Table 3.
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.
| Non-neoplastic liver lesion |
Treatment duration |
Furan (mg/kg BW) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 0 | 0.02 | 0.044 | 0.092 | 0.2 | 0.44 | 0.92 | 2 | |||
| Cholangio-fibrosis | 36 weeks | Overall ratea | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 6/20 (30%) | 17/20 (85%) | 19/20 (95%) |
| CAFEb | P < 0.001 | P = 0.010 | P < 0.001 | P < 0.001 | ||||||
| Average severityc | 1.0 | 1.1 | 1.2 | |||||||
| 60 weeks | Overall ratea | 0/20 (0%) | 0/10 (0%) | 0/10 (0%) | 0/10 (0%) | 0/10 (0%) | 10/10 (100%) | 10/10 (100%) | 8/10 (80%) | |
| CAFEb | P < 0.001 | P < 0.001 | P < 0.001 | P < 0.001 | ||||||
| Average severityc | 1.1 | 1.6 | 2.1 | |||||||
| 2 years | Overall ratea | 0/149 (0%) | 0/150 (0%) | 0/99 (0%) | 1/100 (1%) | 38/50 (76%) | 49/49 (100%) | 47/50 (94%) | 49/49 (100%) | |
| Poly-3 testd | P < 0.001 | P = 0.422 | P < 0.001 | P < 0.001 | P < 0.001 | P < 0.001 | ||||
| Average severityc | 1.0 | 1.7 | 2.6 | 3.4 | 3.9 | |||||
| Mixed cell foci | 36 weeks | Overall rate | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 1/20 (5%) | 0/20 (0%) | 1/20 (5%) | 5/20 (25%) |
| CAFE | P < 0.001 | P = 0.500 | P = 0.500 | P = 0.024 | ||||||
| Average severity | -e | - | - | - | - | - | - | - | ||
| 60 weeks | Overall rate | 1/20 (5%) | 0/10 (0%) | 1/10 (10%) | 0/10 (0%) | 1/10 (10%) | 1/10 (10%) | 3/10 (30%) | 6/10 (60%) | |
| CAFE | P < 0.001 | P = 0.667N | P = 0.563 | P = 0.667N | P = 0.563 | P = 0.563 | P = 0.095 | P = 0.002 | ||
| Average severity | -e | - | - | - | - | - | ||||
| 2 years | Overall rate | 7/149 (5%) | 7/150 (5%) | 6/99 (6%) | 3/100 (3%) | 5/50 (10%) | 3/49 (6%) | 6/50 (12%) | 13/49 (27%) | |
| Poly-3 test | P < 0.001 | P = 0.588 | P =0.418 | P = 0.364N | P = 0.170 | P = 0.485 | P = 0.056 | P < 0.001 | ||
| Average severity | -e | - | - | - | - | - | - | - | ||
| Biliary tract hyperplasia | 36 weeks | Overall rate | 1/20 (5%) | 1/20 (5%) | 0/20 (0%) | 1/20 (5%) | 0/20 (0%) | 0/20 (0%) | 6/20 (30%) | 19/20 (95%) |
| CAFE | P < 0.001 | P = 0.756 | P = 0.500N | P = 0.756 | P = 0.500N | P = 0.500N | P = 0.046 | P < 0.001 | ||
| Average severity | 1.0 | 1.0 | 1.0 | 1.3 | 1.8 | |||||
| 60 weeks | Overall rate | 7/20 (35%) | 3/10 (30%) | 1/10 (10%) | 2/10 (20%) | 1/10 (10%) | 2/10 (20%) | 3/10 (30%) | 8/10 (80%) | |
| CAFE | P < 0.001 | P = 0.560N | P = 0.154N | P = 0.344N | P = 0.154N | P = 0.344N | P = 0.560N | P = 0.025 | ||
| Average severity | 1.0 | 1.0 | 2.0 | 1.0 | 1.0 | 1.0 | 1.3 | 2.5 | ||
| 2 years | Overall rate | 89/149 (60%) | 86/150 (57%) | 59/99 (60%) | 56/100 (56%) | 29/50 (58%) | 25/49 (51%) | 32/50 (64%) | 43/49 (88%) | |
