On the interpretation of bioaerosol exposure measurements and impacts on health

Journal of the Air & Waste Management Association

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On the interpretation of bioaerosol exposure measurements and impacts on health Hamza Mbareche, Lidia Morawska & Caroline Duchaine To cite this article: Hamza Mbareche, Lidia Morawska & Caroline Duchaine (2019) On the interpretation of bioaerosol exposure measurements and impacts on health, Journal of the Air & Waste Management Association, 69:7, 789-804, DOI: 10.1080/10962247.2019.1587552 To link to this article: https://doi.org/10.1080/10962247.2019.1587552

Published online: 28 May 2019.

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JOURNAL OF THE AIR & WASTE MANAGEMENT ASSOCIATION 2019, VOL. 69, NO. 7, 789–804 https://doi.org/10.1080/10962247.2019.1587552

REVIEW PAPER

On the interpretation of bioaerosol exposure measurements and impacts on health Hamza Mbarechea,b, Lidia Morawskac, and Caroline Duchaine

a,b

a

Centre de recherche de l’institut universitaire de cardiologie et de pneumologie de Québec, Quebec City, Quebec, Canada; bDépartement de biochimie, de microbiologie et de bio-informatique, Faculté des sciences et de génie, Université Laval, Quebec City, Quebec, Canada; c School of Chemistry, Physics, and Mechanical Engineering, Department of Environmental Technologies, Queensland University of Technology, Brisbane, Queensland, Australia ABSTRACT

PAPER HISTORY

Bioaerosols are recognized as one of the main transmission routes for infectious diseases and are responsible for other various types of health effects through inhalation and potential ingestion.

Associating exposure with bioaerosol and health problems is challenging, and adequate exposure monitoring is a top priority for aerosol scientists. The multiple factors affecting bioaerosol content, the variability in the focus of each bioaerosol exposure study, and the variations in experimental design and the standardization of methods make bioaerosol exposure studies very difficult.

Therefore, the health impacts of bioaerosol exposure are still poorly understood. This paper presents a brief description of a state-of-the-art development in bioaerosol exposure studies supported by studies on several related subjects. The main objective of this paper is to propose new considerations for bioaerosol exposure guidelines and the development of tools and study designs to better interpret bioaerosol data. The principal observations and findings are the discrepancy of the applicable methods in bioaerosol studies that makes result comparison impossible. Furthermore, the silo mentality helps in creating a bigger gap in the knowledge accumulated about bioaerosol exposure. Innovative and original ideas are presented for aerosol scientists and health scientists to consider and discuss. Although many examples cited herein are from occupational exposure, the discussion has relevance to any human environment. This work gives concrete suggestions for how to design a full bioaerosol study that includes all of the key elements necessary to help understand the real impacts of bioaerosol exposure in the short term.

The creation of the proposed bioaerosol public database could give crucial information to control the public health.

Implications: How can we move toward a bioaerosol exposure guidelines? The creation of the bioaerosol public database will help accumulate information for long-term association studies and help determine specific exposure biomarkers to bioaerosols. The implementation of such work will lead to a deeper understanding and more efficient utilization of bioaerosol studies to prevent public health hazards.

Received August 1, 2018 Revised February 21, 2019 Accepted February 21, 2019

Introduction The average human inhales 12,000–14,000 L of air every day while at rest. Any physical activity raises one’s breathing rate and also the amount of air processed by the lungs. Therefore, air quality plays a key role in human health. The biological components of air are referred to as bioaerosols and consist of a combination of viable and nonviable microorganisms (e.g., bacteria, fungi, and viruses) and antigenic compounds of biological origin (e.g., animal and plant debris, endotoxins, mycotoxins, (1→3)-β-D-glucan, proteins, and any other microbial metabolites; Després et al. 2012; Macher et al. 1999; Tuck 2002). From natural processes to industrial activities, microorganisms (or microbes) and their components can be aerosolized from any given source (e.g., human, soil, CONTACT Caroline Duchaine Caroline.Duchaine@bcm.ulaval.ca Québec, 2725 Chemin Ste-Foy, Québec G1V 4G5, Canada. © 2019 A&WMA

water; Hospodsky et al. 2012; Paez-Rubio et al. 2005; Taha et al. 2006).

By definition, exposure is the concentration of the agents multiplied by the volume of inhaled air.

Obviously, elevated concentrations lead to elevated exposures when people are subjected to these concentrations. In indoor environments, concentrations of bioaerosols depend on human occupancy levels (indoor sources), building conditions, air exchange rate, and human activities, as well as outdoor concentrations (outdoor sources) (Buttner and Stetzenbach 1993; Ghosh et al. 2013; Kulmala, Asmi, and Pirjola 1999; Nasir and Colbeck 2010). Moreover, bioaerosols at high concentrations could have an impact on people living in close proximity to a concentrated source, as

Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de

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bioaerosols can stay suspended in the air for long periods of time and can travel long distances depending on the size of the individual particles (O’Connor et al.

2010, 2017).

Bioaerosols are recognized as one of the main transmission routes for infectious diseases (Eames et al.

