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Inhalation toxicology
Hemisphere Pub. Corp.
Inhalation toxicology

Hemisphere Pub. Corp.

0895-8378

Inhalation toxicology/Journal Inhalation toxicologySCIISTP
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    Influence of aerodynamic particle size on botulinum neurotoxin potency in mice

    Jeremy A. BoydstonJohn J. YeagerJill R. TaylorPaul A. Dabisch...
    7页
    查看更多>>摘要：Objective: For many agents, the aerodynamic particle size can affect both the virulence and disease course in animal models. Botulinum neurotoxins (BoNTs), which are widely known as potential bioterrorism agents, have been shown to be toxic via multiple routes of exposure, including small particle inhalation (1-3 μm MMAD). However, the impact of larger particle sizes on the potency of BoNT has not been previously reported. In this study, we compared the potency of BoNT in small and large particle aerosols. Materials and methods: Outbred mice (ICR (CD-1?)) were exposed to BoNT-containing aerosols with differing mass median aerodynamic diameters (MMADs) of 1.1,4.9, and 7.6 microns. The effects of bioaerosol sampler and inhalation exposure modality were studied. Results and discussion: Collecting aerosolized BoNT onto gelatin filters or into liquid impingers resulted in equivalent estimates of aerosol concentration. Nose-only and whole-body inhalation exposure resulted in nearly identical estimates of the median lethal dose (LD50). The LD50 for inhaled BoNT increased approximately 50-fold when the median aerodynamic particle size was increased from 1.1 to 4.9 μm, from 139 (95% CI: 111-185) to 7324 (95% CI: 4287-10891) mouse intraperitoneal median lethal doses (MIPLD50). These results demonstrate the importance of aerodynamic particle size and regional deposition patterns with regards to BoNT inhalational toxicity. Conclusions: These data will be useful for medical countermeasure development, as well as biodefense preparedness modeling by demonstrating that the estimates of dose and toxicity of an inhaled aerosol containing BoNT can be significantly affected by a range of factors.
      原文链接:
    • NSTL

    Long-term exposure to formaldehyde induced down-regulation of SPO11 in rats

    Pan GeXiang ZhangYan-qi YangMo-qi Lv...
    10页
    查看更多>>摘要：Objective: Formaldehyde, a ubiquitous environmental contaminant, has long been suspected of causing male reproductive injury, but the underlying molecular mechanism remains largely unknown. SPO11 is a meiosis-related gene, whose absence can cause spermatogenesis arrest. Materials and methods: The present study aimed to explore the role of SPO11 in male reproductive injury induced by long-term formaldehyde exposure, so as to further understand the molecular mechanism of formaldehyde-induced male reproductive toxicity. Adult male Sprague-Dawley rats (n = 24, 245 ± 22 g) were randomly divided into four groups of six (n = 6) and were exposed to formaldehyde gas at doses of 0 (control), 0.5, 2.46 and 5 mg/m3, respectively, via inhalation for 8 consecutive weeks. Results and dissussion: The expression levels of SPO11 were detected in testicular tissues by realtime quantitative polymerase chain reaction, immunofluorescence, and Western blot. The results indicated that the expression of SPO11 was inhibited by formaldehyde exposure in a dose-dependent manner. Furthermore, the histopathological results showed that testicular seminiferous tubules were atrophied, spermatogenic cells were decreased and the lumina were oligozoospermic in the 2.46 and 5 mg/m3 formaldehyde exposure groups. Combined with the morphometric results, we found that the downregulated expression levels of SPO11 were consistent with the changes of testicular seminiferous tubule diameter and seminiferous epithelium height in testicular tissue, suggesting that SPO11 might be one of the main targets of formaldehyde reproductive toxicity. Conclusions: In conclusion, our findings indicated that SPO11 might be related to male reproductive injuries induced by long-term formaldehyde exposure.
      原文链接:
    • NSTL

    Discrepancies of asbestos body and fiber content between formalin-fixed and corresponding paraffin embedded lung tissue

