What:    Two-day peer consultation meeting to assess a proposal for hexavalent chromium mode of action research
When: July 28-29, 2009 
Where: The Williams and Ida Friday Center, Chapel HIll, NC

 

Toxicology Excellence for Risk Assessment (TERA) was engaged as an independent third party to convene a Science Advisory Board that provided 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 and the studies were conducted by The Hamner Institute.  ToxStrategies engaged TERA to independently organize and conduct the Science Advisory Board; all expenses associated with conducting the SAB came thru ToxStrategies.  Initial funding for the project was provided by the Aerospace Industry Association through its membership. 

 

The National Toxicology Program recently completed a two-year cancer bioassay for sodium dichromate dehydrate in drinking water (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 is being 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 these studies is 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 are 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 will be determined 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.

 

The Science Advisory Board will be established to provide peer consultation on study design as well as on the interpretation of the study findings.  The SAB will review the proposed research plan to ensure that the appropriate studies are conducted and to ensure that the studies are of high quality.

 

FINAL Chromium Peer Consultation - Volume I Report(pdf)

FINAL Chromium Peer Consultation - Volume II Appendices(pdf)

 

Draft Framework Document (pdf)

Appendix & Attachments (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 was issued in late 2009 (see link to report above) and 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:

 

▪  Southern Research Institute is conducting the Mouse 7 and 90 day drinking water studies. 

▪  Southern Research Institute is conducting the Rat 7 and 90 day drinking water studies. 

▪  Dr. Travis O’Brian, Department of Pharmacology and Physiology, The George Washington University, is conducting in-vivo mutation analyses and working with Brooks Rand analytical laboratory to evaluate DNA-Cr adducts

▪  Mr. Sean Hayes and Mr. Chris Kirman at Summit Toxicology are performing the physiologically based pharmacokinetic modeling.  Kinetic data is being collected by Southern Research Institute and Brooks Rand laboratory. 

▪  Dr. Tim Zacharewski, Center for Integrative Toxicology, Michigan State University, is conducting the genomics analyses

▪  Dr. Howard Shertzer. Department of Environmental Health, University of Cincinnati Medical Center, is conducting the GSH/GSSG analyses

 

Due to laboratory limitations, the various studies were conducted in a staggered fashion. The first study to be completed is mouse the 90-day study, which includes the toxicokinetic, biochemical and pathological analyses that have been completed on tissues from that study.  Subsequent studies use tissues from the 90-day mouse study, including the toxicogenomics, mutation analyses, and cytogenetic analyses. A similar approach will be taken with data and associated analyses for the 90-day rat study.  Once all of the analyses are complete in both species, the overall study data will be 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 will also be synthesized to develop a PBPK model for oral exposure to Cr+6 and this model will include the target tissues identified in the NTP 2-yr study.  

 

ToxStrategies has engaged TERA to conduct peer reviews of the individual mode of action studies described above and the PBPK models developed from the collected data.  The peer reviews of the individual studies will be conducted as letter reviews from members of the original SAB, supplemented with ad hoc members with specialized expertise as needed.  As soon as the reviews are completed, the final peer review reports will be available by clicking the links below:

 

▪  Mouse 90-day study

▪  Mouse genomics/Mouse DNA Adducts

▪  Rat DNA Cr Adducts

▪  Pharmacokinetic data/Mouse and Rat PK model/Human PK model

▪  Rat 90-day study/Rat Genomics

▪  In vivo Mutation data/High Content Imaging

 

For more information, contact Joan Strawson (strawson@tera.org or 910.528.9768)