A recent review published in the journal Leukemia & Lymphoma examined potential relationships between leukemogenesis, Agent Orange (AO), and a dioxin commonly found as a contaminant of AO. The review was written by Rory M. Shallis, MD, and Steven D. Gore, MD, of the Yale University School of Medicine and Yale Cancer Center in New Haven, Connecticut.
AO is an herbicide that was deployed as a defoliant in Vietnam during the Vietnam War, and it contains a mixture of 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). As Drs Shallis and Gore noted in their review, 2,4,5-T has been considered by the US Veterans’ Administration (VA) to often be contaminated by a dioxin called 2,3,7,8-tetrachlorodiobenzo-p-dioxin (TCDD). The authors also explained that TCDD has been associated with carcinogenicity, including greater risks of some hematologic malignancies.
In their review that was focused on acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), the authors explained that studies exploring connections between AO and AML/MDS have been limited by a low incidence of AML/MDS and by factors related to study design. However, Drs Shallis and Gore presented available, relevant literature-based findings involving AO and leukemogenicity.
One aspect of the biological plausibility for a relationship between TCDD exposure and AML/MDS is related to the ability of this dioxin — which has a long half-life of 4 to 15 years — to accumulate in adipose tissue, according to the authors. “Dioxin exposure can therefore be considered a ‘time-release’ formulation of a potential carcinogen, which may be important with diseases with long latency periods such as AML/MDS,” the authors wrote in their report.
Drs Shallis and Gore additionally described preclinical evidence for leukemogenicity with AO, including an effect of TCDD on the aryl hydrocarbon receptor (AHR), which is important to the health of hematopoietic stem and progenitor cell (HSPC) health. “TCDD-induced AHR defects have been implicated in HSPC injury and leukemogenesis,” they wrote. They also described chromosomal abnormalities potentially associated with benzene, which they explained is a possible metabolite of dioxin or TCDD metabolism.
Drs Shallis and Gore presented multiple epidemiological studies evaluating dioxin exposure and discussed reported risks of a variety of disease- and mortality-related outcomes. For example, a retrospective analysis of a population of residents in TCDD-contaminated areas near a chemical reactor explosion in 1976 showed an elevated rate of cancers in these residents. In an affected zone with follow-up through 1996, the relative risk of myeloid leukemia was 2.41 (95% CI, 1.12-5.18).
The authors wrote in their report that “acknowledgment by the VA that AO was contaminated by TCDD, the known carcinogenicity of TCDD, the strong biological rationale for TCDD-mediated leukemogenesis and the increased risk of myeloid leukemia/AML-related death in analogous TCDD-exposed retrospective cohorts should serve as meaningful evidence to support the claim of the innumerable veterans that their AML/MDS was related to AO exposure.”
Shallis RM, Gore SD. Agent Orange and dioxin-induced myeloid leukemia: a weaponized vehicle of leukemogenesis. Leuk Lymphoma. Published online February 2, 2022. doi:10.1080/10428194.2022.2034156