Metabolism and urinary excretion kinetics of di(2-ethylhexyl) adipate (DEHA) in four human volunteers after a single oral dose

Nehring, Alexandra; Bury, Daniel; Ringbeck, Benedikt; Kling, Hans-Willi; Otter, Rainer; Weiß, Tobias; Brüning, Thomas; Koch, Holger M.

doi:10.1016/j.toxlet.2019.12.006

Cited by 32 publications

(38 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The latter measure i.e. the concentration (mg/L), the volume of the void (ml) and the times between voids (hours)) – (see for example Nehring et al (2020) represents the underlying trends in concentration response data in a more precise manner than expressing the metabolite concentration relative to creatinine concentration. These measurements were compared to corresponding predictions from the PBPK model using the statistical models depicted in Eqs.…”

Section: Methodsmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Methodsmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…DIBP was detected in several products in the toy category with relatively high concentrations. Recently, DEHA has started appearing in products, as it is an alternative to DEHP [36,37].…”

Section: Discussionmentioning

confidence: 99%

Phthalate Plasticizers in Children’s Products and Estimation of Exposure: Importance of Migration Rate

Kim

Chun

Jung

et al. 2020

IJERPH

View full text Add to dashboard Cite

Plasticizers are added to diverse consumer products including children’s products. Owing to their potential for endocrine disruption, the use of phthalate plasticizers is restricted in many children’s products. In this study, exposure to five phthalate esters (dibutylphthalate, di(2-ethylhexyl) phthalate (DEHP), diethyl phthalate, di-isobutyl phthalate, and diisononyl phthalate (DINP)) and an alternative (di-ethylhexyl adipate) was assessed by the use of children’s products based on chemical analysis of 3345 products purchased during 2017 and 2019 in Korea. Plasticizers were found above the detection limits in 387 products, and DEHP and DINP were the two most predominantly detected plasticizers. Deterministic and probabilistic estimation of the margin of exposure at a screening level revealed that the use of children’s products might be an important risk factor. However, it is also highly likely that the exposure could be overestimated, because the migration rate was estimated based solely on the content of plasticizers in children’s products. Chemical migration is a key process determining the absorption of plasticizers from products; thus, further refinements in experimental determination or model estimation of the migration rate are required.

show abstract

“…However, their excretion rates seem to be low and the preliminary results suggested that their application may be limited to the highly exposed populations [ 76 ]. Indeed, a very recent pharmacokinetic study reported mean urinary excretion rates of three oxidized metabolites in humans between 0.05 % and 0.20 % [ 33 ]. Among them, mono-5-carboxy-2-ethylpentyl adipate seems to be the most suitable biomarker of exposure to DEHA in HBM, which was confirmed by the pilot HBM study [ 77 ].…”

Section: Identification Of Potential Wbe Biomarkers Of Human Exposurementioning

confidence: 99%

“… Compound Biomarker Excretion rate (%) a Ref. Di-2-ethylhexyl adipate (DEHA) Mono-2-ethylhexyl adipate (MEHA) NA [ 76 ] b Mono-5-carboxy-2-ethylpentyl adipate (5cx-MEPA) 0.20 (0.17–0.24) [ 33 ] c Mono-2-ethylhydroxyhexyl adipate (5OH-MEHA) 0.07 (0.03–0.10) Mono-(2-ethyl-5-oxohexyl) adipate (5oxo-MEHA) 0.05 (0.01–0.06) Di(2-ethylhexyl) terephthalate (DEHTP) 1-Mono-(2-ethyl-5-carboxyl-pentyl) terephtahalate (5cx-MEPTP) 13.0 (7.0–20.4) [ 79 ] d 1-Mono-(2-ethyl-5-hydroxy-hexyl) terephtahalate (5OH-MEHTP) 1.8 (1.3–2.4) 1-Mono-(2-ethyl-5-oxo-hexyl) terephtahalate (5oxo-MEHTP) 1.0 (0.57–1.6) 1-Mono-(2-carboxyl-methyl-hexyl) terephtahalate (2cx-MEHTP) 0.28 (0.17–0.42) Di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) Cyclohexane-1,2-dicarboxylate-mono-(7-hydroxy-4-methyl) octyl ester (OH-MINCH) 10.7 (7.7–12.9) [ 81 ] d 14.5 (9.2–17.6) [ 82 ] e Cyclohexane-1,2-dicarboxylic mono oxoisononyl ester (oxo-MINCH) 2.0 (1.5–2.6) [ 81 ] d 4.8 (2.9−7.5) [ 82 ] e Cyclohexane-1,2-diarboxylic mono carboxyisononyl ester (cx-MINCH) 2.0 (1.8–2.3) [ 81 ] ...…”

Section: Identification Of Potential Wbe Biomarkers Of Human Exposurementioning

confidence: 99%

“…However, these papers did not focus exclusively on biomarkers of exposure to environmental contaminants and, therefore, did not systematically evaluate rather complex and scattered pharmacokinetic and HBM data to propose the most promising biomarker(s) for many potentially harmful environmental contaminants. Moreover, some pharmacokinetic [ [30] , [31] , [32] , [33] ] and WBE studies [ [19] , [20] , [21] , [22] , [23] , [24] , [25] , 34 ] relevant for this topic were published very recently.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Metabolism and urinary excretion kinetics of di(2-ethylhexyl) adipate (DEHA) in four human volunteers after a single oral dose

Cited by 32 publications

References 62 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

Phthalate Plasticizers in Children’s Products and Estimation of Exposure: Importance of Migration Rate

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

Contact Info

Product

Resources

About