6
Health Effects from Exposure to Indoor PM

This chapter presents the findings of the committee’s review of recent literature on the health effects associated with exposure to particulate matter in indoor environments, including cardiovascular and pulmonary disease, birth outcomes, neurological and psychiatric effects, and endocrine disease. Sections focus on the physiological mechanisms hypothesized to link exposure to cellular changes and factors that influence an individual’s susceptibility to developing clinical symptoms associated with exposure. Where relevant, early preclinical biomarkers that indicate cellular or biological changes associated with potential effects from exposure to indoor particulate matter are discussed. The chapter concludes with the committee’s recommendations to the indoor air research community and to the Environmental Protection Agency (EPA) and other funders of that research.

INTRODUCTION

The Lancet Commission on pollution and health reports that pollution is responsible for approximately 9 million deaths per year globally, of which the greatest proportion is attributable to ambient air pollution and household air pollution, with ambient fine particulate matter being the largest contributing risk factor in ambient air pollution (Fuller et al., 2022). Household air pollution includes not only pollutants from outdoors, but also air pollution from indoor sources, which may include allergens sources (pets, pests, fungi), microbes, the burning of biomass, and non-biomass combustion. Globally, much of this burden is attributable to biomass fuel burning (WHO, 2022); other sources of indoor air pollution have been less studied. The National Academies have conducted two series of workshops on the health risks of indoor exposure to particulate matter. In 2016 a series of experts in this area outlined the major areas of concern, including respiratory, cardiovascular, reproductive, and neurological and psychological effects (NASEM, 2016). The experts at this initial workshop pointed to the epidemiological challenges of characterizing the contribution of indoor exposure to particulate matter, separate from that of outdoor air pollution, in the development of disease.

In 2022 the National Academy of Engineering held a second virtual workshop series in which health effects were again summarized and potential mitigation approaches were discussed (NAE, 2022). The areas that were emphasized in that workshop included cardiovascular and pulmonary effects, including a discussion of important susceptibility factors.

Approach

Much of what is known about the health effects of exposure to particulate matter has been derived from measurements of outdoor air pollution, with the primary emphasis in the past being on the effects on the respiratory system. The past two decades have greatly expanded the

focus on health effects on other body systems as well. More recently, in 2017, a joint statement was published by the European Respiratory Society and the American Thoracic Society of a general framework for interpreting the adversity of the human health effects of air pollution (Thurston et al., 2017). This framework is used in this chapter to apply and transfer this knowledge to the understanding of health effects associated with indoor exposure to particulate matter. Figure 6-1 shows the biological systems that have been associated with health effects associated with exposure to outdoor air pollution. Its content reflects the fact that populations breathing indoor air are exposed to a mixture of outdoor air pollution that has entered the indoor environment and additional PM_2.5 exposure generated from sources inside homes and other buildings. Given the significant contribution of PM_2.5 of outdoor origin to the indoor environment, the figure of health effects is relevant in reviewing potential health effects associated with exposure in indoor environments.

As described in the previous chapters, air pollution, either indoor or outdoor, consists of particulate matter and gaseous contaminants. For the purposes of describing human health effects, it is difficult, if not impossible, to separate the influence of these different components of indoor air on the resulting health conditions, though there have been outdoor studies that have documented certain gaseous components with specific increased risk for health effects. Research focused on this level of specificity on the harmful components of different elements of indoor air pollution is just beginning. This chapter also includes important toxicology papers that are

informative for understanding the mechanisms by which PM_2.5 exerts its effects on different body systems.

Studies of health effects associated with exposure to ambient air pollution necessarily capture health effects that occur from both outside and indoor exposure. An important caveat when considering such studies is that outdoor air pollution concentrations are just a proxy of “exposure” to the outdoor sources of air pollution and that a more appropriate assessment would incorporate an estimation of penetration of outdoor air pollution to indoor spaces and the time spent indoors. The implications are that, depending on how indoor fine PM exposure is defined and assessed, part of its health effects are attributable to PM of outdoor origin.

The committee did not attempt to conduct a systematic review of all literature on the health effects of exposure to indoor particulate matter, but rather highlighted the major studies and reviews in this area. Where necessary, this chapter uses the results of studies of outdoor exposure to illuminate the mechanisms that may be driving these effects in human populations. Health effects related to chemical exposures from particulates are addressed in the National Academies’ Why Indoor Chemistry Matters report (NASEM, 2022).

The dependency upon literature describing the association between particulate matter and health effects varies by the type of body system. In general, the literature on pulmonary and cardiovascular effects associated with indoor air pollution is much more established than that of other body systems, such as neurological and reproductive effects. In the review of different body systems, there was an attempt to focus primarily on literature from studies conducted in the United States, if possible. Finally, epidemiological studies that involve interventions to reduce exposure to particulate matter and the effects on health outcomes are the focus of Chapter 7.

Environmental and Vulnerability Considerations

As discussed in Chapter 5, exposure to PM_2.5 indoors varies across certain subgroups and may be higher or more prevalent among communities of color and populations living in poverty. These same groups have disproportionate burdens of different types of diseases associated with exposure to particulate matter. Underlying health conditions can disproportionately increase one’s risk of exhibiting a health condition related to PM_2.5 exposure, and the elderly, pregnant people and infants and children have disproportionate risks for exhibiting health conditions associated with exposure to environmental contaminants. Effects may be amplified by inequities in circumstance (such as older housing stock, denser occupancy, and characteristics of ventilation systems), co-existing stressors (additional toxic exposures, poor nutrition, and the like), access to care, and other social determinants of health. The chapter thus includes studies that illustrate how the social determinants of health and environmental exposures result in differences in health risks.

RESPIRATORY HEALTH EFFECTS

PM_2.5 exerts its effects on the lower respiratory tract in part due to its size. This size fraction penetrates to the small airways, including the terminal bronchioles. The majority of the ultrafine fraction deposits in the nasal, pharyngeal and laryngeal parts of the airway, but this fraction also penetrates to the alveoli (Oberdörster et al., 2005). Because of their small size, they can cross the endothelial and epithelial barriers, entering the circulation, and can also be taken up by cells. PM elicits inflammation and oxidative stress responses in the airway, and the

immunologic pathways by which some biologic components of PM exert respiratory effects are well understood. These effects include the elicitation of allergic immune responses and eosinophilic inflammation by allergens among those who are sensitized to the allergen and elicitation of innate immune responses through the TLR4 receptor for endotoxin. PM from combustion elicits neutrophilic immune responses in the airways.

The section that follows discusses the respiratory health effects of PM_2.5. The bioaerosols examined include environmental allergens, non-pathogenic/non-infectious microbes and their components, infectious microbes, and others. Chemicals may include organic and inorganic compounds as well as metals. Although the report does not include a review of the voluminous literature on smoking, secondhand smoke is addressed in its capacity as a major contributor to indoor PM_2.5. The approach taken is to review the major epidemiological literature focused on respiratory effects of indoor fine PM, including those that include biomarkers of effects.

Acute Effects: Clinical Effects, Inflammation, and Lung Function

Indoor PM_2.5 has been implicated in a range of clinical, biologic, and physiologic manifestations of asthma and chronic obstructive pulmonary disease (COPD), including symptoms, exacerbations, quality of life, inflammation, and lung function. Indoor PM_2.5 exposure has also been linked to symptoms in populations without lung disease.

Multiple epidemiologic and intervention studies have established indoor PM_2.5 as a cause of asthma symptoms and exacerbations in children with asthma as well as respiratory infections such as influenza, COVID-19, RSV, and other common respiratory viruses. In one study, there was a 7–14 percent increase in days with asthma symptoms or rescue medication use with each 10 µg/m³ increase in indoor PM_2.5 (McCormack et al., 2011). These populations, which were socially and economically disadvantaged, tended to be exposed to high levels of indoor PM_2.5. There is scant literature concerning adults, but one epidemiologic study reported associations between both ambient PM_2.5 and a measure of indoor PM and respiratory symptoms among adults with asthma (Balmes et al., 2014). There are several trials that have tested an intervention aimed at reducing indoor PM_2.5 concentrations (Fisk, 2013). Two trials were conducted in populations exposed to secondhand smoke, and they are discussed below. One trial, which was not blinded, tested HEPA air cleaners among a population of rural Latino/a children who were not exposed to secondhand smoke at home and had poorly controlled asthma (Drieling et al., 2022). The primary outcome of the Asthma Control Test (ACT) score did not differ between groups; however secondary analyses found that assignment to the HEPA air cleaner group was associated with a reduced risk of poorly controlled asthma, symptoms in the past 2 weeks, and urgent clinical visits compared with the control group (Drieling et al., 2022).

