Abstract
Physiology-Based BioKinetic (PBBK) models are of increasing interest in modern risk assessment, providing quantitative information regarding the absorption, metabolism, distribution, and excretion (ADME). They focus on the estimation of the effective dose at target sites, aiming at the identification of xenobiotic levels that are able to result in perturbations to the biological pathway that are potentially associated with adverse outcomes. The current study aims at the development of a lifetime PBBK model that covers a large chemical space, coupled with a framework for human biomonitoring (HBM) data assimilation. The methodology developed herein was demonstrated in the case of bisphenol A (BPA), where exposure analysis was based on European HBM data. Based on our calculations, it was found that current exposure levels in Europe are below the temporary Tolerable Daily Intake (t-TDI) of 4 μg/kg_bw/day proposed by the European Food Safety Authority (EFSA). Taking into account age-dependent bioavailability differences, internal exposure was estimated and compared with the biologically effective dose (BED) resulting from translating the EFSA temporary total daily intake (t-TDI) into equivalent internal dose and an alternative internal exposure reference value, namely biological pathway altering dose (BPAD); the use of such a refined exposure metric, showed that environmentally relevant exposure levels are below the concentrations associated with the activation of biological pathways relevant to toxicity based on High Throughput Screening (HTS) in vitro studies.
Highlights
One of the main applications of internal dosimetry is the integration of exposure and human biomonitoring (HBM) data
The use of the Physiology-Based BioKinetic (PBBK) model coupled to the algorithm for exposure reconstruction resulted in the estimation of daily intake starting from HBM data
Starting from HBM data collection and using a human physiology-based biokinetic model with an exposure reconstruction algorithm, exposure to bisphenol A (BPA) in the European population was estimated coupled with an exposure reconstruction algorithm, exposure to BPA in the European population to be almost two orders of magnitude lower than the respective European Food Safety Authority (EFSA) temporary Tolerable Daily Intake (t-TDI) of 4 μg/kg_bw/day
Summary
One of the main applications of internal dosimetry is the integration of exposure and human biomonitoring (HBM) data. Internal dosimetry aims at (i) deriving the time course of the toxicants in human tissues, with a particular focus on susceptible developmental stages; (ii) providing a comprehensive interpretation of the HBM data related to the cohorts, for quantifying individual exposome; and (iii) deriving Biologically Effective Dose (BED) values for associating them with adverse outcomes. Towards these aims, a lifetime generic Physiology-Based BioKinetic (PBBK) model [1]. BED could be used for the quantification of the effect of extracellular perturbations on metabolic states, coupling the PBBK model with metabolic regulatory networks and defining the feedback loop that connects clearance and metabolite production rates to metabolism regulation [7] via dynamic flux balance analysis (FBA) [8]
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