Table 8.
BMD and BMDL values (in mg/kg-bw-day) at the 10th percentile of all affected genes in an IPA pathway for each proposed key event. A BMD/BMDL ratio greater than 10 indicates a poor model fit and is indicated as not applicable (N.A.). The number of genes modelled were 8 for lung, 5 for liver and 40 for forestomach. The BMDLs proposed as PODs are shaded and bolded.
| Liver | Lung | Forestomach | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| 3day+4hr | 3day+24hr | 28day+3day | 28day+3day | 28day+3day | |||||||
| Key Event | Pathway Title | BMD | BMDL | BMD | BMDL | BMD | BMDL | BMD | BMDL | BMD | BMDL |
| 1. BaP binding to AhR (Molecular Initiating Event). | |||||||||||
| 2. Induction of P450. 3. BaP Metabolism to Reactive Metabolites. | Aryl Hydrocarbon Signaling | 13.9 | 10.7 | 32.9 | 20.8 | 24.1 | 16.8 | 17.2 | 7.7 | 14.6 | 8.2 |
| Xenobiotic Metabolism Signaling | 13.6 | 10.1 | 20.0 | 4.3 | 27.5 | 14.1 | 29.8 | 13.9 | 13.5 | 7.9 | |
| NRF2-mediated Oxidative Stress Response | 40.1 | 18.6 | 29.7 | 6.9 | 31.4 | 21.3 | 28.0 | 18.6 | 15.4 | 9.0 | |
| Glutathione-mediated Detoxification | 70.3 | 49.6 | 82.1 | 54.4 | < 5 genes | < 5 genes | 15.3 | 9.0 | |||
| 4. DNA Adducts and DNA Damage. | p53 Signaling | 63.4 | 45.5 | 22.0 | 12.5 | 29.6 | 13.6 | 13.5 | 7.7 | 11.4 | 7.4 |
| Cell Cycle: G1/S Checkpoint Regulation | 75.7 | 43.8 | 8.1 | 1.0 | 24.6 | 12.4 | 11.7 | 8.9 | 18.5 | 7.7 | |
| Cell Cycle: G2/M DNA Damage Checkpoint Regulation | 77.1 | 29.9 | 79.7 | 43.3 | < 5 genes | 14.8 | 3.7 | 22.1 | 13.1 | ||
| Cell Cycle Control of Chromosomal Replication | 104.1 | 65.0 | 70.7 | 39.7 | 42.2 | 17.2 | Unperturbed | 12.8 | 8.0 | ||
| 5. Mutations. | |||||||||||
| 6. Altered Cell Signalling, Proliferation, and Apoptosis. | Apoptosis Signaling | 68.6 | 38.9 | 54.1 | 34.5 | 51.5 | 32.7 | 27.6 | 14.6 | 12.7 | 7.9 |
| Induction of Apoptosis by HIV1 | 64.6 | 36.8 | 22.0 | 7.2 | < 5 genes | 26.5 | 12.1 | 15.3 | 9.0 | ||
| LPS-stimulated MAPK Signaling | 26.9 | 15.6 | 23.0 | 14.9 | 35.0 | 20.2 | 24.3 | 12.1 | 15.0 | 8.8 | |
| Myc Mediated Apoptosis Signaling | 26.2 | 5.2 | 15.4 | 1.9 | < 5 genes | 30.6 | 7.0 | 15.0 | 8.9 | ||
| p38 MAPK Signaling | 53.4 | 35.3 | 26.5 | 19.3 | 25.3 | 11.9 | 23.3 | N.A. | 19.1 | 10.1 | |
| PPAR Signaling | 69.2 | 37.4 | 6.5 | N.A. | 42.9 | 28.6 | 27.0 | N.A. | 18.5 | 10.1 | |
| Retinoic acid Mediated Apoptosis Signaling | 73.8 | 50.3 | 58.2 | 36.3 | < 5 genes | < 5 genes | 19.6 | 9.1 | |||
| TGF-beta Signaling | 73.5 | 45.9 | 13.3 | 1.5 | 25.3 | 11.9 | 9.2 | N.A. | 12.8 | 8.0 | |
| UVA-Induced MAPK Signaling | 75.1 | 58.0 | 56.5 | 36.9 | 29.0 | 13.4 | 16.8 | N.A. | 15.9 | 8.0 | |
| VEGF Signaling | 63.4 | 31.7 | 9.9 | N.A. | 26.5 | 11.6 | 21.2 | 7.4 | 15.1 | 8.6 | |
| Wnt/beta-catenin Signaling | 15.8 | N.A. | 36.0 | 25.1 | 23.7 | 6.7 | 23.0 | 7.7 | 25.1 | 10.8 | |
| 7. Tumorigenesis (Adverse Outcome). | HER-2 Signaling in Breast Cancer | 61.5 | 39.3 | 31.9 | 16.6 | 33.7 | 19.5 | 22.9 | 10.1 | 16.1 | 8.2 |
| Prostate Cancer Signaling | 88.7 | 47.4 | 16.4 | 2.2 | 37.0 | 22.7 | 22.9 | N.A. | 15.8 | 9.0 | |
| Bladder Cancer Signaling | 78.4 | 47.8 | 6.7 | 2.3 | 44.9 | 29.6 | 17.2 | 9.5 | 21.6 | 8.6 | |
| Role of Tissue Factor in Cancer | 5.6 | N.A. | 20.3 | 2.3 | 24.7 | N.A. | 20.1 | 11.1 | 15.1 | 7.9 | |
| Thyroid Cancer Signaling | 60.8 | 46.5 | 45.7 | 28.4 | < 5 genes | 33.4 | 19.2 | 15.6 | 7.6 | ||
| Endometrial Cancer Signaling | 26.2 | 19.1 | 43.7 | 27.4 | 35.0 | 20.2 | 30.0 | 10.0 | 16.2 | 9.3 | |
| Estrogen-Dependent Breast Cancer Signaling | 38.7 | 24.5 | 59.7 | 38.4 | 37.0 | 22.0 | 18.7 | 7.6 | 13.0 | 7.5 | |
| Hereditary Breast Cancer Signaling | 75.4 | 53.2 | 11.1 | 2.2 | 28.7 | 13.3 | 26.6 | 17.3 | 14.7 | 8.8 | |
| Molecular Mechanisms of Cancer | 30.4 | 15.6 | 16.3 | 1.8 | 26.5 | 11.9 | 13.4 | 6.8 | 16.8 | 8.9 | |
| Colorectal Cancer Metastasis Signaling | 35.0 | 9.0 | 16.8 | 2.2 | 26.8 | 13.1 | 19.0 | 7.8 | 16.2 | 8.1 | |
| Non-Small Cell Lung Cancer Signaling | 62.8 | 37.8 | 20.4 | 5.9 | < 5 genes | 40.5 | 25.1 | 15.9 | 7.8 | ||
| Basal Cell Carcinoma Signaling | 21.5 | 13.0 | 29.0 | 20.7 | 43.9 | 27.1 | 17.3 | 10.0 | 18.2 | 9.7 | |
| Small Cell Lung Cancer Signaling | 38.9 | 24.2 | 59.2 | 36.6 | < 5 genes | 23.9 | 11.0 | 15.4 | 7.7 | ||
| Lowest BMDL 10th percentile regardless of MOA | 6.3 | 0.8 | 0.3 | 0.2 | 25.4 | 5.3 | 15.7 | 2.1 | 16.1 | 4.5 | |
| CXCR4 Signaling | Notch Signaling | Rac Signaling | Cellular Effects of Sildenafil (Viagra) | Phenylalanine Degradation IV (Mammalian, | |||||||