Predictors for dioxin accumulation in residents living in Da Nang and Bien Hoa, Vietnam, many years after Agent Orange use.

Agent Orange (AO) was the main defoliant used by the US in Vietnam from 1961 to 1971; AO was contaminated with dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, or TCDD). Three major dioxin "hot spots" remain from previous AO storage and use at former US bases at Bien Hoa, Da Nang, and Phu Cat, posing potential health risks for Vietnamese living on or near these hot spots. We evaluated potential risk factors contributing to serum TCDD levels in Vietnamese residents at and near contaminated sites in Da Nang and Bien Hoa, Vietnam. We used multiple linear regression to analyze possible associations of blood dioxin concentrations with demographic, socioeconomic, lifestyle, and dietary risk factors for residents living on or near these hot spots. For the Da Nang study, fish farming on the site, living on property flooded from monsoon rains, and age were among the factors showing significant positive associations with serum TCDD concentrations. For the Bien Hoa study, fish farmers working at this site and their immediate family members had significantly higher serum TCDD concentrations. Our results suggest that water-related activities, especially fish-farming, at the hot spots increased the risk of exposure to dioxin.

Agent Orange exposure and attributed health effects in Vietnam veterans.

Serum dioxin studies of Vietnam (VN) veterans, military historical records of tactical herbicide use in Vietnam, and the compelling evidence of the photodegradation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other aspects of environmental fate and low bioavailability of TCDD are consistent with few, if any, ground troop veterans being exposed to Agent Orange. That conclusion, however, is contrary to the presumption by the Department of Veterans Affairs (DVA) that military service in Vietnam anytime from January 9, 1962 to May 7, 1975 is a proxy for exposure to Agent Orange. The DVA assumption is inconsistent with the scientific principles governing determinations of disease causation. The DVA has nonetheless awarded Agent Orange-related benefits and compensation to an increasing number of VN veterans based on the presumption of exposure and the published findings of the Institute of Medicine that there is sufficient evidence of a "statistical association" (a less stringent standard than "causal relationship") between exposure to tactical herbicides or TCDD and 15 different human diseases. A fairer and more valid approach for VN veterans would have been to enact a program of "Vietnam experience" benefits for those seriously ill, rather than benefits based on the dubious premise of injuries caused by Agent Orange.

Diabetes and cancer in veterans of Operation Ranch Hand after adjustment for calendar period, days of spraying, and time spent in Southeast Asia.

BACKGROUND: The Air Force Health Study was launched in 1980 as part of a Federal effort to resolve the Agent Orange issue. OBJECTIVES: To study diabetes and cancer with additional adjustment for days of spraying, calendar period of service, and time spent in Southeast Asia (SEA). METHODS: This was a longitudinal study of veterans of Operation Ranch Hand, the unit responsible for spraying Agent Orange and other 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-contaminated herbicides in Vietnam from 1962 to 1971. RESULTS: Associations between TCDD and diabetes and between TCDD and cancer in Ranch Hand veterans are strengthened after adjustment for calendar period of service, days of spraying, and, for cancer, time spent in SEA. CONCLUSIONS: Calendar period of service, days of spraying, and time spent in SEA are important confounders in the Air Force Health Study.

Agent Orange, dioxins, and other chemicals of concern in Vietnam: update 2006.

OBJECTIVE: The objective of this study was to find sites in Vietnam where there was human exposure from Agent Orange herbicide sprayed between 1962 and 1971, as determined by congener-specific measurement of dioxins, including 2,3,7,8-tetrachlorodibenzodioxin (TCDD), the dioxin that contaminated Agent Orange, in blood. METHODS: Blood was collected from residents of eight heavily sprayed regions in the south of Vietnam and analyzed for TCDD and in some cases the dioxin-like dibenzofurans and dioxin-like PCBs. RESULTS: Six of the eight newly studied sites did not show substantial or any elevated TCDD in blood. Marked elevation of TCDD in Vietnamese blood was found in one new location with a suggestion of slightly elevated TCDD in a second location. CONCLUSIONS: In newly studied locations in Vietnam, we found some persons with elevation of TCDD consistent with exposure to dioxin from Agent Orange. In our previous studies, we found PCBs, PCDDs, and PCDFs as well as pesticides in human milk, blood, or in food. Health effects from Agent Orange need to be differentiated from effects caused by chemicals other than TCDD from Agent Orange.

