J Nanopart Res (2012) 14:1007 DOI 10.1007/s11051-012-1007-1
PERSPECTIVES
Responsible nanotechnology development Gianluigi Forloni
Received: 12 September 2011 / Accepted: 18 June 2012 / Published online: 14 July 2012 Ó Springer Science+Business Media B.V. 2012
Abstract Nanotechnologies have an increasing relevance in our life, numerous products already on the market are associated with this new technology. Although the chemical constituents of nanomaterials are often well known, the properties at the nano level are completely different from the bulk materials. Independently from the specific application the knowledge in this field involves different type of scientific competence. The accountability of the nanomaterial research imply the parallel development of innovative methodological approaches to assess and manage the risks associated to the exposure for humans and environmental to the nanomaterials for their entire life-cycle: production, application, use and waste discharge. The vast numbers of applications and the enormous amount of variables influencing the characteristics of the nanomaterials make particularly difficult the elaboration of appropriate nanotoxicological protocols. According to the official declarations exist an awareness of the public institutions in charge of the
Special Issue Editors: Paolo Milani, Mary F.E. Ebeling This article is part of the Topical Collection on Technology Transfer and Commercialization of Nanotechnology G. Forloni (&) Department of Neuroscience, Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Via La Masa 19, 20156 Milan, Italy e-mail:
[email protected]
regulatory system, about the environmental, health and safety implications of nanotechnology, but the scientific information is insufficient to support appropriate mandatory rules. Public research programmers must play an important role in providing greater incentives and encouragement for nanotechnologies that support sustainable development to avoid endangering humanity’s well being in the long-term. The existing imbalance in funds allocated to nanotech research needs to be corrected so that impact assessment and minimization and not only application come high in the agenda. Research funding should consider as a priority the elimination of knowledge gaps instead of promoting technological application only. With the creation of a public register collecting nanomaterials and new applications it is possible, starting from the information available, initiate a sustainable route, allowing the gradual development of a rational and informed approach to the nanotoxicology. The establishment of an effective strategy cannot ignore the distinction between different nanoparticles on their use and the type of exposure to which we are subjected. Categorization is essential to orchestrate toxicological rules realistic and effective. The responsible development of nanotechnology means a common effort, by scientists, producers, stakeholders, and public institutions to develop appropriate programs to systematically approach the complex issue of the nanotoxicology. Keywords Health Nanotoxicology Environment Risk assessment Social responsibility
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Nanotechnology: the public perception and the real data Nanotechnologies are an emerging technological field evolving with a high speed and promising to bring about improvements, provide new products and services, enable increased and new human individual abilities, and generally redesign the relationships through innovation in many different sectors. Main expectancy in the nanotechnology applications is in the areas of environmental protection, renewable energy, medicine, and electronics, although, with the exception of electronics, other are the fields of application where nanotechnological products have already reached the market: cosmetics, textiles, housing and construction, sport items. According to the Roco’s for the beginning of protyping of nanoparticles of the first generation were passive (nanostructured metals, polymers ceramics) in 2005 with the second generation they became active (3D transistors, targeted drugs, etc.), in 2010 the third generation is a further elaboration to form system of nanosystems (guided assembling, 3D networking) and finally in 2015 we will have the molecular nanosystems by atomic design (Roco 2006, 2007). Despite the numerous applications and the presence on the market of more than one thousand products associated to nanotechnology, the potential risks for human health as well as the consequence of nanomaterial dispersion in the environmental are poorly known and poorly investigated (Nel et al. 2006; Maynard et al. 2006). When the Royal Society and the Royal Academy of Engineering published in (2004) their widely cited report Nanotechnology opportunities and uncertain, various international institutions started to bring in consideration initiatives to approach the toxicological aspect associated to the widespread diffusion of nanomaterials (European Commission 2004; European NanoSafe Report 2004). After almost a decade, the level of awareness of public opinion on the potential risks associated to nanotechnology is still modest (Oberdo¨ster et al. 2005). The general attitude toward this modern science is, at the moment, quite positive or neutral, some enterprises have used the nanolabel as a means of publicity and marketing, even independently from the real content of nano-engineered particles in their items. A recent survey (Special Eurobarometer 2010) revealed that only 50 % of the Europeans have heard about
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nanotechnology (in US the percentage is about 60 %) and 27 % of them considering nanotechnology not good for them or their family, while 37 % are not agree with this point of view. To have a comparison: 84 % have heard about genetic modified (GM) food and more than 60 % have negative attitude towards it. The administration of survey questionnaire to Italian population with at least high school education showed a positive attitude toward nanotechnology (more than 90 % of the 80 % that have heard about it), specially referred to nanomedicine. However, the survey highlights the lack of information, more than 90 % of respondents believed that not having enough information about nanotechnology risks and its advantages (Bottini et al. 2011). The major initiatives proposed for the involvement of public opinion in decision-making related to programs in nanotechnology should take account for this lack of information and the various factors that influence the perception of this new technology (Kahan et al. 2009). An open public consultation defined ‘‘Towards strategic nanotechnology action plain 2010–201500 has been established by EC between December 2009 and February 2010 to support the preparation of a new action plan for nanotechnologies in Europe for 2010–2015. It was designed to collect the views of both experts active in the field and the public at large regarding the benefits, risks, concerns, and awareness of nanotechnologies. The action plan also sought their opinions on future directions for governance and all relevant policies for the integrated, safe and responsible development and commercialization of nanotechnologies and nanotechnology-enabled processes and products. 716 responses have been collected, two-third of the individual responses (61 % of the total) were given by researchers. The individual non-researchers were 22.8 %, the industrial 17.8 %, non governative organization (NGO) were 5.3. Despite the general positive opinion toward the nanotechnologies, with the exceptions of NGO that were not convinced, the responses about the risks associated to the nanotechnology is considered the main concern through all categories. For individual researchers, the major concern is the possible toxicity of poorly understood nanomaterials (70 %) followed closely by the possible effects of nanomaterials on workers’ health (63 %) and on the environment (55 %). Individual non-researchers are concerned not only about these areas (in the range of 65–70 %) but also about the lack of adequate information imparted
