- Email: [email protected]
Are asthmatics more sensitive to irritants?
International Journal of Hygiene and Environmental Health 226 (2020) 113488
Contents lists available at ScienceDirect
International Journal of Hygiene and Environmental Health journal homepage: www.elsevier.com/locate/ijheh
Are asthmatics more sensitive to irritants?
T
Gunnar Johanson Integrative Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
ARTICLE INFO
ABSTRACT
Keywords: Assessment factor Benchmark concentration analysis Exposure limit Guidance value Sulfur dioxide Vulnerable groups
Asthma is a heterogeneous inflammatory disease characterized by increased airway hyper-responsiveness to external stimuli such as irritants. One may speculate that asthmatics are more sensitive to irritants in the air than healthy subjects, i.e. react at lower concentrations. We reviewed the scientific support for this speculation and investigated to what extent asthma is considered when setting exposure limits and guidance values. We found that the experimental studies comparing healthy and asthmatic subjects are often inconclusive. Still, the available studies are underused, by expert committees and industry alike. Data for a few irritants suggest that asthmatics are up to three-fold more sensitive than the healthy. The most abundant data were found for sulfur dioxide. Here, a benchmark concentration analysis suggests a nine-fold difference in sensitivity. Based on these data a default assessment factor of 10 is suggested when setting exposure limits and guidance values for irritants.
1. Main text 1.1. Background Asthma is a highly heterogeneous, chronic inflammatory airway disease characterized by increased, reversible airway hyper-responsiveness, i.e. an increased tendency of contraction of the airways by external stimuli such as allergens, cold air and irritants. In asthmatic individuals the airway walls are already inflamed and thickened, thus the contraction during an asthmatic attack results in increased flow resistance and, therefore, difficulties to breathe. Asthma is a common disease with prevalences ranging from 1% to 18% across the world, the prevalence in Sweden being 8%. About 235 million persons are affected worldwide, with an increasing trend (GINA, 2019; WHO, 2019). A wide range of diagnostic tools and definitions has been used in studies addressing the relation between environmental exposure and asthma. These tools range form self-reported asthma, symptoms questionnaires, diagnosis by a doctor and spirometric lung function tests to bronchial challenge test. Ideally, asthma has been diagnosed according to strict criteria (ATS, 1987; GINA, 2019). 1.2. Irritants and asthma The World Health Organization (WHO) has stated that “The stron-
gest risk factors for developing asthma are inhaled substances and particles that may provoke allergic reactions or irritate the airways”. It is also well known that irritants may exacerbate already existing asthma (WHO, 2019). Therefore, the question rises: Are asthmatics more sensitive also to single exposures to low concentrations of irritants? This is an important aspect in risk management of chemical exposures, in particular when setting exposure limits and guidance values intended to protect not only healthy subjects but also vulnerable groups. We therefore investigated the issue as a part of a doctoral thesis work (Johansson, 2016). The first study (Johansson et al., 2012) addresses to what extent asthmatics are considered when setting acute limit and guidance values. We departed from the Acute Exposure Guidance Level (AEGL) values established by the US National Research Council, as the AEGL guidance document clearly identifies asthmatics as susceptible individuals that should be accounted for. Out of the 176 AEGL substances/support documents that we reviewed, 146 used irritation to set an AEGL value. Out of the 146, 14 used studies with asthmatic subjects to set the value (Table 1). How then were these 14 used in support documents from other organizations (listed in Table 2)? We found that these organizations, setting short-term values for either the general population or for workers often omit or disregard the asthma studies used by the AEGL committee. We argue that the toxicological documentation should (1) examine asthma studies when available, (2) state
E-mail address: [email protected]. https://doi.org/10.1016/j.ijheh.2020.113488 Received 31 October 2019; Received in revised form 20 January 2020; Accepted 10 February 2020 1438-4639/ © 2020 Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
International Journal of Hygiene and Environmental Health 226 (2020) 113488
G. Johanson
Table 1 The 14 substances used to set AEGL values based on studies with asthmatics (extracted from Table 4 in Johansson et al., 2012). Acetaldehyde Ammonia Chlorine Formaldehyde Hydrogen chloride Hydrogen sulfide Methyl methacrylate
Table 3 Substances for which an attempt was made to derive overall estimated differential response factors (EDRFs) based on controlled exposure of healthy and untreated asthmatic volunteers (extracted from Table 3 in Johansson et al., 2016a).
