Agent Orange Exposure and Monoclonal Gammopathy of Undetermined Significance

Landgren, Ola; Shim, Youn K.; Michalek, Joel E.; Costello, Rene; Burton, Deborah; Ketchum, Norma S.; Calvo, Katherine R.; Caporaso, Neil E.; Raveché, Elizabeth; Middleton, Dan; Marti, Gerald E.; Vogt, Robert F.

doi:10.1001/jamaoncol.2015.2938

Cited by 57 publications

(53 citation statements)

References 43 publications

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“…A few personal risk factors of MGUS include black race, autoimmune disease, prior infections or exposure to herbicides242526. MGUS is associated with the risk of bone fractures and of arterial and venal thrombosis2728.…”

Section: Discussionmentioning

confidence: 99%

The Incidence of Senile Cataract and Glaucoma is Increased in Patients with Plasma Cell Dyscrasias: Etiologic Implications

Hemminki

Försti

Tuuminen

et al. 2016

Sci Rep

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Plasma cell dyscrasias, including monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), Waldenström macroglobulinemia (WM) and light chain AL amyloidosis, are characterized by clonal expansion of plasma cells which produce a vast amount of an immunoglobulin-derived M-protein. We noted that MGUS diagnosis often coincided with diagnoses of senile cataract and glaucoma and tested the associations of MGUS, MM, WM and AL amyloidosis with subsequent eye diseases identified from the Swedish patient registers between 1997 and 2012. Standardized incidence ratios (SIRs) for senile cataract was significantly increased to 1.80 after MGUS, 1.70 after MM, 1.85 after WM and 2.31 after AL amyloidosis. The SIR for glaucoma was 1.60 after MGUS, 1.76 after WM and 2.18 after AL amyloidosis. All SIRs decreased systematically from age below 60 years to over 79 years, but most risks were also significant in age group over 79 years. The M-protein and the related increase in blood viscosity could be a novel etiologic discovery for these common eye diseases. As MGUS prevalence is around 3% at 60 years and close to 10% at age over 80 years, its contribution to the eye disease burden is expected to be remarkably high.

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Section: Discussionmentioning

confidence: 99%

The Incidence of Senile Cataract and Glaucoma is Increased in Patients with Plasma Cell Dyscrasias: Etiologic Implications

Hemminki

Försti

Tuuminen

et al. 2016

Sci Rep

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“…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 in the controls. The TCDD levels were measured from samples collected in 1987 or back-calculated based on predicted half-life if samples were collected later.…”

mentioning

confidence: 81%

“…[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).…”

mentioning

confidence: 88%

“…The study by Landgren 8 has brought clarity to the risk of AO exposure and plasma cell disorder. It also highlights the importance of tissue banking that allows investigation of a number of unanswered questions using modern methods.…”

Section: 12mentioning

confidence: 99%

“…The Institute of Medicine 7 has identified a predisposition to 7 types of malignant neoplasms in veterans exposed to AO. Four of these, including 1 reported by Landgren et al,8 are Bcell lymphoid neoplasms, raising an interesting question as to why B cells are at a greater risk of transformation. Newer tech-…”

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confidence: 97%

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Association of Agent Orange With Plasma Cell Disorder

Munshi

2015

JAMA Oncol

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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...

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Exposure to Agent Orange and Risk of Bladder Cancer Among US Veterans

et al. 2023

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ImportanceTo date, limited data exist regarding the association between Agent Orange and bladder cancer, and the Institute of Medicine concluded that the association between exposure to Agent Orange and bladder cancer outcomes is an area of needed research.ObjectiveTo examine the association between bladder cancer risk and exposure to Agent Orange among male Vietnam veterans.Design, Setting, and ParticipantsThis nationwide Veterans Affairs (VA) retrospective cohort study assesses the association between exposure to Agent Orange and bladder cancer risk among 2 517 926 male Vietnam veterans treated in the VA Health System nationwide from January 1, 2001, to December 31, 2019. Statistical analysis was performed from December 14, 2021, to May 3, 2023.ExposureAgent Orange.Main Outcomes and MeasuresVeterans exposed to Agent Orange were matched in a 1:3 ratio to unexposed veterans on age, race and ethnicity, military branch, and year of service entry. Risk of bladder cancer was measured by incidence. Aggressiveness of bladder cancer was measured by muscle-invasion status using natural language processing.ResultsAmong the 2 517 926 male veterans (median age at VA entry, 60.0 years [IQR, 56.0-64.0 years]) who met inclusion criteria, there were 629 907 veterans (25.0%) with Agent Orange exposure and 1 888 019 matched veterans (75.0%) without Agent Orange exposure. Agent Orange exposure was associated with a significantly increased risk of bladder cancer, although the association was very slight (hazard ratio [HR], 1.04; 95% CI, 1.02-1.06). When stratified by median age at VA entry, Agent Orange was not associated with bladder cancer risk among veterans older than the median age but was associated with increased bladder cancer risk among veterans younger than the median age (HR, 1.07; 95% CI, 1.04-1.10). Among veterans with a diagnosis of bladder cancer, Agent Orange was associated with lower odds of muscle-invasive bladder cancer (odds ratio [OR], 0.91; 95% CI, 0.85-0.98).Conclusions and RelevanceIn this cohort study among male Vietnam veterans, there was a modestly increased risk of bladder cancer—but not aggressiveness of bladder cancer—among those exposed to Agent Orange. These findings suggest an association between Agent Orange exposure and bladder cancer, although the clinical relevance of this was unclear.

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Agent Orange Exposure and Monoclonal Gammopathy of Undetermined Significance

Cited by 57 publications

References 43 publications

The Incidence of Senile Cataract and Glaucoma is Increased in Patients with Plasma Cell Dyscrasias: Etiologic Implications

The Incidence of Senile Cataract and Glaucoma is Increased in Patients with Plasma Cell Dyscrasias: Etiologic Implications

Association of Agent Orange With Plasma Cell Disorder

Exposure to Agent Orange and Risk of Bladder Cancer Among US Veterans

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