Prevalence of Microscopic Findings in male Rats Treated with NNK by Nose-Only Inhalation for 14 days
| Lesion . | . | Sham 0 mg/kg . | Vehicle 0 mg/kg . | Low 0.8 mg/kg . | Mid 3.2 mg/kg . | Mid High 12.5 mg/kg . | High 50 mg/kg . | Haber Mid 3.2 mg/kg . | Haber Mid High 12.5 mg/kg . | Haber High 50 mg/kg . |
|---|---|---|---|---|---|---|---|---|---|---|
| Nose degeneration, olfactory epithelium | Incidencea | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severityb | 0.0 | 0.0 | 0.0 | 2.0 | 3.0 | 4.0 | 2.0 | 3.0 | 4.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-valuec,d | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose regeneration, olfactory epithelium | Incidence | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 3.0 | 4.0 | 1.0 | 3.0 | 4.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose necrosis, olfactory epithelium | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 0/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 1.0 | 0.0 | 1.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 100 | 100 | 0 | 100 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | — | — | ||
| Nose atrophy, olfactory epithelial glands | Incidence | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 3.0 | 4.0 | 4.0 | 3.0 | 4.0 | 4.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose inflammation, acute | Incidence | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 2.0 | 2.0 | 1.0 | 2.0 | 2.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose depletion, goblet cells | Incidence | 0/10 | 0/10 | 2/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 2.0 | 3.3 | 3.8 | 4.0 | 3.6 | 3.8 | 4.0 | |
| % incidence | 0 | 0 | 20 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | .237 | <.001 | <.001 | <.001 | — | — | — | ||
| Nose degeneration, transitional epithelium | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 10/10 | 0/6 | 5/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.1 | 1.0 | 0.0 | 1.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 80 | 100 | 100 | 83 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | .696 | — | ||
| Nose regeneration, transitional epithelium | Incidence | 0/10 | 0/10 | 0/10 | 2/10 | 8/10 | 10/10 | 3/6 | 5/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 1.8 | 2.0 | 1.0 | 1.8 | 2.0 | |
| % incidence | 0 | 0 | 0 | 20 | 80 | 100 | 50 | 83 | 100 | |
| CAFE p-value | <.001 | — | .237 | <.001 | <.001 | .242 | .696 | — | ||
| Nose necrosis, transitional epithelium | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 10/10 | 0/6 | 5/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 1.0 | 0.0 | 1.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 80 | 100 | 0 | 83 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | .696 | — | ||
| Nose atrophy, glands, sinus | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 4/10 | 4/10 | 2/6 | 2/6 | 3/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.2 | 1.7 | 1.5 | 1.5 | 1.3 | |
| % incidence | 0 | 0 | 0 | 0 | 40 | 40 | 33 | 33 | 43 | |
| CAFE p-value | <.001 | — | — | .043 | .043 | .125 | .608N | .646 | ||
| Larynx metaplasia, squamous | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 9/10 | 10/10 | 0/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 3.0 | 0.0 | 1.5 | 3.0 | |
| % incidence | 0 | 0 | 0% | 0 | 90 | 100 | 0 | 100 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | .625 | — | ||
| Larynx cellular alteration, epithelium | Incidence | 0/10 | 5/10 | 7/10 | 9/10 | 10/10 | 0/10e | 6/6 | 6/6 | 0/7d |
| Severity | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| % incidence | 0 | 50 | 70 | 90 | 100 | 0 | 100 | 100 | 0 | |
| CAFE p-value | ||||||||||
| Trachea depletion, goblet cell | Incidence | 0/10 | 0/10 | 0/10 | 1/10 | 4/10 | 9/10 | 3/6 | 2/6 | 4/7 |
| Severity | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| % incidence | 0 | 0 | 0 | 10 | 40 | 90 | 50 | 33 | 57 | |
| CAFE p-value | <.001 | — | .500 | .043 | <.001 | .118 | .608N | .162N | ||
| Lung regeneration, epithelium, bronchiole | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 1/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.6 | 2.0 | 1.0 | 1.3 | 2.0 | |
| % incidence | 0 | 0 | 0 | 0 | 100 | 100 | 17 | 100 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | .375 | — | — | ||
| Liver necrosis, centrilobular | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 0/6 | 0/6 | 5/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 0.0 | 0.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 0 | 80 | 0 | 0 | 71 | |
| CAFE p-value | <.001 | — | — | — | <.001 | — | — | .559N | ||
| Liver infiltration cellular, mononuclear cell, centrilobular | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 0/6 | 0/6 | 5/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 0.0 | 0.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 0 | 80 | 0 | 0 | 71 | |
| CAFE p-value | <.001 | — | — | — | <.001 | — | — | .559N | ||
| Thymus atrophy | Incidence | 0/10 | 0/10 | 0/10 | 1/10 | 1/10 | 2/10 | 1/6 | 4/6 | 4/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 1.0 | 2.0 | 1.0 | 2.0 | 2.0 | |
| % incidence | 0 | 0 | 0 | 10 | 10 | 20 | 17 | 67 | 57 | |
| CAFE p-value | .053 | — | .500 | .500 | .237 | .625 | .036 | .145 |
