Veterans and Agent Orange Update 2000 (2001) / Chapter Skim
Currently Skimming:
10 Other Health Effects
10 Other Health Effects
Pages 463-522
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 463... ...
Each section concludes with the committee's finding regarding the strength of the evidence in epidemiologic studies, biologic plausibility, and evidence regarding Vietnam veterans. CHLORACNE Background Chloracne is recognized to be an outcome of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
|
From page 464... ...
Kimbrough suggests that Ranch Hand veterans have too narrow and too low a range of blood levels from which to draw conclusions and also that the time elapsed after exposure until the studies were performed may have introduced confounding factors such as aging, obesity, and onset of diabetes, all of which change blood lipid levels in ways that may not affect skin changes and that may obscure relationships with chloracne. One new study to shed light on the elusive threshold for development of chloracne was contributed by Coenraads et al.
|
From page 465... ...
This study classified troops by serum dioxin levels and may be considered definitive. Synthesis Chloracne is clearly associated with exposure to high levels of cyclic organochlorine compounds.
|
From page 466... ...
Increased Risk of Disease Among Vietnam Veterans Vietnam veterans in the AFHS study were not found to have chloracne. Because chloracne appears shortly after exposure, regresses over time, and does not appear after a long latency, no new cases from wartime exposures are expected.
|
From page 467... ...
An adequate diet may be protective against manifestations of the disease following exposure to TCDD, at least in most people. This finding may explain why PCT was not observed among Ranch Hand participants and was not identified as a health problem among Vietnam veterans exposed to Agent Orange.
|
From page 468... ...
Increased Risk of Disease Among Vietnam Veterans PCT is an early response to TCDD and therefore no new cases due to wartime exposure are expected among Vietnam veterans. RESPIRATORY DISORDERS Background In Update 1998, only passing mention was made of inflammation and immune function in relation to respiratory disorders and their possible association with exposure to Agent Orange.
|
From page 469... ...
Aside from rare hereditary disorders and occupational exposures, the cause of emphysema is overwhelmingly cigarette smoking. Emphysema is identified by pulmonary function studies and often by chest films.
|
From page 470... ...
For practical purposes, CORD should be understood to include all three disorders occurring together, any two of them if they occur together, and either chronic bronchitis or emphysema if it occurs separately. Further, there is some evidence to suggest that these conditions are associated biologically, through common hereditary predisposition, and may be associated with an increased risk of lung cancer for a given history of cigarette smoking.
|
From page 471... ...
However, the net effect of TCDD exposure is unpredictable. The effect of TCDD may be to reduce or vary the expression of immune response in the lung.
|
From page 472... ...
This pattern is consistent with an effect, primarily among males, at the highest exposure levels but is not sufficient to conclude that there is an exposure-response relationship for respiratory disorders as a whole. Mortality from respiratory disorders in the adult Seveso population, as in most populations in developed societies of the world, is driven by deaths from chronic obstructive pulmonary disease, which is overwhelmingly attributable to cigarette smoking.
|
From page 473... ...
They state that "early deaths among persons with impaired respiratory systems may have been caused by the social and emotional impact of the disaster" and imply that changes in the immune response as a result of TCDD exposure may have altered the inflammatory response to cigarette smoking in earlier stages of the habit, presumably enhancing the adverse effects, accelerating the loss of lung function, and hastening the onset of COPD (Bertazzi et al., 1998~. This mechanism is speculative and not further defined.
|
From page 474... ...
Synthesis New evidence suggests that there may be an increased risk for nonmalignant respiratory disorders, particularly chronic obstructive pulmonary disease, among individuals exposed to TCDD. This association is based on small numbers, is not adjusted for smoking, and is not internally consistent.
|
From page 475... ...
A discussion of toxicological studies that comprise the biologic basis for an association between exposure to TCDD or herbicides and toxicity end points is contained in Chapter 3; a general summary of the biologic basis for various end points is presented in the conclusion to this chapter. Increased Risk of Disease Among Vietnam Veterans There are insufficient data on nonmalignant respiratory disorders in Vietnam veterans to draw a specific conclusion as to whether or not they are at increased risk.
|
From page 476... ...
