The Impact of Agent Orange Exposure on Prostate Cancer Outcomes.

PURPOSE: In this study we explored the effect of Agent Orange exposure on prostate cancer survival in VA (Veterans Affairs) patients receiving androgen deprivation therapy for advanced prostate cancer. MATERIALS AND METHODS: We retrospectively examined the association between Agent Orange exposure in men with prostate cancer in national VA databases who were being treated with androgen deprivation therapy. Patients were diagnosed with prostate cancer from 2000 to 2008 with followup through May 2016. Clinical, pathological and demographic variables were compared by Agent Orange exposure. Associations of Agent Orange with overall survival, skeletal related events and cancer specific survival were performed using adjusted Cox proportional hazard models after IPSW (inverse propensity score weighted) adjustment. RESULTS: Overall 87,344 patients were identified. The 3,475 Agent Orange exposed patients were younger (p <0.001), had lower prostate specific antigen (p = 0.002) and were more likely to receive local therapy and chemotherapy (p <0.001) than the 83,869 nonexposed patients. The Charlson comorbidity index was similar in the groups (p = 0.40). After IPSW adjustment Agent Orange exposure was associated with improved overall survival (HR 0.84, 95% CI 0.73-0.97, p = 0.02). However, no difference was observed in the risk of skeletal related events (HR 1.04, 95% CI 0.80-1.35, p = 0.77) or cancer specific survival (HR 0.79, 95% CI 0.60-1.03, p = 0.08). CONCLUSIONS: Agent Orange exposure was associated with a decreased risk of death in men receiving androgen deprivation therapy for advanced prostate cancer. It does not appear to be associated with worse oncologic outcomes.

Impact of presumed service-connected diagnosis on the Department of Veterans Affairs healthcare utilization patterns of Vietnam-Theater Veterans: A cross-sectional study.

During the Vietnam War, the US military sprayed almost 20 million gallons of Agent Orange (AO), an herbicide contaminated with dioxin, over Vietnam. Approximately, 2.7 million US military personnel may have been exposed to AO during their deployment. Ordinarily, veterans who can demonstrate a nexus between a diagnosed condition and military service are eligible for Department of Veterans Affairs (VA) service-connected disability compensation. Vietnam Veterans have had difficulty, however, establishing a nexus between AO exposure and certain medical conditions that developed many years after the war. In response, VA has designated certain conditions as "presumed service connected" for Vietnam Veterans who were present and possibly exposed. Veterans with any of these designated conditions do not have to document AO exposure, making it easier for them to access the VA disability system. The extent to which VA healthcare utilization patterns reflect easier access afforded those with diagnosed presumptive conditions remains unknown. In this cross-sectional study, we hypothesized that Vietnam Veterans with diagnosed presumptive conditions would be heavier users of the VA healthcare system than those without these conditions. In our analysis of 85,699 Vietnam Veterans, we used binary and cumulative logit multivariable regression to assess associations between diagnosed presumptive conditions and VA healthcare utilization in 2013. We found that diagnosed presumptive conditions were associated with higher odds of 5+ VHA primary care visits (OR = 2.01, 95% CI: 1.93-2.07), 5+ specialty care visits (OR = 2.11, 95% CI: 2.04-2.18), emergency department use (OR = 1.22, 95% CI: 1.11-1.34), and hospitalization (OR = 1.23, 95% CI: 1.17-1.29). Consistent with legislative intent, presumptive policies appear to facilitate greater VA system utilization for Vietnam Veterans who may have been exposed to AO.

Serine alleviates oxidative stress via supporting glutathione synthesis and methionine cycle in mice.

