Toxicity testing of poorly soluble particles, lung overload and lung cancer

Bevan, Ruth; Kreiling, Reinhard; Levy, Leonard S.; Warheit, David B.

doi:10.1016/j.yrtph.2018.10.006

Cited by 31 publications

(32 citation statements)

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“…24 and Heinrich et al [ 3 ] Table 9). Moreover, the findings of Mauderly et al and Heinrich et al are in agreement with other studies showing that development of lung cancer in rats after inhalation of poorly soluble low toxicity particles (PSLT) occurs only under conditions of excessive lung particle overload [ 4 , 5 ]. Therefore, the conclusion by Saber et al [ 1 ] that lung cancer occurs in the absence of impaired clearance is not supported by data for PSLT.…”

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confidence: 86%

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Comment on Saber et al. (2019), “Commentary: the chronic inhalation study in rats for assessing lung cancer risk may be better than its reputation”

et al. 2020

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In their Commentary Saber et al. (Part Fibre Toxicol 16: 44, 2019) argue that chronic inhalation studies in rats can be used for assessing the lung cancer risk of insoluble nanomaterials. The authors make several significant errors in their interpretation and representation of the underlying science. In this Letter to the Editor we discuss these inaccuracies to correct the scientific record. When the science is recounted accurately it does not support Saber et al's statements and conclusions.

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confidence: 86%

“…3 Düsseldorf University, Düsseldorf, Germany. 4 Cabot Corporation, Billerica, MA, USA. 5 Cranfield University, Cranfield, UK.…”

Section: Authors' Contributionsmentioning

confidence: 99%

Comment on Saber et al. (2019), “Commentary: the chronic inhalation study in rats for assessing lung cancer risk may be better than its reputation”

et al. 2020

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“…The lungs are the first organs within the human body to be continuously exposed to particulates within inhaled air. Several studies have described the toxicological implications of particulates within the lungs leading to pronounced inflammation and reduced lung function [1,2]. There is increasing evidence suggesting that exposure to the particulate matter (PM) component of ambient air pollution, including that derived from traffic-generated sources, can contribute to or exacerbate lung disorders such as asthma, chronic obstructive pulmonary disorder (COPD), bronchitis, and idiopathic pulmonary fibrosis (IPF) [3,4].…”

Section: Introductionmentioning

confidence: 99%

Exposure to diesel exhaust particles results in altered lung microbial profiles, associated with increased reactive oxygen species/reactive nitrogen species and inflammation, in C57Bl/6 wildtype mice on a high-fat diet

et al. 2021

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Background Exposure to traffic-generated emissions is associated with the development and exacerbation of inflammatory lung disorders such as chronic obstructive pulmonary disorder (COPD) and idiopathic pulmonary fibrosis (IPF). Although many lung diseases show an expansion of Proteobacteria, the role of traffic-generated particulate matter pollutants on the lung microbiota has not been well-characterized. Thus, we investigated the hypothesis that exposure to diesel exhaust particles (DEP) can alter commensal lung microbiota, thereby promoting alterations in the lung’s immune and inflammatory responses. We aimed to understand whether diet might also contribute to the alteration of the commensal lung microbiome, either alone or related to exposure. To do this, we used male C57Bl/6 mice (4–6-week-old) on either regular chow (LF) or high-fat (HF) diet (45% kcal fat), randomly assigned to be exposed via oropharyngeal aspiration to 35 μg DEP, suspended in 35 μl 0.9% sterile saline or sterile saline only (control) twice a week for 30 days. A separate group of study animals on the HF diet was concurrently treated with 0.3 g/day of Winclove Ecologic® Barrier probiotics in their drinking water throughout the study. Results Our results show that DEP-exposure increases lung tumor necrosis factor (TNF)-α, interleukin (IL)-10, Toll-like receptor (TLR)-2, TLR-4, and the nuclear factor kappa B (NF-κB) histologically and by RT-qPCR, as well as Immunoglobulin A (IgA) and Immunoglobulin G (IgG) in the bronchoalveolar lavage fluid (BALF), as quantified by ELISA. We also observed an increase in macrophage infiltration and peroxynitrite, a marker of reactive oxygen species (ROS) + reactive nitrogen species (RNS), immunofluorescence staining in the lungs of DEP-exposed and HF-diet animals, which was further exacerbated by concurrent DEP-exposure and HF-diet consumption. Histological examinations revealed enhanced inflammation and collagen deposition in the lungs DEP-exposed mice, regardless of diet. We observed an expansion of Proteobacteria, by qPCR of bacterial 16S rRNA, in the BALF of DEP-exposed mice on the HF diet, which was diminished with probiotic-treatment. Conclusions Our findings suggest that exposure to DEP causes persistent and sustained inflammation and bacterial alterations in a ROS-RNS mediated fashion, which is exacerbated by concurrent consumption of an HF diet.

