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Physiology-based toxicokinetic modelling of aluminium in rat and man

A sufficient quantitative understanding of aluminium (Al) toxicokinetics (TK) in man is still lacking, although highly desirable for risk assessment of Al exposure. Baseline exposure and the risk of contamination severely limit the feasibility of TK studies administering the naturally occurring isot...

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Autores principales: Hethey, Christoph, Hartung, Niklas, Wangorsch, Gaby, Weisser, Karin, Huisinga, Wilhelm
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380244/
https://www.ncbi.nlm.nih.gov/pubmed/34390355
http://dx.doi.org/10.1007/s00204-021-03107-y
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author Hethey, Christoph
Hartung, Niklas
Wangorsch, Gaby
Weisser, Karin
Huisinga, Wilhelm
author_facet Hethey, Christoph
Hartung, Niklas
Wangorsch, Gaby
Weisser, Karin
Huisinga, Wilhelm
author_sort Hethey, Christoph
collection PubMed
description A sufficient quantitative understanding of aluminium (Al) toxicokinetics (TK) in man is still lacking, although highly desirable for risk assessment of Al exposure. Baseline exposure and the risk of contamination severely limit the feasibility of TK studies administering the naturally occurring isotope (27)Al, both in animals and man. These limitations are absent in studies with (26)Al as a tracer, but tissue data are limited to animal studies. A TK model capable of inter-species translation to make valid predictions of Al levels in humans—especially in toxicological relevant tissues like bone and brain—is urgently needed. Here, we present: (i) a curated dataset which comprises all eligible studies with single doses of (26)Al tracer administered as citrate or chloride salts orally and/or intravenously to rats and humans, including ultra-long-term kinetic profiles for plasma, blood, liver, spleen, muscle, bone, brain, kidney, and urine up to 150 weeks; and (ii) the development of a physiology-based (PB) model for Al TK after intravenous and oral administration of aqueous Al citrate and Al chloride solutions in rats and humans. Based on the comprehensive curated (26)Al dataset, we estimated substance-dependent parameters within a non-linear mixed-effect modelling context. The model fitted the heterogeneous (26)Al data very well and was successfully validated against datasets in rats and humans. The presented PBTK model for Al, based on the most extensive and diverse dataset of Al exposure to date, constitutes a major advancement in the field, thereby paving the way towards a more quantitative risk assessment in humans. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00204-021-03107-y.
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spelling pubmed-83802442021-09-08 Physiology-based toxicokinetic modelling of aluminium in rat and man Hethey, Christoph Hartung, Niklas Wangorsch, Gaby Weisser, Karin Huisinga, Wilhelm Arch Toxicol Toxicokinetics and Metabolism A sufficient quantitative understanding of aluminium (Al) toxicokinetics (TK) in man is still lacking, although highly desirable for risk assessment of Al exposure. Baseline exposure and the risk of contamination severely limit the feasibility of TK studies administering the naturally occurring isotope (27)Al, both in animals and man. These limitations are absent in studies with (26)Al as a tracer, but tissue data are limited to animal studies. A TK model capable of inter-species translation to make valid predictions of Al levels in humans—especially in toxicological relevant tissues like bone and brain—is urgently needed. Here, we present: (i) a curated dataset which comprises all eligible studies with single doses of (26)Al tracer administered as citrate or chloride salts orally and/or intravenously to rats and humans, including ultra-long-term kinetic profiles for plasma, blood, liver, spleen, muscle, bone, brain, kidney, and urine up to 150 weeks; and (ii) the development of a physiology-based (PB) model for Al TK after intravenous and oral administration of aqueous Al citrate and Al chloride solutions in rats and humans. Based on the comprehensive curated (26)Al dataset, we estimated substance-dependent parameters within a non-linear mixed-effect modelling context. The model fitted the heterogeneous (26)Al data very well and was successfully validated against datasets in rats and humans. The presented PBTK model for Al, based on the most extensive and diverse dataset of Al exposure to date, constitutes a major advancement in the field, thereby paving the way towards a more quantitative risk assessment in humans. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00204-021-03107-y. Springer Berlin Heidelberg 2021-08-14 2021 /pmc/articles/PMC8380244/ /pubmed/34390355 http://dx.doi.org/10.1007/s00204-021-03107-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Toxicokinetics and Metabolism
Hethey, Christoph
Hartung, Niklas
Wangorsch, Gaby
Weisser, Karin
Huisinga, Wilhelm
Physiology-based toxicokinetic modelling of aluminium in rat and man
title Physiology-based toxicokinetic modelling of aluminium in rat and man
title_full Physiology-based toxicokinetic modelling of aluminium in rat and man
title_fullStr Physiology-based toxicokinetic modelling of aluminium in rat and man
title_full_unstemmed Physiology-based toxicokinetic modelling of aluminium in rat and man
title_short Physiology-based toxicokinetic modelling of aluminium in rat and man
title_sort physiology-based toxicokinetic modelling of aluminium in rat and man
topic Toxicokinetics and Metabolism
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380244/
https://www.ncbi.nlm.nih.gov/pubmed/34390355
http://dx.doi.org/10.1007/s00204-021-03107-y
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