Nitric acid Nitrogen dioxide Sulfur dioxide Sulfuric acid Tear gas (O-Chlorobenzylidenemalonitrile) 1,1,1,2-Tetrafluoroethane (HFC-134a) Toluenediisocyanate (TDI)
Table 2 Programs examined with respect to acute limit and guidance values (extracted from Table 1 in Johansson et al., 2012). AEGL ERPG MRL REL VSTAF DECOS MAK SCOEL SE-OEL TLV
Acute Exposure Guideline Levels (USA) Emergency Response Planning Guidelines (USA) Minimal Risk Levels (USA) Reference Exposure Levels (California) French Acute Toxicity Threshold Values (France) Dutch Expert Committee on Occupational Standards Maximum Concentration at the Workplace (Germany) Scientific Committee on Occupational Exposure Limits (European Commission) Swedish Occupational Exposure Limits Threshold Limit Values (USA)
Test substance
EDRFa
Test substance
EDRFa
Acetaldehyde Ammonia Ammonium bisulfate Ammonium nitrate Ammonium sulfate Carbon black particles Chlorine
3 ? >1
Nitrogen dioxide Ozone Sodium bisulfate
>1 >1 ?
? ? ?
Sodium nitrate Sulfur dioxide Sulfuric acid
? >2 >1
2
?
Ferric sulfate Formaldehyde Nitric oxide
? 1 ?
Tear gas (OChlorobenzylidenemalonitrile) Toluenediisocyanate (TDI) Zinc ammonium sulfate
Mixtures and combined exposures Carbon aerosol and sulfuric acid Diesel particles in ambient air (indoor, Sweden) Environmental tobacco smoke Nitrogen dioxide and sulfur dioxide Ozone in ambient air (Los Angeles) Ozone and limonene Ozone and nitrogen dioxide Ozone and sulfur dioxide Ozone, sulfur dioxide and sulfuric acid Ozone and sulfuric acid PM2.5 in urban air
how these asthma studies were used or why they not were used, and (3) clearly state when asthma studies are lacking. The second study (Johansson et al., 2016a) is a systematic review of the scientific literature regarding controlled exposure of healthy and untreated (i.e. not using corticosteroids) asthmatic volunteers to irritant gases and vapors. For each agent, we identified the lowest observed adverse effect concentration (LOAEC). An “estimated differential response factor” (EDRF) was calculated as the LOAEC in the healthy divided by the LOAEC in the asthmatics. In total, we found 89 studies covering 19 chemicals (Table 3). For 9 of the 19, data were inconclusive, i.e. no EDRF could be derived. For two substances, EDRF equalled 1, suggesting no difference in sensitivity between healthy and asthmatic subjects. Three chemicals had ratios definitely higher than 1, namely acetaldehyde with an overall EDRF of 3 based on three studies, chlorine with an EDRF of 2 (from one study), and sulfur dioxide with EDRF > 2 (from 8 studies, for details see Johansson et al., 2016a, supplementary data). For the remaining five chemicals, it could only be concluded that the EDRF is > 1. This means that no adverse effects were seen among the healthy even at the highest tested concentration, therefore the LOAEC is unknown for the healthy. Meanwhile, adverse effects were seen at the highest exposure level in the asthmatics indicating the LOAEC for this group. In addition, 11 mixtures (14 studies) were investigated. Of these, environmental tobacco smoke, ozone in ambient air, and ozone + sulfur dioxide had EDRFs > 1. For nitrogen dioxide, we found several studies that had exposed healthy voluteers only or asthmatics only but not combined in the same study. A combined analysis of these data showed adverse effects (reduced forced expiratory volume in 1 s (FEV1) and increased specific airway resistance (Sraw)) in the asthmatics but not in the healthy, but only from physical exercise and not from nitrogen dioxide at any exposure level. The richest data were found for sulfur dioxide, for which a benchmark concentration (BMC) analysis was carried out. Mouth only exposure to sulfur dioxide at resting conditions showed a 20% increase (BMC20) in SRaw at 3.7 mg/m3 in the asthmatics versus 33.7 mg/m3 in the healthy, suggesting an EDRF of 9. The BMC-based estimate should be given more weight, as it was derived for the most data rich substance and included all 8 available studies on sulfur dioxide. We concluded that an assessment factor of 10 is warranted to account for asthma when setting limit or guidance values for chemicals with irritation as the critical effect.
a
>1 1
? 1 >1 ? >1 ? ? >1 ? 1 ?
