Unravelling sex-specific BPA toxicokinetics in children using a pediatric PBPK model

Deepika, Deepika; Sharma, Raju Prasad; Schuhmacher, Marta; Sakhi, Amrit Kaur; Thomsen, Cathrine; Chatzi, Leda; Vafeiadi, Marina; Quentin, Joane; Slama, Rémy; Gražulevičienė, Regina; Andrušaitytė, Sandra; Waiblinger, Dagmar; Wright, John; Yang, Tiffany; Urquiza, José; Vrijheid, Martine; Casas, Maribel; Domingo, José L.; Kumar, Vikas

doi:10.1016/j.envres.2022.114074

Cited by 5 publications

(6 citation statements)

References 60 publications

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“…Sex- and age-specific physiologically based pharmacokinetic models (PBPK) might provide the additional insights to mechanistic explanations of these sex/gender differences. The pediatric PBPK models have currently reached a sufficient level of maturity for successful application in studies of environmental chemicals [ 52 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

Lysmeral Exposure in Children and Adolescences Participating in the German Environmental Survey (2012–2015): Integrating Sex/Gender into Analysis

Fichter

Groth

Fiedler

et al. 2022

IJERPH

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Comprehensive consideration of the biological and social diversities of sex and gender as well as their interdependencies is mostly missing in human biomonitoring (HBM) studies. Using the INGER sex/gender concept as theoretical background, we analyzed differences in exposure to lysmeral, a compound commonly found as a fragrance in cosmetics, personal care, and household products, in 2294 children and adolescents in Germany using decision tree, regression, and mediation analysis. The variables “sex assigned at birth” and “age”, as well as well as use of personal care products and fabric conditioner proved to have the highest explanatory value. Mediating effects of behaviour associated with societal gender expectations were observed, as the use of cosmetics correlated highly with lysmeral metabolites concentrations in girls between 6 and 17 years, with the strongest effect in adolescents between 14 and 17 years old. In the youngest age group (3–5 years) boys showed higher concentration of the metabolite tert-butylbenzoic acid (TBBA) compared to girls of the same age but only if TBBA urine concentrations were normalized on creatinine. Our study offers the first retrospective sex/gender assessment of HBM data. It demonstrates the possibilities to rethink and broaden sex/gender analysis in existing HBM-studies and highlights the need for inclusion of new sex/gender concepts in the design of new studies.

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Section: Discussionmentioning

confidence: 99%

Lysmeral Exposure in Children and Adolescences Participating in the German Environmental Survey (2012–2015): Integrating Sex/Gender into Analysis

Fichter

Groth

Fiedler

et al. 2022

IJERPH

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“…Multi-compartment models often provide detailed information about various tissues and, most importantly, they include intrinsic physiological processes such as liver metabolism, gut metabolism, kidney transporters and elimination, reabsorption and enterohepatic recirculation (EHR) to capture the linear and non-linear kinetics along with anatomy ( Figure 3 ) [ 3 , 4 , 15 , 16 , 17 ]. However, a point worth mentioning is that adding a lot of compartments often makes the model complex and impractical, since values are required for multiple parameters.…”

Section: Unravelling the Art Of Developing Pbpk Modelsmentioning

confidence: 99%

“…Parameters such as intestinal permeability or dissolution rate can be measured to calculate the k abs . Absorption-related processes such as EHR need to be introduced sometimes to predict the terminal phase of the plasma-concentration time profile ( Figure 4 ) [ 4 , 22 , 23 ]. Compounds that have high biliary excretion, faster absorption rates and limited clearance are the substrates for EHR [ 24 ].…”

Section: Unravelling the Art Of Developing Pbpk Modelsmentioning

confidence: 99%

“…PBPK models are mathematical models encompassing multiple compartments with physiology, anatomy, biochemical and physicochemical parameters for describing ADME (absorption, distribution, metabolism and excretion) of xenobiotics and their metabolites ( Figure 1 ) [ 1 , 2 , 3 , 4 ]. These models vary from empirical, semi-mechanistic to compartmental models based on the complexity of the problem [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…In the past, allometric scaling was used to predict some PK parameters such as clearance and volume of distribution for humans from PK profiles in animals or other species, as well as for sensitive populations such as pediatric, but this scaling fails to predict the parameters in diseased or compromised states. In addition, it is a bit challenging to incorporate the drug–drug interaction or mixture assessments during allometric scaling, which has led to the reduction in popularity of such approaches [ 4 , 5 , 7 ]. PBPK models can overcome such challenges, as they consist of systems data (such as physiology) and biochemical parameters such as metabolism and excretion, including mechanisms such as saturation of enzymes or presence of specific receptors [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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The Role of “Physiologically Based Pharmacokinetic Model (PBPK)” New Approach Methodology (NAM) in Pharmaceuticals and Environmental Chemical Risk Assessment

Deepika

Kumar

2023

IJERPH

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Physiologically Based Pharmacokinetic (PBPK) models are mechanistic tools generally employed in the pharmaceutical industry and environmental health risk assessment. These models are recognized by regulatory authorities for predicting organ concentration–time profiles, pharmacokinetics and daily intake dose of xenobiotics. The extension of PBPK models to capture sensitive populations such as pediatric, geriatric, pregnant females, fetus, etc., and diseased populations such as those with renal impairment, liver cirrhosis, etc., is a must. However, the current modelling practices and existing models are not mature enough to confidently predict the risk in these populations. A multidisciplinary collaboration between clinicians, experimental and modeler scientist is vital to improve the physiology and calculation of biochemical parameters for integrating knowledge and refining existing PBPK models. Specific PBPK covering compartments such as cerebrospinal fluid and the hippocampus are required to gain mechanistic understanding about xenobiotic disposition in these sub-parts. The PBPK model assists in building quantitative adverse outcome pathways (qAOPs) for several endpoints such as developmental neurotoxicity (DNT), hepatotoxicity and cardiotoxicity. Machine learning algorithms can predict physicochemical parameters required to develop in silico models where experimental data are unavailable. Integrating machine learning with PBPK carries the potential to revolutionize the field of drug discovery and development and environmental risk. Overall, this review tried to summarize the recent developments in the in-silico models, building of qAOPs and use of machine learning for improving existing models, along with a regulatory perspective. This review can act as a guide for toxicologists who wish to build their careers in kinetic modeling.

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Human biomonitoring and toxicokinetics as key building blocks for next generation risk assessment

Reale,

Zare Jeddi,

Paini

et al. 2024

Environment International

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Unravelling sex-specific BPA toxicokinetics in children using a pediatric PBPK model

Cited by 5 publications

References 60 publications

Lysmeral Exposure in Children and Adolescences Participating in the German Environmental Survey (2012–2015): Integrating Sex/Gender into Analysis

Lysmeral Exposure in Children and Adolescences Participating in the German Environmental Survey (2012–2015): Integrating Sex/Gender into Analysis

The Role of “Physiologically Based Pharmacokinetic Model (PBPK)” New Approach Methodology (NAM) in Pharmaceuticals and Environmental Chemical Risk Assessment

Human biomonitoring and toxicokinetics as key building blocks for next generation risk assessment

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