Glycol ethers comprise a large class of chemicals with ethylene-based glycol ethers being the most heavily produced. They are widely used for many industrial and domestic purposes and therefore constitute a significant risk for human exposure and toxicity.
While ethylene glycol monomethyl ether (EGME) mainly targets the reproductive, developmental, and immune systems, an increase in the length of the alkyl carbon chain decreases such toxicities and increases the hemolytic activity, with ethylene glycol monobutyl ether (EGBE) being the most potent. Exposure of certain animal species to EGBE causes acute hemolytic anemia. EGBE-induced hemolysis in vivo is preceded by swelling and morphological alterations of rat erythrocytes. In viva, ethylene glycol ethers are metabolized to alkoxyacetic acids, various conjugates, CO2, and ethylene glycol. Inhibition of the alcohol dehydrogenases in rats results in protection against toxicity in association with a drastic decrease in alkoxyacetic acids formation. Further, while EGBE causes minimal or no effect in vitro, butoxyacetic (BAA) causes time- and concentration-dependent swelling, decreased deformability. and hemolysis of erythrocytes. These data clearly proved that activation of EGBE to BAA is a prerequisite for the development of hematotoxicity in vivo. Structure-hemolysis relationship studies demonstrated that BAA is the most efficacious of all alkoxyacetic acids and the presence and position of the ether linkage were very critical for the development of hematotoxicity. Comparison of the in vitro effects of BAA on blood obtained from various mammals showed that rats, mice, hamsters, rabbits, and baboons were highly sensitive, while pigs, dogs, cats, guinea pigs, and humans were minimally affected. These in vitro findings were confirmed in vivo using guinea pigs and rats.
In addition to the hemolytic activity, there is evidence that exposure of animals to ethylene glycol ethers causes myelotoxicity. Administration of EGME or EGEE causes bone marrow hemorrhage and hypocellularity, suppression of granulocyte-macrophage progenitor colony formation, and inhibition of erythropoiesis in rats and mice. Comparison of the bone marrow toxicity of the three major ethylne glycol ethers demonstrated that their potency ranking was EGME> EGEE> EGBE. with EGBE being relatively inactive.
EGBE-induced hemolytic anemia is age-dependent with older rats being more susceptible. Further, erythrocytes obtained from old rats were more susceptible to BAA than those obtained from young rats. Repetitive daily exposure of rats to small doses of EGBE resulted in tolerance with declined sensitivity to EGBE-induced hemolysis. Tolerance to EGBE is apparently related to the fact that older cells are more susceptible to EGBE/BAA, and their hemolysis during initial exposure is followed by their replacement with less susceptible young cells. Calcium channel blockers provided significant protection against EGBE-induced hemolytic anemia in rats, and also against BAA-induced effects on rat blood in vitro. Finally, effects observed in rats are indicative of an interaction of BAA with the erythrocyte membrane. Since there are significant species differences in the sensitivity to ethylene glycol ethers, investigation of the molecular effects of alkoxyacetic acids on the membrane may prove critical to more accurately assess the potential risks of humans exposed to these chemicals.