Physiology-based toxicokinetic modelling of aluminium in rat and man

• Published in: Archives of toxicology 2021-09, Vol.95 (9), p.2977-3000
• Main Authors: Hethey, Christoph, Hartung, Niklas, Wangorsch, Gaby, Weisser, Karin, Huisinga, Wilhelm
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Administration, Oral; Adult; Aluminum; Aluminum Chloride - administration & dosage; Aluminum Chloride - pharmacokinetics; Aluminum Chloride - toxicity; Animal tissues; Animals; Biomedical and Life Sciences; Biomedicine; Brain; Chlorides; Citric acid; Citric Acid - administration & dosage; Citric Acid - pharmacokinetics; Citric Acid - toxicity; Contamination; Datasets; Datasets as Topic; Environmental Health; Exposure; Feasibility studies; Female; Humans; Intravenous administration; Kidneys; Male; Modelling; Models, Biological; Muscles; Nonlinear Dynamics; Occupational Medicine/Industrial Medicine; Oral administration; Parameter estimation; Pharmacology/Toxicology; Physiology; Rats; Risk Assessment; Salts; Species Specificity; Spleen; Tissue Distribution; Toxicokinetics; Toxicokinetics and Metabolism
• ISSN: 0340-5761; 1432-0738; 1432-0738
• DOI: 10.1007/s00204-021-03107-y

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.