Assessing the Safety of Nanomaterials in Food (Online Exclusive)

IFT supports the advancement of innovation and communication surrounding nanoscale science, engineering, and technology to realize the full potential for positive contributions to the food and nutrition needs of our growing global population. During the past five years, IFT has led collaboration and information exchange on food nanotechnology among the regulatory, research, and policy communities through coordination of several International Food Nanoscience Conferences, webinars, and short courses, and establishing a topical section in the Journal of Food Science (IFT 2010). IFT also initiated a collaborative research team that led an assessment of the state of the science on the safety of nanotechnology in food-related applications.

Currently, a significant barrier to innovation is the scientific uncertainty about toxicity of nanomaterials and how safety should be assessed. Engineered nanomaterials present new challenges to toxicology and risk assessment because their surface-active properties can affect their interactions with biological systems. Furthermore, these properties are not necessarily static―they can be affected by the nanomaterial’s surroundings.

With the collaboration and support of IFT, the Grocery Manufacturers of America, International Life Sciences Institute of North America, U.S. Food and Drug Administration (FDA), and Nanotechnology Characterization Laboratory (NCL), CANTOX Health Sciences, an Intertek Co. (Mississauga, Ontario, Canada) conducted a scientific review and analysis of the literature pertaining to the safety of food-related nanoscale materials that were administered orally. Components of this activity and findings, summarized below, were addressed in extensive detail in peer-reviewed publications, namely Journal of Food Science, International Journal of Toxicology, and Critical Reviews in Toxicology.

Physicochemical Parameters
The first component of the literature assessment was the recognition by Card and Magnuson (2009) that a minimum set of physicochemical parameters needs to be established to characterize test materials used in research into the biological activities of nanomaterials, and that articles submitted for publication be evaluated according to how well these physicochemical parameters are characterized and reported. Developed from the characteristics most frequently suggested by six international expert sources, the physicochemical parameters proposed as a minimum that should be characterized regardless of the route of exposure were:

• agglomeration and/or aggregation
• chemical composition
• crystal structure/crystallinity
• particle size/size distribution
• purity
• shape
• surface area
• surface charge
• surface chemistry, including composition and reactivity

Because some parameters could likely be different for a nanomaterial in experimental media than for the nanomaterial in bulk “as received” state, Card and Magnuson indicated that they agree with others that these parameters must also be documented in the experimental exposure media to the greatest extent possible. Card and Magnuson (2009) acknowledged that some parameters, such as purity, would be a challenge to accurately describe or measure, but stated that a dialog on these issues through the attempted reporting of a set of physicochemical parameters would be valuable.

--- PAGE BREAK ---

Assessing Study Quality
Card and Magnuson (2010) developed a two-step “Nano Study Score” method to assess the reliability and quality of reported studies of the toxicity of engineered nanomaterials. The first step evaluates study reliability with a publicly available tool (i.e., ToxRTool, European Centre for the Validation of Alternative Methods) that the assessor uses to systematically evaluate the adequacy of the experimental design and documentation of materials, methods, and results of the study. This step produces a “study score”—ranging from K1 (i.e., reliable without restrictions) to K4 (i.e., not assignable due to insufficient experimental details)—which is derived from answers to questions about study design, test article, test organism, and documented results.

The second step specifically evaluates completeness of the physicochemical characterization of the assessed nanomaterial using the recommended set of minimum physicochemical parameters, and considers whether characterization was conducted in the relevant experimental media. This step produces a “nanomaterial score”—ranging from N0 (i.e., no characterization) to N10 (i.e., extensive characterization). Recognizing that some parameters (e.g., crystallinity) in the minimum set would not be relevant to specific nanomaterials (e.g., carbon nanotubes), the Nano Study Score method might evolve to nanomaterial-specific parameter lists to avoid such issues. Card and Magnuson suggest that the Nano Study Score evaluation can assist in research study design, and contribute to consistent and transparent study reporting, review, and interpretation.

Oral Exposure to Food-Related Nanomaterials
To conduct the comprehensive literature search, Card and others (2011) selected 53 nano-related root terms and used them in relation to 58 terms and root words related to food, food packaging, food safety, oral exposure, and in vitro studies and used these terms to search eight scientific databases. The search revealed 30 articles (21 in vivo, nine in vitro) involving oral exposure of nanomaterials having potential food-related applications, which assessed at least one toxicological endpoint. They then used the Nano Study Score method to review and analyze the identified studies. With this approach, they scored six of the 21 in vivo studies as K1 (i.e., reliable without restriction) and 15 as K2 (i.e., reliable with restrictions, due to lack of key elements of standard experimental design). Of the nine in vitro studies, eight were scored as K1 and one was scored K3 (i.e., unreliable, based on unacceptable methodology).

