Systemic sclerosis, silica exposure and cellular therapies: The sand in the gears?

Systemic sclerosis (SSc) is a chronic orphan autoimmune disease with the highest mortality rate among rheumatic diseases. SSc-related interstitial-lung disease (ILD) remains among the leading causes of SSc-related mortality with still few therapeutic effective strategies. In patients with crystallin silica exposure, SSc is recognized as an occupational disease according to the French social security system (Table 25A of the general insurance regimen). Lympho-ablative or myeloablative immunosuppression followed by autologous hematopoietic stem-cell transplantation (aHSCT) is the only therapeutic approach with demonstrated efficacy, improved survival with disease modifying effects on SSc-fibrotic manifestations (skin disease and ILD) and quality of life. A documented past and/or present occupational silica exposure, with extensive exposure and/or silica-related ILD and/or with persistent silica content in the broncho-alveolar lavage fluid are contra-indications to aHSCT in SSc patients, due to the risk of silica-related malignancy or of SSc relapse. This article aims to discuss alternative options in SSc patients with a history of silica exposure, and how innovative cellular therapies (mesenchymal stromal cells, CAR cells) could represent new therapeutic options for these patients.

Application of Multiple Occupational Health Risk Assessment Models for Crystalline Silica Dust among Stone Carvers.

OBJECTIVE: Silica is the most abundant substance on the Earth's crust and is a proven carcinogen. The aim of this study was to measure the occupational exposure of stone carvers to crystalline silica and to evaluate the health risks.  Methods: This descriptive and analytical cross-sectional study was performed on 79 stone carvers. Inhalation air sampling was performed by the NIOSH7500 method and the amount of silica was determined by X-ray diffraction (XRD). Semi-quantitative and quantitative risk assessments were performed using the methods of the Singapore Department and the US Environmental Protection Agency (EPA), respectively. Mortality due to silicosis and lung cancer were estimated using the Manettej and Rice models. Data were analyzed using SPSS23 software. RESULTS: The mean exposure to total inhalable dust and crystalline silica among the stone carvers was 1.44 and 0.5 mg/m3, respectively. Exposure to total dust and silica was significantly higher than the occupational standard (P <0.0001). Stone carvers' exposure to silica was at very high-risk level, and the carcinogenicity of silica considering two cancer slopes was 7.40 × 10-6 and 3.12 × 10-7 and the risk of non-carcinogenicity was unacceptable. CONCLUSION: The mortality rate due to silicosis was between 3 and 12 people per thousand, and due to lung cancer was 150.24 people per thousand. Based on the results of risk assessment, serious control measures should be implemented in order to reduce workers' exposure to silica.

Risk Assessment of Silicosis and Lung Cancer Mortality associated with Occupational Exposure to Crystalline Silica in Iran.

BACKGROUND: Exposure to crystalline silica has long been identified to be associated with lung diseases. Therefore, the present study aimed to assess the risk of silicosis and lung cancer associated with occupational exposure to crystalline silica in Iran. STUDY DESIGN: It is a systematic review study. METHODS: Different databases were searched, and the Cochrane method was used for the systematic review. Thereafter, cumulative exposure to crystalline silica (mg/m3-y) was calculated in every industry. The relative risk of death from silicosis was performed using Mannetje's method. Based on the geometric mean of exposure, the lung cancer risk of exposure to crystalline silica was also calculated. RESULTS: As evidenced by the results, worker's exposure to silica ranged from a geometric mean of 0.0212- 0.2689 mg/m3 (Recommended standard by the American Conference of Governmental Industrial Hygienists (ACGIH) was 0.025 mg/m3), which is generally higher than the occupational exposure limit recommended by National Institute for Occupational Safety and Health (NIOSH), ACGIH, and occupational exposure limits. The relative risk of silicosis was in the range of 1 to 14 per 1000 people, and the risk of lung cancer in workers ranged from 13-137 per 1000 people. CONCLUSION: Since workers are at considerable risk of cancer due to exposure to silica in Iran, exposure control programs need to be implemented in workplaces to decrease the concentration of silica.

[Occupational health risk assessment of silicosis caused by silica dust exposure in non-ferrous metal mines in 7 provinces from 2019 to 2020].