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to the public on benefits and potential risks (64 %), the lack of knowledge and transparency regarding products on the market containing nanomaterials (59 %), and the lack of proper consumer product information (59 %). Research organizations are mainly concerned about the possible toxicity of poorly understood nanomaterials (79 %) followed closely by the possible effects of nanomaterials on workers’ health (75 %). They are also concerned about Europe lagging behind its competitors in exploiting the benefits of nanotechnologies (61 %). A major issue of concern for industrial respondents is the existence of obstacles to innovation (60 %) followed again by concerns that Europe is lagging behind its competitors in exploiting the benefits of nanotechnologies (56 %). This group is also concerned about the possible toxicity of poorly understood nanomaterials (52 %). NGOs have major concerns in all areas except for the exploitation of benefits from the removal of obstacles to innovation and to being competitive. There were 90 % of these respondents who expressed concerns regarding the possible toxicity of poorly understood nanomaterials and their possible effects on workers’ health. Europe lagging behind and nanomaterial toxicity, together with the lack of tools to implement and enforce existing regulation on environment, health and safety, are the major concerns of public authorities (68–80 %) (SNAP report 2010). The consultation based on personal interest is usually restricted to the operators of the sector but on the other side; involve people with a good knowledge of the issue. Thus, the general opinion coming from this report indicate in the assessment of risks and the regulation system the main concern to approach the nanotechnology. The concept itself of nanomaterial still need to be harmonized with an international accepted definition of nanotechnologies and nanomaterials to avoid inconsistencies along the risk governance cycle and enhance the applicability of existing and future legal frameworks. The term nanotechnology was conied by Norio Tanigouchi in 1974 as processing mainly consists of separation, consolidation, and deformation of materials by one atom or one molecule (Taniguchi 1975). The European commission has introduced a definition of nanomaterial in the cosmetic field (EC regulation 1223/2009): ‘‘insoluble or biopersister and intentionally manufactured material with one or more external dimensions, or an internal structure, on the scale from 1 to 100 nm’’. It is obvious that this wide
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definition exclusively based on the dimensions is just to give a framework but poorly described the real characteristics of the nanomaterial. The correct terminology for nanomaterial is still matter of discussion, recently it has even been proposed to avoid a unique definition (Maynard 2011; Stamm 2011), in the extensive analysis of this issue by Lo¨vestam et al. (2010) the necessity to indicate properties other than size is strongly recommended. Nanomaterial as a whole should be defined as a different class of substances with different properties and behaviors than their correspondent bulk materials. This peculiarity makes the toxicological approach substantially different from the classical way to address the adverse health effects caused by exposure to the material. The fundamental relationship dose–effect has no meaning in the nanoworld; often the effects follow an inverse proportion toward the total concentration. The intrinsic characteristics, such as size confinement, dominance of interfacial phenomena, are far beyond our prediction of what we have known at the macro scale. For instance, the parameters associated to the biological consequence are the concentration (number) of nanoparticles, but also size, shape, crystal structure, solubility, surface area, surface charge, surface coating, and so on (Fig. 2). This enormous variability together with the absence of the correct notion of the exposure and the presence of confounding factors, represented by the nanoparticles naturally formed or deriving from the pollution, make the nanotoxicology field extremely complex (Trout and Schulte 2010). It has been estimated that it could take between 34 and 54 years to perform toxicity tests on existing nanomaterials in United States; the cost of these tests would be between a quarter to one billion dollars (Choi et al. 2009). Research and testing are needed to provide a scientific basis for policy frameworks to deal with uncertainties and risks of nanotechnologies. In particular, there is an urgent need for additional toxicological and ecotoxicological studies, tests and protocols in order to elucidate health and environmental impacts as it has been shown that the available ones (targeted to bulk chemicals and substances) might not be suitable for the assessment of nano-risks. The absence of scientific support makes difficult the preparation of screening procedures in any case transparent and effective communication of the risks of nanotechnologies to society is needed. For instance, the spectrum of asbestos hovers around the use of carbon nanotubes
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since numerous data have been accumulated on the toxicological analogy between the two materials (Morimoto et al. 2011). But also in this case, appropriate distinctions need to be adopted (Kane and Hurt 2008; Murphy et al. 2011). The classical toxicological approach (Fig. 1) to nanomaterial must be maintained but the development of new guide lines to conduct these procedure in the area ‘‘nano’’ are extremely urgent (Fig. 2). The influence of various parameters on the toxic effect of nanoparticles has been shown in different experimental context, here we reported some examples. The inverse relationship of citoxicity and size was systematically approached by Liu et al. (2010), the cytotoxicities of three silver nanoparticles (SNPs) SNP-5, SNP-20, and SNP-50 with different sizes (*5, 20, and 50 nm) using four human cell lines (A549, SGC-7901, HepG2, and MCF-7). Elemental analysis of silver in cells by ICPMS showed that smaller nanoparticles enter cells more easily than larger ones, which may be the cause of higher toxic effects (Liu et al. 2010). The influence of nanoparticles shape has been studied using gold (Au) nanoparticles coated with cetyltrimethylammonium bromide (CTAB) (Tarantola et al. 2011). Spheres with a diameter of (43 ± 4) nm and rods with a size of (38 ± 7) nm 9 (17 ± 3) nm were compared. Spherical gold nanoparticles with identical surface fictionalization are generally more toxic and more efficiently ingested than rod-shaped particles. The higher toxicity of CTAB-coated spheres as compared to rod-shaped
Fig. 1 Flow chart with several steps that characterize the classical toxicological approach from the material characterization until the surveillance
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particles to a higher release of toxic CTAB upon intracellular aggregation (Tarantola et al. 2011). It has been investigated whether modulating the surface charge of 1.5-nm Au NPs-induced changes in cellular morphology, mitochondrial function, mitochondrial membrane potential (MMP), intracellular calcium levels, DNA damage-related gene expression after exposure in a human keratinocyte cell line (HaCaT), The authors showed a significant mitochondrial stress (decreases in MMP and intracellular Ca2? levels) following exposure to the charged Au NPs, but not the neutral Au NPs. The differences observed in the MMP and Ca2? levels, up or down regulation of DNA damage-related gene expression suggested a differential cell death mechanism based on whether or not the Au NPs were charged or neutral These results indicate that surface charge is a major determinant of how Au NPs impact cellular processes, with the charged nanoparticles inducing cell death through apoptosis and neutral NPs leading to necrosis (Schaeublin et al. 2011). The correlation with surface activity more than nanoparticle size has been shown by Warheit et al. (2007) evaluating the pulmonary inflammation and cytotoxicity induced by the exposure to the various alpha-quartz particles Lung tissue evaluations of three of the quartz samples demonstrated ‘‘typical’’ quartzrelated effects–dose-dependent lung inflammatory macrophage accumulation responses concomitant with early development of pulmonary fibrosis. The various alpha-quartz-related effects were similar qualitatively but with different potencies. The range of particle-related toxicities and histopathological effects in descending order were nano scale quartz II = Min-U-Sil quartz [ fine quartz [ nanoscale quartz I [ CI particles. The results demonstrate that the pulmonary toxicities of alpha-quartz particles appear to correlate better with surface activity than particle size and surface area (Sayes et al. 2011). The application of electron microscopy to studies of ultrathin sections of MDCK cells incubated with TiO2 nanoparticles revealed the direct interaction of single amorphous, anatase and brookite nanoparticles with the cell plasma membrane and subsequently different cell responses to the treatment. The crystalline modification determines the pattern of cell plasma membrane reaction to the nanoparticles. Direct contact of the nanoparticles with cell plasma membrane is the primary and critical step of this interaction and defines