Card and others (2011) noted that although they scored most in vitro studies as K1, significant limitations not identified by ToxRTool were present (e.g., lack of discussion of the potential interference of the nanomaterial in the assay). They also found that characterization data were noticeably lacking in the 30 studies; few reported more than five physicochemical parameters for the nanomaterial(s) investigated, although an upward trend in more recently published studies was observed. They stated that to further understand the safety of oral exposure to food-related nanomaterials, there is a great need for toxicology studies of increased breadth, quality, and duration that investigate different types of nanomaterials with a variety of physicochemical characteristics.

Card and colleagues (2011) also reviewed a number of non-toxicity studies that addressed pharmacokinetic/toxicokinetics properties of orally administered nanomaterials, which they considered pertinent to gaining a better understanding of biological activity of orally administered nanomaterials potentially relevant to foods or food manufacturing. For example, they noted that several of the studies (Russell-Jones and others, 1999; Astete and Sabliov, 2006; Rohner and others, 2007; Zha and others, 2008; Chen and others, 2008) reported that nano-formulations can enhance the absorption and bioavailability of nutritional supplements or vitamins. The nano-formulations were achieved through size reduction, encapsulation, emulsion technology, and incorporation of nutrients with specific receptor-mediated uptake. Card and colleagues (2011) also saw evidence among the studies that the toxicity of a nano-formulation of a substance is not always greater than the conventional (non-nano) formulation. Thus, it is possible to generate nanomaterials that provide benefit and do not have adverse biological effects at levels to be used in food-related applications.

--- PAGE BREAK ---

Occurrence, Use, and Safety of Food-Related Nanomaterials
A review (Magnuson and others, 2011) of the process and results of the comprehensive literature assessment is published in the August issue of Journal of Food Science. Read the open-access article “A Brief Review of the Occurrence, Use, and Safety of Food-Related Nanomaterials.”

Included in the review is a brief overview of the occurrence and use of food-related nanomaterials. The authors mentioned the natural presence of nanomaterials and nanostructures in plant and animal products, citing DNA molecules, casein micelles, whey proteins, lactose, muscle structure of meats and fish, and pectin nanostructure of fruits. They indicated that the structure and function of naturally occurring nanomaterials in foods could be modeled to develop new beneficial applications. Examples include the self-assembling properties of milk proteins for encapsulating agents, viscosifiers, and coatings (Graveland-Bikker and others 2006; Semo and others 2007) and the nanostructure of meat and fish proteins for alternative, non-animal protein sources (Yang and others 2007).

Magnuson and others (2011) reviewed the research and development of engineered nanomaterials for a variety of applications, including nutrient and bioactive delivery systems, improved texture and flavor encapsulation; improved microbiological control, food processing, packaging, and package biodegradability; and highly sensitive biosensors for detecting pathogens, allergens, contaminants, and degradants. Novel structures are also being developed for a number of specific uses, such as nanoemulsions for enhanced water solubility/dispersibility of substances.

Magnuson and others (2011) mentioned contaminants as sources of unintentional nanomaterials in foods. Unintentional sources include environmental contamination from other industries, nanomaterials used in agricultural production, unintentional release from nanomaterial-containing food packaging, and residues from nanomaterials used as food processing aids or surface coatings on equipment (Magnuson 2009). Their review described the challenges that nanomaterials present for detection, measurement, modeling, and exposure assessment. Magnuson and others (2011) said the outcome of the literature assessment described by Card and others (2011) shows the need for further food-related and health-related studies, which will advance as nanomaterial-specific analytical tools improve and well-designed safety studies with adequate characterization are conducted.

Since the publication of these papers, the European Food Safety Authority (EFSA) published the first practical guidance for assessing the risks of nanoscience and nanotechnologies in food and feed (EFSA, 2011). Consistent with Card and others (2011), EFSA stressed the importance of adequate physicochemical characterization of the forms of engineered nanomaterials in food/feed products and under testing conditions.

In June, the U.S. FDA announced the availability for comment of draft guidance intended to help industry and others to identify when they should consider the potential implications for regulatory status, safety, effectiveness, or public health impact that may arise with applications of nanotechnology in FDA regulated products. To view the draft guidance, please visit http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/ucm257926.htm. As realization of the need to characterize the nanoproperties of research materials and product applications continues to grow, a challenge for researchers may be the lack of general availability of resources and methodologies for performing the necessary measurements.