Prostate cancer in US Air Force veterans of the Vietnam war.

US Air Force veterans of Operation Ranch Hand sprayed herbicides contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Vietnam from 1962 to 1971. Comparisons served in Southeast Asia (SEA) during the same time period but did not spray herbicides. Here we investigate a potential association between exposure to TCDD and prostate cancer. Data were available for 2516 veterans (1019 Ranch Hand and 1497 Comparison) who participated in at least one of six physical examinations starting in 1982 and had a measurement of serum TCDD. We assigned Ranch Hands to two exposure categories: Lower and Higher, based on their median 20-year cumulative TCDD level. In total, 81 Comparison and 59 Ranch Hand prostate cancers were identified between 1 January 1982 and 31 December 2003. We found no overall increase in the risk of prostate cancer in Ranch Hand veterans versus the Comparisons. There was a positive association in Ranch Hand veterans in the Higher TCDD category who served in SEA before 1969 (RR=2.27, 95% CI 1.11-4.66) when more contaminated herbicides were used, but the number of cases was small (n=15). A within-group comparison found that in Comparison veterans, time served in SEA was associated with an increased risk of prostate cancer (RR=2.18, 95% CI 1.27-3.76, >789 days versus < or =789 days). No increase in the risk of prostate cancer was observed within the Ranch Hand group in association with TCDD or time served in SEA. These analyses suggest that a longer service in SEA and exposures other than TCDD may have increased the risk of prostate cancer in Comparison veterans.

Serum dioxin and peripheral neuropathy in veterans of Operation Ranch Hand.

We studied whether exposure to Agent Orange and its contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), during the Vietnam War is related to peripheral neuropathy. The index subjects were veterans of Operation Ranch Hand, the unit responsible for aerial herbicide spraying in Vietnam from 1962 to 1971. We report peripheral nerve function assessed in 1982, 1985, 1987, 1992 and 1997, nerve conduction velocities measured in 1982, and vibrotactile thresholds of the great toes measured in 1992 and 1997. We assigned each Ranch Hand veteran to one of three exposure categories named "background", "low" and "high", based on his serum dioxin level. Other than the bilateral vibrotactile abnormalities, we consistently found a statistically significant increased risk of all indices of peripheral neuropathy among Ranch Hand veterans in the high exposure category in 1997, and a statistically significant increased risk of diagnosed peripheral neuropathy, incorporating bilateral vibrotactile abnormalities of the great toes, in the high category in 1992. Restricting to the enlisted veterans did not alter these results. Cautious interpretation of these results is appropriate until the relationship between pre-clinical diabetes mellitus and peripheral neuropathy is further evaluated in future examinations.

Serum dioxin and cognitive functioning among veterans of Operation Ranch Hand.

We used the Halstead-Reitan neuropsychological test battery, the Wechsler adult intelligence scale-revised, the Wechsler memory scale, and the wide range achievement test to assess cognitive functioning among Air Force veterans exposed to Agent Orange and its contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), during the Vietnam war The index subjects were veterans of Operation Ranch Hand (N = 937), the unit responsible for aerial herbicide spraying in Vietnam from 1962 to 1971. A comparison group of other Air Force veterans (N= 1,052), who served in Southeast Asia during the same period but were not involved with spraying herbicides served as referents. Cognitive functioning was assessed in 1982, and dioxin levels were measured in 1987 and 1992. We assigned each Ranch Hand veteran to the background, low, or high dioxin exposure category on the basis of a measurement of dioxin body burden. Although we found no global effect of dioxin exposure on cognitive functioning, we did find that several measures of memory functioning were decreased among veterans with the highest dioxin exposure. These results became more distinct when we restricted the analysis to enlisted personnel, the subgroup with the highest dioxin levels. An analysis based on dioxin quintiles in the combined cohort produced consistent results, with veterans in the fifth quintile exhibiting reduced verbal memory function. Although statistically significant, these differences were relatively small and of uncertain clinical significance.

