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E DITORIAL
Environmental challenges for nanomedicine ‘...the presence of nanomedicine residues in the environment is a challenge that we will have to face at some point.’
Anders Baun† & Steffen Foss Hansen †Author
for correspondence Department of Environmental Engineering, Technical University of Denmark, Building 113, 2800 Kgs. Lyngby, Denmark Tel.: +45 4525 1567; Fax: +45 4593 2850; E-mail:
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Along with the possibilities of lighter and stronger materials, clean water and sustainable energy, the development of nanomedicine is one of the primary reasons why huge amounts of public funding are currently going into the development of nanotechnology worldwide. The environmental risks of conventional medical products did not receive much attention until the 1990s; however, the potential environmental side effects have come under increased scientific and regulatory scrutiny in the last decade. In this Editorial, we will take a closer look at scientific and regulatory issues related to the environmental risks of nanomedical products and we will discuss some of the challenges that need to be addressed to ensure that nanomedicines are not only safe for humans but also for the environment. Although the field of nanotechnology is very broad in scope, most attention with regard to human health and environmental risks has evolved around engineered nanoparticles (ENPs), such as C60, carbon nanotubes, metals, metaloxides and quantum dots [1]. At the same time, potential risks related to dendrimers and liposomes have only been raised to a lesser extent. The application of ENPs for medical use offers immense benefits within areas, such as diagnosis, targeted drug delivery and drug development [101]. However, the use of ENPs in nanomedicine has not been subject to much regulatory scrutiny because existing laws and regulatory instruments are believed to also cover medical products based on nanotechnology. The extensive testing requirements prior to marketing of medicine may also contribute to the notion that the potentially negative effects will be discovered prior to marketing, that patients are adequately informed about negative side effects and that the benefits outweigh the risks or the adverse effects, should such be found to occur.
10.2217/17435889.3.5.605 © 2008 Future Medicine Ltd ISSN 1743-5889
The environmental challenges One aspect of nanomedicine is, however, often neglected [2]: what happens after the prescribed use and residues of nanomedicine enter the environment? It is not difficult to imagine that residues of nanomedicine or nano-sized drug carriers could have unexpected effects in the environment because it has been the case for conventional medicine, for which a rapidly increasing number of laboratory studies show ecotoxicological effects [3]. However, to the best of our knowledge, no study exploring the environmental effects of nanomedical products has been published to date [1]. Although environmental exposures may be low, they should nonetheless not be ignored. It is accepted widely that risks to humans ought to be eliminated as much as possible in preclinical research by using in vivo and in vitro experiments and we would argue that this hazard identification strategy should be broadened to include environmental fate and effects as well. Owing to the use patterns of medical products in society today, it is obvious that residues of medical products will eventually be recovered in the environment. This has by now been documented in a number of monitoring studies of conventional pharmaceuticals in wastewater, surface water, ground water and drinking water [3–6]. Hence, the presence of nanomedicine residues in the environment is a challenge that we will have to face at some point. The sooner we start discussions on how to address, regulate and eliminate the environmental risks of nanomedical products, the better equipped we will be for handling unexpected risks [7]. The challenges are multifaceted. At the present stage of development in nanomedicine, the options for targeted drug delivery are studied widely and hold great promise for future drug developments [101]. Here, it is the interaction between ENPs and an active therapeutic agent that often forms the basis for the technological development. Although this interaction is desirable for drug delivery, for instance, owing to an enhanced bioavailability of biologically active compounds, the very same mechanisms may give rise to undesirable effects on nontarget Nanomedicine (2008) 3(5), 605–608
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organisms in the environment. This is in analogy to recent findings, demonstrating that ENPs may interact with already occurring environmental pollutants and change the availability and toxicity of these [8,9]. ‘It is not difficult to imagine that residues of nanomedicine or nano-sized drug carriers could have unexpected effects in the environment...’
