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Key Event Title
Decrease, Lung function
Key Event Components
|respiratory function trait||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Decreased lung function||AdverseOutcome||Karsta Luettich (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Lung surfactant function inhibition leading to decreased lung function||AdverseOutcome||Jorid Birkelund Sørli (send email)||Open for comment. Do not cite||Under Development|
|Oxidative stress [MIE] Leading to Decreased Lung Function [AO]||AdverseOutcome||Karsta Luettich (send email)||Open for comment. Do not cite|
|AHR activation decreasing lung function via AHR-ARNT tox path||KeyEvent||Dianke Yu (send email)||Under development: Not open for comment. Do not cite|
|AHR activation decreasing lung function via P53 tox path||AdverseOutcome||Dianke Yu (send email)||Under development: Not open for comment. Do not cite|
Key Event Description
Lung function is a clinical term referring to the physiological functioning of the lungs, most often in association with the tests used to assess it. Lung function loss can be caused by acute or chronic exposure to airborne toxicants or by an intrinsic disease of the respiratory system.
Although signs of cellular injury are typically exhibited first in the nose and larynx, alveolar-capillary barrier breakdown may ultimately arise and result in local edema (Miller and Chang, 2003). Clinically, bronchoconstriction and hypoxia are seen in the acute phase, with affected subjects exhibiting shortness of breath (dyspnea) and low blood oxygen saturation, and with reduced lung function indices of airflow, lung volume and gas exchange (Hert and Albert, 1994; and How it is Measured or Detected;). When alveolar damage is extensive, the reduced lung function can develop into acute respiratory distress syndrome (ARDS). This severe compromise of lung function is reflected by decreased gas exchange indices (PaO2/FIO2 ≤200 mmHg, due to hypoxemia and impaired excretion of carbon dioxide), increased pulmonary dead space and decreased respiratory compliance (Matthay et al., 2019). Acute inhalation exposures to chemical irritants such as ammonia, hydrogen chloride, nitrogen oxides and ozone typically cause local edema that manifests as dyspnea and hypoxia. In cases where a breakdown of the alveolar capillary function ensues, ARDS develops. ARDS has a particularly high risk of mortality, estimated to be 30-40% (Gorguner and Akgun, 2010; Matthay et al., 2018; Reilly et al., 2019).
Lung function decrease due to reduction in lung volume is seen in pulmonary fibrosis, which can be linked to chronic exposures to e.g. silica, asbestos, metals, agricultural and animal dusts (Meltzer and Noble, 2008; Cheresh et al., 2013; Cosgrove, 2015; Trethewey and Walters, 2018). Additionally. decreased lung function occurs in pleural disease, chest wall and neuromuscular disorders, because of obesity and following pneumectomy (Moore, 2012). Decreased lung function can also be a result of narrowing of the airways by inflammation and mucus plugging resulting in airflow limitation. Decreased lung function is a feature of obstructive pulmonary diseases (e.g. asthma, COPD) and linked to a multitude of causes, including chronic exposure to cigarette smoke, dust, metals, organic solvents, asbestos, pathogens or genetic factors.
How It Is Measured or Detected
Pulmonary function tests are a group of tests that evaluate several parameters indicative of lung size, air flow and gas exchange. Decreased lung function can manifest in different ways, and individual circumstances, including potential exposure scenarios, determine which test is used. The section outlines the tests used to evaluate lung function in humans (https://www.nhlbi.nih.gov/health-topics/pulmonary-function-tests, accessed 22 March 2021) and in experimental animals.
Lung function tests used to evaluate human lung function
The most common (“gold standard”) lung function test in human subjects is spirometry. Spirometry results are primarily used for diagnostic purposes, e.g. to discriminate between obstructive and restrictive lung diseases, and for determining the degree of lung function impairment. Specific criteria for spirometry tests have been outlined in the American Thoracic Society (ATS) and the European Respiratory Society (ERS) Task Force guidelines (Graham et al., 2019). These guidelines consist of detailed recommendations for the preparation and conduct of the test, instruction of the person tested, as well as indications and contraindications, and are complemented by additional guidance documents on how to interpret and report the test results (Pellegrino et al., 2005; Culver et al., 2017).
