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Nanomedicine: , Biology, and Medicine 4 (2008) 167–171 www.nanomedjournal.com Short : and : making hard decisions ⁎ Igor Linkov, PhD,a, F. Kyle Satterstrom, MA,b Lisa M. Corey, MSc aUS Army Engineer Research and Development Center, Brookline, Massachusetts, USA bHarvard University School of Engineering and Applied Sciences, Cambridge, Massachusetts, USA cIntertox Inc., Seattle, Washington, USA

Abstract 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 and risk associated with specific 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. Key words: Nanotoxicology; Risk assessment; Multicriteria decision analysis

Nanomaterials have the potential to revolutionize medi- require allowing for an uncertainty in basic knowledge cine because of their ability to affect organs and tissues at the that is much larger than the uncertainty for other materials molecular and cellular levels. Current research is focused on and pharmaceuticals. To combat the uncertainty, decision the medical applications of nanotechnology, whereas side makers need an understanding of product life cycle and the effects associated with their use, especially the environ- ability to communicate effectively with personnel, stake- mental impacts of their manufacture and disposal, are holders, and regulators. This can be achieved through an generally not taken into consideration during the engineering innovative combination of toxicology, risk assessment process. Incorporating environmental concerns into nano- modeling, and tools developed in the field of multicriteria material engineering and nanomedicine development is decision analysis (MCDA). important, but it greatly increases decision complexity. Even though the risk assessment paradigm successfully Biomedical community needs used by the scientific community since the early 1980s may be generally useful, its application to nanomaterials would Nanomaterials have been promoted as a revolutionary for and , medical device development, and the encapsulation and delivery of drugs, Received 15 April 2007; accepted 28 January 2008. diagnostics, and genes. Advances in nanotechnology have led This study was supported in parts by the US Army Engineer Research to the introduction of many nanomaterials in these areas, and and Development Center. ⁎ the Nanomedicine Initiative of the National Institutes of Health Corresponding author. US Army Engineer Research and Develop- Roadmap for initiative predicts that ment Center, 83 Winchester Street, Suite 1, Brookline, Massachusetts 02446, USA. nanomaterials will begin yielding significant medical benefits E-mail address: [email protected] (I. Linkov). within the next 10 years.

1549-9634/$ – see front . Published by Elsevier Inc. doi:10.1016/j.nano.2008.01.001