? means that data were inconclusive.
The third paper (Johansson et al., 2016b) deals with how REACH registrants consider data on asthmatics when setting derived no-effects levels (DNEL). As of April 2015, 269 chemicals labelled as “May cause respiratory irritation” (H335) were identified in the Classification & Labelling (C&L) Inventory in the European Chemical Agency (ECHA) database. Out of these, 57 sets had data on asthmatics, whereof 23 had been registered under the REACH regulation. Only 9 registrations cited asthma studies (whereof 4 used asthma studies to derive the DNEL), although data from asthmatics were available for all 23 chemicals. In paper four (Johansson et al., 2017), we exposed naive and ovalbumin sensitized mice to chlorine for 15 min and measured lung function by whole body plethysmography before and after metacholine challenge. A 50% respiratory depression (RD50), a measure of sensory irritation, was seen at 5 ppm, in line with previous findings, but with no difference between the naïve and the sensitized mice. The other endpoints examined, respiratory parameters, inflammatory response after 24 h and histopathology of the lungs, also showed no difference between the two groups. We chose clorine as a model substance as it is a well known, highly irritating, high-volume chemical. Other investigators, using sodium hypochlorite (de Genaro et al., 2018), formaldehyde (Larsen et al., 2013), biomass smoke (Hargrove et al., 2019), and diesel engine exhaust (Farraj et al., 2010; Gavett et al., 2015) also found massive effects of ovalbumin sensitisation but little or no clear additional effects of exposure to irritant. It seems that the ovalbumin sensitized mouse is not a relevant model to study susceptibility to irritants in relation to asthma in human. 1.3. Concluding remark In summary, the experimental studies comparing healthy and asthmatic volunteers are often inconclusive. Still, both the examined expert committes and REACH registrants frequently disregard data on asthmatics even when such data are available. Data for a few irritants suggest that asthmatics are up to three-fold more sensitive than the healthy. The most abundant data were found for sulfur dioxide. Here, a 2
International Journal of Hygiene and Environmental Health 226 (2020) 113488
G. Johanson
BMC analysis suggests a nine-fold difference in sensitivity. Although the experimental data on human volunteers are meagre and often inconclusive, our analyses suggest that an AF of 10 is adequate to protect asthmatics from the deleterious respiratory effects of airborne irritants.
resistance after diesel particulate and ozone co-exposure not associated with enhanced lung inflammation in allergic mice. Inhal. Toxicol. 22, 33–41. Gavett, S.H., Wood, C.E., Williams, M.A., Cyphert, J.M., Boykin, E.H., Daniels, M.J., Copeland, L.B., King, C., Krantz, T.Q., Richards, J.H., Andrews, D.L., Jaskot, R.H., Gilmour, M.I., 2015. Soy biodiesel emissions have reduced inflammatory effects compared to diesel emissions in healthy and allergic mice. Inhal. Toxicol. 27, 533–544. GINA, 2019. Global Initiative for Asthma. Global strategy for asthma management and prevention. Available from: www.ginasthma.org. Hargrove, M.M., Kim, Y.H., King, C., Wood, C.E., Gilmour, M.I., Dye, J.A., Gavett, S.H., 2019. Smoldering and flaming biomass wood smoke inhibit respiratory responses in mice. Inhal. Toxicol. 31, 236–247. Johansson, M., 2016. Asthmatics as a Susceptible Population in Health Risk Assessment of Airborne Chemicals. Thesis for Doctoral Degree. Institute of Environmental Medicine. Karolinska Institutet, Stockholm, Sweden, pp. 53. Johansson, M., Gustafsson, A., Johanson, G., Öberg, M., 2017. Comparison of airway response in naive and ovalbumin-sensitized mice during short-term inhalation exposure to chlorine. Inhal. Toxicol. 29, 82–91. Johansson, M.K., Johanson, G., Öberg, M., 2012. How are asthmatics included in the derivation of guideline values for emergency planning and response? Regul. Toxicol. Pharmacol. 63, 461–470. Johansson, M.K., Johanson, G., Öberg, M., 2016a. Evaluation of the experimental basis for assessment factors to protect individuals with asthma from health effects during short-term exposure to airborne chemicals. Crit. Rev. Toxicol. 46, 241–260. Johansson, M.K., Johanson, G., Öberg, M., Schenk, L., 2016b. Does industry take the susceptible subpopulation of asthmatic individuals into consideration when setting derived no-effect levels? J. Appl. Toxicol. 36, 1379–1391. Larsen, S.T., Wolkoff, P., Hammer, M., Kofoed-Sorensen, V., Clausen, P.A., Nielsen, G.D., 2013. Acute airway effects of airborne formaldehyde in sensitized and non-sensitized mice housed in a dry or humid environment. Toxicol. Appl. Pharmacol. 268, 294–299. WHO, 2019. Asthma. World Health Organization.
