Agent Orange Exposure and 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) in Human Milk.

Agent Orange was sprayed in parts of southern Vietnam during the U.S.-Vietnam war and was a mixture of two chlorophenoxy herbicides. The mixture was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD and other dioxins and furans are measurable in the milk of Vietnamese women. We explored whether the TCDD in milk from these women was from Agent Orange and whether lactational exposure can be a mode of transgenerational effects of TCDD from Agent Orange. A review of the world's literature on milk concentrations of polychlorinated compounds showed the presence of TCDD and other dioxins and furans in all countries that have been assessed. The congener profile of these chemicals, that is, the proportion of different congeners in the sample, can be used to assess the source of milk contamination. Measurements in most countries, including contemporary measurements in Vietnam, are consistent with non-Agent Orange exposure sources, including industrial activities and incineration of waste. Models and supporting human data suggest that TCDD from breastfeeding does not persist in a child past adolescence and that the adult body burden of TCDD is independent of whether the individual was breast- or bottle-fed as a child. These findings suggest that exposure to Agent Orange in Vietnam did not result in persistent transgenerational exposure through human milk.

Handler, bystander and reentry exposure to TCDD from application of Agent Orange by C-123 aircraft during the Vietnam War.

Using validated models and methods routinely employed by pesticide regulatory agencies, the absorbed dosages of Agent Orange (AO) herbicide contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were estimated for mixer/loaders, applicators, and individuals in the vicinity of applications of AO by C-123 aircraft during the Vietnam War. Resulting dosages of TCDD were then transformed to estimates of adipose residues, and compared to population biomonitoring of known mixer/loaders and applicators as well as ground troops in Vietnam and civilians in the U.S. Results demonstrate that mixer/loaders and applicators had the greatest exposures and their measured residues of TCDD in adipose were consistent with the estimated exposures. Further, the potentially exposed ground troops, including those who could have been directly sprayed during aerial defoliation, had measured adipose residues that were consistent with those in civilian U.S. populations with no defined source of exposure exposures and both of those cohorts had orders of magnitude less exposure than the mixer/loaders or applicators. Despite the availability of validated exposure modeling methods for decades, the quantitative TCDD dose estimates presented here are the first of their kind for the Vietnam conflict.

Environmental fate and dietary exposures of humans to TCDD as a result of the spraying of Agent Orange in upland forests of Vietnam.

The fate and transport of 2,3,7,8-tetrachloro-p-dibenzodioxin (TCDD) released into the environment of South Vietnam (SVN) as a consequence of the aerial application of the herbicidal defoliant Agent Orange (AO) were simulated for a generic upland forest scenario and followed over a 50-year period (1965, 1968 and 1970 onwards). Modeled concentrations of TCDD in the environment were then used as inputs to a human exposure model, which focused on long-term exposures via the food chain. Intake rates and body burdens of TCDD were estimated for adult males over the course of the simulation period and compared to available biomonitoring data. One of the most important factors determining the magnitude of the simulated human exposure to TCDD was the fraction of the chemical deposited directly to soil (where it was assumed to have a degradation half-life of 10 or 15years) relative to the fraction assumed to remain on/in the forest canopy following the spray application (where it was assumed to have a degradation half-life of ≤48h). The simulated body burdens under the various scenarios considered were broadly consistent with the biomonitoring data from SVN collected in the mid-1980s to late 1990s. Taken together, the modeling results and empirical data suggest that highly elevated exposures to TCDD (i.e., body burdens in the several 100s of pg/g lipid range and greater) were not common among people inhabiting upland forest locations in SVN sprayed with AO and that peak and average body burdens were broadly similar to those of the general population of the U.S. in the 1970s and early 1980s. The model-based assessment is consistent with the 'hot spot' hypothesis i.e., potential exposures to TCDD linked to activities conducted on or near former bases where AO was stored are greater than potential exposures in areas subjected to aerial spraying.

Exposure to TCDD from base perimeter application of Agent Orange in Vietnam.

Using recognized methods routinely employed by pesticide regulatory agencies, the exposures of military personnel that were mixer/loader/applicators (M/L/A) of Agent Orange (AO) for perimeter foliage at bases during the Vietnam War were estimated. From the fraction of TCDD in AO, absorbed dosage of the manufacturing contaminant was estimated. Dermal exposure estimated from spray drift to residents of the bases was calculated using internationally recognized software that accounted for proximity, foliar density of application site, droplet size and wind speed among other factors, and produced estimates of deposition. Those that directly handled AO generally had much higher exposures than those further from the areas of use. The differences in exposure potential varied by M/L/A activity, but were typically orders of magnitude greater than bystanders. However, even the most-exposed M/L/A involved in perimeter application had lifetime exposures comparable to persons living in the U.S. at the time, i.e., ~1.3 to 5 pg TCDD/kg bodyweight.

