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Low Dose Assessment of the Carcinogenicity of Furan in Male F344/N Nctr Rats in a 2-Year Gavage Study

Von Tungeln LS, Walker NJ, Olson GR, Mendoza MC, Felton RP, Thorn BT, Marques MM, Pogribny IP, Doerge DR, Beland FA.
Food Chem Toxicol. (2016), DOI: http://dx.doi.org/10.1016/j.fct.2016.11.015 PMID: 27871980


Publication


Abstract

Furan is a volatile organic chemical that is a contaminant in many common foods. Furan is hepatocarcinogenic in mice and rats; however, the risk to humans from dietary exposure to furan cannot be estimated accurately because the lowest tested dose of furan in a 2-year bioassay in rats gave nearly a 100% incidence of cholangiocarcinoma. To provide bioassay data that can be used in preparing risk assessments, the carcinogenicity of furan was determined in male F344/N NCTR rats administered 0, 0.02, 0.044, 0.092, 0.2, 0.44, 0.92, and 2 mg furan/kg body weight (BW) by gavage 5 days/week for 2 years. Exposure to furan was associated with the development of malignant mesothelioma on membranes surrounding the epididymis and on the testicular tunics, with the increase being significant at 2 mg furan/kg BW. There was also a dose-related increase in the incidence of mononuclear cell leukemia, with the increase in incidence being significant at 0.092, 0.2, 0.92, and 2 mg furan/kg BW. Dose-related non-neoplastic liver lesions included cholangiofibrosis, mixed cell foci, basophilic foci, biliary tract hyperplasia, oval cell hyperplasia, regenerative hyperplasia, and cytoplasmic vacuolization. The most sensitive non-neoplastic lesion was cholangiofibrosis, the frequency of which increased significantly at 0.2 mg furan/kg BW.

Figures


Figure 1. Structures of furan

cis-2-butene-1,4-dial, and the DNA adducts resulting from reaction of cis-2-butene-1,4-dial with DNA. The abbreviations used are: Cyp 2E1, cytochrome P450 2E1; dC, deoxycytidine; dA, deoxyadenosine; dG, deoxyguanosine; dR, deoxyribose; cis-BDA, cis-2-butene-1,4-dial.

Figure 2. Body weights of male F344/N Nctr rats

Body weights of male F344/N Nctr rats administered 0, 0.02, 0.044, 0.092, 0.2, 0.44, 0.92, or 2.0 mg furan/kg BW for 2 years (104 weeks), as a function of the number of weeks on treatment.

Figure 3. Survival of male F344/N Nctr rats

Survival of male F344/N Nctr rats administered 0, 0.02, 0.044, 0.092, 0.2, 0.44, 0.92, or 2 mg furan/kg BW for 2 years (104 weeks), as a function of the number of weeks on treatment. There was a significant (P = 0.021) dose-related decrease in survival; however, compared to the control group (0 mg furan/kg BW), none of the treatment groups had a significant decrease in survival. The Kaplan-Meier estimates for the percent probability of survival at the end of the study were 30, 28, 28, 28, 32, 26, 24, and 16% for 0, 0.02, 0.044, 0.092, 0.2, 0.44, 0.92, and 2 mg furan/kg BW, respectively.

Figure 4. Cholangiofibrosis observed in a male rat treated with 2 mg furan/kg BW for 2 years

The lesion is characterized by dilated and cystic bile ducts filled with mucinous and cellular debris surrounded by dense collagenous connective tissue with a prominent inflammatory cell infiltrate. The epithelium varies from low cuboidal to tall columnar, with hyperbasophilic and pleomorphic cells along with goblet cells and Paneth cells.

Tables


Table 1. Doses of furan and group sizes and predicted incidence of cholangiocarcinoma

Doses of furan and group sizes for each dose administered to male F344/N Nctr rats for 2 years and the predicted incidence of cholangiocarcinoma at 2 years.
a Furan was administered by gavage in corn oil vehicle 5 days/week for 2 years (104 weeks), with interim sacrifices conducted at 36 and 60 weeks.
b The predicted cholangiocarcinoma incidences were derived with the empirical relationship of Peto et al. (1984), using exponents of 2 and 3.

Table 2. Incidences of malignant mesothelioma, cell leukemia, and neoplasms

Incidences of malignant mesothelioma, mononuclear cell leukemia, and hepatocellular neoplasms in male F344/N Nctr rats administered 0, 0.02, 0.044, 0.092, 0.2, 0.44, 0.92, or 2 mg furan/kg BW for 2 years.
a Number of animals with neoplasm/number of animals examined microscopically.
b Beneath the 0 mg furan/kg BW incidences are the P-values associated with the trend test. Beneath the treated group incidences are the P-values corresponding to pair-wise comparisons between the 0 mg furan/kg BW group and each treated group. The Poly-3 test accounts for differential mortality in animals that do not reach the terminal sacrifice. P-values < 0.05 were considered significant and are bolded. An N indicates a lower incidence compared to the 0 mg furan/kg BW group.
c Includes a mesothelioma (not otherwise specified) of the heart atrium.

Table 3. Incidences of non-neoplastic lesions in the liver

Incidences of non-neoplastic lesions in the liver of male F344/N Nctr rats administered 0, 0.02, 0.044, 0.092, 0.2, 0.44, 0.92, or 2 mg furan/kg BW for 36 or 60 weeks or 2 years.
a Number of animals with lesion/number of animals examined microscopically.
b Beneath the 0 mg furan/kg BW incidences are the P-values associated with a Cochran-Armitage linear trend test. Beneath the treated group incidences are the P-values corresponding to pair-wise comparisons, as assessed by a Fisher's Exact test, between the 0 mg furan/kg BW group and each treated group. CAFE refers to Cochran-Armitage linear trend test/Fisher's Exact test. P-values < 0.05 were considered significant and are bolded. An N indicates a lower incidence compared to the 0 mg furan/kg BW group.
c Average severity of the observed lesions. The severity of the lesions was graded as 1, minimal; 2, mild; 3, moderate; and 4, marked.
d Beneath the 0 mg furan/kg BW incidences are the P-values associated with the trend test. Beneath the treated group incidences are the P-values corresponding to pair-wise comparisons between the 0 mg furan/kg BW group and each treated group. The Poly-3 test accounts for differential mortality in animals that do not reach the terminal sacrifice. P-values < 0.05 were considered significant and are bolded. An N indicates a lower incidence compared to the 0 mg furan/kg BW group.
e Severity score not recorded; the lesion was indicated as present or absent.

Table 4. Benchmark dose modeling of incidences

Benchmark dose modeling of incidences of epididymis or testes malignant mesothelioma and cholangiofibrosis in male F344/N Nctr rats administered 0, 0.02, 0.044, 0.092, 0.2, 0.44, 0.92, or 2 mg furan/kg BW for 2 years.
a AIC, Akaike information criterion.
b P-value of fitted model compared to the full model.
c GOF, Goodness-of-fit P-value.
d BMD10, benchmark dose (μmol furan/kg BW) that caused a 10% excess risk of the specified adverse effect over that observed in the appropriate control group.
e BMDL10, lower 95% confidence limit of benchmark dose (μmol furan/kg BW).
f The models were constructed using the cholangiofibrosis incidence in male rats administered 0, 0.02, 0.044, 0.092, 0.2, or 0.44 mg furan/kg BW for 2 years. Satisfactory fits could not be obtained when the 2 highest doses (0.92 and 2 mg furan/kg BW) were included in the calculations.
g Model rejected.

Supplemental Materials


Supplemental Data