Serum dioxin and hepatic abnormalities in veterans of Operation Ranch Hand.

PURPOSE: We studied hepatic abnormalities and indices of hepatic function in relation to exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) in veterans of Operation Ranch Hand, the Air Force unit responsible for the aerial spraying of herbicides in Vietnam from 1962 to 1971. METHODS: The prevalence of ever having liver disease through March 1993, and level of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase (GGT), lactic dehydrogenase (LDH), alkaline phosphatase, and total bilirubin were examined according to serum dioxin levels. RESULTS: We found an increased risk of "other liver disorders" among veterans with the highest dioxin levels [adjusted odds ratio (OR) = 1.6, 95% confidence interval (CI) 1.2 to 2.1], due primarily to increased transaminases or LDH (adjusted OR = 2.7, 95% CI 1.4 to 5.1) and to other nonspecific liver abnormalities (adjusted OR = 1.4, 95% CI 1.0 to 2.0). CONCLUSIONS: Whether the associations observed were causal is unclear from these data.

Recent dioxin contamination from Agent Orange in residents of a southern Vietnam city.

Marked elevation of dioxin associated with the herbicide Agent Orange was recently found in 19 of 20 blood samples from persons living in Bien Hoa, a large city in southern Vietnam. This city is located near an air base that was used for Agent Orange spray missions between 1962 and 1970. A spill of Agent Orange occurred at this air base more than 30 years before blood samples were collected in 1999. Samples were collected, frozen, and sent to a World Health Organization--certified dioxin laboratory for congener-specific analysis as part of a Vietnam Red Cross project. Previous analyses of more than 2200 pooled blood samples collected in the 1990s identified Bien Hoa as one of several southern Vietnam areas with persons having elevated blood dioxin levels from exposure to Agent Orange. In sharp contrast to this study, our previous research showed decreasing tissue dioxin levels over time since 1970. Only the dioxin that contaminated Agent Orange, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), was elevated in the blood of 19 of 20 persons sampled from Bien Hoa. A comparison, pooled sample from 100 residents of Hanoi, where Agent Orange was not used, measured blood TCDD levels of 2 parts per trillion (ppt). TCDD levels of up to 271 ppt, a 135-fold increase, were found in Bien Hoa residents. TCDD contamination was also found in some nearby soil and sediment samples. Persons new to this region and children born after Agent Orange spraying ended also had elevated TCDD levels. This TCDD uptake was recent and occurred decades after spraying ended. We hypothesize that a major route of current and past exposures is from the movement of dioxin from soil into river sediment, then into fish, and from fish consumption into people.

Clinical course of a fatal ingestion of diquat.

CASE REPORT: A 28-year-old male ingested the herbicide diquat. The patient rapidly developed severe gastrointestinal and metabolic disturbances, airway compromise, respiratory failure, renal failure, hemodynamic collapse, and seizures. We describe multiple metabolic abnormalities, an apparent artifact introduced by diquat in the laboratory assay for serum creatinine, serum diquat levels, and the need for emergency airway management.

Serum dioxin and diabetes mellitus in veterans of Operation Ranch Hand.

