INSIGHT | Perspective

Perspective
[Link]

[Link]

A One Health approach to managing the

applications and implications of nanotechnologies
in agriculture
Enzo Lombi 1
*, Erica Donner1, Maria Dusinska2 and Fern Wickson3

The need for appropriate science and regulation to underpin nanosafety is greater than ever as ongoing advances in nanotech-
nology are rapidly translated into new industrial applications and nano-enabled commercial products. Nevertheless, a discon-
nect persists between those examining risks to human and environmental health from nanomaterials. This disconnect is not
atypical in research and risk assessment and has been perpetuated in the case of engineered nanomaterials by the relatively
limited overlap in human and environmental exposure pathways. The advent of agri-nanotechnologies brings both increased
need and opportunity to change this status quo as it introduces significant issues of intersectionality that cannot adequately
be addressed by current discipline-specific approaches alone. Here, focusing on the specific case of nanoparticles, we propose
that a transdisciplinary approach, underpinned by the One Health concept, is needed to support the sustainable development
of these technologies.

R
apid innovation in the field of nanotechnology has produced could be used to control the release of agrichemicals (for example,
continuous sector growth and with it, extensive risk manage- fertilizers and pesticides), to develop target-specifc delivery systems
ment challenges. The volume and variety of engineered nano- for biomolecules (for example, silencing RNA or nucleotides) or to
materials (ENMs) incorporated into commercial products and modify the properties of existing active ingredients (for example,
processes, and their unique emergent properties, have prompted replace soluble Cu with nano-CuO). These new applications will
significant concerns regarding the safety of ENMs for human and add a substantial degree of complexity to what is already a mul-
environmental health and highlighted the need for nanocom- tifaceted hazard, exposure and impact scenario. In particular, the
patible (eco)toxicological assays and dedicated risk assessment. multiple levels of connectivity between human and environmental
Consequently, ‘nanosafety’ has been the focus of sustained research exposure scenarios in agricultural products has the potential to
efforts for over a decade now. The term itself first appeared in the generate unexpected side-effects that a discipline-driven approach
scientific literature in 20051, and the OECD Working Party on may fail to tackle or even recognize. This complexity brings us to
Manufactured Nanomaterials was established shortly afterwards a point where an inter- or ideally transdisciplinary systems-based
in 2006. Since then, human-focused nanosafety research has been approach5, such as that offered by the One Health perspective, is
concerned with the intentional exposure of people to ENMs and required. This is not only needed to ensure safety is understood
in particular nanoparticles (NPs; for example, through nanomedi- and researched across and beyond disciplinary boundaries; it is also
cines, food additives and health supplements), unintentional expo- necessary if we aim to develop safer-by-design agri-nanotechnolo-
sure (for example, released from consumer products, including food gies that are both environmentally sustainable and socially robust.
packaging) and occupational exposure (for example, from indus-
trial processes). By contrast, environmentally focused nanosafety The status quo
research has predominantly targeted inadvertent environmental The current regulatory frameworks and discrete human and envi-
releases of NPs associated with the production, use and disposal ronmental nanosafety research communities are areas that should
of nanofunctionalized consumer products2 (for example, NPs in be targeted for improvement.
personal care products that are released during use to household
wastewater). A notable exception to this relates to the direct use of Immature safety governance frameworks for NPs. One of the
NPs (for example, nano zero-valent iron) for environmental reme- key overarching challenges facing nanotechnology industries,
diation, in which case, the proposed receiving environments are including agri-nanotechnology, is that a clear and transparent
already severely contaminated. As regulatory approval is typically framework for risk governance remains lacking despite more than
required prior to implementing any new remediation technology, a decade of technological innovation in the field6–8. Despite the
this has in effect delayed the uptake of nanoremediation technolo- significant research progress towards understanding ENM haz-
gies in many jurisdictions3, giving risk assessors more time to con- ards and risk, there is still no harmonized basis for ENM risk
duct detailed NP risk assessment for this particular pathway prior governance across different sectors this knowledge can be useful
to product deployment. for. Given the lack of specific regulatory frameworks, the field of
Today, the strong commercial impetus for agricultural innova- nanosafety has increasingly turned towards the development of
tion and the use of nanotechnology to enhance agricultural effi- safety-by-design approaches7,9. Commendable as it is to actively
ciency is bringing new priorities and challenges for both human and pursue risk reduction during the design phase, this approach
environmental risk researchers, assessors and regulators. The appli- alone is insufficient for adequately ensuring safety and broader
cation of nano-enabled agrichemicals in plant production has been governance frameworks are still required10. One of the first steps
widely discussed (for example, ref. 4). For instance, nanotechnologies towards achieving harmonized cross-sectorial risk governance

