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.

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CORRESPONDENCE testing. We tentatively concluded that the associated toxicity stems from the multiple positive charges, which make these polycationic materials capable of active interaction with the anionic surface of tissues and cells (4, 5). Nemery and Hoet also described that the similarity between popcorn worker’s lung and HD-ILD and the Adrystil syndrome in terms of polycation characteristics. Inhalation of diacetyl vapor, the main ingredient in the butter flavoring of popcorn, may lead to an identical presentation via eliciting BO. We agree with this hypothesis. However, we should add discussion about the physical properties of inhaled materials. Vapor can reach alveoli easily, therefore evenly dispersing throughout the entire lungs, and can subsequently be absorbed via diffusion. Thus, patients may not exhibit BO-specific lesions; that is, terminal bronchiole-centered lesions. In contrast, in the case of aerosol intrapulmonary distribution, it depends on particle size. Particles less than 100 nm in size can precipitate more easily around the terminal bronchiole because of the characteristic bronchiolar structure. Micrometersized particles have a relatively large inertia and tend to precipitate in the nasal cavity and upper airway as a result of the reduced tendency of migration along the airway. The conducting airway distal to the lower bronchioles shows an abrupt increase of airflow and turbulence originating from the alveolar distribution structure, leading to an increase in particle precipitation. Furthermore, increased toxicity can result from effective clearance failure caused by the absence of cilia. PHMG particles that evoked HD-ILD in our study were a few tens of nanometers in size and were dispersed in air. We believe that particles containing Acramin FWN would not differ from the PHMG particles, or that some components with nanometer scale from the whole inhalation are the main contributors to BO attack. In addition, butter flavoring vapor cools rapidly in ambient air, followed by nucleation and subsequent growth into nanometer-sized particles; this enlarged material precipitates predominantly in the terminal bronchiole, resulting in BO. We agree with Nemery and Hoet’s opinion that every inhalant should be assumed to be a harmful substance until

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proven otherwise: Not just newly developed substances but also preexisting materials that have been determined to be not toxic via oral or transcutaneous routes should be tested for inhalation toxicity. n Author disclosures are available with the text of this letter at www.atsjournals.org. Eun Joo Lee, M.D., Ph.D.* Korea University College of Medicine Seoul, South Korea Kyuhong Lee, Ph.D. Korea Institute of Toxicology, Jeongeup, South Korea *These authors contributed equally to this work.

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. Moya C, Ant o´ JM, 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. 3. 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. 4. 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. 5. 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.

Copyright © 2015 by the American Thoracic Society

American Journal of Respiratory and Critical Care Medicine Volume 191 Number 1 | January 1 2015

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