Category Archives: risk

Mechanism behind interaction of silver nanoparticles with the cells of the immune system

Scientists have come to a better understanding of the mechanism affecting silver nanoparticle toxicity according to an Aug. 30, 2016 news item on Nanowerk (Note: A link has been removed),

A senior fellow at the Faculty of Chemistry, MSU (Lomonosov Moscow State University), Vladimir Bochenkov together with his colleagues from Denmark succeeded in deciphering the mechanism of interaction of silver nanoparticles with the cells of the immune system. The study is published in the journal Nature Communications (“Dynamic protein coronas revealed as a modulator of silver nanoparticle sulphidation in vitro”).

‘Currently, a large number of products are containing silver nanoparticles: antibacterial drugs, toothpaste, polishes, paints, filters, packaging, medical and textile items. The functioning of these products lies in the capacity of silver to dissolve under oxidation and form ions Ag+ with germicidal properties. At the same time there are research data in vitro, showing the silver nanoparticles toxicity for various organs, including the liver, brain and lungs. In this regard, it is essential to study the processes occurring with silver nanoparticles in biological environments, and the factors affecting their toxicity,’ says Vladimir Bochenkov.

Caption: Increased intensity of the electric field near the silver nanoparticle surface in the excitation of plasmon resonance. Credit: Vladimir Bochenkov

Caption: Increased intensity of the electric field near the silver nanoparticle surface in the excitation of plasmon resonance. Credit: Vladimir Bochenkov

An Aug. 30, 2016 MSU press release on EurekAlert, which originated the news item, provides more information about the research,

The study is devoted to the protein corona — a layer of adsorbed protein molecules, which is formed on the surface of the silver nanoparticles during their contact with the biological environment, for example in blood. Protein crown masks nanoparticles and largely determines their fate: the speed of the elimination from the body, the ability to penetrate to a particular cell type, the distribution between the organs, etc.

According to the latest research, the protein corona consists of two layers: a rigid hard corona — protein molecules tightly bound with silver nanoparticles, and soft corona, consisting of weakly bound protein molecules in a dynamic equilibrium with the solution. Hitherto soft corona has been studied very little because of the experimental difficulties: the weakly bound nanoparticles separated from the protein solution easily desorbed (leave a particle remaining in the solution), leaving only the rigid corona on the nanoparticle surface.

The size of the studied silver nanoparticles was of 50-88 nm, and the diameter of the proteins that made up the crown — 3-7 nm. Scientists managed to study the silver nanoparticles with the protein corona in situ, not removing them from the biological environment. Due to the localized surface plasmon resonance used for probing the environment near the surface of the silver nanoparticles, the functions of the soft corona have been primarily investigated.

‘In the work we showed that the corona may affect the ability of the nanoparticles to dissolve to silver cations Ag+, which determine the toxic effect. In the absence of a soft corona (quickly sharing the medium protein layer with the environment) silver cations are associated with the sulfur-containing amino acids in serum medium, particularly cysteine and methionine, and precipitate as nanocrystals Ag2S in the hard corona,’ says Vladimir Bochenkov.

Ag2S (silver sulfide) famously easily forms on the silver surface even on the air in the presence of the hydrogen sulfide traces. Sulfur is also part of many biomolecules contained in the body, provoking the silver to react and be converted into sulfide. Forming of the nano-crystals Ag2S due to low solubility reduces the bioavailability of the Ag+ ions, reducing the toxicity of silver nanoparticles to null. With a sufficient amount of amino acid sulfur sources available for reaction, all the potentially toxic silver is converted into the nontoxic insoluble sulfide. Scientists have shown that what happens in the absence of a soft corona.

In the presence of a soft corona, the Ag2S silver sulfide nanocrystals are formed in smaller quantities or not formed at all. Scientists attribute this to the fact that the weakly bound protein molecules transfer the Ag+ ions from nanoparticles into the solution, thereby leaving the sulfide not crystallized. Thus, the soft corona proteins are ‘vehicles’ for the silver ions.

This effect, scientists believe, be taken into account when analyzing the stability of silver nanoparticles in a protein environment, and in interpreting the results of the toxicity studies. Studies of the cells viability of the immune system (J774 murine line macrophages) confirmed the reduction in cell toxicity of silver nanoparticles at the sulfidation (in the absence of a soft corona).