--- PAGE BREAK ---

Future Activity
The collaborative research team (i.e., IFT, GMA, ILSI North America, U.S. FDA, and NCL) plans to develop a framework to implement widespread cross-disciplinary and transnational use of minimum characterization and reporting standards for the nanomaterial research community. This next activity is expected to boost the utility of research in improving our understanding of the safety of nanomaterials. FT

Rosetta Newsome, Ph.D., is Director, Science and Policy Initiatives, Institute of Food Technologists ([email protected]).

REFERENCES
Astete, C.E. and Sabliov, C.M. 2006. Synthesis and characterization of PLGA nanoparticles. J. Biomater. Sci. Polym. Ed. 17: 2472-89.

Card, J.W. and Magnuson, B.A. 2009. J. Food Sci. 74(8): vi-vii. Letter to the Editor.
http://onlinelibrary.wiley.com/doi/10.1111/j.1750-3841.2009.01366.x/full.

Card, J.W. and Magnuson, B.A. 2010. A method to assess the quality of studies that examine the toxicity of engineered nanomaterials. Intl. J. Toxicol. 29(4): 402-410.
http://ijt.sagepub.com/content/29/4/402.full.pdf+html.

Card, J.W., Jonaitis, T.S., Tafazoli, S., and Magnuson, B.A. 2011. An appraisal of the published literature on the safety and toxicity of food-related nanomaterials. Crit. Rev. Toxicol. Vol. 41 (1): 20-49.
http://informahealthcare.com/doi/abs/10.3109/10408444.2010.524636.

Chen, H.S., Chang, J.H., and Wu, J.S.B. 2008. Calcium bioavailability of nanonized pearl powder for adults. J. Food Sci. 73: H246-H251.

EFSA. 2011. Guidance on the risk assessment of the application of nanoscience and nanotechnologies in the food and feed chain. A Scientific Opinion of the European Food Safety Authority. EFSA Journal 9(5): 2140. Available at: http://www.efsa.europa.eu/en/efsajournal/doc/2140.pdf. Accessed on Jun. 27, 2011.

Graveland-Bikker, J.F., Schaap, I.A., Schmidt, C.F., and de Kruif, C.G. 2006. Structural and mechanical study of a self-assembling protein Nanotube. Nano Lett. 6(4): 616-21.

IFT. 2010. Nanoscience and nanotechnology: IFT backgrounder. http://www.ift.org/Knowledge-Center/Focus-Areas/Product-Development-and-Ingredient-Innovations/Nanoscience/Nanotechnology-Backgrounder.aspx.

Magnuson, B. 2009. Nanoscale materials in foods: Existing and potential sources. In: Al-Taher, F., Jackson, L., and DeVries, J.W., editors. Intentional and unintentional contaminants in food and feed. Vol. 1020, American Chemical Society Symposium Series, p. 47-55.

Magnuson, B.A., Jonaitis, T.S., and Card, J.W. 2011. A brief review of the occurrence, use, and safety of food-related nanomaterials. J. Food Sci. Vol. 76(6): R126-R133.
http://onlinelibrary.wiley.com/doi/10.1111/j.1750-3841.2011.02170.x/full.

Rohner, F., Ernst, F.O., Arnold, M., Hilbe, M., Biebinger, R., Ehrensperger, F. and others. 2007. Synthesis, characterization, and bioavailability in rats of ferric phosphate nanoparticles. J. Nutr. 137: 614-19.

Russell-Jones, G.J., Arthur, L., and Walker, K. 1999. Vitamin B12-mediated transport of nanoparticles across Caco-2 cells. Int. J. Pharm. 179: 247-55.

Semo, E., Kesselman, E., Danino, D., and Liveny, Y.D. 2007. Casein micelle as a natural nano-capsular vehicle for nutraceuticals. Food Hydrocoll. 21(5, 6): 936-42.

Yang, H., Wang, Y., Lai, S., An H., Li, Y., and Chen, F. 2007. Application of atomic force microscopy as a nanotechnology tool in food science. J. Food Sci. 72(4): R65-R75.

Zha, L.-Y., Xu, Z.-R., Wang, M.-Q., and Gu, L.-Y. 2008. Chromium nanoparticles exhibit higher absorption efficiency than chromium picolinate and chromium chloride in Caco-2 cell monolayers. J. Anim. Physiol. Anim. Nutr. 92: 131-140.