Nanotechnology in animal production—Upstream assessment of applications

Livestock Science 130 (2010) 14–24

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Livestock Science j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / l i v s c i

Nanotechnology in animal production—Upstream assessment of applications☆ Jennifer Kuzma ⁎ Humphrey Institute of Public Affairs, University of Minnesota, 225 Humphrey Center, 301 19th Ave. S. Minneapolis, MN 55455, USA

a r t i c l e

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Keywords: Nanotechnology Policy Technology assessment

a b s t r a c t Agrifood nanotechnology is at critical stage in which analysis and deliberation can help shape funding priorities for research and development, risk assessment, and oversight activities. Significant benefits to society could arise from nanotechnology applied to animal production; however, there is a need to prepare for oversight, health and environmental safety, and other societal issues that are likely to arise from these applications. In this paper, I examine case studies of nanotechnology applied to animal production that are in research and development in order to demonstrate potential future challenges and opportunities associated with their market entry and diffusion. The case studies are analyzed from multiple viewpoints including potential societal benefits and risks, public perception, and other science and technology policy challenges. Broader conclusions about technical and policy preparation are derived from the case studies in order to help inform the development of the field of nanotechnology applied to animal production as it matures. The diversity of nanotechnology applications makes it difficult to discuss nanotechnology as a whole, yet it is suggested that dialogue and deliberation about specific cases and their associated issues prior to market entry can help to ensure the safe, responsible, and equitable deployment of nanotechnology to livestock production. © 2010 Elsevier B.V. All rights reserved.

1. Introduction Nanotechnology is receiving more attention in the past decade for its promise to improve food and agriculture through multiple applications and products. Nanotechnology, or as some prefer nanotechnologies1, has been defined by the U.S. National Nanotechnology Initiative (NNI) as “understanding and control of mater at dimensions of roughly 1 to 100 nm where unique phenomena enable novel applications”

☆ This article is part of the special issue entitled “10th World Conference on Animal Production (WCAP)” guest edited by Norman Casey. ⁎ Tel.: +1 612 625 6337. E-mail address: [email protected]. 1 Many believe that nanotechnology is a conglomerate of long-existing science and technologies, such as materials science, biochemistry, mechanical and chemical engineering, and aerosol science. In addition, some would prefer the use of the term “nanotechnologies” to reflect the diversity of techniques and approaches at the nano-scale (Kuzma, 2007). The author would like to acknowledge these viewpoints. 1871-1413/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.livsci.2010.02.006

(NNI, 2007). Nanotechnology is expected to revolutionize both science and society, and provide multiple benefits (Lane and Kalil, 2005). Special properties of nanomaterials include greater penetrability, reactivity, surface area, and quantum properties due to their size. These properties can allow for the use of less material and new or more efficient chemical and physical reactions in comparison to larger scale materials. Yet, there is concern about nanoparticles and their health and environmental effects for the very same reasons, in that greater toxicity and penetration could occur in biological systems (Oberdorster et al., 2005a; Maynard, 2007). As such, the applications of nanotechnology are thought to warrant special attention in risk analysis, regulatory policy, and oversight (Davies, 2007). Nanotechnology is being applied to food and agriculture, and awareness of agrifood nanotechnology has increased significantly over the past few years. There have been several key reports on agrifood nanotechnology which review the types of applications (Scott and Chen, 2003; Joseph and

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Morrison, 2006; Kuzma and VerHage, 2006), as well as reports that caution about risks and social issues (ETC, 2003; FOE, 2008). Currently, there are only a handful of food-related nanotechnology products on the market (PEN, 2008). Examples of nanomaterials in food products which are on the international market include food packaging nanocomposites to prevent spoilage, food storage containers with silver nanoparticles to inhibit microbial growth, nanoparticles to deliver nutraceuticals in food, and nanoformulations of food for better consistency and taste (FOE, 2008). Examples of nanotechnology applications used on the farm include nanoscale delivery of pesticides and soil-wetting agents (FOE, 2008). Many other applications of nanotechnology for food and agricultural production are being developed in research and development (R&D) settings. Key global challenges are associated with animal production, including environmental sustainability, human health, disease control, and food security. Nanotechnology holds promise for animal health, veterinary medicine, and other areas of animal production (Scott, 2005; Bollo, 2007; Narducci, 2007). In a 2006 database of agrifood nanotechnology R&D projects in the U.S., 26 out of 160 projects were classified as relevant to veterinary medicine, and several more projects were related to animal production (Kuzma and VerHage, 2006). Animal production and nanotechnology is an important area of R&D, however, there is not yet widespread use of it in the market (FOE, 2008). Thus, careful analysis of the potential technical, societal, and policy implications of these emerging applications is timely. The field of social studies of science and technology suggests that the public would like to be included in dialogue about emerging technologies, such as biotechnology and nanotechnology. They prefer mandatory regulation of products, oversight in the hands of trusted and independent actors, and access to information (Cobb and Macoubrie, 2004b; Macoubrie, 2006) . Acceptance of new products is affected by not only perceptions of risks and benefits, but trust in actors (Siegrist, 2000; Siegrist et al., 2007b) and the cultural orientation of messengers (Kahan et al., 2009). Animal production and nanotechnology is likely to spark some of the ethical and social concerns that genetic engineering and biotechnology have for animal production (Thompson, 2007). Animal welfare, safety of animal-derived products, risks to the environment and human health, and industry consolidation are among the many concerns that are likely to extend from biotechnology to nanotechnology. Furthermore, for many of the newest nanotechnology products proposed for livestock production, biotechnology and nanotechnology are inseparable, and the two converge in a particular products or applications. Thus, it is important to include the public as nanotechnology and livestock production matures. One way to involve the public and key stakeholders is through upstream dialogue. Scholars have called for upstream public engagement (UPE) to involve the public in discussions about emerging technological products well prior to market entry (Wilsdon and Willis, 2004). UPE can be complemented by multiple other upstream endeavors, including real-time technology assessment (RTAA), whereby engineers and scientists consider the social consequences of