Vladimir Bochenkov’s challenge was to simulate the plasmon resonance spectra of the studied systems and to create the theoretical model that allowed quantitative determination of silver sulfide content in situ around nanoparticles, following the change in the absorption bands in the experimental spectra. Since the frequency of the plasmon resonance is sensitive to a change in dielectric constant near the nanoparticle surface, changes in the absorption spectra contain information about the amount of silver sulfide formed.

Knowledge of the mechanisms of formation and dynamics of the behavior of the protein corona, information about its composition and structure are extremely important for understanding the toxicity and hazards of nanoparticles for the human body. In prospect the protein corona formation can be used to deliver drugs in the body, including the treatment of cancer. For this purpose it will be enough to pick such a content of the protein corona, which enables silver nanoparticles penetrate only in the cancer cell and kill it.

Here’s a link to and a citation for the paper describing this fascinating work,

Dynamic protein coronas revealed as a modulator of silver nanoparticle sulphidation in vitro by Teodora Miclăuş, Christiane Beer, Jacques Chevallier, Carsten Scavenius, Vladimir E. Bochenkov, Jan J. Enghild, & Duncan S. Sutherland. Nature Communications 7,
Article number: 11770 doi:10.1038/ncomms11770 Published  09 June 2016

This paper is open access.

Harvard University announced new Center on Nano-safety Research

The nano safety center at Harvard University (Massachusetts, US) is a joint center with the US National Institute of Environmental Health  Sciences according to an Aug. 29, 2016 news item on Nanowerk,

Engineered nanomaterials (ENMs)—which are less than 100 nanometers (one millionth of a millimeter) in diameter—can make the colors in digital printer inks pop and help sunscreens better protect against radiation, among many other applications in industry and science. They may even help prevent infectious diseases. But as the technology becomes more widespread, questions remain about the potential risks that ENMs may pose to health and the environment.

Researchers at the new Harvard-NIEHS [US National Institute of Environmental Health Sciences] Nanosafety Research Center at Harvard T.H. Chan School of Public Health are working to understand the unique properties of ENMs—both beneficial and harmful—and to ultimately establish safety standards for the field.

An Aug. 16, 2016 Harvard University press release, which originated the news item, provides more detail (Note: Links have been removed),

“We want to help nanotechnology develop as a scientific and economic force while maintaining safeguards for public health,” said Center Director Philip Demokritou, associate professor of aerosol physics at Harvard Chan School. “If you understand the rules of nanobiology, you can design safer nanomaterials.”

ENMs can enter the body through inhalation, ingestion, and skin contact, and toxicological studies have shown that some can penetrate cells and tissues and potentially cause biochemical damage. Because the field of nanoparticle science is relatively new, no standards currently exist for assessing the health risks of exposure to ENMs—or even for how studies of nano-biological interactions should be conducted.

Much of the work of the new Center will focus on building a fundamental understanding of why some ENMs are potentially more harmful than others. The team will also establish a “reference library” of ENMs, each with slightly varied properties, which will be utilized in nanotoxicology research across the country to assess safety. This will allow researchers to pinpoint exactly what aspect of an ENM’s properties may impact health. The researchers will also work to develop standardized methods for nanotoxicology studies evaluating the safety of nanomaterials.

The Center was established with a $4 million dollar grant from the National Institute of Environmental Health Science (NIEHS) last month, and is the only nanosafety research center to receive NIEHS funding for the next five years. It will also play a coordinating role with existing and future NIEHS nanotoxicology research projects nantionwide. Scientists from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), MIT, University of Maine, and University of Florida will collaborate on the new effort.

The Center builds on the existing Center for Nanotechnology and Nanotoxicology at Harvard Chan School, established by Demokritou and Joseph Brain, Cecil K. and Philip Drinker Professor of Environmental Physiology, in the School’s Department of Environmental Health in 2010.

A July 5, 2016 Harvard University press release announcing the $4M grant provides more information about which ENMs are to be studied,

The main focus of the new HSPH-NIEHS Center is to bring together  scientists from across disciplines- material science, chemistry, exposure assessment, risk assessment, nanotoxicology and nanobiology- to assess the potential  environmental Health and safety (EHS) implications of engineered nanomaterials (ENMs).

