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Veterans and Agent Orange: Update 2014 (2016)

Chapter: 13 Other Chronic Health Outcomes

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Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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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 2014 found:

  • There is now limited or suggestive evidence of an association between hypothyroidism and exposure to the chemicals of interest (COIs) in this report.

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

  • There is sufficient evidence of an association between the COIs and chloracne.
  • There is limited or suggestive evidence of an association between the COIs and early onset peripheral neuropathy and porpohyria cutanea tarda.

No additional scientifically relevant associations between the exposures of concern and adverse chronic health outcomes were noted. The current evidence supports the findings of earlier studies that:

  • No other adverse outcomes had sufficient evidence of an association with the COIs.
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
  • No other adverse outcomes had limited or suggestive evidence of an association with the COIs.
  • There is inadequate or insufficient evidence to determine whether there is an association between the COIs and respiratory disorders, gastrointestinal and digestive disease (including liver toxicity), kidney disease, adverse effects on endocrine function (other than hypothyroidism), eye problems, or bone conditions.

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-tetra-chlorodibenzo-p-dioxin (TCDD), picloram, and cacodylic acid—and several non-cancer health outcomes: respiratory disorders, gastrointestinal and digestive disease (including liver toxicity), adverse effects on thyroid homeostasis, kidney disease, eye problems, and bone conditions. The committee also considers the results of studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals (DLCs) to be informative if they were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of dioxin-like specific congeners. Although 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 because mono-ortho PCBs typically contribute less than 10 percent 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 non-cancer 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, the 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, the design information is summarized with the results; the 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 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

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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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, “non-cancerous respiratory disorders” are all acute and chronic lung diseases (other than cancers), a variety of conditions encompassed by the International Classification of Diseases (ICD), Ninth Revision (ICD-9 460–519) or Tenth Revision [ICD-10 J00–J99]. Acute non-cancerous respiratory disorders include pneumonia and other respiratory infections; they can increase in frequency and severity when the normal defense mechanisms of the lower respiratory tract are compromised. Chronic non-cancerous respiratory disorders generally take two forms: airways diseases and parenchymal diseases. Airway diseases are disorders—among them asthma and chronic obstructive pulmonary disease (COPD)—characterized by an obstruction of the flow of air out of the lungs. COPD, which is also known as chronic obstructive airways disease, includes such disorders as 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 non-cancerous 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 incidence rates of habitual cigarette smoking vary 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 non-Vietnam veterans (Kang et al., 2006; McKinney et al., 1997).

It is well known that the 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 an attenuation of the estimates of relative risk (RR) and to a diminution of statistical power. Moreover, the diagnosis of the primary cause

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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 non-cancerous 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 non-cancerous 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 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,1 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. The committee concluded that although new evidence suggested an increased risk of non-cancerous respiratory disorders, particularly COPD, in people exposed to TCDD, the observation was tentative. Additional information that was available to the committees responsible for Update 2002 (IOM, 2003) and Update 2004 (IOM, 2005) did not change that finding.

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), or in two Australian studies of Vietnam veterans (ADVA, 2005b,c). In contrast, in the US Army Chemical Corps (ACC) cohort of Vietnam

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1Despite loose usage of “Agent Orange” by many people, in numerous publications, and even in the title of this series, this committee uses “herbicides” to refer to the full range of herbicide exposures experienced in Vietnam, while “Agent Orange” is reserved for a specific one of the mixtures sprayed in Vietnam.

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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 to 60 percent, although no differences in the prevalence of respiratory problems were found in the subset of veterans whose serum TCDD was above 2.5 parts per trillion (ppt). However, in new studies of occupational cohorts, no associations were observed with respiratory mortality in a small subcohort of New Zealand phenoxy-herbicide sprayers (’t Mannetje et al., 2005) or with mortality from COPD in private applicators or their spouses in the Agricultural Health Study (AHS) (Blair et al., 2005a).

The committee for Update 2008 (IOM, 2009) evaluated several AHS publications concerning morbidity from particular self-reported respiratory health problems: analyses concerning wheeze (Hoppin et al., 2006c), asthma (Hoppin et al., 2008), “farmer’s lung” or hypersensitivity pneumonitis (Hoppin et al., 2007b), and chronic bronchitis (Hoppin et al., 2007a; Valcin et al., 2007). The 25-year follow-up of mortality in the Seveso population (Consonni et al., 2008) reported some increase in mortality from COPD as had been seen in the 15- and 20-year-mortality follow-ups (Bertazzi et al., 1998, 2001).

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 non-deployed Vietnam-era veterans and in a subset of the original deployed ACC veterans who had reported in an earlier 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 non-deployed groups. A similar pattern in the deployed ACC veterans was observed when they were compared with the US male population (standardized mortality ratio [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 “non-cancerous respiratory system disease” (RR = 2.24, 95% CI 0.42–11.83); this was the only one of these comparisons in which the researchers were able to control for self-reported herbicide exposure, body mass index (BMI), and smoking status. Deaths due to COPD were lower in non-deployed ACC veterans than in males in the US population (SMR = 0.3, 95% CI 0.04–1.07); this is noteworthy because the prevalence of smoking in the non-deployed 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 specifically but did not find increased mortality from non-cancerous respiratory diseases overall (Boers et al., 2010; Collins et al., 2009a,c; 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 the current use of 2,4-D to be associated with an increase in current rhinitis.

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Several new occupational studies were evaluated in Update 2012. An update of the National Institute of Occupational Safety and Health (NIOSH) cohort of pentochlorophenol (PCP) workers (Ruder and Yin, 2011) did not find an association of exposure to the COIs with deaths from all nonmalignant respiratory diseases; however, an excess in COPD deaths (possibly related to duration of employment) was observed in the entire cohort (63 deaths, SMR = 1.38, 95% CI 1.06–1.77), which was reflected in the subgroup exposed to PCP only, but not in the subgroup exposed to both TCDD and PCP. Updated mortality data on workers in two chlorphenoxy herbicide plants in the Netherlands (discussed in Update 2010) were re-analyzed by Boers et al. (2012) using serum measurements from a subcohort of 187 workers to construct a model of TCDD exposure, but no association of TCDD exposure with respiratory diseases was observed. An updated mortality study of workers in a pesticide factory with TCDD contamination (Manuwald et al., 2012) showed no association of nonmalignant respiratory disease with exposure, although an association of respiratory cancers with exposures was found. These cohort studies were unable to control for smoking.

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

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

Since the prior update, Kang et al. (2014) have reported the results of a retrospective study of 4,734 women who served in Vietnam, along with 2,062 women who were stationed in countries near Vietnam and 5,313 women who were not deployed during the Vietnam War. These veterans were identified through military records and followed for 40 years. In a comparison between the Vietnam cohort and the non-deployed cohort, 195 respiratory system disease deaths (SMR = 0.78, 95% CI 0.58–1.05) and 87 cases of COPD (SMR = 0.82, 95% CI 0.52–1.28) were observed. A sub-analysis of nurses who served in Vietnam compared with non-deployed nurses identified 130 cases of respiratory system disease (SMR = 0.73, 95% CI 0.50–1.06) and 56 cases of COPD (SMR = 0.71, 95% CI 0.40–1.28). As in many other cohort studies of mortality, the possibility of Type I statistical errors (i.e., false positives) was considerable due to numerous comparisons, and adjustment for tobacco use was not possible.

Two additional cohort studies of Vietnam War veterans (majority males) from New Zealand and Korea recently reported on respiratory mortality. Starting with a complete roster of New Zealand veterans who served in Vietnam between 1964 and 1972, McBride et al. (2013) determined that 2,783 of these men were alive and residing in New Zealand in 1988, which represented 84 percent of the 3,322 male New Zealand troops who had survived their service in Vietnam. Their mortality experience from 1988 through 2008 and underlying cause of death were obtained from the national verified Mortality Collection. Comparing the veterans

