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4- tert -octylphenol (4- tert -OP) is an ecologically hazardous substance, and exposure to it in the environment has been consistently reported in the past. Despite the hazards and widespread exposure to 4- tert -OP, tools for scientific assessment of 4- tert -OP exposure risk level in humans are lacking. The main purpose of this study was to develop a physiologically-based-toxicokinetic (PBTK) model for 4- tert -OP and to perform quantitative risk assessment of 4- tert -OP in various population groups using the established model. Based on the results of toxicokinetic experiments on male rats, the PBTK model for 4- tert -OP was established and verified, and this was converted to a model for humans through interspecies extrapolation. Based on the previously reported no-observed-adverse-effect-levels for rats, it was possible to estimate the 4- tert -OP reference dose in humans through reverse dosimetry using the model. Biomonitoring data derived from various population groups were applied to the human PBTK model to calculate external exposures and margin of safety for 4- tert -OP for each population group. The PBTK model established in this study adequately explained the toxicokinetic experimental values at acceptable levels and was able to quantitatively predict the 4- tert -OP exposure level in the testes related to male reproductive toxicity. In addition, the degree of external exposure to 4- tert -OP could be scientifically estimated based on biomonitoring values derived from various biological matrices. The reference doses for systemic and reproductive toxicity caused by 4- tert -OP in male humans were calculated to be 0.16 and 1.12 mg/kg/day, respectively. The mean external exposure to 4- tert -OP in each population group estimated based on plasma and urine biomonitoring data was 0.04–66.24 mg/kg/day, showing very large exposure diversity between groups. Exposure risks to 4- tert -OP in populations ranged from safe to risky, suggesting the need for continued monitoring and risk management of 4- tert -OP worldwide. This study provides valuable scientific insight regarding the 4- tert -OP human risk assessment. [Display omitted] • A scientific human risk assessment of 4- tert -OP using PBTK modeling was performed. • PBTK model that can consider reproductive toxicity to men has been newly developed. • Large exposure variability of 4- tert -OP was confirmed between populations. • It was suggested that continuous management and monitoring of 4- tert -OP is necessary. [ABSTRACT FROM AUTHOR]

Age-related changes and interindividual variability in the degree of exposure to hazardous substances in the environment are pertinent factors to be considered in human risk assessment. Existing risk assessments remain in a one-size-fits-all approach, often without due consideration of inter-individual toxicokinetic variability factors, such as age. The purpose of this study was to advance from the existing risk assessment of hazardous substances based on toxicokinetics to a precise human risk assessment by additionally considering the effects of physiologic and metabolic fluctuations and interindividual variability in age. Qualitative age-associated physiologic and metabolic changes in humans, obtained through a meta-analysis, were quantitatively modeled to produce the final biological age algorithm (BAA). The developed BAAs (for males) were extended and applied to the reported testicular reproductive toxicity-focused di-isobutyl-phthalate (DiBP)−mono-isobutyl-phthalate (MiBP) physiologically based toxicokinetic (PBTK) model in males. The advanced PBTK model combined with the BAA was applied to the human risk assessment based on MiBP biomonitoring data. As a result, the specialized DiBP external exposure values for each age could be estimated. Additionally, by applying the Monte Carlo simulation, the distribution of internal exposure diversity among individuals according to the same external exposure dose could be estimated. The contributions of physiologic and metabolic factors to the age-dependent toxicokinetic changes were approximately 93.41–99.99 and 0.01−6.59%, respectively. In addition, the relative contribution of metabolic factors was major in infants and continued to decrease as age increased (up to about age 30 years). This study provides a step-by-step platform that can be widely applied to overcome the limitations of existing toxicokinetic models that still require interindividual pharmacokinetic variability explanations. This will be important for the rationalization and explanation of inter-individual variability in the pharmacokinetics of many substances. [Display omitted] • Precise human risk assessment through application of aging algorithm to PBTK model. • Possible to explain and predict toxicokinetic variability between individuals. • The relative contribution of metabolic factors was larger in infants than in adults. • Physiological factors were more important in toxicokinetics than metabolic changes. [ABSTRACT FROM AUTHOR]