Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 9 (2010) / Chapter Skim
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3 Furan
3 Furan
Pages 136-172
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Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels.
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On the basis of a chronic oral carcinogenicity study in which clear evidence of carcinogenicity was noted in male and female rats and mice, the National Toxicology Program (NTP) classifies furan as "reasonably anticipated to be a human carcinogen" and the International Agency for Research on Cancer (IARC)
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However, oral toxicity data indicate that rats are more sensitive than mice despite PBPK modeling predictions that mice would have a 3fold higher absorbed dose and 2-fold higher integrated liver exposure to furan metabolites than rats. Therefore, there are too many uncertainties about the response to furan of the rat, mouse, and human liver to base an uncertainty factor on PBPK modeling predictions.
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. A modifying factor of 5 was applied to account for a limited data set (only one data set addressing furan toxicity after inhalation exposure was available; this study was not repeated, and there was no information on furan toxicity in other species)
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mg/m3) effects in rats; clinical signs: although the severity of respiratory distress and increased secretory response not reported, no decrease in body weight occurred (Terrill et al.
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1965) , no human data were available regarding acute nonlethal toxicity of this compound.
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2.6. Summary No data were found in the available literature regarding lethal and nonlethal toxicity, developmental and reproductive toxicity, genotoxicity, and carcinogenicity of inhaled furan in humans.
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Animals were observed for 14 days, at which time a gross necropsy was conducted on the surviving animals. Signs of furan intoxication during exposure included respiratory distress, increased secretory response, and death.
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Furan was administered a second time, but this time, respiration could not be restored after cessation. Necropsy revealed marked dilation of the blood vessels in the viscera; blood that was a bright, cherry red; and hyperemic lungs.
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In a later study, 12 male rats per group were exposed for 4 h to furan at 52, 107, or 208 ppm. The liver and blood were sampled after exposure to determine furan concentrations.
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. Nonneoplastic liver lesions that occurred in both male and female treated rats included biliary tract fibrosis, hyperplasia, chronic inflammation, proliferation and hepatocyte cytomegaly, cytoplasmic vacuolization, degeneration, nodular hyperplasia, and necrosis.
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. The NTP concluded that there was clear evidence of carcinogenic activity of furan in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms of the liver and benign pheochromocytomas of the adrenal gland.
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The NTP also concluded that there was clear evidence of carcinogenic activity of furan in male and female B6C3F1 mice after oral exposure based on increased incidences of hepatocellular neoplasms of the liver and benign pheochromocytomas of the adrenal gland. Therefore, NTP classifies furan as "reasonably anticipated to be a human carcinogen" (NTP 2005)
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To more closely mimic the typical in vivo exposure concentrations as predicted by a PBPK model, hepatocytes were then exposed for 1 to 4 h to 2
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Pretreatment with pyrazole completely inhibited furan biotransformation. To validate the PBPK model, the concentration of furan was measured in the blood and liver of rats after a 4-h inhalation exposure to furan at 52, 107, or 208 ppm (12 rats per group)
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The liver exposure to the toxic metabolite of furan followed the same pattern. Steady-state blood concentrations were predicted to be reached approximately 1 h after inhalation exposure to furan at 10 ppm.
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To compare human furan pharmacokinetics with those of rodents, a PBPK model for inhaled furan was developed and validated in rats to predict the absorbed liver dose after inhalation exposure to defined concentrations and durations (Kedderis et al.
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. No information was found concerning a potential mechanism for the development of mononuclear cell leukemia seen in male and female rats exposed to furan.
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At 2 years, almost all dosed rats had developed cholangiocarcinomas (at 2 mg/kg/day and higher) , and male rats had an increased combined incidence of hepatocellular adenomas and carcinomas, while female rats had an increased incidence of hepatocellular adenomas (4 mg/kg/day and higher)
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Nonneoplastic liver lesions included cytoplasmic vacuolization, focal hyperplasia, and mixed cell cellular infiltration; dilation of the bile duct; biliary tract chronic inflammation, fibrosis, and hyperplasia; hepatocyte cytomegaly, degeneration, and necrosis; Kupffer cell pigmentation; and focal atrophy of the liver parenchyma. The incidence of focal hyperplasia of the adrenal medulla was also increased.
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6.2. Summary of Animal Data Relevant to AEGL-2 Groups of Sprague-Dawley male or female rats exposed for 1 h to furan at 1,014, 2,851, or 4,049 ppm exhibited signs of toxicity, including respiratory distress and increased secretory response; mortality was observed at the highest concentration (Terrill et al.
