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'Proximal-type' epithelioid sarcoma: is Agent Orange still at large?

BACKGROUND AND AIMS: Proximal-type epithelioid sarcomas of the perineum are extremely rare. The authors provide an overview of this condition in relation to the history of exposure to Agent Orange. PATIENT AND METHODS: A 54-year-old man presented with a rapidly growing perineal subcutaneous mass that was shown to be a proximal-type epithelioid sarcoma. The case is discussed. An Internet Medline search was performed and the current literature reviewed. RESULTS: Only 4 primary perineal sarcomas have been described in the literature. Epithelioid sarcomas are uncommon, aggressive tumours with a propensity for locoregional recurrence. They are recognised by the US Veterans Affairs department as linked to exposure to Agent Orange, an organochlorine defoliant containing the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, the role of Agent Orange in sarcomagenesis is still controversial. CONCLUSION: Unusual soft tissue swellings in a background of chemical exposure should be investigated thoroughly with a view to early, appropriate treatment.

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Long overlooked historical information on Agent Orange and TCDD following massive applications of 2,4,5-T-containing herbicides, Eglin Air Force Base, Florida.

BACKGROUND: From 1961-1971, The Air Development Test Center, Eglin Air Force Base (AFB), Florida, developed, tested, and calibrated the aerial spray systems used in support of Operation RANCH HAND and the US Army Chemical Corps in Vietnam. Twenty major test and evaluation projects of aerial spray equipment were conducted on four fully instrumented test grids, each uniquely arrayed to match the needs of fixed-wing, helicopter, or jet aircraft. Each of the grids was established within the boundary of Test Area 52A of the Eglin Reservation. METHODS: The tests, conducted under climatic and environmental conditions similar to those in Vietnam, included the use of the military herbicides (Agents) Orange, Purple, White, and Blue. Approximately 75,000 kg of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 76,000 kg of 2,4-dichlorophenoxyacetic acid (2,4-D) were aerially disseminated on an area of less than 3 km2 during the period 1962-1970. Data from the analysis of archived samples suggested that an estimated 3.1 kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), present as a contaminant, were aerially released in the test area. Because most of the vegetation had been removed before establishing the test site in 1961, there was an opportunity to follow ground-based residues independent of canopy interception, and the resulting high solar exposure of initial residues. Studies of the soils, fauna, flora, and aquatic ecosystems of the test grids and associated perimeters of Test Area C-52A (an area totally more than 8 km2) were initiated in 1969 and concluded in 1984. RESULTS AND DISCUSSION: Data from soil samples collected from 1974 through 1984 suggested that less than one percent of the TCDD that was present in soil when sampling began persisted through the ten-year period of sampling. More than 340 species of organisms were observed and identified within the test area. More than 300 biological samples were analyzed for TCDD and detectable residues were found in 16 of 45 species examined. Examination of the ecological niches of the species containing TCDD residues suggested each was in close contact with contaminated soil. Indepth field studies, including anatomical, histological and ultrastructural examinations, spanning more than 50 generations of the Beachmouse, Peromyscus polionotus, demonstrated that continual exposure to soil concentrations of 0.1 to 1.5 parts-per-billion (ng/g) of TCDD, had minimal effects upon the health and reproduction of this species. CONCLUSIONS: Since Agent Orange with its associated TCDD contaminant was aerially disseminated on the test grids, Test Area C-52A provided a 'field laboratory' for what may have happened in Vietnam, had there been no intercepting forest cover. However, in Vietnam a 'typical' mission would have disseminated 14.8 kg of 2,4,5-T/ha, most of which was intercepted by the forest canopy, versus the 876 kg 2,4,5-T/ha on the test grid at Eglin. Moreover, each hectare on the Eglin test grid received at least 1,300 times more TCDD than a hectare sprayed with Agent Orange in Vietnam. The disappearance or persistence of TCDD is dependent upon how it enters the ecosystem. Spray equipment test and evaluations missions at Eglin were generally scheduled and conducted with environmental conditions that were optimal for spray operations. This suggests that conditions favorable for dissemination of herbicide were the same conditions favorable for photodegradation of TCDD. It was likely that 99 percent of the TCDD never persisted beyond the day of application. No long-term adverse ecological effects were documented in these studies despite the massive quantities of herbicides and TCDD that were applied to the site. Reviews by the US Environmental Protection Agency and the National Academy of Sciences' Institute of Medicine did not address the fate of Agent Orange and TCDD as described in these studies from Eglin AFB, Florida.

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The extent and patterns of usage of Agent Orange and other herbicides in Vietnam.