2009; Li et al. 2007; Roy and Milton 2004; Yu et al.

2004) and are responsible for various types of health effects through inhalation and potential ingestion. In fact, acute respiratory infections are a leading killer among infectious diseases (Global Burden of Diseases, Injuries, and Risk Factors Study [GBD] 2016 Risk Factors Collaborators 2017). Therefore, the dispersal of bioaerosols has a major impact on public health due to the presence of highly diverse and dynamic microbial communities in the air of urban and rural environments. Other than infections, human exposure to bioaerosols is associated with a wide range of acute and chronic health problems, such as allergies, asthma, rhinitis, sinusitis, and bronchitis, as well as the dispersal of pathogens and health effects from occupational exposure (Douwes, 2005; Eduard et al. 2012; Heederik and Von Mutius 2012).

Associating exposure with bioaerosol and health problems is challenging, and adequate exposure monitoring is a top priority for aerosol scientists. The majority of bioaerosol exposure studies have focused on the quantification of concentrations of endotoxins, (1→3)-βD-glucan, microbial volatile organic compounds (MVOCs), and particulate matter (PM) and the enumeration of microorganisms (using culture-dependent and independent techniques). Some studies have examined samples from exposed human subjects, including blood samples, upper airway respiratory tract samples (nasal cavity or nasopharynx), sputum, and bronchoalveolar lavage (BAL). Although all of these elements and sample types, when examined together, work well to determine human exposure to bioaerosol, the majority of studies have focused on a single factor or a combination of a small number of them. Additionally, conclusions that can be drawn from human exposure to bioaerosol studies are highly dependent on the design of the study and the methodologies used, from the air sampling strategy and sample processing prior to DNA extraction to the type of analyses applied to the data collected (Mbareche et al., 2019).

The multiple factors affecting bioaerosol content, the variability in the focus of each bioaerosol exposure study, and the variations in experimental design and the standardization of methods make bioaerosol exposure studies very difficult. Therefore, the health impacts of bioaerosol exposure are still poorly understood.

This paper presents a brief description of a state-ofthe-art development in bioaerosol exposure studies, supported by recent studies on several related subjects.

This paper is not a systematic review on bioaerosols, but an opinion paper that proposes new considerations for bioaerosol exposure guidelines and the development of tools and study designs to better interpret bioaerosol data. In addition, innovative and original ideas are presented for aerosol scientists to consider and discuss.

Although many examples cited herein are from occupational exposure, the discussion has relevance to any human environment.

Health problems caused by bioaerosols Potential health problems caused by bioaerosols depend on the pathogenicity or immunogenic potential of specific microorganisms and their compounds as well as other factors, such as environmental conditions that influence the survival of the microorganisms in the air and the behavior of the bioaerosol particles (Mohr 2001). There are two main groups of diseases associated with bioaerosol exposure: noninfectious diseases and infectious diseases.

Noninfectious diseases Bioaerosols are associated with a set of noninfectious diseases such as hypersensitivity, allergies, and asthma (Douwes 2003; Eduard et al. 2012; Heederik and Von Mutius 2012; Olenchock 1994). Continuous exposure to airborne microbes leads to sensitization and to the development of occupational diseases (Lacey and Dutkiewicz 1994). Workers in various environments are still diagnosed with hypersensitivity pneumonitis after occupational exposure to bioaerosols (KraïmLeleu et al. 2016; Tjalvin et al. 2018). Microbial allergens and endotoxins produced by gram-negative bacteria, also known as lipopolysaccharides (LPS), are considered a significant health hazard. Studies have demonstrated that endotoxins could be a common cause of airway and intestinal inflammation and other symptoms such as diarrhea, fatigue, and nose irritation in various occupational environments (Liebers, RaulfHeimsoth, and Brüning 2008). Mycotoxins, defined as secondary metabolites of fungi, are harmful indoor-air contaminants associated with mold growth in buildings and are known to cause several diseases such as cancer, hepatitis, and nephritis (Jarvis and Miller 2005).

A component in the cell wall of fungi, (1→3)-βD-glucan, is believed to play a role in pulmonary inflammation, increased sensitivity to endotoxins, and

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pulmonary embolisms. Both (1→3)-β-D-glucan and endotoxins have been associated with changes in airway responsiveness and chest symptoms after indoor exposure (Fogelmark, Sjostrand, and Rylander 1994; Rylander 1996; Zekovic et al. 2005). Exposure to microbial volatile organic compounds (MVOCs), which are secondary metabolites of fungi and bacteria, has been proven to cause eye and upper airway irritation (Korpi et al. 1999; Schenkel et al. 2015). Furthermore, a recent study identified a possible link between MVOC exposure and childhood asthma and allergies in homes with high humidity (Choi, Schmidbauer, and Bornehag 2017). Finally, biological component of particulate matter of inhalable and respirable sizes (PM2.5 [aerodynamic diameter <2.5 μm] and PM10 [aerodynamic diameter <10 μm]) also plays a significant role in health effects associated with aerosol exposure. These health outcomes include low birth weight, emergency room visits, hospital admissions, respiratory and pulmonary diseases, cardiovascular disease, cancer, noncommunicable diseases, and premature death, among others (Morakinyo et al. 2016).

