Table 9.
Select properties of mutagenicity as key events and application to the Cr(VI) in the small intestine.
| US EPA (2007) | Cr(VI) study results |
| Mutations seen in the presence of low cytotoxicity increase WOE | Mutations not detected in Kras, even in the presence of toxicity. No indications of increased Wnt/β-catenin signaling |
| Mutations in genes that affect carcinogenesis increase WOE | Mutations not detected in Kras, even after 90 days of exposure |
| The target cell/tissue is exposed to the ultimate DNA reactive chemical | Data suggest that intestinal crypts were not directly exposed to Cr(VI) after 7 or 90 days of exposure |
| DNA of target cell is damaged | No evidence of cytogenetic damage at after 7 or 90 days of exposure |
| Tumors observed at multiple sites, in multiple species | Only one tumor location in each species, despite the presence of Cr in multiple tissues |
| Tumor response generally occur early in chronic study (e.g. within 52 weeks) | Tumors in small intestine of mice and oral mucosa of rats did not occur early, and were not associated with lethality or metastases |
| Boobis et al. (2009) | Cr(VI) study results |
| Exposure of target cells to ultimate DNA reactive and mutagenic species – with or without metabolism | Evidence does not support that Cr(VI) is reaching the target cells (i.e. crypts) |
| Reaction with DNA in target cells to produce DNA damage | No evidence of DNA damage, as evidenced by negative results for MN, karyorrhectic nuclei, AI and MI in crypts after 90 days of exposure |
| Misreplication on a damaged DNA template or misrepair of DNA damage | No evidence of DNA damage, as evidenced by negative results for MN, karyorrhectic nuclei, AI and MI in crypts after 90 days of exposure |
| Mutations in critical genes in replicating target cells | No evidence of increased Kras mutation frequency |
| Clonal expansion leads to further mutations in critical genes | No evidence of increased Kras mutation frequency due to Cr or clonal expansion. |
| Imbalanced and uncontrolled clonal growth of mutant cells may lead to preneoplastic lesions | No evidence of preneoplastic lesions |
| Preston & Williams (2005) | Cr(VI) study results |
| Exposure of target cells to ultimate DNA-reactive and mutagenic species | Evidence does not suggest direct damage to crypt cells |
| Reaction with DNA in target cells to produce DNA damage | No apparent cytogenetic damage in crypt cells |
| Replication errors from damaged template | Not readily observable |
| Mutations in critical genes in replicating target cells | No Kras mutations in duodenal mucosa, or changes in Wnt/β-catenin signaling |
| Enhanced cell proliferation | Apparent as early as 7 days of exposure along with mucosal injury |
| Additional mutations induced from DNA damage and replication | No Kras mutations in duodenal mucosa, or changes in Wnt/β-catenin signaling |
| Clonal expansion of mutant cells | Not readily observable |
| Development of preneoplastic lesions and neoplasms | No evidence of neoplasias or preneoplastic lesions in multiple 90-day studies |
| Malignant behavior | Adenomas greatly outnumber adenocarcinomas (NTP, 2008b) |