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their work prior to the development of products from it (Guston and Sarewitz, 2002). In addition, upstream oversight assessment (UOA) has been proposed as a targeted activity that focuses on assessing the technical features of R&D projects, examining potential risks and benefits, exploring data needs for addressing the them, and suggesting societal oversight challenges and opportunities (Kuzma et al., 2008). In this paper, a UOA approach is taken to examine case studies of nanotechnology applied to animal production that are in R&D. Previous reports on nanotechnology and animal production have focused on general applications to veterinary medicine and animal health (Scott, 2005; Bollo, 2007; Narducci, 2007). Here, specific case studies are examined to explore potential benefits and risks and societal implications of broader applications of nanotechnology to livestock production. Issues associated with the case studies are identified with the objective that they be addressed prior to market entry in order to help prepare for the challenges and inform the development of the field. Given the diversity of applications of nanotechnology to livestock production, this case-study and upstream approach can be used as a starting point for public and stakeholder dialogue and engagement in order to ensure the safe, sustainable, and equitable deployment of nanotechnology for addressing global challenges related to livestock production. 2. Case study method The UOA methodology has been previously described (Kuzma et al., 2008). In this analysis, it has been modified to focus more on broader technical, oversight, and policy issues than specific laws and regulations in the United States for overseeing the products. The following questions guided the analysis in this paper: • What are the potential impacts on animal health, human health and the environment associated with the use of nanotechnology? • What are the types of data and information needed to address the uncertainties surrounding risks and benefits of the application? • What are the key oversight issues associated with the case study? Does the nanoscale application warrant additional or new oversight approaches? • What might be the broader social issues surrounding the product or application? Case studies were selected to represent a broad spectrum of potential and future nanotechnology applications to animal production. Several sources of information, including peerreviewed literature, government documents, and information from developers of products, were used to identify applications of nanotechnology for animal production, potential risks and benefits of products, data needs for assessing them, and oversight and societal issues. Literature searches were conducted to identify categories of applications, such as those for veterinary medicine (Scott, 2005) or other aspects or goals of animal production (Scott and Chen, 2003; Kuzma, 2007). Previously identified categories from the literature were considered, adjusted, and augmented to derive the following categories: I) pathogen detection and removal, II) veterinary

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medicine, III) feed improvement and waste remediation, IV) animal breeding and genetics, and V) identity preservation and tracking. These categories are not mutually exclusive, however, and specific cases transcend multiple categories (e.g. DNA delivery through nanocapsules for gene therapy transcends “animal breeding and genetics” and “veterinary medicine”). An agrifood nanotechnology R&D database (Kuzma and VerHage, 2006), published literature, and the web were searched to find examples in the categories. In each category, two specific examples were found that reflected different goals or materials. In total, ten case studies were chosen, two in each category (Table 1). Issues presented by each case study were identified from historical experience and literature associated with other emerging technologies in animal or agricultural production. The following sections are organized by the categories of applications, and two cases are discussed in each section (Sections 3–7). First, the technical elements of each case are described, and then the societal issues are discussed. Cross comparisons of the case studies and broader conclusions about nanotechnology and livestock production are presented in the concluding section. 3. Pathogen detection and removal The use of nanotechnology-based sensors (nanosensors) for detecting pathogens at various points in the food production chain is an active area of R&D. Nanotechnology can enable more sensitive and smaller sensing devices. Less material may be needed for nanosensors to accomplish the same or better level of detection. Nanomaterials are also being used to not only detect, but also bind and remove pathogens on the farm (Kuzma et al., 2008). In this category

of pathogen detection and removal, two examples are examined: 1) a nanotechnology based system to detect and remove foodborne pathogens from poultry and 2) a handheld nano-based detector to alert producers to foot-andmouth disease. The first case illustrates the end goal of human health protection, whereas the latter has the end goals of animal health protection and economic security. Both use nanomaterials to detect and remove pathogens with the ultimate goals of rapid, real-time miniaturized devices for doing so. The company Illuminaria has developed a system, called nanoDETECT for the rapid and portable detection and analysis of DNA (Illuminaria, 2009). This system is based on nanotechnology and is a hand-held device that uses the polymerase chain reaction (PCR) to rapidly detect pathogens in real-time and on-site. The company is targeting the food industry and regulatory agencies for the market for this system. The device is currently available for approximately $20,000. Illuminaria has an exclusive licensing agreement with Cornell University for the technology used in the nanoDETECT system and a patent for the technology. Although the detector is on the market, research and development (R&D) work on integrating the nanoDETECT system with a second system to remove pathogens has been funded by the United States Department of Agriculture (USDA) (Batt and Stelick, 2004). In this project, nanoscale immunomagnetic beads were studied for their ability to bind Salmonella typhimirium on the skin of chickens and remove them using magnetic recovery (Duncanson, 2004). The integrated system with abilities to both detect and remove pathogens before or during food processing of livestock could have great benefits in reducing the risk of food borne illness. However, if the nanoscale beads are used

Table 1 Typology of case studies. Number Category

Case description

Goals

Nanomaterials (if available)