Although two small panel studies of individuals with COPD did not find associations between indoor PM and either lung function or symptoms (Hsu et al., 2011; Linn et al., 1999), these studies each included only about 25 participants, limiting their statistical power. In a more recent and larger longitudinal study of 84 former smokers with COPD, indoor PM_2.5 was associated with respiratory symptoms, rescue medication use, and severe exacerbations (Hansel et al., 2013). This observational study was followed by a randomized trial of a HEPA air cleaner intervention among former smokers with COPD. Those randomized to the active air cleaner intervention did not have significant improvement in respiratory status, as measured by the St. George's Respiratory Questionnaire but did have improvement in respiratory symptoms, the need for rescue medications, and rate of COPD exacerbations. A per-protocol analysis that was defined by using the air cleaner as directed over 80 percent of the time demonstrated a greater

than 50 percent reduction in indoor PM_2.5 concentrations and improvements in symptoms, rescue medication use, and exacerbation risk (Hansel et al., 2013). Notably, those with greater use of the air cleaner and who spent more time at home experienced the greatest benefit. Interactions have also been observed between other environmental factors and indoor PM_2.5 on respiratory health among people with COPD. In one study, indoor heat and indoor PM_2.5 had multiplicative effects on symptoms among a cohort with moderate to severe COPD (McCormack et al., 2016).

Studies have also found associations between indoor PM_2.5 and acute changes in lung function. In an observational study of children with asthma, indoor, but not outdoor, PM_2.5 was associated with decreases in FEV1/FVC (a lung function measure that examines the volume of air that is forcefully exhaled) (Isiugo et al., 2019). In a panel study of children with asthma, indoor/home 24-hour PM concentrations were associated with reductions in FEV1 percent predicted of ~1.6 percent for each 6.7 µg/m³ increase (IQR) in PM_2.5 (Delfino et al., 2004). In an interventional study, peak expiratory flow (PEF) increased with the use of a bedroom air cleaning/ventilation unit among children with asthma (Xu et al., 2010). One study of 125 older adults with COPD observed associations between indoor PM_2.5 and indoor BC and decreases in pre-bronchodilator FEV1 and FVC but found little relationship between ambient PM_2.5 and black carbon levels and lung function indices (Hart et al., 2018).

There is sparse literature and less consistent evidence regarding the effects of indoor PM_2.5 on biomarkers of effect (Gong et al., 2014). In a trial of HEPA air cleaners among rural Latina/o children with asthma, discussed above, assignment to the air cleaner group was associated with a 10 percent greater decrease in measured urinary LTE4 concentration than the control group, but this finding was not statistically significant (95% CI: −20% – 1%) (Drieling et al., 2022). In an observational study of 16 older adults with respiratory disease, for the 7 participants with asthma, higher indoor PM concentrations were associated with higher fractional exhaled nitric oxide, but not lower lung function (Jansen et al., 2005). In an observational study of 19 children with asthma, a model was used to estimate the relative contributions of indoor-generated and ambient-infiltrated PM to total indoor PM_2.5 concentrations in the children’s homes; only the ambient-infiltrated components were associated with changes in exhaled nitric oxide (Koenig et al., 2005). Another study of 16 adults with COPD developed separate estimates of personal exposures to ambient and non-ambient (indoor-generated) PM and found that although total PM_2.5 exposures were dominated by exposures to non-ambient particles (which were not correlated with ambient fine particle exposures or ambient concentrations), only exposure to ambient particles were associated with decreased lung function, decreased systolic blood pressure, increased heart rate, and increased supraventricular ectopic heartbeats (Ebelt et al., 2005). In another study, exhaled breath condensate (EBC) nitrate decreased and pH increased in children with asthma with an air cleaning/ventilating unit. However, it is difficult to attribute the improvement in the EBC markers to decreases in PM or any of its particular components because not only did PM₁₀ decrease, but total VOCs, endotoxin, and allergens also decreased (Xu et al., 2010). Another limitation of this study was that there were two groups of participants and these effects were only observed within one group of participants, but not the other. The authors postulated that that the lack of improvements in EBC markers with use of the air cleaning/ventilation unit in one group may have been due to a lack of a washout period as this group had the system running for 12 weeks and then turned it off for the final 6 weeks of observation under “untreated” conditions. The statistical approach also did not appear to account for repeated measures within individuals, and the study was not blinded. In two studies of 82 adults with COPD, higher indoor black carbon concentrations were associated with higher

concentrations of urinary markers of oxidative stress and systemic markers of inflammation (Garshick et al., 2018), highlighting the potential of outdoor sources of PM penetrating indoors and exerting health effects (Grady et al., 2018). This observation is further supported by an association between higher indoor PM concentrations and greater black carbon content in airway macrophages among former smokers with COPD (Belli et al., 2016).

The sources and composition of PM are likely important in determining its biologic effects, but these characteristics are not captured by conventional volumetric sampling and gravimetric methods or light-scattering measurement methods. Further complicating matters is that, as discussed in Chapter 5, exposure to PM components may be estimated by measuring concentrations in a compartment such as settled dust or by measuring biomarkers of exposure rather than by measuring airborne particle concentrations. For example, the major contributor to indoor PM_2.5 in many populations is secondhand smoke (SHS), and there is a lengthy scientific literature pointing to SHS as a cause of asthma symptoms and exacerbations, and here the exposure metric is often cotinine or nicotine concentrations in a biologic sample. At least two randomized trials of air cleaners in children with asthma exposed to secondhand smoke demonstrated reductions in indoor PM_2.5 and biomarkers of SHS exposure and improvements in asthma, including an increase in symptom-free days (Butz et al., 2011) and reduction in exacerbations. There is scant literature about the effects of secondhand smoke on acute respiratory outcomes in COPD populations (Putcha et al., 2016a). Other combustion sources of indoor PM_2.5 include incense and candle burning. There is little literature concerning the effects of these PM_2.5 sources on respiratory health, and overall the findings are mixed. Incense has been implicated in pulmonary inflammation and linked to chronic respiratory symptoms in some contexts, but not others (Lin et al., 2008). Candle burning as a source of PM_2.5 may be less important in terms of respiratory health effects than other sources of indoor PM_2.5 such as secondhand smoke and cooking with an unvented stove (Lim et al., 2022). Both incense and candle burning are expected to have deleterious effects on the lungs, but their overall public health importance likely varies with degree of exposure and context.

The biologic components of indoor PM also have acute respiratory effects among people with and without asthma. Although the focus of the section is on acute effects, it is notable that—in the case of indoor allergens—acute effects among those who are sensitized to the allergen may be deleterious while their effects on incident asthma (chronic effects) may be beneficial (Behbod et al., 2013).

These bioaerosols—the biologic components of indoor PM—include environmental and food allergens, microbes and their components, infectious agents, and food-derived particles, such as lipids. Indoor allergens are known causes of asthma symptoms, reductions in the quality of life, exacerbations, reductions in lung function, and pulmonary inflammation among those sensitized to the allergens. All of the major indoor allergens have been implicated, including dust mites, cockroaches, furry pets, and mice. There are also emerging data implicating indoor allergens in COPD exacerbations among those sensitized to the allergens (Putcha et al., 2022). Notably, exposure to these allergens is typically estimated by measuring their concentrations in settled dust, and some of these allergens are found on larger particles and so are less likely to be in the PM_2.5 fraction. A large fraction of airborne furry animal allergens (from cats, dogs, and rodents), however, are found in the PM_2.5 fraction. Fungal allergens also exert respiratory effects via an allergic mechanism (e.g., by stimulating immunoglobulin E, or IgE, antibody production), although fungi may also exert their effects through non-IgE-dependent mechanisms, such as through innate immune activation. Although the most common route of exposure to food

allergens by far is through ingestion or contact, food allergens can be aerosolized during cooking, and foods that are pan-fried are the most commonly aerosolized—eggs and fish, for example. These aerosolized food allergens can lead to respiratory symptoms among those who are allergic to these foods.

Microbes and their components have also been implicated in asthma symptoms and exacerbations. The best studied microbial component may be endotoxin (a lipopolysaccharide), which exerts its effects by activating the innate immune system through the TLR4 receptor (Thorne, 2021). It is found in the fine particle fraction and is a cause of respiratory symptoms, fever, and leukocytosis in occupational settings where there are extremely high concentrations. Human exposure studies using doses (20,000 EU), similar to what might be expected for people living in homes burning biomass (100-1000 EU/m³), have shown that endotoxin exposure induces pulmonary inflammation, including both eosinophilic and neutrophilic inflammation (Hernandez et al., 2012). In homes, endotoxin concentrations—which are correlated with pets, mice, and young children in the home—can be measured in settled dust or air samples and are associated with asthma symptoms and exacerbations and may interact with indoor pollutants (indoor NO₂, air nicotine, and traffic-related air pollution, specifically outdoor PM_2.5 and NO₂) to potentiate their effects (Matsui et al., 2013; Mendy et al., 2019; Rosser et al., 2020). However, exposure to microbial components and their sources (animals) during early life may protect against the development of allergy and asthma, highlighting that the effects of these indoor environmental factors vary by stage of life, and may also vary by compartment and genetics (Lynch et al., 2014; Ownby et al., 2002; Sahiner et al., 2014). Importantly, endotoxin in environmental samples co-exists with other microbial components, so some of its effects in epidemiologic studies could be due to other microbial components. There are just a handful of studies of respiratory effects of endotoxin exposure among people with COPD. One study of 84 people with COPD found no associations between home endotoxin and symptoms, rescue medication use, quality of life, or exacerbations (Bose et al., 2016).

