Assessments of Algal Toxicity and PBT Behaviour of Pesticides with No Eco-toxicological Data: Predictive Ability of QSA/(T)R Models.

In the present study, the effect of eight pesticides with no ecotoxicological data on the growth rate of Chlorella vulgaris was measured. The selected pesticides are acetochlor, acetamiprid, boscalid diphenamid, gibberellic acid, ioxynil, diclofop and 2,4,5-T. The algal toxicity (IC50 ) of boscalid could not be determined within its solubility limit. Acetamiprid, diphenamid and gibberellic acid revealed IC50 values>100 mg/L. Among the others, the order of 96-h IC50 of pesticides was found as acetochlor>ioxynil>diclofop>2,4,5-T. The IC50 values were also predicted by using four Quantitative Structure-Activity/(Toxicity) Relationship (QSA/(T)R) models selected from the literature. The predictions of the models provided by QSARINS-Chem module of QSARINS as well as those obtained in our previous studies were compared with the results of experimental algal toxicity tests that were performed in our laboratory. The QSTR model generated for the toxicity of diverse chemicals to freshwater algae was able to correctly predict the toxicity order of the pesticides tested in the present study, confirming the utility of the QSA/(T)R approach. Additionally, Persistence, Bioaccumulation and Toxicity (PBT) Index model provided via the software QSARINS was employed and boscalid and diclofop were found to be PBT chemicals based on the PBT model. The present study will be very helpful when a more holistic approach applied to understand the fate of these chemicals in the environment.

Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis survival.

BACKGROUND: Military veterans may have higher rates of amyotrophic lateral sclerosis (ALS) mortality than non-veterans. Few studies, with sparse exposure information and mixed results, have studied relationships between military-related factors and ALS survival. We evaluated associations between military-related factors and ALS survival among U.S. military veteran cases. METHODS: We followed 616 medical record-confirmed cases from enrollment (2005-2010) in the Genes and Environmental Exposures in Veterans with Amyotrophic Lateral Sclerosis study until death or July 25, 2013, whichever came first. We ascertained vital status information from several sources within the Department of Veterans Affairs. We obtained information regarding military service, deployments, and 39 related exposures via standardized telephone interviews. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals. We adjusted for potential confounding and missing covariate data biases via inverse probability weights. We also used inverse probability weights to adjust for potential selection bias among a case group that included a disproportionate number of long-term survivors at enrollment. RESULTS: We observed 446 deaths during 24,267 person-months of follow-up (median follow-up: 28 months). Survival was shorter for cases who served before 1950, were deployed to World War II, or mixed and applied burning agents, with HRs between 1.58 and 2.57. Longer survival was associated with exposure to: paint, solvents, or petrochemical substances; local food not provided by the Armed Forces; or burning agents or Agent Orange in the field with HRs between 0.56 and 0.73. CONCLUSIONS: Although most military-related factors were not associated with survival, associations we observed with shorter survival are potentially important because of the large number of military veterans.

Peace and Reconciliation.

Susan Schnall speaks about the lingering effects of Agent Orange-and what remains to be done about them.

Neurology in the Vietnam War.

Between December 1965 and December 1971, the United States maintained armed forces in Vietnam never less than 180,000 men and women in support of the war. At one time, this commitment exceeded half a million soldiers, sailors, and airmen from both the United States and its allies. Such forces required an extensive medical presence, including 19 neurologists. All but two of the neurologists had been drafted for a 2-year tour of duty after deferment for residency training. They were assigned to Vietnam for one of those 2 years in two Army Medical Units and one Air Force facility providing neurological care for American and allied forces, as well as many civilians. Their practice included exposure to unfamiliar disorders including cerebral malaria, Japanese B encephalitis, sleep deprivation seizures, and toxic encephalitis caused by injection or inhalation of C-4 explosive. They and neurologists at facilities in the United States published studies on all of these entities both during and after the war. These publications spawned the Defense and Veterans Head Injury Study, which was conceived during the Korean War and continues today as the Defense and Veterans Head Injury Center. It initially focused on post-traumatic epilepsy and later on all effects of brain injury. The Agent Orange controversy arose after the war; during the war, it was not perceived as a threat by medical personnel. Although soldiers in previous wars had developed serious psychological impairments, post-traumatic stress disorder was formally recognized in the servicemen returning from Vietnam.

Influence of dioxin exposure upon levels of prostate-specific antigen and steroid hormones in Vietnamese men.

