Using particle dimensionality-based modeling to estimate lung carcinogenicity of 3D printer emissions.

The use of 3D printing technologies by industry and consumers is expanding. However, the approaches to assess the risk of lung carcinogenesis from the emissions of 3D printers have not yet been developed. The objective of the study was to demonstrate a methodology for modeling lung cancer risk related to specific exposure levels as derived from an experimental study of 3D printer emissions for various types of filaments (ABS, PLA, and PETG). The emissions of 15 filaments were assessed at varying extrusion temperatures for a total of 23 conditions in a Class 1,000 cleanroom following procedures described by ANSI/CAN/UL 2904. Three approaches were utilized for cancer risk estimation: (a) calculation based on PM2.5 and PM10 concentrations, (b) a proximity assessment based on the pulmonary deposition fraction, and (c) modeling based on the mass-weighted aerodynamic diameter of particles. The combined distribution of emitted particles had the mass median aerodynamic diameter (MMAD) of 0.35 µm, GSD 2.25. The average concentration of PM2.5 was 25.21 µg/m3 . The spline-based function of aerodynamic diameter allowed us to reconstruct the carcinogenic potential of seven types of fine and ultrafine particles (crystalline silica, fine TiO2 , ultrafine TiO2 , ambient PM2.5 and PM10, diesel particulates, and carbon nanotubes) with a correlation of 0.999, P < 0.00001. The central tendency estimation of lung cancer risk for 3D printer emissions was found at the level of 14.74 cases per 10,000 workers in a typical exposure scenario (average cumulative exposure of 0.3 mg/m3 - years), with the lowest risks for PLA filaments, and the highest for PETG type.

Toxicological and epidemiological approaches to carcinogenic potency modeling for mixed mineral fiber exposure: the case of fibrous balangeroite and chrysotile.

CONTEXT: Excess mesothelioma risk was observed among chrysotile miners and millers in Balangero, Italy. The mineral balangeroite has been identified in an asbestiform habit from the Balangero chrysotile mine (Italy). Previous studies did not contain a detailed description of the fiber dimensions, thus limiting possible approaches to estimating their carcinogenic potential. OBJECTIVES: To reconstruct excess mesothelioma risk based on characteristics of mixed fiber exposure. METHODS: The lengths and widths of particles from a sample of balangeroite were measured by transmission electron microscopy (TEM). Statistical analysis and modeling were applied to assess the toxicological potential of balangeroite. RESULTS: Balangeroite fibers are characterized as asbestiform, with geometric mean length of 10 µm, width of 0.54 µm, aspect ratio of 19, and specific surface area of 13.8 (1/µm). Proximity analysis shows dimensional characteristics of balangeroite close to asbestiform anthophyllite. Modeling estimates the average potency of balangeroite as 0.04% (95% CI 0.0058, 0.16) based on dimensional characteristics and 0.05% (95% CI-0.04, 0.24) based on epidemiological data. The available estimate of the fraction of balangeroite in the Balangero mine is very approximate. There were no data for airborne balangeroite fibers from the Balangero mine and no lung burden data are available. All estimates were performed using weight fractions of balangeroite and chrysotile. However, based on reasonable assumptions, of the seven cases of mesothelioma in the cohort, about three cases (43%) can be attributed to fibrous balangeroite. CONCLUSION: The presence of different types of mineral fibers in aerosolized materials even in small proportions can explain observed cancer risks.

Dimensions of elongate mineral particles and cancer: A review.

