Introduction

Nanotechnology (NT) is simultaneously an emerging field and one which is converging with other fields. From smaller and faster computers, more accurate medical diagnostic devices [1] and implants to resist infections [2], to stain/water/fire-resistant fabrics [3] and cell-specific drug delivery [4], NT is changing everyday human life for the better. It was estimated that NT market will reach an average growth of 33% between 2002 and 2020 [5], while worldwide patent applications increased tenfold in the first decade of the twenty-first century [6]. Due to their small size and large specific surface area, nanoparticles (NPs) have unique properties which distinguish them from other substances. However, there are concerns that these properties, in combination with the increasing use, could potentially result in occupational, end-user, or environmental risks. As such, identifying and disseminating the risks arising from exposure to hazardous NPs is pivotal.

The application of risk assessment (RA) to nano-enabled products is hindered by uncertainties in terms of NPs’ physicochemical and toxicokinetic properties, environmental fate and transport, exposure dose and (eco)toxicity through the product lifecycle [7]. While research in nanotoxicology has grown, interpreting and conveying the findings to non-experts remain problematic [8]. It is essential to understand the benefits and risks in order to present them to authorities, suppliers, clients and other stakeholders in a coherent way. These uncertainties of risks, economic viability and social impacts could inhibit the realisation of the potential of NT research and development [9]. This is also an ethical issue in that we will see the potential to reduce harm being held back due to sub-optimal protocols inherent in decision-making tools. To draw from meta-debates in the field of applied ethics, frequently, the decision-making tools are not sufficiently nuanced (virtue ethics) to provide an accurate summation of downstream effects (utilitarianism) of the novel products introduction. To date, few RA frameworks and tools relevant to the needs of small and medium enterprises (SMEs) have been developed. Certain tools combine hazard and exposure into control or risk bands, an approach pioneered within the pharmaceutical industry to address early-stage development compounds for which little or no data exists [10]. Brouwer [11] and Sánchez Jiménez [12] compared several RA control banding tools, while Hristozov et al. [13] provided a comprehensive review of frameworks and tools for nano-materials (NMs) RA. Grieger et al.’s [14] evaluation of various risk analysis frameworks for NMs concluded that most were primarily applicable to occupational settings with minor environmental considerations. Subramanian et al. [9] compared five NT frameworks and concluded that integrative assessment using risk analysis and multi-criteria decision analysis could provide decisional tools for NT problems. A decision analysis integrating a bottom-up tool like RA and life cycle assessment (LCA) within a framework, determined by stakeholder needs, was also proposed by Subramanian et al. [15]. A tool that enables SMEs to scan the benefits and risks of NMs at an early stage of decision-making in order to develop sustainable and competitive products is used in this paper [16]. Specifically, the LICARA nanoSCAN (where LICARA stands for life cycle assessment and risk assessment) compares the benefits and risks of emerging nano-enabled products against a reference product to facilitate the development of competitive nano-products. Risks to the public, workers and consumers are assessed, while the benefits are evaluated for economic, environmental and societal opportunities. The SUNDS-tier 1 (due to data gaps) was applied to real-life case studies of new nano-enabled industrial products.

Risk is an inherent part of every activity which must be assessed, and unacceptable levels of risk are mitigated to allow progress. While risk can take many forms, the focus here is the potential risks to human health within the field of NT and how it is approached within the context of extant decision support systems (DSS). The characterisation and assessment of risk, within the broader issue of health and safety, has long been derided as a limiting factor in progress and innovation, yet its purpose is to enable. The understanding of potential risks allows them to be dealt with and the endeavour to proceed safely without consequences. However, RA needs to operate properly just as any component of a machine or wider aspect of a production chain, and where it operates improperly, it can be a limiting factor. We define risk management (RM) as the identification, evaluation and prioritisation of risksFootnote 1 followed by coordinated and economical applications of resources to minimise, monitor and control the probability (or impact) of adverse events or to maximise the realisation of opportunities. Effective RM is both proportional and targeted, while ineffective RM is disproportionate or non-targeted. Where the components of risk, namely hazardous nature and exposure, are well defined, risk can be managed effectively, but where the components are not fully characterised (i.e., data gaps), it is prudent to take a precautionary approach. This means that one should consider a suitable margin of safety to address any unknowns and within the remit of risk, considering that a material may be hazardous or at high levels of possible exposure. This should be updated based on relevant data on exposure (measured or modelled exposure scenarios) or toxicological analysis in in vitro and in vivo systems, or computationally [17]. The implication is that by taking a precautionary approach, unacceptable levels of risk are avoided. This precautionary approach is implicit within the field of NT, just as it is in any technology with data lacunas [18], and the resultant uncertainty gives rise to a de facto conservatism in risk treatment. As noted, effective RM is proportionate, meaning the socioeconomic cost of the RM is proportionate to the risk. Where the precautionary principle promotes approaches that are disproportionate, this can result in excessive institutional caution and the suppression of innovation [19,20,21,22,23,24,25].