SCOPE: Serine lies at the central node linking biosynthetic flux from glycolysis to glutathione synthesis and one-carbon metabolic cycle which are closely related to antioxidant capacity. The present study was conducted to determine the effects of serine supplementation on oxidative stress and its relative mechanisms. METHODS AND RESULTS: Diquat treatment was performed to induce oxidative stress in mice and primary hepatocytes. The results showed that hepatic glutathione anti-oxidant systems were impaired and reactive oxygen species and homocysteine were increased in diquat-induced mice and hepatocytes, while such disadvantageous changes were diminished by serine supplementation both in vivo and in vitro. However, when cystathionine ß-synthase expression was inhibited by interference RNA in hepatocytes, the effects of serine supplementation on the improvement of glutathione synthesis and the alleviation of oxidative stress were diminished. Moreover, when hepatocytes were treated with cycloleucine, an inhibitor of methionine adenosyltransferase, the effects of serine supplementation on the improvement of methionine cycle and the alleviation of DNA hypomethylation and oxidative stress were also diminished. CONCLUSION: Our results indicated that serine supplementation alleviated oxidative stress via supporting glutathione synthesis and methionine cycle, mostly by condensing with homocysteine to synthesize cysteine and providing one-carbon units for homocysteine remethylation.

Dioxins and cytogenetic status of villagers after 40 years of agent Orange application in Vietnam.

We have examined cytogenetic status of the rural population living on dioxin-contaminated territories (DCT, TCDD in soil 2.6 ng/kg) compared to the villagers of the control area (TCDD in soil 0.18 ng kg(-1)). The examination took place almost 40 years after the war. The consequences of some confounding factors (years of residence in the region, farming, and aging) has been examined. Karyological analysis of buccal and nasal epitheliocytes among healthy adult males living on DCT and control area (26 and 35 persons) was conducted. A wide range of cytogenetic (micronuclei, nuclear protrusions), proliferative (binucleated cells and cells with doubled nucleus) and endpoints of cell death (cells with perinuclear vacuoles, with damaged nucleus membrane, condensed chromatin, pyknosis, karyorrhexis, karyolysis) had been analyzed. The frequent amount of cells with nuclear protrusions in both epithelia was slightly decreased in the DСT group. Biomarkers of early and late stages of nuclear destruction in buccal epithelium (cells with damaged nuclear membrane, karyolysis) were elevated significantly in DCT. Higher level of the same parameters was also identified in nasal epithelium. The cytogenetic status of healthy adult males on DCT had got "normalization" by present moment in comparison with our early data. Nevertheless, in exposed group some alteration of the cytogenetic status was being registered (mostly biomarkers of apoptosis). Years of residence (and exposure to dioxins) affected the cytogenetic status of DCT inhabitants, whereas no influence of farming factors (pesticides, fertilizers, etc.) had been discovered. Some biomarkers of proliferation and cell death were affected by aging.

The Air Force Health Study Data and Specimens as a Resource for Researchers.

The Air Force Health Study (AFHS) is perhaps the most thorough longitudinal examination of both the health of military personnel and the health effects of herbicide exposure ever conducted. Data were collected through comprehensive physical examinations, questionnaires, and other records at six time points over a 20-year period; 2,758 subjects participated in at least one examination cycle. Data collected during physical examinations included indices of health status overall and specific endpoints for each organ system. Questionnaire data included sociodemographic information, marital and fertility history, health habits, recreation activities, toxic substances exposure, and military experience. Biospecimens were collected at each examination cycle; serum was collected at all six examinations while other biospecimens, such as semen and whole blood, were collected at one time. More than 200 clinical laboratory tests and measures were performed, with more than 60 of these measured at all six cycles. The vast amount of electronic data and the more than 91,000 unaliquoted biospecimens contained in the repository offer unique opportunities for new research on understanding determinants of health. The Institute of Medicine is the custodian of the AFHS materials and conducted a pilot research program to facilitate new research using the materials. An expert committee issued requests for proposals, created a Web-based form for submissions, reviewed and evaluated potential research studies, and made data and biospecimens available to qualified researchers. This article summarizes the experience of this initiative.

Agent Orange exposure and cancer incidence in Korean Vietnam veterans: a prospective cohort study.