OBJECTIVE: To explore the occupational health risk level of silicosis caused by silica dust exposure in non-ferrous metal mining enterprises. METHODS: Using typical sampling method, 44 non-ferrous metal mining enterprises were selected in seven provinces.37 non-ferrous metal mining enterprises were included, and most of them were underground enterprises(97.30%). Enterprises basic information and silica dust exposure data of key positions were collected by using on-site hygiene investigation and detecting method. Finally, the International Council on Mining and Metals'(ICMM) risk rating table method and occupational hazard risk index method(INDEX) were used to analyze the occupational health risk level of silicosis caused by silica dust exposure in non-ferrous metal mines from total and respirable dust views, respectively. Meanwhile, the square weighted Kappa test was performed to analyze the consistency between two risk assessment method. RESULTS: Medium enterprises(64.69%(40.38%, 73.41%)), silver mining enterprises(84.69%(63.38%, 86.06%)) and antimony mining enterprises(72.22%) had relatively higher silica dust exposure rates. On-site hygiene detecting result showed that:(1) M(P25, P75) of free silica content was 21.18%(17.03%, 30.47%). (2) 1.60(0.86, 2.46)mg/m~3 for total dust concentration, 64.47% total dust concentration samples exceeding Chinese permissible concentration-time weighted average(PC-TWA), 0.68(0.30, 1.18) mg/m~3 for respiratory dust concentration, 50.00% respirable dust concentration samples exceeding Chinese PC-TWA. (3) Medium-sized enterprises, as well as rock drillers and crushers, had higher levels of silica dust exposure. Occupational health risk assessment result showed that:(1) The overall occupational health risk level of silicosis caused by silica dust exposure in non-ferrous metal mining enterprises was medium:(1) In term of total dust, ICMM risk rating table method and INDEX method indicated high and medium risks, respectively(S_(weighted) were 3.52 and 2.79). (2) In term of respirable dust, both ICMM risk rating table and INDEX method indicated medium risks(S_(weighted) were 2.78 and 2.35). (2) Medium-sized enterprises risk level was higher than other two production scales enterprises. ICMM risk rating table method and the INDEX method consistency analyses showed that these two risk assessment method had strong consistencies in terms of total dust or respirable dust(both Kappa values ≥ 0.600). CONCLUSION: The overall occupational health risk level of silicosis caused by silica dust exposure in non-ferrous metal mining enterprises was medium, and the risk levels of medium production-scale mining enterprises, rock driller and crusher were higher.

Assessment of Risk of Rheumatoid Arthritis Among Underground Hard Rock and Other Mining Industry Workers in Colorado, New Mexico, and Utah.

Importance: Respirable silica exposure has been strongly and consistently linked to rheumatoid arthritis (RA) among foundry workers, persons in the construction trades, stone crushers and drillers, and coal miners. However, risk of RA in hard rock mining has not been thoroughly investigated. Objective: To analyze occupational risk of RA in hard rock miners in Colorado, New Mexico, and Utah. Design, Setting, and Participants: This cross-sectional survey study estimated the association between mining industry work and reported RA in a random-digit telephone survey of men 50 years or older living in selected counties with elevated levels of pneumoconiosis mortality (N = 1988). The survey was conducted between January 12 and May 4, 2021. Exposures: Underground hard rock and other mining and related mineral-processing occupations. Main Outcomes and Measures: Report of a clinician diagnosis of RA further defined by treatment with corticosteroids or disease-modifying antirheumatic drugs. Risk was estimated using logistic regression. Results: The analytic sample of 1988 men (survey response rate, 11.1% of all contacts) had a mean (SD) age of 68.6 (10.1) years. Underground hard rock mining was reported by 118 (5.9%); underground mining of other types, predominantly coal mining (no concomitant hard rock), 62 (3.1%); and surface mining or ore processing (no underground), 262 (13.2%). Adjusting for age and smoking and accounting for nonmining silica exposure, mining employment was associated with increased odds of corticosteroid-treated RA (n = 89) (odds ratio, 4.12 [95%, 2.49-6.81]). The odds were similar for RA treated with disease-modifying antirheumatic drugs (n = 80) (odds ratio, 3.30 [95% CI, 1.93-5.66]). Conclusions and Relevance: In this cross-sectional survey study, workers in hard rock and other underground mining and surface mining occupations experienced 3- to 4-fold increased odds of RA. These findings suggest that clinicians should consider patients with relevant work exposures as at higher risk for developing RA.

