LungDepo: modelling the regional particle deposition in the human lung via the Enalos Cloud platform

Abstract

This work presents the development of LungDepo, a freely accessible online web application hosted on the Enalos Cloud platform (https://enaloscloud.novamechanics.com/proplanet/lungdeposition or https://enaloscloud.novamechanics.com/insight/lungdeposition/), which enables users to simulate particle deposition in the human lung across the head airway, the tracheobronchial and the alveolar (pulmonary) regions based on the aerodynamic diameter of inhaled particles. The LungDepo web-based tool offers two modelling approaches: the International Commission on Radiological Protection (ICRP) model and the multiple path particle dosimetry (MPPD) model, to simulate regional particle deposition and assess inhalation toxicity risk. In addition to modeling the fractional regional particle deposition based on the two implemented models, LungDepo offers the computation of the regional deposited mass (mg) and the computation of the regional lung surface area covered by deposited particles (m²) providing statistical analyses of the relative contributions of coarse (2.5–10.0 micron), fine (<2.5 micron) and ultrafine (<0.1 micron) particles. The web-based tool includes predefined modelling scenarios for various particle-bound substances or co-pollutants such as polycylic aromatic hydrocarbons (PAHs) or per- and polyfluoroalkyl substances (PFAS) and micro-sized engineered materials, along with provision for the inclusion of user-defined particle size distributions. The integration of an application programming interface (API) and the development of an intuitive graphical user interface (GUI) facilitate data exchange and integration with external environmental and regulatory toxicity models by simplifying complex tasks and broadening the tool's applicability for diverse users in environmental research, monitoring, and regulatory activities.

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Environmental significance

Every human breath may expose individuals to a toxic cocktail of ultrafine particles and engineered nanomaterials that are silently deposited in the human lungs. In this study, LungDepo is introduced as a free-to-use web application that uses dosimetry models to quantify the deposition of airborne particles within the human respiratory tract. The tool provides statistical analyses of the contributions of coarse (2.5–10.0 μm), fine (<2.5 μm), and ultrafine (<0.1 μm) particles. Designed for non-programmers, LungDepo is accessible to a wide audience and can potentially support broader regulatory frameworks for assessing human inhalation toxicity and safeguarding public health.

1 Introduction

Air pollution results from the release of harmful substances into the atmosphere, originating from a variety of sources, including industrial emissions, vehicle exhaust, and natural events.^1–4 Air pollution is responsible for approximately 9–12 million deaths annually on a global scale.^5,6 The World Health Organization (WHO) identifies six principal air pollutants: particle pollution (particulate matter), ground-level ozone, carbon monoxide, sulfur oxides, nitrogen oxides, and lead.^5,7 These pollutants can be broadly categorized based on their physical state into gases (e.g., ozone, carbon monoxide, nitrogen oxides, sulfur oxides), volatile liquids (e.g., certain organic compounds contributing to ozone formation), and particulate matter (solid or liquid particles suspended in the air, such as fine dust, soot, and aerosols) (Fig. 1B). Among these, particulate matter (PM) has emerged as the most critical air/environmental pollutant, as it is associated with the highest mortality and morbidity rates due to a range of health issues, including cardiovascular and pulmonary diseases, arrhythmias, coughing, chest discomfort and dyspnea.^2,8–16 PM consists of aerosol particles suspended in the air that may be composed of either liquid or solid particulate matter.¹⁷ These particles may be formed in the atmosphere as a result of chemical reactions among various pollutants,⁵ or result from a range of both anthropogenic (road dust, waste-water treatment plants, landfills, construction sites, mining, office equipment, cooking etc.)^18–21 and natural sources (soil, plants, volcanoes, forest fires, sea spray etc.)^2,22 (Fig. 1A). Based on aerodynamic diameter, PM is categorized into three size fractions as coarse (PM₁₀, 2.5–10.0 μm),^5,23 fine (PM_2.5, <2.5 μm)²³ and ultrafine (PM_0.1, <0.1 μm)²⁴ (Fig. 1C). Fine and ultrafine particles are likely to enter the lower airways upon inhalation, causing detrimental respiratory health effects. Particles larger than 10 μm are mostly filtered by the nasal and upper respiratory tract^25,26 (Fig. 1D).

Fig. 1 (A) Key sources of air pollution from both anthropogenic and natural activities, (B) categorized into gases, volatile liquids, and particulate matter of (C) varying sizes, highlighting their penetration potential in the (D) human respiratory tract, distinguishing between the upper and lower respiratory tract.

Understanding the deposition of inhaled particulate matter in the different regions of the respiratory tract is crucial for evaluating, quantifying and predicting inhalation toxicity. The chemical composition of PM is primarily carbonaceous with contributions from inorganic ions (including sulphates, nitrates and metal oxides) and volatile and semi-volatile organic compounds such as polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and per- and polyfluoroalkyl substances (PFAS),^27–29 which can alter biological activity and contribute to carcinogenic, neurotoxic, and endocrine-disrupting effects.^30–34 Fine and ultrafine particles remain airborne longer, penetrate deeper into the lungs, and often carry highly reactive transition metals and oxidized organics, enhancing their toxicity.³⁵ Furthermore, microparticles or micro-sized engineered materials and their agglomerates with aerodynamic diameters between 0.1 and 100 μm such as zinc oxide (ZnO),^36,37 iron oxide (Fe₂O₃),³⁸ titanium dioxide (TiO₂),³⁹ aluminum oxide (Al₂O₃),⁴⁰ copper oxide (Cu₂O),⁴¹ cobalt oxide (Co₃O₄)⁴¹ and nickel hydroxide (Ni(OH)₂)⁴² may pose additional inhalation hazards due to their ability to penetrate deep into the respiratory tract. Engineered micro-sized materials are applied in various industrial and consumer products.³⁹ Consequently, it is crucial to evaluate the effects of inhalation exposure, particularly in terms of pulmonary toxicity, that may arise as a result of their very small dimensions.³⁹