Herbicides including Agent Orange were sprayed by United States forces for military purposes during the Vietnam War (1961-1971) at a rate more than an order of magnitude greater than for similar domestic weed control. In 1974, the US National Academy of Sciences published estimates of the extent and distribution of herbicides sprayed. Here we present revised estimates, developed using more-complete data. The spray inventory is expanded by more than seven million litres, in particular with heavily dioxin-contaminated herbicides. Estimates for the amount of dioxin sprayed are almost doubled. Hamlet census data reveal that millions of Vietnamese were likely to have been sprayed upon directly. Our identification of specific military herbicide targets has led to a more coherent understanding of spraying. Common errors in earlier interpretations of the spray data are also discussed.

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Immunotoxicological effects of Agent Orange exposure to the Vietnam War Korean veterans.

Immunomodulatory effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) demonstrated using animals are thymic atrophy, downregulation of cytotoxic T or B lymphocyte differentiation or activation, whereas human immunotoxicities have not been investigated well. This study was undertaken to evaluate overall immunologic spectrum of the Vietnam War Korean veterans exposed to Agent Orange contaminated with TCDD. Quantity of red blood cells, hemoglobin and hematocrit in the veterans suffered from chronic diseases associated with Agent Orange exposure (Veterans-patient group) were decreased in comparison with those of the veterans without the diseases and the age-matched healthy controls, but no differences in leukocyte populations. Plasma IgG levels were lowered in the veterans than the controls, owing to significant decrease in the IgG1 levels. Increase in the IgE levels was observed in the plasma from the veterans. Alteration of T cell-mediated immunity was also resulted from activation of peripheral blood mononuclear cells with polyclonal T cell activators. Production of IFNgamma, a major cytokine mediating host resistance against infection or tumoregenesis, was lowered in the veterans-patient group. However, production of IL-4 and IL-10, representative cytokines involved with hypersensitivity induction, was enhanced in the patient group. Overall, this study suggests that military service in Vietnam and/or Agent Orange exposure disturbs immune-homeostasis resulting in dysregulation of B and T cell activities.

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Agent Orange exposure and posttraumatic stress disorder.

Evidence of organic psychological deficits in Vietnam veterans exposed to the herbicide Agent Orange was established through a neuropsychological battery. Also, the exposed Vietnam veterans, in contrast to a matched control group of Vietnam veterans, showed a significantly higher rate of posttraumatic stress disorder and its associated features: depression, anxiety, and increased aggression. The latter was subdivided into uncontrollable pressures, verbal violence, violence against objects, assaults, and suicidal thoughts. Active cases of chloracne, a medical indicator, were used to determine Agent Orange exposure.

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Dioxin reservoirs in southern Viet Nam--a legacy of Agent Orange.

In the isolated Aluoi Valley of central Viet Nam, very high levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were measured in soil, fish fat, duck fat, pooled human blood and breast milk samples collected from A So village between 1996 and 1999. The village was situated on a former military base occupied by US Special Forces between 1963 and 1966. TCDD was a contaminant of the herbicide "Agent Orange", aerially sprayed in the valley between 1965 and 1970, and stored at the A So base. Measured levels were lower near the sites of two other former US bases in the valley which had been occupied for shorter periods of time. In areas where Agent Orange had been applied by low-flying aircraft, levels of TCDD in soil, food and human samples were elevated, but lower than those near the three former US bases. We confirm the apparent food chain transfer of TCDD from contaminated soil to cultured fish pond sediments to fish and duck tissues, then to humans as measured in whole blood and breast milk. We theorize that the Aluoi Valley is a microcosm of southern Viet Nam, where numerous reservoirs of TCDD exist in the soil of former military installations south of the former demilitarized zone. Large quantities of Agent Orange were stored at many sites, used in ground and aerial applications, and spilled. TCDD, through various forms of soil disturbance, can be mobilized from these reservoirs after decades below the surface, and subsequently, introduced into the human food chain.

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Mutagenicity testing of agent orange components and related chemicals.

Components of the herbicide Agent Orange--2,4-dichlorophenoxyacetic acid (2,4,-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and their esters, and the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)--and related chemicals were tested for mutagenicity using Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537. No mutagenic activity was observed for any of the chemicals tested.

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Carcinogenicity and teratogenicity vs. psychogenicity: psychological characteristics associated with self-reported Agent Orange exposure among Vietnam combat veterans who seek treatment for substance abuse.

This study asked, "What are the psychological characteristics of Vietnam combat veterans who claim Agent Orange exposure when compared with combat-experienced cohorts who do not report such contamination?" The question was researched among 153 heroin addicts, polydrug abusers, and chronic alcoholics who were seeking treatment: 58 reported moderate to high defoliant exposure while in combat; 95 reported minimal to no exposure while in Vietnam. The null hypothesis was accepted for measures of childhood and present family social climate, premilitary backgrounds, reasons for seeking treatment, patterns and types of illicit drug and alcohol use, interpersonal problems, intellectual functioning, and short-term memory. The null hypothesis was rejected for personality differences, however, those who self-reported high Agent Orange exposure scored significantly higher on MMPI scales F, Hypochondriasis, Depression, Paranoia, Psychasthenia, Schizophrenia, Mania, and Social interoversion. The results suggest that clinicians carefully assess attributional processing of those who report traumatic experience.