    Barbara K. KuhnFabio BarresiHolger DresselBart Vrugt...
    7页
    查看更多>>摘要：Background: Formalin-fixed lung tissue and paraffin blocks containing peripheral lung tissue obtained from subjects with an occupational asbestos exposure are both regarded to be suitable to determine asbestos load. Because sample preparation of paraffin blocks requires a more intense treatment than formalin-fixed tissue, we tested whether asbestos analysis of formalin-fixed lung tissue and paraffin blocks obtained from the same patients deliver comparable results. Materials and methods: We determined numbers of asbestos bodies (AB) and amphibole asbestos fibers (AF) in formalin-fixed lung tissue and corresponding paraffin blocks from 36 patients. For AB counts, samples were digested in sodium hypochlorite. For AF analysis, tissue was freeze-dried and then ashed. Results were reported as numbers of AB and AF per gram dry lung tissue. Results: Both AB counts as well as AF counts were lower in paraffin blocks than formalin-fixed lung tissue. Compared to formalin-fixed tissue, the limit of detection was higher for paraffin blocks, rendering more results from paraffin blocks not interpretable than from formalin-fixed tissue (8 samples versus 1 for AB and 15 samples versus 4 for AF). Discussion and conclusion: Asbestos analysis of paraffin blocks may lead to underestimation of asbestos exposure. This should be considered when assessing occupational asbestos exposure through lung dust analysis in medico-legal evaluation.
      原文链接:
    • NSTL

    Intramuscular cobinamide as an antidote to methyl mercaptan poisoning

    Tara B. Hendry-HoferPatrick C. NgAlison M. McGrathKirsten Soules...
    8页
    查看更多>>摘要：Background: Methyl mercaptan occurs naturally in the environment and is found in a variety of occupational settings, including the oil, paper, plastics, and pesticides industries. It is a toxic gas and deaths from methyl mercaptan exposure have occurred. The Department of Homeland Security considers it a high threat chemical agent that could be used by terrorists. Unfortunately, no specific treatment exists for methyl mercaptan poisoning. Methods: We conducted a randomized trial in 12 swine comparing no treatment to intramuscular injection of the vitamin B12 analog cobinamide (2.0 mL, 12.5 mg/kg) following acute inhalation of methyl mercaptan gas. Physiological and laboratory parameters were similar in the control and cobina-mide-treated groups at baseline and at the time of treatment. Results: All six cobinamide-treated animals survived, whereas only one of six control animals lived (17% survival) (p = 0.0043). The cobinamide-treated animals returned to a normal breathing pattern by 3.8 ±1.1 min after treatment (mean±SD), while all but one animal in the control group had intermittent gasping, never regaining a normal breathing pattern. Blood pressure and arterial oxygen saturation returned to baseline values within 15 minutes of cobinamide-treatment. Plasma lactate concentration increased progressively until death (10.93 ±6.02 mmol [mean±SD]) in control animals, and decreased toward baseline (3.79 ±2.93 mmol [mean±SD]) by the end of the experiment in cobina-mide-treated animals. Conclusion: We conclude that intramuscular administration of cobinamide improves survival and clinical outcomes in a large animal model of acute, high dose methyl mercaptan poisoning.
      原文链接:
    • NSTL

    Phytol, not propylene glycol, causes severe pulmonary injury after inhalation dosing in Sprague-Dawley rats

    Andrew GigliottiHammad IrshadWendy DyeJacob McDonald...
    8页
    查看更多>>摘要：Introduction: The use of vaping pens for inhalation of cannabinoid derived products is rising and has become a popular alternative to smoking combustible products. For efficient product delivery, additives are sometimes added and vaping pens often may include compounds like Phytol or Propylene Glycol as thinning agents. This study aimed at comparing Phytol and Propylene Glycol with respect to potential toxicity and safe use in vaping products. Methods: Male and female Sprague Dawley rats were exposed to 5 mg/L of Phytol or Propylene Glycol for up to 6 hours over up to 14 days and monitored for clinical signs and changes in body weight. Gross necropsy and histopathology of respiratory tissue was performed to assess potential adverse effects. Results: Phytol exposed animals expressed severe clinical signs, body weight loss and mortality after one or two exposure days, leading to termination of all dose groups for this compound. Lung weights were increased and respiratory tissue was severely affected, demonstrating dose-responsive tissue degeneration, necrosis, edema, hemorrhage and inflammation. Propylene Glycol exposed animals did not show any adverse reactions after 14 days of high dose exposure. Conclusions: For Phytol, a low observed adverse effect level (LOAEL) was determined at <109.0/ 10.9 mg/kg/day presented/deposited dose and therefore its use as excipient in vaping product is not recommend; a safe exposure range was not established for Phytol. Propylene Glycol, in contrast, is considered safe with a no observed adverse effect level (NOAEL) at 1151.7/115.2 mg/kg/day pre-sented/deposited dose in rats.
      原文链接:
    • NSTL