Other microbes and components that have been studied are fungal spores and their components and some bacteria-associated molecules, such as Staphylococcus aureus enterotoxins (Davis et al., 2018). Most of this body of work has focused on asthmatic populations, so there is scant literature for COPD. Some fungal spores have average aerodynamic diameters in the 2- to 10-micrometer range and thus can penetrate the conducting airways (Secondo et al., 2021). Fungal spores can cause asthma symptoms and exacerbations, and certain fungi have been linked to more severe asthma and even fatal asthma. Fungal exposure has also been linked to decrements in lung function among COPD patients (Fréalle et al., 2021). Although fungi have allergens that exert their effects in an IgE-dependent manner, there are a variety of fungal molecules that can trigger respiratory symptoms in a non-IgE-dependent manner. Specifically, a variety of fungal molecules, such as mannoproteins, glucans, and chitin, have been implicated as causes of acute respiratory symptoms and inflammation, but disentangling the independent effects of these various constituents is difficult (Cope and Lynch, 2015; D’Evelyn et al., 2021). Beyond specific microbes and microbial components, the application of metagenomic methods to environmental samples in the past decade has resulted in a proliferation of research describing microbial communities in environmental samples. Much of this work has focused on the potential impact of the microbial communities on long-term outcomes, such as incident asthma, and there is scant literature on acute health effects. Moreover, these studies have mostly relied on settled dust reservoir samples, and whether the microbial

communities identified in this type of sample correlate with microbial communities in indoor airborne PM_2.5 is unclear.

Infectious microbes have received much more attention because of the COVID-19 pandemic, which has spotlighted airborne transmission of SARS-CoV-2 as the major mode of its transmission. Other infectious microbes found in the PM_2.5 fraction include other respiratory viruses, such as influenza, measles, and tuberculosis. The supporting evidence comes from animal model studies, aerosol science, and epidemiologic studies and has largely focused on exhaled particles carrying infectious virus, but the results of one animal study suggest that aerosolized fomites could contribute to influenza transmission (Asadi et al., 2020). Airborne infectious microbes are well established causes of acute respiratory effects with particular impact among those with asthma and those with COPD. These observations have important implications for the practical mitigation of PM_2.5, in that strategies that reduce indoor PM_2.5 concentrations should also reduce concentrations of these infectious organisms.

Overall, extending the understanding of health effects of mass concentration of PM_2.5 to include its composition and toxicity will be important for informing practical mitigation strategies as this will lend insight into high-impact targets to intervene. For example, it is possible that targeting particular sources, composition, or biologic activity in PM_2.5 may result in greater health benefits than targeting overall mass concentration. For instance, there is evidence pointing to oxidative potential as a mechanism of PM_2.5 health impacts which could help target interventions (Weichenthal et al., 2016; Sarnat et al., 2016; A. Yang et al., 2016). Other approaches have targeted indoor and outdoor PM by analyzing cellular injury or cytokine production in human cell lines (Monn and Becker, 1999) or assays on rat models (Long et al., 2001).

Acute Effects: Respiratory Tract Infection

Aside from PM_2.5 serving as a vehicle for infectious microbes, PM_2.5 can also increase susceptibility to respiratory tract infection indirectly, although the exact mechanisms by which it acts are unclear. There is a large body of evidence associating outdoor PM_2.5 levels with greater risk of respiratory tract infection among children. Much of the literature on indoor PM_2.5 and respiratory tract infection is from developing countries where biomass burning for cooking and heat has been linked with an increased risk of infection (Simkovich et al., 2019). In the United States, there are a handful of studies that also demonstrate an association between indoor PM_2.5 in homes with wood stoves and lower respiratory tract infection among young children. For example, two studies found that children living in homes with a wood stove were exposed to higher indoor PM concentrations and a higher risk of lower respiratory tract infection than their counterparts who did not live in homes with a wood stove (Walker et al., 2022). These studies enrolled children from poor rural communities where the use of wood stoves for cooking or heat is more common, and there is scant literature focused on other U.S. populations (Robin et al., 1996).

However, secondhand smoke, a major contributor to indoor PM, has been linked to upper and lower respiratory tract infections in young children (Cao et al., 2015). It has also been implicated in invasive bacterial infections in children, longer hospital length of stay for lower respiratory tract infection among atopic infants (Lemke et al., 2013), and chronic rhinosinusitis among adults (Hoehle et al., 2018). Secondhand smoke and indoor air pollution have also been shown to increase the risk of contracting tuberculosis in international studies (Obore et al., 2020).

Although the mechanisms by which indoor PM may increase respiratory tract infection risk are not clear, outdoor PM has been shown to damage airway epithelium and perturb the immune response, highlighting the biologic plausibility of PM increasing susceptibility to infection. The literature focusing on mechanisms by which indoor PM may act is smaller, but a 2022 in vitro study suggested that indoor PM may impair innate immunity by inhibiting the antiviral activity of airway surface liquid (ASL) (Stapleton et al., 2022). Outdoor PM has also been shown to impair the bactericidal effects of ASL (Stapleton et al., 2020), suggesting that PM may impair immunity against both viral and bacterial respiratory tract infections. The literature examining mechanisms by which outdoor PM may increase susceptibility is larger and points to deleterious effects on the airway epithelium and the immune response (Beentjes et al., 2022).

Chronic Respiratory Health Effects

Although there is a growing body of work demonstrating associations between outdoor PM_2.5 and long-term respiratory effects, there is, with few exceptions (e.g, Logue et al. 2012), little literature on indoor PM_2.5. Outdoor PM_2.5 has been linked to incident asthma and COPD as well as long-term effects on lung function—either more rapid decline among adults or reduced lung function growth among children. However, secondhand smoke—a major contributor to indoor PM_2.5—has repeatedly been associated with reduced lung function growth among healthy children (Okyere et al., 2021) and those with underlying conditions, such as cystic fibrosis (Oates et al., 2020). An Australian study observed associations between particular indoor PM_2.5 sources (wood heating, tobacco smoke) and risk of persistent asthma and lung function decline among adults (Dai et al., 2021).

Pulmonary Symptoms in School Environments

While the bulk of the indoor PM literature has focused on homes, children spend a substantial amount of time in schools. The growing body of literature focused on school exposure has identified school buildings being in poor condition as a risk factor for asthma hospitalizations and absenteeism, although these studies did not examine indoor PM directly (Berman et al., 2018; Wu et al., 2023). Schools can have clinically relevant levels of PM and bioaerosols, including fungi and allergens. Although studies examining the health effects of school-based PM exposure are scant, a few studies have reported associations between mouse allergen, fungi, and endotoxin exposures in schools and adverse health effects among children with asthma (Baxi et al., 2019; Lai et al., 2015; Sheehan et al., 2017). PM_2.5 concentrations can be high in schools, and outdoor sources can be major contributors to classroom PM_2.5. School factors such as proximity to idling buses, the age and type of buildings, ventilation, and servicing of the furnace also contribute to school PM_2.5 concentrations (Matthaios et al., 2022). Although there is little literature examining the respiratory effects of school-based PM_2.5 exposure specifically, the concentrations observed in schools have been linked to a variety of respiratory health effects, suggesting that school-based exposure also has deleterious effects on respiratory health.

Susceptibility Factors for Pulmonary Outcomes

Susceptibility to indoor PM_2.5 and its different constituents varies. Young age and advanced age are susceptibility factors for the respiratory effects of outdoor PM_2.5 and are also

likely susceptibility factors for indoor PM_2.5 (Simoni et al., 2015). One study found school-age children at greatest risk for asthma exacerbations in response to exposure to particles of outdoor origin, suggesting that age may also be a susceptibility factor for the respiratory effects of indoor PM_2.5 exposure (Alhanti et al., 2016), but studies examining age as a modifier of indoor PM_2.5 respiratory effects are scant. Obesity is a risk factor for indoor and outdoor PM_2.5 respiratory effects, including on respiratory symptoms and lung function and among asthmatic and healthy populations. Although this result has been found in multiple studies across all ages and several continents, the mechanism by which obesity may confer susceptibility to PM_2.5 respiratory effects is unclear. Researchers have postulated that the underlying inflammatory state or physiologic changes in lung function associated with obesity may be mechanisms. Diet has also been hypothesized as influencing susceptibility to PM_2.5 exposure (Brigham et al., 2023). For example, in one study, omega-6 and omega-3 fatty acid intake via diet modified responses to indoor PM_2.5 exposure among children with asthma (Bose et al., 2019; Brigham et al., 2019). Omega-3 fatty acid intake attenuated the respiratory effects of indoor PM_2.5 exposure, while omega-6 fatty acid intake amplified its effects. For outdoor PM, genetic polymorphisms in genes that are critical for the oxidative stress response have been established as susceptibility factors (Romieu et al., 2010). Whether these same polymorphisms—or polymorphisms in other oxidative stress genes—confer susceptibility to indoor PM_2.5 is unknown. Susceptibility factors for biologic constituents of PM_2.5 are better understood. For example, individuals with IgE sensitization to indoor allergens and foods are susceptible to exposure to these allergens, while those without IgE sensitization are not. For endotoxin, polymorphisms in the CD14/TLR pathway confer susceptibility to its respiratory effects.