Infectious diseases Infectious diseases are caused by bacteria, fungi, and viruses. When any of these become airborne, they can be transmitted to humans via the air. Among bacteria, legionellosis, tuberculosis, and anthrax are infectious diseases that constitute significant public health concerns due to their infectivity even at low doses. Legionella pneumophila, the etiological agent of legionellosis, can be aerosolized from contaminated water (Rowbotham 1980).

Tuberculosis patients can transmit Mycobacterium tuberculosis in droplet nuclei by coughing, sneezing, and talking (Pearson et al. 1992). Anthrax, which is often linked to bioterrorism, is caused by the inhalation of Bacillus anthracis spores (Jernigan et al. 2001). Other examples of bacterial infection through aerosols include Chlamydia psittaci and Pseudomonas aeruginosa (Lyczak, Cannon, and Pier 2000; Morawska 2006). The most common invasive fungal infections are aspergillosis (Aspergillus fumigatus), candidiasis (Candida albicans), cryptococcosis (Cryptococcus neoformans), mucormycosis (Rhizopus oryzae), pneumocystis (Pneumocystis jirovecii), coccidioidomycosis (Coccodioides immitis), histoplasmosis (Histoplasma capsulatum), paracoccodioidomycosis (Paracoccidioides brasilliensis), and penicilliosis (Penicillium marneffei), all of which can be transmitted through aerosol spore exposure (Brown et al.

2012). Finally, viruses that are readily transmitted by bioaerosols include severe acute respiratory syndrome (SARS) virus, enteric viruses, respiratory syncytial virus (RSV), hantavirus, varicella–zoster virus, mumps virus,

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rubella virus, and influenza A and B viruses (Bonifait et al. 2015; Gershon 2008; Hjelle and Glass 2000; Lindsley et al. 2010; Matricardi et al. 2000; Tellier 2009; Teltsch and Katzenelson 1978; Uyeki, Bresee 2007; Booth et al. 2005). It was suggested that other viruses, such as norovirus, could reach human’s digestive system through inhalation and swallowing (Bonifait et al. 2015). Although obvious evidence of viral airborne transmission is available, the Centers for Disease Control and Prevention (CDC) are still skeptical about the subject of airborne transmission from one patient to the other (CDC 2018).

Exposure studies and health risks Several studies have shown that when indoor/outdoor concentration ratios are examined, the outdoor environment always acts as a source for the bioaerosols collected in indoor environments, in homes without water damage or mold growth (Adam et al. 2015; Lee et al. 2006). In a study by Frankel and collaborators, outdoor air significantly affects indoor exposure, which are influenced by temperature, relative humidity, and air exchange rates (Frankel et al. 2012). Bioaerosol studies in outdoor urban areas have typically included the space outside of high-rise apartment buildings, hospitals, schools, and parks, or any other urban location. These studies have focused mainly on characterizing and quantifying the microbial content in bioaerosols. Some of them focused solely on bacteria and/or fungi, others also examined endotoxins, (1→3)β-D-glucan, and PM10 (Abbasi and Samaei 2018; Fang et al. 2007; Fatahinia et al. 2018; LeBouf, Yesse, and Rossner 2012; Lee and Jo 2006; Mota et al. 2008; Rathnayake et al. 2016). Very few studies have included the health effects of outdoor bioaerosol exposure in their studies (Karottki et al. 2014).

Biowaste facilities are commonly studied to assess workers’ exposure because of the intense microbial activity involved in waste degradation and because of the types of activities performed by workers (Bonifait et al. 2017; Dubuis et al. 2017; Mbareche et al. 2017a; Van Kampen et al. 2014; Wéry 2014; Wouters et al.

2006). Farms are another example of workplace settings where bioaerosol exposure is complex. Agricultural practices have become more intensive due to increasing population growth and the food demands associated with this growth. Farms typically hold a large number of animals (e.g., pigs, poultry, cattle), mainly in indoor settings and at high densities. The variety of possible sources associated with these conditions leads to complex mixtures of microorganisms within bioaerosols emitted from farms (Douglas et al. 2018; Gilbert and Duchaine 2009; Just et al. 2011; Lanier et al. 2010;

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Létourneau et al. 2010; Milner 2009; Nehme et al. 2008; Tsapko et al. 2011). This dynamic microbial composition puts farm workers and nearby residents at higher risk for health issues such as accelerated declines in lung function, changes in blood pressure, nasal inflammation, secretory immunity, infectious diseases, and dermatological and gastrointestinal health problems (Iversen et al. 2000; O’Connor et al. 2010, 2017; Schiffman et al. 2005). The respiratory health of farmers has been the subject of controversy given the recent hygiene hypothesis that stipulates that exposure to microbes resulting from intensive farming during early life could be beneficial to health later in life. Hence, exposure to bioaerosols in farming environments may be a double-edged sword: with a protective effect against atopy and also causing inflammation that leads to nonallergic asthma (Douwes, Pearce, and Heederik 2002; Heederik et al. 2007; Stiemsma et al. 2015; Strachan 1989). A similar type of effect was observed in swine building workers where the use of respiratory protection resulted in inflammatory and respiratory reactions after returning to work without protection.