IA

Nanodetector and immunomagnetic bead removal of S. typhi from chicken skin Nanodetector for Foot and Mouth Virus (FMV) Nanoparticles to deliver growth hormone to pigs Nanoparticles for delivery of vaccines into sheep or other livestock Nanoparticles to bind Camplyobacter in turkey

Food safety and human health

Antibodies with magnetic marker

Animal health and farm security

Nano-structured gold films, Single chain antibody Porcine somatotropin (pST) in PLGA-nanocapsule Polystyrene nano-beads linked to antigens

Pathogen detection and removal

B IIA

Veterinary medicine

B

IIIA

B IVA B

VA

B

Feed improvement and waste safety Animal breeding and genetics

Identity preservation and tracking

Increased production, economics of production Animal health, farm management

Environmental and human health safety, economics of production

Nanoparticles to detect contaminants in animal feed Nanofibers to deliver genes to animal cells Nanoparticles to assist in the delivery genes into livestock for genetic engineering of traits DNA chip to detect cytochrome b genes in feed and food

Animal health, food safety, environmental safety, and economics of production Generally to improve speed and ease (economics) of genetic manipulation; otherwise, depends on trait. Generally to improve speed and ease (economics) of genetic manipulation; otherwise, depends on trait. General improvement of animal health given non-viral vectors. Animal health, feed and food safety

Nanobarcodes to trace feed and animals from farm to fork.

Food and feed safety, market preservation.

Unknown polymeric nanoparticles (“P”) (PS-PEGmannose used as example) Europium nanoparticles Vertically Arrayed Carbon Nanofibres (VCNF) Silica nanoparticles

Oligonucleotide probes on glass surface using photonano-lithography Antibodies linked to gold and silver, and other metal-based nanobars

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in food processing, data on their collection from chicken skins would be needed to ensure that a high concentration is not left over in human food. Although the beads are not suspected to be highly toxic, data for risk assessment for this application is needed before widescale use. Oversight issues for this application might be complicated given its point of use in the farm to fork chain. For example, in the United States, The Poultry Products Inspection Act (1957) would likely come into play, but authorities of USDA and the Federal Food and Drug Administration (FDA) might be unclear. USDA provides for voluntary federal inspection of poultry and poultry products during processing, whereas FDA has authority for poultry product recalls if they are adulterated (CRS, 2008). If the beads were used in processing plants, both agencies could have an important role in oversight. Another societal issue involves access to the detection technology. It is currently under an exclusive licensing agreement and may not be available to small producers or developing countries. The second example in this category involves a hand-held detector for foot-and-mouth disease (FMD) virus. This work was funded by the USDA and is in R&D by Playtpus Technologies, LLC (Israel, 2002). In this project, the researchers proposed to make nanostructured gold films functionalized with a single chain antibody specific for the FMD virus. The gold films would have topography that matches the size of small viruses like FMD, enabling their detection. Platypus' technology relies on the sensitivity and movement of liquid crystals at the nano-scale in the presence of the target molecule. The company holds a patent for fabricating surfaces that control the orientation of liquid crystals in the presence and absence of specific target molecules (Platypus, 2008), and in this case FMD virus. FMD is a devastating disease of cattle and other ruminants that had severe consequences in the United Kingdom (Ward et al., 2004). Thus, a rapid, sensitive test for the virus prior to disease symptoms could have great benefits to animal health, and economic security of livestock producers and nations. In this case, nanotechnology is the key to enabling sensitive detection at a very small scale and its application poses little to risk (nanomaterials are bound in a hand-held detector) and great societal benefits. Policy issues again include the availability of the technology to all countries, given the intellectual property sought on the detection technology. Careful deployment of the detection systems would also need to be considered, as unnecessary panic and trade actions could result from false detection of FMD virus. 4. Veterinary medicine Previous reports broadly review the potential for nanotechnology in veterinary medicine (Scott, 2005; Bollo, 2007; Narducci, 2007). Applications are diverse, including injecting nanoshells of gold for cancer treatment, quantum dots for in vivo disease diagnosis, and nanoparticles for gene delivery. There is also speculation in the literature that eventually diseases could be detected, controlled, and treated in a “timecontrolled, spatially targeted, self-regulated, remotely regulated, pre-programmed” fashion through “smart systems integration” that rely on nanotechnology (Scott, 2005). However, significant research is needed in order to achieve

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the integration of the components, which will involve a convergence of nanotechnology, biotechnology, information technology, and geographical information systems. In this analysis, no specific examples were found of work in this area from the literature and web searches conducted, although it is likely occurring. Instead, two nearer-term applications of nanotechnology to veterinary medicine were chosen: the first uses nanospheres to deliver animal drugs, and the second involves nanoparticles to improve animal vaccination generally. Both projects are designed to improve the efficiency of drug delivery in animal production through the use of nanotechnology. The first case involves the timed release of growth hormones in swine to overcome the need to inject them on a daily basis. The researchers are exploring the use of poly (D,L-lactide-co-glycolide) copolymer (PLGA) nanocapsules to deliver porcine somatotropin (pST) in a time-controlled fashion (Luo, 2003). PLGA is generally non-toxic and approved by the FDA for human drug use. The nanocapsules would passively deliver the hormone by dissolving slowly. It is not clear whether this nano-scale formulation of a currently used and approved animal drug would need to undergo additional review by regulatory agencies. The FDA has jurisdiction for new animal drugs, and its current policy is to treat nanotechnology products like their larger scale counterparts (FDA, 2007). Nano-scale formulations of livestock hormones might be grandfathered in for approval and deemed substantially equivalent. In this case, that approach might be appropriate given the low toxicity of the nanocapsule and its use as only a delivery agent. Risks seem to be minimal in this case. However, in other cases, special review of the nanoparticle-based drug delivery could be important for ensuring food and animal safety. For example, active nanostructures for cancer treatment are being developed for use in livestock production and human medicine (Kitchell, 2001). Here, the researchers proposed to use “nanohybrid clay materials” containing inorganic materials such as magnesium and aluminum, and biomolecules as targeting molecules designed to specifically bind cancer cells and deliver drugs or genes to them. This approach could have great benefits by reducing the side effects of chemotherapy, but uncertainties surrounding the safety to animals and of animal-derived products would need to be addressed. Despite the minimal safety concerns associated with the use of PLGA-pST nanomaterials, this application could lead to adverse public perception given objections to the use of growth hormones such as pST in livestock. The general concerns about the safety of meat and poultry derived from growth-hormone treated livestock and the welfare of animals would likely persist and possibly affect general perceptions of nanotechnology for livestock production. Trade between the U.S., European Union and other countries could also be affected, as meat from hormone treated livestock is banned in some countries (Brower, 2001). Upstream public engagement and education could be valuable in this case to distinguish between general concerns associated with hormones in livestock production and the use of nanotechnology. The second case involves the delivery of animal vaccines using nanotechnology. Adjuvants formulated with nanobeads of polystyrene are being developed to increase vaccine