Proper function of the immune system is exquisitely sensitive to disruptions in physiologic homeostasis. The immune response is highly redundant, and several different mechanisms may be employed to eliminate an antigen.
|
From page 477... ...
Summary of VAO, Update 1996, and Update 1998 The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the herbicides used in Vietnam or the contaminant dioxin and immune system disorders. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding.
|
From page 478... ...
In another group of workers exposed in 1951-1984 in a plant that produced organochlorine herbicides, pesticides, and opioids, peripheral blood lymphocytes were obtained from several cohorts of control or TCDD-exposed individuals (Germolec, l999~. The lymphocytes were mitogen stimulated in culture alone or in the presence of TCDD.
|
From page 479... ...
Immune parameters were measured in veterans of Operation Ranch Hand in 1992 (Michalek et al., 1999a; AFHS, 2000~. Test groups included a comparison group (Air Force veterans who served in Southeast Asia during the same period as the Ranch Hand veterans but were not involved in spraying herbicides)
|
From page 480... ...
Nevertheless, the available data indicate that the universal immunosuppressive effects observed in laboratory animals have not been confirmed in humans. Conclusions Strength of Evidence in Epidemiologic Studies There is no information contained in the research reviewed for this report to change the conclusion that there is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides (2,4-D,2,4,5
|
From page 481... ...
Increased Risk of Disease Among Vietnam Veterans No evidence is available to associate defects in the immune response with Agent Orange exposure. A more thorough discussion of the issue of increased risk of disease among Vietnam veterans is included in Chapter 1.
|
From page 482... ...
This review, which focused on information published since the deliberations of the Update 1998 committee, resulted in the report Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000~. The committee responsible for that report found there was limited/suggestive evi
|
From page 483... ...
. The relationship between serum dioxin levels and diabetes morbidity in a NIOSH study of dioxin-exposed workers from chemical plants in New Jersey and
|
From page 484... ...
, and there was no support for a doseresponse trend in risk of diabetes across the four levels of serum dioxin. The chemical workers also had a slight and statistically nonsignificant elevation in fasting serum glucose levels; in detailed analyses of current and half-life extrapolated dioxin levels, only the subgroup with the highest half-life extrapolated concentration (1,860-30,000 pg/g)
|
From page 485... ...
published a study of serum dioxin and diabetes that focused exclusively on comparison veterans enrolled in the Ranch Hand study. These individuals were Air Force veterans who served in Southeast Asia between 1962 and 1971 but were not involved in the spraying of herbicides; in addition, all comparison veterans were required to have serum dioxin levels at or below 10 ng/kg in order to represent individuals with background levels of exposure.
|
From page 486... ...
Finally, there was a significant positive association between 1987 serum dioxin levels and diabetes (RR = 1.5, 1.21.7; Model 4~. The unadjusted form of Model 4 also yielded a statistically significant positive relationship; the unadjusted forms of Models 2 and 3 did not.
|
From page 487... ...
. The authors found an excess of diabetes among male veterans and a deficit among female veterans when comparing the number of Vietnam veterans responding yes to the question, Since yourfirst day of service in Vietnam, have you been told by a doctor that you have diabetes?
|
From page 488... ...
suggest that dioxin exposure may be associated with an increased risk of developing diabetes. The association in each study is modest and imprecise, but the rough consistency across studies compensates in part for the imprecision.
|
From page 489... ...
Recently published studies of humans report a compensatory metabolic relation between dioxin and insulin regulation in Air Force Health Study participants (Michalek et al., l999b) , an apparent association between serum dioxin levels and fasting glucose levels among nondiabetic AFHS comparison group members with less than 10 ppt serum dioxin (Longnecker and Michalek, 2000)
|
From page 490... ...
2 2,4,5-T and TCP production workers 11 26 9 4 SMR = 0.7 (0~2-1.9)
|
From page 491... ...