Future Industries Institute, University of South Australia, Mawson Lakes, Australia. 2NILU-Norwegian Institute for Air Research, Kjeller, Norway.
1

GenØk Centre for Biosafety, Siva Innovation Centre, Tromsø, Norway. *e-mail: [Link]@[Link]
3

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of nanotechnologies is data sharing11. This transfer of knowl- simple environmental matrices26, but in many contexts, a reliance
edge across different nanotechnology fields is needed not only to on modelling will almost certainly remain. ENM hazard charac-
advance nanosafety research, but also to support the development terization is also highly problematic in the environmental context
and implementation of reliable frameworks for risk assessment because even though protocols have been developed27, the con-
and decision-making and to facilitate risk communication with tinuous, and difficult to reproduce, transformations of ENMs in
relevant stakeholders (for example, industry, regulators, insurance the environment (from dissolution to agglomeration and changes
companies, civil society organizations and the general public)7,8 in composition and surface properties) make this task particularly
The European Commission’s recent call to develop transdisci- challenging. In addition to the scientific challenges involved, the
plinary risk governance frameworks based on a clear understand- determination of environmental hazard is also complicated by the
ing of nanotechnology risks, management practices and societal diverse range of values that have to be navigated when defining
perceptions is a positive sign of moving beyond the current status what constitutes environmental harm and deciding how to handle
quo of immature and underdeveloped cross-sectorial governance12. scientific uncertainty and ambiguity28.
Under this call, three large international projects (RiskGONE,
NanoRIGO and Gov4Nano) have recently received financial sup- Human nano-risk challenges. Strategies for toxicity testing are essen-
port and it will be worth monitoring their outputs for their poten- tial in human hazard and risk assessment29 and toxicity can be
tial to provide sound overarching frameworks for nanotechnology investigated in silico, in vitro or in vivo. Oxidative stress has been
risk governance. Nevertheless, even the establishment of overarch- shown to be an underlying mechanism of possible toxicity of ENMs,
ing cross-sectorial frameworks is not all that is needed if we are to causing both immunotoxicity and genotoxicity. However, novel tox-
achieve good governance of agri-nanotechnologies. Deeper changes icity pathways, particularly epigenetic toxicity, have been also sug-
in the way research and risk assessment are conceptualized and per- gested30,31. This means that various toxicity testing strategies may
formed are also required. be selected. Human health ENM risk assessment also necessarily
involves consideration of multiple exposure pathways (inhalation,
A disconnect between human and environmental nanosafety. ingestion, dermal absorption or injection) and may differ consider-
Currently, most nanosafety researchers operate within two distinct ably depending on the source of exposure. For instance, the devel-
epistemic communities13,14. On the one side, the human health risk opment of nano-enabled drug delivery systems will be subject to
community has a primary interest in mammalian cells, tissues and safety requirements that differ from those needed for food additives.
organisms (for example, lymphocytes, skin and mice), while on the Food additives are a particularly relevant example in the con-
other side, environmental health risk researchers focus predomi- text of this article as one of the potential risks associated with the
nantly on other branches of the tree of life (for example, single-cell use of nano-agrichemicals relates to the possibility that they could
organisms, plant tissues, invertebrates and fish). Until recently, be present in plant materials for human consumption32. In other
there has been limited direct collaboration and knowledge exchange words, both food additives and agrichemicals are intentionally
between these communities, despite the clear potential for value. added during food production, albeit at different stages. The topic
