An evaluation of the mode of action framework for mutagenic carcinogens case study II: Chromium (VI)

@article{McCarroll2010AnEO,
  title={An evaluation of the mode of action framework for mutagenic carcinogens case study II: Chromium (VI)},
  author={Nancy E McCarroll and Nagalakshmi Keshava and Jonathan Chen and Gregory S. Akerman and Andrew D. Kligerman and Esther Rinde},
  journal={Environmental and Molecular Mutagenesis},
  year={2010},
  volume={51}
}
In response to the 2005 revised U.S Environmental Protection Agency's (EPA) Cancer Guidelines, a strategy is being developed to include all mutagenicity and other genotoxicity data with additional information to determine whether the initiating step in carcinogenesis is through a mutagenic mode of action (MOA). This information is necessary to decide if age‐dependent adjustment factors (ADAFs) should be applied to the risk assessment. Chromium (VI) [Cr (VI)], a carcinogen in animals and humans… 
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Highly Influential Citations
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Ten factors for considering the mode of action of Cr(VI)-induced gastrointestinal tumors in rodents.
Assessment of the mutagenic potential of Cr(VI) in the oral mucosa of Big Blue® transgenic F344 rats
TLDR
High (∼180,000 times expected human exposure), tumorigenic concentrations of Cr( VI) did not significantly increase mutations in the gingival epithelium, and suggest that Cr(VI) does not act by a mutagenic MOA in the rat oral cavity.
Comparison of in vivo genotoxic and carcinogenic potency to augment mode of action analysis: Case study with hexavalent chromium.
Application of the U.S. EPA Mode of Action Framework for Purposes of Guiding Future Research: A Case Study Involving the Oral Carcinogenicity of Hexavalent Chromium
TLDR
An MOA analysis was conducted to evaluate small intestinal tumors observed in mice chronically exposed to relatively high concentrations of hexavalent chromium in drinking water, highlighting the need for obtaining critical toxicokinetic and toxicodynamic data in the target tissue and in the low-dose range.
Chromium (III) and chromium (VI) as important players in the induction of genotoxicity - current view.
TLDR
The aim of this review is to present the current knowledge about the induction of genotoxicity from two forms of chromium: trivalent (III) and hexavalent (VI).
Factors influencing mutagenic mode of action determinations of regulatory and advisory agencies.
  • D. Eastmond
  • Biology
    Mutation research. Reviews in mutation research
  • 2012
Assessment of Mechanistic Data for Hexavalent Chromium-Induced Rodent Intestinal Cancer Using the Key Characteristics of Carcinogens
TLDR
No plausible alternative MOAs (or key events) were identified in addition to those previously proposed for Cr(VI) small intestine tumors, with activity generally limited to the two recognized MOAs.
Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans
TLDR
The weight of evidence supports a cytotoxic MOA with the following key events: absorption of Cr(VI) from the intestinal lumen, toxicity to intestinal villi, crypt regenerative hyperplasia and clonal expansion of mutations within the crypt stem cells, resulting in late onset tumorigenesis.
Mechanistic Insights from the NTP Studies of Chromium
TLDR
Tissue distribution studies in additional groups of male rats and female mice demonstrated higher Cr concentrations in tissues following exposure to Cr( VI) compared to controls and Cr(III) exposure at a similar external dose, indicating that some of the Cr(VI) escaped gastric reduction and was distributed systemically.
Development of a cancer-based chronic inhalation reference value for hexavalent chromium based on a nonlinear-threshold carcinogenic assessment.
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