The $4 million dollar HSPH based Center  which is the only Nanosafety Research  Center to be funded by NIEHS this funding cycle, … The new HSPH-NIEHS Nanosafety Center builds upon the nano-related infrastructure in [the] collaborating Universities, developed over the past 10 years, which includes an inter-disciplinary research group of faculty, research staff and students, as well as state-of-the-art platforms for high throughput synthesis of ENMs, including metal and metal oxides, cutting edge 2D/3D ENMs such as CNTs [carbon nanotubes] and graphene, nanocellulose, and advanced nanocomposites, [emphasis mine] coupled with innovative tools to assess the fate and transport of ENMs in biological systems, statistical and exposure assessment tools, and novel in vitro and in vivo platforms for nanotoxicology research.

“Our mission is to integrate material/exposure/chemical sciences and nanotoxicology-nanobiology   to facilitate assessment of potential risks from emerging nanomaterials.  In doing so, we are bringing together the material synthesis/applications and nanotoxicology communities and other stakeholders including industry,   policy makers and the general public to maximize innovation and growth and minimize environmental and public health risks from nanotechnology”, quoted by  Dr Philip Demokritou, …

This effort certainly falls in line with the current emphasis on interdisciplinary research and creating standards and protocols for researching the toxicology of engineered nanomaterials.

Faster predictive toxicology of nanomaterials

As more nanotechnology-enabled products make their way to the market and concerns rise regarding safety, scientists work to find better ways of assessing and predicting the safety of these materials, from an Aug. 13, 2016 news item on Nanowerk,

UCLA [University of California at Los Angeles] researchers have designed a laboratory test that uses microchip technology to predict how potentially hazardous nanomaterials could be.

According to UCLA professor Huan Meng, certain engineered nanomaterials, such as non-purified carbon nanotubes that are used to strengthen commercial products, could have the potential to injure the lungs if inhaled during the manufacturing process. The new test he helped develop could be used to analyze the extent of the potential hazard.

An Aug. 12, 2016 UCLA news release, which originated the news item, expands on the theme,

The same test could also be used to identify biological biomarkers that can help scientists and doctors detect cancer and infectious diseases. Currently, scientists identify those biomarkers using other tests; one of the most common is called enzyme-linked immunosorbent assay, or ELISA. But the new platform, which is called semiconductor electronic label-free assay, or SELFA, costs less and is faster and more accurate, according to research published in the journal Scientific Reports.

The study was led by Meng, a UCLA assistant adjunct professor of medicine, and Chi On Chui, a UCLA associate professor of electrical engineering and bioengineering.

ELISA has been used by scientists for decades to analyze biological samples — for example, to detect whether epithelial cells in the lungs that have been exposed to nanomaterials are inflamed. But ELISA must be performed in a laboratory setting by skilled technicians, and a single test can cost roughly $700 and take five to seven days to process.

In contrast, SELFA uses microchip technology to analyze samples. The test can take between 30 minutes and two hours and, according to the UCLA researchers, could cost just a few dollars per sample when high-volume production begins.

The SELFA chip contains a T-shaped nanowire that acts as an integrated sensor and amplifier. To analyze a sample, scientists place it on a sensor on the chip. The vertical part of the T-shaped nanowire converts the current from the molecule being analyzed, and the horizontal portion amplifies that signal to distinguish the molecule from others.

The use of the T-shaped nanowires created in Chui’s lab is a new application of a UCLA patented invention that was developed by Chui and his colleagues. The device is the first time that “lab-on-a-chip” analysis has been tested in a scenario that mimics a real-life situation.

The UCLA scientists exposed cultured lung cells to different nanomaterials and then compared their results using SELFA with results in a database of previous studies that used other testing methods.

“By measuring biomarker concentrations in the cell culture, we showed that SELFA was 100 times more sensitive than ELISA,” Meng said. “This means that not only can SELFA analyze much smaller sample sizes, but also that it can minimize false-positive test results.”

