Nanotoxicology and nanomedicine: making hard decisions

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1 Available online at Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) Short Communication: Toxicology Nanotoxicology and nanomedicine: making hard decisions Igor Linkov, PhD, a, F. Kyle Satterstrom, MA, b Lisa M. Corey, MS c a US Army Engineer Research and Development Center, Brookline, Massachusetts, USA b Harvard University School of Engineering and Applied Sciences, Cambridge, Massachusetts, USA c Intertox Inc., Seattle, Washington, USA Abstract Key words: Current nanomaterial research is focused on the medical applications of nanotechnology, whereas side effects associated with nanotechnology use, especially the environmental impacts, are not taken into consideration during the engineering process. Nanomedical users and developers are faced with the challenge of balancing the medical and societal benefits and risks associated with nanotechnology. The adequacy of available tools, such as physiologically-based pharmacokinetic modeling or predictive structure-activity relationships, in assessing the toxicity and risk associated with specific nanomaterials is unknown. Successful development of future nanomedical devices and pharmaceuticals thus requires a consolidated information base to select the optimal nanomaterial in a given situation understanding the toxicology and potential side effects associated with candidate materials for medical applications, understanding product life cycle, and communicating effectively with personnel, stakeholders, and regulators. This can be achieved through an innovative combination of toxicology, risk assessment modeling, and tools developed in the field of multicriteria decision analysis (MCDA). Published by Elsevier Inc. Nanotoxicology; Risk assessment; Multicriteria decision analysis Nanomaterials have the potential to revolutionize medicine because of their ability to affect organs and tissues at the molecular and cellular levels. Current research is focused on the medical applications of nanotechnology, whereas side effects associated with their use, especially the environmental impacts of their manufacture and disposal, are generally not taken into consideration during the engineering process. Incorporating environmental concerns into nanomaterial engineering and nanomedicine development is important, but it greatly increases decision complexity. Even though the risk assessment paradigm successfully used by the scientific community since the early 1980s may be generally useful, its application to nanomaterials would Received 15 April 2007; accepted 28 January This study was supported in parts by the US Army Engineer Research and Development Center. Corresponding author. US Army Engineer Research and Development Center, 83 Winchester Street, Suite 1, Brookline, Massachusetts 02446, USA. address: igor.linkov@usace.army.mil (I. Linkov). require allowing for an uncertainty in basic knowledge that is much larger than the uncertainty for other materials and pharmaceuticals. To combat the uncertainty, decision makers need an understanding of product life cycle and the ability to communicate effectively with personnel, stakeholders, and regulators. This can be achieved through an innovative combination of toxicology, risk assessment modeling, and tools developed in the field of multicriteria decision analysis (MCDA). Biomedical community needs Nanomaterials have been promoted as a revolutionary technology for cell and tissue engineering, medical device development, and the encapsulation and delivery of drugs, diagnostics, and genes. Advances in nanotechnology have led to the introduction of many nanomaterials in these areas, and the Nanomedicine Initiative of the National Institutes of Health Roadmap for Medical Research initiative predicts that nanomaterials will begin yielding significant medical benefits within the next 10 years /$ see front matter. Published by Elsevier Inc. doi: /j.nano Please cite this article as: I. Linkov, F.K. Satterstrom, L. Corey, Nanotoxicology and nanomedicine: making hard decisions. Nanomedicine: NBM 2008;4: , doi: /j.nano

