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

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 andperibronchial 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.

1. Binks SP. Occupational toxicology and the control of exposure to pharmaceutical agents at work. Occup Med (Lond). 2003;53(6):363–370. doi: 10.1093/occmed/kqg116

2. Gorokhova LG, Ulanova EV, Shavtsova GM, Erdeeva SV, Blazhina ON. Health state of workers in chemical and pharmaceutic industry. Meditsina Truda i Promyshlennaya Ekologiya. 2018;(6):38-42. (In Russ.) doi: 10.31089/1026-9428-2018-6-38-42

3. Arabei SV, Hindziuk AV. Working conditions and occupational health risk of workers in the anticancer drugs production plant. Zhurnal Grodnenskogo Gosudarstvennogo Meditsinskogo Universiteta. 2022;20(5):526- 530. (In Russ.) doi: 10.25298/2221-8785-2022-20-5-526-530

4. Milovanović A, Jakovljević B, Milovanović J, et al. Morbidity patterns of workers employed in pharmaceutical-chemical industry. Srp Arh Celok Lek. 2007;135(3- 4):184–190. (In Serbian.) doi: 10.2298/sarh0704184m

5. Yu WL, Zhou JJ, Zou JF, et al. Investigation of occupational health status of female workers in pharmaceutical industry of Shandong and Gansu provinces. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2011;29(9):650-652. (In Chinese.) doi: 10.3760/cma.j.issn.1001-9391.2011.09.004

6. Geydan DM, Timofeeva SS. [Occupational diseases in pharmaceutical workers.] In: Safety – 2023. Problems of Technosphere Safety of the Modern World: Proceedings of the XXVIII All-Russian Student Scientific and Practical Conference with international participation, Irkutsk, April 19–21, 2023. Irkutsk: Irkutsk National Research Technical University; 2023:264-267. (In Russ.)

7. Lelyukh PYu, Terpigoreva IV. [Causes of occupational diseases in pharmaceutical workers and methods of their prevention.] In: Mavlyutov Readings: Proceedings of the XVI All-Russian Youth Scientific Conference, Ufa, October 25–27, 2022. Ufa: Ufa State Aviation Technical University; 2022;4:189-191. (In Russ.)

8. Vasilkevich VM, Bogdanov RV, Drozdova EV. Actual issues of hygienic regulation and creation of safe working conditions at pharmaceutical manufacturing enterprises. Meditsina Truda i Promyshlennaya Ekologiya. 2020;60(10):640-644. (In Russ.) doi: 10.31089/1026-9428-2020-60-10-640-644

9. Dzhangozina DM, Temireeva KS, Amanzhol IA, et al. [Factors of production activities affecting working conditions of pharmaceutical workers.] Mezhdunarodnyy Zhurnal Eksperimental’nogo Obrazovaniya. 2009;(3):31- 33. (In Russ.)

10. Bakhonina EI, Matuzov GL, Fazylova LI, Khaybullina RR. Working conditions and occupational diseases of pharmaceutical workers. Neftegazovoe Delo. 2024;(3):92-105. (In Russ.) doi: 10.17122/ogbus-2024-3-92-105

11. Gathuru IM, Buchanich JM, Marsh GM, Dolan DG. Health hazards in the pharmaceutical industry. Pharmaceut Reg Affairs. 2015;4(3):145. doi: 10.4172/2167-7689.1000145

12. Goossens A, Hulst KV. Occupational contact dermatitis in the pharmaceutical industry. Clin Dermatol. 2011;29(6):662- 668. doi: 10.1016/j.clindermatol.2011.08.011

13. Semenova VN, Stepanova AE, Krashenina GI, et al. Hygienic regulation – current status and problems. Universum: Medicine and Pharmacology. 2023;7(100):28- 31. (In Russ.) doi: 10.32743/UniMed.2023.100.7.15673

14. Khamidulina KhKh, Tarasova EV. [Modern approaches to harmonization of hygienic regulation of chemicals with international requirements.] In: Innovative Approaches to Solving Sanitary, Hygienic, and Biomedical Problems of Population Health: Proceedings of the Republican Scientific and Practical Conference with international participation dedicated to the 90th Anniversary of the Research Institute of Sanitation, Hygiene and Occupational Diseases, Tashkent, July 16, 2024. Tashkent; 2024:207-208. (In Russ.)

15. Dorne JL, Ragas AM, Frampton GK, Spurgeon DS, Lewis DF. Trends in human risk assessment of pharmaceuticals. Anal Bioanal Chem. 2007;387(4):1167-1172. doi: 10.1007/s00216-006-0961-9

16. PubChem. Articaine hydrochloride. Accessed September 9, 2023. https://pubchem.ncbi.nlm.nih.gov/compound/Articaine-hydrochloride#datasheet=LCSS

17. Vasilkevich VM, Evtereva AA, Chernyshova EV. On the results of the initial toxicological assessment of the pharmaceutical substance articaine hydrochloride. Vestnik Vitebskogo Gosudarstvennogo Meditsinskogo Universiteta. 2024;23(2):59-68. (In Russ.) doi: 10.22263/2312-4156.2024.2.59

18. Matchinin AA, Katelnikova AE, Kryshen KL. Specific techniques of bronchoalveolar lavage collecting from laboratory animals. Laboratory Animals for Science. 2019;(4):37-43. (In Russ.) doi: 10.29296/2618723X-2019-04-06

19. Pankova VB, Fedina IN, Nakatis YaA, Lavrenova GV. Upper respiratory tract diseases caused by exposure to industrial aerosols. Rossiyskaya Rinologiya. 2016;24(4):30- 36. (In Russ.) doi: 10.17116/rosrino201624430-36

20. Lavrentieva NE. Occupational respiratory disease in pharmaceutical workers. Vrach-Aspirant. 2012;55(6.2):363- 368. (In Russ.)