Oral administration of TiO2 nanoparticles during early life impacts cardiac and neurobehavioral performance and metabolite profile in an age- and sex-related manner.

BACKGROUND: Nanoparticles (NPs) are increasingly incorporated in everyday products. To investigate the effects of early life exposure to orally ingested TiO2 NP, male and female Sprague-Dawley rat pups received four consecutive daily doses of 10 mg/kg body weight TiO2 NP (diameter: 21 ± 5 nm) or vehicle control (water) by gavage at three different pre-weaning ages: postnatal day (PND) 2-5, PND 7-10, or PND 17-20. Cardiac assessment and basic neurobehavioral tests (locomotor activity, rotarod, and acoustic startle) were conducted on PND 20. Pups were sacrificed at PND 21. Select tissues were collected, weighed, processed for neurotransmitter and metabolomics analyses. RESULTS: Heart rate was found to be significantly decreased in female pups when dosed between PND 7-10 and PND 17-20. Females dosed between PND 2-5 showed decrease acoustic startle response and when dosed between PND 7-10 showed decreased performance in the rotarod test and increased locomotor activity. Male pups dosed between PND 17-20 showed decreased locomotor activity. The concentrations of neurotransmitters and related metabolites in brain tissue and the metabolomic profile of plasma were impacted by TiO2 NP administration for all dose groups. Metabolomic pathways perturbed by TiO2 NP administration included pathways involved in amino acid and lipid metabolism. CONCLUSION: Oral administration of TiO2 NP to rat pups impacted basic cardiac and neurobehavioral performance, neurotransmitters and related metabolites concentrations in brain tissue, and the biochemical profiles of plasma. The findings suggested that female pups were more likely to experience adverse outcome following early life exposure to oral TiO2 NP than male pups. Collectively the data from this exploratory study suggest oral administration of TiO2 NP cause adverse biological effects in an age- and sex-related manner, emphasizing the need to understand the short- and long-term effects of early life exposure to TiO2 NP.

Intravenous administration of three multiwalled carbon nanotubes to female rats and their effect on urinary biochemical profile.

This study was conducted to investigate the influence of outer diameter (OD) and length (L) of multiwalled carbon nanotubes (MWCNTs) on biodistribution and the perturbation of endogenous metabolite profiles. Three different-sized carboxylated MWCNTs (NIEHS-12-2: L 0.5-2 µm, OD 10-20 nm, NIEHS-13-2: L 0.5-2 µm, OD 30-50 nm, and NIEHS-14-2: L 10-30 µm, OD 10-20 nm) in water were administered to female Sprague-Dawley rats as a single intravenous dose of 1 mg/kg MWCNTs. Biodistribution in liver, lung, spleen, and lymph nodes was evaluated in tissue sections at 1 and 7 days' post-dosing using enhanced darkfield microscopy and hyperspectral imaging. Nuclear magnetic resonance (NMR) analysis was used for biochemical profiling and pathway mapping of endogenous metabolites in urine collected at 24-h intervals prior to dosing, at Day 1 and Day 7. At Day 1 and Day 7, all three MWCNTs were observed in liver. NIEHS-12-2 was observed in spleen, whereas NIEHS-13-2 and NIEHS-14-2 were not. All three MWCNTs were observed in lymph nodes and lung at Day 7. The urinary biochemical profile showed the highest positive fold change (FC) at Day 7 for the metabolites acetate, alanine, and lactate, whereas 1-methylnicotinamide, 2-oxoglutarate, and hippurate had some of the lowest FCs for all three MWCNTs. This study demonstrates that the observed tissue location of MWCNTs is size dependent. Overlaps in the perturbation of endogenous metabolite profiles were found regardless of their size, and the biochemical responses were more profound at Day 7 compared with Day 1, indicating a delayed biological response to MWCNTs.

Biodistribution, cardiac and neurobehavioral assessments, and neurotransmitter quantification in juvenile rats following oral administration of aluminum oxide nanoparticles.

