J Korean Med Sci.  2022 Apr;37(13):e101. 10.3346/jkms.2022.37.e101.

Review of Inhalation Health Risks Involving Chloromethylisothiazolinone (CMIT) and Methylisothiazolinone (MIT) Used as Disinfectants in Household Humidifiers

Affiliations
  • 1Department of Environmental Health, Korea National Open University, Seoul, Korea
  • 2Department of Anthropology, Johns Hopkins University, Baltimore, MD, USA
  • 3Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
  • 4Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, Korea
  • 5Chemical Safety Management Department, Nakdong River Basin Environmental Office, Ministry of Environment, Changwon, Korea
  • 6Graduate School of Public Health and Healthcare Management, The Catholic University of Korea, Seoul, Korea
  • 7National Cancer Control Institute, National Cancer Center, Goyang, Korea
  • 8Department of Pediatrics, Childhood Asthma and Atopy Center, Humidifier Disinfectant Health Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Abstract

The association between lung injury and exposure to humidifier disinfectant (HD) containing a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) has been controversial in South Korea. This study conducts a literature review in order to evaluate the likelihood of CMIT/MIT reaching the lower part of the respiratory tract and causing lung injury. A literature review focused on the inhalation risk of HD containing a mixture of CMIT and MIT. The major contents included the physicochemical properties of CMIT and MIT contained in HDs and methodological reviews on substance analysis, toxicity tests and clinical cases. HD products marketed in South Korea have been reported to contain approximately 1–2% CMIT and 0.2–0.6% MIT along with magnesium nitrate (20–25%), magnesium chloride (0.2–1.0%), and water (70–75%). The types of CMIT and MIT dispersed into the air and deposited in the respiratory tract are assumed to be either gaseous substances or nanoparticles mixed with magnesium salts. The result of the literature review including clinical cases of lung injury among CMIT/MIT HD product users, demonstrated that these chemicals likely reach the lower respiratory tract and accordingly cause lung injury. A number of humidifier disinfectant-associated lung injury cases with clinical evidence should be prioritized in risk assessment of HD containing CMIT and MIT, even though there might be insufficient evidence in all related areas, including inhalation exposure assessment studies, animal testing, and epidemiological studies.

Keyword

CMIT; MIT; Humidifier Disinfectant-Associated Lung Injury; Inhalation; Lung Toxicity