BACKGROUND: During the Vietnam War, US and allied military sprayed approximately 77 million liters of tactical herbicides including Agent Orange, contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. To the authors' knowledge, few studies to date have examined the association between Agent Orange exposure and cancer incidence among Korean veterans who were exposed to Agent Orange during the Vietnam War. METHODS: An Agent Orange exposure index, based on the proximity of the veteran's military unit to the area that was sprayed with Agent Orange, was developed using a geographic information system-based model. Cancer incidence was followed for 180,251 Vietnam veterans from 1992 through 2003. RESULTS: After adjustment for age and military rank, high exposure to Agent Orange was found to significantly increase the risk of all cancers combined (adjusted hazards ratio [aHR], 1.08). Risks for cancers of the mouth (aHR, 2.54), salivary glands (aHR, 6.96), stomach (aHR, 1.14), and small intestine (aHR, 2.30) were found to be significantly higher in the high-exposure group compared with the low-exposure group. Risks for cancers of all sites combined (aHR, 1.02) and for cancers of the salivary glands (aHR, 1.47), stomach (aHR, 1.03), small intestine (aHR, 1.24), and liver (aHR, 1.02) were elevated with a 1-unit increase in the exposure index. CONCLUSIONS: Exposure to Agent Orange several decades earlier may increase the risk of cancers in all sites combined, as well as several specific cancers, among Korean veterans of the Vietnam War, including some cancers that were not found to be clearly associated with exposure to Agent Orange in previous cohort studies primarily based on Western populations.

High cortisol and cortisone levels are associated with breast milk dioxin concentrations in Vietnamese women.

OBJECTIVE: Dioxin (polychlorinated dibenzodioxins+polychlorinated dibenzofurans) is one of the most toxic chemical substances known. Although it is suspected to cause endocrine disruption, very few epidemiological studies have been carried out on its effects on human steroid hormones. The aim of this study was to elucidate the association of dioxin exposure with steroid hormone levels in the saliva and serum of Vietnamese women. STUDY DESIGN: Two areas, namely Phu Cat (hot spot) and Kim Bang (nonexposed area), were selected for the study. The study subjects consisted of 51 and 58 women respectively. Saliva, blood, and breast milk samples were collected from the subjects in both the areas. METHODS: Cortisol, cortisone, DHEA, androstenedione, estrone, and estradiol levels in serum and saliva were determined by liquid chromatography-tandem mass spectrometry; dioxin concentrations in breast milk were measured by gas chromatography-mass spectrometry. RESULTS: Dioxin concentrations in the breast milk of women from the dioxin hot spot were three to four times higher than those in the breast milk of women from the nonexposed area. Good correlations were found between the levels of six steroid hormones in saliva and those in serum respectively. Salivary and serum cortisol and cortisone levels in women from the dioxin hot spot were significantly higher than those in women from the nonexposed area (P<0.001) and those in all the subjects were positively associated with dioxin concentrations in Vietnamese women (P<0.01). CONCLUSION: These results suggest that dioxin influences steroidogenesis in humans. Saliva samples can be used for hormone analysis and are therefore excellent specimens in epidemiological studies.

Dispelling the 'bitter fog': fighting chemical defoliation in the American West.

Little doubt remains about the influence of Rachel Carson's Silent Spring in changing the consciousness of not just Americans, but citizens around the world, regarding the relationship between human beings and the natural world. Less has been done about the specific ways Carson's book inspired individual activists to continue challenging pesticide policy within the United States in the decades after the book's publication. The stories of three western women fighting the use of Agent Orange herbicides - the phenoxy herbicides 2,4-D and 2,4,5-T - illustrate the influence and mixed success of environmental activism after Silent Spring.

Herbicide exposure and veterans with covered service in Korea. Final rule.

This document adopts as a final rule the Department of Veterans Affairs' (VA) proposal to amend VA adjudication, medical, and vocational rehabilitation and employment regulations to incorporate relevant provisions of the Veterans Benefits Act of 2003. Specifically, this document amends VA regulations regarding herbicide exposure of certain veterans who served in or near the Korean demilitarized zone and regulations regarding spina bifida in their children. It also amends VA's medical regulations by correcting the Health Administration Center's hand-delivery address.

The use of epidemiological evidence in the compensation of veterans.