Acknowledgements This commentary summarizes my presentation at the International Conference on Risk Assessment of Indoor Air Chemicals (Indoor Air Toxicology) held in Berlin 16–18 September 2018. The studies by Johansson et al. cited herein were supported by grants from the Swedish National Board of Health and Welfare (grant no. 28336/2011, 44668/2012, 36940/2013, 36319/2014) and the Swedish Research Council for Health, Working Life and Welfare (Forte, grant no. 20120294). References ATS, 1987. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986. Am. Rev. Respir. Dis. 136, 225–244. de Genaro, I.S., de Almeida, F.M., Hizume-Kunzler, D.C., Moriya, H.T., Silva, R.A., Cruz, J.C.G., Lopes, R.B., Righetti, R.F., de Paula Vieira, R., Saiki, M., Martins, M.A., Tiberio, I., Arantes-Costa, F.M., Saraiva-Romanholo, B.M., 2018. Low dose of chlorine exposure exacerbates nasal and pulmonary allergic inflammation in mice. Sci. Rep. 8, 12636. Farraj, A.K., Boykin, E., Ledbetter, A., Andrews, D., Gavett, S.H., 2010. Increased lung
3
Contents lists available at ScienceDirect
International Journal of Hygiene and Environmental Health journal homepage: www.elsevier.com/locate/ijheh
Are asthmatics more sensitive to irritants?
T
Gunnar Johanson Integrative Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
ARTICLE INFO
ABSTRACT
Keywords: Assessment factor Benchmark concentration analysis Exposure limit Guidance value Sulfur dioxide Vulnerable groups
Asthma is a heterogeneous inflammatory disease characterized by increased airway hyper-responsiveness to external stimuli such as irritants. One may speculate that asthmatics are more sensitive to irritants in the air than healthy subjects, i.e. react at lower concentrations. We reviewed the scientific support for this speculation and investigated to what extent asthma is considered when setting exposure limits and guidance values. We found that the experimental studies comparing healthy and asthmatic subjects are often inconclusive. Still, the available studies are underused, by expert committees and industry alike. Data for a few irritants suggest that asthmatics are up to three-fold more sensitive than the healthy. The most abundant data were found for sulfur dioxide. Here, a benchmark concentration analysis suggests a nine-fold difference in sensitivity. Based on these data a default assessment factor of 10 is suggested when setting exposure limits and guidance values for irritants.
