Dosimetry and acute toxicity of inhaled butadiene diepoxide in rats and mice

Butadiene diepoxide (BDO2), a metabolite of 1,3-butadiene (BD) and potent m utagen, is suspected to be a proximate carcinogen in the multisite tumorige nesis in B6C3F1 mice exposed to ED. Rats, in contrast to mice, do not form much BDO2 when exposed to ED, and they do not form cancers after exposure t o the low levels of ED at which mice develop lung and heart tumors. Tests w ere planned to determine the direct carcinogenic potential of BDO2 in simil arly exposed rats and mice, to see if they would develop tumors of the lung (the most sensitive target organ in ED-exposed mice) or other target tissu es. 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 ro utes to B6C3F1 mice and Sprague-Dawley rats. The studies were needed to aid in the design of the carcinogenesis study. Initial studies using intraperi toneal injection of BDO2 were designed to determine the rate at which each of the species cleared the compound from the body; the clearance was equall y fast in both species. A second study was designed to determine if the hig hly reactive BDO2, when deposited in the lung, would enter the bloodstream from the lung; intratracheally instilled BDO2 did enter the bloodstream, in dicating that exposure via the lungs would result in BDO2 reaching other or gans of the body. In a third study, rats and mice were exposed by inhalatio n for 6 h to 12 ppm EDO2 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 re ceived a higher dose/g tissue than did rats, consistent with the higher min ute volume/kg body weight of the mice. The inhalation dosimetry study was f ollowed by a histopathology study to determine the acute toxicity to rodent s following a single, 6-h exposure to 18 ppm BDO2. No clinical signs of tox icity were observed; lesions were confined to the olfactory epithelium wher e areas of necrosis were observed. Analysis of bronchoalveolar lavage fluid did not indicate pulmonary inflammation. Based on these findings, an attem pt was made to expose rats and mice repeatedly (for 7 days) to 10 and 20 pp m BDO2, but these exposure concentrations proved too toxic, due to inflamma tion of the nasal mucosa and occlusion of the nasal airway, a lesion that c annot be tolerated by obligate nose breathers. Finally, the toxicity of rat s and mice exposed 6 h/day for 5 days to 0, 2.5, or 5.0 ppm BDO2 was determ ined. The repeated exposures caused no clinical signs of toxicity, nor were any lesions observed in the respiratory tract or other major organs. There fore, the final design selected for the carcinogenesis study comprised expo sing the rats and mice for 6 h/day, 5 days/week for 6 weeks to 0, 2.5, or 5 .0 ppm BDO2.