VIETNAM VETERANS New Studies AFHS, 2000 Air Force Ranch Hand veterans and (Numerous analyses comparisons discussed in text) Longnecker and Ranch Hand unexposed referents only, Michalek, 2000 OR by quartile and serum dioxin concentration Quartile 1: <2.8 ng/kg (pg/g)
|
From page 492... ...
All Ranch Hands 146 1.1 (0.9-1.4) O'Toole et al., 1996 Australian Vietnam veterans 12 1.6 (0.4-2.7)
|
From page 493... ...
Update of the Scientific Literature Occupational and Environmental Studies No new findings have appeared in occupational or environmental studies in the peer-reviewed epidemiologic literature regarding dioxin exposure and the occurrence of elevated lipids or lipoproteins since publication of the last VAO series report. Recently published results for triglyceride and HDL cholesterol levels of chemical plant workers in New Jersey and Missouri (Calvert et al., 1998; Sweeney et al., 1997/98)
|
From page 494... ...
No elevation in triglyceride level was evident in Ranch Hands with low or background levels of dioxin. Synthesis The new reports from the Air Force Health Study offer useful but incomplete evidence on the association between dioxin exposure and lipid abnormalities.
|
From page 495... ...
A discussion of animal toxicological studies that could contribute to a biologic basis for an association between exposure to TCDD and herbicides and toxicity end points is contained in Chapter 3; a general summary of the biologic basis for various end points is presented in the conclusion to this chapter. Increased Risk of Disease Among Vietnam Veterans As indicated above, the most recent AFHS study (AFHS, 2000)
|
From page 496... ...
so~ ca ca · - ~ c)
|
From page 497... ...
O O cd _I ~ z z ~ h-l o v do z oo v)
|
From page 498... ...
Peptic ulcer disease is characterized as gastric ulcer or duodenal ulcer, depending on the anatomic site of origin. Peptic ulcer disease occurs when the corrosive action of gastric acid and pepsin exceeds the normal mucosal defense mechanisms protecting against ulceration.
|
From page 499... ...
Cigarette smoking has also been linked to duodenal ulcer prevalence and mortality. Finally, psychological factors, particularly chronic anxiety and psychological stress, may act to exacerbate duodenal ulcer disease.
|
From page 500... ...
, a poorly understood condition called primary biliary cirrhosis, chronic right-sided heart failure, and a variety of less common metabolic and drug-related causes. Summary of VAO, Update 1996, and Update 1998 The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the herbicides used in Vietnam or the contaminant dioxin and gastrointestinal and digestive disease, including liver toxicity.
|
From page 501... ...
(1998) conducted a review of early and long-term effects of dioxin exposure following a 1976 industrial accident in Seveso, Italy, where a large population was exposed to a substantial amount of relatively pure 2,3,7,8TCDD.
|
From page 502... ...
. There was no association between serum dioxin level and incidence among Ranch Hand veterans for this outcome.
|
From page 503... ...
. Analyses that factored serum dioxin levels yielded a statistically significant excess among Ranch Hand veterans in the high dioxin category (1.5,1.12.1; Model 3, adjusted)
|
From page 504... ...
Synthesis Evaluation of the impact of herbicide and dioxin exposure on noncancer gastrointestinal ailments is more difficult than some of the other outcomes examined in this report. Clinical experience suggests that medical history and physical examination are undependable diagnostic tools for some of these ailments, making incidence data more problematic.
|
From page 505... ...
A discussion of toxicological studies that comprise the biologic basis for an association between exposure to TCDD or herbicides and toxicity end points is contained in Chapter 3; a general summary of the biologic basis for various end points is presented in the conclusion to this chapter. Increased Risk of Disease Among Vietnam Veterans The available data on Vietnam veterans do not permit a conclusion about whether they are at elevated risk for gastrointestinal and digestive diseases.
|
From page 506... ...
Workers exposed to phenoxy herbicides, chlorophenols, and contaminants were at increased risk of death from all circulatory diseases (45 deaths in the exposed, 16 deaths in the nonexposed; RR = 1.4,0.8-2.5) , ischemic heart disease (33 deaths in the exposed, 10 deaths in the nonexposed; RR = 1.8, 0.9-3.6)
|
From page 507... ...
