Concentration-dependent TCDD elimination kinetics in humans: toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort

Abstract

Serial measurements of serum lipid 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations in 36 adults from Seveso, Italy, and three patients from Vienna, Austria, with initial serum lipid TCDD concentrations ranging from 130 to 144,000 ppt, were modeled using a modified version of a previously published toxicokinetic model for the distribution and elimination of dioxins. The original model structure accounted for a concentration-dependent increase in overall elimination rate for TCDD due to nonlinear distribution of TCDD to the liver (secondary to induction of the binding protein CYP1A2), from which elimination takes place via a first-order process. The original model structure was modified to include elimination due to lipid partitioning of TCDD from circulation into the large intestine, based on published human data. We optimized the fit of the modified model to the data by varying the hepatic elimination rate parameter for each of the 39 people. The model fits indicate that there is significant interindividual variability of TCDD elimination efficiency in humans and also demonstrate faster elimination in men compared to women, and in younger vs. older persons. The data and model results indicate that, for males, the mean apparent half-life for TCDD (as reflected in changes in predicted serum lipid TCDD level) ranges from less than 3 years at serum lipid levels above 10,000 ppt to over 10 years at serum lipid levels below 50 ppt. Application of the model to serum sampling data from the cohort of US herbicide-manufacturing workers assembled by the National Institute of Occupational Safety and Health (NIOSH) indicates that previous estimates of peak serum lipid TCDD concentrations in dioxin-exposed manufacturing workers, based on first-order backextrapolations with half-lives of 7-9 years, may have underestimated the maximum concentrations in these workers and other occupational cohorts by several-fold to an order of magnitude or more. Such dose estimates, based on a single sampling point decades after last exposure, are highly variable and dependent on a variety of assumptions and factors that cannot be fully determined, including interindividual variations in elimination efficiency. Dose estimates for these cohorts should be re-evaluated in light of the demonstration of concentration-dependent elimination kinetics for TCDD, and the large degree of uncertainty in back-calculated dose estimates should be explicitly incorporated in quantitative estimates of TCDD's carcinogenic potency based on such data.

Serum concentrations of chlorinated dibenzo-p-dioxins, furans and PCBs, among former phenoxy herbicide production workers and firefighters in New Zealand

“…In linear regression adjusting for occupation, female sex was generally associated with higher serum concentrations for most compounds except for PCB#189, which was a pattern very similar to that observed for BMI. Although in New Zealand general population studies, serum concentrations of TCDD and other POPs have not been found to be different between men and women ('t Mannetje et al 2013), in a study of highly exposed individuals men had faster elimination of TCDD compared to women (Aylward et al 2005) which may explain our findings.…”

“…Given that the relationship between current serum measurements and 'actual' historical exposure is subject to inter-individual variations in elimination efficiency (Aylward et al 2005), and the elimination rate is also shown to be dose-dependent (Aylward et al 2005), our backcalculated TCDD exposure based on a single half-life for all participants is only an approximate indication of historical serum concentrations. Nevertheless, this study has shown that 20 years after production of 2,4,5-T had ceased, levels of TCDD and PeCDD were elevated in former workers from specific locations and occupations within the production plant.…”

Serum dioxin levels in former chlorophenol workers

“…In all, 30 of the 52 chlorophenol workers had 2,3,7,8-TCDD levels, which were higher than background found in this study of 6.0 ppt. We estimate that the mean level of 2,3,7,8-TCDD present in the serum of these 30 workers on the date workplace exposure terminated was 267 ppt (ranging from 8 to 1184 ppt) assuming a 9-year half-life, 582 ppt (ranging from 10 to 2641 ppt) assuming a 7-year half-life, and 1928 ppt (ranging from 22 to 17,847) when the toxicokinetic model proposed by Aylward et al (2005) is used.…”

“…The first method assumes a one-compartment first-order kinetic model with a half-life of 9 or 7 years (Flesch-Janys et al, 1996). The second method uses a recently developed toxicokinetic model elimination of 2,3,7,8-TCDD (Aylward et al, 2005). This model takes into account the concentration dependent elimination of 2,3,7,8-TCDD to the liver as well as the lipid partitioning from circulation into the large intestines.…”

TCDD exposure estimation for workers at a New Zealand 2,4,5-T manufacturing facility based on serum sampling data

“…Exposure estimation based on serum sampling data, work history records, and pharmacokinetic modeling has been used as a tool for assessing historical occupational exposures to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in workers involved in the manufacture of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) (Ott and Zober 1996;Steenland et al, 2001;Crump et al, 2003;Aylward et al, 2005a). Because TCDD is highly persistent in human tissues, elevated exposures occurring many years before measurement in serum can be detected.…”