This suggests that a protective adaptation was acquired due to long-term exposure (Bønløkke et al. 2012a).

Workplaces such as wastewater treatment plants and metal-working workshops have also received attention regarding workers’ exposure to bioaerosols (Niazi et al.

2015; Park, Park, and Lee 2010; Teixeira et al. 2016; Uhrbrand et al. 2017; Veillette et al. 2004). The majority of work-environment exposure studies focused on the characterization and quantification of the microbial content in bioaerosols. Some targeted bacteria and/or fungi and/or viruses by using culture-based approaches or using culture-independent approaches such as quantitative polymerase chain reaction (qPCR) for quantification and high-throughput sequencing (HTS) for an in-depth microbial diversity analysis. Others added endotoxin and (1→3)-β-D-glucan quantification into the design of the study. The discrepancy of bioaerosol sources in various work environments not only put workers at higher health problems risks but also

makes bioaerosol exposure studies less predictable in terms of applicable methods. In other words, it is difficult to predict what method to apply to best describe the air of a new environment.

Analytical methods to study bioaerosols and their components Choice of bioaerosol sampler is crucial when considering a sampling strategy. Many parameters affecting the efficiency of the collected particles rely on the type of samplers, passive or active sampling using several different types of bioaerosol samplers such as impingers, cyclones, impactors, and filters. Recent studies mentioned these parameters to consider and compared different air samplers to help scientist make better choices (Mbareche et al.

2017b, 2018a; Zhen et al. 2018). The choice of methods used to quantify and describe the biological content of aerosols greatly influences the results. Table 1 presents the most commonly applied analytical methods used to study the etiological agents in bioaerosols that are known to be hazardous to human health.

Endotoxins The Limulus amebocyte lysate (LAL) test, which uses an extract from the amebocytes of the horseshoe crab (Limulus polyphemus) and reacts with bacterial endotoxins, is probably the technique most used for endotoxin quantification. However, multiple factors, from the type of filters used for collection to the storage conditions, affect the outcome of quantification (Douwes et al. 1995; Hoppe Parr et al. 2017). Some variations to the standard LAL assay can be applied under particular conditions. For example, measurements of the turbidity of the LAL extract can be used instead of an end point chromogenic LAL assay (Neun and Dobrovolskaia 2011). Several other commercial kits have been developed for endotoxin detection. Pyrogene

by Lonza ((Valais, Switzerland) and Endolisa by Hyglos (Bavaria, Germany) use the recombinant factor C (rFC)

Table 1. The most used analytical methods to study different etiological agents in bioaerosols.

Etiological agents Endotoxins (LPS) Mycotoxins MVOCs (1→3)-β-D-Glucan Bacteria Fungi

Analytical methods LAL GC-MS; HPLC SPME/GC-MS ELISA; LAL Culture; qPCR; HTS Culture; qPCR; HTS

Viruses

Culture; qPCR; HTS

References Blechova and Pivodova 2001 Bloom et al. 2009; Jargot and Melin 2013 Garcia-Alcega et al. 2017 Douwes 2005; Alwis and Milton 2006 Duquenne 2018; Nehme et al. 2008; Serrano-Silva and Calderòn-Ezquerro, 2017 Viegas et al. 2018; Dannemiller et al. 2014; Cuadros-Orellana et al. 2013 Madonna et al. 1999; Brisebois et al. 2018; Prussin, Marr, and Bibby 2014

Notes. LAL = Limulus amebocyte lysate; ELISA = enzyme-linked immunosorbent assay; GC-MS = gas chromatography–mass spectrometry; HPLC = highperformance liquid chromatography; qPCR = real-time polymerase chain reaction; HTS = high-throughput sequencing.

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to detect the presence of LPS. HEK-Blue by InvivoGen (San Diego, CA, USA) uses the membrane receptor Toll-like receptor 4 (TLR4), which makes cellular culture necessary. PyroDetect by Merck (xx, xx) quantifies the LPS using interleukin-1β.

Mycotoxins For mycotoxins, gas chromatography coupled with mass spectrometry (GC-MS) and high-performance liquid chromatography (HPLC) are the definitive methods for characterizing mycotoxins in aerosol samples (Bloom et al. 2009; Jargot and Melin 2013). Enzymelinked immunosorbent assays (ELISAs) can also be used to quantify mycotoxins, although they are mostly used with urine specimens from exposed workers (Brewer et al. 2013). Due to volatile characteristics MVOCs, the most established method that allows for both the identification and quantification of MVOCs is GC-MS with solid-phase microextraction (SPME; Garcia-Alcega et al. 2017). For (1→3)-β-D-glucan, both ELISA and LAL have been successful for making measurements from aerosol samples (Alwis and Milton 2006; Douwes 2005).

Microorganisms To study microorganisms, the culture approach has traditionally been used for quantification and diversity assessment of the culturable portion of bioaerosols.

