US EPA (2007)
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Cr(VI) study results
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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 |
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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)
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Cr(VI) study results
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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)
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Cr(VI) study results
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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
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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) |