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effectiveness without the inflammatory responses that arise from the use of other adjuvants (Scheerlinck et al., 2006) Scheerlinck et al. (2006) linked polystyrene nanoparticles to ovalbumin and then injected them into sheep. They found no adverse reactions at the injection sites when compared to controls (Scheerlinck et al., 2006) and hypothesize that the small, nanometer size of the adjuvant (50 nm) mimics the size of viruses and is thus well-tolerated by animal cells. Avoiding side effects of vaccination through the use of nanobead adjuvants could improve animal health and onfarm production. There seem to be few risks to animals associated with the nano-beads in this case, as polystyrene is generally non-toxic. However, longer term studies on the safety of animal products derived from the use of nanobead adjuvants for vaccines might be needed, although one can expect the products to be safe, given the low dose of vaccines and biocompatibility of the polystyrene beads. This application would likely fall under laws that govern veterinary biologics or new animal drugs, which in the U.S. are executed by the USDA and FDA. Another important case study of nanotechnology for veterinary medicine includes the delivery of genetic material in nanoparticles for gene therapy. It is discussed in the “animal breeding and genetics” category, as it involves the introduction of genetic material and thus overlaps the two categories. 5. Feed improvement and waste remediation For animal, human, and environmental health, and optimal farm-scale economics, the quality and safety of inputs, outputs, and by-products of animal production are crucial. This category focuses on the use of nanotechnology to enhance the safety of animal feed and waste. In both cases, nanotechnology is an enabling tool. The first case study focuses on the detection of pathogens in turkey litter, and thus overlaps with the “pathogen detection and removal” category. The second case study uses nanoparticles to enhance detection of a variety of chemical and microbial contaminants in feed. Poultry production facilities have been encouraged to become more environmentally friendly, as they have been significant sources of air, water, and soil pollution, as well as human pathogens. The project in this case study focuses on remediation methods for turkey litter via the use of polymeric nanoparticles to bind and remove Campylobacter sp. (Grimes, 2001). Poultry is a key source of Campylobacter infection in humans, and its prevalence on carcasses is very high (close to 100% in some cases) (Keener et al., 2006). Currently, there are few good options for reducing Campylobacter in poultry production and processing (Keener et al., 2006). In this project, the researchers proposed to reduce Campylobacter in vivo using polymeric nanoparticles fed to turkey (Grimes, 2001). Here, the treatment of feed and waste converge. Although the project description does not specify the composition of nanoparticles, a similar case was analyzed in our previous work (Kuzma et al., 2008). Latour et al. (2003) proposed a project to develop a nanoparticle consisting of a polystyrene (PS) base, polyethylene gycol (PEG) linker, and mannose targeting-biomolecule that adheres to E. coli (Latour et al., 2003). The idea is that the particles would bind the pathogens in the gut of livestock to prevent colonization and

growth. Pathogens would be removed in the waste. Similar particles could be designed specifically for Campylobacter in turkey, as proposed in this case (Grimes, 2001). Nanoparticles in feed could provide a commercial alternative to non-therapeutic uses of antibiotics in poultry production. Antimicrobial resistance seems to be increasing in foodborne pathogens such as Campylobacter, with consequences for human foodborne disease treatment (Anderson et al., 2003) The nanoparticles could replace traditional sub-therapeutic uses of antibiotics such as tetracyclines, penicillins, macrolides, and lincomycin which are also used in human medicine and decrease the development of antibiotic-resistant bacteria. However, there might be some risks to animal health from the use of the nanoparticles and concern about these particles ending up in animal-derived food products. Health risks of PS-PEG nanoparticles have been previously investigated (Taylor et al., 2004; Molugu et al., 2006), and in one recent toxicological study with mannoselinked PS-PEG nanoparticles, low level toxic effects to human colon fibroblasts were observed (Molugu et al. 2006). However, overall, PEG has a low degree of immunogenicity and antigenicity and is essentially chemically inert (Moghimi, 2002), and no effects were observed for other cell types and tissues (Molugu et al., 2006). Although the benefits could be potentially great from the use of these particles, more toxicology tests seem warranted before wide-scale use. More detailed studies are needed to determine if and where the particles accumulate in animal tissue, the impacts on meat and poultry products, and environmental exposure and effects from animal wastes containing the particles. Oversight challenges associated with this case study largely stem from its convergent nature. This application spans technologies (nano and biotechnology) and sectors (farm, ecosystems, food production), and oversight authorities do not seem clear. Regulations for animal production on the farm exist, but there are several statutes and agencies involved in food production and safety, which can sometimes lead to ineffectiveness, gaps and overlaps (NRC, 1998). Before such nanoparticles go into widespread use on the farm, authorities and agencies will need to be coordinated to ensure effective oversight. In the U.S., the particles could be regulated as “animal drugs” (regardless of administration route), “feed additives,” “feed ingredients” by the FDA or “veterinary biologics” by the USDA, and the environmental effects of these nanoparticles would need to be considered under the National Environmental Protection Act (1969) and Clean Water Act (1977) which is administered by the Environmental Protection Agency (EPA). Broader oversight issues associated with this case study include public perception of the long-term risks and benefits of using these targeted nanoparticles in comparison to using antibiotics. There is considerable public skepticism concerning the sub-therapeutic use of antibiotics in animal feed. It seems as if nanoparticles for pathogen removal on farm and in vivo could evoke positive or negative reactions, depending on stakeholder trust, access to information, risks and benefits, and effective oversight (Macoubrie, 2005; Siegrist et al., 2007b). The second case in this category involves the use of nanoparticles to amplify the detection and degradation of chemical or microbial contaminants in feed. Europium nanoparticles are used to detect enzymes, such as hydrolases

