoking is not associated with every disease of the lungs, it is the major cause of airways disorders, contributes to some interstitial disease, and compromises host defenses in such a way that people who smoke are generally more susceptible to some types of pneumonia. Cigarette-smoking also makes almost every respiratory disorder more severe and symptomatic than would otherwise be the case. The frequency of cigarette-smoking as a habit varies with occupation, socioeconomic status, and generation. For those reasons, cigarette-smoking is a major confounding factor in interpreting the literature on risk factors for respiratory disease other than smoking. Vietnam veterans are reported to smoke more heavily than non-Vietnam veterans (McKinney et al., 1997).

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

The committee responsible for VAO found there to be 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 the respiratory disorders specified above. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change that finding. Update 2000 drew attention to findings from the Seveso cohort that suggested a higher mortality from nonmalignant respiratory disorders among those, particularly males, more heavily exposed to TCDD. Those findings were not replicated in several other relevant studies, although one showed an increase that did not attain statistical significance. The committee for Update 2000 concluded that although new evidence suggested an increased risk of nonmalignant respiratory disorders, particularly COPD, among people exposed to TCDD, the observation is tentative and the information insufficient to determine whether an association exists between the exposures of interest and respiratory disorders.

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Update of the Scientific Literature

In the one occupational study published since Update 2000, 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 nonmalignant respiratory disorders (Burns et al., 2001). That fewer deaths were observed in all exposure categories compared to the national rates and latency groups studied than expected suggests a strong healthy-worker effect.

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

Synthesis

No new studies provide evidence of a direct risk of nonmalignant respiratory disorders in adults since those reviewed in Update 2000 (IOM, 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 between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and nonmalignant acute or chronic respiratory disorders.

Biologic Plausibility

Lung tissue has been found to have high concentrations of the aryl hydrocarbon receptor (AhR), which mediates the effects of TCDD, and recent data have shown that both cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1A2 (CYP1A2) are expressed in lung biopsy specimens from human subjects. It is biologically plausible that exposure to TCDD may result in acute and chronic lung disorders. Furthermore, it is noted that a major risk factor for these disorders is cigarette-smoking. These cytochrome P450 (CYP) enzymes are responsible, in part, for the activation of such chemicals as those found in tobacco smoke (which also contains AhR ligands) to more-toxic intermediates, so it is also biologically plausible that exposure to TCDD may synergize the toxic effects of a variety of other chemicals to which human lung tissue is exposed.

Suggested Citation:"9. Other Health Effects." 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 nonmalignant respiratory disorders in Vietnam veterans to draw a specific conclusion as to whether Vietnam veterans are at increased risk for those disorders.

IMMUNE SYSTEM DISORDERS

The immune system is responsible for protecting the body against invasion by infectious microorganisms and the development of cancer. The two major immune responses are the innate and the adaptive responses. The innate response is more general; the adaptive response is specific and confers immunologic memory. The principle reactive cells of the immune system are the leukocytes (white blood cells), which include neutrophils, eosinophils, lymphocytes, blood monocytes, and macrophages, which are widely distributed in tissues and include histiocytes, dendritic cells, and antigen-presenting cells. The major lymphatic organs are the lymph nodes, spleen, thymus, palatine tonsil, and Peyer's patches. The immune response consists of a complex and sophisticated network of events involving cells and their secretory products, and optimal function of the immune system results from a delicate balance in cellular interactions and responses. Disruption of those events can result in a compromised immune response, with the response either suppressed or enhanced.

A suppressed immune response can result in reduced resistance to infections or neoplasia. The immune system has considerable reserve, so the degree of suppression necessary for increased susceptibility to disease can depend heavily on factors involving the invading microorganism, the host response to the invasion, and the ability of the microorganism or cancer cells to escape immunosurveillance. If they are sufficiently weakened, impairment of host defenses can result in severe and recurrent infections with opportunistic microorganisms or can predispose the host to neoplasia.

The immune response can also be hyperstimulated or unable to curtail a normal immune reaction, and this can result in contact hypersensitivity, allergy (atopy and asthma), and autoimmune disease. Many of those conditions are not life-threatening, but asthma and autoimmune disease can result in death. Asthma usually occurs when foreign antigen-specific immunoglobulins bind to the surface of mast cells releasing histamine which causes constriction of pulmonary airways. Autoimmune disease is the pathologic consequence of an immune response to autologous (self) antigens in which the immune system attacks its own body' s cells, tissues, or organs.

This section presents information on the effects of herbicide and TCDD exposure on the human immune system and susceptibility to disease other than neoplasia. Information regarding herbicide exposure and neoplasia in humans is presented in Chapter 6.

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
Summary of VAO and Update 1996, Update 1998, and Update 2000

The committees responsible for VAO, Update 1996, Update 1998, and Update 2000, 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 immune system disorders. Reviews of the studies underlying those findings are in the previous reports (IOM, 1994, 1996, 1999, 2001).

Update of the Scientific Literature

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

Synthesis

TCDD is a known immunosuppressant in laboratory animals. In fact, it is one of the most potent immunotoxicants known to exist in the environment. Therefore, it would be expected to be immunosuppressive in humans. To date, however, the immune effects described in humans exposed to TCDD have been marginal and highly inconsistent, ranging from increasing the immune response to decreasing the immune response to having no effect. Furthermore, no pattern of increased infectious disease has developed in people exposed to high concentrations of TCDD or other herbicides that were used in Vietnam. Investigations in humans in the last several years, including several recent studies reviewed in Update 2000 that looked at numerous immune measures in workers exposed to TCDD and in veterans of Operation Ranch Hand, have failed to demonstrate a consistent positive association between TCDD exposure (in utero, perinatally, or postnatally) and immune effects. No studies available in humans during the last 2 years change those findings. As mentioned in Update 2000, many of the immune measures assessed in humans are related to nonfunctional end points often considered biomarkers. The consistent immunosuppressive effects observed in laboratory animals that have been exposed to TCDD have not been confirmed in humans.

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:"9. Other Health Effects." 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 immune suppression or autoimmunity.

Biologic Plausibility

A large number of studies in animals indicate that one of the organ systems most sensitive to TCDD toxicity is the immune system; the effects are species-specific and strain-specific. TCDD can alter the number and function of immune cells in some animals. Studies of the effect of exposure to TCDD on immune response in the mouse after infection with influenza A demonstrate that the humoral and cell-mediated response is suppressed and cytolytic activity is preserved. Chapter 3 discusses recent toxicologic studies that make up the biologic basis of an association between exposure to TCDD or herbicides and toxic end points.

Increased Risk of Disease Among Vietnam Veterans

No evidence is available to associate defects in the immune response with exposure to the herbicides or TCDD.

DIABETES

Primary diabetes (that is, diabetes that is not secondary to another known disease or condition, such as pancreatitis or pancreatic surgery) is a heterogeneous metabolic disorder characterized by hyperglycemia and quantitative or qualitative deficiency of insulin action (Orchard et al., 1992). Two main types have been recognized: insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). In June 1997, the American Diabetes Association (ADA, 1997) suggested a revised classification, with IDDM being termed type 1 and NIDDM termed type 2. This new terminology is used in the remainder of this review except when the older diagnostic criteria are appropriate.

Type 2 diabetes accounts for about 90% of cases of primary diabetes. Onset rarely occurs before 30 years of age, but incidence increases steadily with age thereafter. It is generally accepted that the main factors for increased risk of type 2 diabetes include age (older people are at higher risk), obesity, central fat deposition, a history of gestational diabetes (if female), physical inactivity, ethnicity (for example, prevalence is greater in blacks and Hispanics), and, perhaps most important, a family history of type 2 diabetes. The relative contributions of those features, however, are controversial.

The etiology of type 2 diabetes is unclear, but three major components have been proposed: peripheral insulin resistance (thought by many to be primary) in target tissues (such as muscle, adipose tissue, and liver); a defect in beta-cell

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

insulin secretion, and hepatic glucose overproduction. Defects at many intracellular sites could account for the impaired insulin action and secretion in type 2 diabetes (Kruszynska and Olefsky, 1996). The insulin receptor itself, insulin-receptor tyrosine kinase activity, insulin-receptor substrate proteins, insulin-regulated glucose transporters, enhanced protein kinase C activity, TNF-α, rad (ras associated with diabetes), and prohormone convertase 1 (PC1) have all been proposed as potential mediators of insulin resistance. Impaired insulin secretion has been linked to hyperglycemia itself, to abnormalities of glucokinase and hexokinase activity, and to abnormal fatty-acid metabolism. Finally, an increasing number of “other” types of diabetes have been described that are linked to specific genetic mutations, such as maturity-onset diabetes of youth, which results from a variety of mutations of the beta-cell glucokinase gene.

Pathogenetic diversity and diagnostic uncertainty are two of the more important problems associated with the epidemiologic study of diabetes. Given the multiple likely pathogenetic mechanisms leading to diabetes—which include diverse genetic susceptibilities (ranging from autoimmunity to obesity) and a variety of potential environmental and health-behavior factors (such as viruses, nutrition, and activity) —it is probable that many agents or behaviors contribute to diabetes risk, especially in genetically susceptible people. The multiple mechanisms may also lead to heterogeneous responses to various exposures. Because up to half the affected diabetic population is undiagnosed, the potential for ascertainment bias is high (more intensively followed groups or those with more frequent health care contact are more likely to be diagnosed), and the need for formal standardized testing (to detect nondiagnosed cases) is great. Furthermore, it may be difficult to differentiate cases that develop during early to middle age (20 –44 years) into type 1 or type 2.