| Lesion . | . | Sham 0 mg/kg . | Vehicle 0 mg/kg . | Low 0.8 mg/kg . | Mid 3.2 mg/kg . | Mid High 12.5 mg/kg . | High 50 mg/kg . | Haber Mid 3.2 mg/kg . | Haber Mid High 12.5 mg/kg . | Haber High 50 mg/kg . |
|---|---|---|---|---|---|---|---|---|---|---|
| Nose degeneration, olfactory epithelium | Incidencea | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severityb | 0.0 | 0.0 | 0.0 | 2.0 | 3.0 | 4.0 | 2.0 | 3.0 | 4.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-valuec,d | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose regeneration, olfactory epithelium | Incidence | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 3.0 | 4.0 | 1.0 | 3.0 | 4.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose necrosis, olfactory epithelium | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 0/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 1.0 | 0.0 | 1.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 100 | 100 | 0 | 100 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | — | — | ||
| Nose atrophy, olfactory epithelial glands | Incidence | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 3.0 | 4.0 | 4.0 | 3.0 | 4.0 | 4.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose inflammation, acute | Incidence | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 2.0 | 2.0 | 1.0 | 2.0 | 2.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose depletion, goblet cells | Incidence | 0/10 | 0/10 | 2/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 2.0 | 3.3 | 3.8 | 4.0 | 3.6 | 3.8 | 4.0 | |
| % incidence | 0 | 0 | 20 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | .237 | <.001 | <.001 | <.001 | — | — | — | ||
| Nose degeneration, transitional epithelium | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 10/10 | 0/6 | 5/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.1 | 1.0 | 0.0 | 1.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 80 | 100 | 100 | 83 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | .696 | — | ||
| Nose regeneration, transitional epithelium | Incidence | 0/10 | 0/10 | 0/10 | 2/10 | 8/10 | 10/10 | 3/6 | 5/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 1.8 | 2.0 | 1.0 | 1.8 | 2.0 | |
| % incidence | 0 | 0 | 0 | 20 | 80 | 100 | 50 | 83 | 100 | |
| CAFE p-value | <.001 | — | .237 | <.001 | <.001 | .242 | .696 | — | ||
| Nose necrosis, transitional epithelium | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 10/10 | 0/6 | 5/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 1.0 | 0.0 | 1.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 80 | 100 | 0 | 83 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | .696 | — | ||
| Nose atrophy, glands, sinus | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 4/10 | 4/10 | 2/6 | 2/6 | 3/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.2 | 1.7 | 1.5 | 1.5 | 1.3 | |
| % incidence | 0 | 0 | 0 | 0 | 40 | 40 | 33 | 33 | 43 | |
| CAFE p-value | <.001 | — | — | .043 | .043 | .125 | .608N | .646 | ||
| Larynx metaplasia, squamous | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 9/10 | 10/10 | 0/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 3.0 | 0.0 | 1.5 | 3.0 | |
| % incidence | 0 | 0 | 0% | 0 | 90 | 100 | 0 | 100 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | .625 | — | ||
| Larynx cellular alteration, epithelium | Incidence | 0/10 | 5/10 | 7/10 | 9/10 | 10/10 | 0/10e | 6/6 | 6/6 | 0/7d |
| Severity | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| % incidence | 0 | 50 | 70 | 90 | 100 | 0 | 100 | 100 | 0 | |
| CAFE p-value | ||||||||||
| Trachea depletion, goblet cell | Incidence | 0/10 | 0/10 | 0/10 | 1/10 | 4/10 | 9/10 | 3/6 | 2/6 | 4/7 |
| Severity | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| % incidence | 0 | 0 | 0 | 10 | 40 | 90 | 50 | 33 | 57 | |
| CAFE p-value | <.001 | — | .500 | .043 | <.001 | .118 | .608N | .162N | ||
| Lung regeneration, epithelium, bronchiole | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 1/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.6 | 2.0 | 1.0 | 1.3 | 2.0 | |
| % incidence | 0 | 0 | 0 | 0 | 100 | 100 | 17 | 100 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | .375 | — | — | ||
| Liver necrosis, centrilobular | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 0/6 | 0/6 | 5/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 0.0 | 0.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 0 | 80 | 0 | 0 | 71 | |
| CAFE p-value | <.001 | — | — | — | <.001 | — | — | .559N | ||
| Liver infiltration cellular, mononuclear cell, centrilobular | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 0/6 | 0/6 | 5/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 0.0 | 0.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 0 | 80 | 0 | 0 | 71 | |
| CAFE p-value | <.001 | — | — | — | <.001 | — | — | .559N | ||
| Thymus atrophy | Incidence | 0/10 | 0/10 | 0/10 | 1/10 | 1/10 | 2/10 | 1/6 | 4/6 | 4/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 1.0 | 2.0 | 1.0 | 2.0 | 2.0 | |
| % incidence | 0 | 0 | 0 | 10 | 10 | 20 | 17 | 67 | 57 | |
| CAFE p-value | .053 | — | .500 | .500 | .237 | .625 | .036 | .145 |
Number of animals with the lesion per number of animals examined microscopically.