From a morphological perspective, the human respiratory system consists of two distinct structural regions. The first consists of the extrathoracic airways, termed as the head airways (HA) consisting of the nose, mouth, pharynx and larynx. The second consists of the tracheobronchial (TB) airway trees and the alveolar (AL) regions⁴³ (Fig. 1D). Deposition in the HA and TB regions act as barriers to safeguard the AL region, which constitutes the air–blood barrier, from potential irritation or harmful particles.⁴⁴ In the AL region, where the airway walls lacks a mucus layer, deposited insoluble particles are effectively cleared by the alveolar macrophages.⁴³ However, soluble particles deposited in the AL region may dissolve and pass through the alveolar membranes, entering the systemic circulation.^43,45 Numerous factors affect the regional deposition of particles within the human lungs, primarily dependent on an individuals' pulmonary physiology such as breathing patterns and lung geometry.^46,47 Additionally, the physicochemical characteristics of inhaled particles, such as their size, size distribution, density, shape, charge, surface properties, hygroscopicity (ability to absorb moisture from the surrounding air) and the interactions between particles and pulmonary surfactant play a critical role.^35,48–50 Of these factors, the size of inhaled particles is considered as the key predominant factor affecting the fate and regional deposition of particles in the human lungs.⁵¹ Coarser size particles (PM₁₀) tend to lodge in the throat and/or the bronchi, whereas fine and ultrafine particles can travel deeper into the airways of the respiratory tract, reaching the alveoli, binding with proteins that support (opsonising) or hamper (disopsonising) recognition by macrophages and influence crossing of anatomical barriers, and penetrating into the bloodstream.^2,8,52

The experimental determination of particle deposition within the human respiratory tract poses significant challenges in both in vivo and in vitro studies. In vivo studies are ethically problematic, while in vitro models have significant limitations in accurately replicating realistic physiological conditions.⁵³ To overcome these limitations, particle dosimetry models have been extensively developed over the past decades to calculate the regional deposition patterns of inhaled aerosols.^54–56 It is still challenging however, to accurately measure and quantify analytically the deposition of particles in the respiratory tract due to the intricate interplay between the structural morphology of lungs (that differs between individuals) and the hydrodynamic flow field within the airways, which constantly undergoes dynamic changes.⁴⁴ According to Hofmann,⁵⁷ existing particle dosimetry models are categorized based on lung morphometry and mathematical modelling techniques into semi-empirical models,^58–60 one-dimensional cross-section or “trumpet” models,^61–64 mechanistic models,^65–70 and computational fluid and particle dynamics (CFPD)-based models.^71–75 Among the most widely used particle dosimetry models are two semi-empirical models that combine (first-principle) mechanistic frameworks with experimental (empirical) data:^57,58,76 the ICRP66 model developed by the International Committee of Radiological Protection (ICRP) in 1994 (ref. 58) (which has since been updated to ICRP130),⁵⁹ and the NCRP model developed by the National Council on Radiation Protection and Measurements (NCRP) in the USA, in 1997.⁶⁰ Additionally, mechanistic models such as the deterministic asymmetric branching model, also known as the multiple pathway particle dosimetry (MPPD) model, introduced in 2001,^77,78 and the stochastic asymmetric branching model, referred to as IDEAL (inhalation, deposition and exhalation of aerosols in the lung), developed between 1990 and 1992,^69,70,79 which derive deposition fractions directly from classical flow equations. The clearance mechanisms of particles are not discussed here, as they are beyond the scope of the present work.

The objective of this work is to introduce a publicly accessible web application, LungDepo, designed to facilitate users including policy-makers, public health professionals and risk assessors in employing the ICRP and MPPD models for the quantification of particle deposition within the three anatomical compartments of the human lungs: the head airways (HA), the tracheobronchial region (TB), and the alveolar region (AL). Designing and developing a web application in the context of inhalation toxicity is essential for providing accessible and efficient tools that can be utilized by a wide range of users without the need for advanced mathematical or programming skills. Well-designed graphical user interfaces (GUI) are crucial for enabling users with limited technical expertise to navigate and apply complex models for assessing inhalation risks. This accessibility promotes broader use of the models, enabling researchers, healthcare professionals, and policymakers to efficiently conduct evaluations and make informed decisions. Additionally, incorporating application programming interfaces (API) capabilities enhances the flexibility of the web application, allowing it to integrate with external datasets, automate processes, and support the implementation of customized workflows. This facilitates collaboration across different research domains and accelerates innovation in the design of safer materials and substances and evaluation of the potential impacts of mitigation measures to reduce exposures to particles. LungDepo is hosted on the Enalos Cloud platform facilitating its integration with other freely accessible web applications within the framework of nano-informatics, including several human health related models such as the integrated approach to testing and assessment (IATA) for lung exposure and toxicity.^80–82 The Enalos Cloud platform also offers access to several other models including NanoBioAccumulate,⁸³ which simulates nanomaterial uptake and elimination in aquatic and soil invertebrates; MicroPlasticFate,⁸⁴ which provides the dynamic and steady-state modeling of the environmental fate of micro- and nanoplastics across key environmental scales and compartments; and UANanoDock,⁸⁵ which predicts protein adsorption onto nanoparticles. Beyond nano-informatics, the Enalos Cloud platform also hosts web applications in cheminformatics,^86,87 and machine learning,^88,89 providing a versatile infrastructure for developing, deploying, and accessing predictive models in materials and life sciences.

