Toxicological Sciences, Vol 51, 146-152, Copyright © 1999 by Society of Toxicology
RF Henderson, FF Hahn, JM Benson, EB Barr, WE Bechtold, DG Burt and AR Dahl
Butadiene diepoxide (BDO2), a metabolite of 1,3-butadiene (BD) and potent
mutagen, is suspected to be a proximate carcinogen in the multisite
tumorigenesis in B6C3F1 mice exposed to BD. Rats, in contrast to mice, do
not form much BDO2 when exposed to BD, and they do not form cancers after
exposure to the low levels of BD at which mice develop lung and heart
tumors. Tests were planned to determine the direct carcinogenic potential
of BDO2 in similarly exposed rats and mice, to see if they would develop
tumors of the lung (the most sensitive target organ in BD-exposed mice) or
other target tissues. The objective of the current series of studies was to
assess the acute toxicity and dosimetry to blood and lung of BDO2
administered by various routes to B6C3F1 mice and Sprague-Dawley rats. The
studies were needed to aid in the design of the carcinogenesis study.
Initial studies using intraperitoneal injection of BDO2 were designed to
determine the rate at which each of the species cleared the compound from
the body; the clearance was equally fast in both species. A second study
was designed to determine if the highly reactive BDO2, when deposited in
the lung, would enter the bloodstream from the lung; intratracheally
instilled BDO2 did enter the bloodstream, indicating that exposure via the
lungs would result in BDO2 reaching other organs of the body. In a third
study, rats and mice were exposed by inhalation for 6 h to 12 ppm BDO2 to
determine blood and lung levels of the compound. Concentrations of BDO2 in
the lung immediately after the exposure were 2 to 3 times higher than in
the blood in both species (approximately 500 and 1000 pmol/g blood in the
rat and mouse, respectively). As expected, mice received a higher dose/g
tissue than did rats, consistent with the higher minute volume/kg body
weight of the mice. The inhalation dosimetry study was followed by a
histopathology study to determine the acute toxicity to rodents following a
single, 6-h exposure to 18 ppm BDO2. No clinical signs of toxicity were
observed; lesions were confined to the olfactory epithelium where areas of
necrosis were observed. Analysis of bronchoalveolar lavage fluid did not
indicate pulmonary inflammation. Based on these findings, an attempt was
made to expose rats and mice repeatedly (for 7 days) to 10 and 20 ppm BDO2,
but these exposure concentrations proved too toxic, due to inflammation of
the nasal mucosa and occlusion of the nasal airway, a lesion that cannot be
tolerated by obligate nose breathers. Finally, the toxicity of rats and
mice exposed 6 h/day for 5 days to 0, 2.5, or 5.0 ppm BDO2 was determined.
The repeated exposures caused no clinical signs of toxicity, nor were any
lesions observed in the respiratory tract or other major organs. Therefore,
the final design selected for the carcinogenesis study comprised exposing
the rats and mice for 6 h/day, 5 days/week for 6 weeks to 0, 2.5, or 5.0
ppm BDO2.
ARTICLES
Dosimetry and acute toxicity of inhaled butadiene diepoxide in rats and mice
Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87185, USA. rhenders@Irri.org
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