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Veterans and Agent Orange: Update 2012 (2014)

Chapter: 13 Other Chronic Health Outcomes

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Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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13


Other Chronic Health Outcomes

Chapter Overview

Based on new evidence and a review of prior studies, the committee for Update 2012 did not find any new significant associations between the relevant exposures and adverse chronic health outcomes other than those addressed in earlier chapters. Current evidence supports the findings of earlier studies that:

•  No other adverse outcomes had sufficient evidence of an association with the chemicals of interest.

•  No other adverse outcomes had limited or suggestive evidence of an association with the chemicals of interest.

•  There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and respiratory disorders, gastrointestinal and digestive diseases (including liver toxicity), adverse effects on thyroid homeostasis, eye problems, or bone conditions.

In previous updates that considered short-term adverse outcomes (see Appendix B), committees found

•  There is sufficient evidence of an association between the chemicals of interest and chloracne.

•  There is limited or suggestive evidence of an association between the chemicals of interest with early onset peripheral neuropathy and porpohyria cutanea tarda.

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

This chapter discusses data on the possible association between exposure to the herbicides used in Vietnam—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), picloram, and cacodylic acid and several noncancer health outcomes: respiratory disorders, gastrointestinal and digestive diseases (including liver toxicity), adverse effects on thyroid homeostasis, eye problems, and bone conditions. The committee also considers results of studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals to be informative if they were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners. While all studies reporting TEQs based on PCBs were reviewed, those studies that reported TEQs based only on mono-ortho PCBs (which are PCBs 105, 114, 118, 123, 156, 157, 167, and 189) were given very limited consideration since mono-ortho PCBs typically contribute less than 10% to total TEQs, based on the World Health Organization (WHO) revised toxicity equivalency factors (TEFs) of 2005 (La Rocca et al., 2008; van den Berg et al., 2006).

In previous updates, chloracne and porphyria cutanea tarda were considered with the chronic noncancer conditions. They are accepted as being associated with dioxin exposure, but when they occur it happens within a matter of months of the exposure. In Update 2010, the two health outcomes were moved to an appendix on short-term effects along with transient early-onset peripheral neuropathy, which had previously been discussed in the chapter on neurologic disorders.

For each type of health outcome, background information is followed by a brief summary of the findings described in earlier reports by the Institute of Medicine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. In the discussion of the most recent scientific literature, studies are grouped by exposure type (Vietnam-veteran, occupational, or environmental). For articles that report on only a single health outcome and are not revisiting a previously studied population, design information is summarized with the results; design information on other studies can be found in Chapter 6. A synopsis of toxicologic and clinical information related to the biologic plausibility that the chemicals of interest (COIs) can influence the occurrence of a health outcome is presented next and followed by a synthesis of all the material reviewed. Each health outcome section ends with the present committee’s conclusions regarding the strength of the evidence that supports an association with the COIs. The categories of association and the committee’s approach to categorizing the health outcomes are discussed in Chapters 1 and 2.

RESPIRATORY DISORDERS

For the purposes of this report, noncancerous respiratory disorders comprise acute and chronic lung diseases other than cancer. Acute noncancerous respiratory disorders include pneumonia and other respiratory infections; they can

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

increase in frequency and severity when the normal defense mechanisms of the lower respiratory tract are compromised. Chronic noncancerous respiratory disorders generally take two forms: airways disease and parenchymal disease. Airways disease encompasses disorders—among them asthma and chronic obstructive pulmonary disease (COPD)—characterized by obstruction of the flow of air out of the lungs. COPD is also known as chronic obstructive airways disease and includes emphysema and chronic bronchitis. Parenchymal disease, or interstitial disease, generally includes disorders that cause inflammation and scarring of the deep lung tissue, including the air sacs and supporting structures. Parenchymal disease is less common than airways disease and is characterized by reductions in lung capacity, although it can include a component of airway obstruction. Some severe chronic lung disorders, such as cystic fibrosis, are hereditary; because Vietnam veterans received health screenings before entering military service, few severe hereditary chronic lung disorders are expected in that population.

The most important risk factor for many noncancerous respiratory disorders is inhalation of cigarette smoke. Although exposure to cigarette smoke is not associated with all diseases of the lungs, it is the major cause of many airways disorders, especially COPD; it contributes to some interstitial disease; and it 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 it would otherwise be. The frequency of habitual cigarette-smoking varies with occupation, socioeconomic status, and generation. For those reasons, cigarette-smoking can be a major confounding factor in interpreting the literature on risk factors for respiratory disease. Vietnam veterans are reported to smoke more heavily than do non-Vietnam veterans (Kang et al., 2006; McKinney et al., 1997).

It is well known that causes of death from respiratory diseases, especially chronic diseases, are often misclassified on death certificates. Grouping various respiratory diseases for analysis, unless they all are associated with a given exposure, will lead to attenuation of the estimates of relative risk (RR) and to a diminution of statistical power. Moreover, diagnosis of the primary cause of death from respiratory and cardiovascular diseases is often inconsistent. In particular, when a person had both conditions concurrently and both contributed to death, there may be some uncertainty about which cause should be selected as the primary underlying cause. In other instances, errors may arise in selecting one underlying cause in a complex chain of health events (for example, if COPD leads to congestive heart failure and then to respiratory failure).

Many study populations are small, so investigators group deaths from all noncancerous respiratory diseases into one category that combines pneumonia, influenza, and other diseases with COPD and asthma. The committee notes that an association between the group of all noncancerous respiratory diseases with any of the COIs would be too nonspecific to be clinically meaningful; at most, such a pattern would be an indication that within this broad classification the

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

incidence of some particular disease entity might be affected by an exposure to a COI.

Conclusions from VAO and Previous Updates

The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994), concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and the respiratory disorders specified above. Additional information available to the committees responsible for Veterans and Agent Orange: Update 1996 (IOM, 1996) and Update 1998 (IOM, 1999) did not change that finding.

Update 2000 (IOM, 2001) drew attention to findings in the Seveso cohort that suggested a higher mortality from noncancerous respiratory disorders in study subjects, particularly males, who were 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 responsible for Update 2000 concluded that although new evidence suggested an increased risk of noncancerous respiratory disorders, particularly COPD, in people exposed to TCDD, the observation was tentative and the information insufficient to determine whether there is an association between exposures to the COIs and respiratory disorders. Additional information available to the committee responsible for Update 2002 (IOM, 2003) did not change that finding.

Update 2004 (IOM, 2005) included a new cross-sectional study of people who lived near a wood-treatment plant (Dahlgren et al., 2003). Soil and sediment samples from a ditch in the neighborhood contained dioxins and furans. Although exposed residents reported a greater frequency of chronic bronchitis by history (17.8% vs 5.7%; p < 0.0001) and asthma by history (40.5% vs 11.0%; p < 0.0001) than a “non-exposed” control group, the committee concluded that selection bias and recall bias limited the utility of the results and that there was a possibility of confounding in that history of tobacco use was not accounted for adequately.

Update 2006 (IOM, 2007) reviewed a number of studies of veterans of the Vietnam War. Mortality from respiratory diseases was not found to be higher than expected in the Centers for Disease Control and Prevention Vietnam Experience Study (Boehmer et al., 2004), in the Air Force Health Study (AFHS) (Ketchum and Michalek, 2005), and in two Australian studies of Vietnam veterans (ADVA, 2005b,c). In contrast, in the US Army Chemical Corps (ACC) cohort of Vietnam veterans, Kang et al. (2006) found that the prevalence of self-reported noncancerous respiratory problems diagnosed by a doctor was significantly increased by about 40–60%, although no differences in the prevalence of respiratory problems was found in the subset of veterans whose serum TCDD was above 2.5 parts per trillion (ppt).

In addition, Update 2006 addressed new studies of potentially exposed oc-

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

cupational cohorts. No associations with respiratory mortality were found in a small subcohort of New Zealand phenoxy-herbicide sprayers included in the International Agency for Research on Cancer cohort (’t Mannetje et al., 2005). In the Agricultural Health Study (AHS), no associations between the herbicide and mortality from COPD were found in private applicators or their spouses (Blair et al., 2005). There was also an AHS analysis (Hoppin et al., 2006a) of specific pesticide exposures and the self-reported prevalence of wheeze that showed an association with “current” exposure to 2,4-D.

Several additional new AHS publications were reviewed in Update 2008 (IOM, 2009) concerning morbidity from particular self-reported respiratory health problems: analyses concerning wheeze (Hoppin et al., 2006b), asthma (Hoppin et al., 2008), “farmer’s lung” or hypersensitivity pneumonitis (Hoppin et al., 2007a), and chronic bronchitis (Hoppin et al., 2007b; Valcin et al., 2007). The 25-year followup of mortality in the Seveso population through 2001 (Consonni et al., 2008) was also considered in Update 2008; again there was some increase in mortality from COPD as had been seen in the earlier mortality followup reviewed in Update 2000.

New literature considered in Update 2010 raised considerable concern that a pattern of COPD might be coming into focus. Cypel and Kang (2010) reported cause-specific mortality through 2005 in an ACC cohort of deployed and nondeployed Vietnam-era veterans and in a subset of the original deployed ACC veterans who reported in a morbidity study whether they had sprayed herbicide (Kang et al., 2006). Cypel and Kang (2010) reported a statistically significant excess mortality from COPD (RR = 4.82, 95% confidence interval [CI] 1.10–21.18) when comparing the deployed and nondeployed groups. A similar pattern in the deployed ACC veterans was observed when they were compared with the US male population (SMR = 1.62, 95% CI 0.99–2.51). When the subgroups of deployed ACC veterans who had and had not reported spraying herbicides were compared, the sprayers had an elevated risk for death due to the less specific category of “noncancerous respiratory system disease” (RR = 2.24, 95% CI 0.42–11.83); this was the only one of these comparisons able to control for self-reported herbicide exposure, body-mass index, and smoking status. Deaths due to CODP were lower in non-deployed ACC veterans relative to males in the US population (standardized mortality ratio [SMR] = 0.3, 95% CI 0.04–1.07); this is noteworthy because the prevalence of smoking in the nondeployed ACC veterans was about twice that in men in the US population (Kang et al., 2006). Publications evaluated in Update 2010 that studied industrial cohorts did not report on COPD but did not find increased mortality from noncancerous respiratory diseases overall (Boers et al., 2010; Collins et al., 2009a,b; McBride et al., 2009a). In the AHS cohort, Hoppin et al. (2009) did not find increased morbidity from asthma associated with 2,4-D or 2,4,5-T use; Slager et al. (2009) found current use of 2,4-D to be associated with an increase in current rhinitis.

Table 13-1 summarizes the results of the relevant studies.

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TABLE 13-1 Selected Epidemiologic Studies—Noncancer Respiratory Disease (Shaded Entries Are New Information for This Update)

Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
VIETNAM VETERANS
US Vietnam Veterans

US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)

All COIs

Mortality

Through 1999—Ranch Hand personnel (n =1,262) vs SEA veterans (19,078) (respiratory disease, ICD-9 460–519)

          8 1.2 (0.6–2.5) Ketchum and Michalek, 2005

US VA Cohort of Army Chemical Corps—Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 nondeployed) serving during Vietnam era (07/01/1965–03/28/1973)

All COIs

Incidence—Self-reported respiratory disease diagnosed by doctor

CATI survey of stratified sample: 1,499 deployed (795 with TCDD measured) vs 1,428 nondeployed (102 with TCDD measured)

Kang et al., 2006

Deployed vs nondeployed

    267 1.4 (1.1–1.8)

Sprayed herbicides in Vietnam (n = 662) vs never (n = 811)

    140 1.6 (1.2–2.1)

Mortality—respiratory disease

Through 2005

Cypel and Kang, 2010

Deployed veterans (2,872) vs nondeployed (2,737)

Respiratory system disease

32 vs 8 2.2 (1.0–4.9)

Pneumonia, influenza

12 vs 6 1.3 (0.5–3.6)

COPD

20 vs 2 4.8 (1.1–21.2)

ACC deployed men in Kang et al. (2006) reported sprayed herbicide vs did not spray

Respiratory system disease

          8 2.2 (0.4–11.8)

Pulmonary disease (COPD)

          6 3.6 (0.4–32.1)

Through 1991 (respiratory system disease)

11 vs 2 2.6 (0.5–12.2) Dalager and Kang, 1997
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed All COIs
Incidence

Physical health— ORs from pulmonary-function tests (case definition: ≥ 80% predicted value)

CDC, 1988

FEV1

  254 0.9 (0.7–1.1)
Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

FVC

177 1.0 (0.8–1.3)

FEV1/FVC

152 1.0 (0.8–1.3)

Mortality

1965–2000 (noncancerous respiratory mortality, ICD-9 460–519)

  20 0.8 (0.5–1.5) Boehmer et al., 2004

US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973

All COIs

1965–1988

Watanabe and Kang, 1996

Army, deployed (n = 27,596) vs nondeployed (n = 31,757)

648 0.8 (p < 0.05)

Marine Corps, deployed (n = 6,237) vs nondeployed (n = 5,040)

111 0.7 (p < 0.05)