Severity was graded as 1, minimal; 2, mild; 3, moderate; and 4, marked. NA = not applicable.
p-Values under the vehicle column are the results of the Cochran-Armitage trend test. p-Values under the treatment column are the results of a Fisher’s Exact comparison to the Vehicle Control.
p-Values under the Haber Mid, Haber Mid High, and Haber High columns are the results of a Fisher’s Exact comparison to the main Toxicology Mid, Mid High, and High, respectively. A “N” indicates that the Haber incidence was less than the main Toxicology incidence.
Cellular alteration of the larynx was not present in the male High Toxicology or High Haber rats because squamous metaplasia was present at the base of the epiglottis in these rats rather than cellular alteration.
Prevalence of Microscopic Findings in male Rats Treated with NNK by Nose-Only Inhalation for 14 days
| Lesion . | . | Sham 0 mg/kg . | Vehicle 0 mg/kg . | Low 0.8 mg/kg . | Mid 3.2 mg/kg . | Mid High 12.5 mg/kg . | High 50 mg/kg . | Haber Mid 3.2 mg/kg . | Haber Mid High 12.5 mg/kg . | Haber High 50 mg/kg . |
|---|---|---|---|---|---|---|---|---|---|---|
| Nose degeneration, olfactory epithelium | Incidencea | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severityb | 0.0 | 0.0 | 0.0 | 2.0 | 3.0 | 4.0 | 2.0 | 3.0 | 4.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-valuec,d | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose regeneration, olfactory epithelium | Incidence | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 3.0 | 4.0 | 1.0 | 3.0 | 4.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose necrosis, olfactory epithelium | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 0/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 1.0 | 0.0 | 1.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 100 | 100 | 0 | 100 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | — | — | ||
| Nose atrophy, olfactory epithelial glands | Incidence | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 3.0 | 4.0 | 4.0 | 3.0 | 4.0 | 4.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose inflammation, acute | Incidence | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 2.0 | 2.0 | 1.0 | 2.0 | 2.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose depletion, goblet cells | Incidence | 0/10 | 0/10 | 2/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 2.0 | 3.3 | 3.8 | 4.0 | 3.6 | 3.8 | 4.0 | |
| % incidence | 0 | 0 | 20 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | .237 | <.001 | <.001 | <.001 | — | — | — | ||
| Nose degeneration, transitional epithelium | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 10/10 | 0/6 | 5/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.1 | 1.0 | 0.0 | 1.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 80 | 100 | 100 | 83 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | .696 | — | ||
| Nose regeneration, transitional epithelium | Incidence | 0/10 | 0/10 | 0/10 | 2/10 | 8/10 | 10/10 | 3/6 | 5/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 1.8 | 2.0 | 1.0 | 1.8 | 2.0 | |
| % incidence | 0 | 0 | 0 | 20 | 80 | 100 | 50 | 83 | 100 | |
| CAFE p-value | <.001 | — | .237 | <.001 | <.001 | .242 | .696 | — | ||
| Nose necrosis, transitional epithelium | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 10/10 | 0/6 | 5/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 1.0 | 0.0 | 1.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 80 | 100 | 0 | 83 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | .696 | — | ||
| Nose atrophy, glands, sinus | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 4/10 | 4/10 | 2/6 | 2/6 | 3/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.2 | 1.7 | 1.5 | 1.5 | 1.3 | |
| % incidence | 0 | 0 | 0 | 0 | 40 | 40 | 33 | 33 | 43 | |
| CAFE p-value | <.001 | — | — | .043 | .043 | .125 | .608N | .646 | ||
| Larynx metaplasia, squamous | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 9/10 | 10/10 | 0/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 3.0 | 0.0 | 1.5 | 3.0 | |
