Functional UDP-glucuronyltransferase 2B15 polymorphism and bisphenol A concentrations in blood: results from physiologically based kinetic modelling
Bisphenol A (BPA) is a chemical in widespread use that is under scientific discussion due to its endocrine activity. Controversies exist about how to interpret reportedly high blood concentrations measured in uncontrolled situations. Physiologically based pharmaco-/toxicokinetic modelling resulted i...
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| Published in | Archives of toxicology Vol. 87; no. 7; pp. 1257 - 1264 |
|---|---|
| Main Authors | , , |
| Format | Journal Article |
| Language | English |
| Published |
Berlin/Heidelberg
Springer-Verlag
01.07.2013
Springer Nature B.V |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0340-5761 1432-0738 1432-0738 |
| DOI | 10.1007/s00204-013-1022-8 |
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| Abstract | Bisphenol A (BPA) is a chemical in widespread use that is under scientific discussion due to its endocrine activity. Controversies exist about how to interpret reportedly high blood concentrations measured in uncontrolled situations. Physiologically based pharmaco-/toxicokinetic modelling resulted in 10–100-fold lower blood concentrations than those reported. Moreover, in controlled situations, BPA did not exceed the level of detection (<0.3 ng/ml) in human blood or urine. Using a validated human PBK model, this study investigated the influence of functionally relevant polymorphic UGT2B15, the enzyme mediating BPA metabolism, on the BPA concentration–time profile in human blood. Maximum concentrations (
C
max
) and areas under the curves (AUCs) in blood from high and low metabolisers differed by a factor of 4.7 and 4.6, respectively (doses: 1 and 0.05 μg/kg/day). Low metabolisers excreted a greater proportion of BPA via the sulphate pathway compared to high metabolisers. This finding explains why
C
max
and AUC increased to a smaller extent, as predicted from in vitro data obtained with transfected cells possessing only the UGT2B15 variants. The highest
C
max
value calculated in the subject with the lowest metabolic clearance was roughly 40 pg/ml, which is far lower than reported high blood concentrations, which in turn cannot be explained by genetically impaired UGT2B15 activity. From the risk assessment perspective, our results indicate that the traditional uncertainty factor is sufficient to account for the variability in the polymorphic glucuronidation of BPA. |
|---|---|
| AbstractList | Bisphenol A (BPA) is a chemical in widespread use that is under scientific discussion due to its endocrine activity. Controversies exist about how to interpret reportedly high blood concentrations measured in uncontrolled situations. Physiologically based pharmaco-/toxicokinetic modelling resulted in 10-100-fold lower blood concentrations than those reported. Moreover, in controlled situations, BPA did not exceed the level of detection (<0.3 ng/ml) in human blood or urine. Using a validated human PBK model, this study investigated the influence of functionally relevant polymorphic UGT2B15, the enzyme mediating BPA metabolism, on the BPA concentration-time profile in human blood. Maximum concentrations (C(max)) and areas under the curves (AUCs) in blood from high and low metabolisers differed by a factor of 4.7 and 4.6, respectively (doses: 1 and 0.05 μg/kg/day). Low metabolisers excreted a greater proportion of BPA via the sulphate pathway compared to high metabolisers. This finding explains why C(max) and AUC increased to a smaller extent, as predicted from in vitro data obtained with transfected cells possessing only the UGT2B15 variants. The highest C(max) value calculated in the subject with the lowest metabolic clearance was roughly 40 pg/ml, which is far lower than reported high blood concentrations, which in turn cannot be explained by genetically impaired UGT2B15 activity. From the risk assessment perspective, our results indicate that the traditional uncertainty factor is sufficient to account for the variability in the polymorphic glucuronidation of BPA.Bisphenol A (BPA) is a chemical in widespread use that is under scientific discussion due to its endocrine activity. Controversies exist about how to interpret reportedly high blood concentrations measured in uncontrolled situations. Physiologically based pharmaco-/toxicokinetic modelling resulted in 10-100-fold lower blood concentrations than those reported. Moreover, in controlled situations, BPA did not exceed the level of detection (<0.3 ng/ml) in human blood or urine. Using a validated human PBK model, this study investigated the influence of functionally relevant polymorphic UGT2B15, the enzyme mediating BPA metabolism, on the BPA