Summary of Previous IOM Reports

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 diabetes. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change that finding.

In 1999, in response to a request from the Department of Veterans Affairs (VA), IOM called together a committee to conduct an interim review of the scientific evidence regarding type 2 diabetes. That review, which focused on information published since the deliberations of the Update 1998 committee, resulted in the report Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000). The committee responsible for that report found that there was limited or suggestive evidence of an association between type 2 diabetes and exposure to at least one of the chemicals of interest (2,4-D,

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid). The committee responsible for Update 2000 upheld the finding of the Herbicide/Dioxin Exposure and Type 2 Diabetes committee. Reviews of the studies underlying those findings can be found in the earlier reports (see Table 9-1 for a summary).

Update of the Scientific Literature

Relatively little new information has been reported on the association between TCDD and the risk of diabetes. The potential link between TCDD and diabetes was mentioned briefly in two general review articles on the overall health effects of TCDD (Kogevinas, 2001; Sweeney and Mocarelli, 2000). A more specific review on environmental risk factors for diabetes included a detailed overview of the literature on 2,3,7,8-TCDD (Longnecker and Daniels, 2001); this review shared the conclusion of Update 2000 that the findings on TCDD and the etiology of diabetes were somewhat suggestive but still inconclusive.

Occupational Studies

A cross-sectional study was conducted in 1998 to assess the health status of workers exposed to high concentrations of polychlorinated dibenzo-p-dioxins (PCDD) at the Bika Center municipal waste incinerator in Japan (Kitamura et al., 2000). Data were collected on 92 of the 146 people employed at Bika Center since it was opened in 1988. Eight workers reported a history of diabetes, and a logistic-regression model (including age and body mass index) was used to assess the association between quartiles of PCDD and the prevalence of diabetes. The coefficients for the model were not shown; the authors indicated in the text that none of the ORs for diabetes in relation to PCDD were statistically significant.

In another study, the association between TCDD and diabetes was re-examined in a combined analysis of data from the Ranch Hand study of Vietnam veterans and a National Institute for Occupational Safety and Health (NIOSH) study of TCDD-exposed workers at chemical plants in New Jersey and Missouri (Steenland et al, 2001). The results of those studies had been reported separately in Update 1998 (Henriksen et al., 1997) and Update 2000 (Calvert et al., 1999), respectively. The combined analysis was conducted in an attempt to improve the precision of the estimates and to address differences between the studies in definition of exposure and outcome and in adjustment for potential confounders.

The NIOSH study sample of 541 was reduced by 55 subjects (31 women, 16 men from the neighborhood comparison group with TCDD above 10 ppt, and eight exposed men with missing TCDD data) to match the criteria in the Ranch Hand sample. The fasting-glucose component of the definition of diabetes in the NIOSH sample was also modified (from fasting glucose of 140 mg/dL to 126 mg/ dL) to approximate the Ranch Hand definition more closely. The Ranch Hand

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 9-1 Selected Epidemiologic Studies—Diabetes

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

OCCUPATIONAL

New Studies

Kitamura et al., 2000

Workers exposed to PCDD at a municipal waste incinerator

8

Not statistically significant*

Steenland et al., 2001

Highly exposed industrial cohorts (N = 5,132)

   
 

Exposed vs nonexposed for Ranch Hands

147

1.2 (0.9–1.5)

 

Exposed vs nonexposed for NIOSH

28

1.2 (0.7–2.3)

Studies Reviewed in Update 2000

Calvert et al., 1999

Workers exposed to 2,4,5-T and derivatives

 

All workers

26

1.5 (0.8–2.9)

 

Serum TCDD <20 pg/g (ng/kg) of lipid

7

2.1 (0.8–5.8)

 

Serum 20 <TCDD <75 pg/g (ng/kg) of lipid

6

1.5 (0.5–4.3)

 

Serum 75 < TCDD <238 pg/g (ng/kg) of lipid

3

0.7 (0.2–2.6)

 

Serum 238 <TCDD <3,400 pg/g (ng/kg) of lipid

10

2.0 (0.8–4.9)

Steenland et al., 1999

Highly exposed industrial cohorts (N = 5,132)

 

Diabetes as underlying cause

26

1.2 (0.8–1.7)

 

Diabetes among multiple causes

89

1.1 (0.9–1.3)

 

Chloracne subcohort (N = 608)

4

1.1 (0.3–2.7)

Vena et al., 1998

Exposed production workers and sprayers in 12 countriesa

33

2.3 (0.5–9.5)

Steenland et al., 1992b

Dioxin-exposed workers—mortality rates

 

Diabetes as underlying cause

16

1.1 (0.6–1.8)

 

Diabetes among multiple causes

58

1.1 (0.8–1.4)

Studies Reviewed in Update 1998

Sweeney et al., 1997/98

NIOSH production workers

Ramlow et al., 1996

Pentachlorophenol production workers

4

SMR = 1.2 (0.3–3.0)

Studies Reviewed in Update 1996

Ott et al., 1994

Trichlorophenol production workers

 

p = 0.06

Von Benner et al., 1994

West German chemical production workers

N/A

N/A

Zober et al., 1994

BASF production workers

10

0.5 (0.2–1.0)

Studies Reviewed in VAO

Sweeney et al., 1992

NIOSH production workers

26

1.6 (0.9–3.0)

Henneberger et al., 1989

Paper and pulp workers

9

1.4 (0.7–2.7)

Cook et al., 1987

Production workers

4

SMR = 0.7 (0.2–1.9)

Moses et al., 1984

2,4,5-T and TCP production workers

22 (chloracne)

2.3 (1.1–4.8)

May, 1982

TCP production workers

2

*

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Pazderova-Vejlupkova et al., 1981

2,4,5-T and TCP production workers

11

*

ENVIRONMENTAL

New Study

Masley et al., 2000

Population based survey in Saskatchewan

28

*

Studies Reviewed in Update 2000

Bertazzi et al., 2001

Seveso residents—20-year follow-up

 

Zone A females

2

1.3 (0.3–5.1)

 

Zone B males

6

0.9 (0.4–2.0)

 

Zone B females

18

1.8 (1.1–2.9)

Cranmer et al., 2000

Non-diabetic residents near the Vertac/Hercules Superfund site OR are for high insulin subjects with TCDD >15ppt (7 subjects) compared to persons with TCDD <15ppt (62 subjects)

   
 

Fasting (high insulin level, >4.5 µIU/ml)

3

8.5 (1.5–49.4)

 

30-minute insulin (high insulin level, >177 µIU/ml)

3

7 (1.3–39.0)

 

60-minute insulin (high insulin level, >228 µIU/ml)

4

12 (2.2–70.1)

 

120-minute insulin (high insulin level, >97.7 µIU/ml)

6

56 (5.7–556)

Bertazzi et al., 1998

Seveso residents—15-year follow-up

 

Zone A females

2

1.8 (0.4–7.0)

 

Zone B males

6

1.2 (0.5–2.7)

 

Zone B females

13

1.8 (1.0–3.0)

Pesatori et al., 1998

Seveso residents—15-year follow-up

 

Zone A females

2

1.8 (0.4–7.3)

 

Zone B males

6

1.3 (0.6–2.9)

 

Zone B females

13

1.9 (1.1–3.2)

 

Zone R males

37

1.1 (0.8–1.6)

 

Zone R females

74

1.2 (1.0–1.6)

VIETNAM VETERANS

Studies Reviewed in Update 2000

AFHS, 2000

Air Force Ranch Hand veterans and comparisons

(Numerous analyses discussed in text)

Longnecker and Michalek, 2000

Ranch Hand unexposed referents only, OR by quartile and serum dioxin concentration

   
 

Quartile 1: <2.8 ng/kg (pg/g)

26

1.00—referent

 

Quartile 2: 2.8–<4.0 ng/kg

25

0.9 (0.5–1.7)c

 

Quartile 3: 4.0–<5.2 ng/kg

57

1.8 (1.0–3.0)c

 

Quartile 4: ≥5.2 ng/kg

61

1.6 (0.9–2.7)c

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

CDVA, 1998a

Australian Vietnam veterans—male

2,391 reportedb (6% of respondents)

1,780 expected (1,558–2,003)

CDVA, 1998b

Australian Vietnam veterans— female

5 reportedd (2% of respondents)

10 expected (9–11)

Henriksen et al., 1997

Ranch Hands—high-exposure group

 

Glucose abnormalities

60

1.4 (1.1–1.8)

 

Diabetes prevalence

57

1.5 (1.2–2.0)

 

Use of oral medications for diabetes

19

2.3 (1.3–3.9)

 

Serum insulin abnormalities

18

3.4 (1.9–6.1)

Studies reviewed in Update 1998

Henriksen et al., 1997

Ranch Hands

 

High-exposure category

57

1.5 (1.2–2.0)

 

All Ranch Hands

146

1.1 (0.9–1.4)

O'Toole et al., 1996

Australian Vietnam veterans

12

1.6 (0.4–2.7)d

Studies Reviewed in VAO

AFHS, 1991

Air Force Ranch Hand veterans

85

p = 0.001,

p = 0.028

AFHS, 1984

Air Force Ranch Hand veterans

158

p = 0.234

a May include some of the same subjects covered in the NIOSH cohorts addressed in the other references cited in the occupational-cohorts category.

b Not discussed in this report, but discussed as new studies in Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000).

c Adjusted for age, race, body mass index, waist size, family history of diabetes, body mass index at time dioxin was measured, serum triglycerides, and military occupation.

