Category Archives: health and safety

Nanoparticles in baby formula

Needle-like particles of hydroxyapatite found in infant formula by ASU researchers. Westerhoff and Schoepf/ASU, CC BY-ND

Needle-like particles of hydroxyapatite found in infant formula by ASU [Arizona State University] researchers. Westerhoff and Schoepf/ASU, CC BY-ND

Nanowerk is featuring an essay about hydroxyapatite nanoparticles in baby formula written by Dr. Andrew Maynard in a May 17, 2016 news item (Note: A link has been removed),

There’s a lot of stuff you’d expect to find in baby formula: proteins, carbs, vitamins, essential minerals. But parents probably wouldn’t anticipate finding extremely small, needle-like particles. Yet this is exactly what a team of scientists here at Arizona State University [ASU] recently discovered.

The research, commissioned and published by Friends of the Earth (FoE) – an environmental advocacy group – analyzed six commonly available off-the-shelf baby formulas (liquid and powder) and found nanometer-scale needle-like particles in three of them. The particles were made of hydroxyapatite – a poorly soluble calcium-rich mineral. Manufacturers use it to regulate acidity in some foods, and it’s also available as a dietary supplement.

Andrew’s May 17, 2016 essay first appeared on The Conversation website,

Looking at these particles at super-high magnification, it’s hard not to feel a little anxious about feeding them to a baby. They appear sharp and dangerous – not the sort of thing that has any place around infants. …

… questions like “should infants be ingesting them?” make a lot of sense. However, as is so often the case, the answers are not quite so straightforward.

Andrew begins by explaining about calcium and hydroxyapatite (from The Conversation),

Calcium is an essential part of a growing infant’s diet, and is a legally required component in formula. But not necessarily in the form of hydroxyapatite nanoparticles.

Hydroxyapatite is a tough, durable mineral. It’s naturally made in our bodies as an essential part of bones and teeth – it’s what makes them so strong. So it’s tempting to assume the substance is safe to eat. But just because our bones and teeth are made of the mineral doesn’t automatically make it safe to ingest outright.

The issue here is what the hydroxyapatite in formula might do before it’s digested, dissolved and reconstituted inside babies’ bodies. The size and shape of the particles ingested has a lot to do with how they behave within a living system.

He then discusses size and shape, which are important at the nanoscale,

Size and shape can make a difference between safe and unsafe when it comes to particles in our food. Small particles aren’t necessarily bad. But they can potentially get to parts of our body that larger ones can’t reach. Think through the gut wall, into the bloodstream, and into organs and cells. Ingested nanoscale particles may be able to interfere with cells – even beneficial gut microbes – in ways that larger particles don’t.

These possibilities don’t necessarily make nanoparticles harmful. Our bodies are pretty well adapted to handling naturally occurring nanoscale particles – you probably ate some last time you had burnt toast (carbon nanoparticles), or poorly washed vegetables (clay nanoparticles from the soil). And of course, how much of a material we’re exposed to is at least as important as how potentially hazardous it is.

Yet there’s a lot we still don’t know about the safety of intentionally engineered nanoparticles in food. Toxicologists have started paying close attention to such particles, just in case their tiny size makes them more harmful than otherwise expected.

Currently, hydroxyapatite is considered safe at the macroscale by the US Food and Drug Administration (FDA). However, the agency has indicated that nanoscale versions of safe materials such as hydroxyapatite may not be safe food additives. From Andrew’s May 17, 2016 essay,

Hydroxyapatite is a tough, durable mineral. It’s naturally made in our bodies as an essential part of bones and teeth – it’s what makes them so strong. So it’s tempting to assume the substance is safe to eat. But just because our bones and teeth are made of the mineral doesn’t automatically make it safe to ingest outright.

The issue here is what the hydroxyapatite in formula might do before it’s digested, dissolved and reconstituted inside babies’ bodies. The size and shape of the particles ingested has a lot to do with how they behave within a living system. Size and shape can make a difference between safe and unsafe when it comes to particles in our food. Small particles aren’t necessarily bad. But they can potentially get to parts of our body that larger ones can’t reach. Think through the gut wall, into the bloodstream, and into organs and cells. Ingested nanoscale particles may be able to interfere with cells – even beneficial gut microbes – in ways that larger particles don’t.These possibilities don’t necessarily make nanoparticles harmful. Our bodies are pretty well adapted to handling naturally occurring nanoscale particles – you probably ate some last time you had burnt toast (carbon nanoparticles), or poorly washed vegetables (clay nanoparticles from the soil). And of course, how much of a material we’re exposed to is at least as important as how potentially hazardous it is.Yet there’s a lot we still don’t know about the safety of intentionally engineered nanoparticles in food. Toxicologists have started paying close attention to such particles, just in case their tiny size makes them more harmful than otherwise expected.

Putting particle size to one side for a moment, hydroxyapatite is classified by the US Food and Drug Administration (FDA) as “Generally Regarded As Safe.” That means it considers the material safe for use in food products – at least in a non-nano form. However, the agency has raised concerns that nanoscale versions of food ingredients may not be as safe as their larger counterparts.Some manufacturers may be interested in the potential benefits of “nanosizing” – such as increasing the uptake of vitamins and minerals, or altering the physical, textural and sensory properties of foods. But because decreasing particle size may also affect product safety, the FDA indicates that intentionally nanosizing already regulated food ingredients could require regulatory reevaluation.In other words, even though non-nanoscale hydroxyapatite is “Generally Regarded As Safe,” according to the FDA, the safety of any nanoscale form of the substance would need to be reevaluated before being added to food products.Despite this size-safety relationship, the FDA confirmed to me that the agency is unaware of any food substance intentionally engineered at the nanoscale that has enough generally available safety data to determine it should be “Generally Regarded As Safe.”Casting further uncertainty on the use of nanoscale hydroxyapatite in food, a 2015 report from the European Scientific Committee on Consumer Safety (SCCS) suggests there may be some cause for concern when it comes to this particular nanomaterial.Prompted by the use of nanoscale hydroxyapatite in dental products to strengthen teeth (which they consider “cosmetic products”), the SCCS reviewed published research on the material’s potential to cause harm. Their conclusion?

The available information indicates that nano-hydroxyapatite in needle-shaped form is of concern in relation to potential toxicity. Therefore, needle-shaped nano-hydroxyapatite should not be used in cosmetic products.

This recommendation was based on a handful of studies, none of which involved exposing people to the substance. Researchers injected hydroxyapatite needles directly into the bloodstream of rats. Others exposed cells outside the body to the material and observed the effects. In each case, there were tantalizing hints that the small particles interfered in some way with normal biological functions. But the results were insufficient to indicate whether the effects were meaningful in people.

As Andrew also notes in his essay, none of the studies examined by the SCCS OEuropean Scientific Committee on Consumer Safety) looked at what happens to nano-hydroxyapatite once it enters your gut and that is what the researchers at Arizona State University were considering (from the May 17, 2016 essay),

The good news is that, according to preliminary studies from ASU researchers, hydroxyapatite needles don’t last long in the digestive system.

This research is still being reviewed for publication. But early indications are that as soon as the needle-like nanoparticles hit the highly acidic fluid in the stomach, they begin to dissolve. So fast in fact, that by the time they leave the stomach – an exceedingly hostile environment – they are no longer the nanoparticles they started out as.

These findings make sense since we know hydroxyapatite dissolves in acids, and small particles typically dissolve faster than larger ones. So maybe nanoscale hydroxyapatite needles in food are safer than they sound.

This doesn’t mean that the nano-needles are completely off the hook, as some of them may get past the stomach intact and reach more vulnerable parts of the gut. But the findings do suggest these ultra-small needle-like particles could be an effective source of dietary calcium – possibly more so than larger or less needle-like particles that may not dissolve as quickly.