US VA Study of Male Vietnam Veterans Wounded in Combat

All COIs

Mortality through December 1991

Bullman and Kang, 1996

Noncancerous respiratory mortality (ICD-9 460–519)

  43 0.9 (0.7–1.2)

US VA Cohort of Monozygotic

All COIs

Twins—Vietnam-era

Incidence of respiratory conditions, deployed vs undeployed

Eisen et al., 1991

Present at time of survey

  nr 1.4 (0.8–2.4)

At any time since service

  nr 1.4 (0.9–2.0)

Required hospitalization

  nr 1.8 (0.7–4.2)

State Studies of US Vietnam Veterans

923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans (mortality from noncancerous respiratory disease, ICD-8 460–519)

Anderson et al., 1986

Vietnam veterans vs expected deaths calculated from proportions for:

  10

Nonveterans

0.5 (0.3–0.8)

All veterans

0.8 (0.4–1.5)

Vietnam-era veterans

1.0 (0.5–1.8)

International Vietnam-Veteran Studies

Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters during 5/23/1962–7/1/1973 vs Australian population

All COIs

Mortality

All branches, return–2001

ADVA, 2005b

Respiratory system disease

239 0.8 (0.7–0.9)
Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

COPD

128 0.9 (0.7–1.0)

Navy

Respiratory system disease

  50 0.8 (0.6–1.0)

COPD

  28 0.9 (0.6–1.3)

Army

Respiratory system disease

162 0.8 (0.7–0.9)

COPD

  81 0.9 (0.7–1.0)

Air Force

Respiratory system disease

  28 0.6 (0.4–0.9)

COPD

  18 0.8 (0.4–1.2)

1980–1994

CDVA, 1997a

Noncancerous respiratory mortality (ICD-9 460–519)

1964–1979

    3 0.1 (0.0–0.3)

1980–1994

  92 0.9 (0.7–1.1)

Chronic obstructive airways disease (ICD-9 460–496)

  47 0.9 (0.7–1.2)

Sample of 1,000 Male Australian Vietnam

All COIs
Veterans—prevalence

450 interviewed 2005–2006 vs respondents to 2004–2005 national survey

O’Toole et al., 2009

Chronic lower respiratory disease

nr

Bronchitis

nr 2.9 (2.2–3.6)

Emphysema

nr 2.0 (1.3–2.7)

Asthma

nr 1.3 (1.0–1.6)

Hay fever, allergic rhinitis

nr 1.2 (0.96–1.4)

Chronic sinusitis

nr 1.7 (1.5–2.0)

Other diseases of respiratory system

nr 15.4 (11.7–19.1)

641 interviewed 1990–1993 vs respondents to 1989–1990 national survey

O’Toole et al., 1996

Asthma

nr 0.9 (0.5–1.4)

Bronchitis, emphysema

nr 4.1 (2.8–5.5)

Other

nr 4.0 (2.2–5.9)

Australian Conscripted Army National Service (18,940 deployed vs 24,642 nondeployed)

All COIs

Mortality

1966–2001

ADVA, 2005c

Respiratory diseases

  18 1.1 (0.6–2.2)

COPD

    8 1.0 (0.3–2.8)

1982–1994

CDVA, 1997b

1965–1982

    2 2.6 (0.2–30.0)

1982–1994

    6 0.9 (0.3–2.7)
Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates

Mortality 1939–1992

Phenoxy herbicides, chlorophenols Kogevinas et al., 1997

21,863 exposed workers

Men

        252 0.8 (0.7–0.9)

Women

            7 1.1 (0.4–2.2)

British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)

MCPA

Mortality through 1983 (noncancerous respiratory diseases, ICD-9 460–519)

           93 0.6 (0.5–0.8) Coggon et al., 1986

British Production Workers at 4 plants (included in IARC cohort)

Dioxins, but TCDD unlikely; MCPA Coggon et al., 1991

Mortality 1963–1985 (noncancerous respiratory diseases, ICD-9 460–519)

            8 0.7 (0.3–1.3)

Dutch production workers in Plant A and Plant B, combined (Plant A, 1,020 workers; Plant B, 1,036 workers) (in IARC cohort)

Dioxins; 2,4-D, 2,4-DP; 2,4,5-T; 2,4,5-TCP MCPA; MCPP

Mortality 1955–2006 (diseases of the respiratory system)

           52 1.0 (0.8–1.2) Boers et al., 2012

Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)

Dioxins, 2,4,5-T, 2,4,5-TCP

Mortality 1955–2006 (HRs for lagged TCDD plasma levels)

Boers et al., 2012

Diseases of the respiratory system

          31 1.0 (0.8–1.3)

Mortality 1955–2006

19 vs 12 1.0 (0.4–2.3) Boers et al., 2010

Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort)

2,4-D; MCPA; MCPP; highly chlorinated dioxins unlikely
Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

Mortality 1965–2006

6 vs 15 0.5 (0.2–1.2) Boers et al.,

German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 month in 1951–1976) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4,5-TCP 2010

Mortality 1951–1992 (ICD-9 460–519)

            2 0.9 (0.1–3.1) Becher et al., 1996

German Production Workers at Bayer Plant in Dormagen (520 men working > 1 month in 1965–1989) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP

Mortality 1965–1989 (ICD-9 460–519)

            0 0.0 Becher et al., 1996

German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 month in 1957–1987) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP

Mortality 1956–1989 (ICD-9 460–519)

            4 0.6 (0.2–1.6) Becher et al., 1996

BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)

Focus on TCDD

Incidence

Through 1989 (n = 158 men exposed within 1 yr of accident vs 161 other BASF employees 1953–1969)

Zober et al., 1994

All noncancerous respiratory diseases (ICD-9 460–419)

          nr 33.7/31.0 (p = 0.22)

Upper respiratory tract infections (ICD-9 460–478)

          nr 12.0/9.0 (p = 0.00)

Pneumonia, influenza (ICD-9 480–487)

          nr 17.4/18.8 (p = 0.08)
COPD (ICD-9 490–496)           nr 8.0/7.5 (p = 0.31)

Mortality

1953–1992 (noncancerous respiratory)

            1 0.1 (0.0–0.8) Ott and Zober, 1996

German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 month in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)

Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP
Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

Mortality 1952–2007 (ICD-9 codes 460–519)

  33 0.6 (0.4–0.9) Manuwald et al., 2012

Men

  25 0.6 (0.4–0.9)

Women

    8 0.7 (0.3–1.4)

Mortalilty 1952–1989 (ICD-9 460–519)

  10 0.5 (0.3–1.0) Becher et al., 1996

New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram

Mortality 1969–2004

McBride et al., 2009a

Ever-exposed workers

  12 0.8 (0.4–1.4)

Never-exposed workers

    2 0.4 (0.0–1.5)

Production Workers (713 men and 100 women worked > 1 month in 1969–1984)

Mortality 1969–2000

    9 0.9 (0.4–1.8) ’t Mannetje et al., 2005

Sprayers (697 men and 2 women on register of New Zealand applicators, 1973–1984)

Mortality 1973–2000

    6 0.7 (0.2–1.2) ’t Mannetje et al., 2005

NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)

Dioxins, phenoxy herbicides

Through 1993 (noncancerous respiratory, ICD-9 460–519)

  86 0.9 (0.7–1.1) Steenland et al., 1999

Monsanto workers (n = 240) involved in 2,4,5-T production (1948–1969) and 163 unexposed workers, results of clinical examination July 1979—morbidity

Suskind and Hertzberg, 1984

“Abnormal” outcome on pulmonary-functions tests:

FEV1 (< 80% predicted)

  32 2.81 (p = 0.02)

FVC (< 80% predicted)

  35 2.25 (p = 0.03)

FEV1/FVC (< 70%)

  32 2.97 (p = 0.01)

FEF25–75 (< 80% predicted)

  47 1.86 (p = 0.05)

All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, Michigan) (in IARC and NIOSH cohorts)

2,4,5-T; 2,4,5-TCP

1942–2003 (n = 1,615)

  44 0.8 (0.6–1.0) Collins et al., 2009a
Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, Washington, and Wichita, Kansas) and workers who made PCP and TCP at two additional plants (in Midland, Michigan, and Sauget, Illinois)

2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011

Respiratory disorders (ICD-9 codes 460–466, 470–478, 480–487, 490–519)

1940–2005 (n = 2,122)

  94 1.0 (0.8–1.3)

PCP and TCP (n = 720)

  21 0.7 (0.5–1.1)
PCP (no TCP) (n = 1,402)   73 1.2 (0.9–1.5)

Pneumonia (ICD-9 codes 480–486)

1940–2005 (n = 2,122)

  19 0.7 (0.4–1.0)

PCP and TCP (n = 720)

    8 0.9 (0.4–1.8)

PCP (no TCP) (n = 1,402)

  11 0.5 (0.3–1.0)

COPD (ICD-9 codes 490–492, 496)

1940–2005 (n = 2,122)

  63 1.4 (1.1–1.8)

PCP and TCP (n = 720)

  10 0.7 (0.3–1.3)

PCP (no TCP) (n = 1,402)

  53 1.7 (1.3–2.2)

Dow 2,4-D Production Workers (1945–1982 in Midland, Michigan) (subset of all TCP-exposed workers) excluded

2,4-D, lower chlorinated dioxins

Through 1994 (n = 1,517)

Burns et al., 2001

Noncancerous respiratory (ICD-8 460–519)

    8 0.4 (0.2–0.7)

Pneumonia

    4 0.6 (0.2–1.4)

Dow PCP Production Workers (1937–1989 in Midland, Michigan) (not in IARC and NIOSH cohorts)

Low chlorinated dioxins, 2,4-D

Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP)

  19 0.7 (0.4–1.2) Collins et al., 2009b

Mortality 1940–1989 (n = 770)

Ramlow et al., 1996

Noncancerous respiratory mortality (ICD-8 460–519)

  14 0.9 (0.5–1.5)

Cumulative PCP exposure

< 1 unit

    3 0.6 (0.2–1.9)

≥ 1 unit

  11 0.4 (0.8–2.5)

Pneumonia (ICD-8 480–486)

    6 1.1 (0.4–2.4)

Emphysema (ICD-8 492)

    4 1.3 (0.4–3.3)

Preliminary NIOSH Cross-Sectional Medical Study—workers in production of sodium trichlorophenol, 2,4,5-T ester contaminated with TCDD—morbidity

Chronic bronchitis and COPD

    2 nr Sweeney et al., 1997/98
Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

ORs for increase in 1 ppt of serum TCDD compared to unexposed workers

Calvert et al., 1991

Chronic bronchitis

nr 0.5 (0.1–2.6)

COPD

nr 1.2 (0.5–2.8)

OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)

CANADA—cross-sectional study of self-reported prevalence of self-reported asthma (n = 83) in male farmers (n = 1,939) in Saskatchewan (1982–1983)

Phenoxy herbicides Asthmatics vs nonasthmatics Senthilselvan et al., 1992

Phenoxyacetic herbicide use

  71 85.5% vs 88.5%

UNITED STATES

US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916 men), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; followups with CATIs 1999–2003 and 2005–2010

Phenoxy herbicides

Incidence

Prevalence of allergic (n = 127) and nonallergic (n = 314) asthma in male farmers and commercial applicators

Hoppin et al., 2009

Men with allergic asthma exposed to:

2,4,5-T

  38 1.4 (1.0–2.2)

2,4-D

110 1.6 (0.9–2.7)

Men with nonallergic asthma exposed to:

2,4,5-T

  88 1.2 (0.9–1.6)

2,4-D

264 1.2 (0.9–1.6)

Prevalence of atopic (n = 282) or nonatopic asthma (n = 420) reported by women (> 19 yrs of age) at enrollment (1993–1997)

Hoppin et al., 2008

Women reporting atopic asthma exposed to:

2,4-D

  52 1.5 (1.1–2.1)

Dicamba

  11 1.1 (0.6–2.1)

Women reporting nonatopic asthma exposed to:

2,4-D

  66 1.1 (0.8–1.4)

Dicamba

  13 0.7 (0.4–1.3)

Prevalence of chronic bronchitis at enrollment (n = 654) in private applicators exposed to:

Hoppin et al., 2007b
Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

2,4-D

  78 1.1 (0.9–1.4)

2,4,5-T

  28 1.5 (1.3–1.8)

2,4,5-TP

    9 1.7 (1.3–2.3)

Dicamba

  48 1.0 (0.8–1.2)

Prevalence of chronic bronchitis at enrollment in nonsmoking farm women (n = 21,541) exposed to:

0.9 (0.7–1.1) Valcin et al., 2007

2,4-D

  16 1.2 (0.9–1.6)

2,4,5-T

    1 1.0 (0.4–2.5)

Dicamba

    5 1.1 (0.6–2.0)

Mortality

Enrollment through 2007, vs state rates

Waggoner et al., 2011

Respiratory system diseases

Applicators (n = 1,641)

346 0.4 (0.3–0.4)

Spouses (n = 676)

  92 0.3 (0.2–0.4)

Pneumonia

Applicators (n = 1,641)

  76 0.4 (0.3–0.5)

Spouses (n = 676)

  17 0.3 (0.2–0.5)

COPD

Applicators (n = 1,641)