Predictors of health-related quality of life among semi-precious stone mineworkers exposed to silica dust.

OBJECTIVE: The study aimed to comparatively evaluate HRQOL in miners of semi-precious stones with and without silicosis, and determine the associated factors, as well as the performance of two different questionnaires in measuring HRQOL. METHODS: In a cross-sectional study of 348 male miners (129 with silicosis) who underwent an interview and spirometry, HRQOL was assessed using the World Health Organization Quality of Life (WHOQOL-BREF) questionnaire and the Saint George's Respiratory Questionnaire (SGRQ). RESULTS: Miners with silicosis were older, had less schooling, worked more hours daily, and had longer exposure to silica. They also had worse scores of QoL in both questionnaires. Respiratory symptoms and %FEV1 were contributing factors for the models of total health and all the domains of the SGRQ, and 40% of the variability of the general health domain of WHOQOL-BREF was due to dyspnea, wheezing, %FEV1, and pack-years of cigarette smoking. Respiratory symptoms, lung function, pack-years of cigarette smoking, years of education, and average monthly income were contributing factors for the models of the different domains of the WHOQOL-BREF. CONCLUSIONS: Our study revealed impaired HRQOL in semi-precious stone miners evaluated using both questionnaire tools of SGRQ and WHOQOL-BREF, of which SGRQ had superior performance. Respiratory symptoms, functional impairment, and pack-years of cigarette smoking were the most important determinants of the workers' general HRQOL.

Exploring Flow Cytometry-Based Micronucleus Scoring for Reliable Nanomaterial Genotoxicity Assessment.

The increased use of engineered nanomaterials (ENM) such as SiO2 and TiO2 in industrial products, especially in food, raises concerns with regard to their effect on human health. In particular, ENM-induced genotoxicity is crucial to investigate, since DNA damage can cause induction or promotion of carcinogenesis. However, current in vitro and in vivo nanogenotoxicological data are highly contradictory, which impedes interpretation and extrapolation. Hence, robust, reliable, and ideally scalable in vitro methods for nanogenotoxicity assessment are of great interest. This work aimed at evaluating the suitability of flow cytometry-based micronuclei scoring for reliable nanogenotoxicological assessment in human intestinal cells. Therefore, we have evaluated the genotoxicity of differently sized SiO2 and TiO2 from different sources (food-relevant, commercially available, and laboratory-synthesized) using the well-established alkaline single cell gel electrophoresis (Comet assay) and the micronucleus (MN) assay employing a flow cytometric readout. Our study demonstrates that physiologically relevant doses of several types of SiO2 and TiO2 did not cause genotoxicity, as assessed by the Comet assay, and the MN flow cytometry assay under the particular experimental conditions described. To improve data reliability, we identified ENM-induced interferences with flow cytometric scoring employing a set of interference controls, which is generally applicable for any nanomaterial and any cell line. In conclusion, flow cytometry-based MN scoring appears to be a promising methodology in nanogenotoxicity testing since data acquisition and analysis are significantly faster, highly scalable in terms of throughput, and less operator-dependent compared to the traditional microscopic evaluation. In particular, ENM-induced false-positive or false-negative results, which have not been addressed sufficiently in the literature, can be detected easily, thus enhancing data reliability.

A probabilistic approach for economic evaluation of occupational health and safety interventions: a case study of silica exposure reduction interventions in the construction sector.

BACKGROUND: Construction workers are at a high risk of exposure to various types of hazardous substances such as crystalline silica. Though multiple studies indicate the evidence regarding the effectiveness of different silica exposure reduction interventions in the construction sector, the decisions for selecting a specific silica exposure reduction intervention are best informed by an economic evaluation. Economic evaluation of interventions is subjected to uncertainties in practice, mostly due to the lack of precise data on important variables. In this study, we aim to identify the most cost-beneficial silica exposure reduction intervention for the construction sector under uncertain situations. METHODS: We apply a probabilistic modeling approach that covers a large number of variables relevant to the cost of lung cancer, as well as the costs of silica exposure reduction interventions. To estimate the societal lifetime cost of lung cancer, we use an incidence cost approach. To estimate the net benefit of each intervention, we compare the expected cost of lung cancer cases averted, with expected cost of implementation of the intervention in one calendar year. Sensitivity analysis is used to quantify how different variables affect interventions net benefit. RESULTS: A positive net benefit is expected for all considered interventions. The highest number of lung cancer cases are averted by combined use of wet method, local exhaust ventilation and personal protective equipment, about 107 cases, with expected net benefit of $45.9 million. Results also suggest that the level of exposure is an important determinant for the selection of the most cost-beneficial intervention. CONCLUSIONS: This study provides important insights for decision makers about silica exposure reduction interventions in the construction sector. It also provides an overview of the potential advantages of using probabilistic modeling approach to undertake economic evaluations, particularly when researchers are confronted with a large number of uncertain variables.