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 diabetes?”

ABBREVIATIONS: N/A, not applicable; TCP, trichlorophenol, HDL, high-density lipoprotein; OR, odds ratio; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid.

sample and definition of outcome were essentially unchanged. Accordingly, there was little change in the association between the dichotomous definition of exposure and diabetes in the Ranch Hand sample (OR = 1.18 in the new analysis and 1.11 in the original analysis). The OR for the sample association in the NIOSH data, however, was reduced from 1.49 to 1.22. The later analysis of a dose-response relationship between diabetes and TCDD at the time of examination was based on quartiles from the distribution of TCDD for both samples combined. The highest quartile (TCDD concentration ≥ 78 ppt) was associated with a markedly increased risk of diabetes in Ranch Hand subjects (OR = 3.2, 95% CI 1.8–5.7). There was no evidence of a dose-response relationship in the data from

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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the NIOSH sample and no excess risk for the highest quartile (OR = 0.84, 95% CI: 0.4–1.8) in this analysis. A similar pattern of findings was obtained in the analysis of back-extrapolated TCDD concentrations.

Environmental Studies

Masley et al. (2000) administered a population-based survey in 1995 in a rural area of southern Saskatchewan to investigate the effects of environmental and agricultural exposure on the health of rural populations. Data were collected from 369 farming households (727 adult respondents) and 163 nonfarming households (262 adult respondents). Health concerns in the survey included self-reported diagnosis of diabetes. A history of diabetes was reported by only 28 people and was not related to farm vs nonfarm status. No information was presented on the validity of this measure of diabetes.

Vietnam-Veteran Studies

No relevant Vietnam-veteran studies have been published since Update 2000 (IOM, 2001) other than the combined NIOSH and Ranch Hand analysis (Steenland et al., 2001) discussed above.

Synthesis

New publications on diabetes since Update 2000 include two cross-sectional studies and a joint analysis of two previously published studies. The cross-sectional studies by Kitamura et al. (2000) and Masley et al. (2000) include weak and indirect tests of the association between herbicide exposure and diabetes. The study by Kitamura et al. (2000) is based on 92 workers at a municipal waste incinerator. There is no comparison group from a nonexposed worksite. The exposure in this study is PCDD concentration in the blood, with no separate analysis of TCDD in relation to diabetes or other health outcomes. Both cross-sectional studies rely on self-report for the measurement of diabetes, and neither study presents data on the validation of the self-reported diagnosis. The study sample of Masley et al. (2000) is larger (989 adult respondents), but the small number of cases (28) suggests an insensitive measure of diabetes. In addition, the exposure in this study is a crude comparison of living in a farming vs a nonfarming household. Given the limitations of measurement in these studies, the null findings with respect to diabetes cannot be interpreted as strong evidence of no association.

The modest relationship between plasma TCDD and diabetes in the Ranch Hand veterans and the chemical-plant workers of New Jersey and Missouri has already been summarized in Update 1998 and Update 2000, respectively. In the new joint analysis of the data, the association between diabetes and TCDD in the

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

chemical-plant workers is essentially eliminated, precluding a pooled analysis of the two study populations. Steenland et al. (2001) do not formally analyze the reasons for the change in the results in the chemical-plant workers. The explanation may include the change in the definition of diabetes (suggesting that border-line cases were more common in the nonexposed) or the selective impact of removal of the 55 subjects from the analysis (perhaps a disproportionate number of exposed cases) to match the eligibility criteria of the Ranch Hand study. It should be noted that the initial analysis of the chemical-plant workers (Calvert et al., 1999) is not invalid, but the joint analysis reveals that the results were not robust.

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 diabetes.

Biologic Plausibility

Evaluating the potential of TCDD to induce clinical diabetes in animals has been impaired by the lack of an appropriate animal model of type 2 diabetes. However, TCDD effects on triglycerides and high-density lipoproteins, glucose transport, protein kinase C, and other lipoproteins in animals suggest that TCDD could stimulate development of diabetes. Several studies have demonstrated that TCDD treatment decreases glucose transport and alters lipoprotein degradation in adipose-tissue cell lines. That might constitute a physiologic mechanism for linking TCDD exposure to diabetes. Nevertheless, until appropriate animal models are developed to show the etiology and pathogenesis of diabetes, the ability of TCDD to induce diabetes in animals will remain elusive.

Increased Risk of Disease Among Vietnam Veterans

Available data allow for the possibility of an increased risk of type 2 diabetes in Vietnam veterans. It must be noted, however, that studies indicate that the increased risk, if any, posed by herbicide or TCDD exposure appears to be small. The known predictors of diabetes risk—family history, physical inactivity, and obesity—continue to greatly outweigh any suggested increased risk posed by wartime exposure to herbicides.

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

LIPID AND LIPOPROTEIN DISORDERS

Plasma lipid (notably cholesterol) concentrations have been shown to predict cardiovascular disease and are considered fundamental to the underlying atherosclerotic process (Kuller and Orchard, 1988). The two major types of lipids, cholesterol and triglycerides, are carried in the blood attached to proteins to form lipoproteins, which are classified according to their density. Very-low-density lipoprotein (VLDL—the major “triglyceride” particle) is produced in the liver and is progressively catabolized (hydrolyzed) mainly by an insulin-mediated enzyme (lipoprotein lipase) to form intermediate-density lipoprotein (IDL) or VLDL remnants. Most of the VLDL remnants are rapidly cleared by the liver LDL receptors (types B and E); the rest form low-density lipoprotein (LDL), the major “bad” cholesterol particle. This LDL is cleared by LDL receptors in the liver and other tissues. The “good” cholesterol particle, high-density lipoprotein (HDL), is produced in the small intestine and the liver and also results from the catabolism of VLDL. LDL is thought to be involved in the delivery of cholesterol to the tissues, whereas HDL is involved in “reverse” transport and facilitates the return of cholesterol to the liver for biliary excretion (LaRosa, 1990).

Disorders of lipoprotein metabolism usually result from overproduction or decreased clearance of lipoproteins or both. Common examples are hypercholes-terolemia, which may be familial (due to an LDL receptor genetic defect) or polygenic (due to multiple minor genetic susceptibilities); familial hypertriglyc-eridemia (sometimes linked to susceptibility to diabetes); and mixed hyperlipid-emias in which both cholesterol and triglycerides are elevated. The mixed hyperlipidemias group includes familial combined hyperlipidemia, which is thought by many to result from hepatic overproduction of VLDL and apoprotein B, and type III dyslipidemia, which involves defective clearance of IDL–VLDL remnants and a buildup of those atherogenic particles. Although the bulk of blood lipid concentration is genetically determined, diet, activity, and other factors (concurrent illness, drugs, age, gender, hormones, and so on) do have major effects. In particular, the saturated-fat content of the diet might raise LDL concentrations via decreased LDL-receptor activity, whereas obesity and a high-carbohydrate diet may increase VLDL triglycerides and possibly are linked to insulin resistance and reduced lipoprotein lipase activity. Intercurrent illness may increase the triglyceride concentration and decrease the cholesterol concentration. Diabetes is also associated with increased triglycerides and decreased HDL cholesterol, whereas other diseases (such as thyroid and renal disorders) often result in hyper-cholesterolemia. It is evident, therefore, that multiple host and environmental factors influence lipid and lipoprotein concentrations and that those influences must be accounted for before the effect of a new factor can be assessed (LaRosa, 1990). In the current context, obesity as a primary determinant of both triglyceride and TCDD concentrations has to be fully controlled for in any analysis. Furthermore, the ability of acute or chronic illness to raise triglyceride and glucose concentrations and lower HDL and LDL cholesterol must be recognized.

Suggested Citation:"9. Other Health Effects." 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 exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and lipid and lipoprotein disorders. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding. Reviews of the studies underlying the finding may be found in the earlier reports (see Table 9-2 for a summary).

Update of the Scientific Literature

An occupational study by Kitamura et al. (2000) of 92 workers at a municipal waste incinerator in Japan included measures of serum PCDD and self-reported history of a number of diseases and health-related conditions. Eight of the 92 subjects reported having been diagnosed with high cholesterol. The sample was divided into quartiles of PCDD concentration for the purpose of analysis, and a logistic-regression model (including terms for age and body mass index) was used to assess the association between PCDD and the prevalence of hyperlipidemia. The authors reported a statistically significant OR for this association (OR = 6.08, p = 0.023), but they did not indicate whether that OR was derived from the contrast of specific quartiles or from a single ordinal variable.

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

Synthesis

Only one new study on lipids is reviewed in this volume, and its contribution to the literature is limited for a number of reasons. The study is cross-sectional, so there is no opportunity to establish that the exposure clearly preceded the outcome. The sample is small, the exposure is an aggregate measure of PCDD (with TCDD as only one component), and the measure of high cholesterol is based on self-report with no additional information on its validity. Because of those limitations, the study does not change the inconclusive status of the epidemiologic evidence on the relationship between exposure to herbicides and high serum lipids.