165 0.3 (0.3–0.4)

Spouses (n = 676)

  50 0.3 (0.2–0.4)

Asthma

Applicators (n = 1,641)

    8 0.8 (0.3–1.6)

Other respiratory diseases

Applicators (n = 1,641)

  97 0.6 (0.5–0.7)

Spouses (n = 676)

  21 0.4 (0.3–0.6)

Enrollment through 2000, vs state rates

Blair et al., 2005

Private applicators (men and women)

  50 0.2 (0.2–0.3)

Spouses of private applicators (> 99% women)

  15 0.3 (0.2–0.7)

US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of noncancerous respiratory diseases (ICD-8 460–519)

Herbicides

Forest conservationists

  80 0.8 (0.6–1.0) Alavanja et al., 1989

Florida Licensed Pesticide Applicators (common phenoxy use assumed but not documented; had been listed by Blair et al., 1983)

Herbicides

Pesticide applicators in Florida licensed 1965–1966 (n = 3,827)—mortality through 1976 from noncancerous respiratory diseases (ICD-8 460–519)

Herbicides Blair et al., 1983
    2 0.9 (nr)

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

Any pesticide (dose-response by length of licensure)

    8 0.6 (nr)

< 10 yrs

    8 1.5 (nr)

10–19 yrs

    4 1.7 (nr)

≥ 20 yrs

ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9 171) TCDD

Mortality

25-yr followup to 2001—men and women

Consonni et al., 2008

Respiratory disease (ICD-9 460–519)

Zone A

    9 1.4 (0.7–2.7)

Zone B

  48 1.0 (0.8–1.4)

Zone R

341 1.0 (0.9–1.1)

COPD (ICD-9 490–493)

Zone A

    7 2.5 (1.2–5.3)

Zone B

  26 1.3 (0.9–1.9)

Zone R

175 1.2 (1.0–1.4)

20-yr followup to 1996

Bertazzi et al., 2001

Respiratory disease (ICD-9 460–519)

  44 1.0 (0.8–1.4)

Zone A

    9 1.9 (1.0–3.6)

Zone B

  35 1.3 (0.9–2.0)

COPD (ICD-9 490–493)

  29 1.5 (1.1–2.2)

Zone A

    7 3.3 (1.6–6.9)

Zone B

  22 1.3 (0.9–2.0)

15-yr followup to 1991—men

Bertazzi et al., 1998

Respiratory disease (ICD-9 460–519)

Zone A

    5 2.4 (1.0–5.7)

Zone B

  13 0.7 (0.4–1.2)

Zone R

133 1.1 (0.9–1.3)

COPD (ICD-9 490–493)

Zone A

    4 3.7 (1.4–9.8)

Zone B

    9 1.0 (0.5–1.9)

Zone R

  74 1.2 (0.9–1.5)

15-yr followup to 1991—women

Bertazzi et al., 1998

Respiratory disease (ICD-9 460–519)

Zone A

    2 1.3 (0.3–5.3)

Zone B

  10 1.0 (0.5–1.9)

Zone R

  84 1.0 (0.8–1.2)

COPD (ICD-9 490–493)

Zone A

    1 2.1 (0.3–14.9)
Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

Zone B

    8 2.5 (1.2–5.0)

Zone R

  37 1.3 (0.9–1.9)

10-yr followup to 1986—men (Zones A, B, R)

Bertazzi et al., 1989a

Respiratory disease (ICD-9 460–519)

  55 1.0 (0.7–1.3)

Pneumonia (ICD-9 480–486)

  14 0.9 (0.5–1.5)

COPD (ICD-9 490–493)

  31 1.1 (0.8–1.7)

10-yr followup to 1986—women (Zones A, B, R)

Bertazzi et al., 1989a

Respiratory disease (ICD-9 460–519)

  24 1.0 (0.7–1.6)

Pneumonia (ICD-9 480–486)

    9 0.8 (0.4–1.6)

COPD (ICD-9 490–493)

    8 1.0 (0.5–2.2)

Cross-sectional study of residents near wood treatment plant (creosote, PCP) in Mississippi, who were plaintiffs (n = 199) in lawsuit vs subjects in comparable area (n = 115) without known exposures

Dioxin, furans Prevalence in exposed vs nonexposed Dahlgren et al., 2003

Chronic bronchitis

By history

21.7% vs 4.3% (p < 0.0001)

Diagnosed by physician

17.8% vs 5.8% (p < 0.0001)

Chronic bronchitis

By history

40.5% vs 11.0% (p < 0.0001)

Diagnosed by physician

13.1% vs 12.0%

ns
Other International Environmental Studies

SWEDEN

Swedish fishermen (high consumption of fish with persistent organochlorines)

Organochlorine compounds Svensson et al., 1995

Mortality

East Coast

    4 0.5 (0.1–1.2)

West Coast

  43 0.8 (0.6–1.1)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; 2,5-DCP, 2,5-dichlorophenol; CATI, computer-assisted telephone interviewing; CI, confidence interval; COI, chemical of interest; COPD, chronic obstructive pulmonary disease; FEF25–75, forced midexpiratory flow; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD-8, International Classification of Diseases, Eighth Revision; ICD-9, International Classification of Diseases, Ninth Revision; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; MOS, months of service; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not significant; OR, odds ratio; PCP, pentachlorophenol; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veterans Affairs.

aGiven when available; results other than estimated risk explained individually.

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

Update of the Epidemiologic Literature

Vietnam-Veteran, Environmental, and Case-Control Studies

No Vietnam-veteran studies, environmental studies, or case-control studies of exposure to the COIs and respiratory disorders have been published since Update 2010.

Occupational Studies

Ruder and Yiin (2011) reported COPD mortality from 1940 to 2005, relative to US referent rates, in a cohort of 2,122 US pentachlorophenol (PCP) production workers in four plants in the National Institute for Occupational Safety and Health (NIOSH) dioxin cohort. The workers in all four plants were exposed to PCP and to its contaminating polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs). An all-male subcohort of 720 in two plants was also exposed to TCDD, a contaminant of trichlorophenol (TCP) used in production processes in the plants. Deaths from all nonmalignant respiratory diseases did not differ from US rates in the PCP-only group (21 deaths, SMR = 0.73, 95% CI 0.45–1.11) or for the PCP-plus-TCDD group (73 deaths, SMR = 1.15, 95% CI 0.90–1.45). In the PCP-plus-TCDD group, no increase was reported in COPD (10 deaths, SMR = 0.68, 95% CI 0.33–1.25) or in pneumonia (8 deaths, SMR = 0.90, 95% CI 0.39–1.77). In the PCP-only group, there were excess deaths due to COPD (53 deaths, SMR = 1.71, 95% CI 1.28–2.24) but a decrease of marginal significance in deaths from pneumonia (11 deaths, SMR = 0.54, 95% CI 0.270.96). COPD mortality in the combined subcohorts was elevated (63 deaths, SMR = 1.38, 95% CI 1.06–1.77) and generally increased with duration of employment, but reached the level of statistical significance only in the third quartile of duration (182–650 days) of work in any PCP operation (21 deaths, SMR = 1.78, 95% CI 1.10–2.72). The completeness and maturity of this cohort of US PCP workers are strengths of the study. A major limitation is that no information on smoking was available, and this greatly limits conclusions regarding the contribution of these agents to the increase in mortality from COPD. Furthermore, although there was potential for occupational exposure to TEQs in the entire cohort, the subcohort that had potential TCDD exposure did not have increased mortality from COPD. As found earlier by Bodner et al. (2003), the authors noted that there was no difference in mortality between the 236 workers who had diagnoses of chloracne and other workers.

Boers et al. (2012) reported on the mortality experience of workers in two chlorophenoxy-herbicide plants in the Netherlands by using semi-quantitative measures of TCDD exposure. Factory A had 1,167 workers from 1955 to 1985 and produced 2,4,5-T and 2,4,5-TCP, which can be contaminated with TCDD. Factory B had 1,143 workers from 1965 to 1986 and produced 2,4-D, which was

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

contaminated with dioxin congeners other than TCDD. Plasma concentrations of TCDD in 187 workers were used to develop a predictive model for TCDD exposure at the end of employment for each worker, and a Cox proportionalhazards model was used to investigate associations between time-varying TCDD exposure and cause-specific mortality. No relationship was found between TCDD exposure and respiratory diseases. Hazard ratios (HRs) for predicted TCDD concentrations and diseases of the respiratory system were not increased in the entire cohort (HR = 0.97, 95% CI 0.81–1.15 for each unit increase in TCDD exposure on the log scale) and in workers in Factory A (HR = 1.04, 95% CI 0.84–1.28). This publication was a followup of an earlier article on this updated cohort (Boers et al., 2010); it used exposed versus nonexposed exposure categories based on job classification and found that the exposed did not have significantly increased risks of nonmalignant diseases of the respiratory system.

Manuwald et al. (2012) updated mortality though 2007 in a cohort of 1,589 male and female workers employed for at least 3 months during 1952–1984 in a factory in Hamburg, Germany, that produced various herbicides and insecticides, including 2,4,5-T contaminated with TCDD and other higher-chlorinated dioxins and furans. SMRs were calculated by using the population of Hamburg as a reference group. Death due to nonmalignant respiratory diseases was decreased in men (SMR = 0.60, 95% CI 0.39–0.89) and in the total cohort (SMR = 0.62, 95% CI 0.43–0.87), but the smaller group of women did not differ from the referent (n = 389, SMR = 0.70, 95% CI 0.30–1.37). The prevalence of smoking was not controlled for in this study but is suggested not to differ from that in the general population (Flesch-Janys et al., 1995). The results are in contrast with the significant increase in the SMR for respiratory cancer, cancer of the larynx, and cancers of the trachea, bronchus, and lung reported in the cohort.

Waggoner et al. (2011) reported mortality in the AHS from the time of enrollment (1993–1997) through 2007. SMRs in pesticide applicators and their spouses (89,656) in Iowa and North Carolina were calculated from state-specific rates. Death due to COPD was significantly decreased in applicators (165 deaths, SMR = 0.31, 95% CI 0.26–0.36) and their spouses (50 deaths, SMR = 0.27, 95% CI 0.20–0.35). Waggoner et al. (2011) also examined deaths due to pneumonia, asthma, and other respiratory diseases. As was the case with COPD, deaths due to pneumonia and other respiratory disease were significantly decreased in applicators (76 deaths from pneumonia, SMR = 0.40, 95% CI 0.31–0.50; 97 deaths from other causes, SMR = 0.60, 95% CI 0.49–0.73) and were null for asthma (8 deaths, SMR = 0.79, 95% CI 0.34–1.56). The AHS has been generating valuable information on the COIs for a number of years, but these results, like those in Alavanja et al. (2005) and Blair et al. (2005), are not herbicide-specific and so are not regarded as being fully informative for the committee’s task.

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

Biologic Plausibility

Evaluation of the biologic plausibility of induction of or contribution to the development of lung diseases by COIs is hampered by the lack of animal models for studying such endpoints as COPD or asthma because these diseases usually develop in humans in response to additional co-factors (smoking and air pollution). Activation of the aryl hydrocarbon receptor (AHR) by TCDD, however, has been shown to modify expression of genes in the lung that code for inflammatory cytokines, matrix metalloproteases, and mucin production (Wong et al., 2010). These results are consistent with changes associated with a variety of lung diseases—such as bronchitis, asthma, small-airways disease, and lung remodeling (fibrosis)—and support the role of AHR activation in the development of lung injury. AHR activation in vitro in NCI H441 in the Clara cells also activates an IL-1b-to-COX-2-mediated process, which leads to increased mucin production. That process might be facilitated via differentiation of the Clara cell to a mucinproducing, goblet-like cell phenotype. One of the major clinical characteristics of COPD is mucous-cell or goblet-cell hyperplasia in the airways. MUC5AC is a major gel-forming mucin that is frequently elevated in various airway diseases (Rose and Voynow, 2006; Voynow et al., 2006). Lee et al. (2010) reported that TCDD induced time-dependent increases in MUC5AC mRNA and protein synthesis in primary normal human bronchial epithelial cells and in an immortalized normal human bronchial epithelial cell line (HBE1). Recently, Lee et al. (2011) reported that TCDD induced the expression of MUC5AC mRNA and protein and the expression of CYP1A1 in both primary normal human bronchial epithelial cells and the immortalized cell line HBE1. TCDD-induced expression of the mucin gene is consistent with mucous-cell or goblet-cell hyperplasia, which in turn is an element of the pathogenesis of COPD. It is also plausible that the induction of CYP1A1 and CYP1B1 enzymes in the lung by TCDD could result in the metabolism of several chemicals found in tobacco smoke to more toxic intermediates. Exposure to TCDD could thus increase the toxic effects of tobacco smoke and increase respiratory disease. In practice, however, this is not necessarily true, as demonstrated by Uno et al. (2006).