CARDIOVASCULAR HEALTH OUTCOMES

There is a robust body of literature providing strong evidence that ambient fine PM is associated with adverse cardiovascular health effects (Brook et al., 2010; Newman et al., 2020; Rajagopalan and Landrigan, 2021; Rajagopalan et al., 2018). Large studies in the United States have demonstrated that short-term increases in PM are associated with an increased risk of heart attacks, heart failure events, and strokes requiring emergency department visits or hospitalizations. Further, increases in both short-term and long-term outdoor PM have been associated with increases in cardiovascular deaths.

Published studies of the health effects of indoor PM exposure have typically focused on short-term health effects. A notable exception is the body of evidence demonstrating the health benefits related to the reduction of secondhand smoke in the context of indoor smoking bans (Meyers et al., 2009; Oliver, 2022). Studies have demonstrated that indoor smoking bans have resulted in reductions in cardiovascular events, such as acute myocardial infarction by up to 40% and acute cerebrovascular disease by up to 29% (Pechacek and Babb, 2004). Studies of the cardiovascular health effects of indoor PM have generally focused on intermediate endpoints that have been conceptualized as mediators of cardiovascular health effects or proposed as clinically relevant. Pathways that may explain the cardiovascular health effects of indoor PM include systemic inflammation and oxidative stress responses; activation of the coagulation cascade; alteration of cardiac autonomic response and conduction; and changes in vasomotor tone of the circulatory system. The clinical endpoints include biomarkers of systemic inflammation and oxidative stress, blood pressure, pulse rate, heart rate variability, and electrocardiogram changes. Outcomes such as acute myocardial infarction and episodes of heart failure were not identified in

the studies reviewed, and few (if any) studies examined chronic exposure. The sample sizes of the studies of indoor PM were relatively small, particularly when compared with the population studies that have demonstrated cardiovascular health effects of outdoor air pollution. Most of the studies were observational with sample sizes of less than 100 participants. Although interventions are the focus of Chapter 7, findings from some intervention studies contribute to the evidence base that informs potential causality.

Acute Effects on the Cardiovascular System

Blood Pressure

Blood pressure is a physiologic measurement that is one of the major risk factors for cardiovascular disease. The consequences of higher blood pressure include coronary artery disease, heart failure, and cardiovascular death. Higher blood pressure is also associated with stroke, chronic kidney disease, and diabetes as well as other chronic conditions (Fuchs and Whelton, 2020). Studies of outdoor PM have consistently demonstrated that increases in PM_2.5 are associated with increases in blood pressure, with increases of 10 µg/m³ being associated with changes in the range of 1- to 3-mmHg elevations in systolic and diastolic blood pressure (Cai et al., 2016; Giorgini et al., 2016; Liang et al., 2014; B.-Y. Yang et al., 2018). Controlled chamber studies and experimental models have also demonstrated this association (Cosselman et al., 2012; Hudda et al., 2021; Münzel et al., 2017; Urch et al., 2005, found in Rajagopalan et al., 2018).

Studies that have investigated the association between indoor PM and blood pressure, heart rate, and electrocardiogram (ECG) changes have demonstrated mixed results. For example, several small studies conducted in the United States did not detect an association. Jansen et al. (2005) studied blood pressure and heart rate in 16 individuals with asthma and COPD and did not find an association between indoor PM and pulse or blood pressure. Linn et al. (1999) studied 30 individuals with severe COPD and conducted monitoring near and inside participant homes. Outcomes included lung function, blood pressure, pulse oximeter, and ECG. Indoor PM was not associated with blood pressure or ECG changes. Brook et al. (2011) separately analyzed associations between cardiovascular outcomes and both community-level ambient PM_2.5 concentrations and personal PM_2.5 concentration measurements (by vest monitors) of 65 nonsmoking subjects, finding that a 10 μg/m³ increase in total personal-level PM_2.5 exposure was associated with systolic blood pressure elevation but that community PM_2.5 levels were not associated with cardiovascular outcomes. International studies that focus on biomass fuel use, including those conducted in China, Guatemala, and Peru, provide more consistent evidence of the association between indoor particulate matter and increases in blood pressure. One review article found that eight cross-sectional studies reported an association between higher blood pressure or prevalence of hypertension, while two cross sectional studies did not find an association (Fatmi and Coggon, 2016).

Intervention studies also provide evidence of the association between indoor PM and blood pressure, and several studies have demonstrated improvements in blood pressure with reductions in PM concentrations. Morishita et al. (2018) studied 40 non-smoking older adults in an intervention study in economically disadvantaged senior housing and found that the use of indoor portable air filtration for 3 days led to significant reductions in systolic blood pressure and a trend toward reduction in diastolic blood pressure. A crossover study in China of 35 college students living in dormitories detected improvement in blood pressure with an air cleaner

intervention for 48 hours that resulted in a 57 percent reduction in PM_2.5 (96.2 vs 41.3 μg/m³) (R. Chen et al., 2015). Another air cleaner intervention crossover trial in China demonstrated blood pressure reduction among college students with PM reduction of 54 percent (53.1 vs 24.3 μg/m³) with use of an air cleaner for 9 days (H. Li et al., 2017). In one of the only longer-term intervention studies of which the committee is aware, Chuang et al. (2017) introduced an air filtration intervention to air conditioners in the homes of 200 participants in Taipei, Taiwan, and found that increased levels of PM_2.5 were associated with increased blood pressure over the course of the year. However, many of the clinical trials of portable air cleaners have included blood pressure and heart rate and have not found an association between PM reduction and blood pressure improvement. International studies in Guatemala and Bolivia reported a reduction in blood pressure (BP) with the use of improved stoves (Alexander et al., 2015; McCracken et al., 2007).

Vascular Physiology and Function

Vascular physiology and function are often measured with surrogate measures in research studies to assess vascular function. These surrogate measures include the assessment of carotid intimal media thickness, brachial artery diameter, flow mediated dilatation, and endothelial function/microvascular function (reactive hyperemia–peripheral arterial tonometry with EndoPat sensors). In a crossover study of 21 elderly nonsmoking couples in Copenhagen, air filtration with a HEPA filter for 48 hours led to a 62 percent reduction in indoor particulate matter concentrations (12.6 to 4.6 µg/m³) and an 8 percent improvement in microvascular score (Bräuner et al., 2008). In a study of healthy adults in British Columbia, a HEPA filter intervention for 7 days led to improvement in PM_2.5 concentrations by 60 percent (11.2 vs 4.6 µg/m³) and reactive hyperemia index of 9.4 percent (Allen et al., 2011). Other intervention trials did not demonstrate improvement in that index (Kajbafzadeh et al., 2015; Karottki et al., 2013; Weichenthal et al., 2013).

Cardiac Autonomic Dysfunction and Conduction

Cardiac autonomic dysfunction (heart rate variability) and conduction (ECG changes) have been proposed as an effector pathway by which air pollution leads to increased cardiovascular events. Heart rate variability (HRV) reflects the ability to adapt to the body’s changing physiologic demands, and greater variability is associated with better outcomes. Several studies examined the association between outdoor PM and HRV. The association was more pronounced among those with pre-existing cardiovascular disease. Raju et al. (2023) studied 85 former smokers with COPD and detected an association between indoor PM_2.5 and ultrafine particles and HRV among former smokers with a diagnosis of COPD. HRV was assessed using the standard deviation of the average NN intervals and the root mean square of successive differences approaches to measuring the variability between heart beats measured on an ECG. Though the sample size was smaller, the effect sizes were larger for ultrafine particles, which could suggest that these smaller particles are more potent. Liao et al. (1999) studied 26 elderly individuals and found that increases in PM_2.5 (indoors and immediately outside the home) were associated with lower heart rate variability in the elderly. Zanobetti et al. (2009) studied 48 individuals who were hospitalized for coronary artery disease for 1 year following the hospitalization. Exposures included ambient and in-home PM_2.5 and black carbon. Indoor black carbon and indoor PM_2.5 were associated with the ECG finding of t wave alternans, a marker of cardiac electrical instability. An international study demonstrated a benefit of reducing wood

smoke exposure (mean 266 to 102 μg/m³) with reduction in T-wave inversions among women living in Guatemala but did not detect changes in heart rate variability (McCracken et al., 2011).