Reference

1. de Groot AC, Weyland JW. Kathon CG: a review. J Am Acad Dermatol. 1988; 18(2 Pt 1):350–358. PMID: 3279090.
Article
2. United States Environmental Protection Agency (USEPA). Reregistration Eligibility Decision (RED) - methylisothiazolinone. Accessed September 12, 2021. https://archive.epa.gov/pesticides/reregistration/web/pdf/3092.pdf .
3. He K, Huang J, Lagenaur CF, Aizenman E. Methylisothiazolinone, a neurotoxic biocide, disrupts the association of SRC family tyrosine kinases with focal adhesion kinase in developing cortical neurons. J Pharmacol Exp Ther. 2006; 317(3):1320–1329. PMID: 16547166.
Article
4. Park DU, Lee S, Lim HK, Kim SY, Kim J, Park J, et al. Comprehensive review on humidifier disinfectant (HD) products, focusing on the number of products and their disinfectant type. J Environ Health Sci. 2020; 46(5):481–494.
5. Kim HJ, Lee MS, Hong SB, Huh JW, Do KH, Jang SJ, et al. A cluster of lung injury cases associated with home humidifier use: an epidemiological investigation. Thorax. 2014; 69(8):703–708. PMID: 24488371.
Article
6. Kim WY, Hong SB. Humidifier disinfectant-associated lung injury: six years after the tragic event. Tuberc Respir Dis (Seoul). 2017; 80(4):351–357. PMID: 28905528.
Article
7. Park DU, Park SK, Kim J, Park J, Ryu SH, Park JH, et al. Characteristics of exposure to chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) among humidifier disinfectant-associated lung injury (HDLI) patients in South Korea. Molecules. 2020; 25(22):5284.
Article
8. United States Food & Drug Administration (USFDA). Fortification recovery. Elemental analysis manual for food and related products–3.4 Special calculations. Accessed February 8, 2022. https://www.fda.gov/media/89649/download .
9. The Dutch Board for the Authorisation of Plant Protection Products and Biocides (Ctgb). Het College Voor de Toelating van Gewasbeschermingsmiddelen en Biociden (In Dutch). Accessed February 8, 2022. https://ctgb.blob.core.windows.net/documents/e861464aef37a72a411ded6344da4888_20110154_13660_01.html .
10. European Chemical Agency (ECHA). Brief profile: Reaction mass of 2-methyl-2H-isothiazol-3-one and 5-chloro-2-methyl-2H-isothiazol-3-one. Accessed February 21, 2021. https://echa.europa.eu/brief-profile/-/briefprofile/100.136.387 .
11. The Cosmetic Ingredient Review (CIR). Amended safety assessment of methylchloroisothiazolinone and methylisothiazolinone as used in cosmetics. 2020. Accessed February 21, 2021. https://online.personalcarecouncil.org/ctfa-static/online/lists/cir-pdfs/FR787.pdf .
12. Ryu SH, Park DU, Lee E, Park S, Lee SY, Jung S, et al. Humidifier disinfectant and use characteristics associated with lung injury in Korea. Indoor Air. 2019; 29(5):735–747. PMID: 31278778.
Article
13. Health Canada (HC). 2-Methyl-4-isothiazolin-3-one. Registration decision RD2014-02. Accessed November 11, 2021. https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/cps-spc/alt_formats/pdf/pubs/pest/_decisions/rd2014-02/rd2014-02-eng.pdf .
14. Friis UF, Menné T, Thyssen JP, Johansen JD. A patient’s drawing helped the physician to make the correct diagnosis: occupational contact allergy to isothiazolinone. Contact Dermat. 2012; 67(3):174–176.
Article
15. Kaae J, Menné T, Thyssen JP. Presumed primary contact sensitization to methylisothiazolinone from paint: a chemical that became airborne. Contact Dermat. 2012; 66(6):341–342.
Article
16. Kaur-Knudsen D, Menné T, Christina Carlsen B. Systemic allergic dermatitis following airborne exposure to 1,2-benzisothiazolin-3-one. Contact Dermat. 2012; 67(5):310–312.
Article
17. Lundov MD, Mosbech H, Thyssen JP, Menné T, Zachariae C. Two cases of airborne allergic contact dermatitis caused by methylisothiazolinone in paint. Contact Dermat. 2011; 65(3):176–179.
Article
18. National Institute of Environmental Research (NIER). Review on the Association between the Use of Humidifier Disinfectant and Health Effect Focusing on Asthma, Interstitial Lung Disease and Pneumonia. Research Report No. NIER-GP2021-051. Incheon, Korea: NIER;2021.
19. Daftary AS, Deterding RR. Inhalational lung injury associated with humidifier “white dust”. Pediatrics. 2011; 127(2):e509–e512. PMID: 21199854.
Article
20. Park SK, Seol HS, Park HJ, Kim YS, Ryu SH, Kim J, et al. Experimental determination of indoor air concentration of 5-chloro-2-methylisothiazol-3(2H)-one/ 2-methylisothiazol-3(2H)-one (CMIT/MIT) emitted by the use of humidifier disinfectant. Environ Anal Health Toxicol. 2020; 35(2):e2020008. PMID: 32600006.
Article