The reasons for this limited interaction across the communities of ingested NPs has recently been reviewed previously33. Currently,
becomes apparent upon considering key differences in the chal- it appears that only a few types of NPs are specifically used as food
lenges they face. additives: TiO2 (as a whitening agent), SiO2 (as a filler) and nano-
Zn and Fe oxides (as dietary supplements). Sohal et al.33 reported
Environmental nano-risk challenges. The identification of relevant that 39 studies published between 2007 and 2017 met the selection
environmental exposure scenarios, or ‘problem framing’ as defined criteria for inclusion in their review and of these, only 21% used
by Bos et al.15 and Owen and Handy16, has been highly challenging food grade ENMs for testing. This is rather surprising and indicates
in itself due to the largely incidental/accidental nature of the release that in the emerging area of nano-risk assessment for agrichemicals,
of many NPs to the environment. Moreover, the key characteristics there is a need to establish clear recommendations for toxicological/
that are known to be relevant to NP toxicity (for example, size, sur- risk assessment investigations33. Even though only a limited range of
face identity, shape, aggregation and so on17,18) effectively need to be ENMs are relevant in the context of direct human exposure through
considered as dynamic properties once NPs enter natural receiving food, the risk assessment of these materials is far from complete
environments, even when working with simple standardized test and consolidated. For instance, a recent article reporting possible
environments19. As a result, determining the environmental rel- chronic intestinal inflammation and carcinogenic effects from TiO2
evance of NPs is not a trivial matter. For instance, one could argue (ref. 34) prompted the French government to consider banning this
that silver sulfide NPs should be prioritized for risk assessment widely used pigment from foodstuff35.
rather than the pristine metallic silver NPs used in product formu- The relatively low level of connection between human and envi-
lations because silver sulfidation is a dominant process that occurs ronmental nanosafety research has occurred partly due to the lim-
rapidly under a wide range of environmental conditions, signifi- ited relevance of environmental exposure pathways (not including
cantly changing the core chemistry of the particles20,21. Nevertheless, nano-industry working environments) to human exposure (Fig. 1).
most ecotoxicity testing has been done using pristine metallic silver Human exposure typically occurs through inhalation, ingestion,
NPs. Similarly, the surface functionalization of pristine NPs is also injection/insertion and skin absorption36. Excluding occupational
known to change substantially once they are exposed to ambient exposure, dermal exposure occurs through cosmetic and sun-
environments, but this process is rarely simulated or considered screen use, and from medical preparations, although the mecha-
in laboratory studies22. Despite these complexities, potential envi- nisms and extent of this exposure pathway are not fully understood
ronmental release scenarios have been developed and employed to and an increasing number of studies indicate that ENMs, includ-
derive predicted environmental concentrations (PECs) of ENMs ing NPs, are incapable of overcoming the intact skin barrier37.
in the environment using advanced modelling approaches such as This pathway is also likely to vary considerably on the basis of
probabilistic material flow analysis23. These results go some way individual habits, sex, age and other socio-economic factors. The
towards filling the knowledge void, but are very difficult to verify inhalation pathway is the most significant route for occupational
empirically due to the extreme challenges in detecting and quan- exposure to NPs, with inhalation of sprays and therapeutics quan-
tifying ENMs in complex environmental matrices24,25. New devel- titatively less important at present38. The ENM ingestion pathway
opments in single-particle time-of-flight mass spectroscopy may is dominated by food additives used to change/mask taste, tex-
provide a way out of this impasse analytically, at least for the more ture and appearance. However, incidental release of ENMs from