Limitations of existing environmental regulation in relation to nanomedicine The principles for inclusion of environmental issues in the risk assessment of medical products in the USA and the EU are defined in guidance documents published by the US FDA [10] and the European Medicines Agency [11]. In the EU, all new marketing authorization applications are required to undergo an environmental risk assessment following a tiered assessment procedure. One significant difference in the EU risk assessment approach for medical products compared with that of industrial chemicals is the inclusion of a prescreening stage involving a rough calculation of the predicted environmental concentration for surface water with an action limit of 0.01 ppb [11]. Thus, if the estimated environmental concentration is below this value and ‘no other environmental concerns are apparent’ [11], no further actions are to be taken for the medical product in terms of environmental risk assessment. In the USA, the FDA guideline [10] prescribes that, in general, an environmental assessment is required for new drug applications with some exemptions possible. However, if the expected introduction concentration in the environment exceeds 1 ppb, no exemptions can be made. These approaches, in which the estimated environmental concentrations are used as trigger values for further action, are problematic if the current regulation of medical products is transferred directly to regulation of nanomedical products. These concentration limits are not a sciencebased set and can by no means be interpreted as ‘environmentally safe concentrations’ for medical products in general (also mentioned in the European guideline [11]) nor for nanomedical products specifically. Here, a predefined action limit will be especially problematic because the new properties of nano-based products are expected to also affect their environmental profiles, as argued by several authors [12,13]. 606
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We agree that an initial weighing of benefits versus harm may be needed to avoid over-regulation. However, it should be stressed that the evaluation of environmental fate and effects of ENPs used in medical products is significantly different from that of conventional pharmaceuticals. The establishment of a fixed value for a level-of-noconcern, for which the benefits outweigh the risks, is not justifiable scientifically given the present level of knowledge. Not only is the amount of laboratory data limited and field studies and exposure models nearly nonexistent, but we may not even know the ecotoxicological end points to investigate or how to measure exposure to ENPs in the environment. Although a general paradigm in toxicology prescribes that ‘the dose that makes the poison’ and most regulatory frameworks are based on the assumption that there is a correlation between mass and toxicity, this might not be the case for nanoparticles. A number of studies have pointed out that other properties, such as surface area, surface chemistry and so on, might be better descriptors for nanoparticles with regard to a number of toxicological end points [14,15]. For nanoparticles, this opens up a question of how to determine the relevant exposure concentration in ecotoxicological laboratory studies and in the environment. This is also acknowledged in the 2007 opinion from the European Commission’s Scientific Committee for Emerging and Newly Identified Health Risks (SCENIHR) stating that amendments have to be made to the existing technical guideline for risk assessment of chemicals because: ‘due to the physico–chemical properties of nanoparticles, their behaviour and their potential adverse effects are not solely dependent on exposure in terms of the mass concentration …’ [15]. Even though environmentally relevant concentrations of ENPs still remain to be measured and models to predict these seem to be some years down the road, most would agree with the statement that ‘No exposure equals no risk of hazardous effect’. In traditional (eco)toxicology, it is also a general paradigm that low exposures yield lower risks of effects compared with higher exposures. However, the abovementioned interaction of ENPs with biologically active substances may alter this view. If the bioavailablity is changed, a change in the biological effects is to be expected and this may turn out to be very difficult to predict or to include in existing environmental risk assessment schemes. Although exposures at present future science group
Environmental challenges for nanomedicine – EDITORIAL