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:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 9-2 Selected Epidemiologic Studies—Lipid and Lipoprotein Disorders

Reference

Study Population

Exposed Cases

Estimated (95% CI) Relative Risk

OCCUPATIONAL

New Studies

Kitamura et al., 2000

Workers exposed to PCDD at a municipal waste incinerator— elevated cholesterol

8

6.1, p = 0.02

Studies Reviewed in Update 1998

Calvert et al., 1996

Workers (N = 273) exposed to 2,4,5-T and derivatives vs. matched referents (N = 259)

   
 

OR for abnormal total cholesterol concentration

   
 

Overall

95

1.1 (0.8–1.6)

 

High TCDD

18

1.0 (0.5–1.7)

 

OR for abnormal HDL cholesterol concentration

   
 

Overall

46

1.2 (0.7–2.1)

 

High TCDD

15

2.2 (1.1–4.7)

 

OR for abnormal mean total to HDL cholesterol ratio

   
 

Overall

131

1.1 (0.8–1.6)

 

High TCDD

36

1.5 (0.8–2.7)

 

OR for abnormal mean triglyceride concentration

   
 

Overall

20

1.0 (0.5–2.0)

 

High TCDD

7

1.7 (0.6–4.6)

Ott and Zober, 1996a

Production workers

42

 
 

Cholesterol

 

NSE

 

Triglycerides

 

NSE

 

HDL cholesterol

 

Increased; p = 0.05

Studies Reviewed in VAO

Martin, 1984a

Production workers

 

Workers with some exposure

53

 
 

Cholesterol

 

Increased; p < 0.005

 

Triglycerides

 

Increased; p < 0.005

 

HDL cholesterol

 

NSE

 

Workers with chloracne

39

 
 

Cholesterol

 

Increased; p < 0.05

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Cases

Estimated (95% CI) Relative Risk

 

Triglycerides

 

Increased; p < 0.01

 

HDL cholesterol

 

NSE

Moses et al., 1984b

TCP and 2,4,5-T production workers

118

 
 

Cholesterol

 

NSE

 

Triglycerides

 

NSE

Suskind and Hertzberg, 1984a

TCP production workers

204

 
 

Cholesterol

 

NSE

 

Triglycerides

 

NSE

 

HDL cholesterol

 

NSE

May, 1982a

TCP production workers

94

 
 

Cholesterol

 

NSE

 

Triglycerides

 

NSE

Pazderova-Vejlupkova et al., 1981a

TCP and 2,4,5-T production workers

55

 
 

Cholesterol

 

NSE

 

Triglycerides

 

Increased VLDL; p = 0.01

ENVIRONMENTAL

Studies Reviewed in VAO

Assennato et al., 1989a

Adults exposed near Seveso Zone A subjects who developed chloracne

193

 
 

Cholesterol

 

NSE

 

Triglycerides

 

NSE

Mocarelli et al., 1986a

Children exposed near Seveso

63

 
 

Cholesterol

 

NSE

 

Triglycerides

 

NSE

VIETNAM VETERANS

Studies Reviewed in Update 2000

AFHS, 2000

Air Force Ranch Hand veterans

858

 
 

Cholesterol

 

NSE

 

Triglycerides

 

NSE

Studies reviewed in Update 1998

AFHS, 1996c

Longitudinal analysis (1992 examination data)

884

 
 

Cholesterol

 

NSE (cholesterol: HDL ratio)

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

 

Triglycerides

 

NSE

 

HDL cholesterol

 

NSE (cholesterol: HDL ratio)

O'Toole et al., 1996d

Australian Vietnam veterans

20

 
 

Cholesterol

 

3.0 (1.3–4.7)

Studies reviewed in VAO

AFHS, 1991e

Serum dioxin analysis (1987 examination data)

283–304 f

 
 

Cholesterol

 

p = 0.175

 

Triglycerides

 

p < 0.001g

 

HDL cholesterol

 

p < 0.001

AFHS, 1990h

Original exposure group analysis (1987 examination data)

8–142f

 
 

Cholesterol

 

1.2 (0.9–1.5)

 

Triglycerides

 

1.3 (0.9–1.8)

 

HDL Cholesterol

 

1.0 (0.4–2.4)

AFHS, 1984i;

Wolfe et al., 1990i

Air Force Ranch Hand veterans to herbicide spraying (1982 data)

1,027

 
 

Cholesterol

 

NSE

 

Triglycerides

 

NSE

 

HDL cholesterol

 

NSE

ap-values comparing means with controls. Univariate analysis.

bp-values comparing means in production workers with later chloracne with those without.

c Comparing change over time between exposed and comparison groups.

d Compared with Australian population.

e Comparing mean dioxin across lipid groups.

f Number of exposed Ranch Hand veterans with “high” lipid values.

g Continuous analysis.

h Model 1, Ranch Hands vs comparisons–adjusted.

i Comparing means.

NOTE: Estimated risk and 95% CI reported unless p-values are specified.

ABBREVIATIONS: HDL, high-density lipoprotein; NSE, no significant effect; OR, odds ratio; PCDD, polychlorinated dibenzodioxin; TCP, trichlorophenol; VLDL, very-low density lipoprotein.

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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 lipid and lipoprotein disorders.

Biologic Plausibility

Although animal studies suggest potential mechanisms whereby TCDD may cause lipid disturbances, human data (such as those from lipoprotein kinetic studies) are still needed to determine whether and how TCDD-exposed subjects have altered lipoprotein metabolism. Chapter 3 discusses recent animal toxicity studies that could contribute to a biologic basis of an association between exposure to TCDD and herbicides and toxicity end points, and a general summary of the biologic basis of various end points is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

As discussed in Update 2000 (IOM, 2001), the most recent Air Force Health Study (AFHS, 2000) reports an inconsistent association between TCDD exposure and lipid abnormalities in US veterans of Vietnam. The data are insufficient to permit a conclusion about whether they are at increased risk for these disorders.

GASTROINTESTINAL AND DIGESTIVE DISEASE, INCLUDING LIVER TOXICITY

This section covers a variety of conditions encompassed by ICD-9 codes 520–579. Conditions in this category include diseases of the esophagus, stomach, intestines, rectum, liver, and pancreas. Additional details on peptic ulcer and liver disease—the two conditions most often discussed in the literature reviewed—are provided below. The symptoms and signs of gastrointestinal disease and liver toxicity are highly varied and often vague.

The essential function of the gastrointestinal tract is to absorb nutrients and eliminate waste products. This complex task involves numerous chemical and molecular interactions on the mucosal surface, as well as complex local and distant neural and endocrine factors. One of the most common conditions affecting the gastrointestinal tract is motility disorder, which may be present in up to 15% of adults. The most convenient way of categorizing diseases that affect the gastrointestinal system is by the affected anatomic segment. The conditions include esophageal disorders that predominantly affect swallowing, gastric disorders related to acid secretion, and conditions affecting the small and large intestine and reflected in alterations in nutrition, mucosal integrity, and motility. Some systemic disorders can also affect the gastrointestinal system (for example inflammatory, vascular, infectious, and neoplastic conditions).

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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Peptic Ulcer Disease

Peptic ulcer disease refers to ulcerative disorders of the gastrointestinal tract that are caused by the action of acid and pepsin on the stomach duodenal mucosa. Peptic ulcer disease is characterized as gastric ulcer or duodenal ulcer, depending on the anatomic site of origin. Peptic ulcer disease occurs when the corrosive action of gastric acid and pepsin exceeds the normal mucosal defense mechanisms that protect against ulceration. About 10% of the population has clinical evidence of duodenal ulcer during their lifetimes, and a similar percentage are affected by gastric ulcer. The peak incidence for duodenal ulcer occurs in the fifth decade of life, and the peak for gastric ulcer occurs about 10 years later. The natural history of duodenal ulcer is one of spontaneous remission (healing) and recurrences. It is estimated that 60% of healed duodenal ulcers recur in the first year and 80–90% within 2 years.

Increasing evidence indicates that the bacterium Helicobacter pylori (H. pylori) may be closely linked to peptic ulcer disease (both duodenal and gastric). This bacterium colonizes the gastric mucosa in 95–100% of patients with duodenal ulcer and 75–80% of patients with gastric ulcer. Healthy subjects in the United States under 30 years old have gastric colonization rates of about 10%. Over the age of 60 years, colonization rates exceed 60%. Colonization alone, however, is not sufficient for the development of ulcer disease; only 15–20% of subjects with H. pylori colonization will develop ulcer disease in their lifetimes.

There are other risk factors for peptic ulcer disease. Genetic predisposition appears to be important; first-degree relatives of duodenal ulcer patients have about 3 times the general population's risk of developing duodenal ulcer. Some blood groups are associated with increased risk of duodenal ulcer, and HLA-B5 antigen appears to be increased among white males with duodenal ulcer. Cigarette-smoking has also been linked to duodenal ulcer prevalence and mortality. Finally, psychologic factors, particularly chronic anxiety and psychologic stress, may act to exacerbate duodenal ulcer disease.

Liver Disease

Blood tests reflecting liver function are the mainstay of diagnosis of liver disease. Increases in serum bilirubin and in the serum activity of some hepatic enzymes—including aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and γ-glutamyltransferase (GGT)—are commonly noted in liver disorders. The relative sensitivity and specificity of these enzymes for diagnosing liver disease vary, and several different tests may be required for diagnosis. The only regularly reported abnormality in liver function associated with TCDD exposure in humans is an increase in GGT. Estimated serum activity of this enzyme constitutes a sensitive indicator of a variety of conditions, including alcohol and drug hepatotoxicity, infiltrative lesions of the liver, parenchymal liver disease,

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

and biliary tract obstruction. Increases are noted after many chemical and drug exposures that are not followed by evidence of liver injury. The confounding effects of alcohol ingestion (often associated with increased GGT) make interpretation of changes in GGT in exposed people difficult (Calvert et al., 1992). Moreover, an increase in GGT may be considered a normal biologic adaptation to chemical, drug, or hormone exposure.

