Cover Story By David W. Hobson, PhD
Risks an issue in pharma, biotech
IMAGE COURTESY OF BYRON CHEATHAM, CYTOVIVA INC. , AND DAVID W. HOBSON, NANOTOX INC.
Human ovarian cancer cell undergoing apoptosis resulting from internalization of a cytotoxic nanopharmaceutical (cytoxin nanoparticles).
Nanotechnology, by technical definition, is the understanding and control of matter at dimensions between approximately one and 100 nanometers. The term “nanomaterial” includes all nanosized materials, including engineered nanoparticles, incidental nanoparticles, and other nano-objects, like those that exist in nature, including smoke particles, atmospheric dust, volcanic ash, and ocean spray. Because this is a size range in which particles can exhibit unique phenomena that enable novel applications, these same unique features are raising questions from the public, government, and industry about the potential for toxicity and the exposure risks of these fascinating and potentially quite useful particles.
The toxicological database developed for use in the assessment of risks from nanoparticles in pharmaceutical and biotechnological products is growing steadily. Some nanoparticles demonstrate little or no potential for harm, while others may be more problematic. Although increasing evidence indicates that exposure to some engineered nanoparticles can cause adverse health effects in laboratory animals, insufficient toxicological evidence exists at this time to recommend the specific medical screening of workers potentially exposed to engineered nanoparticles. While the data for risk assessment of nanomaterials is gathered and becomes more definitive, researchers and manufacturing personnel in the pharmaceutical and biotech industries are urged to develop and use procedures that prevent inhalation, oral, and dermal exposures to nanoparticles (see Table 1, p. 14).
In the pharmaceutical and biotech industries, the development and use of nanotechnology involve manipulating matter at the nano scale for inclusion in products, in the manufacture and packaging of products, and in the imaging, measuring, and modeling of products and processes that involve nanomaterials. The range of possible uses of nanomaterials in these industries is vast and quite promising. Nanotechnology has the potential to provide tremendous opportunities for advancing medical science across a wide landscape of disciplines. Successful commercialization of nanotechnology in pharmaceutical and medical science has already happened, without the fanfare perhaps anticipated by some futurists, but rather as a seamless introduction of new products and advanced processes and procedures that could only have improved significantly with the introduction of specifically designed nanotechnologies.
So, do the pharmaceutical and biotech industries do something with the development of safe nanotechnologies and the management of risk from this emerging new technology platform that other industries typically are not doing? Well, actually, yes, because concern for safety in the use of new active pharmaceutical ingredients, excipients, packaging components, delivery systems, and devices has been a part of the common theme within these industries for over one hundred years. With regard to toxicity and safety, the pharmaceutical and biotech industries are generally well established in their thinking, as are the major worldwide regulatory bodies that must review and approve new products such as those that incorporate the use of a new nanomaterial. In the U.S., for example, at least 15 new pharmaceuticals approved since 1990 have utilized nanotechnology in their design and drug delivery systems (see Table 2, p. 15). In each case, the development and review of safety data was conducted on a case-by-case basis using the best available methods and procedures with an understanding that post-marketing vigilance for safety issues would be ongoing.
In developing nanoparticles for incorporation into pharmaceutical formulations, some simple guidelines may help to avoid toxicological problems. When possible, select biodegradable nanoparticle components. Size and shape particles to achieve their specific targets, and avoid spaces where they might interrupt untargeted critical cellular or tissue processes. Develop particles that are eliminated at the end of their useful lifetime. Unless the target is the immune system, take steps in particle sizing and surface characteristics to avoid recognition and processing by the immune system. Pay attention to the operating pH range of the formulation in relation to the zeta potential and agglomeration state of nanoparticles. And always validate assumptions regarding the formulation safety of priority prototype formulations with actual toxicology study data.
The toxicological database developed for use in the assessment of risks from nanoparticles in pharmaceutical and biotechnological products is growing steadily. Some nanoparticles demonstrate little or no potential for harm, while others may be more problematic.
Because living things are exposed to many forms of natural nanoparticles, sometimes on a near continuous basis, there are obviously levels of exposure to some types of nanoparticles that do not produce sufficient toxicity and exposure combinations to result in substantial risks to plants, animals, and humans. There are also natural nanoparticles, like viruses, that can be quite harmful to living things. Therefore, when we engineer nanoparticles for use in pharmaceutical applications, we must learn what makes a particle more or less harmful so we can avoid unacceptable risks by design. Toxicologic data for engineered nanoparticles that do not exist in nature has been increasing steadily over the past two decades to include lessons learned from the pharmaceutical development and manufacturing of ever-smaller microparticles in the 1980s and the results from studies completed on nanoparticles by university, government, and industry scientists.