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Fig. 2 Description of the various aspects that need to be considered by nanotoxicological approach (Fadeel and Garcia-Bennett 2010 modified)
the subsequent response of the cell. Different crystalline modifications could induce different chemical reactions, and so alter macromolecular structure of cell membrane differently (Ryabchikova et al. 2010). Three metal oxide nanoparticles on primary culture mast cells: nonporous SiO2, mesoporous SiO2 nonporous anatase TiO2. Increase of uptake efficiency in the following order: nonporous SiO2 \ porous SiO2 \ nonporous TiO2 Both nonporous and porous SiO2 nanoparticles cause a decrease in the number of molecules released per granule, with nonporous SiO2 having a larger impact on cell function (Maurer-Jones et al. 2010). Together with experimental data, in analogy with in the toxicology of classical chemical products, in silico methods and mathematical models predicting the toxic potential of nanoproducts can be applied (Tomalia 2009, 2010; Puzyn et al. 2011). The 3D QSAR methods has been developed based the previous experimental tests to analyze the binding of fullerenes to the molecules of interest (Bosi et al. 2003). Other theoretical methodologies have been explored to
evaluate the dynamic of interaction between nanoparticles and macromolecules (Durdagi et al. 2008, 2009).
Principles and processes Several initiatives based on correct principles of precaution and sustainability have been promoted in the last few years by the scientific community, industrial manufactures and regulatory organs to create a framework for the development appropriate procedures to evaluate the potential toxicity of nanomaterial. Implementation of the regulatory mechanisms to address the risk associated to nanotechnology in North America and European Union as well as in the other countries around the world, is in progress. For instance, in EU within 2011 should have been completed the register of the nanomaterials on the market. The complete inventory of the nanomaterials is preliminary to all other analysis, voluntary initiative in this sense are also available (http://www.nanotech project.org), but this aspect need to be addressed by
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the public institutions. Both voluntary and mandated programs have been implemented worldwide to provide data on the safety of nanomaterials. There are a number of database that have been established to provide information on the effect of nanomaterial at the biological level, Organization for Economic Cooperation (OECD) has organized a Database on Research into the Safety of Manufactured Nanomaterials (www.oecd.org/env/nanosafety). OECD has also established a working group with a prioritized list of 14 nanoparticle that have been tested as a reference base for evaluating the safety of manufactured nanomaterials. Similarly, following the nanotechnology white paper (EPA 2007) a Nanoscale Materials Stewardship Programme (EPA 2009) has been established to document the toxicity profiles and physically characterization for both commercial and research nanostructured material. However, although numerous data have been produced in response to specific calls for proposal of nanosafety projects or by independent studies in the various fields of nanotoxicology, we are still far away from an appropriate methodology useful to be elaborate in the context of standard operative process for screening procedures. The policy makers and the main institutions are probably now at the good level of awareness, ready to receive and adequate scientific input to develop mandatory procedures but the lack of consistent data is a gap that need to be bridged. Each scientific group has proposed one or more models, generally in vitro (Ma 2009), where a single nanoparticle in a specific condition showed a certain level of toxicity. This information although is scientifically correct, it is strongly influenced by the experimental conditions, as pointed out before, numerous properties in the material characterization influence the toxicological studies, size, shape, state of aggregation, dispersion, surface properties, etc. On the other hand, it is neither feasible nor sensible to conduct safety evaluations in the same conditions for all nanomaterials in current or future production, therefore flexible criteria based on currently knowledge of similar material should be adopted (Linkov et al. 2009). The adequate categorization based on the location of the nanoscale structure in the system/material before their hazards can be assessed and propose a categorization framework that enables scientists and regulators to identify the categories of nanomaterials systematically (Foss Hansen et al. 2007). Since in general the nanomaterial have been
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studied and have been manufactured for some specific application, in order to design a characterization protocol, information from the manufacturer or other sources should be collected and evaluated (Powers et al. 2009). In this sense only a strict collaboration between experts in nanotechnology, manufacturers and biomedical scientists can correctly orient the nanotoxicological studies, a new area of research that need to be build. Also the voluntary initiatives can be particularly relevant for the nature of nanotechnology constantly evolving. Their role would not replace the public regulation, but inform the regulation and to complement existing and future actions. The flexibility, adaptability, relative ease of implementation, and potential for constructive engagement of multiple partners commend them as a part of an oversight strategy (Fiorino 2010). Public power, business and non-government organization should create a multistakeholder entity to provide a interdisciplinary forum for discussing nanotechnology issues and serve as clearinghouse for information. However, this collaborative activity cannot function without an adequate and responsible support of the scientific community, the accountability of the scientists is, at moment, essential to assess a correct relationship between safety procedures and nanotechnology market and to provide the fundamental elements to develop an appropriate regulamentation. The concept of accountability is relevant in all forms of scientific development but this become essential when new territories are explored, as reported in the nanocode project, specific guidelines should be considered in the area of nanotechnology. From the practical point of view, for a new nanomaterial and mainly for new applications of the previous identified nanomaterial, an adequate exploration of the potential risks associated to the specific utilization must be performed from the beginning. The type and the period of exposure of the biological organisms and the dispersion in the environment can be predicted with a certain level of approximation during the development of the application. The contest in this case become fundamental, it is impossible and relatively useless to give a unique indication, it is necessary to categorize the area of application, not only to evaluate the risk assessment, but also to consider the level of acceptable risk. A strict collaboration should be create between the scientists involve in the development of new nanomaterial and the subjects in charge of the toxicological
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evaluation; the responsibility must be shared from the initial steps. In some areas like cosmetics, drug development, or food preparation, this condition should be obvious, the consequence on human health is (or should be) part of the process required to take in consideration new products for the market. In other areas of application of nanotechnology, like electronics, clothing or energy, the association between use and undesired consequences is less immediate but the potential risks need to be considered on the basis of the data knowledge. The documentation with the description of the innovative nanomaterial or a new application of already known nanomaterial must include also toxicological information with the potential risks explored and non explored, the public authority on the basis of updating criteria can require further investigation or specific survey (Ponce De Castillo 2011). It is clear that the regulatory requirements cannot be the same for any kind of nanomaterials and the accumulation of new nanotoxicological results can modify the specific necessary requirements.