, the test for trend was statistically significant (p < .05) for all circulatory diseases and for ischemic heart disease, but this was influenced primarily by a protective effect in the lowest two quintiles of exposure (e.g., RR = 0.7 and 0.7 for circulatory diseases)
|
From page 508... ...
, but an analysis by military occupation showed that among enlisted ground personnel, Ranch Hand veterans were at somewhat increased risk (24 deaths in Ranch Hand veterans; SMR = 1.5, 1.0-2.2~. Data on morbidity were reported from the Air Force Health Study 1997 Follow-up Examination Results (AFHS, 2000~.
|
From page 509... ...
Ischemic heart disease was reported by 25 (16-34) female veterans.
|
From page 510... ...
, and no adjustment is possible for pre-exposure level of blood pressure. A general measure of heart disease is more prevalent among Ranch Hand veterans and some categories of increased dioxin levels, but the gradients of risk are inconsistent and more information is needed to determine the validity of the outcome measure.
|
From page 511... ...
Summary of VAO, Update 1996, and Update 1998 The Department of Veterans Affairs asked the committee responsible for this report to address the possible association between exposure to the herbicides used in Vietnam or the contaminant dioxin and AL-type primary amyloidosis, a condition that has not been examined in previous Veterans and Agent Orange reports. Update of the Scientific Literature The committee identified a single report that addressed exposure to the herbicides used in Vietnam and amyloidosis.
|
From page 512... ...
Conclusions Strength of Evidence in Epidemiologic Studies There is inadequate/insufficient evidence to determine whether an association exists between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and AL-type primary amyloidosis.
|
From page 513... ...
The committee also regarded evidence from several small studies that are free from bias and confounding, and that show an association that is consistent in magnitude and direction, as sufficient evidence for an association. Health Outcomes with Limited/Suggestive Evidence of Association In Update 1996 and Update 1998, the committee found limited/suggestive evidence of an association between herbicide or dioxin exposure and porphyria cutanea tarda.
|
From page 514... ...
Since Update 1998, the committee responsible for this report has been asked to address the possible association between exposure to the herbicides used in Vietnam or the contaminant dioxin and AL-type primary amyloidosis. Based on the scientific literature reviewed, there is inadequate/insufficient evidence to determine whether an association exists between herbicide or dioxin exposure and AL-type primary amyloidosis.
|
From page 515... ...
Liver toxicity is species specific; mice and rats are susceptible to TCDDinduced liver toxicity, but guinea pigs and hamsters are not. It is possible that liver toxicity is associated with susceptibility to liver cancer, but the extent to which TCDD effects mediate noncancer end points is not clear.
|
From page 516... ...
Studies in mice, rats, guinea pigs, and monkeys indicate that TCDD suppresses the function of certain components of the immune system in a dose-related manner; that is, as the dose of TCDD increases, its ability to suppress immune function increases. TCDD suppresses cell-mediated immunity, primarily by affecting the T cell arm of the immune response, including a decrease in the number and response of certain types of T cells.
|
From page 517... ...
Investigating the biological mechanisms underlying TCDD's toxic effects continues to be a very active area of research, and subsequent updates of this report might have more and better information on which to base conclusions, at least for that compound. Increased Risk of Disease Among Vietnam Veterans Under the Agent Orange Act of 1991, the committee is asked to determine (to the extent that available scientific data permit meaningful determinations)
|
From page 518... ...
1998. Serum dioxin, chloracne, and acne in veterans of Operation Ranch Hand.
|
From page 519... ...
A report of the 1996 retrospective cohort study of Australian Vietnam veterans. Canberra: Department of Veterans' Affairs.
|
From page 520... ...
2000. Serum dioxin level in relation to diabetes mellitus among Air Force veterans with background levels of exposure.
|
From page 521... ...
1996. The Australian Vietnam Veterans Health Study: II.
|
From page 522... ...
1990. Health status of Air Force veterans occupationally exposed to herbicides in Vietnam.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.