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and epoxidases, that degrade foreign, toxic compounds common in feed (Hammock, 2003). Europium emits light at a very specific wavelength when excited and improves the sensitivity of biochemical assays (Harma et al., 2001). The europium nanoparticles would be used to develop rapid assays at higher sensitivity, lower cost and better ease of use. The development of rapid methods for the identification of foreign compounds in feed is important for animal health and safety of food derived from animal products. Most assays using these nanoparticles for feed detection would be conducted in laboratory settings or on prepared samples, therefore, there are few safety issues involved with them. Safety of workers should receive some attention, however, if used in a wide-scale or in the field. Europium is a rare earth, heavy metal (atomic number 63) and is classified as moderately to highly toxic, although there are few toxicity studies on it. The Material Safety Data Sheet (MSDS) indicates that “the rare earth elements exhibit low toxicity by ingestion exposure. However, the intraperitoneal route is highly toxic while the subcutaneous route is poison to moderately toxic. The production of skin and lung granuloma after exposure to them requires extensive protection to prevent such exposure” (ESPI, 2008). Disposal of waste from the feed assays and protection of workers, including those on the farm, should be carefully considered before widespread use. A potential oversight issue is whether nanoparticles containing Europium would be considered a “new chemical” under the Toxic Substances Control Act (TSCA) in the U.S. or under the Registration, Evaluation and Chemicals Act (REACH) in the EU, given that the bulk chemical is already registered under existing laws. There is no current international policy on whether nanochemicals should be treated as “new” under existing laws and whether they should require additional safety testing in comparison to the bulk materials. Some have argued that there should be such a policy (Davies, 2007) given the special properties of nanomaterials, including increased reactivity, toxicity at lower doses, adsorption, and penetration through living systems (Oberdorster et al., 2005a). Another example in this category involves the use of nanoparticles containing DNA to track hydrological flows through agricultural landscapes, which has been previously examined (Kuzma et al., 2008), but is worth noting here to illustrate the diversity of applications in this category. The nanoparticles used in this project are composed of PLGAchitosan shells containing various sequences of DNA (Walter et al., 2005). They are designed for release into the environment and used to track sources and movement of agricultural waste. This application has important potential benefits for increasing basic understanding of watersheds and locating sources of non-point source (NPS) pollution. Given the diversity of DNA sequences and abilities to detect low amounts (e.g. through the polymerase chain reaction), this application of nanotechnology could greatly enhance abilities to determine where NPS originates, travels, and resides in agroecosystems. For this application, it is important to investigate how the encapsulated DNA molecules interact with organisms in the environment and what oversight systems would be employed to ensure environmental safety given its convergent nature (reviewed in (Kuzma et al., 2008). Public perception of the release of DNA into the environment would also need to be considered.

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6. Animal breeding For centuries, animals have been bred for important characteristics such as disease resistance, improved performance and growth, and product quality. In the past decade, genetic engineering of several livestock species has been achieved. Genetic engineering can speed the process of introducing desirable traits into livestock and allows for the introduction of entirely new ones (NRC, 2002). Pharmaceutical production in the milk of cows and goats has been possible through GE, and animals are being engineered for resistance to diseases like BSE, improved meat quality, and better feed processing to eliminate pollutants in their waste (reviewed in (van Eenennmaan, 2005). In the U.S., the FDA recently provided guidance on a regulatory approval process for genetically engineered fish as “new animal drugs” under the Federal Food, Drug, and Cosmetic Act (FDA, 2008). Currently, no GE livestock have been approved for consumption, although a glowing GE fish is available for purchase in pet stores. GE of livestock is faced with technical challenges that nanotechnology might be able to overcome. In this category, two examples of genetic engineering through the use of nanoparticles are examined. The first uses nanoparticles bound on a matrix to deliver DNA into livestock embryos for temporal expression and selection of genes. The second involves free-standing nanoparticles to deliver genes into embryos for germline modification of livestock or into adult animal tissues for gene therapy. Both case studies are not, to the knowledge of the author, being specifically applied to livestock breeding, but they have been described for mammalian genetic engineering. Therefore, the ultimate purpose of the engineering (e.g. particular traits or DNA introduced) is not the focus of the discussion, but the technique and nanomaterials used are. Microinjection to deliver DNA into mammalian cells is time-consuming and needs to be precise, using micropipets and micromanipulators to dispense very small volumes of material past into the nucleus. Microinjection is the common method for mammalian genetic engineering and the making of GE livestock. A novel method of DNA delivery has recently been described using arrays of vertically aligned carbon nanofibers (VACNFs) (McKnight et al., 2003). Cells are pressed onto the DNA-coated VACNFs which then penetrate the cells and introduce the DNA. VACNFs could help to overcome the tedious microinjection involved in genetic manipulation of livestock as well as allow for the temporal expression of genes that are not introduced into the inheritable genetic material of embryos but could affect them at crucial times (McKnight et al., 2003). This temporary expression could ameliorate the concerns that have accompanied GE livestock, including safety of GE animal food and products, cross contamination of GE livestock with non-GE varieties, and long-term effects on animal health and welfare from introduced genes (NRC, 2002, 2004). The VACNF technique could also be used to select livestock embryos with certain genetic characteristics. Hundreds of VACNFs could be aligned on a microarray screen multiple embryos at a time for desirable traits, and thus lead to more economic and efficient methods of livestock breeding. The second case also involves nanoparticles for delivery of DNA into livestock, but they are free-floating rather than