Recently, molecular approaches, including qPCR and HTS, have offered a broader overview of the quantity and the quality of microbes in aerosol samples (Brisebois et al. 2018; Cuadros-Orellana et al. 2013; Dannemiller et al. 2014; Nehme et al. 2008; Prussin, Marr, and Bibby 2014; Serrano-Silva and Calderòn-Ezquerro 2017).

Contrary to other air pollutants, there is no method allowing for bioaerosols to be measured in real time, which makes their surveillance more challenging. One close attempt in this direction was made 20 years ago with the biodetector ultraviolet aerodynamic particle size spectrometer (UVAPS) developed by TSI Instruments (xx, xx). The detection of viable bioaerosols is based on fluorescence and has a particle range size up to 20 µm (Agranovski et al. 2003a). Beside the rapidity of analyses, UVAPS present major disadvantages. Considering the fact that detection is based on fluorescence, fluorescent nonbiological particles may interfere with the measurements, and many biological particles have very similar fluorescent characteristics, which can also be conflictive. However, it has been used for some specific applications such as the

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influence of aerosol fungal spores or to study the effect of airborne bacterial stress (Agranovski et al. 2003b; Kanaani et al. 2007). More recent work using hierarchical cluster analysis showed improved classification selectivity of UVAPS on bacteria, fungi, and pollens (Kaliszewski et al. 2013). The development of an affordable and more selective technique for real-time monitoring of bioaerosols can certainly push this field of research further.

Summary of health markers Health markers used to evaluate the health impact of bioaerosol exposure have not been standardized.

Here, we present a summary of the measures typically used when health impact was included in the experimental design of bioaerosol studies.

Cardiopulmonary markers including blood pressure, pulse, and heart rate variability are often considered (Cole-Hunter et al. 2018). Lung function is evaluated using spirometry and often the Tiffeneau-Pinelli index (FEV1/FVC; forced expiratory volume in the first second/forced vital capacity) to compare exposed subjects with nonexposed controls (Farokhi, Heederik, and Smit 2018; Magzamen et al. 2018).

Blood samples from exposed subjects are commonly used to investigate inflammatory mechanisms or as exposure markers, either by measuring total and specific immunoglobins (IgE and IgG) or by determining blood levels of neutrophils, cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], or interleukin-6 [IL-6]). and the acute-phase proteins serum amyloid A (SAA) and C-reactive protein (CRP) (Blais-Lecours et al. 2011; Bønløkke et al.

2009; Brauner et al. 2017; Cormier et al. 1997, 2000; Eduard 1995; Faridi et al. 2017; Madsen et al. 2016; Müller et al. 2006; Van Kampen et al. 2016).

However, these biomarkers of exposure indicating health, biological effects, or susceptibility of individuals do not always give clear information about workers’ exposure (Douwes et al. 2003). In some cases, there are no differences in IgG antibodies levels to molds detected in the air between workers and unexposed controls (Zhang et al. 2012). Likewise, sputum, BAL, and nasal lavage can also be used for inflammatory cell quantification (Bønløkke et al.

2012b; Hoffmann et al. 2005; Huijskens et al. 2016).

Other noninvasive methods that are used to assess the health impacts of bioaerosols include self-reporting, usually based on questionnaires (either self-administered or with the help of a health professional). The American Thoracic Society has developed a standardized respiratory-symptom questionnaire that is easy to complete

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(http://www.healthstatus.sgul.ac.uk/). Information collected includes physical health symptoms such as headaches, nausea, wheezing, asthma, coughing, phlegm production, aches and pains, chest tightness, the presence of skin rashes, and gastrointestinal tract problems. These are described using frequency and psychological distress scales. Data collected may also include a history of recent illnesses and number of missed workdays due to particular symptoms (Aatamila et al. 2011; Borlee et al. 2015; Mazan et al. 2009; Pavilonis, Sanderson, and Merchant 2013). A recent study described the development of a questionnaire to assess the health effects of bioaerosols that can be used to investigate outbreaks of occupational diseases (Basu et al. 2018)

Difficulty in linking health hazards to bioaerosol exposure HTS approaches have generated massive amounts of taxonomy data describing the complex dynamic microbial community in indoor and outdoor aerosol samples all around the world. Unfortunately, much of these data have been categorized according to the environments from which the samples were collected without addressing the broader context of general bioaerosol exposure hazards. Furthermore, very few environmental exposure markers have been identified, and none have been validated and used for exposure assessment.

Threshold limit values (TLVs) are reference levels of substances that workers can be exposed to without any health effects. They have been proposed extensively for chemical substance exposure (American Conference of Governmental Industrial Hygienists [ACGIH] 2018).

And although the impact of bioaerosols on health is known, exposure limits have only been established for some components, particularly endotoxins. For bioaerosols, exposure limits are known as no observed effect levels (NOELs) and have been limited to endotoxins (90 EU/m3). The limits are based on airway inflammation observed in exposed workers (Samadi, Wouters, and Heederik 2013). The established NOELs are confusing because of the large variations associated with the different environments being studied. For example, endotoxin concentrations of 1 EU/m3 correlated with pulmonary and respiratory problems in indoor buildings in the midwestern United States (Reynolds et al.