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Consumer
products

Landfill/incineration

Domestic use
Ingestion

WWTP Soil Food

Inhalation

Occupational Air
Dermal

Animals
Production

Injection Water
+
Plants

Sediments
Medical use
Microorganisms

Human exposure Environmental exposure

Hospital use

Fig. 1 | Human and environmental exposure pathways not considering agri-nanotechnology. The solid lines indicate the main exposure pathways while
the broken lines are theoretical, and currently most likely negligible, exposure pathways. WWTP, wastewater treatment plant.

lipsticks, packaging materials and NPs used for delivery of drugs mental nanorisk community. It involves material characterization,
and other compounds and in beverages also contribute to this release, fate and exposure modelling (to obtain PECs), hazard
pathway39. Direct injection of NPs for imaging or clinical treat- characterization (to derive predicted no-effect concentrations;
ment or exposure to implants that have been nanofunctionalized PNECs) and risk characterization (often by comparing PECs and
is highly person-specific. Overall, it must be concluded that the PNECs). This framework is conceptually similar to those used to
natural environment (that is, excluding working environments) is assess other potential environmental pollutants but with addi-
likely contributing relatively little to human exposure at present, tional challenges due the complexity of NPs and their behaviour
with the strongest link apparently being through food grown on in the environment. A similar framework can be used for human
soils that receive wastewater biosolids, which in most cases is the risk assessment15. However, these two approaches have not been
primary environmental exposure route40. integrated to date.
Due to these inherent differences in focus in the early days of The development and adoption of agri-nanotechnologies argu-
nano-risk assessment the status quo in nano-risk research and ably brings new impetus and opportunity to transcend the current
assessment became characterized by a separation between the fields human and environmental health nanosafety divide. Indeed, failure
of human and environmental nanotoxicology. Despite the very to do so may potentially lead to large gaps and oversights. Emergence
significant research efforts in both, cross-disciplinary interactions of unexpected side effects due to unrecognized system continuities
and information exchange has been comparatively limited, even often occurs when breakthrough technologies with multiple points
with respect to analytical techniques, where an immediate benefit of contact between the human and ecological spheres are introduced
is apparent41. Moreover, even though risk assessment frameworks but assessed according to separate disciplinary-based expertise. In
that cover both human and environment aspects have been devel- the case of agri-nanotechnologies, we argue that an interdisciplin-
oped15 their application still typically remains discipline-specific ary and ideally transdisciplinary approach, such as that embodied
with little interaction between assessors in different areas. This is in the One Health concept, is both appropriate and necessary.
perhaps not surprising in the case of ENM risk assessment as a lack
of cross-fertilization between human and environmental toxicol- One Health
ogy has long been recognized even in more established fields of One Health is an approach to research and collaboration where mul-
research. For instance, the potential to use human pharmacology tiple disciplines—working locally, nationally and globally—unite
data in ecotoxicology has been advocated for a considerable time42 in the quest to attain optimal health for humans, animals and the
but only a limited number of examples are present in the literature environment, recognizing that each of these entities are integrated
(for example, ref. 43). within a system45. It is also an approach in which different types of
A strategy for environmental risk assessment of NPs recently stakeholders are recognized as having important roles and knowl-
put forward44 demonstrates the current approach for the environ- edge to effect change within the system. This approach has proven