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 13-1 Selected Epidemiologic Studies—Non-Cancer 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 All COIs
Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 non-deployed) serving during Vietnam era (07/01/1965–03/28/1973)
Incidence—Self-reported respiratory disease diagnosed by doctor
CATI survey of stratified sample: 1,499 deployed (795 with TCDD measured) vs 1,428 non-deployed (102 with TCDD measured) Kang et al., 2006
Deployed vs non-deployed 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 non-deployed (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 non-deployed All COIs
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Incidence
Physical health— ORs from pulmonary-function tests (case definition: ≥ 80% predicted value) CDC, 1988a
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)
Mortality
1965–2000 (non-cancerous 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 non-deployed (n = 31,757 ) 648 0.8 (p < 0.05)
Marine Corps, deployed (n = 6,237) vs non-deployed (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
Non-cancerous respiratory mortality (ICD-9 460–519) 43 0.9 (0.7–1.2)
US VA Cohort of Female Vietnam-era Veterans served in Vietnam (n = 4,586; nurses only = 3,690); non-deployed (n = 5,325; nurses only = 3,282) All COIs Kang et al., 2014
Mortality (through 2004)
Respiratory system disease 195 0.8 (0.6–1.1)
COPD 87 0.8 (0.5–1.3)
Vietnam nurses only
Respiratory system disease 130 0.7 (0.5–1.1)
COPD 56 0.7 (0.4–1.3)
US VA Cohort of Monozygotic Twins—Vietnam-era All COIs
Incidence of respiratory conditioins, deployed vs non-deployed 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)
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
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 non-cancerous respiratory disease, ICD-8 460–519) Anderson et al., 1986a,b
Vietnam veterans vs expected deaths calculated from proportions for: 10
Non-veterans 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 5/23/1962–7/1/1973 vs Australian population All COIs
Mortality
All branches, return–2001 ADVA, 2005a
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)
1980–1994 CDVA, 1997a
Non-cancerous 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 Veterans—prevalance All COIs
450 interviewed 2005–2006 vs respondents to 2004–2005 national survey O’Toole et al., 2009
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
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., 1996b
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 non-deployed) 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)
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975) All COIs McBride et al., 2013
Mortality (1988–2008)
Respiratory disease (not COPD) 12 0.4 (0.2–0.7)
COPD 18 0.8 (0.5–1.2)
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs) All COIs
Prevalence (01/2000–09/2005)—log EOI scores Yi et al., 2014a
Diseases of the respiratory system (J00–J99) 1.0 (1.0–1.0)
Pneumonia not due to influenza (J12–J18) 1.0 (1.0–1.0)
COPD (J40–J44, J47) 1.0 (1.0–1.0)
Chronic bronchitis (J41–J42) 1.0 (1.0–1.0)
Emphysema (J43) 1.0 (1.0–1.0)
Bronchiectasis (J47) 1.0 (1.0–1.1)
Asthma (J45–J46) 1.0 (1.0–1.0)
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Prevalence (01/2000–09/2005)—categorized high (n = 36,813) vs low (n = 59,615) (86.8% vs 86.0%)
Diseases of the respiratory system (J00–J99) 1.0 (1.0–1.1)
Pneumonia not due to influenza (J12–J18) 1.0 (1.0–1.1)
COPD (J40–J44, J47) 1.0 (1.0–1.0)
Chronic bronchitis (J41–J42) 1.1 (1.0–1.1)
Emphysema (J43) 0.9 (0.8–1.1)
Bronchiectasis (J47) 1.2 (1.1–1.3)
Asthma (J45–J46) 1.0 (1.0–1.1)
Mortality (1992–2005) (adjusted HRs) Yi et al., 2014b
Diseases of the respiratory system (J00–J98) 446 1.0 (1.0–1.1)
Pneumonia not due to influenza (J12–J18) 107 1.0 (0.9–1.1)
COPD (J40–J44, J47) 115 1.0 (1.0–1.3)
Asthma (J45–J46) 75 1.0 (0.9–1.1)
Mortality (01/2000–09/2005)—categorized high (n = 266) vs low (n = 180) (86.8% vs 86.0%)
Diseases of the respiratory system (J00–J98) 1.2 (1.0–1.5)
Pneumonia not due to influenza (J12–J18) 1.0 (0.7–1.5)
COPD (J40–J44, J47) 1.7 (1.2–2.6)
Asthma (J45–J46) 0.9 (0.6–1.4)
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 (non-cancerous respiratory diseases, ICD-9 460–519) 93 0.6 (0.5–0.8) Coggon et al., 1986
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
British Production Workers at 4 plants (included in IARC cohort) Dioxins, but TCDD unlikely; MCPA Coggon et al., 1991
Mortality 1963–1985 (non-cancerous 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
Mortality 1965–2006 6 vs 15 0.5 (0.2–1.2) Boers et al., 2010
German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 mo in 1951–1976) (in IARC cohort as of 1997) and women—no results Dioxins; 2,4,5-TCP
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 mo 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 mo 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
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
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 non-cancerous 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 (non-cancerous 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 mo 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
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 mo 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)
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
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 (non-cancerous 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)
FEF 25–75 (< 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, MI) (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., 2009b
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL) 2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
Respiratory disorders (ICD-9 460–466, 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-9 480–486)
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-9 490–492, 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, MI) (subset of all TCP-exposed workers) excluded 2,4-D, lower chlorinated dioxins
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Through 1994 (n = 1,517) Burns et al., 2001
Non-cancerous 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, MI) (not in IARC and NIOSH cohorts) Low chlorinated dioxins, 2,4-D
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) Mortality 1940–1989 (n = 770) 19 0.7 (0.4–1.2) Collins et al., 2009c
Ramlow et al., 1996
Non-cancerous 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
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 non-asthmatics Senthilselvan et al., 1992
Phenoxyacetic herbicide use 71 85.5% vs 88.5%
Saskatchewan Rural Health Study—8,153 adults completed mailed questionnaires; 482 self-reported cases of doctor-diagnosed chronic bronchitis Herbicides Pahwa et al., 2012b
Herbicide—ever exposed occupationally 264 1.2 (1.0–1.5)
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
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; follow-ups 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., 2007a
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)
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
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., 2005a,b
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 non-cancerous 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 non-cancerous respiratory diseases (ICD-8 460–519) 2 Herbicides
0.9 (nr)
Blair et al., 1983
Any pesticide (dose–response by length of licensure)
< 10 yrs 8 0.6 (nr)
10–19 yrs 8 1.5 (nr)
≥ 20 yrs 4 1.7 (nr)
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
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) TCDD
Mortality (ICD-9)
25-yr follow-up to 2001—men and women Consonni et al., 2008
Respiratory disease (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 (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 follow-up to 1996 Bertazzi et al., 2001
Respiratory disease (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 (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 follow-up to 1991—men Bertazzi et al., 1998
Respiratory disease (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 (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 follow-up to 1991—women Bertazzi et al., 1998
Respiratory disease (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 (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)
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
10-yr follow-up to 1986—men (Zones A, B, R) Bertazzi et al., 1989a
Respiratory disease (460–519) 55 1.0 (0.7–1.3)
Pneumonia (480–486) 14 0.9 (0.5–1.5)
COPD (490–493) 31 1.1 (0.8–1.7)
10-yr follow-up to 1986—women (Zones A, B, R) Bertazzi et al., 1989a
Respiratory disease (460–519) 24 1.0 (0.7–1.6)
Pneumonia (480–486) 9 0.8 (0.4–1.6)
COPD (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 unexposed Dahlgren et al., 2003b
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
JAPAN
2,253 Japanese from general population not occupationally exposed to dioxins, aged 15–76 yrs in 2002–2008, Total Serum TEQ Nakamoto et al., 2013
Asthma (40 cases in men; 53 cases in women) 93
Quartile 1 1.0
Quartile 2 1.1 (0.6–2.0)
Quartile 3 1.0 (0.5–1.9)
Quartile 4 1.1 (0.5–2.4)
p-trend = 0.88
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
SWEDEN
Swedish fishermen (high consumption of fish with persistent organochlorines) Organochlorine compounds Svensson et al., 1995a
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-trichlorophenoxy-acetic 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; CDC, US Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; COPD, chronic obstructive pulmonary disease; EOI, Exposure Opportunity Index; 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, 8th revision; ICD-9, International Classification of Diseases, 9th 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.

to the general male population of New Zealand, the risk of death from all nonmalignant respiratory diseases (excluding COPD) was significantly lower (SMR = 0.40, 95% CI 0.21–0.70), but for COPD specifically no difference was apparent (SMR = 0.78, 95% CI 0.46–1.23). These authors were also unable to adjust for potential confounders, particularly tobacco use.

Yi et al. (2014a,b) applied the Stellman model (Stellman et al., 2003b) in an effort to quantify exposures in the Korean Veterans Health Study. With 446 deaths from respiratory disease, an analysis of the individual Exposure Opportunity Index (EOI) scores found a slightly elevated hazard ratio (HR = 1.04, 95% CI 0.99–1.09) after adjusting for age and rank in Vietnam (Yi et al., 2014b). A comparison of the 180 deaths in the low-exposure category with the 266 deaths in the high-exposure category generated a significant risk (HR = 1.24, 95% CI 1.02–1.50). The authors further explored specific respiratory diseases by exposure category and found 115 total deaths associated with COPD, with 80 of these occurring in the high-exposure group (HR = 1.73, 95% CI 1.16–2.60). No significant associations of exposure to the COIs were seen for pneumonia (HR = 1.02, 95% CI 0.69–1.50, 57 cases in high, 50 in low) or asthma (HR = 0.88, 95% CI 0.55–1.42, 36 cases in high, 39 in low). Importantly, information on smoking habits was not available for this cohort during follow-up through 2003.