The impact of different approaches to exposure assessment on understanding non-malignant respiratory disease risk in taconite miners.

INTRODUCTION: We examined the association between cumulative silica exposures in taconite mining and non-malignant respiratory disease (NMRD) using a comprehensive assessment of current and historical exposure measurements in a cross-sectional study of Minnesota taconite mining workers. We also explored the impact of exposure measurement methods by comparing estimated exposure risk from two different exposure measurement modeling approaches. METHODS: Miners were screened with an occupational and medical history questionnaire, spirometry testing and chest x-rays per ILO guidelines. Current and historical occupational exposure assessments were obtained, the former measuring about 679 personal samples over the period of the study for respirable dusts, including silica, in 28 major job functions. Cumulative silica exposure ((mg/m3) × years) was estimated as a cumulative product of time worked and year-specific silica job exposure concentrations. Chest x-ray abnormalities were based on B-reader agreement with a third B-reader for arbitration. Forced vital capacity (FVC) less than lower limits of normal for age, height, race and gender was used to determine spirometric restrictive ventilatory defect (RVD). Prevalence ratios (PR) of exposure-outcome associations, with 95% confidence intervals (CI), were estimated using multivariate Poisson regression. RESULTS: Cumulative silica exposure was associated with RVD prevalence (PR = 1.41, 95% CI = 1.09-1.81) and prevalence of parenchymal abnormalities on chest x-ray (PR = 1.30, 95% CI = 1.00-1.69) using exposure estimates based primarily on current study measurements, and assuming unchanged historical exposure trend. Conversely, when exposures were defined incorporating available actual historical values, no associations were observed between silica exposure and either RVD (PR = 0.76, 95% CI = 0.41-1.40) or parenchymal (PR = 0.87, 95% CI = 0.45-1.70) outcomes. CONCLUSIONS: This study demonstrated that the estimated association between silica dust exposure and lung disease is highly sensitive to the approach used to estimate cumulative exposure. Cumulative values based on conservative estimates of past exposure, modeled from recently measured respirable silica, showed an association with restriction RVD on spirometry. Silica exposure was also significantly associated with increased parenchymal findings on chest x-ray using this approach. Conversely, these findings were absent when actual available historical data was used to estimate cumulative silica exposure. These differences highlight the challenges with estimating occupational dust exposure, the potential impact on calculated exposure risk and the need for long term quality exposure data gathering in industries prone to risk from inhaled respirable dusts.

Assessment of neurotoxicity induced by different-sized Stöber silica nanoparticles: induction of pyroptosis in microglia.

With the wide application of Stöber silica nanoparticles and their ability to access the brain, it is crucial to evaluate their neurotoxicity. In this study, we used three in vitro model cells, i.e., N9, bEnd.3 and HT22 cells, representing microglia, microendothelial cells and neurons, respectively, to assess the neurotoxicity of Stöber silica nanoparticles with different sizes. We found that Stöber silica nanoparticles almost had no effect on the viability of bEnd.3 and HT22 cells. In contrast, they induced size-dependent toxicity in N9 cells, which represent the residential macrophages of the central nervous system. Further mechanistic study demonstrated that the toxicity in N9 cells was related to their surface silanol display. In addition, we demonstrated that Stöber silica nanoparticles induced the production of mitochondrial ROS, release of IL-1ß, cleavage of GSDMD, and occurrence of pyroptosis in N9 cells. Features of pyroptosis were also observed in primary microglia and macrophage J774A.1. In conclusion, these findings were helpful for the safety consideration of Stöber silica nanoparticles considering their wide applications in our daily life.

Replacing amalgam with a high-viscosity glass-ionomer in restoring primary teeth: A cost-effectiveness study in Brasilia, Brazil.

