Time-to-tumor dose threshold analysis for intratracheal particle instillation-induced lung tumors in a large carcinogenicity study.

Abstract

BACKGROUND AND OBJECTIVES: A comprehensive time-to-tumor analysis of the 16 dose groups which received intratracheal instillations of "respirable granular bio-durable particles without known significant specific toxicity" (GBP) in a large carcinogenicity study with rats should be conducted. METHODS: The primary lung tumors were mathematically treated as observed in an incidental context (non-fatal occult tumors), based on biological observations and on the fact that lifetime was not considerably reduced even in groups with high tumor frequency. Maximum likelihood estimates of the parameters of time-to-tumor multistage Weibull models were calculated. RESULTS: Retained dust volume is a highly significantly better dose measure than instilled dust mass, where particle size is taken into account; there is no empirical support for a dose threshold from this study. CONCLUSIONS: Carcinogenicity studies with intratracheal instillation can lead to results that are relevant for the assessment of relative carcinogenic potencies of particles. A dose threshold for GBP is not supported.