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Insulin sensitivity following agent orange exposure in Vietnam veterans with high blood levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Our objective was to determine whether insulin sensitivity was related to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Vietnam veterans exposed to Agent Orange. Air Force veterans of Operation Ranch Hand, the unit responsible for spraying Agent Orange and other herbicides in Vietnam from 1962 to 1971, and comparison veterans who did not spray herbicides were included. We measured insulin sensitivity (S(I)) using a frequently sampled iv glucose tolerance test in a matched study of 29 matched pairs of veterans and a quantitative insulin sensitivity check index (QUICKI) based on fasting glucose and insulin in 71 matched pairs. No group differences were found with regard to the mean values of S(I), QUICKI, TNFalpha, adiponectin, and two measures of insulin secretion. However, S(I) and QUICKI decreased significantly with regard to TCDD (P = 0.01 and 0.02). A corresponding pattern (although not significant) was found for blood levels of TNFalpha and adiponectin. These data suggest that high blood TCDD levels may promote an insulin-resistant state, but the magnitude of this effect appeared to be small, such that an 18-fold increase in blood TCDD due to increased exposure resulted in only a 10% change in S(I) in the 29 matched pairs.

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Agent orange and the risk of gestational trophoblastic disease in Vietnam.

There have been claims of an increased risk for gestational trophoblastic disease (i.e., hydatidiform mole and choriocarcinoma) in Vietnam since the period of Agent Orange sprayings. In 1990, we conducted a case-control study in Ho Chi Minh City to investigate risk factors for gestational trophoblastic disease in Vietnam. Eighty-seven married women, all of whom had a recent pathologic diagnosis of gestational trophoblastic disease, identified in the Obstetrical and Gynecological Hospital, were included in the study. Eighty-seven married women who were admitted mainly in the surgery departments of the same hospital were the controls, and they were matched to cases for age and area of residence. Odds ratios (ORs), adjusted for matching variables and other potential confounders, were estimated with unconditional logistic regression. A statistically significant trend in risk was observed with previous live births (p = .01). Cases were found to eat less meat per wk (OR = 0.4, 95% confidence interval [95% CI] = 0.2-0.9 for > or = five meat dishes) and to own fewer consumer goods than controls. An increase in risk was associated with the breeding of pigs (OR = 5.7, 95% CI = 1.2-27.6 for raising three or more pigs). A cumulative Agent Orange exposure index was constructed, using the patient's complete residence history. No significant difference was found between cases and controls for this index (OR = 0.7, 95% CI = 0.2-1.8 for high-exposure category), nor was such a difference noted for the agricultural use of pesticides.

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External Qi therapy to treat symptoms of Agent Orange Sequelae in Korean combat veterans of the Vietnam War.

We investigated the efficacy of Qi therapy as a non-pharmacological treatment for various symptoms presented by Korean combat veterans of the Vietnam War with Agent Orange Sequelae. Nine subjects volunteered to receive 30 minutes of Qi therapy, twice per day for 7 days. There was marked improvement in 89% of the patients with impaired physical activity, 86% of those with psychological disorder, 78% of those with heavy drug use, and 67% of those with fatigue, indigestion and high blood glucose levels. This data suggests that Qi therapy combined with conventional treatment has positive effects in reducing and managing the pain, psychosomatic disorders, and substance abuse in patients with Agent Orange Sequelae. We cannot completely discount the possible influence of the placebo effect, and more objective, clinical measures are needed to study the long-term effects of Qi therapy.

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Agent Orange toxicity: a quantitative perspective.

1 The minimum toxic dose of tetrachloro-dibenzo-p-dioxin (TCDD) for man has been calculated from monkey and human data to be 0.1 microgram kg-1. 2 The amount of TCDD which man takes in from his environment is about 1/2050 of that present in one square metre of his immediate environment. 3 The average concentration of TCDD present in Vietnam immediately after spraying Agent Orange was 8 microgram m-2. 4 A soldier directly sprayed would attain an internal body concentration of 7 X 10(-5) microgram kg-1 or 1/1750 of the minimum toxic dose; soldiers moving through previously sprayed areas would ingest much less. 5 These quantitative aspects indicate that the dioxin sprayed with Agent Orange in Vietnam cannot have caused systemic illnesses in Vietnam veterans or birth defects in their children.

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The logic of a controversy: the case of Agent Orange in Australia.

