The development of forestomach tumours in the mouse following exposure to 2-butoxyethanol by inhalation: studies on the mode of action and relevance to humans.
2-Butoxyethanol, a forestomach carcinogen in mice exposed by inhalation, has been shown to enter the forestomach as a result of grooming and ingestion of material condensed on the skin and fur during exposure. The material entering the stomach concentrates in the forestomach region and persists for at least 48 h post-exposure. Mice given single oral doses of either 2-butoxyethanol or 2-butoxyacetic acid, daily for 10 days, developed a marked hyperkeratosis in the forestomach. 2-Butoxyacetic acid was more potent than 2-butoxyethanol, the NOEL for the former being 50 mg/kg and for the latter, 150 mg/kg. Although a dose dependent increase in cell replication was also seen with both chemicals, the results were confounded by a high labelling rate in the controls. There was no evidence of significant binding of radiolabelled 2-butoxyethanol to proteins in stomach tissues. 2-Butoxyethanol was metabolised in vitro in both mouse and rat forestomach and glandular stomach fractions by alcohol dehydrogenases forming 2-butoxyacetaldehyde which was rapidly converted by aldehyde dehydrogenases to 2-butoxyacetic acid. There was a marked species difference in alcohol dehydrogenase activity between rats and mice with the maximum rates up to one order of magnitude greater in mouse than rat. The alcohol and aldehyde dehydrogenases were heavily concentrated in the stratified squamous epithelium of the forestomach of both rats and mice whereas in the glandular stomach the distribution was more diffuse. In human stomach both enzymes were evenly distributed throughout the epithelial cells of the mucosa. It is concluded that 2-butoxyethanol is ingested following inhalation exposure and concentrates in the forestomach where it is metabolised to 2-butoxyacetic acid which causes cellular damage, increased cell replication and hyperkeratosis. These changes are believed to lead to the tumours seen in mice exposed to 2-butoxyethanol for a lifetime. Differences in structure and enzyme distribution between the rodent and human stomach suggest that the responses seen in the mouse are unlikely to occur in humans.
Green
Trevor
T
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, SK10 4TJ, Cheshire, UK. trevor.green@syngenta.com
Toghill
Alison
A
Lee
Robert
R
Moore
Richard
R
Foster
John
J
D000280:Administration, Inhalation; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D002455:Cell Division / Q000187:drug effects; D005026:Ethylene Glycols / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005766:Gastrointestinal Contents / Q000737:chemistry; D006651:Histocytochemistry; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D011485:Protein Binding; D051381:Rats; D012997:Solvents / Q000008:administration & dosage / Q000633:toxicity*; D013274:Stomach Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology
D005026:Ethylene Glycols; D012997:Solvents; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase; C017096:n-butoxyethanol