Translational toxicokinetics of chloromethylisothiazolinone/ methylisothiazolinone: Radioactivity-associated materials-physiologically based toxicokinetic modeling and human dose extrapolation

초록

Chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) are widely used biocides in various industrial and household products. Owing to their high reactivity and potential to form multiple metabolites, concerns regarding their human toxicity and health risks have increased. Although numerous toxicological studies have been conducted, most have relied on rodent-based exposure data without quantitative extrapolation to human kinetics. This study aimed to establish a physiologically based toxicokinetic (PBTK) model based on radioactivity-associated materials (RAM) for CMIT/MIT to enable time-and tissue-resolved prediction of internal doses and to extrapolate the model to human systems for refined risk assessment and reference dose (RfD) estimation. The RAM-PBTK model was developed using experimental tissue distribution data from radiolabeled CMIT/MIT administered to rats via oral, intranasal, and intratracheal routes. The model incorporated physiological compartments, blood flow rates, and route-specific absorption and elimination parameters. The model equations were solved using the fourth-order Runge-Kutta numerical method and optimized through iterative fitting. Model performance was validated using visual predictive checks, residual analysis, two-fold error, and robustness testing. Human-specific physiological parameters and allometric scaling were applied to extrapolate the model to humans. Monte-Carlo simulations were conducted to assess inter-individual variability, and reverse dosimetry was performed to estimate human RfDs across multiple exposure scenarios. The RAM-PBTK model accurately reproduced observed tissue concentrations of CMIT/MIT-associated radioactivity in rats and demonstrated predictive robustness. Human extrapolation yielded realistic tissue-specific concentration-time profiles. Reverse dosimetry identified maximum allowable exposure doses (RfDs: 0.02-0.59 mg/kg/day) for each route of administration, under which the simulated CMIT/MIT-associated radioactivity concentrations in all target tissues remained below the no-observed-adverse-effect concentration threshold (0.5 mu g/mL). These findings indicate protective and route-specific internal exposure limits. This study presents the first application of a RAM-integrated PBTK model for CMIT/MIT, enabling the prediction of tissue-and time-specific internal exposure across species.

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