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particularly important in the area of (microbiological) food safety, limited to relatively few classes of ENMs, the range of agri-nano-
zoonoses and antimicrobial resistance46. It has been endorsed by technologies that will be developed will be much more diverse and,
the World Health Organization (WHO), the Food and Agriculture in some cases, will directly carry toxic substances (that is, nanode-
Organization of the United Nations (FAO), the World Organization livery system for pesticides).
for Animal Health (OIE) and numerous national governments. Such an increase in the complexity of the possible pathways of
In the context of this article, the FAO definition is relevant as it exposure and the multiple points of contact between human, ani-
includes food safety as well as human, animal and environmental mal, environmental and food domains highlights the relevance of
health: “The One Health vision is a unifying force to safeguard the One Health concept and the value in adopting an interdisciplin-
human and animal health, to reduce disease threats and to ensure a ary approach to risk research and assessment. This is essential to
safe food supply through effective and responsible management of identify opportunities for health improvements and optimize risk
natural resources.” mitigation strategies over-riding compartments and discipline
Here we will briefly introduce the concept of One Health as divides55. Furthermore, such an approach would offer the opportu-
applied to antimicrobial resistance as there are several parallels with nity to identify potential indirect benefits of agri-nanotechnologies,
the use of agri-nanotechnologies. Rapidly evolving and spreading which may otherwise be overlooked. Examples of complex, indirect
antibiotic resistance is a complex phenomenon driven by antimicro- risk-and-reward questions that may be best studied using a One
bial use, for different reasons and with different degrees of need, in Health approach include:
human health, and in the animal, environmental and food sectors47.
In particular, the inappropriate use and overuse of antibiotics in • Could mass commercialization of antimicrobial NPs and their
human medicine48 and as growth promoters in animal husbandry, potential use in agriculture undermine their biomedical poten-
as well as insufficient treatment of waste streams, have come under tial by driving the environmental development/spread of anti-
increasing scrutiny for their role in driving the rapid development microbial resistance?
and transmission of multidrug-resistant pathogens49. For instance, • Could NPs increase colloid-facilitated transport of pesticides to
the use of antimicrobials for animal production has been reported water bodies and contaminate the (human) food chain?
to represent about 80% of the total antimicrobials used in the USA50 • Could agri-nanotechnologies increase the efficiency of
with global predictions indicating a significant increase in their agrichemicals to a point where they reduce off-target effects on
use due to growth in consumer demand for livestock products51. non-target organisms (including humans)?
There is now broad consensus that transfer of antimicrobial resis- • Could nano-enabled agrichemicals offer novel mechanisms or
tance occurs between food-producing animals and humans46 with exposure pathways that make them more efficient but increase
increasing evidence that human activities increase the environmen- the range of non-target organisms or organs affected, or act as
tal resistome52,53. carriers of other pollutants?
The advent of agri-nanotechnologies has the potential to sig- • Could agri-nanotechnologies substantially reduce the carbon
nificantly increase the direct release of ENMs into the environment footprint of agriculture with corresponding benefits for envi-
and add a significant pathway of exposure to humans through the ronmental and human health?
food chain. This has several similarities to the issue of antimicrobial
resistance: (i) it provides an exposure continuum and interlinkages
between human, animal, environmental and food health; (ii) it is A One Health approach for nanosafety in agriculture
both driven and mediated by agricultural activities and (iii) it is Successful implementation examples of the One Health principles
driven by increasing demand for food production (fuelled largely and approach are emerging in a variety of contexts. For instance,
by increased demand for animal-based products54 and large food Boqvist et al.56 recently reviewed the One Health issues related to
waste in affluent industrialized nations) and compounded by popu- microbiological food safety in Europe, and Lammie et al.49 sum-
lation growth. marized the progress on addressing antimicrobial resistance. This
The first point above is particularly significant as it drastically latter study also provided an excellent overview of the numerous
changes the exposure scenario depicted in Fig. 1, where the main implementations of One Health principles in national and global
exposure pathways to human and environmental endpoints are policies, testifying to the fact that, at least in the area of antibiotic
separate or have minimal feedback loops. Given the introduction resistance, these principles are actively being translated into opera-
and widespread use of agri-nanotechnologies (limited to plant pro- tional and legislative outcomes. For instance, nations worldwide are
duction in this article), a much more complex exposure scenario increasingly moving to restrict and ban the use of key antibiotics as
can be envisaged (Fig. 2). In particular, large-scale release of agri- growth promoters in animal husbandry as it is now clear that this
nanotechnologies could significantly increase human exposures in practice can inadvertently increase antibiotic resistance in human
various ways. First of all, through the ‘contamination’ of the food and animal pathogens57.
chain with the ENMs used for their production. This of course will Despite the successes to date, operationalizing a One Health
be a function of a number of socio-technical parameters such as approach in any new area of research presents significant chal-
their partitioning and persistence both pre- and post-harvest, the lenges. Lebov et al.58 have recently provided a framework for One
impacts of food processing and cooking, diet, legislation, informa- Health that includes a case study based on the application of biosol-
tion available, acceptance to consumers and so on. However, if the ids in agriculture. This example is highly relevant in the context of
direct and intentional application of nanotechnologies to agricul- this paper as the risk of contamination of the food chain and poten-
tural environments increases substantially, other indirect pathways tial effects on human and environmental health when biosolids are
of exposure due to the leaching, spray-drifting and runoff of NPs inappropriately used in agriculture are not dissimilar to those that
to non-target environments may become significant. In either sce- can be envisaged in the case of unregulated adoption of agri-nan-
nario, it is likely that the NPs to which humans are exposed could otechnologies. We have therefore used the proposed framework58
be substantially different to the pristine NPs that are used in the to begin a theoretical conceptualization of what a One Health
original agri-nanotechnologies. This also represents a distinction approach for agri-nanotechnologies may involve. The approach
and complication in comparison to the status quo where most of of Lebov et al.58 includes a conceptualization phase and a planning
the human exposure at present is due to largely pristine NPs used phase. In the case study provided, the planning phase includes data
directly in food, beverages or biomedical applications. Moreover, sourcing as a substantial amount of information is already available
whereas current human exposure through food and beverages is regarding potential risks related to biosolids use in agriculture. In

