환경성질환과 환경유해인자의 연관성을 규명하기 위한 독성 연구 고찰 = A Systematic Review of Toxicological Studies to Identify the Association between Environmental Diseases and Environmental Factors

다국어 초록 (Multilingual Abstract)

Background: The occurrence of environmental disease is known to be associated with chronic exposure to toxic chemicals, including waterborne contaminants, air/indoor pollutants, asbestos, ingredients in humidifier disinfectants, etc. Objectives: In this study, we reviewed toxicological studies related to environmental disease as defined by the Environmental Health Act in Korea and toxic chemicals. We also suggested a direction for future toxicological research necessary for the prevention and management of environmental disease. Methods: Trends in previous studies related to environmental disease were investigated through PubMed and Web of Science. A detailed review was provided on toxicological studies related to the humidifier disinfectants. We identified adverse outcome pathways (AOPs) that can be linked to the induction of environmental diseases, and proposed a chemical screening system that uses AOP, chemical toxicity big data, and deep learning models to select chemicals that induce environmental disease. Results: Research on chemical toxicity is increasing every year, but there is a limitation to revealing a clear causal relationship between exposure to chemicals and the occurrence of environmental disease. It is necessary to develop various exposure- and effect-biomarkers related to disease occurrence and to conduct toxicokinetic studies. A novel chemical screening system that uses AOP and chemical toxicity big data could be useful for selecting chemicals that cause environmental diseases. Conclusions: From a toxicological point of view, developing AOP related to environmental diseases and a deep learning-based chemical screening system will contribute to the prevention of environmental diseases in advance.

목차 (Table of Contents)

• I. 서 론 II. 환경성질환에 관한 연구 추세 III. 가습기살균제로 인한 폐질환과 화학물질의 연관성 규명을 위한 독성학적 연구 IV. 환경성질환 예방관리를 위한 독성학적 연구의 방향 V. 결 론 Conflict of Interest References

참고문헌 (Reference)

1 백운석, "환경유해인자로 인한 건강피해 구제제도의 개선방안에 관한 고찰" 한국환경연구원 12 (12): 75-100, 2013

2 안종주, "석면과 환경성 질환" 한국환경보건학회 35 (35): 538-541, 2009

3 최길용, "대기오염에 따른 환경성 질환의 인자분석: Big Data를 통한 Google 트렌드 데이터의 분석 및 영향" 한국환경보건학회 44 (44): 563-571, 2018

4 National Health Insurance Service, "“Allergic rhinitis”has the highest number of patients under the age of 10"

5 이은, "Two Cases of Chloromethylisothiazolinone and Methylisothiazolinone-associated Toxic Lung Injury" 대한의학회 33 (33): 1-8, 2018

6 Lee YH, "Toxicity of humidifier disinfectant polyhexamethylene guanidine hydrochloride by two-week whole body-inhalation exposure in rats" 33 (33): 265-277, 2020

7 Song MK, "Time-course transcriptomic alterations reflect the pathophysiology of polyhexamethylene guanidine phosphate-induced lung injury in rats" 31 (31): 457-467, 2019

8 Song J, "Time course of polyhexamethyleneguanidine phosphate-induced lung inflammation and fibrosis in mice" 345 : 94-102, 2018

9 Jung KH, "The policy direction on environment diseases and environmental risk of children health" 152 : 100-111, 2009

10 Ministry of Environment, "Systemic Response to Environmental Diseases such as Investigations on the Occurrence of Atopic Skin Diseases in Children"

11 Ministry of Environment, "Status of Environmental Health Center (’21.09.06)"

12 Prüss-Üstün A, "Preventing Disease through Healthy Environments: Towards an Estimate of the Environmental Burden of Disease" World Health Organization 2006

13 Song JA, "Polyhexamethyleneguanidine phosphate induces severe lung inflammation, fibrosis, and thymic atrophy" 69 : 267-275, 2014

14 Park JS, "Polyhexamethylene guanidine phosphate-induced ROS-mediated DNA damage caused cell cycle arrest and apoptosis in lung epithelial cells" 44 (44): 415-424, 2019

15 Kim HR, "Polyhexamethylene guanidine phosphate aerosol particles induce pulmonary inflammatory and fibrotic responses" 90 (90): 617-632, 2016

16 Park EJ, "Methylisothiazolinone induces apoptotic cell death via matrix metalloproteinase activation in human bronchial epithelial cells" 62 : 104661-, 2020

17 Park EJ, "Lung fibroblasts may play an important role in clearing apoptotic bodies of bronchial epithelial cells generated by exposure to PHMG-P-containing solution" 286 : 108-119, 2018

18 Lee JD, "Integration of transcriptomics, proteomics and metabolomics identifies biomarkers for pulmonary injury by polyhexamethylene guanidine phosphate(PHMG-p), a humidifier disinfectant, in rats" 94 (94): 887-909, 2020

19 Lee YH, "Immunohistochemical characterization of oxidative stress in the lungs of rats exposed to the humidifier disinfectant polyhexamethylene guanidine hydrochloride" 32 (32): 311-317, 2019

