Mechanistic Insights from the NTP Studies of Chromium

Abstract

Hexavalent chromium (Cr(VI)) is a contaminant of water and soil and is a human lung carcinogen. Trivalent chromium (Cr(III)), a proposed essential element, is ingested by humans in the diet and in dietary supplements such as chromium picolinate (CP). The National Toxicology Program (NTP) demonstrated that Cr(VI) is also carcinogenic in rodents when administered in drinking water as sodium dichromate dihydrate (SDD), inducing neoplasms of the oral cavity and small intestine in rats and mice, respectively. In contrast, there was no definitive evidence of toxicity or carcinogenicity following exposure to Cr(III) administered in feed as CP monohydrate (CPM). Cr(VI) readily enters cells via nonspecific anion channels, in contrast to Cr(III), which cannot easily pass through the cell membrane. Extracellular reduction of Cr(VI) to Cr(III), which occurs primarily in the stomach, is considered a mechanism of detoxification, while intracellular reduction is thought to be a mechanism of genotoxicity and carcinogenicity. Tissue distribution studies in additional groups of male rats and female mice demonstrated higher Cr concentrations in tissues following exposure to Cr(VI) compared to controls and Cr(III) exposure at a similar external dose, indicating that some of the Cr(VI) escaped gastric reduction and was distributed systemically. The multiple potential pathways of Cr-induced genotoxicity will be discussed.

Oxidative Stress Markers and Histological Analysis in Diverse Organs from Rats Treated with a Hepatotoxic Dose of Cr(VI): Effect of Curcumin

“…Under these conditions, Cr(VI) failed to enhance the frequency of DNA-protein crosslinks and did not cause oxidative DNA damage in the stomach and duodenum. The extracellular reduction of Cr(VI) to Cr(III), which occurs primarily in the stomach, is considered a mechanism of detoxification [72]. Acute oral administration of Cr(VI) resulted in epithelial cell injury and the decrease in antioxidant activities associated with oxidative stress in the intestine [73][74][75].…”

Integration of mechanistic and pharmacokinetic information to derive oral reference dose and margin‐of‐exposure values for hexavalent chromium

“…For reasons unclear to the present authors, summary tables in the NTP (2008) report and peer‐reviewed published version (Stout, Herbert, Kissling, et al, 2009) list the incidences of diffuse epithelial hyperplasia based on the number of animals necropsied rather than tissues examined. A second peer‐reviewed publication related to the NTP (2008) cancer bioassay simply lists hyperplasia incidence based on “ N  = 50,” without any specification of whether N refers to the number of animals or number of tissues examined (Witt et al, 2013). …”

Does the EU migration level of chromium VI in toys need to be lowered?

“…However, reduction of chromium VI in blood is not rapid enough to prevent the uptake in other organs. Animal studies showed relatively increased levels of chromium VI in the liver, kidney, and spleen, while RBC and plasma chromium levels were only modestly elevated after exposure to chromium VI (Costa, 1997;Thomann et al, 1994;Witmer et al, 1989;Collins et al, 2011;Witt et al, 2013). Thompson et al (2011Thompson et al ( , 2012 reported significant increases in total chromium concentrations in the oral cavity, glandular stomach, duodenum, jejunum, and ileum of rats and mice following 90 days of exposure to sodium dichromate dihydrate in drinking water.…”

“…Sodium dichromate caused cancer of the oral cavity in rats and of the gastro-intestinal tract in mice. It was concluded that there is clear evidence of carcinogenic activity of orally administered sodium dichromate dihydrate in male and female F344 rats and clear evidence of carcinogenic activity in male and female B6C3F1 mice (NTP, 2008;Witt et al, 2013). IARC (2012) also concluded that there is sufficient evidence in experimental animals for the carcinogenicity of chromium VI compounds after oral exposure.…”