Specific Respiratory Toxicity of the Pharmaceutical Substance Articaine Hydrochloride Following Chronic Inhalation Exposure

Abstract

Introduction: In the Republic of Belarus, no hygienic standards or methods of control in the workplace air have been developed for the group of modern amide local anesthetics, including articaine hydrochloride. Objectives: To study the specific toxic effect of the pharmaceutical substance articaine hydrochloride on the respiratory system, to establish limiting indicators and threshold concentrations for chronic inhalation exposure for subsequent justification of the safe level of the substance in the workplace air of a pharmaceutical facility. Materials and methods: Experimental studies were carried out on 36 outbred albino rats intranasally exposed to various concentrations (2, 10 and 50 mg/m3) of the pharmaceutical substance during 4 months. At the end of the experiment, we collected bronchoalveolar lavage fluid and tested it for cytokine concentrations and cellular structure. The trachea, bronchi and lungs were isolated from euthanized animals for pathomorphological studies. Statistical data processing was performed using parametric and nonparametric tests in Statistica 13 software. Differences between groups were considered significant at p < 0.05. Results: The specific toxic effect of the pharmaceutical substance on the bronchopulmonary system at different levels (2-10-50 mg/m3) of inhalation exposure to articaine hydrochloride was manifested by the maximum development of pathomorphological structural changes at the highest concentration of 50 mg/m3, such as a statistical increase in the thickness of the interalveolar septa of the lungs by 1.85 times, the appearance of pronounced perivascular and peribronchial infiltration in the lungs in more than half of the rats. Changes in the composition of bronchoalveolar lavage were characterized by a significant increase in the cellular inflammatory component and transformation of the cytokine profile. At the exposure of 50 mg/m3, an increase in the content of lymphocytes and neutrophils was noted by 6.09 and 3.4 times, respectively, the appearance of plasma cells and an increase in the concentration of IL-1 and IL-6 by 2.0 and 3.2 times. Conclusions: The dose-dependent morphological, cytological, and functional changes in the respiratory organs and lavage characterize the exposure concentration of 2 mg/m3 as practically ineffective, 10 mg/m3 as threshold, and 50 mg/m3 as effective in terms of the toxic effects under study.