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[Link]

Consumer
products

Landfill/incineration

Domestic use
Ingestion

WWTP Soil Food

Inhalation

Occupational Air
Dermal

Animals
Production

Injection Water
+
Plants
Occupational
(for example, farmers)

Sediments
Medical use
Microorganisms

Human exposure Environmental exposure

Spraying the chemicals
Hospital use in the field

Agri-nanotechnologies
exposure

Fig. 2 | Human and environmental exposure pathways become much more complex when agri-nanotechnologies are added to the scenario
reported in Fig. 1.

the case of agri-nanotechnologies, where the information available or mandated by risk management? Similarly, how do chemical com-
is still limited, planning and execution should be separated (Fig. 3). panies communicate the safety requirements? How are these then
The conceptualization phase is critical as it includes both the passed on by suppliers or extension officers? Is this sufficient? In
problem/hypotheses definition and the identification of collabo- this context, the final goal of a One Health project would extend
rating teams. Although definition of hypotheses and objectives to include the integration of natural, social (including economic)
within individual areas can be a relatively simple task if they fall and health sciences in a humanities (or legislative) context together
within a specific discipline, the strength and the challenge of a One with the inclusion of a range of other relevant stakeholders such as
Health approach lies in the intersectionality aspects. It is at this research funders, farmers, civil society organizations and local com-
level that unexpected issues can be raised, which would otherwise munity groups (transdisciplinarity60).
be overlooked by one-dimensional approaches. This also means Hypotheses that are commonly tested in human, environmen-
that technical knowledge, which remains a conditio sine qua non tal and animal health in relation to nanotechnologies are reported
in risk assessment, needs to be integrated with knowledge of con- in Fig. 3, along with examples of questions that could arise from
sumer behaviour, food trends, economic incentives and political the intersectionality of these areas. This clearly does not represent
necessities to provide a holistic understanding of complex issues. an exhaustive list but should provide some example of the type of
In other words, hypotheses at the intersection of different domains interactions that can be addressed through a One Health approach.
require interdisciplinarity or even transdisciplinarity rather than Lebov et al.58 suggest the use of visualization to explore potential
simply multidisciplinarity. According to the definitions provided intersections between disciplines. This could be accomplished using
by Choi and Pak59 this requires moving beyond the simple assem- causal diagrams or directed acyclic graphs61 for instance; these are
blage of different forms of disciplinary expertise (multidisciplinar- often used in clinical settings and risk assessment. To some extent,
ity) toward the analysis, synthesis and harmonization of knowledge the definition of these key questions will drive the composition of
from different disciplines into a coherent whole (interdisciplinar- the collaborative teams required through an iterative process. In
ity). However, an interdisciplinary approach would still have signifi- taking a One Health approach, such teams should not be limited to
cant limitations as this would still be limited to a largely academic scientists or researchers but should also involve stakeholders such
discourse. Knowing the real risks of (nano-)agrichemicals to both as practitioners, policymakers, managers and community members.
human health and the environment would improve when there is a In the case of agri-nanotechnologies, this would also include farm-
better understanding of how farmers use and apply them. Do they ers, relevant industry representatives and consumers.
follow the recommendations provided and if not, why not? What The planning phase possibly represents the most challeng-
are the social, economic and ecological pressures they face that may ing stage of the investigation as by their very nature, One Health
mean they do not follow the rules assumed during risk assessment study designs are complex and have to cover different disciplines

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Conceptualization Planning

Hypothesis examples Team

Harmonization of QA/QC and ENMs characterization

Mathematicians, statisticians, modellists, ethicists, sociologists, NGOs,

Occupational exposure Human toxicologists
Human Testing for statistical power
of farmers will have detrimental General practitioners

consumer groups, farming groups, funding agencies and so on

health
effects Health regulators ...
Prioritization
Development of
anti-microbial resistance ‘Reality’ checks (such as, agronomist inputs)

Ecotoxicologists
Environmental Agri-nanotechnologies will Environmental chemists
health dominate environmental exposure Environmental regulators
Ethicists ...
Run-off pesticides will
increase and contaminate the Execution
(human) food chain
Animal toxicologists
Animal Exposure of off-target Veterinary Data collection
health wildlife will increase Animal regulators ...
Data harmonization and integration

Efficacy will reduce

Synthesis of findings
the carbon footprint

Integration of public/stakeholder views

Food will contain ENMs Nutritionists
Food
with altered characteristics in comparison Food regulators
health Development of implementation/minimization strategies
to pristine NMs NGOs ...

Fig. 3 | A possible One Health framework for the risk assessment of agri-nanotechnologies. The purple hypotheses are representative examples of
One Health issues while the other boxes are more directly linked to a specific health area (for example, limited intersectionality). NGOs, non-governmental
organizations.