Intriguingly, recent research has indicated that calcium phosphate nanoparticles form naturally in our stomachs and go on to be an important part of our immune system. It’s possible that rapidly dissolving hydroxyapatite nano-needles are actually a boon, providing raw material for these natural and essential nanoparticles.

While it’s comforting to know that preliminary research suggests that the hydroxyapatite nanoparticles are likely safe for use in food products, Andrew points out that more needs to be done to insure safety (from the May 17, 2016 essay),

And yet, even if these needle-like hydroxyapatite nanoparticles in infant formula are ultimately a good thing, the FoE report raises a number of unresolved questions. Did the manufacturers knowingly add the nanoparticles to their products? How are they and the FDA ensuring the products’ safety? Do consumers have a right to know when they’re feeding their babies nanoparticles?

Whether the manufacturers knowingly added these particles to their formula is not clear. At this point, it’s not even clear why they might have been added, as hydroxyapatite does not appear to be a substantial source of calcium in most formula. …

And regardless of the benefits and risks of nanoparticles in infant formula, parents have a right to know what’s in the products they’re feeding their children. In Europe, food ingredients must be legally labeled if they are nanoscale. In the U.S., there is no such requirement, leaving American parents to feel somewhat left in the dark by producers, the FDA and policy makers.

As far as I’m aware, the Canadian situation is much the same as the US. If the material is considered safe at the macroscale, there is no requirement to indicate that a nanoscale version of the material is in the product.

I encourage you to read Andrew’s essay in its entirety. As for the FoE report (Nanoparticles in baby formula: Tiny new ingredients are a big concern), that is here.

Titanium dioxide nanoparticles have subtle effects on oxidative stress genes?

There’s research from the Georgia Institute of Technology (Georgia Tech; US) suggesting that titanium dioxide nanoparticles may have long term side effects. From a May 10, 2016 news item on ScienceDaily,

A nanoparticle commonly used in food, cosmetics, sunscreen and other products can have subtle effects on the activity of genes expressing enzymes that address oxidative stress inside two types of cells. While the titanium dioxide (TiO2) nanoparticles are considered non-toxic because they don’t kill cells at low concentrations, these cellular effects could add to concerns about long-term exposure to the nanomaterial.

A May 9, 2016 Georgia Tech news release on Newswire (also on EurekAlert), which originated the news item, describes the research in more detail,

Researchers at the Georgia Institute of Technology used high-throughput screening techniques to study the effects of titanium dioxide nanoparticles on the expression of 84 genes related to cellular oxidative stress. Their work found that six genes, four of them from a single gene family, were affected by a 24-hour exposure to the nanoparticles.

The effect was seen in two different kinds of cells exposed to the nanoparticles: human HeLa* cancer cells commonly used in research, and a line of monkey kidney cells. Polystyrene nanoparticles similar in size and surface electrical charge to the titanium dioxide nanoparticles did not produce a similar effect on gene expression.

“This is important because every standard measure of cell health shows that cells are not affected by these titanium dioxide nanoparticles,” said Christine Payne, an associate professor in Georgia Tech’s School of Chemistry and Biochemistry. “Our results show that there is a more subtle change in oxidative stress that could be damaging to cells or lead to long-term changes. This suggests that other nanoparticles should be screened for similar low-level effects.”

The research was reported online May 6 in the Journal of Physical Chemistry C. The work was supported by the National Institutes of Health (NIH) through the HERCULES Center at Emory University, and by a Vasser Woolley Fellowship.

Titanium dioxide nanoparticles help make powdered donuts white, protect skin from the sun’s rays and reflect light in painted surfaces. In concentrations commonly used, they are considered non-toxic, though several other studies have raised concern about potential effects on gene expression that may not directly impact the short-term health of cells.

To determine whether the nanoparticles could affect genes involved in managing oxidative stress in cells, Payne and colleague Melissa Kemp – an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University – designed a study to broadly evaluate the nanoparticle’s impact on the two cell lines.

Working with graduate students Sabiha Runa and Dipesh Khanal, they separately incubated HeLa cells and monkey kidney cells with titanium oxide at levels 100 times less than the minimum concentration known to initiate effects on cell health. After incubating the cells for 24 hours with the TiO2, the cells were lysed and their contents analyzed using both PCR and Western Blot techniques to study the expression of 84 genes associated with the cells’ ability to address oxidative processes.

Payne and Kemp were surprised to find changes in the expression of six genes, including four from the peroxiredoxin family of enzymes that helps cells degrade hydrogen peroxide, a byproduct of cellular oxidation processes. Too much hydrogen peroxide can create oxidative stress which can damage DNA and other molecules.

The effect measured was significant – changes of about 50 percent in enzyme expression compared to cells that had not been incubated with nanoparticles. The tests were conducted in triplicate and produced similar results each time.

“One thing that was really surprising was that this whole family of proteins was affected, though some were up-regulated and some were down-regulated,” Kemp said. “These were all related proteins, so the question is why they would respond differently to the presence of the nanoparticles.”

The researchers aren’t sure how the nanoparticles bind with the cells, but they suspect it may involve the protein corona that surrounds the particles. The corona is made up of serum proteins that normally serve as food for the cells, but adsorb to the nanoparticles in the culture medium. The corona proteins have a protective effect on the cells, but may also serve as a way for the nanoparticles to bind to cell receptors.

Titanium dioxide is well known for its photo-catalytic effects under ultraviolet light, but the researchers don’t think that’s in play here because their culturing was done in ambient light – or in the dark. The individual nanoparticles had diameters of about 21 nanometers, but in cell culture formed much larger aggregates.

In future work, Payne and Kemp hope to learn more about the interaction, including where the enzyme-producing proteins are located in the cells. For that, they may use HyPer-Tau, a reporter protein they developed to track the location of hydrogen peroxide within cells.

The research suggests a re-evaluation may be necessary for other nanoparticles that could create subtle effects even though they’ve been deemed safe.

“Earlier work had suggested that nanoparticles can lead to oxidative stress, but nobody had really looked at this level and at so many different proteins at the same time,” Payne said. “Our research looked at such low concentrations that it does raise questions about what else might be affected. We looked specifically at oxidative stress, but there may be other genes that are affected, too.”

Those subtle differences may matter when they’re added to other factors.

“Oxidative stress is implicated in all kinds of inflammatory and immune responses,” Kemp noted. “While the titanium dioxide alone may just be modulating the expression levels of this family of proteins, if that is happening at the same time you have other types of oxidative stress for different reasons, then you may have a cumulative effect.”

*HeLa cells are named for Henrietta Lacks who unknowingly donated her immortal cell line to medical research. You can find more about the  story on the Oprah Winfrey website, which features an excerpt from the Rebecca Skloot book “The Immortal Life of Henrietta Lacks.” By the way, on May 2, 2016 it was announced that Oprah Winfrey would star in a movie for HBO as Henrietta Lacks’ daughter in an adaptation of the Rebecca Skloot book. You can read more about the proposed production in a May 3, 2016 article by Benjamin Lee for the Guardian.

Getting back to titanium dioxide nanoparticles and their possible long term effects, here’s a link to and a citation for the Georgia Tech team’s paper,

TiO2 Nanoparticles Alter the Expression of Peroxiredoxin Antioxidant Genes by Sabiha Runa, Dipesh Khanal, Melissa L. Kemp‡, and Christine K. Payne. J. Phys. Chem. C, Article ASAP DOI: 10.1021/acs.jpcc.6b01939 Publication Date (Web): April 21, 2016

Copyright © 2016 American Chemical Society

This paper is behind a paywall.