Chui said, “The results are significant because SELFA measurement allows us to predict the inflammatory potential of a range of nanomaterials inside cells and validate the prediction with cellular imaging and experiments in animals’ lungs.”

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

Semiconductor Electronic Label-Free Assay for Predictive Toxicology by Yufei Mao, Kyeong-Sik Shin, Xiang Wang, Zhaoxia Ji, Huan Meng, & Chi On Chui. Scientific Reports 6, Article number: 24982 (2016) doi:10.1038/srep24982 Published online: 27 April 2016

This paper is open access.

Two nano workshops precede OpenTox Euro conference

The main conference OpenTox Euro is focused on novel materials and it’s being preceded by two nano workshops. All of of these events will be taking place in Germany in Oct. 2016. From an Aug. 11, 2016 posting by Lynn L. Bergeson on Nanotechnology Now,

The OpenTox Euro Conference, “Integrating Scientific Evidence Supporting Risk Assessment and Safer Design of Novel Substances,” will be held October 26-28, 2016. … The current topics for the Conference include: (1) computational modeling of mechanisms at the nanoscale; (2) translational bioinformatics applied to safety assessment; (3) advances in cheminformatics; (4) interoperability in action; (5) development and application of adverse outcome pathways; (6) open science applications showcase; (7) toxicokinetics and extrapolation; and (8) risk assessment.

On Oct. 24, 2016, two days before OpenTox Euro, the EU-US Nano EHS [Environmental Health and Safety] 2016 workshop will be held in Germany. The theme is: ‘Enabling a Sustainable Harmonised Knowledge Infrastructure supporting Nano Environmental and Health Safety Assessment’ and the objectives are,

The objective of the workshop is to facilitate networking, knowledge sharing and idea development on the requirements and implementation of a sustainable knowledge infrastructure for Nano Environmental and Health Safety Assessment and Communications. The infrastructure should support the needs required by different stakeholders including scientific researchers, industry, regulators, workers and consumers.

The workshop will also identify funding opportunities and financial models within and beyond current international and national programs. Specifically, the workshop will facilitate active discussions but also identify potential partners for future EU-US cooperation on the development of knowledge infrastructure in the NanoEHS field. Advances in the Nano Safety harmonisation process, including developing an ongoing working consensus on data management and ontology, will be discussed:

– Information needs of stakeholders and applications
– Data collection and management in the area of NanoEHS
– Developments in ontologies supporting NanoEHS goals
– Harmonisation efforts between EU and US programs
– Identify practice and infrastructure gaps and possible solutions
– Identify needs and solutions for different stakeholders
– Propose an overarching sustainable solution for the market and society

The presentations will be focused on the current efforts and concrete achievements within EU and US initiatives and their potential elaboration and extension.

The second workshop is being held by the eNanoMapper (ENM) project on Oct. 25, 2016 and concerns Nano Modelling. The objectives and workshop sessions are:

1. Give the opportunity to research groups working on computational nanotoxicology to disseminate their modelling tools based on hands-on examples and exercises
2. Present a collection of modelling tools that can span the entire lifecycle of nanotox research, starting from the design of experiments until use of models for risk assessment in biological and environmental systems.
3. Engage the workshop participants in using different modelling tools and motivate them to contribute and share their knowledge.

Indicative workshop sessions

• Preparation of datasets to be used for modelling and risk assessment
• Ontologies and databases
• Computation of theoretical descriptors
• NanoQSAR Modelling
• Ab-initio modelling
• Mechanistic modelling
• Modelling based on Omics data
• Filling data gaps-Read Across
• Risk assessment
• Experimental design

We would encourage research teams that have developed tools in the areas of computational nanotoxicology and risk assessment to demonstrate their tools in this workshop.

That’s going to be a very full week in Germany.

You can register for OpenTox Euro and more here.

Building a regulatory framework for nanotechnology in India

For the second time in less than six weeks (the first time is described in my June 13, 2016 posting on India’s draft guidelines for the safe handling of nanomaterials) I’ve stumbled across an article about the need for more nanotechnology safety measures in India. From a June 23, 2016 article by Prateek Sibal for The Wire (Note: Links have been removed),

India ranks third in the number of research publications in nanotechnology, only after China and the US. This significant share in global nanotech research is a result of sharp focus by the Department of Science and Technology (DST) to research in the field in the country. The unprecedented funding of Rs 1,000 crore for the Nano Mission was clearly dictated by the fact that India had missed the bus on the micro-electronic revolution of the 1970s and its attendant economic benefits that countries like China, Taiwan and South Korea continue to enjoy to this day.

