Multisite Carcinogenicity and Respiratory Toxicity of Inhaled 1-Bromopropane in Rats and Mice

National Institute of Environmental Health Sciences, National Toxicology Program, Research Triangle Park, North Carolina 27709, USA.
Toxicologic Pathology (Impact Factor: 2.14). 08/2011; 39(6):938-48. DOI: 10.1177/0192623311416374
Source: PubMed


Two-year 1-bromopropane (1-BP) inhalation studies were conducted because of the potential for widespread exposure, the lack of chronic toxicity and carcinogenicity data, and the known carcinogenicity of structurally related compounds. Male and female F344/N rats and B6C3F1/N mice were exposed by inhalation to 0, 62.5 (mice only), 125, 250, or 500 (rats only) ppm 1-BP for 6 hr/day, 5 days/week for 105 weeks. Exposure of male and female rats to 1-BP resulted in significantly increased incidences of adenomas of the large intestine and skin neoplasms. In male rats, the incidence of malignant mesothelioma of the epididymis was statistically significantly increased at 500 ppm, but the biological significance of this common lesion is unclear. Incidences of pancreatic islet adenoma in male rats were significantly increased at all concentrations relative to concurrent controls but were within the historical control range for inhalation studies. There was no evidence of carcinogenic activity of 1-BP in male B6C3F1 mice; however, significantly increased incidences of alveolar/bronchiolar neoplasms of the lung were present in female mice. Exposure to 1-BP also resulted in increased incidences of nonneoplastic lesions in the nose of rats and mice, the larynx of rats and male mice, the trachea of female rats and male and female mice, and the lungs of mice. Inflammatory lesions with Splendore Hoeppli (S-H) material were present primarily in the nose and skin of exposed male and female rats, indicating that 1-BP caused immunosuppression.

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Available from: Mark F Cesta, Feb 03, 2014
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    • "50 ppm of 1-BP also decreased sperm count and sperm motility and increased sperms with abnormal heads in all 3 strain mice, whereas rats exposed to 200 ppm of 1-BP for 12 weeks showed no changes in sperm count and sperm motility (Ichihara et al., 2000b), suggesting mice are far more susceptible than rats. Most recently, a long-term inhalation animal study from the National Toxicological Program (NTP) found that exposure of male and female F344/N rats to 1-BP significantly increased the incidences of adenomas of the large intestine and skin neoplasms (Morgan et al., 2011; NTP, 2013). In male rats, the incidence of malignant mesothelioma was statistically significantly increased at 500 ppm. "
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    ABSTRACT: 1-Bromopropane (1-BP) was introduced into the workplace as an alternative to ozone-depleting solvents and increasingly used in manufacturing industry. The potential exposure to 1-BP and the current reports of adverse effects associated with occupational exposure to high levels of 1-BP have increased the need to understand the mechanism of 1-BP toxicity in animal models as a mean of understanding risk in workers. Physiologically based pharmacokinetic (PBPK) model for 1-BP has been developed to examine two metabolic pathway assumptions for gas-uptake inhalation study. Based on previous gas-uptake experiments in the Fischer 344 rat, the PBPK model was developed by simulating the 1-BP concentration in a closed chamber. In the model, we tested the hypothesis that metabolism responsibilities were shared by the p450 CYP2E1 and glutathione (GSH) conjugation. The results showed that two metabolic pathways adequately simulated 1-BP closed chamber concentration. Furthermore, the above model was tested by simulating the gas-uptake data of the female rats pretreated with 1-aminobenzotrizole (ABT), a general P450 suicide inhibitor, or DL-buthionine (S,R)-sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, prior to exposure to 800 ppm 1-BP. The comparative investigation on the metabolic pathway of 1-BP through the PBPK modeling in both sexes provides critical information for understanding the role of p450 and GSH in the metabolism of 1-BP and eventually helps to quantitatively extrapolate current animal studies to human. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email:
    Toxicological Sciences 01/2015; 145(1). DOI:10.1093/toxsci/kfv018 · 3.85 Impact Factor
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    • "Furthermore, genetically modified mice deficient in the oxidative regulatory pathway Nrf2 also demonstrated increased hepatotoxicity (Liu et al., 2009, 2010). In a recent long-term animal study from the NTP (Morgan et al., 2011; NTP, 2013), inhalation exposure of male and female F344/N rats to 1-BP resulted in significantly increased incidences of adenomas of the large intestine and skin neoplasms. In male rats, the incidence of malignant mesothelioma was statistically significantly increased at 500 ppm. "
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    ABSTRACT: Abstract 1. The objectives of the current studies were to evaluate the factors influencing the toxicokinetics of 1-bromopropane (1-BP) in rodents after intravenous (IV) and inhalation exposure. 2. F-344 rats were administered 1-BP via IV bolus injection at 5 and 20 mg/kg and blood concentration determined versus time. F-344 rats and B6C3F1 mice were also exposed to starting inhalation concentrations 70, 240, 800 and 2700 ppm 1-BP in a closed gas uptake system and chamber 1-BP levels were monitored for 6 h. Plasma bromide concentrations were determined to estimate total metabolized dose. Rats were pretreated with chemical inhibitors of cytochrome P450 and glutathione (GSH) synthesis, prior to exposure to 1-BP at 800 ppm within inhalation chambers. 3. Systemic clearance of 1-BP in rat was rapid and decreased with increasing dose. As inhalation chamber concentration of 1-BP increased, the terminal elimination rates decreased. Half-life of 1-BP in rats following inhibition of P450 (9.6 h) or depletion of GSH (4.1 h) increased relative to controls (2.0 h) at 800 ppm. The percentage of 1-BP metabolized decreased with increasing inhalation exposure. Hepatic levels of GSH were significantly lowered regardless of the exposure level in both rats and mice. Chamber concentration-time curves were fit to a two compartment model which was used to estimate metabolic rate constants. 4. These data suggest that in rat, 1-BP clearance is saturable and that elimination is highly dependent on both P450 and GSH-dependent metabolism. This investigation in rodents may provide an understanding of interspecies differences in toxicokinetics and eventually aid translation of animal studies to human risk assessment.
    Xenobiotica 01/2014; 44(7). DOI:10.3109/00498254.2013.879624 · 2.20 Impact Factor