1. Main text 1.1. Background Asthma is a highly heterogeneous, chronic inflammatory airway disease characterized by increased, reversible airway hyper-responsiveness, i.e. an increased tendency of contraction of the airways by external stimuli such as allergens, cold air and irritants. In asthmatic individuals the airway walls are already inflamed and thickened, thus the contraction during an asthmatic attack results in increased flow resistance and, therefore, difficulties to breathe. Asthma is a common disease with prevalences ranging from 1% to 18% across the world, the prevalence in Sweden being 8%. About 235 million persons are affected worldwide, with an increasing trend (GINA, 2019; WHO, 2019). A wide range of diagnostic tools and definitions has been used in studies addressing the relation between environmental exposure and asthma. These tools range form self-reported asthma, symptoms questionnaires, diagnosis by a doctor and spirometric lung function tests to bronchial challenge test. Ideally, asthma has been diagnosed according to strict criteria (ATS, 1987; GINA, 2019). 1.2. Irritants and asthma The World Health Organization (WHO) has stated that “The stron-
gest risk factors for developing asthma are inhaled substances and particles that may provoke allergic reactions or irritate the airways”. It is also well known that irritants may exacerbate already existing asthma (WHO, 2019). Therefore, the question rises: Are asthmatics more sensitive also to single exposures to low concentrations of irritants? This is an important aspect in risk management of chemical exposures, in particular when setting exposure limits and guidance values intended to protect not only healthy subjects but also vulnerable groups. We therefore investigated the issue as a part of a doctoral thesis work (Johansson, 2016). The first study (Johansson et al., 2012) addresses to what extent asthmatics are considered when setting acute limit and guidance values. We departed from the Acute Exposure Guidance Level (AEGL) values established by the US National Research Council, as the AEGL guidance document clearly identifies asthmatics as susceptible individuals that should be accounted for. Out of the 176 AEGL substances/support documents that we reviewed, 146 used irritation to set an AEGL value. Out of the 146, 14 used studies with asthmatic subjects to set the value (Table 1). How then were these 14 used in support documents from other organizations (listed in Table 2)? We found that these organizations, setting short-term values for either the general population or for workers often omit or disregard the asthma studies used by the AEGL committee. We argue that the toxicological documentation should (1) examine asthma studies when available, (2) state
E-mail address: [email protected]. https://doi.org/10.1016/j.ijheh.2020.113488 Received 31 October 2019; Received in revised form 20 January 2020; Accepted 10 February 2020 1438-4639/ © 2020 Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
International Journal of Hygiene and Environmental Health 226 (2020) 113488
G. Johanson
Table 1 The 14 substances used to set AEGL values based on studies with asthmatics (extracted from Table 4 in Johansson et al., 2012). Acetaldehyde Ammonia Chlorine Formaldehyde Hydrogen chloride Hydrogen sulfide Methyl methacrylate
Table 3 Substances for which an attempt was made to derive overall estimated differential response factors (EDRFs) based on controlled exposure of healthy and untreated asthmatic volunteers (extracted from Table 3 in Johansson et al., 2016a).
Nitric acid Nitrogen dioxide Sulfur dioxide Sulfuric acid Tear gas (O-Chlorobenzylidenemalonitrile) 1,1,1,2-Tetrafluoroethane (HFC-134a) Toluenediisocyanate (TDI)
Table 2 Programs examined with respect to acute limit and guidance values (extracted from Table 1 in Johansson et al., 2012). AEGL ERPG MRL REL VSTAF DECOS MAK SCOEL SE-OEL TLV
Acute Exposure Guideline Levels (USA) Emergency Response Planning Guidelines (USA) Minimal Risk Levels (USA) Reference Exposure Levels (California) French Acute Toxicity Threshold Values (France) Dutch Expert Committee on Occupational Standards Maximum Concentration at the Workplace (Germany) Scientific Committee on Occupational Exposure Limits (European Commission) Swedish Occupational Exposure Limits Threshold Limit Values (USA)
Test substance
EDRFa
Test substance
EDRFa
Acetaldehyde Ammonia Ammonium bisulfate Ammonium nitrate Ammonium sulfate Carbon black particles Chlorine
3 ? >1
Nitrogen dioxide Ozone Sodium bisulfate
>1 >1 ?
? ? ?
Sodium nitrate Sulfur dioxide Sulfuric acid
? >2 >1
2
?
Ferric sulfate Formaldehyde Nitric oxide
? 1 ?
