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5667842 
Journal Article 
Development and validation of PBPK model for DEHP and its metabolites: Application to cohort and case-control studies 
Prasad Sharma, R; Schuhmacher, M; Kumar, V 
2017 
1 
Toxicology Letters
ISSN: 0378-4274
EISSN: 1879-3169 
280 
Suppl. 1 
S284-S284 
English 
WOS:000425486700723 
DEHP and its metabolites have a short half-life. The temporal variability in their exposure over a long period of time from the different source such as food, diet, cosmetics, toys, medical products and food wraps, leads to a stable microenvironmental exposure causing a pseudo steady state concentration in humans. DEHP is converted to its primary monoester metabolite (MEHP) in the body which is further metabolizes into different chemical forms such as: 5OHMEHP, 5oxoMEHP, 5cxMEPP and 2cx-MMHP. In a rat study it has been found that the potency of DEHP and its metabolite MEHP for hepatotoxicity and reproductive toxicity is very high. A simple pharmacokinetic modeling has been developed that accounts for major metabolites. However, a target tissue dosimetry model of PKPD is lacking, which is especially important for chemicals like DEHP that undergo extensive enterohepatic recirculation to produce toxic metabolites increasing effective exposure to liver. The objective of this study is to develop and validate a PBPK model for DEHP and its metabolites. The model simulates different exposure scenarios for different cohort studies. The study also accounted for uncertainty and variability to develop a PBPK model for different parameters such as metabolic, physicochemical and physiology. The model was validated using control human kinetic study data that represents the time course of the DEHP and its metabolites in blood and urine. This validated model was used for simulation of the time course of chemicals in blood, urine and other organs, for selected cohort population studies accounting for population exposure variability.