concentration-time profile in human blood. Maximum concentrations (C(max)) and areas under the curves (AUCs) in blood from high and low metabolisers differed by a factor of 4.7 and 4.6, respectively (doses: 1 and 0.05 μg/kg/day). Low metabolisers excreted a greater proportion of BPA via the sulphate pathway compared to high metabolisers. This finding explains why C(max) and AUC increased to a smaller extent, as predicted from in vitro data obtained with transfected cells possessing only the UGT2B15 variants. The highest C(max) value calculated in the subject with the lowest metabolic clearance was roughly 40 pg/ml, which is far lower than reported high blood concentrations, which in turn cannot be explained by genetically impaired UGT2B15 activity. From the risk assessment perspective, our results indicate that the traditional uncertainty factor is sufficient to account for the variability in the polymorphic glucuronidation of BPA. Bisphenol A (BPA) is a chemical in widespread use that is under scientific discussion due to its endocrine activity. Controversies exist about how to interpret reportedly high blood concentrations measured in uncontrolled situations. Physiologically based pharmaco-/toxicokinetic modelling resulted in 10–100-fold lower blood concentrations than those reported. Moreover, in controlled situations, BPA did not exceed the level of detection (<0.3 ng/ml) in human blood or urine. Using a validated human PBK model, this study investigated the influence of functionally relevant polymorphic UGT2B15, the enzyme mediating BPA metabolism, on the BPA concentration–time profile in human blood. Maximum concentrations ( C max ) and areas under the curves (AUCs) in blood from high and low metabolisers differed by a factor of 4.7 and 4.6, respectively (doses: 1 and 0.05 μg/kg/day). Low metabolisers excreted a greater proportion of BPA via the sulphate pathway compared to high metabolisers. This finding explains why C max and AUC increased to a smaller extent, as predicted from in vitro data obtained with transfected cells possessing only the UGT2B15 variants. The highest C max value calculated in the subject with the lowest metabolic clearance was roughly 40 pg/ml, which is far lower than reported high blood concentrations, which in turn cannot be explained by genetically impaired UGT2B15 activity. From the risk assessment perspective, our results indicate that the traditional uncertainty factor is sufficient to account for the variability in the polymorphic glucuronidation of BPA. Bisphenol A (BPA) is a chemical in widespread use that is under scientific discussion due to its endocrine activity. Controversies exist about how to interpret reportedly high blood concentrations measured in uncontrolled situations. Physiologically based pharmaco-/toxicokinetic modelling resulted in 10-100-fold lower blood concentrations than those reported. Moreover, in controlled situations, BPA did not exceed the level of detection (<0.3 ng/ml) in human blood or urine. Using a validated human PBK model, this study investigated the influence of functionally relevant polymorphic UGT2B15, the enzyme mediating BPA metabolism, on the BPA concentration-time profile in human blood. Maximum concentrations (C sub(max)) and areas under the curves (AUCs) in blood from high and low metabolisers differed by a factor of 4.7 and 4.6, respectively (doses: 1 and 0.05 mu g/kg/day). Low metabolisers excreted a greater proportion of BPA via the sulphate pathway compared to high metabolisers. This finding explains why C sub(max) and AUC increased to a smaller extent, as predicted from in vitro data obtained with transfected cells possessing only the UGT2B15 variants. The highest C sub(max) value calculated in the subject with the lowest metabolic clearance was roughly 40 pg/ml, which is far lower than reported high blood concentrations, which in turn cannot be explained by genetically impaired UGT2B15 activity. From the risk assessment perspective, our results indicate that the traditional uncertainty factor is sufficient to account for the variability in the polymorphic glucuronidation of BPA. Bisphenol A (BPA) is a chemical in widespread use that is under scientific discussion due to its endocrine activity. Controversies exist about how to interpret reportedly high blood concentrations measured in uncontrolled situations. Physiologically based pharmaco-/toxicokinetic modelling resulted in 10-100-fold lower blood concentrations than those reported. Moreover, in controlled situations, BPA did not exceed the level of detection (<0.3 ng/ml) in human blood or urine. Using a validated human PBK model, this study investigated the influence of functionally relevant polymorphic UGT2B15, the enzyme mediating BPA metabolism, on the BPA concentration-time profile in human blood. Maximum concentrations (C ^sub max^) and areas under the curves (AUCs) in blood from high and low metabolisers differed by a factor of 4.7 and 4.6, respectively (doses: 1 and 0.05 [mu]g/kg/day). Low metabolisers excreted a greater proportion of BPA via the sulphate pathway compared to high metabolisers. This finding explains why C ^sub max^ and AUC increased to a smaller extent, as predicted from in vitro data obtained with transfected cells possessing only the UGT2B15 variants. The highest C ^sub max^ value calculated in the subject with the lowest metabolic clearance was roughly 40 pg/ml, which is far lower than reported high blood concentrations, which in turn cannot be explained by genetically impaired UGT2B15 activity. From the risk assessment perspective, our results indicate that the traditional uncertainty factor is sufficient to account for the variability in the polymorphic glucuronidation of BPA.[PUBLICATION ABSTRACT] Bisphenol A (BPA) is a chemical in widespread use that is under scientific discussion due to its endocrine activity. Controversies exist about how to interpret reportedly high blood concentrations measured in uncontrolled situations. Physiologically based pharmaco-/toxicokinetic modelling resulted in 10-100-fold lower blood concentrations than those reported. Moreover, in controlled situations, BPA did not exceed the level of detection (<0.3 ng/ml) in human blood or urine. Using a validated human PBK model, this study investigated the influence of functionally relevant polymorphic UGT2B15, the enzyme mediating BPA metabolism, on the BPA concentration-time profile in human blood. Maximum concentrations (C(max)) and areas under the curves (AUCs) in blood from high and low metabolisers differed by a factor of 4.7 and 4.6, respectively (doses: 1 and 0.05 μg/kg/day). Low metabolisers excreted a greater proportion of BPA via the sulphate pathway compared to high metabolisers. This finding explains why C(max) and AUC increased to a smaller extent, as predicted from in vitro data obtained with transfected cells possessing only the UGT2B15 variants. The highest C(max) value calculated in the subject with the lowest metabolic clearance was roughly 40 pg/ml, which is far lower than reported high blood concentrations, which in turn cannot be explained by genetically impaired UGT2B15 activity. From the risk assessment perspective, our results indicate that the traditional uncertainty factor is sufficient to account for the variability in the polymorphic glucuronidation of BPA. |
| Author | Partosch, Falko Mielke, Hans Gundert-Remy, Ursula |
| Author_xml | – sequence: 1 givenname: Falko surname: Partosch fullname: Partosch, Falko organization: Institut für Klinische Pharmakologie und Toxikologie, Charité Universitätsmedizin Berlin – sequence: 2 givenname: Hans surname: Mielke fullname: Mielke, Hans organization: Federal Institute for Risk Assessment (BfR) – sequence: 3 givenname: Ursula surname: Gundert-Remy fullname: Gundert-Remy, Ursula email: ursula.gundert-remy@bfr.bund.de organization: Institut für Klinische Pharmakologie und Toxikologie, Charité Universitätsmedizin Berlin, Federal Institute for Risk Assessment (BfR) |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/23404680$$D View this record in MEDLINE/PubMed |
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| Keywords | Bisphenol A Physiologically based kinetic modelling Systemic availability Risk assessment Polymorphically expressed UGT2B15 metabolism Internal exposure |
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| Snippet | Bisphenol A (BPA) is a chemical in widespread use that is under scientific discussion due to its endocrine activity. Controversies exist about how to interpret... |
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| SubjectTerms | Area Under Curve Benzhydryl Compounds - blood Benzhydryl Compounds - pharmacokinetics Biological Availability Biomedical and Life Sciences Biomedicine Biotransformation Bisphenol A Blood Endocrine Disruptors - blood Endocrine Disruptors - pharmacokinetics Environmental Health Enzymes Genotype Glucuronosyltransferase - genetics Glucuronosyltransferase - metabolism Half-Life Humans Metabolic Clearance Rate Metabolism Models, Biological Occupational Medicine/Industrial Medicine Pharmacogenetics Pharmacology/Toxicology Phenols - blood Phenols - pharmacokinetics Phenotype Polymorphism Polymorphism, Genetic Risk Assessment Toxicokinetics and Metabolism Toxicology |
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| Title | Functional UDP-glucuronyltransferase 2B15 polymorphism and bisphenol A concentrations in blood: results from physiologically based kinetic modelling |
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