Nanosafety Cluster newsletter—excerpts from the Spring 2016 issue

The European Commission’s NanoSafety Cluster Newsletter (no.7) Spring 2016 edition is some 50 pp. long and it provides a roundup of activities and forthcoming events. Here are a few excerpts,

“Closer to the Market” Roadmap (CTTM) now finalised

Hot off the press! the Cluster’s “Closer to the Market” Roadmap (CTTM)  is  a  multi-dimensional,  stepwise  plan  targeting  a framework to deliver safe nano-enabled products to the market. After some years of discussions, several consultations of a huge number of experts in the nanosafety-field, conferences at which the issue of market implementation of nanotechnologies was talked  about,  writing  hours/days,  and  finally  two public consultation rounds, the CTTM is now finalized.

As stated in the Executive Summary: “Nano-products and nano-enabled applications need a clear and easy-to-follow human and environmental safety framework for the development along the innovation chain from initial idea to market and beyond that facilitates  navigation  through  the  complex  regulatory and approval processes under which different product categories fall.

Download it here, and get involved in its implementation through the Cluster!
Authors: Andreas Falk* 1, Christa Schimpel1, Andrea Haase3, Benoît Hazebrouck4, Carlos Fito López5, Adriele Prina-Mello6, Kai Savolainen7, Adriënne Sips8, Jesús M. Lopez de Ipiña10, Iseult Lynch11, Costas Charitidis12, Visser Germ13

NanoDefine hosts Synergy Workshop with NSC projects

NanoDefine  organised  the  2nd Nanosafety  Cluster  (NSC)  Synergy Workshop  at  the  Netherlands  House  for Education  and  Research  in Brussels  on  2nd  February  2016. The  aim  was  to  identify  overlaps and synergies existing between different projects that could develop into
outstanding cooperation opportunities.

One central issue was the building of a common ontology and a European framework for data management and analysis, as planned within eNanoMapper, to facilitate a closer interdisciplinary collaboration between  NSC projects and to better address the need for proper data storage, analysis and sharing (Open Access).

Unexpectedly, there’s a Canadian connection,

Discovering protocols for nanoparticles: the soils case
NanoFASE WP7 & NanoSafety Cluster WG3 Exposure

In NanoFASE, of course, we focus on the exposure to nanomaterials. Having consistent and meaningful protocols to characterize the fate of nanomaterials in different environments is therefore of great interest to us. Soils and sediments are in this respect very cumbersome. Also in the case of conventional chemicals has the development of  protocols for fate description in terrestrial systems been a long route.

The special considerations of nanomaterials make this job even harder. For instance, how does one handle the fact that the interaction between soils and nanoparticles is always out of equilibrium? How does one distinguish between the nanoparticles that are still mobile and those that are attached to soil?

In the case of conventional chemicals, a single measurement of a filtered soil suspension often suffices to find the mobile fraction, as long one is sure that equilibrium has been attained. Equilibrium never occurs in the case of  nanoparticles, and the distinction between attached/suspended particles is analytically less clear to do.

Current activity in NanoFASE is focusing at finding protocols to characterize this interaction. Not only does the protocol have to provide meaningful parameters that can be used, e.g. in modelling, but also the method itself should be fast and cheap enough so that a lot of data can be collected in a reasonable amount of time. NanoFASE is  in a good position to do this, because of its focus on fate and because of the many international collaborators.

For  instance,  the Swedish  Agricultural  University (Uppsala)  is  collaborating  with  McGill  University (Montreal, Canada [emphasis mine]), an advisory partner to NanoFASE, in developing the OECD [Organization for Economic Cooperation and Development] protocol for column tests (OECD test nr 312:  “Leaching in soil columns”). The effort is led by Yasir Sultan from Environment Canada and by Karlheinz Weinfurtner from the Frauenhofer institute in Germany. Initial results show the transport of nanomaterials in soil columns to be very limited.

The OECD protocol therefore does not often lead to measurable breakthrough curves that can be modelled to provide information about  nanomaterial  mobility  in  soils  and  most  likely  requires adaptations  to  account  for  the  relatively  low mobility  of  typical pristine nanomaterials.

OECD 312 prescribes to use 40 cm columns, which is most likely too long to show a breakthrough in the case of nanoparticles. Testing in NanoFASE will therefore focus on working with shorter columns and also investigating the effect of the flow speed.

The progress and the results of this action will be reported on our website (www.nanofase.eu).

ENM [engineered nanomaterial] Transformation in and Release from Managed Waste Streams (WP5): The NanoFASE pilot Wastewater Treatment Plant is up and running and producing sludge – soon we’ll be dosing with nanoparticles to test “real world” aging.

Now, wastewater,

ENM [engineered nanomaterial] Transformation in and Release from Managed Waste Streams (WP5): The NanoFASE pilot Wastewater Treatment Plant is up and running and producing sludge – soon we’ll be dosing with nanoparticles to test “real world” aging.

WP5 led by Ralf Kaegi of EAWAG [Swiss Federal Institute of Aquatic Science and Technology] (Switzerland) will establish transformation and release rates of ENM during their passage through different reactors. We are focusing on wastewater treatment plants (WWTPs), solid waste and dedicated sewage sludge incinerators as well as landfills (see figure below). Additionally, lab-scale experiments using pristine and well characterized materials, representing the realistic fate relevant forms at each stage, will allow us to obtain a mechanistic understanding of the transformation processes in waste treatment reactors. Our experimental results will feed directly into the development of a mathematical model describing the transformation and transfer of ENMs through the investigated reactors.

I’m including this since I’ve been following the ‘silver nanoparticle story’ for some time,

NanoMILE publication update: NanoMILE on the air and on the cover

Dramatic  differences  in  behavior  of  nano-silver during  the  initial  wash  cycle  and  for  its  further dissolution/transformation potential over time depending on detergent composition and form.

In an effort to better relate nanomaterial aging procedures to those which they are most likely to undergo during the life cycle of nano-enhanced products, in this paper we describe the various transformations which are possible when exposing Ag engineered nanoparticles (ENPs) to a suite of commercially available washing detergents (Figure 1). While Ag ENP transformation and washing of textiles has received considerable attention in recent years, our study is novel in that we (1) used several commercially available detergents allowing us to estimate the various changes possible in individual homes and commercial washing settings; (2) we have continued  method  development  of  state  of  the  art nanometrology techniques, including single particle ICP-MS, for the detection and characterization of ENPs in complex media; and (3) we were able to provide novel additions to the knowledge base of the environmental nanotechnology research community both in terms of the analytical methods (e.g. the first time ENP aggregates have been definitively analyzed via single particle ICP-MS) and broadening the scope of “real world” conditions that should be considered when understanding AgENP through their life cycle.

Our findings, which were recently published in Environmental Science and Toxicology (2015, 49: 9665), indicate that the washing detergent chemistry causes dramatic differences in ENP behavior during the initial wash cycle and has ramifications for the dissolution/transformation potential of the Ag ENPs over time (see Figure 2). The use of silver as an  antimicrobial  treatment  in  textiles  continues  to garner  considerable  attention.  Last  year  we  published  a manuscript in ACS Nano that considered how various silver treatments to textiles (conventional and nano) both release  nano-sized  material  after  the  wash  cycle  with  similar chemical  characteristics.  That  study  essentially conveyed that multiple silver treatments would become more similar through the product life cycle. Our newest  work expands this by investigating one silver ENP under various washing conditions thereby creating more varied silver products as an end result.

Fascinating stuff if you’ve been following the issues around nanotechnology and safety.

Towards the end of the newsletter on pp. 46-48, they list opportunities for partnerships, collaboration, and research posts and they list websites where you can check out job opportunities. Good Luck!

Arbro Pharmaceuticals and its bioavailable curcumin

Curcumin (a constituent of the spice turmeric) is reputed to have health benefits and has been used in traditional medicine in Asia (notably India) for millenia. Recently scientists have been trying to render curcumin more effective which means increasing its bioavailability (my Nov. 7, 2014 posting features some of that research). According to an April 29, 2016 Arbro Pharmaceuticals press release, the goal of increased bioavailability has been reached and a product is now available commercially,

Arbro Pharmaceuticals has launched SNEC30, a patented highly bioavailable self-nanoemulsifying curcumin formulation in the dosage of 30mg.