2 168 I. Linkov et al / Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) Despite the widespread use of nanomaterials, understanding of the toxicity and potential health risks associated with nanomaterial use is extremely limited. In fact, toxicity issues related to nanomaterials used in nanomedicine are often ignored. 1,2 Thus, along with the development of novel nanoparticles, experts in related scientific fields are calling for a simultaneous assessment of the toxicological and environmental effects of nanoparticles. 3 Recent in vivo and in vitro studies have suggested that inhalation and dermal absorption of some nanomaterials may have adverse health effects, 3,4 and the use of medical products containing nanomaterials may lead to chronic health risks. 5 Spurred by such reports, regulatory agencies, as well as the popular and scientific media, are shifting their focus from the initial euphoria about the potential of the technology to concern about possible deleterious effects resulting from nanomaterial manufacture and use. The US Environmental Protection Agency (EPA) has raised concerns about the use of nanosilver in several consumer products already on the market. Uncertainty about the health impacts associated with nanotechnologies and their potentially uncontrolled market growth has resulted in calls from environmental and political bodies to limit the use of nanomaterials, increase the stringency of governmental regulations, and, in extreme cases, ban the use of nanomaterials completely. A better understanding of these materials is clearly needed, yet experience with inorganic and organic chemicals may not be directly relevant to nanomaterials, in that their physical and biological properties are often determined by novel relationships between their size, structure, and the presence of added functional groups. A framework of underlying questions remains to be addressed: What are the specific nanomaterial properties that should be characterized for nanomedical applications? What data are available on nanomedicine toxicity, exposure, and environmental fate and transport? Where are the data gaps? How do nanomaterial characteristics contribute to toxicity in relation to nanomedical applications? How do specific delivery mechanisms influence nanomedicine toxicity? What is the role of concurrent exposures to multiple nanomedicines and pharmaceuticals? Difficulties in applying traditional risk assessment framework A risk assessment has four general components: hazard identification, toxicity assessment, exposure assessment, and risk characterization. Nanomaterials can easily be identified as a potential hazard, but they present many complications to the subsequent three steps. When a nanomaterial is used for a medical application, it is intentionally given to a patient because of some unique property that its size (and often chemistry) imparts. For example, the nanosized particles may have the ability to access different tissues than larger particles, such as crossing the blood-brain barrier, or to be tagged with specific antibodies to home in on and be taken up by specific cells. Nevertheless, nanomaterials can cause side effects, and a toxicity assessment requires knowledge of their metabolism and distribution in the body. A variety of techniques are currently available for determining the distribution of a nanomedicine in a patient, such as radiolabeling, which can be used to evaluate distribution and uptake into specific cells and tissues. Distribution depends on several factors, including the mechanism of targeting. Cancer cells can be targeted using antibody conjugation to a medication; direct targeting can be enabled so the nanomedicine can be taken up by specific cells; and nanomedicine can passively diffuse into tissues or cells, for example taking advantage of the leaky endothelia in the blood vessels around some solid tumors. In each case it is possible for the medicine to reach a different population of unintended cells. This situation is complicated by the possibility of making use of many different delivery routes, including oral, transdermal, intravenous, and inhalation. Further considerations include whether the nanomaterial stays localized or re-enters the circulatory system and how it is used or metabolized. Specific nanomaterials will bring with them their own specific factors to consider. Multiple variables could also influence nanomedicine exposure assessment, including characterization of variations in biological reactivity, size, shape, charge, and route of administration, as well as factors that complicate the straightforward estimation of exposure (e.g., metabolism, excretion, adduction to biological molecules, etc.). For example, several studies on carbon nanotubes have shown that the toxicity and distribution of nanoparticles is dependent upon the presence of functional groups, impurities, fiber length, and aggregation status. 6,7 When a nanomaterial is not used for a medical application but exposure is instead environmental, exposure estimation may be even less straightforward. Given estimates of exposure and toxicity, the final step involved in estimating the hazard of contaminant exposure is the characterization of the dose-response function, that is, the likelihood of adverse health effects at varying degrees of exposure. By necessity, a dose-response assessment must be developed separately for each nanomaterial. Given the required effort, detailed dose-response assessments will not be possible for all nanomaterials. Decision tools and databases should be developed to facilitate use of all available information as well as proxy data for making the best judgment on dose-response. Risk to individuals can then be quantitatively and qualitatively determined. However, unlike the reference doses used by the EPA in health risk assessments for the general population, safety standards for

