Elsevier

Food and Chemical Toxicology

Volume 98, Part B, December 2016, Pages 134-147
Food and Chemical Toxicology

Integrated exposure and risk characterization of bisphenol-A in Europe

https://doi.org/10.1016/j.fct.2016.10.017Get rights and content

Highlights

  • Integrated exposure and risk analysis of bisphenol-A in Europe.

  • Toxicokinetic modelling allowed us to account for age-dependent differences.

  • Internal exposure to developing fetus during pregnancy is low.

  • Infants hosted in neonatal intensive care units are the most vulnerable group.

  • Internal dosimetry estimation caters for more robust risk characterization of BPA.

Abstract

The current study aims at a comprehensive risk characterization of bisphenol A (BPA) supported by an integrated exposure modelling framework that comprises far field and near field exposure modelling coupled to a dynamic lifetime PBTK model. Exposure analysis was done on European data of BPA food residues and human biomonitoring (HBM). The latter were further assimilated through an advanced exposure reconstruction modelling framework to estimate the corresponding external and internal systemic dose of BPA and its metabolites. Special attention was paid on the assessment of exposure to BPA during critical developmental stages such as gestation by modelling the mother-fetus toxicokinetic interaction. Our findings showed that current exposure levels in Europe are below the temporary Tolerable Daily Intake (t-TDI) of 4 μg/kg_bw/d proposed by the European Food Safety Authority. Taking into account age-dependent bioavailability differences, internal exposure of premature neonates hosted in intensive care units was reckoned close to the biologically effective dose (BED) resulting from translating the EFSA temporary total daily intake (t-TDI) into equivalent internal dose. Use of the ToxCast21 Biological Pathway Altering Dose (BPAD) as an alternative internal exposure reference value, resulted in increased margins of safety compared to the conventional exposure/risk characterization scheme.

Introduction

Exposure to BPA and the potential adverse health effects constitute one of the hottest public health topic. The main controversy regards the toxicokinetic behavior of BPA; although BPA glucuronidation (the dominant detoxification mechanism) is complete and rapid, due to the reduced metabolic capacity of infants-neonates, there is still ample opportunity for internal exposure (Edginton and Ritter, 2009, Ginsberg and Rice, 2009). Existing biomonitoring studies regarding BPA exposure cannot provide valuable information with regard to toxicokinetics, because almost all of them track only urinary metabolites (BPA-glu), rendering them useful only for assessing the overall uptake. Due to the rapid metabolism of BPA to BPA-glu, the extent of binding (a fraction of 0.95) to red blood cells and plasma proteins, and limitations of the analytical techniques, the related biomonitoring studies either fail to detect free-BPA in the plasma or the detected values are attributed to background contamination from labware and indoor dust (Dekant and Völkel, 2008). The latter hypothesis is, however, strongly contested (Vandenberg et al., 2010). Contradiction is further amplified by toxicity testing results. BPA was found to produce adverse neurodevelopmental effects in rats given an oral dose that was considered environmentally relevant; the results were, however, seriously criticized by regulatory authorities (EFSA, 2006, EFSA, 2008) mainly based on the validity of the applied methods (not GLP compliant). Additional arguments included the relevance of bioavailability for the same normalized oral dose among rodents and humans, due to substantial differences in the BPA excretion mechanism (for humans only via urine, for rodents via feces and urine due to hepatobilic recirculation) and the consequent rates of elimination (elimination half-life of 5.3 h and 10.5 h for humans and rodents respectively).

There are four critical reviews targeting the main controversies about BPA. Ginsberg and Rice (2009) focused on the toxicokinetic arguments, providing a comprehensive review on biomonitoring data and the uncertainties that relate to perinatal and infancy detoxification pathways. They report that beside the detoxification pathways of glucuronidation and sulfation, the presence of enzymes necessary for infant development is also responsible for BPA-Glu deconjugation, possibly increasing the bioavailability of BPA. Vandenberg et al. (2009), besides their own contribution to BPA toxicity testing, compiled an informative review on the overall controversies (exposure, toxicokinetics and toxicity testing) and the way in which regulatory authorities evaluate the research findings, highlighting the importance of non-monotonic dose-response relationships and the related effects of low doses, as well as the increased susceptibility during the critical periods of perinatal and neonatal exposure. Beronius et al. (2010) published a critical review on the BPA risk assessment reports issued by regulatory authorities worldwide, illustrating the impact of differences in risk assessment policy and expert judgment and highlighting the importance of transparency in the risk assessment process. The latest review paper written by Vandenberg et al. (2010) relies on the widespread exposure to BPA evaluating more than 80 biomonitoring studies including a variety of biological fluids and BPA forms (conjugated or free), and focusing on the reliability of studies measuring free BPA in the plasma. The authors concluded that the majority of the studies detecting non negligible free-plasma BPA concentrations in blood fulfill the criteria for considering them as reliable and as such they should be taken into account in the risk assessment process.