Data gaps in the field of NTs are well documented [26,27,28], and their introduction into DSS tends to short circuit the decision-making process. In effect, the process is stalled in the early data-contingent stage of a continuum. At this stage, precaution becomes the main consideration with a more balanced utilitarian approach held in abeyance until information on NMs increases in granularity. There is an opportunity to develop new methods of analysis and assessment that are more succinct and economical in capturing and elucidating the challenging socio-technological use cases of NMs. Such methods need to adapt to the specific use cases of NMs to identify and assess the context-specific benefits and risks as they arise in particular risk/governance fields and in a form that is communicable. In other words, more metricised thinking which attempts to factor in future welfare tradeoffs is postponed. Sheskin and Baumard [29] used the term “utility calculation” to signal this set of relationships. From the field of law, Posner [30] wrote of “utilitarian’s need for dependable metrics”. Here we employ the term utilitarian to describe the classic method of assessing future outcomes as seen in such schematics as the “trolley problem” and its many variations [31]. Implicit here is the notion of calculus and its association with Bentham. The data lacunas have the potential to deny an opportunity to use methods of analysis and assessment that are succinct and with an economic grounding to capture and elucidate the challenging socio-technological use cases of NMs. Such methods need to adapt to the specific use cases in order to identify and assess the context-specific benefits and risks as they arise in particular risk/governance fields and in a communicable form.

A symbiotic correlation exists between the concepts of risk and ethics. RM concerns the distribution of risk among stakeholders, and risk toleration is an important part of any Risk Governance (RG) regime. In terms of technology development, there is a consensus regarding the need to create robust RG regimes which encapsulate standards of responsibility and sustainability. Ethical apparatus operates in both cases. The development of NT is one branch of emerging technology that has stimulated a particular focus on the ethical underpinnings of RG regimes. In the European context, this has been reflected in research calls in the NT discipline, which have informed a number of sizable cross-European research consortia [32, 33] and increased academic journal outputs [9, 34,35,36,37]. While there has been substantial progress in fields such as nanotoxicology, certain problems continue to impede stakeholder abilities to accurately assess risks to both humans and the environment [38,39,40]. For instance, there are still conspicuous gaps in regulatory regimes, the science on the properties of many NPs, and there is an absence of credible curated data sets [26, 41]. There is also a widespread public perception on the need for caution. As a principle stakeholder in this area, the insurance industry believes that prevailing academic confusion and discord have inevitably problematised their ability to formulate accurate risk metrics for NPs related activities [42, 43]. Therefore, it is self-evident that a more nuanced and adaptive approach is needed, and this discussion focuses on the SUNDS system.Footnote 2

From Precautionary Principle to Hybrid Approaches

The industrial, commercial and societal benefits represented by the new scientific age of NTs are often vaunted as integral to human progress. NT carries a complex societal risk phenomenon in terms of the uncertainty and knowledge deficit. As such, the types of RA which have traditionally informed decision-making protocols have proved inadequate because they lack sufficient malleability and adaptability to capture and respond to the risk phenomenon. In light of this, the fluctuating scenarios regarding a lack of regulation and technology impact assessments have increasingly been identified as both a political issue and a meta-ethical philosophical conundrum [44]. Moreover, NT creates further uncertainty because, at the nano-scale, materials can behave differently to that of the parent material both in terms of its physicochemical properties and interaction with biological systems. Such uncertainty drives the need for a precautionary approach, often manifested in the use of large “uncertainty factors” [45]. This stymies conventional verification processes and the regulatory basis of causal relations to assess, validate and roll-out key concepts such as responsibility and accountability. The most apparent challenges involve accurately assessing the NM risk phenomenon. While there are commonalities with other risk mitigation regimes, there are also significant differences to be considered where a piecemeal context-specific approach is often required.

Nano-ethics is also challenged by the complexity of the nano-scale phenomenon, where the scope and lack of verifiable causal chains feed into the contentious realm of individuated responsibility and accountability. This addresses the problem and challenge of “many hands” [46,47,48,49]. When adverse outcomes arise as a result of errors in foresight or anticipating risks, questions of responsibility [46] and accountability [48] are inevitably raised but seldom answered. This speaks to an intrinsic tension between lack of accountability and moral responsibility, which arguably undermines both bottom-up and top-down decisional frameworks.

In light of the identifiable challenges to both top-down and bottom-up frameworks of responsible decision-making, we contend that a hybrid decisional approach that extends beyond the simple application of the precautionary principle is required. At the very least, such an approach would better inform decision-making in terms of the risk/benefit framing. A hybrid decision matrix would offer a layered relational model of strengths and weaknesses regarding framing and possible use of NT, which may take account of knowledge deficiencies and any absence of data. Moreover, it would effectively harness the ability to factor in multiple methods in new ways as methodological clusters formulated to adapt and more accurately capture context-specific risk relations. This allows a more robust and informed response that potentially avoids the danger of short-circuiting the RA process which can occur in systems driven by the precautionary principle. While forms of hard governance, such as policy and regulation, and soft governance, such as nano-ethics and technology assessments, may be limited, they offer valuable components to the decision-making process. Both are equally beneficial in introducing and contextualising general ideals of the precautionary principle, responsible research and innovation to formulate a process of informed decision-making. That said, the risks presented by unregulated technologies, which lack adequate research and consensus, underscore notable concerns. This phenomenon may be more accurately rehearsed by constructing a case and context-specific decision matrix informed by both top-down and bottom-up framework considerations.