Curcumin is the active ingredient of turmeric or haldi, which has been widely used in traditional medicine and home remedies in India for hundreds of years.

Clinical research conducted over the last 25 years has shown curcumin to be effective against various diseases like cancer, pain, inflammation, arthritis, ulcers, psoriasis, arteriosclerosis, diabetes and many more pro-inflammatory conditions.

Despite its effectiveness against so many medical conditions, scientists have come to believe that curcumin’s true potential has been limited by its poor bioavailability which is caused by the fact that it has poor solubility and extensive pre-systemic metabolism.

Arbro Pharmaceuticals partnered with Jamia Hamdard University to carry out research and develop a novel formulation, which can overcome curcumin’s poor bioavailability. The development project was jointly funded by Arbro and the Department of Science and Technology, Government of India under its DPRP (Drug and Pharmaceutical Research Programme) scheme.

SNEC30 is the outcome of this joint research and is based on a novel self-nanoemulsifying drug delivery systems (SNEDDS) for which patents have been filed and the US patent has been granted.

“There has been tremendous interest in the therapeutic potential of curcumin but its poor bioavailability was a limiting factor, our research group together with Arbro took the challenge and applied nanotechnology to overcome this limitation and achieve highest ever bioavailability for curcumin,” said Dr. Kanchan Kohli, Asst. Prof, Faculty of Pharmacy, Jamia Hamdard University, who is one of the main developers of the formulation.

Nanotechnology is the engineering of functional systems at the molecular scale (CRN – Centre for Responsible Nanotechnology). The name stems from the fact that the structures are in the nano-metre (10-9 mm) in range. In pharmaceutics, nano-formulations are used for targeted drug-delivery, particularly in cancer therapy. It also finds numerous other applications in medicine.

“Just 30mg of curcumin that is contained in one capsule of SNEC30 has shown higher blood levels than what can be achieved by consuming the curcumin content of 1kg of raw haldi or turmeric,” said Mr. Vijay Kumar Arora, Managing Director, Arbro Pharmaceuticals.

About Arbro Pharmaceuticals:

Arbro Pharmaceuticals is a 30-year-old research oriented company with its own research and development, testing and manufacturing facilities. Arbro has been manufacturing and exporting hundreds of formulations under its own brand name to more than 10 countries.

I am not endorsing this product but if you are interested the SNEC30 website is here. I believe Arbro Pharmaceuticals’ headquarters, the company which produces SNEC30, are located in India.

Identifying minute amounts of nanomaterial in environmental samples

It’s been a while since I’ve had a story from one of Germany’s Franhaufer Institutes. Their stories are usually focused on research that’s about to commercialized but that’s not the case this time according to an April 28, 2016 news item on Nanowerk,

It is still unclear what the impact is on humans, animals and plants of synthetic nanomaterials released into the environment or used in products. It’s very difficult to detect these nanomaterials in the environment since the concentrations are so low and the particles so small. Now the partners in the NanoUmwelt project have developed a method that is capable of identifying even minute amounts of nanomaterials in environmental samples.

An April 28, 2016 Fraunhofer Institute press release, which originated the news item, provides more detail about the technology and about the NanoUmwelt project along with a touch of whimsy,

Tiny dwarves keep our mattresses clean, repair damage to our teeth, stop eggs sticking to our pans, and extend the shelf life of our food. We are talking about nanomaterials – “nano” comes from the Greek word for “dwarf”. These particles are just a few billionths of a meter small, and they are used in a wide range of consumer products. However, up to now the impact of these materials on the environment has been largely unknown, and information is lacking on the concentrations and forms in which they are present there. “It’s true that many laboratory studies have examined the effect of nanomaterials on human and animal cells. To date, though, it hasn’t been possible to detect very small amounts in environmental samples,” says Dr. Yvonne Kohl from the Fraunhofer Institute for Biomedical Engineering IBMT in Sulzbach.

A millionth of a milligram per liter 

That is precisely the objective of the NanoUmwelt project. The interdisciplinary project team is made up of eco- and human toxicologists, physicists, chemists and biologists, and they have just managed to take their first major step forward in achieving their goal: they have developed a method for testing a variety of environmental samples such as river water, animal tissue, or human urine and blood that can detect nanomaterials at a concentration level of nanogram per liter (ppb – parts per billion). That is equivalent to half a sugar cube in the volume of water contained in 1,000 competition swimming pools. Using the new method, it is now possible to detect not just large amounts of nanomaterials in clear fluids, as was previously the case, but also very few particles in complex substance mixtures such as human blood or soil samples. The approach is based on field-flow fractionation (FFF), which can be used to separate complex heterogeneous mixtures of fluids and particles into their component parts – while simultaneously sorting the key components by size. This is achieved by the combination of a controlled flow of fluid and a physical separation field, which acts perpendicularly on the flowing suspension.

For the detection process to work, environmental samples have to be appropriately processed. The team from Fraunhofer IBMT’s Bioprocessing & Bioanalytics Department prepared river water, human urine, and fish tissue to be fit for the FFF device. “We prepare the samples with special enzymes. In this process, we have to make sure that the nanomaterials are not destroyed or changed. This allows us to detect the real amounts and forms of the nanomaterials in the environment,” explains Kohl. The scientists have special expertise when it comes to providing, processing and storing human tissue samples. Fraunhofer IBMT has been running the “German Environmental Specimen Bank (ESB) – Human Samples”since January 2012 on behalf of Germany’s Environment Agency (UBA). Each year the research institute collects blood and urine samples from 120 volunteers in four cities in Germany. Individual samples are a valuable tool for mapping the trends over time of human exposure to pollutants. ”In addition, blood and urine samples have been donated for the NanoUmwelt project and put into cryostorage at Fraunhofer IBMT. We used these samples to develop our new detection method,” says Dr. Dominik Lermen, manager of the working group on Biomonitoring & Cryobanks at Fraunhofer IBMT. After approval by the UBA, some of the human samples in the ESB archive may also be examined using the new method.

Developing new cell culture models

Nanomaterials end up in the environment via different pathways, inter alia the sewage system. Human beings and animals presumably absorb them through biological barriers such as the lung or intestine. The project team is simulating these processes in petri dishes in order to understand how nanomaterials are transported across these barriers. “It’s a very complex process involving an extremely wide range of cells and layers of tissue,” explains Kohl. The researchers replicate the processes in a way as realistic as possible. They do this by, for instance, measuring the electrical flows within the barriers to determine the functionality of these barriers – or by simulating lung-air interaction using clouds of artificial fog. In the first phase of the NanoUmwelt project, the IBMT team succeeded in developing several cell culture models for the transport of nanomaterials across biological barriers. IBMT worked together with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME, which used pluripotent stem cells to develop a model for investigating cardiotoxicity. Empa, the Swiss partner in the project, delivered a placental barrier model for studying the transport of nanomaterials between mother and child.

