Human and experimental toxicology of diquat poisoning: Toxicokinetics, mechanisms of toxicity, clinical features, and treatment.

Diquat (1,1'-ethylene-2,2'-bipyridinium ion; DQ) is a nonselective quick-acting herbicide, which is used as contact and preharvest desiccant to control terrestrial and aquatic vegetation. Several cases of human poisoning were reported worldwide mainly due to intentional ingestion of the liquid formulations. Its toxic potential results from its ability to produce reactive oxygen and nitrogen species through redox cycling processes that can lead to oxidative stress and potentially cell death. Kidney is the main target organ due to DQ toxicokinetics and redox cycling. There is no antidote against DQ intoxications, and the efficacy of treatments currently applied is still unsatisfactory. The aim of this work was to review the most relevant human and experimental findings related to DQ, characterizing its chemistry, activity as herbicide, mechanisms of toxicity, consequences of poisoning, and potential therapeutic approaches taking into account previous experience in developing antidotes for paraquat, a more toxic bipyridinium herbicide.

A review of Agent Orange and its associated oncologic risk of genitourinary cancers.

Agent Orange is an herbicide sprayed widely in Vietnam that is linked to a variety of malignancies in as early as 1991.Since then, there has been concern for, and subsequent interest in studying, the potential connection between Agent Orange and other malignancies. In the past 2 decades, there have been significant changes in the opinion of the National Academy of Science regarding Agent Orange and certain genitourinary malignancies. Herein, we review the literature regarding the potential link between Agent Orange and various urological cancers, including prostate, bladder, testicular, and renal cancers.

Exploring exposure to Agent Orange and increased mortality due to bladder cancer.

BACKGROUND: During the Vietnam War, many veterans were exposed to Agent Orange (AO), a chemical defoliant containing varying levels of the carcinogen dioxin. The health effects of AO exposure have been widely studied in the VA population. Here we review and interpret data regarding the association between AO exposure and bladder cancer (BC) mortality. MAIN FINDINGS: Data evaluating the association between AO and BC is limited. Methods characterizing exposure have become more sophisticated over time. Several studies support the link between AO exposure and increased mortality due to BC, including the Korean Veterans Health Study. CONCLUSIONS: Available data suggest an association with exposure to AO and increased mortality due to BC. In patients exposed to AO, increased frequency of cystoscopic surveillance and potentially more aggressive therapy for those with BC may be warranted but utility of these strategies remains to be proven. Additional research is required to better understand the relationship between AO and BC.

Wartime toxin exposure: recognising the silent killer.

Wartime toxin exposures have been implicated in the genesis of malignancy in war veterans. Agent Orange, one toxin among many, has been linked to malignancy and the subcomponent phenoxyacetic acid has been associated with soft tissue sarcomas (STSs). This case demonstrates the association between a wartime toxin exposure (Agent Orange) and subsequent cancer development. Ultimately, we aim to highlight the importance of simple, specific questions in the patient history to account for previous wartime toxin exposures.

Agent Orange exposure and prevalence of self-reported diseases in Korean Vietnam veterans.

OBJECTIVES: The aim of this study was to evaluate the association between Agent Orange exposure and self-reported diseases in Korean Vietnam veterans. METHODS: A postal survey of 114 562 Vietnam veterans was conducted. The perceived exposure to Agent Orange was assessed by a 6-item questionnaire. Two proximity-based Agent Orange exposure indices were constructed using division/brigade-level and battalion/company-level unit information. Adjusted odds ratios (ORs) for age and other confounders were calculated using a logistic regression model. RESULTS: The prevalence of all self-reported diseases showed monotonically increasing trends as the levels of perceived self-reported exposure increased. The ORs for colon cancer (OR, 1.13), leukemia (OR, 1.56), hypertension (OR, 1.03), peripheral vasculopathy (OR, 1.07), enterocolitis (OR, 1.07), peripheral neuropathy (OR, 1.07), multiple nerve palsy (OR, 1.14), multiple sclerosis (OR, 1.24), skin diseases (OR, 1.05), psychotic diseases (OR, 1.07) and lipidemia (OR, 1.05) were significantly elevated for the high exposure group in the division/brigade-level proximity-based exposure analysis, compared to the low exposure group. The ORs for cerebral infarction (OR, 1.08), chronic bronchitis (OR, 1.05), multiple nerve palsy (OR, 1.07), multiple sclerosis (OR, 1.16), skin diseases (OR, 1.05), and lipidemia (OR, 1.05) were significantly elevated for the high exposure group in the battalion/company-level analysis. CONCLUSIONS: Korean Vietnam veterans with high exposure to Agent Orange experienced a higher prevalence of several self-reported chronic diseases compared to those with low exposure by proximity-based exposure assessment. The strong positive associations between perceived self-reported exposure and all self-reported diseases should be evaluated with discretion because the likelihood of reporting diseases was directly related to the perceived intensity of Agent Orange exposure.

Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels and their association with age, body mass index, smoking, military record-based variables, and estimated exposure to Agent Orange in Korean Vietnam veterans.

OBJECTIVES: The aim of this study was to examine the levels of serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and evaluate their association with age, body mass index, smoking, military record-based variables, and estimated exposure to Agent Orange in Korean Vietnam veterans. METHODS: Serum levels of TCDD were analyzed in 102 Vietnam veterans. Information on age, body mass index, and smoking status were obtained from a self-reported questionnaire. The perceived exposure was assessed by a 6-item questionnaire. Two proximity-based exposures were constructed by division/brigade level and battalion/company level unit information using the Stellman exposure opportunity index model. RESULTS: The mean and median of serum TCDD levels was 1.2 parts per trillion (ppt) and 0.9 ppt, respectively. Only 2 Vietnam veterans had elevated levels of TCDD (>10 ppt). The levels of TCDD did not tend to increase with the likelihood of exposure to Agent Orange, as estimated from either proximity-based exposure or perceived self-reported exposure. The serum TCDD levels were not significantly different according to military unit, year of first deployment, duration of deployment, military rank, age, body mass index, and smoking status. CONCLUSIONS: The average serum TCDD levels in the Korean Vietnam veterans were lower than those reported for other occupationally or environmentally exposed groups and US Vietnam veterans, and their use as an objective marker of Agent Orange exposure may have some limitations. The unit of deployment, duration of deployment, year of first deployment, military rank, perceived self-reported exposure, and proximity-based exposure to Agent Orange were not associated with TCDD levels in Korean Vietnam veterans. Age, body mass index and smoking also were not associated with TCDD levels.

Agent Orange Exposure and Prevalence of Self-reported Diseases in Korean Vietnam Veterans / 예방의학회지

OBJECTIVES: The aim of this study was to evaluate the association between Agent Orange exposure and self-reported diseases in Korean Vietnam veterans. METHODS: A postal survey of 114 562 Vietnam veterans was conducted. The perceived exposure to Agent Orange was assessed by a 6-item questionnaire. Two proximity-based Agent Orange exposure indices were constructed using division/brigade-level and battalion/company-level unit information. Adjusted odds ratios (ORs) for age and other confounders were calculated using a logistic regression model. RESULTS: The prevalence of all self-reported diseases showed monotonically increasing trends as the levels of perceived self-reported exposure increased. The ORs for colon cancer (OR, 1.13), leukemia (OR, 1.56), hypertension (OR, 1.03), peripheral vasculopathy (OR, 1.07), enterocolitis (OR, 1.07), peripheral neuropathy (OR, 1.07), multiple nerve palsy (OR, 1.14), multiple sclerosis (OR, 1.24), skin diseases (OR, 1.05), psychotic diseases (OR, 1.07) and lipidemia (OR, 1.05) were significantly elevated for the high exposure group in the division/brigade-level proximity-based exposure analysis, compared to the low exposure group. The ORs for cerebral infarction (OR, 1.08), chronic bronchitis (OR, 1.05), multiple nerve palsy (OR, 1.07), multiple sclerosis (OR, 1.16), skin diseases (OR, 1.05), and lipidemia (OR, 1.05) were significantly elevated for the high exposure group in the battalion/company-level analysis. CONCLUSIONS: Korean Vietnam veterans with high exposure to Agent Orange experienced a higher prevalence of several self-reported chronic diseases compared to those with low exposure by proximity-based exposure assessment. The strong positive associations between perceived self-reported exposure and all self-reported diseases should be evaluated with discretion because the likelihood of reporting diseases was directly related to the perceived intensity of Agent Orange exposure.

