‘OXICOLOGY AND APPLIED PHARMACOLOGY 60, 313-323 (1981) Factors Influencing the Phagocytosis, Neoplastic Transformation, and Cytotoxicity of Particulate Nickel Compounds in Tissue Culture Systems MAX COSTA, MARIA P. ABBRACCHIO, AND JEANNIE SIMMONS-HANSEN Division of Toxicology. Department of Pharmacology, The University of Texas. Medical School at Houston, P.O. Box 20708. Houston, Texas 77025 Received January 19. 1981; accepted April 22, 1981 Factors Influencing the Phagocytosis, Neoplastic Transformation, and Cytotoxicity of Par- ticulate Nickel Compounds in Tissue Culture Systems. COSTA, M., ABBRACCHIO, M. P., AND SIMMONS-HANSEN, J. (1981). Toxicol. Appl. Pharmacol. 60, 313-323. Seven particulate nickel compounds were studied for their cell transformation activity using cultured Syrian hamster embryo cells and for their phagocytotic activity in cultured Chinese hamster ovary cells. The crystalline nickel compounds (aNi&. cuNiS, and NiJSel) had significantly more cell transforming activity and were more actively phagocytized than the other nickel com- pounds examined (amorphous NB, metallic Ni, Ni302, and NiO). Therefore, the crystalline structure of nickel compounds is one factor influencing their toxic activity upon biological systems. A second influencing factor was the particle size of the water-insoluble nickel com- pounds. Particles of crystalline aNiS ranging from 2 to 4 pm were phagocytized six times more than aNiS particles having mean diameters of 5-6 am. Differences in amorphous NiS particle size had little effect on its already low susceptibility to be phagocytized by cells and ability to cause a reduction of cell plating efficiency. The presence of Mn dust inhibited the neoplastic transformation of crystalline nickel sulfide and also reduced the phagocytosis of crystalline aNiS and aNi& particles by cultured cells. The phagocytosis of crystalline NiS particles was inhibited by the presence of amorphous NiS, Mn or MnCl?. Therefore, the presence of noncarcinogenic metals which are not themselves actively phagocytized diminishes the transforming effects of crystalline metal compounds probably by reducing their internal- ization. Various metabolic inhibitors such as dansylcadaverine, cycloheximide, and actino- mycin D reduced the phagocytosis of crystalline aNiS. Crystalline nickel sulfide compounds in- (Sunderman, 1979). The induction of ma- duced various types of cancers at exposure lignant tumors in experimental animals by sites following administration by inhalation Ni3S2 was dose dependent resulting in a high (Ottolenghi et al., 1977; Yarita and Net- incidence of tumors at the site of adminis- tesheim, 1978), by intramuscular injection tration (Sunderman, 1979). These studies in (Sunderman et al., 1980), by intrarenal in- experimental animals coupled with the epi- jection (Jasmin and Riopelle, 1976), by in- demiological studies implicating nickel com- tratesticular injection (Damjanov et al., pounds as causes of respiratory cancers in 1978) and by intraocular administration nickel refinery workers demonstrate a need (Sunderman et al., 1980). A number of an- to understand the cellular mechanisms of imal species also have been examined with carcinogenesis by nickel compounds (Les- respect to Ni3S2 carcinogenesis (See Sun- sard et al., 1978; Kreyberg, 1978; Doll et derman, 1979 for review). In some of these al., 1977). In particular structure/activity studies, amorphous nickel monosulfide (NiS) relationships are of interest because the also was tested but it failed to induce cancer striking differences in potency among nickel 313 0041-008X/81/110313-11%02.00/0 Copyright 0 1981 by Academic Pras. Inc. All rights of reproduction in any form reserved.