Acute inhalation studies with irritant aerosols: technical issues and relevance for risk characterization

Abstract

Current testing conventions for inhalation toxicity studies require that solid and non-volatile liquid compounds are converted to respirable aerosol, which is often achieved by laboratory-specific technical methodologies. So far, internationally harmonized approaches are lacking that would allow comparison of results from inhalation studies with 'contrived' test aerosols taking into account the actual particle size of the product as it might be encountered in normal handling and use. The focus of this paper is to consider aerosols of irritant substances eliciting their mode of action on sites of initial deposition within the respiratory tract of rats. Assessment is based on conventional endpoints, such as mortality (LC(50)), and sublethal endpoints that include an analysis for the concentration-effect relationship of protein in bronchoalveolar lavage fluid (BAL-protein) as a sensitive, early marker of lung edema. This retrospective analysis also addresses whether common denominators can be found for different aerosol sizes of direct and indirect irritants, such as monomeric and polymeric diphenylmethane-4,4'-diisocyanate (mMDI and pMDI), naphthylene diisocyanate (NDI), dicyclohexylmethane-4,4'-diisocyanate (HMDI), 2,4-triisopropyl-benzene-diisocyanate (TRIDI) and substances (e.g., chlorofluoroalkyl side-chain fungicides) known to decompose to irritant intermediates in the lining fluids of the airways. Collectively, this analysis shows that for irritant aerosols both the concentration and the particle size are equally important for the outcome of the test, independent of whether the endpoint chosen is lethality or BAL protein. The scientific value of 1-h exposures to high aerosol concentrations, as required by some regulations, could be challenged because high concentrations and high respirability of aerosol appear to be mutually exclusive, as shown for mMDI and NDI (LC(50 )>2000 mg/m(3)). Thus, for a meaningful risk characterization, test results from inhalation studies with 'contrived properties' due to the specific techniques employed need to be compared with the real properties of substances as marketed, handled and used.

Acute Nose-Only Exposure of Rats to Phosgene. Part I: Concentration × Time Dependence of LC50s, Nonlethal-Threshold Concentrations, and Analysis of Breathing Patterns

“…In brief, after complete exsanguination, the excised lungs were weighed and then lavaged twice with 5 ml saline (kept at 37 • C) per rat and the 2 washings combined. More details of the lavage technique have been published elsewhere (Pauluhn, 2002(Pauluhn, , 2004a(Pauluhn, , 2004b(Pauluhn, , 2004c. Samples of bronchoalveolar lavage fluid were analyzed for factors indicative of a lower respiratory tract injury and especially endpoints considered to be sensitive markers of instability of or damage to the alveolar capillary barrier.…”

Simultaneous Measurement of the Effective Density and Chemical Composition of Ambient Aerosol Particles

“…Environmentally, the chemical and physical properties influence particle optical properties and their ability to act as cloud condensation nuclei (CCN); the optical properties and CCN ability dictate the magnitude of the direct and indirect effects of particles on climate, respectively ( − ). Health impacts are influenced by the chemical toxicity of the particle and the ability of particles to penetrate deep into the lung ( − ). Furthermore, environmental and health effects are exacerbated by increased particle concentrations ( , ).…”

Acute Nose-Only Exposure of Rats to Phosgene. Part II. Concentration × Time Dependence of Changes in Bronchoalveolar Lavage During a Follow-Up Period of 3 Months

“…The design of this study took into account published evidence from previous inhalation studies with phosgene gas in mice and rats (Currie et al, 1987;Hatch et al, 2001;Duniho et al, 2002;Sciuto et al, 2003) and other lower respiratory tract irritants in rats (Pauluhn, 2000a(Pauluhn, , 2000b(Pauluhn, , 2002(Pauluhn, , 2004a(Pauluhn, , 2004b(Pauluhn, , 2004c, utilizing endpoints sensitive in detecting irritantrelated pulmonary injury. Although mice may be useful for FIG.…”