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), picloram, and cacodylic acid—and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a contaminant of 2,4,5-T, and several noncancer health outcomes: respiratory disorders, immune-system disorders, diabetes, lipid and lipoprotein disorders, gastrointestinal and digestive disease (including liver toxicity), circulatory disorders, and adverse effects on thyroid homeostasis. The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners.
In previous updates, chloracne and porphyria cutanea tarda (PCT) were considered along with these chronic noncancer conditions. These are conditions that are quite well accepted to be associated with dioxin exposure, but when they occur this happens within a matter of months of the exposure. In this update these two health outcomes have been 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 disorder.
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 (IOM) Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. In the discussion of the most recent scientific literature, studies are grouped by exposure type (Vietnam veteran, occupational, or environmental). For articles that report on only a single health outcome and that are not revisiting a previously studied population, design information is summarized
with the results; design information on other studies can be found in Chapter 5. A synopsis of toxicologic and clinical information related to the biologic plausibility that the chemicals of interest can influence the occurrence of a health outcome is presented next and followed by a synthesis of all the material reviewed. Each health-outcome section ends with the present committee’s conclusions regarding the strength of the evidence that supports an association with the chemicals of interest. The categories of association and the committee’s approach to categorizing the health outcomes are discussed in Chapters 1 and 2.
For the purposes of this report, noncancerous respiratory disorders comprise acute and chronic lung diseases other than cancer. Acute noncancerous respiratory disorders include pneumonia and other respiratory infections; they can increase in frequency and severity when the normal defense mechanisms of the lower respiratory tract are compromised. Chronic noncancerous respiratory disorders generally take two forms: airways disease and parenchymal disease. Airways disease encompasses disorders, among them asthma and chronic obstructive pulmonary disease (COPD), characterized by obstruction of the flow of air out of the lungs. COPD is also known as chronic obstructive airways disease and includes emphysema and chronic bronchitis. Parenchymal disease, or interstitial disease, generally includes disorders that cause inflammation and scarring of the deep lung tissue, including the air sacs and supporting structures; parenchymal disease is less common than airways disease and is characterized by reductions in lung capacity, although it can include a component of airway obstruction. Some severe chronic lung disorders, such as cystic fibrosis, are hereditary. Because Vietnam veterans received health screenings before entering military service, few severe hereditary chronic lung disorders are expected in that population.
The most important risk factor for many noncancerous respiratory disorders is inhalation of cigarette smoke. Although exposure to cigarette smoke is not associated with all diseases of the lungs, it is the major cause of many airways disorders, especially COPD; it contributes to some interstitial disease; and it compromises host defenses in such a way that people who smoke are generally more susceptible to some types of pneumonia. Cigarette-smoking also makes almost every respiratory disorder more severe and symptomatic than it would otherwise be. The frequency of habitual cigarette-smoking varies with occupation, socioeconomic status, and generation. For those reasons, cigarette-smoking can be a major confounding factor in interpreting the literature on risk factors for respiratory disease. Vietnam veterans are reported to smoke more heavily than are non-Vietnam veterans (Kang et al., 2006; McKinney et al., 1997).
It is well known that causes of death from respiratory diseases, especially chronic diseases, are frequently misclassified on death certificates. Grouping various respiratory diseases for analysis, unless they all are associated with a given
exposure, will lead to attenuation of the estimates of relative risk (RR) and to a diminution of statistical power. Moreover, diagnosis of the primary cause of death from respiratory and cardiovascular diseases (CVDs) is often inconsistent. In particular, when persons have both conditions concurrently and both contributed to death, there may be some uncertainty about which cause should be selected as the primary underlying cause. In other instances, errors may arise in selecting one underlying cause in a complex chain of health events (for example, if COPD leads to congestive heart failure and then to respiratory failure).
Many study populations are small, so investigators group deaths from all noncancerous respiratory diseases into one category that combined pneumonia, influenza, and other diseases with COPD and asthma. The committee notes that an association for the grouping of all noncancerous respiratory diseases with any of the chemicals of interest would be too nonspecific to be clinically meaningful; at most, such a pattern would be an indication that within this broad classification some particular disease entity might be impacted by an exposure of interest.
Conclusions from VAO and Previous Updates
The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994) concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest 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.
Veterans and Agent Orange: Update 2000 (IOM, 2001) drew attention to findings on the Seveso cohort that suggested a higher mortality from noncancerous respiratory disorders in study subjects, particularly males, who were more heavily exposed to TCDD. Those findings were not replicated in several other relevant studies, although one showed an increase that did not attain statistical significance. The committee responsible for Update 2000 concluded that although new evidence suggested an increased risk of noncancerous respiratory disorders, particularly COPD, in people exposed to TCDD, the observation was tentative and the information insufficient to determine whether there is an association between exposures to the chemicals of interest and respiratory disorders. Additional information available to the committee responsible for Veterans and Agent Orange: Update 2002 (IOM, 2003) did not change that finding.
Veterans and Agent Orange: Update 2004 (IOM, 2005) included a new cross-sectional study of residents near a wood-treatment plant (Dahlgren et al., 2003). Soil and sediment samples from a ditch in the neighborhood contained dioxins and furans. Although exposed residents reported a greater frequency of chronic bronchitis by history (17.8% vs 5.7%; p < 0.0001) and asthma by history (40.5% vs 11.0%; p < 0.0001) than a “nonexposed” control group, the committee
concluded that selection bias and recall bias limited the utility of the results and that there was a possibility of confounding in that history of tobacco use was not accounted for adequately.
Veterans and Agent Orange: 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 (Ketchum and Michalek, 2005), and in two Australian studies of Vietnam veterans (ADVA, 2005b,c). In contrast, in the US Army Chemical Corps cohort of Vietnam veterans, Kang et al. (2006) found that the prevalence of self-reported noncancerous respiratory problems diagnosed by a doctor was significantly increased by about 40–60%, although no differences in the prevalence of respiratory problems was found in the subset of veterans whose serum TCDD was above 2.5 ppt.
In addition, Update 2006 addressed new studies of potentially exposed occupational cohorts. No associations with respiratory mortality were found in a small subcohort of New Zealand phenoxy-herbicide sprayers included in the International Agency for Research on Cancer (IARC) cohort (’t Mannetje et al., 2005). In the Agricultural Health Study (AHS), no associations between the herbicide and mortality from COPD were found in private applicators or their spouses (Blair et al., 2005). There was also an AHS analysis (Hoppin et al., 2006a) of specific pesticide exposures and the self-reported prevalence of wheeze that showed an association with “current” exposure to 2,4-D.
Several additional new AHS publications were reviewed in Veterans and Agent Orange: Update 2008 (IOM, 2009) concerning morbidity from particular self-reported respiratory health problems: another analysis concerning wheeze (Hoppin et al., 2006b), asthma (Hoppin et al., 2008), “farmer’s lung” or hypersensitivity pneumonitis (Hoppin et al., 2007a), and chronic bronchitis (Hoppin et al., 2007b; Valcin et al., 2007). The 25-year follow-up of the mortality of the Seveso population through 2001 (Consonni et al., 2008) was also considered in Update 2008; again there was some elevation in mortality from COPD as had been seen in the earlier mortality follow-up reviewed in Update 2000.
Table 11-1 summarizes the results of the relevant studies.
Update of the Epidemiologic Literature
The Army Chemical Corps (ACC) cohort is of particular interest because the members deployed to Vietnam had potential exposure to the chemicals of interest second only to that of the Ranch Hand veterans. Cypel and Kang (2010) reported the cause-specific mortality through 2005 in ACC veterans who served in Vietnam between July 1, 1965–March 28, 1973 (n = 2,872) and ACC veterans
|Reference||Study Population||Exposed Casesa||Exposure of Interest/
|US Air Fork Health Study—Ranch Hand veterans vs SEA veterans||All COIs|
|Ketchum and Michalek, 2005||Rand Hand personnel (n = 1,262) vs SEA veterans (19,078)—respiratory disease (ICD-9 460–519)
Mortality through 1999
|AFHS, 1996||Mortality through 1993||2||0.5 (0.1–1.6)|
|US VA Cohort of Army Chemical Corps||All COIs|
|Cypel and Kang, 2010||Deployed veterans (2,872) vs nondeployed (2.737)—mortality ihrough 2005
Respiratory system disease
Pneumonia and influenza
ACC deployed men in Kang et aJ. (2006)
reported sprayed herbicide vs did not spray
Respiratory system disease
Pulmonary disease (COPD)
32 vs 8
12 vs 6
20 vs 2
|Kang et al., 2006||Self-reported morbidity 1999—noncancerous respiratory problems diagnosed by doctor Deployed (n = 1,499) vs nondeployed (n = 1,428)||267||1.4 (1.1–1.8)|
|Sprayed herbicides in Vietnam vs never||140||1.6 (1.2–2.1)|
|Cypeland||Deployed veterans (2,872) vs nondeployed|
|Dalager and Kang, 1997||Mortality through 1991
Respiratory system disease
|11 vs 2||2.6 (0.5–12.2)|
|US CDC Vietnam Experience Study||All COIs|
|Boehmer et al., 2004||Vietnam Experience Cohort
Noncancerous respiratory mortality (ICD-9 460–519)
|CDC, 1988||Cross-sectional study, with medical examinations, of US Army Vietnam veterans vs nondeployed US Army veterans
Odds ratios from pulmonary-function tests
(case definition: ≥ 80% predicted value)
