Urinary cadmium and stroke - a case-cohort study in Danish never-smokers

Background: and Purpose: Cadmium has been associated with risk of cardiovascular events, including stroke. Human cadmium exposure occurs primarily through diet and tobacco smoke. Recent cohort studies have found an association with stroke, but residual confounding from smoking, could not be ruled out. We therefore conducted a case-cohort study to evaluate whether cadmium is associated with stroke in never-smokers. Methods: The Danish Diet Cancer and Health cohort consists of Danes 50–64 years old, recruited in 1993–1997. From never-smoking cohort members without previous cancer or stroke we sampled a sub-cohort of 1200 persons. We also identified all (n = 534) cases in the cohort with a validated stroke diagnosis between baseline and 2009. We quantified cadmium and creatinine concentrations from baseline urine samples and used cadmium per creatinine as our main exposure metric. We used Cox proportional hazards models to estimate hazard ratios (HRs) with age as time scale and adjusting for BMI, education and urinary cotinine with and without stratification by sex. Results: The median urinary cadmium concentration was 0.21 μg cadmium/g creatinine in cases and 0.19 μg/g in the sub-cohort. The majority (83%) of stroke cases were diagnosed with ischemic stroke. The HR for stroke in the highest quartile of exposure (median 0.44 μg/g creatinine) was 1.11 (95% CI: 0.79–1.54) compared with the lowest quartile (median 0.10 μg/g creatinine). The HR per inter quartile range (IQR, 0.19 μg/g creatinine) was 1.02 (95% CI: 0.92–1.12). Among men, the HR per IQR higher levels of cadmium (0.16 μg/g creatinine) was 1.18 (95% CI: 0.92–1.52), and 1.00 (95% CI: 0.89–1.12) among women. Adjusting for creatinine or using osmolality instead of creatinine standardization generally attenuated observed relationships. Conclusions: Our results do not support that low levels of cadmium exposure among never-smokers are strongly associated with risk of stroke, although results varied somewhat by sex and method of accounting for urinary dilution.