2001). On the other hand, Haglind and Rylander showed that cotton milk workers had a decrease of the FEV1 due to endotoxin exposure. The estimated NOEL at which no changes occurred in FEV1 was 330 EU/m3 (Rylander, Haglind, Lundholm 1985). In swine confinement buildings, endotoxin concentration of 7.40 EU/ m3 were associated with clinically important symptoms,

such as headaches, eye irritation, and nausea (Schiffman et al. 2005). Other examples of endotoxin concentration in swine livestock operations reached 3250 EU/m3 (Thorne et al. 2009). To date, there is no established NOEL for (1→3)-β-D-glucan exposure in spite of the ambiguous evidence of health effects.

Likewise, mycotoxins and MVOCs have received less attention compared with endotoxins in terms of NOELs. For microbes, no NOELs have been established for bioaerosol concentrations. Yet, several values have been proposed for culturable fungi and bacteria, which differ from country to country, varying from 800 colony-forming units [CFU]/m3 in Korea to 10,000 CFU/ m3 in the Netherlands, Germany, and Canada (Ghosh, Lal, and Srivastava 2015; Goyer et al. 2001). To date, few studies has described the health effects of bioaerosol exposure solely based on fungal and bacterial concentrations. As suggested my Madsen and colleagues, microbial composition is a major factor in determining the health effects associated with bioaerosol exposure (Madsen et al. 2012). The variety of analytical methods used may make the results from studies using environmental samples incomparable. Therefore, the American Conference of Governmental Industrial Hygienists (ACGIH 2009) developed a guide for occupational exposure values that is meant to serve as a standard for the experimental design of bioaerosol studies.

However, in addition to being based only on culture methods, there is a paucity of data establishing the exposure-response relationship. This statement is true not only for workers, but for the general community as well, which creates a real gap in knowledge about community exposure. There is an urgent need for new ideas and concrete propositions to move toward standardization of methods to help establish bioaerosol exposure guidelines. sentially, the strength of the current knowledge resides in the development of more precise analytical methods for bioaerosol measurement and monitoring.

When used adequately, these methods can offer accurate data with minimum loss/error. Nevertheless, exposure limits are still lacking due to, amongst others, the heterogeneity of the methods used, lack of standardized detection methods, and limited new analysis methods that identify the risk potential and give definite bioaerosol data interpretation.

Moving toward new bioaerosol exposure guidelines In the research related to establishing new guidelines for bioaerosol exposure that includes new molecular techniques and direct implications on health, it is

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important to shift attention to new ways of designing bioaerosol exposure studies in order to prevent the replication of previous flaws (e.g., different study designs, methods, and analyses, which makes it impossible to compare the results). Here, the goal of exposure guidelines refers to health-related exposure limits. In the following section, we present five concrete suggestions that will facilitate an open dialog in the aerosol science community. Figure 1 presents a visual representation of the ideas presented.

Core microbiome of bioaerosols Recently, several new ways of looking at microbes have been introduced, including advanced HTS methods such as amplicon-based methods and metagenomics. In various environments, microbes are now considered a community instead of single, independent microorganisms. For example, pathogenesis in the gut is now examined by looking at the microbial community as a whole instead of at individual pathogens. Healthy subjects can become diseased by the introduction of a patients’ gut microbiome and vice versa (Vonaesch, Anderson, and Sansonetti 2018). Similarly, a core microbiome of aerosols may be specific to particular occupational environments that are influenced by specific types of sources. The idea proposed here is to start looking at bioaerosols as

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a microbial community that is changing across time and space rather than individual pathogens. Recent studies using HTS have found a strong correlation between the microbial communities of particular sources and the corresponding bioaerosols (Handorean et al. 2015; Mbareche et al. 2017a, 2018b; Wang et al. 2018). A worldwide collaborative effort could allow for the identification of core microbiomes for bioaerosols through a public database specifically for bioaerosols. Verified high-quality sequences obtained from HTS platforms could be deposited in a particular section of the database according to the environment sampled. Additionally, metagenomics data could serve as potential environmental exposure markers in the future, as environmental genes from thousands of samples would be available to all researchers interested in evaluating the new markers. Sequences from composting environments retrieved from various places around the world by different research groups could lead to the identification of a core microbiome of bioaerosols from compost. The same idea can be applied to any indoor/ outdoor occupational and general community exposure environment of interest. Furthermore, information obtained by HTS methods can help make better cultivation conditions and improve the capacity to isolate rare microorganisms present in air samples. This complementarity will give a better look at the complexity of aerosol samples using both methods (Gutleben et al. 2018).

Figure 1. A graphic representation of the key elements of the bioaerosol public database. The “study design” section includes all of the key parts of a bioaerosol exposure study. The “markers” section is an example of the information needed for all of the environments studied in order to realize long-term associations and create a better link between bioaerosol exposure and health studies.

