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Q&A About Current Research on Hexavalent Chromium


What is Hexavalent Chromium?
What are the Natural Sources of Hexavalent Chromium?
What Is the Drinking Water Standard Related to Hexavalent Chromium?
Is the Current Drinking Water Standard for Chromium Protective of Human Health?
What Does the Latest Research Show about the Effects of Hexavalent Chromium in Drinking Water?
Why Did ACC Support New Research on Hexavalent Chromium?
What is the Scope of the New Hexavalent Chromium Research?
How Is the New Mode of Action Research Different from the NTP Research?
Who Conducted the New Research?
Where Can I Find the New Hexavalent Chromium Research?

What is Hexavalent Chromium?

Hexavalent chromium, also called chromium-6 or Cr6, is a compound used to create pigments and prevent corrosion in dyes, paints, primers, inks, and plastics. Chromic acid is also electroplated onto metals to create shiny decorative and protective coatings.

Hexavalent chromium can occur naturally in the environment and be man-made.

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What Are the Natural Sources of Hexavalent Chromium?

Starting from the mineral chromite, the element chromium occurs naturally in the environment and can be found in multiple forms including the essential micronutrient trivalent chromium (Cr3) and hexavalent chromium (Cr6). The mineral chromite is found as a rock in many parts of the U.S. Hexavalent chromium is soluble in water and therefore found naturally in ground water where the mineral chromite exists. The Agency for Toxic Substances and Disease Registry (ATSDR) states that the average levels of hexavalent chromium in groundwater in the U.S. is between one and five parts per billion (ppb).

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What Is the Drinking Water Standard Related to Hexavalent Chromium?

Since 1991, the U.S. Environmental Protection Agency (EPA) has had an enforceable drinking water standard which sets a maximum contaminant level (MCL) of 100 ppb for all forms of chromium, including hexavalent chromium. The MCL was based on the best science available at the time. EPA has stated that all water utilities meet the current regulatory standard and that the federal MCL is considered protective of human health.

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Is the Current Drinking Water Standard for Chromium Protective of Human Health?

EPA established the current drinking water standard for total chromium to protect human health from all forms of chromium, including hexavalent chromium. A significant volume of new research and peer-reviewed studies related to hexavalent chromium in drinking water has been published, contributing to the body of scientific literature that EPA can consider in its review of the science on hexavalent chromium. Through this review, EPA will evaluate whether the current drinking water standard for total chromium continues to be protective of human health.

As part of this process, EPA’s Integrated Risk Information System (IRIS) program is developing a draft health risk assessment for hexavalent chromium, which is expected in 2013.

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What Does the Latest Research Show about the Effects of Hexavalent Chromium in Drinking Water?

A series of state of the art, peer-reviewed studies provides clear data that can help regulators confidently set safe drinking water standards for hexavalent chromium. These studies show that there was no observed toxicity in rodents exposed to concentrations of hexavalent chromium in drinking water at the current maximum contaminant level (MCL) of 100 ppb for total chromium. In fact, at hexavalent chromium concentrations ten times the current drinking water exposure limit for total chromium, there was no observed toxicity in the rodents.

Specifically, these studies examined high-, medium- and low-level exposures to hexavalent chromium in drinking water, including the current drinking water standard for total chromium. At the lowest dose tested, 100 ppb of hexavalent chromium in drinking water, which is the same as the drinking water standard for total chromium, no toxicity was observed in the test animals. No toxicity was observed at 1,400 ppb—more than 10 times the current drinking water exposure limit for total chromium. In fact, researchers did not observe toxicity in the rodents until the hexavalent chromium dose was 5,000 ppb—50 times the total chromium drinking water standard. At 5,000 ppb and higher levels of exposure, the water the rodents were drinking was extremely yellow in color because of the high concentration of hexavalent chromium. The researchers also found that the biochemical, genetic, and pathology effects changed in a non-linear fashion as the doses increased, supporting what scientists call a threshold response.

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Why Did ACC Support New Research on Hexavalent Chromium?

In 2008, the National Toxicology Program (NTP) released the results of a study of hexavalent chromium on rodents that was designed to determine whether the chemical can cause cancer at extremely high doses; however, NTP did not examine the mode of action, meaning how the chemical can cause cancer at the cellular level of an organism. Because the NTP study did not examine mode of action, which is important for scientists and regulators to understand when evaluating risk, the Hexavalent Chromium Panel of the American Chemistry Council (ACC) decided to sponsor extensive studies that investigated not only which levels of hexavalent chromium in drinking water can result in adverse effects like cancer, but also how high doses of hexavalent chromium can cause cancer in rodents. The studies also developed data describing the differences between rodents and humans in their ability to process and detoxify hexavalent chromium.

Later, in September 2010, EPA released a draft Integrated Risk Information System (IRIS) assessment for hexavalent chromium that relied on the NTP study, which tested the chemical in rodents only at extremely high levels. In May 2011, EPA’s independent, expert peer review panel identified data gaps in the existing hexavalent chromium research and “urged EPA to consider the results of research that would soon be completed and peer-reviewed that could provide relevant scientific information that may inform the findings of the assessment.” The new, peer-reviewed research on mode of action sponsored by ACC fills these data gaps.

For a detailed summary of the mode of action studies and their outcomes, a presentation from ToxStrategies is available here.

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What is the Scope of the New Hexavalent Chromium Research?

The new research on mode of action builds upon and expands the 2008 NTP study and was specifically designed to help answer questions raised as a result of that study using EPA’s guidelines as the framework for collecting data.

This research includes four multifaceted studies using cutting-edge science and advanced approaches for toxicity testing, including:

  1. Comprehensive examination of the genomic changes that precede tumor formation;
  2. Biochemical and cytogenetic investigations to evaluate mutations, genotoxicity, and other potential key events in the mode of action;
  3. An in vitro high-content imaging study to investigate key events of the mode of action; and
  4. A pharmacokinetic study (absorption, distribution and deposition of hexavalent chromium in tissues in the body) to develop the data supporting physiologically-based pharmacokinetic (PBPK) models.

EPA has stated that it is desirable to have a PBPK model when developing its assessments. Therefore, as part of the new hexavalent chromium research, data were collected that allowed scientists to build a PBPK model to provide a strong scientific approach for extrapolation across species (rodents to humans) and from the high doses that induced tumors in mice to environmentally-relevant exposures in humans.

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How Is the New Mode of Action Research Different from the NTP Research?

The NTP study is a well-run, classic two-year bioassay designed to evaluate whether an effect is observed when animals, usually rodents, are exposed to a high doses of a chemical. The concentrations of hexavalent chromium NTP administered in its drinking water bioassay far exceed typical environmental exposures. The rodents in the NTP bioassay were exposed to hexavalent chromium at 5,000-180,000 parts per billion, while humans are typically exposed to the chemical at concentrations between one and five parts per billion, according to the ATSDR. Scientists have suggested that the high doses used in the NTP study may have overwhelmed normal protective mechanisms that are thought to limit the carcinogenic potential of hexavalent chromium following ingestion.

In contrast, the new research was designed to generate data describing how and when the effects reported by NTP occur—in other words, the mode of action of a chemical.

Thus, the new research builds upon and extends the NTP study. Importantly, the new research studies were conducted in the same research laboratory, with the same laboratory director, using the same laboratory conditions (same animal species, same animal cages, same animal chow, same source of drinking water, etc.) as the NTP study. The experimental animals were exposed to the same NTP doses and two lower doses to better characterize the effects at drinking water concentrations meeting the federal total chromium drinking water standard.

Mode of action information is very important when trying to extrapolate the findings of the NTP study to humans who are exposed to substantially lower concentrations. As described in the EPA cancer risk assessment guidelines, extrapolating results of animal studies at high doses to humans at much lower doses should ideally be based upon an understanding of the mode(s) of action underlying the development of tumors in an animal study.

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Who Conducted the New Research?

The Hexavalent Chromium Panel of the ACC sponsored the research. To ensure high-quality, independent scientists conducted the research, ACC hired leading investigators from ToxStrategies to direct, manage, and oversee the scientific investigations and technical specialists involved in this multi-dimensional study. The ToxStrategies Project Management team contracted with leading universities, testing laboratories, modeling experts, and an independent peer review organization. ToxStrategies is a highly respected scientific consulting firm that works with universities, governments and the business community.

The mode of action research studies were conducted by a highly qualified team of experts from 13 different organizations. Those organizations and their contributions to the research are listed below:

  • ToxStrategies: project coordination and risk assessment
  • Summit Toxicology: toxicokinetics and risk assessment
  • Southern Research Institute: treatment, biochemical, histopathology
  • Michigan State University: genomics
  • George Washington University Medical Center: mutations, Cr-DNA binding studies
  • University of Cincinnati Medical Center: GSH/GSSG
  • Duke University Medical Center: human gastric fluid
  • Environmental Standards: analytical oversight, data validation
  • Thermo Fisher: high content analysis in cultured cells
  • Experimental Pathology Laboratory: cytogenetics
  • National Center Toxicological Research: mutation analysis
  • Brooks Rand: DNA and tissue analysis
  • Applied Speciation: reduction rate studies

In addition to the scientific experts performing the research, the independent, non-profit organization Toxicology Excellence for Risk Assessment (TERA) conducted its own review of the research protocols in advance of the studies being conducted. The key draft manuscripts and underlying data were reviewed by this independent, peer review group prior to journal submission. The findings of TERA’s peer-review activities on hexavalent chromium can be found here.

As with all quality research, the investigators submitted their study findings to the same peer-reviewed journals as government and academic scientists use. These journals then conducted another independent peer review of each manuscript prior to publication.

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Where Can I Find the New Hexavalent Chromium Research?

The 14 papers are peer-reviewed, published, and available below.

  1. Thompson, C.M., L.C. Haws, M.A. Harris, N.M. Gatto, and D.M. Proctor. 2011. 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. Toxicological Sciences. 119(1): 20-40.
     
    Paper: http://toxsci.oxfordjournals.org/content/119/1/20.full.pdf+html?sid=896b4c7e-b535-4884-aa79-261ecc512de8

    Supplemental data: http://toxsci.oxfordjournals.org/content/119/1/20/suppl/DC1

  2. Thompson, C.M., D.M. Proctor, L.C. Haws, C.D. Hébert, S.D. Grimes, H.G. Shertzer, A.K. Kopec, J.G. Hixon, T.R. Zacharewski, and M.A. Harris. 2011. Investigation of the Mode of Action Underlying the Tumorigenic Response Induced in B6C3F1 Mice Exposed Orally to Hexavalent Chromium. Toxicological Sciences. 123(1):58-70.

    Paper: http://toxsci.oxfordjournals.org/content/123/1/58.full.pdf+html?sid=d185e9e8-71d0-415b-9e2d-97ca5844207c

    Supplemental data: http://toxsci.oxfordjournals.org/content/123/1/58/suppl/DC1

  3. Thompson, C.M., D.M. Proctor, M. Suh, L.C. Haws, C.D. Hébert, J.F. Mann, H.G. Shertzer, J.G. Hixon, and M.A. Harris. 2011. Comparison of the effects on hexavalent chromium in the alimentary canal of F344 rats and B6C3F1 mice following exposure in drinking water: Implications for carcinogenic modes of action. Toxicological Sciences. 125(10): 79-90.

    Paper: http://toxsci.oxfordjournals.org/content/125/1/79.full.pdf+html?sid=d7c79f9a-4b38-46d1-953e-81449fd02eae

    Supplemental data: http://toxsci.oxfordjournals.org/content/125/1/79/suppl/DC1

  4. Thompson, C.M., D.M. Proctor, and M.A. Harris. 2012. Duodenal GSH/GSSG Ratios in Mice Following Oral Exposure to Cr(VI). Toxicological Sciences. 126(1): 287-288. doi:10.1093/toxsci/kfr337.

    Letter to Editor: http://toxsci.oxfordjournals.org/content/126/1/287.full.pdf+html

  5. Kopec, A.K., S. Kim, A.L. Forgacs, T.R. Zacharewski, D.M. Proctor, M.A. Harris, L.C. Haws, and C.M. Thompson. 2012. Genome-wide gene expression effects in B6C3F1 mouse intestinal epithelia following 7 and 90 days of exposure to hexavalent chromium in drinking water. Toxicology and Applied Pharmacology. 259(1):13-26.

    Paper: http://www.sciencedirect.com/science/article/pii/S0041008X11004480

  6. Kopec, A.K., C.M. Thompson, S. Kim, A.L. Forgacs, and T.R. Zacharewski. 2012. Comparative toxicogenomic analysis of oral Cr(VI) exposure effects in rat and mouse small intestinal epithelia. Toxicology and Applied Pharmacology. 262(2):124-138.
     
    Paper: http://www.ncbi.nlm.nih.gov/pubmed/22561333

  7. Thompson, C.M., J.G. Hixon, D.M. Proctor, L.C. Haws, M. Suh, J.D. Urban, and M.A. Harris. 2012. Assessment of Genotoxic Potential of Cr(VI) in the Mouse Duodenum: An In Silico Comparison with Mutagenic and Nonmutagenic Carcinogens Across Tissues. Regulatory Toxicology and Pharmacology. 64(1): 68-76.

    Paper: http://www.sciencedirect.com/science/article/pii/S0273230012001134?v=s5

  8. Proctor, D.M., M. Suh, L.L. Aylward, C.R. Kirman, M.A. Harris, C.M. Thompson, H. Gurleyuk, R. Gerads, L.C. Haws, and S.M. Hays. 2012. Hexavalent Chromium Reduction Kinetics in Rodent Stomach Contents. Chemosphere. 89 (5): 487-493.

    Paper: http://www.sciencedirect.com/science/article/pii/S0045653512005978.

  9. Thompson, C.M., Y. Federov, D.D. Brown, M. Suh, D.M. Proctor, L. Kuriakose, L.C. Haws, and M.A. Harris. 2012. Assessment of Cr(VI)-Induced Genotoxicity Using High Content Analysis. PLoS ONE. 7(8): e42720. doi:10.1371/journal.pone.0042720.

    Paper: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0042720

  10. Kirman, C.R., S.M. Hays, L.L. Aylward, M. Suh, M.A. Harris, C.M. Thompson, L.C. Haws, and D.M. Proctor. 2012. Physiologically Based Pharmacokinetic Model for Rats and Mice Orally Exposed to Chromium Physiologically Based Pharmacokinetic Model for Rats and Mice Orally Exposed to Chromium. Chemico-Biological Interactions. 200(1):45-64.

    Paper: http://dx.doi.org/10.1016/j.cbi.2012.08.016

  11. Thompson, C.M, D.M. Proctor, M. Suh, L.C. Haws, and M.A. Harris. 2013. Mode of Action Underlying Development of Rodent Small Intestinal Tumors Following Oral Exposure to Hexavalent Chromium and Relevance to Humans. Critical Reviews in Toxicology. 43(3):244-274.

    Paper: http://informahealthcare.com/doi/abs/10.3109/10408444.2013.768596

  12. Kirman, C.R., LL Aylward, M. Suh, M.A. Harris, CM. Thompson, LC. Haws, D.M. Proctor, W. Parker, and S.M. Hays. 2013. Physiologically Based Pharmacokinetic Model for Humans Orally Exposed to Chromium. Chemico-Biological Interactions. 204(1):13-27.

    Paper: http://www.sciencedirect.com/science/article/pii/S0009279713000823

  13. O'Brien, T.J., H. Ding, M. Suh, CM. Thompson, B.L. Parsons, M.A. Harris, L.C. Haws, W.A. Winkelman, J.C Wolf, J.G. Hixon, A.M. Schwartz, M.B. Myers, L.C Haws, and D.M. Proctor. 2013. Assessment of K-Ras mutant frequency and micronucleus incidence in the mouse duodenum following 90-days of exposure to Cr(VI) in drinking water. Mutation Research. Available April 9, 2013.

    Paper: http://www.sciencedirect.com/science/article/pii/S1383571813000752

  14. Thompson, CM., C.R. Kirman, D.M. Proctor, LC Haws, M. Suh, S.M. Hays, and M.A. Harris. 2013. A Chronic Oral Reference Dose for Hexavalent Chromium—Induced Intestinal Cancer. Accepted Journal of Applied Toxicology. June 2, 2013.

    Paper: http://onlinelibrary.wiley.com/doi/10.1002/jat.2907/pdf

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