Age- and concentration-dependent elimination half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso children

Abstract

Objective: Pharmacokinetic and statistical analyses are reported to elucidate key variables affecting 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elimination in children and adolescents.

Design: We used blood concentrations to calculate TCDD elimination half-life. Variables examined by statistical analysis include age, latency from exposure, sex, TCDD concentration and quantity in the body, severity of chloracne response, body mass index, and body fat mass.

Participants: Blood was collected from 1976 to 1993 from residents of Seveso, Italy, who were < 18 years of age at the time of a nearby trichlorophenol reactor explosion in July 1976.

Results: TCDD half-life in persons < 18 years of age averaged 1.6 years while those > or =18 years of age averaged 3.2 years. Half-life is strongly associated with age, showing a cohort average increase of 0.12 year half-life per year of age or time since exposure. A significant concentration-dependency is also identified, showing shorter half-lives for TCDD concentrations > 400 ppt for children < 12 years of age and 700 ppt when including adults. Moderate correlations are also observed between half-life and body mass index, body fat mass, TCDD mass, and chloracne response.

Conclusions: Children and adolescents have shorter TCDD half-lives and a slower rate of increase in half-life than adults, and this effect is augmented at higher body burdens.

Relevance: Modeling of TCDD blood concentrations or body burden in humans should take into account the markedly shorter elimination half-life observed in children and adolescents and concentration-dependent effects observed in persons > 400-700 ppt.

Figure 1

Peak TCDD concentration versus ages of Seveso children. Highest reported blood lipid TCDD concentrations for 27 female and 20 male Seveso residents who were < 18 years of age in 1976 and had at least two valid samples.

Figure 2

TCDD half-life versus age of Seveso children. Linear regression analysis of entire cohort (25 females, 20 males) with the half-life since peak TCDD measurement plotted against the person’s age at time of subsequent sampling. See “Materials and Methods” for outliers identified and excluded. See also Table 1.

Figure 3

TCDD half-life versus subsequent blood lipid TCDD concentration for Seveso children < 12 years of age. Data subset excluding all measurements in persons ≥12 years of age, including 13 females and 9 males (43 values). TCDD concentrations above the transition range of 300–400 ppt correspond to uniformly shorter half-lives. Similar trends were apparent when all ages were included, with an observed transition of approximately 700 ppt. See also Table 1.

Figure 4

Individual TCDD half-life versus age for peak TCDD > 2,000 ppt. Subset includes only persons with ≥3 valid half-lives and peak blood lipid TCDD concentration > 2,000 ppt. Each symbol represents an individual with at least three half-life estimates. Linear regression was performed by individual showing parallel slopes (mean ± SD 0.12 ± 0.036 year/year) and 7 of 10 individuals with r² ≥0.91 (data not shown). Similar trends were found for 7 individuals with 3 or more valid half-lives and peak TCDD < 2000 ppt, showing parallel slopes (0.14 ± 0.062 year/year) and 5 of 7 individuals with r² ≥0.88 (data not shown).

Figure 5

Individual trends for TCDD half-life versus age for peak exposure at < 7 years of age. Subset includes only persons with ≥3 valid half-lives and < 7 years of age at time of peak blood lipid TCDD concentration. Each symbol represents an individual with at least three half-life estimates. Linear regression was performed by individual showing parallel slopes (mean ± SD 0.09 ± 0.027 year/year) and 6 of 7 individuals with r² ≥0.93 (data not shown).

Figure 6

TCDD Mass in the body fat versus age of Seveso children for peak TCDD mass > 10,000 ng. Subset including only persons with ≥3 valid half-lives and peak TCDD mass > 10,000 ng. Each symbol represents an individual with at least three TCDD mass determinations. (A) TCDD mass in linear scale; TCDD mass = 50,000 ng to help visualize trends apparent < 10,000 ng at time of sampling. (B) TCDD mass in log scale with no truncation of data. The estimated transition point for shorter TCDD half-life is > 7,000 ng. See also Table 1.