and include knowledge from a range of different stakeholders. One area that would be boosted in importance under a One
Harmonizing quality controls/assurance procedures, characteriza- Health perspective is what we would call ‘comparative nanotoxicol-
tion protocols (also a key point in ENM studies) and ensuring that ogy’. Many have argued that a thorough understanding of the nano-
experimental designs provide sufficient analytical and statistical specific mechanisms of action and toxicity is required before ENMs
power for the different endpoints investigated requires consider- with improved characteristics (that is, high efficacy and low toxicity)
able coordination. Furthermore, it is to be expected that, despite can be consistently developed22,69,70. Yet studies that compare, side
these harmonization efforts, data will be diverse and will include by side, the mechanisms of action or toxicity in environmental and
both quantitative and qualitative information as well as measured human endpoints are virtually absent from the literature although
and modelled data. Hence, statistical and mathematical strategies at a few review articles cover both human and environmental toxicol-
this stage may be necessary for ensuring that the available informa- ogy (for example, refs. 71,72). For instance, a literature review compar-
tion can usefully be combined and used to test the hypotheses set ing the toxicity of Ag, ZnO and CuO NPs on the basis of various
in the conceptualization phase. The planning phase, and the execu- environmentally relevant test species and mammalian cells in vitro
tion phase that follows, should also try to leverage the range of tech- revealed that toxicity varied by up to four orders of magnitude
nical expertise available across disciplines, which could provide a between endpoints73. This variation could be due to genuine differ-
significant advantage over discipline-specific studies. For instance, ences in susceptibility between the tested organisms/cells or to the
specific ENM characterization or analytical requirements could be variation in toxicity of the NPs tested in the different studies (due,
serviced by one or a few specific teams with the most appropriate for instance, to size, surface chemistry or shape). However, it can-
expertise. This would result, at the same time, in more comparable not be excluded that confounding factors due to differential interac-
and robust datasets. tion of the NPs with experimental materials (for example, media and
An inclusive framework such as the one described here would containers) also play a role. These operationally defined issues have
also have the advantage of bringing together all the necessary been reported in the literature74–76 but more needs to be done to get
stakeholders to ensure that the most appropriate implementa- to the core of the differences in toxicity that have been observed. To
tion/minimization strategies are developed and acted upon in tackle this issue in 2017 the so called Malta Initiative was launched,
order to promote appropriate risk governance. For instance, in the with the aim to speed up validation and adaptation of nanospecific
case of nano-agritechnologies, farmer groups could play a criti- OECD test guidelines for physico-chemical properties, acute toxicity
cal role not only in the planning and execution phases but also in and systemic and chronic effects against humans and ecosystems77.
the implementation of a One Health strategy as recently argued A One Health approach could create the conditions for com-
through the Farmer First Health Paradigm62. Engaging with pub- parative nanotoxicology to progress rapidly. This is an essential step
lic and stakeholder views and combining these with more analytical before a safe-by-design approach can prove successful. In fact, while
processes such as risk assessment has been advocated in frameworks safety by design has gained much attention in the area of ENMs
for responsible innovation60,63,64 and in the development and use of var- development and many see it as a promising approach78,79, it has also
ious deliberative/analytic models for decision-making65–68. Experience been argued that safety by design is hardly achievable at this stage
with these types of integrative approaches can also be brought to bear as “there is no reliable and complete body of knowledge on the risks
on the development of a One Health perspective and framework. of ENMs that can simply be incorporated into design processes”10.
A complete body of knowledge would arguably have to include
Indirect benefits of adopting a One Health perspective the sort of unexpected and intersectional issues that can only be
Bringing together a diverse community of researchers and stake- comprehensively addressed through comparative nanotoxicology
holders has several indirect benefits that could progress the devel- and a One Health approach. While there are some new initiatives,
opment and safety of nanotechnology applications in agriculture. such as the NanoREG2 ([Link] project that will