Cirrhosis of the liver is the most commonly reported liver disease in epidemiologic studies of herbicide or TCDD exposure. Pathologically, cirrhosis reflects irreversible chronic injury of the liver, with extensive scarring and resulting loss of liver function. Clinical symptoms and signs include jaundice, edema, abnormalities in blood clotting, and metabolic disturbances. Cirrhosis may lead to portal hypertension with associated gastroesophageal varices, enlarged spleen, abdominal swelling due to ascites, and ultimately hepatic encephalopathy, which may progress to coma. It is generally not possible to distinguish the various causes of cirrhosis by the clinical signs and symptoms or pathologic characteristics. The most common cause of cirrhosis in North America and many parts of Western Europe and South America is excessive alcohol consumption. Other causes include chronic viral infection (hepatitis B or hepatitis C), a poorly understood condition called primary biliary cirrhosis, chronic right-sided heart failure, and a variety of less common metabolic and drug-related causes.

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 gastrointestinal and digestive disease, including liver toxicity. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding. Reviews of the studies underlying the finding can be found in the earlier reports.

Update of the Scientific Literature
Occupational Studies

Geusau et al. (2001) describe two cases of heavy TCDD intoxication and present a 2-year follow-up, including clinical, biochemical, hematologic, endocrine, and immunologic measures. Patient 1, a 30-year-old woman, presented with chloracne and had the highest TCDD concentration ever recorded in a human (144,000 pg/g of blood fat); and Patient 2, a 27-year-old woman who worked in the same room as Patient 1, had 26,000 pg/g of blood fat. Both women experienced gastrointestinal symptoms, including nausea, vomiting, epigastric pain, and loss of appetite. Those gastrointestinal symptoms lasted about 4 months.

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Liver-function studies during this time were within the normal limits except for one value in Patient 1 of alkaline phosphatase at 1.5 times the upper limit of normal. Apart from the chloracne and gastrointestinal symptoms, few clinical signs or symptoms were observed in the patients in the acute phase of the intoxication.

Environmental Studies

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

Vietnam-Veteran Studies

Michalek et al. (2001) published a report evaluating hepatic abnormalities in Vietnam veterans of Operation Ranch Hand. The authors examined exposure to TCDD and the prevalence of liver disease and hepatomegaly through March 1993 in relation to tests of liver function at the 1992 physical examination. Hepatomegaly among veterans in the high-exposure category was slightly higher than that in nonexposed veterans in the comparison category (adjusted OR = 1.4; 95% CI 0.7–3.1). The prevalence of nonspecific liver disorders (coded as ICD-9 573.0– 573.9) increased across categories of TCDD exposure and among Ranch Hands in the high-exposure category; this prevalence was about 60% greater than in the nonexposed group. The association between GGT and TCDD category is puzzling in that the mean GGT in the high-exposure group was significantly increased among veterans with history of light to moderate drinking. The authors conclude that evidence of clinically significant liver disease was limited to the increase in hepatomegaly. The increased GGT, however, could have been due to confounding.

Synthesis

Evaluation of the effect of herbicide and TCDD exposure on noncancer gastrointestinal ailments is more difficult than evaluation of the effect on some of the other outcomes examined in this report. Clinical experience suggests that medical history and physical examination are undependable diagnostic tools for some of these ailments, so incidence data are more problematic. The strong interdependence between characteristics of a given person (weight and laboratory indexes of hepatic function and health) and body burden of TCDD complicate the already difficult task of assessing association.

The latest AFHS report (Michalek et al., 2001) found an increased risk of other liver disorders among veterans with the highest TCDD concentrations: primarily increased transaminase and other nonspecific liver abnormalities. It is unclear whether the observed association is related to TCDD exposure.

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×
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 gastrointestinal and digestive diseases.

Biologic Plausibility

The liver is a primary target organ of TCDD in animals. Therefore TCDD would be expected to induce liver toxicity in humans at appropriate doses. Direct effects of TCDD and herbicides on other gastrointestinal and digestive diseases have not been seen. Chapter 3 discusses recent toxicologic studies that form the biologic basis of an association between exposure to TCDD or herbicides and toxicity end points.

Increased Risk of Disease Among Vietnam Veterans

The available data on Vietnam Ranch Hand veterans do not permit a conclusion about whether they are at increased risk for gastrointestinal and digestive diseases. There is no evidence that Vietnam veterans are at greatly increased risk for serious liver disease.

CIRCULATORY DISORDERS

This section covers a variety of conditions encompassed by ICD-9 codes 390–459, including hypertension, heart failure, arteriosclerotic heart disease, peripheral vascular disease, and cerebrovascular disease. In morbidity studies, various methods were used to assess the circulatory system, including analysis of symptoms or history, physical examination of the heart and peripheral arteries, Doppler measurements of peripheral pulses, electrocardiography (ECG), and chest radiography. Doppler measurements and physical examination of pulses in the arms and legs are used to detect decreases in pulse strength, which can be caused by thickening and hardening of the arteries. ECG can be used to detect heart conditions and such abnormalities as arrhythmia (abnormal heart rhythm), heart enlargement, and previous heart attack. Chest radiography can be used to assess enlargement of the heart, which can result from heart failure and other heart conditions. Mortality studies attribute cause of death to circulatory disorders with various degrees of diagnostic confirmation.

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

There is growing evidence that exposure to inorganic arsenic is a risk factor for cardiovascular disease, and cacodylic acid (DMA) is a metabolite of inorganic arsenic. As discussed in Chapter 2, 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 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 circulatory disorders. Additional information available to the committees responsible for Update 1996, Update 1998, and Update 2000 did not change that finding. Reviews of the studies underlying the finding can be found in the earlier reports.

Update of the Scientific Literature
Occupational Studies

Burns et al. (2001) conducted a study of mortality in a cohort of 1,517 male workers involved in the manufacture or formulation of 2,4-D at a Dow chemical plant in 1945–1994. Mortality in the study cohort was compared with mortality in all white US males. Standardized mortality ratios (SMRs) were computed separately for assumed incubation periods of 0 and 20 years. For all diseases of the circulatory system (ICDA-8 390–458), the SMR in the absence of an incubation period was 95 (based on 158 deaths, 95% CI 80–111). The assumption of a 20-year incubation led to an SMR of 105 (130 deaths, 95% CI 87–124). The corresponding SMRs for all-cause mortality in this cohort were 90 and 94, respectively.

A cross-sectional study was conducted in 1998 to assess the association between serum PCDD and a variety of health conditions in a sample of workers employed at a municipal waste incinerator in Japan (Kitamura et al., 2000). Fourteen of the 92 workers participating in the study reported a history of hypertension. No information was provided on the date of this diagnosis relative to dates of employment at the plant. The sample was divided by quartile of PCDD concentration, and a logistic-regression model was fitted (with terms for age and body-mass index) to examine the association between PCDD and the prevalence of self-reported hypertension. The coefficients for the categories of PCDD were reported as not statistically significant, but the values of the coefficients and their standard errors were not given.

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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Environmental Studies

Mortality from cardiovascular diseases was examined by Revich et al. (2001) in their study of multiple health outcomes among residents of Chapaevsk, a Russian city with dioxin contamination of the air, soil, and water from a local chemical plant. The authors reported that mortality from cardiovascular diseases in men was 1.14 times greater than the mortality rate for Russia as a whole and that the difference in mortality was especially pronounced in men 30–49 years old. The rates were also elevated compared with the Samara region in general. However, they also noted that trends in mortality were directly related to trends in unemployment; this suggests the simultaneous effects of other aspects of the environment in the area.

A survey conducted in a rural area of southern Saskatchewan was administered to 727 adult residents of farming households and 262 residents of nonfarming households (Masley et al., 2000). The survey included questions about the use of pesticides and fertilizers and a number of health conditions and symptoms that might be associated with agricultural exposures. Physician-diagnosed hypertension and heart disease were reported by 154 and 44 survey respondents, respectively. Neither condition was associated with residing on a farm. No information was provided on the validity of measurement of the self-reported health conditions, and the report did not examine more-specific associations with pesticide or fertilizer use.

Vietnam-Veteran Studies

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

Synthesis

The new studies that have examined hypertension as an outcome used self-reported history of a physician diagnosis for the definition of this variable. Neither study provided data on validation from medical records or direct measurement of blood pressure in a subset of the study population. Some misclassification is likely, with false negatives (nondiagnosed hypertension) being more common than false positives, especially among men. The studies by Kitamura et al. (2000) and Masley et al. (2000) also use nonspecific assessment of exposure. Masley et al. (2000) compare people from farming and nonfarming households, and give no information on the extent of herbicide use by the former. Kitamura et al. (2000) use PCDD exposure for the analysis of their study population of municipal-incinerator workers; this composite measure includes many exposures in addition to TCDD, and no comparisons are made with workers from another setting where such exposures are absent. It is possible that the null findings on hypertension in

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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these studies reflect the influence of misclassification that led to bias toward the null.

The occupational cohort study by Burns et al. (2001) found that mortality due to circulatory conditions among the workers was similar to that experienced by US white males in general. Mortality analyses of other occupational cohorts have tended to find cardiovascular effects among the more highly exposed workers, but a dose-specific analysis of the data on this outcome was not reported despite the availability of the data and of enough deaths for analysis. The ecologic finding of increased cardiovascular mortality in Chapaevsk compared with the Samara region in general and Russia in general is an interesting preliminary result, but Revich et al. (2001) concede that trends in cardiovascular mortality have also been associated with unemployment in Chapaevsk. A challenge of additional research in this setting will be to evaluate the etiologic role of TCDD exposure in the larger context of health-related social changes and in concert with the influence of individual-level risk factors, such as smoking, diet, and physical activity.