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“…Utilizing in vitro methods with human cells follows the principle of the 3Rs (replacement, refinement and reduction of laboratory animals) and has the potential to improve the relevance of nanosafety assessment for humans [1]. It has been shown, for example, that rats are an inappropriate model for predicting human lung cancer risk following chronic particle overload inhalation exposures [3]. In vitro studies are easier to control and reproduce, faster to perform, and more cost-effective than animal studies [4].…”

Section: Introductionmentioning

confidence: 99%

“…According to this definition, macrophage clearance rather than particle dissolution determines the particle residence time in the lung. PSPs (and PSLTs) are also viewed as particles with no specific inherent toxicity [3,9]. PSLTs are often regarded as one group, but it is important that within this group, particles can be differentiated based on their variations in bioactivity [10].…”

Section: Introductionmentioning

confidence: 99%

Grouping of Poorly Soluble Low (Cyto)Toxic Particles: Example with 15 Selected Nanoparticles and A549 Human Lung Cells

2019

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Poorly soluble, low (cyto)toxic particles (PSLTs) are often regarded as one group, but it is important that these particles can be further differentiated based on their bioactivity. Currently, there are no biological endpoint based groupings for inhaled nanoparticles (NPs) that would allow us to subgroup PSLTs based on their mode of action. The aim of this study was to group NPs based on their cytotoxicity and by using the in vitro response of the endo-lysosomal system as a biological endpoint. The endo-lysosomal system is a main cellular loading site for NPs. An impaired endo-lysosomal system in alveolar type II cells may have serious adverse effects on the maintenance of pulmonary surfactant homeostasis. The 15 different NPs were tested with human lung adenocarcinoma (A549) cells. The highly soluble NPs were most cytotoxic. With respect to PSLTs, only three NPs increased the cellular load of acid and phospholipid rich organelles indicating particle biopersistence. All the rest PSLTs could be regarded as low hazardous. The presented in vitro test system could serve as a fast screening tool to group particles according to their ability to interfere with lung surfactant metabolism. We discuss the applicability of the suggested test system for bringing together substances with similar modes-of-action on lung epithelium. In addition, we discuss this approach as a benchmark test for the comparative assessment of biopersistence of PSLTs.

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Toxicity testing of poorly soluble particles, lung overload and lung cancer

Cited by 31 publications

References 50 publications

Comment on Saber et al. (2019), “Commentary: the chronic inhalation study in rats for assessing lung cancer risk may be better than its reputation”

Comment on Saber et al. (2019), “Commentary: the chronic inhalation study in rats for assessing lung cancer risk may be better than its reputation”

Exposure to diesel exhaust particles results in altered lung microbial profiles, associated with increased reactive oxygen species/reactive nitrogen species and inflammation, in C57Bl/6 wildtype mice on a high-fat diet

Grouping of Poorly Soluble Low (Cyto)Toxic Particles: Example with 15 Selected Nanoparticles and A549 Human Lung Cells

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