EVALUATION OF CHEMICAL MYELOTOXICITY USING AN IN VIVO LEUKEMIA TRANSPLANT MODEL

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A leukemia transplant model for F344 rat leukemia was developed to investigate the mechanism(s) of carcinogenicity in a defined tumor model and to help discriminate between age-induced and chemically-enhanced leukemia. Retrospective analyses acetaminophen suggested that the chemical reduced the tumor latency period and accelerated the expression of leukemia only in the female, but not in the male transplant recipients. A prospective analysis of the potential association between propylene glycol monomethyl ether and leukemia was also evaluated: there was no effect of the chemical at any dose level on tumor progression in rats given leukemia transplant. The influence of cyclo-hexanone oxime or butanone oxime on glycol alkyl ether toxicity were negative, even though it was reported that oximes might interfere with the metabolism of ethers to alcohol and thus enhance toxicity. Structure-activity studies of dimethyl phosphate esters were continued because these chemicals were shown to be associated with increased incidences of leukemia. Additional studies with the transplant assay addressed structure-activity relationships for chemicals that were negative for leukemic trends. The aldehyde and acid metabolites of ethylene glycol monomethyl ether (2-ME) did not affect tumor progression in the leukemia transplant model: the anti-leukemic activity was restricted to the parent compound, 2-ME. Because aniline derivatives reduced the incidence of leukemia and the spleen is a primary site for the tumor proliferation. Investigations of the structure-activity relationships between p-chloraniline, HCI or N, N-dimethylaniline, splenic fibrosis, and leukemia were begun.