Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Volume 4 (2000) / Chapter Skim
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B14 Furan
B14 Furan
Pages 307-329
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James, Ph.D. Johnson Space Center Toxicology Group Medical Operations Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Furan is a volatile, clear, colorless liquid that turns brown upon standing.
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The fraction of inhaled furan retained was not affected by tidal volume changes but was directly related to concentrations inhaled (Egle and Gochberg 19791 Administration of furan by oral gavage leads to absorption from the gastrointestinal tract into the portal vein and to the liver. In rats, it has been sho~vn that the rate of furan metabolism in hepatocytes greatly exceeds the ability of furan to be delivered by the blood flow to the liver (Kedderis and Held ~ 996~; hence, little unmetabolized furan should reach the general circulation after passing through the liver.
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The labeling distributed in the tissues represented approximately 15% of the total dose administered. The label in liver included no unmetabolized furan, and none of the label was bound to DNA; most of the label was associated with protein and could not be extracted from it.
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In rats, furan is bioactivated by a cytochrome-P-450-dependent pathway to one or more metabolites that uncouple oxidative phosphorylation, deplete cellular ATE, and induce DNA double-strand breaks before cell death (Mugford and Kedderis 1997~. Errors in repair of the DNA breaks have been hypothesized to result in mutations and contribute to the neoplastic effects of furan (Mugford and Kedderis ~997~.
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Oral exposure induced a copious flow of bloody saliva, watery fluid from the nose, marked hyperemia of lungs and dilation of blood vessels, and gastrointestinal-tract hemorrhages (Koch and Cahan 1925~. Other symptoms of oral exposure include cherry-red blood, soft swollen kidneys, and liver resembling the first stages of chloroform poisoning (Koch and Cahan 1925~.
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for Sprague-Dawley rats exposed to analytical concentrations of 1000, 2850, or 4050 ppm in a dynamic Hinnerstype chamber; lethality was observed only at the highest exposure concentration. Signs of toxicity during exposure included respiratory distress, increased secretory responses, and, at the highest concentration, death, which in many instances, was delayed until the end of the first week or the beginning of the second week after exposure.
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Maronpot, National Toxicology Program, NIEHS, personal commun., 19941. Carcinogenicity No studies have been reported on the carcinogenicity of inhaTed furan vapors; however, furan has been sho~vn to be a potent, multi-target carcinogen by the oral route.
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3 1 4 SMA CS FOR SELECTED AIRBORNE CONTAMINANTS TABLE 14-1 Neoplastic Lesions in 2-y Study of 50 Rats and 50 Mice Doses, mg/kg Species Sex Neoplasm 0 2 4 8 15 Rat Male Monocytic leukemia 8 11 17 25 Cholangiocarcinoma 0 43 48 49 Hepatocellular 1 5 22 35 adenoma/carcinoma Rat Female Monocytic leukeumia 8 9 17 21 Cholangiocarcinoma 0 49 50 48 Hepatocellular 0 2 4 7 adenoma/carcinoma Mice Male Hepatocellular adenoma/carcinoma Female Hepatocellular 7 adenoma/carcinoma 26 - 44 50 34 50 TABLE 14-2 Bioassay Incidences of Cholangiocarcinomas in Rats in the NTP 9 months 15 months 24 months Dose, mg/kg Male Female Male Female Male Female 0 0/10 0/10 0/10 0/10 0/50 0/50 2 5/10 4/10 7/10 9/10 43/50 49/50 4 7/10 9/10 9/10 9/10 48/50 50/50 8 10/10 10/10 6/10 7/10 49/50 48/50 adenomas and hepatocellular carcinomas in mate and female mice and rats and mononuclear-cell leukemias in male and female rats.
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Furan does induce chromosomal aberrations and sister chromatic exchanges in cultured Chinese hamster ovary cells in vitro, with and without metabolic activation, and induces forward mutations in cultured mouse L5 1 78Y lymphoma cells (NTP 1993~. It induces chromosomal aberrations, but not sister chromatic exchanges, in bone-marrow cells of mice injected ip (NTP 1993~.
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study have a background incidence of hepatocellular carcinomas of 50%. in that case and on the basis of the data alone, furan appears to induce mouse-liver tumors by a direct genotoxic mechanism involving activation of oncogenes.
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317 V: · _4 Cal · _.
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Setting long-term exposure standards for furan inhalation is a challenge because of the serious deficiencies in the data base and the implications that it could be highly carcinogenic based on liver tumors induced in rodents given furan by oral Savage. The data base is deficient because there are no inhalation exposures except for two acute exposures that report very different LCso values.
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(1972) used GC-MS analysis of vapor from freshly baked white bread to show that furan was a major component of the 15 compounds identified.
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The species factor was less than the usual factor of 10 because pharmacokinetic data indicate that, on a milligram-per-kilogram bodyweight basis, humans have a Tower rate of metabolism of inhaled furan vapors than do rats when exposed to 10 ppm (Kedderis and Held 19961. The species extrapolation factor was not reduced to 1 because it was uncertain whether human liver would be more susceptible than rat liver to furan toxicity.
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Several recent investigations have elucidated the mechanisms of furan carcinogenesis, and those findings can be used to estimate safe concentrations for bolus oral ingestion. The weight of evidence is that furan, or an active metabolite of furan, affects DNA indirectly through a mechanism involving cytotoxicity and does not react directly with the DNA in target cells.
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of furan must be in sufficient concentration in the target tissue to uncouple oxidative phosphorylation and substantially reduce ATP production. That will occur only if the concentration of metabolite~s)
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The 95% lower confidence on the BED, 0.09 mg/kg/d, was taken to be a NOAEL in rats by oral gavage. Alternatively, the NRC SMACs subcommittee noted that 2 mg/kg/d, 5 d/w for 9 mo seemed to be a LOAEL for a severe effect (cancer)
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1991~. Hence, the respiratory system ofthe rats received substantial exposure to furan during the oral gavage study, but there were no furan-associated neoplasms or other lesions in the respiratory system.
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Both acute and chronic inhalation studies are needed to improve the descriptive toxicity database. These studies should include assessment of sublethal end points, tissue-specif~c metabolic activation, and DNA lesions in target tissues.
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Robertson.1963. Mass spectrometric determination ofthe volatile components from ground coffee.
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1992. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants.
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