Please cite this article as: I. Linkov, F.K. Satterstrom, L. Corey, Nanotoxicology and nanomedicine: making hard decisions. Nanomedicine: NBM 2008;4:167-171, doi:10.1016/j.nano.2008.01.001. 168 I. Linkov et al / Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) 167–171 Despite the widespread use of nanomaterials, under- When a nanomaterial is used for a medical application, it standing of the toxicity and potential health risks associated is intentionally given to a patient because of some unique with nanomaterial use is extremely limited. In fact, toxicity property that its size (and often chemistry) imparts. For issues related to nanomaterials used in nanomedicine are example, the nanosized particles may have the ability often ignored.1,2 Thus, along with the development of to access different tissues than larger particles, such as novel , experts in related scientific fields are crossing the -brain barrier, or to be tagged with specific calling for a simultaneous assessment of the toxicological antibodies to home in on and be taken up by specific cells. and environmental effects of nanoparticles.3 Recent in vivo Nevertheless, nanomaterials can cause side effects, and a and studies have suggested that inhalation and toxicity assessment requires knowledge of their metabolism dermal absorption of some nanomaterials may have adverse and distribution in the body. A variety of techniques are health effects,3,4 and the use of medical products containing currently available for determining the distribution of a nanomaterials may lead to chronic health risks.5 Spurred by nanomedicine in a patient, such as radiolabeling, which can such reports, regulatory agencies, as well as the popular and be used to evaluate distribution and uptake into specific scientific media, are shifting their focus from the initial cells and tissues. Distribution depends on several factors, euphoria about the potential of the technology to concern including the mechanism of targeting. cells can be about possible deleterious effects resulting from nano- targeted using antibody conjugation to a medication; direct material manufacture and use. targeting can be enabled so the nanomedicine can be taken The US Environmental Protection Agency (EPA) has up by specific cells; and nanomedicine can passively diffuse raised concerns about the use of nanosilver in several into tissues or cells, for example taking advantage of the consumer products already on the market. Uncertainty leaky endothelia in the blood vessels around some solid about the health impacts associated with tumors. In each case it is possible for the medicine to reach and their potentially uncontrolled market growth has a different population of unintended cells. This situation resulted in calls from environmental and political bodies to is complicated by the possibility of making use of many limit the use of nanomaterials, increase the stringency different delivery routes, including oral, transdermal, intra- of governmental regulations, and, in extreme cases, ban the venous, and inhalation. Further considerations include use of nanomaterials completely. A better understanding of whether the nanomaterial stays localized or re-enters the these materials is clearly needed, yet experience with and how it is used or metabolized. inorganic and organic chemicals may not be directly relevant Specific nanomaterials will bring with them their own to nanomaterials, in that their physical and biological specific factors to consider. properties are often determined by novel relationships Multiple variables could also influence nanomedicine between their size, structure, and the presence of added , including characterization of varia- functional groups. tions in biological reactivity, size, shape, charge, and route A framework of underlying questions remains to of administration, as well as factors that complicate the be addressed: straightforward estimation of exposure (e.g., metabolism, excretion, adduction to biological , etc.). For • What are the specific nanomaterial properties that example, several studies on nanotubes have shown should be characterized for nanomedical applications? that the toxicity and distribution of nanoparticles is • What data are available on nanomedicine toxicity, dependent upon the presence of functional groups, impu- exposure, and environmental fate and transport? rities, fiber length, and aggregation status.6,7 When a • Where are the data gaps? nanomaterial is not used for a medical application but • How do nanomaterial characteristics contribute to exposure is instead environmental, exposure estimation may toxicity in relation to nanomedical applications? be even less straightforward. • How do specific delivery mechanisms influence Given estimates of exposure and toxicity, the final step nanomedicine toxicity? involved in estimating the hazard of contaminant exposure • What is the role of concurrent exposures to multiple is the characterization of the dose-response function, that is, and pharmaceuticals? 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 Difficulties in applying traditional risk required effort, detailed dose-response assessments will assessment framework not be possible for all nanomaterials. Decision tools and databases should be developed to facilitate use of all A risk assessment has four general components: hazard available information as well as proxy data for making the identification, toxicity assessment, exposure assessment, and best judgment on dose-response. Risk to individuals can then risk characterization. Nanomaterials can easily be identified be quantitatively and qualitatively determined. However, as a potential hazard, but they present many complications to unlike the reference doses used by the EPA in health risk the subsequent three steps. assessments for the general population, safety standards for I. Linkov et al / Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) 167–171 169 agencies such as the US Food and Drug Administration can and objectives can be revised based on the performance of a be variable. Drugs designed to treat extreme forms of management alternative, changing societal values, or disease, such as cancer and acquired immunodeficiency institutional learning. An ideal governance framework syndrome, may not be required to give patients more than a would be adaptive,13 and a combination of adaptive limited margin of safety. management and MCDA would provide a powerful frame- work for a wide range of environmental management Risk-based decision analysis problems, including nanotechnologies. It would allow structured, clear decisions to be made and also the As with any new technology or science, developing a adjustment of those decisions based on their performance.14 framework for selecting appropriate nanomaterials and making medical decisions with uncertainty and incomplete Proposed approach information is the current challenge for the field of nano- technology. Understanding nanomaterial toxicity requires Integrating this heterogeneous and uncertain information multiple sets of information because of both the complexity demands a systematic and understandable framework to of nanomaterials and the often-limited database of relevant organize scarce technical information and expert judgment. experimental studies. One of the tools widely used in risk Current work for the EPA and US Department of Defense12 assessment applications in similar situations is the weight-of- shows that MCDA methods provide a sound approach to evidence approach. Weight-of-evidence considerations are management of heterogeneous information and risks. required in assessing risks to ecological receptors.8 The EPA Our approach for making efficient decisions on appro- and other agencies use a weight-of-evidence approach in priate nanomaterials for medical applications will allow joint evaluating the potential carcinogenicity and toxicity of consideration of the medical factors and side effects along environmental contaminants.9 Traditionally, assessors weigh with associated uncertainties relevant to selection of various lines of evidence and apply professional judgment alternative nanomaterials and treatments. It will follow a and/or calculations to decide where the weight of evidence systematic decision framework developed by Linkov et al10 lies—that is, whether the various lines of evidence point to A generalized MCDA process will follow two basic themes: potential risk in the case of each receptor or not. Much of (1) generating alternative nanomaterials and treatment this effort, however, is not initially transparent. Even options, success criteria, and value judgments; and (2) though weight-of-evidence considerations may include ranking the alternatives by applying value weights. The first some quantification, this approach often results in arbitrary part of the process generates and defines choices, perfor- weight selection and thus in risk estimates that include an mance levels, and preferences. The latter section methodi- unquantified degree of uncertainty and potential bias. cally prunes nonfeasible alternatives by first applying Thus, we have introduced MCDA as a tool for integrating screening mechanisms (e.g., significant toxicity, excessive heterogeneous information for regulatory decision making cost) and then ranking in detail the remaining alternative for nanomaterials.10 nanomaterials by MCDA techniques that use the various We believe that MCDA could be applied widely to criteria levels generated by toxicity models, experimental support decisions on the border of nanomedicine and data, or expert judgment. Although it is reasonable to expect nanotoxicology. The advantages of using MCDA techniques that the process may vary in specific details among nano- over other less structured decision-making methods are medical applications and project types, emphasis should be numerous: MCDA provides a clear and transparent metho- given to designing an adaptive management structure that dology for making decisions and also provides a formal way uses adaptive learning as a means for incorporating changing for combining information from disparate sources. These decision priorities or new knowledge from toxicity testing or qualities make decisions made through MCDA more other data into nanotechnology strategy selection or change. thorough and defensible than decisions made through less The tools used within group decision making and structured methods. For example, MCDA could be used to scientific research are essential elements of the overall support weight-of-evidence evaluation of nanomaterials.11 decision process. The applicability of the tools is symbolized Moreover, MCDA could be easily linked with adaptive in Figure 1 by solid lines (direct involvement) and dotted management for nanomedicine development. In an adaptive lines (indirect involvement). Decision analysis tools help to management paradigm, the uncertainty in nanomaterial risks generate and map technical data as well as individual would be acknowledged, and strategies would be formulated judgments into organized structures that can be linked with to manage or reduce the uncertainty. The basic adaptive other technical tools from risk analysis, modeling, monitor- management process is straightforward: one chooses a ing, and cost estimations. Decision analysis software can management action, monitors the effects of the action, and also provide useful graphical techniques and visualization adjusts the action based on the monitoring results and methods to express the gathered information in under- updated social and economic factors.12 During the adaptive standable formats. When changes occur in the requirements management process, in contrast to traditional management, or the decision process, decision analysis tools can respond changes are expected and discussed, learning is emphasized, efficiently to reprocess and iterate with the new inputs. This 170 I. Linkov et al / Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) 167–171

