TY  - JOUR
A1  - Hethey, Christoph Philipp
A1  - Hartung, Niklas
A1  - Wangorsch, Gaby
A1  - Weisser, Karin
A1  - Huisinga, Wilhelm
T1  - Physiology-based toxicokinetic modelling of aluminium in rat and man
JF  - Archives of toxicology : official journal of EUROTOX
N2  - 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 Al-27, both in animals and man. These limitations are absent in studies with Al-26 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 Al-26 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 Al-26 dataset, we estimated substance-dependent parameters within a non-linear mixed-effect modelling context. The model fitted the heterogeneous Al-26 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.
KW  - PBTK
KW  - Toxicokinetics
KW  - Al-26
KW  - Aluminium
Y1  - 2021
U6  - https://doi.org/10.1007/s00204-021-03107-y
SN  - 0340-5761
SN  - 1432-0738
VL  - 95
IS  - 9
SP  - 2977
EP  - 3000
PB  - Springer
CY  - Berlin ; Heidelberg
ER  -