The precautionary principle has become increasingly topical and popularised for a number of reasons, including the framing of high-profile global risks such as climate change, genetically modified organisms, gene editing and the use of chemical agents. The increasing observance of the principle may also be attributed to the changing social landscape regarding traditionally paternalistic state or top-down forms of government. The changing political climates, environmentalism and a better-informed polity of recent decades have instantiated the formation and dominance of new governance models. This is most striking in EU stipulations which enjoin RG to comprise a multi-stakeholder format of decision-making regarding regulation, policy and state governance. The benefits of such approaches reside in their facility to synthesise numerous divergent contributions into a highly-informed legislature support structure. In many ways, it is this alignment of creating a forum of knowledge-informed decision-making which has strengthened the appeal of the precautionary principle since its framing mechanism inherently incorporates the driving values of care and caution when tackling data gaps, scientific limitations, opposing views, lack of consensus or uncertainty [50].

Steel purports that the precautionary principle essentially aims “to promote timely and reasonable responses to serious threats to health and the environment even in the face of substantial scientific uncertainty” [45, 50]. This emphasises the need to step back from the context of politically weighted criticisms and consider the principle in terms of a guideline towards informed decisionality. In any event, this does not offer effective responses to the criticisms laid against the precautionary principle, partly because it is generally held as a means to counter uncertainty. This paper argues for the need to factor in uncertainty in framing the context, as the uncertainty of NT is more complex, multifaceted and novel than is usual, and mere regulation and governance cannot provide timely response to this innovation [51] let alone overcome its ontological and temporal challenges. Such shortcomings must not lead to the adoption of a watered-down precautionary principle methodology: on the contrary, we maintain that more nuances are required. Thus, this paper advocates for the adoption of supplementary protocols that can ultimately reinforce good governance and avoid a repressively conservative approach to the roll-out of NT. While there is as yet no definitive or accepted definition of the precautionary principle as a general motif of care, we posit that when appropriately contextualised to a given technological application or scenario, it can act as a powerful decision tool. Without contextualisation, however, the precautionary principle can be misconstrued as weak.

Materials and Methods

The development of antibacterial medical textiles is currently on the rise since there is a growing need to treat infected patients and prevent hospital-acquired (nosocomial) infections and community-acquired transmission of infections to non-infected populations [51, 52]. Such infections cause death, trauma, recurrent loss of work hours and longer patient stay following surgical procedures, with the concomitant loss of billions of euros every year. The literature underscores the adverse effects of nosocomial infections on patient outcomes, the difficulties in decreasing the incidence of such infections and the considerable clinical and economic benefits of potential reductions [53,54,55,56]. Within this context, a DSS on assessing infection restraining technologies, such as NTs, and potential benefits is essential. However, the absence of precise hazard, exposure and functionality data on NPs used in DSS could distort and protract the process [57, 58]. The integration of antimicrobial inorganic NPs into medical textiles is one of many promising strategies to ensure aseptic conditions in hospitals [59]. There are risk and ethics issues that arise; thus, the inclusion of relevant criteria in decision-making tools is to avoid a default to the precautionary principle.

Nano-silver NPs (AgNPs) are widely used antimicrobial agents incorporated in functional textiles such as socks, shoes and bandages [60, 61]. However, the leaching of silver ions raises hazard concerns on environmental risks and safety at use [62, 63] as studies have reported low efficiency and low washing stability, particularly within high-temperature hospital laundry regimes [64]. Alternatives for AgNPs are now emerging as antibacterial agents, such as titania (TiO2), silica (SiO2) or zinc oxide (ZnO) [61]. SONO (http://www.fp7-sono.eu/), an EU-FP7 funded project (2009–2013), demonstrated the production of antimicrobial fabrics based on the sonochemical process for silver alternative coatings. The products were tested in hospitals with high efficiency for prevalent hospital bacteria [65]. The fabrics retained their efficacy after 100 washing cycles at 75 °C, a feature rarely achievable by products functionalised with AgNPs [66, 67]. Based on SONO technologies, another EU-funded project, PROTECT (http://protect-h2020.eu/), is working on up-scaling and marketing a one-step reproducible process based on sonochemical techniques for biocompatible antimicrobial nano-coating surfaces of products such as textiles and upholstery fabrics for public areas such as hospitals.

The case study investigated here refers to textiles and upholstery fabrics intended for public areas and hospitals produced under the PROTECT (http://protect-h2020.eu/) project. The products are coated with inorganic oxides (ZnO, CuO) (case I), mixtures of doped metal and metal oxides, e.g. TiO2-shell/SiO2-core, Zn0.89Cu0.11O and gallium-doped carbon dots (Ga@CD) (case II) and conjugated organics polymers (polypyrrole, PPy) (case III). These NPs are used to obtain biocompatible nanostructured surfaces with enhanced antimicrobial properties and without analogue at the market, aiming at the control of bacterial contamination and infection transmission.

The production lines comprise of two one-step antimicrobial finish processes, namely, a sonochemical continuous roll-to-roll (R2R) and a spray R2R coating technique (Fig. 1). Compared to main existing manufacturing routes, the one-step coating technologies are simple, fast and reproducible. More information on the implemented technologies can be found in [68,69,70,71].