|US VA Mortality Study of Army and Marine Veterans (ground troops serving July 4, 1965–March 1, 1973)||All COIs|
|Watanabe and Kang, 1996||Mortality of US Vietnam veterans who died during 1965–1988, PMR analysis of noncancerous respiratory mortality (ICD-8 460–519)|
|Army||648||0.8 (p < 0.05)|
|Marine Corps||111||0.7 (p < 0.05)|
|Reference||Study Population||Exposed Casesa||Exposure of Interest/
|US VA Cohort of Monozygotic Twins
Eisen et al., 1991
|Incidence in deployed vs nondeployed
monozygotic twins who servedin US military
|during Vietnam era|
|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)|
|Other US VA Vietnam Veteran Studies||All COIs|
|Bullman and||Male Vietnam veterans who were wounded in|
|Kang, 1996||combat vs US population|
|Noncancerous respiratory mortality (ICD 9||43||0.9 (0.7–1.2)|
|State Studies of US Vietnam Veterans||All COIs|
|Anderson||White males with Wisconsin death certificate|
|et al., 1986||(1968–1978), mortality from noncancerous|
|respiratory disease (ICD-8 460–519)|
|Vietnam veterans vs expected deaths|
|calculated from proportions for:||10|
|All veterans||0.8 (0.4–1.5)|
|Vietnam-era veterans||1.0 (0.5–1.8)|
|Australian Vietnam Veterans vs Australian Population||All COIs|
|ADVA,||Third Australian Vietnam Veterans Mortality|
|Deployed veterans vs Australian population|
|Respiratory system diseases||239||0.8 (0.7–0.9)|
|Respiratory system diseases||50||0.8 (0.6–1.0)|
|Respiratory system diseases||162||0.8 (0.7–0.9)|
|Respiratory system diseases||28||0.6 (0.4–0.9)|
|CDVA,||Mortality of male Australian Vietnam veterans|
|1997a||vs Australian population|
|Noncancerous respiratory mortality (ICD-9|
|Chronic obstructive airways disease|
|(ICD-9 490–496)||47||0.9 (0.7–1.2)|
|Reference||Study Population||Exposed Casesa||Exposure of Interest/
|Australian Conscripted Army National Service (deployed vs nondeployed)||All COIs|
|ADVA, 2005c||Mortality 1966–2001
|CDVA,||Mortality from noncancer respiratory disease|
|Australian Army Vietnam Veterans—sample of 1,000 vs Australian||All COIs|
|National Helth Survey—self-reported chronic conditions||Relative Prevalence|
|O’Toole||Veterans interviewed 2005–2006 (n = 450) vs|
|et al., 2009||2004–2005 National Survey results|
|Chronic lower respiratory disease||nr|
|Hay fever and allergic rhinitis||nr||1.2 (0.96–1.4)|
|Chronic sinusitis||nr||1.7 (1.5–2.0)|
|Other diseases of the respiratory system||nr||15.4 (11.7–19.1)|
|O’Toole||Veterans interviewed 1990–1993 (n = 641) vs|
|et al., 1996||1989–1990 National Survey results|
|Bronchitis, emphysema||nr||4.1 (2.8–5.5)|
|IARC Phenoxy Herbicides Cohort (mortality vs national mortality||Dioxin, phenoxy|
|Kogevinas||Mortality in international workers producing|
|et al., 1997||or applying phenoxy herbicides, noncancerous|
|respiratory mortality (ICD-9 460–519),|
|NIOSH Mortality Cohort (12 US plants, production 1942–1984)||Dioxin, phenoxy|
|(included in IARC cohort)||herbicides|
|Steenland||NIOSH mortality study of chemical workers at|
|et al., 1999||12 plants in US exposed to TCDD|
|Noncancerous respiratory mortality (ICD-9|
|Preliminary NIOSH Cross-Sectional Medical Study—workers||in||Dioxin, phenoxy|
|production of||sodium trichlorophenol, 2,4,5-T ester contaminated||with||herbicides|
|Sweeney||Chronic bronchitis and COPD||2||nr|
|Reference||Study Population||Exposed Casesa||Exposure of Interest/
|Calvert||Odds ratios for increase in 1 ppt of serum|
|et al., 1991||TCDD compared to unexposed workers|
|Chronic bronchitis||nr||0.5 (0.1–2.6)|
|Monsanto Production Workers—Nitro, WV, 2,4,5-T plant||Dioxin, phenoxy herbicides|
|Suskind and Hertzberg, 1984||Cross-sectional study, 1979, comparing exposed with nonexposed workers for “abnormal”outcome on pulmonary-functions tests:|
|FEV1 (< 80% predicted)||2.81 (p = 0.02)|
|FVC (< 80% predicted)||2.25 (p = 0.03)|
|FEV1/FVC (< 70%)||2.97 (p = 0.01)|
|FEF25-75 (< 80% predicted)||1.86 (p = 0.05)|
|Dow Chemical Company—Midland, MI (included in IARC and||Dioxin, phenoxy|
|et al., 2009a||respiratory disease (ICD-10 J00–J99)|
|TCP workers||44||0.8 (0.6–1.0)|
|et al., 2009b||respiratory disease (ICD-10 J00–J99)|
|PCP workers without TCP exposure||19||0.7 (0.4–1.2)|
|Burns et al.,||Mortality of 2,4-D workers, 1945–1994|
|2001||Noncancerous respiratory (ICD-8 460–519)||8||0.4 (0.2–0.7)|
|Ramlow||Mortality of PCP workers, 1940–1989|
|et al., 1996||Noncancerous respiratory mortality (ICD-8|
|Cumulative PCP exposure|
|< 1 unit||3||0.6 (0.2–1.9)|
|≥ 1 unit||11||1.4 (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)|
|BASF Production Workers—German workers exposed to trichlorophenol contaminated with TCDD from 1953 accident (included in IARC cohort)||Dioxin, phenoxy
|Ott and||Noncancerous respiratory mortality through||1||0.1 (0.0–0.8)|
|Zober, 1996||1993 vs West German rates (n = 243 men)|
|Zober et al.,||Prevalence—cohort (n = 158), reference (n =|
|1994||161) (illness episodes per 100 person–years,|
|All noncancerous respiratory diseases (ICD-9|
|460–519)||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 or 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)|
|Reference||Study Population||Exposed Casesa||Exposure of Interest/
|Dutch Production Workers (included in IARC cohort)||Dioxin, phenoxy|
|Boers et al., 2010||Dutch chlorophenoxy workers Diseases of the respiratory system|
|Factory A (HR for exposed vs unexposed)||19 vs 12||1.0 (0.4–2.3)|
|Factory B (HR for exposed vs unexposed)||6 vs 15||0.5 (0.2–1.2)|
|German Production Workers (included in IARC cohort)||Dioxin, phenoxy|
|Becher et al., 1996||Four German facilites for production of phenoxy herbicides, chlorophenols, noncancerousrespiratory mortality (ICD-9 460–519)|
|Boehringer Ingelheim||10||0.5 (0.3–1.0)|
|Bayer Uerdingen||2||0.9 (0.1–3.1)|
|BASF Ludwigshafen||4||0.6 (0.2–1.6)|
|New Zealand Production Workers—Dow plant in Plymouth, NZ included in IARC cohort)||Dioxin, phenoxy herbicides|
|McBride||Dow trichlorophenol workers in Plymouth, NZ|
|et al., 2009a||Ever-exposed workers||12||0.8 (0.4–1.4)|
|’t Mannetje||New Zealand phenoxy herbicide workers,|
|et al., 2005||noncancerous respiratory mortality (ICD-9|
|United Kingdom Production Workers (included in IARC cohort)||Dioxin, phenoxy herbicides|
|Coggon||Production of phenoxy herbicides,||8||0.7 (0.3–1.3)|
|et al., 1991||chlorophenols in four British plants, mortality|
|from noncancerous respiratory diseases,|
|Coggon||British plant manufacturing MCPA, mortality||93||0.6 (0.5–0.8)|
|et al., 1986||from noncancerous respiratory diseases (ICD-9|
|Agricultural Health Study||Herbicides|
|Hoppin et al., 2009||US AHS—prevalence at enrollment among male agricultural workers of:|
|Slager et al.,||US AHS—commercial pesticide applicators||1,664|
|2009||Current rhinitis and exposure to:|
|Reference||Study Population||Exposed Casesa||Exposure of Interest/
|Hoppin et al., 2008||US AHS—prevalence at enrollment among farm women of:|
|Atopic asthma having exposure to:|
|Nonatopic asthma having exposure to:|
|Hoppin et al., 2007a||US AHS—prevalence at enrollment of self-reported farmer’s lung (hypersensitivitypneumonitis)|
|Private applicators exposed to phenoxy herbicides||392||1.2 (0.8–1.7)|
|Spouses exposed to phenoxy herbicides||16||1.4 (0.7–2.7)|
|Hoppin et al., 2007b||US AHS—prevalence at enrollment of chronic bronchitis in private applicators exposedto:|
|2,4,5-T (lifetime days)||28||1.5 (1.3–1.8)|
|> 55||4||1.0 (0.6–1.5)|
|2,4,5-TP (lifetime days)||9||1.7 (1.3–1.3)|
|> 55||2||1.4 (0.8–2.5)|
|Valcin et al., 2007||US AHS—prevalence at enrollment of chronic bronchitis in nonsmoking farm women exposedto:||0.9 (0.7–1.1)|
|Hoppin et al., 2006a||US AHS—cross-sectional study of wheeze in commercial applicators with current useof:|
|Reference||Study Population||Exposed Casesa||Exposure of Interest/
|Hoppin et al., 2006b||US AHS—prevalence at enrollment of wheeze (added adjustment for exposure to herbicidechlorimuron-ethyl)|
|Private applicators with current use of:|
|Commercial applicators with current use of:|
|Blair et al.,||US AHS—COPD mortality|
|2005||Private applicators||50||0.2 (0.2–0.3)|
|Other Agricultural Studies||Herbicides|
|Senthilselvan et al., 1992||Cross-sectional study of self-reported prevalence of self-reported asthma (n = 83)in male farmers (n = 1,939) in Saskatchewan (1982–1983)||Asthmatics vs nonasthmatics|
|Phenoxyacetic herbicide use||71||85.5% vs 88.5%|
|Herbicide and Pesticide Applicators||Herbicides|
|Blair et al., 1983||Licensed pesticide applicators, Florida, noncancerous respiratory diseases, (ICD-8460–519)||2||0.9 (nr)|
|Analyses by length of licensure|
|≥ 10 yrs||8||0.6 (nr)|
|10–19 yrs||8||1.5 (nr)|
|≥ 20 yrs||4||1.7 (nr)|
|Alavanja||PMR study of US Department of Agriculture||80||0.8 (0.6–1.0)|
|et al., 1989||soil, forest conservationists, mortality 1970–|
|1979 from noncancerous respiratory diseases|
|Seveso, Italy Residential Cohort||TCDD|
|Consonni et al., 2008||25-yr follow-up of Seveso residents—mortality
Respiratory disease (ICD-9 460–519)
|Zone A||9||1.4 (0.7–2.7)|
|Zone B||48||1.0 (0.8–1.4)|
|Zone R||341||1.0 (0.9–1.1)|
|COPD (ICD-9 490–493)|
|Zone A||7||2.5 (1.2–5.3)|
|Zone B||26||1.3 (0.9–1.9)|
|Zone R||175||1.2 (1.0–1.4)|
|Reference||Study Population||Exposed Casesa||Exposure of Interest/
|Bertazzi et al., 2001||20-yr follow-up of Seveso residents—mortality
Respiratory disease (ICD-9 460–519)
|Zone A||9||1.9 (1.0–3.6)|
|Zone B||35||1.3 (0.9–2.0)|
|COPD (ICD-9 490–493)||29||1.5 (1.1–2.2)|
|Zone A||7||3.3 (1.6–6.9)|
|Zone B||22||1.3 (0.9–2.0)|
|Bertazzi et al., 1998;||15-yr follow-up of Seveso residents—mortality Respiratory disease (ICD-9 460–519)|
|et al., 1998||Men||5||2.4 (1.0–5.7)|
|COPD (ICD-9 490–493)|
|Bertazzi et al., 1989a,b (results from||10-yr follow-up on Seveso residents—mortality in Zones A, B, and R Respiratory disease(ICD-9 460–519)|
|Bertazzi et al., 1989a)||Men||55||1.0 (0.7–1.3)|
|Pneumonia (ICD-9 480–486)|
|COPD (ICD-9 490–493)|
|Reference||Study Population||Exposed Casesa||Exposure of Interest/
|Other Environmental Studies|
|Dahlgren et al., 2003||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||Dioxins, furans Prevalence in exposed vs nonexposed|
|21.7% vs 4.3% (p < 0.0001)|
|Diagnosed by physician||17.8% vs 5.8%|
|(p < 0.0001)|
|By history of wheeze||40.5% vs 11.0%|
|(p < 0.0001)|
|Diagnosed by physician||13.1% vs 12.0%|
|Svensson||Swedish fishermen exposed to TCDD, mortality||TCDD|
|et al., 1995||from bronchitis or emphysema (ICD-7|
|East coast||4||0.5 (0.2–1.2)|
|West coast||43||0.8 (0.6–1.1)|
ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; ACC, Army Chemical Corps; AHS, Agricultural Health Study; CI, confidence interval; COI, chemical of interest; COPD, chronic obstructive pulmonary disease; FEF25-75, forced midexpiratory flow; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD-8, International Classification of Diseases, 8th revision; ICD-9, International Classification of Diseases, 9th revision; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MI, Michigan; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not significant; NZ, New Zealand; PCP, pentachlorophenol; PMR, proportionate mortality ratio; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veterans Affairs; WV, West Virginia.
