CORRESPONDENCE 13. Ollier M, Chamoux A, Naughton G, Pereira B, Dutheil F. Chest CT scan screening for lung cancer in asbestos occupational exposure: a systematic review and meta-analysis. Chest 2014;145:1339-1346. 14. Tammemagi ¨ MC, Katki HA, Hocking WG, Church TR, Caporaso N, Kvale PA, Chaturvedi AK, Silvestri GA, Riley TL, Commins J, et al. Selection criteria for lung-cancer screening. N Engl J Med 2013;368: 728–736. 15. Field JK, Oudkerk M, Pedersen JH, Duffy SW. Prospects for population screening and diagnosis of lung cancer. Lancet 2013; 382:732–741. 16. Patz EF Jr, Pinsky P, Gatsonis C, Sicks JD, Kramer BS, Tammemagi ¨ MC, Chiles C, Black WC, Aberle DR; NLST Overdiagnosis Manuscript Writing Team. Overdiagnosis in low-dose computed tomography screening for lung cancer. JAMA Intern Med 2014;174: 269–274. 17. Detterbeck FC. Overdiagnosis during lung cancer screening: is it an overemphasised, underappreciated, or tangential issue? Thorax 2014;69:407–408.
Copyright © 2015 by the American Thoracic Society
Humidifier Disinfectant–associated Interstitial Lung Disease and the Ardystil Syndrome To the Editor: In their recent letter, Park and colleagues (1) demonstrated that humidifier disinfectant–associated interstitial lung disease that affected children and women in Korea between 2006 and 2011 (2–4) was probably caused by the biocide polyhexamethylene guanidine (PHMG). Recently, PHMG has also been shown to be highly toxic after intratracheal instillation in mice (5) and to be cytotoxic for various types of cells, including lung cells (6). Yet PHMG was considered to be a safe disinfectant, causing little skin irritation (7), and it was even claimed that it was harmless (8). The Korean PHMG-associated interstitial lung disease outbreak is strikingly reminiscent of the history of the Ardystil syndrome in the 1990s. The Ardystil syndrome is an interstitial lung disease that appeared first in Spain (mainly in a factory named Ardystil) (9) and then in Algeria (10) among textile workers who had applied paints of the Acramin type by air-spraying. These paints were considered to be nonhazardous because of their very low oral toxicity and low dermal irritation potential in experimental animals, and no health problems had been associated with their application as pastes in screen printing. However, outbreaks of severe organizing pneumonia with bronchiolitis obliterans occurred in workers who had been exposed to aerosols containing Acramin FWN (dissolved in solvents) (9, 10). Subsequent studies demonstrated severe lung toxicity in experimental animals exposed to Acramin FWN and the related Acramin FWR by intratracheal instillation (11, 12) and by inhalation (13), and both agents also proved highly toxic for various types of cells, including alveolar macrophages and type 2 pneumocytes (14). The most likely explanation for the cellular toxicity of these polymeric compounds was their polycationic nature (i.e., the presence of multiple positive Author Contributions: B.N. and P.H.H. contributed both to the conception and writing of this letter.