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Environmental exposure markers

Collaborations with physicians and decision makers

To overcome challenges associated with bioaerosol exposure studies, the aerosol science community has identified the need to explore new alternatives for assessing bioaerosol exposure. For example, the identification of markers associated with exposure could help ascertain which environments pose the highest risks (Fung and Mikhaylova 2014; Garcia-Alcega et al. 2017). Recent studies have identified a strong correlation between the bacterial community of the upper respiratory tract (nasal cavity and nasopharynx) of exposed subjects and the bioaerosols collected from the environment they were exposed to, using an HTS approach (Mbareche et al., manuscript in preparation; Kraemer et al. 2018).

Although these findings are interesting on their own, going one step further, the shared taxa between the bioaerosol core microbiome and upper respiratory tract samples from exposed individuals could be the starting point for identifying an environmental marker to be used for exposure studies. Therefore, including a nasal or nasopharynx sampling regime along with bioaerosol sampling in the design of all occupational exposure studies can help with the creation of a list of potential biological markers. Chemical information such as pH and the type of chemical compounds present in aerosols can be used to distinguish fingerprints for bioaerosols from indoor/outdoor environments (Shi et al. 2017). This information can also be helpful for determining environmental markers associated with aerosol exposure. Additionally, health measurements are the key element in associating exposure with health problems. Immunological profiling using whole-blood assays on exposed individuals could be used for cell-specific cytokine expression or specific antigen characterization. Respiratory functions could also be added along with questionnaires to determine the health impact associated with exposure in specific environments.

Including all of these analytical approaches in the design of bioaerosol studies is not always realistic, but by including as many of these measures as possible, we believe that we might identify environmental markers of exposure.

Using these approaches together, we hypothesize that these markers do not consist of single features but are combinations of biological and chemical factors that are consistently associated with specific immunological profiles and a reduction in respiratory functions. The combination of multiple markers ought to be qualitative and not quantitative. In brief, the idea is to develop a database that allow us to create associations, in the long term, between a type of environment, its multiple markers, and the health outcomes observed. From a practical point of view, this can be resource intensive, but greatly informative.

Including clinical data collected by physicians (when available) could help aerosol scientists in designing health studies with reliable exposure data collected from exposure studies. Physicians could communicate with bioaerosol researchers if they observe a pattern in a group of patients with similar symptoms and who are linked to a particular working environment or a community setting. Bioaerosol researchers could conduct an exposure study with the goal of determining whether there is an association between specific symptoms and the type of aerosols the patients are exposed to (including the elements discussed previously in “Core microbiome of bioaerosols” and “Environmental exposure markers”).

Practical outcomes would consist primarily of determining risky environments and prevent adverse health effect of exposed population. Another beneficial collaboration is between public health decision makers and researchers.

One example of this is a project currently being conducted by our bioaerosol research group. The focus of the project is a fungus called Serpula lacrimans that causes dry rot and damage to building material. This fungus has caused major problems in the homes of many Quebecers by damaging the foundation and indoor materials. After public outcry, the Quebec government invested research money in a study aimed to improve our knowledge of Serpula lacrimans in Quebec homes. The outcome will provide extensive information and improve the ability to predict how building characteristics will impact the microbes present in these structures. An example of a situation that would have benefitted greatly from this type of relationship (between governmental administration and academic laboratories) was during the 2012 Legionella crisis in Quebec City. Better and faster communication between public health officials and local experts on the subject could have identified the source more rapidly and prevented the outbreak from spreading.

One positive outcome was that this crisis led to new regulations allowing for the use of molecular techniques, in this case qPCR, to monitor Legionella in cooling towers (Trudel et al. 2014). Overall, if public health decision makers work in close collaboration with aerosol scientists and health scientists, it could help us better understand the risks of bioaerosol exposure, in particular in residential or occupational environments.

Use of standards Conclusions from bioaerosol exposure studies are affected by the procedural choices during every step of the study. These choices include sampling techniques, sample processing prior to DNA extraction (for

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molecular biology), and the analyses used to obtain the results (Mbareche et al. submitted). Therefore, the path toward the standardization of bioaerosol exposures/ concentrations is a tumultuous one. One solution that can help us move forward is the adoption of standard protocols developed by other research groups. One section of the bioaerosol public database could include protocols that have been tested, approved, and peerreviewed for publication. For example, a recent study developed a new filtration-based protocol for fungal cell recovery from air samples that resulted in significantly higher outcomes for qPCR quantification and for fungal diversity analysis using HTS (Mbareche et al., manuscript in preparation). The authors strongly recommend the use of the latter technique when designing a fungal bioaerosol exposure study. The same concept of establishing the most effective techniques for studying specific components of bioaerosols can be applied to viruses, endotoxins, etc. The bioaerosol public database would have a list of standardized protocols for any procedure that affects the outcome of bioaerosol exposure studies. The success of such a suggestion relies on the use of the protocols by every bioaerosol research group when conducting a relevant study.

Bioaerosol public database Practically, the bioaerosol public database will have different sections for each of the elements discussed above: peer-reviewed standardized sampling protocols, sample processing, and analytical methods for the microbial content of bioaerosols (bacteria, fungi, viruses, endotoxins, mycotoxins, (1→3)-β-D-glucan, and MVOCs); HTS (amplicon-based and metagenomics) sequences retrieved from any type of indoor/outdoor environment studied, environmental markers (biological and chemical) linked to any type of indoor/outdoor environment studied; and health measurements of exposed individuals (blood assays, respiratory functions, and questionnaires). In the long term, the compilation of this massive amount of information, and the use of advanced bioinformatics algorithms to treat that information, can lead to studies of association bringing bioaerosol exposure assessment into a new era.

