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

IMPORTANCE: To 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. OBJECTIVE: To examine the association between bladder cancer risk and exposure to Agent Orange among male Vietnam veterans. DESIGN, SETTING, AND PARTICIPANTS: This 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. EXPOSURE: Agent Orange. MAIN OUTCOMES AND MEASURES: Veterans 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. RESULTS: Among 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 RELEVANCE: In 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.