Men and women serving in the U.S. military are exposed to diverse agents that may affect their health, causing injury and disease while they are in the service or after discharge. This case study addresses the compensation of veterans for injury and illnesses arising from exposures received during military service and focuses on the presumptions that are made around compensation of veterans for conditions arising after their service. Presumptions are made because of evidence gaps related to exposure and causation. The current process for evidence review related to causation involves Institute of Medicine (IOM) committees that evaluate evidence relevant to association. The Veterans Administration uses the IOM reports in making presumptions. A new approach was recommended by an IOM committee: a transparent, evidence-based approach that would lead to decisions by means of an explicit process. The Committee set out six principles as a foundation for its framework: stakeholder inclusiveness, evidence-based decisions, transparent process, flexibility, consistency, and the use of causation, not just association, as the basis for decision making. The committee also called for needed tracking of exposure and associated health outcomes during and after military service. This case study covers "lessons learned" around evidence synthesis, causal inferences, and decision-making.

Paternal exposure to Agent Orange and spina bifida: a meta-analysis.

The objective of this study is to conduct a meta-analysis of published and unpublished studies that examine the association between Agent Orange (AO) exposure and the risk of spina bifida. Relevant studies were identified through a computerized literature search of Medline and Embase from 1966 to 2008; a review of the reference list of retrieved articles and conference proceedings; and by contacting researchers for unpublished studies. Both fixed-effects and random-effects models were used to pool the results of individual studies. The Cochrane Q test and index of heterogeneity (I(2)) were used to evaluate heterogeneity, and a funnel plot and Egger's test were used to evaluate publication bias. Seven studies, including two Vietnamese and five non-Vietnamese studies, involving 330 cases and 134,884 non-cases were included in the meta-analysis. The overall relative risk (RR) for spina bifida associated with paternal exposure to AO was 2.02 (95% confidence interval [CI]: 1.48-2.74), with no statistical evidence of heterogeneity across studies. Non-Vietnamese studies showed a slightly higher summary RR (RR = 2.22; 95% CI: 1.38-3.56) than Vietnamese studies (RR = 1.92 95% CI: 1.29-2.86). When analyzed separately, the overall association was statistically significant for the three case-control studies (Summary Odds Ratio = 2.25, 95% CI: 1.31-3.86) and the cross sectional study (RR = 1.97, 95% CI: 1.31-2.96), but not for the three cohort studies (RR: 2.11; 95% CI: 0.78-5.73). Paternal exposure to AO appears to be associated with a statistically increased risk of spina bifida.

Coca (Erythroxylum coca) Control is Affected by Glyphosate Formulations and Adjuvants.

The aerial spray program for the eradication of coca in Colombia uses Glyphos, a local formulation of glyphosate tank-mixed with an adjuvant product, Cosmo-Flux. There are some potential risks to amphibians from direct overspraying of shallow waters. In order to evaluate potential alternative mixtures, a field experiment was conducted at the Center of National Training of Police Operations in Tolima province, Colombia. Plants of coca were established with irrigation and grown to 75 cm tall. A randomized split-plot design experiment was laid out and sprayed with a range of glyphosate formulations and different adjuvants using an experimental ground sprayer. Assessments were made of plant vigor, height, and above-ground standing crop (fresh weight) 3 wk after application. Resprouting of plants was assessed at 9 wk after treatment. Unformulated glyphosate applied as the product Rodeo gave poorer control of coca than two formulated products, Roundup Biactive (from Europe) and Colombian Glyphos. In general, these products performed well without added adjuvants, giving control similar to that of the eradication mixture with Cosmo-Flux. There was some evidence that addition of the adjuvant Silwet L-77 and to a lesser extent Mixture B (from the United Kingdom) gave more rapid herbicide symptoms. There were also indications that glyphosate rates of less than 3.69 kg acid equivalents (a.e.)/ha could give control in the range of 95%. Depending on the environmental risk requirements, the experiment indicates that, should other spray mixtures be required, there are potential alternatives. These would require extensive field testing to cover different environmental conditions, different coca varieties, and particularly aerial application, prior to a recommendation. Should the glyphosate product require changing, Roundup Biactive may be considered. Should the adjuvant require changing, then on the basis of this research, Silwet L-77 and Mixture B would be good candidates for further evaluation.