Tear gas (OChlorobenzylidenemalonitrile) Toluenediisocyanate (TDI) Zinc ammonium sulfate
Mixtures and combined exposures Carbon aerosol and sulfuric acid Diesel particles in ambient air (indoor, Sweden) Environmental tobacco smoke Nitrogen dioxide and sulfur dioxide Ozone in ambient air (Los Angeles) Ozone and limonene Ozone and nitrogen dioxide Ozone and sulfur dioxide Ozone, sulfur dioxide and sulfuric acid Ozone and sulfuric acid PM2.5 in urban air
how these asthma studies were used or why they not were used, and (3) clearly state when asthma studies are lacking. The second study (Johansson et al., 2016a) is a systematic review of the scientific literature regarding controlled exposure of healthy and untreated (i.e. not using corticosteroids) asthmatic volunteers to irritant gases and vapors. For each agent, we identified the lowest observed adverse effect concentration (LOAEC). An “estimated differential response factor” (EDRF) was calculated as the LOAEC in the healthy divided by the LOAEC in the asthmatics. In total, we found 89 studies covering 19 chemicals (Table 3). For 9 of the 19, data were inconclusive, i.e. no EDRF could be derived. For two substances, EDRF equalled 1, suggesting no difference in sensitivity between healthy and asthmatic subjects. Three chemicals had ratios definitely higher than 1, namely acetaldehyde with an overall EDRF of 3 based on three studies, chlorine with an EDRF of 2 (from one study), and sulfur dioxide with EDRF > 2 (from 8 studies, for details see Johansson et al., 2016a, supplementary data). For the remaining five chemicals, it could only be concluded that the EDRF is > 1. This means that no adverse effects were seen among the healthy even at the highest tested concentration, therefore the LOAEC is unknown for the healthy. Meanwhile, adverse effects were seen at the highest exposure level in the asthmatics indicating the LOAEC for this group. In addition, 11 mixtures (14 studies) were investigated. Of these, environmental tobacco smoke, ozone in ambient air, and ozone + sulfur dioxide had EDRFs > 1. For nitrogen dioxide, we found several studies that had exposed healthy voluteers only or asthmatics only but not combined in the same study. A combined analysis of these data showed adverse effects (reduced forced expiratory volume in 1 s (FEV1) and increased specific airway resistance (Sraw)) in the asthmatics but not in the healthy, but only from physical exercise and not from nitrogen dioxide at any exposure level. The richest data were found for sulfur dioxide, for which a benchmark concentration (BMC) analysis was carried out. Mouth only exposure to sulfur dioxide at resting conditions showed a 20% increase (BMC20) in SRaw at 3.7 mg/m3 in the asthmatics versus 33.7 mg/m3 in the healthy, suggesting an EDRF of 9. The BMC-based estimate should be given more weight, as it was derived for the most data rich substance and included all 8 available studies on sulfur dioxide. We concluded that an assessment factor of 10 is warranted to account for asthma when setting limit or guidance values for chemicals with irritation as the critical effect.
a
>1 1
? 1 >1 ? >1 ? ? >1 ? 1 ?
? means that data were inconclusive.
The third paper (Johansson et al., 2016b) deals with how REACH registrants consider data on asthmatics when setting derived no-effects levels (DNEL). As of April 2015, 269 chemicals labelled as “May cause respiratory irritation” (H335) were identified in the Classification & Labelling (C&L) Inventory in the European Chemical Agency (ECHA) database. Out of these, 57 sets had data on asthmatics, whereof 23 had been registered under the REACH regulation. Only 9 registrations cited asthma studies (whereof 4 used asthma studies to derive the DNEL), although data from asthmatics were available for all 23 chemicals. In paper four (Johansson et al., 2017), we exposed naive and ovalbumin sensitized mice to chlorine for 15 min and measured lung function by whole body plethysmography before and after metacholine challenge. A 50% respiratory depression (RD50), a measure of sensory irritation, was seen at 5 ppm, in line with previous findings, but with no difference between the naïve and the sensitized mice. The other endpoints examined, respiratory parameters, inflammatory response after 24 h and histopathology of the lungs, also showed no difference between the two groups. We chose clorine as a model substance as it is a well known, highly irritating, high-volume chemical. Other investigators, using sodium hypochlorite (de Genaro et al., 2018), formaldehyde (Larsen et al., 2013), biomass smoke (Hargrove et al., 2019), and diesel engine exhaust (Farraj et al., 2010; Gavett et al., 2015) also found massive effects of ovalbumin sensitisation but little or no clear additional effects of exposure to irritant. It seems that the ovalbumin sensitized mouse is not a relevant model to study susceptibility to irritants in relation to asthma in human. 1.3. Concluding remark In summary, the experimental studies comparing healthy and asthmatic volunteers are often inconclusive. Still, both the examined expert committes and REACH registrants frequently disregard data on asthmatics even when such data are available. Data for a few irritants suggest that asthmatics are up to three-fold more sensitive than the healthy. The most abundant data were found for sulfur dioxide. Here, a 2
International Journal of Hygiene and Environmental Health 226 (2020) 113488
G. Johanson
BMC analysis suggests a nine-fold difference in sensitivity. Although the experimental data on human volunteers are meagre and often inconclusive, our analyses suggest that an AF of 10 is adequate to protect asthmatics from the deleterious respiratory effects of airborne irritants.
