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Exposure to Agent Orange was associated with a modestly increased risk of bladder cancer among Vietnam War veterans, according to a retrospective cohort study.

Among over 2.5 million male veterans, exposure to Agent Orange was associated with a relative 4% higher risk of bladder cancer (HR 1.04, 95% CI 1.02-1.06, P<0.001), reported Stephen Williams, MD, MBA, of the University of Texas Medical Branch at Galveston, and colleagues.

"These results support prior investigations and further support bladder cancer to be designated as an Agent Orange-associated disease," they wrote in .

In an email to MedPage Today, Williams noted that this "study is the largest study to date using the largest equal-access system, which found an association between Agent Orange and and bladder cancer risk. This association was modest, but important, and we controlled for known risk factors, including smoking and deployment."

There was no association between Agent Orange exposure and the aggressiveness of bladder cancer, with those with exposure having a lower odds of diagnosis of muscle-invasive bladder cancer (MIBC; OR 0.91, 95% CI 0.85-0.98, P=0.009).

"Although we cannot determine causality given the retrospective nature of our study design, this observation may be due to earlier bladder cancer detection in the group exposed to Agent Orange," the authors wrote. "Moreover, given the increasing number of Agent Orange-related diseases, routine urinalysis and subsequent workup and/or screening may be initiated and may lead to earlier detection and less-advanced bladder cancer disease."

Notably, Williams and team found that Agent Orange exposure was associated with an increased risk of bladder cancer among veterans younger than the median age at service entry (HR 1.07, 95% CI 1.04-1.10), while no significant association was seen for veterans older than the median age (HR 1.03, 95% CI 0.99-1.05, P=0.04 for interaction).

"Thus, younger Vietnam veterans exposed to Agent Orange with potentially more life-years to develop bladder cancer were at greatest risk," they wrote. "This finding is critical because bladder cancer is more commonly diagnosed in older individuals, corresponding to the age of most Vietnam veterans who may have been exposed to Agent Orange."

The authors also found a decreased risk of bladder cancer among Black veterans versus white veterans (HR 0.65, 95% CI 0.63-0.67), and the same was true for other racial groups (HR 0.76, 95% CI 0.72-0.80). There was an increased risk of bladder cancer among current smokers versus never smokers (HR 2.02, 95% CI 1.97-2.07).

Marine Corps veterans had the greatest risk of bladder cancer (HR 1.07, 95% CI 1.04-1.10) compared with Army veterans. In addition, Agent Orange exposure was associated with an increased risk for bladder cancer among veterans who entered the military between 1969 and 1975 (HR 1.08, 95% CI 1.04-1.12).

Notably, those with the highest socioeconomic status were most likely to be diagnosed with bladder cancer (HR 1.07, 95% CI 1.05-1.10).

While there was a decreased odds of diagnosis of MIBC overall, odds were increased among Black versus white veterans (OR 1.16, 95% CI 1.05-1.28), while veterans with the highest socioeconomic status had the lowest odds of receiving a diagnosis of MIBC (OR 0.88, 95% CI 0.80-0.96). Current smokers (OR 1.10, 95% CI 1.00-1.21) and former smokers (OR 1.08, 95% CI 1.00-1.18) had higher odds of an MIBC diagnosis compared with veterans who never smoked.

In explaining the rationale behind the study, Williams and colleagues noted that while Veterans Affairs (VA) has designated bladder cancer as a cancer caused by Agent Orange exposure, a comprehensive analysis of Agent Orange exposure and bladder cancer had yet to be conducted. They suggested that this is "mainly due to the small numbers of exposed cases, the lack of ability to identify Agent Orange exposure, and the lack of an ability to control for known confounders, particularly smoking, a major bladder cancer risk factor."

For this study, Williams and team included 2,517,926 male Vietnam veterans treated in the VA Health System nationwide from January 2001 through December 2019. Median age at VA entry was 60.

A quarter of these veterans had Agent Orange exposure, while the remainder had no exposure.

During a follow-up of 28,672,655 person-years, there were a total of 50,781 bladder cancer diagnoses -- 2.1% among veterans exposed to Agent Orange and 2.0% among those unexposed. The incidence of bladder cancer was 1.84 versus 1.75 cases per 1,000 person-years, respectively.

Williams and colleagues said that they cannot exclude potential selection bias and misclassification bias.

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