In Fig. 1, the case study is presented comprising of the two sonochemical technologies and the NPs used to create diverse products such as functional textiles (bed sheets sets, pyjamas) and upholstery products such as carpets and curtains. The combination of coating technologies with different NPs results in six different cases to be tested with the DSS. Three cases regarding the R2R sonochemical coating for each NP category (sonochemical cases I, II and III) and three cases for R2R spray (spray cases I, II and III). Each case is characterised by its hazard classification and manufacturing technology.

The NPs are categorised according to the hazard classification bands in Stoffenmanager Nano and the NP list therein [72]. The hazard bands are labelled from A to E, with A standing for the harmless ones and E for the most harmful based on toxicological data and information regarding the parental material. The NPs list includes involved in the test program under the OECD Working Party on Manufactured Nanomaterials [73] supplemented by NPs included in other studies [72]. As no sufficient toxicological data are available currently for a thorough hazard assessment, the NP hazard banding in Stoffenmanager Nano is based on the limited data reported by the OECD (by using expert judgment) or based on the hazardous potential of its parental material [72]. These NPs are assigned to relatively high hazard bands (C through E). For NPs that are widely used, partly characterised and the parental material is not classified as CMR, hazard bands D or C are proposed depending on particle size. Hazard band C applies when the primary particle diameter exceeds 50 NP and hazard band D for smaller particles. NPs are assigned to hazard band E when their parental material is classified for carcinogenicity, mutagenicity, reproduction toxicity or sensitisation. In all other cases, hazard band D is applied. If the parental material is not specified, hazard band E is assigned for precautionary purposes.

In our case, ZnO and CuO were grouped into inorganic oxides with harmful and irritating inhalation hazards (case I of Stoffenmanager Hazard band B). Regarding TiO2-shell/SiO2-core, Zn0.89Cu0.11O and Ga@CD components, SiO2 and ZnO are included in the above mentioned list. However, the inhalation hazard is unknown, and their particle size is below 50 nm. Therefore, they are grouped into case II of Stoffenmanager Hazard band E. Finally, although included in the Stoffenmanager list, polymers were assigned a different category with sizes above 50 nm, getting a lower hazard score. Polymers in our study belong to case III of Stoffenmanager Hazard band D.

The Decision Support System: SUNDS-tier 1

The DSS applied here (SUNDS, https://sunds.gd) is a software tool created in SUN EU-funded project (http://www.sun-fp7.eu/). The software-based system is accessible online and facilitates early-stage framework design through a user elicitation process and inclusion of criteria preferences in the decision-making [9]. SUNDS includes two different DSS, one for RA of NMs used in consumer products and the BIORIMA DSS for RA of nano-biomaterials used in medical devices and advanced therapy medicinal products (ATMPs). In this article, we refer to the former. In cases of limited data, SUNDS-tier 1 is used to screen out worst cases and refine further research and development on best practices and uncertainties. In addressing new coating technologies and materials, we used SUNDS-Tier 1 to bypass data shortage concerning human and environmental toxicity. SUNDS-tier 1 comprises LICARA NanoSCAN [16], a delimited screening-level assessment tool used to assist an SME in checking competing products through a risk/benefit analysis. The tool provides a semi-quantitative evaluation of the environmental, social and economic benefits of the product, along with any ecological, occupational or consumer health risks [16]. LICARA circumvents issues of uncertainty by factoring in the sensitivity of missing parameters in the decision model through a modular process. In brief, Tier 1 comprises six benefit and risk modules which are integrated on a final, two-dimensional benefit-risk scale, which is divided into four quadrants. A detailed description of the modules can be found in the analysis by van Harmelen et al. [16]. This tool is designed for assessing one NM at a time. Stoffenmanager Nano applicability was previously evaluated via four NPs activities for their risk level and potential control schemes [74], while Zalk et al. [75] addressed twenty-seven actual industrial activities. In addition, Stoffenmanager Nano has been tested in industrial workplaces studied in the EU-funded SCAFFOLD project (http://scaffold.eu-vri.eu/). Overall, the tool performed well when validated against expert judgement. However, some uncertainties in the application, e.g., the complexity of a construction environment, were not addressed, and additionally, hazard uncertainty, e.g., particle size relevant toxicity, was obscured under defaulting worst-case scenario.

The single scores for each benefit and risk module are derived from an average of the scores of a number of sub-module relevant criteria. As uncertainty is treated conservatively by assigning worst-case scenario values, the assignation of the worst case scenario inevitably results in the distortion of DSS. It is this decision-making routine that is problematic from a wider ethical standpoint. The assignation of the worst-case scenario effectively short-circuits proper discussion about the merits or otherwise of introducing novel approaches to production processes. Limiting, for instance, occupational exposure due to new manufacturing practices for materials of no scientifically established cause-effect relationships has no differential effect to the assessment results under the precautionary principle; unknown hazards still impose the worst-case scenario. The seventh box captures consumer health risks estimated in order to assess exposure potential, exposure routes and hazard-based upon parts of NanoRiskCat (http://nanodb.dk/en/nanoriskcat/). Information about the hazard of the NM is taken from Stoffenmanager Nano, as specified in the fifth box. Finally, the exposure and hazard levels are scored for LICARA nanoSCAN following the hazard/exposure figure shown below.