Despite the amount of work being done, most new nanoparticles cannot be easily classified with respect to their potential for toxicity and for exposure, and their risk remains unknown. Therefore, toxicologists have no recourse but to do studies and obtain data to properly establish knowledge of toxicity that can be combined with evaluations for the potential for exposure. This strategy will help them arrive at an estimate of risk for a particular application or use scenario that can be used to develop safe working procedures and practices. At present, despite some proposed methods, no readily available means of simulating or modeling such evaluations exists. So our best available information must be obtained by credible scientists working under conditions in which data is checked for quality and results for reproducibility; as a result of this often lengthy process, determination of risk can be delayed by years for some types of potential toxicity.
Nanotechnology, like plastics and synthetic polymers in medicine decades ago, provides a new and very broad technological platform that is already being incorporated into the advancement of medical science. This technology is already affecting new pharmaceutical entities, advanced formulations, improved drug delivery, diagnostic imaging, clinical diagnostics, nanomedicines, and medical devices, with a growing number of uses in the pipelines of small to mid-sized companies.
Momentum is steadily building for the successful development of additional nanotech products to diagnose and treat disease. Nanotechnology is also addressing many unmet needs in the pharmaceutical industry, including the reformulation of drugs to improve their bioavailability or toxicity profiles. Medical nanotechnology is expected to advance over at least three different generations or phases, beginning with the introduction of simple nanoparticulate and nanostructural improvements to current product and process types, then moving on to nanoproducts and nanodevices that are limited only by the imagination and the technology itself.
State of the Science
With all the promise and new development opportunities that nanotechnology brings to the pharmaceutical and biotechnology industries, it is not surprising that there is a demand for toxicologic data to support safety determinations and risk assessments. Nanomaterials safety has been an active concern among toxicologists for at least a decade now, with much research being actively funded worldwide to address safety issues (see Figure 1, p. 16). Significant advancements in the methods and procedures for the characterization of nanoparticles, as well as in the testing and evaluation of nanomaterials toxicity, are proving useful in the creation of safe products and in the development of safe practices for product development.
Nanoparticles that are at the forefront of ongoing toxicologic investigations and are of interest to the pharmaceutical and biotechnology industries include metal oxides such as titanium dioxide and zinc oxide, carbon nanomaterials such as single- and multi-walled nanotubes and fullerenes, liposomal and polymeric nanoparticles, dendrimers, and various types of nanoemulsions. The National Cancer Institute has an active screening program to characterize nanoparticles that may be of value in treating cancer. The program is producing excellent results that will yield a better understanding of, and define potential toxicities for, some types of nanoparticles. At this time, even though there have been reports by some industries of possible nanoparticle toxicity, there has been no reported toxicity for any nanoparticles that are in development or in use by the pharmaceutical or biotechnology industries.
While the data for risk assessment of nanomaterials is gathered and becomes more definitive, researchers and manufacturing personnel in the pharmaceutical and biotech industries are urged to develop and use procedures that prevent inhalation, oral, and dermal exposures to nanoparticles.
Nanoparticles can be inhaled, ingested, or absorbed through the skin, and can penetrate cells, even into the cell nucleus, where they come in close contact with genetic material if sufficiently small. They can be recognized and processed by the immune system and are sometimes particulate forms of known carcinogens. Thus, the potential for substantial toxic effects is present and must be respected in their design, handling, and use.
Exactly how being nanosized affects the biodistribution, kinetics, and toxicity of a material is the subject of many current investigations and will continue as long as new nanomaterials are developed for pharmaceutical and medical applications. A few things are certain: When it comes to toxicity, size does matter, as do shape, surface characteristics, charge state, and aggregation state. Numerous studies have borne this out over the past decade, leading some to believe that these differences are substantial enough to warrant a new branch of toxicology called “nanotoxicology.” In this proposed new field, particle characterization, dose preparation, toxicokinetics, tissue localization, interpretation of effects, and other factors would require specialized training, methods, equipment, and procedures that would differ significantly from mainstream toxicology.