Acute noncancerous respiratory disorders, including pneumonia and other respiratory infections, also can be increased in frequency and severity when the normal defense mechanisms of the lower respiratory tract are compromised. Thus, exposure to chemicals that affect those mechanisms could exacerbate respiratory disorders. There is no evidence that the herbicides used in Vietnam alter such defense mechanisms. However, several laboratory studies have shown that treatment of mice with TCDD increases their mortality after infection with influenza virus (Burleson et al., 1996; Warren et al., 2000). Treatment with TCDD also suppressed the animals’ ability to generate an immune response to the virus (Mitchell and Lawrence, 2003). The mechanism underlying increased influenza mortality was not related to the suppression of the immune response

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

to influenza by TCDD but appeared to involve an increase in the inflammatory response associated with an increased flow of neutrophils into the lung (Mitchell and Lawrence, 2003). Teske et al. (2008) investigated the mechanism by which AHR activation influences the pulmonary immune response to viral infection. They demonstrated that the enhanced migration of neutrophils to the infected lung is caused by AHR-driven events extrinsic to the immune system; this suggests that AHR-mediated events within the lung influence neutrophil recruitment, and thereby alter the outcome of respiratory viral infection. Neutrophils produce several toxic products (which kill pathogens), so it is possible that excess neutrophils in the lung produce excess collateral damage and pathologic changes that increase mortality.

Chiba et al. (2012) recently reviewed the role of the AHR in the pathology of asthma and COPD. The authors suggest that AHR activation by TCDD and dioxin-like compounds in cigarette smoke promotes inflammation and the exacerbation of asthma and COPD through the arachidonic acid cascade, cell differentiation, cell-cell adhesion interactions, cytokine expression, and mucin production. Thus, it is biologically plausible that exposure to TCDD results in exacerbation of acute lung disease that is associated with reduced immune responses or of chronic lung diseases, including COPD, that are associated with increased inflammatory responses.

Synthesis

Noncancerous Respiratory Disease (Without Further Specification)

Results of the studies of mortality from noncancerous respiratory diseases reported in Update 2008 and earlier VAO reports (ADVA, 2005b,c; Anderson et al., 1986; Becher et al., 1996; Blair et al., 1983, 2005; Boehmer et al., 2004; Bullman and Kang, 1996; Burns et al., 2001; Coggon et al., 1986, 1991; Consonni et al., 2008; Crane et al., 1997a; Ketchum and Michalek, 2005; Kogevinas et al., 1997; Ott and Zober, 1996; Ramlow et al., 1996; Steenland et al., 1999; Svensson et al., 1995; ’t Mannetje et al., 2005; Zober et al., 1994) did not support the hypothesis that exposures to herbicides or TCDD are associated with the general category of noncancerous respiratory diseases.

A study of the prevalence of self-reported physician-confirmed respiratory problems in a subset of ACC personnel (Kang et al., 2006) was reviewed in Update 2006. Comparison of deployed with nondeployed veterans indicated an association (odds ratio [OR] = 1.41, 95% CI 1.13–1.76), as did comparison of those who reported spraying herbicides in Vietnam with those who did not (OR = 1.62, 95% CI 1.26–2.05). In the subset of subjects whose serum TCDD concentrations had been determined, however, people who had respiratory problems were evenly distributed above and below the median, and this argues against the association with herbicide exposure.

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

Another study of the ACC cohort (Cypel and Kang, 2010) that addressed the mortality experience of the entire cohort was considered in Update 2010. An increase in mortality due to respiratory disease was statistically significant when the deployed veterans were compared with men in the US population (SMR = 1.58, 95% CI 1.08–2.23). That observation contrasts with four occupational studies that did not report an association of death due to noncancerous respiratory disease with exposures to herbicides or TCDD (Boers et al., 2010; Collins et al., 2009a,b; McBride et al., 2009a). Similarly, a study of Finnish fishermen found that an increase in serum dioxin TEQs was not associated with mortality from noncancerous respiratory disorders (Turunen et al., 2008).

In the current update, four occupational studies of exposures to the COIs were consistent in reporting no increase in mortality due to pneumonia and the broad category of non-malignant diseases of the respiratory system (Boers et al., 2012; Manuwald et al., 2012; Ruder and Yiin, 2011; Waggoner et al., 2011).

The committee does not believe that scientific conclusions (other than that the evidence is inadequate) can be reached with regard to health outcomes that are defined vaguely, for example, by combining a wide array of disparate respiratory health outcomes into one large category of noncancerous respiratory disease. The nonspecificity of the respiratory conditions reported in these studies makes it exceedingly difficult to draw any conclusions regarding specific respiratory conditions.

Chronic Obstructive Pulmonary Disease

Ruder and Yiin (2011) reported a significant increase in COPD mortality, relative to US referent rates, in a cohort of 2,122 US PCP production workers in four plants in the NIOSH Dioxin Registry. The workers in all four plants were exposed to PCP and to its contaminating PCDDs and PCDFs. That no information on smoking was available, however, greatly limits conclusions regarding the contribution of these agents to the increase in mortality due to COPD. Table 13-2 summarizes the findings with the relevant information from previous studies.

In an earlier study of mortality in a cohort of Vietnam-era veterans who had served in the ACC, as of 1991, the deployed ACC veterans had a nonsignificant adjusted RR of 2.59 for death due to noncancerous respiratory diseases compared with their nondeployed peers (Dalager and Kang, 1997). The study by Cypel and Kang (2010) added 14 years of observation and found an increased risk of death from noncancerous respiratory diseases on the cusp of statistical significance (RR = 2.20, 95% CI 0.99–4.91). For COPD in particular, they reported a statistically significant excess mortality in deployed ACC veterans (RR = 4.82, 95% CI 1.10–21.18) compared with nondeployed ACC veterans. A similar pattern of excess COPD mortality in the deployed veterans persisted when comparisons were made with the US male population (SMR = 1.58, 95% CI 1.08–2.23). In accord with those mortality data, a morbidity survey of 2,927 of the ACC veterans

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TABLE 13-2 Selected Epidemiologic Studies—COPD and Pulmonary Function (Shaded Entries Are New Information for This Update)

Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
VIETNAM VETERANS
US Vietnam Veterans

US VA Cohort of Army Chemical Corps—Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 nondeployed) serving during Vietnam era (07/01/1965–03/28/1973)

All COIs

Through 2005—Mortality

Cypel and Kang, 2010

Deployed veterans (2,872) vs nondeployed (2,737)

Respiratory system disease

32 vs 8 2.2 (1.0–4.9)

COPD

20 vs 2 4.8 (1.1–21.2)

ACC deployed men in Kang et al. (2006) reported sprayed herbicide vs did not spray

Respiratory system disease

    8 2.2 (0.4–11.8)

Pulmonary disease (COPD)

    6 3.6 (0.4–32.1)

US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed

All COIs

Incidence

Physical health—ORs from pulmonary-function tests (case definition: ≥ 80% predicted value)

CDC, 1988

FEV1

254 0.9 (0.7–1.1)

FVC

177 1.0 (0.8–1.3)

FEV1/FVC

152 1.0 (0.8–1.3)
International Vietnam-Veteran Studies

Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters during 5/23/1962–7/1/1973 vs Australian population

All COIs

Mortality

All branches, return–2001

ADVA, 2005b

Respiratory system disease

239 0.8 (0.7–0.9)

COPD

128 0.9 (0.7–1.0)

Navy

Respiratory system disease

  50 0.8 (0.6–1.0)

COPD

  28 0.9 (0.6–1.3)

Army

Respiratory system disease

162 0.8 (0.7–0.9)

COPD

  81 0.9 (0.7–1.0)

Air Force

Respiratory system disease

  28 0.6 (0.4–0.9)

COPD

  18 0.8 (0.4–1.2)
Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

1980–1994

CDVA, 1997a

Noncancerous respiratory mortality (ICD-9 460–519)

Chronic obstructive airways disease (ICD-9 460–496)

  47 0.9 (0.7–1.2)
Australian Conscripted Army National Service (18,940 deployed vs 24,642 nondeployed) Mortality All COIs

1966–2001

ADVA, 2005c

Respiratory diseases

  18 1.1 (0.6–2.2)

COPD

    8 1.0 (0.3–2.8)
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates

BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)

Focus on TCDD

Incidence

Through 1989 (n = 158 men exposed within 1 yr of accident vs 161 other BASF employees 1953–1969)

Zober et al., 1994

All noncancerous respiratory diseases (ICD-9 460–419)

  nr 33.7/31.0 (p = 0.22)

COPD (ICD-9 490–496)

  nr 8.0/7.5 (p = 0.31)
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997) Dioxins, phenoxy herbicides

Monsanto workers (n = 240) involved in 2,4,5-T production (1948–1969) and 163 unexposed workers, results of clinical examination July, 1979—morbidity

Suskind and Hertzberg, 1984

“Abnormal” outcome on pulmonary-functions tests:

FEV1 (< 80% predicted)

  32 2.81 (p = 0.02)

FVC (< 80% predicted)

  35 2.25 (p = 0.03)

FEV1/FVC (< 70%)

  32 2.97 (p = 0.01)

FEF25–75 (< 80% predicted)

  47 1.86 (p = 0.05)
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Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, Washington, and Wichita, Kansas) and workers who made PCP and TCP at two additional plants (in Midland, Michigan, and Sauget, Illinois)

2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011

1940–2005 (n = 2,122)

  63 1.4 (0.1–1.8)

PCP and TCP (n = 720)

  10 0.7 (0.3–1.3)

PCP (no TCP) (n = 1,402)

  53 0.7 (0.3–2.2)

Preliminary NIOSH Cross-sectional Medical Study—workers in production of sodium trichlorophenol, 2,4,5-T ester contaminated with TCDD—morbidity

Chronic bronchitis and COPD

    2 nr Sweeney et al., 1997/98

ORs for increase in 1 ppt of serum TCDD compared to unexposed workers

Calvert et al., 1991

Chronic bronchitis

  nr 0.5 (0.1–2.6)

COPD

  nr 1.2 (0.5–2.8)
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)

UNITED STATES

US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916 men), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; followups with CATIs 1999–2003 and 2005–2010 Mortality (COPD)

Phenoxy herbicides

Enrollment through 2007, vs state rates

SMR Waggoner et al., 2011

Applicators (n = 1,641)

165 0.3 (0.3–0.4)

Spouses (n = 676)

  50 0.3 (0.2–0.4)

Enrollment through 2000, vs state rates

Blair et al., 2005

Private applicators (men and women) Spouses of private applicators (> 99% women)

  50
  15
0.2 (0.2–0.3) 0.3 (0.2–0.7)
ENVIRONMENTAL
Seveso, Italy, Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9 171) TCDD
Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

Mortality

25-yr followup to 2001—men and women

Consonni et al., 2008

COPD (ICD-9 490–493)

Zone A

    7 2.5 (1.2–5.3)

Zone B

  26 1.3 (0.9–1.9)

Zone R

175 1.2 (1.0–1.4)

20-yr followup to 1996

Bertazzi et al., 2001

COPD (ICD-9 490–493)

  29 1.5 (1.1–2.2)

Zone A

    7 3.3 (1.6–6.9)

Zone B

  22 1.3 (0.9–2.0)

15-yr followup to 1991—men

Bertazzi et al., 1998

COPD (ICD-9 490–493)

Zone A

    4 3.7 (1.4–9.8)

Zone B

    9 1.0 (0.5–1.9)

Zone R

  74 1.2 (0.9–1.5)

15-yr followup to 1991—women

Bertazzi et al., 1998

COPD (ICD-9 490–493)

Zone A

    1 2.1 (0.3–14.9)

Zone B

    8 2.5 (1.2–5.0)

Zone R

  37 1.3 (0.9–1.9)

10-yr followup to 1986—men (Zones A, B, R)

Bertazzi et al., 1989a

COPD (ICD-9 490–493)

  31 1.1 (0.8–1.7)

10-yr followup to 1986—women (Zones A, B, R)

Bertazzi et al., 1989a

COPD (ICD-9 490–493)

    8 1.0 (0.5–2.2)

NOTE: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; COPD, chronic obstructive pulmonary disease; FEF25–75, forced midexpiratory flow; FEV1 forced expiratory volume in 1 second; FVC, forced vital capacity; IARC, International Agency for Research on Cancer; ICD-9, International Classification of Diseases, Ninth Revision; MOS, months of service; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; OR, odds ratio; PCP, pentachlorophenol; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veterans Affairs.

aGiven when available; results other than estimated risk explained individually.

(deployed and nondeployed) conducted in 1999–2000 (Kang et al., 2006) found a significant increase in the broader category of self-reported noncancerous respiratory conditions in deployed ACC veterans (OR = 1.41, 95% CI 1.13–1.76) which was also significantly related to reported use of herbicides in Vietnam (OR = 1.62, 95% CI 1.28–2.05); it used a multiple logistic regression mode: with adjustments for age, race, body-mass index, rank, and smoking. Among the deployed ACC veterans who had participated in the morbidity study, only 120

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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deaths had occurred by the end of 2005, so when Cypel and Kang (2010) assessed mortality associated with self-reported herbicide use, adjusted for smoking status, the estimated increase in COPD (adjusted RR = 3.55) had a 95% CI spanning 2 orders of magnitude (0.39–32).

