Scientific letter
Chlorine Inhalation Challenge in Humans: Development of a New Closed-Circuit Methodology
Prueba de provocación bronquial con cloro en humanos: desarrollo de una nueva metodología con circuito-cerrado
a Centre intégré universitaire de santé et des services sociaux du Nord-de-l’Île-de-Montréal, Hôpital du Sacré-Cœur de Montréal, Université de Montréal, Montréal, Quebec, Canada
b CIBER Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
c Institut de Recherche Robert Sauvé en Santé et Sécurité au Travail, Canada
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array:1 [ 0 => array:2 [ "paginaInicial" => "440" "paginaFinal" => "442" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Iñigo Ojanguren, Yves Cloutier, Simone Chaboillez, Catherine Lemiere" "autores" => array:4 [ 0 => array:3 [ "nombre" => "Iñigo" "apellidos" => "Ojanguren" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 1 => array:3 [ "nombre" => "Yves" "apellidos" => "Cloutier" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 2 => array:3 [ "nombre" => "Simone" "apellidos" => "Chaboillez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:4 [ "nombre" => "Catherine" "apellidos" => "Lemiere" "email" => array:1 [ 0 => "catherine.lemiere@umontreal.ca" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Centre intégré universitaire de santé et des services sociaux du Nord-de-l’Île-de-Montréal, Hôpital du Sacré-Cœur de Montréal, Université de Montréal, Montréal, Quebec, Canada" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "CIBER Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Institut de Recherche Robert Sauvé en Santé et Sécurité au Travail, Canada" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Prueba de provocación bronquial con cloro en humanos: desarrollo de una nueva metodología con circuito-cerrado" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2161 "Ancho" => 1583 "Tamanyo" => 115507 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Components of the closed-circuit apparatus.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Depending on the concentrations, the inhalation of chlorine can cause conditions of various severity such as acute respiratory distress syndrome (ARDS),<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> reactive airway dysfunction syndrome (RADS),<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> or low dose irritant-induced asthma (LDIIA).<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> Mice models of chlorine exposure have used high levels of chlorine ranging from 400 to 800<span class="elsevierStyleHsp" style=""></span>ppm for 5–30<span class="elsevierStyleHsp" style=""></span>min. The chlorine exposure was performed by diluting Cl<span class="elsevierStyleInf">2</span> gas in a chamber using a nose-only exposure chamber or even full-body cylindrical chambers.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">4,5</span></a> In humans although allergen<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> or occupational sensitizer<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> exposures have been fairly well standardized, few chlorine exposure methods have been reported: (1) painting a dilution of sodium hypochlorite onto a cardboard<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a>; (2) Dilution of chlorine gas with humidified medical grade air in a mixing chamber to the concentration of 0.4 and 1<span class="elsevierStyleHsp" style=""></span>ppm<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a>; (3) nebulization of 30<span class="elsevierStyleHsp" style=""></span>ml of commercial bleach (5% sodium hypochlorite) to reach a chlorine concentration of 0.4<span class="elsevierStyleHsp" style=""></span>ppm.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> However, the reliability, accuracy and safety of these chlorine inhalation methods have not been reported, which probably has prevented further performance of chlorine challenges.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The aim of this study was to describe a closed-circuit apparatus designed to expose humans to chlorine gas in a safe manner.