Independent Peer Consultation for Hexavalent Chromium Mode of Action Research
Toxicology Excellence for Risk Assessment (TERA) was engaged as an independent third party to convene a Science Advisory Board to provide guidance on the design and conduct of a series of studies investigating the mode of action by which hexavalent chromium is carcinogenic in rats and mice following drinking water exposure. The research project was organized by ToxStrategies. ToxStrategies engaged TERA to independently organize and conduct the Science Advisory Board and follow up reviews; all expenses associated with conducting the SAB came through ToxStrategies. Initial funding for the project was provided by the Aerospace Industry Association through its membership and later funding from the American Chemistry Council.
The National Toxicology Program released a two-year cancer bioassay for sodium dichromate dehydrate in drinking water in 2007 (NTP, 2007) that reported intestinal tumors in mice and oral mucosal tumors in rats following lifetime exposure to hexavalent chromium. State and Federal regulatory agencies are likely to re-evaluate their drinking water regulations for hexavalent chromium and will consider using the NTP cancer bioassay to develop an oral cancer slope factor for hexavalent chromium. In the absence of additional data concerning the mode of action underlying the tumorigenic responses, cancer risk assessment guidance recommends that an oral slope factor be derived using a default linear dose response model. Therefore, a research program was initiated to investigate the mode(s) of action underlying these tumorigenic responses in rodents in order to determine the shape of the dose response curve and the human relevance of these responses, prior to the development of an oral slope factor for hexavalent chromium.
The overall goal of the research program was to understand the contribution of different modes of action for hexavalent chromium across a broad range of doses in order to provide both statistical and biological understanding of thresholds for chromium carcinogenicity. While high concentration tumors in laboratory animals indicates some level of genotoxicity, these tumors may also arise in the presence of other cellular responses, including cytotoxicity, inflammation, and high levels of oxidative stress. These secondary responses were expected to lead to dose-dependent transitions where Cr(III) and Cr(VI) DNA reactivity finally lead to DNA damage, mutation, and transformation. The contributions of these various pathways over the range of doses and concentrations were evaluated by a combination of genome-wide microarray analyses in intact animals, high data content imaging of activation of key DNA-damage pathways, and consideration of dose dependences in dosimetry.
July 2009 – Science Advisory Board Peer Consultation Meeting on the Proposed Research Program
The Science Advisory Board was established to provide peer consultation on study design as well as on the interpretation of the subsequent study findings. The SAB reviewed the proposed research plan to ensure that the appropriate studies would be conducted and to ensure that the studies would be of high quality. The SAB met in July 2009. Below are links to the final peer consultation report and the Draft Research Framework document (and its appendices) that was the basis for the peer consultation.
Report of July 2009 Chromium Peer Consultation - Volume I Report (pdf)
Report of July 2009 Chromium Peer Consultation - Volume II Appendices(pdf)
Draft Framework Document (pdf)
Appendix & Attachments for Draft Framework Document (pdf)
Peer Review of Individual Chromium Mode of Action Studies
As described above, TERA convened a Science Advisory Board that provided guidance on a protocol for a series of studies investigating the mode of action by which hexavalent chromium is carcinogenic in rats and mice following drinking water exposure in July 2009. The final report of the July peer review expressed the expert panel’s recommendations on studies designed to assess chromium’s mode of action following a 90-day drinking water exposure in mice and rats. Following release of the peer report, ToxStrategies incorporated the panel’s recommendations and engaged several research laboratories to conduct the proposed studies:
Due to laboratory limitations, the various studies were conducted in a staggered fashion. The first study to be completed was the mouse 90-day study. Subsequent studies used tissues from the 90-day mouse study, including the toxicogenomics, mutation analyses, and cytogenetic analyses. A similar approach was taken with data and associated analyses for the 90-day rat study. With the completed analyses in both species, the overall study data were evaluated collectively using a weight-of-the-evidence-based approach to determine if the data are sufficient to draw conclusions about the MOA(s) underlying the toxic/carcinogenic responses. Data were also used to develop a PBPK model for oral exposure to Cr+6 and this model included the target tissues identified in the NTP 2-year study (NTP 2007).
ToxStrategies engaged TERA to conduct expert reviews of the draft manuscripts describing and reporting on the studies and the PBPK model. These reviews were conducted as letter reviews using members of the original Science Advisory Board that reviewed the research plan, supplemented with additional experts. Below are links to reports of these reviews.
Physiologically based pharmacokinetic (PBPK) human model
For more information, contact Jacqueline Patterson (patterson@tera.org)