Other studies of US Vietnam veterans, including the Operation Ranch Hand cohort, have found no significant increase in mortality due to the broader classification of noncancerous respiratory mortality (Anderson et al., 1986; Boehmer et al., 2004; Ketchum and Michalek, 2005) but have not addressed causes of death as specific as COPD. The Vietnam Experience Study (CDC, 1988) did not find evidence of compromised lung function; there have been no integrated publications on specific aspects of respiratory morbidity in the Ranch Hand cohort. Studies of the full cohort of male Australian Vietnam veterans vs the general population (ADVA, 2005b; CDVA, 1997a) and of deployed vs nondeployed Australian Army National Service (conscripted) veterans (ADVA, 2005c; CDVA, 1997b) also showed no suggestion of increased mortality from COPD or noncancerous respiratory disorders.

Almost all the studies of mortality in industrial cohorts considered in the VAO updates assessed only the nonspecific category of mortality due to noncancerous respiratory disease, and no significant excesses were reported (Becher et al., 1996; Burns et al., 2001; Kogevinas et al., 1997; Ott and Zober, 1996; Steenland et al., 1999; ’t Mannetje et al., 2005). Only an earlier mortality study of Dow Chemical Company TCP workers (Ramlow et al., 1996) reported on a more specific type of respiratory death, emphysema, which was not significantly increased. Only three studies of morbidity related to COPD in industrial populations have been considered in the VAO updates. Increases in the ORs for measures of abnormal pulmonary function were reported in workers at a 2,4,5-T plant in Nitro, West Virginia (Suskind and Hertzberg, 1984), but the other two cross-sectional studies of COPD prevalence had negative findings. Zober et al. (1994) found that episodes of COPD in workers at a BASF plant in Germany were not associated with TCDD exposure. The NIOSH cross-sectional study of production workers exposed to TCDD (Calvert et al., 1991) did not show an increase in COPD or chronic bronchitis or in altered pulmonary function measures associated with increased serum TCDD concentration in workers compared with a community-based referent population.

Waggoner et al. (2011) reported mortality in the AHS from the time of enrollment (1993–1997) through 2007. Death due to COPD was significantly decreased in applicators and their spouses. An early agricultural study (Senthilselvan et al., 1992) found no relationship between self-reported asthma and the use of phenoxy herbicides. Recently, the AHS has generated a number of publications with COPD-related findings. First, Blair et al. (2005) found significant decreases in mortality due to COPD in private applicators and their spouses compared with state rates, which may be due to the healthy-worker effect and the inability to adjust for low tobacco use. Analyses, with adjustment for smoking, of self-reported

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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prevalence at enrollment (1993–1997) and prior exposure to phenoxy herbicides found indications of associations with chronic bronchitis in farmers (mostly men) that were significant for 2,4,5-T and 2,4,5-TP (Hoppin et al., 2007b) but only a 20% nonsignificant increase in nonsmoking farm women (Valcin et al., 2007); some association of phenoxy herbicide exposure with allergic asthma was evident (significant for 2,4-D in women and 2,4,5-T in men), but the association with nonallergic asthma in men (Hoppin et al., 2009) or women (Hoppin et al., 2008) was not so clear. The AHS has been generating valuable information on the COIs for a number of years, but these results, like those in Alavanja et al. (2005) and Blair et al. (2005), are not herbicide-specific and so are not regarded as being fully informative for the committee’s task.

Mortality studies of the Seveso incident have reported an emerging picture of increased risk of death from COPD (Bertazzi et al., 1998, 2001; Consonni et al., 2008; Pesatori et al., 1998) with higher and significant RRs found in the zone (A) closest to the accident and somewhat lower RRs in the outlying zones. Adjustment for smoking has not been possible for the Seveso cohort. In the only other relevant environmental study, Svensson et al. (1995) assumed that TCDD exposure was higher because of fish consumption by Swedish fishermen but found no increase in mortality from bronchitis or emphysema. Dahlgren et al. (2003) reported that the prevelance of chronic bronchitis was positively associated with environmental exposure to creosote and PCP emissions from a wood-processing plant, but strong concerns about bias are raised by the fact that the study sample was composed of plaintiffs in a lawsuit. There have been no other studies of environmental exposure to the COIs and COPD-related morbidity.

The large increase in relative risk of mortality from COPD in the ACC cohort that served in Vietnam (Cypel and Kang, 2010) motivated the committee to request additional information from Cypel and Kang (March 3, 2011, reply is available on request from the VAO public-access file). The committee learned that the six deaths from “pulmonary disease” among deployed ACC veterans in the morbidity study (Table 5 in the 2010 paper) were indeed COPD cases; among the nondeployed ACC veterans in the morbidity study, there had been only one death from respiratory disease, and it had not been from COPD; and all the respiratory deaths had been in smokers. Conclusions from analysis of COPD mortality in the ACC morbidity-study subset are limited by the very small number of deaths that had occurred by the end of 2005 and by the fact that this subset cannot be considered representative of the entire ACC cohort in that its members were all alive in 1999. Information on smoking status is available only on the people who participated in the 1999–2000 morbidity survey (of the 2,972 subjects, 71.5% of the deployed vs 60.1% of the nondeployed smoked), so the researchers lacked the ability to adjust the RR of COPD mortality in the entire ACC cohort (5,609). Because cigarette-smoking is the major cause of COPD, the committee viewed this as strongly constraining the conclusions that could be drawn from the ACC data overall.

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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The committee for Update 2010 consulted with Paul Enright, of the University of Arizona, a medical expert on COPD. That consultation increased concern (as delineated at the beginning of this section on respiratory diseases) that causes of death from COPD are frequently misclassified on death certificates. The common presence of comorbid conditions in people who have COPD makes it difficult to deduce a single contributing cause of death. Furthermore, it was emphasized that COPD is often incorrectly diagnosed in prevalence investigations, and there is considerable debate about the appropriate diagnosic criteria for COPD, particularly in relation to the normal decrease in capacity with age (Celli and Halbert, 2010a,b; Enright and Brusasco et al., 2010a,b).

Thus, the committee for Update 2010 concluded that it could not base a conclusion about an association with COPD on mortality data, given the questionable nature of death-certificate information on COPD and the routine inability to adjust for smoking. That committee said that additional studies of the incidence of COPD, based on rigorous criteria for its diagnosis and adjustment for smoking, would be particularly valuable in resolving whether there is evidence to support an association with exposure to the COIs.

The small amount of new data provided to the current committee did not alter its concurrence with the conclusions of the Update 2010 committee. The Department of Veterans Affairs informed the present committee that it has undertaken a morbidity followup on the ACC cohort, taking heed of the previous committee’s suggestions, but it will be more than a year before results are released.

Other Specific Respiratory Diseases

There is still not a coherent body of epidemiology evidence to support conclusions as to whether the risks of other particular respiratory problems are associated with exposure to the COIs.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence of an association between exposure to the COIs and mortality from all noncancerous respiratory diseases or from COPD specifically. There is also inadequate or insufficient evidence of an association between exposure to the COIs and the prevalence of respiratory diseases, such as wheeze or asthma, COPD, and farmer’s lung.

GASTROINTESTINAL AND DIGESTIVE DISEASES, INCLUDING LIVER TOXICITY

This section discusses a variety of conditions encompassed by the International Classification of Diseases, Ninth Revision (ICD-9, codes 520–579): dis-

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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eases of the esophagus, stomach, intestines, rectum, liver, and pancreas. 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 functions of the gastrointestinal tract are to absorb nutrients and eliminate waste. Those complex tasks involve numerous chemical and molecular interactions on the mucosal surface and complex local and distant neural and endocrine activity. One common condition of the gastrointestinal tract is motility disorder, which might be present in 15% of adults. The most convenient way to categorize diseases that affect the gastrointestinal system is according to the effected anatomic segment. Esophageal disorders predominantly affect swallowing; gastric disorders are related to acid secretion; and conditions that affect the small and large intestines are reflected in alterations in nutrition, mucosal integrity, and motility. Some systemic disorders (inflammatory, vascular, infectious, and neoplastic conditions) also affect the gastrointestinal system.

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 or duodenal mucosa. Peptic-ulcer disease is characterized as gastric or duodenal ulcer, depending on the site of origin. Peptic-ulcer disease occurs when the corrosive action of gastric acid and pepsin overcomes the normal mucosal defense mechanisms that protect against ulceration. About 10% of the population has clinical evidence of duodenal ulcer at some time in life; a similar percentage is affected by gastric ulcer. The incidence of duodenal ulcer peaks in the fifth decade, and the incidence of gastric ulcer about 10 years later.

Evidence increasingly indicates that the bacterium Helicobacter pylori is linked to peptic-ulcer disease (both duodenal and gastric). H. pylori colonizes the gastric mucosa in 95–100% of patients who have duodenal ulcer and in 75–80% of patients who have gastric ulcer. Healthy people 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 who have H. pylori colonization will develop ulcers in their lifetimes. Other risk factors include genetic predisposition (such as some blood and human leukocyte antigen [HLA] types), cigarette-smoking, and psychologic factors (chronic anxiety and stress).

Liver Disease

Blood tests that reflect liver function are the mainstay of diagnosis of liver disease. Increases in serum bilirubin and in the serum concentrations of some hepatic enzymes—aspartate aminotransferase, alanine aminotransferase, alkaline

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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phosphatase, and γ-glutamyltransferase (GGT)—are commonly noted in liver disorders. The relative sensitivity and specificity of those enzymes for diagnosing liver disease vary, and diagnosis can require several tests. The only regularly reported abnormality in liver function associated with TCDD exposure in humans is an increase in GGT. Estimated serum activity of that enzyme is a sensitive indicator of a variety of conditions, including alcohol and drug hepatotoxicity, infiltrative lesions of the liver, parenchymal liver disease, 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 use (often associated with increased GGT) make interpretation of changes in GGT in exposed people difficult (Calvert et al., 1992). An increase in GGT can be considered a normal biologic adaptation to chemical, drug, or hormone exposure.

Cirrhosis is the most commonly reported liver disease in epidemiologic studies of herbicide or TCDD exposure. Cirrhosis is irreversible chronic injury of the liver with extensive scarring and resulting loss of function. Clinical symptoms and signs include jaundice, edema, abnormalities in blood clotting, and metabolic disturbances. Cirrhosis can lead to portal hypertension with associated gastroesophageal varices, enlarged spleen, abdominal swelling attributable to ascites, and ultimately hepatic encephalopathy that can progress to coma. It generally is impossible to distinguish the various causes of cirrhosis by using 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 are chronic viral infection (hepatitis B or hepatitis C), the poorly understood condition primary biliary cirrhosis, chronic right-sided heart failure, and a variety of less common metabolic and drug-related conditions.

Conclusions from VAO and Previous Updates

Some studies that have been reviewed by previous VAO committees focused on liver enzymes, and others reported specific liver diseases. Evaluation of the effects of herbicide and TCDD exposure on noncancer gastrointestinal ailments is challenging in that clinical experience suggests that medical history and physical examination are undependable diagnostic tools for some ailments, so incidence data are sometimes problematic. The strong interdependence among the characteristics of a given person (such as weight and laboratory indexes of hepatic function and health) and TCDD body burden complicates the already difficult task of assessing association.

Most of the analyses of occupational or environmental cohorts have had insufficient numbers of cases to support confident conclusions. Study of the International Agency for Research on Cancer cohort of phenoxy-herbicide and chlorophenol production workers and sprayers (Vena et al., 1998), the only study that had a relatively large number of observations, found less digestive system

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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disease and cirrhosis mortality in exposed workers than in nonexposed controls. A study that compared Australian veterans with the general population (O’Toole et al., 1996) suggested a higher incidence of stomach and duodenal ulcers in both men and women, but the information was self-reported and the analyses were not controlled for confounding influences.

A report from the AFHS (2000) found a significantly higher percentage of other liver disorders in the Ranch Hand veterans in the high-dioxin category than in the Southeast Asia comparison subjects. The excesses were primarily of transaminase and other nonspecific liver abnormalities. Data were consistent with an interpretation of a dose–response relationship, but other explanations were also plausible. There have been later reports (AFHS, 2005) of some abnormalities in liver enzymes in the Ranch Hand cohort, including decreasing C4 complement as dioxin increased; abnormal triglyceride concentrations also increased as the 1987 dioxin concentration increased. Mortality studies of the Ranch Hand cohort, however, have not found increased mortality related to gastrointestinal or liver disease (Ketchum and Michalek, 2005).

A study of ACC Vietnam veterans reported in Update 2006 found an increased rate of hepatitis associated with Vietnam service but not with a history of spraying herbicide (Kang et al., 2006). Likewise, the Australian Vietnam-veterans study (ADVA, 2005b) did not find an increase in liver disease in military personnel who served in Vietnam compared with the general population of Australia.

Update 2008 reviewed the mortality results through 2001 for the Seveso cohort in Italy (Consonni et al., 2008) and found no excess of deaths related to digestive diseases or related specifically to cirrhosis.