116
charges on the nitrogen atoms), as their in vitro toxicity could be abolished by heparin, which has multiple negative charges (15). Interestingly, PHMG is also a polycationic agent and shows a remarkable structural similarity with the agents that caused the Ardystil syndrome (Figure 1). We, therefore, propose that the Korean humidifier disinfectant–associated interstitial disease and the Ardystil syndrome share common clinical and pathologic features, especially the bronchiolocentric distribution of the interstitial lung lesions, because they were caused by the inhalation of agents of a similar nature; namely, polycationic compounds. Of note, flock worker’s lung (16), characterized by lymphocytic (peri)bronchiolitis (17), was caused by the inhalation of (fragments of) microfibers of nylon, a “nontoxic” polymer with multiple positively charged nitrogen atoms. Beyond the lesson that inhaled polycationic compounds are toxic for the lungs, a more general point must be made with regard to chemical safety. Indeed, the outbreaks described here are not the only instances of serious human lung disease caused by chemicals that were thought to be innocuous, but subsequently proved to be harmful for the lungs on inhalation. A similar scenario applied to popcorn worker’s lung. This lung disease, characterized by bronchiolitis obliterans, occurred in workers who had been exposed [in the microwave popcorn industry (18, 19), the chemical industry (20), or more recently, the coffee industry (21)] to vapors of a butter flavor considered safe for use as a food ingredient. Diacetyl, a major component of butter flavoring, bears no chemical resemblance to the polycations involved in the Korean outbreak or the Ardystil syndrome, but its potent respiratory toxicity was also demonstrated experimentally only after human disease had occurred (22). The general lesson of all these recent outbreaks of respiratory disease is that chemicals should never be considered harmless for the lungs unless this has been demonstrated by appropriate testing for pulmonary toxicity. This precautionary principle is
CH3
O
O
CH3
(CH2)3 N (CH2)3 NH C NH (CH2)6 NH C NH (CH2)3 N (CH2)3 Acramin FWR (Polyurea) O
O
(CH2)2 NH (CH2)2 NH C (CH2)4 C NH (CH2)2 NH (CH2)2 Acramin FWN (Polyamideamine)
NH
NH
NH
(CH2)6 NH N NH (CH2)6 NH N NH (CH2)6 NH N NH (CH2)6 PHMG (Polyhexamethylene guanidine)
Figure 1. Structural formulae of the polymers implicated in the causation of interstitial lung disease and subsequently found to be toxic by inhalation in experimental animals. The first two compounds are components of the Acramin paint system implicated in the Ardystil syndrome, and the third compound is a disinfectant (polyhexamethylene guanidine) implicated in the Korean outbreaks of humidifier disinfectant–associated interstitial lung disease. These polymers are characterized by the presence of multiple nitrogen atoms that are positively charged at physiologic pH.
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 1 | January 1 2015
CORRESPONDENCE valid whether or not chemicals are designed or manufactured to be aerosolized, and it applies to a wide variety of circumstances such as, for example, components and natural or synthetic ingredients in electronic cigarettes, as well as cleaning agents and biocides for use in homes, hospitals, swimming pools, paints, metal working fluids, and so on. In other words, potentially inhaled agents must be deemed hazardous until proven innocent. n Author disclosures are available with the text of this letter at www.atsjournals.org. Benoit Nemery, M.D., Ph.D. Peter H. Hoet, Ph.D. KU Leuven Center for Environment and Health Leuven, Belgium
References 1. Park S, Lee K, Lee EJ, Lee SY, In KH, Kim HK, Kang MS. Humidifier disinfectant–associated interstitial lung disease in an animal model induced by polyhexamethylene guanidine aerosol [letter]. Am J Respir Crit Care Med 2014;190:706–708. 2. Kim KW, Ahn K, Yang HJ, Lee S, Park JD, Kim WK, Kim JT, Kim HH, Rha YH, Park YM, et al. Humidifier disinfectant-associated children’s interstitial lung disease. Am J Respir Crit Care Med 2014;189:48–56. 3. Kim HJ, Lee MS, Hong SB, Huh JW, Do KH, Jang SJ, Lim CM, Chae EJ, Lee H, Jung M, et al. A cluster of lung injury cases associated with home humidifier use: an epidemiological investigation. Thorax 2014; 69:703–708. 4. Hong SB, Kim HJ, Huh JW, Do KH, Jang SJ, Song JS, Choi SJ, Heo Y, Kim YB, Lim CM, et al.; Korean Unknown Severe Respiratory Failure Collaborative; Korean Study Group of Respiratory Failure. A cluster of lung injury associated with home humidifier use: clinical, radiological and pathological description of a new syndrome. Thorax 2014;69:694–702. 5. Song JA, Park HJ, Yang MJ, Jung KJ, Yang HS, Song CW, Lee K. Polyhexamethyleneguanidine phosphate induces severe lung inflammation, fibrosis, and thymic atrophy. Food Chem Toxicol 2014; 69:267–275. 6. Jung HN, Zerin T, Podder B, Song HY, Kim YS. Cytotoxicity and gene expression profiling of polyhexamethylene guanidine hydrochloride in human alveolar A549 cells. Toxicol In Vitro 2014;28: 684–692. 7. Ohta S, Misawa Y, Miyamoto H, Makino M, Nagai K, Shiraishi T, Nakagawa Y, Yamato S, Tachikawa E, Zenda H. A comparative study of characteristics of current-type and conventional-type cationic bactericides. Biol Pharm Bull 2001; 24:1093–1096. 8. Oule´ MK, Azinwi R, Bernier AM, Kablan T, Maupertuis AM, Mauler S, Nevry RK, Dembel ´ e´ K, Forbes L, Diop L. Polyhexamethylene guanidine hydrochloride-based disinfectant: a novel tool to fight meticillin-resistant Staphylococcus aureus and nosocomial infections. J Med Microbiol 2008;57:1523–1528. 9. Moya C, Anto´ JM, Newman Taylor AJ; Collaborative Group for the Study of Toxicity in Textile Aerographic Factories. Outbreak of organising pneumonia in textile printing sprayers. Lancet 1994;344: 498–502. 10. Ould Kadi F, Mohammed-Brahim B, Fyad A, Lellou S, Nemery B. Outbreak of pulmonary disease in textile dye sprayers in Algeria. Lancet 1994;344:962–963. 11. Clottens FL, Verbeken EK, Demedts M, Nemery B. Pulmonary toxicity of components of textile paint linked to the Ardystil syndrome: intratracheal administration in hamsters. Occup Environ Med 1997; 54:376–387. 12. Pauluhn J. Repeated pulmonary function measurements in rats after intratracheal instillation of a polyamine textile pigment component. Inhal Toxicol 2000;12:591–604.
