WASHINGTON–Based on a new review, two conditions–one extremely common and the other rare–appear to be related to herbicide exposure during the Vietnam War era.

That’s according to the latest in a series of congressionally mandated biennial reviews of the evidence of health issues that may be linked to exposure to Agent Orange and other herbicides used during the Vietnam War.

The panel found sufficient evidence of an association for hypertension and monoclonal gammopathy of undetermined significance (MGUS). The report, Veterans and Agent Orange: Update 11 (2018), focused on the scientific literature published between Sept. 30, 2014, and Dec. 31, 2017.

Background information in the review noted that, from 1962 to 1971, the U.S. military made wide use of herbicides. The reasons were to eliminate thick jungle canopy that could conceal opposition forces, destroy crops that benefited the enemy and to clear areas for U.S. bases and outlying encampments.

Agent Orange, which contained the most toxic form of dioxin, was the most commonly used chemical mixture. The committee focused on herbicides and their effects on an estimated 2.6 million to 4.3 million servicemembers who served in some fashion in the theater of operation.

The new review moved hypertension to the category of “sufficient” evidence of an association; the widespread condition estimated to affect 1 in 3 adults in the United States, overall, previously had been in the “limited or suggestive” category. The sufficient category indicates there is enough epidemiologic evidence to conclude there is a positive association.

Herbicide Spray

Contributing to the findings was a recent study of U.S. Vietnam veterans by researchers from the VA finding self-reported hypertension rates were highest among former military personnel who had the greatest opportunity for exposure to these chemicals. The study published in the Journal of Occupation and Environmental Medicine in 2016 examined hypertension risk in Army Chemical Corps (ACC) veterans who sprayed defoliant in Vietnam.2

VA researchers determined that herbicide-spray-history (OR adjusted [95%confidence interval {CI}] = 1.74[1.44,2.11]) and Vietnam-service-status (OR adjusted = 1.26 [1.05,1.53]) were significantly associated with SRH when analyzing data from the 2013 health survey of 3,086 ACC veterans. The association was highest when comparing Vietnam-service-sprayers to non-Vietnam-service-non-sprayers.

In addition, the committee concluded that there also was sufficient evidence of an association between exposure to at least one of the chemicals of interest and MGUS, a newly considered condition. This finding is based on a 2015 JAMA Oncology report in which investigators found a statistically significant higher prevalence of MGUS in Vietnam veterans involved in herbicide spray operations than in comparison veterans.3

The prospective cohort study conducted in 2013 to 2014, tested for MGUS in serum specimens collected and stored in 2002 by the Air Force Health Study and included former U.S. Air Force personnel who participated in Operation Ranch Hand (and other U.S. Air Force personnel who had similar duties in Southeast Asia during the same time period (1962 to 1971) but were not involved in herbicide spray missions.  

MGUS is considered to be a clinically silent condition that is a precursor to multiple myeloma, although only an estimated 1% of MGUS cases progress to multiple myeloma each year.

The biggest debate occurred over the association between herbicides and development of Type 2 diabetes. The committee from the National Academies of Sciences, Engineering, and Medicine said it could not come to a consensus on whether available evidence continued to be limited or suggestive, or merited elevation to sufficient.

The report noted that clinical studies consistently indicated a relationship between well-characterized exposures to dioxin and dioxinlike chemicals and measures of diabetes health outcomes in diverse cohorts, including Vietnam veteran populations. The risk factors for diabetes, such as age, obesity and family history of the disease, were controlled for in the analyses of most studies reviewed.

Some members of the committee argued, however, that the lack of exposure specificity and the potential for residual uncontrolled confounding influences complicated attribution of the outcome to herbicides used in Vietnam. A finding of limited or suggestive evidence means that epidemiologic research results suggest an association between exposure to herbicides and a particular outcome, but a firm conclusion is limited because chance, bias and confounding factors could not be ruled out with confidence.

The review also responded to a request by the VA, which funds the studies, to evaluate three specific health outcomes:

  • possible generational health effects that may be the result of herbicide exposure among male Vietnam veterans,
  • myeloproliferative neoplasms, and
  • glioblastoma multiforme.

As for the first issue, the review suggested that studies on the health effects of paternal chemical exposures on their descendants are fairly uncommon and that none address Vietnam veterans specifically. The panel urged further specific study of the health of descendants of male Vietnam veterans.

A lack of evidence also affected response on the question about myeloproliferative neoplasms and myelodysplastic syndromes, which are diseases of the blood cells and bone marrow. The committee said its search of epidemiologic literature uncovered only one relevant study which had been previously discussed in an update. Again, more research was urged.

The group came to a conclusion, however, on evidence of association for exposure to the chemicals of interest and glioblastoma and other brain cancers. The review said that remains inadequate or insufficient.

Noting the brain cancer is a rare result of herbicide exposure, which is often imprecise, the committee urged the VA to focus on treatment of the conditions instead of trying to prove connection.

The panel also defended the VA’s slow movement toward associating more conditions with Agent Orange exposure, pointing out, “Despite many criticisms of the conduct of studies of Vietnam veterans’ health, including weaknesses and shortcomings in particular papers as well as widespread issues in the literature, the committee wishes to emphasize that the difficulty in conducting research on Vietnam veteran health issues should not act as a barrier to carrying out such work. There are many questions regarding veterans’ health that cannot be adequately answered by examining superficially analogous exposures and outcomes in other populations. It is only through research on veterans themselves that the totality of the military service experience can be properly accounted for.”

The review emphasized, however, that the need for more research continues.

“Although progress has been made in understanding the health effects of military herbicide exposure and the mechanisms underlying these effects, significant gaps in knowledge remain,” the report concluded. “The committee restated recommendations for research activities outlined in previous updates in this series, including toxicologic, mechanistic, and epidemiologic research. Such work should include efforts to gain more complete knowledge through the integration of information in existing U.S. Department of Defense and VA databases.”

1. National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. https://doi.org/10.17226/25137.

2. Cypel YS, Kress AM, Eber SM, Schneiderman AI, Davey VJ. Herbicide Exposure, Vietnam Service, and Hypertension Risk in Army Chemical Corps Veterans. J Occup Environ Med. 2016 Nov;58(11):1127-1136. PubMed PMID: 27820763.

3. Landgren O, Shim YK, Michalek J, Costello R, Burton D, Ketchum N, Calvo KR, Caporaso N, Raveche E, Middleton D, Marti G, Vogt RF Jr. Agent Orange Exposure and Monoclonal Gammopathy of Undetermined Significance: An Operation Ranch Hand Veteran Cohort Study. JAMA Oncol. 2015 Nov;1(8):1061-8. doi: 10.1001/jamaoncol.2015.2938. PubMed PMID: 26335650; PubMed Central PMCID: PMC5701511.