It has been demonstrated by others that metal ions can affect the immunocompetence of the B- or T-lymphocytes both in vivo and in vitro. It has also been reported that both cAMP and cGMP are involved with lymphocyte transformation although there are conflicting views as to the specific role of each. Our studies have shown the Pb2 ion, Cd2 ion and Cr3 ion at a concentration of 10 to the minus 7th power M in the culture medium or 0.01 ppm in the drinking water of mice for 4 weeks can significantly alter lymphocyte DNA, RNA and protein turnover enzyme activity and blastogenesis and thus modify the immunocompetence of the animal. This has been supported by our preliminary findings with respect to the resistance to MOPC-104E tumors. Pb2 ion and Cd2 ion and Cr3 ion increased the resistance to the tumor. We prepare to extend our previous in vitro and in vivo studies and examine the effect of exposure to trace metals on the functional response of the lymphocytes. Among the procedures will be: measurement of lymphocyte transformation (DNA, RNA, protein synthesis, enzyme activity, blastogenesis); Metal effects on mitogen binding, precursor uptake, cell-free macromolecule synthesis; Plaque forming cell response; cell mediated immune response. To examine the effect at the cellular level, we will investigate: cell types and interactions involved; cyclic nucleotide metabolism and the role of calcium. These experiments should generate data that will demonstrate the mechanisms by which metal ions bring about their cellular effects and the possible role in the etiology of disease of the immune system.