OBJECTIVES: When planning primary oral health care services the cost implications of adopting new intervention practices are important, especially in resource-strapped countries. Although on a trajectory to be phased-out, amalgam remains the standard of care in many countries. METHODS: Adopting a government perspective, this study compared the costs of performing amalgam and ART/high-viscosity glass-ionomer cement (HVGIC) restorations and the consequences of failed restorations over 3 years in suburban Brasilia, Brazil. Cost data were collected prospectively; cost estimates were developed for the study sample and a projection of 1000 single- and 1000 multiple-surface restorations per group. Probabilistic sensitivity analysis was conducted in TreeAge Pro. RESULTS: Results were mixed. For single-surface restorations, ART/HVGIC will cost US$51 per failure prevented, while for multiple-surface restorations, ART/HVGIC was cost-effective with a savings of US$11 compared to amalgam. Probabilistic sensitivity analysis (Monte Carlo simulation) predicted amalgam would be cost-effective 49.2% of the time compared to HVGIC at 50.6% of the time at a willingness to pay threshold of US$237 per failure prevented. Personnel accounted for more than half the cost burden for both methods; instruments and supplies accounted for about one third. The per restoration cost to replace amalgam with HVGIC ranges from US$1 to a savings of US$0.84. CONCLUSION: Replacing amalgam with a high-viscosity glass-ionomer as part of the ART method comes at a minimal increase in cost for governments. Increasing the number of restorations seems to diminish the cost burden. CLINICAL SIGNIFICANCE: ART/HVGIC could be considered a viable alternative to amalgam in primary teeth.

Critical review of the safety assessment of nano-structured silica additives in food.

The development of nano-materials is viewed as one of the most important technological advances of the 21st century and new applications of nano-sized particles in the production, processing, packaging or storage of food are expected to emerge soon. This trend of growing commercialization of engineered nano-particles as part of modern diet will substantially increase oral exposure. Contrary to the proven benefits of nano-materials, however, possible adverse health effects have generally received less attention. This problem is very well illustrated by nano-structured synthetic amorphous silica (SAS), which is a common food additive since several decades although the relevant risk assessment has never been satisfactorily completed. A no observed adverse effect level of 2500 mg SAS particles/kg body weight per day was derived from the only available long-term administration study in rodents. However, extrapolation to a safe daily intake for humans is problematic due to limitations of this chronic animal study and knowledge gaps as to possible local intestinal effects of SAS particles, primarily on the gut-associated lymphoid system. This uncertainty is aggravated by digestion experiments indicating that dietary SAS particles preserve their nano-sized structure when reaching the intestinal lumen. An important aspect is whether food-borne particles like SAS alter the function of dendritic cells that, embedded in the intestinal mucosa, act as first-line sentinels of foreign materials. We conclude that nano-particles do not represent a completely new threat and that most potential risks can be assessed following procedures established for conventional chemical hazards. However, specific properties of food-borne nano-particles should be further examined and, for that purpose, in vitro tests with decision-making cells of the immune system are needed to complement existing in vivo studies.

Prediction models and risk assessment for silicosis using a retrospective cohort study among workers exposed to silica in China.

This study aims to develop a prognostic risk prediction model for the development of silicosis among workers exposed to silica dust in China. The prediction model was performed by using retrospective cohort of 3,492 workers exposed to silica in an iron ore, with 33 years of follow-up. We developed a risk score system using a linear combination of the predictors weighted by the LASSO penalized Cox regression coefficients. The model's predictive accuracy was evaluated using time-dependent ROC curves. Six predictors were selected into the final prediction model (age at entry of the cohort, mean concentration of respirable silica, net years of dust exposure, smoking, illiteracy, and no. of jobs). We classified workers into three risk groups according to the quartile (Q1, Q3) of risk score; 203 (23.28%) incident silicosis cases were derived from the high risk group (risk score ≥ 5.91), whilst only 4 (0.46%) cases were from the low risk group (risk score < 3.97). The score system was regarded as accurate given the range of AUCs (83-96%). This study developed a unique score system with a good internal validity, which provides scientific guidance to the clinicians to identify high-risk workers, thus has important cost efficient implications.

[Toxicological assessment of nanostructured silica. IV. Immunological and allergological indices in animals sensitized with food allergen and final discussioin].

