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

On This Page

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 1 (51 KB)

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 2 (91 KB)

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 3 (156 KB)

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.

Figure 4 (376 KB)

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 1 (13 KB)

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 2 (15 KB)

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 3 (18 KB)

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.

Table 4 (14 KB)