Background: Lead is classified as a probable human carcinogen. However, its role in renal cell cancer (RCC) has not been established. Calcium and vitamin D may off-set toxicity in vivo. Methods: In this nested case-control study, whole blood lead, total serum calcium, and serum 25-hydroxyvitamin Dlevels were measured in blood drawn prior to diagnosis among male smokers participating in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Single-nucleotide polymorphisms (SNP) in five genes (CALB1, TRPV5, TRPV6, VDR, and ALAD) related to lead toxicity or calcium transport were genotyped. Logistic and linear regressions were used to determine RCC risk and time to diagnosis (respectively), adjusting for other risk factors. Results: Among 154 newly diagnosed cases and 308 matched controls, RCC was associated with higher whole blood lead [OR = 2.0; 95% confidence interval (CI), 1.0-3.9; quartile 4 (Q4) vs. Q1, P trend = 0.022] and CALB1 rs1800645 (P trend = 0.025, minor 'T' allele frequency = 0.34). Higher total serum calcium (P trend ≤ 0.001) was associated with reduced RCC risk. Total serum calcium and 25-hydroxyvitamin D levels did not alter the association observed with lead. Time from enrollment to RCC diagnosis was positively associated with serum calcium (P trend = 0.002) and 25-hydroxyvitamin D (P trend = 0.054) among cases. Conclusions: Higher blood lead concentrations, below the 10 mg/dL level of concern, were associated with RCC, independent from serum calcium and CALB1 promoter polymorphism. Impact: Increased risk of RCC is associated with lower serum calcium and higher whole blood lead in smokers. The clinical prognostic value of serum calcium and vitamin D in RCC should be further investigated.
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