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The d-ala-d activity in erythrocytes (RBC), femur bone marrow, liver and brain of mice was determined using a modification of the method of Berlin and Schaller (1974). In vitro incubation of lead acetate (PbAc) with these tissues resulted in a dose-dependent inhibition of the d-ala-d activity. The lead concentration which caused a 50% inhibition of the d-ala-d activity after 10 min incubation [ED-50(10 min)] was 0.78 mg PbAc/femur bone marrow, 3.72 micrograms PbAc/ml RBC, 15.85 micrograms PbAc/g brain and 43.05 micrograms PbAc/g liver. An increase in the incubation time to 60 min reduced these ED-50 values between 44% for the erythrocytic enzyme and 67% for the brain enzyme. In vivo treatment of mice with oral lead administration (absorbed dose range: 1-100 micrograms PbAc/kg b.w.) for 1 or 3 months led to a dose-dependent and organ-specific inhibition of the d-ala-d activity. After 3 months of oral lead supply the maximum enzyme inhibition (54%) was found in the bone marrow. At the same time the lowest enzyme inhibition could be seen in the brain which retained 73% of its activity. The erythrocytic and liver enzyme activity was 71% and 72% resp. of the appropriate control. Within 3 weeks after completing the oral lead administration the brain enzyme activity was completely restored. The erythrocytic and liver enzyme activities were still significantly, but not very markedly inhibited, whereas the bone marrow d-ala-d remained seriously depressed. According to these experiments, the lead dose which causes a long term inhibition of the bone marrow and erythrocytic d-ala-d activities is assumed to range between 50 and 100 micrograms PbAc/kg b.w. and day, as an absorbed dose.

The half-life of the indian ink elimination (carbon clearance method) was used as a measure of the RES activity. A significant increase of the RES activity in mice was found already after a single intraperitoneal (i.p.) administration of 20, 50, or 100 micrograms PbAc/kg body weight (b.w.). A significant RES stimulation could also be demonstrated after a single or 10-day oral administration of lead at doses of 10-1,000 micrograms PbAc/kg b.w. No RES stimulation occurred, however, after 30-day oral administration of lead. On determining the reactivity of the RES to 1 microgram endotoxin/kg b.w. it was found that it was already limited after a single and 10-day oral lead administration. After 30-day oral administration of lead (doses 10-1,000 micrograms PbAc/kg b.w.) the reactivity of the RES was completely suppressed. After a single and 10-day oral administration of lead (doses 10-1,000 micrograms PbAc/kg b.w.) we observed a marked leucocytosis. This effect was most clearly seen after a dose of 100 micrograms PbAc/kg b.w.; the leucocyte counts were increased by up to 50% in comparison with controls. After 30-day oral administration of lead, such a leucocytosis was no longer detectable. In accordance with the findings on the RES, the leucocytosis that is normally induced in the animals by 1 microgram endotoxin/kg b.w. was significantly reduced or completely suppressed both after single and also after 10 and 30 days' oral administration of lead at doses of 100 and 1,000 micrograms PbAc/kg b.w. These results show that the resistance state of the mouse is impaired already by low doses of lead.

Lead levels in whole blood could be determined reliably up to a lower limit of 2 micrograms/100 ml blood, using a modified micromethod of the graphite tube furnace technique. Lead contents of various tissues were also determined by using the automated graphite tube furnace after wet ashing of the organs with nitric acid in autoclaves. Animal experiments with mice showed no measurable increase in blood lead level after a single, 10- or 30-days oral administration of lead in doses of 10--1000 micrograms lead acetate/kg body weight/day. However, these doses led to a rise in tissue lead content. There was a clear dependence of tissue lead content on type of organ examined, lead dose and duration of lead exposure. According to our experiments, the threshold dose which leads to a long-term increase in tissue lead content is assumed to be about 100 micrograms lead acetate/kg body weight/day, orally administered.

The influence of lead on the number of nucleated bone marrow cells and pluripotent stem cells in femur bone marrow was investigated in mice. It was found that neither a single nor 10 days' oral administration of lead at doses of 10-1,000 micrograms PbAc/kg b.w. led to any change in the bone marrow cellularity. After 1 month's oral administration of 1,000 micrograms PbAc/kg b.w., on the other hand, there was a significant reduction of nucleated bone marrow cells and pluripotent stem cells in the femur bone marrow of up to 20% in comparison with controls. Within 14 days after completing the lead administration, however, normal values in the bone marrow cellularity were found again. Three months' oral administration of lead at doses of 100 and 1,000 micrograms PbAc/kg b.w. led to a significant reduction in nucleated bone marrow cells and pluripotent stem cells in the femur bone marrow of up to 28% compared with the controls. In contrast to the experiments with 1 month's oral administration of lead the regeneration of the bone marrow was not completed 14 days after completing the administration of the lead. These results show that lead at doses above 100 micrograms PbAc/kg b.w. causes on long-term administration a clear reduction of the nucleated bone marrow cells combined with a depressed regeneration ability of the pluripotent stem cells.