Principles and practical consequences As innovative materials and technological advanced services a responsible management of nanomaterials should be based on the fundamental principles of sustainable development and the precautionary principle (Gee 2009). Due to the rapid development in the area and the great lack of knowledge about risks the precautionary principle should be adopted before producing and introducing nanomaterials in the market. The lack of a minimal evaluation on the consequence of exposure to new (or already used) for the human health and environmental is not only unacceptable on the line of principle but leading the possibility that a single episode of not controlled toxicity might negatively affect the entire field. In the ‘‘Late lessons from early warnings for nanotechnology’’ by Foss Hansen et al. (2008) it is pointed out that: ‘‘a new technology will only be successful if those promoting it can show is safe, but history is littered with examples of promising technologies that never fulfilled the true potential and/or caused untold damage because early warnings were ignored’’. The authors resumed a report by European Environment Agency (EEA) where the 14 cases were explored to
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show how the lack of consideration of the early warnings had led to a failure to protect human health and environment. The expert group identified 12 ‘‘late lessons’’ applicable also to nanotechnology, they can be summarized in 1–3 heed the warnings, to bring in consideration the warning signs, the novel properties of nanomaterial the capacity to pass biological barrier and potentially to accumulate in organs can produce long-term irreversible impacts (Moore 2006). The global response to these warnings is erratic, the public institution being slow to gather essential data on production, use and personal protection measures. Foss Hansen et al. (2008) mentioned that a number of reports make specific recommendations on developing responsive research strategies. Call for proposals in the FP7 European program reflects some of these recommendations and single countries, as mentioned before, have developed environmental, healthy and safety integrated programmes. The FP7 call in the Nanoscience nanotechnologies materials and new production technologies—NMP-2012 is entitled ‘‘systematic investigations of the mechanisms and effects of engineered nanomaterial interactions with living systems and/or the environment’’. According to the expected impact: ‘‘the research approach should be innovative and represent a significant advance beyond the current state-of-the-art, towards (i) increased understanding of the role of nanoparticle–biomolecule interactions in nanoparticle-induced impacts in living systems; (ii) gene or protein fingerprints or biomarkers with potential for determination of specific pathogenic mechanisms; (iii) new methods for systems toxicology leading to safer final nanoproducts through providing targets for engineering refinements of products; (iv) a framework for categorization of nanomaterials on the basis of their bioaccumulation/biopersistence and a set of risk-factors for specific end-points, pathogenesis mechanisms; and (v) a screening platform for nanomaterials as part of a ‘‘safe nanomaterials by design’’ strategy. Projects should focus on the provision of solutions to the long-term challenge of nanosafety and nanoregulation, and on the generation of high quality, systematic data enabling the identification of noobserved-adverse-effect levels (NOAELs) as well as QSARs and modeling. Outputs should be tailored to address the needs of each of the stakeholder communities, including the modeling community. The content of this call demonstrate two relevant concepts: the EU has well identified the main problems associated to
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the use of the nanomaterial. All the key words mentioned in this article are also reported in the expected impact or in the call itself: innovative approach, screening platform, categorization, QSARs modeling, biopersistence, genotoxicity, indirect exposure, etc. but, on the other hand, if the call covers so many topics generally expressed, the level of knowledge in the contest of nanotoxicology is really modest. Lessons 4 and 11 referring to the necessity to reduce the interdisciplinary and institutional obstacles to learning and action. In the area of nanotoxicology, the interdisciplinary contribution is essential; chemistry, physics, computer science, health, and environmental science are involved to understand nanomaterial properties and risks. The opportunities of a close relationship between the various disciplines is commonly accepted but a constant cross talking is not easy to establish. The flexibility of the criteria adopted is also critical to cover all the potential risks associated to a specific nanomaterial. Lessons 5 and 8 suggested to stay in the ‘‘real world’’. Research and development community often believe that basic research will ultimately solve real world problems through a one-way process of knowledge diffusion and they not need to worry about health and safety. On the contrary the basic researchers, as mentioned before, must be involved as well as biomedical experts in informing policy decisions. This includes making use of the information that workers and users can bring to regulatory appraisal approaches, although nanotechnology is a complex issue, the point of view also of non-specialist can be equally valid to find the best procedures. Another concept that need to be considered is a reasonable evaluation of the final destination of the products to be taken in consideration. Most of the nanoproducts (*1,200) present on the market are of ‘‘accessory’’ nature, e.g., they do not serve impelling human or environmental needs, such as health, safety, pollution prevention and remediation, etc., but rather minor necessities (cosmetics, textiles, sport items, etc.), but they might expose humans and the environment to greater risks. The development of nanotechnologies and nanomaterials needs to be prioritized in view of contributing to the wellbeing of societies (including positive environmental implications) and particularly of those mostly in need. In doing this potential unwanted and unpredictable impacts also need to be prevented. Nano-research and technical application should be driven by real societal needs and priorities
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and based on ecological, social and sustainable development considerations and not on the ‘‘marketability’’ of products only. Although this concept is reasonable, it is difficult to elaborate the regulatory point of view on the basis of the final destination of the product but the marketability needs must be temperate according to the risk/benefits evaluation. Nanotechnology is proclaimed to have a tremendous potential to address major global challenges like cancer, renewable energy, and provision of clean water. Yet precisely because of the widespread applications of nanotechnology, citizens around the world are as much as stakeholders in the technology as the governments and industry promoting it. But so far, their engagement has been very limited. Evaluation of alternative solution (lesson 7), retain regulatory independence (lesson 10) and avoid paralysis by analysis (lesson 12) conclude the suggestions by EEA report. The tendency to justify relevant investment in the new technology by promoting its application to every conceivable problem minimizing the risks and the possible alternative with the result that the most fashionable solution is preferred to the most appropriate. The independency of the authority that make the policy decision is a value that cannot be underestimate. Although we are convinced that voluntary initiatives involving not only no-profit foundation but also business people with specific interests in nanotechnology are appreciable and probably indispensable to develop appropriate safety procedures, the roles must be clearly established. On the other hand, the influence of the ‘‘independent’’ experts to direct the interest to their own area of competence for funding or prestigious reasons, can also alter the correct elaboration of policy decision but in this case, an adequate comparison between experts and a strong political guide should overcome the problem. Finally, a correct balance between information and action should be considered to avoid the risk of immobility. As we noted above, a large number of questions are still on the table and the progress in knowledge is extremely slow. The absence of systematic data in the different fields cannot be the alibi to avoid any kind of risk assessment for the single product I believe that specific ‘‘safety protocol’’ must be the framework established according to the general information on the area of application and the specific data availability on the destine of the nanoproduct. The pre-market registration of a specific nanomaterial should follow the upper part of the flow chart
