WHAT CAN SCIENCE OFFER CHILDREN OF AGENT ORANGE?

BY CLAUDIA GARY

About two generations after the last American troops left Vietnam, scientific research has finally confirmed things that many veterans have strongly suspected for decades. Although the Department of Veterans Affairs has acknowledged a connection between dioxins such as TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and various illnesses in veterans who were exposed to them in Vietnam, the VA so far has recognized only a very limited array of birth defects found in the offspring of such veterans. Scientists believe that further research may reveal much more in the way of dioxin-related birth defects.

Structural defects—those that are visible—seem to represent only a small portion of the damage. As Betty Mekdeci wrote in these pages in 2007: “When compared to non-veterans’ children, the children of Vietnam veterans have shown consistent increases in learning, attention, and behavioral disorders; all types of skin disorders; problems with tooth development; allergic conditions and asthma; immune system disorders including chronic infections; some childhood cancers; and endocrine problems including thyroid disorders and childhood diabetes. More and more studies of prenatal exposures to dioxins and similar chemicals are adding support for these associations.” Some of these problems are not detected until later in life.

Mekdeci is the executive director of Birth Defects Research for Children, Inc. Her article was reprinted in the San Francisco Medical Journal. The National Birth Defect Registry, which Mekdeci founded in the early 1990s, has recorded thousands of such cases and helped launch research studies. The Vietnam veterans questionnaire used in her registry was developed in conjunction with the New Jersey Agent Orange Commission. More information about the registry and BDRC can be found at www.birthdefects.org For Mekdeci’s article, go to www.vva.org/veteran/1207/veteran1207.html

HOW DIOXINS CAUSE DAMAGE

What makes TCDD particularly dangerous is the shape of the molecule. “Because it just happens to have a shape that fits into a receptor that causes many different kinds of toxicity, dioxin is clearly one of the most toxic chemicals known to man,” said Dr. R. Thomas Zoeller, Professor of Biology at the University of Massachusetts. Zoeller specializes in thyroid hormone action on brain development and environmental disruption of thyroid hormone action.

How does this toxic effect work? “There is good evidence that dioxin increases thyroid hormone clearance from the blood,” Zoeller said. “The liver plays a role in managing how much thyroid hormone is in the blood at any one time, and dioxin activates enzymes in the liver that clear thyroid hormone. But dioxin also goes into the nucleus of cells and causes changes that I don’t think we fully understand. It probably has a direct action on the ability of thyroid hormone to function in cells, [including] in the brain. These mechanisms are probably the most important. Thyroid hormone plays a role during the development of brain structure.”

Asked about recent important developments in dioxin research, Zoeller said: “The Environmental Protection Agency recently reviewed dioxin toxicity for their standard-setting process, and they used thyroid function as the most sensitive index of toxicity. So I think it’s clear that dioxin is well known to influence the thyroid system, and that [the relationship between dioxin exposure and the thyroid] is an important public health concern.”

One thing that complicates the research, however, is the difficulty in measurement. “I don’t think we have a good handle on ways of visualizing or of measuring toxic effects on the thyroid system,” Zoeller said, “because we are learning more and more that chemicals in the environment can interfere with thyroid hormone action in ways that are not represented in serum levels of hormones” as measured in the blood.

IS DIOXIN EXPOSURE LINKED TO AUTISM AND ADHD?

”When a syndrome or disorder like autism reaches an incidence level of one child in eighty-eight,” Zoeller said, citing the most recent rates, “I think we should all be very concerned.” Does the thyroid interact with the functioning and development of the nervous system? “Absolutely,” he said. “Thyroid hormone plays an important role. But I think in most cases, thyroid hormone interacts with many factors. That makes it a very complicated system to study.”

Dr. Erin Bell, Associate Professor of Environmental Health Sciences, Epidemiology, and Biostatistics at the University of Albany (SUNY) School of Public Health, specializes in examining the association of adverse reproductive outcomes with occupational and environmental exposures. “We are very interested in looking at autism and ADHD [attention deficit hyperactivity disorder],” Bell said. These are “of clear interest to the research community; the interest is not limited to Vietnam veterans, but their exposures are of continued interest for those of us evaluating the health effects of pesticides and other chemicals like dioxin. In general, we are looking at those chemicals that may interfere with the hormonal system. These are referred to as endocrine disruptors.