Biomarkers and Inflammation

Studies of exposure to indoor air pollution have used biomarkers of inflammation in the blood (e.g., C reactive protein [CRP], interleukin-6 [IL-6]) and oxidative stress, as well as endothelial function (e.g., soluble vascular adhesion molecule-1 [sVCAM-1]), and coagulation. Findings may provide insight about to the pathways by which indoor PM exerts health effects. Delfino et al. (2008) studied 29 non-smoking elderly individuals investigating the association between both outdoor and indoor air pollution and systemic inflammation. The investigators reported associations between outdoor air pollution and CRP, IL-6, sTNF-RII, Sp-selectin and noted that associations with indoor pollution were consistent. However, the associations between indoor PM and the biomarker outcomes in isolation were less convincing.

Bose et. Al (2015) studied 50 individuals with COPD and detected an association between indoor PM and elevated white blood cell count, including neutrophils and lymphocytes. Garshick et al. (2018) studied 85 individuals with COPD and found that indoor black carbon was associated with CRP and results suggested a greater effect among those who were not taking statins. Findings were similar for interleukin 6 (IL-6), but there was no association with sVCAM1. While statin therapy is anti-inflammatory, these results suggest that statin therapy may have the potential to mitigate the inflammatory consequences of indoor pollution exposure and similar findings have been reported in the outdoor PM literature (Ostro et al., 2015). Brugge et al. (2017) studied ultrafine particulate pollution in 23 homes in Massachusetts and evaluated in-home HEPA filtration for 3 weeks compared to sham filtration for 3 weeks with a crossover study design. Despite reducing particle number concentrations by 50–85 percent in most homes, there was no evidence of beneficial effect on biomarkers of inflammation for HEPA as compared to sham filtration periods. The investigators also examined the association between ultrafine particle number concentration and did not find evidence of a positive association.

PM Composition and Cardiovascular Health Effects

Studies have investigated metals as a component of indoor PM and reported health outcomes. Bräuner et al. (2008) conducted a crossover trial of air cleaners among 21 elderly couples. Microvascular function was assessed using reactive hyperemia–peripheral arterial tonometry with EndoPat sensors. Personal exposure to iron, potassium, copper, zinc, arsenic, and lead in the fine particulate fraction was associated with changes in microvascular function. Hsu et al. (2011) reported that nickel in indoor and personal PM samplers was associated with increased heart rate among individuals with COPD, but these findings were representative of only nine participants from New York, and this association was not detected among the 15 individuals with COPD who were enrolled in Seattle. Studies investigating PM measured outdoors have demonstrated an association between a particle radioactivity and cardiac arrhythmias among a high-risk population (Peralta et al., 2020) and studies in populations with COPD have demonstrated associations between in-home gamma radiation PM exposures and systemic inflammation (CRP, IL-6 and sVCAM-1) and oxidative stress (Huang et al., 2020; 2021). These findings may suggest the need to consider activities that generate PM or sources and composition of PM in evaluating health effects.

Hammond et al. (2014) reported findings of the Detroit Exposure and Aerosol Research Study (DEARS) in a subset of 50 nonsmoking adults who underwent cardiovascular assessment in addition to an indoor environment assessment. The indoor environment assessment included continuous PM assessment and completion of household activity diaries. Participants contributed a maximum of 5 days in the summer and 5 days in the winter. Activities that significantly increased PM included cooking, candles, smoking, open windows, and product use. The investigators found heterogeneity in the associations between household activities likely to influence PM source and cardiovascular outcomes, including heart rate, blood pressure, brachial artery diameter, and flow-mediated dilatation. The exploratory nature of the study suggests that future studies that include consideration of source and composition may be informative and advance understanding of the pathways by which PM elicits health effects. The aforementioned long-term filtration study by Chuang et al. (2017) found that long-term (1-year) air-conditioner filter use reduced VOC as well as PM concentrations in homes in Taiwan and that filtration resulted in a reduction in inflammation and oxidative stress and blood pressure.

Susceptibility Factors for Cardiovascular Outcomes

Vulnerable populations at increased risk for the cardiovascular health effects associated with exposure to indoor particulate matter include children with asthma, elderly adults, and adults with asthma, chronic obstructive pulmonary disease (COPD), and heart disease. Studies of air pollution measured outdoors have demonstrated that the adverse impacts of particulate pollution may be amplified among those living in more disadvantaged areas (Hazlehurst et al., 2018; Wing et al., 2017). Some studies specifically enrolled participants who were of lower income (Padró-Martínez et al., 2015).

Individual characteristics may also confer susceptibility, and these characteristics may be differentially distributed among populations. Obesity is such a trait. Raju et al. (2023) described effect modification by body mass, suggesting that obese individuals with COPD may be more susceptible to the cardiovascular effects of indoor PM. The finding that obesity may enhance susceptibility to indoor PM has also been demonstrated in respiratory health effects among both children with asthma and adults with COPD (K. D. Lu et al., 2013; McCormack et al., 2015; Wu et al., 2018). Studies of outdoor pollution have also suggested that diabetes is a susceptibility factor for cardiovascular outcomes associated with PM exposure. Given the overlap between obesity and metabolic dysfunction, it is possible that underlying metabolic dysfunction could be a pathway by which obese individuals are more susceptible to the adverse effects of PM. The findings that statin therapy may mitigate PM health effects may also provide insight as to potential pathways that confer susceptibility and resistance to PM health effects.

Diet has also been identified as a modifiable risk factor that exaggerates or attenuates air pollution health effects in studies of air pollution measured outdoors. For example, in the U.K. Biobank Study, outdoor PM_2.5 was associated with an increased risk of all-cause mortality as well as of coronary vascular disease and coronary heart disease mortality; a healthy diet and, specifically, vegetable intake attenuated the association between PM_2.5 and mortality (Wang et al., 2022).

CANCER OUTCOMES

Air pollution has been classified as carcinogenic to humans by the International Agency for Research on Cancer (IARC) based on evidence from both epidemiological and animal studies, although there have been few studies focused on the attributable risk related to the exposures that occur within the indoor environment. There is substantial evidence to support a causal link between levels of outdoor air pollution, and especially PM, with lung cancer incidence and mortality (Turner et al., 2020). In addition to lung cancer, outdoor sources of air pollution have been associated with colorectal, gastric, renal, and bladder cancer (Schraufnagel et al., 2019). Secondhand smoke, exposure to which may occur outdoors or indoors, has long been recognized as carcinogenic (IARC, 2012; NTP, 2016). Much of what is known about the association between indoor air pollution and cancer has been generated from studies of biomass burning in low- and middle- income countries and primarily focused on lung cancer (Lee et al., 2020).

Mechanistic studies have demonstrated that components of air pollution alter the length of telomeres and the expression of genes involved in DNA damage and repair. Chen et al. In a case–control study of patients with lung cancer, K.-C. Chen et al. (2022) analyzed pleural fluid for evidence of internal exposure dose to substances shown to have an association with lung cancer. Excluding current smokers, they found individuals with lung cancer were more likely to report habitual cooking at home and indoor incense burning. Indoor wood-burning fireplaces have also been studied in relation to the risk of breast cancer. In a U.S. study, White et al. (2014) analyzed population-based case–control data and found that synthetic log burning was associated with increased risk of breast cancer, but not wood logs alone. The same investigators in a prospective study of sister study participants found that having an indoor wood-burning stove or fireplace in the longest adult residence was associated with a higher breast cancer risk, and the risk increased with frequency of use (White and Sandler, 2017). A similar increased risk of breast cancer related to indoor biomass cooking was observed in a large study based in the China Kadoorie Biobank (Liu et al., 2021). Compared with long-term clean fuel users, women burning solid biomass fuels to cook had elevated odds of being diagnosed with breast cancer. Those who had switched from solid to clean fuels did not have an excess risk of breast cancer.

NEUROLOGICAL OUTCOMES

With the increasing evidence of the association of ultrafine particle exposure and cardiovascular effects and the physiological interactions between the vascular system and the brain, the possibility of a pathway between vascular changes as risk factors for cognitive decline and psychological conditions (NASEM, 2016) merits attention. In addition to the vascular pathway, multiple studies have demonstrated that solid ultrafine particles are able to penetrate the brain via the nose and olfactory nerve (Oberdörster et al., 2004). Animal models have shown that, within the brain, PM alters neurotransmitter levels, triggering oxidative stress, inflammation, and other biochemical changes (Sirivelu et al., 2006). The link between these neurological effects and health outcomes such as cognitive decline, autism, and depression have been hypothesized. You et al. (2022) published a review of the association of particulate matter and neurological outcomes such as dementia in the elderly and neurological changes across all age groups. They summarized potential neurological mechanisms in human and animal studies that suggest that PM-induced neurodegenerative pathology includes neurotoxicity,

neuroinflammation, oxidative stress, and damage to the blood–brain barrier and neurovascular units.

While there is a growing body of evidence of the association between airborne particles and neurological outcomes, it remains unknown which particle components have the most serious neuro-toxicological profiles. The various components of indoor air pollution, such as the particles, gaseous components, organic compounds, and toxic metals, may have different effects on neurological systems. Most of the epidemiological studies of particulate matter and neurological outcome have focused on the link between PM₁₀ and PM_2.5 in air pollution and include studies of adults, pregnant people, and young children. As described in previous chapters, outdoor air pollution is a major component of the indoor air environment in addition to PM being generated by indoor sources. Studies focused on exposures that occur indoors and potential neurobehavioral and cognitive effects such as in offices and schools are increasingly being pursued.

