EVALUATION OF CHEMICAL MYELOTOXICITY USING AN IN VIVO LEUKEMIA TRANSPLANT MODEL

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Up to 30% of the Fischer 344/N strain of rats used in the NTP 2- year toxicity and carcinogenicity studies develop spontaneous leukemia commencing at about 18 months, which reduces the sensitivity for the detection of chemical leukemogenesis. An in vivo cell transplant model was developed to transfer leukemic spleen cells from a rat with spontaneous leukemia into young, healthy recipient rats. After expression of the disease leukemic spleen cells from those rats were again used for transplantation to maintain the leukemic cell line in vivo. The morphological and biochemical responses in organs and cells from the transplanted rats were characterized to better discriminate between age- induced and chemically-enhanced leukemia. The tumor morphology in the spontaneous and transplanted cases was identical, but the time to expression of the tumor was reduced from 18 months to 2 months. Changes in the activities of malate dehydrogenase, glucose-6-phosphate dehydrogenase, and acetylcholinesterase from the leukemic blood and spleen mononuclear cells provided consistent and unequivocal biochemical evidence of leukemia prior to other common clinical signs of the disease. These tumor marker enzymes demonstrated progressive changes in the course of leukemia that were directly associated with the severity of the disease. The validity of the model for predicting the long-term leukemogenic potency of chemicals was demonstrated by conducting short-term studies with 2-ethoxyethanol and pyridine, chemicals that respectively decreased and increased the incidence of leukemia in previous 2- year carcinogenicity tests. Similar studies are underway with additional positive and negative leukemogenic chemicals to confirm that the leukemia transplant model could detect both the presence and absence of carcinogenic activity in chemicals with structural dissimilarities, and to provide a valid data base for future investigations.