Comparison of the hazards posed to amphibians by the glyphosate spray control program versus the chemical and physical activities of coca production in Colombia.

This study evaluates the cumulative multifactorial physical and chemical impacts resulting from coca production on amphibian populations in comparison with the potential impacts produced by the herbicide glyphosate (Glyphos), which, mixed with the surfactant Cosmo-Flux, is used in the spray control program for illicit crops in Colombia. Using similar worst-case assumptions for exposure, several other pesticides used for coca production, including mancozeb, lambda cyhalothrin, endosulfan, diazinon, malathion, and chlorpyrifos, were up to 10- to 100-fold more toxic to frogs than the Glyphos-Cosmo-Flux mixture. Comparing hazard quotients based on application rates, several of these compounds demonstrated hazards 3-383 times that of formulated glyphosate. Secondary effects, particularly of insecticides, are also a concern, as these agents selectively target the primary food source of amphibians, which may indirectly impact growth and development. Although the potential chemical impacts by other pesticides are considerable, physical activities associated with coca production, particularly deforestation of primary forests for new coca plots, portend the greatest hazard to amphibian populations. The entire production cycle of cocaine has been linked to ecosystem degradation. The clearing of pristine forests for coca propagation in Colombia is well documented, and some of these regions coincide with those that contain exceptional amphibian biodiversity. This is particularly problematic as coca production encroaches more deeply into more remote areas of tropical rain forest. Transportation of disease, including the chitrid fungus, to these remote regions via human intrusion may also adversely affect amphibian populations. Therefore, the cumulative impacts of coca production, through habitat destruction, application of agrochemicals, and potential transmission of disease, are judged to pose greater risks to amphibian populations in coca-growing regions than the glyphosate spray control program.

Toxicity of formulated glyphosate (glyphos) and cosmo-flux to larval Colombian frogs 1. Laboratory acute toxicity.

The spraying of coca (Erythroxylum coca) with glyphosate in Colombia has raised concerns about possible impacts on amphibians. There are few toxicity data for species other than those from temperate regions, and these have not been generated with the combination of formulated glyphosate (Glyphos) and the adjuvant, Cosmo-Flux (coca mix) as used in coca control in Colombia. In order to characterize toxicity of the spray mixture to frogs from Colombia, Gosner stage-25 tadpoles of Scinax ruber, Dendropophus microcephalus, Hypsiboas crepitans, Rhinella granulosa, Rhinella marina, Rhinella typhonius, Centrolene prosoblepon, and Engystomops pustulosus were exposed to the coca mix at concentrations of glyphosate ranging from 1 to 4.2 mg a.e./L diluted in dechlorinated tap water in glass containers. Cosmo-Flux was added to Glyphos in the proportion of 2.3% v/v, as used in aerial application for coca control. Exposures were for 96 h at 23 +/- 1.5 degrees C with 12:12-h light/dark cycle. Test solutions were renewed every 24 h. Concentrations, measured within the first hour and at 24 and 96 h using enzyme-linked immunosorbent assay (ELISA) (Abraxis, LLC), ranged from 70 to 130% of nominal values. LC50 values ranged from 1200 to 2780 microg glyphosate acid equivalents (a.e.)/L for the 8 species tested. Data suggest that sensitivity to Roundup-type formulations of glyphosate in these species is similar to that observed in other tropical and temperate species. In addition, sensitivity of larval amphibians to Roundup-type formulations spans a relatively narrow range. Finally, toxicity of the mixture as used to spray coca was likely driven by the surfactant in the glyphosate formulation, as the addition of Cosmo-Flux did not enhance toxicity above those reported for Vision = Roundup.

Toxicity of formulated glyphosate (glyphos) and cosmo-flux to larval and juvenile colombian frogs 2. Field and laboratory microcosm acute toxicity.