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 specific circulatory disorders (such as coronary artery disease, myocardial infarction, stroke, and hypertension) or circulatory conditions in general. As noted in earlier reports, important sources of uncertainty include the quality of measurement of health outcomes, incomplete assessment of confounding, and inconsistency of findings among magnitudes of exposure.

Biologic Plausibility

There have been reports of developmental defects in the cardiovascular system of TCDD-treated birds and fish. Recently, a dose-dependent increase in myocardial fibrosis has been observed in marmosets acutely exposed to relatively low doses of TCDD. In addition, subchronic treatment of hyperlipidemic ApoE-deficient mice with TCDD caused a trend for earlier onset and greater severity of atherosclerotic lesions compared with vehicle-treated mice. Notably, ApoE-deficient mice have a lipoprotein profile similar to that of humans with type III hyperlipoproteinemia and develop extensive aortic and coronary atherosclerosis with lesions that are similar to those observed in humans. Therefore, there are

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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data that suggest some biologic plausibility of an association between TCDD exposure and increased risk of cardiovascular disease. However, it is clear that additional studies are needed to confirm the relationships and to determine the relevance to humans. Chapter 3 discusses recent animal toxicity studies that could contribute to a biologic basis of an association between exposure to TCDD and herbicides and toxicity end points, and a general summary of the biologic basis of various end points is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

The available data on Vietnam veterans do not permit a conclusion about whether they are at an increased risk for circulatory disorders.

AL AMYLOIDOSIS

Amyloidosis (ICD-9 code 277.3) refers to a group of diseases in which insoluble fibrillar proteins (amyloid) accumulate in tissues to a point that causes organs to malfunction. There are several types of amyloidosis. The disease was formerly characterized by whether it was primary (occuring in the absence of a discernible preceding disease that led to it) or secondary to another disease. Currently, however, the disease is classified on the basis of the structure of the subunit fibril protein. In the type of amyloidosis reviewed here, light chain-associated (AL) amyloidosis (also sometimes referred to as primary amyloidosis), the light chain of immunoglobulin molecules is the aberrant protein (Gertz, 1999). AL amyloidosis is the most common form of systemic amyloidosis in the United States.

The study of systemic amyloidosis is difficult because it is also a complication that occurs in about 15–20% of patients with multiple myeloma (a disease of the bone marrow). Differentiation of the amyloid associated with myeloma from that of AL amyloidosis is artificial because the amyloid is of similar genesis and tissue distribution, and the conditions are more appropriately considered as parts of the spectrum of the same basic disease process.

Amyloidosis, like multiple myeloma, occurs mainly in people 50–70 years old and in more males than females. Annual incidence is estimated to be about one per 100,000, or over 2,000 new cases per year in the United States (Solomon, 1999).

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

The VA identified AL amyloidoisis as a concern after Update 1998 and therefore it was specifically looked at by the committee responsible for Update 2000. That committee concluded that there was inadequate or insufficient evi-

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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dence 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 AL amyloidosis.

Update of the Scientific Literature

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

Synthesis

The association between TCDD exposure and AL amylodosis seen in one study in mice may or may not apply to human beings and cannot be readily interpreted with respect to the future risk for Vietnam veterans.

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 AL amyloidosis.

Biologic Plausibility

An association has been reported between AL amyloidosis and TCDD exposure in a single study in mice, but the TCDD exposure was relatively intense and may or may not be relevant to Vietnam veterans. Chapter 3 discusses recent animal toxicity studies that could contribute to a biologic basis of an association between exposure to TCDD and herbicides and toxicity end points, and a general summary of the biologic basis of various end points is presented at the end of this chapter.

Increased Risk of Disease Among Vietnam Veterans

There is no evidence to suggest that Vietnam veterans are at an increased risk of developing AL amyloidoisis. The disorder is rare. However, veterans of the Vietnam era and their generation are only now entering the age when AL amyloidosis is most likely to occur.

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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ENDOMETRIOSIS

Earlier volumes of Veterans and Agent Orange (IOM, 1994, 1996, 1999, 2001) did not address the association between the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and endometriosis. This section reviews the evidence on that health outcome.

Endometriosis (ICD-9 617) is a disease that affects over 5 1/2 million women in the United States and Canada (Endometriosis Association, 2002). Endometrium is the tissue that lines the inside of the uterus and is built up and shed each month during menstruation. In endometriosis, endometrium is found outside the uterus— usually in other parts of the reproductive system, the abdomen, or the tissues near the reproductive organs. That misplaced tissue develops into growths or lesions that continue to respond to hormonal changes in the body and break down and bleed each month in concert with a woman's menstrual cycle. Unlike blood released from endometrium in the uterus, blood released from the tissue in endometriosis has no way to leave the body, and this results in inflammation, internal bleeding, and degeneration of blood and tissue from the growth and can cause scarring, pain, infertility, adhesions, and intestinal problems.

Several theories exist as to why endometriosis occurs, including that the disease has a genetic component, but the cause remains unknown. It has been proposed that endometrium is distributed through the body via blood or the lymphatic system; that menstrual tissue backs up into the fallopian tubes, implants in the abdomen, and grows; and that all women experience some form of tissue backup during menstruation and that only those with immune system or hormonal problems experience the tissue growth associated with endometriosis. Despite numerous symptoms that can indicate endometriosis in the body, diagnosis of the disease can be determined only through laparoscopy or a more invasive surgical technique. Several treatments for endometriosis are available, but there is no cure.

Suspicion that TCDD is involved in the etiology of endometriosis started after the observation that the incidence of endometriosis was higher in monkeys treated with low doses of TCDD than in control monkeys. Experimental and epidemiologic studies have been conducted. A number of the epidemiologic studies have investigated non-dioxin-like PCBs, and some have also looked at TCDD or dioxin-like compounds.

Review of the Scientific Literature

Mayani et al. (1997) analyzed blood TCDD concentrations in 79 women who were being evaluated for infertility, 44 of whom were diagnosed with endometriosis using laparoscopy. All the women had resided in Jerusalem for at least 10 years and were of similar socioeconomic status. The authors found that eight of the 44 women with endometriosis were positive for TCDD (18%) compared with one of the 35 controls (3%), for an OR of 7.6 (95% CI 0.87–169.7).

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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The number of subjects in the study, however, is small, and the ethnic distribution differed among controls and patients with endometriosis. Triglycerides were measured and did not differ between groups, but TCDD measurements were not adjusted for blood lipids. Furthermore, the limit of detection—what was considered testing positive for TCDD —is not clear in the study, although a review article states that it was 2 ppt (Birnbaum and Cummings, 2002).

Pauwels et al. (2001) assessed whether TCDD toxic equivalents (TEQs) in serum are associated with endometriosis in an infertile population of women who enrolled in fertility treatment at one of the collaborating centers for reproductive medicine in Belgium in 1996–1998. The case –control study evaluated 42 women with endometriosis (cases) and 27 controls with infertility related to tubal disease, tuboperitoneal factors, cervical factors, or uterine factors but without endometriosis. The authors report no association between median total TEQs and endometriosis in infertile women. The lack of association was evident even in a subgroup of patients with very high exposures (TEQs at over 100 pg/g of serum lipids). Adjustments for potential confounders, such as body-mass index and alcohol consumption, did not change the overall results. Therefore, dioxin-like compounds do not appear to contribute to endometriosis among infertile women. Given the design of the study, it offers no information on the association between infertility and specific exposure to TCDD.

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

Synthesis

Of the two studies that investigate the association between TCDD or TCDD-like compounds and endometriosis, one (Mayani et al., 1997) shows an increased OR (7.6), but the confidence interval was very wide (0.87–169.7). The other (Pauwels et al., 2001) did not show a significant association between exposure to dioxins and endometriosis. Both studies, however, are relatively small.

Conclusions
Strength of Evidence from Epidemiologic Studies

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 endometriosis.

Biologic Plausibility

There is evidence from animal studies that TCDD can exacerbate or cause endometriosis, including a recent report that demonstrated increased endometrio-

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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sis in rhesus monkeys exposed to TCDD. One study, however, did not show any increase in surgically induced endometriosis with TCDD exposure. Other evidence does demonstrate that TCDD inhibits progesterone-associated transforming growth factor β2 (TGFβ2) expression and endometrial matrix metalloproteinase suppression; those effects have been suggested as mechanisms underlying an association between TCDD and endometriosis. The ability of TCDD to alter the expression of several growth factors, cytokines, and hormones may also mediate the promotion of endometriosis. Notably, the AhR and several AhR target genes are expressed in human endometriotic tissues. Because animal data and the sparse human data support the possible biologic plausibility of an association between TCDD exposure and endometriosis, that possible association should continue to be investigated.

Increased Risk of Disease Among Vietnam Veterans

There are insufficient data on endometriosis in Vietnam veterans to draw a specific conclusion as to whether Vietnam veterans are at increased risk for this disorder.

THYROID HOMEOSTASIS

Earlier volumes of Veterans and Agent Orange (IOM, 1994, 1996, 1999, 2001) did not address the thyrotoxic potential of TCDD and the herbicides used in Vietnam. This section reviews the evidence of that health outcome.