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are low, the additional complexity of the exposure scenarios have led some researchers to deem that quantitative assessment of the risks would be virtually impossible [16]. Another issue that makes ENPs different from conventional chemicals is their ability to aggregate on release into the environment. Aggregated particles are generally considered to be less prone to biological uptake, however, some caution should be exerted before assuming that aggregated ENPs are inherently environmentally safe. Aggregation behavior in the environment (and organisms) is described sparsely. Aggregation in the laboratory is concentration dependent and smaller aggregates are formed at lower initial concentrations. If toxicity is linked to aggregation size, this observation has great implications for our traditional understanding of concentration–response relationships. Thus, higher concentrations of ENPs may not necessarily give rise to higher effects. Furthermore, if larger and benign aggregates are ingested, they may be broken down in the organism yielding smaller – and perhaps less benign – aggregates. For these reasons, the apparently trivial statement of ‘less exposure equals lower effects’ should be scrutinized seriously before it can be considered valid for ENPs released to the environment. As discussed, there are several shortcomings to existing approaches for determining the ecotoxicity of nanomedical products. For two of the other parameters used today to identify environmentally hazardous compounds, that is, persistence and bioaccumulation, the SCENIHR concluded that: ‘The criteria for used for persistence, bioaccumulation and toxicity (PBT) assessment applied for substances in soluble form should be assessed for applicability to nanoparticles’ [15]. Thus, the present use of the octanol–water coefficient (as a surrogate value for bioaccumulation data to signify environmental concern) in the US and EU guidelines for risk assessment of medical products [10,11] should not be transferred to a regulation for nanomedicines unless strong scientific evidence supports this.
exposure assessments. Thus, we claim that the present level of scientific knowledge is at a prehazard-identification stage and agree with Owen and Handy [17], who state that emphasis in riskassessment frameworks for nanomaterials should be placed on problem formulation and prioritization in the coming years. In the meantime, we believe that a proactive attitude towards environmental regulation of ENPs needs to be adopted [7]. Scientists and developers of nanomedicine, as well as environmental chemists, ecotoxicologists and regulators, need to come together and start addressing these issues in a truly interdisciplinary fashion to ensure that the right questions are being asked and addressed. In our discussions with nanotech scientists and developers, we often encounter the fear that regulation may act as a brake on development and there is a frequent reference to ‘nonscientific over-regulation as it has been the case for other emerging technologies’ – the genetically modified organism case being mentioned most frequently. We would claim that regulation has limited influence on the first stages of traditional drug discovery and hence this is not hampered by regulation. Later on in the development sequence, regulation can indeed be a determining factor as to whether the newly discovered active substance or application will in fact be a commercially available product. However, that is not different than the situation for conventional medical products. In a similar way, a preliminary pre-market dataset has to be developed for nanobased pharmaceuticals and medical applications of nanotechnologies. This has to be done without hesitation to demonstrate a truly proactive approach to address the concerns that are always related to emerging technologies.
The way forward In traditional risk-assessment terminology, the state-of-knowledge on environmental fate and effects of nanomaterials is not sufficient to provide relevant answers to questions asked as a result of the initial hazard identification. Subsequently, it is not possible to perform scientifically validated environmental effect and
To assist decision making when developing nanomedical products, emphasis has to be put on design criteria identifying which nanomaterials are of the greatest environmental concern owing to their inherent properties in combination with intended use pattern. Although the scientific literature on nanoecotoxicology and environmental exposure is sparse, a number of recommendations
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‘Not only is the amount of laboratory data limited and field studies and exposure models nearly nonexistent, but we may not even know the ecotoxicological end points to investigate or how to measure exposure to ENPs in the environment.’
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for selection hazard-relevant characteristics have been published [1,14,18]. Furthermore, the OECD Working Party on Manufactured Nanomaterials has made similar recommendations recently [19]. These lists may form a basis for a regulatory gathering of data to be used for risk-management decisions at a later point in time. Although nanomedical products will probably enter the environment, their fate and effects are not well understood with respect to fundamental issues, such as bioavailability, bioaccumulation, toxicity, environmental transformation and interactions with other environmental contaminates, as well as the applicability of current environmental fate and transport models to nanomaterials [20]. Thus, a thorough consideration of environmental (as well as health and safety) implications already in the design phase of nanomedical products will facilitate decisions Bibliography 1.
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