Single ingestion of di-(2-propylheptyl) phthalate (DPHP) by male volunteers: DPHP in blood and its metabolites in blood and urine

Klein, Dominik; Kessler, Winfried; Pütz, Christian; Semder, Brigitte; Kirchinger, W.; Langsch, Angelika; Gries, Wolfgang; Otter, Rainer; Gallien, Anna K. E.; Wurzenberger, Xaver; Filser, Johannes G.

doi:10.1016/j.toxlet.2018.05.010

Cited by 19 publications

(33 citation statements)

References 17 publications

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“…Elimination of secondary metabolites of DPHP is increased over a 24-h period compared to a model that does not account for this route. (Klein et al, 2018) interpreted the first harmonic of secondary metabolites in urine specimens as evidence of the lymphatic route, however our simulations indicate that a sharp peak could not be achieved from lymphatic uptake, in contrast, enterohepatic recirculation could account for such sharp peaks. We are unaware of previous work that has suggested strong evidence of enterohepatic recirculation from urinary metabolite measurements.…”

Section: Discussionmentioning

confidence: 68%

“…Elimination of second order metabolites OH-MPHP and cx-MPHP from blood was rapid. The urine samples provided evidence of enterohepatic recirculation with up to three visible harmonics following peak exposure, at intervals of approximately 8 hours; this is a new insight from our modelling that was not discussed by Klein et al (2018). The evidence for the lymphatic route was weaker from urinary metabolite data, since binding of DPHP and MPHP results in a prolonged elimination process, and the fraction entering via the lymphatic route is modest compared to the hepatic route.…”

Section: Discussionmentioning

confidence: 72%

“…1. The model was adapted to account for a majority fraction of DPHP passing through the GI tract without being absorbed, as suggested by BM data, ranging from 75% (Wittassek and Angerer 2008;Leng et al, 2014) to 94% (Klein et al, 2018).…”

Section: The Pbpk Modelmentioning

confidence: 99%

“…53306-54-0, marketed under the trade name Palatinol ® 10-P, is a high molecular weight branched phthalate ester which is used in the manufacture of polyvinyl chloride (PVC) products. DPHP can be found in cables, car interiors, carpet backing, pool liners, roofing membranes or tarpaulins, and consumer products such as shoes and artificial leather ( Klein et al, 2018 ). Typical contents of DPHP in end-use products vary between 30 and 60% (w/w), 10.1–48.2% (w/w).…”

Section: Introductionmentioning

confidence: 99%

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Development, Testing, Parameterisation and Calibration of a Human PBPK Model for the Plasticiser, Di-(2-propylheptyl) Phthalate (DPHP) Using in Silico, in vitro and Human Biomonitoring Data

et al. 2021

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A physiologically based pharmacokinetic model for Di-(2-propylheptyl) phthalate (DPHP) was developed to interpret the biokinetics in humans after single oral doses. The model was parameterized with in vitro and in silico derived parameters and uncertainty and sensitivity analysis was used during the model development process to assess structure, biological plausibility and behaviour prior to simulation and analysis of human biological monitoring data. To provide possible explanations for some of the counter-intuitive behaviour of the biological monitoring data the model included a simple lymphatic uptake process for DPHP and enterohepatic recirculation (EHR) for DPHP and the mono ester metabolite mono-(2-propylheptyl) phthalate (MPHP). The model was used to simultaneously simulate the concentration-time profiles of blood DPHP, MPHP and the urinary excretion of two metabolites, mono-(2-propyl-6-hydroxyheptyl) phthalate (OH-MPHP) and mono-(2-propyl-6-carboxyhexyl) phthalate (cx-MPHP). The availability of blood and urine measurements permitted a more robust qualitative and quantitative investigation of the importance of EHR and lymphatic uptake. Satisfactory prediction of blood DPHP and urinary metabolites was obtained whereas blood MPHP was less satisfactory. However, the delayed peak of DPHP concentration relative to MPHP in blood and second order metabolites in urine could be explained as a result of three processes: 1) DPHP entering the systemic circulation from the lymph, 2) rapid and very high protein binding and 3) the efficiency of the liver in removing DPHP absorbed via the hepatic route. The use of sensitivity analysis is considered important in the evaluation of uncertainty around in vitro and in silico derived parameters. By quantifying their impact on model output sufficient confidence in the use of a model should be afforded. This approach could expand the use of PBPK models since parameterization with in silico techniques allows for rapid model development. This in turn could assist in reducing the use of animals in toxicological evaluations by enhancing the utility of “read across” techniques.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 72%