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take important steps forward by developing large databases collat- regulation of nanotechnologies has been fraught with challenges28.
ing results from numerous projects on human and environmental This is even the case for the food sector despite the limited number
nanotoxicology, for comparative nanotoxicology to deliver valuable of materials currently employed as food additives98. For instance, a
inputs to risk assessment and regulation, further steps beyond the recent article documented the struggle of the Australian regulatory
collation of information will be required. The information will, for authority to even acknowledge the use of ENMs in Australian foods
example, need to be systematically compared and new empirical until 201599. The use of ENMs in agriculture is even more com-
investigations designed on the basis of the findings. plicated since it needs to consider safety for humans and farmed
A One Health perspective would also greatly facilitate the animals (through occupational exposure and food/feed) and the
exchange of knowledge and expertise between medical- and agri- environment.
nanotechnologists. For instance, nanodelivery systems have been a It could be argued here that in the case of plant protection prod-
focus of intense research for their potential to control the release ucts (PPPs, such as pesticides and herbicides) the current regulation
of drugs and stabilize labile molecules (for example, proteins, pep- could be sufficient as ‘new chemistries’ already require extensive
tides or silencing RNA) from continuous degradation80. Although it human and environmental risk assessment before a product can
is likely that the same principles can be applied to plant systems81, enter the market. However, simply relying on the current approach
the development of nanotechnologies to enhance crop productiv- used for PPPs may in fact not be sufficient in this case because:
ity is, comparatively, in its infancy4. To date, research in this area
is mainly related to nanoparticulate soil fertilizers and encapsu- • It is not clear whether the use of nanocarriers would require
lated herbicides82,83. This research activity pales in comparison to comprehensive new testing of specific formulations.
the depth of knowledge already generated about the potential use • It is uncertain whether existing chemistries, and a simple change
of nanomedicines for drug delivery in humans. There is therefore in particle dimensions, would trigger a need for new testing or
clearly the potential for significant advance through an increased not (for example, in the case of Zn and Cu oxides that are already
level of interaction, knowledge sharing and knowledge co-creation commercially available as micronized products for which the
across these fields. ‘chemistry’ would not change).
Another area where adopting a transdisciplinary One Health • At present, nanospecific, standardized testing protocols are not
perspective will be important, is in navigating the acceptance for available in many jurisdictions.
agri-nanotechnologies in the public domain. The social acceptance
of nanotechnologies has not suffered from the same high level of Nanomaterials are known to easily change characteristics as they
public criticism and political debate as that experienced by biotech- move through different environmental compartments and these
nologies. This is perhaps partly due to the fact that nanotechnology transformations are far from being understood at the level required
innovation has to date primarily focused on creating new materials to perform robust risk assessment.
rather than altering living beings or food systems. In some parts of the These remaining questions and uncertainties regarding the reg-
globe there has also been significant investment in public outreach ulatory status of many NPs used in agrifood settings, the level of
and engagement activities early in the development of nanotechnol- scrutiny being applied, and the reliability of the available knowledge
ogy development, policy and funding programmes, and although mean that regulating nano-agrichemicals according to existing sys-
many of these efforts may be criticized for using limited concep- tems alone may be insufficient. Indeed, there are indications that
tualizations of ‘the public’84 or simply working to legitimate exist- the situation may be equivalent to testing an organic pesticide with-
ing investments in the field85, these efforts may also have impacted out considering the properties of its degradation products.
the levels of public criticism86–89. However, a large-scale, intentional Finally, it could also be argued that current regulatory require-
distribution of ENMs into agricultural environments, especially to ments for PPPs have also found to be lacking in several cases.
enhance crop productivity, could certainly generate similar con- The massive loss of insect biodiversity and the impacts of this on
cerns for nanotechnologies as those raised against GMOs. A recent broader ecological health being one current example indicating that
study in the US90 shows that public perceptions of GMOs are, for pesticide regulation has not been as effective as we need it to be
example, correlated to a tendency to support labelling of nano- (for example, ref. 100). A One Health approach to the emerging issue
enabled products, and food is always a culturally charged domain of NP use in agriculture could open the way to developing a more
to enter. At present, various surveys testing the consumer knowl- holistic approach to pest and pesticide management in agriculture.
edge of food-relevant nanotechnologies show that understanding
in the general population is low91–94. Multiple studies have shown Challenges for the future
that willingness to pay for nano-enabled products and nanofoods The One Health concept has been very successful in drawing
is largely influenced by perceived benefits95 and trust in the food together disparate research, surveillance and mitigation activities,
industry96. Willingness-to-pay studies have, however, also shown a and players in the fields of zoonoses and antimicrobial resistance.
reluctance to pay more for nanofoods even if there could be health However, as recently reviewed101, there is still a long road ahead as
benefits32. Frewer97, who recently reviewed the literature on con- a number of barriers prevent the One Health approach from reach-
sumer acceptance and rejection of emerging agrifood technologies, ing its full potential. Some of the most obvious barriers relate to
concludes though that consumers are not necessarily averse to tech- the abatement of disciplinary divides and the creation of knowledge
nological development in the agrifood sector. This means that social between various stakeholders with different backgrounds and inter-
acceptance rests on a complex interaction of factors that includes ests such as scientists, farmers, regulators, industry, NGOs and con-
a weighing of costs and benefits, an assessment of the quality and sumer groups.
sufficiency of the available information and the level of trust in Despite these challenges, a One Health approach to complex
the producers of both the nanoproducts and the associated safety problems and systems can provide a way to engage multiple disci-
knowledge. Adopting a One Health perspective can help this pro- plines and actors to ensure a more comprehensive perspective. In
cess by actively recognizing the interconnected nature of social the case of agriculture and food systems, we argue that it is essential
and biological systems and working to incorporate both different to include actors engaged in the system in practice (such as farmers,
disciplines and stakeholders in knowledge building and decision- agronomists, extension officers and so on) to assist decision-making
making processes. regarding NP use and regulation. This is both to obtain more com-
A One Health perspective could also facilitate the development of plete knowledge of the system and to ensure that any recommenda-
appropriate regulatory frameworks for nano-agritechnologies. The tions for management actions are viable and likely to be enacted.

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77. Malta Initiative Workshop Brussels. Nanosafety Cluster (11 December Journal peer review information: Nature Nanotechnology thanks Kristen Lyons and the
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78. Le, T. C. et al. An experimental and computational approach to the Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in
development of ZnO nanoparticles that are safe by design. Small 12, published maps and institutional affiliations.
3568–3577 (2016). © Springer Nature Limited 2019

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