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Yi et al. (2014a) used insurance claim data from January 2000 through September 2005 to evaluate disease prevalence in Korean Veterans Health Study participants. Diseases of the respiratory system were positively associated with the log of EOI scores (odds ratio [OR] = 1.01, 95% CI 1.00–1.01), but a comparison between the high-exposure group and the low-exposure group found no significant association (OR = 1.02, 95% CI 0.99–1.06). COPD was positively associated with the log EOI scores (OR = 1.01, 95% CI 1.00–1.01) and when the high- and low-exposure groups were compared (OR = 1.04, 95% CI 1.01–1.07). Significant findings were also reported in comparisons between the high- and low-exposure groups for pneumonia not due to influenza (OR = 1.04, 95% CI 1.00–1.09), chronic bronchitis (OR = 1.05, 95% CI 1.02–1.08), bronchiectasis (OR = 1.06, 95% CI 1.06–1.27), and asthma (OR = 1.04, 95% CI 1.01–1.08), but the findings for emphysema were not statistically significant (OR = 0.94, 95% CI 0.83–1.05).

Occupational Studies

As part of the Saskatchewan Rural Health Study, Pahwa et al. (2012b) examined the prevalence of chronic bronchitis (CB) in farm and non-farm rural residents of Saskatchewan, Canada. This two-phase, prospective study collected baseline health data on 8,261 males and females at least 18 years of age using self-administered, mailed questionnaires. The authors report on 8,153 subjects, finding 482 who reported doctor-diagnosed CB. The prevalence of CB in farm residents was 5.3 percent versus 6.4 percent in non-farm residents. Although some information on herbicide exposure was gathered (unadjusted OR = 1.24, 95% CI 1.02–1.50), there was essentially no exposure specificity, making this study of minimal use to the committee.

The above results in terms on exposures no more specific than “herbicide exposure” are of only marginal relevance in assessing the relationship between respiratory disease and exposure to the COIs for VAO’s purposes. The committee notes three additional new publications (de Jong et al., 2014; Sapbamrer and Nata, 2014; Tual et al., 2013) that assessed relationships between adverse respiratory outcomes and various agricultural risk factors with exposure characterizations that are not informative for this report.

Environmental Studies

In a cross-sectional study of 1,063 men and 1,201 women living throughout Japan (who had not been occupationally exposed to dioxins), Nakamoto et al. (2013) gathered fasting blood samples between 2002 and 2010 for assessment of environmental exposure to DLCs. Blood levels and the corresponding TEQs were determined for dioxin-like polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and PCBs. In addition to estimating a trend across all quartiles (pg/g lipid), logistic regression adjusted for age, sex, smoking

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

habit, drinking habit, regional block, and survey year was used to estimate the odds of self-reported asthma in the upper three quartiles versus the lowest quartile for PCDDs and PCDFs combined (PCDD/Fs), PCBs, and all DLCs. None of the results for self-reported asthma were at all indicative of association with any of these three exposure groupings.

Biologic Plausibility

An evaluation of the biologic plausibility of the induction of or contribution to the development of lung diseases by the COIs is hampered by a lack of animal models for studing such endpoints as COPD or asthma because these diseases usually develop in humans in response to additional co-factors (smoking and air pollution).

2,4-D has been shown to be toxin to a human fibroblast cell line (WI-38) in culture via disruption of the tubulin-microtubule network (Ganguli et al., 2014). Activation of the aryl hydrocarbon receptor (AHR) by TCDD has been shown to modify the expression of six genes in human bronchial epithelial cells in culture, although this study used a low-throughput analysis that likely missed many AHR targets (Jin et al., 2012). In both human cell line (NCI H441, derived from Clara cells from a bronchiolar adenocarcinoma) and the lungs of C57BL/6 mice, TCDD exposure induced genes that code for inflammatory cytokines, matrix metalloproteases, and mucin production (Wong PS et al., 2010). AHR activation in the NCI H441 cells also activates a process involving IL-1b and COX-2, which leads to increased mucin production. That process might be facilitated via differentiation of the Clara cell to a mucin-producing, 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). JH Lee et al. (2010) reported 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). YC 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. 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 (Beamer and Shephard, 2013).

Acute non-cancerous respiratory disorders, including pneumonia and other respiratory infections, can also be increased in frequency and severity when the normal defense mechanisms of the lower respiratory tract are compromised. Thus, an exposure to chemicals that affect those mechanisms could exacerbate respiratory

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

disorders. There is no evidence that the specific herbicides used in Vietnam alter such defense mechanisms. However, several laboratory studies have shown that the treatment of mice with TCDD increases their mortality after infection with the 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 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.

It is also plausible that the induction of CYP1A1 and CYP1B1 enzymes in the lung by TCDD could result in the metabolism of other chemicals into more toxic intermediates. Exposure to TCDD could thus increase the toxic effects of several components of tobacco smoke and thus increase respiratory disease. In practice, however, this is not always the case, as Uno et al. (2006) demonstrated in mouse strains with the genes for CYP1A1 and CYP1B1 knocked out that showed increased sensitivity to benzo[a]pyrene (B[a]P). 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 DLCs 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. A recent systemic review that examined the results from 23 papers (chosen from an initial set of more than 4,000 publications) identified pesticides as contributing to asthma, particularly in children, and perhaps to COPD, as well. This review, however, did not shed specific insight into TCDD or the other COIs (Doust et al., 2014). Thus, it is biologically plausible that exposure to TCDD results in the 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

Non-Cancerous Respiratory Disease (Without Further Specification)

Results of the studies of mortality from non-cancerous respiratory diseases reported in Update 2008 and earlier VAO reports (ADVA, 2005b,c; Anderson et

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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al., 1986a; Becher et al., 1996; Blair et al., 1983, 2005a; 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, 1996a; Ramlow et al., 1996; Steenland et al., 1999; Svensson et al., 1995b; ’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 non-cancerous 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 non-deployed veterans indicated an association (odds ratio [OR] = 1.41, 95% CI 1.13–1.76), as did a 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, which argues against the association with herbicide exposure.

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 non-cancerous respiratory disease with exposures to herbicides or TCDD (Boers et al., 2010; Collins et al., 2009b,c; McBride et al., 2009a). Similarly, a study of Finnish fisherman found that an increase in serum dioxin TEQs was not associated with mortality from non-cancerous respiratory disorders (Turunen et al., 2008).

In Update 2012, four occupational studies of exposures to the COIs were consistent in reporting no increase in mortality due to pneumonia and the broad category of nonmalignant diseases of the respiratory system (Boers et al., 2012; Manuwald et al., 2012; Ruder and Yiin, 2011; Waggoner et al., 2010).

Finally in the current update, there were studies of three cohorts of Vietnam-era veterans (Kang et al., 2014; McBride et al., 2013; Yi et al., 2014a,b) and several new environmental and occupational studies, but no additional data convincingly contributed consistent evidence of either enhanced mortality or an increased risk associated with exposures to the COIs for specific or nonspecific nonmalignant respiratory diseases.

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 non-cancerous respiratory disease. The nonspecificity of the respiratory conditions reported in these studies makes it exceedingly difficult to draw any conclusions regarding specific respiratory conditions.

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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 PCDD/Fs. The fact that no information on smoking was available, however, greatly limits the possible 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 service in the ACC, as of 1991, the deployed ACC veterans had a non-significant adjusted RR of 2.59 for death due to non-cancerous respiratory diseases compared with their non-deployed 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 non-cancerous 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 non-deployed 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 (deployed and non-deployed) conducted in 1999–2000 (Kang et al., 2006) found a significant increase in the broader category of self-reported non-cancerous respiratory conditions in deployed ACC veterans (OR = 1.41, 95% CI 1.13–1.76), which was also significantly related to the reported use of herbicides in Vietnam (OR = 1.62, 95% CI 1.28–2.05); the study used a multiple logistic regression model with adjustment for age, race, BMI, rank, and smoking. Among the deployed ACC veterans who had particated in the morbidity study, only 120 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 Ranch Hand cohort, found no significant increase in mortality due to the broader classification of noncancerous respiratory mortality (Anderson et al., 1986a; Boehmer et al., 2004; Ketchum and Michalek, 2005) but did not address causes of death as specific as COPD. The Vietnam Experience Study (CDC, 1988a) 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 versus the general population (ADVA, 2005b; CDVA, 1997a) and of deployed versus non-deployed Australian Army National Service (conscripted) veterans (ADVA, 2005c; CDVA, 1997b)

