BackgroundHexavalent chromium [Cr(VI)] is a human carcinogen after inhalation exposure. Humans also ingest Cr(VI) from contaminated drinking water and soil; however, limited data exist on the oral toxicity and carcinogenicity of Cr(VI).ObjectiveWe characterized the chronic oral toxicity and carcinogenicity of Cr(VI) in rodents.MethodsThe National Toxicology Program (NTP) conducted 2-year drinking water studies of Cr(VI) (as sodium dichromate dihydrate) in male and female F344/N rats and B6C3F1 mice.ResultsCr(VI) exposure resulted in increased incidences of rare neoplasms of the squamous epithelium that lines the oral cavity (oral mucosa and tongue) in male and female rats, and of the epithelium lining the small intestine in male and female mice. Cr(VI) exposure did not affect survival but resulted in reduced mean body weights and water consumption, due at least in part to poor palatability of the dosed water. Cr(VI) exposure resulted in transient microcytic hypochromic anemia in rats and microcytosis in mice. Nonneoplastic lesions included diffuse epithelial hyperplasia in the duodenum and jejunum of mice and histiocytic cell infiltration in the duodenum, liver, and mesenteric and pancreatic lymph nodes of rats and mice.ConclusionsCr(VI) was carcinogenic after administration in drinking water to male and female rats and mice.

Trivalent chromium (Cr(III)) has been proposed to be an essential element, which may increase sensitivity to insulin and thus participate in carbohydrate and lipid metabolism. Humans ingest Cr(III) both as a natural dietary constituent and in dietary supplements taken for weight loss and antidiabetic effects. Chromium picolinate (CP), a widely used supplement, contains Cr(III) chelated with three molecules of picolinic acid and was formulated in an attempt to improve the absorption of Cr(III). In order to examine the potential for CP to induce chronic toxicity and carcinogenicity, the NTP conducted studies of the monohydrate form (CPM) in groups of 50 male and female F344/N rats and B6C3F1 mice exposed in feed to concentrations of 0, 2,000, 10,000 or 50,000 ppm for 2 years; exposure concentrations were selected following review of the data from NTP 3-month toxicity studies. Exposure to CPM did not induce biologically significant changes in survival, body weight, feed consumption, or non-neoplastic lesions in rats or mice. In male rats, a statistically significant increase in the incidence of preputial gland adenoma at 10,000 ppm was considered an equivocal finding. CPM was not carcinogenic to female rats or to male or female mice.

The U.S. National Toxicology Program (NTP) has carried out extensive rodent toxicology and carcinogenesis studies of radiofrequency radiation (RFR) at frequencies and modulations used in the U.S. telecommunications industry. This report presents partial findings from these studies. The occurrences of two tumor types in male Harlan Sprague Dawley rats exposed to RFR, malignant gliomas in the brain and schwannomas of the heart, were considered of particular interest and are the subject of this report. The findings in this report were reviewed by expert peer reviewers selected by the NTP and National Institutes of Health (NIH). These reviews and responses to comments are included as appendices to this report, and revisions to the current document have incorporated and addressed these comments. When the studies are completed, they will undergo additional peer review before publication in full as part of the NTP's Toxicology and Carcinogenesis Technical Reports Series. No portion of this work has been submitted for publication in a scientific journal. Supplemental information in the form of four additional manuscripts has or will soon be submitted for publication. These manuscripts describe in detail the designs and performance of the RFR exposure system, the dosimetry of RFR exposures in rats and mice, the results to a series of pilot studies establishing the ability of the animals to thermoregulate during RFR exposures, and studies of DNA damage. (1) Capstick M, Kuster N, Kuhn S, Berdinas-Torres V, Wilson P, Ladbury J, Koepke G, McCormick D, Gauger J, and Melnick R. A radio frequency radiation reverberation chamber exposure system for rodents; (2) Yijian G, Capstick M, McCormick D, Gauger J, Horn T, Wilson P, Melnick RL, and Kuster N. Life time dosimetric assessment for mice and rats exposed to cell phone radiation; (3) Wyde ME, Horn TL, Capstick M, Ladbury J, Koepke G, Wilson P, Stout MD, Kuster N, Melnick R, Bucher JR, and McCormick D. Pilot studies of the National Toxicology Program’s cell phone radiofrequency radiation reverberation chamber exposure system; (4) Smith-Roe SL, Wyde ME, Stout MD, Winters J, Hobbs CA, Shepard KG, Green A, Kissling GE, Tice RR, Bucher JR, and Witt KL. Evaluation of the genotoxicity of cell phone radiofrequency radiation in male and female rats and mice following subchronic exposure.SUMMARYThe purpose of this communication is to report partial findings from a series of radiofrequency radiation (RFR) cancer studies in rats performed under the auspices of the U.S. National Toxicology Program (NTP).1 This report contains peer-reviewed, neoplastic and hyperplastic findings only in the brain and heart of Hsd:Sprague Dawley® SD® (HSD) rats exposed to RFR starting in utero and continuing throughout their lifetimes. These studies found low incidences of malignant gliomas in the brain and schwannomas in the heart of male rats exposed to RFR of the two types [Code Division Multiple Access (CDMA) and Global System for Mobile Communications (GSM)] currently used in U.S. wireless networks. Potentially preneoplastic lesions were also observed in the brain and heart of male rats exposed to RFR.The review of partial study data in this report has been prompted by several factors. Given the widespread global usage of mobile communications among users of all ages, even a very small increase in the incidence of disease resulting from exposure to RFR could have broad implications for public health. There is a high level of public and media interest regarding the safety of cell phone RFR and the specific results of these NTP studies. Lastly, the tumors in the brain and heart observed at low incidence in male rats exposed to GSM-and CDMA-modulated cell phone RFR in this study are of a type similar to tumors observed in some epidemiology studies of cell phone use. These findings appear to support the International Agency for Research on Cancer (IARC) conclusions regarding the possible carcinogenic potential of RFR.2It is important to note that this document reviews only the findings from the brain and heart and is not a complete report of all findings from the NTP’s studies. Additional data from these studies in Hsd:Sprague Dawley® SD® (Harlan) rats and similar studies conducted in B6C3F1/N mice are currently under evaluation and will be reported together with the current findings in two forthcoming NTP Technical Reports.