The thyroid gland secretes the hormones thyroxine (T4) and triiodothyronine (T3), which stimulate metabolic rate. The thyroid also secretes calcitonin, a hormone that controls calcium concentration in the blood and storage of calcium in bones. Secretion of T4 and T3 is under the control of thyroid-stimulating hormone (TSH), which is secreted by the anterior pituitary gland. Iodine plays a central role in thyroid physiology both as a constituent of thyroid hormones and as a regulator of glandular function. Control of circulating concentrations of these hormones is regulated primarily by a negative-feedback pathway that involves three organs: the thyroid, which produces thyroid hormones, and the pituitary and hypothalamus, which help to maintain optimal T3 and T4 concentrations. In the hypothalamus–pituitary–thyroid feedback scheme, the hypothalamus stimulates the pituitary through thyrotropin-releasing hormone (TRH) to produce TSH, which triggers the thyroid to produce T4 and T3. Cells in the hypothalamus and pituitary respond to concentrations of circulating T4 and T3. When T4 and T3 are low, the pituitary is stimulated to deliver more TSH to the thyroid to increase T4 and T3 output. When circulating T4 and T3 are high, they signal to reduce the output of TRH and TSH. This negative-feedback loop maintains hormone homeostasis. Chemical-induced alterations in thyroid homeostasis can adversely affect the development of many organ systems, including the nervous and repro-

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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ductive systems. Most adverse effects are caused by lack of thyroid hormone alone rather than by increases in TSH.

Effects on the thyroid can be stimulatory (hyperthyroidism) or suppressive (hypothyroidism). Graves' disease is an example of hyperthyroidism; cretinism is an extreme example of hypothyroidism. Insufficient iodine intake resulting in goiter is usually not associated with either hyperthyroidism or hypothyroidism.

TCDD affects the concentrations of thyroid hormones; the effects appear to be species-dependent and may reflect both the dose and the duration of exposure (IOM, 2001). TCDD influences the metabolism of thyroid hormones and TSH. However, contrasting results confuse interpretation of the effects of TCDD on the production and activity of the hormones.

Review of the Scientific Literature
Environmental Studies

Studies of environmental exposure have emphasized thyroid alterations in prenatal and early childhood development rather than in adults.

Pluim et al. (1992) evaluated 38 mother–infant pairs in Amsterdam, the Netherlands, selected for normal birthweight and no complications. Total T4 and thyroxine-binding globulin (TBG) were measured in all samples, which included plasma from maternal delivery blood, cord blood, and infant 1-week and 11-week samples. TSH was measured in cord blood and in many of the 1-week and 11-week samples; total T3, free T4, and reverse T3 were measured in cord; and total T3 was measured at 11 weeks. Concentrations of dioxins and dibenzofurans were measured in breast-milk samples taken 3 weeks after delivery and expressed in nanograms per kilogram of milk fat; these were multiplied by their toxic equivalency factors and summed to obtain a total TEQ. The mother–infant pairs were categorized into two groups, above and below the median TEQ, and these two groups were compared. In cord blood, the concentrations of total T4 and TBG were suggestively higher (0.05 < p < 0.10) in the high exposure group, but no other measurements approached significance. At 1 week, total T4 and the ratio of total T4 to TBG were significantly greater in the high-exposure than the low-exposure group, and the same was true at 11 weeks, when, in addition, TSH concentrations were also significantly higher. When only infants who were breastfed for the full 11 weeks were considered, only the ratio of total T4 to TBG remained significantly different between the two groups. Finally, in a subset of the births for which values were obtained in both the cord and 1-week samples, the increases in total T4 and in TBG were substantially higher in the high-exposure group. Concerns about those results are related to the size of the study sample and the loss of nearly one-fourth of the maternal-blood samples (nine) and five of the cord-blood samples for all thyroid measurements; several more samples were insufficient for some of the analyses.

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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In a larger series (105 mother–infant pairs) in Rotterdam, the Netherlands, Koopman-Esseboom and colleagues (1994) conducted similar analyses. Blood was collected from the mothers during the last month of pregnancy and from the cord after birth for measurement of PCBs; breast milk was collected in the second week after delivery for measurement of dioxins, dibenzofurans, and planar PCBs. TEQs were calculated from those measurements. Total T4, total T3, free T4, and TSH were measured in maternal plasma taken during the last month of pregnancy and 9–14 days after delivery, and in newborn infants' plasma taken at 2 weeks and 3 months. TEQ correlated negatively with maternal pregnancy total T3 and maternal postdelivery total T3 and total T4; similar associations were seen for planar PCB TEQ and total PCB and TEQ, and the associations with total T3 were also observed for nonplanar PCB TEQ. In addition, all four TEQ measurements correlated positively with infant 2-week TSH, and all except the nonplanar PCB TEQ were positively associated with the infant 3-month TSH.

Longnecker and colleagues (2000) examined PCB concentrations in breast-milk specimens, without adjustment for lipids, in relation to thyroid hormones in cord serum in a population with background exposure. They found little evidence of an association, although the direction of the coefficient for TSH in multiple-regression analysis was consistent with findings in other studies: increases in TSH with increases in PCBs. No congener-specific analysis was conducted, so no information on dioxin-like PCBs was available. Because non-dioxin-like PCBs are the most abundant, and PCBs are contaminated with furans, this study is not very informative for the effects of TCDD or the herbicides used in Vietnam.

Both studies with information on TEQs suggest some alterations in thyroid-hormone homeostatis in relation to TCDD and dioxin-like compounds, but the results are only partially consistent. Both studies observe changes in total T4, but in Koopman-Esseboom et al. (1994) this finding is in maternal plasma, not cord or newborn infant 2-week or 3-month plasma, whereas Pluim et al. (1992) found higher T4 at both 1 and 11 weeks in the infant. The studies are consistent with regard to increases in TSH, which are not observed at birth (both studies) or at 1 week (Koopman-Esseboom et al., 1994), but are found at 2 weeks (Pluim et al., 1992), 11 weeks (Koopman-Esseboom et al., 1994) and 3 months (Pluim et al., 1992). According to Kimbrough and Krouskas (2001), TSH concentrations undergo large changes shortly after birth.

Calvert et al. (1999) examined TCDD-exposed workers at two plants who were engaged in the production of 2,4,5-T or one of its derivatives. Referents were residents in the neighborhood of each worker, matched by age, race, and sex. Examinations were conducted in 1987–1988, and blood was collected. Serum specimens were analyzed for TCDD, total T4, TSH, and thyroid hormone binding resin, and the free T4 index was calculated. The mean TCDD concentration for the four categories of exposure were 11, 40, 135, and 729 pg/g of lipid, whereas the comparison group had a mean TCDD concentration of 7 pg/g of lipid. The results showed that workers had a significantly higher adjusted mean

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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free T4 index than referents (p = 0.02), and the highest index was among those with the highest half-life extrapolated TCDD (p = 0.004), but a clear dose-response relationship was not observed (p = 0.02). The mean total T4 was also suggestively higher in workers than in referents (p = 0.07). No association was observed with TSH.

Vietnam-Veteran studies

Pavuk et al. (in press) examined thyroid-hormone status in the AFHS cohort. At each of the 1982, 1985, 1987, 1992, and 1997 examinations, there was a trend toward an increasing concentration of TSH, which was not accompanied by changes in circulating T4 or in the percentage uptake of T3 (measured only in the earlier years). In a repeated-measures linear regression adjusted for age, race, and military occupation, the low-exposure and high-exposure Ranch Hands had TSH significantly higher than the comparison population, and the trend test showed a significant linear increase over the comparison and background-, low-, and high-exposure groups (p = 0.002). No changes in microsomal or antithyroid antibodies were observed, nor was there any evidence of changes in clinical thyroid disease. The percentage with abnormally high TSH was higher at each examination (ORs 1.4–1.9) in the high-exposure Ranch Hand group than in the comparison population, but these findings were not very precise.

Synthesis

Based on numerous animal experiments and several epidemiologic studies, TCDD and dioxin-like compounds exhibit an influence on thyroid homeostasis. These effects are hypothesized to provide a mechanism by which TCDD may affect early development of neurologic and sensory organs and motor function. Increases in TSH in three human studies without evidence of increases in T4 indicate that the infants (selected for uncomplicated gestation, labor, and delivery) and the Ranch Hand Air Force personnel studied were able to adapt to the changes that may have been induced by the higher body burdens of TCDD and TEQ. The possibility of neurodevelopmental effects secondary to mild hypothyroidism induced in early pregnancy by TCDD or dioxin-like compounds cannot be excluded (Vulsma, 2000).

Conclusions
Strength of Evidence from Epidemiologic Studies

There is inadequate or insufficient evidence of 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 adverse effects on thyroid homeostasis. In humans,

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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some effects on thyroid homeostasis have been observed, mainly after exposure in the perinatal period, but the functional importance of those changes is unclear because adaptive capacity may be adequate to accommodate them.

Biologic Plausibility

TCDD is known to affect concentrations of T4, T3, and TSH. However, the effects have lacked consistency in demonstrating either a definite hyperthyroidism or hypothyroidism after exposure to TCDD. Nevertheless, long-term exposure of animals to TCDD usually results in suppressed T4 and T3 and stimulated TSH. Chapter 3 discusses recent toxicologic studies relevant to the biologic plausibility of the effects of TCDD and the herbicides on the thyroid gland.

Risk in Vietnam Veterans

The relevant studies conducted on thyroid alterations that focus primarily on perinatal effects mediated through the mother would be related primarily to the offspring of female Vietnam veterans. Those studies demonstrated biologic changes in TSH without accompanying effect on the health of the children. Similarly, the AFHS demonstrated biologic changes in TSH without accompanying effect on the health of the Ranch Hands.