Most studies on the relationship between Agent Orange and prostate cancer have focused on US veterans of the Vietnam War. There have been few studies focusing on the relationship between levels of prostate-specific antigen (PSA) and dioxins or steroid hormones in Vietnamese men. In 2009-2011, we collected blood samples from 97 men who had resided in a "dioxin hotspot" and 85 men from a non-sprayed region in Vietnam. Then levels of PSA, dioxins, and steroid hormones were analyzed. Levels of most dioxins, furans, and non-ortho polychlorinated biphenyls were higher in the hotspot than those in the non-sprayed region. Levels of testosterone, dehydroepiandrosterone, and estradiol differed significantly between the hotspot and the non-sprayed region, but there were no correlations between levels of PSA and steroid hormones and dioxins in either of the two regions. Our findings suggest that PSA levels in Vietnamese men are not associated with levels of dioxin or steroid hormones in these two regions.

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.

Disparities in Infant Mortality Due to Congenital Anomalies on Guam.

In the 1970's and 1980's, there were large inter-village disparities in infant mortality due to congenital anomalies on Guam. A village-level analysis was conducted to determine if these disparities can be explained by behavioral (ie, median age of village females, village fertility ratio), structural (ie, population density, persons per household, single mother households per village, married females per village), and environmental (ie, living in a village where Agent Orange (AO) spraying was conducted) factors. Village-level data for live births and infant mortality due to congenital anomalies (1970-1989) was collected from Guam's Office of Vital Statistics. Data on median age of village females, village fertility ratio, population density, persons per household, single mother households, and married females were obtained from the 1980 US Census. Estimates of village-level AO use were provided through personal communications, and villages were dichotomized into AO and non-AO spray areas. Village location was classified by usual residence of the mother. Linear regression was used to determine associations between infant mortality due to congenital anomalies and the behavioral, structural, and environmental factors. The association between AO spray area and infant mortality due to congenital anomalies was statistically significant under univariable (B [95%CI] = 1.88 [0.64,3.11], P = .005) and multivariable conditions (B [95%CI] = 2.02 [0.08,3.96], P = .042). These results suggest that infants born to mothers whose usual residence was in an AO spray area on Guam are at an increased risk of mortality due to congenital anomalies. Further studies using individual-level data are needed to validate these results.

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.

A critical review of the epidemiology of Agent Orange or 2,3,7,8-tetrachlorodibenzo-p-dioxin and lymphoid malignancies.

PURPOSE: Establishing a causal relationship between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and risk of specific lymphoid cancers, including non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and multiple myeloma (MM), would be useful for risk assessment. METHODS: This article systematically and critically reviews epidemiologic studies of the association between exposure to TCDD or TCDD-contaminated herbicides and risk of lymphoid malignancies. These include studies of military, industrial, accidental environmental, and general environmental exposure to Agent Orange or TCDD. RESULTS: Collectively, the epidemiologic evidence from industrial cohorts suggests a positive association with NHL mortality, but results are not consistent across other studies, a clear exposure-response gradient is not evident, and data are insufficient to conclude that the association is causal. Furthermore, available studies provide little information on NHL incidence or specific NHL subtypes. Epidemiologic studies do not show an association of TCDD exposure with HL, whereas the indication of a positive association with MM in a limited number of studies, but not others, remains to be confirmed in additional research. Exposure classification error and small numbers are important limitations of the available epidemiologic studies. CONCLUSIONS: Overall, a causal effect of TCDD on NHL, HL, MM, or subtypes of these lymphoid malignancies has not been established.

Public health assessment of dioxin-contaminated fish at former US airbase, Bien Hoa, Vietnam.

Ponds at the former US airbase at Ben Hoa, Vietnam are contaminated with Agent Orange. The ponds had been used for aquaculture, and in all likelihood, fish from those ponds have been sold to the public. We assessed human exposure to 2,3,7,8-tetrachloro-dibenzo-dioxin (2,3,7,8-TCDD) in fish samples from the ponds. For on-base tilapia, muscle concentrations 2,3,7,8-TCDD ranged from 1.4 to 32.7 pg/g. Fat concentrations ranged from 73.3 to 3990 pg/g. Estimated human exposure doses exceed international guidelines and exceed 2,3,7,8-TCDD's lowest adverse effect levels. The Bien Hoa fishponds are a completed human pathway for TCDD exposure.

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.

Post-Vietnam military herbicide exposures in UC-123 Agent Orange spray aircraft.

