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Estimating previous serum TCDD concentrations in an occupationally exposed cohort using a PDPK model.

Dankovic-DA; Anderson-MF
Toxicologist 2002 Mar; 66(1-S):50
This study estimated previous serum concentrations of 2, 3, 7, 8-tetrachlorodibenzo-rho-dioxin (TCDD) in 134 male workers involved in producing sodium trichlorophenol or a derivative. These workers conceived children either during or after this employment. The estimated TCDD concentrations at the time of conception of children were used in a male reproductive health study (in press). Serum TCDD concentrations were estimated with a PBPK model. Available data were serum TCDD level at the end of the study, dates of employment in dioxin-related processes, and body mass index (BMl) at the end of the study and an earlier time point.. A linear regression model estimated missing BMI values for 23 workers who had only one measured BMI. Each worker was assumed to have constant "background" exposure to TCDD, estimated from measured serum TCDD values in 79 controls. Individual occupational TCDD exposure rates were estimated for each worker based on final measured serum TCDD concentration and dates of exposure in TCDD-related processes. TCDD elimination in the PBPK model is proportional to hepatic TCDD concentration; the major site of storage is the fat compartment. The hepatic elimination rate constant for TCDD in this model was previously estimated from the Air Force Ranch Hand study. Although the instantaneous elimination rate of TCDD in the model is first-order, changes in body far composition over time lead to non-linear kinetics. Unlike other simple first-order models, the volume of distribution of TCDD varies as BMI changes over time. The major conclusions are: (1) the retrospective serum TCDD concentrations are highly dependent on changes in body fat; and (2) data on individual body weight changes, as well as on TCDD exposures, should be gathered when modeling the long-term pharmacokinetic behavior of TCDD in humans. Use of this BMI-linked PBPK model for TCDD permits the investigator to distinguish between plasma kinetics and the whole-body kinetics of TCDD.
Humans; Workers; Reproductive-hazards; Dioxins; Body-retention
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The Toxicologist. Society of Toxicology 41st Annual Meeting and ToxExpo, March 17-21, 2002, Nashville, Tennessee