aGiven when available; results other than estimated risk explained individually.
who did not serve in Vietnam (n = 2,737). Observed deaths for the ACC Vietnam veteran cohort were compared with expected deaths for US men, as well as being contrasted between the deployed and nondeployed veterans. In addition, mortality was also examined in a subset of the original Vietnam cohort who either reported spraying herbicide (n = 662) or not spraying herbicide (n = 811); the morbidity of this subset was analyzed by Kang et al. (2006). Cypel and Kang (2010) reported a statistically significant excess mortality (adjusted RR = 4.82, 95% confidence interval [CI] 1.10–21.18) when 20 deaths from COPD among ACC Vietnam vet-
erans were compared to 2 COPD deaths among ACC veterans who did not serve in Vietnam. A similar pattern of elevated excess COPD mortality among the ACC Vietnam veterans was observed when comparisons were made with the US male population (standardized mortality ratio [SMR] = 1.62, 95% CI 0.99–2.51), not quite reaching the traditional 0.05 level of statistical significance. When the subgroup of ACC Vietnam veterans who reported spaying herbicides was compared to the ACC Vietnam veterans who did not report spraying herbicides, a nonsignificantly elevated risk for death due to the less specific category of noncancerous respiratory system disease was reported (adjusted RR = 2.24, 95% CI 0.42–11.83). Although this comparison did not report mortality due specifically to COPD, it is important to note that this is the only comparison that controlled not only for self-reported herbicide exposure and body mass index (BMI), but also for smoking status, a major risk factor for COPD. Comparisons with the large cohort of ACC veterans who served in Vietnam benefit from a larger sample size (n = 2,737), but are limited due to lack of information on confounding factors, including smoking, alcohol use, dietary habits, and post-service occupational exposure. In Kang et al. (2006), 71% of ACC Vietnam veterans were regular smokers, while 60% of ACC non-Vietnam veterans were regular smokers, which is about twice the rate of smoking in US males. The high self-reported rate of current smoking in the ACC Vietnam veterans could have directly contributed to elevated COPD in this group when compared to the general US male population. In addition to not controlling for smoking and other risk factors for COPD, another limitation of the mortality study of Cypel and Kang (2010) is the reliance on death certificates for information on causes of death. Disease diagnosis at time of death and International Classification of Diseases (ICD) classification are factors that may impact the quality of cause of death statistics from death certificates. Detection bias and potential lack of uniformity of access to the health-care system in the ACC cohort are other concerns. COPD is commonly associated with other comorbidities that could have been included on death certificates, including angina, myocardial infarction, respiratory infection, pneumonia, and cardiac disorders (Soriano et al., 2005). Lung function tests are necessary for an accurate diagnosis of COPD but are rarely done. Another factor that may contribute to the observed increase in COPD mortality in the ACC Vietnam veterans, relative to the ACC non-Vietnam veterans, is the low number of only two deaths due to COPD in the cohort of 2,737 ACC non-Vietnam veterans. Deaths due to COPD were lower in ACC non-Vietnam veterans relative to males in the US population (SMR = 0.3, 95% CI 0.04–1.07), which is noteworthy because the prevalence of smoking in the ACC non-Vietnam veterans was about twice that of the comparison group of males in the US population. In summary, although Cypel and Kang (2010) reported an increase in mortality due to COPD in ACC Vietnam veterans, the relative strength of this study is limited by a number of factors, including reliance on death certificates, known limitations in the accuracy and consistency with which COPD is reported as a cause of death, and not controlling for smoking, which is a major risk factor for COPD.
The self-reported physical and mental health of Australian Vietnam veterans, from the 2004–2005 National Health Survey Interview, was compared with age- and gender-matched data from the Australian general population (O’Toole et al., 2009). The relative prevalences (RPs) of several chronic lower respiratory diseases were significantly elevated in the Australian Vietnam Veterans (n = 450) for bronchitis (RP = 2.90, 95% CI 2.18–3.63), emphysema (RP = 2.03, 95% CI 1.32–2.74), and asthma (RP = 1.33, 95% CI 1.01–1.64). For the condition, “other diseases of the respiratory system,” the relative prevalence was markedly elevated (RP = 15.41, 95% CI 11.71–19.11), but there was no further description of this category. The relative prevalence of chronic sinusitis was also significantly elevated (RP = 1.73, 95% CI 1.45–2.01), while hay fever and allergic rhinitis was not significantly elevated (RP = 1.16, 95% CI 0.96–1.36). It is noteworthy that, with the exception of hay fever and allergic rhinitis, the relative prevalences of all noncancerous diseases of the respiratory system were elevated in this cohort of Australian Vietnam veterans, but it is not possible to draw any sound conclusions from this study, which relied solely on self-reported health data. The committee had serious concerns that the results reported in O’Toole et al. (2009) were compromised by recall bias and other methodologic problems.
A third follow-up in Dutch chlorophenoxy herbicide manufacturing workers (n = 2,106) investigated the cause specific mortality as of the end of 2006 (Boers et al., 2010). No increase in the hazard ratio (HR) for death due to diseases of the respiratory system was found in exposed relative to nonexposed workers in factories A (HR = 1.00, 95% CI 0.43–2.29) and B (HR = 0.46, 95% CI 0.18–1.15).
Mortality rates in trichlorophenol workers in Midland, Michigan, with exposure to TCDD were assessed for the period 1942–2003 (Collins et al., 2009a). The standardized mortality ratio of the workers (n = 1,615) compared with the US population were not increased for death due to noncancerous respiratory disease (SMR = 0.8, 95% CI 0.6–1.0). In a related study, the mortality rates were assessed in 773 workers exposed to dioxins in the manufacture of pentachlorophenol at a plant in Midland, Michigan (Collins et al., 2009b). The standardized mortality ratio for the workers compared with the US and Michigan population were not increased for death due to noncancerous respiratory disease (SMR = 0.8, 95% CI 0.5–1.1).
Mortality was also assessed at the end of 2004 in 1,599 workers exposed to TCDD at a trichlorophenol plant in New Zealand (McBride et al., 2009a). SMRs for death due to noncancerous respiratory disease were not increased in ever- exposed workers (SMR = 0.8, 95% CI 0.4–1.4) or in never-exposed workers (SMR = 0.4, 95% CI 0.0–1.5) compared with the New Zealand population. McBride et al. (2009b) have also published mortality findings through 2004 from this plant that include all workers employed at the site from 1969 to 2003
(n = 1,754, also 247 deaths). The results of McBride et al. (2009b) have not been included because they were diluted by inclusion of a set of workers with no possible opportunity for TCDD exposure and no observed deaths.
Hoppin et al. (2009) assessed pesticide use and adult-onset asthma, defined as doctor-diagnosed asthma after the age of 20 years, in a cohort of 19,704 male farmers in the AHS. For ever-use of 2,4,5-T, there were elevated but not significant risks for allergic asthma (odds ratio [OR] = 1.44, 95% CI 0.96–2.14) and nonallergic asthma (OR = 1.20, 95% CI 0.93–1.56). For ever-use of 2,4-D, there were elevated, but not significant risks for allergic asthma (OR = 1.56, 95% CI 0.91–2.69) and nonallergic asthma (OR = 1.19, 95% CI 0.86–1.64). This analysis was adjusted for age, US state, smoking, high pesticide exposure events, and BMI. In another AHS report, Slager et al. (2009) investigated the association between current rhinitis and pesticide use in 2,245 Iowa commercial pesticide applicators. Current use of 2,4-D was associated with a significant increase in current rhinitis (OR = 1.34, 95% CI 1.09–1.64, adjusted for age, education status, and growing up on a farm) relative to those who had not used it in the past year.
Mortality in Finnish fisherman (n = 6,410) and their wives (n = 4,260) as of 2005 was assessed relative to the general Finnish population (Turunen et al., 2008). The average fish consumption and serum concentrations of fish-derived fatty acids and environmental contaminants (TEQs from dioxins and PCBs) were higher among the fishermen and their wives than among the general population from the same region. However, the fishermen and their wives had lower mortality for diseases of the respiratory system, pneumonia, bronchitis, and emphysema.
Evaluation of the biological plausibility of chemicals of interest inducing or contributing to the development of lung diseases is hampered by the lack of animal models to study endpoints such as COPD or asthma, because these diseases usually develop in humans in response to additional co-factors (i.e., smoking/ air pollution). Activation of AH receptor (AHR) by TCDD, however, has been shown to modify expression of genes in the lung that code for inflammatory cytokines, matrix metalloproteases (MMPs), and mucin production (Wong et al., 2010). These results are consistent with changes associated with a variety of lung diseases, such as bronchitis, asthma, small airway disease, and lung remodeling (fibrosis), and support the role of AHR activation in the development of lung injury. AHR activation in vitro in NCI H441 in the Clara cells also activates an IL-1b–to–COX-2–mediated process, which leads to increased mucin production. This 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/goblet cell hyperplasia in the airways. In a related study, Lee et al. (2010) reported that TCDD induced a time-dependent elevation of MUC5AC mRNA and protein synthesis in primary normal human bronchial epithelial cells and in an immortalized normal human bronchial epithelial cell line (HBE1). MUC5AC is a major gel-forming mucin that is frequently elevated in various airway diseases (Rose and Voynow, 2006; Voynow et al., 2006).
Acute noncancerous respiratory disorders, including pneumonia and other respiratory infections, also can be increased in frequency and severity when the normal defense mechanisms of the lower respiratory tract are compromised. Thus exposure to chemicals that affect those mechanisms could exacerbate respiratory disorders. There is no evidence that the herbicides used in Vietnam alter such defense mechanisms. However, several laboratory studies have shown that treatment of mice with TCDD increases their mortality after infection with influenza virus (Burleson et al., 1996; Warren et al., 2000). Treatment with TCDD also suppressed the animals’ ability to generate an immune response to the virus (Mitchell and Lawrence, 2003). The mechanism underlying increased influenza mortality was not related to the suppression of the immune response 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). Neutrophils produce several toxic products (which kill pathogens), so it is possible that excess numbers of neutrophils in the lung produce excess collateral damage and pathologic changes that increase mortality.
