ABSTRACT
A review of the toxicity studies of fibers by an expert panel has concluded that no single short-term in vitro test or a battery of tests can be used to predict the carcinogenicity potential of fibrous particles, and a 90-day subchronic inhalation test was recommended [12]. A two-tier approach was recommended by the ILSI panel experts for in vivo assays [3]. Tier 1 in vivo assays are proposed for pulmonary, oral, and skin exposures. Tier 1 evaluations include markers of inflammation, oxidant stress, and cell proliferation in the portal of entry and selected remote organs and tissues. Tier 2 evaluations are proposed only for pulmonary exposures. A four-week inhalation study by nose-only or whole-body exposure in male or female rats with up to three months’ observation is recommended for evaluating the toxicity and carcinogenic potential of nanomaterials. When inhalation exposure is not feasible, the panel concluded that other pulmonary exposure methods may be acceptable. Evaluation includes markers of damage, oxidant stress, cell proliferation, the degree/intensity and duration of pulmonary inflammation, and cytotoxic effects and histopathology of pulmonary and extrapulmonary organs/tissues. The tier 2 studies are aimed at obtaining additional information with respect to the deposition, translocation, biokinetics, and biopersistence of the nanomaterials to aid in interpreting the results for risk assessment. A similar testing strategy to assess the safety of nanomaterials was recommended by an expert panel convened at a European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) workshop [13]. Recently, a short-term rat inhalation study (STIS) for nanomaterials has been developed within the European FP6 project NanoSafe2 and the German BMBF project nanoCare [14]. The recommended STIS is a 28-day study with 5-day inhalation exposure (nose only) in male Wistar rats and a 3 weeks’ postexposure period. It comprises a comprehensive scheme of biological effects and marker determination in order to generate appropriate information on early key elements of pathogenesis, such as inflammatory reactions in the lung and indications of effects in other organs. BALF analysis, gross examination, and histological examination are conducted either immediately after the last exposure or three days after exposure and at termination of the study. Information on the persistence, progression, and/or regression of effects is obtained, and organ burden in the lung and potential translocation to other
tissues are addressed. The STIS uses less animals and resources, and the rankings of different nanomaterials relative to their potential to induce adverse effects by the STIS have been shown to be comparable to those of the corresponding subchronic and chronic studies [14, 15]. While the STIS cannot replace traditional chronic and subchronic inhalation studies, it may provide a tool for comparing toxicity of different nanomaterials and prioritizing them for further toxicity testing. This approach has been proposed to the OECD working party on manufactured nanomaterials.