At the same time, the success of the Nano Mission is not limited to research but also involves training the required human resource for further advancement in the field. An ASSOCHAM and TechSci Research study reported in 2014: “From 2015 onwards, global nanotechnology industry would require about two million professionals and India is expected to contribute about 25% professionals in the coming years.”

A missing element in India’s march towards becoming a nanotechnology powerhouse is the lack of focus on risk analysis and regulation. A survey of Indian practitioners working in the area of nano-science and nanotechnology research showed that 95% of the practitioners recognised ethical issues in nanotech research. Some of these concerns relate to the possibly adverse effects of nanotechnology on the environment and humans, their use as undetectable weapon in warfare, and the incorporation of nano-devices as performance enhancers in human beings.

One reason for lack of debate around ethical, and public-health and -safety, concerns around new technologies could be the exalted status that science and its practitioners enjoy in the country. A very successful space program and a largely indigenous nuclear program has ensured that policymakers spend much of their time feting achievements of Indian science than discussing the risks associated with new technologies or improving regulation.

After describing some of the studies raising health concerns, Sibal describes the issue for policymakers (Note: Links have been removed),

The challenge that remains in front of policymakers is that of regulating a field where vast areas of knowledge are still being investigated and are unknown. In this situation, over-regulation may end up stifling further development while under-regulation could expose the public to adverse health effects. Further, India’s lack of investment in risk studies only sustains the lull in the policy establishment when it comes to nanotech regulations.

The Energy and Resources Institute has extensively studied regulatory challenges posed by nanotechnology and advocates that an “incremental approach holds out some promise and offers a reconciliation between the two schools- one advocating no regulation at present given the uncertainty and the other propounding a stand-alone regulation for nanotechnology.”

Kesineni Srinivas, the Member of Parliament from Vijayawada, has taken cognisance of the need for incremental regulation in nanotechnology from the view point of public health and safety. (Disclosure: The author worked with the Vijayawada MP on drafting the legislation on nanotechnology regulation, introduced in the winter session of Parliament, 2015.)

In December 2015, Srinivas introduced the Insecticides (Amendment) Bill in the Lok Sabha to grant only a provisional registration to insecticides containing nanoparticles with a condition that “it shall be mandatory for the manufacturer or importer to report any adverse impact of the insecticide on humans and environment in a manner specified by the Registration Committee.” This is an improvement over the earlier process of granting permanent registration to insecticides. However, the fate of the bill remains uncertain as only 14 private member bills have been passed in Parliament since the first Lok Sabha in 1952.

Prateek Sibal will be joining Sciences Po (the Paris Institute of Political Sciences), Paris, as a Charpak Scholar in 2016.

I always appreciate these pieces as they help me to adjust my Canada-, US-, Commonwealth- and European-centric views.

Nano and food discussion for beginners

I try to make sure there are a range of posts here for various levels of ‘nanotechnology sophistication’ but over time I’ve given less attention to ‘beginner’ posts, i.e., pieces where nanotechnology basics are explained as best as possible. This is largely due to concerns about repetition; I mean, how many times do you want to read that nano means one billionth?

In that spirit, this June 22, 2016 news item on Nanowerk about food and nanotechnology provides a good entry piece that is not terribly repetitive,

Every mouthful of food we eat is teeming with chemical reactions. Adding ingredients and cooking helps us control these reactions and makes the food taste better and last longer. So what if we could target food at the molecular level, sending in specially designed particles to control reactions even more tightly? Well, this is exactly what scientists are trying to do and it has already produced some impressive results – from food that tastes salty without the health risks of adding salt, to bread that contains healthy fish oil but without any fishy aftertaste.

But while this nanotechnology could significantly enhance our food, it also raises big questions about safety. We only have to look at the strong reaction against genetically modified foods to see how important this issue is. How can we ensure that nanotechnology in food will be different? Will our food be safe? And will people accept these new foods?