Although AHR expression was shown to be required for TCDD to increase neutrophils in the lungs, the cells expressing AHR were not the neutrophils themselves or other immune cells, and this suggests that lung parenchyma was being directly affected by TCDD (Teske et al., 2008). However, the concentration of Clara cell secretory protein, an inflammatory mediator produced by lung-associated Clara cells, was not altered by TCDD in mouse lung. Thus, the mechanisms underlying the increase in mortality after influenza infection remain to be determined. On the basis of those findings, it is biologically plausible that exposure to TCDD results in exacerbation of acute lung disease that is associated with reduced immune responses or of chronic lung diseases including COPD, that is associated with increased inflammatory responses. It is also plausible that the induction of CYP1A1 and CYP1B1 enzymes in the lung by TCDD result in the metabolism of several chemicals found in tobacco smoke to more toxic intermediates. Exposure to TCDD would thus increase the toxic effects of tobacco smoke and increase respiratory disease.
Noncancerous Respiratory Disease (without further specification) Results of the studies of mortality from noncancerous respiratory diseases reported in Update 2008 and earlier VAO reports (ADVA, 2005b,c; Anderson et al., 1986;
Becher et al., 1996; Blair et al., 1983, 2005; Boehmer et al., 2004; Bullman and Kang, 1996; Burns et al., 2001; Coggon et al., 1986, 1991; Consonni et al., 2008; Crane et al., 1997a; Ketchum and Michalek, 2005; Kogevinas et al., 1997; Ott and Zober, 1996; Ramlow et al., 1996; Steenland et al., 1999; Svensson et al., 1995; ’t Mannetje et al., 2005; Zober et al., 1994) do not support the hypothesis that exposures to herbicides or TCDD are associated with the general category of noncancerous respiratory diseases.
A study of the prevalence of self-reported physician-confirmed respiratory problems in a subset of US Army Chemical Corps personnel (Kang et al., 2006) was reviewed in Update 2006. Comparison of deployed to nondeployed veterans indicated an association (OR = 1.41, 95% CI 1.13–1.76), as did comparison of those who reported spraying herbicides in Vietnam to those who did not (OR = 1.62, 95% CI 1.26–2.05). In the subset of subjects for whom serum TCDD concentrations had been determined, however, individuals with respiratory problems were evenly distributed above and below the median, which argues against the association arising from herbicide exposure.
In the current update, another study of ACC Vietnam veterans (Cypel and Kang, 2010), this time on the mortality experience of the entire cohort, was considered. Elevation in mortality due to respiratory system disease was statistically significant when the deployed veterans were compared to males in the US population (SMR = 1.58, 95% CI 1.08–2.23). This observation is in contrast to four new occupational studies, which did not report an association of death due to noncancerous respiratory disease with exposures to herbicides and/or TCDD (Boers et al., 2010; Collins et al., 2009a,b; McBride et al., 2009a). Similarly, a study in Finnish fisherman found that elevation of serum dioxin TEQs was not associated with noncancerous respiratory mortality (Turunen et al., 2008).
The committee does not believe that scientific conclusions can be based on health outcomes that are defined vaguely, for example, by combining a wide array of disparate respiratory health outcomes into one large category of noncancerous respiratory disease. The nonspecificity of the types of respiratory conditions reported in these studies makes it exceedingly difficult to draw any conclusions regarding specific respiratory conditions.
COPD In an earlier study of mortality, as of 1991, the ACC Vietnam veteran cohort had a nonsignificant adjusted RR of 2.59 for death due to noncancerous respiratory system diseases when compared with their non-Vietnam peers (Dalager and Kang, 1997). The study by Cypel and Kang (2010) added 14 years of observation and found an increased risk of death from noncancerous respiratory diseases on the cusp of statistical significance (adjusted RR = 2.20, 95% CI 0.99–4.91). For COPD in particular, they reported a statistically significant excess mortality in ACC Vietnam veterans (adjusted RR = 4.82, 95% CI 1.10–21.18), when compared to ACC veterans who did not serve in Vietnam. A similar pattern of excess COPD mortality among the ACC Vietnam veterans per-
sisted when comparisons were made with the US male population (SMR = 1.58, 95% CI 1.08–2.23). In accord with these mortality data, a morbidity survey of 2,927 of these ACC veterans (deployed and nondeployed) conducted in 1999– 2000 (Kang et al., 2006) had found a significant increase in the broader category of self-reported noncancerous respiratory conditions in ACC Vietnam veterans (adjusted OR = 1.41, 95% CI 1.13–1.76), which was also significantly related to reported use of herbicides in Vietnam (adjusted OR = 1.62, 95% CI 1.28–2.05), using a multiple logistic regression model with adjustments 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 risk among them for self-reported herbicide use, adjusted for smoking status, the estimated increase for COPD (3.55) had a 95% CI spanning two orders of magnitude (0.39–32). Other studies of American Vietnam veterans, including the Ranch Hand cohort, have found no significant increase in mortality due to the broader classification of noncancerous respiratory mortality (Anderson et al., 1986; Boehmer et al., 2004; Ketchum and Michalek, 2005) but have not addressed causes of death as specific as COPD. The Vietnam Experience Study (CDC, 1988) did not find evidence of compromised lung function; as yet, there have been no integrated publications on specific aspects of respiratory morbidity in the Ranch Hand cohort.
The self-reported physical and mental health of Australian Vietnam veterans in 2005–2006 was compared with age- and gender-matched data gathered in the 2004–2005 national survey of the Australian general population (O’Toole et al., 2009). While COPD was not specified as a condition in this study, the relative prevalences of bronchitis (RP = 2.90, 95% CI 2.18–3.63) and emphysema (RP = 2.03, 95% CI 1.32–2.74) were significantly elevated in the Australian Vietnam veterans (n = 450); these conditions are clinical conditions consistent with COPD. In an earlier iteration of this study for health status of Australian army Vietnam veterans in 1990–1993, O’Toole et al. (1996) had reported a four-fold excess prevalence in chronic bronchitis and emphysema over the results of the 1989– 1990 national survey. The committee did have concerns, however, that the results of the studies conducted by O’Toole et al. were compromised by recall bias and other methodologic problems. Studies of the full cohort of male Australian Vietnam veterans vs the general population (ADVA, 2005b; CDVA, 1997a) and of deployed vs nondeployed Australian Army National Service (conscripted) veterans (ADVA, 2005c; CDVA, 1997b) showed no suggestion of increased mortality from COPD or noncancerous respiratory deaths.
Almost all the studies of mortality in industrial cohorts considered in the VAO updates assessed only the nonspecific category of mortality due to noncancerous respiratory disease, and no significant excesses were reported (Becher et al., 1996; Burns et al., 2001; Kogevinas et al., 1997; Ott and Zober, 1996; Steenland et al., 1999; ’t Mannetjie et al., 2005). Only an earlier mortality study of Dow 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 odds ratios 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 episodes of COPD among 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 altered pulmonary function measures associated with elevated serum TCDD concentration in workers compared to a community-based referent population.
An early agricultural study (Senthilselvan et al., 1992) found no relationship between self-reported asthma and the use of phenoxy herbicides. Recently, the Agricultural Health Study has generated a number of publications with COPD-related findings. First, Blair et al. (2005) found significant decreases in mortality due to COPD in both private applicators and their spouses in comparison to state rates, which may be due to the healthy worker effect and the inability to adjust for low tobacco use. Analyses with adjustment for smoking of self-reported prevelance at enrollment (1993–1997) and prior exposure to phenoxy herbicides found indications of associations for chronic bronchitis in farmers (mostly men) significant for 2,4,5-T and 2,4,5-TP (Hoppin et al., 2007b), but only a 20% nonsignificant increase among nonsmoking farm women (Valcin et al., 2007); some association with phenoxy herbicide exposure was evident for allergic asthma (significant for 2,4-D in women and 2,4,5-T in men), but not so clear for nonallergic asthma in men (Hoppin et al., 2009) or women (Hoppin et al., 2008).
Mortality studies of the Seveso incident have reported an emerging picture of increased risks 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 for the outlying zones. Adjustment for smoking has not been possible for the Seveso cohort. In the only other relevant environmental study, Svensson et al. (1995) assumed TCDD exposure was elevated from fish consumption among Swedish fishermen but found no increase in mortality from bronchitis or emphysema. Dahlgren et al. (2003) reported that the prevelance of chronic bronchitis was positively associated with environmental exposure to creosote and pentachlorophenol 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 chemicals of interest and COPD-related morbidity.
As discussed in more detail in Chapter 5, the committee had reservations about the validity of the multitude of significant findings reported by O’Toole et al. (2009), including those for increased prevalence of two respiratory condi-
tions consistent with COPD (bronchitis and emphysema) among the Australian Vietnam Veterans. It was the large increase in relative risk of mortality from COPD in the ACC cohort that served in Vietnam (Cypel and Kang, 2010) that motivated the committee to go beyond its comprehensive review of all studies reporting morbidity or mortality associated with COPD and exposure to the chemicals of interest. In addition to its standard review process, the committee consulted in open session with Paul Enright of the University of Arizona, a medical expert on COPD, who has investigated occupational lung diseases for the Centers for Disease Control and Prevention (CDC) and has been responsible for the development of national and international clinical practice guidelines for pulmonary function testing.
From the March 3, 2011, reply of Drs. Cypel and Kang (available upon request from the VAO public access file) to several questions, the committee learned that the six deaths from “pulmonary disease” among deployed ACC veterans from the morbidity study (Table 5 in the 2010 paper) were indeed COPD cases; among the nondeployed ACC veterans from the morbidity study there had only been one death from respiratory system disease, and it had not been from COPD; and all the respiratory deaths had been smokers. Conclusions from analysis of COPD mortality in the ACC morbidity-study subset are limited by the very small number of deaths that had occurred by the end of 2005 and by the fact that this subset cannot be considered representative of the entire ACC cohort in that they were all alive in 1999. In response to the committee’s inquiry as to whether they could adjust the full set of ACC mortality for smoking status, Cypel and Kang replied that a greater percentage of ACC veterans who served in Vietnam smoked, compared to the non-Vietnam cohort (71.5% vs 60.1%). This information, however, was only available for the individuals participating in the 1999–2000 morbidity survey (n = 2,927), so they lacked the ability to adjust the relative risk of COPD mortality in the entire ACC cohort (n = 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’s consultation with Dr. Enright increased its concern (as delineated at the beginning of this section on respiratory diseases) that causes of death from COPD are frequently misclassified on death certificates. The common presence of comorbid conditions in individuals with COPD makes it difficult to deduce a single contributing cause of death. Furthermore, it was emphasized that COPD is often incorrectly diagnosed in prevalance investigations, and there is currently considerable debate about the appropriate diagnosic criteria for COPD, particularly in relation to factoring normal decreased capacity with age (Celli and Halbert, 2010a,b; Enright and Brusasco et al., 2010a,b).
Thus, the committee concluded that it could not base a conclusion about association for COPD on mortality data given the very questionable nature of death certificate information on COPD and the routine inability to adjust for
smoking. The committee believes morbidity data for COPD would be much more informative than mortality findings. Additional studies of the incidence of COPD, using rigorous criteria for its diagnosis and with adjustment for smoking would be particularly valuable in resolving whether there is evidence to support anssociation with exposure to the chemicals of interest.