Little is known about the uptake, biodistribution, and biological responses of nanoparticles (NPs) and their toxicity in developing animals. Here, male and female juvenile Sprague-Dawley rats received four consecutive daily doses of 10 mg/kg Al2 O3 NP (diameter: 24 nm [transmission electron microscope], hydrodynamic diameter: 148 nm) or vehicle control (water) by gavage between postnatal days (PNDs) 17-20. Basic neurobehavioral and cardiac assessments were performed on PND 20. Animals were sacrificed on PND 21, and selected tissues were collected, weighed, and processed for histopathology or neurotransmitter analysis. The biodistribution of Al2 O3 NP in tissue sections of the intestine, liver, spleen, kidney, and lymph nodes were evaluated using enhanced dark-field microscopy (EDM) and hyperspectral imaging (HSI). Liver-to-body weight ratio was significantly increased for male pups administered Al2 O3 NP compared with control. HSI suggested that Al2 O3 NP was more abundant in the duodenum and ileum tissue of the female pups compared with the male pups, whereas the abundance of NP was similar for males and females in the other tissues. The abundance of NP was higher in the liver compared with spleen, lymph nodes, and kidney. Homovanillic acid and norepinephrine concentrations in brain were significantly decreased following Al2 O3 NP administration in female and male pups, whereas 5-hydroxyindoleacetic acid was significantly increased in male pups. EDM/HSI indicates intestinal uptake of Al2 O3 NP following oral administration. Al2 O3 NP altered neurotransmitter/metabolite concentrations in juvenile rats' brain tissues. Together, these data suggest that orally administered Al2 O3 NP interferes with the brain biochemistry in both female and male pups.

Disposition of intravenously or orally administered silver nanoparticles in pregnant rats and the effect on the biochemical profile in urine.

Few investigations have been conducted on the disposition and fate of silver nanoparticles (AgNP) in pregnancy. The distribution of a single dose of polyvinylpyrrolidone (PVP)-stabilized AgNP was investigated in pregnant rats. Two sizes of AgNP, 20 and 110 nm, and silver acetate (AgAc) were used to investigate the role of AgNP diameter and particle dissolution in tissue distribution, internal dose and persistence. Dams were administered AgNP or AgAc intravenously (i.v.) (1 mg kg-1 ) or by gavage (p.o.) (10 mg kg-1 ), or vehicle alone, on gestation day 18 and euthanized at 24 or 48 h post-exposure. The silver concentration in tissues was measured using inductively-coupled plasma mass spectrometry. The distribution of silver in dams was influenced by route of administration and AgNP size. The highest concentration of silver (µg Ag g-1 tissue) at 48 h was found in the spleen for i.v. administered AgNP, and in the lungs for AgAc. At 48 h after p.o. administration of AgNP, the highest concentration was measured in the cecum and large intestine, and for AgAc in the placenta. Silver was detected in placenta and fetuses for all groups. Markers of cardiovascular injury, oxidative stress marker, cytokines and chemokines were not significantly elevated in exposed dams compared to vehicle-dosed control. NMR metabolomics analysis of urine indicated that AgNP and AgAc exposure impact the carbohydrate, and amino acid metabolism. This study demonstrates that silver crosses the placenta and is transferred to the fetus regardless of the form of silver. Copyright © 2016 John Wiley & Sons, Ltd.

Microfluidics meets metabolomics to reveal the impact of Campylobacter jejuni infection on biochemical pathways.