Next, the partners want to use their method to measure the concentrations of nanoparticles in a wide variety of environmental samples. They will then analyze the results obtained so as to be in a better position to assess the behavior of nanomaterials in the environment and their potential danger for humans, animals, and the environment. “Our next goal is to detect particles in even smaller quantities,” says Kohl. To achieve this, the scientists are planning to use special filters to remove distracting elements from the environmental samples, and they are looking forward to develop new processing techniques.
NanoUmwelt – the objective

The NanoUmwelt research project was launched in October 2014 and will last for 36 months. Its objective is to develop methods for detecting minute amounts of nanomaterials in environmental samples. Using this information, the project partners will assess the effect of nanomaterials on humans, animals, and the environment. They are focusing on commercially significant, slowly degradable, metallic (silver, titanium dioxide), carbonic (carbon nanotubes) and polymer-based (polystyrene) nanomaterials.

http://www.nanopartikel.info/projekte/laufende-projekte/nanoumwelt

NanoUmwelt – the partners

The German Federal Ministry for Education and Research (BMBF) is providing the NanoUmwelt project with 1.8 million euros of funding as part of its NanoCare program. Led by Postnova Analytics GmbH, ten further partners are collaborating together on the project. Besides the Fraunhofer Institutes for Biomedical Engineering IBMT and for Molecular Biology and Applied Ecology IME, these partners include Germany’s Environment Agency, Empa (the Swiss Federal Laboratories for Materials Science and Technology), PlasmaChem GmbH, Senova GmbH (biological sciences and engineering), fzmb GmbH (Research Centre of Medical Technology and Biotechnology), the universities of Trier and Frankfurt, and the Rhine Water Control Station in Worms.

http://www.nanopartikel.info/projekte/laufende-projekte/nanoumwelt

How small is nano?

A nanometer (nm) is a billionth of a meter. To put this into context: the size of a single nanoparticle relative to a football is the same as that of a football relative to the earth. In the main, nanoscopic particles are not new materials. It’s simply that the increased overall surface area of these tiny particles gives them new functionalities as against larger particles of the same material.


The German Environmental Specimen Bank  

The German Environmental Specimen Bank (ESB) provides the country’s Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety (BMUB) with a scientific basis both for adopting appropriate measures concerning environment and nature conservation and for monitoring the success of those measures. The human samples collected by the Fraunhofer Institute for Biomedical Engineering IBMT on behalf of Germany’s Environment Agency (UBA) give an overview of human exposure to environmental pollutants.

https://www.umweltprobenbank.de/de

Assuming I’ve understood this correctly, the NanoUmwelt project will be ending in 2017 (36 months in total) and the researchers have expended 1/2 of the time (18 months) allotted to developing a technique for measuring nanomaterials of heretofore unheard of quantities in environmental samples. With that done, researchers are now going to use the technique with human samples over the next 18 months.

Harmonized nano terminology for environmental health and safety

According to Lynn Bergeson’s April 11, 2016 posting on Nanotechnology Now, the European Commission’s Joint Research Centre (JRC) has published a document about harmonizing terminology for environmental health and safety of nanomaterials,

The European Commission (EC) Joint Research Center (JRC) recently published a report entitled NANoREG harmonised terminology for environmental health and safety assessment of nanomaterials, developed within the NANoREG project: “A common European approach to the regulatory testing of nanomaterials.”

The NANoREG harmonised terminology for environmental health and safety assessment of nanomaterials (PDF)  has an unexpected description for itself on p. 8 (Note: A link has been removed),

Consistent  use  of  terminology  is  important  in  any  field  of  science  and  technology  to ensure  common  understanding  of  concepts  and  tools among  experts  and  different stakeholders, such as regulatory authorities, industry and consumers. Several  terms  in  the  field of  environmental  health  and  safety  (EHS)  assessment of nanomaterials  (hereinafter  NMs) have  been  indeed  defined  or  used  by  the  scientific community and various organisations, including   international   bodies,   European authorities, and industry associations.

This  is true  for multidisciplinary  projects  such  as  NANoREG, which  aims  at supporting regulatory  authorities, and  industry,  in  dealing  with EHS issues  of  manufactured NMs (‘nanoEHS’) (http://cordis.europa.eu/project/rcn/107159_en.html,www.nanoreg.eu). Terminology  thus  plays  an  important  role  in  NANoREG’s internal  process  of producing diverse types of output with regulatory relevance (e.g. physicochemical characterisation and test protocols, grouping and read-across approaches, exposure models, a framework for  safety  assessment  of NMs,  etc.). The  process  takes  place  in a  collaborative  effort across severalNANoREG work packages or tasks,  involvingquite a  few partners. Moreover,  the  different  types  of NANoREG output (‘deliverables’) are  addressed  to  a large  audience  of  scientists,  industry  and  regulatory  bodies,  extending beyond  Europe. Hence, a coordinated initiative has been undertaken by the Joint Research Centre (JRC) to harmonise the use of specific wording within NANoREG.

The objective of this JRC report is to disseminate the harmonised terminology that has been developed and used with in NANoREG. This collection of key terms has been agreed upon by all  project  partners and adopted  in  their  activities  and  related  documents, as recommended by the NANoREG internal Guidance Document.

Accordingly,  Section  2  of  the  report  illustrates  the  methodology  used  i)  to  select  key terms  that  form  the  ‘NANoREG  Terminology’,  ii)  to  develop  harmonised  ‘NANoREG Definitions’, and iii) it also explains the thinking that led to the choices made in drafting a  definition.  In  Section  3,  those  definitions, adopted  by  the  project  Consortium,  are reported  in  a  table  format  and  constitute  the  ‘NANoREG  Harmonised  Terminology’. Section 4 summarises the existing literature definitions that have been used as starting point to elaborate, for each key term, a NANoREG Definition. It also shortly discusses the reason(s) behind the choices that have been made in drafting a definition.

2. Methodology

The NANoREG Harmonised Terminology illustrated in this report is not a ‘dictionary’ [emphasis mine] that collects a long list of well-known, well-defined scientific and/or regulatory terms relevant to  the  field  of nanoEHS.  Rather,  the  NANoREG Harmonised  Terminology  focuses  on  a relatively short list of key terms that may be interpreted in various ways, depending on where the reader is located on the globe or on the reader’s scientific area of expertise. Moreover,  it  focuses  on  few  terms  that  are  specifically relevant  in  a  REACH [Registration, Evaluation, Authorization, & Restriction of Chemicals]  context, which represents the regulatory framework of reference for NANoREG.

This is having it both ways. As I read it, what they’re saying is this: ‘Our document is not a dictionary but here are the definitions we’re using and you can use them that way if you like’.

You can find a link to the ‘harmonisation’ document and one other related document on this page.

The Canadian nano scene as seen by the OECD (Organization for Economic Cooperation and Development)

I’ve grumbled more than once or twice about the seemingly secret society that is Canada’s nanotechnology effort (especially health, safety, and environment issues) and the fact that I get most my information from Organization for Economic Cooperation and Development (OECD) documents. That said, thank you to Lynne Bergeson’s April 8, 2016 post on Nanotechnology Now for directions to the latest OECD nano document,

The Organization for Economic Cooperation and Development recently posted a March 29, 2016, report entitled Developments in Delegations on the Safety of Manufactured Nanomaterials — Tour de Table. … The report compiles information, provided by Working Party on Manufactured Nanomaterials (WPMN) participating delegations, before and after the November 2015 WPMN meeting, on current developments on the safety of manufactured nanomaterials.

It’s an international roundup that includes: Australia, Austria, Belgium, Canada, Germany, Japan, Korea, the Netherlands, Switzerland, Turkey, United Kingdom, U.S., and the European Commission (EC), as well as the Business and Industry Advisory Committee to the OECD (BIAC) and International Council on Animal Protection in OECD Programs (ICAPO).