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reported in Fig. 1. A clear categorization defined by the area application (i.e., electronics, cosmetics, pharmaceutical, alimentary, etc.) defined the requirements in terms of nanotoxicology. The description and the specific function of the new nanomaterial, the hazard associated to the potential exposure for each step of the entire life-cycle, from the production to the discharge as a trash must be provided. According to the information obtained by the producer on the potential way of exposure appropriate biological tests must be reported as indicate by the updating scientific literature. These indications can oriented the risk analysis requirement that need to be elaborate on the basis of previous results with similar materials if available or new data produced in the specific contest. The definition of potential exposure is essential to establish what kind of results are necessary to support the positive pre-registration process. The estimation of the number of nanoparticles (single or aggregates) in a specific volume, the type of exposure (by inhalation, intradermic or by ingestion alone or with food and beverage) together with the release in the environment independently of the human exposure are elements necessary to indicate appropriate test. A possible solution is to initially consider the intrinsic properties (diversity and similarity from the previous material or application), available toxicological information on the analogs, the potential exposure and the real benefits deriving from the use of those nanomaterials. In the cases that these four conditions did not positively converge in precautional approach, an adequate research activity for a direct evaluation of the risks become the only way to reach the market. A mandatory study must be proposed on the basis of as yet unknown aspects associated with the use of the specific nanoparticles. A realistic assessment of the type of exposure of humans and/or the dispersion in the environment must be produced together with plane of toxicological experiments (McCall 2011) where the level of tolerability must be established in advance by in vitro and possibly in vivo approaches. The first set of results will determine whether further investigation will be necessary, the pre-registration protocol will be evaluated and approved by the public authority that can give recommendations on the safety rules. The most complicated issue is what to do with the materials already on the market, a realistic possibility is to take inventory of the nanoproducts and based on the producers indication establish the level of possible
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dispersion in the enviroment and the contact with living organisms. The progressive availability of more targeted investigative protocols should influence not only the market access of new nanoproducts, but also enable a retrospective evaluation from the toxicological point of view of products already present, beginning with those of some problematic aspects has already emerged. The process must necessarily be dynamic and always endeavor to obtain a reasonable period of time a comprehensive framework that allows to place according to the toxicological criteria, all known nanomaterials. The different level of potential risk should also drive the creation of monitoring campaigns to establish in the real world which is the dispersion and persistence in the environment and contact with the human organism. These requirements should became progressively mandatory for the corporates that intend to continue to manufacture and market products that directly or inderectly are associated to the production of nanoparticles. Starting from the inventory of the twelve hundred products avaible on the market it is possible create a simple ‘‘safety form’’ for each product where are summarized all the information available useful for a risk assessment mentioned above for the pre-registration protocol (intrinsic characteristics, toxicological data available, amount of production, and fate, benefits or technological advancement associated to the use). As noted before, in some areas such as health, pharmacology, cosmetics and food, toxicological evaluation is intrinsic in the process of developing a new product, although, new protocols must be developed with regard to nanomaterials. Furthermore, the public initiatives mentioned above (EPA and OECD) and the scientific production can be organized to give the necessary support to categorize the different nanomaterials and their application in terms of hazard associated. The evaluation of the exposure is the main problem since numerous subjects are involved in the life-cycle of nanoparticles, like any other products, the precautionary principle should cover the entire life-cycle of the nanoparticles. Life-cycle assessments—including manufacturing, transport, product use, and end of life management—are necessary on materials and products. An interesting dissertation on the exposure assessment has been reported by SCHNIR report in 2006, the various factors influencing the exposure to nanoparticles are considered and tentative models are
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proposed. The type of exposure can be different among manufacturing workers, personnel that manipulate nanotechnological materials for professional reasons, consumers and operators exposed during the waste disposal or recycling. The conditions of exposure are extremely different and it is obvious that in the risk assessment the duration and nature of exposure is essential. Similarly, the environmental dispersion of nanoparticles can be substantially different according to the various nanotechnological material manipulations. The electronic material provide a potential exposure only for the workers, the washing products mainly for professional users, in the paint production there is no dispersion of nanoparticles until the paint has been applied to the walls or surfaces. The traceability of the nanomaterial is another relevant aspect that need to be considered in the risk assessment, specific indications in this sense can be part of the requirements to allow the commercialization (Ponce De Castillo 2011). Along this line the European Consortium Nanocup (2006–2009, www.nanocup.eu) devoted to establish a common position point on nanotechnology elaborated by civil society representatives, environmental associations, unions members, and academic experts, in the final recommendations underlined the concept that no further market introduction should be allowed for products containing manufactured nanomaterials which could lead to exposure of consumers or the environment. Such a restriction should be applied until appropriate impact and safety assessment tests are developed in order to provide the necessary scientific proof that these materials and products are safe for the environment and human health. Those products already on the market should be regulated according to the REACH approach of ‘‘no data, no market’’, and should therefore be removed from commercial circulation as established by the European Resolution on April 24th, 2009. Urgent action should be started in relation to free nanoparticles against which there is no protection (e.g., workers and consumers cannot choose not to breathe them). Free nanoparticles should be treated and labeled as a new class of substances and research into their potential hazards should keep pace with new developments. At the European level, the REACH legislation should be revised in order to make sure that nanomaterials do not evade it by not reaching the threshold of 1 ton/year of manufacture or import (Proceedings conference Nanocap 2009).