Hence, to evaluate both the benefits and risks of the nano-product, it is assumed that each benefit and risk category is equally important, presented in a graph where each is being represented on its own normalised axis (Fig. 7). It should be noted that the benefits on the horizontal axis are net benefits, indicating that the nano-product is an improvement over the conventional product. If the nano-product has fewer benefits, the indicator falls out of the benefit-risk square, meaning that it does not seem worthwhile developing this product further from a benefit-risk point of view. The error bars represent the incompleteness of the analysis, indicating the possible minimum and maximum score due to the ambiguity added by unanswered questions. The input information used in SUNDS-tier 1 and Stoffenmanager Nano tool are presented in detail in Tables 1 and 2. The input variables are derived from information contained in PROTECT project reports regarding analysis of market potential, business plans, toxicological hazard estimation through in vitro studies, exposure estimations and environmental impact assessments.

Table 1 Input variables for SUNDS-tier 1. The inputs values correspond to both sonochemical technologies and case studies scenarios
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Table 2 Stoffenmanager-nano input variables for three source domains: manufacturing, processing and application. Input variables are defined for the different NP cases used and the two sonochemical categories
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Results

The argument presented here is a nuanced one around the operation of the precautionary principle in the area of NM risk. We are not arguing against the principle per se, nor do we reject it in favour of a regulatory orientation more in line with the politics of laissez-faire. Rather the argument we seek to make is that the operation of the precautionary principle can impact decision-making in an arbitrary fashion and that in terms of temporality, the triggering of the principle in the context of scarce data can lead to framing effects on the overall RG process. The risk resides in the fact that by defaulting to the precautionary principle too early, users may lose NT benefits due to an abundance of process and caution (Fig. 2). The benefits and risks are presented for each of the three main categories (dark-coloured bars) and their underlying issues (light-coloured bars) in Figs. 3, 4, 5 and 6. The dark-coloured bars are averages of the underlying scores of the light-coloured bars assuming that each underlying issue is equally important. Exceptions are occupational health risks, where the worst underlying risk is taken as an overall occupational risk score.

Fig. 1
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The case studies investigated in this article

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Fig. 2
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Exposure and hazard levels scores of LICARA nanoSCAN

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Fig. 3
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Benefits of the new nano-enabled products compared to conventional products for both technologies (spray and sonochemical coating processes) determined by the LICARA nanoSCAN

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Fig. 4
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Risks of spray and sonochemical technologies for the new nano-enabled products using the non-OECD components: mixed dopant metal oxides and metals nanoparticles and gallium-doped carbon dots; and OECD components (SiO2 core) below 50 nm

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Fig. 5
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Risks of spray and sonochemical technologies for the new nano-enabled products for the different scenarios using the inorganic nanoparticles (ZnO and CuO)

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Fig. 6
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Risks of spray and sonochemical technologies for the new nano-enabled products for the different scenarios using organic polymers (polypyrrole)

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Benefits

The benefits of nano-products are presented on an axis ranging from 0 to 1, where 1 indicates the highest possible, positive benefit (i.e. in all aspects better than the conventional alternative). Thus, a score close to 0 means “neutral”, as good as the conventional alternative.

Figure 3 shows the relative benefits of the nano-enabled products in our case and demonstrates positive environmental (average score = 0.61), economic (average score = 0.5) and societal benefits (average score = 1). The input variables needed in the module for each case were identical regardless of the technology or the NPs. The reduced energy consumption by 70% for all pilot lines without compromising the production volumes is qualitatively accounted for through selecting better as the Energy consumption of the manufacturing process option. The uncertainty in environmental benefits (shown by the error whiskers in Figure 3) is attributed to a lack of information on waste generation during the manufacturing stage (Can the wastewater treatment facility eliminate the nano-products emissions? and Can the waste incineration facility eliminate the nano-product's emissions?). The same practice for dealing with the similar information gap appeared in the nano-copper-based biocidal paint case study described by Subramanian et al. [9].

One of the main reasons for the interest in innovation in textiles is that porous materials, synthetic microfibres and membranes used commercially over the past 30 years have been commoditised. This may be attributed to the accessibility of blockbuster technologies due to patent expirations. The commodification subsequently reduced the profit margin and the market share. By contrast, the textile manufacturers from the PROTECT consortium will offer competitive advantages in terms of enhanced performance, reduced production cost, safety and sustainability. The economic benefits of the nano-enabled products are mainly predicated on market potential (normalised score = 1) in a medium sized market (novel and more efficient antimicrobial and biocompatible nano-size coating agents). Profitability is improving in medical textiles in terms of operational cost during the manufacturing stage (one-step coating process, low cost due to low energy and water consumption). Thus, there are no discernible advantages regarding the development stage for the moment, since the PROTECT project ends in 2021 (time-to-market is 1– < 5 years), and no high volume of materials can be realised until that time (pilot lines of the first years will be upgraded to market potential after the fourth year). Nonetheless, the social benefits (module 3) of technological breakthrough (increased product efficiency coupled with smart bacteria-sensing textile with the capacity to detect living bacteria on fabrics), highly skilled labour force (new technology in the marketplace supported by in situ monitoring and automation) and improved public health (through novel antimicrobial products with durable performance) are clear advancements. Improved hygiene in hospital environments and prevention of cross-infections will show economic and social benefits of scale, resulting from such reduced needs for treatment of infectious diseases acquired during hospitalisation.