Section: The Pbpk Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development, Testing, Parameterisation and Calibration of a Human PBPK Model for the Plasticiser, Di-(2-propylheptyl) Phthalate (DPHP) Using in Silico, in vitro and Human Biomonitoring Data

et al. 2021

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“…Biomarkers of the most prominent phthalates, including those already used in WBE studies [ [19] , [20] , [21] , [22] ], are given in Table 3 . It is noteworthy that rather different excretion profiles of some compounds, such as DPHP, were reported [ 68 , 69 ] and, in these cases, additional pharmacokinetic studies are also recommended.…”

Section: Identification Of Potential Wbe Biomarkers Of Human Exposurementioning

confidence: 99%

Wastewater-based epidemiology to assess human exposure to personal care and household products – A review of biomarkers, analytical methods, and applications

Senta

Rodríguez-Mozaz

Corominas

et al. 2020

Trends in Environmental Analytical Chemistry

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Humans are nowadays exposed to numerous chemicals in our day-to-day life, including parabens, UV filters, phosphorous flame retardants/plasticizers, bisphenols, phthalates and alternative plasticizers, which can have different adverse effects to human health. Estimating human’s exposure to these potentially harmful substances is, therefore, of paramount importance. Human biomonitoring (HBM) is the existing approach to assess exposure to environmental contaminants, which relies on the analysis of specific human biomarkers (parent compounds and/or their metabolic products) in biological matrices from individuals. The main drawback is its implementation, which involves complex cohort studies. A novel approach, wastewater-based epidemiology (WBE), involves estimating exposure from the analysis of biomarkers in sewage (a pooled urine and feces sample of an entire population). One of the key challenges of WBE is the selection of biomarkers which are specific to human metabolism, excreted in sufficient amounts, and stable in sewage. So far, literature data on potential biomarkers for estimating exposure to these chemicals are scattered over numerous pharmacokinetic and HBM studies. Hence, this review provides a list of potential biomarkers of exposure to more than 30 widely used chemicals and report on their urinary excretion rates. Furthermore, the potential and challenges of WBE in this particular field is discussed through the review of pioneer WBE studies, which for the first time explored applicability of this novel approach to assess human exposure to environmental contaminants. In the future, WBE could be potentially applied as an “early warning system”, which could promptly identify communities with the highest exposure to environmental contaminants.

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Esters of Aromatic Diacids (Phthalates)

Greim

2023

Patty's Toxicology

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Phthalate esters are used as plasticizers for a variety of plastic materials; those of C8 and above are used to add flexibility to polyvinyl chloride (PVC). They also are used with vinyl and cellulose resins to lend toughness and flexibility. They are commonly used in wire and cable coverings, moldings, vinyl consumer products, and medical devices. Some low‐molecular‐weight phthalate esters (e.g., methyl, ethyl, and butyl) are preferentially used as industrial solvents and in consumer products, such as ink and lacquer. Phthalates occur mainly in liquid form with high boiling ranges and very low vapor pressures, both contributing to the high stability of these materials. The critical health effects of phthalate esters like DEHP, butylbenzyl phthalate (BBP), di‐ iso ‐butyl phthalate (DIBP), di‐ n ‐butyl phthalate (DNBP), and dipentyl phthalate (DPP) are their interaction with the endogenous production of fetal testicular testosterone in rats. This impairs the reproduction of rodents by decreasing sperm production so that ECHA has labeled this group as toxic for reproduction (1B), whereas high molecular phthalates (HMP) such as DINP do not warrant classification for effects on sexual function, fertility, and developmental toxicity. Currently, di‐isononylphthalate (DINP) is replacing di(2‐ethylhexyl) phthalate (DEHP) widely in industrial and consumer products. Photodegradation half‐lives of dimethyl‐ and diethylphthalate are about 14 and 3 days, respectively, those of the other esters below 1 day. Half‐lives of aerobic degradation differ largely. The acute aquatic EC or LD50 values determined in algae, daphnids, and minnows mostly did not show effects at the solubility limits. Legal limits of European Commission (EC) for phthalates in plastic layer in direct contact with food are as follows: DBP up to 0.3 mg/kg, BBP, up to 30 mg/kg, DEHP, up to 1.5 mg/kg, sum of DINP and DIDP up to 9 mg/kg.

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Single ingestion of di-(2-propylheptyl) phthalate (DPHP) by male volunteers: DPHP in blood and its metabolites in blood and urine

Cited by 19 publications

References 17 publications

Development, Testing, Parameterisation and Calibration of a Human PBPK Model for the Plasticiser, Di-(2-propylheptyl) Phthalate (DPHP) Using in Silico, in vitro and Human Biomonitoring Data

Development, Testing, Parameterisation and Calibration of a Human PBPK Model for the Plasticiser, Di-(2-propylheptyl) Phthalate (DPHP) Using in Silico, in vitro and Human Biomonitoring Data

Wastewater-based epidemiology to assess human exposure to personal care and household products – A review of biomarkers, analytical methods, and applications

Esters of Aromatic Diacids (Phthalates)

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