| % incidence | 0 | 0 | 0% | 0 | 90 | 100 | 0 | 100 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | .625 | — | ||
| Larynx cellular alteration, epithelium | Incidence | 0/10 | 5/10 | 7/10 | 9/10 | 10/10 | 0/10e | 6/6 | 6/6 | 0/7d |
| Severity | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| % incidence | 0 | 50 | 70 | 90 | 100 | 0 | 100 | 100 | 0 | |
| CAFE p-value | ||||||||||
| Trachea depletion, goblet cell | Incidence | 0/10 | 0/10 | 0/10 | 1/10 | 4/10 | 9/10 | 3/6 | 2/6 | 4/7 |
| Severity | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| % incidence | 0 | 0 | 0 | 10 | 40 | 90 | 50 | 33 | 57 | |
| CAFE p-value | <.001 | — | .500 | .043 | <.001 | .118 | .608N | .162N | ||
| Lung regeneration, epithelium, bronchiole | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 1/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.6 | 2.0 | 1.0 | 1.3 | 2.0 | |
| % incidence | 0 | 0 | 0 | 0 | 100 | 100 | 17 | 100 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | .375 | — | — | ||
| Liver necrosis, centrilobular | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 0/6 | 0/6 | 5/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 0.0 | 0.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 0 | 80 | 0 | 0 | 71 | |
| CAFE p-value | <.001 | — | — | — | <.001 | — | — | .559N | ||
| Liver infiltration cellular, mononuclear cell, centrilobular | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 0/6 | 0/6 | 5/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 0.0 | 0.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 0 | 80 | 0 | 0 | 71 | |
| CAFE p-value | <.001 | — | — | — | <.001 | — | — | .559N | ||
| Thymus atrophy | Incidence | 0/10 | 0/10 | 0/10 | 1/10 | 1/10 | 2/10 | 1/6 | 4/6 | 4/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 1.0 | 2.0 | 1.0 | 2.0 | 2.0 | |
| % incidence | 0 | 0 | 0 | 10 | 10 | 20 | 17 | 67 | 57 | |
| CAFE p-value | .053 | — | .500 | .500 | .237 | .625 | .036 | .145 |
| Lesion . | . | Sham 0 mg/kg . | Vehicle 0 mg/kg . | Low 0.8 mg/kg . | Mid 3.2 mg/kg . | Mid High 12.5 mg/kg . | High 50 mg/kg . | Haber Mid 3.2 mg/kg . | Haber Mid High 12.5 mg/kg . | Haber High 50 mg/kg . |
|---|---|---|---|---|---|---|---|---|---|---|
| Nose degeneration, olfactory epithelium | Incidencea | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severityb | 0.0 | 0.0 | 0.0 | 2.0 | 3.0 | 4.0 | 2.0 | 3.0 | 4.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-valuec,d | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose regeneration, olfactory epithelium | Incidence | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 3.0 | 4.0 | 1.0 | 3.0 | 4.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose necrosis, olfactory epithelium | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 0/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 1.0 | 0.0 | 1.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 100 | 100 | 0 | 100 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | — | — | ||
| Nose atrophy, olfactory epithelial glands | Incidence | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 3.0 | 4.0 | 4.0 | 3.0 | 4.0 | 4.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose inflammation, acute | Incidence | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 2.0 | 2.0 | 1.0 | 2.0 | 2.0 | |
| % incidence | 0 | 0 | 0 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | — | <.001 | <.001 | <.001 | — | — | — | ||
| Nose depletion, goblet cells | Incidence | 0/10 | 0/10 | 2/10 | 10/10 | 10/10 | 10/10 | 6/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 2.0 | 3.3 | 3.8 | 4.0 | 3.6 | 3.8 | 4.0 | |
| % incidence | 0 | 0 | 20 | 100 | 100 | 100 | 100 | 100 | 100 | |
| CAFE p-value | <.001 | .237 | <.001 | <.001 | <.001 | — | — | — | ||
| Nose degeneration, transitional epithelium | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 10/10 | 0/6 | 5/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.1 | 1.0 | 0.0 | 1.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 80 | 100 | 100 | 83 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | .696 | — | ||
