Several substrains of C3H show markedly different responses to endotoxin. C3H/HeJ mice have markedly reduced endotoxin-induced mortality, macrophage responses, B-lymphocyte responses, and hematopoietic responses in irradiated mice. C3HeB/FeJ mice have much larger "normal" responses to endotoxin. By exchanging bone marrow (BM) in these two substrains, we hoped to determine whether the hematopoietic cellular response or the non-transplantable environmental cell response was the cause of the various differences observed. It has already been shown by others that the low or absent B-lymphocyte responses of the C3H/HeJ are due to alteration in the cells. Similarly, the lack of production of the granulocyte colony-stimulating factor (CSF) by macrophages and the inhibitor prostaglandin E after endotoxin is a defect of the cell. Our first concern was whether mortality after large doses of endotoxin was related to responses by the cells of the hematopoietic system. In a preliminary study, C3H/HeJ or C3H/FeJ mice were exposed to a lethal dose (950 rads) of gamma radiation and salvaged by injection of 6-9 x 106 BM cells. After the donor BM had replaced that of the host (> 45 days), animals were given an intraperitoneal injection of 500 micrograms Salmonella typhosa endotoxin. This dose invariably kills all the C3HeB/FeJ (eB) mice and spares all the C3H/HeJ (He) mice. The results showed: eB + eB BM, 17/17 dead or 100%; eB + He BM, 23/26 dead or 88%; He + He BM, 0/6 or 0% dead; and He + eB BM, 6/9 or 67% dead. These preliminary studies suggest that mortality after endotoxin is partly due to hematopoietic cell responses and partly due to environmental factors. This is in agreement with the data of others suggesting some of the responses are under single gene control (CSF production, B-lymphocyte responses) and some are under multigene control (mortality and splenic granulocyte stem cell responses). In this light, we have begun to consider variations in lethal response for various strains. Data to date are as follows: after 500 microgram Salmonella typhosa LPS-B; 20/20 dead; HeJ, 0/20 dead; HeN, 3/5 dead; HeJ-(+/+ of the Wx line), 6/7 dead and HeJ(Wx), 6/8 dead.