title: Hemolytic anemia, thrombosis, and infarction in male and female F344 rats following gavage exposure to 2-butoxyethanol.
abstract: 2-butoxyethanol (BE; ethylene glycol monobutyl ether) is used extensively in the manufacture of a wide range of domestic and industrial products which may result in human exposure and toxicity. BE causes severe hemolytic anemia in male and female rats and mice. In a recent report, female F344 rats exposed to 500 ppm BE by inhalation and sacrificed moribund on day 4 of treatment exhibited disseminated thrombosis associated with infarction in several organs. In contrast, no such lesions were observed in male rats similarly exposed to BE. Additional studies were therefore undertaken to compare the effects of BE in rats of both sexes. Rats received 250 mg BE/kg/day by gavage for 1, 2 or 3 days and were sacrificed 24 or 48 hr after the last dose. Control rats received 5 ml/kg water. Progressive time-dependent hemolytic anemia--macrocytic, hypochromic, and regenerative--was observed in both sexes of rats exposed to BE. Additionally, BE caused significant morphological changes in erythrocytes, first observed 24 hr after a single dose, including stomatocytosis, macrocytosis with moderate rouleaux formation, and spherocytosis. These morphological changes became progressively more severe as BE dosing continued and included the occasional occurrence of schistocytes and ghost cells, rouleaux formation in rats of both sexes, and an increased number of red blood cells with micronuclei in female rats. Overall, the progression of hemolytic anemia and morphological changes as a function of the number of days of exposure varied with gender and suggested a faster onset of hemolysis in female rats. The range of BE-related histopathological changes noted in both sexes was comparable; however, while these lesions were observed in female rats following a single dose, similar effects were first observed in males after 3 consecutive days of exposure to BE. Pathological changes involved disseminated thrombosis in the lungs, nasal submucosa, eyes, liver, heart, bones and teeth, with evidence of infarction in the heart, eyes, teeth and bones. Hemoglobinuric nephrosis and splenic extramedullary hematopoiesis were also noted. An apparent correlation between the severity of hemolytic anemia and subsequent disseminated thrombosis in BE-treated rats is proposed. Thrombosis may be related to intravascular hemolysis, which could be triggered by procoagulant release and/or alterations in erythrocyte morphology, as well as increased rigidity.
authors.affiliation: National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. Ghanayem@niehs.nih.gov
authors.forename: B I
authors.initials: BI
authors.lastname: Ghanayem
authors.forename: P H
authors.initials: PH
authors.lastname: Long
authors.forename: S M
authors.initials: SM
authors.lastname: Ward
authors.forename: B
authors.initials: B
authors.lastname: Chanas
authors.forename: M
authors.initials: M
authors.lastname: Nyska
authors.forename: A
authors.initials: A
authors.lastname: Nyska
mesh_terms: D000284:Administration, Oral; D000743:Anemia, Hemolytic / Q000139:chemically induced* / Q000473:pathology; D000747:Anemia, Hypochromic / Q000139:chemically induced / Q000473:pathology; D000748:Anemia, Macrocytic / Q000139:chemically induced / Q000473:pathology; D000818:Animals; D004912:Erythrocytes / Q000187:drug effects / Q000473:pathology; D005026:Ethylene Glycols / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology; D006461:Hemolysis / Q000187:drug effects; D007238:Infarction / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D009804:Odontoblasts / Q000187:drug effects / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D012737:Sex Factors; D012997:Solvents / Q000008:administration & dosage / Q000633:toxicity*; D013927:Thrombosis / Q000139:chemically induced* / Q000473:pathology; D014070:Tooth / Q000187:drug effects / Q000473:pathology
chemical_list: D005026:Ethylene Glycols; D012997:Solvents; C017096:n-butoxyethanol