Tempest in a chromium teapot
Weight of evidence has always been counter to carcinogenicity by ingestion at environmentally relevant levels, author says
As a possible water contaminant, chromium first became famous based on the movie “Erin Brockovich,” released in 2000 and about Hinkley, Calif. At the moment, hexavalent chromium, also written as Cr VI, is one of the chemicals, or ions, of interest to the U.S Environmental Protection Agency (USEPA) and the State of California as possible drinking water contaminants to be reregulated.
This comes after a National Toxicology Program (NTP) reported results of a high dose feeding study in rats and mice in 2008, where cancers were found in the animals at high doses, but not at lower doses. There has been a rush of anxiety concerning public water supplies, several pre-regulatory “risk assessments” and research activity dealing with the hypothetical that microgram per liter (parts per billion) amounts in drinking water might have a carcinogenic risk, albeit very small.
The question is whether it is plausible that ingesting microgram amounts of chromium VI could be a risk. Chromium and its salts are common chemicals that have many uses, including in ferroalloys for making stainless steel, for corrosion control in cooling systems, electroplating and as pigments. Chromium exists in nature primarily as chromium III and some chromium VI, but there are industrial discharges that contain chromium VI. Some small amounts could actually be formed in drinking water from oxidation of chromium III, if present, by disinfectants. Dietary intake of total chromium (probably mostly chromium III) ranges up to a few hundred micrograms per day. Chromium III is a likely essential nutrient and is obtainable as chromium picolinate as a dietary supplement.
Chromium VI is a strong oxidizing agent and it has been considered to be a lung carcinogen by inhalation for many years. Occupational health studies have implicated chromium VI as a lung carcinogen for workers in industries such as roasting of chromite ore.
Conversion after ingestion
Because chromium VI is a strong oxidizing agent, especially under acidic conditions, it is highly reactive and readily reduced to chromium III by numerous substances, so there is a serious question whether chromium VI survives to any significant extent prior to reduction to chromium III after ingestion in food or water. Moreover, the gastrointestinal tract, beginning with oral saliva, is a chemical reduction environment that contains many organic reducing agents like thiols (e.g. glutathione) and inorganic reducing agents like hydrogen sulfide, nitrite, iodide and ferrous iron. Earlier studies have demonstrated rapid reduction of chromium VI in human saliva, gastric juice and blood with estimated reduction capacities in the hundreds of milligrams per day.
The drinking water concentrations of chromium VI used in the NTP bioassays in rats and mice ranged from a low of 5 mg/L to 180 mg/L, and the cancers were observed only at the high doses, and not at low doses. The study concluded that there was clear evidence of carcinogenicity in the rats and mice under test conditions, but how that extreme test finding relates to human risk under environmental conditions is the province of regulatory agencies and the regulatory process. Even the NTP report cited the lack of effects at lower doses and suggested the effects at high doses were possibly due to exceeding the animals’ innate chemical reductive capabilities at those doses.
A 2011 outside expert review of the draft risk assessment commissioned by USEPA concluded that even very high doses of chromium VI were only weakly mutagenic at doses that were toxic to the cells, and that it was likely that the observed mutagenesis was really caused by selection and proliferation of surviving cells at the high doses, rather than mutations of cells. This observation alone raises serious doubts as to whether chromium VI would be genotoxic and carcinogenic by ingestion.
Regarding human occupational epidemiology studies, a 2010 meta analysis of 32 studies after 1950 where workers were inhaling and swallowing substantial amounts of chromium VI, causing discolored saliva and gastrointestinal distress, did not identify any significant increases of cancer in the gastrointestinal tract.
Retrospective tracking of the Hinkley, Calif., population has not resulted in detections of increases of total cancers or any cancer types beyond what would be expected for that type of population, and actually a bit less than expected.
Adequate control till now?
Chromium has been regulated in drinking water at 50 ppb since the U.S. Public Health Service (USPHS) standards of 1946, which very conservatively assumed all was potentially chromium VI. The USEPA national primary drinking standard was 50 ppb and later raised to the current 100 ppb, concluding that chromium VI is an inhalation carcinogen but not a carcinogen by ingestion.
Yet a report of detections of chromium VI in some drinking water supplies at parts per billion levels has led to a flurry of analytical studies of drinking waters. Chromium has been added to the 4th Unregulated Contaminant Monitoring Rule that will be issued this year by USEPA. The State of California has published a risk assessment that arrived at a purported lifetime risk of 1/1,000,000 from daily consumption of 0.02 micrograms per liter (20 parts per trillion), and it is currently actively preparing a revised drinking water regulation. USEPA also issued a draft risk assessment two years ago that was based upon the California assessment, but has since delayed completing that assessment or proposing a regulation, pending completion of a major, independent, peer-reviewed and approximately $5 million research effort funded by the chemical industry to understand the mechanisms for high-dose carcinogenicity and low dose lack of carcinogenicity in animal studies. Those studies are mostly completed and are now being reported.
The USPHS probably got it right in 1946, but a lot of stress and expense has been generated by over-interpretation of the 2008 NTP report. The weight of evidence has always been counter to carcinogenicity by ingestion at environmentally relevant levels. It is not unlikely that the final conclusion will be that there is negligible risk of human cancer from chromium VI at levels found in some drinking waters because much, if not all, of the small amount of ingested chromium from drinking water or food is rapidly chemically reduced to chromium III. Therefore, it does not survive to reach an at-risk organ, such as it did in the rat and mouse that was affected at the very high test doses that were thousands of times greater than a human would receive. But there would be political push back to a conclusion that there was no actionable risk.
So, the final question is whether the risk assessors and regulators will be willing to let science or politics carry the day. The legal test involves having a rational basis for the decision. That’s why regulatory processes deserve active participation by knowledgeable stakeholders and very critical mainstream scientific peer review. One wonders why so much effort and expense has occurred on such an apparently questionable and trivial risk concern.