Other Specific Respiratory Diseases Adding to the AHS papers on wheeze and farmer’s lung reviewed in Update 2008, the literature for this update contained two more AHS reports addressing the prevalance of respiratory problems in relation to exposure to specific pesticides. The findings presented on asthma in male and female farmers did not constitute evidence of an association with the herbicides of interest.
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 chemicals of interest and mortality from all noncancerous respiratory diseases or from COPD specifically. There is also inadequate or insufficient evidence of an association between exposure to the chemicals of interest and the prevalence of respiratory diseases, such as wheeze or asthma, COPD, and farmer’s lung.
This section discusses a variety of conditions encompassed by ICD-9 520– 579: 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 might be present in 15% of adults. The most convenient way to categorize diseases that affect the gastrointestinal system is according to the effected anatomic segment. Esophageal disorders predominantly affect swallowing; gastric disorders are related to acid secretion; and conditions that affect the small and large intestines are reflected in alterations in nutrition, mucosal integrity, and motility. Some systemic disorders (inflammatory, vascular, infectious, and neoplastic conditions) also affect the gastrointestinal system.
Peptic-ulcer disease refers to ulcerative disorders of the gastrointestinal tract that are caused by the action of acid and pepsin on the stomach or duodenal mucosa. Peptic-ulcer disease is characterized as gastric or duodenal ulcer, depending on the site of origin. Peptic-ulcer disease occurs when the corrosive action of gastric acid and pepsin overcomes the normal mucosal defense mechanisms that protect against ulceration. About 10% of the population has clinical evidence of duodenal ulcer at some period in life; a similar percentage is affected by gastric ulcer. The incidence of duodenal ulcer peaks in the fifth decade and the incidence of gastric ulcer about 10 years later.
Evidence increasingly indicates that the bacterium Helicobacter pylori is linked to peptic-ulcer disease (both duodenal and gastric). H. pylori colonizes the gastric mucosa in 95–100% of patients with duodenal ulcer and in 75–80% of patients with gastric ulcer. Healthy subjects in the United States under 30 years old have gastric colonization rates of about 10%. Over the age of 60 years, colonization rates exceed 60%. Colonization alone, however, is not sufficient for the development of ulcer disease; only 15–20% of subjects with H. pylori colonization will develop 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).
Blood tests that reflect liver function are the mainstay of diagnosis of liver disease. Increases in serum bilirubin and in the serum concentrations of some hepatic enzymes—aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and γ-glutamyltransferase (GGT)—are commonly noted in liver disorders. The relative sensitivity and specificity of those enzymes for diagnosing liver disease vary, and diagnosis can require several tests. The only regularly reported abnormality in liver function associated with TCDD exposure in humans is an increase in GGT. Estimated serum activity of that enzyme is a sensitive indicator of a variety of conditions, including alcohol and drug hepatotoxicity, infiltrative lesions of the liver, parenchymal liver disease, and biliary tract obstruction. Increases are noted after many chemical and drug exposures that are not followed by evidence of liver injury. The confounding effects of alcohol use (often associated with increased GGT) make interpretation of changes in GGT in exposed people difficult (Calvert et al., 1992). An increase in GGT can be considered a normal biologic adaptation to chemical, drug, or hormone exposure.
Cirrhosis is the most commonly reported liver disease in epidemiologic studies of herbicide or TCDD exposure. Cirrhosis is irreversible chronic injury of the liver with extensive scarring and resulting loss of liver function. Clinical symptoms and signs include jaundice, edema, abnormalities in blood clotting, and metabolic disturbances. Cirrhosis can lead to portal hypertension with associ-
ated gastroesophageal varices, enlarged spleen, abdominal swelling attributable to ascites, and ultimately hepatic encephalopathy that can progress to coma. It generally is impossible to distinguish the various causes of cirrhosis by using clinical signs and symptoms or pathologic characteristics. The most common cause of cirrhosis in North America and many parts of western Europe and South America is excessive alcohol consumption. Other causes are chronic viral infection (hepatitis B or hepatitis C), the poorly understood condition primary biliary cirrhosis, chronic right-sided heart failure, and a variety of less common metabolic and drug-related conditions.
Conclusions from VAO and Previous Updates
Studies that have been reviewed by previous committees have consisted of some focusing on liver enzymes and others that have reported specific liver diseases. Evaluation of the effect of herbicide and TCDD exposure on noncancer gastrointestinal ailments is challenging in that clinical experience suggests that medical history and physical examination are undependable diagnostic tools for some ailments, so incidence data are sometimes problematic. The strong interdependence among the characteristics of a given person (such as weight and laboratory indexes of hepatic function and health) and TCDD body burden complicates the already difficult task of assessing association.
Most of the analyses of occupational or environmental cohorts have had insufficient numbers of cases to support confident conclusions. The IARC cohort of phenoxy herbicide and chlorophenol production workers and sprayers (Vena et al., 1998), the only study with a relatively large number of observations, found less digestive system disease and cirrhosis mortality in exposed workers than in nonexposed controls. A study comparing Australian veterans to the general population (O’Toole et al., 1996) suggested a higher incidence of stomach and duodenal ulcers in both men and women, but the information was self-reported and the analyses were not controlled for confounding influences.
A report from the AFHS (2000) found a significantly higher percentage of other liver disorders in the Ranch Hand veterans in the high-dioxin category than in the SEA comparison subjects. The excesses were primarily of transaminase and other nonspecific liver abnormalities. Data were consistent with an interpretation of a dose–response relationship, but other explanations were also plausible. There have been subsequent reports (AFHS, 2005) of some abnormalities in liver enzymes in the Ranch Hand cohort, including decreasing C4 complement as dioxin increased; abnormal triglyceride concentrations also increased as the 1987 dioxin concentration increased. Mortality studies of the Ranch Hand cohort, however, have not found increased mortality related to gastrointestinal or liver disease (Ketchum and Michalek, 2005).
A study of Army Chemical Corps Vietnam veterans reported in Update 2006 found an increased rate of hepatitis associated with Vietnam service but
not with a history of spraying herbicide (Kang et al., 2006). Likewise, the Australian Vietnam-veterans study (ADVA, 2005b) did not find an increase in liver disease in military personnel who served in Vietnam compared with the general population of Australia.
Update 2008 reviewed the mortality results through 2001 for the Seveso cohort in Italy (Consonni et al., 2008) and found no excess in deaths related to digestive diseases or in the subset of deaths specifically related to cirrhosis.
The reports to date have been inconsistent, and interpretation of 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 chemicals of interest and gastrointestinal and digestive disease, including liver toxicity. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 has not changed that conclusion.
Update of the Epidemiologic Literature
Cypel and Kang (2010) examined the risk of disease-related mortality of the Army Chemical Corps veterans who handled or sprayed herbicides in Vietnam in comparison with their non-Vietnam veteran peers or US men. Thirty digestive system deaths were observed, 21 in the Vietnam cohort and 9 in the non-Vietnam cohort. The adjusted relative risk was 1.80 (95% CI 0.80–4.03). All but two of the cases were cirrhosis of the liver (adjusted RR = 1.74, 95% CI 0.77–3.94).
O’Toole et al. (2009) published a follow-up study of a random sample of Australian veteran National Servicemen who had been deployed to Vietnam and completed the Australian Bureau of Statistics Health Interview Survey along with several other measures of psychiatric health and combat experience when contacted by mail in 2005–2006. Self-reported health status was compared to the results for the general Australian population on this survey instrument; the comparability of the circumstances of administration of the survey is not clear. Approximately 50,000 Australians were deployed during the Vietnam War, and using military databases the investigators randomly selected 1,000 veterans for follow-up. In the second wave of interviews with this sample, only 450 of the original sample responded (51% of those not known to have died). Of 67 long-term conditions with reported results, the prevalences of 47 were said to be significantly higher than in the general population experience and 4 more to be significantly lower. The prevalence of diseases of the esophagus was 4.5% (RP = 1.89, 95% CI 1.08–2.69). The prevalence of stomach/duodenal/gastrointestinal
ulcer was 11% (RP = 2.11, 95% CI 1.65–2.57). Irritable bowel was reported by 2.2% of the responders (RP = 4.19, 95% CI 1.62–6.76). The reported prevalence of gallstones (2.2%) was not elevated (RP = 1.19, 95% CI 0.66–4.31). The committee had serious concerns that the results reported in O’Toole et al. (2009) were compromised by recall bias and other methodologic problems.
Boers et al. (2010) examined digestive system (noncancer) deaths in the third follow-up results of a retrospective cohort study of two Dutch chlorophenoxy herbicide manufacturing factories, producing mainly 2,4,5-T (Factory A) and 4-chloro-2-methylphenoxyacetic acid, 4-chloro-2-methylphenoxy propanoic acid, and 2,4-D (Factory B). The cohort consists of all persons working in one of the two factories during 1955–1985 (Factory A) or 1965–1986 (Factory B). Six cases of deaths due to digestive causes were observed in Factory A (HR = 0.60, 95% CI 0.18–2.01). No digestive system deaths were observed in Factory B.
A pair of papers reported on the mortality experience of workers employed by Dow Chemical Company in Midland, Michigan, in the production of trichlorophenol (TCP) (Collins et al., 2010a) or pentachlorophenol (PCP) (Collins et al., 2010b) from 1937 to 1980. Collins et al. (2009a) examined the mortality experience of the 1,615 workers in this cohort who had been involved in TCP production. The mean duration of follow-up was 36.4 years. Two cases of death from stomach or duodenal ulcers were observed (SMR = 0.8, 95% CI 0.1–2.9). Six cases of death by cirrhosis were observed (SMR = 0.4, 95% CI 0.1–0.8).
In the companion paper, Collins et al. (2009b) described the mortality experience of 773 workers who were exposed to chlorinated dioxins other than TCDD in the production of PCP. Seventy-five percent of the cohort has been followed for more than 27 years. SMRs were calculated comparing the PCP workers with the general US population and the population of the state of Michigan. The authors examined exposure response using both internal and external comparisons. There were five observed deaths from ulcers of the stomach and duodenum (SMR = 3.0, 95% CI 1.0–7.1). When one case was removed because of concurrent TCP and associated TCDD exposure, the SMR remained 3.0, but the 95% CI widened to 0.8–7.6. There was no trend for increasing risk of death from ulcers with increasing TEQs. With eight observed deaths from cirrhosis, the risk for the workers was at expected levels (SMR = 1.0, 95% CI 0.4–2.0), but a proportional hazards model based on this small number of cases showed some increase in risk of death from cirrhosis with increasing TEQs (SMR = 2.0, 95% CI 0.5–5.2). In a previous study of these workers, Ramlow et al. (1996) had reported increased risks of death from stomach ulcers and from cirrhosis, but the SMRs for both these conditions were lower in this follow-up study.
