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 manifestation 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 cellular biochemistry, and oncogenetic expressions and transplanted cases were similar, but the time to tumor was reduced from 18 months to 2 months. The accuracy and sensitivity of the transplant model for predicting the long-term leukemogenic potency of chemicals was confirmed in short-term assays with two chemicals (2-ethoxyethanol, 4-hexylresorcinol) that had decreased, and three chemicals that had increased (pyridine, dichlorvos, 2,4,6- trichlorophenol) the prevalence of leukemia in previous 2-year toxicity and carcinogenicity studies. Additional studies with this transplant model revealed structure-activity relationships between chemicals containing the glycol ether structure and the repression of leukemia.