二癸基二甲基溴化銨於動物之全身性毒性研究

Abstract

二癸基二甲基溴化銨（didecyl dimethyl ammonium bromide, DDAB）為四級銨鹽類（quaternary ammonium compounds, QACs）消毒劑之活性成分之一，廣泛應用於環境與畜牧消毒，然而其於動物之全身性毒性及病理機轉仍缺乏完整研究。本研究首先報告兩例南美長鼻浣熊（Nasua nasua）疑似暴露於含 DDAB 之市售消毒劑 BROMICIDE-500 後死亡之病例。兩例長鼻浣熊皆出現口腔病灶、厭食、虛弱及多器官病變。剖檢與組織病理檢查顯示，以鼻吻周圍皮膚、肺臟及肝臟為主之廣泛性壞死與出血性病變。毒物分析於腸胃內容物、肝臟及肺臟檢出 DDA，支持體內暴露及組織分布。為進一步評估 BROMICIDE-500 所含 DDAB 之全身性毒性，本研究建立小鼠口服暴露模型，以探討其毒性表現及組織病變。結果顯示，85 mg/kg 組迅速出現嚴重呼吸窘迫並於 24 小時內達人道終點；10 mg/kg 組自暴露後第二 天起出現喘氣、精神沉鬱及顯著體重下降，並於第六天達人道終點；其餘各組於暴露後第 8 天實驗終點前均未見明顯臨床異常。高劑量與中劑量組主要病理變化包括舌部水腫或壞死、胃黏膜壞死、肝細胞壞死或退化、肺臟與腎臟鬱血，以及蛛網膜下腔出血。以TUNEL染色僅於口腔、食道及胃部潰瘍性黏膜上皮觀察到少量陽性訊號；相較之下，以HMGB1 免疫組織化學染色可於潰瘍性口腔及胃黏膜病灶中偵測到細胞質陽性。綜合病理形態與特殊染色結果，本研究顯示 DDAB 所致組織損傷以壞死性病變為主，而凋亡可能僅侷限於部分黏膜上皮細胞。本研究結合自然暴露病例與實驗性動物模型，提供 DDAB 全身性毒性之病理特徵及初步致病機轉證據，並建立未來 DDAB 中毒診斷及毒理機轉研究的重要基礎。

Didecyl dimethyl ammonium bromide (DDAB), one of the active ingredients of quaternary ammonium compound (QAC) disinfectants, is widely used for environmental and veterinary disinfection. However, its systemic toxicity and pathological mechanisms in animals remain poorly characterized. This study first describes two fatal cases of suspected exposure to BROMICIDE-500, a commercial disinfectant containing DDAB, in South American coatis (Nasua nasua). Both animals developed oral lesions, anorexia, weakness, and multisystemic lesions. Gross and histopathologic examinations revealed extensive necrotic and hemorrhagic lesions, predominantly involving the perinasal skin, lungs, and liver. Toxicologic analysis detected didecyl dimethyl ammonium (DDA) in the gastrointestinal contents, liver, and lungs, supporting systemic exposure and tissue distribution. To further investigate the systemic toxicity of DDAB, an experimental oral exposure model was established in mice. Thirty-five female ICR mice were assigned to DDAB-equivalent dose groups of 85, 10, 1, or 0.1 mg/kg, together with a propylene glycol (PG) vehicle control group and an untreated control group. Mice receiving 85 mg/kg rapidly developed severe respiratory distress and reached humane endpoints within 24 hours. Mice receiving 10 mg/kg developed panting, depression, and marked body weight loss beginning 2 days after exposure and reached humane endpoints on day 6. No apparent clinical abnormalities were observed in the remaining groups. All surviving animals were euthanized on day 8 after exposure. Major pathological findings in the high- and intermediate-dose groups included tongue edema or necrosis, gastric mucosal necrosis, hepatocellular necrosis or degeneration, pulmonary and renal congestion, and subarachnoid hemorrhage. TUNEL assay demonstrated only limited apoptotic signals in the ulcerative mucosal epithelium of the oral cavity, esophagus, and stomach, whereas HMGB1 immunohistochemistry showed prominent cytoplasmic immunoreactivity within ulcerative lesions of the oral and gastric mucosa. Collectively, the morphologic and immunohistochemical findings suggest that DDAB-induced tissue injury is characterized predominantly by necrosis, whereas apoptosis appears to be limited to a subset of mucosal epithelial cells. By integrating naturally exposed coatis with an experimental mouse model, this study provides pathological evidence of DDAB-induced systemic toxicity and offers insight into its potential mechanisms of tissue injury, thereby establishing a foundation for the diagnosis and future investigation of DDAB intoxication.