Pulmonary Retention of Inhaled Anatase (Tio₂) Aerosols and Lung Tumor Induction in Rats Simulated by a Physiology-Oriented Model

Abstract

A physiology-oriented compartmental kinetics (POCK) model of alveolar retention of respirable, insoluble particles in rats was used to simulate the results of two subchronic inhalation tests with male Fischer rats exposed to submicron anatase TiO₂ particles of either 250 or 20 nm average size (Oberdorster et al., 1994). Earlier, the ultrafine variety had been used in a lifetime study with female Wistar rats (Heinrich & Fuhst, 1992) and the results were also subjected to POCK simulations. The database on anatase was not as extensive as in case of previous studies that used submicrometer carbonaceous aerosols. However, besides the usual results for the patterns of total lung burden and lymph node load, the new subchronic tests provided, for the first time, some data on anatase burdens of both the macrophage pool and the interstitium. Due to the scarcity of the data, the POCK simulation was not entirely unique, but good data representation was achieved with plausible model parameters. The substantial increase in interstitial deposits of the ultrafine anatase in comparison to the coarser sample required an increase by an order of magnitude for the rate coefficient of free particle mass transfer through the epithelial wall. The translocation of overloaded macrophages to the interstitium indicated a similar change, but Wistar rats appeared to have a lower base value. In general, the results of the simulations seem to confirm the usefulness and consistency of the model concept. At the end of the lifetime exposure study with ultra-fine anatase, conducted under high exposure rate indices up to 1330 mg/m³ × h/wk to achieve overload, Heinrich and Fuhst found lung tumors in 32% of the rats. This confirmed that overload carcinogenesis in rats is not related to molecular, DNA-reactive carcinogens. A previously proposed hypothesis of a critical dose for overload carcinogenesis in rats, which had been derived from experimental diesel soot and carbon black aerosol inhalation studies, yielded tumor induction characteristics for ultrafine anatase that were commensurable with the parameter values found for carbonaceous aerosols. This suggests that the integral over the residence time of the interstitial retention may be a consistent relative dose surrogate for overload lung tumor induction in rats. Its critical dose would correspond to a no-effect threshold. For the female Wistar rats and ultrafine anatase, this value was about 4000 mg × days. It matched closely, although probably by coincidence, the value for the female Wistar rats derived earlier from experimental diesel soot data.