Spirometry measures several different parameters during forceful exhalation, including:
- Forced expiratory volume in 1 s (FEV1), the maximum volume of air that can forcibly be exhaled during the first second following maximal inhalation
- Forced vital capacity (FVC), the maximum volume of air that can forcibly be exhaled following maximal inhalation
- Vital capacity (VC), the maximum volume of air that can be exhaled when exhaling as fast as possible
- FEV1/FVC ratio
- Peak expiratory flow (PEF), the maximal flow that can be exhaled when exhaling at a steady rate
- Forced expiratory flow, also known as mid-expiratory flow; the rates at 25%, 50% and 75% FVC are given
- Inspiratory vital capacity (IVC), the maximum volume of air that can be inhaled after a full expiration
A reduced FEV1, with normal or reduced VC, normal or reduced FVC, and a reduced FEV1/FVC ratio are indices of airflow limitation, i.e., airway obstruction as seen in COPD (Moore, 2012). In contrast, airway restriction is demonstrated by a reduction in FVC, normal or increased FEV1/FVC ratio, a normal spirometry trace and potentially a high PEF (Moore, 2012).
Lung capacity or lung volumes can be measured using one of three basic techniques: 1) plethysmography, 2) nitrogen washout, or 3) helium dilution. Plethysmography consists of a series of sequential measurements in a body plethysmograph, starting with the measurement of functional residual capacity (FRC), the volume of gas present in the lung at end-expiration during tidal breathing. Once the FRC is known, expiratory reserve volume (ERV; the volume of gas that can be maximally exhaled from the end-expiratory level during tidal breathing, i.e., the FRC), vital capacity (VC; the volume change at the mouth between the positions of full inspiration and complete expiration), and inspiratory capacity (IC; the maximum volume of air that can be inhaled from FRC) are determined, and total lung capacity (TLC; the volume of gas in the lungs after maximal inspiration, or the sum of all volume compartments) and residual volume (RV; the volume of gas remaining in the lung after maximal exhalation) are calculated (Weinstock and McCannon, 2017).
The other two techniques used to measure lung volumes—helium dilution and nitrogen washout—are based on the principle of conservation of mass: [initial gas concentration] x [initial volume of the system] = [final gas concentration] x [final volume of the system]. The nitrogen washout method is based on the fact that nitrogen is present in the air, at a relatively constant amount. The subject is given 100% oxygen to breathe, and the expired gas, which contains nitrogen in the lung at the beginning of the test, is collected. When no more nitrogen is noted in the expirate, the volume of air expired and the entire amount of nitrogen in that volume are measured, and the initial volume of the system (FRC) can be calculated. In the helium dilution method, a known volume and concentration of helium is inhaled by the subject. Helium, an inert gas that is not absorbed significantly from the lungs, is diluted in proportion to the lung volume to which it is added. The final concentration of helium is then measured and FRC calculated (Weinstock and McCannon, 2017).
Measurements of lung volumes in humans are technically more challenging than spirometry. However, they complement spirometry (which cannot determine lung volumes) and may be a preferred means of lung function assessment when subject compliance cannot be reasonably expected (e.g. in pediatric subjects) or where forced expiratory maneuvers are not possible (e.g. in patients with advanced pulmonary fibrosis). There are recommended standards for lung volume measurements and their interpretation in clinical practice, issued by the ATS/ERS Task Force (Wanger et al., 2005; Criée et al., 2011).
Finally, indices of gas exchange across the alveolar-capillary barrier are tested by diffusion capacity of carbon monoxide (DLCO) studies (also referred to as transfer capacity of carbon monoxide, TLCO). The principle of the test is the increased affinity of hemoglobin to preferentially bind carbon monoxide over oxygen (Weinstock and McCannon, 2017). Complementary to spirometry and lung volume measurements, DLCO provides information about the lung surface area available for gas diffusion. Therefore, it is sensitive to any structural changes affecting the alveoli, such as those accompanying emphysema, pulmonary fibrosis, pulmonary edema, and ARDS. Recommendations for the standardization of the test and its evaluation have been outlined by the ATS/ERS Task Force (Graham et al., 2017). An isolated reduction in DLCO with normal spirometry and in absence of anemia suggests an injury to the alveolar-capillary barrier, as for example seen in the presence of pulmonary emboli or in patients with pulmonary hypertension (Weinstock and McCannon, 2017; Lettieri et al., 2006; Seeger et al., 2013). Reduced DLCO together with airflow obstruction (i.e., reduced FEV1) indicates lung parenchymal damage and is commonly observed in smokers and in COPD patients (Matheson et al., 2007; Harvey et al., 2016), whereas reduced DLCO with airflow restriction is seen in patients with interstitial lung diseases (Dias et al., 2014; Kandhare et al., 2016).