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Develop a pre-market registration and approval framework, as proposed here, should require registration of public and private research, and test-based assessment and approval of near-market uses of nanomaterials. This information should then be put into a publicly available inventory, as part of a coherent and comprehensive policy framework on nano. This would serve to identify what possible future uses of nanomaterials could be developed. Systematically assess what products are proposed to be put on the market and would help to ensure swifter and more targeted management of these. Introduction of mandatory labeling for products containing nanoparticles and/or nanomaterials introduced in the market. Although existing voluntary codes for the responsible use of nanoscaled materials (e.g., the European Commission’s code of conduct for responsible nanosciences and nanotechnologies research, see below) provide orientation, guidance and benchmarks for the responsible research, production, and use of nanomaterials, they will fail to reduce risks and respond to public concerns, unless they become mandatory. The public’s understanding should not only be limited to application potentials and future opportunities (which in most occasions have not achieved the status of expectation and are simply just assumed) of the new technologies/materials but particularly on their actual risks. The potential of nanotechnologies to transform the social, economic, and political landscape makes it essential that the public fully participate in a deliberative decision-making process. Public research programs need to play an important role in providing greater incentives and encouragement for nanotechnologies that support sustainable development and do not endanger humanity’s well being in the long-term. The existing imbalance in funds allocated to nanotech research needs to be corrected so that impact assessment and minimization and not only application come high in the agenda. Not only the specific project devoted to collect information on the nanosafety procedures but all the new projects receiving EU funding should be required to include a sustainability assessment and appropriate decision-making mechanisms, including public participation. The participation of citizens and transparency in the way public money is spent in developing emerging technologies. In particular, focus should be given to the needs of the poor and not just at improving national
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corporate competitiveness in nanotechnologies. Universities and Research Institutes receive much of their funding for nano-research through government programs and, to a lesser extent, through partnerships with the private sector. Much of this funding goes to research that supports corporate interests and improved quality of life in developed countries. On the contrary they could play an important role in managing innovation to ensure that developing countries can reap the benefits from publicly funded research. The process of democratization of nanotechnology is part of the responsible development of this new technology; over the past decade nanotechnology has been the subject of a large number of public engagement exercises although the impact on the government policy has been minimal (Cormick 2012). The complexity of the public engagement, the identification of stakeholders, the right way to elaborate the process to obtain an informative opinion not only from engaged people are all difficult tasks. The ways to have constructive contribution from non-expert in science policy decision are numerous, finding of communicative tools to obtain informative opinion is a science apart (Stirling 2012) that need specific application within the peculiar contest of nanotechnology. On the other hand, over the rights to have part in the decisionmaking process, the views of non-expert, often raises questions and a new understanding of a topic useful to consider more fully the scientific evidence. However, it is difficult to establish who really represents the public interests, the more simple approach to this issue is to extend at different stakeholders, consumers and citizen the faculty to contribute to the decisional process. Thus, the policymakers should consider the contribution for nanotechnology programs not only by experts directly involved in the development of this new technology that tend to enphasize to positive perspectives rather than consider the detriments originating by unknown toxicological risks. To promote a correct exchange between science and society, the scientists must be prepared to produce programs not only scientifically valid but also communicable to the people with diverse backgrounds or without specific scientific knowledge. Access to funding should be considered for proposals that adequately address a shared need, scientific objectives must be translated into a layman language to be understood by nonexperts. According to this concept several experiences
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have been proposed in the nanotechnologic field, as reported by Tourney (2011) the public engagement with nanotechnology it is a difficult test of democratization of science but remains one of the best laboratories creating ways for non-experts to have constructive role in science decision policy decision. In order to meet human development, it is important to anticipate the impacts of governmental and commercial policies through the active involvement of civil society and the public in any discussion related to nano-developments. As indicated by Morris et al. (2011), the responsibility addressing the information resides with those who produce nanomaterials as it does with those who regulate them. Those who manufacture and market nanomaterials to play a leadership role in tasking action to anticipate and minimize any potential negative impacts on humans and environment by controlling releases or identifying or eliminating those material properties that may produce adverse environment impact. Although some of the potential benefits of nanotechnologies may be years away, the technology is usually controlled by developed countries and multinational corporations, for example through patents and conditions in technology licenses that primarily benefit consumers in the North and lead to a deeper divide between developed and developing countries. Two of the main area of application of nanotechnology are the medicine and the environment, however, the principles of meaning, sustainability, precaution are specifically considered for this area to protect human and animal health and environment. The principles mentioned above were also exploited by Magnette, the Belgian Minister for Energy, Environment, Sustainable Development, and Consumer Protection, (EU Conference 2010) that proposed to create a specific register for nanomaterials under the Registration, Evaluation, REACH program and to implement mandatory labeling for nanomaterials used in consumer products. According to Magnette, the next European Environment and Health Action Plan is expected to address the challenge of nanomaterials among its priority areas. In 2011, the European Commission (EC) must also respond to the April 2009 European Parliament (EP) resolution on the regulatory aspects of nanomaterials. The resolution calls for various ‘‘ambitious’’ measures to ensure safety with regard to nanomaterials and nanotechnology (Magnette 2011). Magnette put forward five
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proposals from the Belgian Presidency of the European Union (EU) that are intended to respond to consumer needs while ensuring their safety: 1.
2.
3. 4.
5.
define the obligation to inform the consumer of the presence of nanomaterials in consumer products; ensure the traceability of the chain so as to be able to return to the source, if necessary. Regarding this aspect, it would be obligatory to maintain a register of nanomaterials; identify the most appropriate regulatory path at the EU level for risk evaluation and management; encourage member states, during this transitory period, to take up the responsibility and draw up integrated national strategies and concrete measures in favor of risk management, information, and monitoring; and regulate the claims made on labels of products containing nanomaterials.
