The toxicity of 2-Butoxyethanol

Introduction

2-Butoxyethanol (ethylene glycol monobutyl ether; 2-BE) is a glycol ether used in several commercial and domestic products due to its hydrophilic and lypophilic properties[1].

Exposure

Human exposure is most likely to occur from inhalation and dermal absorption during the use of such products, and the UK occupational exposure standards (OES) set by HSE are 25 ppm (8 h TWA) and 50 ppm (15 min STEL). The UK biological monitoring health guidance value for urinary (free) butoxyacetic acid (BAA) measured post-shift is 240 mmol/mol creatinine. 2-BE and, more predominantly, its main metabolite, BAA, has been shown to cause hemolytic anaemia in laboratory animals. 2-BE is metabolised mainly via alcohol and aldehyde dehydrogenase (forming BAA), cytochrome P450 (forming ethylene glycol and carbon dioxide), and other minor pathways. BAA is required to develop hematotoxicity and, in humans, is excreted in the urine as both a free acid and (unlike rats) as the corresponding glutamine conjugate (BAA–GLN). The degree of conjugation varies extensively between individuals and within an individual, as shown by Rettenmeier et al., Corley et al., Johanson et al. and Jones and Cocker. Hence, it has been suggested that whilst free BAA in the blood may be a good marker of the risk associated with exposure to 2-BE (it is the active metabolite which causes haemolytic anaemia), its measurement in urine does not always accurately reflect the full extent of 2-BE exposure. Therefore, this creates uncertainty when interpreting studies that only consider free BAA in the urine[2].

Toxicity

2-Butoxyethanol is a widely used solvent in industrial and consumer products that has been shown to increase liver hemangiosarcomas in male B6C3F1 mice following chronic inhalation exposure. No increase in hemangiosarcomas was observed in similarly exposed female mice or male and female rats. 2-Butoxyethanol was shown to be negative for DNA reactivity in standard genotoxicity assays and bacterial mutagenesis assays, suggesting that the liver tumour response results from indirect or nongenotoxic mechanisms. Metabolism of 2-butoxyethanol occurs through alcohol and aldehyde dehydrogenases, yielding 2-butoxyacetaldehyde and 2-butoxyacetic acid, respectively. Although 2-butoxyethanol itself was negative for genotoxicity, the question remains whether the aldehyde metabolite is capable of reducing DNA damage in the target tissue of 2-butoxyethanol carcinogenicity.

Oxidative damage and DNA synthesis have previously been proposed to involve the selective induction of neoplasia in the mouse liver. Increases in the oxidative DNA lesion 8- hydroxydeoxyguanosine (OH8dG) were detected in the liver of mice subchronically exposed to 2-butoxyethanol, an increase that correlated with increased DNA synthesis. In mouse hepatocytes, no increase in oxidative DNA damage was seen following treatment with 2-butoxyethanol or 2-butoxyacetic acid, suggesting that the induction of oxidative damage seen in vivo occurred through an indirect effect of 2-butoxyethanol exposure. Exposure to 2- butoxyethanol results in hemolysis of RBCs in rodents. To address the effect of hemolysis, iron was evaluated for its ability to induce oxidative damage in mouse hepatocytes and significantly increased OH8dG levels. In the Syrian hamster embryo (SHE) cell transformation assay, 2-butoxyethanol or 2-butoxyacetic acid failed to induce morphological transformation, whereas ferrous sulfate increased cellular transformation. Iron increased DNA strand breaks in SHE cells, measured using the comet assay. These results provide evidence supporting the fact that the induction of oxidative DNA damage and carcinogenicity seen following 2-butoxyethanol exposure in vivo occurs through indirect or Oxidative damage, and DNA synthesis has previously been proposed to be involved in the selective induction of neoplasia in the mouse liver. Increases in the oxidative DNA lesion 8- hydroxydeoxyguanosine (OH8dG) were detected in the liver of mice subchronically exposed to 2-butoxyethanol, an increase that correlated with increased DNA synthesis. In mouse hepatocytes, no increase in oxidative DNA damage was seen following treatment with 2-butoxyethanol or 2-butoxyacetic acid, suggesting that the induction of oxidative damage seen in vivo occurred through an indirect effect of 2-butoxyethanol exposure. Exposure to 2- butoxyethanol results in hemolysis of RBCs in rodents. To address the effect of hemolysis, iron was evaluated for its ability to induce oxidative damage in mouse hepatocytes and significantly increased OH8dG levels. In the Syrian hamster embryo (SHE) cell transformation assay, 2-butoxyethanol or 2-butoxyacetic acid failed to induce morphological transformation, whereas ferrous sulfate increased cellular transformation. Iron increased DNA strand breaks in SHE cells, measured using the comet assay. These results provide evidence supporting the fact that the induction of oxidative DNA damage and carcinogenicity seen following 2-butoxyethanol exposure in vivo occurs through indirect or secondary effects rather than a direct effect of 2-butoxyethanol or metabolites.

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