Lung function tests used to evaluate experimental animal lung function
Because spirometry requires active participation and compliance of the subject, it is not commonly used in animal studies. However, specialized equipment such as the flexiVent system (SCIREQ®) are available for measuring FEV, FVC and PEF in anesthetized and tracheotomized small laboratory animals. Other techniques such as plethysmography or forced oscillation are increasingly preferred for lung function assessment in small laboratory animals (McGovern et al., 2013; Bates, 2017).
In small laboratory animals, plethysmography can be used to determine respiratory physiology parameters (minute volume, respiratory rate, time of pause and time of break), lung volume and airway resistance of conscious animals. Both whole body and head-out plethysmography can be applied, although there is a preference for the latter in the context of inhalation toxicity studies, because of its higher accuracy and reliability (OECD, 2018a; Hoymann, 2012).
Gas diffusion tests are not frequently performed in animals, because reproducible samplings of alveolar gas are difficult and technically challenging (Reinhard et al., 2002; Fallica et al., 2011). Modifications to the procedure employed in humans have, however, open possibilities to obtain a human-equivalent DLCO measure or the diffusion factor for carbon monoxide (DFCO)—a variable closely related to DLCO, which can inform on potential structural changes in the lungs that have an effect on gas exchange indices (Takezawa et al., 1980; Dalbey et al., 1987; Fallica et al., 2011; Limjunyawong et al., 2015).
Domain of Applicability
Pulmonary function tests reflect the physiological working of the lungs. Therefore, the AO is applicable to a variety of species, including (but not limited to) rodents, rabbits, pigs, cats, dogs, horses and humans, independent of life stage and gender.
Evidence for Perturbation by Stressor
Acute exposure of healthy young adult subjects (aged 19 to 35 years, non-smokers) to 0.06 ppm ozone for 6.6 h resulted in a 1.71 + 0.50% (mean + SEM) decrease in FEV1 and a 2.32 + 0.41% decrease in FVC compared with air exposure (Kim et al., 2011).
A US-based study found inverse associations between increasing lifetime exposure to ozone (estimated median: 36; interquartile range 29–45; range 19–64) and FEF75 and FEF25–75 in adolescents (aged 18–20 years) (Tager et al., 2005).
In a Dutch cross-sectional study in school children (aged 7–13 years), NOx exposure from industrial emissions per interquartile range of 7.43 μg/m3 had a significantly lower percent predicted peak expiratory flow (PEF) (-3.67%, 95%CI -6.93% to -0.42%). Children exposed to NOx (per interquartile range of 7.43 μg/m3) also had a significantly lower percent forced vital capacity (FVC) and percent predicted 1-s forced expiratory volume (FEV1) (− 2.73 95%CI -5.21 to -0.25) (Bergstra et al., 2018).
The European Study of Cohorts for Air Pollution Effects (ESCAPE), a meta-analysis of 5 cohort studies on the association of air pollution with lung function, found that a 10 μg/m3 increase in NO2 exposure was associated with lower levels of FEV1 (−14.0 mL, 95% CI −25.8 to −2.1) and FVC (−14.9 mL, 95% CI −28.7 to −1.1), and an increase of 20 μg/m3 in NOx exposure was associated with a lower level of FEV1, by −12.9 mL (95% CI −23.87 to −2.0) and of FVC, by −13.3 mL (95% CI −25.9 to −0.7) (Adam et al., 2015).
A smoking history of > 20 pack-years decreased pulmonary function including forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC, and forced expiratory flow at 25–75% (FEF25–75%) (Kuperman and Riker, 1973).
In the Framingham Heart Study, cigarette smoking showed an inverse association with FVC and FEV1% (Ashley et al., 1975).
In the international Seven Countries Study, there was a dose-effect relationship between pack-years and forced expiratory volume in 0.75 s (FEV0.75) in continuous smokers without chronic bronchitis (Pelkonen et al., 2006).
In 34 male subjects aged between 15–18 years who smoked FVC was lower than in an age-matched male group that did not smoke. The most common duration of cigarette smoking was 1–3 years (47%) and the maximal number of cigarettes smoked per day was less than or equal to 10 cigarette(s) per day (88%) (Tantisuwat and Thaveeratitham, 2014).