Nanomedicine an important support The application of nanotechnology in health care defined nanomedicine and more recently for a specific area involving biological systems nanobiomedicine offer new opportunities to improve medical therapies and diagnosis in all relevant pathological conditions including cancer, cardiovascular, and neurodegenerative disorders. As in the other fields, the availability of nanomaterial in different forms could have a revolutionary impact for the treatments and diagnosis. The nanomaterial might give new tools for the control of drug target delivery of multi-tasking medicines, imaging diagnosis, tissue replacement, and surgical aid (Cattaneo et al. 2010; Burgess et al. 2010; GarciaBennett et al. 2011; Menjoge et al. 2010). Although only few formulations are commercially available now, 43 nanomedicine are in European Medicine Agency (EMA) pipelines and 800 clinical trials using nanoproducts are ongoing. Drugs and diagnostics based on nanoparticles also present challenges for regulatory agencies such as the US Food and Drug Administration (FDA) and the EMA, which do not yet have specific guidance documents for nanoparticles per se, but have published recommendations on the subject. Existing medical regulations are expected to apply to nano-enabled drugs and diagnostics, but
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additional regulations, which consider their applicability to nanoparticles, may be required. However, in this contest the nanomedicine is considered for the essential support that can give to the nanotoxicology in terms of biological consequence of the exposure to structured nanomaterial (Fadeel and Garcia-Bennett 2010). The most advanced research applications are in the cancer therapy but also the area of tissue regeneration can be substantially improved with nanostructures surface/scaffolds. For instance, the ratio risk/ benefit is normally evaluated in the pharmacological approach as well as in all medical practice. All the various aspects influencing the biological activities of nanomaterials need to be carefully considered when therapeutic or diagnostic properties are investigated (Nijhara and Balakrishnan 2006). Either experimental or theoretical models developed in nanomedicine can give some pieces of information to better understand the toxicological consequence of the exposure to nanomaterials. The close collaboration between pharmacologists and toxicologists can be extremely productive in the evaluation of models in the pharmacodynamic/pharmacokinetics of nanoparticles although the aim could be the opposite to show efficacy in the drug delivery or, on the contrary, to exclude biological consequences due to nanomaterial with different use. This approach has been developed in the FP7 project Nanotest, the authors stated that to better understand of how properties of NPs define their interactions with cells tissues and organs in exposed humans is a considerable scientific challenge, but one that must be addressed if there is to be safe and responsible use of biomedical nanoparticles (Dusinska et al. 2009).
Nanocode project Within the frame of ‘‘NanoCode: implementing the European Commission Code of Conduct for Nanotechnologies on responsible N&N research’’ It has been recently published the synthesis report provides the findings of the international, quantitative and qualitative NanoCode survey about the European Code of Conduct for Responsible Nanosciences and Nanotechnologies Research (EU-CoC). The results summarized in this report give insights into stakeholder’s patterns of awareness, their expectations, attitudes and appraisals. The survey analyzes the
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degree of compliance and commitment, identifies recommendations for the communication, possible incentives, disincentives and monitoring of the EU-CoC. 304 European and international experts contributed to the NanoCode survey between August and October 2010. Furthermore, about 150 experts had been involved in qualitative interviews or focus groups in the different countries between October 2010 and January 2011. A large part of them were involved in academic research (62 %), 16 % in business and the other belong to the institution or civil society. According to the report with respect to this large and inhomogeneous sample, the results offer a surprisingly unambiguous tendency. Large percentage of experts considered to NanoCode initiative an appropriate instrument for encouraging a dialogue about health, safety, environmental, ethical, social, and legal issues. Despite that only 20 % of the participants stated that their organization adopted a code. The principles of accountability, inclusiveness, precaution and sustainability need to be revised for a large part of participants. For several governments and organizations, a revision of the content and wording of the EU-CoC were identified as a precondition for further engagement and possible future adoption of the EU-CoC. In general a minimal percentage of subjects knew about NanoCode and among them, very few have been involved personally to take part in the debate about the EU-CoC. A closer view to the broader French sample delivers some explanations. Here, the majority of participants could be described as ‘‘normal’’ scientists in the labs, universities, research institutions and companies and not as central key experts. In this broader group of participants from all stakeholder groups—by the way the primary target group of the EU, which should apply the EU-CoC in practice—the level of awareness went down to about 30 %. Counting the type A-country results without the broader French sample, the awareness increased up to an average of 84 % (58 out of 69); in countries such as The Netherlands and Germany nearly each of the participants knew the EU-CoC. Only in the group of key experts from the International Organizations and from Typ A-countries (with an extense nanotechnology programme) who had been closely involved by the EU-Commission the level of awareness of the Code of Conduct could be described
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as sufficiently high with about 70 % who really know the CoC. The lack of communication between the European Commission and the governmental bodies in the Member States and, in the next step, between the Member States’ governments and the national key experts has to be considered. Without an improvement of the awareness and appropriate communication strategies for different target groups compliance will be fairly difficult to achieve. Seven principles have been proposed meaning, sustainability, precaution, inclusiveness, excellence, innovation, and accountability. Six of seven principles received an agreement of more than 80 %. Interviewees agreed most with the principles of sustainability (90 %) and excellence (90 %). Only Accountability and Inclusiveness raised some opposition. Thereby, 52 (17 %) of 296 respondents disagreed rather or strongly with the principle of accountability. 11 % disagreed with the principle of Inclusiveness. Several criticisms on the concept of accountability have been raised in all countries considered. Compared to accountability, only slight disagreement was received for inclusiveness (11 %). Interviewees substantiated that an inclusiveness of stakeholders and their concerns could be more appropriate for companies than for basic researchers. About the recommendations from the survey participants, it is interesting to note that about half of them wished a better balance of risks and benefits in the EU-CoC’s principles. This concept rose by stakeholders make in evidence what we mentioned at the beginning about the necessity to consider the final destination of the nanoproduct. The necessity to be more specific in the EU-CoC has been raised by more than two-third of participants; the EU-CoC is too general and needs specific guidelines for different fields of application. One national group suggested to distinguish among embedded structures, nanostructures, nanostructured materials and nanomaterials. The subjects in favor of a more specific approach one-size-fits-all indications has some risk in terms of communication and innovation of nanotechnology with no effects on the target group. On the other hand, another group of participants recommended almost the opposite in the sense that sustainability, precaution, inclusiveness, excellence, and innovation should not be restricted to the nanotechnology. The thesis is that specific CoC for