Correspondence
13. Nemery B, Clottens FL, Hoet PH, Pauluhn J, Mohr U. Toxicological research into the etiology of the ardystil syndrome. In: Chiyotani K, Hosoda Y, Aizawa Y, editors. Advances in the Prevention of Occupational Respiratory Diseases. (Proceedings of the 9th International Conference on Occupational Respiratory Diseases, Kyoto, 13–16 October 1997). Amsterdam: Elsevier; 1998. pp. 536–539. 14. Hoet PH, Gilissen LP, Leyva M, Nemery B. In vitro cytotoxicity of textile paint components linked to the “Ardystil syndrome”. Toxicol Sci 1999;52:209–216. 15. Hoet PH, Gilissen L, Nemery B. Polyanions protect against the in vitro pulmonary toxicity of polycationic paint components associated with the Ardystil syndrome. Toxicol Appl Pharmacol 2001;175:184–190. 16. Kern DG, Crausman RS, Durand KT, Nayer A, Kuhn C III. Flock worker’s lung: chronic interstitial lung disease in the nylon flocking industry. Ann Intern Med 1998;129:261–272. 17. Eschenbacher WL, Kreiss K, Lougheed MD, Pransky GS, Day B, Castellan RM. Nylon flock-associated interstitial lung disease. Am J Respir Crit Care Med 1999;159:2003–2008. 18. Kreiss K, Gomaa A, Kullman G, Fedan K, Simoes EJ, Enright PL. Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant. N Engl J Med 2002;347:330–338. 19. Akpinar-Elci M, Travis WD, Lynch DA, Kreiss K. Bronchiolitis obliterans syndrome in popcorn production plant workers. Eur Respir J 2004; 24:298–302. 20. van Rooy FG, Rooyackers JM, Prokop M, Houba R, Smit LA, Heederik DJ. Bronchiolitis obliterans syndrome in chemical workers producing diacetyl for food flavorings. Am J Respir Crit Care Med 2007;176: 498–504. 21. Huff S, Stocks JM, Saito R, Bilhartz P, Levin J, Glazer C, Bailey R, Cummings K, Kreiss K, McCague AB; Centers for Disease Control and Prevention (CDC). Obliterative bronchiolitis in workers in a coffee-processing facility - Texas, 2008-2012. MMWR Morb Mortal Wkly Rep 2013;62:305–307. 22. Hubbs AF, Battelli LA, Goldsmith WT, Porter DW, Frazer D, Friend S, Schwegler-Berry D, Mercer RR, Reynolds JS, Grote A, et al. Necrosis of nasal and airway epithelium in rats inhaling vapors of artificial butter flavoring. Toxicol Appl Pharmacol 2002;185: 128–135.
