A research to develop a predicting system of mammalian subacute toxicity. I. Prediction of subacute toxicity using the biological parameters of acute toxicities.
Predicting equations of subacute toxicity were developed by analyzing rat acute and subacute toxicity data of 56 chemicals of various structures. Minimum or 10% effect level in acute or subacute toxicity was estimated as a "biological parameter". Good regression equations were established between the geometrical means ("combined parameters") of any two of the parameters of acute and subacute toxicities and introduction of log P to the equations improved the correlations with a statistically significant multiple regression coefficient. The lowest predicted effect level of the subacute toxicity, which is selected from the data calculated by the above several correlations, can predict the upper limit of the no observed effect level. In recent years, for research and development of new chemical substances, it becomes one of the important factors that these have a lower environmental load in nature. Eventually, it becomes essential to evaluate not only their acute effects on human or environments, but also their chronic influences when they are to be exposed for a long period of time, and the cost for such verification is becoming a breaking factor for research and development. Thus, the development of a new technique which estimates the environmental load of a chemical substance including toxic effects on human with lower cost is now being attempted. For example, the development of in vitro new alternative methods using cultured cells, the utilization of a data base or software which relates mammalian and environmental toxicities and so on are internationally carried forwards. As for the latter, quantitative structure-activity relationship (QSAR) techniques have been applied practically to decide appropriate toxicity tests needed for regulatory purposes by EPA/TSCA, ITC/TSCA and FDA/FDAA in the USA. In addition, it was concluded recently in a joint meeting of EU and US-EPA that the approach by QSAR techniques was useful to specify the new chemical substances which are to be required toxicological examinations. In these QSAR techniques, however, while there are some considerations about common mechanisms of toxicity among chemicals with a similar structure (Congeneric chemicals, Congeners) for establishing of correlation formulas, for chemicals with various structures (Non-congeneric chemicals, Non-congeners) there often lack such common considerations. In addition, biological or physiological factors which are basic toxic indices are often ignored. In a previous study, we researched acute and subacute oral toxicities of industrial common chemicals in rats and reported the followings; 1) their subacute toxicological spectrum in target organs/tissues and morphologic changes was very limited and specific, 2) the important targets were liver, kidneys, blood (spleen) and stomach and these are considered the sites of dominant exposure due to the kinetics of chemical substances, 3) the morphological changes were hepatocellular hypertrophy, deposition of substance in renal tubules, extramedullary hematopoiesis in spleen and mucous lesion in stomach, and these are implying adaptation such as induction of drug-metabolizing enzymes, overload to renal function, anemia from erythrocyte destruction, and direct reaction, respectively, 4) there seems to occur a series of direct and adaptive reactions to exclude the "foreign compounds" which do not show any specific biological activities, 5) it is also considered that there is a possibility to establish a correlation between toxicological findings or target organs/tissues of both acute and subacute toxicities by their continuity. Therefore, in the present study, a predicting equation of subacute (28-day repeated dose) toxicity is attempted to develop from acute (single dose) toxicity data by considering both common mechanisms and biological factors for non-congeneric industrial chemical substances.