The Wide Angle: Nanotech Tests Not All the Same

Many potential uses exist for nanomaterials in biomedical applications, some of which are very exciting. Turning potential into practical value, however, requires demonstration not only of efficacy but also of safety.

Historically, safety studies have relied on standard protocols developed and evaluated by multiple labs around the world, and recognized by regulatory agencies such as the U.S. Food and Drug Administration, Environmental Protection Agency and U.S. Department of Agriculture. But nanotechnology is a relatively new field, and although these protocols may be applicable to nanoparticles, it's necessary to conclusively demonstrate this before drawing conclusions based on their results.

A big challenge arises when scientists try to apply tests developed for small molecules to nanoparticles.

Nanoparticles include a diverse family of molecular entities, that differ significantly in their properties even within the same class of material. For this reason, each nanoparticle should be considered on a case-by-case basis, and scientists should be cautious about making generalizations.

For example, if a study shows toxicity of one type of carbon nanotube formulation, it does not mean that all carbon nanotubes are equally toxic.

It's even more speculative to try to apply conclusions from nanotube studies to other types of nanoparticles (e.g., liposomes, dendrimers, quantum dots, etc.).

Research suggests that a nanoparticle's size and surface functionality determines its toxicity, and that these properties can be manipulated to decrease toxicity. Quite often, toxicity observed for nanoparticles is not caused by the nanoparticles themselves, but by other chemical or biological contaminants present in the formulation. Once identified, such contaminants can often be removed (by filtration, for example) and the purified nanoparticles then show no detectable toxicity.

More Challenges
Another challenge is that due to the diverse physicochemical properties of nanoparticles, they may interfere with standard assays, resulting in either false-positive or false-negative results.

A false-positive result is when a test indicates that a particular effect has happened, not because it's real, but because of a problem with the test. A false-negative result is when a test indicates that no effect has occurred because the effect is hidden by a problem with the test itself.

Because tests done in vitro -- in an environment outside the living organism -- may be subject to such false-positive and false-negative results, some experts suggest that the only conclusive way to determine nanoparticle toxicity is to administer the particles in vivo -- inside animals.

Studies in animals, however, may also give inconclusive results if they are not designed properly. For example, one recently published animal study on carbon nanotubes demonstrated no toxicity, but this study was conducted in mice that were specifically bred to lack certain immune cells. These mice may not react to conditions that would otherwise cause reactions in mice with fully functioning immune systems.

Another published study used mice that had the immune cells, but injected nanotubes into the space inside animals that contains the intestines, stomach and liver to explore whether nanotubes might pose an inhalation risk similar to asbestos. But injection is not inhalation. So this study did not answer the fundamental question of whether carbon nanotubes cause comparable toxicities to asbestos.

A third study, published earlier and not cited by either of the two later studies, used animals that had functioning immune systems and administered the nanotubes via inhalation. The study showed no toxicity. The different results observed in these studies illustrate how critical study design is to arriving at scientifically sound results.

Proceed With Caution
Since both in vitro and in vivo tests of nanoparticle biocompatibility may yield spurious results if they're not conducted carefully, scientists and the public should treat new results with caution and avoid making generalizations.

We need more basic research to understand nanoparticle properties and their interaction with biological systems before arriving at a final scheme for nanoparticle safety studies. Such research also helps define the relationship of laboratory test results to potential toxicities in people.

As long as scientists exercise due diligence in their approach to study design and interpretation, we will continue to learn how to safely bring the promise of nanotechnology to biomedical applications.

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