SUMMARY

On the basis of the occupational, environmental, and veterans studies reviewed, the committee reached one of four conclusions about the strength of the evidence regarding association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and each of the health effects discussed in this chapter. As explained in Chapter 2, the conclusions reflect the committee's judgment that if an association between exposure and an outcome exists, it would be found in a large, well-designed epidemiologic study in which exposure to herbicides or TCDD was sufficiently high, well characterized, and appropriately measured on an individual basis. To be consistent with the charge to the committee by the secretary of veterans affairs in Public Law 102-4 and with accepted standards of scientific reviews, the distinctions between the conclusions are based on statistical association, not on causality. The committee used the same criteria to categorize diseases by the strength of the evidence as were used in VAO, Update 1996, Update 1998, and Update 2000.

Health Outcomes with Sufficient Evidence of an Association

For diseases in this category, a positive association between herbicides and the outcome must be observed in studies in which chance, bias, and confounding

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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can be ruled out with reasonable confidence. The committee also regarded evidence from several small studies that are free of bias and confounding and that show an association that is consistent in magnitude and direction as sufficient to conclude that there is an association.

In VAO, Update 1996, Update 1998, and Update 2000, the committee 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 chloracne. The scientific literature continues to support the classification of chloracne in the category of sufficient evidence. On the basis of the literature, no additional health effects discussed in this chapter satisfy the criteria necessary for this category.

Health Outcomes with Limited or Suggestive Evidence of Association

For this category, the evidence must suggest an association between herbicides and the outcome 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, but the results of other studies might be inconsistent.

In Update 1996, Update 1998, and Update 2000, the committee 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 porphyria cutanea tarda. The scientific literature continues to support the classification of this disorder in the category of limited or suggestive evidence.

On the basis of its evaluation of available scientific evidence, the committee responsible for the Type 2 Diabetes report 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 type 2 diabetes. Evidence reviewed in the present report continues to support that finding.

No other changes have been made in the list of health outcomes in the category of limited or suggestive evidence.

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

The scientific data on many of the health effects reviewed by the committee were inadequate or insufficient to determine whether an association exists between exposure to the chemicals of interest and the health outcome. For the health effects in this category, the available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. For example, studies fail to control for confounding or

Suggested Citation:"9. Other Health Effects." 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 inadequate exposure assessment. This category includes nonmalignant respiratory disorders, such as asthma in isolation, pleurisy, pneumonia, and tuberculosis; immune system disorders (immune suppression and autoimmunity); lipid and lipoprotein disorders; gastrointestinal diseases; digestive diseases; liver toxicity; circulatory disorders; AL amyloidosis; endometriosis; and thyroid homeostasis disorders.

Health Outcomes with Limited or Suggestive Evidence of No Association

To classify outcomes in this category, several adequate studies covering the full range of exposure that human beings are known to encounter must be consistent in not showing a positive association between exposure to herbicides and the outcome at any magnitude of exposure. The studies must also have relatively narrow confidence intervals. A conclusion of “no association” is inevitably limited to the conditions, magnitudes of exposure, and periods of observation covered by the available studies. In addition, the possibility of a very small increase in risk at the exposure studied can never be excluded.

The committees responsible for VAO, Update 1996, Update 1998, and Update 2000 concluded that none of the health outcomes discussed in this chapter had limited or suggestive evidence of no association with the exposures of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid). The most recent scientific evidence continues to support that conclusion.

Biologic Plausibility

This section summarizes the biologic plausibility of a connection between exposure to TCDD or herbicides and various noncancer health effects on the basis of data from animal and cellular studies. The preceding discussions of individual health outcomes include a discussion of biologic plausibility for the specific effects. Details of the committee's evaluation of data from recent toxicologic studies are presented in Chapter 3.

TCDD has been shown to elicit a diverse spectrum of effects in animal and experimental studies, including immunotoxicity, hepatotoxicity, chloracne, loss of body weight, induction of phase I and phase II drug-metabolizing enzymes, modulation of hormone systems, and modulation of factors associated with the regulation of cellular differentiation and proliferation. Those effects depend on sex, strain, age, and species.

Effects of TCDD on the liver include modulation of the rate at which hepatocytes multiply, increasing the rate of death of other types of liver cells, increasing the fat content of liver cells, decreasing bile flow, and increasing proteins and substances that are precursors to heme synthesis. TCDD also increases the amount of some enzymes in the liver, but this effect is not necessarily considered toxic. Liver toxicity is species-specific; mice and rats are susceptible to TCDD-induced

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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liver toxicity, but guinea pigs and hamsters are not. It is possible that liver toxicity is associated with susceptibility to liver cancer, but the extent to which TCDD effects mediate noncancer end points is not clear. TCDD has been shown to inhibit hepatocyte DNA synthesis, decrease hepatic plasma membrane epidermal growth factor receptor, inhibit hepatic pyruvate carboxylase activity, induce porphyrin accumulation in fish and chick embryo hepatocyte cultures, and alter liver enzyme concentrations and activity. Hepatomegaly has occurred after high subchronic doses. The mechanism of TCDD hepatoxicity is not established, but most studies are consistent with the hypothesis that the effects of TCDD are mediated by the AhR, a protein in animal and human cells to which TCDD can bind. The TCDD–AhR complex is thought to bind DNA and to lead to changes in transcription (genes are differentially regulated) that alter cell function. Although structural differences in the AhR have been identified in various species, this receptor operates in a similar manner in animals and humans. Animal data support a biologic basis of TCDD's toxic effects. Because of the many species and strain differences in TCDD responses, however, the extent to which animal data inform the evaluation of human health outcomes is controversial.

The myocardium has also been shown to be a target of TCDD toxicity. TCDD inhibits myocardium contraction possibly through effects on adenosine 3',5'-cyclic-monophosphate.

The immune system is one of the most sensitive to TCDD toxicity. Studies in mice, rats, guinea pigs, and monkeys indicate that TCDD suppresses the function of some components of the immune system in a dose-related manner; that is, as the dose of TCDD increases, its ability to suppress immune function increases. TCDD suppresses cell-mediated immunity, primarily by affecting the T-cell arm of the immune response, including a decrease in the numbers and responses of some types of T cells. It is not known whether TCDD directly affects T cells. TCDD may indirectly affect T cells and cell-mediated immunity by altering thymus function or cytokine production. The generation of antibodies by B cells, an indication of humoral immunity, may also be affected by TCDD. Effects of arachidonic acid have been hypothesized to mediate TCDD's immunotoxicity, but recent evidence indicates that not all of TCDD's immunotoxic effects are mediated by arachidonic acid. As with other effects of TCDD, the immunotoxic effects are species-specific and strain-specific. Increased susceptibility to infectious disease has been reported after TCDD administration. In addition, TCDD increased the number of tumors that formed in mice after injection of tumor cells. It should be emphasized, however, that very little change in the overall immune competence of the intact animals (animals not challenged experimentally with a pathogen or tumor cells) has been reported. Despite considerable laboratory research, the mechanisms underlying the immunotoxic effects of TCDD are still unclear, but most studies are consistent with the hypothesis that the effects are mediated by the AhR. TCDD's wide range of effects on growth regulation, hormone systems, and other factors could also mediate its immunotoxicity. As with

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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other TCDD-mediated effects, the similarity in function of the AhR among animals and humans suggests a possible common mechanism of immunotoxicity. Nevertheless, the available data have not confirmed in humans the universal immunosuppressive effects observed in laboratory animals.

TCDD has been shown to induce differentiation in human keratinocytes. TCDD has been reported to decrease an acidic type I keratin involved in epidermal development and to lead to keratinocyte hyperproliferation and skin irritations, such as chloracne. The data provide a biologically plausible mechanism for the induction of chloracne by TCDD.

Although there is not extensive data on the health effects of the herbicides discussed in this report, effects have been seen in a number of organs in laboratory animals. The liver is a target organ for 2,4-D, 2,4,5-T, and picloram, with effects similar to those induced by TCDD. Some kidney toxicity was reported in animals exposed to 2,4-D and cacodylic acid. Exposure to 2,4-D has also been associated with effects on blood, such as reduced heme and red cells. Cacodylic acid was reported to induce renal lesions in rats. Other studies provide evidence that 2,4-D binds covalently to hepatic proteins and lipids; the molecular basis of the interaction and its biologic consequences are unknown. 2,4,5-T has been shown to be a weak myelotoxin.

Few studies have been conducted on the potential immunotoxicity of the herbicides used in Vietnam. Effects on the immune system of mice were reported for 2,4-D administered at doses that were high enough to produce clinical toxicity, but these effects did not occur at low doses. The potential for picloram to act as a contact sensitizer (that is, to produce an allergic response on the skin) was tested, but other aspects of its immunotoxicity were not examined.

The foregoing suggests that a connection between TCDD or herbicide exposure and human toxic effects is, in general, biologically plausible. However, definitive conclusions about the presence or absence of a mechanism for the induction of specific toxicity by these compounds in humans are complicated by the 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. Investigating the biologic mechanisms underlying TCDD's toxic effects continues to be the subject of active research, and future updates of this report might 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 is asked to determine (to the extent that available scientific data permit meaningful determinations) the increased risk of disease in veterans exposed to herbicides and TCDD during their service in Vietnam. Little is known about health risks for Vietnam veterans;

Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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where specific information is available, it is discussed under the specific health outcome.

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Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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Suggested Citation:"9. Other Health Effects." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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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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