The LungDepo web application presented in this study is specifically designed to offer a user-friendly GUI that supports the application of complex models for computing the mass deposition (of particles themselves or based on concentrations of adsorbed co-pollutants), the lung surface area covered by deposited particles and the relative contributions of inhaled particulates classified by their size (coarse, fine and ultrafine) in the various regions of the human lungs. As regulators and industry increasingly shift towards the implementation of safe and sustainable by design (SSbD) principles for the design of chemicals and materials, the LungDepo web application provides valuable insights into how new materials can be engineered to reduce harmful effects on human health as well as visualizing the impacts of altering the particle size distributions through specific emissions mitigation measures. Additionally, LungDepo features predefined scenario models to simulate the deposition of several airborne substances and micro-sized engineered materials in the human lungs depending on the breathing frequency and concentration of airborne particles.

2 Particle (aerosol) deposition models

2.1 ICRP model

The ICRP model, integrated within the LungDepo web application employs the simplified deposition equations proposed by Hinds in 1999.⁴⁴ These equations are applicable for the calculation of fractional deposition of particles in the size range from 0.001 to 100 μm. Several studies have employed the Hinds equations for the ICRP model to study the respiratory deposition of aerosols.^90,91

This model provides calculations for the deposition efficiency of inhaled particles across three distinct regions of the respiratory tract: the head airways (HA), the tracheobronchial region (TB), and the alveolar region (AR). The deposition efficiency of particles across these three distinct regions is calculated as follows:

where D_p,i (μm) is the aerodynamic diameter of the particle in each size fraction and IF_i is the inhalable fraction of all particles.

Fig. 2, presents the analytical calculation of the deposition efficiency (fraction) in the three regions of the human lung as a function of the aerodynamic particle size, ranging from 0.001 μm to 100 μm, using the simplified equations proposed by Hinds⁴⁴ for the ICRP model. The x-axis, which represents the aerodynamic diameter of particles, is displayed on a logarithmic scale. As shown in Fig. 2, the ICRP model suggests that particles with aerodynamic diameter of less than 10 μm are inhaled at nearly 100%. In contrast, particles larger than 10 μm in diameter exhibit a significantly reduced inhalable fraction, becoming lodged within the head airways of the human lung. Ultrafine particles with aerodynamic diameter of less than 0.1 μm (PM_0.1) exhibit significant deposition efficiencies, reaching up to 50% in the alveolar region and approximately 30% in the tracheobronchial regions.

Fig. 2 Deposition efficiency (fraction) computed based on the simplified equations proposed by Hinds⁴⁴ for the ICRP model, plotted against the aerodynamic particle diameter in the range 0.001–100 μm.

2.2 MPPD model

The MPPD model, integrated within the LungDepo web application, is specifically tailored to align with human symmetric lung geometry as proposed by Yeh and Schum.⁶⁵ This model is the recommended default human geometry by the U.S. Environmental Protection Agency (EPA).⁹² The functional residual capacity (FRC), the volume of air present in the lungs at the end of passive expiration in a 70 kg average-sized male, is set at 3300 mL, while the upper respiratory tract (URT) volume is designated at 50 mL. The inhalation pathway is specified as nasal, with inhaled particles considered to be spherical in shape, spanning a size range from 0.001 to 100 μm. The breathing parameters are defined as 12 breathes per minute, a tidal volume (the volume of gas inhaled and exhaled with each breath) of 625 mL, and an inspiratory fraction (inspiratory capacity/total lung capacity) of 0.5.

Fig. 3, presents the analytical calculation of the deposition efficiency (fraction) for particles deposited in the three regions of the human lungs using the MPPD model version 3.04, developed by Applied Research Associates Inc.^78,93 based on the conditions described in the previous paragraph. The analysis reveals three notable discrepancies between the outcomes of the ICRP model and the MPPD model. Firstly, the ICRP model estimates the AL deposition efficiency for ultrafine particles to be approximately 50%, whereas the MPPD model yields a lower estimate of approximately 30%. Secondly, regarding the deposition efficiency for ultrafine particles in the TB region, the MPPD model estimates the efficiency to be approximately 50%, contrasting with the ICRP model's lower estimate of around 30%. According to the ICRP model, the inhalation efficiency for particles with an aerodynamic diameter up to 100 μm declines to approximately 60%. In contrast, the MPPD model suggests that all particles within this diameter range (100%) continue to be inhaled.

Fig. 3 Deposition efficiency (fraction) computed using the MPPD model version 3.04, developed by Applied Research Associates Inc.,^78,93 plotted against the aerodynamic particle diameter in the range 0.001–100 μm.

2.3 Deposition mass flow rate

The total mass deposition rate, m_deposition (mg h⁻¹), is estimated by:where c_particles is the concentration of particles (mg m⁻³), V_particles is the human breathing rate (m³ h⁻¹), t_exposure is the exposure duration (measured in hours), f_i is the normalized probability density for particle size D_p,i (expressed as decimal fraction, i.e., 10% is represented as 0.1) and DE_i is the particle deposition efficiency calculated using either the ICRP or MPPD model.⁹⁴

2.4 Lung surface area on which particles are deposited

The LungDepo web application integrates the computation of the total surface area of the lung covered by deposited particles (measured in m²), to assess the extent of particle coverage across the HA, TB and AL regions.

