A new approach for risk assessment of pulmonary toxicants: a preliminary study using didecyldimethylammonium chloride

doi: 10.1007/s11356-024-34905-3

Jun Woo Kim¹, Yu Bin Han², Kyu Hyuck Chung³, Yong Joo Park³

¹ Inhalation Toxicology Center for Airborne Risk Factors, Korea Institute of Toxicology, Jeongeup 56212, Republic of Korea
² College of Pharmacy, Korea University, Sejong 30019, Republic of Korea
³ College of Pharmacy, Kyungsung University, Busan 48434, Republic of Korea

Highlights

• Inhalation toxicity of didecyldimethylammonium chloride (DDAC) was assessed using a next-generation risk assessment approach.
• Point of departure was determined by analyzing cellular transcriptome based on the adverse outcome pathway.
• Human equivalent concentration was compared with a review of human DDAC exposure estimated by multiple-path particle dosimetry model and aerosol exposure of DDAC in vitro assay.

Abstract
Current human risk assessments often rely on animal toxicity data to establish point of departure (POD) values, followed by the application of uncertainty factors. Consequently, there is growing interest in alternative toxicity testing methods that reduce reliance on animal models. In this study, we propose a novel approach for inhalation toxicity risk assessment that integrates in silico and in vitro methods. Human primary alveolar epithelial cells were exposed to aerosolized didecyldimethylammonium chloride (DDAC) to assess cytotoxicity. This was followed by transcriptome analysis and biological pathway investigation, utilizing adverse outcome pathway (AOP), to calculate the POD. Additionally, human DDAC exposure was simulated using a multiple-path particle dosimetry (MPPD) model to predict exposure levels in the human alveolar region via inhalation. The results from in silico and in vitro studies were then compared, and a comprehensive risk assessment was performed. The POD for AOP 452 key events—oxidative stress, infammation, epithelial-mesenchymal transition (EMT), apoptosis, and autophagy—was found to range between 19.0 and 23.89 ng/cm², according to benchmark dose calculation tools. The estimated human exposure to DDAC in the alveolar region under actual exposure conditions was 0.164 ng/cm²/day, resulting in a margin of exposure (MOE) ranging from 121 to 145, suggesting caution regarding DDAC inhalation exposure. This study presents a novel risk assessment method that compares estimated human inhalation exposure values to in vitro results, applying the human equivalent concentration concept. Our fndings demonstrate the potential for conducting human risk assessments using both in silico and in vitro methods as alternatives to traditional in vivo studies.

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