Additional analyses of the mortality experience of the ACC veterans were reviewed in Update 2010 (Cypel and Kang, 2010). There was about an 80% excess of digestive system or cirrhosis deaths observed in veterans who handled or sprayed herbicides in Vietnam compared with non-Vietnam veteran peers, but chance could not be excluded as an explanation. A survey of self-reported health problems of Australian veterans indicated an excess of a variety of gastrointestinal problems, including diseases of the esophagus, ulcer, and irritable bowel syndrome but not gallstones (O’Toole et al., 2009); however, multiple methodologic weaknesses—including a low response rate, lack of specific exposure information, and the inherent problems associated with self-reported health conditions—make the findings of this study unpersuasive. Several mortality studies of various occupational cohorts exposed to COIs were reviewed (Boers et al., 2010; Collins et al., 2010a,b; McBride et al., 2009a,b). Those studies have been inconsistent but generally found no statistically significance increases in deaths from either ulcers or cirrhosis, although Collins et al. (2009b) found an increase in stomach and duodenal ulcer deaths in 773 workers who were exposed to chlorinated dioxins other than TCDD in the production of PCP.

Thus, the reports have been inconsistent, and interpretation of individual studies is difficult because of a lack of information on alcohol consumption and

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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other risk factors. In the studies that showed the strongest association between potential exposure and gastrointestinal disease (specifically cirrhosis), there was strong evidence that excess alcohol consumption was the cause of the cirrhosis.

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and gastrointestinal and digestive disease, including liver toxicity. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010 did not change that conclusion.

Update of the Epidemiologic Literature

Vietnam-Veteran, Environmental, and Case-Control Studies

No Vietnam-veterans studies, environmental studies, or case-control studies of exposure to the COIs and gastrointestinal and digestive disease have been published since Update 2010.

Occupational Studies

Four updated mortality analyses of occupational cohorts exposed to COIs with information on gastrointestinal and digestive disease have been published since Update 2010.

Boers et al. (2012) reanalyzed mortality data from two Dutch chemical manufacturing plants focusing on TCDD exposure. Exposure estimates were derived by using blood TCDD concentrations measured in a subsample of workers in the two plants and back-extrapolating to exposures in different departments in the plants. No TCDD was generated during the manufacturing of 2,4-D in plant B, so TCDD exposure was limited to workers in plant A, which manufactured 2,4,5-T and other chemicals. The study included all workers employed from 1955 through 1985 with mortality followup until December 31, 2006. Causes of 12 deaths were attributed to the digestive system (ICD-10 codes K00-K92). There was no evidence of an increase in mortality with increasing TCDD exposure. For workers in plant A, the HR for each log-unit increase in TCDD concentration was 0.74 (95% CI 0.48–1.15) after adjustment only for age.

Ruder and Yiin (2011) examined the mortality experience of 2,122 workers who had been employed at plants manufacturing PCP from 1940 to 2005. In the total cohort, 46 deaths were attributed to diseases of the digestive system; this was consistent with the mortality experience of the US population generally (SMR = 0.98, 95% CI 0.72–1.30). There were 15 digestive system deaths in the 720 workers who were exposed to both PCP and TCP; this also was not more than expected (SMR = 0.96, 95% CI 0.54–1.58). The results were effectively the

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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same for those who had not had any opportunity for occupational exposure to TCDD (SMR = 0.99, 95% CI 0.68–1.39).

Manuwald et al. (2012) reported on the mortality experience of 1,191 men and 398 women who were employed full-time for at least 3 months at a German plant that manufactured 2,4,5-T. Deaths were ascertained through 2007, 23 years after the plant’s closure. The report updates several previous reports (Becher et al., 1996; Flesch-Janys et al., 1995; Manz et al., 1991). For each worker, total cumulative exposure to TCDD was calculated as the sum of the cumulative exposures in each of the workplaces where the worker had been employed. In neither men nor women were deaths from digestive system causes significantly increased on the basis of the expected mortality pattern derived from regional administrative data (SMRmen = 1.09, 95% CI 0.76–1.51; SMRwomen = 0.59, 95% CI 0.21–1.28). Deaths from liver cirrhosis were 22 of 36 deaths from diseases of the digestive system in men and three of six in women. The number of cirrhosis deaths in men was somewhat higher than expected, but chance could not be ruled out (SMR = 1.26, 95% CI 0.79–1.90).

Waggoner et al. (2011) reported on the mortality experience in 1993–2005 of pesticide applicators and their spouses in the AHS and found no evidence of an association between status as an applicator or an applicator’s spouse with mortality from digestive causes. In fact, the applicators had significantly fewer than expected deaths from digestive system diseases overall and from cirrhosis and other liver diseases. The AHS has been generating valuable information on the COIs for a number of years, but these results are not herbicide-specific and so are not regarded as being fully informative for the committee’s task.

Biologic Plausibility

The liver is a primary target for the toxicity of many chemicals. It is the first organ that encounters chemicals absorbed from the gastrointestinal tract and is responsible for metabolizing them to water-soluble chemicals that can be excreted in the urine. Because the liver has many detoxifying enzymes that efficiently metabolize many chemicals, liver toxicity is usually associated only with high-dose acute exposure or lower-dose chronic exposure. The liver can be damaged if metabolism of a chemical results in the production of a reactive intermediate that is more toxic than the parent chemical. Changes in serum concentrations of liver enzymes are biomarkers of liver toxicity, and their magnitude correlates with the degree of liver damage. Exposure of laboratory animals to high doses of 2,4-D, 2,4,5-T, and TCDD is known to cause liver damage. The mechanisms by which the phenoxy herbicides damage the liver is based on inhibition of mitochondrial function by blocking of oxidative phosphorylation; this leads to loss of generation of adenosine triphosphate, death of cells, and hepatic necrosis and fibrosis. TCDD-induced hepatotoxicity is mediated by activation of the AHR, which leads to changes in gene transcription and associated changes in cell function. Changes

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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in gene expression are associated with several physiologic processes, oxidative stress, and apoptosis (Boverhof et al., 2005, 2006). TCDD-mediated hepatic steatosis is characterized by the accumulation of triglyceride due to the combined up-regulation of CD36/fatty acid translocase and fatty acid transport proteins, suppression of fatty acid oxidation, inhibition of hepatic export of triglycerides, increase in peripheral fat mobilization, and increased hepatic oxidative stress (Lee et al., 2010). Exposure of rats to TCDD over a 2-year period (NTP, 2004) also produced several changes in the liver, including hepatocyte hypertrophy, multinucleated hepatocytes, inflammation, pigmentation, diffuse fatty change, necrosis, bile duct hyperplasia, bile duct cyst, nodular hyperplasia, portal fibrosis, and cholangiofibrosis.

The AHR displays species differences; for example, the human and mouse AHR C-terminal region sequences share only 58% of amino acid sequence identity. Compared with the mouse AHR (mAHR), the human AHR (hAHR) has about 10-fold lower relative affinity for TCDD; the difference has been attributed to the amino acid residue valine 381 in the ligand-binding domain of the hAHR (Flaveny et al., 2009; Ramadoss and Perdew, 2004). Species differences associated with AHR activation are supported by the divergence in the transcriptomic responses to TCDD in mouse, rat, and human liver (Boutros et al., 2008, 2009; Carlson et al., 2009; Kim et al., 2009). In a recent study, gene-expression changes were compared in adult female primary human and rat hepatocytes exposed to TCDD in vitro (Black et al., 2012). Whole-genome microarrays found that TCDD produced divergent gene-expression profiles in rat and human hepatocytes, both on an ortholog basis (conserved gene in different species) and on a pathway basis. For commonly affected orthologs or signaling pathways, the human hepatocytes were about 15-fold less sensitive than rat hepatocytes. Such findings are consistent with epidemiologic studies that have shown humans to be less sensitive to TCDD-induced hepatotoxicity. However, it should be noted that those in vitro human hepatocyte studies may not reflect the in vivo response of human liver to TCDD.

Few health-relevant effects of phenoxy herbicides or TCDD on the gastrointestinal tract, even after high exposure, have been reported. Thus, the animal data do not support a plausible link between herbicide exposure and gastrointestinal toxicity in Vietnam veterans.

Synthesis

Reports of increased risk of abnormal liver-function tests have been mixed, but evidence is lacking that Vietnam veterans are at greatly increased risk for serious liver disease, peptic ulcers, or other specific gastrointestinal diseases. Data on other populations exposed to COIs also do not suggest a strong connection. The studies are limited primarily to analyses of mortality. The possibility of a relationship between dioxin exposure and subtle alterations in the liver and

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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in lipid metabolism cannot be ruled out, but clinically important effects on the gastrointestinal system have not been demonstrated.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and gastrointestinal and digestive diseases.

THYROID HOMEOSTASIS

Clinical disruptions of thyroid function include various disorders grouped in ICD-9 as codes 242.8 and 246.8. The thyroid secretes the hormones thyroxine (T4) and triiodothyronine (T3), which stimulate and help to regulate metabolism throughout the body. 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. Iodine operates in thyroid physiology both as a constituent of thyroid hormones and as a regulator of glandular function. Concentrations of those circulating hormones are regulated primarily by a negative-feedback pathway that involves three organs: the thyroid, the pituitary, and the hypothalamus. In the hypothalamus-pituitary-thyroid feedback scheme, the hypothalamus releases thyrotropin-releasing hormone (TRH), which stimulates the pituitary 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, which increases T4 and T3 output. When circulating T4 and T3 are high, they signal to reduce the output of TRH and TSH. The negative-feedback loop maintains hormone homeostasis.

Disruption of thyroid homeostasis can be stimulatory (hyperthyroidism) or suppressive (hypothyroidism). Both conditions are diagnosed on the basis of blood concentrations of thyroid hormones, TSH, and other proteins (antithyroid antibodies). The prevalence of thyroid dysfunction in adults in the general population ranges from 1% to 10%, depending on the group, the testing setting, sex, age, method of assessment, and the presence of conditions that affect thyroid function. People who have subclinical (biochemical) conditions may or may not show other evidence (signs or symptoms) of thyroid dysfunction.

In hypothyroidism, the body lacks sufficient thyroid hormone. Overt hypothyroidism is seen as a high serum concentration of TSH and a low serum concentration of free T4. Subclinical hypothyroidism is defined as a high serum concentration of TSH and a normal serum concentration of free T4. People who have hypothyroidism typically have symptoms of low metabolism. Studies

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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consistently show that subclinical hypothyroidism is common and occurs more frequently in women than in men (Canaris et al., 2000; Hollowell et al., 2002; Sawin et al., 1985). In the Framingham study, for example, among 2,139 people 60 years old or older, 14% of women and 6% of men had subclinical hypothyroidism (Sawin et al., 1985). Subclinical hypothyroidism is a risk factor for overt hypothyroidism. Studies have reported association of hypothyroidism with a wide variety of other conditions.

The term hyperthyroidism may involve any disease that results in overabundance of thyroid hormone. Clinical or overt hyperthyroidism is characterized as a low serum concentration of TSH and high serum concentration of free T4. Subclinical hyperthyroidism is defined as a low serum concentration of TSH and a normal serum concentration of free T4. The prevalence of subclinical hyperthyroidism was estimated at about 1% in men and 1.5% in women over 60 years old (Helfand and Redfern, 1998). Conditions associated with hyperthyroidism include Graves disease and diffuse toxic goiter. Like hypothyroidism, hyperthyroidism is more common in women than in men, and although it occurs at all ages, it is most likely to occur in people more than 15 years old. A form of hyperthyroidism called neonatal Graves disease occurs in infants born to mothers who have Graves disease. Occult hyperthyroidism may occur in patients more than 65 years old and is characterized by a distinct lack of typical symptoms.

It is important to distinguish between potential effects on adults and effects that may occur during development. In adults, the thyroid is able to compensate, within reason, for mild or moderate disruption (such as that caused by hyperplasia or goiter). In contrast, the fetus is highly sensitive to alterations in thyroid hormones, and alterations in thyroid homeostasis can hamper the development of many organ systems, including the nervous and reproductive systems; such findings are discussed in Chapter 10, which addresses potential effects of Vietnam veterans’ exposure to herbicides on their offspring. Only observations on adults are considered here.

Summary of Previous Updates

Koopman-Esseboom et al. (1994) found an association between dioxin-like congeners and markers of disrupted thyroid homeostasis. The report focused on TCDD and maternal thyroid function during pregnancy and therefore is less relevant to the experience of the predominantly male Vietnam veterans.

Extensive assessment of endocrine function, including a series of thyroid-function tests, was carried out in connection with the Operation Ranch Hand study (AFHS, 1991b). It failed to show any difference in thyroid function between exposed and control veterans. When individual TCDD readings had been obtained for subjects in the AFHS, however, Pavuk et al. (2003) found statistically significantly increased TSH measures from the 1985 and 1987 examinations in the high-exposure category and a significant increasing trend across the

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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three TCDD categories in data gathered during the 1982, 1985, 1987, and 1992 examinations. Other studies of veterans of the Vietnam War have not documented an increased risk of thyroid disease.