The total deposited surface area of particles, A_deposition, is calculated as:

where N_i is the number of particles (deposited) in the specific region of the lung and A_i is the surface area (m²) for a given particle aerodynamic diameter, D_p,i, respectively.

The number N_i of particles deposited for a given particle aerodynamic diameter, D_p,i is given by:

where m_i is the mass for a given particle aerodynamic diameter (measured in mg), given by:where ρ is the density of the particles (g cm⁻³).

The surface area, A_i, assuming the particles are spherical, is given by:

A_i = π·D²_p,i (9)

3 The LungDepo web application

The LungDepo web application is designed with a user-centric approach and is developed utilizing the ZK framework – an open-source Ajax web application framework implemented in Java.⁹⁵ This web application is hosted on the Enalos Cloud platform (https://enaloscloud.novamechanics.com/proplanet/lungdeposition/ or https://enaloscloud.novamechanics.com/insight/lungdeposition/)⁹⁶ and is freely accessible to all users without cost or login requirements, as it is provided as freeware (free-to-use software with closed-source code).

Fig. 4 presents the graphical user interface (GUI) of the LungDepo web application. In this example, the chosen model is the ICRP, accompanied by a predefined scenario for the particle size distribution of PFAS in particulate matter collected from a coastal area, as reported in the study by Lin et al.⁹¹ Once the model and scenario related to particle size distribution are selected, two intuitive graphical plots are generated. The first plot represents the normalized probability density of the aerodynamic diameter size distribution of the particulate matter. The second plot shows the deposition efficiency, expressed as a fraction, across the relevant range of particle sizes. In the example shown, the concentration of exposure to particulate matter is set at 6.644 × 10⁻⁷ mg m⁻³, with a respiratory volume rate reflective of a female in a sitting position, set at 0.39 m³ h⁻¹. The exposure duration is defined as 3600 seconds. By selecting the ‘enable advanced options’ check box, the user can specify the density of particles, which is set to 1 g cm⁻³ in this example. Also, the user can define the total surface area of the HA, TB and AL regions, measured in m². Upon selecting the ‘calculate dose’ button, users can obtain the lung regional deposited doses of particles, measured in milligrams (mg) and as a percentage (%). Here, the percentage represents the fraction of the total deposited mass that occupies the surface area of a specific lung region relative to the total mass deposited across the entire lung. Additionally, users can retrieve the deposited dose of particles per regional lung surface area (mg m⁻²), the surface area (of the lung region) covered by deposited particles (m²) and the ratio of the surface area covered by deposited particles to the total regional lung area, expressed as percentage (%). The output also includes the relative contributions of particles classified by size in the three different regions of the human lung, measured in percentage. This classification includes coarse particles larger than 2.5 μm, fine particles less than 2.5 μm, and ultrafine particles smaller than 0.1 μm. Additionally, there is an option to download the results via the ‘Download Dose Data’ button.

Fig. 4 Display of the web interface of the LungDepo tool for a scenario in which the ICRP model is selected alongside a predefined particle size distribution. The results show the distribution of the different size fractions of the particles in the three regions of the lung.

The user may choose from a dropdown menu that includes the ICRP and MPPD models. Additionally, for the scenario pertaining to particle size distribution, users can select from a range of predefined examples representing various substances that may be constituents of particulate matter. These substances include⁹¹ perfluorobutanoic acid (PFBA),⁹¹ perfluorobutane sulfonate (PFBS),⁹¹ corn starch,⁹⁷ chitosan,⁹⁸ glycerol,⁹⁹ zinc oxide (ZnO),¹⁰⁰ acetic acid,¹⁰¹ silane-based¹⁰² and siloxane-based¹⁰³ substances, 2-octenylsuccinic anhydride,¹⁰⁴ sodium alginate,¹⁰⁵ alkyl ketene dimers (AKDs)¹⁰⁶ and polycyclic aromatic hydrocarbons (PAHs)¹⁰⁷ substances as reported in previous studies. Users have the option to upload a custom scenario as well pertaining to the size distribution of the substance of interest within particulate matter. Additionally, for the respiratory volume rate, users may choose from predefined scenarios established by the ICRP model, which takes into account gender as well as varying activity levels, such as sitting, light exercise, or heavy exercise.⁴³ To support broader applicability, LungDepo includes a step-by-step user guide, which is directly available within the web application interface, explaining how to upload a custom particle size distribution in .txt format and how to manually define all relevant input parameters, including particle concentration, respiratory volume rate, exposure duration, particle density, and lung region surface areas to ensure that users can apply easily LungDepo to a wide variety of compounds and exposure scenarios.

