Human Blood Concentrations of Dichlorodiphenyltrichloroethane (DDT) Extrapolated from Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling

Abstract

The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for dichlorodiphenyltrichloroethane [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, DDT] in humans based on metabolic parameters determined in vitro using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and an established rat PBPK model. The model consists of an absorption compartment, a metabolizing liver compartment, and a central compartment for DDT. Evaluation of the rat model was performed by making comparisons between predicted concentrations in blood and in vivo experimental pharmacokinetic values obtained from rats after daily oral treatment with DDT (10 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of DDT in vitro were established from data from rat liver microsomes and from pooled human liver microsomes. The ratio of intrinsic clearance values of DDT based on rat in vivo and rat in vitro experiments was used as the scaling factor for estimating in vivo hepatic intrinsic clearance in humans in the final human PBPK model. These results indicate that a simplified PBPK model for DDT is useful for a forward dosimetry approach in rats and/or humans and for estimating blood concentrations of other related compounds resulting from exposure to low chemical doses.

Screening of chemicals for human bioaccumulative potential with a physiologically based toxicokinetic model

“…However, similar results were obtained. In addition, we had included, subject to the availability of data in the literature, several compounds: PCBs, PFOS and DDT (Parham and Portier 1998 ; Loccisano et al 2011 ; Yamazaki et al 2010 ). The list of selected chemicals as well as their physico-chemical parameters has been provided in the Supplementary Material, Table 1.…”

Blood Concentrations of 1,4-Dioxane in Humans after Oral Administration Extrapolated from In Vivo Rat Pharmacokinetics, In Vitro Human Metabolism, and Physiologically Based Pharmacokinetic Modeling

“…3,20) Evaluation of a previously developed rat model was performed by comparing the blood concentrations predicted by PBPK modeling in silico and experimental biokinetic values from plasma and urine obtained from rats in vivo after repeated oral treatment with 1,4-dioxane at an NOAEL. To overcome the species differences in animals and humans, the traditional parallelogram technique used in systems biology, 21) namely the concept of animal-human-in vitro-in vivo parallelogram in the risk assessment system 22,23) , was adapted for this study to estimate the value of in vivo human hepatic clearance from in vitro data (Table 3). In summary, the present study indicates that simplified PBPK modeling for 1,4-dioxane is useful for a forward dosimetry approach in rats and humans to estimate blood concentrations of 1,4-dioxane and other related 1,4-dioxane-like compounds from low chemical doses such as those at the NOAEL.…”

Developmental Exposure to Endocrine Disrupter DDT Interferes with Age-Related Involution of Thymus

“…The rats were sacrificed by zoletil overdosage in the post-pubertal period at the age of 10 weeks. The average daily intake of DDT after weaning was 2.90 ± 0.12 µg/kg bw, which corresponded to DDT consumption by humans with food products with consideration for differences in DDT metabolism in rats and humans [ 51 ]. The absence of DDT, its metabolites, and related organochlorine compounds in tap water and chow was confirmed by gas chromatography in Moscow Federal Budgetary Institution of Public Health.…”