Serum 2,3,7,8-Tetrachlorodibenzo-p-dioxin Levels and Their Association With Age, Body Mass Index, Smoking, Military Record-based Variables, and Estimated Exposure to Agent Orange in Korean Vietnam Veterans / 예방의학회지

OBJECTIVES: The aim of this study was to examine the levels of serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and evaluate their association with age, body mass index, smoking, military record-based variables, and estimated exposure to Agent Orange in Korean Vietnam veterans. METHODS: Serum levels of TCDD were analyzed in 102 Vietnam veterans. Information on age, body mass index, and smoking status were obtained from a self-reported questionnaire. The perceived exposure was assessed by a 6-item questionnaire. Two proximity-based exposures were constructed by division/brigade level and battalion/company level unit information using the Stellman exposure opportunity index model. RESULTS: The mean and median of serum TCDD levels was 1.2 parts per trillion (ppt) and 0.9 ppt, respectively. Only 2 Vietnam veterans had elevated levels of TCDD (>10 ppt). The levels of TCDD did not tend to increase with the likelihood of exposure to Agent Orange, as estimated from either proximity-based exposure or perceived self-reported exposure. The serum TCDD levels were not significantly different according to military unit, year of first deployment, duration of deployment, military rank, age, body mass index, and smoking status. CONCLUSIONS: The average serum TCDD levels in the Korean Vietnam veterans were lower than those reported for other occupationally or environmentally exposed groups and US Vietnam veterans, and their use as an objective marker of Agent Orange exposure may have some limitations. The unit of deployment, duration of deployment, year of first deployment, military rank, perceived self-reported exposure, and proximity-based exposure to Agent Orange were not associated with TCDD levels in Korean Vietnam veterans. Age, body mass index and smoking also were not associated with TCDD levels.

Assessing possible exposures of ground troops to Agent Orange during the Vietnam War: the use of contemporary military records.