The LungDepo web application incorporates a representational state transfer (REST) application programming interface (API) that enhances both its functionality and usability. This is shown in Fig. 5. The functionality of the ‘POST’ and ‘GET’ requests for the endpoints https://enaloscloud.novamechanics.com/proplanet/apis/lungdeposition, https://enaloscloud.novamechanics.com/proplanet/apis/lungdeposition/scenario and https://enaloscloud.novamechanics.com/proplanet/apis/lungdeposition/respiratoryVolumeRate, respectively, were tested using Postman (see Fig. S1, S3 and S4†). The same tests were performed using Swagger. The API documentation is publicly accessible via the Swagger user interface (see Fig. 5) at https://enaloscloud.novamechanics.com/proplanet/swagger-ui/index.html#/ and the underlying specification at https://enaloscloud.novamechanics.com/proplanet/apis/swagger.json. Fig. S2† demonstrates the use of Swagger to perform a ‘/lungdeposition’ POST request, using the same input data as shown in Fig. S1† (which used Postman), confirming consistency of the output across tools. This testing ensured that the expected responses were returned for each request type. In section S2 of the ESI,† robustness tests for the ‘/lungdeposition’ POST query are presented by submitting extreme input scenarios. Specifically, two high-value and two low-value test cases were constructed using exaggerated concentrations, nanoparticle densities and tidal surface areas across the alveolar, tracheobronchial, and head airway regions, using both the ICRP and MPPD models implemented in LungDepo. All tests were performed using Postman and, in every case, the API successfully returned results, confirming the robustness and reliability of its implementation under a wide range of input conditions. A REST API allows the LungDepo web application to interact with external systems and services in a standardized way, facilitating the exchange of data between the application and other tools, databases, or platforms. This means that users can access the application's features programmatically, enabling integration with broader research ecosystems and allowing for automation of tasks, such as data input, analysis, and reporting. Additionally, the REST API provides scalability and flexibility, allowing different users – whether researchers, developers, or public health professionals – to customize their workflows by integrating the web application into their existing systems. For instance, researchers can automate the analysis of large-scale datasets to simulate particle deposition under various conditions or integrate LungDepo with other modeling tools to enhance the breadth of their inhalation toxicity studies.

Fig. 5 LungDepo is available through a REST API to enable programmatic access and integration with other models, tools and into an IATA for hazard and risk assessment.

Furthermore, a REST API facilitates collaboration by enabling multiple users to access the same application from different locations or systems, allowing for shared research efforts and cross-platform compatibility. This makes the application more adaptable to different research needs, supporting a wide range of use cases – from routine regulatory assessments to advanced scientific research in inhalation toxicology. By providing a flexible and interoperable interface, a REST API significantly expands the reach and impact of the LungDepo web application, helping users make more informed decisions in evaluating inhalation toxicity, evaluating the impact of exposure mitigation measures such as air filtration, and designing materials by application of the SSbD principles. Integrating the LungDepo web application into the Enalos Cloud Platform further enhances its capabilities by allowing users to access other web applications hosted on the same platform, including the integrated approach to testing and assessment (IATA) for lung exposure and toxicity.^80–83 This integration fosters a collaborative environment where different tools can be used together to provide comprehensive insights and support multifaceted research efforts.

4 Case studies

4.1 Particle-bound PFAS

The ICRP and MPPD dosimetry models incorporated into the LungDepo web application are used to estimate the deposited doses and surface area on which inhaled particulate-bound per- and polyfluoroalkyl substances (PFAS) are deposited across the three distinct regions of the human lung. The relative contributions of inhaled PFAS associated with particles of different sizes are also computed. The predictions generated by LungDepo (using the input data from Lin et al.⁹¹), are compared with the findings reported by Lin et al.⁹¹ to verify the accuracy and robustness of the ICRP and MPPD models as integrated within the web application.

Lin et al.⁹¹ conducted extensive work quantifying the (normalized) particle size distribution of particle-bound PFAS and the sum concentrations of gaseous and particulate PFAS emitted from various reference sites, including wastewater treatment plants (WWTPs), landfills, coastal areas and natural reserve sites. They investigated collectively 49 PFAS and reported the particulate concentrations of each, measured in picograms of PFAS per cubic meter in the air (pg m⁻³). The total concentrations were designated as Σ PFAS. The normalized distribution of total PFAS (Σ PFAS) on the different size fractions in the particulate matter, along with the total particulate concentrations of PFAS from different sampling locations as reported by Lin et al.,⁹¹ have been included as predefined scenarios in the LungDepo web application. Among the predefined scenarios the normalized distributions of PFBA and PFBS are included, as obtained from the study of Lin et al.⁹¹

Fig. 6A, presents the predicted mass deposition rate (pg h⁻¹) of inhaled PFAS at or near a landfill site using the ICRP and MPPD models in LungDepo as compared to those calculated by Lin et al.⁹¹ also using the ICRP model, while Fig. 6B presents the corresponding predicted mass deposition percentage (%) within the three distinct regions of the human lung calculated from the LungDepo model (this was not calculated by Lin et al.,⁹¹ and is one of the new features of LungDepo). The corresponding figures for predicted exposures based on PFAS emissions at coastal and natural reserve sites and at WWTPs are provided in the supplemental information file (Fig. S9–S18†). These calculations were performed using the ICRP and MPPD dosimetry models integrated within the LungDepo web application, alongside the findings reported in the study by Lin et al.⁹¹ to validate and verify the accuracy of the calculation outputs generated by the LungDepo web application. Lin et al.⁹¹ used the simplified equations proposed by Hinds,⁴⁴ similar to our approach in this study, to calculate the mass deposition rate of inhaled PFAS based on the ICRP model. As can be observed in Fig. 6A, the mass deposition rate calculated by the LungDepo web application is consistent with that reported by Lin et al.⁹¹ thereby verifying the calculations performed in relation to the ICRP dosimetry model. The total mass of inhaled PFAS deposited, as estimated by both the ICRP and MPPD models, is approximately 110 pg h⁻¹. Specifically, the ICRP model predicts that the contributions to the HA, TB and AL region are roughly 77%, 5% and 18%, respectively. The MPPD model predicts that the contributions to the HA, TB and AL region are around 66%, 13% and 21%, respectively. These discrepancies are attributed to the different deposition efficiencies predicted by the two models, as shown in Fig. 2 and 3, respectively. The particle size distribution of the PFAS, as reported in the study by Lin et al.,⁹¹ spanned from 0.08 to 25 μm. The distribution exhibited a peak at an aerodynamic diameter of 0.78 μm that corresponded to an inhalation probability of around 17%. It is evident from Fig. 2 and 3, that for particles with an aerodynamic diameter of approximately 0.78 μm, the ICRP model predicts slightly higher deposition efficiency in the HA, estimated at around 8%, compared to the 5% predicted by the MPPD model. Conversely, the deposition efficiency in the TB region, according to the ICRP model, is lower at approximately 1.7%, whereas the MPPD model predicts a value of around 5%. The differences predicted between the MPPD and ICRP models are minor and reflect the improved lung geometry in the MPPD model.

