Naturally occurring food substances may constitute safety hazards. The risks associated with plant-derived pyrrolizidine alkaloids have been extensively evaluated. Petasites japonicus (common Japanese name, fuki) is a widely consumed water-soluble pyrrolizidine alkaloid-producing plant. In this study, neopetasitenine (acetylfukinotoxin) was selected as a model food substrate (for which human phar-macokinetics were estimated) because of its high concentration in fuki, along with petasitenine (fukino-toxin), its carcinogenic deacetylated metabolite. Although neopetasitenine was rapidly absorbed and converted to petasitenine after oral administration of 1.0 mg/kg in rats, petasitenine was slowly cleared from plasma. Forward dosimetry was conducted using in silico simplified physiologically based pharmacoki-netic (PBPK) modeling formulated on experimental pharmacokinetic rat data. From ~2 hr after the oral administration of neopetasitenine in rats, the plasma concentrations of petasitenine were higher than those of neopetasitenine under the present conditions. A human PBPK model was established following an allo-metric scaling approach applied to rat parameters (without considering interspecies factors) to estimate human intrinsic hepatic clearances from empirical rat values. Human in silico neopetasitenine and peta-sitenine plasma concentration curves were simulated after daily oral administrations of 3.0 and 1.3 mg/kg neopetasitenine. These doses were taken from reported acute/short-term cases of pyrrolizidine alkaloid toxicity. In vitro hepatotoxicity of neopetasitenine and petasitenine was caused by their high concentrations in the medium for human hepatocyte-like cell line HepaRG cells as an index of lactate dehydrogenase leakage. Neopetasitenine was estimated to be rapidly absorbed and converted to deacetylated carcinogenic petasitenine, even after hepatotoxic doses of 1.0 mg/kg in humans. If the water-soluble pyrrolizidine alkaloid-producing plant P. japonicus were daily consumed as food, current simulation results suggest that dangerous amounts of deacetylated petasitenine could be continuously present in human plasma. © 2021, Japanese Society of Toxicology. All rights reserved.