Nanotechnology is an emerging technology that creates and uses materials and particles at the scale of a nanometre, one billionth of a metre. To get an understanding of just how small this is, if you imagine a nanoparticle was the size of a football then an animal like a sheep would be as big as our planet.

Working with such small particles allows us to create materials and products with improved properties, from lighter bicycles and more durable beer bottles to cosmetic creams with better absorption and toothpastes that stop bacteria from growing. Being able to change a material’s properties means nanotechnology can help create many innovative food products and applications that change the way we process, preserve and package foods.

For example, nanotechnology can be used for “smart” packaging that can monitor the condition of foods while they are stored and transported. When foods are contaminated or going off, the sensors on the packaging pick up gases produced by bacteria and change colour to alert anyone who wants to eat the food.

A June 22, 2016 essay by Seda Erdem (University of Stirling; UK) on The Conversation, which originated the news item, provides more information in this excerpt,

Silver is already used in healthcare products such as dental equipment for its antibacterial properties. Nano-sizing silver particles improves their ability to kill bacteria because it increases the surface area of silver the bacteria are exposed to. Israeli scientists found that also coating packaging paper with nano-sized silver particles [also known as silver nanoparticles] combats bacteria such as E. coli and extends product shelf life.

Another example of nanotechnology’s use in food manufacturing is nano-encapsulation. This technology has been used to mask the taste and odour of tuna fish oil so that it could be used to enrich bread with heart healthy Omega-3 fatty acids. Fish oil particles are packed into a film coating that prevents the fish oil from reacting with oxygen and releasing its smell. The nanocapsules break open only when they reach the stomach so you can receive the health benefits of eating them without experiencing the odour.

Meanwhile, researchers at Nottingham University are looking into nanoscale salt particles than can increase the saltiness of food without increasing the amount of salt.

As with silver, breaking salt into smaller nanosize increases its surface area. This means its flavour can be spread more efficiently. The researchers claim this can reduce the salt content of standard crisps by 90% while keeping the same flavour.

Despite all the opportunities nanotechnology offers the food industry, most developments remain at the research and development stage. This slow uptake is due to the lack of information about the health and environmental impacts of the technology. For example, there is a concern whether ingested nanomaterials migrate to different parts of the body and accumulate in certain organs, such as liver and kidneys. This may then affect the functionality of these organs in the medium to long term.

Unknown risks

However, our knowledge of the risks associated with the use of nanomaterials is incomplete. These issues need to be better understood and addressed for the public to accept nanotechnology in food. This will also depend on the public’s understanding of the technology and how much they trust the food industry and the regulatory process watching over it.

Research has shown, for example, that consumers are more likely to accept nanotechnology when it is used in food packaging rather than in food processing. But nanotechnology in food production was seen as more acceptable if it increased the food’s health benefits, although consumers weren’t necessarily willing to pay more for this.

In our recent research, we found no strong attitudes towards or resistance to nanotechnology in food packaging in the UK. But there was still concern among a small group of consumers about the safety of foods. This shows how important it will be for food producers and regulators to provide consumers with the best available information about nanotechnology, including any uncertainties about the technology.

There you have it.

nanoIndEx publishes guidance document on assessing exposure to airborne nanomaterials

Lynn Bergeson’s June 21, 2016 posting on Nanotechnology Now announced a newly published guidance document from the European Union’s nanoIndEx,

… The guidance document summarizes the key findings of the project, and is intended to present the state of the art in personal exposure assessment for nanomaterials. The conclusions section states: “Unfortunately, many nanotoxicological studies have used excessive, unrealistically high doses of [manufactured nanomaterials] and it is therefore debatable what their findings mean for the lower real-world exposures of humans. Moreover, it is not clear how to establish realistic exposure dose testing in toxicological studies, as available data on occupational exposure levels are still sparse.” According to the guidance document, future studies should focus on the potentially adverse effects of low-level and realistic exposure to manufactured nanomaterials, especially through the use of exposure doses similar to those identified in environmental sampling.