Microfluidic devices that are currently being used in pharmaceutical research also have a significant potential for utilization in investigating exposure to infectious agents. We have established a microfluidic device cultured with Caco-2 cells, and utilized metabolomics to investigate the biochemical responses to the bacterial pathogen Campylobacter jejuni. In the microfluidic devices, Caco-2 cells polarize at day 5, are uniform, have defined brush borders and tight junctions, and form a mucus layer. Metabolomics analysis of cell culture media collected from both Caco-2 cell culture systems demonstrated a more metabolic homogenous biochemical profile in the media collected from microfluidic devices, compared with media collected from transwells. GeneGo pathway mapping indicated that aminoacyl-tRNA biosynthesis was perturbed by fluid flow, suggesting that fluid dynamics and shear stress impacts the cells translational quality control. Both microfluidic device and transwell culturing systems were used to investigate the impact of Campylobacter jejuni infection on biochemical processes. Caco-2 cells cultured in either system were infected at day 5 with C. jejuni 81-176 for 48 h. Metabolomics analysis clearly differentiated C. jejuni 81-176 infected and non-infected medias collected from the microfluidic devices, and demonstrated that C. jejuni 81-176 infection in microfluidic devices impacts branched-chain amino acid metabolism, glycolysis, and gluconeogenesis. In contrast, no distinction was seen in the biochemical profiles of infected versus non-infected media collected from cells cultured in transwells. Microfluidic culturing conditions demonstrated a more metabolically homogenous cell population, and present the opportunity for studying host-pathogen interactions for extended periods of time.

Distribution and biomarker of carbon-14 labeled fullerene C60 ([(14) C(U)]C60 ) in pregnant and lactating rats and their offspring after maternal intravenous exposure.

A comprehensive distribution study was conducted in pregnant and lactating rats exposed to a suspension of uniformly carbon-14 labeled C60 ([(14) C(U)]C60 ). Rats were administered [(14) C(U)]C60 (~0.2 mg [(14) C(U)]C60 kg(-1) body weight) or 5% polyvinylpyrrolidone (PVP)-saline vehicle via a single tail vein injection. Pregnant rats were injected on gestation day (GD) 11 (terminated with fetuses after either 24 h or 8 days), GD15 (terminated after 24 h or 4 days), or GD18 (terminated after 24 h). Lactating rats were injected on postnatal day 8 and terminated after 24 h, 3 or 11 days. The distribution of radioactivity in pregnant dams was influenced by both the state of pregnancy and time of termination after exposure. The percentage of recovered radioactivity in pregnant and lactating rats was highest in the liver and lungs. Radioactivity was quantitated in over 20 tissues. Radioactivity was found in the placenta and in fetuses of pregnant dams, and in the milk of lactating rats and in pups. Elimination of radioactivity was < 2% in urine and feces at each time point. Radioactivity remained in blood circulation up to 11 days after [(14) C(U)]C60 exposure. Biomarkers of inflammation, cardiovascular injury and oxidative stress were measured to study the biological impacts of [(14) C(U)]C60 exposure. Oxidative stress was elevated in female pups of exposed dams. Metabolomics analysis of urine showed that [(14) C(U)]C60 exposure to pregnant rats impacted the pathways of vitamin B, regulation of lipid and sugar metabolism and aminoacyl-tRNA biosynthesis. This study demonstrated that [(14) C(U)]C60 crosses the placenta at all stages of pregnancy examined, and is transferred to pups via milk.

Distribution and biomarkers of carbon-14-labeled fullerene C60 ([(14) C(U)]C60 ) in female rats and mice for up to 30 days after intravenous exposure.

A comprehensive distribution study was conducted in female rats and mice exposed to a suspension of uniformly carbon-14-labeled C60 ([(14) C(U)]C60 ). Rodents were administered [(14) C(U)]C60 (~0.9 mg kg(-1) body weight) or 5% polyvinylpyrrolidone-saline vehicle alone via a single tail vein injection. Tissues were collected at 1 h and 1, 7, 14 and 30 days after administration. A separate group of rodents received five daily injections of suspensions of either [(14) C(U)]C60 or vehicle with tissue collection 14 days post exposure. Radioactivity was detected in over 20 tissues at all time points. The highest concentration of radioactivity in rodents at each time point was in liver, lungs and spleen. Elimination of [(14) C(U)]C60 was < 2% in urine and feces at any 24 h time points. [(14) C(U)]C60 and [(14) C(U)]C60 -retinol were detected in liver of rats and together accounted for ~99% and ~56% of the total recovered at 1 and 30 days postexposure, respectively. The blood radioactivity at 1 h after [(14) C(U)]C60 exposure was fourfold higher in rats than in mice; blood radioactivity was still in circulation at 30 days post [(14) C(U)]C60 exposure in both species (<1%). Levels of oxidative stress markers increased by 5 days after exposure and remained elevated, while levels of inflammation markers initially increased and then returned to control values. The level of cardiovascular marker von Willebrand factor, increased in rats, but remained at control levels in mice. This study demonstrates that [(14) C(U)]C60 is retained in female rodents with little elimination by 30 days after i.v. exposure, and leads to systemic oxidative stress.