Fig. 6 Predictions of PFAS mass deposition at a landfill site in Hong Kong (based on input data from Lin et al.), computed using the ICRP and MPPD models integrated within LungDepo. (A) Deposition in pg h⁻¹ compared with Lin et al.; (B) deposition in % of Σ PFAS, comparing ICRP and MPPD results.⁹¹

The total mass deposition and the contributions of different particle sizes of the particles to which the PFAS are bound, as calculated here using input data (on PFAS concentration and particle size distribution) retrieved from the study of Lin et al.,⁹¹ are found to be consistent and comparable to the findings reported in the study of Guo et al.⁹⁰ Guo et al.,⁹⁰ reported that the mass deposition of eight PFAS within the human lungs, in the urban atmosphere of Shanghai, China is approximately 361 pg h⁻¹, indicating that the coarse PFAS particles contribute the most to the particle and PFAS load in the HA region. They also reported that PFAS particles with an aerodynamic diameter of less than 2.1 μm account for approximately 72.5% of the particle deposition in the AL region. This observation is comparable with the results presented here that demonstrated that fine and ultrafine particles contribute approximately 75–80% to the total deposition in the AL region.

The LungDepo web application offers further advanced analytical features for calculating the regional percentage contributions of the three distinct particle size categories (coarse, fine and ultrafine particles) as well as the computation of the deposited dose per regional area (mg m⁻²) and evaluation of the percentage of the regional surface area on which particles have deposited relative to the total regional area (as a percentage) which can also be thought of as lung surface area in which effective lung function (e.g., oxygen exchange) will likely be reduced. As can be seen in Fig. 7, both ICRP and MPPD models predict that coarse particles predominate in the HA region. In more detail, the MPPD model predicts this percentage to be slightly higher at around 89% of the total particle load, whereas ICRP predicts that coarse particles constitute around 74%. In the TB region, the MPPD model indicates that fine particles predominate corresponding to around 55% of the total particle load, whereas ICRP model indicates equal contribution between fine and coarse particles. In the AL region, both models predict that fine particles predominate this region with percentages around 60–65% and ultrafine particles contributing to around 15% of the total particle load here.

Fig. 7 Contributions (expressed as percentages of the Σ PFAS) of inhaled Σ PFAS associated with particles of different sizes (collected from a landfill site in Hong Kong by Lin et al.⁹¹) as calculated using the ICRP and MPPD models integrated within the LungDepo web application.

The predicted deposition dose per lung regional area of people in close proximity to the landfill, using the ICRP model, is found to be 5.03 × 10⁻⁵ mg m⁻² in the HA region, 2.19 × 10⁻⁷ mg m⁻² in the TB region and 2.34 × 10⁻⁹ mg m⁻² in the AL region. The corresponding computations using the MPPD model yielded values of 4.24 × 10⁻⁵ mg m⁻² in the HA region, 5.84 × 10⁻⁷ mg m⁻² in the TB region and 2.80 × 10⁻⁹ mg m⁻² in the AL region. Although the predicted particles' coverage in the AL region is relatively low, in the order of 10⁻⁹ mg m⁻², as observed by both models, the computed mass of PFAS deposited in the AL region, which is found to be 20–25 pg h⁻¹, should be of concern regarding potential toxicological effects and health implications. While there are as yet limited health-based guidance values or limit values for individual or total PFAS concentrations in air, some suggestions are that annual exposure to PFOA (for example) should be limited to 0.0053 μg m⁻³.¹⁰⁸ The European Food Safety Authority has advised a tolerable weekly intake (TWI) for total PFAS via food of 0.63 ng kg⁻¹ from food and water for example.¹⁰⁹ In parallel, the U.S. Environmental Protection Agency (EPA) has set maximum contaminant levels (MCLs) in drinking water at or near zero for several PFAS compounds, including PFOA and PFOS, reflecting increasing concern over their health impacts and a shift toward more protective regulatory thresholds.¹¹⁰

4.2 Particle-bound total PAH

Polycyclic aromatic hydrocarbons (PAHs) represent another class of particle-bound organic compounds that may have significant adverse health effects upon human inhalation. The atmospheric presence of PAHs in both gas and particulate phases raises significant concerns, particularly due to the fine sizes of particle-bound PAHs that range from 0.1 to 10 μm (ref. 107 and 111) and which can penetrate deeply into the human respiratory system upon inhalation, potentially leading to significant health impacts. Furthermore, the concentrations of PAHs in the atmosphere are notably higher than those of PFAS, typically ranging from a few to hundreds of nanograms per cubic meter¹¹² Atmospheric particle-bound PAHs are primarily formed from the incomplete combustion of carbon-based materials^113–115 which are characterized by high biochemical persistence due to the existence of dense π electrons on the aromatic rings.^116,117