“Scientists are looking at those chemicals that would disrupt the endocrine system and whether they are related to autism and ADHD. This is a younger field; we are just beginning to have large epidemiological studies to look at these things. The literature is reviewed every two years [for the Veterans and Agent Orange report, published by the Institute of Medicine], so I would anticipate that for the next VAO report they would have more literature to be able to look at these kinds of outcomes.”

THE LINK BETWEEN PATERNAL EXPOSURE AND BIRTH DEFECTS

“Most studies focus on maternal exposures during pregnancy, with regard to reproductive outcomes,” Bell said. “However, in the pesticide literature there are other studies that look at paternal, as well as maternal, occupational exposures to pesticides. And so they have been able to explore paternally mediated reproductive outcomes.”

There are two possible routes for this, she said. “One is that there is some chromosomal damage at the time of exposure that would then be delivered via sperm. Or, you have exposure that is delivered to the mother through the semen, so that the mother is exposed while pregnant.”

Since the life cycle of sperm is 90 days, “once [servicemen were] removed from exposure in a 90-day period, most of the time any damage from the chemical should be remediated at that point past 90 days. But again we still look at it, and there are some exposures where that would not be the case.”

For current studies, she said, “the question of whether paternal exposures can lead to adverse birth outcomes is a consistent research question, independent of Vietnam veterans. And pesticide studies now ask about paternal exposures in the three months prior to conception, because if there’s going to be an effect from the male, that’s when it would most likely happen.”

Although the potential for exposure is there, Bell added, “the literature has not provided consistent evidence that these exposures are associated with birth defects. Spina bifida is one exception, and that is discussed in the VAO report.”

The toughest challenge, Bell said, “is trying to understand the paternal exposure. Most of the literature does focus on maternal exposures. And much of the literature looks at all pesticides combined, rather than dioxins specifically or herbicides that are of interest to the committee. And so those are ongoing challenges.”

Bell said that “one of the improvements we’ve made is to look at individual birth defects. A lot of the previous literature, due to the challenges of studying birth defects, combined all the defects together into one group. And that would be similar to combining all cancers together. We think that different defects will have different risk factors, just as different cancers have different risk factors. With funding and with better support, we would be able to better look at dioxin with regard to specific defects. That would help us in terms of understanding this issue.”

Bell noted that “there is very little funding to look at birth defects,” even though “there is a great deal of interest in the research community to examine risk factors of birth defects.” This is the case, she said, “independent of the Vietnam veterans; it is just not something that is on the radar screen of a lot of people.”

BRIDGING INFORMATION GAPS

Dr. Mary K. Walker, Regent’s Professor in Pharmacology and Toxicology at the University of New Mexico, chaired the VAO committee and wrote the preface to the 2010 update of its report. The latest major studies on paternal exposure to Agent Orange, she said, were “identified back in 1996, in the update where spina bifida was connected with exposure to chemicals in Agent Orange. Since that time, the VAO committee, through the Institute of Medicine, has continued to review any information in the literature related to exposure to the chemicals [dioxins] that were components of AO, and potential birth defects.”

When asked why there have been so few known studies related to paternal exposure during that time, Walker said: “Possibly one explanation would be that until more recently, the biological plausibility of birth defects related to paternal exposure was not well understood. And I think in the last five to seven years, we are starting to understand the biology better.” Such research, then, was not a focus “until the biology caught up in understanding how paternal exposure could contribute to birth defects.” Since these things have been understood more recently, she said, “I think now we are starting to see more interest in looking at, and designing, those types of epidemiology studies.”

Asked whether it might be possible now to reexamine information from previous studies, Walker said: “I would say that the information should be present in the databases that exist from the VA, as well as the individuals in whom we have some assessment of what their exposures were—particularly the Ranch Hand cohort as well as the Army Chemical Corps cohort. That information is already present and could be looked at again.”

Additional studies could be done in some cases based on existing data, now that the biological plausibility is understood regarding a connection between paternal exposure and birth defects. This was already among the VAO committee’s suggestions for future research. Some of the areas of concern, Walker said, are “neurological deficits,” since there is “evidence from the animal literature that those are endpoints that would be of interest.” Others would include “thyroid hormone deficits, as well as possibly cardiovascular disease that develops in the offspring later in life.”