As usual, I’m focusing on Canada. From the DEVELOPMENTS IN DELEGATIONS ON THE SAFETY OF MANUFACTURED NANOMATERIALS – TOUR DE TABLE Series on the Safety of Manufactured Nanomaterials No. 67,

CANADA
National  developments  on  human  health  and  environmental  safety  including  recommendations, definitions, or discussions related to adapting or applying existing regulatory systems or the drafting of new laws/ regulations/amendments/guidance materials A consultation document on a Proposed Approach to Address Nanoscale Forms of Substances on the Domestic  Substances  List was  published  with  a  public  comment  period  ending on  May  17,  2015. The proposed approach outlines the Government’s plan to address nanomaterials considered in commerce in Canada (on  Canada’s  public inventory).  The  proposal is a stepwise  approach to  acquire  and  evaluate information,  followed  by  any  necessary  action. A  follow-up  stakeholder  workshop  is  being  planned  to discuss  next  steps  and  possible  approaches  to prioritize  future  activities. The  consultation document  is available at: http://www.ec.gc.ca/lcpe-cepa/default.asp?lang=En&n=1D804F45-1

A mandatory information gathering survey was published on July 25, 2015. The purpose of the survey is to collect information to determine the commercialstatus of certain nanomaterials in Canada. The survey targets  206  substances  considered  to  be  potentially  in commerce  at  the  nanoscale. The  list  of  206 substances was developed using outcomes from the Canada-United States Regulatory Cooperation Council (RCC)  Nanotechnology  Initiative  to  identify nanomaterial  types. These  nanomaterial  types  were  cross-referenced  with  the Domestic  Substances  List to  develop  a  preliminary  list  of  substances  which are potentially intentionally manufactured at the nanoscale. The focus of the survey aligns with the Proposed Approach to  Address  Nanoscale  Forms  of  Substances  on  the Domestic  Substances  List (see  above)  and certain  types  of  nanomaterials  were  excluded  during the  development  of  the  list  of  substances. The information  being  requested  by  the  survey  includes substance  identification,  volumes,  and  uses.  This information will feed into the Government’s proposed approach to address nanomaterials on the Domestic Substances List. Available at: http://gazette.gc.ca/rp-pr/p1/2015/2015-07-25/html/notice-avis-eng.php

Information on:

a.risk  assessment  decisions, including  the  type  of:  (a)  nanomaterials  assessed; (b) testing recommended; and (c) outcomes of the assessment;

Four substances were notified to the program since the WPMN14 – three surface modified substances and  one  inorganic  substance.  No  actions,  including  additional  data requests,  were  taken  due  to  low expected  exposures  in  accordance  with  the New  Substances  Notifications  Regulations  (Chemicals and Polymers) (NSNR) for two of the substances.  Two of the substances notified were subject to a Significant New Activity Notice. A Significant New Activity notice is an information gathering tool used to require submission  of  additional  information  if  it  is suspected  that  a  significant  new  activity  may  result in  the substance becoming toxic under the Canadian Environmental Protection Act, 1999.

b.Proposals, or modifications to previous regulatory decisions

As  part  of  the  Government’s  Chemicals  Management Plan,  a  review  is  being  undertaken  for  all substances  which  have  been  controlled through  Significant  New  Activity  (SNAc)  notices (see  above).  As part  of  this  activity,  the  Government  is  reviewing past  nanomaterials  SNAc  notices  to  see  if  new information  is  available  to  refine  the  scope  and information  requirements.    As  a  result  of  this  review, 9 SNAc  notices  previously  in  place  for  nanomaterials have  been  rescinded.    This  work  is  ongoing,  and  a complete review of all nanomaterial SNAcs is currently planned to be completed in 2016.

Information related to good practice documents

The Canada-led,  ISO  standards project, ISO/DTR  19716 Nanotechnologies — Characterization  of cellulose  nanocrystals, [emphasis mine] initiated  in  April 2014, is  now at Committee  Draft  (CD)  3-month  ISO ballot, closing    Aug 31, 2015. Ballot comments will be addressed during JWG2 Measurement and Characterization working  group meetings  at  the 18th Plenary  of  ISO/TC229, Nanotechnologies,  being held in Edmonton, Alberta, Sep. 28 – Oct. 2, 2015.

Research   programmes   or   strategies   designed   to  address   human   health   and/   or environmental safety aspects of nanomaterials

Scientific research

Environment Canada continues to support various academic and departmental research projects. This research has to date included studying fate and effects of nanomaterials in the aquatic, sediment, soil, and air  compartments. Funding  in  fiscal  2015-16  continues  to  support  such  projects,  including  sub-surface transportation, determining key physical-chemical parameters to predict ecotoxicity, and impacts of nano-silver [silver nanoparticles]  addition  to  a  whole  lake  ecosystem [Experimental Lakes Area?]. Environment  Canada  has  also  partnered  with  the National Research  Council  of  Canada  recently  to  initiate  a project  on  the  development  of  test  methods  to identify surfaces of nanomaterials for the purposes of regulatory identification and to support risk assessments. In addition,  Environment  Canada  is  working  with  academic laboratories in  Canada  and  Germany  to  prepare guidance to support testing of nanoparticles using the OECD Test Guideline for soil column leaching.

Health  Canada  continues  its  research  efforts  to  investigate  the  effects  of  surface-modified  silica nanoparticles. The   aims   of   these   projects   are  to:   (1) study the importance of size and surface functionalization;  and  (2)  provide a genotoxic profile and  to  identify  mechanistic  relationships  of  particle properties  to  elicited  toxic  responses.  A manuscript reporting  the in  vitro genotoxic,  cytotoxic and transcriptomic  responses  following  exposure  to  silica  nanoparticles  has  recently  been  submitted to  a  peer reviewed journal and is currently undergoing review. Additional manuscripts reporting the toxicity results obtained to date are in preparation.

Information on public/stakeholder consultations;

A consultation document on a Proposed Approach to Address Nanoscale Forms of Substances on the Domestic  Substances  List was  published  with a  public  comment  period ending  on May  17,  2015  (see Question  1).  Comments  were  received  from approximately  20  stakeholders  representing  industry and industry  associations,  as  well  as  non-governmental  organizations. These  comments  will  inform  decision making to address nanomaterials in commerce in Canada.

Information on research or strategies on life cycle aspects of nanomaterials

Canada, along with Government agencies in the United States, Non-Governmental Organizations and Industry,  is  engaged  in  a  project  to  look  at releases  of  nanomaterials  from  industrial  consumer  matrices (e.g., coatings). The objectives of the NanoRelease Consumer Products project are to develop protocols or
methods (validated  through  interlaboratory  testing) to  measure  releases  of  nanomaterials  from  solid matrices as a result of expected uses along the material life cycle for consumer products that contain the nanomaterials. The  project  is  currently  in  the  advanced  stages  of Phase  3  (Interlaboratory  Studies).  The objectives of Phase 3 of the project are to develop robust methods for producing and collecting samples of CNT-epoxy  and  CNT-rubber  materials  under  abrasion  and  weathering scenarios,  and  to  detect  and quantify, to the extent possible, CNT release fractions. Selected laboratories in the US, Canada, Korea and the European Community are finalising the generation and analysis of sanding and weathering samples and the    results    are    being    collected    in    a   data    hub    for    further    interpretation    and    analysis.

Additional details about the project can be found at the project website: http://www.ilsi.org/ResearchFoundation/RSIA/Pages/NanoRelease1.aspx

Under the OECD Working Party on Resource Productivity and Waste (WPRPW), the expert group on waste containing nanomaterials has developed four reflection papers on the fate of nanomaterials in waste treatment  operations.  Canada  prepared the  paper  on  the  fate  of  nanomaterials in  landfills;  Switzerland on the  recycling  of  waste  containing  nanomaterials;  Germany  on  the  incineration  of  waste  containing nanomaterials;  and  France  on  nanomaterials  in wastewater  treatment.  The  purpose  of  these  papers is to provide  an  overview  of  the  existing  knowledge  on the  behaviour  of  nanomaterials  during  disposal operations and identify the information gaps. At the fourth meeting of the WPRPW that took place on 12-14 November 2013, three of the four reflection papers were considered by members. Canada’s paper was presented and discussed at the fifth meeting of the WPRPRW that took place on 8-10 December 2014. The four  papers  were  declassified  by  EPOC  in  June  2015, and  an  introductory  chapter  was  prepared  to  draw these  papers  together. The introductory  chapter  and accompanying  papers  will  be  published in  Fall  2015. At  the sixth  meeting  of  the  WPRPW  in  June – July  2015,  the  Secretariat  presented  a  proposal  for an information-sharing  platform  that  would  allow  delegates  to  share research  and  documents  related  to nanomaterials. During a trial phase, delegates will be asked to use the platform and provide feedback on its use at the next meeting of the WPRPW in December 2015. This information-sharing platform will also be accessible to delegates of the WPMN.