Using the probability density size distribution as reported by Lv et al.¹⁰⁷ and the concentrations from the sum of 12 PAHs measured by Voliotis et al.²⁹ during cold (January–March 2013) and warm (May–July 2013) seasons at an urban traffic site in Thessaloniki (northern Greece), the mass deposition rate (ng h⁻¹) of particle-bound PAHs is calculated. The respiratory volume rate is set to 1.7 m³ s⁻¹ to be consistent with the study of Voliotis et al.²⁹ This volumetric rate corresponds to light activity levels in adults. The mass deposition rate is computed using the ICRP and MPPD models integrated within the LungDepo web application. The results were compared to those reported by Voliotis et al.,²⁹ who utilized the MPPD model with the stochastic lung option, applying a functional residual capacity (FRC) of 3389 mL. In contrast, the MPPD model integrated within the LungDepo web application is fitted based on a Yeh/Schum symmetric lung geometry model with an FRC of 3300 mL. Nevertheless, as presented in Fig. 8A and B respectively, the predicted outcomes from the MPPD model using LungDepo and the outcomes predicted by Voliotis are in close agreement during both cold and warm seasons. This comparison further assures the validity of the implementation of the MPPD model integrated within the LungDepo web application. The predicted outcome based on the ICRP model overestimates the mass deposition of particle-bound PAHs. This discrepancy as discussed previously is attributed to the different computations of deposition efficiency as evidenced in Fig. 2 and 3.

Fig. 8 Predictions of the mass deposition in human male adult lung measured in ng h⁻¹ of PAHs during the cold season (A) and warm season (B) at an urban traffic site as computed using the ICRP and MPPD models integrated within LungDepo and compared against the previous study²⁹ (whose data was used as the input to the LungDepo model).²⁹

As can be seen in Fig. 8A and B, the mass deposition of particle-bound PAHs during the cold season is significantly higher, predicted to be approximately 18–20 ng h⁻¹, compared to the warm season, where deposition levels are predicted to be around 6–8 ng h⁻¹. This observation aligns with previous studies that reported higher concentrations of PAHs during cold seasons due to the increase from seasonal emission sources such as domestic heating etc.^118–122 and lower concentrations of PAHs during warm seasons due to the rise of temperature and concentrations of atmospheric oxidants such as ozone and radicals.^123–126

4.3 Engineered microparticles (MPs)

In addition to the toxic organic compounds that can bound onto particulate matter, micro-sized engineered materials, with an aerodynamic diameter between 0.1 and 100 μm, have also been addressed as potential risks for environmental and occupational lung diseases following inhalation.¹²⁷ Engineered microparticles (MPs), which are classified as ultrafine particles (<0.1 μm), can be found in both indoor and outdoor aerosols.¹²⁸ Due to their small sizes, these particles can penetrate deep into the respiratory tract, potentially inducing pulmonary inflammation and other adverse health effects due to their ability to cross the air-lung barrier.^129,130

A case study presented by Tsiros et al.¹³¹ is used to examine the robustness and accuracy of the LungDepo web application to predict the mass of TiO₂ deposited in the three different human lung regions, following the exposure of female and male workers to 22 nm ultrafine TiO₂ particles under light exercise during an 8 hour work shift. Tsiros et al.,¹³¹ employed the ICRP model using the Hinds approach,⁴⁴ and the MPPD model for assessing the risk exposure of female and male workers exposed to a concentration of 5.85 mg m⁻³ of TiO₂ ultrafine particles, considering a particle density (assuming spherical particles) of approximately 4.26 g cm⁻³ and a count median diameter of the particles (CMD) of 0.02 μm. Fig. 9A and B, present the mass deposition measured in mg calculated using the ICRP and MPPD models integrated within the LungDepo web application, following the exposure of a male or female, respectively to 22 nm ultrafine TiO₂ particles during an 8 hour work shift under light exercise. The ICRP model predicts that the largest mass of deposited TiO₂ microparticles is in the AL region, estimated at approximately 33 mg for males and 28 mg for females. This finding underscores the significant risk of pulmonary inflammation that may result from the 8 hour (workday) exposure to TiO₂ ultrafine particles, to both males and females. This observation is in perfect agreement with the calculations conducted by Tsiros et al.,¹³¹ using the ICRP model. Using the MPPD model integrated within the LungDepo web application, it is observed that the predicted mass of TiO₂ deposited in the alveolar (AL) region is also considerable, approximately 20 mg for males and 16 mg for females however, the largest accumulation of TiO₂ is predicted to be in the TB region. This discrepancy between the two models can be described through the calculation of deposition efficiency for particles measuring 0.022 μm, as illustrated in Fig. 2 and 3. It is noteworthy to state that although Tsiros et al.,¹³¹ used the same lung geometry for MPPD model as used in this study, they considered variable exposure (30 minutes of active emissions per hour) in contrast to the MPPD model used in this study which was fitted based on a constant exposure scenario. This distinction largely explains the differences observed in the predictions yielded by the MPPD model integrated within the LungDepo web application and the predictions yielded by the MPPD model utilized by Tsiros et al.¹³¹

Fig. 9 Predictions of the mass deposition measured in ng h⁻¹ of TiO₂ ultrafine particles, following the exposure of male (A) and female (B) workers to 22 nm TiO₂ under light exercise during an 8-hour work shift as computed using the ICRP and MPPD models integrated within LungDepo.