| Poly-3 test | P < 0.001 | P = 0.308N | P =0.440N | P = 0.303N | P = 0.419N | P = 0.195N | P = 0.341 | P = 0.002 | ||
| Average severity | 1.4 | 1.6 | 1.5 | 1.6 | 2.0 | 2.9 | 3.2 | 3.6 | ||
| Oval cell hyperplasia | 36 weeks | Overall rate | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 1/20 (5%) | 16/20 (80%) |
| CAFE | P < 0.001 | P = 0.500 | P < 0.001 | |||||||
| Average severity | 1.0 | 2.2 | ||||||||
| 60 weeks | Overall rate | 0/20 (0%) | 0/10 (0%) | 0/10 (0%) | 0/10 (0%) | 0/10 (0%) | 0/10 (0%) | 3/10 (30%) | 7/10 (70%) | |
| CAFE | P < 0.001 | P = 0.030 | P < 0.001 | |||||||
| Average severity | 1.3 | 2.3 | ||||||||
| 2 years | Overall rate | 14/149 (9%) | 15/150 (10%) | 10/99 (10%) | 8/100 (8%) | 7/50 (14%) | 6/49 (12%) | 14/50 (28%) | 33/49 (67%) | |
| Poly-3 test | P < 0.001 | P = 0.484 | P =0.500 | P = 0.434N | P = 0.284 | P = 0.360 | P < 0.001 | P < 0.001 | ||
| Average severity | 2.2 | 2.5 | 2.0 | 2.1 | 2.1 | 2.7 | 3.1 | 3.1 | ||
| Bile duct subcapsular hyperplasia | 36 weeks | Overall rate | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 1/20 (5%) | 12/20 (60%) | 19/20 (95%) | 20/20 (100%) |
| CAFE | P < 0.001 | P = 0.500 | P < 0.001 | P < 0.001 | P < 0.001 | |||||
| Average severity | 1.0 | 1.1 | 1.2 | 1.8 | ||||||
| 60 weeks | Overall rate | 0/20 (0%) | 0/10 (0%) | 0/10 (0%) | 0/10 (0%) | 1/10 (10%) | 9/10 (90%) | 10/10 (100%) | 7/10 (70%) | |
| CAFE | P < 0.001 | P = 0.333 | P < 0.001 | P < 0.001 | P < 0.001 | |||||
| Average severity | 1.0 | 1.1 | 1.5 | 1.9 | ||||||
| Hepatocyte hypertrophy | 36 weeks | Overall rate | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 1/20 (5%) | 0/20 (0%) | 2/20 (10%) | 12/20 (60%) |
| CAFE | P < 0.001 | P = 0.500 | P = 0.244 | P < 0.001 | ||||||
| Average severity | 2.0 | 1.5 | 1.8 | |||||||
| 60 weeks | Overall rate | 0/20 (0%) | 0/10 (0%) | 0/10 (0%) | 0/10 (0%) | 0/10 (0%) | 5/10 (50%) | 4/10 (40%) | 8/10 (80%) | |
| CAFE | P < 0.001 | P = 0.002 | P = 0.008 | P < 0.001 | ||||||
| Average severity | 2.2 | 1.5 | 2.1 | |||||||
| Periportal cytoplasmic alteration | 36 weeks | Overall rate | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 7/20 (35%) | 19/20 (95%) |
| CAFE | P < 0.001 | P = 0.004 | P < 0.001 | |||||||
| Average severity | 1.1 | 2.0 | ||||||||
| 60 weeks | Overall rate | 0/20 (0%) | 0/10 (0%) | 0/10 (0%) | 1/10 (10%) | 0/10 (0%) | 1/10 (10%) | 7/10 (70%) | 8/10 (80%) | |
| CAFE | P < 0.001 | P = 0.333 | P = 0.333 | P < 0.001 | P < 0.001 | |||||
| Average severity | 2.0 | 1.0 | 1.6 | 2.0 | ||||||
| Subcapsular fibrosis | 36 weeks | Overall rate | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 3/20 (15%) | 14/20 (70%) | 20/20 (100%) | 20/20 (100%) |