However, toxicology is a broad scientific discipline that has historically been open to changes in technology, always seeking to identify and characterize any harmful effects to biological systems from new and emerging sources. And, to date, there have been no new or unique pathological or toxicologic effects or manifestations from nanotechnology that have not been previously recognized by other forms of chemicals or particles. Perhaps, with further study, this will change, but toxicologists will always be vigilant for a wide variety of potential effects that now include genomic or “omic” effects that are being elucidated for known toxicants as well as nanomaterials.
At present, the most deleterious effects of specific nanomaterials that have been confirmed with animal models include a potential for genotoxic effects with specific nanoparticles and deep pulmonary deposition with irritation and inflammation following exposures to carbon nanotubes that could potentially lead to longer term effects following repeated exposures over extended periods. The potential for some industrial nanomaterials such as carbon nanotubes to be carcinogenic or to cause reproductive or developmental toxicity is currently being studied.
As more toxicologic research is conducted and completed over the next few years, a clearer picture of the potential for specific types of nanomaterials to produce toxicity will likely emerge. With this increasing knowledge, many hope that techniques for the screening and rapid identification of potential toxicities can be developed to help guide nanomaterials developers toward the design of inherently safe engineered nanomaterials. With the amount of current effort directed toward this end in many parts of the world, some degree of success appears quite possible, and the likelihood of safe nanomaterials “by design” is a worthy and rewarding goal for teams of nanoengineers and toxicologists.
Figure 1. NNI Funding – Four-Year Profile for Environmental Health & Safety
IMAGE COURTESY OF DAVID W. HOBSON, PHD
The four-year funding profiles for various U.S. agencies under the National Nanotechnology Initiative (NNI).
Regulations and Risks
Even with all the effort to identify toxicities and evaluate potential exposures and risks from nanomaterials, however, there are currently no formally implemented regulations for safe work practices with nanomaterials, nor are there any that apply specifically to controlling the release of manufactured nanomaterials into the environment. Furthermore, the risks associated with the use and handling of many different current types of nanoparticles still have not been completely evaluated, and there are knowledge gaps for which much research is ongoing (see Figure 2, above).
There is clear evidence that international regulations pertaining specifically to nanomaterials are on the horizon, particularly with respect to environmental protection. The relatively recent Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation of the European Union currently has no provisions referring explicitly to nanomaterials. But coverage of nanomaterials is included under the “substance” definition, and manufacturers and importers will have to submit a registration dossier for nanomaterials that contains information related to toxicity and potential hazards for amounts that they manufacture or import at or above one metric ton per year.
The Commission of the European Communities carefully monitors the implementation of REACH with respect to nanomaterials. The commission has implied that risks from certain nanoscale substances would be addressed through the REACH regulation if they were identified as being “substances of very high concern” as defined in Article 57, for example, nanomaterials that are found to be persistent, bio-accumulative, and toxic. Similarly, the U.S. Environmental Protection Agency recognizes nanomaterials as a potential for concern and is considering this issue as it plans the modernization of the Toxic Substances Control Act, which doesn’t currently cover nanomaterials.
Figure 2. Drivers for Testing: General
IMAGE COURTESY OF DAVID W. HOBSON, PHD
This figure shows the potential exposure sources and routes that encompass the risk assessment framework for nanomaterials.
U.S. Food and Drug Administration (FDA) scientists and reviewers are generally aware of the increasing use of nanomaterials in the products they regulate, including pharmaceuticals and biotechnology products. FDA scientists and staff are becoming more knowledgeable about nanotechnology and have been working with companies toward developing safe nanotechnology products for several years. In 2007, the FDA issued a position paper on nanotechnology. It has also hosted a public hearing on the subject and participates vigorously in the Alliance for NanoHealth, which is dedicated to forging relationships among key agency personnel, university researchers, and industry scientists to facilitate the development of innovative, safe, and effective medical nanoproducts. The advancement of the toxicological knowledge necessary to promote the development of such nanoproducts through substantial funding to the FDA is also the intent of a recently submitted bill, The Nanotechnology Safety Act of 2010 (S.2942).
Ongoing studies by the National Institute for Occupational Safety and Health (NIOSH) to help with the establishment of workplace exposure criteria for some nanomaterials also address the need to assess both toxicologic effects and potential risks from occupational exposure. One such study involves the development of a relatively standardized concept of dose and the determination of how dose should be expressed for a material that has both chemical and particulate characteristics. NIOSH has posted several material safety data sheets for nanomaterials on its Web site .