Copyright © 2015 by the American Thoracic Society
Reply: Is Every Inhalant Safe? From the Authors: We appreciate the thoughtful comments provided by Nemery and Hoet on our study of humidifier disinfectant-associated interstitial lung disease (HD-ILD) in an animal model, induced by polyhexamethylene guanidine (PHMG) aerosol (1). First, they point out that there is a common clinical and pathologic background between HD-ILD in Korea and the Ardystil syndrome in Spain. With the Ardystil syndrome, a bronchiolitis obliterance (BO) manifestation associated with exposure to aerosols containing Acramin FWN, and it was noted that the polymeric compound also has a polycationic nature, and this characteristic explains this resemblance (2). In fact, we already discussed the pulmonary toxicity of PHMG, in contrast to its safety on cutaneous or oral exposure (3). Polymers are generally a safe material, and many restriction authorities exempt these materials from toxicity
Supported by grant 2012001370006 from the Korea Environmental Industry & Technology Institute.
117
Copyright © 2015 by the American Thoracic Society
Humidifier Disinfectant–associated Interstitial Lung Disease and the Ardystil Syndrome To the Editor: In their recent letter, Park and colleagues (1) demonstrated that humidifier disinfectant–associated interstitial lung disease that affected children and women in Korea between 2006 and 2011 (2–4) was probably caused by the biocide polyhexamethylene guanidine (PHMG). Recently, PHMG has also been shown to be highly toxic after intratracheal instillation in mice (5) and to be cytotoxic for various types of cells, including lung cells (6). Yet PHMG was considered to be a safe disinfectant, causing little skin irritation (7), and it was even claimed that it was harmless (8). The Korean PHMG-associated interstitial lung disease outbreak is strikingly reminiscent of the history of the Ardystil syndrome in the 1990s. The Ardystil syndrome is an interstitial lung disease that appeared first in Spain (mainly in a factory named Ardystil) (9) and then in Algeria (10) among textile workers who had applied paints of the Acramin type by air-spraying. These paints were considered to be nonhazardous because of their very low oral toxicity and low dermal irritation potential in experimental animals, and no health problems had been associated with their application as pastes in screen printing. However, outbreaks of severe organizing pneumonia with bronchiolitis obliterans occurred in workers who had been exposed to aerosols containing Acramin FWN (dissolved in solvents) (9, 10). Subsequent studies demonstrated severe lung toxicity in experimental animals exposed to Acramin FWN and the related Acramin FWR by intratracheal instillation (11, 12) and by inhalation (13), and both agents also proved highly toxic for various types of cells, including alveolar macrophages and type 2 pneumocytes (14). The most likely explanation for the cellular toxicity of these polymeric compounds was their polycationic nature (i.e., the presence of multiple positive Author Contributions: B.N. and P.H.H. contributed both to the conception and writing of this letter.
116
charges on the nitrogen atoms), as their in vitro toxicity could be abolished by heparin, which has multiple negative charges (15). Interestingly, PHMG is also a polycationic agent and shows a remarkable structural similarity with the agents that caused the Ardystil syndrome (Figure 1). We, therefore, propose that the Korean humidifier disinfectant–associated interstitial disease and the Ardystil syndrome share common clinical and pathologic features, especially the bronchiolocentric distribution of the interstitial lung lesions, because they were caused by the inhalation of agents of a similar nature; namely, polycationic compounds. Of note, flock worker’s lung (16), characterized by lymphocytic (peri)bronchiolitis (17), was caused by the inhalation of (fragments of) microfibers of nylon, a “nontoxic” polymer with multiple positively charged nitrogen atoms. Beyond the lesson that inhaled polycationic compounds are toxic for the lungs, a more general point must be made with regard to chemical safety. Indeed, the outbreaks described here are not the only instances of serious human lung disease caused by chemicals that were thought to be innocuous, but subsequently proved to be harmful for the lungs on inhalation. A similar scenario applied to popcorn worker’s lung. This lung disease, characterized by bronchiolitis obliterans, occurred in workers who had been exposed [in the microwave popcorn industry (18, 19), the chemical industry (20), or more recently, the coffee industry (21)] to vapors of a butter flavor considered safe for use as a food ingredient. Diacetyl, a major component of butter flavoring, bears no chemical resemblance to the polycations involved in the Korean outbreak or the Ardystil syndrome, but its potent respiratory toxicity was also demonstrated experimentally only after human disease had occurred (22). The general lesson of all these recent outbreaks of respiratory disease is that chemicals should never be considered harmless for the lungs unless this has been demonstrated by appropriate testing for pulmonary toxicity. This precautionary principle is
CH3
O
O
CH3
(CH2)3 N (CH2)3 NH C NH (CH2)6 NH C NH (CH2)3 N (CH2)3 Acramin FWR (Polyurea) O
O
(CH2)2 NH (CH2)2 NH C (CH2)4 C NH (CH2)2 NH (CH2)2 Acramin FWN (Polyamideamine)
NH
NH
NH
(CH2)6 NH N NH (CH2)6 NH N NH (CH2)6 NH N NH (CH2)6 PHMG (Polyhexamethylene guanidine)
Figure 1. Structural formulae of the polymers implicated in the causation of interstitial lung disease and subsequently found to be toxic by inhalation in experimental animals. The first two compounds are components of the Acramin paint system implicated in the Ardystil syndrome, and the third compound is a disinfectant (polyhexamethylene guanidine) implicated in the Korean outbreaks of humidifier disinfectant–associated interstitial lung disease. These polymers are characterized by the presence of multiple nitrogen atoms that are positively charged at physiologic pH.
