Assessment of the Haemolytic Activity of 2-Butoxyethanol and its Major Metabolite, Butoxyacetic Acid, in Various Mammals Including Humans

Abstract

2-Butoxyethanol (BE) is a glycol ether produced in volumes exceeding 335 million pounds/year for industrial and domestic uses. BE causes acute haemolytic anaemia in rats and some other mammals. While BE is inactive in vitro, 2-butoxyacetic acid (BAA) is a potent haemolytic agent in vivo and in vitro. This finding suggests that metabolic activation of BE to BAA is required for haemolysis of erythrocytes to occur in vivo. Haemolysis of red blood cells (RBC) by BAA is preceded by swelling (increased mean cell volume [MCV] and haematocrit [HCT]). In an attempt to assess the potential risk to humans exposed to BE, studies were designed to determine the in vitro effect of BAA on RBCs from 10 mammalian species including humans. Blood samples from each mammalian species (n=3-5) were incubated with BAA at a final concentration of 0 (vehicle), 1 or 2 mM and kept at 37°C in a gently shaking water bath. Complete blood counts (CBCs) were measured at 0, 1, 2 and 4 h. BAA caused a time- and concentration-dependent increase in MCV and HCT of blood from rats, mice and hamsters (rodents), rabbits (lagomorphs), and baboons (primates). In contrast, blood from pigs (artiodactyis), dogs and cats (carnivores), guinea pigs (rodents/marsupials), and humans (primates), was minimally affected by BAA. These results were confirmed in guinea pigs and rats in vivo. Gavage administration of BE (250 mg kg-1) to rats resulted in increased MCV and HCT followd by haemolysis (decreased RBCs). Identical treatment with BE resulted in no significant change in these parameters in guinea pigs. These data clearly demonstrated that BE-induced haemolytic anaemia is species-dependent. This information may prove important for selecting appropriate animal models for use in the assessment of the health risk to humans exposed to BE. Future studies will focus on the cellular basis of the differential sensitivity of RBCs from various mammals to BAA.