The study, updated every two years since 1994, is produced by an Institute of Medicine committee, “a group of individuals who have reviewed the literature in greatest detail and summarized it in a comprehensive way,” Walker said. “So I think that the recommendations that have come out by the committee are probably the ones that are the most relevant. The recommendation is that new studies should evaluate offspring of Vietnam veterans for what would be considered defined clinical health conditions that develop later in life. ADHD would be an excellent example. But more broadly, the recommendations of the committee identified three particular areas: neurological disease, immune dysfunction, and diseases that may be caused by disruption of the endocrine system.”

Who would carry out the proposed studies? Walker suggested that they would probably be “academics who have epidemiology experience,” since these are the groups that have conducted such studies in the past. Although universities most likely would perform the studies, she said, “the VA would certainly need to be an advocate.” Although VA funding “would be great,” she said, whether or not they can directly provide funding, it would be extremely helpful for the VA to be “an advocate to say that these are the sorts of things that are information gaps” that we need to fill.

Summing up the two major information gaps that the committee identified, Walker said the “studies on offspring need to be conducted following paternal exposure without maternal exposure,” along with studies “assessing clinically defined disease, focusing on neurological immunological, and endocrine-related diseases.”

Notable among the published recommendations are that “work needs to be undertaken without delay to address questions regarding the potential for paternally mediated, clinically defined health outcomes in offspring; and the effective utilization of the VA’s medical database.” The report goes on to recommend “improved linkage and sharing between DOD and VA [including improved] collection of exposure data during current deployments, so the impasses associated with missing exposure information will not impede investigations of health consequences in future veterans, as has been the case for Vietnam veterans.”

Another prominent recommendation is: “Available information should be gleaned from existing cohort studies.” This would include data on the Army Chemical Corps, the largest cohort of Vietnam veterans exposed directly to herbicides and TCDD.

WHAT CAN BE DONE NOW?

Avoiding risk and making the environment safer is a major and necessary focus. But since it is impossible to undo past exposure to dioxins, what can be done for veterans and their children who are already affected by dioxin exposure?

Betty Mekdeci suggested that specially staffed centers could be created to provide evaluation and services for children with suspected—if not proven—dioxin-related birth defects and diseases. “We would have scientists with expertise in the types of disciplines related to chemical exposures and adverse reproductive outcomes,” she said. “They would study the children; they would make recommendations for treatments that the families wouldn’t have access to in another place—maybe including non-embryonic stem cell work or monoclonal antibodies—and send a treatment plan back to their regular doctor. I believe that through this plan, we could not only leverage the most help for the most children, but we also would be learning things that we could extrapolate to the civilian environment.” Mekdeci compared this concept to the children’s environmental centers run by the National Institute for Environmental Health Sciences.

Meanwhile, although a healthy diet and lifestyle are important for everyone, Zoeller pointed out that “Vietnam veterans and their children, and maybe even their grandchildren, should be especially vigilant and should have annual physicals and make sure their health care providers are particularly vigilant. Often, for example, diabetes isn’t really picked up until it’s acutely symptomatic. That really shouldn’t happen. People who are at risk of diabetes should have frequent checkups. The same goes for heart disease.”

It is also essential to keep an eye on what the scientific community is doing. In some cases there are opportunities to suggest or participate in ongoing studies. In all cases, staying informed can be helpful in facing the future and taking effective action.

“I don’t think we have a really good understanding of all of thyroid hormone’s effects and how to measure those effects,” Zoeller said. “So there can be a lot of debate about whether thyroid hormone or thyroid disruption plays a role in the symptoms of Vietnam veterans, and it’s the same with autism. I think we need very targeted research on how to evaluate thyroid hormone action.”

FURTHER READING

The Institute of Medicine’s VAO report is online. The PDF version is free, and the format makes it easy to search for sections of particular interest. Walker’s preface, for example, starts on page ix; a diagram of the TCDD molecule can be found on page 88; the chapter on Reproductive Effects and Impacts on Future Generations starts on page 540; and the Committee’s conclusions and recommendations begin on page 759. The most recent update of the VAO report (released in September 2011) may be downloaded from www.iom.edu/Reports/2011/Veterans-and-Agent-Orange-Update-2010.aspx

George Claxton, the former chair of VVA’s Agent Orange/Dioxin Committee, made valuable contributions to this article.

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