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bound to a matrix as in the case of VACNFs. Due to the growing concerns over the toxicity and immunogenicity of viral DNA delivery systems for mammalian GE, DNA delivery via nonviral routes has become more desirable. Silica nanoparticles are being investigated for the delivery of DNA into mammalian cells (Luo et al., 2004). Dense silica nanoparticles enhance the uptake of DNA by cells at their surface and increase the efficiency of DNA delivery when compared to other chemical transfection systems that are not based on viruses. Silica nanoparticles bind and to protect plasmid DNA in vitro and could thus be used to modify animal cells in vitro (Kneuer et al., 2000). The researchers hold a patent on the silica nanoparticle technology with the following claims: “1. A method of enhancing the delivery of nucleic acids into cells in vitro comprising the steps of: a) forming nucleic acid-transfecting agent complexes; b) contacting the nucleic acid-transfecting agent complexes with silica nanoparticles to form nucleic acid-transfecting agentnanoparticle complexes; and c) incubating the nucleic acid-transfecting agent-nanoparticle complexes with the cells so as to allow the nucleic acid-transfecting agentnanoparticle complexes to sediment on to the cells during or prior to transfection, wherein the delivery of said nucleic acids into said cells is enhanced by said complexes, and wherein the transfecting agent is selected from the group consisting of lipid agent and polymer agent.” (Luo et al., 2000) The use of non-viral enabled transfection systems could greatly improve the process of genetic engineering of livestock and help address concerns about the impact of viral vectors on animal health. Viral vectors in human gene therapy have been suspected in death and leukemia-like disorders (Thomas et al., 2003). The use of nanotechnology for DNA delivery could provide benefits to animal health and the safety of animalderived products. However, the safety of the silica nanoparticles and their effects on early embryo development posttreatment warrant some investigation, although they have been shown to have little toxicity (Luo et al., 2004). Public reaction to this nexus between nanotechnology and biotechnology would need to be considered, and animal products derived from GE livestock with silica nanoparticles would likely be perceived as having similar social, ethical, and safety concerns as those derived from other GE methods. Regulatory oversight for GE animals made via nanoparticle transfection would likely be subject to the same laws as other GE animals, although authorities should be examined to ensure that this is the case. Another issue is access to the technology of silica nanoparticles for GE, as the claims in the patent for nanoparticle silica transfection systems are broad. Other biotechnology patents on enabling methods for genetic engineering in agricultural biotechnology have posed problems to researchers in academe, smaller companies, and developing countries (Graff et al., 2003). 7. Identity preservation and supply-chain tracking Knowing where livestock and their feed sources come from and are going helps to prevent the spread of diseases

such as foot-and-mouth, tuberculosis, avian influenza, and bovine spongiform encelphalopathy (BSE). Identity preservation and tracking has been the subject of intense activity and research. In the United States, a National Animal Identification System (NAIS) has been established to encourage those who work with livestock to register their premises so that disease control experts can better track the origin of contagious diseases in the event of a crisis, accidental or otherwise (USDA, 2009). Nanotechnology-based detection and tracking systems are being developed for streamlining and enhancing identification and tracking systems. This category considers two examples of its use for identification and tracking of animal feed and food products through the supply chain. The first example utilizes nanotechnology in a hand-held device, the FoodExpertID, that detects animal cytochrome b genes in food or feed products (bioMerieux, 2004). In the device, tens of thousands of oligonucleotide probes are synthesized onto a glass using photo-nano-lithography. The device embeds DNA microarray or chip technology to bind to specific vertebrate cytochrome b genes and enable the detection and identification of multiple species in sample. The profile of cytochrome b genes can be translated into the origins of the food or feed sample and the identification of the types of animals used for the product. The product is being targeted for use in the feed and food industries. In the words of the manufacturing company, “FoodExpert-ID software is based on the unique DNA signature of the product. This report constitutes the ‘Identity Card’ of the animal species entering into the composition of the product, thereby providing an invaluable tool to ensure labelling accuracy. FoodExpert-ID contributes to traceability and quality assurance in the food and feed industry through species identification at every step of the manufacturing chain ‘from farm to fork’” (bioMerieux, 2004). The small size of the device with a high density of individual cytochrome b assays enables multi-sampling on a smaller chip, potentially decreasing the cost of production and environmental waste, as well as the efficiency of use (i.e. more reactions per assay). Enhanced animal and product safety, regulatory compliance, and product integrity are all potential benefits of this technology. For example, cattle feed could be screened for ruminant protein for compliance with the feed safety regulations to prevent the spread of BSE through contaminated feed. There are few risks to human, animal health or the environment that accompany the use of this device. Privacy issues, intellectual property, and other legal issues could arise from the deployment of the devices. For example, companies could test other companies' products to see whether the products are what they claim to be or to reveal secret mixtures in food or feed products. A second case in this category involves nanotechnology bar codes for supply chain tracking. Like the FoodExpertID chip discussed above, nanobarcodes have been proposed for use in monitoring and tracking of feed supply components. For example, Jayarao et al. (2009) propose to use nanobarcodes particles that are made of metals such as platinum, gold, silver and nickel stripes to track rendered animal byproducts and ensure that they do not end up in ruminant feed so that the spread of BSE does not occur (Jayarao et al., 2009).