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 risk analysis. This structured process would be of great tools allows users to have a unique and valuable role in the benefit to decision making in nanotechnology manage- decision process without attempting to apply either type of ment, where there is currently no structured approach for tool beyond its intended scope. making justifiable and transparent decisions with explicit Three basic groups of stakeholders (nanotechnology trade-offs between social and technical factors (e.g., managers and decision makers, scientists and engineers, using a cancer medication with the potential for adverse and patients or nanomedicine users) are symbolized in side effects). Figure 1 by dark lines for direct involvement and dotted lines for less direct involvement. Although the actual Discussion membership and function of these three groups may overlap or vary, the roles of each are essential in Because the nanomedical field is growing, it is important maximizing the utility of human input into the decision to be proactive in response to stakeholder concerns and process. Each group has its own way of viewing the values. Although nanotechnology holds great promises for problem, its own method of envisioning solutions, and its the future, there is apprehension that there may be unseen own responsibility. Nanotechnology managers spend most adverse effects. Although the potential for adverse effects is of their effort defining the problem’s context and the unknown at this time, researchers and developers must make overall constraints on the decision. In addition, they may decisions on how to continue to grow the field while have responsibility for final nanomaterial selection. balancing the safety of the public. Likewise, consumers Patients and technology recipients may provide input in and patients need to understand the level of risk, if any, defining nanomedical and nanomaterial alternatives, but associated with the use of nanomedicines and make they contribute the most input in helping formulate decisions based on the best information available to them. performance criteria and making value judgments to The MCDA framework links heterogeneous information on weight success criteria. Depending on the problem and causes, effects, and risks for different nanomaterials with context, patients and users may have some responsibility decision criteria and weightings elicited from decision in ranking and selecting the final nanomaterial use makers, allowing visualization and quantification of the alternative. Scientists and engineers have the most trade-offs involved in the decision-making process. The focused role in that they provide the measurements or proposed framework can also be used to prioritize research estimations for the desired criteria that determine the and information-gathering activities and thus can be useful success of various nanomaterials and alternatives. for value-of-information analysis. New data are constantly The result of the entire process is a comprehensive, being researched and presented. With the growth of this structured process for selecting the optimal alternative in powerful scientific database, MCDA offers an innovative any given situation, drawing from stakeholder preferences and effective way to integrate and evaluate the wealth of and value judgments as well as scientific modeling and knowledge relating to nanomedicines. I. Linkov et al / Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) 167–171 171 References 8. US Environmental Protection Agency. 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