Based on the actual knowledge, the determination of bioaerosol exposure guidelines is ambitious.

One promising consideration that might help make a step toward bioaerosol exposure guidelines rely on setting exposure-response curves. A recent systematic review on the evaluation of exposureresponse relationship for health effects of bioaerosols concluded that none of the analyzed studies

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provided suitable dose-response relationships. One of the reasons stated is the diversity of employed measuring methods (Walser et al. 2015). Other reasons include the absence of accurate dose-response data, the diversity of health effects (each person can react differently to the same exposure), and inadequate exposure assessment. Occupational exposure studies can take a step forward and gain much more information by applying HTS methods to better understand who is present, what are they doing, and how are they interacting with each other and with the different parameters of the environment. Ultimately, the information cumulated using these approaches in different types of environments can lead to finding better environmental markers to assess exposure. Thus, these environmental markers, which can be specific to different environments, could be used to obtain health-related exposure limits. Furthermore, the environmental markers and the exposure limits can be specific to different health outcomes.

Another key element for the elaboration of exposure-response relationships and exposure limits is the epidemiological studies. Indeed, one of the main goals of the exposure characterization is to provide information for epidemiological studies, which are essential tools for health risk assessment and elaboration of guidelines. The data collected using the proposed approaches herein can be used to carry out epidemiological investigations by describing the distribution of bioaerosols.

The use of the standardized protocols proposed in the bioaerosol public database and the large data set that can be generated and accumulated over the years will provide reliable exposure-response curves.

As an analogy to PM2.5 and PM10, important information is collected from standard measurement methods, thus more rigorous exposure–response curves are generated, which are used by the World Health Organization (WHO) to set guidelines. This example is used to emphasize the idea of using standardized methods to study bioaerosol exposure.

For bioaerosols, the closest related guidelines was the WHO Dampness and Mold 2009 Guideline (Morawska 2010). Taking into account the challenges related to setting guidelines to bioaerosol exposure, which are primarily standardization of measurements and exposure limits, the main focus of the WHO guideline was on prevention or minimization of dampness and microbial growth in building structures (WHO 2009). An alternative for guideline consideration would consist of distinguishing normal from abnormal bioaerosols,

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qualitatively and quantitatively, in specific climatic zones and microenvironments. A related example was proposed for airborne fungal concentrations in schools of different regions based on the distinction between natural and high concentrations of fungi (Salonen et al. 2015). This information could be incorporated in the bioaerosol public database to keep track of what is measured and how and accumulate the large data set on bioaerosol exposure studies. An international scientific organization could be responsible for the creation of the database such as the National Institutes of Health (NIH) for the Human Microbiome Project. Although having bioaerosol exposure guidelines may seem far from becoming a reality in the near future, raising the level of knowledge on bioaerosols and combining forces of different aerosol scientists can certainly bring this reality within reach.

About the authors Hamza Mbareche is a Ph.D. student in the Department of Biochemistry, Microbiology and Bioinformatics at Laval University, Quebec City, Quebec, Canada.

Lidia Morawska is a full professor in the Faculty of Science and Engineering, Physics, and Mechanical Engineering, Environmental Technologies in Queensland University of Technology, Brisbane, Queensland, Australia. She is also a member of the Institute of Health Biomedical Innovation.

Caroline Duchaine is a full professor in the Department of Biochemistry, Microbiology and Bioinformatics at Laval University, Quebec City, Quebec, Canada, and a senior researcher at CRIUCPQ where she leads the Bioaerosols Research Group. She is also head of the Quebec Bioaerosols and Respiratory Viruses Strategic Group of the Quebec Respiratory Health Network.

ORCID Caroline Duchaine

http://orcid.org/0000-0002-9912-0349

Conclusion This work gives concrete suggestions for how to design a full bioaerosol study that includes all of the key elements necessary to help understand the real impacts of bioaerosol exposure in the short term. The creation of the bioaerosol public database will help accumulate information for long-term association studies and help determine specific environmental markers of exposure. We suggest that the WHO lead the discussions on the ideas mentioned in this paper and evaluate the involvement of the scientific aerosol community.

Ultimately, the implementation of such work will lead to a deeper understanding and more efficient utilization of bioaerosol studies, in addition to giving the WHO valuable information for creating future bioaerosol exposure guidelines.

Acknowledgment The work was inspired by discussions during the 5th Workplace and Indoor Aerosols Conference in Cassino, Italy. The authors thank Amanda Kate Toperoff and Michi Waygood for English revision of the manuscript. C.D. is the head of the Bioaerosols and Respiratory Viruses Strategic Group of the Quebec Respiratory Health Network.

Funding H.M. is a recipient of the FRQNT Ph.D. scholarship and received a short internship scholarship from the Quebec Respiratory Health Network.

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