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The metal stripes on the nanobarcodes can be varied to individualize the product like a fingerprint and read with an optical microscope for product identification. The width and composition of the stripes can be varied like conventional product bar codes to provide individual tags that can be quickly scanned. Nanoplex Technologies, a start-up company acquired by Oxonica in 2006, is also working on similar Nanobarcodes™, including ones made of platinum, palladium, nickel and cobalt. In their nanobarcodes, metallic stripes are also linked to antibodies to detect analytes in the product (Nanoplex, Technologies, 2006). The diameter of these barcodes ranges from 50 nm to microns, and the length from 200 nm to microns. The company has proprietary software for decoding the nanobarcodes (Nathan, 2009). Unlike the first case study using the external FoodExpertID device, nanobarcodes could be directly added to products and feed, and injected into livestock as they move through the breeding and production chain. In the words of Scott (2005): “The future of the meat industry may well depend on an ability to track all stages in the life of the product, including the birth of the animal, its medical history, and its movements between the ranch, the slaughterhouse and the meat-packing plant, right through to the consumer's table. Of course, a major issue exists with regard to biodegradable nanoparticles in the steak!”(Scott, 2005) The use of nanobarcodes for animal breeding is also being considered. Ones that have the ability to detect analytes could be used for assessing the hormonal state of dairy and swine animals in vivo to better control the timing of breeding (Scott, 2005). In this case, the nanobarcodes would be implanted under the skin and sensed remotely using infrared fluorescence. The covert use of these tags and the ability to read them remotely with only proprietary software needs to be considered with respect to the social and ethical ramifications. These applications concern some consumer groups, as they believe that the ability of nanobarcodes to serve as identification tags could have downsides with regard to privacy and information piracy. Tags could be added to animals and their products without consumer or stakeholder knowledge, and private information on the use of products could be collected (ETC, 2003; FOE, 2008). If nanobarcodes linked to antibodies for the detection of analytes are used, they could possibly enter the body and collect information on human genetics or healthstates. Environmental and health risks and benefits should also be considered. If the nanobarcodes are used in animals or human food products themselves, any potential risks from the metals or antibodies used would need to be studied. Regardless, the nanobarcodes could have great benefits for tracking feed contaminants, tracing animals and their products, and ensuring the safety of food. 8. Summary Animal production faces great challenges in light of a growing human population, the increased need for animal products, and continued environmental degradation and constraints. Nanotechnology can help to address these challenges. It is not a silver bullet, but involves an enabling

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set of applications, methods, and tools that can be of assistance if appropriately deployed within social contexts. The above cases illustrate the potential benefits of nanotechnology in improving the economics of production, animal health, environmental safety, product safety and quality, and human health (Table 1). The applications of nanotechnology to animal production are very diverse. This paper has examined several, but they are just a sample of what is in R&D and what is possible for future market deployment. It is clear from the diversity of above cases that discussing nanotechnology as a whole, and even within the constraints of livestock production, is very difficult. Risks, benefits and societal issues depend on the specific area of application, composition of the nanomaterials, methods of deployment, and the ultimate goals. However, the product-basis of issues should not prevent us from trying to think upstream about nanotechnology and livestock as a field of development. Upstream analysis can help us to maximize benefits and minimize risks, develop sound oversight systems, address socioeconomic impacts, and engage the public not only for democratic and ethical reasons, but also to ensure confidence in nanotechnology and animal production. Five primary categories were developed based on goals and point of application in the animal production: pathogen detection and removal, veterinary medicine, feed improvement and waste safety, animal genetics & breeding, and identity preservation and tracking. Two brief cases were presented in each category to illustrate the diversity within categories and to help understand the types of issues which will likely accompany nanotechnology in livestock production. From this analysis, it is clear that the societal issues do not neatly align with the categories of applications, although some generalizations can be made. Adverse public perception seems to be of most concern in the area animal breeding and genetics, privacy issues in the area of identity preservation and tracking, food and environmental safety in the use of free-standing nanoparticles to remove pathogens in vivo, and animal welfare in veterinary medicine. However, many issues transcend category boundaries. Intellectual property rights and access to the technologies for developing countries or small-scale, resource poor producers in any nation is one overarching issue (Invernizzi and Foladori, 2005). The cases in this paper highlighting IPR issues include those in pathogen detection and removal system, animal breeding and genetics, and identity preservation and tracking categories. It is important to note that most of the issues associated with nanotechnology and animal production, including those discussed in this paper, are not unique to nanotechnology, but reflect larger science and technology policy issues that society wrestles with for any emerging technology. One notable exception is the quantitative level of risk of free-floating nanoparticles to human health and the environment. Current regulatory standards are mass or concentration based, and given the increased toxicology of nanoparticles at lower doses when compared to larger or bulk versions of products, this is a significant concern (Maynard, 2007). As discussed previously, nanoparticles have been shown to penetrate through biological systems more readily and exhibit greater reactivity (Oberdorster et al., 2005b). Whenever nanoparticles are injected into