Outdoor Air Pollution and Neurological Outcomes

The research on the association between ambient air pollution and neurological effects is characterized by studies of specific populations such as workers, the elderly, pregnant people, and veterans and an array of different outcomes such as cognition, depression, other psychiatric diagnoses, and admissions. Researchers in the United States conducted a cross-sectional study to determine if PM_2.5 in air pollution was associated with cognitive function in a national sample of older adults (Ailshire and Clarke, 2015). EPA monitoring data were linked with cognitive function of participants in the 2001/2002 Americans’ Changing Lives Study (n = 780). An association was reported between older adults living in areas with high concentrations of PM_2.5 and error rates on cognitive function tests. Bakolis et al. (2021) conducted a prospective longitudinal population-based mental health survey of 1,698 adults in southeast London from 2008 to 2013. Adjusting for socioeconomic status and exposure to road noise, they found evidence of 18–30 percent increased odds of common mental disorders among the persons with increased exposure to PM_2.5 along with other air pollutants. However, a study in the United States of 570 participants in the U.S. Veterans Administration Normative Aging Study found no association between PM_2.5 levels at residential address and Brief Symptom Inventory psychiatric symptom levels, although positive associations were found for other air pollution components (Qiu et al., 2022a). Bastain et al. (2021) published a study of the association between prenatal exposure to ambient air pollution and maternal depression at 12 months after childbirth in a cohort of 180 predominantly economically disadvantaged Hispanic/Latina women. They reported that second-trimester PM_2.5 exposure was associated with increased depression at 12 months postpartum and exposure to NO₂ was associated with almost a two-fold increase in postpartum depression.

A 2022 study was the first to describe the association of ambient residential long-term average predicted concentrations of particle components with the risk of psychiatric hospitalizations (Qiu et al., 2022). In this study, the Health Cost and Utilization Project’s state inpatient databases, which cover residents of eight U.S. states, were used to examine correlations between psychiatric hospitalizations and 14 constituents of PM_2.5 by the ZIP code of residence. The results found an association with PM_2.5 constituents such as sulfate, Fe, Pb, and Zn.

Two published reviews have examined the association between ambient air pollution and neurological conditions in adults. In a systematic review Dimakakou et al. (2018) reported a positive association between ambient air pollution, including PM_2.5, and neurodegeneration risks

such as dementia and cognitive decline. They found similar evidence of an association with indoor work-related exposure to PM_2.5. More recently, Boronni et al. (2022) published a review and meta-analysis of 39 studies on the association between ambient air pollution, including PM_2.5, and depression. They reported an increased risk of depression associated with long-term ambient PM_2.5 concentrations and with short-term exposure to other components of air pollution. While they acknowledged the publication bias, they reported that the association between PM_2.5 and depression was strengthened by the absence of heterogeneity and the inclusion of both long- and short-term exposure studies. The strength of the results of the studies that were being published, led Taylor et al. (2021) to develop a model that estimated the prevalence of expected cases of major depressive disorder in multiple scenarios and concluded that indoor PM_2.5 might contribute to 476,000 cases of major depressive disorder in the United States (95% confidence interval [CI] = 11,000–1,100,000).

Outdoor Air Pollution and Prenatal and Childhood Neurological Effects

There have been multiple reports of relationships between prenatal and early childhood exposures to ambient air pollution, including PM_2.5, and neurological outcomes, primarily behavioral effects and school performance. In a study of prenatal and early childhood exposures to traffic-related air pollution and neurobehavioral health outcomes in over 1,000 children, Harris et al. (2016) conducted parental and classroom teacher evaluations of behavioral ratings on executive function. Exposures were estimated using validated spatiotemporal models to predict residential ambient concentrations of PM_2.5 and black carbon. Only a slight association was found between PM_2.5 exposures during gestation and early childhood and teacher ratings, and none of the parent-rated outcomes suggested adverse effects. However, another study reported an association between ambient air pollution and academic achievement (W. Lu et al., 2021). Lu et al. examined outdoor PM_2.5 and other air pollutants and their associations with average academic test scores in third- to eighth-grade students in the United States from 2010 to 2016, controlling for urbanicity, socioeconomic status, and race/ethnicity. The authors found that ambient PM_2.5 concentration was associated with both lower scores in math and English language/arts test scores.

Several studies focused on outdoor PM_2.5 exposure during pregnancy and effects on neurobehavioral performance in offspring. Chiu et al. (2016) assessed gestational exposure to ambient PM_2.5 in 267 full-term urban children and its association with neurobehavioral outcomes. They found a positive association between gestational exposure at different windows of susceptibility and poorer function across memory and attention domains with variable associations based on sex. Ahmed et al. (2022) studied the association between ambient PM_2.5 and mental and behavioral development in children using data from the Mothers and their Children’s Health study in Australia, with ambient PM_2.5 levels estimated using a land use regression model. Residential proximity to roadways was also studied for early life exposure during pregnancy, the first year of life, and all of the children’s lifetime. Children exposed to moderate and high ambient PM_2.5 exposure had higher odds of emotional and behavioral problems and gross motor delays.

A number of studies have been published on the association between gestational and early life exposures to outdoor PM_2.5 and autism in children (Becerra et al., 2013; Kalkbrenner et al., 2015; Raz et al., 2015; Talbott et al., 2015; Volk et al., 2013; Weisskopf et al., 2015). Raz et al. (2015) used models of predicted ambient PM₁₀ and PM_2.5 levels from 1988 to 2007 to estimate maternal exposures pre-, during, and 9 months after pregnancy to identify women who

had children diagnosed with autism, finding an increased risk of autism in offspring who had higher PM_2.5 prenatal exposure, particularly during the third trimester. Associations between traffic pollution around schools and direct measures of brain maturation measured with magnetic resonance imaging have also been reported in children aged 8–12 years (Pujol et al., 2016). Air pollution exposure was associated with brain changes of a functional nature, with no evident effect on brain anatomy, structure, or membrane metabolites.

Trombley (2023) published a review of 17 papers to examine the relationship between ambient PM_2.5 exposure and mental health outcomes (emergent and general psychiatric outcomes, neurodevelopmental disorders, stress and anxiety and depression) in children and adolescents. The author reported that there was evidence supporting a possible correlation between ambient PM_2.5 exposure and adolescent mental health outcome but that the data were not consistent and that more research is needed.

Indoor Exposure to PM_2.5 and Neurological Effects

There is a scarcity of population-based studies of indoor air pollution and neurological health effects in adults. A study of 628 households in the United Arab Emirates examined a number of indoor air pollutants, including particulate matter, collecting health information from household members using in-person interviews (Yeatts et al., 2012). Significant associations were reported for health symptoms and pollutants such as SO₂, NO₂, and H₂S, but not for PM_2.5 specifically. Burning incense daily was associated with an increased likelihood of headaches, difficulty concentrating, and forgetfulness. Cedeño Laurent et al. (2021) reported on declines in neurobehavioral performance in office workers in six countries. They found that higher indoor PM_2.5 levels were associated with slower response times and reduced accuracy and that the association was evident only at levels above 12 µg/m³.

While there is a scarcity of studies reporting associations between indoor air quality and health impacts, studies of neurobehavioral performance in children do exist. Vrijheid et al. (2012) studied the association of gas cooking during pregnancy with infant neurodevelopment in a prospective birth cohort study in Spain. Neurodevelopment was measured at age 11–22 months using the Bayley Scales of Infant Development. Gas cookers, present in 44 percent of homes, were related to a small decrease in the mental development score compared with the use of other cookers. The negative association with gas cooking was relatively consistent across strata defined by social class, education, and other covariates. A similar study was conducted in Sri Lanka assessing indoor air pollution and neurodevelopmental measures at 1.5 and 3.0 years. Two-hour area measures of particulate matter in the home were obtained. They found children in wood-burning households had lower cognitive and motor scores. Unit increases in log-transformed indoor PM_2.5 were significantly associated with decrements in cognitive function, suggesting potential a neurotoxic impact on child’s cognitive scores with the impact continuing through early childhood (Sathiakumar et al., 2019).

The association between indoor air quality in schools and learning outcomes among children has been an area of concern. At the population level, the question has been asked if green schools influence the overall academic performance of the children in those schools (Vakalis et al., 2021). More than 2,000 schools in the U.S. are LEED-certified but have not been evaluated comprehensively for their effect on school performance. A review by Vakalis et al. (2021) synthesized the literature in this area and reported that the building components of LEED certification are associated with positive learning outcomes and improved indoor air quality and acoustic performance appear to have the most effect. This review did not however establish an

association between LEED certification and reduction in indoor fine PM. This comprehensive review points to the difficulties in associating specific learning outcomes with the variety of components associated with green buildings, including indoor air quality but also noise, thermal conditions, ambient air pollution and siting of the school, lighting, and other factors. In general, the study design, the academic outcomes measured, and the different LEED components vary greatly in the investigations, but in general green schools are associated with better performance. While these findings are not surprising, there is a need for prospective studies of the health impacts of replacing old structures with renovated or new buildings and the subsequent impact on student learning.

