Agricultural glyphosate use and early-onset colorectal cancer mortality in the United States

PURPOSE Early-onset colorectal cancer (CRC) (diagnosis before age 50 years) incidence has risen dramatically. Individuals born in the 1990s compared to the 1960s have a four-fold higher risk for early-onset CRC. Recent evidence suggests that risk factors experienced in early life and/or emerging in relatively later generations may play an etiologic role in early-onset CRC. One environmental exposure potentially contributing to the surge in early-onset CRC is glyphosate, the most widely utilized herbicide in the world that substantially increased in usage following the introduction of glyphosate-resistant crops in 1996. Glyphosate is hypothesized to promote colorectal carcinogenesis through mechanisms such as gut microbiome dysbiosis. Our objective was to conduct an epidemiologic study examining the association between agricultural glyphosate use and risk for early-onset CRC-specific mortality in the United States. METHODS We extracted mortality and sociodemographic data from death certificates of all individuals in the United States who died from early-onset CRC (defined as death before age 50) (ICD-9 153.0-153.4, 153.6-154.1; ICD-10 C18.0, C18.2-C18.9, C19, C20) from 1989-2023 from the National Center for Health Statistics. Annual average glyphosate use was estimated by linking nationwide agricultural pesticide application data from the United States Geological Survey with the year and county of residence at death. Quasi-Poisson regression with robust standard errors was used to estimate mortality rate ratios (MRRs) with 95% confidence intervals (CIs) for the association between glyphosate use and early-onset CRC-specific mortality risk adjusted for individual-level age, sex, race, ethnicity, year, marital status, and education level, and county-level socioeconomic status. RESULTS A total of 108,315 deaths from CRC among those <50 years old were included in this study. We observed a statistically significant dose-response relationship, in which higher annual average glyphosate use was associated with incremental increases in risk for CRC-specific mortality (adjusted MRR highest quintile (>5.74 kg/km2) vs. lowest quintile (<=0.08 kg/km2): 1.10, 95% CI 1.06-1.13; p trend <0.0001). CONCLUSIONS Higher agricultural glyphosate use was associated with increased risk for early-onset CRC-specific mortality in the United States. Future research should further explore the role of glyphosate in early-onset CRC through examining incidence outcomes and life-course exposures using residential address histories.