You can find the 49pp PDF here or here. To whet your appetite, here’s a bit from the introduction to the “Exposure to Airborne Nanomaterials; A Guidance Document,”

… While human exposure to MNMs may in principle occur during any stage of the material’s lifecycle, it is most likely in workplaces, where these materials are produced or handled in large quantities or over long periods of time. Inhalation is considered as the most critical uptake route, because the small particles are able to penetrate deep into the lung and deposit in the gas exchange region. Inhalation exposure to airborne nanomaterials therefore needs to be assessed in view of worker protection.

Exposure to airborne particles can generally best be assessed by measuring the individual exposure in the personal breathing zone (PBZ) of an individual. The PBZ is defined as a 30 cm hemisphere around mouth and nose [2]. Measurements in the PBZ require instruments that are small and light-weight. The individual exposure specifically to MNMs [manufactured nanomaterials, sometimes also known as engineered nanomaterials or nanoparticles] has not been assessable in the past due to the lack of suitable personal samplers and/or monitors. Instead, most studies related to exposure to MNMs have been carried out using either bulky static measurement equipment or not nanospecific personal samplers. In recent years, novel samplers and monitors have been introduced that allow for an assessment of the more nanospecific personal exposure to airborne MNMs. In the terminology used in nanoIndEx, samplers are devices that collect particles on a substrate, e.g. a filter
of flat surface, for subsequent analysis, whereas monitors are real-time instruments that deliver
information on the airborne concentrations with high time resolution. Scientifically sound investigations on the accuracy, comparability and field applicability of these novel samplers and monitors had been lacking. … (p. 4 print; p. 6 PDF)

There’s also a brief description of the nanoindEX project in the Introduction,

The three-year project started on June 1st, 2013, and has been funded under the frame of SIINN, the ERA-NET [European Research Area Network] for a Safe Implementation of Innovative Nanoscience and Nanotechnology [SINN]. The aim of the project was to scrutinise the instrumentation available for personal exposure assessment concerning their field readiness and usability in order to use this information to generate reliable data on personal exposure in real workplaces and to eventually widely distribute the findings among the interested public. This Guidance Document you are holding in your hands summarises the key findings of the project. (p. 5 print; p. 7 PDF)

As I understand it, the area of most concern where nanotoxicology is concerned would be inhalation of nanoparticles into the lungs as the body has fewer protections in the respiratory tract than it has elsewhere, e.g. skin or digestive system.

Lungs: EU SmartNanoTox and Pneumo NP

I have three news bits about lungs one concerning relatively new techniques for testing the impact nanomaterials may have on lungs and two concerning developments at PneumoNP; the first regarding a new technique for getting antibiotics to a lung infected with pneumonia and the second, a new antibiotic.

Predicting nanotoxicity in the lungs

From a June 13, 2016 news item on Nanowerk,

Scientists at the Helmholtz Zentrum München [German Research Centre for Environmental Health] have received more than one million euros in the framework of the European Horizon 2020 Initiative [a major European Commission science funding initiative successor to the Framework Programme 7 initiative]. Dr. Tobias Stöger and Dr. Otmar Schmid from the Institute of Lung Biology and Disease and the Comprehensive Pneumology Center (CPC) will be using the funds to develop new tests to assess risks posed by nanomaterials in the airways. This could contribute to reducing the need for complex toxicity tests.

A June 13, 2016 Helmholtz Zentrum München (German Research Centre for Environmental Health) press release, which originated the news item, expands on the theme,

Nanoparticles are extremely small particles that can penetrate into remote parts of the body. While researchers are investigating various strategies for harvesting the potential of nanoparticles for medical applications, they could also pose inherent health risks*. Currently the hazard assessment of nanomaterials necessitates a complex and laborious procedure. In addition to complete material characterization, controlled exposure studies are needed for each nanomaterial in order to guarantee the toxicological safety.

As a part of the EU SmartNanoTox project, which has now been funded with a total of eight million euros, eleven European research partners, including the Helmholtz Zentrum München, want to develop a new concept for the toxicological assessment of nanomaterials.

Reference database for hazardous substances

Biologist Tobias Stöger and physicist Otmar Schmid, both research group heads at the Institute of Lung Biology and Disease, hope that the use of modern methods will help to advance the assessment procedure. “We hope to make more reliable nanotoxicity predictions by using modern approaches involving systems biology, computer modelling, and appropriate statistical methods,” states Stöger.

