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Event: 1250

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Decrease, Lung function

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Decrease, Lung function

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
respiratory function trait decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
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

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
Adult High

Sex Applicability

No help message More help
Term Evidence
Mixed High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

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

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

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

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

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.

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. For KEs that are designated as an AO, one additional field of information (regulatory significance of the AO) should be completed, to the extent feasible. If the KE is being described is not an AO, simply indicate “not an AO” in this section.A key criterion for defining an AO is its relevance for regulatory decision-making (i.e., it corresponds to an accepted protection goal or common apical endpoint in an established regulatory guideline study). For example, in humans this may constitute increased risk of disease-related pathology in a particular organ or organ system in an individual or in either the entire or a specified subset of the population. In wildlife, this will most often be an outcome of demographic significance that has meaning in terms of estimates of population sustainability. Given this consideration, in addition to describing the biological state associated with the AO, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to describe regulatory examples using this AO. More help

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).

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Bates, J.H.T. (2017). CORP: Measurement of lung function in small animals. Journal of Applied Physiology. 123, 1039-1046.

Baumgartner, K.B., Samet, J.M., Coultas, D.B., Stidley, C.A., Hunt, W.C., Colby, T.V., and J.A. Waldron (2000). Occupational and environmental risk factors for idiopathic pulmonary fibrosis: a multicenter case-control study. Collaborating Centers. American Journal of Epidemiology 152, 307-315.

Celli, B. R. (2010). Predictors of mortality in COPD. Respiratory Medicine 104, 773-779.

Cheresh, P., Kim, S.J., Tulasiram, S., and D.W. Kamp (2013). Oxidative stress and pulmonary fibrosis. Biochimica et Biophysica Acta, 1832, 1028–1040.

Cosgrove, M.P. (2015). Pulmonary fibrosis and exposure to steel welding fume. Occupational Medicine (Lond) 65, 706-712.

Criée, C.P., Sorichter, S., Smith, H.J., Kardos, P., Merget, R., Heise, D., Berdel, D., Köhler, D., Magnussen, H., Marek, W. and H. Mitfessel (2011). Body plethysmography–its principles and clinical use. Respiratory medicine 105, 959-971.

Dalbey, W., Henry, M., Holmberg, R., Moneyhun, J., Schmoyer, R. and S. Lock (1987). Role of exposure parameters in toxicity of aerosolized diesel fuel in the rat. Journal of Applied Toxicology 7; 265-275.

Dias, O.M., Baldi, B.G., Costa, A.N., C.R. Carvalho (2014). Combined pulmonary fibrosis and emphysema: an increasingly recognized condition. Jornal Brasileiro de Pneumologia 40, 304-312. 

Fallica, J., Das, S., Horton, M., and W. Mitzner (2011). Application of carbon monoxide diffusing capacity in the mouse lung. Journal of Applied Physiology 110, 1455–1459.

Gorguner, M., and M. Akgun (2010). Acute inhalation injury. The Eurasian Journal of Medicine 42, 28–35.

Graham, B.L., Brusasco, V., Burgos, F., Cooper, B.G., Jensen, R., Kendrick, A., MacIntyre, N.R., Thompson, B.R. and J. Wanger (2017). 2017 ERS/ATS standards for single-breath carbon monoxide uptake in the lung. European Respiratory Journal 49, 1600016.

Graham, B.L., Steenbruggen, I., Miller, M.R., Barjaktarevic, I.Z., Cooper, B.G., Hall, G.L., Hallstrand, T.S., Kaminsky, D.A., McCarthy, K., McCormack, M.C. and C.E. Oropez (2019). Standardization of spirometry 2019 update. An official American Thoracic Society and European Respiratory Society technical statement. American Journal of Respiratory and Critical Care Medicine 200, e70-e88.

Harvey, B.G., Strulovici-Barel, Y., Kaner, R.J., Sanders, A., Vincent, T.L., Mezey, J.G. and R.G. Crystal (2016). Progression to COPD in smokers with normal spirometry/low DLCO using different methods to determine normal levels. European Respiratory Journal 47, 1888-1889.

Hert, R. and R.K. Albert (1994). Sequelae of the adult respiratory distress syndrome. Thorax 49, 8-13.

Hoymann, H.G. (2012). Lung function measurements in rodents in safety pharmacology studies. Frontiers in Pharmacology 3, 156.

Johnson, J. D., and W. M. Theurer (2014). A stepwise approach to the interpretation of pulmonary function tests. American Family Physician 89, 359-366.

 Kandhare, A.D., Mukherjee, A., Ghosh, P. and S.L. Bodhankar (2016). Efficacy of antioxidant in idiopathic pulmonary fibrosis: A systematic review and meta-analysis. EXCLI Journal 15, 636.

Lee, H. M., Liu, M. A., Barrett-Connor, E., and N. D. Wong (2014). Association of Lung Function with Coronary Heart Disease and Cardiovascular Disease Outcomes in Elderly: The Rancho Bernardo Study. Respiratory Medicine 108, 1779–1785.

Lettieri, C.J., Nathan, S.D., Barnett, S.D., Ahmad, S. and A.F. Shorr (2006). Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest 129, 746-752.

Limjunyawong, N., Fallica, J., Ramakrishnan, A., Datta, K., Gabrielson, M., Horton, M., and W. Mitzner (2015). Phenotyping mouse pulmonary function in vivo with the lung diffusing capacity. Journal of visualized experiments: JoVE 95, e52216.

Matheson, M.C., Raven, J., Johns, D.P., Abramson, M.J. and E.H. Walters (2007). Associations between reduced diffusing capacity and airflow obstruction in community-based subjects. Respiratory Medicine 101, 1730-1737.