The spraying of coca (Erythroxylum coca) with glyphosate (coca mixture, a combination of formulated glyphosate, Glyphos, and an adjuvant, Cosmo-Flux) in Colombia has raised concerns about possible impacts on amphibians. Although acute LC50 for 8 species of Colombian frogs ranged from 1.2 to 2.78 mg acid equivalents (a.e.)/L, these exposures were conducted in the laboratory in the absence of sediments and organic matter such as would occur under realistic field conditions. In order to assess the effects of overspray of frog habitat under field conditions, Gosner stage 25 tadpoles of Rhinella granulosa, R. marina, Hypsiboas crepitans, and Scinax ruber were placed in outdoor microcosms made from polyethylene plastic fish ponds (2.07 m in diameter, 37 cm high) in an experimental area in Tolima, Colombia. The bottoms of the microcosms were covered with a 3-cm layer of local soil and they were filled to a depth of 15 cm (above the sediment) with local spring water. After up to 100 tadpoles of each frog species were placed in the microcosms, they were sprayed with the coca mixture at concentrations greater and less than the normal application rate (3.69 kg glyphosate a.e./ha). Mortality at 96 h in the control microcosms was between 0 and 16% and LC50 values were between 8.9 and 10.9 kg glyphosate a.e./ha (equivalent to initial concentrations of 5963 to 7303 microg glyphosate a.e./L). Mortality >LC50 was only observed in the tested species when the application rate was >2-fold the normal application rate. In other experiments, juvenile and adult terrestrial stages of frogs were exposed by direct spraying to a range of concentrations of coca mixture. Juveniles and adults were exposed in plastic food containers (19 x 19 cm). The bottom of the container was filled with moistened soil and leaf litter to a depth of 1 cm and 0.5 cm, respectively. Mortality in the controls was low, from 0 to 10%, and from 0 to 35% at the normal application rate. LC50 values ranged between 4.5 kg a.e./ha and 22.8 kg a.e./ha, 1.5- to 6-fold greater than the normal application rate. Data indicate that, under realistic worst-case exposure conditions, the mixture of Glyphos and Cosmo-Flux as used for control of coca in Colombia exerts a low toxicity to aquatic and terrestrial stages of anurans and that risks to these organisms under field conditions are small.

Risks to Colombian amphibian fauna from cultivation of coca (Erythroxylum coca): a geographical analysis.

The Colombian amphibian fauna is among the richest known in the world, with about 20 species of salamanders (order Caudata), 35 of the limbless caecilians (order Gymnophiona), and more than 700 species of frogs and toads (order Anura) recorded from localities within the country. The potential effects of exposure to glyphosate on amphibians arising from production of illegal crops (coca) were examined. The analysis was based on (1) behavior and ecology of species and (2) proximities of actual museum records to localities in which illegal crops are being grown and the subset of those that have been sprayed with glyphosate. Based on data on the location of amphibians collected in Colombia, records were obtained for 193 species (28% of the national diversity) of frogs and toads found in localities within 10 km of areas where coca is grown. Further analyses with ARC MAP software allowed for measurement of the direct distance separating collection locations for frogs, known coca fields, and areas where aerial spraying was being conducted. Records in or near coca fields included data for 11 of 13 families of frogs and toads known to be present in Colombia. Only Ceratophryidae and Pipidae were not reported from these locations and appear not to be at risk. For eight species (Dendrobates truncatus, Craugastor raniformis, Pristimantis gaigeae, Smilisca phaeota, Elachistocleis ovale, Hypsiboas crepitans, Trachycephalus venulosus, and Pseudis paradoxa) selected to represent several habitat preferences and life-cycle strategies, large areas of their distributions lie outside coca production regions and their populations as a whole are at low risk. For a limited number of species that barely enter Colombian territory, the consequences of coca production may be more serious and may have placed several species of frogs at risk. These include Ameerega bilingua, Dendropsophus bifurcus, Pristimantis colomai, P. degener, P. diadematus, P. quaquaversus, P. variabilis, and Trachycephalus jordani. Other species may also be at risk but exact numbers are unknown since few investigations were undertaken in these areas during the past 30 yr. The main ranges for these species were assumed to be in Ecuador.