The Air Force health study: an epidemiologic retrospective.

In 1979, the U.S. Air Force announced that an epidemiologic study would be undertaken to determine whether the Air Force personnel involved in Operation Ranch Hand-the program responsible for herbicide spraying in Vietnam-had experienced adverse health effects as a result of that service. In January 1982 the Air Force Health Study (AFHS) protocol was approved and the 20 year matched cohort study consisting of independent mortality, morbidity and reproductive health components was initiated. This controversial study has been criticized regarding the study's potential scientific limitations as well as some of the administrative aspects of its conduct. Now, almost 30 years since the implementation of the AFHS and nearly a decade since the final follow up examinations, an appraisal of the study indicates that the results of the AFHS do not provide evidence of disease in the Ranch Hand veterans caused by their elevated levels of exposure to Agent Orange.

Logarithmic dose transformation in epidemiologic dose-response analysis: use with caution.

Dose-response models based on the logarithm of dose or exposure are utilized in the analysis of both toxicological and epidemiologic data. While the applications are similar, fundamental differences in the studies conducted by each discipline affects the interpretation of the use of the logarithmic dose transformation. Using numerical illustrations and examples from the literature, this paper explores the implications of using logarithmic dose transformation in epidemiologic studies and provides some caveats for consideration in interpreting epidemiologic studies based upon logarithmic dose transformation.

Assessing exposure to allied ground troops in the Vietnam War: a quantitative evaluation of the Stellman Exposure Opportunity Index model.

The Exposure Opportunity Index (EOI) is a proximity-based model developed to estimate relative exposure of ground troops in Vietnam to aerially applied herbicides. We conducted a detailed quantitative evaluation of the EOI model by using actual herbicide spray missions isolated in time and space. EOI scores were calculated for each of 36 hypothetical receptor location points associated with each spray mission for 30 herbicide missions for two time periods - day of herbicide application and day 2-3 post-application. Our analysis found an enormous range of EOI predictions with 500-1000-fold differences across missions directly under the flight path. This quantitative examination of the EOI suggests that extensive testing of the model's code is warranted. Researchers undertaking development of a proximity-based exposure model for epidemiologic studies of either Vietnam veterans or the Vietnamese population should conduct a thorough and realistic analysis of how precise and accurate the model results are likely to be and then assess whether the model results provide a useful basis for their planned epidemiologic studies.

Assessing exposure to allied ground troops in the Vietnam War: a comparison of AgDRIFT and Exposure Opportunity Index models.

The AgDRIFT aerial dispersion model is well validated and closely related to the AGDISP model developed by the USDA Forest Service to determine on- and off-target deposition and penetration of aerially applied pesticide through foliage of trees. The Exposure Opportunity Index (EOI) model was developed to estimate relative exposure of ground troops in Vietnam to aerially applied herbicides. We compared the output of the two models to determine whether their predictions were in substantial agreement, but found a total lack of concordance. While the AgDRIFT model estimated that ground-level deposition through foliage was reduced more than 20 orders of magnitude at less than 1 km from the flight line, the EOI model predicted deposition declines less than one order of magnitude 4 km from the flight line. Interestingly the EOI model predicts a four-fold variability in EOI on the flight line, where exposure should be essentially invariant because the spray apparatus is designed to apply herbicide at a constant rate. We believe that the EOI model cannot be used to provide individual exposure estimates for the purpose of conducting epidemiologic studies. Moreover, evaluation of the position data for both herbicide spray swaths and troop locations, together with the actual patterns of spray deposition predicted by the AgDRIFT model, suggests that precise individual-level exposure assessments for ground troops in Vietnam are impossible. However, we suggest that well-validated tools like AgDRIFT can be used to estimate exposure to groups of individuals.

Perspective: risk apportionment and disease intervention strategies.

The ultimate public health objective is the ability to predict and prevent disease, and not necessarily to identify an exhaustive list of potential disease risk factors. For any important public health outcome with multiple and potentially interrelated risk factors, an improved understanding of the contribution of individual and combinations of modifiable risk factors to the disease burden is essential for formulating an appropriate public health strategy. Partitioning techniques that divide the combined impact of multiple risk factors into exposure-specific components while taking into account the potential interrelations among those components, have been described in the epidemiological literature. In this article, we review and compare the available methods and options for such apportionment and apply them in a more general public health context as a method of selecting and prioritizing coronary heart disease (CHD) prevention strategies.