CONTEXT: Based on a decade-long exploration, dimensions of elongate mineral particles are implicated as a pivotal component of their carcinogenic potency. This paper summarizes current understanding of the discovered relationships and their importance to the protection of public health. OBJECTIVES: To demonstrate the relationships between cancer risk and dimensions (length, width, and other derivative characteristics) of mineral fibers by comparing the results and conclusions of previously published studies with newly published information. METHODS: A database including 59 datasets comprising 341,949 records were utilized to characterize dimensions of elongate particles. The descriptive statistics, correlation and regression analysis, combined with Monte Carlo simulation, were used to select dimensional characteristics most relevant for mesothelioma and lung cancer risk prediction. RESULTS: The highest correlation between mesothelioma potency factor and weight fraction of size categories is achieved for fibers with lengths >5.6 µm and widths ≤0.26 µm (R = 0.94, P < 0.02); no statistically significant potency was found for lengths <5 µm. These results are consistent with early published estimations, though are derived from a different approach. For combinations of amphiboles and chrysotile (with a consideration of a correction factor between mineral classes), the potency factors correlated most highly with a fraction of fibers longer than 5 µm and thinner than 0.2 µm for mesothelioma, and longer than 5 µm and thinner than 0.3 µm for lung cancer. Because the proportion of long, thin particles in asbestiform vs. non-asbestiform dusts is higher, the cancer potencies of the former are predicted at a significantly higher level. The analysis of particle dimensionality in human lung burden demonstrates positive selection for thinner fibers (especially for amosite and crocidolite) and prevailing fraction of asbestiform habit. CONCLUSION: Dimensions of mineral fibers can be confirmed as one of the main drivers of their carcinogenicity. The width of fibers emerges as a primary potency predictor, and fibers of all widths with lengths shorter than 5 µm seem to be non-impactful for cancer risk. The mineral dust with a fibrous component is primarily carcinogenic if it contains amphibole fibers longer than 5 µm and thinner than 0.25 µm.

Elongate mineral particles (EMP) characteristics and mesothelioma: Summary and resolution for session I of the Monticello II conference.

The summary contains a consensus opinion regarding the current state of the science about the dimensions of Elongate Mineral Particles (EMPs) as a factor impacting their carcinogenicity.

Excitable systems: A new perspective on the cellular impact of elongate mineral particles.

We investigate how the geometry of elongate mineral particles (EMPs) in contact with cells influences esotaxis, a recently discovered mechanism of texture sensing. Esotaxis is based on cytoskeletal waves and oscillations that are nucleated, shaped, and steered by the texture of the surroundings. We find that all EMPs studied trigger an esotactic response in macrophages, and that this response dominates cytoskeletal activity in these immune cells. In contrast, epithelial cells show little to no esotactic response to the EMPs. These results are consistent with the distinct interactions of both cell types with ridged nanotopographies of dimensions comparable to those of asbestiform EMPs. Our findings raise the question of whether narrow, asbestiform EMPs may also dominate cytoskeletal activity in other types of immune cells that exhibit similar esotactic effects. These findings, together with prior studies of esotaxis, lead us to the hypothesis that asbestiform EMPs suppress the migration of immune cells and activate immune signaling, thereby outcompeting signals that would normally stimulate the immune system in nearby tissue.

Dimensional characteristics of the major types of amphibole mineral particles and the implications for carcinogenic risk assessment.

Context: Though some significant advances have been made in recent decades to evaluate the importance of size and morphology (habit) of elongate mineral particles (EMPs), further research is needed to better understand the role of each dimensional metric in determining the levels of cancer potency.Objective: To determine dimensional parameters most relevant for predicting cancer potency of durable elongate particles, specifically amphibole and durable silicate minerals generally.Methods: A database on dimensional and other relevant characteristics of elongate amphibole mineral particles was created, containing particle-by-particle information for 128 099 particles. Integral statistical characteristics on dimensionality of various amphibole types and morphological habits of EMPs were calculated, compared, and correlated with published mesothelioma and lung cancer potency factors.Results: The highest absolute Pearson correlation (r = 0.97, r2 = 0.94, p < 0.05) was achieved between mesothelioma potency (RM) and specific surface area. The highest correlation with adjusted lung cancer potency was found with particle aspect ratio (AR) (r = 0.80, r2 = 0.64, p < 0.05). Cluster analysis demonstrates that fractions of thin fibers (width less than 0.15 and 0.25 µm) also closely relate both to lung cancer and RM. Asbestiform and non-asbestiform populations of amphiboles significantly differ by dimensionality and carcinogenic potency.Conclusions: Dimensional parameters and morphological habits of EMPs are the main drivers for the observable difference in cancer potency among amphibole populations.

Letter to the Editor: Epidemiology holds a key to the validation of toxicological models for elongate mineral particles.