The fourth occupational mortality study was of workers in the Dow Agro-Sciences plant in New Plymouth, New Zealand, who were potentially exposed to 2,3,7,8-TCDD (McBride et al., 2009a). Workers who had been employed
between January 1969 and October 2003 were followed to the end of 2004, and SMRs were calculated using national mortality rates. A total of 1,754 workers were included in the study, but 22% were lost to follow-up. No cases of death due to stomach or duodenal ulcer were observed. The four cases of cirrhosis deaths among exposed workers were more than expected on the basis of the national population (SMR = 2.5, 95% CI 0.7–6.5), while no deaths from cirrhosis were observed among the never-exposed workers. McBride et al. (2009b) have also published mortality findings through 2004 from this plant that include all workers employed at the site from 1969–2003 (n = 1,754, also 247 deaths). The results of McBride et al. (2009b) have not been included because they were diluted by inclusion of a set of workers with no possible opportunity for TCDD exposure and no observed deaths.
No environmental studies of gastrointestinal diseases have been published since the 2008 review.
The liver is a primary target for the toxicity of many chemicals. It is the first organ that encounters chemicals absorbed from the gastrointestinal tract and is responsible for metabolizing them to water-soluble chemicals that can be excreted in the urine. Because the liver has many detoxifying enzymes that efficiently metabolize many chemicals, liver toxicity is usually associated only with high-dose acute exposure or chronic exposure to lower doses. The liver can be damaged if metabolism of a chemical results in the production of a reactive intermediate that is more toxic than the parent chemical. Changes in serum concentrations of liver enzymes are biomarkers for liver toxicity, and their magnitude correlates with the degree of liver damage. Exposure of laboratory animals to high doses of 2,4-D, 2,4,5-T, and TCDD is known to cause liver damage. The mechanisms by which the phenoxy herbicides damage the liver is based on inhibition of mitochondrial function by blocking of oxidative phosphorylation; this leads to loss of generation of adenosine triphosphate, death of cells, and hepatic necrosis and fibrosis. TCDD-induced hepatotoxicity is mediated by activation of the AHR, which leads to changes in gene transcription and associated changes in cell function. Changes in gene expression are associated with several physiologic processes, oxidative stress, and apoptosis (Boverhof et al., 2005, 2006). TCDD-mediated hepatic steatosis is characterized by the accumulation of triglyceride due to the combined up-regulation of CD36/fatty acid translocase and fatty acid transport proteins, suppression of fatty acid oxidation, inhibition of hepatic export of triglycerides, increase in peripheral fat mobilization, and increased hepatic oxidative stress (Lee et al., 2010). Exposure of rats to TCDD over a 2-year period (NTP, 2004)
also produced several changes in the liver, including hepatocyte hypertrophy, multinucleated hepatocytes, inflammation, pigmentation, diffuse fatty change, necrosis, bile duct hyperplasia, bile duct cyst, nodular hyperplasia, portal fibrosis, and cholangiofibrosis.
The AHR displays interspecies differences; for example the human and mouse AHR C-terminal region sequences share only 58% amino acid sequence identity. Compared with the mouse AHR (mAHR), the human AHR (hAHR) has approximately 10-fold lower relative affinity for TCDD, which has been attributed to the amino acid residue valine 381 in the ligand-binding domain of the hAHR (Flaveny et al., 2009; Ramadoss and Perdew, 2004). Species differences associated with AHR activation are supported by the divergence in the transcriptomic responses to TCDD in mouse, rat, and human liver (Boutros et al., 2008, 2009; Carlson et al., 2009; Kim et al., 2009), but it should be noted that these in vitro human hepatocyte studies may not reflect the in vivo response of human liver to TCDD. In vitro studies with transformed cell lines and primary hepatocytes cannot replicate the complexity of a tissue response that is important in eliciting the toxic responses observed in vivo (Dere et al., 2006).
Few health-relevant effects of phenoxy herbicides or TCDD on the gastrointestinal tract, even after high levels of exposure, have been reported. Thus, the animal data do not support a plausible link between herbicide exposure and gastrointestinal toxicity in Vietnam veterans.
Reports of increased risk of abnormal liver-function tests have been mixed, but evidence is lacking that Vietnam veterans are at greatly increased risk for serious liver disease, peptic ulcers, or other specific gastrointestinal diseases. The possibility of a relationship between dioxin exposure and subtle alterations in the liver and in lipid metabolism cannot be ruled out, but effects on the GI system of clinical importance have not been demonstrated.
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 chemicals of interest and gastrointestinal and digestive diseases.
Clinical disruptions of thyroid function include various disorders grouped in ICD-9 242.8 and 246.8. The thyroid gland secretes the hormones thyroxine (T4) and triiodothyronine (T3), which stimulate and help to regulate metabolism
throughout the body. The thyroid also secretes calcitonin, a hormone that controls calcium concentration in the blood and storage of calcium in bones. Secretion of T4 and T3 is under the control of thyroid-stimulating hormone (TSH), which is secreted by the anterior pituitary gland. Iodine operates in thyroid physiology both as a constituent of thyroid hormones and as a regulator of glandular function. Concentrations of those circulating hormones are regulated primarily by a negative-feedback pathway that involves three organs: the thyroid, the pituitary, and the hypothalamus. In the hypothalamus–pituitary–thyroid feedback scheme, the hypothalamus releases thyrotropin-releasing hormone (TRH), which stimulates the pituitary to produce TSH, which triggers the thyroid to produce T4 and T3. Cells in the hypothalamus and pituitary respond to concentrations of circulating T4 and T3. When T4 and T3 are low, the pituitary is stimulated to deliver more TSH to the thyroid, which increases T4 and T3 output. When circulating T4 and T3 are high, they signal to reduce the output of TRH and TSH. This negative-feedback loop maintains hormone homeostasis.
Disruption of thyroid homeostasis can be stimulatory (hyperthyroidism) or suppressive (hypothyroidism). Both conditions are diagnosed on the basis of blood concentrations of thyroid hormones, TSH, and other proteins (antithyroid antibodies). The prevalence of thyroid dysfunction in adults in the general population ranges from 1% to 10%, depending on the group, the testing setting, sex, age, method of assessment, and the presence of conditions that affect thyroid function. People with 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% of women and 6% of men had subclinical hypothyroidism (Sawin et al., 1985). Subclinical hypothyroidism is a risk factor for overt hypothyroidism. Studies have reported association of hypothyroidism with a wide variety of other conditions.
The term hyperthyroidism may involve any disease that results in overabundance of thyroid hormone. Clinical or overt hyperthyroidism is characterized as a low serum concentration of TSH and high serum concentration of free T4. Subclinical hyperthyroidism is defined as a low serum concentration of TSH and a normal serum concentration of free T4. The prevalence of subclinical hyperthyroidism was estimated at about 1% in men and 1.5% in women over 60 years old (Helfand and Redfern, 1998). Conditions associated with hyperthyroidism include Graves disease and diffuse toxic goiter. Like hypothyroidism, hyper-
thyroidism 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, within reason, to compensate for mild or moderate disruption (such as that caused by hyperplasia or goiter). In contrast, the fetus is highly sensitive to alterations in thyroid hormones, and alterations in thyroid homeostasis can hamper the development of many organ systems, including the nervous and reproductive systems; such findings are discussed in Chapter 8, which addresses potential consequences of Vietnam veterans’ exposure to herbicides on their offspring. Only observations on adults are considered here.
Summary of Previous Updates
Koopman-Esseboom et al. (1994) found an association between dioxin-like congeners and markers of disrupted thyroid homeostasis, this report focused on TCDD and maternal thyroid function during pregnancy and therefore is less relevant to the experience of the predominantly male Vietnam veterans.
Extensive assessment of endocrine function including a series of thyroid function tests was carried out in connection with the Ranch Hand study (AFHS, 1991b). These studies failed to show any difference in thyroid function between exposed and control veterans. When individual TCDD readings had been obtained for subjects in the AFHS, however, Pavuk et al. (2003) found statistically significantly increased TSH measures from the 1985 and 1987 examinations in the high-exposure category and a significant increasing trend across the 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 levels in TCDD-exposed workers, but there was no dose–response with serum TCDD levels. Bloom et al. (2006) found indications of an inverse relationship between the sum of dioxin-like compounds and the concentration of free T4 in anglers in New York State, but no association between the sum of dioxin-like compounds 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 with effects somewhat stronger in individuals over 60 years of age and women more than men.
The committee for Update 2008 concurred with previous committees that there was inadequate or insufficient evidence of an association between exposure to the chemicals of interest and clinical or overt adverse effects on thyroid homeostasis. Prior committees have also noted increasing evidence of an association between exposure to certain chemicals of interest and changes in markers of thyroid function below the threshold of clinical symptoms, perhaps because of the adaptive capacity of the adult system to accommodate such variation.
The Table 11-2 summarizes findings from studies that have examined the association between dioxin-like congeners and markers of thyroid function.
Update of the Scientific Literature
O’Toole et al. (2009) published a follow-up study on the 641 veterans from a random sample of 1,000 drawn from the Australian roster of Army veterans (both regular enlistment and National Service conscription) deployed to Vietnam who had been interviewed in 1990–1993. In 2005–2006, 450 veterans in the original sample were interviewed, with 391 individuals participating in both phases of this study. Self-reported health status of these Vietnam veterans was compared to that of the general Australian population based on responses gathered in the Australian 2004–2005 National Health Survey. Of 67 long-term conditions with reported results, the prevalences of 47 were found to be significantly higher among the veterans than in the general population experience. The prevalence of diseases of the thyroid was 2.2% (RP = 1.39, 95% CI 0.54–2.24). The committee had serious concerns that the results reported in O’Toole et al. (2009) were compromised by recall bias and other methodologic problems.
Goldner et al. (2010) published a study of pesticide use and self-reported history of physician-diagnosed thyroid disease among women in the Agricultural Health Study. No significant associations were observed between thyroid disease and ever having used 2,4-D, 2,4,5-T, or dicamba. Among individuals with 2,4-D exposure, there were 46 cases of hyperthyroidism (OR = 0.93, 95% CI 0.68–1.3), 147 cases of hypothyroidism (OR = 0. 96, 95% CI 0.8–1.1), and 87 other thyroid conditions (OR = 1.2, 95% CI 0.95–1.5). Among individuals exposed to 2,4,5-T, there were 7 cases of hypothyroidism (OR = 1.01, 95% CI 0.46–2.2). Among individuals exposed to dicamba there were 17 cases of hyperthyroidism (OR = 1.3, 95% CI 0.79–2.1), 27 cases of hypothyroidism (OR = 0.66, 95% CI 0.45–0.98), and 19 other thyroid conditions (OR = 0.96, 95% CI 0.60–1.5).