Chlorine dioxide (ClO 2 ) is an effective drinking water disinfectant, but sodium chlorate (NaClO 3 ) has been identi ed as a potentially harmful disinfection by-product . Studies were performed to describe the developmen t of thyroid lesions in animals exposed to NaClO 3 in the drinking water. Male and female F344 rats and B6C3F 1 mice were exposed to 0, 0.125, 0.25, 0.5, 1.0, or 2.0 g/L NaClO 3 for 21 days. Additional male F344 rats were exposed to 0, 0.001, 0.01, 0.1, 1.0, or 2.0 g/L NaClO 3 for 90 days. Female F344 rats were exposed to 0, 0.5, 1.0, 2.0, 4.0, or 6.0 g/L of NaClO 3 for 105 days. Thyroid tissues were processed by routine methods for light microscopi c examination, and follicular cell hyperplasia was diagnosed using a novel method. Thyroid hormone levels were altered signi cantly after 4 and 21 days. NaClO 3 treatment induced a concentration-dependen t increase in the incidence and severity of thyroid follicular cell hyperplasia. Male rats are more sensitive to the effects of NaClO 3 treatment than females. Follicular cell hyperplasi a was not present in male or female B6C3F 1 mice. These data can be used to estimate the human health risk that would be associated with using ClO 2 , rather than chlorine, to disinfect drinking water.

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In National Toxicology Program 2-year studies, hexavalent chromium [Cr(VI)] administered in drinking water was clearly carcinogenic in male and female rats and mice, resulting in small intestine epithelial neoplasms in mice at a dose equivalent to or within an order of magnitude of human doses that could result from consumption of chromium-contaminated drinking water, assuming that dose scales by body weight(3/4) (body weight raised to the 3/4 power). In contrast, exposure to trivalent chromium [Cr(III)] at much higher concentrations may have been carcinogenic in male rats but was not carcinogenic in mice or female rats. As part of these studies, total chromium was measured in tissues and excreta of additional groups of male rats and female mice. These data were used to infer the uptake and distribution of Cr(VI) because Cr(VI) is reduced to Cr(III) in vivo, and no methods are available to speciate tissue chromium. Comparable external doses resulted in much higher tissue chromium concentrations following exposure to Cr(VI) compared with Cr(III), indicating that a portion of the Cr(VI) escaped gastric reduction and was distributed systemically. Linear or supralinear dose responses of total chromium in tissues were observed following exposure to Cr(VI), indicating that these exposures did not saturate gastric reduction capacity. When Cr(VI) exposure was normalized to ingested dose, chromium concentrations in the liver and glandular stomach were higher in mice, whereas kidney concentrations were higher in rats. In vitro studies demonstrated that Cr(VI), but not Cr(III), is a substrate of the sodium/sulfate cotransporter, providing a partial explanation for the greater absorption of Cr(VI).

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.

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