| Nose regeneration, transitional epithelium | Incidence | 0/10 | 0/10 | 0/10 | 2/10 | 8/10 | 10/10 | 3/6 | 5/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 1.8 | 2.0 | 1.0 | 1.8 | 2.0 | |
| % incidence | 0 | 0 | 0 | 20 | 80 | 100 | 50 | 83 | 100 | |
| CAFE p-value | <.001 | — | .237 | <.001 | <.001 | .242 | .696 | — | ||
| Nose necrosis, transitional epithelium | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 10/10 | 0/6 | 5/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 1.0 | 0.0 | 1.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 80 | 100 | 0 | 83 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | .696 | — | ||
| Nose atrophy, glands, sinus | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 4/10 | 4/10 | 2/6 | 2/6 | 3/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.2 | 1.7 | 1.5 | 1.5 | 1.3 | |
| % incidence | 0 | 0 | 0 | 0 | 40 | 40 | 33 | 33 | 43 | |
| CAFE p-value | <.001 | — | — | .043 | .043 | .125 | .608N | .646 | ||
| Larynx metaplasia, squamous | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 9/10 | 10/10 | 0/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 3.0 | 0.0 | 1.5 | 3.0 | |
| % incidence | 0 | 0 | 0% | 0 | 90 | 100 | 0 | 100 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | — | .625 | — | ||
| Larynx cellular alteration, epithelium | Incidence | 0/10 | 5/10 | 7/10 | 9/10 | 10/10 | 0/10e | 6/6 | 6/6 | 0/7d |
| Severity | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| % incidence | 0 | 50 | 70 | 90 | 100 | 0 | 100 | 100 | 0 | |
| CAFE p-value | ||||||||||
| Trachea depletion, goblet cell | Incidence | 0/10 | 0/10 | 0/10 | 1/10 | 4/10 | 9/10 | 3/6 | 2/6 | 4/7 |
| Severity | NA | NA | NA | NA | NA | NA | NA | NA | NA | |
| % incidence | 0 | 0 | 0 | 10 | 40 | 90 | 50 | 33 | 57 | |
| CAFE p-value | <.001 | — | .500 | .043 | <.001 | .118 | .608N | .162N | ||
| Lung regeneration, epithelium, bronchiole | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 10/10 | 10/10 | 1/6 | 6/6 | 7/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 1.6 | 2.0 | 1.0 | 1.3 | 2.0 | |
| % incidence | 0 | 0 | 0 | 0 | 100 | 100 | 17 | 100 | 100 | |
| CAFE p-value | <.001 | — | — | <.001 | <.001 | .375 | — | — | ||
| Liver necrosis, centrilobular | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 0/6 | 0/6 | 5/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 0.0 | 0.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 0 | 80 | 0 | 0 | 71 | |
| CAFE p-value | <.001 | — | — | — | <.001 | — | — | .559N | ||
| Liver infiltration cellular, mononuclear cell, centrilobular | Incidence | 0/10 | 0/10 | 0/10 | 0/10 | 0/10 | 8/10 | 0/6 | 0/6 | 5/7 |
| Severity | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 1.0 | 0.0 | 0.0 | 1.0 | |
| % incidence | 0 | 0 | 0 | 0 | 0 | 80 | 0 | 0 | 71 | |
| CAFE p-value | <.001 | — | — | — | <.001 | — | — | .559N | ||
| Thymus atrophy | Incidence | 0/10 | 0/10 | 0/10 | 1/10 | 1/10 | 2/10 | 1/6 | 4/6 | 4/7 |
| Severity | 0.0 | 0.0 | 0.0 | 1.0 | 1.0 | 2.0 | 1.0 | 2.0 | 2.0 | |
| % incidence | 0 | 0 | 0 | 10 | 10 | 20 | 17 | 67 | 57 | |
| CAFE p-value | .053 | — | .500 | .500 | .237 | .625 | .036 | .145 |
Number of animals with the lesion per number of animals examined microscopically.
Severity was graded as 1, minimal; 2, mild; 3, moderate; and 4, marked. NA = not applicable.
p-Values under the vehicle column are the results of the Cochran-Armitage trend test. p-Values under the treatment column are the results of a Fisher’s Exact comparison to the Vehicle Control.
p-Values under the Haber Mid, Haber Mid High, and Haber High columns are the results of a Fisher’s Exact comparison to the main Toxicology Mid, Mid High, and High, respectively. A “N” indicates that the Haber incidence was less than the main Toxicology incidence.
Cellular alteration of the larynx was not present in the male High Toxicology or High Haber rats because squamous metaplasia was present at the base of the epiglottis in these rats rather than cellular alteration.
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