Risks

The risks posed by nano-products are presented on a scale varying from 0 to 1. Scores below 0.3 indicate “low risks”, and scores between 0.33 and 0.67 indicate “medium risks”. A score of higher than 0.67 corresponds to “high risk”. It should be noted that high risks may not be mitigated by high benefits; in such a case, a product is considered being too “risky” and unacceptable to the public. Figures 4, 5 and 6 illustrate the risk estimation for three different types of NPs and both coating technologies. The occupational and consumer health risk assessment of the NPs are calculated by Stoffenmanager Nano. The highest risk in all cases is associated with the potential effect in Module 4 (redox activity or oxygen radical formation).

OECD components (TiO2-shell/SiO2-core) and non-OECD components (Ga@CD, Zn0.89Cu0.11O) below 50 nm show the highest risk and uncertainty (Fig. 5) since size is a significant factor in Stoffenmanager. Inorganic oxides NPs demonstrate lower risks (Figs. 4, 5 and 6) as their toxicities are included in Stoffenmanager databases, albeit not as a mixture. As ZnO or CuO has been shown to be harmful to human cells [76,77,78], they were included as harmful or irritating. However, it should be recognised that basing RA decisions solely on in vitro data, even from a control banding perspective, can be problematic. The toxicological reality of simplified in vitro models offers a relatively poor correlation to human health outcomes [79], which is why so few in vitro models are found within regulatory testing and, when they are found, are part of integrated testing strategies with further confirmatory testings. From a dosimetric point of view, doses applied are often unfeasibly high and offer little opportunity for extrapolation to human equivalent concentrations for use in RA [80, 81]. This is not to say that such simplified in vitro models are of little or no use, it is simply that a more nuanced consideration of the input data and assumptions may be required.

In relation to Zn0.89Cu0.11O, there are no studies currently available which measure the in vitro toxicity of the mixed dopant metal oxides and metals. The assumption that they would behave like ZnO would result in the same risk, but due to uncertainties, the mixture ranks higher. Organic polymers (Fig. 6) show a similar pattern. Although polymers are classified as having a low potential effect due to their low redox and catalytic activity [82], the inhalation toxicity for the specific compound is not known. Once again, this uncertainty results in higher occupational risk estimation compared to inorganic NPs. Since polymers are included in the OECD list of the Stoffenmanager Nano tool, they are deemed to be of less risk compared to other components (Fig. 6) due to larger size (> 50 nm). No relevant data is currently available on Ga@CD. Since elemental carbon is considered to be a low toxicity material, carbon dots are generally considered of low toxicity [83]. However, gallium is a reactive metal that can initiate redox catalytic cycle. Moreover, as it is also photoactive [83], the toxicity of these doped carbon dots increases when irradiated [84], but it should be considered that photoactivity is mostly relevant to external routes of exposure (e.g. dermal) where there is the possibility of light exposure as opposed to internal routes such as the lung surface after inhalation with the absence of light.

In terms of public health and environmental risks, the most significant contributor in the Stoffenmanager ontology is potential effects based on free radical activity and oxidative stress. From a toxicological perspective, free-radical activity and oxidative stress are key drivers of many adverse health effects [85], but as noted by Damoiseaux et al. [86], oxidative stress is hierarchical in nature and not all-or-nothing. Low to mild levels of oxidative stress activate a homeostatic response in an attempt to restore the redox equilibrium [87, 88], and such free radical activity may be biologically ineffective and, therefore, from a health perspective, irrelevant. Higher levels of oxidative stress leading to activation of oxidant sensitive transcription factors such as MAPK and Nf-kappa B may lead to a pro-inflammatory response which from a health perspective may be of importance [89, 90]. Although again it must be considered that inflammation is a natural response and where it is proportional, self-limiting and fully resolving it may be seen as an adaptive rather than adverse response [91, 92]. Such nuances are important in hazard assessment but are not easy to capture in a binary approach that considers free-radical activity as a yes or no approach [93,94,95]. In this case study, system knowledge referring to impurities, origins, end-users of the NP and environment related factors is well defined, and no discernible risks are foreseen. The impact of the absence of toxicological human inhalation data in the case of non-OECD NPs is clear and affects the potential effect metric significantly.

Regarding the occupational risk (Figs. 4, 5 and 6), the same Stoffenmanager Nano values were applied concerning the machine processing. The two technologies diverge as a consequence of exposure frequency during manufacturing: once a week versus 4–5 days a week for spray and sonochemical technology, respectively (Table 2). Figures 4, 5 and 6 below illustrate our argument. Different exposure inputs result to exposure band changes, while hazard bands remain identical. In terms of consumer risks, the products show exposure potential when particles are bound to the surface as opposed to being comprised in the bulk of the product. This can result in higher scoring for the consumer than occupational risk, despite the fact that the former is based on the estimation of the latter. However, the portion of consumer population potentially exposed is low (fraction of households less than 5%).