This paper is the final in a series of publications on the assessment of subacute oral toxicity of nanostructured silica (SiO2). Preparation studied was a commercial nanopowder of SiO2, obtained by hydrolysis of tetrachlorosilane in the gaseous phase with the size of primary nanoparticles (NPs) of 5­30 nm. The experiment was conducted in 95 male Wistar rats weighing 150­180 g, divided into 6 groups numbering 25 (group 1), 26 (group 2), 11 (groups 3­6) of animals. The aqueous dispersion of SiO2 after sonication was administered to animals of groups 2, 4 and 6 for 28 days by intragastric gavage at a dose of 100 mg/kg of body weight per day. Animals of groups 1, 3, and 5 were treated with deionized water. On the 1st, 3d, 5th and 21st day of experiment the rats of groups 1, 2, 3 and 4 were sensitized intraperitoneally with hen's egg ovalbumin (OVA) adsorbed to aluminum hydroxide. Intravenous administration of the challenge dose OVA to rats in groups 1 and 2 was carried out on the 29th day. In the same period animals of groups 3­6 were bled for analysis of cellular immunity. There were evaluated the severity of systemic anaphylaxis reaction, the level of specific IgG antibodies to OVA in sensitized animals, state of erythrocytes, platelets and leukocytes of peripheral blood using standard methods. Using flow cytometry there were measured contents of lymphocyte populations of B-lymphocytes (CD45RA+), total T-lymphocytes (CD3+), T-helper cells (CD4+), T-cytotoxic cells (CD8+), NKcells (CD161a+), phagocytic activity of polymorphonuclear leukocytes in respect of latex particles. Serum levels of TNFα and IL-10 cytokines were determined by ELISA. The result showed that NPs SiO2, at dose of 100 mg/kg body weight had no any marked effect on severity of active anaphylactic shock and level of specific antibodies. The changes in cellular immunity under the influence of nanomaterial had similar direction in sensitized and non-sensitized animals and were more pronounced in the latter. Based on the discussion of the results, together with data from previous publications it was concluded that oral maximum level without observable adverse effect (NOAEL) of nanostructured SiO2 is located below 100 mg/kg body weight.

[Toxicological assessment of nanostructured silica. III. Microecological, hematological indices, state of cellular immunity].

This paper is the third in a series of publications on the experimental study of subacute oral toxicity of nanostructured silicon dioxide (SiO2). We used commercial nanostructured SiO2, obtained by hydrolysis of tetrachlorosilane in the gaseous phase, with the size of the primary nanoparticles (NPs) of 5-30 nm. The aqueous dispersion of SiO2 after treatment with ultrasound was administered to rats with initial weight of 80 +/- 5 g for the first 30 days by intragastric gavage and further for 60 days with diets in doses of 0.1; 1.0; 10 and 100 mg/kg body weight per day. Animals of the control group were treated with deionized water. The amount of basic and transient populations of gut microbiocenosis, hematological indexes were measured using standard methods. Specific content of the B-lymphocytes (CD45RA+), total T-lymphocytes (CD3+), T-helper cells (CD4+), T-cytotoxic cells (CD8+), NK-cells (CD161a+) in general population of lymphocytes was evaluated byflow cytometry; serum cytokine levels of TNF-alpha, IL-6, IL-10 were determined by ELISA. No significant changes in the qualitative and quantitative composition of the intestinal microbiota populations regardless of the dose of administered nanomaterial have been found. This gave reason to believe that the postulated mechanism of the toxic effects of the NPs of SiO2, mediated by modification of the composition of the intestinal microflora and the corresponding changes in its functional activity, apparently, is not realized. The main target of nanostructured SiO2 was the T-cellular system of the immune system of animals, that was manifested in the significant decrease of the number of leukocytes (33%), number of T-helper cells (13%), CD4/CD8 ratio (27%) and increasing the number of cytotoxic lymphocytes (19%) and the level of TNF-alpha (590%). The value of the maximum dose (NOAEL) of nanostructured SiO2, has no effect on T-cell immunity was not more than 100 mg/kg body weight per day.

[Toxicological assessment of nanostructured silica. I. Integral indices, adducts of DNA, tissue thiols and apoptosis in liver].

