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. 2015 Nov;1(8):1061-8.
doi: 10.1001/jamaoncol.2015.2938.

Agent Orange Exposure and Monoclonal Gammopathy of Undetermined Significance: An Operation Ranch Hand Veteran Cohort Study

Ola Landgren  1 , Youn K Shim  2 , Joel Michalek  3 , Rene Costello  4 , Debra Burton  4 , Norma Ketchum  3 , Katherine R Calvo  5 , Neil Caporaso  4 , Elizabeth Raveche  6 , Dan Middleton  2 , Gerald Marti  7 , Robert F Vogt Jr  8
Affiliations

Agent Orange Exposure and Monoclonal Gammopathy of Undetermined Significance: An Operation Ranch Hand Veteran Cohort Study

Ola Landgren et al. JAMA Oncol. 2015 Nov.

Abstract

Importance: Multiple myeloma has been classified as exhibiting "limited or suggestive evidence" of an association with exposure to herbicides in Vietnam War veterans. Occupational studies have shown that other pesticides (ie, insecticides, herbicides, fungicides) are associated with excess risk of multiple myeloma and its precursor state, monoclonal gammopathy of undetermined significance (MGUS); however, to our knowledge, no studies have uncovered such an association in Vietnam War veterans.

Objective: To examine the relationship between MGUS and exposure to Agent Orange, including its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in Vietnam War veterans.

Design, setting, and participants: This was a prospective cohort study conducted in 2013 to 2014, testing for MGUS in serum specimens collected and stored in 2002 by the Air Force Health Study (AFHS). The relevant exposure data collected by the AFHS was also used. We tested all specimens in 2013 without knowledge of the exposure status. The AFHS included former US Air Force personnel who participated in Operation Ranch Hand (Ranch Hand veterans) and other US 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 (comparison veterans). Agent Orange was used by the US Air Force personnel who conducted aerial spray missions of herbicides (Operation Ranch Hand) in Vietnam from 1962 to 1971. We included 479 Ranch Hand veterans and 479 comparison veterans who participated in the 2002 follow-up examination of AFHS.

Exposures: Agent Orange and TCDD. Serum TCDD levels were measured in 1987, 1992, 1997, and 2002.

Main outcomes and measures: Risk of MGUS measured by prevalence, odds ratios (ORs), and 95% CIs.

Results: The 479 Ranch Hand veterans and 479 comparison veterans had similar demographic and lifestyle characteristics and medical histories. The crude prevalence of overall MGUS was 7.1% (34 of 479) in Ranch Hand veterans and 3.1% (15 of 479) in comparison veterans. This translated into a 2.4-fold increased risk for MGUS in Ranch Hand veterans than comparison veterans after adjusting for age, race, BMI in 2002, and the change in BMI between 2002 and the time of blood draw for TCDD measurement (adjusted OR, 2.37; 95% CI, 1.27-4.44; P=.007).

Conclusions and relevance: Operation Ranch Hand veterans have a significantly increased risk of MGUS, supporting an association between Agent Orange exposure and multiple myeloma.

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Figures

Figure 1
Figure 1
Adjusted Odds Ratios of MGUS among US Veterans Associated with TCDD Exposure and Operation Ranch Hand Abbreviations: OR, odds ratio; 95% CI, 95% confidence interval; MGUS, monoclonal gammopathy of undetermined significance; TCDD, 2,3,7,8- tetrachlorodibenzo-p-dioxin. Adjusted ORs were estimated for cohort status and for 2,3,7,8-TCDD in separate logistic regression models. Both models included the following covariates: age in 2002 in 5 year increments, race, body mass index in 2002 in increments of 2 units, and change in body mass index between 2002 and at the time of blood draw for the TCDD measurement. Lipid-adjusted TCDD concentrations were either measured in 1987 or, if not measured, reconstructed for the 1987 level using TCDD concentrations measured between 1992 and 2002. Dioxin results below the limit of detection were calculated as the limit of detection divided by the square root of 2. Two Ranch Hand Veterans who had missing BMI or lipid-adjusted TCDD were excluded, leaving 956 Veterans in the analysis.
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