21. Park DU, Zoh KE, Kim J, Choi S, Kwon JH, Jun H, et al. A scientific critique of a Korean Court’s acquittal for involuntary manslaughter related to 5-chloro-2-methylisothiazol-3 (2H)-one/2-methylisothiazol-3 (2H)-one (CMIT/MIT), a humidifier disinfectant (HD) Part I: Material safety, exposure and delivery to target organ from an HD perspective. J Environ Health Sci. 2021; 47(2):111–122.
22. Lee SY, Park DU, Do KH, Jang SJ, Hong SJ. The pathological findings of chloromethylisothiazolinone and methylisothiazolinone-associated lung injury. J Korean Med Sci. 2019; 34(14):e102. PMID: 30977311.
Article
23. Lee E, Son SK, Yoon J, Cho HJ, Yang SI, Jung S, et al. Two cases of chloromethylisothiazolinone and methylisothiazolinone-associated toxic lung injury. J Korean Med Sci. 2018; 33(16):e119. PMID: 29651817.
Article
24. Cho HJ, Park DU, Yoon J, Lee E, Yang SI, Kim YH, et al. Effects of a mixture of chloromethylisothiazolinone and methylisothiazolinone on peripheral airway dysfunction in children. PLoS One. 2017; 12(4):e0176083. PMID: 28453578.
Article
25. Nemery B, Hoet PH. Humidifier disinfectant-associated interstitial lung disease and the Ardystil syndrome. Am J Respir Crit Care Med. 2015; 191(1):116–117. PMID: 25551352.
Article
26. Filipczak PT, Senft AP, Seagrave J, Weber W, Kuehl PJ, Fredenburgh LE, et al. NOS-2 inhibition in phosgene-induced acute lung injury. Toxicol Sci. 2015; 146(1):89–100. PMID: 25870319.
Article
27. Kerger BD, Fedoruk MJ. Pathology, toxicology, and latency of irritant gases known to cause bronchiolitis obliterans disease: does diacetyl fit the pattern? Toxicol Rep. 2015; 2:1463–1472. PMID: 28962489.
Article
28. Kumar H, Singh VB, Meena BL, Gaur S, Singla R. Paraquat poisoning: a case report. J Clin Diagn Res. 2016; 10(2):OD10–OD11.
Article
29. Bourke SJ, Convery RP, Stenton SC, Malcolm RM, Hendrick DJ. Occupational asthma in an isothiazolinone manufacturing plant. Thorax. 1997; 52(8):746–748. PMID: 9337839.
Article
30. Heyder J. Deposition of inhaled particles in the human respiratory tract and consequences for regional targeting in respiratory drug delivery. Proc Am Thorac Soc. 2004; 1(4):315–320. PMID: 16113452.
Article
31. Kang BH, Kim MS, Park YC. Intra-tracheal administration of the disinfectant chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) in a pregnant mouse model for evaluating causal association with stillbirth. J Environ Health Sci. 2018; 44(5):468–479.
32. Korea Centers for Disease Control and Prevention. Development of Toxicological Index Identifying Causality between Humidifier Disinfectants and Its’ Diseases. Cheongju, Korea: Korea Centers for Disease Control and Prevention;2019.
33. Choi S, Chung K, Jeon J. Development of inhalation toxicity evaluation and attribution techniques for identifying humidifier disinfectants damage. Accessed September 6, 2021. https://scienceon.kisti.re.kr/commons/util/originalView.do?cn=TRKO201800023157&dbt=TRKO&rn= .
34. United States Environmental Protection Agency (USEPA). Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. Updated 1994. Accessed September 12, 2021. https://www.epa.gov/sites/default/files/2014-11/documents/rfc_methodology.pdf .
35. Song MK, Kim DI, Lee K. Kathon induces fibrotic inflammation in lungs: the first animal study revealing a causal relationship between humidifier disinfectant exposure and eosinophil and Th2-mediated fibrosis induction. Molecules. 2020; 25(20):4684.
Article
36. Kim J, Ju YS, Lee JH, Park DU, Park J, Byun K, et al. A Study on Health Damage of Humidifier Disinfectants Using National Health Insurance Big Data (II) National Institute of Environmental Research, 2019. NIER Research Report No. NIER-SP2020-052. Incheon, Korea: NIER;2020.
37. Dinwiddie R, Sharief N, Crawford O. Idiopathic interstitial pneumonitis in children: a national survey in the United Kingdom and Ireland. Pediatr Pulmonol. 2002; 34(1):23–29. PMID: 12112793.
Article
38. Griese M, Haug M, Brasch F, Freihorst A, Lohse P, von Kries R, et al. Incidence and classification of pediatric diffuse parenchymal lung diseases in Germany. Orphanet J Rare Dis. 2009; 4(1):26. PMID: 20003372.
Article
39. Park DU, Zoh KE, Kim J, Choi S, Lee Sy, Jun H. A scientific critique of a Korean Court’s acquittal for involuntary manslaughter related to 5-chloro-2-methylisothiazol-3(2H)-one/2-methylisothiazol-3(2H)-one (CMIT/MIT), a humidifier disinfectant (HD) Part II: Animal experiments, criteria for HD lung injury, and causality on individual levels. J Environ Health Sci. 2021; 47(3):193–204.
Full Text Links
  • JKMS
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr