Hexavalent chromium (Cr(VI)) is a form of the element chromium, which is one of the most abundant chemical elements found in the earth’s crust. There are two potential sources of hexavalent chromium in drinking water – natural sources such as rocks, minerals, and other geology, and localized industrial runoff. Typical U.S. drinking water supplies contain naturally occurring chromium.
National and international regulatory agencies have set drinking water standards to protect the public from all forms of chromium (Cr(VI) and Cr(III)) in drinking water. Cr(III), also known as trivalent chromium, can also be naturally present in drinking water and is a micronutrient that is essential for metabolism. The human body naturally detoxifies low levels of Cr(VI) into non-toxic Cr(III), no matter the source. The EPA, for example, has a drinking water standard of 100 parts per billion (ppb) for total chromium. See what various regulatory agencies have to say about hexavalent chromium here.
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 in rocks 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).
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. EPA's MCL of 100 ppb assumes 100% 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.
EPA established the current drinking water standard for total chromium to protect human health from all forms of chromium, including hexavalent chromium, and the 100 ppb standard is based on an assumption that you have 100% hexavalent chromium in the water. 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 assessment for hexavalent chromium, which is expected in 2021.
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 standard 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 standard 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.
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 primarily 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.
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:
- Comprehensive examination of the genomic changes that precede tumor formation;
- Biochemical and cytogenetic investigations to evaluate mutations, genotoxicity, and other potential key events in the mode of action;
- An in vitro high-content imaging study to investigate key events of the mode of action; and
- 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.
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 the animals’ normal ability to detoxify low levels 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.