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The chlorine-generating closed-circuit inhalation challenge apparatus has four main components (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>): (1) a chlorine generation system; (2) an exposure chamber with a pressure control system; (3) a monitoring device; and (4) a delivery device. Chlorine is generated in a gaseous form by a portable electrochemical gas generator CAL 2000 LT (Advanced Calibration Designs, Inc., Tucson, Arizona, USA), able to deliver a concentration up to 50<span class="elsevierStyleHsp" style=""></span>ppm at 0.5<span class="elsevierStyleHsp" style=""></span>L/min. This type of generator is versatile, has a very stable gas output that can be adjusted to different outlet concentrations and is available for a multitude of products; hydrogen sulfide, hydrogen cyanide or chlorine dioxide. The 0.5<span class="elsevierStyleHsp" style=""></span>L/min chlorine gas mixture produced by this generator was mixed with a fresh-air airflow at the inlet of an exposure chamber. This airflow needed to be adjusted at 20<span class="elsevierStyleHsp" style=""></span>L/min in order to allow the production of the targeted 1<span class="elsevierStyleHsp" style=""></span>ppm concentration of chlorine in the chamber. The value of this airflow was roughly established by mass balance calculation and was finely tuned through experimentations. The exposure chamber consisted of a vertical stainless steel cylinder (size<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>15<span class="elsevierStyleHsp" style=""></span>cm diameter<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>0.5<span class="elsevierStyleHsp" style=""></span>m long); an exhaust pump is connected to the outlet of this exposure chamber through an electro pneumatic proportional valve VEF (SMC Inc.). The opening of this valve is controlled by an automated regulation system in order to keep the pressure in the exposure chamber slightly under the ambient pressure in order to avoid the contamination of the surroundings. At equilibrium, the airflow coming in the chamber is almost the same as the one exiting it.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Three opening ports were located at mid-length of the exposure chamber. One port was connected to a MultiRAE monitor (RAE Systems by Honeywell, San Jose, CA, USA) equipped internally with a sampling pump that continuously monitored chlorine concentrations. Another port was connected to a piezo-resistive pressure sensor, which continuously monitored the pressure in the chamber. This sensor sends a signal to the automated regulating system that controls the opening of the outlet valve. When the subjects breathed from the exposure chamber, they reduced the pressure in the chamber. Automatically, this lower pressure is sensed by the regulating system that reacts by closing the outlet valve in order to maintain the pressure in the chamber around its set point (slightly negative, −0.2<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleHsp" style=""></span>H<span class="elsevierStyleInf">2</span>O). The last port allows the inhalation of the chlorine mixture through a mouthpiece by a system of unidirectional valves. Expired air by the subject is evacuated out of the laboratory through a venting system.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The delivered concentrations of chlorine gas were continuously monitored and recorded.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The chlorine inhalation challenge was tested in four healthy subjects with normal respiratory function and normal airway responsiveness who were exposed to 1<span class="elsevierStyleHsp" style=""></span>ppm of chlorine gas for 15<span class="elsevierStyleHsp" style=""></span>min. This level of exposure corresponds to the threshold limit value-short-term exposure level in Canada. A stabilized chlorine concentration of 1<span class="elsevierStyleHsp" style=""></span>ppm was reached after 1<span class="elsevierStyleHsp" style=""></span>h. The study was approved by the Research Ethics Committee of Sacré-Coeur Hospital and all subjects signed an informed consent form.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The mean chlorine concentration obtained for the four subjects was 1.01<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.034<span class="elsevierStyleHsp" style=""></span>ppm.</p><p id="par0040" class="elsevierStylePara elsevierViewall">No subject reported any smell of chlorine or any respiratory symptoms following the chlorine exposure. FEV<span class="elsevierStyleInf">1</span> and airway responsiveness did not change after exposure to chlorine.</p><p id="par0045" class="elsevierStylePara elsevierViewall">This study is the first to describe a closed-circuit system designed for generating chlorine at low concentrations, delivering highly stable concentrations of chlorine under secure conditions.</p><p id="par0050" class="elsevierStylePara elsevierViewall">D’Alessandro et al.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> performed chlorine exposure by diluting chlorine gas with medical air, which has a potential risk of gas leaking.</p><p id="par0055" class="elsevierStylePara elsevierViewall">No data describing the variability of the delivered chlorine concentrations was reported in a study using a nebulization of commercial bleach for generating chlorine exposure.