Association of Agent Orange With Plasma Cell Disorder

Abstract

Our understanding of multiple myeloma (MM) has significantly improved in recent years with the availability of modern laboratory techniques. Molecular investigations have identified a wide heterogeneity in myeloma at the genomic and epigenomic levels 1-3 and provided improved understanding of the disease pathogenesis. However, etiological factors are not well characterized. Besides older age, male sex, and African American ancestry, association of other features remain ill defined. Exposure to ionizing radiation is the strongest single factor linked to an increased risk of MM. Although association with exposure to benzene and petroleum products and to agricultural chemicals including Agent Orange (AO) have been considered as potential risk factors, their precise relationship remains unclear.A meta-analyses of 32 peer-reviewed studies on the association between farming and exposure to pesticides showed a consistent significant association between MM and farming. [4][5][6] However, a report by the Institute of Medicine 7 indicates that there is limited or suggestive evidence of an association between the chemicals of interest (AO) and MM, AL amyloidosis, and laryngeal, lung, and prostate cancer. The study by Landgren et al 8 in this issue of the JAMA Oncology now provides further evidence of an association between AO exposure and development of plasma cell disorder. The study reports a 7.1% prevalence of monoclonal gammopathy of undetermined significance (MGUS) in 479 Operation Ranch Hand veterans exposed to AO while serving as US Air Force personnel conducting aerial spray missions of herbicides in Vietnam (between 1962 and 1971) compared with a 3.1% prevalence in controls who were not exposed (adjusted odds ratio, 2.37; P = .007). The results are more meaningful because the authors also identified, in the group exposed to AO and developing MGUS, significantly higher serum levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an unintended contaminant of AO that is considered responsible for most of the adverse effects of AO. Although this study associated risk of MGUS with AO exposure, the fact that all MM cases originate from MGUS 9 provides the first scientific evidence for a direct link between MM and AO exposure. The strengths of this study include well-characterized samples, a long follow-up period (25 years), and availability of measurements of toxin exposure. A similar association between pesticide exposure and risk of MGUS has been demonstrated in the Agricultural Health Study, 10 in which the ageadjusted prevalence of MGUS was 1.9-fold (95% CI, 1.3-to 2.7-fold) higher among male pesticide applicators, and there was a suggestion that specific pesticides are causatively linked to myelomagenesis. In the study by Landgren et al, 8 the similar frequency of MGUS between age groups 60 to 69 years and 70 years or older in AO-exposed participants may indicate that all of those predisposed may develop MGUS at an earlier age with lack of further increase, which is observed with advancing age and was also observed i...

The Association of Agent Orange (AO) Exposure with Monoclonal Gammopathy of Undetermined Significance (MGUS) to Multiple Myeloma (MM) Progression: A Population-based Study of Vietnam War Era Veterans

“…10,30 AO and other herbicidal agents had varying levels of TCDD, the most carcinogenic component. [7][8][9][10] Agents Pink, Green, and Purple, used from January 1962 to November 1965, have some of the highest recorded levels. 11,12 Our results suggest that there may be a dose-dependent relationship between higher levels of TCDD exposure and progression as our study shows that the high exposure group (1/9/1962 and 11/30/1965) has the highest risk of progression.…”

“…A contaminant commonly found in AO and the other herbicidal agents, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is its most carcinogenic component. [7][8][9][10] All agents had varying levels of TCDD with Agents Pink, Green, and Purple having almost 16 times the amount compared to AO (up to 66ppm versus 13ppm for AO). 11 Agents Pink, Green, and Purple were largely used from January 1962 to November 1965 whereas Agent Orange was used from December 1965 to December 1970.…”

The Association of Agent Orange Exposure with the progression of monoclonal gammopathy of undetermined significance to multiple myeloma: a population-based study of Vietnam War Era Veterans

“…Agent Orange (AO) exposure is associated with an increased risk of both MGUS and MM [ 1 , 2 ]. The term “Agent Orange” has been broadly used to refer to all the herbicidal agents (i.e., Agents Pink, Green, Purple, White, Orange, and Blue) used during the Vietnam War Era (1/9/1962–5/7/1975).…”