Validation of intratracheal instillation as an alternative for aerosol inhalation toxicity testing

Sabaitis, C. P.; Leong, B. K. J.; Rop, D. A.; Aaron, C.S.

doi:10.1002/(sici)1099-1263(199903/04)19:2<133::aid-jat549>3.0.co;2-9

Cited by 18 publications

(18 citation statements)

References 6 publications

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“…However, after we reduced the dosing volume of the instillant and changed the dosing technique from ITI to intratracheal fast instillation (modified from the method initially developed by Sabaitis et al, 1999), we did not lose another mouse because of CNT administration and did not see CNTs remaining in the airways. Shvedova et al (2005), who used the pharyngeal aspiration technique in their large-scale (∼1000 animals) study, did not report animal deaths or CNTs not entering the alveolar region.…”

Section: A Highlights Of the Pulmonary Toxicity Studies-agreements Amentioning

confidence: 66%

“…It is also difficult to generate a controlled CNT concentration in a chamber and monitor particle size and the actual exposure level. Even with more workable dusts or powders of other compounds, the technical difficulty and cost associated with inhalation toxicity experimentation have led investigators to assess the effects of these aerosols in the lungs by intratracheal instillation (ITI) (Driscoll et al, 2000;Leong et al, 1998;Sabaitis et al, 1999).…”

Section: Toxicological Studies and Toxicity Of Manufactured Carbomentioning

confidence: 99%

“…Because a few animals died of suffocation in our pilot study, in our core study we reduced the volume of the dose to 50 µl/mouse and modified the instillation technique (Lam et al, 2004) by adopting the intratracheal fast instillation of Sabaitis et al (1999). We also replaced parenteral ketamine/xylazine anesthetic with isoflurane inhalation anesthetic to achieve quick anesthesia induction and reduce mucus production.…”

Section: Study Of Several Single-wall Carbon Nanotube Products In Micmentioning

confidence: 99%

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A Review of Carbon Nanotube Toxicity and Assessment of Potential Occupational and Environmental Health Risks

Lam

James

McCluskey

et al. 2006

Critical Reviews in Toxicology

1,097

654

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Nanotechnology has emerged at the forefront of science research and technology development. Carbon nanotubes (CNTs) are major building blocks of this new technology. They possess unique electrical, mechanical, and thermal properties, with potential wide applications in the electronics, computer, aerospace, and other industries. CNTs exist in two forms, single-wall (SWCNTs) and multi-wall (MWCNTs). They are manufactured predominately by electrical arc discharge, laser ablation and chemical vapor deposition processes; these processes involve thermally stripping carbon atoms off from carbon-bearing compounds. SWCNT formation requires catalytic metals. There has been a great concern that if CNTs, which are very light, enter the working environment as suspended particulate matter (PM) of respirable sizes, they could pose an occupational inhalation exposure hazard. Very recently, MWCNTs and other carbonaceous nanoparticles in fine (<2.5 µm) PM aggregates have been found in combustion streams of methane, propane, and natural-gas flames of typical stoves; indoor and outdoor fine PM samples were reported to contain significant fractions of MWCNTs. Here we review several rodent studies in which test dusts were administered intratracheally or intrapharyngeally to assess the pulmonary toxicity of manufactured CNTs, and a few in vitro studies to assess biomarkers of toxicity released in CNT-treated skin cell cultures. The results of the rodent studies collectively showed that regardless of the process by which CNTs were synthesized and the types and amounts of metals they contained, CNTs were capable of producing inflammation, epithelioid granulomas (microscopic nodules), fibrosis, and biochemical/toxicological changes in the lungs. Comparative toxicity studies in which mice were given equal weights of test materials showed that SWCNTs were more toxic than quartz, which is considered a serious occupational health hazard if it is chronically inhaled; ultrafine carbon black was shown to produce minimal lung responses. The differences in opinions of the investigators about the potential hazards of exposures to CNTs are discussed here. Presented here are also the possible mechanisms of CNT pathogenesis in the lung and the impact of residual metals and other impurities on the toxicological manifestations. The toxicological hazard assessment of potential human exposures to airborne CNTs and occupational exposure limits for these novel compounds are discussed Address correspondence to Chiu-wing Lam, JSC Toxicology Group, Space Life Sciences, NASA Johnson Space Center, SF23/Wyle, Houston, TX 77058, USA. E-mail: Chiu-wing. 189This document is a U.S. government work and is not subject to copyright in the United States. 190C.-W. LAM ET AL. in detail. Environmental fine PM is known to form mainly from combustion of fuels, and has been reported to be a major contributor to the induction of cardiopulmonary diseases by pollutants. Given that manufactured SWCNTs and MWCNTs were found to elicit pathological changes in the lungs, and SWCNTs...

