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Environmental Factor

October 2011

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Superfund study examines carcinogenicity of nickel nanoparticles

By Nancy Lamontagne
October 2011

Agnes Kane, M.D., Ph.D.

Kane, above, spoke at a 2009 meeting on asbestos sponsored by the NIEHS Superfund Research Program, held in Chapel Hill, N.C. (Photo courtesy of Steve McCaw)

metallic nickel particles: left to right, nano-sized and micro-sized

Human lung epithelial cells were exposed to the same doses of nano-sized, left, or micro-sized, right, metallic nickel particles. Activated HIF-1 alpha pathways (green) appear mostly in the cells exposed to the nanoparticles. (Photo courtesy of Agnes Kane)

NIEHS-funded researchers at Brown University have published a study showing evidence that nickel nanoparticles activate a cellular pathway that contributes to cancer in human lung cells. The study( Exit NIEHS was published online Aug. 9 in Toxicological Sciences.

Materials produced on a nanoscale have different properties than they do at larger scales, and these unique properties make nanomaterials attractive for use in medicine, electronics, and energy production. The Brown University researchers studied various types of nickel nanoparticles, which are used in sensors and energy storage devices, as well as for a catalyst for making certain types of carbon nanotubes. Inhalation exposure to nickel and nickel oxide nanoparticles could occur during manufacturing processes, yet the potential carcinogenicity of these nanoparticles is not known.

Micron-sized particles of poorly soluble nickel compounds are known carcinogens, but the same is not true for metallic nickel. To explore how particle size affects toxicological properties, Agnes Kane, M.D., Ph.D.( Exit NIEHS, and a team of pathologists, engineers, and chemists exposed in vitro human lung epithelial cells to metallic nickel and nickel oxide nanoparticles, and to larger metallic nickel micro-scale particles.  

Activating a pathway implicated in tumor growth

The researchers observed release of nickel II ions 24 to 48 hours after uptake of metallic nickel and nickel oxide nanoparticles, but not after uptake of metallic nickel microparticles. Nickel II ions have been associated with the carcinogenicity of nickel.

In addition, the metallic nickel nanoparticles activated the HIF-1 alpha pathway and also caused cytotoxicity, while the larger micron-sized nickel particles did not. The HIF-1 alpha pathway normally helps trigger genes that support a cell during hypoxia and is also known to encourage tumor cell growth. Nickel exploits the HIF-1 alpha pathway by tricking the cell into thinking hypoxic conditions are present, and the subsequent pathway activation may give premalignant tumor cells a head start, Kane said.

Surface area may be the key to toxicity

According to the researchers, the nanoscale metallic nickel particles might be more harmful and potentially carcinogenic because, for the same amount of metal by mass, they have a greater surface area than microparticles. This makes the nanoparticles much more chemically reactive.

The work also showed a difference in how nickel nanoparticles and nickel oxide nanoparticles react with cells. Cells exposed to nickel oxide nanoparticles died quickly, leaving no opportunity for cancer to develop. However, metallic nickel nanoparticles were less likely to kill the cells, which could allow the HIF-1 alpha pathway to lead to the cell becoming cancerous.

Implications of the study

Kane said cancer typically depends on a number of changes, and cautions that the study examined only the short-term effects of nickel nanoparticle exposure in cells in a lab, not long-term exposure in a whole organism. Still, she said that the findings should raise clear concerns about handling nickel nanoparticles. For example, precautions should be taken during manufacturing to prevent airborne exposure.

In addition, the researchers suggest that screening assays used to evaluate the toxicity of nickel nanoparticles should include cellular bioavailability of metal ions and activation of the HIF-1 alpha pathway. These assays could be used to screen other commercial nanomaterials that contain nickel and nickel oxide, including nanowires, carbon nanotubes, and nickel nanocomposites used in medical implants and for drug delivery.

Kane's research is supported by two NIEHS Superfund Research Program grants and a grant from the U.S. Environmental Protection Agency.

Citation: Pietruska JR, Liu X, Smith A, McNeil K, Weston P, Zhitkovich A, Hurt R, Kane AB( Exit NIEHS. 2011. Bioavailability, intracellular mobilization of nickel, and HIF-1{alpha} activation in human lung epithelial cells exposed to metallic nickel and nickel oxide nanoparticles. Toxicol Sci; doi: 10.1093/toxsci/kfr206 [Online 9 August 2011].

(Nancy Lamontagne is a staff writer with MDB, a contractor for the NIEHS Superfund Research Program and Worker Education and Training Program.)

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