BACKGROUND: During the Vietnam War, approximately 20 million gallons of herbicides, including ~10.5 million gallons of dioxin-contaminated Agent Orange, were sprayed by about 34 UC-123 aircraft that were subsequently returned to the United States, without decontamination or testing, to three Air Force reserve units for transport operations (~1971-1982). In 1996, observed dioxin contamination led to withdrawal of these UC-123s from public auction and to their smelting in 2009. Current Air Force and Department of Veterans Affairs policies stipulate that "dried residues" of chemical herbicides and dioxin had not lead to meaningful exposures to flight crew and maintenance personnel, who are thus ineligible for Agent Orange-related benefits or medical examinations and treatment. Sparse monitoring data are available for analysis. METHODS: Three complementary approaches for modeling potential exposures to dioxin in the post-Vietnam war aircraft were employed: (1) using 1994 and 2009 Air Force surface wipe data to model personnel exposures and to estimate dioxin body burden for dermal-oral exposure for dried residues using modified generic US Environmental Protection Agency intake algorithms; (2) comparing 1979 Air Force 2,4- dichlorophenoxyacetic acid and 2,4-5-trichlorophenoxyacetic acid air samples to saturated vapor pressure concentrations to estimate potential dioxin exposure through inhalation, ingestion and skin contact with contaminated air and dust; and (3) applying emission models for semivolatile organic compounds from contaminated surfaces to estimate airborne contamination. RESULTS: Model (1): Body-burden estimates for dermal-oral exposure were 0.92 and 5.4pg/kg body-weight-day for flight crew and maintainers. The surface wipe concentrations were nearly two orders of magnitude greater than the US Army guidance level. Model (2): measured airborne concentrations were at least five times greater than saturated vapor pressure, yielding dioxin estimates that ranged from 13.2-27.0pg/m(3), thus supporting the likelihood of dioxin dust adsorption. Model (3): Theoretical models yielded consistent estimates to Model 2, 11-49pg/m(3), where the range reflects differences in experimental value of dioxin vapor pressure and surface area used. Model (3) results also support airborne contamination and dioxin dust adsorption. CONCLUSIONS: Inhalation, ingestion and skin absorption in aircrew and maintainers were likely to have occurred during post-Vietnam use of the aircraft based on the use of three complementary models. Measured and modeled values for dioxin exceeded several available guidelines. Deposition-aerosolization-redeposition homeostasis of semivolatile organic compound contaminants, particularly dioxin, is likely to have continually existed within the aircraft. Current Air Force and Department of Veterans Affairs policies are not consistent with the available industrial hygiene measurements or with the widely accepted models for semivolatile organic compounds.

Association between Agent Orange exposure and nonmelanotic invasive skin cancer: a pilot study.

BACKGROUND: Agent Orange, or 2,3,7,8-tetrachlorodibenzodioxin, has been shown to cause indirect DNA damage, producing malignancies. However, its connection to nonmelanotic invasive skin cancer is unclear. This study investigated whether 2,3,7,8-tetrachlorodibenzodioxin exposure increases the incidence of this cancer. METHODS: The authors retrospectively reviewed the medical records of 100 consecutive male patients with Fitzpatrick skin types I through IV who enrolled in the Agent Orange registry at the Veterans Affairs Hospital of Washington, D.C., between August of 2009 and January of 2010. RESULTS: The study population's mean age was 65.7 years (range, 56 to 80 years). 2,3,7,8-Tetrachlorodibenzodioxin exposure included living or working in contaminated areas (56 percent), actively spraying it (30 percent), or traveling in contaminated areas (14 percent). Fifty-one percent of patients had nonmelanotic invasive skin cancer; 43 percent had chloracne; and 26 percent had other malignancies, such as prostate (14 percent), colon (3 percent), or bladder cancer (2 percent). The nonmelanotic invasive skin cancer incidence rate in the study population (51 percent) was significantly higher than the national age-matched incidence rate (23.8 percent; p < 0.001). High Fitzpatrick skin type score (p = 0.010) and dark eye color (p = 0.036) were associated with a decreased incidence of the cancer. Exposure by means of active spraying (73 percent versus 67 percent; p = 0.003) and presence of chloracne (81 percent versus 28 percent; p < 0.001) were associated with increased nonmelanotic invasive skin cancer incidence rates. CONCLUSIONS: 2,3,7,8-Tetrachlorodibenzodioxin exposure appears to be associated with the development of nonmelanotic invasive skin cancer. Further studies are warranted to determine the relative risk within this patient population and to determine appropriate management strategies. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

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.