The authors reply to the comments of Drs. Gualtieri and di Giuseppe on the short communication by Wylie and Korchevskiy - Carcinogenicity of fibrous glaucophane: how to fill data gaps? (2021 Current Research in Toxicology Volume 2, pp. 202-203). The role of epidemiology in establishing the toxicity of elongate mineral particles is emphasized. The validation of quantitative structure-activity relationship (QSAR) models by disease outcome is mentioned as one of the most important tools in advancing the new approaches in mineral particle toxicology.

Dimensional determinants for the carcinogenic potency of elongate amphibole particles.

CONTEXT: Carcinogenic properties of particulates depend, among other factors, on dimensional characteristics that affect their ability to reach sensitive tissue, to be removed or retained, and to interact with the cells. OBJECTIVE: To model mesothelioma and lung cancer potency of amphibole particles based on their dimensional characteristics and mineral habit (asbestiform vs. nonasbestiform) utilizing epidemiological data and detailed size information. METHODS: The datasets from recently created depository of dimensional information of elongate mineral particles were used to correlate mesothelioma and lung cancer potency with the fraction of particles in a specific size range and the ratio of length and width in different powers. In addition, the cancer potency factors were estimated and compared for 30 asbestiform, 15 nonasbestiform, and 10 mixed datasets. RESULTS: For particles longer than 5 µm, the highest correlation with mesothelioma potency was achieved for width <0.22 µm, and with lung cancer <0.28 µm. The statistical power of the correlation was observed to lose significance at a maximum width of 0.6-0.7 µm. Mesothelioma potency correlated with length in the power of 1.9 divided by width in the power of 2.97, lung cancer potency with length in the power of 0.4 divided by width in the power of 1.17. The predicted cancer potencies of asbestiform, nonasbestiform, and mixed categories were significantly different. CONCLUSION: While additional studies in this direction are warranted, this paper should serve as an additional confirmation for the role of fiber dimensions in the carcinogenicity of amphibole elongate mineral particles (EMPs).

Carcinogenicity of fibrous glaucophane: How should we fill the data gaps?

•The modeled glaucophane mesothelioma potency is 0.0085 % vs. 0.5 % for riebeckite.•Lung cancer potency of glaucophane is 0.36 % vs. 4.82 % for Australian crocidolite.•The fibrosity index of glaucophane (0.77) is typical for non-asbestiform amphiboles.

Prevention through design: insights from computational fluid dynamics modeling to predict exposure to ultrafine particles from 3D printing.

Fused filament fabrication (FFF) 3D printers are increasingly used in industrial, academic, military, and residential sectors, yet their emissions and associated user exposure scenarios are not fully described. Characterization of potential user exposure and environmental releases requires robust investigation. During operation, common FFF 3D printers emit varying amounts of ultrafine particles (UFPs) depending upon feedstock material and operation procedures. Volatile organic compounds associated with these emissions exhibit distinct odors; however, the UFP portion is largely imperceptible by humans. This investigation presents straightforward computational modeling as well as experimental validation to provide actionable insights for the proactive design of lower exposure spaces where 3D printers may be used. Specifically, data suggest that forced clean airflows may create lower exposure spaces, and that computational modeling might be employed to predict these spaces with reasonable accuracy to assist with room design. The configuration and positioning of room air ventilation diffusers may be a key factor in identifying lower exposure spaces. A workflow of measuring emissions during a printing process in an ANSI/CAN/UL 2904 environmental chamber was used to provide data for computational fluid dynamics (CFD) modeling of a 6 m2 room. Measurements of the particle concentrations in a Class 1000 clean room of identical geometry were found to pass the Hanna test for agreement between model and experimental data, validating the findings.

Using benchmark dose modeling for the quantitative risk assessment: Carbon nanotubes, asbestos, glyphosate.

