Lessmann Frederik, Schütze André, Weiss Tobias, Langsch Angelika, Otter Rainer, Brüning Thomas, Koch Holger M
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-Universität Bochum (IPA), Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Germany.
BASF SE, Ludwigshafen, Germany.
Arch Toxicol. 2016 Jul;90(7):1659-67. doi: 10.1007/s00204-016-1715-x. Epub 2016 Apr 26.
Di(2-ethylhexyl) terephthalate (DEHTP) is used as a substitute for di(2-ethylhexyl) phthalate (DEHP), an ortho-phthalate-based plasticizer that is classified and labeled due to its toxicity to reproduction. In this study the metabolism and urinary excretion kinetics of DEHTP were investigated by single oral dosage of 50 mg DEHTP to three male volunteers (resulting in individual dosages between 0.55 and 0.59 mg/kg body weight). Separate urine samples were consecutively collected for 48 h. In analogy to DEHP, we quantified specific side-chain-oxidized monoester metabolites of DEHTP (5OH-MEHTP, 5oxo-MEHTP, 5cx-MEPTP and 2cx-MMHTP) by HPLC-MS/MS with online sample clean-up and isotope dilution. All postulated metabolites were detectable in all samples after dosage. The predominant, specific urinary metabolite was 5cx-MEPTP representing about 13.0 % of the applied dose as mean of the three volunteers (range 7.0-20.4 %) in urine, followed by 5OH-MEHTP (mean: 1.8 %; range 1.3-2.4 %) and 5oxo MEHTP (mean: 1.0 %; range 0.6-1.6 %). 2cx-MMHTP was a minor metabolite representing only 0.3 % (range 0.2-0.4 %). In total, about 16.1 % of the dose was recovered in urine as the above investigated specific metabolites within 48 h with the major share (95 %) being excreted within the first 24 h. Investigation of the glucuronidation patterns revealed that the carboxy-metabolites are excreted almost completely in their free form (>90 %), whereas for 5OH-MEHTP and 5oxo-MEHTP, glucuronidation is preferred (>70 %). With this study we provide reliable urinary excretion factors to calculate DEHTP intakes based on metabolite concentrations in environmental and occupational studies.
对苯二甲酸二（2-乙基己基）酯（DEHTP）被用作邻苯二甲酸二（2-乙基己基）酯（DEHP）的替代品，DEHP是一种基于邻苯二甲酸酯的增塑剂，因其对生殖系统的毒性而被分类和标记。在本研究中，通过对三名男性志愿者单次口服50mg DEHTP（个体剂量在0.55至0.59mg/kg体重之间）来研究DEHTP的代谢和尿排泄动力学。连续收集48小时的单独尿液样本。与DEHP类似，我们通过在线样品净化和同位素稀释的HPLC-MS/MS对DEHTP的特定侧链氧化单酯代谢物（5OH-MEHTP、5oxo-MEHTP、5cx-MEPTP和2cx-MMHTP）进行定量。给药后所有样本中均可检测到所有假定的代谢物。主要的特定尿代谢物是5cx-MEPTP，作为三名志愿者尿液中应用剂量的平均值，约占13.0%（范围7.0-20.4%），其次是5OH-MEHTP（平均值：1.8%；范围1.3-2.4%）和5oxo-MEHTP（平均值：1.0%；范围0.6-1.6%）。2cx-MMHTP是一种次要代谢物，仅占0.3%（范围0.2-0.4%）。在48小时内，总共约16.1%的剂量以上述研究的特定代谢物形式在尿液中回收，其中大部分（95%）在最初24小时内排出。对葡萄糖醛酸化模式的研究表明，羧基代谢物几乎完全以游离形式排出（>90%），而对于5OH-MEHTP和5oxo-MEHTP，葡萄糖醛酸化是首选（>70%）。通过本研究，我们提供了可靠的尿排泄因子，以便在环境和职业研究中根据代谢物浓度计算DEHTP摄入量。