Information related to exposure measurement and exposure mitigation.

Canada and the Netherlands are co-leading a project on metal impurities in carbon nanotubes. A final version  of  the  report  is  expected  to  be ready for WPMN16. All  research has  been completed (e.g. all components are published or in press and there was a presentation by Pat Rasmussen to SG-08 at the Face-to-Face Meeting in Seoul June 2015). The first draft will be submitted to the SG-08 secretariat in autumn 2015. Revisions  will  be  based  on  early  feedback  from  SG-08  participants.  The  next  steps  depend  on  this feedback and amount of revision required.

Information on past, current or future activities on nanotechnologies that are being done in co-operation with non-OECD countries.

A webinar between ECHA [European Chemicals Agency], the US EPA [Environmental Protection Agency] and Canada was hosted by Canada on April 16, 2015. These are  regularly  scheduled  trilateral  discussions  to keep  each  other  informed  of  activities  in  respective jurisdictions.

In  March 2015, Health  Canada  hosted  3  nanotechnology knowledge  transfer sessions  targeting Canadian  government  research  and  regulatory  communities  working  in  nanotechnology.  These  sessions were  an  opportunity  to  share  information  and perspectives  on  the  current  state  of  science supporting  the regulatory  oversight  of  nanomaterials with  Government.  Presenters  provided  detailed  outputs  from  the OECD WPMN including: updates on OECD test methods and guidance documents; overviews of physical-chemical properties, as well as their relevance to toxicological testing and risk assessment; ecotoxicity and fate   test   methods;   human   health   risk   assessment   and   alternative   testing   strategies;   and exposure measurement  and  mitigation.  Guest  speakers  included  Dr  Richard  C.  Pleus  Managing  Director  and  Director of Intertox, Inc and Dr. Vladimir Murashov Special Assistant on Nanotechnology to the Director of National Institute for Occupational Safety and Health (NIOSH).

On   March   4-5, 2015, Industry   Canada   and   NanoCanada co-sponsored  “Commercializing Nanotechnology  in  Canada”,  a  national  workshop  that brought  together  representatives  from  industry, academia and government to better align Canada’s efforts in nanotechnology.  This workshop was the first of  its  kind  in  Canada. It  also  marked  the  official  launch  of  NanoCanada (http://nanocanada.com/),  a national  initiative  that  is  bringing  together stakeholders  from  across  Canada  to  bridge  the  innovation  gap and stimulates emerging technology solutions.

It’s nice to get an update about what’s going on. Despite the fact this report was published in 2016 the future tense is used in many of the verbs depicting actions long since accomplished. Maybe this was a cut-and-paste job?

Moving on, I note the mention of the Canada-led,  ISO  standards project, ISO/DTR  19716 Nanotechnologies — Characterization  of cellulose  nanocrystals (CNC). For those not familiar with CNC, the Canadian government has invested hugely in this material derived mainly from trees, in Canada. Other countries and jurisdictions have researched nanocellulose derived from carrots, bananas, pineapples, etc.

Finally, it was interesting to find out about the existence of  NanoCanada. In looking up the Contact Us page, I noticed Marie D’Iorio’s name. D’Iorio, as far as I’m aware, is still the Executive Director for Canada’s National Institute of Nanotechnology (NINT) or here (one of the National Research Council of Canada’s institutes). I have tried many times to interview someone from the NINT (Nils Petersen, the first NINT ED and Martha Piper, a member of the advisory board) and more recently D’Iorio herself only to be be met with a resounding silence. However, there’s a new government in place, so I will try again to find out more about the NINT, and, this time, NanoCanada.

Inhaling buckyballs (C60 fullerenes)

Carbon nanotubes (also known as buckytubes) have attracted most of the attention where carbon nanomaterials and health and safety are concerned. But, University of Michigan researchers opted for a change of pace and focused their health and safety research on buckyballs (also known as C60 or fullerenes) according to a Feb. 24, 2016 news item on Nanowerk,

Scientists at the University of Michigan have found evidence that some carbon nanomaterials can enter into immune cell membranes, seemingly going undetected by the cell’s built-in mechanisms for engulfing and disposing of foreign material, and then escape through some unidentified pathway. [emphasis mine]

The researchers from the School of Public Health and College of Engineering say their findings of a more passive entry of the materials into cells is the first research to show that the normal process of endocytosis-phagocytosis isn’t always activated when cells are confronted with tiny Carbon 60 (C60 ) molecules.

A Feb. 23, 2016 University of Michigan news release (also on EurekAlert but dated Feb. 24, 2016), which originated the news item, provides more detail about the research,

… This study examined nanomaterials known as carbon fullerenes, in this case C60, which has a distinct spherical shape.

Over the last decade, scientists have found these carbon-based materials useful in a number of commercial products, including drugs, medical devices, cosmetics, lubricants, antimicrobial agents and more. Fullerenes also are produced in nature through events like volcanic eruptions and wildfires.

The concern is that however exposed, commercially or naturally, little is known about how inhaling these materials impacts health.

“It’s entirely possible that even tiny amounts of some nanomaterials could cause altered cellular signaling,” said Martin Philbert, dean and professor of toxicology at the U-M School of Public Health.

Philbert said much of the previously published research bombarded cells with large amounts of particle clusters, unlike a normal environmental exposure.

The U-M researchers examined various mechanisms of cell entry through a combination of classical biological, biophysical and newer computational techniques, using models developed by a team led by Angela Violi to determine how C60 molecules find their way into living immune cells of mice.

They found that the C60 particles in low concentrations were entering the membrane individually, without perturbing the structure of the cell enough to trigger its normal response.

“Computational modeling of C60 interacting with lipid bilayers, representative of the cellular membrane, show that particles readily diffuse into biological membranes and find a thermodynamically stable equilibrium in an eccentric position within the bilayer,” said Violi, U-M professor of mechanical engineering, chemical engineering, biomedical engineering, and macromolecular science and engineering.

“The surprising contribution of passive modes of cellular entry provides new avenues for toxicological research, as we still don’t know exactly what are the mechanisms that cause this crossing.”

So, while the buckyballs enter cells, they also escape from them somehow. I wonder if the mechanisms that allow them to enter the cells are similar to the ones that allow them to escape. Regardless, here’s a link to and a citation for the paper,

C60 fullerene localization and membrane interactions in RAW 264.7 immortalized mouse macrophages by K. A. Russ, P. Elvati, T. L. Parsonage, A. Dews, J. A. Jarvis, M. Ray, B. Schneider, P. J. S. Smith, P. T. F. Williamson, A. Violi and M. A. Philbert. Nanoscale, 2016, 8, 4134-4144 DOI: 10.1039/C5NR07003A First published online 25 Jan 2016

This paper is behind a paywall.

Hypersensitivity to nanomedicine: the CARPA reaction

There is some intriguing research (although I do have a reservation) into some unexpected side effects that nanomedicine may have according to a Feb. 23, 2016 news item on phys.org,

Keywords such as nano-, personalized-, or targeted medicine sound like bright future. What most people do not know, is that nanomedicines can cause severe undesired effects for actually being too big! Those modern medicines easily achieve the size of viruses which the body potentially recognizes as foreign starting to defend itself against —a sometimes severe immune response unfolds.

The CARPA-phenomenon (Complement Activation-Related PseudoAllergy) is a frequent hypersensitivity response to nanomedicine application. Up to 100 patients worldwide suffer from severe reactions, such as cardiac distress, difficulty of breathing, chest and back pain or fainting each day when their blood gets exposed to certain nanoparticles during medical treatment. Every 10 days one patient even dies due to an uncontrollable anaphylactoid reaction.

