Model-Inferred Hypothesis of A Critical Dose for Overload Tumor Induction by Diesel Soot and Carbon Black

Abstract

The application of the POCK model of pulmonary clearance and retention to new experimental results of chronic inhalation studies with rats exposed for 2 yr to diesel exhaust or carbon black is reported. For the first time in lifetime studies with these carbonaceous aerosols, experimental data became available for paniculate mass burdens in the lung-associated lymph nodes. Furthermore, seven out of eight lifetime runs used exposure rate indices causing lung overload and lung tumors. The simulations of the POCK model were consistent with previous POCK representations of diesel soot and carbon black exposure studies. The new data on lifetime patterns of lymph node loads, however, required an adjustment of the interstitial kinetics in order to account for the apparent lymph-node load stagnation after about 1 yr of chronic exposures leading to lung overload. The consistently observed coincidence of lymph-node load stagnation and tumor induction in the new exposure studies occurred always in a situation where overload caused a pronounced increase of the interstitial particle burden. These observations were thought to support a hypothesis that assumed the time integral of the interstitial burden as an effective relative dose for a rat-specific overload carcinogenesis. Depending on aerosol material and rat strain, common critical values of this dose relating to both lymph-node load stagnation and tumor induction were postulated and calculated by using the model-inferred simulation data. The low precision of the experimental data indicating lymph-node load stagnation rendered the results semiquantitative. However, a plausible evaluation of the sparse empirical dose-response data of overload carcinogenesis for the two carbonaceous aerosols yielded no-effect thresholds commensurable and compatible with the critical dose values.