Human biomonitoring of the alternative plasticizer Di(2-ethylhexyl) terephthalate (DEHTP) - Method development and application for the investigation of human metabolism and risk based exposure…

Di(2-ethylhexyl) terephthalate (DEHTP) is used as an alternative plasticizer in flexible polyvinylproducts like food contact materials, toys and medical devices. Given its advantageous toxicologicalprofile, it is increasingly used to replace classical ortho-phthalate based plasticizers like di(2-ethylhexyl) phthalate (DEHP), that are regulated and phased out due to their proven reprotoxiceffects. Human biomonitoring (HBM) has established itself as a valuable tool for exposureassessment to environmental chemicals. For plasticizers like DEHP, the determination of specific sidechain oxidized monoester metabolites in urine by on-line solid phase extraction liquidchromatography-tandem mass spectrometry (on-line SPE LC-MS/MS) is already applied ininternational population studies to assess exposure and to assist in risk assessment/management.Since significant and increasing exposures to DEHTP in the general population have to be expected,the main goal of this thesis has been the development of an on-line SPE LC-MS/MS method for thesensitive quantification of specific DEHTP metabolites in human urine. The developed method hasthen been applied to elucidate human metabolism of DEHTP in an oral volunteer study. Thederivation of metabolic conversion factors allows back-calculation from urinary metabolite levels toactual amounts taken up (daily intake) in population studies. In a first exposure assessment of adultsand children, we could prove a ubiquitous exposure to DEHTP. By now, general exposure levels seemto be far below levels of concern. However, a maximum exposure above health based guidancevalues (HBM-I) has been detected in one case. In the last part of this thesis, high-resolution massspectrometry (HR-MS) by LC-Quadrupole-Orbitrap-MS has been applied in a software assistedunknown metabolite screening approach. Besides confirmation of the previously developedbiomarkers, further metabolites have been tentatively identified.The results of this thesis show that DEHTP exposure is omnipresent already and increasingexposures are highly likely. The developed method and derived conversion factors will allow toclosely follow trends in exposure and advise regulatory measures if needed.