Articles producció científica> Enginyeria Química

Development of a human physiologically based pharmacokinetic (PBPK) model for phthalate (DEHP) and its metabolites: a bottom up modeling approach

  • Identification data

    Identifier: imarina:4683713
  • Authors:

    Sharma RP, Schuhmacher M, Kumar V
  • Others:

    Author, as appears in the article.: Sharma RP, Schuhmacher M, Kumar V
    Department: Enginyeria Química
    URV's Author/s: Kumar, Vikas / Schuhmacher Ansuategui, Marta
    Keywords: System biology Physiologically-based pharmacokinetic (pbpk) model Phthalate Pharmacokinetics Human biomonitoring pbpk mehp ivive human health risk assessment human biomonitoring endocrine disruptors dehp
    Abstract: DEHP exposure to human comes from different sources such as food, diet, cosmetics, toys, medical products, and food wraps. Recently, DEHP was categorized as non-persistent endocrine disrupting compounds (EDCs) by the world health organization (WHO). Rat experimental studies showed that phthalate and its metabolite(s) can cause hepatic, developmental and reproductive toxicity. In human, DEHP rapidly metabolizes into a toxic metabolite MEHP. This MEHP further metabolizes into the different chemical forms of 5OH-MEHP, 5oxo-MEHP, 5cx-MEPP and phthalic acid. A simple DEHP pharmacokinetics model has been developed, but with a limited number of metabolites. A chemical like DEHP which extensively metabolised indicate the need of a detail metabolic kinetics study. A physiological based pharmacokinetics (PBPK) model of the DEHP considering all the major metabolites in human, has not been developed yet. The objective of this study is to develop a detailed human PBPK model for the DEHP and its major metabolites by using a bottom-up modelling approach with the integration of a in vitro metabolic data. This approach uses an in-vitro-in-vivo extrapolation (IVIVE) and a quantitative structure-activity relationship (QSAR) method for the parameterization of the model. Monte Carlo simulations were performed to estimate the impact of parametric uncertainty onto the model predictions. First, the model was calibrated using the control human kinetic study that represents the time course of DEHP metabolites concentration in both the blood and the urine. Then, the model was evaluated against the published independent data on different dosing scenarios. The results of model predictions for the DEHP metabolites in both the blood and the urine were well within the range of experimentally observed data. The model also captured the similar trend of time course profile to the observed data, shows model good predictability power. The current developed PBPK model can futher be used for the prediction of the time course of chemical concentrations for the different exposure scenarios not only in the blood and the urine but also in the other compartments. Moreover, this model can also be used to explore different biomonitoring studies for the human health risk assessment and might be useful for integrative toxicological study in improving exposure-target tissue dose-response relationship.
    Thematic Areas: Zootecnia / recursos pesqueiros Toxicology Saúde coletiva Química Psicología Odontología Nutrição Medicine (miscellaneous) Medicina veterinaria Medicina ii Medicina i Materiais Interdisciplinar Historia Geociências General medicine Farmacia Engenharias iv Engenharias iii Engenharias ii Engenharias i Educação física Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Ciências ambientais Ciência de alimentos Biotecnología Biodiversidade Astronomia / física
    ISSN: 03784274
    Author's mail: vikas.kumar@urv.cat marta.schuhmacher@urv.cat
    Author identifier: 0000-0002-9795-5967 0000-0003-4381-2490
    Last page: 162
    Record's date: 2024-09-07
    Journal volume: 296
    Papper version: info:eu-repo/semantics/submittedVersion
    Link to the original source: https://www.sciencedirect.com/science/article/abs/pii/S0378427418314656
    Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
    Papper original source: Toxicology Letters. 296 152-162
    APA: Sharma RP, Schuhmacher M, Kumar V (2018). Development of a human physiologically based pharmacokinetic (PBPK) model for phthalate (DEHP) and its metabolites: a bottom up modeling approach. Toxicology Letters, 296(), 152-162. DOI: 10.1016/j.toxlet.2018.06.1217
    Article's DOI: 10.1016/j.toxlet.2018.06.1217
    Entity: Universitat Rovira i Virgili
    Journal publication year: 2018
    First page: 152
    Publication Type: Journal Publications
  • Keywords:

    Medicine (Miscellaneous),Toxicology
    System biology
    Physiologically-based pharmacokinetic (pbpk) model
    Phthalate
    Pharmacokinetics
    Human biomonitoring
    pbpk
    mehp
    ivive
    human health risk assessment
    human biomonitoring
    endocrine disruptors
    dehp
    Zootecnia / recursos pesqueiros
    Toxicology
    Saúde coletiva
    Química
    Psicología
    Odontología
    Nutrição
    Medicine (miscellaneous)
    Medicina veterinaria
    Medicina ii
    Medicina i
    Materiais
    Interdisciplinar
    Historia
    Geociências
    General medicine
    Farmacia
    Engenharias iv
    Engenharias iii
    Engenharias ii
    Engenharias i
    Educação física
    Ciências biológicas iii
    Ciências biológicas ii
    Ciências biológicas i
    Ciências ambientais
    Ciência de alimentos
    Biotecnología
    Biodiversidade
    Astronomia / física
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