Deborah K. Watkins

Implications of estimates of residential organophosphate exposure from dialkylphosphates (DAPs) and their relevance to risk

Recent epidemiological studies have claimed to associate a variety of toxicological effects of organophosphorus insecticides (OPs) and residential OP exposure based on the dialkyl phosphates (DAPs; metabolic and environmental breakdown products of OPs) levels in the urine of pregnant females. A key premise in those epidemiology studies was that the level of urinary DAPs was directly related to the level of parent OP exposure. Specific chemical biomarkers and DAPs representing absorbed dose of OPs are invaluable to reconstruct human exposures in prospective occupational studies and even in non-occupational studies when exposure to a specific OP can be described. However, measurement of those detoxification products in urine without specific knowledge of insecticide exposure is insufficient to establish OP insecticide exposure. DAPs have high oral bioavailability and are ubiquitously present in produce at concentrations several-fold greater than parent OPs. Studies relying on DAPs as an indicator of OP exposure that lack credible information on proximate OP exposure are simply measuring DAP exposure and misattributing OP exposure.

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 studys 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.

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.

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 models 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.

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.

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 worlds 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.

Reply to "agent Orange exposure modeling: fallacies and errors".

journals, and with only the mildest of disclaimers: ‘‘This work was supported by the Dow Chemical Company and Monsanto Company,’’ without the additional disclosure that these two companies were the major suppliers of military herbicides during the Vietnam War and were at the time of the Ginevan et al. manuscript’s submission, acceptance and publication, defendants in two active federal class-action lawsuits brought by parties who claim injury as a result of exposure to spraying. Publication of their paper, with its incorrect data and its fundamentally incorrect and negative interpretations, at best adds confusion to the literature. At worst it might be seen as a successful effort by paid consultants to bolster the legal defense of major suppliers of military herbicides and to manufacture scientific uncertainty.

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.

Exposure estimates in epidemiological studies of Korean veterans of the Vietnam War

In the past year, several papers on health outcomes in Korean veterans of the Vietnam War have been published. All of these papers base their exposure classifications on an ‘E4 score’ which is a proximity-based measure of ‘exposure opportunity’ calculated from a model developed at Columbia University. Calculation of an Exposure Opportunity Index (EOI) or E4 score from this model requires two inputs:

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.