A dose–response relation was found between smoking and lower levels of FEV1/FVC and FEF25–75 in children between 10-18 years of age (Gold et al., 1996).
In a study of 147 asthmatics, FEV1%predicted was significantly lower in ex-smokers and current smokers compared with never-smokers (Broekema et al., 2009).
In a 6-year longitudinal study in Japanese-American men, FEV1 was lowest in current smokers (2702 mL) and in former smokers (2817 mL) at baseline. These 2 groups experienced a steeper annual decline in FEV1 (-34.4 and -22.8 mL/year, respectively, adjusted by height and age at baseline) compared with never-smokers (-20.3 mL/year) (Burchfiel et al., 1995).
Diesel engine exhaust
In a study of 733 adult females who had lived in the Tokyo metropolitan area for more than 3 years, the higher the level of air pollution, the more significantly the FEV1 was reduced (Sekine et al., 2004).
In a study in 29 healthy subjects, exposure to DE inside diesel-powered trains for 3 days was associated with reduced lung function (Andersen et al., 2019).
In workers who tested diesel engines in an assembly unit of a manufacturing plant, FEV1, FEV1/FVC, FEV25-75 and MEF were significantly reduced compared to non-exposed workers (Zhang et al., 2017).
A Taiwanese study in 1016 children between 6 and 15 years of age reported that lifetime exposure to to 25–85 μg/m3 PM10 were associated with lower FEV1, FVC, and FEF25-75 (Tsui et al., 2018).
The Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) found that an increase of 10 μg/m3 in annual mean concentration of PM10 was associated with 3.4% lower FVC and 1.6% lower FEV1 (Ackermann-Liebrich et al., 1997).
In the Health Survey for England, a 10 mg/m3 difference in PM10 across postcode sectors was associated with a lower FEV1 by 111 mL, independent of active and passive smoking, social class, region and month of testing (Forbes et al., 2009).
A 7 μg/m3 increase in five year means of PM10 (interquartile range) was associated with a 5.1% (95% CI: 2.5%–7.7%) decrease in FEV1, a 3.7% (95% CI: 1.8%–5.5%) decrease in FVC in the German SALIA study (Schikowski et al., 2005).
The ESCAPE project, a meta-analysis of 5 European cohorts/studies from 8 countries, reported that an increase of 10 μg/m3 in PM10 was associated with a lower level of FEV1 (−44.6 mL, 95% CI:−85.4– −3.8) and FVC (−59.0 mL, 95% CI: −112.3– −5.7) (Adam et al., 2015).
Regulatory Significance of the Adverse Outcome
Established regulatory guideline studies for inhalation toxicity focus on evident clinical signs of systemic toxicity, including death, or organ-specific toxicity following acute and (sub)chronic exposure respectively. In toxicological and safety pharmacological studies with airborne test items targeting the airways or the lungs as a whole, lung function is a relevant endpoint for the characterization of potential adverse events (OECD, 2018a; Hoymann, 2012). Hence, the AO “decreased lung function” is relevant for regulatory decision-making in the context of (sub)chronic exposure (OECD, 2018b; OECD, 2018c).
Regulatory relevance of the AO “decreased lung function” is evident when looking at the increased risk of diseases in humans following inhalation exposure, and because of its links to other comorbidities and mortality.
To aid diagnosis and monitoring of fibrosis, current recommendations include both the recording of potential environmental and occupational exposures as well as an assessment of lung function (Baumgartner et al., 2000). The latter typically confirms decreased lung function as demonstrated by a loss of lung volume. As the disease progresses, dyspnea and lung function worsen, and the prognosis is directly linked to the decline in FVC (Meltzer and Noble, 2008).
Chronic exposure to cigarette smoke and other combustion-derived particles results in the development of COPD. COPD is diagnosed on the basis of spirometry results as laid out in the ATS/ERS Task Force documents on the standardization of lung function tests and their interpretation (Pellegrino et al., 2005; Culver et al., 2017, Graham et al., 2019). Rapid rates of decline in the lung function parameter FEV1 are linked to higher risk of exacerbations, increased hospitalization and early death (Wise et al., 2006; Celli, 2010). Reduced FEV1 also poses a risk for serious cardiovascular events and mortality associated with cardiovascular disease (Sin et al., 2005; Lee et al., 2015).
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