Matthay, M.A., Zemans, R.L., Zimmerman, G.A., Arabi, Y.M., Beitler, J.R., Mercat, A., Herridge, M., Randolph, A.G. and C.S. Calfee (2019). Acute respiratory distress syndrome. Nature Reviews Disease Primers 5, 1-22.

McGovern, T.K., Robichaud, A., Fereydoonzad, L., Schuessler, T.F., and J.G. Martin (2013) Evaluation of respiratory system mechanics in mice using the forced oscillation technique. Journal of Visualized Experiments 75, e50172.

Meltzer, E.B., and P.W. Noble (2008). Idiopathic pulmonary fibrosis. Orphanet Journal of Rare Diseases, 3, 8.

Miller, K. and A. Chang (2003). Acute inhalation injury. Emergency Medicine Clinics of North America 21, 533-557.

Miller, M.R., Crapo, R., Hankinson, J., Brusasco, V., Burgos, F., Casaburi, R., Coates, A., Enright, P., van der Grinten, C.M., and P. Gustafsson (2005a). General considerations for lung function testing. European Respiratory Journal 26, 153-161.

Miller, M.R., Hankinson, J., Brusasco, V., Burgos, F., Casaburi, R., Coates, A., Crapo, R., Enright, P., van der Grinten, C., and P. Gustafsson (2005b). Standardisation of spirometry. European Respiratory Journal 26, 319-338.

Moore, V.C. (2012). Spirometry: step by step. Breathe 8, 232-240.

OECD (2018a). OECD Guidance Document on Inhalation Toxicity Studies, GD 39.

OECD (2018b), Test No. 412: Subacute Inhalation Toxicity: 28-Day Study, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris, https://doi.org/10.1787/9789264070783-en.

OECD (2018), Test No. 413: Subchronic Inhalation Toxicity: 90-day Study, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris, https://doi.org/10.1787/9789264070806-en.

Park, Y., Ahn, C., and T.H. Kim (2021) Occupational and environmental risk factors of idiopathic pulmonary fibrosis: a systematic review and meta-analyses. Scientific Reports 11, 4318.

Prada-Dacasa, P., Urpi, A., Sánchez-Benito, L., Bianchi, P., A. Quintana (2020). Measuring Breathing Patterns in Mice Using Whole-body Plethysmography. Biological Protocols 10, e3741.

Pellegrino, R., Viegi, G., Brusasco, V., Crapo, R., Burgos, F., Casaburi, R., Coates, A., van der Grinten, C., Gustafsson, P., and J. Hankinson (2005). Interpretative strategies for lung function tests. European Respiratory Journal 26, 948-968.

Raghu, G., Remy-Jardin, M., Myers, J.L., Richeldi, L., Ryerson, C.J., Lederer, D.J., Behr, J., Cottin, V., Danoff, S.K., Morell, F., and K.R. Flaherty (2018). Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. American Journal of Respiratory and Critical Care Medicine 198, e44-e68.

Reilly, J.P., Zhao, Z., Shashaty, M.G., Koyama, T., Christie, J.D., Lanken, P.N., Wang, C., Balmes, J.R., Matthay, M.A., Calfee, C.S. and L.B. Ware (2019). Low to moderate air pollutant exposure and acute respiratory distress syndrome after severe trauma. American Journal of Respiratory and Critical,Care Medicine 199, 62-70.

Reinhard. C., Eder, G., Fuchs, H., Ziesenis, A., Heyder, J. and H. Schulz H (2002). Inbred strain variation in lung function. Mammalian Genome 13, 429-437.

Seeger, W., Adir, Y., Barberà, J.A., Champion, H., Coghlan, J.G., Cottin, V., De Marco, T., Galiè, N., Ghio, S., Gibbs, S. and F.J. Martinez (2013). Pulmonary hypertension in chronic lung diseases. Journal of the American College of Cardiology 62 Suppl. 25, D109-D116.

Sin, D. D., Wu, L., and S. P. Man (2005). The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. Chest 127, 1952-1959.

Takezawa, J., Miller, F.J. and J.J. O'Neil (1980). Single-breath diffusing capacity and lung volumes in small laboratory mammals. Journal of Applied Physiology 48, 1052-1059.

Trethewey, S. P., and G. I. Walters (2018). The Role of Occupational and Environmental Exposures in the Pathogenesis of Idiopathic Pulmonary Fibrosis: A Narrative Literature Review. Medicina (Kaunas, Lithuania) 54, 108.

Vestbo, J., Anderson, W., Coxson, H.O., Crim, C., Dawber, F., Edwards, L., Hagan, G., Knobil, K., Lomas, D.A., MacNee, W. and E.K. Silverman (2008). Evaluation of COPD longitudinally to identify predictive surrogate end-points (ECLIPSE). Eur Respir J 31, 869-73.

Wanger, J., Clausen, J.L., Coates, A., Pedersen, O.F., Brusasco, V., Burgos, F., Casaburi, R., Crapo, R., Enright, P., Van Der Grinten, C.P.M. and P. Gustafsson (2005). Standardisation of the measurement of lung volumes. European respiratory journal 26, 511-522.

Weinstock, T, and J. McCannon (2017). Pulmonary Medicine. Pulmonary Function Testing. https://www.pulmonologyadvisor.com/home/decision-support-in-medicine/pulmonary-medicine/pulmonary-function-testing/ (accessed 22 March 2021). Decision Support in Medicine, LLC.

Wise, R. A. (2006). The value of forced expiratory volume in 1 second decline in the assessment of chronic obstructive pulmonary disease progression. American Journal of Medicine 119, 4-11.