Figure 7 shows the two-dimensional space of benefits and risks for the spray and sonochemical technologies (and the NP groups (I, II, III)). It should be noted that while all approaches share the same benefits, they differ in risks. Inorganic oxides NP coatings (I) are a sound alternative to silver following either manufacturing technology since the results lay on the “go ahead” regime. OECD components (III) of large particles such us polymers are a viable alternative when manufactured through the R2R spray technology and offers a marginally beneficial alternative when formed by sonochemical process. The results are inconclusive for mixtures of particles or of small size OECD components (II) due to the high overall uncertainty of risks. These are depicted in the graph by the long perpendicular line segment, laying mostly though, in the “go ahead” regime: in between, an “Undecided” area exists (yellow-coloured) where benefits and risks are more or less equally important and where distinguishing the value of the nano-product from that of the conventional product is infeasible.

Fig. 7
figure 7

Decision analysis of the spray (top row) and sonochemical (bottom row) coating processes using the LICARA nanoSCAN. Uncertainty bars are depicted in each graph. Three cases are shown, inorganic oxides NPs (left column, I), non- and OECD components below 50 nm (central column, II) and organic polymers above 50 NP (right column, III)

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Discussion

For over a decade, it has been evident that NT offers immense opportunities for society. However, in order to properly harness this potential, many challenges and uncertainties surrounding the RA of NPs remain to be addressed. Legal risk is an element that perhaps merits more attention in that extant liability regimes do impact on the sustainability of the sector. Here case law around exposure and toxicity can play an important role. Overall, NMs’ risk remains something of a test case for a combination of hard and soft lawmaking and the involvement of stakeholders in that process [96]. This is a complex risk governance challenge that Nanorigo and two other EU projects funded under NMP 13 (RiskGone and Gov4Nano) are currently seeking to address. Part of that answer from the Nanorigo perspective resides in the creation of a risk governance council whose operation would be underpinned by a risk governance framework. In general terms, much of this discussion focuses on individual and societal health benefits, and on well-being and human enhancement, as well as the risks of the nano-enabled products. The Tier 1 assessment of case studies suggests that overall benefits outweigh the risks. Indeed, a plethora of benefits and low exposures but potential high risks due to unknown hazard potential were observed in the case of mixtures or small (< 50 nm) OECD components. In order to move to the “go ahead” area, van Harmelen et al. [16] provide three options epigraphically: (1) more data to perform an in-depth assessment; (2) mitigation measures to minimise exposure; and (3) maximise benefits.

From Semi-Quantitative to Quantitative Analysis

Fine NP mixtures for the nano-enabled products increase the uncertainties surrounding risks such as inhalation hazard, which must be addressed in a higher tier assessment. While SUNDS provides a Tier 2 quantitative risk measure [97], due to the lack of dose–response in vivo relationships and exposure data, the approach is not possible in this case. Connecting incomplete data and uncertainties can result in an under-protective or overly conservative assessment of human health risks, resulting in either an unacceptable degree of risk or stifled innovation. The tool will push beyond state of the art by addressing uncharted issues of uncertainty related to NPs risk [35].

Hazard Assessment

The Stoffenmanager Nano tool yields conservative risk estimations to unknown NPs, particularly if the size is less than 50 nm, triggering the precautionary principle. The Zn0.89Cu0.11O mixture (< 50 nm) has demonstrated multiple times higher antimicrobial efficiency [98] than inorganic oxide NPs alone against multi-drug-resistant bacteria. While this feature contributes to superior product performance offering societal benefits such as aseptic hospital conditions, this case also incurs the highest degree of uncertainty. Although its real-life benefits may be greater, such benefits were not reflected in the application of the tool (see Fig. 3). Furthermore, the potential of redox activity was available in SUNDS for metal oxide NPs (medium redox capacity) for unfactionalised polymers and SiO2 coated with TiO2 while unknown for mixed metal oxides NPs and gallium doped with carbon dots.

ZnO or CuO were included as harmful or irritating in the predefined Stoffenmanager Nano input templates. However, it should be recognised that basing RA decisions solely on in vitro data, even from a control banding perspective, can be problematic. This is because it is a toxicological reality that simplified in vitro models offer relatively poor correlation to human health outcomes [79]. Considering the example of ZnO, it is known that nano-ZnO is cytotoxic to cells in culture, including skin keratinocytes [99, 100] and therefore could be viewed as a possible dermal irritant. However, the application of nano-ZnO direct to keratinocytes in culture is far removed from the application of nano-ZnO to human skin, which is to the surface layer of the epidermis [101]. For exposure to occur to viable keratinocytes, nano-ZnO must penetrate the stratum corneum, which, as studies have shown, is a barrier to NPs penetration [102, 103]. As such, ZnO may not be quite the risk to dermal health as simplified single cell in vitro test models predict, and this is reflected in the fact that nano-ZnO is widely used as a barrier in sunscreen and has been considered to pose no risk when applied to the skin up to a concentration of 25% in sunscreen products by the EU Scientific Committee on Consumer Safety (SCCS) [104].