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animals, released or deposited into the environment, or end up in the food or feed supply, there is reason to be diligent about collecting data for risk assessment and taking more careful routes of regulatory approval. Oversight issues seem to be most prominent for convergent nanotechnology products that span technologies (e.g. bio-, information, and nano-technologies), media (e.g. land, water, air), sectors of the food supply chain (e.g. on-farm, processing, retail), and intended uses (e.g. detection, monitoring, improved health), as they often do not fall neatly under the arm of one law, agency, or industry (Kuzma et al., 2008). In other cases, the laws and institutions responsible for oversight may be clear, but the main issue is whether the nanoscale application would trigger pre-market review, especially when the macro- or micro-scale version of the product has already been approved. Given the special toxicological and penetration properties of nanomaterials, grandfathering nanobased products under the approval of larger scale versions could be problematic for ensuring safety (Davies; Davies, 2007; Maynard, 2007). Government organizations are currently considering how best to oversee the applications and products of nanotechnology. The European Food Safety Authority recently published a report on food and feed safety and nanotechnology, which supports the importance of risk assessment and stresses the special properties of nanoparticles which warrant attention (EFSA, 2009). The report highlights the uncertainty stemming from a lack of data and information on feed and food safety and nanotechnology, stating that “specific uncertainties apply to the difficulty to characterize, detect and measure ENMs (engineering nanomaterials) in food/feed and biological matrices and the limited information available in relation to aspects of toxicokinetics and toxicology. There is limited knowledge of current usage levels and (likely) exposure from possible applications and products in the food and feed area.” Some NGOs are carefully following agrifood nanotechnology and raising concerns about oversight (ETC, 2003; FOE, 2008), although agrifood nanotechnology oversight has not been an area of government focus in the United States. Most of the U.S. oversight debate has been focused on chemicals, cosmetics, and consumer product oversight. In these areas, several non-profit organizations are concerned with oversight approaches and have petitioned agencies for tighter regulations. These groups have suggested principles for oversight that are based on mandatory, nano-specific regulations, transparency, and public participation (ICTA, 2007). In areas of uncertainty, whether in risk assessment or oversight regimes, it has been suggested that the public be consulted and informed, in order to engender trust, reduce fear, and impart abilities to control their own exposure (Slovic, 1987; NRC, 1996). Public attitudes towards nanotechnology are being actively studied, and results suggest that there is not a wide-spread fear or adverse association with it yet. One study suggests that nanotechnology is seen overall as less risky than biotechnology (Currall et al., 2006). However, public attitudes and acceptance highly depends on the type of product being considered (Siegrist et al., 2007a). Applications that involve free-standing nanoparticles in

animals, animal-derived products, or the environment may be of greatest concern to the public in comparison to sensors or laboratory assays based on nanotechnology for which human, animal, or environmental exposure is very low. This is consistent with the results of Siegrist et al. (2007a) in that the public was more willing to accept nanoparticles bound in food packaging materials than free-standing nanoparticles in food. Other studies suggest that the public is excited about the benefits of nanotechnology, but prefers mandatory oversight, access to information, and opportunities for input (Cobb and Macoubrie, 2004a; Macoubrie, 2006). Public input into decision making about emerging technologies oversight is important for normative and democratic reasons and has also been suggested as a way to improve decision making in the face of uncertainty. Traditional paradigms for risk analysis (i.e., a linear risk assessment, risk management, and risk communication paradigm) have focused on using technical information for assessment and management and then communicating the final results and decisions to the public (NRC, 1983). However, there has been a shift in thinking about the role of key stakeholders to more direct and active inclusion at various stages in the risk analysis process. The National Academy of Sciences' National Research Council has argued for active participation of “interested and affected” parties in upstream planning for risk analysis and at other key stages (NRC, 1996). There are historical examples in which analytical-deliberative approaches to risk analysis have improved the results of the analysis and led to appropriate mitigation solutions that would not have otherwise been considered by experts (NRC, 1996). Deliberative engagement efforts should be considered for several applications of agrifood nanotechnology, especially those related to technological applications that have been contentious in the past and evoke important value choices (e.g. engineered DNA, antibiotics in food), as well as those that lead to direct animal or human exposure, such as free-floating nanoparticles in animal products, animal care, or the environment. The case study approach used in this paper could prove useful for a starting point for analytical-deliberative processes and public engagement. Upstream public engagement (Wilsdon and Willis, 2004) could focus on specific examples of nanotechnology applied to livestock production in order to help stakeholders and decision makers set funding priorities, coordinate oversight mechanisms, and address social and ethical issues of most concern to the public (Kuzma et al., 2008). Examination of emerging nanoproducts through an upstream oversight assessment (UOA) process is not intended to predict the future with accuracy, but rather to help anticipate issues and data, resource, and coordination needs. Analyses such as this one can be used to begin more comprehensive and nuanced conversations among interested publics, diverse experts, stakeholders, and policy makers to ensure the safe, responsible, and equitable deployment of nanotechnology for livestock production, so that the benefits of it in the face of global challenges can be fully realized. Acknowledgements This work was supported in part by National Science Foundation NIRT Grant SES-0608791. Any opinions, findings, and conclusions or recommendations expressed in this article are those of the authors and do not necessarily reflect the

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views of the National Science Foundation. The author would like to thank Laura Yerhot, Research Assistant and MS candidate at the Humphrey Institute, for her initial literature review on the subject.

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