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nanotechnology is not necessary since all research need to be developed in a precautionary way. Both opinions need to be considered but in a relatively simple way, we can interpreted the apparent opposite indications with a general adhesion to the principle of responsible science that for the nanotechnology field can specifically declined in the EU-CoC. Several suggestions have been made on the possibility to improve awareness and communication, the details can be find directly in the report, here I would like to underline that an improvement of the awareness is strongly recommended. More than the half of the participants are convinced that EU-CoC should have ‘‘teeth’’ in terms of sanctions and penalties in the case of not compliance. However, a very large number of participants are also in favor of an elaboration of a strategy of incentives rather than to do pressure only with disincentives. Apparently is also popular the idea that the encouragement of a good practice would be more useful than penalties, the carrot better than stick approach. In terms of incentives the publication of list of subjects, research/institution who have complied with the EU-CoC principles and guidelines, a ‘‘EU responsible’’ label has been proposed to certificate the best practice. However, the monitoring and the developing the ‘‘teeth’’ have been also considered as essential for a correct development of the nanotechnology field. In fact only 19 % of the participants disagreed that the EU-CoC would need ‘‘teeth’’. It is obvious that the adoption of ‘‘teeth’’ is in contrast with the voluntary character as it has been designed by the EU originally. As indicated in the report if the destine of EU-CoC is to remain voluntary, the concept and wording has to be reviewed with care in order to avoiding wrong expectations. In my opinion, the voluntary character of the EU-CoC must be maintained in an initial phase but the evolution in a mandatory rules is the natural development that characterize the passage from a pioneer period when the recommendations need to be tested in the practice and an efficient level of monitoring and control of the procedures according to clear guidelines. The point is to establish the duration of the first period and when we can pass to a mandatory regiment. The web-based communication is strongly considered an adequate tool to improve a structured informational exchange and as a monitoring system by the survey participants: in conclusion, the participants identified the EU-CoC as a relevant instrument for a complementing regulation and for
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encouraging a dialogue about health, safety, environmental, ethical, social, and legal issue. All these single aspects associated to the research in nanotechnology need to be adequately improved while EU must take some decisions on the specific/general and voluntary/mandatory in a short time, to give the appropriate direction at this important instrument.
Institutional activities Numerous voluntary and mandatory programs have been developed to provide information on the use, diffusion and potential risk associated to nanomaterials. The US National Nanotechnology Initiative (NNI), announced in 2000, kicked off the funding boom: federal spending jumped from US$ 464 million in 2001 to nearly $1.8 billion in 2011. China, Germany, Japan, and Korea soon followed in setting up national nanotechnology programs, and the European Union (EU) designated nanotechnology as a research priority in 2002. More than 60 countries now have national nanotechnology programmes. The European Chemicals Agency (ECHA) is compiling an inventory of nanomaterials included in the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) registration dossiers and Classification, Labeling, and Packaging (CLP) notifications for the European Commission (EC) in response to the 2009 European Parliament communication on nanomaterials. The detailed results from the inventory would be available from the end of 2011, and the inventory may be disseminated at a later date, but this has not yet been discussed. According to the ECHA has found three registration dossiers and 14 CLP notifications in which ‘‘nanomaterial’’ was selected as the form of the substance. The ECHA will be able to identify 50-60 REACH registration dossiers that include information on nanomaterials that will be sent to the Joint Research Centre for assessment under a separate project to address if and how information on nanomaterials is included in REACH registration dossiers. Furthermore, three REACH implementation projects on nanomaterials devoted to are on going. The US Environmental Protection Agency (US EPA), in conjunction with the UK Environmental Nanoscience Initiative (UKENI) are developing a program devoted to identify: (1) integrated model(s) of fate, behavior, bioavailability and effects for several important and
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representative nanomaterial classes over key environmental pathways using intrinsic material properties and life cycle analysis as a starting point for model development; (2) validate and refine these model(s) through interdisciplinary research, addressing key assumptions and areas of uncertainty; and (3) develop effective methods and tools to detect, assess, and monitor the presence of nanomaterials in biological and environmental samples. The outputs of this program will be used to further scientific understanding of the fate, behavior, bioavailability, and effects of nanomaterials and risk management policy development. According to my suggestions indicated in the above paragraphs this program can be implemented on the basis of updating ‘‘safety form’’ collecting all the relevant information useful for a risk assessment for each new nanomaterial or application as well as already commercialized nanoproducts.
Conclusions The nanotechnology is an innovative area of research and development that can find application in almost all essential aspects of our life, numerous examples are already on the market. The success of nanotechnology has not been associated with a parallel development of the adequate methodology to assess and manage the risks connected to the application of nanostructured material. Nanomaterial traceability, registration of the products and the evaluation of the exposure, are fundamental elements for an adequate surveillance. It can deliver specific objectives like supporting manufactures to who take responsibility for their products. Responsible nanotechnology innovation involves enforcement into practice, research strategy should consider as a priority the elimination of knowledge gaps instead of promoting technological application only. A roadmap towards the safer development and use of nanomaterials in their different applications should be developed and implemented. A possible initial solution is the creation of a mandatory preregistration process for new nanomaterial considering the intrinsic properties and application (diversity and similarity from the previous material and area of application), availability of toxicological information on the analogs, the potential exposure and/or environmental dispersion and persistence (total amount and fate during the entire life-cycle) and the real
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benefits deriving from the use of the new nanomaterials. If the four aspects do not give sufficient guarantees of relative tolerability, a specific study must be produced to allow market access of the new material. Similarly a safety form based on the same concepts can be progressively prepared by the producers for all the nanomaterials already on the market. Further sustainability assessment of technologies tools must be developed, for their more systematic use in both research and product development, these instruments will be used to extend and improve the risk assessment requirements. The public authorities should organize public participation initiatives that seek public opinion on the development and use of nanotechnologies, to get a clearer understanding of which, if any, specific technologies (their impacts, benefits, etc.) are acceptable to society and to act on these opinions. Such initiatives are also needed to help shape the governance structures within which future decisions affecting nanomaterials development will be made, including public involvement and decisionmaking in guiding research and research funding by identifying what is acceptable and beneficial. Only a combination of efforts by the subjects with responsibility, researchers, public authorities, manufacturers together with the workers organizations, environmental and consumer association and all the stakeholders can adequately address the challenge of complexity proposed by nanotoxicology.
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