Saenen et al. (2016) measured attention, short-term memory, and visual information processing speed in 310 school age children and monitored PM_2.5 and PM₁₀ exposure with portable monitors both in schools and the child’s residence on the same day or up to 2 days before the examination (for recent exposure) and 365 days before the examination (for chronic exposure). They reported that increasing classroom PM_2.5 exposure was associated with declining performance on two neurobehavioral tests. Other neurobehavioral changes were observed in relation to recent residential outdoor PM_2.5 exposure and chronic exposure at the residence. Sunyer et al. (2015), conducted a prospective study of 2,715 school aged children in Spain exposed to varying levels of air pollution in close proximity to their schools. Children were tested four times over a year, and air pollution, including ultrafine particle number concentration, was measured twice both outside and inside the classroom. Cognitive development was assessed with neurobehavioral tests, and linear mixed effects models were adjusted for age, sex, maternal education, socioeconomic status, and air pollution exposure at home. Children from highly polluted schools had a smaller growth in cognitive development than children from the paired lowly polluted schools, both in crude and adjusted models. Children attending schools with higher levels of ultrafine particles both indoors and outdoors experienced substantially smaller growth in all the cognitive measurements. These associations remained when controlled for type of school, educational quality, commuting, and smoking at home.

An association between indoor air pollution exposure during pregnancy and autistic-like behavior in offspring has also been reported. Yang et al. (2022) analyzed data from the Longhua Child Cohort Study in China which enrolled 65,317 preschool children. Associations between maternal exposure to four sources of indoor air pollution (e.g., cooking, environmental tobacco smoke, mosquito coils, and home decoration) during pregnancy, and preschool children’s autistic traits were analyzed using multivariate logistic regression. The study found that maternal exposure to indoor air pollution from four different sources during pregnancy was associated with the presence of children’s autistic-like behaviors, with a suggested dose–response relationship and additive interactions.

REPRODUCTIVE OUTCOMES

In the past two decades, a number of studies have examined the association of exposure to particulate matter and adverse reproductive outcomes (Ghazi et al., 2021; Jo et al., 2020; Saenen et al., 2019). The possible biological mechanism is the impact of fine particulate matter on pulmonary and placental inflammation during pregnancy, subsequently affecting gas and nutrition exchange and reducing the level of oxygen available to the fetus. The large majority of reports have focused on ambient pollution, and in more recent years there have been reports of exposure to particulate matter from wildfires and reproductive effects. There has been to date a

scarcity of reports that look specifically at indoor particulate matter exposure and reproductive outcomes.

Outdoor Air Pollution and Reproductive Outcomes

The association between outdoor air pollution and pregnancy outcomes provides some evidence of a potential link between indoor air pollution and these outcomes, though the evidence is not as robust as that found for cardiovascular and respiratory outcomes. Li et al. (2017) published a systematic review and meta-analysis of the association between ambient fine particulate matter and preterm birth or term low birth weight. In a review of studies published prior to July 2016, they found a significantly increased risk of preterm birth with an interquartile increase in ambient PM_2.5 concentrations throughout pregnancy (odds ratio [OR] = 1.03; CI = 1.01–1.05) but stressed the need for prospective cohort studies and personal exposure measurements to better characterize the observed relationship. An ongoing prospective cohort study of pregnancy, MADRES, suggested that there appears to be critical windows of exposure to ambient air pollution and effects on in utero fetal growth (Peterson et al., 2022). Participants had daily ambient air pollutant concentrations measured including PM_2.5. A significant sensitive window of susceptibility during the gestational weeks 4–16 was associated with PM_2.5 and fetal weight. Weeks 1–23 exposure to PM_2.5 was also associated with smaller fetal abdominal circumference, suggesting that exposure to particulate matter in early to mid-pregnancy, but not preconception or late pregnancy, may have critical implications on fetal growth.

In a review of ambient air pollution and pregnancy outcomes, Klepac et al. (2018) identified several environmental public health challenges inherent in current investigations, noting that inconsistent findings have been reported, perhaps due to the different outcomes studied, the observed gestational windows of exposure, exposure assessment methods, and statistical methods. In their review of 96 studies, they reported that particulate matter and ozone over the entire pregnancy were significantly associated with a higher risk for preterm birth and that most studies have been retrospective, linking routine ambient air monitoring and birth records data. Their meta-analysis of the pooled effect estimates of the 28 studies reviewed indicated that exposure to particulate matter in entire pregnancy was significantly associated with a higher risk for preterm birth (1.09; CI = 1.3–1.16) for PM₁₀ and 1.24 (CI = 1.08–1.41) for PM_2.5. More recent studies have been published that add additional evidence of a link between ambient PM_2.5 and pregnancy outcomes. Singleton births occurring in 2004 in metropolitan counties of Atlanta, Georgia, were compared to county-level daily air quality index controlling for potential pregnancy confounders (Zhu et al., 2019). County-level daily Air Quality Index (AQI) was used to estimate individual exposure levels of PM_2.5 for each study participant. A higher rate of preterm birth was observed in the offspring whose mothers were exposed to ambient PM_2.5 with an average air quality index values (AQI) greater than 50 during pregnancy compared with AQI less than 50. Mothers with exposure to ambient PM_2.5 greater than 50 during the entire pregnancy were at increased risk of preterm birth (OR = l.15; CI = 1.07–1.25).

Wildfire Exposure and Reproductive Outcomes

Recent studies of health outcomes from wildfire exposure are particularly relevant to the link of reproductive outcomes with indoor air exposure, given the propensity for wildfire smoke to encroach into the home environment. PM_2.5 is a major constituent of wildfire smoke and is hypothesized to be associated with harmful reproductive effects, including preterm birth.

Heft-Neal et al. (2022) investigated the link between preterm births in California from 2006 to 2012 and satellite-based estimates of wildfire plume boundaries and high-resolution gridded estimates of surface PM_2.5 concentrations. They reported that each additional day of exposure to any wildfire smoke during pregnancy was associated with an 0.49 percent (95% CI = 0.41–0.59%) increase in risk of preterm birth (<37 weeks). The increased risk suggested stronger associations with exposure later in pregnancy. Surprisingly, the health impact differed greatly by baseline smoke exposure, with mothers in regions with infrequent smoke exposure experiencing substantially larger impacts than mothers in regions where smoke is more common. Wildfire exposure and adverse pregnancy outcomes were also investigated by Abdo et al. (2019) using ground-based monitors and remote sensing data stratified by ZIP code. Exposure to wildfire smoke PM_2.5 over the full gestation and exposure during the second trimester were associated with pre-term birth (OR = 1.076; CI = 1.016–1.139). Exposure during the first trimester was associated with decreased birth rate (−5.7 g/(µg/m³)).

Amjad et al. (2021) conducted a review of eight published studies from four countries that included almost 2 million births. Exposure was determined by multiple methods, including measurement of PM_2.5, PM₁₀, ozone, and hot spots. Overall, the results of this review have little utility for PM_2.5 given the inclusion of multiple exposures associated with wildfires. An integrative review of 16 studies between 2012 and 2022 of wildfire exposure and birth outcomes has been published. Eleven studies reported an association between in utero exposure and impacts on birth weight and length of gestation. A small number of studies focused on gestational diabetes and gestational blood pressure, differences in sex ratio, birth defects, and mental health morbidity (Evans et al., 2022).

Indoor Exposure to PM_2.5 and Reproductive Outcomes

The committee’s review of indoor exposure to PM_2.5 and reproductive outcomes identified only one study, which was inconclusive. Shezi et al. (2022) reported on maternal exposure to indoor PM_2.5 and adverse birth outcomes in Durban, South Africa. They assessed several birth outcomes among 800 women, including birthweight, gestational age, low birth weight, and preterm delivery in this prospective study. The homes of 300 of the 800 pregnant people were monitored, with repeated sampling done in 30 homes. A predictive model was used to estimate PM_2.5 levels in unmeasured homes. The mean (SD) indoor PM_2.5 concentration was 37 (29) µg/m³. The exposures in the indoor environment were attributed to a combination of 168 variables assessed during walkthroughs such as type of house, wall, roof and floor, number of residents, smoking, cooking, cleaning and candle use, mold and dampness, heating and ventilation characteristics, presence of windows, and nearby outdoor pollution generating activities. The odds ratio of low birth weight and preterm delivery was 1.75 (95% CI = 1.47–2.09) and 1.21 (95% CI = 1.06–1.39), respectively, per interquartile increase (18 µg/m³) in indoor PM_2.5 exposure. Infant sex was found to be an effect modifier for both birthweight and gestational age.