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A PBPK simulation of inhalation exposure to furan predicted that the absorbed dose of furan in mice and rats would be ~10- and 3.5-fold higher, respectively, than that in humans, while the integrated liver exposure to furan metabolites would be ~6and 3-fold higher, respectively, than that in humans. However, oral toxicity data indicate that the rat is more sensitive than the mouse despite PBPK modeling predictions that the mouse would have a 3-fold higher absorbed dose and 2-fold higher integrated liver exposure to furan metabolites than the rat.
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. A modifying factor of 5 was applied to account for a limited data set (only one data set addressing furan toxicity after inhalation exposure was available)
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A PBPK simulation of inhalation exposure to furan predicted that the absorbed dose of furan in mice and rats would be ~10- and 3.5fold higher, respectively, than that in humans, while the integrated liver exposure to furan metabolites would be ~6- and 3-fold higher, respectively, than that in humans. However, oral toxicity data indicate that the rat is more sensitive than the mouse despite PBPK modeling predictions that the mouse would have a 3-fold higher absorbed dose and 2-fold higher integrated liver exposure to furan metabolites than the rat.
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. A modifying factor of 5 was applied to account for a limited data set (only one data set addressing furan toxicity after inhalation exposure was available)
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AEGL-3 values are derived from the highest nonlethal concentration in rats, AEGL-2 values are based on the threshold for adverse effects in rats, and insufficient data were available to derive AEGL-1 values.
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or if other organs are also affected. The studies would also determine whether inhalation exposure to furan produces a direct contact effect, such as irritation.
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1993. Kinetic analysis of furan biotransformation by F-344 rats in vivo and in vi tro.
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2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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Cn × t = k (this document; default of n = 1 for shorter Time-scaling: to longer exposure periods and n = 3 for longer to shorter exposure periods) Uncertainty factors: 10 for interspecies variability 3 for intraspecies variability Modifying factor: 5 for limited data set Total uncertainty factors and modifying factor: 150 C/uncertainty factors)
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Uncertainty factors: 10 for interspecies variability 3 for intraspecies variability Modifying factor: 5 for limited data set Combined uncertainty factors and modifying factor: 150 (C/uncertainty factors) n × t = k Calculations: [(2,851 ppm)
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167 Furan C3 × 0.167 h = 6866.2 ppm-h 10-min AEGL-3: C3 = 41,114.97 ppm C = 34.5 ppm = 35 ppm C3 × 0.5 h = 6866.2 ppm-h 30-min AEGL-3: C3 = 13,732.4 ppm C = 23.9 ppm = 24 ppm 1-h AEGL-3: C × 1 h = 19.01 ppm-h C = 19.01 ppm C = 19 ppm C1 × 4 h = 19.01 ppm-h 4-h AEGL-3: C1 = 4.75 ppm C = 4.8 ppm C1 × 8 h = 19.01 ppm-h C1 = 2.376 ppm C = 2.4 ppm
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End Point/Concentration/Rationale: Exposure concentration of 1,014 ppm for 1 h in rats. Although the severity of the reported clinical signs (respiratory distress, increased secretory response)
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A PBPK simulation of inhalation exposure to furan predicted that the absorbed dose of furan in mice and rats would be ~10- and 3.5-fold higher, respectively, than that in humans, while the integrated liver exposure to furan metabolites would be ~6- and 3-fold higher, respectively, than that in humans. However, oral toxicity data indicate that the rat is more sensitive than the mouse despite PBPK modeling predictions that the mouse would have a 3-fold higher absorbed dose and 2-fold higher integrated liver exposure to furan metabolites than the rat.
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From page 170... ...
A PBPK simulation of inhalation exposure to furan predicted that the absorbed dose of furan in mice and rats would be ~10- and 3.5-fold higher, respectively, than that in humans, while the integrated liver exposure to furan metabolites would be ~6- and 3-fold higher, respectively, than that in humans. However, oral toxicity data indicate that the rat is more sensitive than the mouse despite PBPK modeling predictions that the mouse would have a 3-fold higher absorbed dose and 2-fold higher integrated liver exposure to furan metabolites than the rat.
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Data Adequacy: Only limited data were available to assess the inhalation toxicity of furan.
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172 Acute Exposure Guideline Levels APPENDIX C Category Plot for Furan FIGURE 3-1 Category plot of animal toxicity data for furan compared with AEGL values.
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