Exposure Assessment

The conceptual process for the assessment of risk in plant designs for manufacturing nano-enabled products involves considerations specific to the production steps [71]. All information required by the tool could be obtained and used to assess exposure. The only notable limitation is the source domain for handling the nano-products. Abrasion and fracturing as a release process of nano-enabled end products (handling of products from occupational and end-users’ perspectives) are not an option and cannot be addressed by Stoffenmanager Nano. While it can be done via the generic Stoffenmanager software (https://stoffenmanager.com/), the latter does not provide the outcome (bands, hazard and exposure scores) required in SUNDS-tier 1. Stoffenmanager Nano was used with the available options, which better simulated the aforementioned missing release process. Moreover, it was assumed that regular maintenance practices were in place, in addition to good ventilation. All cases resulted in low exposure bands in the Stoffenmanager Nano tool. Sonochemical R2R process poses more exposure than spray R2R technology in terms of exposure frequency difference (4/5 days per week versus 1 day per week in NP manufacturing for sonochemical and spray technology, respectively).

Difficulties with Precautionary Principle

Drawing on the work of the EU-funded ASINA project, in this context, prevention means avoiding the diffusion of bacteria using antimicrobial materials. Antibiotic-resistant infections are a global health care concern and cause a heavy economic burden due to higher costs of treatments and reduced productivity, which in EU accounts for around EUR 1.5 billion per year in health care costs and productivity losses.Footnote 3

Control banding was proposed as an approach to implement the precautionary principle for RM decision-making in the cases when the available data or knowledge were insufficient for conducting the regulatory RA of MNs [13]. The core problem of the precautionary principle is that it is extremely difficult to quantify the acceptable level of risk [105]. As such, it is impossible to evaluate the existing legislative measures which could be based on the precautionary principle. In many areas of the law, and especially under legislation governing the EU, this principle is now mandatory and can only be restricted in the event of plausible scientific evidence that no harm shall arise from the enactment of the activity in question [106].

The application of the precautionary principle has, on occasion, been problematic in some sectors with critics pointing to a detrimental impact to standard risk assessment processes [107]. Decisions around application of the principle have been somewhat unclear due to ambiguities relative to the perceived uncertainties of the anticipated risk and political nature of such decisions. A well-cited article [108] was highly critical of the application of the principle, in particular the application of the “strong” form arguing that it damaged innovation and was applied unevenly [108, 109]. The argument posited here is different, we are not taking a position contra rather cautioning against the potential for "short circuiting" and the development welfare related arguments for and against a particular process or product. There are clearly instances where the application of the precautionary principle is appropriate, but thought is needed around its impact on adjacent regulatory processes. Our argument, to some extent, is chronological in that data lacunas should not stop a more generalised risk governance process. The distinction made by Peterson [109] between a “decision rule” and an “epistemic principle” may be useful in this regard. In light of this, it is recommended that invoking the precaution should be guided by clear evidence of the potential hazards posed by the action or decision to be taken [110]. Within the field of techno-sciences, the principle has been applied to the risk assessment of NPs due to the yet unknown level of risk inherent in such materials. However, since techno-sciences are created and managed by human beings, it follows that the inherent risk should not be borne solely by techno-scientific products such as NPs [111].

As the LICARA nanoSCAN assesses the risks of NPs based on a precautionary approach, only in a few cases the risk will be low. The precautionary principle has proven a useful tool in guiding decisions and actions which could potentially pose harms to the environment and human life [107, 112]. However, given the fact that this principle is deemed sufficient, even when there is no scientific evidence to substantiate the risk, the application of the principle in various fields is questionable. For instance, in the risk assessment of NP, this principle has fallen short in prescribing workplace protection measures or acting as the regulatory principle of the techno-sciences.

A methodology to formulate realistic hypotheses for the toxicity of unknown nanoparticles with simplified exposure models which enable non-specialists to analyse potential risk on future production lines is therefore proposed by [71]. The ensuing paper proposes a practical implementation in the absence of experimental data, for the specific case-study of spray and sonochemical coating processes.

Conclusions

As decision-making tools become increasingly ubiquitous across a wide range of economic activities, the numerous critiques have focused on the dangers of a lack of nuance or potential failures to account for certain factors. A number of fundamental problems reside within metric-based approaches; in some instances, these are as basic as key information eliding the metric. However, in the case of NP risk, uncurated data is most often the issue. While in the absence of data a precautionary approach may be merited, this is not always and unvaryingly the case. The use of alternative evaluation methods to supplement data could result in shifting the discussion-making process away from simple precaution towards a more utilitarian approach.

Risk is implicit in the adoption of the precautionary principle, either overtly or otherwise. On occasions, the SUNDs model assumes the precautionary principle – with the absence of certain categories of information as the driver. This paper makes the case that the latent presence of the precautionary principle must be interrogated and the model supplemented with all available information types as necessary. The case study adopted is particularly instructive as the potential benefits are clear and the risks resulting from delay are tangible.

Our analysis confirms that in the case of antimicrobial textiles and despite the many clear benefits, the practice of using mixtures of dopant metal oxides and metals encounters continuing research and development challenges due to the uncertainties related to hazard. The profiles of inorganic and polymer NPs align with products with proven low risk and high economic and societal benefits. The application to case studies therefore derived a number of significant insights into how the apparent conflicts between innovation, (eco)toxicological risks and environmental and socioeconomic impacts can be clarified and resolved by simple, low-cost identification assessments, defining the optimum manufacturing direction.