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 1 | January 1 2015
CORRESPONDENCE valid whether or not chemicals are designed or manufactured to be aerosolized, and it applies to a wide variety of circumstances such as, for example, components and natural or synthetic ingredients in electronic cigarettes, as well as cleaning agents and biocides for use in homes, hospitals, swimming pools, paints, metal working fluids, and so on. In other words, potentially inhaled agents must be deemed hazardous until proven innocent. n Author disclosures are available with the text of this letter at www.atsjournals.org. Benoit Nemery, M.D., Ph.D. Peter H. Hoet, Ph.D. KU Leuven Center for Environment and Health Leuven, Belgium
References 1. Park S, Lee K, Lee EJ, Lee SY, In KH, Kim HK, Kang MS. Humidifier disinfectant–associated interstitial lung disease in an animal model induced by polyhexamethylene guanidine aerosol [letter]. Am J Respir Crit Care Med 2014;190:706–708. 2. Kim KW, Ahn K, Yang HJ, Lee S, Park JD, Kim WK, Kim JT, Kim HH, Rha YH, Park YM, et al. Humidifier disinfectant-associated children’s interstitial lung disease. Am J Respir Crit Care Med 2014;189:48–56. 3. Kim HJ, Lee MS, Hong SB, Huh JW, Do KH, Jang SJ, Lim CM, Chae EJ, Lee H, Jung M, et al. A cluster of lung injury cases associated with home humidifier use: an epidemiological investigation. Thorax 2014; 69:703–708. 4. Hong SB, Kim HJ, Huh JW, Do KH, Jang SJ, Song JS, Choi SJ, Heo Y, Kim YB, Lim CM, et al.; Korean Unknown Severe Respiratory Failure Collaborative; Korean Study Group of Respiratory Failure. A cluster of lung injury associated with home humidifier use: clinical, radiological and pathological description of a new syndrome. Thorax 2014;69:694–702. 5. Song JA, Park HJ, Yang MJ, Jung KJ, Yang HS, Song CW, Lee K. Polyhexamethyleneguanidine phosphate induces severe lung inflammation, fibrosis, and thymic atrophy. Food Chem Toxicol 2014; 69:267–275. 6. Jung HN, Zerin T, Podder B, Song HY, Kim YS. Cytotoxicity and gene expression profiling of polyhexamethylene guanidine hydrochloride in human alveolar A549 cells. Toxicol In Vitro 2014;28: 684–692. 7. Ohta S, Misawa Y, Miyamoto H, Makino M, Nagai K, Shiraishi T, Nakagawa Y, Yamato S, Tachikawa E, Zenda H. A comparative study of characteristics of current-type and conventional-type cationic bactericides. Biol Pharm Bull 2001; 24:1093–1096. 8. Oule´ MK, Azinwi R, Bernier AM, Kablan T, Maupertuis AM, Mauler S, Nevry RK, Dembel ´ e´ K, Forbes L, Diop L. Polyhexamethylene guanidine hydrochloride-based disinfectant: a novel tool to fight meticillin-resistant Staphylococcus aureus and nosocomial infections. J Med Microbiol 2008;57:1523–1528. 9. Moya C, Anto´ JM, Newman Taylor AJ; Collaborative Group for the Study of Toxicity in Textile Aerographic Factories. Outbreak of organising pneumonia in textile printing sprayers. Lancet 1994;344: 498–502. 10. Ould Kadi F, Mohammed-Brahim B, Fyad A, Lellou S, Nemery B. Outbreak of pulmonary disease in textile dye sprayers in Algeria. Lancet 1994;344:962–963. 11. Clottens FL, Verbeken EK, Demedts M, Nemery B. Pulmonary toxicity of components of textile paint linked to the Ardystil syndrome: intratracheal administration in hamsters. Occup Environ Med 1997; 54:376–387. 12. Pauluhn J. Repeated pulmonary function measurements in rats after intratracheal instillation of a polyamine textile pigment component. Inhal Toxicol 2000;12:591–604.