BACKGROUND: Potential exposure of ground troops in Vietnam to Agent Orange and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) remains controversial despite the passage of 30 years since the Vietnam War. Because of uncertainty over the serum dioxin levels in ground troops at the end of their service in Vietnam, attempts have been made to develop a methodology for characterizing exposure of ground troops in Vietnam to Agent Orange and other herbicides based upon historical reconstruction from military records. Historical information is often useful in evaluating and modeling exposure, but such information should be reasonably accurate, complete, and reliable. METHODS: This paper reviews the procedures and supporting historical information related to the spraying of herbicides in Vietnam. The historical information is classified into two categories: procedural information and operational information. Procedural information covered the process and procedures followed in spraying herbicides from US Air Force fixed wing aircraft (Operation RANCH HAND) in Vietnam, and included approval procedures for spray missions, the criteria required to conduct a mission, the control exercised by the Forward Air Controller and the Tactical Air Control Center and the characteristics of the equipment used to apply the herbicides. Operational information includes data from the RANCH HAND Daily Air Activities Reports, which included geographic locations of specific spray missions, the amount of herbicide sprayed by a specific mission, reports of battle damage to spray aircraft, reports of fighter aircraft support for aerial spray missions, and any comments, such as reasons for canceling a mission. RESULTS: Historical information demonstrates that herbicide spray missions were carefully planned and that spraying only occurred when friendly forces were not located in the target area. RANCH HAND spray missions were either not approved or cancelled if approved when there were friendly forces in the area designated for spraying. Stringent criteria had to be met before spray missions could be approved. The operational information shows that spray missions for both defoliation and crop destruction were conducted in an extremely hostile environment. Heavy 'fighter suppression' with antipersonnel ordnance was used to minimize the impact of hostile ground fire on RANCH HAND aircraft. Procedures were in place that prohibited movement of troops into sprayed areas immediately after a mission due to the possible presence of unexploded ordnance delivered by fighter aircraft supporting RANCH HAND missions. The optimal nature of the spray equipment and application procedures minimized the possibility of significant spray drift. Conclusions. Few friendly troops were sprayed by fixed wing aircraft during Operation RANCH HAND, which delivered 95% of all defoliants used in Vietnam. Similarly, few troops were sprayed during helicopter or surface-based spray operations, which constituted the remaining 5% of defoliants. Detailed policies and procedures for approval and execution of spray missions ensured that friendly forces were not located in the areas targeted for spraying. Fighter aircraft assigned to accompany each spray mission frequently suppressed much of the hostile fire with bombs and other ordnance. Confirmed clearance of the target area was necessary to avoid friendly casualties. Historical records establish that these policies and procedures were strictly followed. Exposure of troops whether from direct spraying or movement through areas recently sprayed was very unlikely. The wartime military records of troop positions and herbicide operations are valuable for some purposes, but have specific limitations in exposure reconstruction. The completeness and accuracy of the geographic data (maps used by RANCH HAND and military ground units) were dependent upon the inherent precision of the map, the accuracy with which it depicted surface features, and the completeness and accuracy of the information on which it is based. Navigation by the crew using visual orientation and reference to the map was the only means that aircrew on spray missions had for establishing their locations. A Forward Air Controller independent of Operation RANCH HAND was present at the location of each spray target immediately before and during spraying operations to verify the target location and ensure that friendly forces were clear of the target area. Anecdotal reports of direct spraying of troops in Vietnam likely reflect the RANCH HAND missions spraying insecticide for mosquito control at regular intervals from March 1967 through February 1972. Outlook. The distribution and levels of serum dioxin in RANCH HAND veterans and the US Army Chemical Corps Vietnam veterans (the unit responsible for helicopter and ground-based spray operations) are distinguishable from typical levels in the population decades after the Vietnam conflict. An exposure model similar to that proposed in the 2003 report of the Institute of Medicine's Committee on 'Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam' was tested in 1988 by the Centers for Disease Control and Prevention and found to be a poor predictor of absorbed dose of TCDD. Military records during the Vietnam War lack the precision to determine that troops were directly sprayed with herbicides during Operation RANCH HAND, especially given the procedures in place to ensure clearance of friendly forces from the target area and the lack of elevated serum levels of TCDD in ground troops judged to have operated in heavily sprayed areas.

Specter orange.

Nearly 30 years after the Vietnam War, a chemical weapon used by U.S. troops is still exacting a hideous toll on each new generation in Vietnam. The dioxin (TCCD) that contaminated the herbicide Agent Orange is one of the most toxic molecules known to science. The contaminant persists in the soil. The United States has done nothing to combat the medical and environmental catastrophe that is overwhelming the country.

'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.

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.

Incidence of CTCL in Vietnam veterans.

The causative factors of cutaneous T-cell lymphoma (CTCL) are unclear. Exposure to herbicides has been linked to the development of other lymphomas. Three Vietnam Veterans with CTCL treated at a photopheresis unit in New Jersey report positive histories of exposure to Agent Orange, a herbicide used during the war.

Vaginally applied diquat intoxication.

CASE REPORT: We report the case of a woman who introduced 20 mL of diquat concentrate intravaginally. Abdominal pain, vomiting, diarrhea, burning chest pains, and somnolence appeared within the first 24 hours. The vulva and vagina were corrosively inflamed. Acute renal failure appeared on the third day and was treated by 6 hemodialyses over 6 days. The patient was dysarthric with spastic tetraparesis for 3 months. The electroencephalogram, diffusely slow on day 3, was normal on day 28. The electromyoneurogram was normal at all times. Biopsy of a peripheral nerve performed on day 57 following intoxication showed no myelin or axonal alterations.

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.