    The role of lysosomal ion channels in lysosome dysfunction

    Rebekah L. KendallAndrij Holian
    14页
    查看更多>>摘要：Lysosomes offer a unique arrangement of degradative, exocytic, and signaling capabilities that make their continued function critical to cellular homeostasis. Lysosomes owe their function to the activity of lysosomal ion channels and transporters, which maintain concentration gradients of H+, K+, Ca2+, Na+, and Cl across the lysosomal membrane. This review examines the contributions of lysosomal ion channels to lysosome function, showing how ion channel function is integral to degradation and autophagy, maintaining lysosomal membrane potential, controlling Ca2+ signaling, and facilitating exocytosis. Evidence of lysosome dysfunction in a variety of disease pathologies creates a need to understand how lysosomal ion channels contribute to lysosome dysfunction. For example, the loss of function of the TRPML1 Ca2+ lysosome channel in multiple lysosome storage diseases leads to lysosome dysfunction and disease pathogenesis while neurodegenerative diseases are marked by lysosome dysfunction caused by changes in ion channel activity through the TRPML1, TPC, and TMEM175 ion channels. Autoimmune disease is marked by dysregulated autophagy, which is dependent on the function of multiple lysosomal ion channels. Understanding the role of lysosomal ion channel activity in lysosome membrane permeability and NLRP3 inflammasome activation could provide valuable mechanistic insight into NLRP3 inflammasome-mediated diseases. Finally, this review seeks to show that understanding the role of lysosomal ion channels in lysosome dysfunction could give mechanistic insight into the efficacy of certain drug classes, specifically those that target the lysosome, such as cationic amphiphilic drugs.
      原文链接:
    • NSTL

    Impaired exercise capacity in electrostatic polyester powder paint workers

    Ukbe SirayderDeniz Inal-InceCihangir AcikFerhan Soyuer...
    11页
    查看更多>>摘要：Purpose: Limited number of studies investigated the effects of Electrostatic powder paints (EPP) on human health. We investigated the effects of EPP exposure on lung function, exercise capacity, and quality of life, and the factors determining exercise capacity in EPP workers. Methods: Fifty-four male EPP workers and 54 age-matched healthy male individuals (control group) were included. Lung function and respiratory muscle strength were measured. The lower limit of normal (LLN) cut-points for FEV1 and FEV1/FVC were calculated. An EPT was used to evaluate bronchial hyperactivity. The handgrip and quadriceps muscle strength were evaluated using a hand-held dynamometer. An ISWT was used to determine exercise capacity. The physical activity level was questioned using the IPAQ. The SGRQ and NHP were used to assessing respiratory specific and general quality of life, respectively. Results: Duration of work, FEV1, MIP, handgrip strength, and ISWT distance were significantly lower, and the change in FEV1 after EPT and %HRmax were significantly higher in the EPP group compared to the control group (p < 0.05). There were no subjects with a < LLN for FEV1 and FEV1/FVC in both groups. In the EPP group, ISWT distance was significantly related to age, height, duration of work, FEV1, change in FEV1 after EPT, MIP, MEP, handgrip strength, IPAQ, SGRQ, and NHP total scores (p < 0.05). The change in FEV1 after EPT, MIP, and duration of work explained % 62 of the variance in the ISWT distance (p < 0.001). Conclusions: Changes in lung function based on LLN for the FEV1 and FEV1/FVC were not clinically relevant in EPP workers. Exercise capacity is impaired in EPP workers. Degree of exercise-induced bronchospasm, inspiratory muscle strength, and duration of work are the determinants of exercise capacity in EPP workers.
      原文链接:
    • NSTL

    Lung toxicity and gene expression changes in response to whole-body inhalation exposure to cellulose nanocrystal in rats

