Human Plasma and Urine Concentrations of Triethylamine and Its <i>N</i>-Oxide after Oral Administration Extrapolated Using Pharmacokinetic Modeling: Comparison with Trimethylamine and Its <i>N</i>-Oxide

In Japan, the simple N-substituted substances triethylamine and trimethylamine have been designated possibly hazardous air pollutants also requiring further investigation to protect the aquatic environment. Triethylamine is relevant to human biomonitoring in manufacturing workers because of its possible adverse effects; in contrast, trimethylamine exposure from normal daily dietary consumption is considered nontoxic. Although a role for flavin-containing monooxygenase 3 in the metabolism of triethylamine was recently reported, no simplified physiologically based pharmacokinetic (PBPK) model to estimate human plasma and urinary levels of triethylamine and its N-oxide has currently been developed. In this study, in silico human plasma and urine concentrations of triethylamine were estimated after virtual oral administration using a newly established triethylamine PBPK model. The results were compared with our previously established trimethylamine PBPK model. In silico plasma and urinary concentration curves were generated after single virtual administrations of triethylamine and trimethylamine. After 28 d of daily exposure to reported maximum oral doses of triethylamine and trimethylamine from the public water supply of 0.02 and 0.68 µg/kg body weight/d, respectively, the mean modeled urinary levels for the final day were 3.7 and 1.1 pmol/mL. The proposed occupational standard of 10 mg triethylamine/m³ of air reportedly corresponds to a urinary excretion of approx. 0.4 nmol/mL. The results of the current forward dosimetry analyses, therefore, indicate at least a two-order safety margin (drinking water versus occupational standard) for triethylamine. The present PBPK model for triethylamine and its N-oxide could estimate daily exposures using forward dosimetry and thereby facilitate risk assessment in humans.