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> The monitoring of chlorine levels and their stability were not reported after painting chlorine onto a cardboard.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The chlorine closed-circuit system described here has several advantages over the few chlorine exposure methods previously reported. It produces very stable chlorine concentrations without leaking risks and allows a continued monitoring of the chlorine concentrations with great accuracy. The results obtained in the four tested patients showed highly reproducible values with no variability, once the targeted chlorine concentrations were achieved.</p><p id="par0065" class="elsevierStylePara elsevierViewall">The main limitation of this apparatus is related to the building of the automated control system that controls the pressure in the chamber and the opening of the outlet valve that might require trained personnel. This may restrict its accessibility to centers with the resources for such purposes. Another limitation relates to the costs of the different commercially available devices used to build the system. However, the same apparatus can be used to generate other types of irritants agents such as ammonia.</p><p id="par0070" class="elsevierStylePara elsevierViewall">In conclusion, we describe for the first time the closed-circuit methodology for a safe, accurate and reproducible exposure to chlorine gas. This system will be very useful to investigate the pathophysiology of irritant-induced asthma in humans. Whether test maybe useful in cases of occupational caused by chloramines will need to be investigated in the future.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2161 "Ancho" => 1583 "Tamanyo" => 115507 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Components of the closed-circuit apparatus.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Reactive airways dysfunction syndrome (RADS). 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This study was supported by <span class="elsevierStyleGrantSponsor" id="gs3">Fundacio Catalana de Pneumologia</span> (FUCAP).</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/03002896/0000005400000008/v1_201808020445/S0300289617304222/v1_201808020445/en/main.assets" "Apartado" => array:4 [ "identificador" => "49741" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Scientific Letters / Cartas científicas" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/03002896/0000005400000008/v1_201808020445/S0300289617304222/v1_201808020445/en/main.pdf?idApp=UINPBA00003Z&text.app=https://archbronconeumol.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0300289617304222?idApp=UINPBA00003Z" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 3 | 1 | 4 |
| 2024 October | 40 | 34 | 74 |
| 2024 September | 58 | 16 | 74 |
| 2024 August | 62 | 41 | 103 |
| 2024 July | 49 | 30 | 79 |
| 2024 June | 80 | 27 | 107 |
| 2024 May | 71 | 26 | 97 |
| 2024 April | 46 | 26 | 72 |
| 2024 March | 61 | 31 | 92 |
| 2024 February | 32 | 26 | 58 |
| 2023 March | 11 | 2 | 13 |
| 2023 February | 49 | 20 | 69 |
| 2023 January | 40 | 32 | 72 |
| 2022 December | 89 | 26 | 115 |
| 2022 November | 65 | 22 | 87 |
| 2022 October | 96 | 35 | 131 |
| 2022 September | 65 | 29 | 94 |
| 2022 August | 50 | 40 | 90 |
| 2022 July | 43 | 48 | 91 |
| 2022 June | 53 | 37 | 90 |
| 2022 May | 53 | 54 | 107 |
| 2022 April | 52 | 29 | 81 |
| 2022 March | 61 | 47 | 108 |
| 2022 February | 44 | 24 | 68 |
| 2022 January | 47 | 40 | 87 |
| 2021 December | 47 | 39 | 86 |
| 2021 November | 47 | 48 | 95 |
| 2021 October | 57 | 45 | 102 |
| 2021 September | 38 | 43 | 81 |
| 2021 August | 37 | 35 | 72 |
| 2021 July | 35 | 31 | 66 |
| 2021 June | 51 | 33 | 84 |
| 2021 May | 55 | 40 | 95 |
| 2021 April | 135 | 91 | 226 |
| 2021 March | 120 | 29 | 149 |
| 2021 February | 81 | 26 | 107 |
| 2021 January | 62 | 24 | 86 |
| 2020 December | 68 | 29 | 97 |
| 2020 November | 65 | 28 | 93 |
| 2020 October | 49 | 14 | 63 |
| 2020 September | 27 | 16 | 43 |
| 2020 August | 72 | 22 | 94 |
| 2020 July | 3 | 0 | 3 |
| 2020 June | 1 | 0 | 1 |
| 2020 May | 4 | 0 | 4 |
| 2020 March | 22 | 19 | 41 |
| 2020 February | 40 | 22 | 62 |
| 2020 January | 52 | 16 | 68 |
| 2019 December | 35 | 24 | 59 |
| 2019 November | 38 | 20 | 58 |
| 2019 October | 24 | 14 | 38 |
| 2019 September | 33 | 21 | 54 |
| 2019 August | 31 | 16 | 47 |
| 2019 July | 27 | 17 | 44 |
| 2019 June | 28 | 7 | 35 |
| 2019 May | 43 | 19 | 62 |
| 2019 April | 39 | 19 | 58 |
| 2019 March | 58 | 25 | 83 |
| 2019 February | 29 | 21 | 50 |
| 2019 January | 3 | 1 | 4 |
| 2018 December | 13 | 6 | 19 |
| 2018 October | 2 | 0 | 2 |
| 2018 September | 2 | 2 | 4 |
| 2018 March | 0 | 1 | 1 |
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