| CAFE | P < 0.001 | P = 0.115 | P < 0.001 | P < 0.001 | P < 0.001 | |||||
| Average severity | 1.3 | 1.1 | 1.3 | 1.8 | ||||||
| 60 weeks | Overall rate | 0/20 (0%) | 0/10 (0%) | 0/10 (0%) | 0/10 (0%) | 4/10 (40%) | 9/10 (90%) | 10/10 (100%) | 7/10 (70%) | |
| CAFE | P < 0.001 | P = 0.008 | P < 0.001 | P < 0.001 | P < 0.001 | |||||
| Average severity | 1.0 | 1.1 | 1.5 | 1.9 | ||||||
| Subcapsular chronic inflammation | 36 weeks | Overall rate | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 2/20 (10%) | 14/20 (70%) | 20/20 (100%) | 20/20 (100%) |
| CAFE | P < 0.001 | P = 0.244 | P < 0.001 | P < 0.001 | P < 0.001 | |||||
| Average severity | 1.0 | 1.1 | 1.3 | 1.8 | ||||||
| 60 weeks | Overall rate | 0/20 (0%) | 0/10 (0%) | 0/10 (0%) | 0/10 (0%) | 8/10 (80%) | 9/10 (90%) | 10/10 (100%) | 7/10 (70%) | |
| CAFE | P < 0.001 | P < 0.001 | P < 0.001 | P < 0.001 | P < 0.001 | |||||
| Average severity | 1.0 | 1.1 | 1.5 | 1.9 | ||||||
| Subcapsular pigmentation | 36 weeks | Overall rate | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) | 2/20 (10%) | 14/20 (70%) | 20/20 (100%) | 20/20 (100%) |
| CAFE | P < 0.001 | P = 0.244 | P < 0.001 | P < 0.001 | P < 0.001 | |||||
| Average severity | 1.0 | 1.1 | 1.3 | 1.8 | ||||||
| 60 weeks | Overall rate | 0/20 (0%) | 0/10 (0%) | 0/10 (0%) | 0/10 (0%) | 8/10 (80%) | 9/10 (90%) | 10/10 (100%) | 7/10 (70%) | |
| CAFE | P < 0.001 | P < 0.001 | P < 0.001 | P < 0.001 | P < 0.001 | |||||
| Average severity | 1.0 | 1.1 | 1.5 | 1.9 | ||||||
| Basophilic foci | 2 years | Overall rate | 28/149 (19%) | 16/150 (11%) | 19/99 (19%) | 18/100 (18%) | 11/50 (22%) | 13/49 (27%) | 10/50 (20%) | 21/49 (43%) |
| Poly-3 test | P < 0.001 | P = 0.036N | P = 0.536 | P = 0.445N | P = 0.485 | P = 0.164 | P = 0.390 | P < 0.001 | ||
| Average severity | -e | - | - | - | - | - | - | - | ||
| Regenerative hyperplasia | 2 years | Overall rate | 0/149 (0%) | 1/150 (1%) | 1/99 (1%) | 2/100 (2%) | 1/50 (2%) | 1/49 (2%) | 7/50 (14%) | 12/49 (24%) |
| Poly-3 test | P < 0.001 | P = 0.498 | P = 0.419 | P = 0.158 | P = 0.290 | P = 0.276 | P < 0.001 | P < 0.001 | ||
| Average severity | 4.0 | 4.0 | 2.5 | 3.0 | 2.0 | 3.6 | 3.9 | |||
| Cytoplasmic vacuolization | 2 years | Overall rate | 23/149 (15%) | 23/150 (15%) | 14/99 (14%) | 19/100 (19%) | 12/50 (24%) | 18/49 (37%) | 23/50 (46%) | 37/49 (76%) |
| Poly-3 test | P < 0.001 | P = 0.548 | P = 0.493N | P = 0.280 | P = 0.153 | P = 0.001 | P < 0.001 | P < 0.001 | ||
| Average severity | 2.3 | 2.2 | 2.1 | 2.3 | 3.0 | 3.0 | 2.8 | 3.3 | ||
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.