resistance after diesel particulate and ozone co-exposure not associated with enhanced lung inflammation in allergic mice. Inhal. Toxicol. 22, 33–41. Gavett, S.H., Wood, C.E., Williams, M.A., Cyphert, J.M., Boykin, E.H., Daniels, M.J., Copeland, L.B., King, C., Krantz, T.Q., Richards, J.H., Andrews, D.L., Jaskot, R.H., Gilmour, M.I., 2015. Soy biodiesel emissions have reduced inflammatory effects compared to diesel emissions in healthy and allergic mice. Inhal. Toxicol. 27, 533–544. GINA, 2019. Global Initiative for Asthma. Global strategy for asthma management and prevention. Available from: www.ginasthma.org. Hargrove, M.M., Kim, Y.H., King, C., Wood, C.E., Gilmour, M.I., Dye, J.A., Gavett, S.H., 2019. Smoldering and flaming biomass wood smoke inhibit respiratory responses in mice. Inhal. Toxicol. 31, 236–247. Johansson, M., 2016. Asthmatics as a Susceptible Population in Health Risk Assessment of Airborne Chemicals. Thesis for Doctoral Degree. Institute of Environmental Medicine. Karolinska Institutet, Stockholm, Sweden, pp. 53. Johansson, M., Gustafsson, A., Johanson, G., Öberg, M., 2017. Comparison of airway response in naive and ovalbumin-sensitized mice during short-term inhalation exposure to chlorine. Inhal. Toxicol. 29, 82–91. Johansson, M.K., Johanson, G., Öberg, M., 2012. How are asthmatics included in the derivation of guideline values for emergency planning and response? Regul. Toxicol. Pharmacol. 63, 461–470. Johansson, M.K., Johanson, G., Öberg, M., 2016a. Evaluation of the experimental basis for assessment factors to protect individuals with asthma from health effects during short-term exposure to airborne chemicals. Crit. Rev. Toxicol. 46, 241–260. Johansson, M.K., Johanson, G., Öberg, M., Schenk, L., 2016b. Does industry take the susceptible subpopulation of asthmatic individuals into consideration when setting derived no-effect levels? J. Appl. Toxicol. 36, 1379–1391. Larsen, S.T., Wolkoff, P., Hammer, M., Kofoed-Sorensen, V., Clausen, P.A., Nielsen, G.D., 2013. Acute airway effects of airborne formaldehyde in sensitized and non-sensitized mice housed in a dry or humid environment. Toxicol. Appl. Pharmacol. 268, 294–299. WHO, 2019. Asthma. World Health Organization.
Acknowledgements This commentary summarizes my presentation at the International Conference on Risk Assessment of Indoor Air Chemicals (Indoor Air Toxicology) held in Berlin 16–18 September 2018. The studies by Johansson et al. cited herein were supported by grants from the Swedish National Board of Health and Welfare (grant no. 28336/2011, 44668/2012, 36940/2013, 36319/2014) and the Swedish Research Council for Health, Working Life and Welfare (Forte, grant no. 20120294). References ATS, 1987. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986. Am. Rev. Respir. Dis. 136, 225–244. de Genaro, I.S., de Almeida, F.M., Hizume-Kunzler, D.C., Moriya, H.T., Silva, R.A., Cruz, J.C.G., Lopes, R.B., Righetti, R.F., de Paula Vieira, R., Saiki, M., Martins, M.A., Tiberio, I., Arantes-Costa, F.M., Saraiva-Romanholo, B.M., 2018. Low dose of chlorine exposure exacerbates nasal and pulmonary allergic inflammation in mice. Sci. Rep. 8, 12636. Farraj, A.K., Boykin, E., Ledbetter, A., Andrews, D., Gavett, S.H., 2010. Increased lung
3