Targeting inhaled therapy beyond the lungs.

Pulmonary disease has been the primary target of inhaled therapeutics for over 50 years. During that period, increasing interest has arisen in the use of this route of administration to gain access to the systemic circulation for the treatment of a number of diseases beyond the airways. In order to effectively employ this route, the barriers to transport from the lungs following deposition of aerosols must be considered, including the nature of the disease (whether proximal, as in pulmonary hypertension, or distal, as in diabetes). Delivery to the systemic circulation begins with the efficiency of aerosol generation and subsequent deposition in the airways and proceeds to the influence of mechanisms of clearance, including absorption, metabolism, and mucociliary and cell-mediated transport, on the residence time of the drugs in the lungs. The nature of the drug (small or large molecules/low or high molecular weight), susceptibility to degradation and general physicochemical properties play a role in the chemistry of its formulation, physics of aerosol delivery and biology of disposition.

The role of particle physico-chemical properties in pulmonary drug delivery for tuberculosis therapy.

There is increasing interest in the use of inhaled aerosol drug therapy for the treatment of tuberculosis (TB). A number of methods of preparation of particles have been employed including spray drying, solvent evaporation, emulsion and phospholipid methods to create microparticles, macroaggregated nanoparticles, solid lipid nanoparticles and liposomes. Each of these methods involves the use of different proportions of additives to aid in the particle formation or to achieve important physico-chemical properties such as ease of dispersion. While these approaches all have merit their practical value is limited by constraints on dose and means of delivery as an aerosol in order to achieve a therapeutic effect. A review of a number of approaches is presented and placed in the context of the need for effective aerosol delivery systems for the treatment of TB as a guide to selection of appropriate excipients, processes and delivery strategies to support product development activities.

Investigation of eight cellulose nanomaterials' impact on Differentiated Caco-2 monolayer integrity and cytotoxicity.

The potential applications of cellulose nanomaterials (CNMs) as food additives or in food packaging, present a possible source of human ingestion. While micron- and macro-scale cellulose products are classified as Generally Regarded As Safe, the safety of ingested nano-scale cellulose is largely unknown. Using fully differentiated Caco-2 cells, the perturbation of intestinal barrier function and cytotoxicity was investigated for four nanocellulose crystals (CNCs) and four nanocellulose fibrils (CNFs) following 24 h of exposure at 50 µg/mL. Scanning electron microscope showed some aggregation of both CNCs and CNFs. X-ray photoelectron spectroscopy analyses showed that carbon and oxygen were the main elements. The zeta-potential for CNMs formulated in cell culture medium showed a negative surface charge. Two CNMs increased cell membrane permeability and three CNMs decreased the cell metabolic activity. While three CNMs lead to cytotoxic responses, no changes in apparent permeability coefficient (Papp) for dextran or tight junction integrity were found. Our results show that three CNMs induce cytotoxicity in differentiated Caco-2 cells, demonstrating the need to understand the role of size and shape. The interaction between CNMs and the intestinal epithelium needs to be evaluated to understand potential intestinal barrier dysfunction and resulting health implications following CNM ingestion.

Fabrication of Nylon-6 and Nylon-11 Nanoplastics and Evaluation in Mammalian Cells.

Microplastics (MPs) and nanoplastics (NPs) exist in certain environments, beverages, and food products. However, the ultimate risk and consequences of MPs and NPs on human health remain largely unknown. Studies involving the biological effects of small-scale plastics have predominantly used commercially available polystyrene beads, which cannot represent the breadth of globally dominant plastics. Nylon is a commodity plastic that is used across various industry sectors with substantial global production. Here, a series of well-characterized nylon-11 and nylon-6 NPs were successfully fabricated with size distributions of approximately 100 nm and 500 nm, respectively. The facile fabrication steps enabled the incorporation of fluorescent tracers in these NPs to aid the intracellular tracking of particles. RAW 264.7 macrophages were exposed to nylon NPs in a dose-dependent manner and cytotoxic concentrations and cellular uptake were determined. These well-characterized nylon NPs support future steps to assess how the composition and physicochemical properties may affect complex biological systems and ultimately human health.