Using the advanced functionalities of the LungDepo web application, it has been observed that both the ICRP and MPPD models predict the surface area occupied by deposited particles per the regional area to be around 2–3% in the AL region, around 250% in the TB region and around 2500% in the HA region. These findings clearly indicate that inhalation of 22 nm ultrafine TiO₂ particles for 8 hours work shift, could potentially lead to significant pulmonary inflammation and other adverse health implications for both males and females.

4.4 Domain of applicability and user interaction

Following the presentation of the case studies demonstrating the applicability of the LungDepo web application for predicting the mass deposition of particle-bound toxic organic compounds and engineered micro-sized materials, it is important to note also that the web application integrates predefined (normalized) size distribution data for a variety of additional substances. This feature enables users to explore diverse scenarios involving various combinations of materials and chemicals, including perfluorobutyl sulfonate (PFBS), perfluorobutanoic acid (PFBA), corn starch, chitosan, glycerol, zinc oxide (ZnO), acetic acid, silane- and siloxane-based materials, 2-octenylsuccinic anhydride, sodium alginate, and alkyl ketene dimer (AKD). Furthermore, the web application accommodates the integration of user-defined particle size distributions, thereby enhancing the analytical flexibility of the tool. This signifies that the LungDepo web application can serve as a valuable tool for accurate and robust evaluation of the potential impacts of inhaled materials on the human respiratory tract by environmental regulatory agencies. Also, the web application can be utilized to investigate and assess the carcinogenic risks associated with inhalation exposure to these substances by calculating the inhalation cancer risk (ICR) metric.

Future extensions of LungDepo could include parameterisation of different lung sizes/breathing rates and functional residual capacities to cover also children and vulnerable populations (e.g., pregnant women, the elderly, people with asthma, emphysema or other lung-related conditions, and obesity) which will influence both exposure and susceptibility to additional health effects arising from air pollution.^132,133

5 Conclusions

This paper presents the LungDepo web application for the prediction of the mass deposition of inhaled particles and particle-associated organic pollutants within the respiratory tract. LungDepo is a freely accessible web application hosted on the Enalos Cloud platform (https://enaloscloud.novamechanics.com/proplanet/lungdeposition or https://enaloscloud.novamechanics.com/insight/lungdeposition/), which enables researchers to assess potential hazards and risks associated with the inhalation of particulate matter, toxic organic compounds bound to particles, micro-sized engineered materials or their combinations. The robustness and validity of LungDepo, utilizing either the ICRP or MPPD models, has been confirmed through several case studies comparing its predictions with the model calculations performed in previous studies,^{29,90,91,107,131} including the mass deposition of particle-bound PFAS,^90,91 PAH aerosol^29,107 and micro-sized engineered material such as of TiO₂.¹³¹ Its broad applicability is further demonstrated by integrating predefined case studies with (normalized) size distribution data for various substances, including perfluorobutyl sulfonate (PFBS), perfluorobutanoic acid (PFBA), corn starch, chitosan, glycerol, zinc oxide (ZnO), acetic acid, silane- and siloxane-based materials, 2-octenylsuccinic anhydride, sodium alginate, and alkyl ketene dimer (AKD). Further enhancements are planned to extend the range of pollutants and combinations available, and to enable tuning of the lung volume and residual capacity to allow modelling of the exposures and consequent risks of especially vulnerable individuals.

The enhanced user interaction and flexibility of the LungDepo web application is affirmed by its user-friendly GUI, which facilitates users with no programming knowledge to perform calculations using the ICRP and MPPD models for prediction of the mass deposition of inhaled particles and aerosols in the human lungs. The tool also features REST API integration that facilitates interaction with other web applications and software such as for integrated exposure, hazard and risk assessment, thereby promoting efficient data exchange and enhancing interoperability. This integration opens new opportunities for collaborative research and a thorough evaluation of inhalation toxicity, ultimately contributing to the design and development of inherently safer materials through application of the SSbD principles.

In this study, clearance mechanisms of deposited particles were not considered. To more accurately assess the risk from inhaled particles to human lungs, future work will integrate comprehensive physiologically-based pharmacokinetic (PBPK) models within LungDepo, such as the one presented in the work of Tsiros et al.¹³¹ The inclusion of additional variants of MPPD models fitted to alternative lung geometric models, such as the Yeh/Schum 5-Lobe, the stochastic lung, the Weibel etc. will also be considered. Finally, the variable exposure conditions featured in the MPPD model version 3.04, developed by Applied Research Associates Inc.^78,93 will also be integrated within LungDepo in future upgrades.

Data availability

All data utilised in the manuscript is extracted from literature, and the curated datasets are in the process of being uploaded to the free-to-access NanoPharos database https://db.nanopharos.eu/Queries/Datasets.zul.

Author contributions

Conceptualization, D. M., D.-D. V.; methodology, D. M.; software, D. M., A. T.; supervision, G. M., J. S., I. L, A. A.; writing – original draft preparation, D. M.; writing – review and editing, D. M., D.-D. V., P. K., A. T., G. M., J. S., A. R., I. L., A. A.; funding acquisition, A. A.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This research was funded by the European Union's Horizon 2020 research and innovation program via the PROPLANET project under grant agreement number 101091842 and the INSIGHT project under grant agreement number 101137742. The authors would like to thank Periklis Tsiros for the fruitful discussions, and his suggestions and advice for integrating additional statistical measures into the LungDepo web application to enable in-depth analysis of the regional deposition of particles in the human lungs.

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Footnote

† Electronic supplementary information (ESI) available: ESI file is included, providing a comprehensive analysis of the outcomes generated using the LungDepo web-tool. See DOI: https://doi.org/10.1039/d5en00299k

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