Animal Models

Hakkinen, Pertti J.; Witschi, Hanspeter

doi:10.1007/978-3-642-69521-6_4

Cited by 3 publications

(2 citation statements)

References 65 publications

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“…The physiology of the respiratory system has been well characterized in this species [208,209] and much of the information on drug -induced effects on ventilatory control and mechanisms of airway disease has been obtained in the rat [164,210] . The physiology of the respiratory system has been well characterized in this species [208,209] and much of the information on drug -induced effects on ventilatory control and mechanisms of airway disease has been obtained in the rat [164,210] .…”

Section: Species Selectionmentioning

confidence: 99%

Current Practices in Safety Pharmacology

Bass¹,

Siegl²,

Gintant³

et al. 2007

Preclinical Development Handbook

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Section: Species Selectionmentioning

confidence: 99%

Current Practices in Safety Pharmacology

Bass¹,

Siegl²,

Gintant³

et al. 2007

Preclinical Development Handbook

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“…Rats and dogs are considered appropriate species for general use in safety pharmacology studies of the respiratory system. The physiology of the respiratory system has been well characterised in both of these species [47] and much of the information on drug‐induced effects on ventilatory control and mechanisms of airway disease has been obtained from these species [4,48]. These species are also readily available from animal vendors, are easy to handle, and have the appropriate temperament for conscious respiratory measurements.…”

Section: Design Of Respiratory Function Safety Studiesmentioning

confidence: 99%

Assessment of respiratory function in safety pharmacology

Murphy

2002

Fundamemntal Clinical Pharma

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Workshop Summary: Phosgene-Induced Pulmonary Toxicity Revisited: Appraisal of Early and Late Markers of Pulmonary Injury From Animal Models With Emphasis on Human Significance

Pauluhn

Carson

Costa

et al. 2007

Inhalation Toxicology

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A workshop was held February 14, 2007, in Arlington, VA, under the auspices of the Phosgene Panel of the American Chemistry Council. The objective of this workshop was to convene inhalation toxicologists and medical experts from academia, industry and regulatory authorities to critically discuss past and recent inhalation studies of phosgene in controlled animal models. This included presentations addressing the benefits and limitations of rodent (mice, rats) and nonrodent (dogs) species to study concentration x time (C x t) relationships of acute and chronic types of pulmonary changes. Toxicological endpoints focused on the primary pulmonary effects associated with the acute inhalation exposure to phosgene gas and responses secondary to injury. A consensus was reached that the phosgene-induced increased pulmonary extravasation of fluid and protein can suitably be probed by bronchoalveolar lavage (BAL) techniques. BAL fluid analyses rank among the most sensitive methods to detect phosgene-induced noncardiogenic, pulmonary high-permeability edema following acute inhalation exposure. Maximum protein concentrations in BAL fluid occurred within 1 day after exposure, typically followed by a latency period up to about 15 h, which is reciprocal to the C x t exposure relationship. The C x t relationship was constant over a wide range of concentrations and single exposure durations. Following intermittent, repeated exposures of fixed duration, increased tolerance to recurrent exposures occurred. For such exposure regimens, chronic effects appear to be clearly dependent on the concentration rather than the cumulative concentration x time relationship. The threshold C x t product based on an increased BAL fluid protein following single exposure was essentially identical to the respective C x t product following subchronic exposure of rats based on increased pulmonary collagen and influx of inflammatory cells. Thus, the chronic outcome appears to be contingent upon the acute pulmonary threshold dose. Exposure concentrations high enough to elicit an increased acute extravasation of plasma constituents into the alveolus may also be associated with surfactant dysfunction, intra-alveolar accumulation of fibrin and collagen, and increased recruitment and activation of inflammatory cells. Although the exact mechanisms of toxicity have not yet been completely elucidated, consensus was reached that the acute pulmonary toxicity of phosgene gas is consistent with a simple, irritant mode of action at the site of its initial deposition/retention. The acute concentration x time mortality relationship of phosgene gas in rats is extremely steep, which is typical for a local, directly acting pulmonary irritant gas. Due to the high lipophilicity of phosgene gas, it efficiently penetrates the lower respiratory tract. Indeed, more recent published evidence from animals or humans has not revealed appreciable irritant responses in central and upper airways, unless exposure was to almost lethal concentrations. The comparison of acute inhalation s...

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Animal Models

Cited by 3 publications

References 65 publications

Current Practices in Safety Pharmacology

Current Practices in Safety Pharmacology

Assessment of respiratory function in safety pharmacology

Workshop Summary: Phosgene-Induced Pulmonary Toxicity Revisited: Appraisal of Early and Late Markers of Pulmonary Injury From Animal Models With Emphasis on Human Significance

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