Updated weight of evidence for an association between adverse reproductive and developmental effects and exposure to disinfection by-products.

Disinfection by-products (DBP) are produced when water is treated with chemical disinfectants. Some toxicological and epidemiological studies suggest an association between DBP exposure and adverse reproductive and developmental effects. In a previous critical review, [Graves, C.G., Matanoski, G.M., Tardiff, R.G., 2001. Weight of evidence for an association between adverse reproductive and developmental effects and exposure to disinfection by-products: a critical review. Regul. Toxicol. Pharmacol. 34, (2) 103-124] evaluated the weight of evidence for this exposure and these effects. This investigation updates the previous evaluation and considers all toxicological and epidemiological evidence since the earlier review and reassesses the weight-of-evidence for all of the data on the various effects, outcome by outcome. The updated toxicity weight of evidence found little indication of previously unreported reproductive or developmental toxicity. In particular, the recently published findings of an exceptionally well conducted cohort study of broad scope found no impact of chlorination by-products on the highly controversial outcome of spontaneous abortion, unlike predecessor studies of more limited methodology, leading the authors to recommend no further epidemiologic pursuit for this hypothesis since the cohort was scrutinized very closely and dispelled any concern of such an association. The updated epidemiologic weight of evidence demonstrated that no association with DBP exposure exists for over a dozen outcomes including low and very low birth weight, preterm delivery, some specific congenital anomalies, and neonatal death. The analysis found inconsistent or very weak results for all congenital anomalies/birth defects, all central nervous system anomalies, neural tube defects, and spontaneous abortion. As in the previous article, the updated weight of evidence suggested a positive association with DBP exposure and some measure of growth retardation such as intrauterine growth retardation, small for gestational age, term low birth weight, and small body length or head circumference. Exposure assessment in most epidemiological studies remains inadequate to definitively demonstrate any association of small magnitude.

A risk analysis model of the relationship between beverage consumption from school vending machines and risk of adolescent overweight.

Risk analysis is a widely used tool to understand problems in food safety policy, but it is seldom applied to nutrition policy. We propose that risk analysis be applied more often to inform debates on nutrition policy, and we conduct a risk assessment of the relationship of regular carbonated soft drink (RCSD) consumption in schools and body mass index (BMI) as a case study. Data for RCSD consumption in schools were drawn from three data sets: the Continuing Survey of Food Intake by Individuals 1994-1996, 1998 (CSFII), the National Health and Nutrition Examination Survey 1999-2000 (NHANES), and the National Family Opinion (NFO) WorldGroup Share of Intake Panel (SIP) study. We used the largest relationship between RCSD and BMI that was published by prospective observational studies to characterize the maximum plausible relationship in our study. Consumption of RCSD in schools was low in all three data sets, ranging from 15 g/day in NFO-SIP to 60 g/day in NHANES. There was no relationship between RCSD consumption from all sources and BMI in either the CSFII or the NHANES data. The risk assessment showed no impact on BMI by removing RCSD consumption in school. These findings suggest that focusing adolescent overweight prevention programs on RCSD in schools will not have a significant impact on BMI.

Assessment of the national antimicrobial resistance monitoring system (NARMS) and its value in critical decision-making.

This paper reviews the United States National Antimicrobial Resistance Monitoring System (NARMS). The data from this system have been used as the core basis of a recent proposal to stop the use of fluoroquinolones in poultry production, in an effort to reduce or remove a perceived threat to human health due to alleged increasing fluoroquinolone resistance among human Campylobacter isolates. An increase in resistance has the potential to render fluoroquinolone therapy of human gastrointestinal infections less effective. This review finds no evidence in the NARMS data to suggest that a rise in resistant Campylobacter isolates has occurred since fluoroquinolones were introduced for use in poultry. In addition, this review identifies a number of shortcomings in the NARMS program. These include lack of an overall sampling design, biases in the collection of isolates from animal samples, noncompliance of state departments of public health with NARMS protocols, lack of such basic data as genotype information on the organisms isolated, and, for animal samples, lack of measurements of bacterial load. Taken together, these problems indicate that the present NARMS data very likely overestimate resistance levels, and, at best, do not provide reliable information to quantify the extent and temporal trends of antimicrobial resistance in Campylobacter and other enteric organisms from human and animal populations. Ways to improve the quantitative rigor of the NARMS program and identify other data such as 'meta' data for human and animal samples, and data on the magnitude of other potential reservoirs of infection, including healthy humans, are suggested. Implementing these proposals would greatly enhance the value of the NARMS program as a tool for quantitative decision-making and aid in improving the quality of our food supply and human health care.