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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 non-deployed) serving during Vietnam era (07/01/1965–03/28/1973) All COIs
Through 2005—Mortality Cypel and Kang, 2010
Deployed veterans (2,872) vs non-deployed (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 non-deployed All COIs
Incidence
Physical health—ORs from pulmonary-function tests (case definition: ≥ 80% predicted value) CDC, 1988a
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)
US VA Cohort of Female Vietnam-era Veterans served in Vietnam (n = 4,586; nurses only = 3,690); non-deployed (n = 5,325; nurses only = 3,282) All COIs Kang et al., 2014
Mortality (through 2004)
Through 2004—COPD 87 0.8 (0.5–1.3)
Vietnam nurses only—COPD 56 0.7 (0.4–1.3)
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population All COIs
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Mortality
All branches, return–2001 ADVA, 2005a
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)
1980–1994 CDVA, 1997a
Non-cancerous 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 non-deployed)
All COIs
Mortality
1966–2001 ADVA, 2005c
Respiratory diseases 18 1.1 (0.6–2.2)
COPD 8 1.0 (0.3–2.8)
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975) All COIs McBride et al., 2013
Mortality (1988–2008)
Respiratory disease (not COPD) 12 0.4 (0.2–0.7)
COPD 18 0.8 (0.5–1.2)
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10) All COIs
Prevalence (01/2000–09/2005)—log EOI scores Yi et al., 2014a
Diseases of the respiratory system (J00–J99) 1.0 (1.0–1.0)
COPD [J40–J44, J47] 1.0 (1.0–1.0)
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Prevalence (01/2000–09/2005)—categorized high (n = 36,813) vs low (n = 59,615) (86.8% vs 86.0%)
Diseases of the respiratory system (J00–J99) 1.0 (1.0–1.1)
COPD [J40–J44, J47] 1.0 (1.0–1.0)
Mortality (1992–2005) (adjusted HRs) Yi et al., 2014b
Diseases of the respiratory system (J00–J98) 446 1.0 (1.0–1.1)
COPD [J40–J44, J47] 115 1.0 (1.0–1.3)
Mortality (01/2000–09/2005)—categorized high (n = 266) vs low (n = 180) (86.8% vs 86.0%) Diseases of the respiratory system (J00–J98) 1.2 (1.0–1.5)
COPD [J40–J44, J47] 1.7 (1.2–2.6)
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 non-cancerous 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)
FEF 25–75 (< 80% predicted) 47 1.86 (p = 0.05)
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
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, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL) 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; follow-ups 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., 2005a
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)
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." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Mortality
25-yr follow-up 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 follow-up 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 follow-up 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 follow-up 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 follow-up 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 follow-up 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; EOI, Exposure Opportunity Index; 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-9, International Classification of Diseases, 9th 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.

also showed no suggestion of increased mortality from COPD or non-cancerous 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

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

et al., 1996; Burns et al., 2001; Kogevinas et al., 1997; Ott and Zober, 1996a; Steenland et al., 1999; ’t Mannetje et al., 2005). Only an earlier mortality study of Dow 2,4,5-trichlorophenol (2,4,5-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. (2005a) found significant decreases in mortality due to COPD in private applicators and their spouses compared with state rates, which may have been due to the healthy-worker effect and the inability to adjust for low tobacco use. Analyses, with adjustment for smoking, of self-reported 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., 2007a) but only a 20 percent non-significant 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. (2005a), 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. (1995b) assumed that TCDD exposure was higher in Swedish fishermen because of fish consumption but found no increase in mortality from bronchitis or emphysema. Dahlgren et al. (2003b)

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

reported that the prevalance of chronic bronchitis was positively associated with an 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 law suit. 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 the deployed ACC veterans in the morbidity study (Table 5 in the 2010 paper) were indeed COPD cases; among the non-deployed 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 an 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 percent of the deployed versus 60.1 percent of the non-deployed 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.

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 the 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, 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 available to the committee for Update 2012 did not alter its concurrence with the conclusions of the Update 2010 committee.

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

This update includes new data that do not add coherence to this issue; Kang et al. (2014) and McBride et al. (2013) report data that are not suggestive of an association of exposure to herbicides in Vietnam with COPD, while the data from the Korean Veterans Health Study (Yi et al., 2014a,b) report an exposure-associated increase in both COPD mortality and prevalence after applying the Stellman model to assess exposure to herbicides. In view of this, we are unable to alter our prior stance. We are mindful of a prior commitment by the US Department of Veterans Affairs to undertake a morbidity follow-up on the ACC cohort, but the status of this work remains unknown to the committee and its results have yet to be published. Accordingly, we continue to concur with prior committee findings.

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 non-cancerous 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 specified by ICD-9 520–579 or ICD-10 K00–K95: diseases 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 is present in about 15 percent 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,

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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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 percent of the population has clinical evidence of duodenal ulcer at some time in their 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 to 100 percent of patients who have duodenal ulcer and in 75 to 80 percent of patients who have gastric ulcer. Healthy people in the United States under 30 years old have gastric colonization rates of about 10 percent. Over the age of 60 years, colonization rates exceed 60 percent. Colonization alone, however, is not sufficient for the development of ulcer disease; only 15 to 20 percent 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 (ALT), alkaline phosphatase, and β-glutamyltransferase (GGT)—are commonly noted in liver disorders. The relative sensitivity and specificity of those enzymes for diagnosing liver disease vary, and a 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 the interpretation of changes

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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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 a 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, an 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. An evaluation of the effects of herbicide and TCDD exposure on non-cancer 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. A 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 disease and cirrhosis mortality in exposed workers than in non-exposed controls. A study that compared Australian veterans with the general population (O’Toole et al., 1996b) 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 Ranch Hand veterans in the high-dioxin category had excesses of transaminase and other nonspecific laboratory measures of liver function than Southeast Asia comparison subjects. The data were consistent with an interpretation of a

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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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. However, mortality studies of the Ranch Hand cohort have not found increased mortality related to gastrointestinal or liver disease (Ketchum and Michalek, 2005).

A study of ACC Vietnam veterans found an increased rate of hepatitis associated with Vietnam service but not with a history of spraying herbicide (Kang et al., 2006). Additional analyses of the mortality experience of the ACC veterans were reviewed in Update 2010 (Cypel and Kang, 2010). There was about an 80 percent 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.

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. 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, a lack of specific exposure information, and the inherent problems associated with self-reported health conditions—make the findings of this study unpersuasive.

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

Several mortality studies of various occupational cohorts exposed to the COIs were reviewed (Boers et al., 2010, 2012; Collins et al., 2010a,b; Manuwald et al., 2012; McBride et al., 2009a,b; Ruder and Yiin, 2011). Those studies have been inconsistent but generally found no statistically significant increases in deaths from either ulcers or cirrhosis, although Collins et al. (2009c) 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 interpreting individual studies is difficult because of a lack of information on alcohol consumption and 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 subsequent updates did not change that conclusion.

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

The relationship between possible herbicide exposure and liver and gastric-ulcer disease was described in a sample of Korean Vietnam-era veterans in three publications by Yi et al. (2013, 2014a,b). The study is described in detail in Chapter 6. Using health insurance claims data, the adjusted prevalence of peptic-ulcer disease was found to be 3 percent higher in those with high putative exposure compared to low exposure (OR = 1.03, 95% CI 1.01–1.06) after adjusting for several behavioral, demographic and service-related factors. For liver disease, there was a small but statistically significant elevation in the prevalence of liver cirrhosis (OR = 1.08, 95% CI 1.01–1.16) and a significant log-linear relationship between an exposure opportunity score and the odds of having cirrhosis (p = 0.007). When using self-reported health information, herbicide exposure was weakly but significantly associated with chronic hepatitis and enterocholitis (ORs ≤ 1.12) when the exposures were based on the division-/brigade-level exposure data, but not when using data derived from battalion/company data.

In the mortality study in the same cohort (Yi et al., 2014b) there was no association between putative log-transformed exposure and mortality from peptic ulcers (hazard ratio [HR] per 1 log unit increase in estimated exposure = 0.98, 95% CI 0.84–1.15). However, there was a statistically significant relationship between the estimated exposure and deaths from liver cirrhosis (HR per 1 log unit increase in estimated exposure = 1.05, 95% CI 1.02–1.08). Highly exposed veterans had a 17 percent elevation in the mortality from cirrhosis compared with those with low exposure (HR = 1.17, 95% CI 1.05–1.30). Deaths from alcoholic liver disease were also elevated in the more highly exposed veterans (HR = 1.43, 95% CI 1.16–1.77).

Environmental Studies

Nakamoto et al. (2013) assembled a sample of 2,264 adult Japanese who were not occupationally exposed to dioxins. The presence of gastric ulcers was determined by self-report. There were no statistically significant associations with ulcer disease and either serum levels of dioxin-like PCDD/Fs, dioxin-like PCBs, or total TEQs after adjusting for age, sex, smoking, drinking, region, survey year, and BMI (p = 0.07, p = 0.22, and p = 0.29, respectively).

Yorita Christensen et al. (2013) reported the association between blood levels of 37 environmental pollutants and ALT levels in the National Health and Nutrition Examination Survey (NHANES) data. The analytic sample included 1,345 persons aged 12 years and older. Those who reported high alcohol intake or self-reported liver disease were excluded as were persons who had ALT levels greater than 81 U/L. In general, blood levels of DLCs were not significantly correlated

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

with ALT levels. The exception was 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, which was associated with only a slight elevation (< 1 percent).

Occupational and Case-Control Studies

No occupational or case-control studies of exposure to the COIs and gastrointestinal and digestive disease have been published since Update 2012.