|Reference||Study Population||Exposed Cases||Exposure of Interest/
|VIETNAM Air Force H||VETERANS ealth Study||All COIs|
|Pavuk et al., 2003||Ranch Hands (RH) in AFHS cohort—1987 findings|
|THS uptake by TCDD category||Normal = 0–3 µIU/ml|
|Comparisons (SEA veterans—no TCDD||1,247||0.83|
|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||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 means by||Normal = 25%–35%|
|Comparisons (SEA veterans—no TCDD||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)|
|Australian Deployed Army Vietnam Veterans vs General Population||All COIs|
|O’Toole||Australian Vietnam veterans vs age-|
|et al., 2009||and sex-matched data from general|
|Disorders of the thyroid gland||450||1.4 (95% CI 0.5–2.2)|
|National Institute for Occupational Safety and Health||Dioxin, phenoxy herbicides|
|Calvert||TCDD-exposed workers employed > 15 yrs|
|et al., 1999||earlier in 1 of 2 US 2,4,5-T plants vs matched|
|TSH mU/l||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|
|228 ≤ TCDD < 3,400||64||1.8 (0.3) p = 0.65|
|Referents (< 20)||257||1.9 (0.1)|
|Reference||Study Population||Exposed Cases||Exposure of Interest/
|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|
|228 ≤ TCDD < 3,400||64||100.1 (2.2) p = 0.58|
|Referents (< 20)||257||98.8 (1.1)|
|Free T4 index umol/l|
|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|
|228 ≤ TCDD < 3,400||64||27.7 (0.6) p = 0.19|
|Referents (< 20)||257||26.8 (0.3)|
|Agricultural Health Study||Herbicides|
|Goldner||Thyroid disease among female spouses in||2,4-D, 2,4,5-T, dicamba|
|et al., 2010||Iowa and North Carolina (1993–2003)|
|Self-reported 2,4-D exposure||46||0.9 (95% CI 0.7–1.3)|
|Self-reported 2,4,5-T exposure||3||NA|
|Self-reported dicamba exposure||17||0.8 (95% CI 0.8–2.1)|
|Self-reported 2,4-D exposure||147||0.96 (95% CI 0.8–1.1)|
|Self-reported 2,4,5-T exposure||7||1.0 (95% CI 0.5–2.2)|
|Self-reported dicamba exposure||27||0.7 (95% CI 0.5–0.98)|
|Other thyroid conditions|
|Self-reported 2,4-D exposure||87||1.2 (95% CI 0.95–1.5)|
|Self-reported 2,4,5-T exposure|
|Self-reported dicamba exposure||19||0.96 (95% CI 0.6–1.5)|
|Other Occupational Studies|
|Johnson||Sprayers in Victoria, Australia||2,4,5-T, 2,4-D|
|et al., 2001||TSH vs estimated serum TCDD level||32||Normal = 0.3–5.0µIU/|
|Based on local levels||0.2|
|Based on individual sampling LDs||–.03|
|Based on back extrapolation||–0.4 (p < 0.05)|
|T4 vs estimated serum TCDD level||32||Normal = 0.045–2.125|
|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)|
|Reference||Study Population||Exposed Cases||Exposure of Interest/
|National Health and Nutrition Examination Survey||2,4-D|
|Schreine-||NHANES III—analysis of data from|
|machers,||subjects with detectable limits of urinary|
|Detectable 2,4-D||102||1.6 mU/L|
|Non-detectable 2,4-D||625||1.7 mU/L|
|Detectable 2,4-D||102||8.5 µg/dl|
|Non-detectable 2,4-D||625||8.6 µg/ml|
|Turyk et al.,||NHANES (1999–2002, 2001–2002)—||dl TEQs, dl PCBs|
|2007||Association with TEQs in individuals without|
|T4||402||–0.12 (–0.61 to 0.37)|
|TSH||402||–0.09 (–0.38 to 0.20)|
|T4||497||–0.47 (–0.97 to 0.04)|
|TSH||497||–0.02 (–0.20 to 0.16)|
|T4||310||–0.19 (–0.70 to 0.33)|
|TSH||309||0.15 (–0.14 to 0.44)|
|T4||386||–0.58 (–1.26 to 0.10)|
|TSH||385||0.06 (–0.15 to 0.35)|
|Other Enviromental Studies|
|Dallaire||Cross-sectional study of Inuit residents of||607||dl PCBs/ correlation of|
|et al., 2009||Nunavik (Québec, Canada)||dl-congeners (adjusted)|
|fT3||–0.03 (p < 0.05)|
|Abdelouahab||Cross-sectional study of freshwater fish||dl PCBs/ dl PCB|
|et al., 2008||consumers from two Canadian communities||congeners β estimates|
|TSH||0.55 (p < 0.001)|
|T4||–2.19 (p < 0.05)|
|Reference||Study Population||Exposed Cases||Exposure of Interest/
|Meeker||Adult men recruited from Massachusetts||341||dl PCBs|
|et al., 2007||infertility clinic (2000–2003)|
|T3||0.02 (95% CI 0.05–|
|fT4||0.01 (95% CI 0.01–|
|TSH||0.93 (95% CI 0.84–|
|Bloom et al.,||Sportfish anglers from New York exposed to||38||PCDDs,|
|2006||dioxin-like compounds in diet||PCDFs, dl PCBs|
|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)|
|Nagayama||Japanese patients exposed in 1968 during||16||PCDDs, PCDFs,|
|et al., 2001||the Yusho incident; blood collected from||dl PCBs|
|participants 1996 and 1997|
|TSH correlation coefficient||0.01 (p = 0.97)|
|T4 correlation coefficient||0.03 (p = 0.9)|
|T3 correlation coefficient||–0.09 (p = 0.74)|
|Environment||al Studies of Pregnant Women|
|Zhang et al.,||Cross-sectional study of a Chinese||50||PCDDs, PCDFs,|
|2010||community in the vicinity of an electronic-||dl PCBs|
|waste recycling plant—maternal serum T4|
|levels at 16 weeks gestation (correlations|
|with contaminant levels in cord blood)|
|dl PCBs||r = –0.413 (p = 0.01)|
|PCDD/Fs||r = –0.198 (p = 0.21)|
|Chevrier et al., 2008||CHAMACOS study—334 pregnant women from Salinas Valley, CA, providing blood at 26wk gestation||dl PCBs β (95% CI)|
|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)|
|Foster et al.,||Cross-sectional examination of serum from||150||dl compounds|
|2005||pregnant women attending Canadian prenatal|
|TSH correlation coefficient||ns (value nr)|
|T4 correlation coefficient||ns (value nr)|
|Reference||Study Population||Exposed Cases||Exposure of Interest/
|Koopman-Esseboom et al., 1994||Part of the prospective longitudinal Dutch PCB/Dioxin study; 105 healthy mother-infantpairs living in or around Rotterdam, recruited June 1990–February 1992||Dioxins and PCBs|
|Maternal serum correlations with dioxin||78|
|T4||–0.4 (p ≤ .001)|
|T3||–0.5 (p ≤ .001)|
ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenol; AFHS, Air Force Health Study; CA, California; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; LD, level of detection; NA, not available; NHANES, National Health and Nutrition Examination Survey; nr, no relationship; ns, nonsignificant; PCB, polychlorinated biphenyls; PCDD, polychlorinated dibenzo-p-dioxins; 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.
Dallaire et al. (2009) studied thyroid function and plasma concentrations of polyhalogenated compounds in Inuit adults, including measurement of a number of dioxin-like compounds. Dioxin-like compounds were detected in 72.6% of the samples (n = 607). The positive correlation for TSH and the negative one for free T4 with concentrations of dioxin-like compounds were no longer significant when adjusted for sex, age, BMI, plasma lipids, smoking, education, and consumption of fish and alcohol. A similar unadjusted correlation was found with free T4. The negative correlation with free T3 levels remained significant with adjustment (p < 0.05). This population is exposed to a complex mixture of organochlorine compounds, making it difficult to isolate the effects of dioxin-like compounds.
Zhang et al. (2010) published a cross-sectional study of a Chinese community exposed to an electronic-waste recycling plant. Maternal serum and cord whole blood collected from 25 pregnant women in Zone A (exposed) and 25 pregnant women in Zone B (nonexposed) was analyzed to determine the association between thyroid hormone levels in their serum at 16 weeks gestation and polybrominated dibenzofuran, PCDD/F, and PCB exposures. Body burdens of the
three contaminants in cord blood were significantly higher in Zone A. Levels of T4 and TSH in serum in Zone A were significantly lower than those in Zone B (p < 0.05). An inverse trend was reported between the major groupings of persistent organic pollutants and T4. However there was no statistically significant association between ΣTEQ-PCDD/Fs, XPBDE, and T4. A significant negative correlation was found between ΣTEQ PCB and T4 (p < 0.0091). No correlations were observed between the PBDE, PCDD/F, and PCB exposures and the thyroid hormones T3 and TSH.
The CHAMACOS project has studied the cohort of births between October 1999 and October 2000 to women enrolled at the Center for the Health Assessment of Mothers and Children of Salinas in California. Chevrier et al. (2008) measured TSH, free T4, and total T4 levels in 334 women who had provided blood samples at 26 weeks gestation (or before delivery in 14 cases). Changes in free T4 and total T4 (adjusted for age and BMI) per 10-fold increase in exposure expressed in terms of PCB TEQs, mono-ortho PCB TEQs were presented. Such results were also reported for PCBs 118 and 156, the only two dioxin-like PCBs among the 19 PCBs (of 34 congeners measured) that were detected in at least 75% of the subjects. None of the associations for these particular measures were significant. It was stated without presenting data that TSH was not associated with these PCBs or any other of the persistent organic pollutants measured. Results on thyroid functions in the infants from these pregnancies (Chevrier et al., 2007) were discussed in Chapter 8.
Schreinemachers (2010) examined the association of recent exposure to 2,4-D with T4 and TSH in conjunction with indicators of lipid and glucose metabolism in 737 healthy subjects examined in NHANES III (1988-1994). Because only 14% of the values of urinary 2,4-D were above the limit of detection (LOD), it was decided to use urinary 2,4-D as a binary variable, above versus below the LOD, in linear regression analyses with adjustment for sex, age, BMI, ethnicity, smoking, urinary creatinine, alcohol consumption, education, income, and number of hours fasting before blood draw. No significant association was found between having detectable levels of 2,4-D or not and TSH levels (1.57 with 0.05 standard error [SE] vs 1.67 with 0.13 SE mg/L, respectively). Those having T4 below the median (8.5 µg/dl), who were hypothesized to be more sensitive, were analyzed separately, and a negative association was found for 2,4-D exposure with high density lipoprotein (HDL) levels (β = –0.09, 95% CI –0.16 to –0.02), but not with triglyceride levels (β = 1.79, 95% CI –0.18 to 3.76) or non-HDL levels (β = –0.27, 95% CI –1.30 to 0.76).
There has been considerable study of maternal exposure and perinatal effects on thyroid function, which is not directly applicable to the adult exposure of the Vietnam veterans whose own health is the primary concern of these updates. A discussion of these materials can be found in Chapter 8 on possible adverse effects on the offspring of Vietnam veterans.
The influence of TCDD on thyroid hormone homeostasis has been measured in numerous animal studies, with exposure associated with changes in serum concentrations of T4, T3, and TSH. In most studies, TCDD exposure is associated with a hypothyroid state, including reduced circulating T3 and T4 and increased TSH, especially after chronic exposure. Reduction in circulating T4 levels is robust and has recently been proposed as a biomarker of effect of dioxin-like compounds (Yang et al., 2010). Female rats exposed chronically to TCDD showed follicular-cell hyperplasia and hypertrophy of thyroid follicles, consistent with overstimulation of the thyroid gland by TSH (TSH increases as a homeostatic response to low T4 levels). TCDD enhances the metabolism of thyroid hormones primarily through an AHR-dependent induction of glucuronyl transferase activity (Kato et al., 2010; Nishimura et al., 2005). Enhanced accumulation of T4 in hepatic tissue of TCDD-treated mice may also contribute to the reduced circulating T4 (Kato et al., 2010).
