Toxicokinetic study of Alternariol monomethyl-ether in pigs as a surrogate animal model for humans

The scientific opinion of EFSA is that the toxicity and in vivo toxicokinetics of Alternaria toxins in humans and livestock are generally lacking so there is not a proper hazard characterization. After decades of research on the occurrence and the toxicity of Alternaria toxins, no regulation has been implemented yet, thus leaving these potential food contaminants in the status of so-called “emerging mycotoxins”. This research project aims to fill the knowledge gaps about the toxicity of alternariol monomethyl-ether (AME) by unveiling toxicokinetic characteristics in vivo. Exploring absorption, distribution, metabolism and excretion (ADME) of toxins in the body is essential for estimating the rate and pathways of toxin metabolism and excretion. The objective of this project it the knowledge of ADME parameters of AME in pigs as a superior surrogate animal model for humans. In the present thesis a toxicokinetic study was conducted in six 4-week-old piglets (Seghers hybrids, Ratterlow Seghers Holding, Lokeren, Belgium) orally and intravenously treated with the mycotoxin to evaluate the systemic exposure by quantifying the concentration of AME in plasma and urine. The trial was characterized by two-way crossover design administration. All pharmacokinetic studies in pigs require sequential blood sampling over a relatively short period of time so, immediately after administration, blood samples and urine samples were taken at different time points post administration. Furthermore, the collection of portal blood allowed to identify possible pre-systemic biotransformation of the mycotoxin. Using appropriate compartmental and non-compartmental kinetic modeling, toxicokinetic parameters were obtained (WinNonlin, Phoenix, USA). It is evaluated the absolute oral bioavailability (%). Both urine and blood samples were collected simultaneously in order to determine the mycotoxin's excretion through the urine and to look into its metabolic conversion. Urine samples were collected without the use of any tools using collecting bags that could only be used on male pigs (anatomically not possible in female piglets). At the end of the study the oral bioavailability of AME is about 9%. This can indicate a considerable first-pass biotransformation or poor oral absorption (pre-systemic, mainly hepatic biotransformation). The volume of AME dispersion and total body clearance are both quite high. The comprehensive biotransformation that resulted in the short elimination half-life is consistent with this. Further research is needed on the toxicodynamic properties of this mycotoxin for risk analysis.