Benchmark dose method is one of the most famous quantitative approaches available for toxicological risks prediction. However, it is not fully clear how occupational health professionals can use it for specific workplace scenarios requiring carcinogen risk assessment. The paper explores the hypothesis that benchmark dose method allows to effectively approximate dose-response data on carcinogenic response, providing reasonable estimations of risks in the situations when a choice between more complex models is not warranted for practical purposes. Three case studies were analyzed for the agents with different levels of scientific confidence in human carcinogenicity: carbon nanotubes, amosite asbestos, and glyphosate. For each agent, a critical study was determined, and a dose-response slope factor was quantified, based on the weighted average lower bound benchmark dose. The linear slope factors of 0.111 lifetime excess cases of lung carcinoma per mg/m3 of MWCNT-7 (in rats exposure equivalent), 0.009 cases of mesothelioma per f/cc-years of cumulative exposure to amosite asbestos, and 0.000094 cases of malignant lymphoma per mg/kg/day of glyphosate (in mice equivalent) were determined. The correlations between the proposed linear predictive models and observed data points were R = 0.96 (R2 = 0.92) for carbon nanotubes, R = 0.97 (R2 = 0.95) for amosite asbestos, and R = 0.89 (R2 = 0.79) for glyphosate. In all three cases, the linear extrapolation yielded comparable level of risk estimations with the "best fit" nonlinear model; for nanoparticles and amosite asbestos, linear estimations were more conservative. By performing a simulation study, it was demonstrated that a weighted average benchmark dose expressed the highest correlation with multistage and quantal-linear models.

Modeling mesothelioma risk factors from amphibole fiber dimensionality: mineralogical and epidemiological perspective.

Amphiboles are common rock-forming minerals but when they form asbestos, they are known carcinogens. Mesothelioma mortality among miners and millers per the unit of asbestiform amphibole exposure varies significantly across cohorts when asbestos exposure measurements are based on the membrane filter method. Because the cohorts were exposed to different occurrences of asbestiform amphibole, variance in mesothelioma potency (RM ) among cohorts is likely due to differences in exposure characteristics not reflected by the membrane filter method. In this paper using both linear and nonlinear models we correlate RM from four mining and milling cohorts with two-dimensional parameters of the exposure. The parameters are based on the proportion of elongated minerals that are >5 µm in length from each occurrence that also have either (a) width ≤ 0.15 µm, or (b) width ≤ 0.25 µm. Based on the models we derived, it was possible to quantify RM for the occurrences of asbestiform amphibole associated with mesothelioma excess but for which epidemiologically based RM has not been published. It was demonstrated that modeled RM for amphibole occurrences in nonasbestiform habits are lower (fibrous glaucophane) or not significant (cleavage fragments). The results of the study can be used in a risk assessment of elongated mineral particles and have implications for public policy and regulations.

Empirical model of mesothelioma potency factors for different mineral fibers based on their chemical composition and dimensionality.

Context: The potency of various mineral fiber types to produce mesothelioma was previously evaluated for numerous cohorts, but the differences in potencies for distinct fiber types have yet to be explained. Objective: To develop an empirical model that would reconstruct mesothelioma potency factors for various types of fiber based on their chemical composition and dimensionality. Methods: Typical chemical composition and dimensionality metrics (aspect ratios) were obtained and combined with mesothelioma potency factors estimated by Hodgson and Darnton method for Quebec chrysotile, South Africa amosite, South Africa and Australian crocidolite, Russian anthophyllite, Libby amphiboles, and Turkey erionite. The forward stepwise log-log regression method was utilized to determine the best combination of input parameters. Results: Mesothelioma potency factors (RM) for selected cohorts were effectively reconstructed utilizing the median aspect ratio of fibers and equivalent fractions of SiO2, total Fe oxides or total equivalent Fe3+ as Fe2O3, and MgO. Modeled potency factors increase as the aspect ratio, SiO2, and total Fe oxide (or Fe2O3) content grow, and as the MgO content diminishes. Correlation coefficients up to 0.999, p < 0.01, were achieved. The models also yield reasonable estimates of mesothelioma potencies for other fiber types, including Bolivian crocidolite, Russian chrysotile, fluoro-edenite, and others. Conclusion: In spite of the empirical approach, the proposed models provide a starting point for targeted studies of mesothelioma mechanisms by elucidating significant contributing physicochemical factors. The models have an exploratory and preliminary character but can potentially be useful to introduce quantitative structure-activity relationship approaches for the toxicology of fibrous minerals.