DIABETES AND METABOLIC SYNDROME

Increasing attention has been directed to understanding how particulate matter inhaled by the lung induces effects in distant organs (Snow et al., 2018). The potential association between exposure to PM_2.5 and the metabolic syndrome is hypothesized to be linked to the

neuroendocrine sympathetic–adrenal–medullary and hypothalamic–pituitary–adrenal stress axes. Animal models are being used to examine the effects of the neuroendocrine system associated with air pollution components, suggesting that chronic exposure to physiological stressors associated with air pollution may lead to increases in allostatic load, or the cumulative burden of exposure to chronic stressors. To date the studies have focused on outdoor air pollution, and reviews point to compelling evidence of a link between metabolic syndrome and exposure to air pollution. In a systematic review and meta-analysis of the association between long-term ambient PM exposure and metabolic syndrome risk, Ning et al. (2021) found that an increase of 5 μg/m³ in annual average ambient PM_2.5 and PM₁₀ concentration was associated with, respectively, a 14 percent and 9 percent increase in metabolic syndrome risk, and they suggested that approximately 12 percent of metabolic syndrome risk could be attributable to ambient PM_2.5 exposure.

Zheng et al. (2022) looked specifically at long-term exposure to PM_2.5 and the components of metabolic syndrome in over 6,000 adults and elderly in 14 districts in south China. They reported that a 10 μg/m³ increase in the 2-year mean PM_2.5 exposure was associated with a higher risk of developing metabolic syndrome, elevated blood glucose level, and hypertriglyceridemia. More recent studies have attempted to partition the effects of exposure to particulate matter and the effects associated with lifestyle factors on the risk of diabetes or metabolic syndrome. For example, Li et al. (2022) conducted an analysis of the interplay between physical activity and air pollution in a large population-based cohort. UK Biobank participants (n = 359,153) without diabetes at baseline were followed for approximately 9 years, and type 2 diabetes was associated with increasing level of ambient PM_2.5. As expected, physical activity was associated with the likelihood of developing type 2 diabetes. There was no effect modification of the associations between physical activity and diabetes by air pollution, indicating that the beneficial effects of physical activity on type 2 diabetes remained stable regardless of the air pollution exposure levels. While the evidence of the link between exposure to PM_2.5 in outdoor air pollution is growing, to date there have been no studies of the link between PM_2.5 in indoor environments and the risk of diabetes or metabolic syndrome.

CONCLUSIONS AND RECOMMENDATIONS

Conclusions

While the literature varies in scope and depth, overall the committee concludes that there is strong evidence that exposure to indoor PM_2.5 has adverse effects on the respiratory and cardiovascular systems and likely other organ systems. Specifically, the epidemiologic evidence points to consistent dose–response relationships between indoor PM_2.5 exposure and respiratory and cardiovascular outcomes, and this evidence combined with toxicologic evidence and bolstered by the vast outdoor PM_2.5 literature directly implicates indoor PM_2.5 as a cause of adverse respiratory and cardiovascular effects. Furthermore, evidence for a role of indoor PM_2.5 in neurologic, metabolic, and reproductive outcomes is less well developed but emerging. The absence of evidence should not be interpreted as indoor PM_2.5 not exerting adverse effects on other organ systems, and instead this gap in knowledge underscores the urgent need for more research. It can thus be concluded that reducing PM_2.5 exposure would have a significant public health benefit.

Compared with the evidence supporting the adverse health consequences of PM measured outdoors, there are fewer studies of health effects of PM measured indoors, and these have substantially smaller sample sizes. Indoor PM health studies are expensive and resource- and labor-intensive. Studies of outdoor PM often assign exposure from national air quality monitoring networks, sometimes adding granularity by spatiotemporal models, and link this to health claims data. These approaches take advantage of the investment that has been made in these data sources and allow studies that include larger sample sizes. This provides the ability to study relatively infrequent events, such as heart attacks and stroke, at the population level. The studies of indoor PM health effects have smaller sample sizes. This is expected, given the complexity of health studies of indoor PM, which require an assessment of exposures that are typically at the household, workplace, or individual level. These studies also require simultaneous evaluation of health outcomes. Given the smaller sample sizes and relatively short duration of follow-up of most studies, the health outcomes are usually ascertained at the individual level using questionnaires, physiologic measures, or biospecimens. As discussed in Chapter 5, recent advances in lower-cost air monitoring equipment have provided the opportunity to increase the scale of indoor PM studies. Studies are still relatively small and often lack statistical power to detect clinical events within a given individual, such as heart attacks or strokes.

Even though indoor PM studies are less common than outdoor PM investigations, outdoor air pollution studies are useful in understanding indoor health effects, because of the significant encroachment of outdoor pollution into indoor spaces, as described in Chapters 4 and 5. To date, studies of indoor PM_2.5 effects on less common health outcomes have been limited. Indoor studies are also limited in examining the relative importance of particular sources and composition and in identifying individual characteristics that confer susceptibility to indoor PM_2.5. Indeed, PM_2.5 mass concentration is a crude measure of airborne particles as it does not capture the multidimensional heterogeneity of fine particles, which includes attributes such as size, shape, composition, source (including particles of outdoor origin), and toxicity, as discussed in Chapter 5. Each of these attributes may influence where particles deposit, the dose of particles, and the biologic effects of the particles. Furthermore, certain characteristics may be more harmful to some people than others, depending on the nature of the particle characteristic and the susceptibility of the person to that characteristic (i.e., allergen containing particle). There is also a limited understanding of two other important topics: the contribution of inequities in indoor PM exposure (in terms of concentration as well as other particle characteristics) to health disparities and susceptible populations, and the health effects of PM_2.5 exposure at school, where a susceptible population (children) spend a significant amount of time. These knowledge gaps are important to address as they have direct implications for practical approaches to mitigating adverse health effects, including health disparities, of indoor PM, the subject of Chapter 7.

Recommendations

The recommendations offered by the committee are directly informed by the knowledge gaps described above. They are directed both to indoor air and particulate matter researchers and to EPA and other funders of such research.

The indoor environment research community should use emerging consumer-grade sensors and statistical modeling to estimate indoor and personal PM exposure at a larger scale to facilitate the conduct of large-scale population-based epidemiologic studies. Such studies are critical to advancing the understanding of (1) the effects of indoor PM on less

common health outcomes and on health disparities; (2) the effects of particle characteristics—beyond mass concentration and including composition, size, shape, and sources—on health; (3) individual and population characteristics that confer susceptibility to indoor PM exposure or to certain “types” of indoor PM; and (4) the relative contribution of particles of indoor and outdoor origin to the health effects of PM exposure.

Relatedly, the indoor environment research community should take better advantage of observational field studies that directly evaluate the effects of reducing PM_2.5 exposure on health. Studies conducted under controlled circumstances offer great advantages to researchers in terms of time, effort, and the ability to manage the myriad potential influences on outcomes, but they yield an incomplete answer to what is perhaps the most salient issue for policy makers: does this resolve what happens in the real world? Advances in technology now permit investigators to gather information at a scale and with a degree of accuracy that was unthinkable only a few years ago. These advances need to be exploited, along with improved measurements to ascertain building and behavioral differences between settings that can affect the effectiveness of interventions.

The indoor environment research community should explicitly incorporate social science and behavioral health science perspectives and expertise in studies of the health impacts of indoor PM_2.5 to better understand how social, cultural, and behavioral factors may influence PM_2.5 exposure and health effects and the implementation of practical mitigation strategies. As this report makes clear, there are systematic differences in exposure to indoor PM and in susceptibility to adverse effects of that exposure that result in disparate health outcome risks for different populations. The research in this area is still relatively sparse, however, and much more needs to be done in order to formulate effective interventions. One straightforward way to address this gap would be to make consideration of social, cultural, and behavioral factors a standard element of studies by including people with such expertise in research teams.

EPA, in collaboration with other governmental entities and private funders, should incentivize schools to partner with the scientific community to conduct school-based prospective cohort studies. There is a glaring need for research that examines the indoor environment where children, adolescents, and young adults spend considerable amounts of their time. Such work will help advance the currently inadequate understanding of the sources and other attributes of school exposure to PM_2.5; its effects on health, learning, and school performance effects; and inequities in that exposure. The work will also help inform practical mitigation targets in school settings.

EPA, in collaboration with other governmental entities and private funders, should prioritize the funding of studies designed to characterize differences in indoor PM_2.5 exposure—including differences in PM_2.5 characteristics—in home and school settings across communities and their contribution to health disparities. As already noted, significant disparities exist in PM_2.5 exposures and exposure impacts. It will not be possible to identify and to formulate practical mitigation strategies for disproportionately affected populations until there is a clear understanding of who is affected by them and how their circumstances shape the determination of effective interventions.

The indoor air research community should support the conduct of studies that evaluate the full impact of policies on PM_2.5 exposure and health, including cost–benefit analyses that incorporate an estimate of the economic and public health costs of not implementing interventions. Governments must balance competing priorities when making

policy determinations. Understanding the costs associated with inaction will allow for better informed decisions on the need for interventions regarding indoor PM_2.5 exposure and mitigation.

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