Elucidating mechanisms of chlorine toxicity: reaction kinetics, thermodynamics, and physiological implications

Abstract

Industrial and transport accidents, accidental releases during recreational swimming pool water treatment, household accidents due to mixing bleach with acidic cleaners, and, in recent years, usage of chlorine during war and in acts of terror, all contribute to the general and elevated state of alert with regard to chlorine gas. We here describe chemical and physical properties of Cl(2) that are relevant to its chemical reactivity with biological molecules, including water-soluble small-molecular-weight antioxidants, amino acid residues in proteins, and amino-phospholipids such as phosphatidylethanolamine and phosphatidylserine that are present in the lining fluid layers covering the airways and alveolar spaces. We further conduct a Cl(2) penetration analysis to assess how far Cl(2) can penetrate the surface of the lung before it reacts with water or biological substrate molecules. Our results strongly suggest that Cl(2) will predominantly react directly with biological molecules in the lung epithelial lining fluid, such as low-molecular-weight antioxidants, and that the hydrolysis of Cl(2) to HOCl (and HCl) can be important only when these biological molecules have been depleted by direct chemical reaction with Cl(2). The results from this theoretical analysis are then used for the assessment of the potential benefits of adjuvant antioxidant therapy in the mitigation of lung injury due to inhalation of Cl(2) and are compared with recent experimental results.

Fig. 1.

The boundary where the rate of reaction of Cl₂ with a substrate S equals the rate of hydrolysis (log [S] = 1.79 − log k_app). Substrates with a product of rate constant (k_app) and concentration [S] that are below the rate of hydrolysis of Cl₂ (61.7 s⁻¹) fall below the line. Conservative estimates based on the reactivities for HOCl for ascorbate (squares), glutathione (triangles), and urate (circles), common small-molecular-weight water-soluble antioxidants found in lung epithelial lining fluid of humans and rats, are also shown on this reactivity map. In aqueous solution, Cl₂ is typically more reactive than HOCl.

Fig. 2.

Products from the reaction of Cl₂ or HOCl with the principal small-molecular-weight water-soluble antioxidants and representative phosphatidylethanolamine and phosphatidylserine.