Unintended human ingestion of nanoplastics and small microplastics through drinking water, beverages, and food sources.

The potential risks on human health from the unintentional ingestion of microplastics (MPs) and nanoplastics (NPs) is an emerging concern. Despite the mounting awareness of small-scale plastics in drinking water, beverages, and food products, little is known about potential downstream effects on human health. Furthermore, very few studies currently exist that focus on NPs and smaller sized MPs, which may be more significant for human exposure given the higher likelihood of smaller-scale particles crossing the intestinal tract. Therefore, this review summarizes the smallest NPs and MPs (NMPs) reported in the literature, focusing on a threshold size range of <50 µm detected in drinking water, beverages, and food (e.g., table salt, seafood). We show that the smallest NMPs reported currently in the literature overwhelmingly originate from drinking water, with prevalent polymer compositions including polyethylene (PE), polypropylene (PP), and polyethylene terephthalate (PET). We further describe NMPs in food products and show that most studies focus on larger size ranges (e.g., <100 µm or 5-250 µm), thereby supporting the need for continued investigations to understand the breadth of contaminants in human ingestion. We cover the current methodologies for sample preparation, size characterization, and polymer identification and further discuss the potential impact of these approaches on the findings and current knowledge of NMPs. This review aims to provide a groundwork to support next steps towards better understanding the oral ingestion of NMPs and the potential impact on human health.

Fabrication of polyethylene terephthalate (PET) nanoparticles with fluorescent tracers for studies in mammalian cells.

Fluorescent nanoparticles (NPs) comprising polyethylene terephthalate (PET) with a hydrodynamic diameter of 158 ± 2 nm were synthesized in a bottom-up approach. Concentration-dependent uptake and cytotoxicity of PET NPs in macrophages are shown. The fabrication of well-characterized NPs, derived from high-commodity polymers, will support future studies to assess effects on biological systems.

Simulated Gastric Digestion and In Vivo Intestinal Uptake of Orally Administered CuO Nanoparticles and TiO2 E171 in Male and Female Rat Pups.

Oral exposure to nanoparticles (NPs) during early life is an understudied area. The goals of this study were to evaluate the effect of pre-weaned rat gastric fluids on 50 nm CuO NPs and TiO2 E171 in vitro, and to evaluate uptake in vivo. The NP uptake was studied in vivo in male and female Sprague-Dawley rat pups following oral administration of four consecutive daily doses of 10 mg/kg CuO NPs, TiO2 E171, or vehicle control (water) between postnatal day (PND) 7-10. Rat pups were sacrificed on either PND10 or PND21. Simulated digestion led to dissolution of CuO NPs at the later ages tested (PND14 and PND21, but not PND7). In vivo intestinal uptake of CuO NPs and TiO2 E171 was observed by hyperspectral imaging of intestinal cross sections. Brightfield microscopy showed that the number of immune cells increased in the intestinal tissue following NP administration. Orally administered NPs led to low intestinal uptake of NPs and an increase in immune cells in the small and large intestine, suggesting that oral exposure to NPs during early life may lead to irritation or a low-grade inflammation. The long-term impact of increased immune cells in the intestinal tract during early life is unknown.

Effects of engineered cerium oxide nanoparticles on bacterial growth and viability.

