Previous work done in this laboratory showed that acute exposure to 2-butoxyethanol (BE; ethylene glycol monobutyl ether) causes severe hemolytic anemia. The present investigations were conducted to elucidate the mechanisms of BE-induced hemolytic anemia. The kinetics of 14C-BE metabolism and clearance were studied in control adult (3-4 mo) and old (12-13 mo) male F344/N rats and in rats treated with pyrazole or probenecid. These studies showed no difference in the half-life (t1/2) of BE in adult and old rats. However, t1/2, area under the curve (AUC), and maximum plasma concentration (MPC) of its major metabolite, butoxyacetic acid (BAA) were significantly greater in older rats. This difference was more pronounced at high doses. Pretreatment of rats with pyrazole resulted in a significant increase in the t1/2 and AUC of BE, but significantly decreased MPC of BAA. Probenecid had no effect on t1/2, AUC, or MPC of BE, but significantly increased the t1/2 and AUC of BAA. The mechanisms of BE-induced hematotoxicity were also investigated in vitro. Incubation of BE with blood from F344 male rats caused no hemolysis and resulted in no metabolic alterations of BE. In contrast, incubation of BAL or BAA caused time- and concentration-dependent swelling of RBCs followed by hemolysis, however, BAA was significantly more efficacious than BAL. These effects of BAA and BAL were associated with a parallel depletion of Blood ATP. Similar in vitro studies indicated that BAA causes minimal swelling or hemolysis of human RBCs at concentrations several fold higher than what is required to cause complete hemolysis of rat RBCs. Further, BAA caused minimal or no effect on human blood ATP levels. Investigation of the Structure-hematotoxicity relation-ships of alkoxyacetic acids in vitro revealed that maximum effect was obtained with an alkoxy chain of 4 carbons (butoxy) and declined with 6 carbons chain (methoxypentoxy). Similar relationships were found in regard to the effect of alkoxyacetic acids on blood ATP.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES021109-02
Application #
3918648
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code