4-tert-Octylphenol: Toxicodynamics & In Vitro Cytotoxicity Assessment

4-tert-Octylphenol, a endocrine-disrupting chemical, is an estrogenic agent. It is also a biodegradation product of non-ionic surfactants alkylphenol polyethoxylates. It induces apoptosis in neuronal progenitor cells in offspring mouse brain. This substance reduces bromodeoxyuridine (BrdU), mitotic marker Ki67, and phospho-histone H3 (p-Histone-H3), resulting in a reduction of neuronal progenitor proliferation. 4-tert-Octylphenol disrupts brain development and behavior in mice, which is promising for reserch of immune response, neuro-related diseases and ethology.

Toxicodynamics assessment of 4-tert-octylphenol

4-tert-octylphenol (4-tert-OP) is an environmentally hazardous substance that is known to cause reproductive toxicity, developmental disorders, and systemic toxicity in the body. Environmental exposure to 4-tert-OP, which has often been reported from the past to recent times, could be because 4-tert-OP has been used in many household products (detergents, emulsifiers, cleaners, etc.) over a long period (Pan and Tsai, 2009). The primary functions of 4-tert-OP and its derivatives in household products include acting as a surfactant in detergents and cleaners, an emulsifying agent in various formulations, a dispersing agent, a wetting agent, a foaming control agent, and a stabilizing agent, contributing to the overall effectiveness and stability of these products. Despite widespread environmental exposure and awareness of its toxicity, a systematic approach to quantitatively assess the 4-tert-OP exposure risk within the population, particularly focusing on toxicity expression, is lacking. To the best of our knowledge, human risk assessment for 4-tert-OP by quantitatively considering the degree of toxicity expression in specific tissues has not previously been reported. The purpose of the present study was to develop a TD model for 4-tert-Octylphenol, link it to the established PBTK model, and then perform a human risk assessment focusing on tissue toxicity. The TD model reported in this study provides a key bridge in the previously limited interpretation of the exposure-toxicity response correlation for 4-tert-OP. Moreover, the risk assessment linked to PBTK provides a valuable approach that advances the understanding and interpretation of the in vivo fate and toxicology of 4-tert-OP.[1]

To establish the PBTK-TD model to assess 4-tert-OP toxicity, the TD model was developed based on the results of toxicity evaluation using human liver, kidney, and testis tissue cell lines. 4-tert-Octylphenol is a hazardous substance that has pervaded the environment (Liu et al., 2017; Liu and Mabury, 2019; Liu et al., 2015; Olaniyan et al., 2020), and conducting direct clinical trials to establish its toxicity on humans is not possible, so TD data for human exposure are limited. As a result, toxicity evaluation using human-derived tissue cell lines was considered to be realistic for predicting the TD of 4-tert-OP. The 4-tert-OP PBTK-TD model proposed in this study was linked to the in vivo kinetic characteristics of 4-tert-Octylphenol exposure to organically interpret the expression of toxicity in each target tissue in an in vivo-in vitro system. The 4-tert-OP risk analysis based on the PBTK-TD model was conducted under the general assumption that the onset of toxicity at the cellular level in target tissues leads to toxicity and functional changes in the corresponding tissue system. Because human risk assessment studies targeting environmental pollutants contain inherent uncertainties that cannot be directly confirmed in humans, prediction of potential toxicity at strict and tight levels is essential. In the future, it will be necessary to explore cell-to-organ toxicity degree correlations to predict the systemic toxicity of 4-tert-Octylphenol at the organ level, which will make TD prediction for in vivo systems more precise.

We enhanced 4-tert-Octylphenol human risk assessment by developing a TD model for 4-tert-OP and predicting target tissue toxicity by linking it with the established PBTK model for this compound. This study is very important for the scientific approach to the previously limited 4-tert-OP toxicity-based exposure risk assessment in the population and serves as an acceleration point for further progressive studies. The results of using the PBTK-TD model confirmed that the overall 4-tert-OP exposure risk corresponded to the safe level. However, the detection of high concentrations of 4-tert-OP in the liver and testis cell lines corresponded to the cautionary and dangerous levels in relation to testicular and liver toxicity, respectively. This suggests that monitoring and management of human exposure to 4-tert-OP needs to be conducted on an ongoing basis. The 4-tert-Octylphenol PBTK-TD model combined with periodic biomonitoring data derived from population groups enables quantitative 4-tert-OP human risk assessment based on the rapid prediction of target tissue toxicity. The derived human risk assessment results can be useful scientific reference material for determining the urgency of regulating and managing 4-tert-OP environmental exposure and setting specific control standards.

In Vitro Investigation of Biological and Toxic Effects of 4-tert-Octylphenol

Environmental pollution originating from anthropogenic activities is one of the major problems plaguing modern society. Many byproducts of industrial processes are released into the environment and enter the food chain, undergoing biomagnification phenomena and representing a serious risk to human health. Among recent emerging pollutants, alkylphenols ethoxylates (APEOs) are a group of non-ionic surfactants used in several industrial applications, such as paper and textile production, pesticides, cosmetics and detergent formulations. The most notable members of APEOs are nonylphenol ethoxylate and octylphenol ethoxylate, which represent approximately 80% and 20% of the APEO production. With the aim of expanding the knowledge on the cytotoxic potential of 4-tert-Octylphenol, we investigated the effect of the most diffused 4-OP isomer, i.e., the branched 4-tert-OP (here simply named 4-OP), on different human cell lines (hepatic, intestinal, pulmonary, epidermal, renal) representing those cell types potentially more exposed to this contaminant. We were interested in highlighting the differences in the sensitivity of each cell type to 4-OP and also to compare the cytotoxicity of 4-tert-Octylphenol with that of 4-NP and a mixture of both, looking for eventual synergic effects of their combination. We also compared our experimental data with ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties predicted in silico. We further focused our attention on the potential damaging effects of 4-OP in a model of human liver cells (HepG2 cell line), as the liver is one of the first lines of defense against xenobiotics, which in some cases may alter organ functions.

With the present study, we highlighted differences in sensitivity to the cytotoxic activity of 4-tert-Octylphenol depending on the cell type. A combination of 4-OP and 4-NP produced synergistic effects in some cases, indicating at least a partially different mechanism of action. 4-OP-induced toxicity caused increased apoptosis but also the dysregulation of homeostatic cell processes, such as UPR, autophagy and the antioxidant response, as revealed by experimentations using a human hepatic cell line. Our findings support the idea that 4-tert-Octylphenol, like other emerging pollutants that are increasingly abundant in the environment, could represent a potential danger to human health.

References

[1]Park, Dae-Han et al. “Exposure risk assessment through toxicodynamics assessment of 4-tert-octylphenol and estimation of new reference values based on human tissue toxicity.” Environmental pollution (Barking, Essex : 1987) vol. 372 (2025): 125969. doi:10.1016/j.envpol.2025.125969

[2]Romanelli AM, Montefusco A, Sposito S, Scafuri B, Caputo I, Paolella G. In Vitro Investigation of Biological and Toxic Effects of 4-Octylphenol on Human Cells. Int J Mol Sci. 2024 Dec 4;25(23):13032. doi: 10.3390/ijms252313032. PMID: 39684746; PMCID: PMC11641860.

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