Interest in engineered nanostructures has risen in recent years due to their use in energy conservation strategies and biomedicine. To ensure prudent development and use of nanomaterials, the fate and effects of such engineered structures on the environment should be understood. Interactions of nanomaterials with environmental microorganisms are inevitable, but the general consequences of such interactions remain unclear, due to a lack of standard methods for assessing such interactions. Therefore, we have initiated a multianalytical approach to understand the interactions of synthesized nanoparticles with bacterial systems. These efforts are focused initially on cerium oxide nanoparticles and model bacteria in order to evaluate characterization procedures and the possible fate of such materials in the environment. The growth and viability of the Gram-negative species Escherichia coli and Shewanella oneidensis, a metal-reducing bacterium, and the Gram-positive species Bacillus subtilis were examined relative to cerium oxide particle size, growth media, pH, and dosage. A hydrothermal synthesis approach was used to prepare cerium oxide nanoparticles of defined sizes in order to eliminate complications originating from the use of organic solvents and surfactants. Bactericidal effects were determined from MIC and CFU measurements, disk diffusion tests, and live/dead assays. For E. coli and B. subtilis, clear strain- and size-dependent inhibition was observed, whereas S. oneidensis appeared to be unaffected by the particles. Transmission electron microscopy along with microarray-based transcriptional profiling was used to understand the response mechanism of the bacteria. Use of multiple analytical approaches adds confidence to toxicity assessments, while the use of different bacterial systems highlights the potential wide-ranging effects of nanomaterial interactions in the environment.

Designing inhalable metal organic frameworks for pulmonary tuberculosis treatment and theragnostics via spray drying.

Inhalable metal organic framework (MOF) aerosols have been developed via spray drying as a therapy for multi-drug resistant (MDR) tuberculosis (TB). The CuPOA2 (pyrazinoate acid) MOFs can be tailored to exhibit a respirable mass median aerodynamic diameter (MMAD) of 2.6 µm. This method is repeated to manufacture Gd0.1Cu0.9(POA)2 MOFs for inhalable theragnostics.

Investigation of Twenty Metal, Metal Oxide, and Metal Sulfide Nanoparticles' Impact on Differentiated Caco-2 Monolayer Integrity.

The use of engineered nanomaterials (ENMs) in foods and consumer products is rising, increasing the potential for unintentional ingestion. While the cytotoxicity of many ENMs has been investigated, less attention has been given to adverse impact on the intestinal barrier integrity. Chronical disruption of gastrointestinal integrity can have far reaching health implications. Using fully differentiated Caco-2 cells, the perturbation of intestinal barrier function and cytotoxicity were investigated for 20 metal, metal oxide, and metal sulfide ENMs. Caco-2 cells were exposed to 50 µg/mL ENMs for 24 hours. ENM formulations were characterized at 0 and 24 hours, and In Vitro Sedimentation, Diffusion and Dosimetry Modeling was applied to calculate the effective dose of exposure during 24 hours. The apparent permeability coefficient (Papp) was determined for fluorescent labeled dextran (3,000 Da) and tight junction integrity was evaluated by immunofluorescence microscopy. Cytotoxicity was investigated by determining lactate dehydrogenase release (LDH) and cell metabolic activity (tetrazolium based MTS) assays. Four ENMs led to significantly increased Papp, (15.8% w/w% Ag-SiO2 nanoparticle (NP), 60 nm CdS NP, 100 nm V2O5 flakes, and 50 nm ZnO NP), while one ENM (20 nm MgO NP) decreased Papp. With the exception of CdS NP, significantly increased Papp was not connected with cell cytotoxicity. The calculated effective dose concentration was not correlated with increased Papp. Our results illustrate that while many metal, metal oxide, and metal sulfide ENMs do not adversely affect monolayer integrity or induce cytotoxicity in differentiated Caco-2 cells, a subset of ENMs may compromise the intestinal integrity. This study demonstrated the use of differentiated Caco-2 monolayer and Papp as an endpoint to identify and prioritize ENMs that should be investigated further. The interaction between ENMs and the intestinal epithelium needs to be evaluated to understand potential intestinal barrier dysfunction and resulting health implications.

Biological interactions between nanomaterials and placental development and function following oral exposure.