Correspondence
13. Nemery B, Clottens FL, Hoet PH, Pauluhn J, Mohr U. Toxicological research into the etiology of the ardystil syndrome. In: Chiyotani K, Hosoda Y, Aizawa Y, editors. Advances in the Prevention of Occupational Respiratory Diseases. (Proceedings of the 9th International Conference on Occupational Respiratory Diseases, Kyoto, 13–16 October 1997). Amsterdam: Elsevier; 1998. pp. 536–539. 14. Hoet PH, Gilissen LP, Leyva M, Nemery B. In vitro cytotoxicity of textile paint components linked to the “Ardystil syndrome”. Toxicol Sci 1999;52:209–216. 15. Hoet PH, Gilissen L, Nemery B. Polyanions protect against the in vitro pulmonary toxicity of polycationic paint components associated with the Ardystil syndrome. Toxicol Appl Pharmacol 2001;175:184–190. 16. Kern DG, Crausman RS, Durand KT, Nayer A, Kuhn C III. Flock worker’s lung: chronic interstitial lung disease in the nylon flocking industry. Ann Intern Med 1998;129:261–272. 17. Eschenbacher WL, Kreiss K, Lougheed MD, Pransky GS, Day B, Castellan RM. Nylon flock-associated interstitial lung disease. Am J Respir Crit Care Med 1999;159:2003–2008. 18. Kreiss K, Gomaa A, Kullman G, Fedan K, Simoes EJ, Enright PL. Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant. N Engl J Med 2002;347:330–338. 19. Akpinar-Elci M, Travis WD, Lynch DA, Kreiss K. Bronchiolitis obliterans syndrome in popcorn production plant workers. Eur Respir J 2004; 24:298–302. 20. van Rooy FG, Rooyackers JM, Prokop M, Houba R, Smit LA, Heederik DJ. Bronchiolitis obliterans syndrome in chemical workers producing diacetyl for food flavorings. Am J Respir Crit Care Med 2007;176: 498–504. 21. Huff S, Stocks JM, Saito R, Bilhartz P, Levin J, Glazer C, Bailey R, Cummings K, Kreiss K, McCague AB; Centers for Disease Control and Prevention (CDC). Obliterative bronchiolitis in workers in a coffee-processing facility - Texas, 2008-2012. MMWR Morb Mortal Wkly Rep 2013;62:305–307. 22. Hubbs AF, Battelli LA, Goldsmith WT, Porter DW, Frazer D, Friend S, Schwegler-Berry D, Mercer RR, Reynolds JS, Grote A, et al. Necrosis of nasal and airway epithelium in rats inhaling vapors of artificial butter flavoring. Toxicol Appl Pharmacol 2002;185: 128–135.
Copyright © 2015 by the American Thoracic Society
Reply: Is Every Inhalant Safe? From the Authors: We appreciate the thoughtful comments provided by Nemery and Hoet on our study of humidifier disinfectant-associated interstitial lung disease (HD-ILD) in an animal model, induced by polyhexamethylene guanidine (PHMG) aerosol (1). First, they point out that there is a common clinical and pathologic background between HD-ILD in Korea and the Ardystil syndrome in Spain. With the Ardystil syndrome, a bronchiolitis obliterance (BO) manifestation associated with exposure to aerosols containing Acramin FWN, and it was noted that the polymeric compound also has a polycationic nature, and this characteristic explains this resemblance (2). In fact, we already discussed the pulmonary toxicity of PHMG, in contrast to its safety on cutaneous or oral exposure (3). Polymers are generally a safe material, and many restriction authorities exempt these materials from toxicity
Supported by grant 2012001370006 from the Korea Environmental Industry & Technology Institute.
117
