Extension and validation of a physiologically based toxicokinetic model for risk assessment of aluminium exposure in humans.

The safety of aluminium (Al) exposure from sources such as food, parenteral nutrition or adjuvanted medicinal products is still a matter of uncertainty. Since toxicokinetic studies in humans are lacking, model predictions are warranted for risk assessment. Recently, we established a physiologically based toxicokinetic (PBTK) model for Al built on a comprehensive toxicokinetic database, which could describe Al biokinetics in rats and human adults after single oral and intravenous doses of soluble Al salts. Since then, we have substantially amended the model, rendering it applicable to accurately represent children and their dynamically changing physiology (including maturating renal function in neonates and increased bone turnover during puberty). Also, additional sources of exposure were implemented, including vaccinations, subcutaneous allergen immunotherapies, food, antacids and parenteral nutrition. The model predictions in plasma and tissues were then compared to own published data and literature Al measurements after exposure from food (human reference values), parenteral nutrition (toxic levels in children and adults), adjuvanted allergen products or vaccines in rats and humans, and whole-body retention data. Al levels were predicted remarkably well, in plasma and toxicologically important tissues like bone, liver and brain. To our knowledge, this is the first Al PBTK model in humans ready for use in regulatory risk assessment, allowing to simulate Al exposure in children and adults from various sources of Al exposure like food and drinking water, Al contaminations in parenteral nutrition solutions, or poorly soluble Al complexes in medicinal products including Al-adjuvanted immunotherapeutics and vaccines.