    Pius JosephChristina M. UmbrightJenny R. RobertsJared L. Cumpston...
    15页
    查看更多>>摘要：Objective: Human exposure to cellulose nanocrystal (CNC) is possible during the production and/or use of products containing CNC. The objectives of the current study were to determine the lung toxicity of CNC and the underlying molecular mechanisms of the toxicity. Methods: Rats were exposed to air or CNC (20 mg/m3, six hours/day, 14d) by whole-body inhalation and lung toxicity and global gene expression profile were determined. Results: Significant increases in lactate dehydrogenase activity, pro-inflammatory cytokine levels, phagocyte oxidant production, and macrophage and neutrophil counts were detected in the bronchoalveolar lavage cells or fluid from the CNC exposed rats. Mild lung histological changes, such as the accumulation of macrophages and neutrophils, were detected in the CNC exposed rats. Gene expression profiling by next generation sequencing identified 531 genes whose expressions were significantly different in the lungs of the CNC exposed rats, compared with the controls. Bioinformatic analysis of the lung gene expression data identified significant enrichment in several biological functions and canonical pathways including those related to inflammation (cellular movement, immune cell trafficking, inflammatory diseases and response, respiratory disease, complement system, acute phase response, leukocyte extravasation signaling, granulocyte and agranulocyte adhesion and diape-desis, IL-10 signaling, and phagosome formation and maturation) and oxidative stress (NRF2-mediated oxidative stress response, production of nitric oxide and reactive oxygen species in macrophages, and free radical scavenging). Conclusion: Our data demonstrated that inhalation exposure of rats to CNC resulted in lung toxicity mediated mainly through the induction of inflammation and oxidative stress.
      原文链接:
    • NSTL

    Risk assessment of components in tobacco smoke and e-cigarette aerosols: a pragmatic choice of dose metrics

    Peter M. J. BosLya G. Soeteman-HernándezReinskje Talhout
    15页
    查看更多>>摘要：Background: Risk assessment of individual tobacco smoke components is important for the purpose of prioritization or selecting chemicals for monitoring products. Smoking is characterized by a highly varying, intermittent exposure and the challenge is to choose the most appropriate dose metric. Methods: Generally, average daily exposure estimates are used as dose metric, without considering temporal determinants. The applicability hereof is discussed in the context of choosing dose metrics for local respiratory tract effects and for systemic effects in a smoking scenario or for the use of e-cigarettes. Results: Using average daily exposure estimates for the smoking scenario can lead to erroneous risk evaluations for several reasons. Inhaled peak air concentrations during a puff can be two to three orders of magnitude higher than the calculated average daily inhaled concentration, which may impact the assessment of both systemic and local health effects. A pragmatic risk assessment is proposed, based on the Margin of Exposure (MoE) approach. The choice of an appropriate dose metric, such as inhaled concentration, inhaled dose or absorbed dose, depends on the type of effect. Temporal characteristics should be considered in the final step of the MoE approach, as is illustrated by two cases, glycerol and benzene. Conclusion: The choice of an appropriate dose metric and inclusion of temporal determinants are important aspects in the risk assessment of individual smoke components. The proposed MoE approach provides the opportunity to weigh smoking-related exposure characteristics during the final step of the risk evaluation.
      原文链接:
    • NSTL

    Predictions of inter- and intra-lobar deposition patterns of inhaled particles in a five-lobe lung model

    Renate Winkler-HeilMajid HussainWerner Hofmann
    17页
    查看更多>>摘要：Objective: To develop a stochastic five-lobe lung model and to compute particle deposition fractions in the five lobes, considering anatomical as well as ventilatory asymmetry. Materials and methods: The stochastic five-lobe lung model was derived from an existing stochastic model for the whole lung, which implicitly contains information on the lobar airway structure. Differences in lobar ventilation and sequential filling of individual lobes were simulated by a stochastic lobar ventilation model. Deposition fractions of inhaled unit density particles in the five lobes were calculated by an updated version of the Monte Carlo deposition code Inhalation, Deposition, and Exhalation of Aerosols in the Lung (IDEAL). Results: Simulations for defined exposure and breathing conditions revealed that the two lower lobes receive higher deposition and the two upper lobes lower deposition, compared to the average deposition for the whole lung. The resulting inter-lobar distribution of deposition fractions indicated that the non-uniform lung morphometry is the dominating effect, while non-uniform ventilation only slightly enhances the lobar differences. The relation between average lobe-specific deposition fractions and corresponding average values for the whole lung allowed the calculation of lobe-specific deposition weighting factors. Discussion: Comparison with limited deposition measurements for upper vs. lower (U/L) and left vs. right (L/R) lobes revealed overall agreement between experimental and theoretical data. Calculations of the L/R deposition ratio for inhaled aerosol boli confirmed the hypothesis of Moller et al. that the right lung is less able to expand at the end of a breath because of the restrictive position of the liver.
      原文链接:
    • NSTL