Evaluation of the in vivo Mutagenicity of Nickel Subsulfide in the Lung of F344 gpt delta Transgenic Rats Exposed by Intratracheal Instillation: A Collaborative Study for the gpt delta Transgenic Rat Mutation Assay

Abstract

This study was conducted to evaluate the effectiveness of a transgenic rat mutation assay using F344 gpt delta rats. We investigated the mutagenic potential in the lung of nickel subsulfide (Ni₃S₂), an insoluble fine-crystalline-metallic compound and a carcinogen in the rodent and human lung. Ni₃S₂ carcinogenicity has been proposed to act via both genotoxic and non-genotoxic mechanisms. Ni₃S₂ was intratracheally instilled into male gpt delta rats at doses of 0.5 and 1 mg/animal once a week for four weeks; these doses of Ni₃S₂ are high enough to induce inflammation in the lung. Following a period of 28 and 90 days after the first administration, the gpt mutant frequencies (MFs) in lung were determined in four independent laboratories, and Spi⁻ selection for larger deletion mutations was done in one laboratory. The gpt MFs of the rats treated with Ni₃S₂ were not increased: all four laboratories obtained similar results with no statistical differences. The Spi⁻ MFs were also not increased by exposure to Ni₃S₂. These results indicate that intratracheally instilled Ni₃S₂ is non-mutagenic in the lung of gpt delta transgenic rats; however, whether Ni₃S₂ is non-mutagenic in the lung or it induces mutations which are not detectable by transgenic rodent mutation assays requires further investigation.