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Section: A Highlights Of the Pulmonary Toxicity Studies-agreements Amentioning

confidence: 66%

Section: Toxicological Studies and Toxicity Of Manufactured Carbomentioning

confidence: 99%

Section: Study Of Several Single-wall Carbon Nanotube Products In Micmentioning

confidence: 99%

See 1 more Smart Citation

A Review of Carbon Nanotube Toxicity and Assessment of Potential Occupational and Environmental Health Risks

Lam

James

McCluskey

et al. 2006

Critical Reviews in Toxicology

1,097

654

View full text Add to dashboard Cite

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“…16 For this purpose, the upper incisors of the anaesthetized rat were held by a rubber band, which was fixed by two pins on the slant board. The tongue was gently moved to one side of the oral cavity, and then fully extended with small blunt forceps (Figure 3).…”

Section: Intratracheal Instillation Using the Avimentioning

confidence: 83%

An automatic video instillator for intratracheal instillation in the rat

Kim

Lee²,

Hwang³

et al. 2010

Lab Anim

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Intratracheal instillation (ITI) of a test compound is an alternative method to inhalation methods that require complex aerosol generation, exposure chambers and airflow monitoring instruments for exposing the lungs of animals to a test compound. For ITI in the rat, a laryngoscope is generally used for endotracheal intubation, and the procedure is difficult to perform. Therefore, we designed and constructed an automatic video instillator (AVI) for the accurate delivery of a dose of a test compound into the trachea of rats. The device has a videocamera probe for image guidance, and a liquid-crystal display for image display. These two items are used to visualize the larynx and trachea for intratracheal insertion of the tubing, and for placing the tip of the instillation tubing beyond the vocal cords for ITI of the test compound. After a 2 h training session on the use of the AVI in an anaesthetized rat, we assessed the utility of the device by ITI of 0.25% (w/v) solution of Evans Blue dye into the lungs of 30 isoflurane-anaesthetized rats. Necropsy examinations were performed on 20 rats immediately after the completion of the procedure, and on 10 rats three days after the procedure. Based on the results of these examinations, we concluded that the device could be used for rapid, reproducible and successful ITI of a test compound into the lungs of a rat by one operator. The pulmonary toxicology of environmental toxins to assess their physicochemical characteristics, such as the effect of particle size and distribution, and the biological response that follows their exposure in humans is studied frequently by either inhalation or intratracheal instillation (ITI) of the toxin in rodents.1 For pulmonary toxicity studies, specialized equipment that includes aerosol generators, airflow monitoring instruments, exposure chambers, exhaust systems and often analytical chemical support is required in order to deliver known amounts of the test compound into the lungs. Consequently, the need for this equipment increases the cost and technical complexity of such studies.2 ITI has become a feasible alternative method for delivering a toxin into the lung of rodents, 3 -6 because the required equipment is less sophisticated than that required for inhalation toxicity studies. 7 -9 This method is also simpler and safer than the inhalation method: many dose levels of compounds with a wide range of physicochemical properties and toxicity can be introduced rapidly into the lungs with minimal risk to the operator. Furthermore, ITI is used often as a screen to determine an appropriate dose range for inhalation toxicity studies. Despite the advantages of ITI over inhalation, the use of ITI for the pulmonary toxicology studies in rodents does have limitations.10 One such limitation is the resultant pulmonary distribution of the toxin. In inhalation studies, the distribution of the test compound in the right and left lungs is uniform, whereas it is non-uniform when using ITI. In addition, Lakatos et al. suggested that oropharynge...

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“…Therefore, all data were collected in a narrow time frame, immediately following the first and only exposure to a stimulus, be it exercise or aerosolized OVA. Breath sounds auscultated by stethoscopes or other devices have been used in rats effectively to model diseases in humans, particularly to assess acute responses to infectious or toxic agents (51,55,57). Moreover, despite the theoretical promise of digital signal processing of lung sounds, human auscultation remains the diagnostic tool of choice (3,16).…”

mentioning

confidence: 99%

A rat model of exercise-induced asthma: a nonspecific response to a specific immunogen

Kodesh¹,

Zaldivar²,

Schwindt³

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Exercise-induced bronchoconstriction (EIB) is common; however, key aspects of its pathogenesis are still unclear. We investigated the feasibility of adapting an established animal model of asthma to investigate the earliest stages of EIB. The hypothesis was that a single exposure to a normally innocuous, and brief, exercise challenge could trigger EIB symptoms in rats previously sensitized to ovalbumin (OVA) but otherwise unchallenged. Brown-Norway rats were sensitized by intraperitoneal injection of OVA at 0 and 2 wk. At week 3, animals were exposed to either aerosolized OVA (SS) or exercise (EXS). A trained, blinded, clinical observer graded EIB by respiratory sounds. Plasma and lung cytokine levels were analyzed. No control rats with or without exercise (EX, CON) showed evidence of EIB. Eighty percent of the SS group demonstrated abnormal breath sounds upon exposure to aerosolized OVA. Approximately 30% of EXS rats sensitized to OVA but exposed only to exercise had abnormal breath sounds. Lung tissue levels of TNF-α, IL-1α, growth-related oncogene/keratinocyte/chemoattractant, and IFN-γ were significantly higher (P < 0.001) in the SS group, relative to all other groups. Changes in most of these cytokines were not notable in the EXS rats, suggesting a different mechanism of EIB. Remarkably, IFN-γ, but not the other cytokines measured, was significantly elevated following brief exercise in both sensitized and unsensitized rats. Exercise led to detectable breathing sound abnormalities in sensitized rats, but less severe than those observed following classical OVA challenge. Precisely how this immune crossover occurs is not known, but this model may be useful in elucidating essential mechanisms of EIB.

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Validation of intratracheal instillation as an alternative for aerosol inhalation toxicity testing

Cited by 18 publications

References 6 publications

A Review of Carbon Nanotube Toxicity and Assessment of Potential Occupational and Environmental Health Risks

A Review of Carbon Nanotube Toxicity and Assessment of Potential Occupational and Environmental Health Risks

An automatic video instillator for intratracheal instillation in the rat

A rat model of exercise-induced asthma: a nonspecific response to a specific immunogen

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