Apart from being activated in a different way, this pseudoallergy has the same symptoms as a common allergy, bearing a crucial difference:  the reaction is taking place without previous sensitizing exposure to a substance, making it hard to predict, whether a person will react to a specific nanodrug or be safe. Intrigued by this vital challenge, János Szebeni from Semmelweis University, Budapest, has been working with scientific verve on the decipherment and prevention of the CARPA phenomenon for more than 20 years. With his invaluable support De Gruyter´s European Journal of Nanomedicine (EJNM) lately dedicated an elaborate compilation of the most recent scientific advances on CARPA, presented by renowned experts on the subject.

A Feb. 23, 2016 De Gruyter Publishers press release, which originated the news item, provides more detail,

Interestingly it´s pigs that turned out to serve as best model for research on the complex pathomechanism, diagnosis and potential treatment of CARPA. “Pigs´ sensitivity equals that of humans responding most vehemently to reactogenic nanomedicines”, Szebeni states.  In a contribution to EJNM´s compilation on CARPA, Rudolf Urbanics and colleagues show that reactions to specific nanodrugs are even quantitatively reproducible in pigs … . Szebeni: “This is absolutely rare in allergy-research. In these animals the endpoint of the overreaction is reflected in a rise of pulmonary arterial pressure, being as accurate as a Swiss watch”. Pigs can thus be used for drug screening and prediction of the CARPAgenic potential of nanomedicines. This becomes increasingly important with the ever growing interest in modern drugs requiring reliable preclinical safety assays during the translation process from bench to bedside. Results might also help to personalize nanomedicine administration schedules during for example the targeted treatment of cancer. The same holds true for a very recently developed in vitro immunoassay. By simply using a patient´s blood sample, it tests for potential CARPA reactions even before application of specific nanodrugs.

Here’s a link to and a citation for the paper,

Lessons learned from the porcine CARPA model: constant and variable responses to different nanomedicines and administration protocols by Rudolf Urbanics, Péter Bedőcs, János Szebeni. European Journal of Nanomedicine. Volume 7, Issue 3, Pages 219–231, ISSN (Online) 1662-596X, ISSN (Print) 1662-5986, DOI: 10.1515/ejnm-2015-0011, June 2015

This paper appears to be open access.

As for reservations, I’m not sure what occasioned the news release so many months post publication of the paperand it should be noted that János Szebeni seems to be the paper’s lead author and the editor of the European Journal of Nanomedicine.

Short term exposure to engineered nanoparticles used for semiconductors not too risky?

Short term exposure means anywhere from 30 minutes to 48 hours according to the news release and the concentration is much higher than would be expected in current real life conditions. Still, this research from the University of Arizona and collaborators represents an addition to the data about engineered nanoparticles (ENP) and their possible impact on health and safety. From a Feb. 22, 2016 news item on phys.org,

Short-term exposure to engineered nanoparticles used in semiconductor manufacturing poses little risk to people or the environment, according to a widely read research paper from a University of Arizona-led research team.

Co-authored by 27 researchers from eight U.S. universities, the article, “Physical, chemical and in vitro toxicological characterization of nanoparticles in chemical mechanical planarization suspensions used in the semiconductor industry: towards environmental health and safety assessments,” was published in the Royal Society of Chemistry journal Environmental Science Nano in May 2015. The paper, which calls for further analysis of potential toxicity for longer exposure periods, was one of the journal’s 10 most downloaded papers in 2015.

A Feb. 17, 2016 University of Arizona news release (also on EurekAlert), which originated the news item, provides more detail,

“This study is extremely relevant both for industry and for the public,” said Reyes Sierra, lead researcher of the study and professor of chemical and environmental engineering at the University of Arizona.

Small Wonder

Engineered nanoparticles are used to make semiconductors, solar panels, satellites, food packaging, food additives, batteries, baseball bats, cosmetics, sunscreen and countless other products. They also hold great promise for biomedical applications, such as cancer drug delivery systems.

Designing and studying nano-scale materials is no small feat. Most university researchers produce them in the laboratory to approximate those used in industry. But for this study, Cabot Microelectronics provided slurries of engineered nanoparticles to the researchers.

“Minus a few proprietary ingredients, our slurries were exactly the same as those used by companies like Intel and IBM,” Sierra said. Both companies collaborated on the study.

The engineers analyzed the physical, chemical and biological attributes of four metal oxide nanomaterials — ceria, alumina, and two forms of silica — commonly used in chemical mechanical planarization slurries for making semiconductors.

Clean Manufacturing

Chemical mechanical planarization is the process used to etch and polish silicon wafers to be smooth and flat so the hundreds of silicon chips attached to their surfaces will produce properly functioning circuits. Even the most infinitesimal scratch on a wafer can wreak havoc on the circuitry.

When their work is done, engineered nanoparticles are released to wastewater treatment facilities. Engineered nanoparticles are not regulated, and their prevalence in the environment is poorly understood [emphasis mine].

Researchers at the UA and around the world are studying the potential effects of these tiny and complex materials on human health and the environment.

“One of the few things we know for sure about engineered nanoparticles is that they behave very differently than other materials,” Sierra said. “For example, they have much greater surface area relative to their volume, which can make them more reactive. We don’t know whether this greater reactivity translates to enhanced toxicity.”

The researchers exposed the four nanoparticles, suspended in separate slurries, to adenocarcinoma human alveolar basal epithelial cells at doses up to 2,000 milligrams per liter for 24 to 38 hours, and to marine bacteria cells, Aliivibrio fischeri, up to 1,300 milligrams per liter for approximately 30 minutes.

These concentrations are much higher than would be expected in the environment, Sierra said.

Using a variety of techniques, including toxicity bioassays, electron microscopy, mass spectrometry and laser scattering, to measure such factors as particle size, surface area and particle composition, the researchers determined that all four nanoparticles posed low risk to the human and bacterial cells.

“These nanoparticles showed no adverse effects on the human cells or the bacteria, even at very high concentrations,” Sierra said. “The cells showed the very same behavior as cells that were not exposed to nanoparticles.”

The authors recommended further studies to characterize potential adverse effects at longer exposures and higher concentrations.

“Think of a fish in a stream where wastewater containing nanoparticles is discharged,” Sierra said. “Exposure to the nanoparticles could be for much longer.”

Here’s a link to and a citation for the paper,

Physical, chemical, and in vitro toxicological characterization of nanoparticles in chemical mechanical planarization suspensions used in the semiconductor industry: towards environmental health and safety assessments by David Speed, Paul Westerhoff, Reyes Sierra-Alvarez, Rockford Draper, Paul Pantano, Shyam Aravamudhan, Kai Loon Chen, Kiril Hristovski, Pierre Herckes, Xiangyu Bi, Yu Yang, Chao Zeng, Lila Otero-Gonzalez, Carole Mikoryak, Blake A. Wilson, Karshak Kosaraju, Mubin Tarannum, Steven Crawford, Peng Yi, Xitong Liu, S. V. Babu, Mansour Moinpour, James Ranville, Manuel Montano, Charlie Corredor, Jonathan Posner, and Farhang Shadman. Environ. Sci.: Nano, 2015,2, 227-244 DOI: 10.1039/C5EN00046G First published online 14 May 2015

This is open access but you may need to register before reading the paper.

The bit about nanoparticles’ “… prevalence in the environment is poorly understood …”and the focus of this research reminded me of an April 2014 announcement (my April 8, 2014 posting; scroll down about 40% of the way) regarding a new research network being hosted by Arizona State University, the LCnano network, which is part of the Life Cycle of Nanomaterials project being funded by the US National Science Foundation. The network’s (LCnano) director is Paul Westerhoff who is also one of this report’s authors.