Numerous animal experiments and several epidemiologic studies have shown that TCDD and dioxin-like compounds appear to exert some influence on thyroid homeostasis. The effects of these substances on thyroid hormone and TSH level in humans still remain to be definitely elucidated (Langer, 2008). Most of the literature to date has focused on the correlations between exposure to dioxin-like PCB congeners in environmentally exposed populations, with many of these studies limited to women and infants. Few studies of thyroid metabolism in the primarily male Vietnam veterans have been published. In the AFHS study considered in Update 2004, Pavuk et al. (2003) reported a trend toward an increasing concentration of TSH that was not accompanied by changes in circulating T4 or T3 in Vietnam veterans. In comparison, T4 has been shown to be susceptible to influence from dioxin-like compounds in epidemiological studies. Notably, in Vietnam veteran studies, there has been no evidence of changes in clinical thyroid disease. Although the overall assessment of the studies to date suggests some variation in thyroid hormone concentrations in relation to TCDD exposure, the functional importance of those changes remains unclear because adaptive capacity should be adequate to accommodate them. It should be noted, however, that although biomarkers of perturbation may be subclinical in most individuals, they may be associated with clear adversity in others.
There is inadequate or insufficient evidence of an association between exposure to the chemicals of interest and clinical or overt adverse effects on thyroid
homeostasis. Some effects have been observed in humans, but the functional importance of the changes reported in the studies reviewed remains unclear because adaptive capacity could be adequate to accommodate them.
With advancing age, loss of vision becomes increasingly common, with about one in six people over 70 years of age having substantial impairment and men and women being similarly affected (NCHS, 2010). The most prevalent ocular problems in current age range of Vietnam veterans are age-related macular degeneration, cataracts, glaucoma, and diabetic retinopathy. Ocular problems involving chemical agents most often arise from acute, direct contact with caustic or corrosive substances that may have permanent consequences. Ocular impairment arising from systemic exposure to toxic agents may be mediated by nerve damage. Cataracts can be induced by chronic internal exposure of the lens to chemicals such as 2,4-dinitrophenol, corticosteroids, and thallium, while glaucoma may arise secondary to any toxic inflammation and also from topical or systemic treatment with anti-inflammatory corticosteroids (Casarett and Doull, 1995).
Update of Epidemiologic Evidence
A cohort of Australian Vietnam veterans (O’Toole et al., 2009) was studied between 1990–1993 and reexamined in 2005–2006. In the original assessment, 641 Australian Vietnam veterans responded from a random sample of 1,000 selected from the list of Army Veterans deemed eligible for previous studies of Agent Orange; 450 from the original sample responded in this most recent assessment. Interviewers administered the Australian Bureau of Statistics National Health Survey that assessed physical health and associated risk factors, a 32-item combat index, an assessment for combat-related PTSD, and an assessment of general psychiatric status. Self-reported health status and conditions were asked. The prevalences of these conditions were compared to those reported by the general population in response to the National Health Survey from 2004–2005. Relative prevalences were calculated standardized to the Australian male population in 5-year age groups. Compared to the general population, the Vietnam veterans had elevated prevalence of all the eye conditions assessed: cataracts (RP = 1.84, 95% CI 1.2–2.47), presbyopia (RP = 3.05, 95% CI 2.73–3.36), color blindness (RP = 1.06, 95% CI 0.71–1.41), and other diseases of the eye (RP = 2.17, 95% CI 1.01–3.34). The committee had serious concerns that the results reported in O’Toole et al. (2009) were compromised by recall bias and other methodologic problems.
There have been several recent reports of ocular activity associated with AHR-induction or TCDD exposure in rats (Sugamo et al., 2009), mice (Takeuchi et al., 2009), and human nonpigmented ciliary epithelial cells (Volotinen et al., 2009).
O’Toole et al. (2009) observed increased risks for several eye conditions among the Australian Vietnam veterans, but the study is limited by the lack of information on exposure to the chemicals of interest to the committee, lack of clinical confirmation of the eye conditions, and considerable likelihood of recall bias.
On the basis of the evidence reviewed here, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and eye conditions.
This section discusses conditions encompassed by ICD-9 733: osteoporosis or decreased bone density. Osteoporosis is a skeletal disorder characterized by a decrease in bone mineral density (BMD) and loss of structural and biomechanical properties of the skeleton, leading to an increased risk of fractures. Although there currently are no practical methods to assess overall bone strength, BMD correlates closely with skeletal load-bearing capacity and fracture risk (Lash, 2009). The World Health Organization (WHO) has developed definitions for osteoporosis based on BMD measurements. The DEXA T-score is the number of the standard deviations from the mean BMD in young adult women, for whom osteoporosis is defined as T-score at any site of –5 or lower, whereas osteopenia is defined as a T-score between –1 and –2.5. Although there are no standardized diagnostic criteria for osteoporosis in men, most authorities use the WHO criteria of a T-score less than –2.5 relative to normal young women. Although men have much higher baseline BMD than women, they seem to have a similar fracture risk for a given BMD (Lash, 2009).
Gender is an important risk factor for osteoporosis with approximately 56% of postmenopausal women having decreased bone mineral density and 6% having osteoporosis (CDC, 2002). While data on the effects of aging on bone loss in women are well known, many health-care providers and patients are less familiar with the prevalence and impact of bone changes in older males (Orwoll et al., 2010). Individual patients have genetic and acquired risks for 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 bone density include long-acting benzodiazepine or anticonvulsant drug use, previous hyperthyroidism, excessive caffeine intake, and standing 4 or fewer hours per day (Lash, 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 polychlorinated dibenzofurans developing irregular calcifications of their skull bones (Miller, 1985) and reports of accidental organochlorine poisonings resulting in osteoporosis (Cripps et al., 1984; Gocmen et al., 1989). However; the epidemiological studies of the association between bone disorders and environmental exposures to organochlorine compounds have been inconsistent.
Summary of Previous Updates
Previous VAO updates have not examined bone density or osteoporosis as a health outcome. This is the first VAO update in which studies examining the association between exposures to the chemicals of interest and decrease in bone density are reviewed.
Update of the Scientific Literature
No Vietnam-veteran or occupational studies concerning the chemicals of interest and bone density or osteoporosis have been published.
Hodgson et al. (2008) studied the relationship between organochlorine exposure and BMD in a subset of 325 members of the Osteoporosis Cadmium as a Risk Factor (OSCAR) cohort who were at least 60 years old. Many of the cohort members lived close to the Baltic coast and may have had PCB exposure from fish consumption and potentially from exposure from a PCB-contaminated river. The cohort contains 1,021 individuals who provided information on employment, residence, smoking, diet, and medical history. Forearm BMD was measured on the distal site of the nondominant forearm with an osteometer using dual energy x-ray absorptiometry. Blood samples were analyzed for total TEQs for five mono-ortho chlorine substituted congeners (PCB 105, 118, 156, 157, and 167) and for the concentration of PCB 118 alone. TEQs for the mono-ortho PCBs ranged from 0.002 to 0.067 pg/mL in men and from 0.003 to 0.053 pg/mL in women. In males,
stepwise multivariate analyses adjusted for age, BMI, and milk consumption found PCB 118 to have a marginally significant negative association with BMD (β = –0.00011, p = 0.079), but TEQ for all five dioxin-like PCBs did not show an association (β = 0.225, p = 0.846). In females, stepwise multivariate analyses adjusted for age, BMI, age at menstruation, and ever-pregnant found PCB 118 alone and TEQ for all five dioxin-like PCBs were positively associated with BMD (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 value) was treated as a binary variable in a similarly adjusted logistic model, there was a significant association with PCB 118 in men (OR = 1.06, 95% CI 1.01–1.12, p = 0.027), but none of the measured organochlorine compounds (also including non-dioxin-like PCB 138, 153, and 180) were predictive for the women.
Animal studies suggest that TCDD may have some influence on bone formation and maintenance. For instance, TCDD exposure via the dam’s milk impaired bone mineralization during postnatal development in mice due to a reduction of the osteoblastic activity, which is caused by TCDD-induced up-regulation in the active form of vitamin D in serum (Nishimura et al., 2009). TCDD altered osteo-genesis (bone formation) in an in vitro osteoblast model, producing alterations in proteins associated with cytoskeleton organization and biogenesis and a decrease in the expression of calcium-binding proteins, which decreases osteoblast calcium deposition (Carpi et al., 2009).
The small amount of epidemiologic information available concerning possible adverse effects on bone structure in association with exposure to the chemicals of interest is based almost entirely on a single dioxin-like PCB. The findings of Hodgson et al. (2008) do not constitute a strong or consistent pattern.
There is inadequate or insufficient evidence of an association between exposure to the chemicals of interest and clinical or overt adverse effects of osteoporosis or loss of bone mineral density.
On the basis of the occupational, environmental, and veterans studies reviewed and in light of information concerning biologic plausibility, the committee reached one of four conclusions about the strength of the evidence regarding
an association between exposure to the chemicals of interest and each of the health outcomes discussed in this chapter. In categorizing diseases according to the strength of the evidence, the committee applied the same criteria (discussed in Chapter 2) that were used in VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008. To be consistent with the charge to the committee by the Secretary of Veterans Affairs in Public Law 102-4 and with accepted standards of scientific reviews, the distinctions between conclusions are based on statistical association.
Health Outcomes with Sufficient Evidence of an Association
For diseases in this category, a positive association between exposure and outcome must be observed in studies in which chance, bias, and confounding can be ruled out with reasonable confidence. On the basis of the literature, none of the health effects discussed in this chapter satisfy the criteria necessary for inclusion in this category.
Health Outcomes with Limited or Suggestive Evidence of an Association
For this category, the evidence must suggest an association between exposure and outcome, although it can be limited because chance, bias, or confounding could not be ruled out with confidence. On the basis of the literature, none of the health effects discussed in this chapter satisfy the criteria necessary for inclusion in this category.
Health Outcomes with Inadequate or Insufficient Evidence to Determine Whether There Is an Association
The scientific data on many of the health outcomes reviewed by the present committee were inadequate or insufficient to determine whether there is an association between exposure to the chemicals of interest and the outcomes. For the health outcomes in this category, the available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. Some studies failed to control for confounding or used inadequate exposure assessment. This category includes noncancerous respiratory disorders, such as COPD, asthma in isolation, pleurisy, pneumonia, and tuberculosis; gastrointestinal diseases; digestive diseases; liver toxicity; disorders of thyroid homeostasis; and disorders of the eyes and bones.
Health Outcomes with Limited or Suggestive Evidence of No Association
To classify outcomes in this category, several adequate studies covering the full range of known human exposure must be consistent in not showing a positive
association between exposure and outcome at any magnitude of exposure. The studies also must have relatively narrow confidence intervals. A conclusion of “no association” is inevitably limited to the conditions, magnitudes of exposure, and periods of observation covered by the available studies. The possibility of a very small increase in risk at the exposure studied can never be excluded.
The committees responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 concluded that none of the health outcomes discussed in this chapter had limited or suggestive evidence of no association with exposure to the chemicals of interest. The most recent scientific evidence continues to support that conclusion.
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