We summarize the literature involving the deposition of nanomaterials within the placenta following oral exposure and the biological interactions between nanomaterials and placental development and function. The review focuses on the oral exposure of metal and metal oxide engineered nanomaterials (ENMs), carbon-based ENMs, and nanoplastics in animal models, with a minor discussion of intravenous injections. Although the literature suggests that the placenta is an efficient barrier in preventing nanomaterials from reaching the fetus, nanomaterials that accumulate in the placenta may interfere with its development and function. Furthermore, some studies have demonstrated a decrease in placental weight and association with adverse fetal health outcomes following oral exposure to nanomaterials. Since nanomaterials are increasingly used in food, food packaging, and have been discovered in drinking water, the risk for adverse impacts on placental development and functions, with secondary effects on embryo-fetal development, following unintentional maternal ingestion of nanomaterials requires further investigation.

International Implications of Labeling Foods Containing Engineered Nanomaterials.

To provide greater transparency and comprehensive information to consumers regarding their purchase choices, the European Parliament and the Council have mandated via Regulation 1169/2011 that foods containing engineered nanomaterials (ENMs) be labeled. This review covers the main concerns related to the use of ENMs in foods and the potential impacts that this type of food labeling might have on diverse stakeholder groups, including those outside the European Union (EU), e.g., in the United States. We also provide recommendations to stakeholders for overcoming existing challenges related to labeling foods containing ENMs. The revised EU food labeling requirements will likely result in a number of positive developments and a number of challenges for stakeholders in both EU and non-EU countries. Although labeling of foods containing ENMs will likely improve transparency, provide more information to facilitate consumer decisions, and build trust among food safety authorities and consumers, critical obstacles to the successful implementation of these labeling requirements remain, including the need for (i) harmonized information requirements or regulations between countries in different regions of the world, (ii) clarification of the regulatory definitions of the ENMs to be used for food labeling, (iii) robust techniques to detect, measure, and characterize diverse ENMs in food matrices, and (iv) clarification of the list of ENMs that may be exempt from labeling requirements, such as several food additives used for decades. We recommend that food industries and food safety authorities be more proactive in communicating with the public and consumer groups regarding the potential benefits and risks of using ENMs in foods. Efforts should be made to improve harmonization of information requirements between countries to avoid potential international trade barriers.

New surface radiolabeling schemes of super paramagnetic iron oxide nanoparticles (SPIONs) for biodistribution studies.

Nanomaterial based drug delivery systems allow for the independent tuning of the surface chemical and physical properties that affect their biodistribution in vivo and the therapeutic payloads that they are intended to deliver. Additionally, the added therapeutic and diagnostic value of their inherent material properties often provides extra functionality. Iron based nanomaterials with their magnetic properties and easily tailorable surface chemistry are of particular interest as model systems. In this study the core radius of the iron oxide nanoparticles (NPs) was 14.08 ± 3.92 nm while the hydrodynamic radius of the NPs, as determined by Dynamic Light Scattering (DLS), was between 90-110 nm. In this study, different approaches were explored to create radiolabeled NPs that are stable in solution. The NPs were functionalized with polycarboxylate or polyamine surface functional groups. Polycarboxylate functionalized NPs had a zeta potential of -35 mV and polyamine functionalized NPs had a zeta potential of +40 mV. The polycarboxylate functionalized NPs were chosen for in vivo biodistribution studies and hence were radiolabeled with (14)C, with a final activity of 0.097 nCi mg(-1) of NPs. In chronic studies, the biodistribution profile is tracked using low level radiolabeled proxies of the nanoparticles of interest. Conventionally, these radiolabeled proxies are chemically similar but not chemically identical to the non-radiolabeled NPs of interest. This study is novel as different approaches were explored to create radiolabeled NPs that are stable, possess a hydrodynamic radius of <100 nm and most importantly they exhibit an identical surface chemical functionality as their non-radiolabeled counterparts. Identical chemical functionality of the radiolabeled probes to the non-radiolabeled probes was an important consideration to generate statistically similar biodistribution data sets using multiple imaging and detection techniques. The radiolabeling approach described here is applicable to the synthesis of a large class of nanomaterials with multiple core and surface functionalities. This work combined with the biodistribution data suggests that the radiolabeling schemes carried out in this study have broad implications for use in pharmacokinetic studies for a variety of nanomaterials.