Calvert et al. (1999) provided evidence of higher adjusted mean free-T4 concentrations in TCDD-exposed workers, but there was no dose–response relationship with serum TCDD. Bloom et al. (2006) found indications of an inverse relationship between the sum of dioxin-like chemicals and the concentration of free T4 in anglers in New York State but no association between the sum of dioxin-like chemicals and TSH or T3. Abdelouahab et al. (2008) described thyroid function in adult freshwater-fish consumers in Canada; dioxin-like congeners were associated with an increase in TSH and a decrease in T4 but below the threshold at which clinical symptoms would be present. An analysis of 1999–2002 National Health and Nutrition Examination Survey (NHANES) data (Turyk et al., 2007) found total T4 to have a weak inverse relationship with serum TEQs; the effect was somewhat stronger in people over 60 years old and in women compared with men.

The committee for Update 2008 concurred with previous committees that there was inadequate or insufficient evidence of an association between exposure to the COIs and clinical or overt adverse effects on thyroid homeostasis. Prior committees had also noted increasing evidence of an association between exposure to some COIs and changes in markers of thyroid function below the threshold of clinical symptoms, perhaps because of the adaptive capacity of the adult system to accommodate such variation.

Several studies of thyroid disease were considered in Update 2010. Goldner et al. (2010) published negative results for an association between phenoxy herbicide exposures and self-reported history of physician-diagnosed thyroid disease in women in the AHS. Clear effects of dioxin-like chemicals on thyroid function were not apparent in Inuit adults (Dallaire et al., 2009), in a cross-sectional study of a Chinese community exposed to an electronic-waste recycling plant (Zhang et al., 2010), or in women enrolled at the Center for the Health Assessment of Mothers and Children of Salinas in California (CHAMACOS; Chevrier et al., 2008). Schreinemachers (2010) did not find associations of recent exposure to 2,4-D with T4 and TSH concentrations in subjects in NHANES III (1988–1994).

Table 13-3 summarizes findings of studies that have examined the association between dioxin-like congeners and markers of thyroid function.

There has been considerable study of maternal exposure and perinatal effects on thyroid function, which is not directly applicable to the adult exposure of the Vietnam veterans whose own health is the primary concern of these updates. A discussion of that material can be found in Chapter 10, on possible adverse effects on the offspring of Vietnam veterans.

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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TABLE 13-3 Selected Epidemiologic Studies—Thyroid Homeostasis

Study Population Exposed Casesa Exposure of Interest/Reported Resultsa Reference
VIETNAM VETERANS
US Vietnam Veterans

US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)

All COIs

Incidence

Cross-sectional analysis of Ranch Hand personnel (n = 1,009) and SEA veterans (n = 1,429); THS, total T4, T3%

Pavuk et al., 2003

THS uptake by TCDD category

Comparisons (SEA veterans—no TCDD spraying)

1,247 Normal = 0–3 μIU/ml

RH background (TCDD ≤ 10 ppt

  409 0.84 (p = 0.88)

RH low (TCDD > 10 ppt, ≤ 94 ppt)

  273 0.87 (p = 0.16)

RH high (TCDD > 94 ppt)

  275 0.90 (p = 0.04)

T4 (thyroxine) means by TCDD category

Normal = 4.5–11.5 μg/dl

Comparisons (SEA veterans—no TCDD spraying)

1,247 7.47

RH background (TCDD ≤ 10 ppt

  409 7.56 (p = 0.19)

RH low (TCDD > 10 ppt, ≤ 94 ppt)

  273 7.54 (p = 0.38)

RH high (TCDD > 94 ppt)

  275 7.56 (p = 0.28)

T3% (triiodothyronin) uptake by TCDD category

Normal 25%–35%

Comparisons (SEA veterans—no TCDD spraying)

1,247 30.7

RH background (TCDD ≤ 10 ppt

  409 30.7 (p = 0.19)

RH low (TCDD > 10 ppt, ≤ 94 ppt)

  273 30.7 (p = 0.98)

RH high (TCDD > 94 ppt)

  275 30.5 (p = 0.24)
International Vietnam-Veteran Study

Sample of 1,000 Male Australian Vietnam Veterans—prevalence

All COIs

450 interviewed 2005–2006 vs respondents to 2004–2005 national survey (disorders of the thyroid gland)

  450 1.4 (95% CI 0.5–2.2) O’Toole et al., 2009
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates

NIOSH Cohort—TCDD-exposed workers from 2,4,5-T plants in Newark, New Jersey, and Verona, Missouri, employed > 15 yrs earlier and matched controls (n = 260)

Calvert et al., 1999
Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Population Exposed Casesa Exposure of Interest/Reported Resultsa Reference

TSH mU/1

Adjusted mean (SE)

All workers

278 2.0 (0.1) p = 0.66

TCDD < 20

  75 2.2 (0.3) p = 0.28

20 ≤ TCDD < 75

  66 2.0 (0.3) p = 0.88

75 ≤ TCDD < 238

  66 1.9 (0.3) p = 0.94

238 ≤ TCDD < 3,400

  64 1.8 (0.3) p = 0.65

Referents (< 20)

257 1.9 (0.1)

T4 nmol/l

Adjusted mean (SE)

All workers

278 101.4 (1.0) p = 0.07

TCDD < 20

  75 102.7 (2.0) p = 0.08

20 ≤ TCDD < 75

  66 99.4 (2.1) p = 0.79

75 ≤ TCDD < 238

  66 102.7 (2.1) p = 0.09

238 ≤ TCDD < 3,400

  64 100.1 (2.2) p = 0.58

Referents (< 20)

257 98.8 (1.1)

Free T4 index nmol/l

Adjusted mean (SE)

All workers

278 27.8 (0.3) p = 0.02

TCDD < 20

  75 2.7.7 (0.5) p = 0.15

20 ≤ TCDD < 75

  66 27.4 (0.6) p = 0.36

75 ≤ TCDD < 238

  66 28.2 (0.6) p = 0.03

238 ≤ TCDD < 3,400

  64 27.7 (0.6) p = 0.19

Referents (< 20)

257 26.8 (0.3)
OCCUPATIONAL—HERBICIDE-USING
WORKERS (not related to IARC sprayer cohorts)

AUSTRALIAN 2,4,5-T in Victoria, Australia (n = 37)

2,4-D; 2,4,5-T Johnson et al., 2001

TSH vs estimated serum TCDD level

  32 Normal = 0.3–5.0μIU/ml

Based on local levels

0.2

Based on individual sampling LDs

–.03

Based on back extrapolation

–1.4 (p < 0.05)
Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Population Exposed Casesa Exposure of Interest/Reported Resultsa Reference

T4 vs estimated serum TCDD level

  32 Normal = 0.045–2.125μg/ml

Based on local levels

0.1

Based on individual sampling LDs

–0.0

Based on back extrapolation

–0.0

T3 vs estimated serum TCDD level

  32 Normal = 0.9–1.9μg/ml

Based on local levels

–0.1

Based on individual sampling LDs

–0.4 (p < 0.05)

Based on back extrapolation

–0.5 (p < 0.01)
UNITED STATES

US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916 men), private/ farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; followups with CATIs 1999–2003 and 2005–2010

Phenoxy herbicides

Incidence

Thyroid disease among female spouses (n = 19,529) in Iowa and North Carolina (1993–2003)

Goldner et al., 2010

Hyperthyroid

Self-reported 2,4-D exposure

  46 0.9 (95% CI 0.7–1.3)

Self-reported 2,4,5-T exposure

    3 NA

Self-reported dicamba exposure

  17 0.8 (95% CI 0.8–2.1)

Hypothyroid

Self-reported 2,4-D exposure

147 0.96 (95% CI 0.8–1.1)

Self-reported 2,4,5-T exposure

    7 1.0 (95% CI 0.5–2.2)

Self-reported dicamba exposure

  27 0.7 (95% CI 0.5–0.98)

Other thyroid conditions

Self-reported 2,4-D exposure

  87 1.2 (95% CI 0.95–1.5)

Self-reported 2,4,5-T exposure

    4 NA

Self-reported dicamba exposure

  19 0.96 (95% CI 0.6–1.5)
Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Population Exposed Casesa Exposure of Interest/Reported Resultsa Reference
ENVIRONMENTAL
National Health and Nutrition Examination Survey 2,4-D

NHANES III—analysis of data from subjects with detectable limits of urinary 2,4-D

Schreinemachers, 2010

TSH

Detectable 2,4-D

102 1.6 mU/L

Non-detectable 2,4-D

625 1.7 mU/L

T4

Detectable 2,4-D

102 8.5 μg/dl

Non-detectable 2,4-D

625 8.6 μg/dl

NHANES (1999–2002, 2001–2002)—Associations with TEQs in individuals without thyroid disease

Turyk et al., 2007

Men (1999–2000)

T4

402 –0.12 (–0.61 to 0.37)

TSH

402 –0.09 (–0.38 to 0.20)

Men (2000–2001)

T4

497 –0.47 (–0.97 to 0.04)

TSH

497 –0.02 (–0.20 to 0.16)

Women (1999–2000)

T4

310 –0.19 (–0.70 to 0.33)

TSH

309 –0.15 (–0.14 to 0.44)

Men (1999–2000)

T4

386 –0.58 (–1.26 to 0.10)

TSH

385 –0.06 (–0.15 to 0.35)
Other Environmental Studies

CANADA

Cross-sectional study of Inuit residents (≥ 18 yrs of age) of Nunavik (Québec, Canada)

607 dl PCBs/ correlation of dl-congeners (adjusted) Dallaire et al., 2009

TSH

0.02

fT4

–0.01

fT3

–0.03 (p < 0.05)
Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Population Exposed Casesa Exposure of Interest/Reported Resultsa Reference

Cross-sectional study of freshwater fish consumers from two Canadian communities

dl PCBs/dl-PCB congeners ß estimates Abdelouahab et al., 2008

Men

124

TSH

0.55 (p < 0.001)

T4

–2.19 (p < 0.05)

T3

–0.01

Women

  87

TSH

0.04

T4

0.04

T3

–0.01

Cross-sectional examination of serum from pregnant women attending Canadian prenatal diagnosis clinic

150 dl compounds Foster et al., 2005

TSH correlation coefficient

ns (value nr)

T4 correlation coefficient

ns (value nr)

CHINA—cross-sectional study of a Chinese community in the vicinity of an electronic-waste recycling plant—maternal serum T4 levels at 16 weeks gestation (correlations with contaminant levels in cord blood)

PCDDs, PCDFs, dl PCBs Zhang et al., 2010

dl PCBs

r = –0.413 (p = 0.01)

PCDD/Fs

r = –0.198 (p = 0.21)

JAPANESE patients exposed in 1968 during Yusho incident; blood collection from participants 1996 and 1997

  16 PCDDs, PCDFs, dl PCBS Nagayama et al., 2001

TSH correlation coefficient

0.01 (p = 0.97)

T4 correlation coefficient

0.03 (p = 0.9)

T3 correlation coefficient

–0.09 (p = 0.74)

THE NETHERLANDS—Part of the prospective longitudinal Dutch PCB/Dioxin study; 105 health mother-infant pairs living in or around Rotterdam, recruited June 1990–February 1992

Dioxins, PCBs KoopmanEsseboom et al., 1994

Maternal serum correlations with dioxin

  78

TEQs

T4

–0.4 (p ≤ 0.001)

T3

–0.5 (p ≤ 0.001)

UNITED STATES

CHAMACOS Study—334 pregnant women from Salinas Valley, California, providing blood at 26 wks gestation

dl PCBs ß (95% CI) Chevrier et al., 2008

Free T4 vs:

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Population Exposed Casesa Exposure of Interest/Reported Resultsa Reference

PCB TEQs (pg/g)

–0.05 (–0.16 to 0.06)

Mono-ortho PCBs (ng/g)

–0.09 (–0.19 to 0.01)

PCB 118 (ng/g)

–0.05 (–0.15 to 0.06)

PCB 156 (ng/g)

–0.06 (–0.13 to 0.01)

Total T4 vs:

PCB TEQs (pg/g)

0.26 (–0.45 to 0.96)

Mono-ortho PCBs (ng/g)

–0.13 (–0.78 to 0.53)

PCB 118 (ng/g)

–0.26 (–0.43 to 0.95)

PCB 156 (ng/g)

–0.05 (–0.52 to 0.42)

Adult men recruited from Massachusetts infertility clinic (2000–2003)

341 dl PCBs Estimated risk Meeker et al., 2007

(95% CI)

T3

0.02 (0.05–0.01)a

fT4

0.01 (0.01–0.05)a

fTSH

0.93 (0.84–1.03)a

Sportfish anglers from New York exposed to dioxin-like compounds in diet

  38 PCDDs, PCDFs, dl PCBs mean/median (range) Bloom et al., 2006

TSH μUL/mL

2.0/1.4 (0.2–15.7)

T4 μg/dL

6.3/6.4 (3.2–10.0)

Free T4 ng/mL

1.1/1.1 (0.9–1.6)

T3 ng/dL

92.6/87.5 (56.0–181.0)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenol; CATI, computer-assisted telephone interviewing; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; IARC, International Agency for Research on Cancer; LD, level of detection; NA, not available; NHANES, National Health and Nutrition Examination Survey; nr, no relationship; ns, nonsignificant; PCB, polychlorinated biphenyls; PCDD, polychlorinated dibenzo-p-dioxins; PCDD/Fs, chlorinated dioxins and furans combined; PCDF, polychlorinated dibenzofurans; ppt, parts per trillion; SE, standard error; SEA, Southeast Asia; RH, Ranch Hand; T3, triiodothyronine; T4, tetraiodothyronine; TCDD, tetrachlorodibenzo-p-dioxin; TEQ, (total) toxic equivalent; TSH, thyroid stimulating hormone.

aAdjusted coefficients for change in thyroid hormone level associated with an interquartile range increase in serum dioxin-like congeners.

