Use of a toxicokinetic model in the analysis of cancer mortality in relation to the estimated absorbed dose of dioxin (2,3,7,8-tetrachlorodibenzo- p-dioxin, TCDD)

Abstract

We performed an analysis of All cancer and Lung cancer mortality in relation to estimated absorbed dose of dioxin (2,3,7,8-tetrachlorodibenzo- p-dioxin, TCDD) in the cohort of chemical workers at 12 US plants assembled by the US National Institute for Occupational Safety and Health (NIOSH) ( n=5172). Estimates of cumulative exposure to TCDD were based on a minimal physiologic toxicokinetic model (MPTK) that accounts for inter- and intra-individual variations in body mass index (BMI) over time. Population-level parameters related to liver elimination and background (input or concentration) of TCDD were estimated from separate data with repeated measures of serum TCDD (US Air Force Health Study). An occupational TCDD input parameter was estimated based on one-point-in-time TCDD data available for a subset ( n=253) of the NIOSH cohort. Model-based time-dependent cumulative dose estimates (area under the curve (AUC) of the lipid-adjusted serum TCDD concentration over time) were obtained for members of the full cohort with recorded body height and weight ( n=4049), as this information is required by the MPTK model to compute dose. Missing-value problems arose in the estimation of the occupational input parameter ( n=42) and in TCDD-dose calculation in the full cohort ( n=886) and they were handled with multiple imputation methods. Risk-regression analyses were based on Cox log-linear models including age at entry, year of entry and duration of employment as categorical covariates in addition to the logarithm of cumulative TCDD dose in ppt-years. Risk sets were stratified on birth cohort. Estimates of the unlagged exposure coefficient in these models were 0.1249 [95% confidence interval (CI) 0.0144, 0.2354] for All cancer and 0.2158 (95% CI 0.02376, 0.4078) for lung cancer. A 10-year lag produced an increase in the estimate for all cancer (0.1539, 95% CI 0.0387, 0.2691), whereas, the estimate for lung cancer was not affected much (0.2125, 95% CI 0.0138, 0.4112). At a dose level of 100 times the background the estimates obtained with a 10-year lag translate into a relative risk of 2.03 (95% CI 1.19–3.45) for all cancer and of 2.66 (95% CI 1.07–6.64) for lung cancer. Higher estimates of the exposure coefficients were obtained after imputation of missing values. This increase in risk seemed due to the inclusion of short-term workers, who may exhibit a higher mortality for reasons other than dioxin exposure.