2-Butoxyethanol (BE) is a massively produced glycol
ether of which more than 230 million pounds was produced in the United States in 1983. It is extensively used in
aerosols and cleaning agents intended for household use. This creates a high potential for human exposure during its manufacturing and use. A single exposure of rats to BE causes severe
hemolytic anemia accompanied by secondary
hemoglobinuria as well as liver and kidney damage. Butoxyacetic
acid (BAA) was earlier identified as a urinary metabolite of BE. In addition, we have recently identified two additional urinary metabolites of BE, namely, BE-
glucuronide and BE-
sulfate conjugates. The current studies were undertaken to investigate the metabolic basis of BE-induced hematotoxicity in male F344 rats. Treatment of rats with
pyrazole (
alcohol dehydrogenase inhibitor) protected rats against BE-induced hematotoxicity and inhibited BE metabolism to BAA.
Pyrazole inhibition of BE metabolism to BAA was accompanied by increased BE metabolism to BE-
glucuronide and BE-
sulfate as determined by quantitative high-performance liquid chromatography analysis of BE metabolites in urine. There was approximately a 10-fold decrease in the ratio of BAA to BE-
glucuronide + BE-
sulfate in the urine of rats treated with
pyrazole + BE compared to rats treated with BE alone. Pretreatment of rats with
cyanamide (
aldehyde dehydrogenase inhibitor) also significantly protected rats against BE-induced hematotoxicity and modified BE metabolism in a manner similar to that caused by
pyrazole. Administration of equimolar doses of BE, the metabolic intermediate
butoxyacetaldehyde, or the ultimate metabolite BAA caused similar hematotoxic effects.
Cyanamide also protected rats against
butoxyacetaldehyde-induced hematotoxicity. Further evidence of the involvement of metabolism in hematotoxicity was demonstrated by the administration of
deuterium-labeled BE (1,1-dideuterio-2-BE) which resulted in a significant delay in the development of hematotoxicity. It is therefore concluded that: a) there is a strong correlation between the amount of BAA in the urine and BE-induced hematotoxicity; b) metabolic activation of BE via alcohol and
aldehyde dehydrogenases is a prerequisite for the development of BE-induced hematotoxicity; and c) hematotoxicity induced by BE can be attributed to its metabolite BAA. Finally, the current studies may prove beneficial in the treatment of acute glycol
ethers poisoning with
alcohol dehydrogenase inhibitors.