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Update of the Epidemiologic Literature

No new epidemiologic studies of occupational or environmental exposure to the COIs or of Vietnam veterans and effects on thyroid homeostasis have been published since Update 2010. Mass media coverage of conference presentations in 2010 created an expectation of results of a study of Graves disease, an autoimmune thyroid condition, but the study had not passed peer review during the publication interval for the present update (Spaulding, 2011).

Biologic Plausibility

The influence of TCDD on thyroid-hormone homeostasis has been measured in numerous animal studies, and exposure has been associated with changes in serum concentrations of T4, T3, and TSH. In most studies, TCDD exposure is associated with a hypothyroid state, including reduced circulating T3 and T4 and increased TSH, especially after chronic exposure. Reduction in circulating T4 concentrations is robust and has recently been proposed as a biomarker of effect of dioxin-like chemicals (Yang et al., 2010). Female rats exposed chronically to TCDD showed follicular-cell hyperplasia and hypertrophy of thyroid follicles that were consistent with overstimulation of the thyroid by TSH (TSH increases as a homeostatic response to low T4 levels) (Yoshizawa et al., 2010). TCDD enhances the metabolism of thyroid hormones primarily through an AHR-dependent induction of glucuronyl transferase activity (Gessner et al., 2012; Kato et al., 2010; Martin et al., 2012; Nishimura et al., 2005). Enhanced accumulation of T4 in hepatic tissue of TCDD-treated mice may also contribute to the reduction circulating T4 (Kato et al., 2010).

Synthesis

Numerous animal experiments and several epidemiologic studies have shown that TCDD and dioxin-like chemicals appear to exert some influence on thyroid homeostasis. The effects of those substances on thyroid hormone and TSH concentrations in humans remain to be definitively elucidated (Langer, 2008). Most of the literature has focused on the correlations between exposure to dioxin-like PCB congeners in environmentally exposed populations, and many of the studies have been limited to women and infants. Few studies of thyroid metabolism in the primarily male Vietnam veterans have been published. In the AFHS study considered in Update 2004, Pavuk et al. (2003) reported a trend toward an increasing concentration of TSH that was not accompanied by changes in circulating T4 or T3 in Vietnam veterans. In comparison, T4 has been shown to be susceptible to an influence of dioxin-like chemicals in epidemiologic studies. Notably, in Vietnam-veteran studies, there has been no evidence of changes in clinical thyroid disease. Although an overall assessment of the studies suggests some variation

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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in thyroid-hormone concentrations in relation to TCDD exposure, the functional importance of the changes remains unclear because adaptive capacity should be adequate to accommodate them. It should be noted, however, that although biomarkers of perturbation may be subclinical in most people they may be associated with clear adversity in others.

Conclusions

There is inadequate or insufficient evidence of an association between exposure to the COIs and clinical or overt adverse effects on thyroid homeostasis. Some effects have been observed in humans, but the functional importance of the changes reported in the studies reviewed remains unclear because adaptive capacity could be adequate to accommodate them.

EYE PROBLEMS

Loss of vision is increasingly common with advanced age, and about one-sixth of people over 70 years old have substantial impairment, men and women being similarly affected (NCHS, 2010). The most prevalent ocular problems in the current age range of Vietnam veterans are age-related macular degeneration, cataracts, glaucoma, and diabetic retinopathy. Ocular problems involving chemical agents most often arise from acute, direct contact with caustic or corrosive substances that may have permanent consequences. Ocular impairment arising from systemic exposure to toxic agents may be mediated by nerve damage. Cataracts can be induced by chronic internal exposure of the lens to such chemicals as 2,4-dinitrophenol, corticosteroids, and thallium; glaucoma may be secondary to any toxic inflammation and from topical or systemic treatment with anti-inflammatory corticosteroids (Casarett and Doull, 1995).

Conclusions from VAO and Previous Updates

Update 2010 considered one study of Australian Vietnam veterans that found they had a higher prevalence of all the eye conditions assessed—cataracts, presbyopia, color blindness, and other diseases of the eye—than the Australian population (O’Toole et al., 2009). However, the committee noted a lack of information on exposure to the COIs and a lack of clinical confirmation of the eye conditions, and it had serious concerns about the possibility that recall bias played a role in the findings. On the basis of the evidence reviewed, Update 2010 concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and eye conditions.

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Update of Epidemiologic Evidence

No epidemiologic studies of exposure to the COIs and eye problems have been published since Update 2010.

Biologic Plausibility

There have been several recent reports of ocular activity associated with AHR induction in or TCDD exposure of rats (Sugamo et al., 2009), mice (Takeuchi et al., 2009), and human nonpigmented ciliary epithelial cells (Volotinen et al., 2009).

Synthesis

Since Update 2010, no additional epidemiologic results have supported the increase in risk of several eye conditions in the Australian Vietnam veterans reported by O’Toole et al. (2009). The reliability of those findings had been of concern to the committee for Update 2010 because of the lack of information on exposure to the COIs, the lack of clinical confirmation of the eye conditions, and the considerable likelihood of recall bias.

Conclusion

Given the lack of additional evidence, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and eye conditions.

BONE CONDITIONS

This section discusses conditions encompassed by ICD-9 code 733.0: osteoporosis, or decreased bone density. Osteoporosis is a skeletal disorder characterized by a decrease in bone mineral density (BMD) and loss of structural and biomechanical properties of the skeleton, which lead to an increased risk of fractures. Although there are no practical methods for assessing overall bone strength, BMD correlates closely with skeletal load-bearing capacity and fracture risk (Lash et al., 2009). WHO has developed definitions of osteoporosis based on BMD measurements. The dual energy X-ray absorptiometry (DEXA) T score is the number of standard deviations from the mean BMD in young women, for whom osteoporosis is defined as T score at any site of -5 or lower, whereas osteopenia is defined as a T score between -1 and -2.5. Although there are no standardized diagnostic criteria for osteoporosis in men, most authorities use the WHO criterion of a T score less than -2.5 relative to normal young women.

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Although men have much higher baseline BMD than women have, they seem to have a similar fracture risk for a given BMD (Lash et al., 2009).

Sex is an important risk factor for osteoporosis; about 56% of postmenopausal women have decreased BMD, and 6% have osteoporosis (CDC, 2002). Data on the effects of aging on bone loss in women are well known, but many health care providers and patients are less familiar with the prevalence and effects of bone changes in older men (Orwoll et al., 2010). Individual patients have genetic and acquired risks of osteoporosis, and the osteoporosis disease process can be without symptoms for decades. It is well known that hormones, vitamins, and pharmaceuticals can have adverse effects on bone. Drug-induced osteoporosis occurs primarily in postmenopausal women, but premenopausal women and men are also significantly affected. Glucocorticoids are the most common cause of drug-induced osteoporosis (Mazziotti et al., 2010). Other risk factors for loss of BMD include use of long-acting benzodiazepine or anticonvulsant drugs, previous hyperthyroidism, excessive caffeine intake, and standing for 4 hours a day or less (Lash et al., 2009).

Several studies have described a link between organochlorine exposure and effects on bone growth, most notably reports of infants exposed in utero to high concentration of PCBs and PCDFs who developed irregular calcifications of their skulls (Miller, 1985) and reports of accidental organochlorine poisoning that resulted in osteoporosis (Cripps et al., 1984; Gocmen et al., 1989). However; the epidemiologic studies of the association between environmental exposures to organochlorine compounds and bone disorder have been inconsistent.

Summary of Previous Updates

Update 2010 was the first VAO update that reviewed studies of the association between exposures to the COIs and decrease in BMD. Results from Hodgson et al. (2008) motivated the inclusion of this health outcome. They studied the relationship between environmental exposures and BMD in a set of 325 members of the Osteoporosis Cadmium as a Risk Factor (OSCAR) cohort who were at least 60 years old. Forearm BMD was measured, and blood samples were analyzed for the five dioxin-like mono-ortho PCB congeners (PCB 105, 118, 156, 157, and 167) and TEQs calculated. In men, PCB 118 had a marginally significant negative association with BMD, but the TEQ for all five dioxin-like mono-ortho PCBs did not show an association. In women, PCB 118 alone and the TEQ for all five dioxin-like mono-ortho PCBs were positively associated with BMD (slope β = 0.00008, p = 0.045; β = 1.652, p = 0.057, respectively). When the risk of low BMD (more than 1 standard deviation below the mean) was treated as a binary variable in an adjusted logistic model, there was a significant association with PCB 118 in men, but none of the measured compounds (also including non-dioxin-like PCBs 138, 153, and 180) was predictive in women.

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

Update of the Epidemiologic Literature

Vietnam-Veteran and Case-Control Studies

No Vietnam veteran or case-control studies of exposure to the COIs and BMD or osteoporosis have been published since Update 2010.

Occupational Studies

The recent update of the AHS (Waggoner et al., 2011) reported an inverse association of death with musculoskeletal and connective tissue diseases. This category is difficult to interpret and may be subject to a healthy-worker effect bias. The AHS has been generating valuable information on the COIs for a number of years, but these results, like those in Alavanja et al. (2005) and Blair et al. (2005), are not herbicide-specific and so are not regarded as being fully informative for the committee’s task.

Environmental Studies

Cho et al. (2011) recently reported that persistent organic pollutants can interact biologically with fat mass and lean mass and affect BMD. The study involved the NHANES population (2,769 participants).

Biologic Plausibility

Animal studies suggest that TCDD may have some influence on bone formation and maintenance. It is known that TCDD can induce chondrocyte apoptosis in culture, which could be an initial event leading to cartilage degradation as observed in arthritis (Yang and Lee, 2010); Lee and Yang (2012) recently demonstrated that this is mediated by reactive oxygen species. In addition, TCDD exposure via the dam’s milk impaired bone mineralization during postnatal development in mice because of a reduction in osteoblastic activity as a result of TCDD-induced up-regulation in the active form of vitamin D in serum (Nishimura et al., 2009). TCDD altered osteogenesis (bone formation) in an in vitro osteoblast model and led to alterations in proteins associated with cytoskeleton organization and biogenesis, a decrease in the expression of calcium-binding proteins, and a decrease in osteoblast calcium deposition (Carpi et al., 2009). In adult rats, TCDD exposure reduced trabecular bone cross-sectional area, but significantly increased total BMD; it was further noted that TCDD decreased expression of the bone-formation marker procollagen type I N-terminal propeptide and increased expression of the bone-resorption marker carboxy-terminal collagen cross-link, suggesting a net loss of bone tissue (Lind et al., 2009). It is also known that exposure to polyaromatic hydrocarbons (such as those in tobacco

Suggested Citation:"13 Other Chronic Health Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

smoke) can affect bone health, and some of these alterations have been shown to be mediated, at least in part by the AHR. That implies that TCDD may alter or modify the effects (Kung et al., 2012; Yan et al., 2011).

Synthesis

The small amount of available epidemiologic information on possible adverse effects of exposure to the COIs on bone structure is based entirely on dioxin-like mono-ortho PCBs, which contribute a small percentage to total TEQs based on all dioxin-like PCBs. The findings of Hodgson et al. (2008) do not constitute a strong or consistent pattern. The alteration in BMD associated with persistent pollutants in the NHANES participants suggests that additional studies of this affect are warranted.

Conclusion

There is inadequate or insufficient evidence of an association between exposure to the COIs and clinical or overt adverse effects of osteoporosis or loss of BMD.

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From 1962 to 1971, the US military sprayed herbicides over Vietnam to strip the thick jungle canopy that could conceal opposition forces, to destroy crops that those forces might depend on, and to clear tall grasses and bushes from the perimeters of US base camps and outlying fire-support bases. Mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the bulk of the herbicides sprayed. The main chemical mixture sprayed was Agent Orange, a 50:50 mixture of 2,4-D and 2,4,5-T. At the time of the spraying, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic form of dioxin, was an unintended contaminant generated during the production of 2,4,5-T and so was present in Agent Orange and some other formulations sprayed in Vietnam.

Because of complaints from returning Vietnam veterans about their own health and that of their children combined with emerging toxicologic evidence of adverse effects of phenoxy herbicides and TCDD, the National Academy of Sciences (NAS) was asked to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various components of those herbicides, including TCDD. Updated evaluations are conducted every two years to review newly available literature and draw conclusions from the overall evidence.Veterans and Agent Orange: Update 2012 reviews peer-reviewed scientific reports concerning associations between health outcomes and exposure to TCDD and other chemicals in the herbicides used in Vietnam that were published in October 2010--September 2012 and integrates this information with the previously established evidence database. This report considers whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemiological methods used to detect the association; the increased risk of disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era; and whether there exists a plausible biological mechanism or other evidence of a causal relationship between herbicide exposure and the disease.

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