Nanostructured amorphous silica (SiO2) is widely used in food additives, pharmaceuticals and cosmetics. Available data on the oral toxicity of this nanomaterial (NM) in vivo, obtained in acute and subacute experiments are contradictory. The purpose of this study is evaluation of some parameters of toxicity of nanostructured SiO2 when orally administered to rats for 3 months. We used commercial SiO2 preparation, obtained by gas-phase hydrolysis of tetrachlorosilane with a size of the primary nanoparticles close to 5-30 nm, which was characterized as NM by several independent methods. SiO2 in the form of sonicated aqueous dispersion was administered to male rats with initial weight of 80 +/- 4 g for the first 30 days by intragastric gavage and then for 62 days with consumed diets in daily dose of 0,1; 1,0; 10 and 100 mg/kg body weight. The control animals received vehicle--deionized water. Weight gain, relative mass of internal organs, intestinal permeability to protein macromolecules (determination of ovalbumin level in blood serum by solid-phase bivalent immunoassay), urinary excretion of oxidative degradation product of DNA 8-oxo-2-deoxyguanosine (8-oxo-G) (by reversed phase HPLC), the level of thiol compounds in liver (spectrophotometrically), liver cell apoptosis (flow cytometer), fixing efficiency of passive avoidance (CRPA) have been measured. It has been shown that three-month administration of nanostructured SiO2 in all doses resulted in animal body weight decrease by 10-15%; a significant increase in adrenal weight was noticed under doses of 1 and 10 mg/kg and urinary 8-oxo-G excretion was significantly reduced at the dose 10 mg/kg. At the maximum dose of NM, 100 mg/kg, after 2 months of administration the number of animals decreased that entered the dark compartment of the experimental setup at initial testing of CRPA. The rest of the studied indices did not experience any significant changes depending on the dose of NM. It is concluded that no toxic effect were expressed in indices studied under the influence of nanostructured SiO2 in rats at daily doses up to 100 mg per kg body weight for 3 months.

Assessment of nanoparticle exposure in nanosilica handling process: including characteristics of nanoparticles leaking from a vacuum cleaner.

Nanosilica is one of the most widely used nanomaterials across the world. However, their assessment data on the occupational exposure to nanoparticles is insufficient. The present study performed an exposure monitoring in workplace environments where synthetic powders are prepared using fumed nanosilica. Furthermore, after it was observed during exposure monitoring that nanoparticles were emitted through leakage in a vacuum cleaner (even with a HEPA-filter installed in it), the properties of the leaked nanoparticles were also investigated. Workers were exposed to high-concentration nanosilica emitted into the air while pouring it into a container or transferring the container. The use of a vacuum cleaner with a leak (caused by an inadequate sealing) was found to be the origin of nanosilica dispersion in the indoor air. While the particle size of the nanosilica that emitted into the air (during the handling of nanosilica by a worker) was mostly over 100 nm or several microns (µm) due to the coagulation of particles, the size of nanosilica that leaked out of vacuum cleaner was almost similar to the primary size (mode diameter 11.5 nm). Analysis of area samples resulted in 20% (60% in terms of peak concentration) less than the analysis of the personals sample.

Exposure-response analysis and risk assessment for lung cancer in relationship to silica exposure: a 44-year cohort study of 34,018 workers.

Crystalline silica has been classified as a human carcinogen by the International Agency for Research on Cancer (Lyon, France); however, few previous studies have provided quantitative data on silica exposure, silicosis, and/or smoking. We investigated a cohort in China (in 1960-2003) of 34,018 workers without exposure to carcinogenic confounders. Cumulative silica exposure was estimated by linking a job-exposure matrix to work history. Cox proportional hazards model was used to conduct exposure-response analysis and risk assessment. During a mean 34.5-year follow-up, 546 lung cancer deaths were identified. Categorical analyses by quartiles of cumulative silica exposure (using a 25-year lag) yielded hazard ratios of 1.26, 1.54, 1.68, and 1.70, respectively, compared with the unexposed group. Monotonic exposure-response trends were observed among nonsilicotics (P for trend < 0.001). Analyses using splines showed similar trends. The joint effect of silica and smoking was more than additive and close to multiplicative. For workers exposed from ages 20 to 65 years at 0.1 mg/m(3) of silica exposure, the estimated excess lifetime risk (through age 75 years) was 0.51%. These findings confirm silica as a human carcinogen and suggest that current exposure limits in many countries might be insufficient to protect workers from lung cancer. They also indicate that smoking cessation could help reduce lung cancer risk for silica-exposed individuals.