Since 1979 the Vietnam Veterans' Association of Australia (VVAA) has claimed that exposure to the herbicide Agent Orange in Vietnam has adversely affected the health of Vietnam veterans and their families. A campaign for government recognition of diseases and disabilities caused by herbicide exposure led in 1983 to the appointment of the Evatt Royal Commission which, after a 2-year inquiry, comprehensively rejected the VVAA's claim. The Evatt Commission's findings have not been accepted by the VVAA and the claim continues to be defended, albeit in a highly qualified form. This controversy exemplifies the way in which a claim can attract public support, and persist despite rejections by Committees of Inquiry. An understanding of the reasons for the persistence of controversy requires an understanding of the logic of rejecting causal claims, the psychology of everyday inductive reasoning, and the interaction between politics and science.

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Correlates of self-reported and objectively determined exposure to Agent Orange.

The authors examined the relationship between 100 Viet Nam veterans' self-reported and objectively determined exposure to the herbicide Agent Orange and the relationship between self- or objective ratings and self-reported psychological and medical problems. Veterans who believed they had been exposed reported more psychological and medical problems than the other veterans but did not differ on "success at living" indices; the medical problems many reported suggested psychosomatic etiologies. Grouped according to objective ratings of herbicide exposure, the veterans did not show such differences in psychological or medical problems. No differences on neuropsychological testing appeared, no matter how the subjects were grouped.

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A geographic information system for characterizing exposure to Agent Orange and other herbicides in Vietnam.

Between 1961 and 1971, U.S. military forces dispersed more than 19 million gallons of phenoxy and other herbicidal agents in the Republic of Vietnam, including more than 12 million gallons of dioxin-contaminated Agent Orange, yet only comparatively limited epidemiologic and environmental research has been carried out on the distribution and health effects of this contamination. As part of a response to a National Academy of Sciences' request for development of exposure methodologies for carrying out epidemiologic research, a conceptual framework for estimating exposure opportunity to herbicides and a geographic information system (GIS) have been developed. The GIS is based on a relational database system that integrates extensive data resources on dispersal of herbicides (e.g., HERBS records of Ranch Hand aircraft flight paths, gallonage, and chemical agent), locations of military units and bases, dynamic movement of combat troops in Vietnam, and locations of civilian population centers. The GIS can provide a variety of proximity counts for exposure to 9,141 herbicide application missions. In addition, the GIS can be used to generate a quantitative exposure opportunity index that accounts for quantity of herbicide sprayed, distance, and environmental decay of a toxic factor such as dioxin, and is flexible enough to permit substitution of other mathematical exposure models by the user. The GIS thus provides a basis for estimation of herbicide exposure for use in large-scale epidemiologic studies. To facilitate widespread use of the GIS, a user-friendly software package was developed to permit researchers to assign exposure opportunity indexes to troops, locations, or individuals.

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The legacy of Agent Orange: empirical evidence from central Vietnam.

This paper seeks to provide a socio-economic impact assessment for Vietnamese victims of the principal US military herbicide, Agent Orange, used during the Vietnam War in the period 1961-71. The study is based on a field survey of 30 affected and 30 unaffected households in Quang Tri province. With this assessment, the paper attempts to address the broader issues of compensation currently available to victims. The coverage and composition of current benefits are deemed inadequate as an effective redress. In view of this, revision of current compensation, the mobilization of an international donor fund and spurred non-governmental support is strongly recommended.

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Correlation between dioxin levels in adipose tissue and estimated exposure to Agent Orange in south Vietnamese residents.

To permit new epidemiologic studies of the effects of dioxin on humans in Vietnam, we evaluated a model for quantifying exposure to Agent Orange (exposure index) based on the residential histories of 27 Vietnamese subjects and on information about spraying from the U.S. Army records (Herbs Tape) and compared this index to the dioxin levels measured in the subjects' adipose tissue. The mean dioxin level was 7.8 ppt, and dioxin and furan isomer profiles were similar to those already reported in industrialized countries. In addition, there was a highly significant correlation between the levels of almost all the isomers, whatever their degree of chlorination. For the group of 27 subjects, we found a Pearson correlation coefficient of 0.36 (P = 0.07) between the dioxin levels and the exposure index after log-transformation of both variables. When the analysis was restricted to the 22 subjects with a positive exposure index, the Pearson correlation coefficient rose to 0.50 (P = 0.02). We conclude that despite the limitations and power conditions of the study, this result is encouraging because it will be useful for future epidemiologic studies in Vietnam.

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"Golf ball liver": agent orange hepatitis.

2,4-Dichlorophenoxyacetic acid (2,4-D) is a selective weedkiller which works by uncoupling oxidative phosphorylation and is in widespread use. It is known as "agent orange". A 65 year old man had acute hepatitis, thought to be caused by exposure to 2,4-D. The patient ingested 2,4-D as a result of habitual licking of his golf ball. Clinical and histological data together with a challenge test confirmed the diagnosis of "golf ball liver".

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