Use of a toxicokinetic model in the analysis of cancer mortality in relation to the estimated absorbed dose of dioxin ž2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD/

We performed an analysis of All cancer and Lung cancer mortality in relation to estimated absorbed dose of dioxin Ž2,3,7,8-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 ŽNIOSH. Žn 5172.. Estimates of cumulative exposure to TCDD were based on a minimal physiologic toxicokinetic model ŽMPTK. that accounts for inter- and intra-individual variations in body mass index ŽBMI. over time. Population-level parameters related to liver elimination and background Žinput or concentration. of TCDD were estimated from separate data with repeated measures of serum TCDD ŽUS Air Force Health Study.. An occupational TCDD input parameter was estimated based on one-point-in-time TCDD data available for a subset Žn 253. of the NIOSH cohort. Model-based time-dependent cumulative dose estimates Žarea under the curve ŽAUC. of the lipid-adjusted serum TCDD concentration over time. were obtained for members of the full cohort with recorded body height and weight Žn 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 Žn 42. and in TCDD-dose calculation in the full cohort Žn 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 ŽCI. 0.0144, 0.2354 for All cancer and 0.2158 Ž95% CI 0.02376, 0.4078. for lung cancer. A 10-year lag produced an increase in the estimate for all cancer Ž0.1539, 95% CI 0.0387, 0.2691., whereas, the estimate for lung cancer was not affected much Ž0.2125, 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