We studied diabetes mellitus and glucose and insulin levels in Air Force veterans exposed to Agent Orange and its contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), during the Vietnam War. The index subjects of the Air Force's ongoing 20-year prospective epidemiologic study are veterans of Operation Ranch Hand (N = 989), the unit responsible for aerial herbicide spraying in Vietnam from 1962 to 1971. Other Air Force veterans who served in Southeast Asia during the same period but were not involved with spraying herbicides serve as Comparisons (N = 1,276). The median serum dioxin level in the Ranch Hand group was 12.2 parts per trillion (ppt) (range = 0-617.8 ppt), and the median dioxin level in the Comparison group was 4.0 ppt (range = 0-10 ppt). We found that glucose abnormalities [relative risk = 1.4; 95% confidence limits (CL) = 1.1, 1.8], diabetes prevalence (relative risk = 1.5; 95% CL = 1.2, 2.0), and the use of oral medications to control diabetes (relative risk = 2.3; 95% CL = 1.3, 3.9) increased, whereas time-to-diabetes-onset decreased with dioxin exposure. Serum insulin abnormalities (relative risk = 3.4; 95% CL = 1.9, 6.1) increased with dioxin exposure in nondiabetics. These results indicate an adverse relation between dioxin exposure and diabetes mellitus, glucose metabolism, and insulin production.

Dioxins and dioxin-like chemicals in blood and semen of American Vietnam veterans from the state of Michigan.

This exposure assessment pilot study tested the hypothesis that elevated blood levels of the dioxin congener 2,3,7,8-TCDD ("TCDD"), due to Agent Orange exposure, in American Vietnam veterans could be demonstrated two to three decades after Vietnam service. A second objective was to determine if dioxins, including TCDD, are present in the semen of adult males. In the early 1990s, blood samples from 50 Vietnam veterans and three pooled semen samples from 17 of them were analyzed by high-resolution gas chromatography-mass spectroscopy for dioxins, dibenzofurans, and the dioxin-like PCBs. Fifty volunteers from the Michigan Vietnam veteran bonus list, which documented Vietnam service, were invited to participate based on their self-reported exposure to Agent Orange in Vietnam. Screening of military and medical records was performed by an epidemiologist and a physician to assure that Agent Orange exposure was possible based on job description, location of service in Vietnam, and military Agent Orange spray records. Elevated 2,3,7,8-TCDD levels, over 20 ppt on a lipid basis, could still be detected in six of the 50 veterans in this nonrandomly selected group. The dioxin and dibenzofuran congeners commonly found in the U.S. population, including TCDD, were also detected in the three pooled semen samples. Quantification and comparison on a lipid basis were not possible due to low lipid concentrations where levels were below the detection limit. Therefore, semen samples were measured and reported on a wet-weight basis. Elevated blood TCDD levels, probably related to Agent Orange exposure, can be detected between two and three decades after potential exposure in some American veterans. Original levels were estimated to be 35-1,500-fold greater that that of the general population (4 ppt, lipid) at the time of exposure. In addition, the detection of dioxins in semen suggests a possible mechanism for male-mediated adverse reproductive outcomes following Agent Orange or other dioxin exposure.

Agent Orange and the Vietnamese: the persistence of elevated dioxin levels in human tissues.

OBJECTIVES: The largest known dioxin contamination occurred between 1962 and 1970, when 12 million gallons of Agent Orange, a defoliant mixture contaminated with a form of the most toxic dioxin, were sprayed over southern and central Vietnam. Studies were performed to determine if elevated dioxin levels persist in Vietnamese living in the south of Vietnam. METHODS: With gas chromatography and mass spectroscopy, human milk, adipose tissue, and blood from Vietnamese living in sprayed and unsprayed areas were analyzed, some individually and some pooled, for dioxins and the closely related dibenzofurans. RESULTS: One hundred sixty dioxin analyses of tissue from 3243 persons were performed. Elevated 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) levels as high as 1832 ppt were found in milk lipid collected from southern Vietnam in 1970, and levels up to 103 ppt were found in adipose tissue in the 1980s. Pooled blood collected from southern Vietnam in 1991/92 also showed elevated TCDD up to 33 ppt, whereas tissue from northern Vietnam (where Agent Orange was not used) revealed TCDD levels at or below 2.9 ppt. CONCLUSIONS: Although most Agent Orange studies have focused on American veterans, many Vietnamese had greater exposure. Because health consequences of dioxin contamination are more likely to be found in Vietnamese living in Vietnam than in any other populations, Vietnam provides a unique setting for dioxin studies.