Differential and Sex-Specific Toxicity of Aspirated Quaternary Ammonium Compounds

Exposure to mitochondria-inhibiting quaternary ammonium compounds (QACs) raises the risk for human asthma and chronic obstructive pulmonary disease (COPD). As QACs do not penetrate gut or skin well, we hypothesized that pulmonary exposure could (1) account for observed levels of QAC in human blood and (2) contribute to the observed increased risk for airway disease from QAC exposure. Mice were exposed to Benzalkonium Chloride (BAC) and didecyl dimethylammonium chloride (DDAC) by oropharyngeal aspiration. QAC aspiration increased mice lethality and lung injury 100-fold vs oral dosing. DDAC caused more lethality and lung injury than BAC. Both QACs were more lethal to males than to females. Inspired QAC doses that produced significant lung injury produced blood QAC levels of 1-150 nM, overlapping human concentrations. Thus, in mice, aspirated QACs are 100-fold more injurious and lethal than ingested QACs, aspirated DDAC is twice as injurious and lethal as BAC, and QAC inspiration sufficient to injure the lungs produces overlapping blood concentrations with humans. These mouse data support the hypotheses that QAC inspiration is a much more efficient route of corporeal penetration than dermal or gut penetration, producing much more lung injury than those other routes, and that airborne QAC exposure could underlie increased human risk for pulmonary disease.