Preliminary efforts to develop PBTK models for BPA were made by Shin et al. (2004) and Teeguarden et al. (2005), but the most comprehensive model, which clearly illustrated metabolic scaling from adults to neonates-infants was developed by Edginton and Ritter (2009). The core finding of their study was that BPA plasma concentrations could be approximately elevent times greater in newborns than in adults exposed to the same weight-normalized dose. In the latest published BPA PBTK model (Mielke and Gundert-Remy, 2009), sulfation was included as an additional metabolic pathway, considering that sulfation activity is well expressed in newborns and it is at least as high as in adults, or even higher. Besides the importance of the additional clearance pathway, this model was much more simplified than the one developed by Edginton and Ritter, with significantly fewer compartments, without considering BPA binding to red blood cells, and without estimating the fate of conjugated metabolites. The estimated steady-state free plasma BPA concentrations in neonates and infants were lower than the ones estimated by Edginton and Ritter due to the addition of sulfation.

The present study aims to quantify external and internal exposure to BPA and to assimilate biomonitoring data in Europe using the integrated modelling framework of the INTEGRA computational platform (Sarigiannis et al., 2014). The overall modelling framework is compiled in a software package (asclXtreme) which allows dynamic simulations through time (not only steady state estimates), as well as implementation of Monte Carlo (MC) sensitivity, uncertainty and variability analysis. INTEGRA is a web-based platform that allows ready access to integrated external and internal exposure modelling to users. Continuous simulation through time allowed the development of a mother-fetus PBTK model parameterized for BPA and its glucuronidated form (BPA-Glu) taking into account the changes in physiologic and metabolic parameters that occur during gestation and early in life. Absorption processes through all potential exposure routes (oral, inhalation and dermal) have been incorporated aiming at investigating route dependent bioavailability differences in BPA. Finally, exposure was reconstructed based on recent European biomonitoring data using an exposure reconstruction algorithm.

Section snippets

Integrated exposure modelling framework

Aggregate exposure assessment is data-intensive, requiring detailed information at every step of the source-to-dose pathway. To accommodate these needs, the INTEGRA modelling framework (Sarigiannis et al., 2014) aims at bringing together all available information for assessing the source-to-dose continuum for the entire life cycle of substances covering an extensive chemical space. The major component of INTEGRA (Fig. 1) is an integrative computational platform that comprises environmental

External exposure estimation based on exposure scenarios

Exposure analysis in this study was carried out through the use of probabilistic data (food residues) and detailed multimedia environmental modelling, taking into account actual emissions to the environment for estimating far field exposure, rather than default values based on the overall production volume and the relevant environmental release categories (ERCs), as described by ECHA (ECHA, 2012). Calculated daily intake for humans exposed via the environmental media includes oral exposure from

Discussion

The study described the application of an integrated modelling framework for assessing exposure to BPA in the EU. Refined analysis of this study, was greatly facilitated by (a) the development of a comprehensive environmental and exposure modelling framework, able to estimate the contribution of all related pathways and routes of exposure and (b) the functional link to a generic PBTK model, that allows the estimation of internal dose under different exposure scenarios, as well as the

Conclusions

The study presented herein uses an integrated methodological framework to estimate population exposure to BPA in the EU, accounting for both far and near field exposure, paying special attention to internal dosimetry in different population subgroups, by employing a generic lifetime PBTK model.

The results of the study showed that current exposure levels of BPA at the general population are below the EFSA t-TDI. For chemicals with widespread consumer applications such as BPA, overall exposure is

Acknowledgments

The authors gratefully acknowledge the financial support of CEFIC under the CEFIC-LRI project B11: Integrated External and Internal Exposure Modelling Platform (INTEGRA) and of the European Commission under grants: CROME-LIFE, which was funded from the LIFE + program (LIFE12 ENV/GR/001040) and HEALS, which was funded from the 7th RTD Framework Programme of the European Union (Grant agreement no: 603946).

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