3 I. Linkov et al / Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) agencies such as the US Food and Drug Administration can be variable. Drugs designed to treat extreme forms of disease, such as cancer and acquired immunodeficiency syndrome, may not be required to give patients more than a limited margin of safety. Risk-based decision analysis As with any new technology or science, developing a framework for selecting appropriate nanomaterials and making medical decisions with uncertainty and incomplete information is the current challenge for the field of nanotechnology. Understanding nanomaterial toxicity requires multiple sets of information because of both the complexity of nanomaterials and the often-limited database of relevant experimental studies. One of the tools widely used in risk assessment applications in similar situations is the weight-ofevidence approach. Weight-of-evidence considerations are required in assessing risks to ecological receptors. 8 The EPA and other agencies use a weight-of-evidence approach in evaluating the potential carcinogenicity and toxicity of environmental contaminants. 9 Traditionally, assessors weigh various lines of evidence and apply professional judgment and/or calculations to decide where the weight of evidence lies that is, whether the various lines of evidence point to potential risk in the case of each receptor or not. Much of this effort, however, is not initially transparent. Even though weight-of-evidence considerations may include some quantification, this approach often results in arbitrary weight selection and thus in risk estimates that include an unquantified degree of uncertainty and potential bias. Thus, we have introduced MCDA as a tool for integrating heterogeneous information for regulatory decision making for nanomaterials. 10 We believe that MCDA could be applied widely to support decisions on the border of nanomedicine and nanotoxicology. The advantages of using MCDA techniques over other less structured decision-making methods are numerous: MCDA provides a clear and transparent methodology for making decisions and also provides a formal way for combining information from disparate sources. These qualities make decisions made through MCDA more thorough and defensible than decisions made through less structured methods. For example, MCDA could be used to support weight-of-evidence evaluation of nanomaterials. 11 Moreover, MCDA could be easily linked with adaptive management for nanomedicine development. In an adaptive management paradigm, the uncertainty in nanomaterial risks would be acknowledged, and strategies would be formulated to manage or reduce the uncertainty. The basic adaptive management process is straightforward: one chooses a management action, monitors the effects of the action, and adjusts the action based on the monitoring results and updated social and economic factors. 12 During the adaptive management process, in contrast to traditional management, changes are expected and discussed, learning is emphasized, and objectives can be revised based on the performance of a management alternative, changing societal values, or institutional learning. An ideal governance framework would be adaptive, 13 and a combination of adaptive management and MCDA would provide a powerful framework for a wide range of environmental management problems, including nanotechnologies. It would allow structured, clear decisions to be made and also the adjustment of those decisions based on their performance. 14 Proposed approach Integrating this heterogeneous and uncertain information demands a systematic and understandable framework to organize scarce technical information and expert judgment. Current work for the EPA and US Department of Defense 12 shows that MCDA methods provide a sound approach to management of heterogeneous information and risks. Our approach for making efficient decisions on appropriate nanomaterials for medical applications will allow joint consideration of the medical factors and side effects along with associated uncertainties relevant to selection of alternative nanomaterials and treatments. It will follow a systematic decision framework developed by Linkov et al 10 A generalized MCDA process will follow two basic themes: (1) generating alternative nanomaterials and treatment options, success criteria, and value judgments; and (2) ranking the alternatives by applying value weights. The first part of the process generates and defines choices, performance levels, and preferences. The latter section methodically prunes nonfeasible alternatives by first applying screening mechanisms (e.g., significant toxicity, excessive cost) and then ranking in detail the remaining alternative nanomaterials by MCDA techniques that use the various criteria levels generated by toxicity models, experimental data, or expert judgment. Although it is reasonable to expect that the process may vary in specific details among nanomedical applications and project types, emphasis should be given to designing an adaptive management structure that uses adaptive learning as a means for incorporating changing decision priorities or new knowledge from toxicity testing or other data into nanotechnology strategy selection or change. The tools used within group decision making and scientific research are essential elements of the overall decision process. The applicability of the tools is symbolized in Figure 1 by solid lines (direct involvement) and dotted lines (indirect involvement). Decision analysis tools help to generate and map technical data as well as individual judgments into organized structures that can be linked with other technical tools from risk analysis, modeling, monitoring, and cost estimations. Decision analysis software can also provide useful graphical techniques and visualization methods to express the gathered information in understandable formats. When changes occur in the requirements or the decision process, decision analysis tools can respond efficiently to reprocess and iterate with the new inputs. This

4 170 I. Linkov et al / Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) Figure 1. Example decision process. Dark lines indicate direct involvement / applicability, and dotted lines indicate less direct involvement / applicability. integration of decision tools and scientific and engineering tools allows users to have a unique and valuable role in the decision process without attempting to apply either type of tool beyond its intended scope. Three basic groups of stakeholders (nanotechnology managers and decision makers, scientists and engineers, and patients or nanomedicine users) are symbolized in Figure 1 by dark lines for direct involvement and dotted lines for less direct involvement. Although the actual membership and function of these three groups may overlap or vary, the roles of each are essential in maximizing the utility of human input into the decision process. Each group has its own way of viewing the problem, its own method of envisioning solutions, and its own responsibility. Nanotechnology managers spend most of their effort defining the problem s context and the overall constraints on the decision. In addition, they may have responsibility for final nanomaterial selection. Patients and technology recipients may provide input in defining nanomedical and nanomaterial alternatives, but they contribute the most input in helping formulate performance criteria and making value judgments to weight success criteria. Depending on the problem and context, patients and users may have some responsibility in ranking and selecting the final nanomaterial use alternative. Scientists and engineers have the most focused role in that they provide the measurements or estimations for the desired criteria that determine the success of various nanomaterials and alternatives. The result of the entire process is a comprehensive, structured process for selecting the optimal alternative in any given situation, drawing from stakeholder preferences and value judgments as well as scientific modeling and risk analysis. This structured process would be of great benefit to decision making in nanotechnology management, where there is currently no structured approach for making justifiable and transparent decisions with explicit trade-offs between social and technical factors (e.g., using a cancer medication with the potential for adverse side effects). Discussion Because the nanomedical field is growing, it is important to be proactive in response to stakeholder concerns and values. Although nanotechnology holds great promises for the future, there is apprehension that there may be unseen adverse effects. Although the potential for adverse effects is unknown at this time, researchers and developers must make decisions on how to continue to grow the field while balancing the safety of the public. Likewise, consumers and patients need to understand the level of risk, if any, associated with the use of nanomedicines and make decisions based on the best information available to them. The MCDA framework links heterogeneous information on causes, effects, and risks for different nanomaterials with decision criteria and weightings elicited from decision makers, allowing visualization and quantification of the trade-offs involved in the decision-making process. The proposed framework can also be used to prioritize research and information-gathering activities and thus can be useful for value-of-information analysis. New data are constantly being researched and presented. With the growth of this powerful scientific database, MCDA offers an innovative and effective way to integrate and evaluate the wealth of knowledge relating to nanomedicines.

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