20 Liu SS, "Hypoxia-induced collagen synthesis of human lung fibroblasts by activating the angiotensin system" 14 (14): 24029-24045, 2013

21 Nemery B, "Humidifier disinfectant-associated interstitial lung disease and the Ardystil syndrome" 191 (191): 116-117, 2015

22 Park YJ, "Guanidine-based disinfectants, polyhexamethylene guanidine-phosphate(PHMGP), polyhexamethylene biguanide(PHMB), and oligo(2-(2-ethoxy)ethoxyethyl guanidinium chloride(PGH)induced epithelial-mesenchymal transition in A549 alveolar epithelial cells" 31 (31): 161-166, 2019

23 Park EJ, "Formation of lamellar body-like structure may be an initiator of didecyldimethylammonium chloride-induced toxic response" 404 : 115182-, 2020

24 Lam J, "Exposure to formaldehyde and asthma outcomes : a systematic review, meta-analysis, and economic assessment" 16 (16): e0248258-, 2021

25 Koh SB, "Environmental diseases" 55 (55): 212-213, 2012

26 Korea Ministry of Government Legislation, "Environmental Health Act"

27 National Institute of Environmental Health Sciences, "Environmental Diseases from A to Z"

28 Park EK, "Elimination of asbestos use and asbestos-related diseases : an unfinished story" 103 (103): 1751-1755, 2012

29 Kim J, "Effects of indoor air pollutants on atopic dermatitis" 13 (13): 1220-, 2016

30 Go HN, "Effects of chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT)on Th2/Th17-related immune modulation in an atopic dermatitis mouse model" 10 (10): 4099-, 2020

31 Jeon H, "Effects of benzalkonium chloride on cell viability, inflammatory response, and oxidative stress of human alveolar epithelial cells cultured in a dynamic culture condition" 59 : 221-227, 2019

32 Pelletier G, "Effects of a 28-day oral exposure to a 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one biocide formulation in Sprague-Dawley rats" 37 (37): 149-155, 2014

33 United States Environmental Protection Agency, "EPA is Moving Towards the Future of Chemical Assessments with New Approach Methods"

34 Jeong J, "Development of adverse outcome pathway for PPARγ antagonism leading to pulmonary fibrosis and chemical selection for its validation : ToxCast database and a deep learning artificial neural network model-based approach" 32 (32): 1212-1222, 2019

35 Tang W, "Deep learning for predicting toxicity of chemicals : a mini review" 36 (36): 252-271, 2018

36 Jung HN, "Cytotoxicity and gene expression profiling of polyhexamethylene guanidine hydrochloride in human alveolar A549 cells" 28 (28): 684-692, 2014

37 Korea Institute of S&T Evaluation and Planning, "Core Technology Development Project for Prevention and Management of Environmental Disease"

38 Su Ho Jeong, "Comparison of air pollution and the prevalence of allergy-related diseases in Incheon and Jeju City" 대한소아청소년과학회 54 (54): 501-506, 2011

39 Leem JH, "Combined approaches using adverse outcome pathways and big data to find potential diseases associated with humidifier disinfectant" 32 : e2017003-, 2016

40 National Health Insurance Service, "Children with atopic dermatitis has a large number of patients in Jeju, and adults in Seoul, Gyeonggi, and Incheon"

41 Zeliger HI, "Causes, mechanisms and prevention of environmental diseases" 1 (1): 1-18, 2015

42 Perkins EJ, "Building and applying quantitative adverse outcome pathway models for chemical hazard and risk assessment" 38 (38): 1850-1865, 2019

43 Choi HY, "Assessment of respiratory and systemic toxicity of Benzalkonium chloride following a 14-day inhalation study in rats" 17 (17): 5-, 2020

44 Musk AW, "Asbestosrelated diseases" 24 (24): 562-567, 2020

45 Kwon EJ, "Analysis of treatment trends for asthma patients over the past 5 years" 13 (13): 56-65, 2019

46 박광식, "An analysis of a humidifier disinfectant case from a toxicological perspective" 환경독성보건학회 31 : 1-4, 2016

47 Jeong MH, "Akt and Notch pathways mediate polyhexamethylene guanidine phosphate-induced epithelial-mesenchymal transition via ZEB2" 380 : 114691-, 2019

48 Lee J, "Adverse postnatal developmental effects in offspring from humidifier disinfectant biocide inhaled pregnant rats" 286 (286): 131636-, 2022

49 Kim HR, "Adverse health effects of humidifier disinfectants in Korea : lung toxicity of polyhexamethylene guanidine phosphate" 41 (41): 711-717, 2016

50 Klimisch HJ, "A systematic approach for evaluating the quality of experimental toxicological and ecotoxicological data" 25 (25): 1-5, 1997

51 Do VQ, "A mixture of chloromethylisothiazolinone and methylisothiazolinone impairs rat vascular smooth muscle by depleting thiols and thereby elevating cytosolic Zn2+ and generating reactive oxygen species" 95 (95): 541-556, 2021

52 Lee J, "A humidifier disinfectant biocide, polyhexamethylene guanidine phosphate, inhalation exposure during pregnancy induced toxicities in rats" 404 (404): 124007-, 2021