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 it 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 the serum concentrations of liver enzymes are biomarkers of liver toxicity, and their magnitudes correlate with the degree of liver damage. The 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 are based on the inhibition of mitochondrial function by the blocking of oxidative phosphorylation; this leads to a loss of generation of adenosine triphosphate, the 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 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 caused by 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 increase in hepatic oxidative stress (Lee JH et al., 2010). Recent evidence suggests that hepatic steatosis produced by TCDD might be mediated by the mitochondria (He et al., 2013). The 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, amino acid sequences in the C-terminal region of human and mouse AHR are only 58 percent identical. Compared with the mouse AHR, the human AHR has about a 10-fold lower

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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relative affinity for TCDD; the difference has been attributed to the amino acid residue valine 381 in the ligand-binding domain of the human AHR (Flaveny et al., 2009; Ramadoss and Perdew, 2004). The existence of species differences associated with AHR activation is supported by the divergence in the transcriptomic and metabolomic responses to TCDD in mouse, rat, and human liver (Boutros et al., 2008, 2009; Carlson et al., 2009; Forgacs et al., 2012, 2013; Kim et al., 2009; Nault et al., 2013). 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 genes 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. Another recent microarray study examining species-specific transcriptomic differences in primary hepatocytes from humans, mice, and rats only identified 16 orthologous genes that were dysregulated by TCDD in all three species (Forgacs et al., 2013). 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 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

Prior to this update there was little convincing evidence of liver toxicity associated with exposure to the COIs. The publications from the Korean veterans study suggest a link between herbicide exposure and liver cirrhosis but not other GI diseases. Korea is notable for its very high rates of liver cirrhosis, which is related to both very high per capita alcohol consumption and high rates of hepatitis B and C infection. Thus, it is imperative that studies of cirrhosis be controlled for the potential confounding effects of these strong and prevalent factors. The prevalence data did control for self-reported alcohol consumption but not for prior infection with viral hepatitis. Possibly, herbicide exposure could potentiate the effect of viral exposures, but this hypothesis cannot be tested without data on infection status of the subjects. Given the absence of any supporting evidence that the COIs cause liver damage and the lack of control for critical potential confounders in the Korean veterans study, the committee concluded that there was inadequate or insufficient evidence to link herbicide exposure to liver cirrhosis.

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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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.

KIDNEY DISEASE

This is the first update for which the literature search identified studies reporting results concerning a possible association between exposure to the COIs and kidney diseases, which are grouped in ICD-9 580–589 or in ICD-10 N00–N29. An average person has two kidneys located in the lower back region; their main function is to use nephrons to filter wastes and excess water out of blood, which results in the production of urine. Kidneys are also responsible for helping to maintain the body’s chemical balance, helping to control blood pressure, and making hormones. When problems arise with kidney function, it is often the result of damaged nephrons, which may leave the kidneys unable to filter blood and thus unable to remove wastes. A disorder characterized by gradual and usually permanent loss of kidney function, resulting in renal failure, is called chronic kidney disease. Diabetes, hypertension, and glomerulonephritis (acute inflammation) can all increase the risk of kidney disease.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

Publications from the Korean Veterans Health Study included findings for non-malignant kidney disease. This study derived EOI scores based on the proximity of the veteran’s unit to sprayed areas using a geographical information system–based model (Stellman et al., 2003b) developed flight records of the US spray missions. In the first article, Yi et al. (2013a) examined the prevalence of self-reported diseases from a postal survey of 114,562 Korean Vietnam veterans with respect to their perceived herbicide exposure as assessed by a six-item questionnaire. Self-reported kidney failure was found to be significantly increased in terms of the perceived exposures, but not when analysis was based on the EOI scores. The more reliable information on the occurrence of disease from 2000 to 2005 gathered from the Insurance Review and Assessment Service of Korea and the Veterans Health Service was analysed in Yi et al. (2014a), but no findings were presented for any form of kidney disease.

Data on vital status and cause of death through 2005 for 180,639 Korean Veterans alive in 1992 were assembled from death records at the National Statistical Office and analyzed by Yi et al. (2014b). The causes of death were classified

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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according to ICD-10 in all instances where 10 or more cases were documented. With adjustment for the veteran’s age in 1992 and rank, no differences were observed in the hazard ratios for acute renal failure [ICD-10 N17] or for chronic renal failure [ICD-10 N18] when analyses were based on the EOI scores either used individually in regression or grouped for a high- versus low-exposure comparison.

Environmental Studies

In a cross-sectional study of 1,063 men and 1,201 women living throughout Japan (who had not been occupationally exposed to dioxins), 47 cases of kidney disease (not otherwise characterized) were reported (Nakamoto et al., 2013). Fasting blood samples were gathered from 2002 to 2010 for assessment of environmental exposure to DLCs. Blood concentrations and the corresponding TEQs were determined individually for dioxin-like PCDDs, PCDFs, and PCBs. With adjustment for age, sex, smoking, drinking, regional block, and survey year, logistic regression on concentration (pg/g lipid) was used to estimate the odds of self-reported kidney disease in the upper three quartiles versus the lowest quartile for dioxin-like PCDD/Fs, for dioxin-like PCBs, and combined for all DLCs. None of these paired comparisons approached significance, but all the estimated ORs versus the lowest quartile were consistently less than one. In addition, trend in concentration across all quartiles was assessed for each grouping of DLCs (p for trend = 0.21, 0.90, and 0.28 for PCDD/Fs, PCBs, and total DLCs, respectively). Overall, there was no indication of association between dioxin-like activity in blood and self-reported kidney disease.

Jayatilake et al. (2013) sought to determine the factors contributing to a form of kidney disease not related to diabetes, hypertension, or any other recognized cause. Recent studies had found chronic kidney disease of uncertain etiology to be prevalent in 2 to 3 percent of adults in Sri Lanka. Screening of endemic areas in the northern interior of the island identified 733 cases, and 4,044 individuals without diabetes or any kidney disease were retained as controls; another 250 controls were gathered in non-endemic coastal areas. In addition to consideration of environmental metal levels, pesticide exposure was addressed by gathering urine samples from 57 cases and 39 controls from non-endemic areas. The samples were analyzed for 11 biomarkers of pesticides, including the COIs 2,4-D, 2,4,5-T, and 2,4,5-TCP. Of these, only 2,4-D was among the seven biomarkers found at concentrations above the limit of detection; 3.5 percent of the cases had 2,4-D concentrations above the reference limit of 0.3 µg/l. Since urinary pesticide results were presented for only the cases, no inference can be made about relative risk for this kidney condition in association with 2,4-D.

Occupational and Case-Control Studies

No occupational or case-control studies of exposure to the COIs and kidney disease have been published since Update 2012.

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Biologic Plausibility

Currently, there are no toxicologic studies relevant to exposure to any of the COIs and the occurrence of any form of nonmalignant kidney disease.

Synthesis

No statistical findings from epidemiology studies concerning kidney disease have been reported previously in the VAO series. The few findings on this health outcome reviewed by the current committee do not present any coherent pattern of an association between exposure to the COIs and kidney disorders.

Conclusion

The committee found that these first epidemiologic results addressing kidney disease in relation to exposure to the COIs constituted inadequate or insufficient evidence of an association between nonmalignant kidney diseases and exposure to the herbicides sprayed in Vietnam.

THYROID HOMEOSTASIS OR OTHER ENDOCRINE FUNCTIONS

This section discusses a variety of conditions related to endocrine function, excluding diabetes and other pancreatic disorders [ICD-9 250–251 or ICD-10 E08–E16], which were discussed in Chapter 12. Clinical disruptions of thyroid function in particular are grouped as ICD-9 240–246 or as ICD-10 E00–E07, E20–21, while the remaining endocrine disorders are grouped as ICD-9 252–259 or as ICD-10 E22–E35.

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 the 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, it triggers a

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

reduction in the output of TRH and TSH. The negative-feedback loop maintains hormone homeostasis.

A 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 percent to 10 percent, depending on the group, the testing setting, sex, age, the 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 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 percent of women and 6 percent of men had subclinical hypothyroidism (Sawin et al., 1985). Subclinical hypothyroidism is a risk factor for overt hypothyroidism. Studies have reported associations of hypothyroidism with a wide variety of other conditions. Chemically induced hypothyroidism can develop because of direct effects on the functional cell types in the thyroid gland or because of an induction of auto-antibodies that destroy thyroid tissue, such as in Hashimoto’s disease, an auto-immune form of thyroiditis.

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 a 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 has been estimated at about 1 percent in men and 1.5 percent in women over 60 years old (Helfand and Redfern, 1998). Conditions associated with hyperthyroidism include diffuse toxic goiter and Graves disease, an autoimmune disease in which antibodies are produced that mimic the activity of TSH. 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 reasonable limits, for mild or moderate disruption (such as that caused by hyperplasia or goiter). In contrast, the fetus is highly sensitive to alterations in

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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 the potential effects of Vietnam veterans’ exposure to herbicides on their offspring. Only observations on adults are considered here.

Summary of Previous Updates

Thyroid homeostasis in humans was first addressed with respect to the COIs by the VAO committee for Update 2002.

Extensive assessment of endocrine function in clinical examinations, including a series of thyroid-function tests, failed to show systematic differences in thyroid function when contrasting veterans who participated in Operation Ranch Hand and control veterans (AFHS, 1991a). In analyzing individual TCDD readings 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 significantly increasing trend across the 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 in the NIOSH Cross-sectional Medical Study, but there was no dose–response relationship with serum TCDD. Bloom et al. (2006) found indications of an inverse relationship between the sum of DLCs and the concentration of free T4 in anglers in New York State but no association between the sum of DLCs 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 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 as compared with men. Clear effects of DLCs on thyroid function were not apparent in Inuit adults (Dallaire et al., 2009) or in a cross-sectional study of a Chinese community exposed to an electronic-waste recycling plant (Zhang J et al., 2010).

In a study focusing on pesticide use, Chevrier et al. (2008) did not find evidence of effects on thyroid function among women enrolled at the Center for the Health Assessment of Mothers and Children of Salinas in California. Goldner et al. (2010) also published negative results for an association between phenoxy-herbicide exposures and self-reported history of physician-diagnosed thyroid disease in women in the AHS. 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).

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Table 13-3 summarizes findings of studies that have examined the association between dioxin-like congeners and markers of thyroid function. Shaded entries are new findings in this update.

As early as 1994, Koopman-Esseboom et al. noted an inverse association between dioxin-like congeners and markers of disrupted thyroid homeostasis in pregnant women. There has been considerable further study of maternal exposure and perinatal effects on thyroid function, which is not directly applicable to the adult exposure of the mostly male 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.

Update of the Scientific Literature

Several 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 2012. Mass media coverage of conference presentations in 2010 created an expectation of results from a study of Graves disease, an autoimmune hyperthyroid condition. Two papers in preparation were mentioned in a descriptive article lacking actual data (Spaulding, 2011); however, because peer-reviewed publications derived from the preliminary findings still have not appeared, VAO committees have had to disregard this study.

Vietnam-Veteran Studies

In an effort to quantify herbicide exposures experienced during the Vietnam War, Yi et al. (2014a,b) generated EOIs for 111,726 men in the Korean Veterans Health Study by applying the Stellman model (Stellman et al., 2003b).

Yi et al. (2014a) gathered morbidity information for January 2000 through September 2005 on 111,726 of these veterans who had responded to a postal questionnaire in 2004. Claims data from the Health Insurance Review and Assessment of Korea and from the Veterans Health Service were searched for ICD-10 diagnoses corresponding to this set of subjects. With adjustment for age, military rank, smoking, drinking, physical activity, household income, herbicide exposure at home, and BMI, logistic regression on the logarithms of the individual EOI scores was performed. The EOI scores were also partitioned into groups with high or low potential for herbicide exposure. Adjusting for the same factors, the prevelances in the high and low groups were compared. Thyroid conditions overall [ICD-10 E00–E07] showed an indication of increased risk with herbicide exposure both in the internal comparison (OR = 1.06, 95% CI 1.00–1.12) and with analysis of individual scores (OR = 1.01, 95% CI 1.00–1.03). The pattern was very similar for both non-iodine-deficiency hypothyroidism [ICD-10 E03]: for high versus low (OR = 1.13, 95% CI 1.01–1.25) and for individual scores (OR = 1.02, 95% CI 1.00–1.05), and for other nontoxic goiter [ICD-10 E04]: for high versus low (OR = 1.14, 95% CI 1.00–1.31) and for individual scores

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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TABLE 13-3 Selected Epidemiologic Studies—Thyroid Homeostasis (Shaded entries are new information for this update)

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); TSH, total T4, T3% Pavuk et al., 2003
TSH 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—prevalance All COIs
450 interviewed 2005–2006 vs respondents to 2004–2005 national survey (disorders of the thyroid gland) 450 1.4 (0.5–2.2) O’Toole et al., 2009
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 42,421) vs low exposure (n = 69,305) (individual EOI scores) (HRs; ICD-10) All COIs
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Reported Resultsa Reference
Prevalence (01/2000–09/2005)—log EOI scores Yi et al., 2014a
Disorders of the thyroid gland [E00–E07] 5,408 1.0 (1.0–1.0)
Non-iodine-deficiency hypothyroidism [E03] 1,444 1.0 (1.0–1.1)
Other nontoxic goiter [E04] 953 1.0 (1.0–1.0)
Thyrotoxicosis (hyperthyroidism) [E05] 2,476 1.0 (1.0–1.0)
Thyroiditis [E06] 423 1.0 (1.0–1.1)
Autoimmune thyroiditis [E06.3] 92 1.2 (1.1–1.3)
Prevalence (01/2000–09/2005)—categorized high (n = 2,134) vs low (n = 3,274) (5.0% vs 4.7%)
Disorders of the thyroid gland [E00–E07] (2,134 vs 3,274) 1.1 (1.0–1.1)
Non-iodine-deficiency hypothyroidism [E03] (598 vs 846) 1.1 (1.0–1.3)
Other nontoxic goiter [E04] (386 vs 567) 1.1 (1.0–1.3)
Thyrotoxicosis (hyperthyroidism) [E05] (951 vs 1,525) 1.0 (0.9–1.1)
Thyroiditis [E06] (175 vs 248) 1.2 (1.0–1.4)
Autoimmune thyroiditis [E06.3] (48 vs 92) 1.9 (1.3–2.9)
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, NJ, and Verona, MO, employed > 15 yrs earlier and matched controls (n = 260) Calvert et al., 1999
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)
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Population Exposed Casesa Exposure of Interest/Reported Resultsa Reference
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 27.7 (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 = 0.3–5.0 µIU/ml
Based on local levels 0.2
Based on individual sampling LDs –.03
Based on back extrapolation –1.4 (p < 0.05)
T4 vs estimated serum TCDD level 32 Normal = 0.045–2.125 µg/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 = 0.9–1.9 µg/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; follow-ups with CATIs 1999–2003 and 2005–2010 Phenoxy herbicides
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Reported Resultsa Reference
Incidence
Thyroid disease among male pesticide sprayers (n = 22,327) in Iowa and North Carolina (1993–2010) Goldner et al., 2013
Self-reported hypothyroid disease (n = 461)
Self-reported 2,4-D exposure 392 1.4 (1.0–1.8)
Self-reported 2,4,5-T exposure 153 1.4 (1.1–1.7)
Self-reported 2,4,5-TP exposure 67 1.4 (1.1–1.8)
Self-reported dicamba exposure 289 1.4 (1.1–1.7)
Hypothyroid disease
Self-reported 2,4-D use, higher than median 207 1.4 (1.1–1.9)
Self-reported 2,4-D use, less than median 177 1.2 (1.0–1.8)
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 (0.7–1.3)
Self-reported 2,4,5-T exposure 3 NA
Self-reported dicamba exposure 17 0.8 (0.8–2.1)
Hypothyroid
Self-reported 2,4-D exposure 147 1.0 (0.8–1.1)
Self-reported 2,4,5-T exposure 7 1.0 (0.5–2.2)
Self-reported dicamba exposure 27 0.7 (0.5–1.0)
Other thyroid conditions
Self-reported 2,4-D exposure 87 1.2 (1.0–1.5)
Self-reported 2,4,5-T exposure 4 NA
Self-reported dicamba exposure 19 1.0 (0.6–1.5)
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
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Reported Resultsa Reference
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)
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)
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Population Exposed Casesa Exposure of Interest/Reported Resultsa Reference
CHINA—cross-sectional study of a Chinese community in the vacinity 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 J et al., 2010
dl PCBs r = –0.413 (p = 0.01)
PCDD/Fs r = –0.198 (p = 0.21)
ITALY—Seveso Women’s Health Study—Industrial accident July 10, 1976; 981 women between infancy and 40 yrs of age at time of accident, who resided in Zones A and B TCDD Chevrier et al., 2014
1996 thyroid hormone measurements (postmenarche at exposure):
TSH 637 9.3 (–0.8–20.3)
Total T4 629 –0.1 (–0.4–0.1)
Free T4 634 0.0 (–0.1–0.1)
Free T3 635 –0.0 (–0.0–0.0)
JAPAN
2,253 Japanese from general population not occupationally exposed to dioxins, aged 15–76 yrs in 2002–2008, Total Serum TEQ Nakamoto et al., 2013
Thyroid disease (10 cases in men; 63 cases in women) 73
Quartile 1 1.0
Quartile 2 1.0 (0.5–2.4)
Quartile 3 1.2 (0.5–2.7)
Quartile 4 0.7 (0.3–1.9)
p-trend = 0.32
Yusho 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 = 0.90)
T3 correlation coefficient –0.09 (p = 0.74)
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Reported Resultsa Reference
KOREA—105 pregnant Korean women provided blood samples the day before delivery dl mono-ortho PCB 118 Kim et al., 2013
β (95% CI)
Free T3 –0.020 (–0.091–0.005)
Total T3 –0.114 (–0.223–0.005)
Free T4 –0.049 (–0.136–0.038)
Total T4 –0.047 (–0.134–0.040)
TSH 0.389 (–0.183–0.960)
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 Koopman-Esseboom 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, CA, providing blood at 26 wks gestation dl PCBs ß (95% CI) Chevrier et al., 2008
Free T4 vs:
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 (95% CI) Meeker et al., 2007
T3 0.02 (0.05–0.01)a
fT4 0.01 (0.01–0.05)a
fTSH 0.93 (0.84–1.03)a
Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Reported Resultsa Reference
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; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; CATI, computer-assisted telephone interviewing; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; dL, deciliter; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; LD, level of detection; ml, milliliter; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; 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.

(OR = 1.01, 95% CI 0.98–1.04). The risk of thyroiditis [ICD-10 E06] overall was not found to be significantly associated with heribicide exposure. The strongest endocrine-related results, however, were for the specific subtype of thyroiditis, auto-immune thyroiditis [ICD-10 E06.3]: for high versus low (OR = 1.93, 95% CI 1.27–2.94) and for individual scores (OR = 1.16, 95% CI 1.05–1.28). The risk of hyperthyroidism [ICD-10 E05] was not significantly different from 1.00.

Yi et al. (2014b) screened the death records of the National Statistical Office for 1992–2005 to establish vital status for 180,639 of these Korean veterans of the Vietnam War. Results for deaths from endocrine diseases were presented only for the broad range of ICD-10 E00–E88, for which no significant association with herbicide exposure was noted for either the high versus low comparison or for the analysis based on individual scores. No information was provided on mortality for subtypes of endocrine conditions, so nothing was revealed about mortality from disorders specifically involving thyroid dysfunction.

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Occupational Studies

Goldner et al. (2013) reported on new results of the prospective AHS in which male private pesticide applicators were asked (by questionnaire) about their use between 1993 and 1997 of 50 specific agents, including 2,4-D, 2,4,5-T, 2,4,5-triphenoxy-proprionic acid (2,4,5-TP) and about any history of physician-diagnosed thyroid disease between 2005 and 2010 (by phone interview). Of 35,505 men with complete pesticide use data, 22,854 provided the requested data about thyroid disease. Among the 22,246 who had data on all the covariates needed for analysis, 175 reported hyperthyroidism, 461 reported hypothyroidism, and 283 reported other thyroid conditions. After adjusting for age, education, and BMI, the ORs of hypothyroidism for ever-use versus never-use were significantly elevated for 2,4-D (OR = 1.35, 95% CI 1.04–1.76, 392 cases), for 2,4,5-T (OR = 1.38, 95% CI 1.12–1.69, 153 cases), and for 2,4,5-TP (OR = 1.39, 95% CI 1.06–1.82, 67 cases). Intensity-weighted data (cumulative days of use) were available for 2,4-D. In comparison with those who had never used 2,4-D, an increased risk of hypothyroidism was seen in both those who had used 2,4-D for more than the median number of days (OR = 1.40, 95% CI 1.06–1.85, 207 cases) and those whose days of 2,4-D use were fewer than the median (OR = 1.34, 95% CI 1.01–1.78, 177 cases), and the p-value for the trend was 0.025. The use of 2,4,5-TP was found to be inversely related to having a history of hyperthyroidism (OR = 0.46, 95% CI 0.23–0.90). None of the phenoxy herbicides was found to be related to having histories of other thyroid diseases. No analyses of arsenic-based herbicides were presented in this paper.

Environmental Studies

In a cross-sectional study of 1,063 men and 1,201 women living throughout Japan (who had not been occupationally exposed to dioxins), 73 cases of thyroid diseases were reported (Nakamoto et al., 2013). Fasting blood samples were gathered from 2002 to 2010 for an assessment of environmental exposure to DLCs. Blood levels and the corresponding TEQs were determined for dioxin-like PCDD/Fs and PCBs. In addition to estimating trend across all quartiles (pg/g lipid), logistic regression with adjustment for age, sex, smoking, drinking, regional block, and survey year was used to estimate the odds of self-reported thyroid diseases in the upper three quartiles versus the lowest quartile for PCDD/Fs, for PCBs, and combined for all DLCs. The results for thyroid diseases showed no association with any of these three exposure groupings (p for trend over the quartiles = 0.75, 0.24, and 0.32, respectively). Because of the lack of information about the particular type of thyroid disorder, these results are not useful for assessing the prevalance of hypothyroidism specifically.

Among women exposed in the Seveso incident, Chevrier et al. (2014) found a significant inverse association between serum concentrations of TCDD in 1976

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

(n = 981) and 1996 (n = 260) with serum total thyroxine (T4), but not with TSH or free T3, which were measured in 1996 (n = 909). This association was stronger for women who were exposed before menarche than for women exposed after menarche. When thyroid hormones were measured again in 2008 (n = 724) and compared with TCDD levels in 1976 and 1996, the association was no longer present.

In their endeavor to derive individual TEFs for DLCs on a more relevant basis than the responses of acutely exposed laboratory animals, Trnovec et al. (2013) generated a set of input data by measuring two aspects of thyroid function (thyroid gland volume and free T4) in 320 adults from an organochlorine-contaminated area in Slovakia. These measures were chosen for the consistency of their response to dioxin-like activity in both animals and humans. Blood samples from these subjects produced readings above the limits of detection (LODs) for all 7 dioxins, 8 of 10 furans, and all but 1 of the 12 PCBs on the 2005 WHO list of DLCs. Unfortunately, for 3 of the 4 non-ortho PCBs (which have stronger dioxin-like activity than the mono-ortho PCBs), so many of the samples had concentraions below the LODs that analyses could not be performed on these congeners. The article focused on describing the derivation of the TEFs and did not present the statistical properties of the assembled input data, but Trnovec et al. (2013) did note that the two thyroid response variables were selected for this human TEF project because they have consistently shown significant inverse relationships with the DLCs.

During 2011, Kim et al. (2013) collected blood samples from 138 pregnant women during the day before delivery at five Korean hospitals. These samples were analyzed for free T3, total T3, free T4, total T4, and TSH and for concentrations of 19 PCB congeners, of which only the mono-ortho PCB 118 has dioxin-like activity. The pattern for PCB 118 was very similar to that of the non–dioxin-like PCBs measured: a positive relationship with TSH and negative associations with the T3 and T4 variables. For PCB 118, only the association with total T3 levels was statistically significant (β = −0.114, 95% CI –0.223 to –0.005), so evidence favoring hypothyroidism was not limited to dioxin-like activity specifically.

In an Italian study that compared urban and rural workers, Ciarrocca et al. (2012) found that their urinary arsenic levels differed by a factor of between 2 and 4. Urinary arsenic was positively correlated with serum TSH and thyroglobulin and negatively with free T3 and T4. In addition to reports on thyroid function, there were some reports on other endocrine measures in humans.

Manh et al. (2013) and Kido et al. (2014) studied steroid hormone levels in the serum and saliva and dioxin concentrations in the breast milk of lactating Vietnamese women living in a so-called “Agent Orange hot spot” (n = 51) or in an area with no suspected exposure (n = 58). Levels of cortisol and corticosterone in serum and saliva were higher in women living in the hot spot area and were positively correlated with breast-milk dioxin concentrations.

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Pituitary and adrenal disorders were reported on in the Korean Vietnam Veterans Health Study (Yi et al., 2014a) (see above in the discussion of results on thyroid function). Comparing the high-EOI-exposure group (95 cases) with the low-exposure group (110 cases), a significantly (p = 0.011) elevated risk was observed for pituitary hypofunction (OR= 1.44, 95% CI 1.09–1.90), while the risk of pituitary hyperfunction was non-significantly elevated (OR = 1.44, 95% CI 0.90–2.30) for 34 and 37 cases, respectively. The odds ratio for hyperaldosteronism was also non-significantly elevated (OR = 1.94, 95% CI 0.66–5.66), but it was based on a very small number of cases (14 total). Analyses using the one unit increase in the EOI approach yielded similar results, although none of the odds ratios was significant.

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. The reduction in circulating T4 concentrations is robust and has recently been proposed as a biomarker of the effect of DLCs (Yang JM et al., 2010). Female rats exposed chronically to TCDD showed follicular-cell hyperplasia and hypertrophy of thyroid follicles that were consistent with an 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). An enhanced accumulation of T4 in hepatic tissue of TCDD-treated mice may also contribute to the reduction in circulating T4 (Kato et al., 2010).

The possibility that arsenic could act as an endocrine disruptor on thyroid hormone–mediated processes has been proposed on the basis of cell culture studies and experiments with the ex vivo amphibian tail metamorphosis assay (Davey et al., 2008). In guinea pigs fed diets containing 50 ppm arsenic as sodium arsenite or arsenic trioxide for 11 weeks, serum (total) T3 and T4 were reduced compared to controls by about 20 to 25 percent and 33 percent, respectively (Mohanta et al., 2014). These data raise the possibility that cacodylic acid may also disrupt thyroid homeostasis, but there are no published epidemiologic studies that have addressed this.

Synthesis

Numerous animal experiments and several epidemiologic studies have shown that TCDD and DLCs exert some influence on thyroid homeostasis, with findings

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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being most consistently indicative of hypothyroidism (Boas et al., 2006, 2012). The underlying molecular mechanisms resulting in these effects on thyroid hormone and TSH concentrations in humans, however, are not as yet fully characterized (Langer, 2008).

Several prior studies of populations environmentally exposed to PCBs found some combination of elevated TSH concentrations and depressed T4 and T3 levels (Bloom et al., 2006; Hagmar et al., 2001a; Persky et al., 2001; Schell et al., 2004), although some (Hagmar et al., 2001b; Sala et al., 2001) found no significant effect. Although the findings in the infants in studies of women and their children are not relevant to effects arising from adult exposure, observations in the mothers themselves contribute to the findings of this chapter. Such studies have tended to support the hypothesis that exposure to DLCs is associated with hypothyroidism (Koopman-Esseboom et al., 1994; Takser et al., 2005), although the recent study on Korean mothers (Kim et al., 2013) did not report strong evidence of this. The new findings concerning thyroid hormones in women from Seveso presented a result fairly consistent with hypothyroidism 20 years after the accident, which had dissipated after another 12 years (Chevrier et al., 2014).

Pavuk et al. (2003) had reported a trend of higher TCDD serum concentrations being associated with increasing concentrations of TSH that was not accompanied by changes in circulating T4 or T3 (which would be interpreted as subclinical hypothyroidism) in participants in the AFHS. This finding in US Vietnam veterans is complemented by the new results from the Korean Vietnam Veterans Health Study. Yi et al. (2014a) found evidence of an increased occurrence of clinical hypothyroid disease, possibly associated with autoimmune hypothyroidism, in association with higher estimated potential herbicide exposure. In addition, the report from the AHS of increased physician-diagnosed hypothyroidism in herbicide applicators with phenoxy herbicide exposure (Golden et al., 2013) supports the notion that this association is real.

An overall assessment of the studies suggests some variation in thyroid-hormone concentrations in relation to exposure to DLCs and possibly the phenoxy compounds themselves. Although the functional importance of the changes may be unclear in some cases, it should be noted that in the new epidemiological studies identified in this update, clinical hypothyroidism was the endpoint. Because of the consistent observations of exposures to the COIs being related to perturbations of thyroid function, and to clinical hypothyroidism in particular, the committee considered the body of epidemiologic data, in combination with strong biologic plausibility, to represent limited or suggestive evidence.

New data from the Korean Vietnam Veterans Health Study suggest that adrenal and possibly pituitary function may also be affected by exposure to DLCs supporting some older literature data. In addition, there are some data to suggest the possibility that arsenic-based herbicides may also affect thyroid function.

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Conclusions

There is limited or suggestive evidence of an association between exposure to the COIs and hypothyroidism. Additional endocrine effects have been observed in conjunction with exposure to the COIs in both humans and animals, but the evidence is inadequate or insufficient to establish an association with herbicide exposure for them.

EYE PROBLEMS

This section discusses eye problems, which are grouped in ICD-9 360–379 or ICD-10 H00–H59. The loss of vision is increasingly common with advanced age, and about one-sixth of people over 70 years old have substantial impairment, with 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 a 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 that the veterans 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. In Update 2012, the committee noted that no epidemiologic studies of exposure to the COIs and eye problems had been published since Update 2010, and they concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and eye conditions.

Update of Epidemiologic Evidence

No epidemiologic studies of exposure to the COIs and eye problems have been published since Update 2012.

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Biologic Plausibility

There have been several recent reports of ocular activity associated with AHR induction in or with TCDD exposure of rats (Sugamo et al., 2009), mice (Takeuchi et al., 2009), and human nonpigmented ciliary epithelial cells (Volotinen et al., 2009). Since Update 2012, Hu et al. (2013) reported that mice harboring the null allele at the AHR locus developed macular age-related degeneration-like pathology.

Synthesis

Since Update 2012, 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 were of concern to the committee for Update 2012 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 osteoporosis, or decreased bone density, which is coded as ICD-9 733.0–733.1 or ICD-10 M80–M81. Osteoporosis is a skeletal disorder characterized by a decrease in bone mineral density (BMD) and a loss of the structural and biomechanical properties of the skeleton, which leads 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). The WHO has defined osteoporosis based on BMD measurements. The diagnostic T-score derived by dual energy x-ray absorptiometry is the number of standard deviations from the mean BMD for healthy women. In women, readings greater than −1.0 are normal, whereas osteopenia is defined by a T-score between −1.0 and −2.5, osteoporosis is defined by a T-score between −2.5 and −5.0, and severe osteoporosis corresponds to a T-score of −5.0 or lower. Diagnostic criteria have not been standardized for osteoporosis in men. Although men have much higher baseline BMD than women, they seem to have a similar fracture risk for a given BMD (Lash et al., 2009), so most authorities apply the same WHO ranges for T-scores calculated relative to normal young women.

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Sex is an important risk factor for osteoporosis; about 56 percent of postmenopausal women have decreased BMD, and 6 percent have osteoporosis (CDC, 2002). 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 the use of long-acting benzodiazepine or anticonvulsant drugs, previous hyperthyroidism, excessive caffeine intake, and routinely standing for less than 4 hours per day (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, epidemiologic studies of the association between environmental exposures to organochlorine compounds and bone disorders have had inconsistent results.

Summary of Previous Updates

Update 2010 was the first VAO update that reviewed studies of the association between exposures to the COIs and a decrease in BMD. Results from Hodgson et al. (2008) motivated the inclusion of this health outcome. The researchers 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, blood samples were analyzed for the five dioxin-like mono-ortho PCB congeners (PCB 105, 118, 156, 157, and 167), and TEQs were 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.

Little additional data were available for review in Update 2012. There were no new studies of Vietnam-era veterans, and neither the single occupational study (Waggoner et al., 2011) nor the environmental study (Cho et al., 2011) reported

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

results with enough exposure specificity to be fully informative for VAO consideration. Furthermore, the category of “bone and connective tissue disorders” reported in Waggoner is difficult to clearly interpret.

Update of the Scientific Literature

Vietnam-Veteran, Occupational, and Case-Control Studies

No Vietnam veteran, occupational, or case-control studies of exposure to the COIs and BMD or osteoporosis have been published since the Update 2012.

Environmental Studies

A recent study of 350 women who were exposed to TCDD as a result of living in Seveso, Italy, during the 1976 chemical explosion examined the relationship of DEXA-assessed bone mineral density and TCDD serum levels (Eskenazi et al., 2014). The results suggested that TCDD levels were associated with some evidence of better bone structure in the 48 women for whom exposure occurred after their age or peak bone mass, which is estimated to happen 2 years after menarche. The study did not support the hypothesis that postnatal TCDD exposure adversely affects adult bone health.

There were two cross-sectional studies recently published addressing the association of exposure to DLCs and bone quality in residents of Canada’s northern regions who are known to be exposed to these compounds as a result of their diet, which includes marine mammals and predatory fish (Paunescu et al., 2013a,b). The cross-sectional study of 249 adult Cree women in James Bay, Canada, reported an increase in dioxin-like PCBs 105 and 108 to be negatively associated with a “stiffness index.” In a similar cross-sectional study of 194 Inuit women aged 35–72 years, neither total plasma DLC levels nor any specific dioxin-like PCB level was associated with ultrasonography-assessed bone strength.

Biologic Plausibility

Animal studies suggest that TCDD may have some influence on bone formation and maintenance. Recent work from Herlin et al. (2013) has shown that the exposure of adult mice to TCDD resulted in harder bone matrix, thinner cortical bone, mechanically weaker bones, and, most notably, increased trabecular bone volume fraction in Ahr(+/+) mice. 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

Suggested Citation:"13 Other Chronic Health Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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 the expression of the bone-formation marker procollagen type I N-terminal propeptide and increased the 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 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). Iqbal et al. (2013) recently addressed this, studying genetically altered mice so that they could understand the contributions of tobacco carcinogens and TCDD. In their work, mice in which the Ahr or Cyp1a1, Cyp1a2, and Cyp1b1 genes were deleted displayed reduced resorption and high bone mass. In contrast, AHR activation by administering B[a]P to wild-type mice increased osteoclastogenesis and bone resorption.

Synthesis

The small amount of available epidemiologic information on the 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 biological data confirm that TCDD is active in bone metabolism, but the pattern of association of exposure to the COIs and subsequent disease is not consistent in the current literature.

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 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 were conducted every two years to review newly available literature and draw conclusions from the overall evidence. Veterans and Agent Orange: Update 2014 is a cumulative report of the series thus far.

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