The lung experts are concentrating primarily on the respiratory tract. The approach involves defining a representative selection of toxic nanomaterials and conducting an in-depth examination of their structure and the various molecular modes of action that lead to their toxicity. These data are then digitalized and transferred to a reference database for new nanomaterials. Economical tests that are easy to conduct should then make it possible to assess the toxicological potential of these new nanomaterials by comparing the test results s with what is already known from the database. “This should make it possible to predict whether or not a newly developed nanomaterial poses a health risk,” Otmar Schmid says.

* Review: Schmid, O. and Stoeger, T. (2016). Surface area is the biologically most effective dose metric for acute nanoparticle toxicity in the lung. Journal of Aerosol Science, DOI:10.1016/j.jaerosci.2015.12.006

The SmartNanoTox webpage is here on the European Commission’s Cordis website.

Carrying antibiotics into lungs (PneumoNP)

I received this news from the European Commission’s PneumoNP project (I wrote about PneumoNP in a June 26, 2014 posting when it was first announced). This latest development is from a March 21, 2016 email (the original can be found here on the How to pack antibiotics in nanocarriers webpage on the PneumoNP website),

PneumoNP researchers work on a complex task: attach or encapsulate antibiotics with nanocarriers that are stable enough to be included in an aerosol formulation, to pass through respiratory tracts and finally deliver antibiotics on areas of lungs affected by pneumonia infections. The good news is that they finally identify two promising methods to generate nanocarriers.

So far, compacting polymer coils into single-chain nanoparticles in water and mild conditions was an unsolved issue. But in Spain, IK4-CIDETEC scientists developed a covalent-based method that produces nanocarriers with remarkable stability under those particular conditions. Cherry on the cake, the preparation is scalable for more industrial production. IK4-CIDETEC patented the process.

Fig.: A polymer coil (step 1) compacts into a nanocarrier with cross-linkers (step 2). Then, antibiotics get attached to the nanocarrier (step 3).

Fig.: A polymer coil (step 1) compacts into a nanocarrier with cross-linkers (step 2). Then, antibiotics get attached to the nanocarrier (step 3).

At the same time, another route to produce lipidic nanocarriers have been developed by researchers from Utrecht University. In particular, they optimized the method consisting in assembling lipids directly around a drug. As a result, generated lipidic nanocarriers show encouraging stability properties and are able to carry sufficient quantity of antibiotics.

Fig.: On presence of antibiotics, the lipidic layer (step 1) aggregates the the drug (step 2) until the lipids forms a capsule around the antibiotics (step 3).

Fig.: On presence of antibiotics, a lipidic layer (step 1) aggregates the drug (step 2) until the lipids forms a capsule around antibiotics (step 3).

Assays of both polymeric and lipidic nanocarriers are currently performed by ITEM Fraunhofer Institute in Germany, Ingeniatrics Tecnologias in Spain and Erasmus Medical Centre in the Netherlands. Part of these tests allows to make sure that the nanocarriers are not toxic to cells. Other tests are also done to verify that the efficiency of antibiotics on Klebsiella Pneumoniae bacteria when they are attached to nanocarriers.

A new antibiotic for pneumonia (PneumoNP)

A June 14, 2016 PneumoNP press release (received via email) announces work on a promising new approach to an antibiotic for pneumonia,

The antimicrobial peptide M33 may be the long-sought substitute to treat difficult lung infections, like multi-drug resistant pneumonia.

In 2013, the European Respiratory Society predicted 3 millions cases of pneumonia in Europe every year [1]. The standard treatment for pneumonia is an intravenous administration of a combination of drugs. This leads to the development of antibiotic resistance in the population. Gradually, doctors are running out of solutions to cure patients. An Italian company suggests a new option: the M33 peptide.

Few years ago, the Italian company SetLance SRL decided to investigate the M33 peptide. The antimicrobial peptide is an optimized version of an artificial peptide sequence selected for its efficacy and stability. So far, it showed encouraging in-vitro results against multidrug-resistant Gram-negative bacteria, including Klebsiella Pneumoniae. With the support of EU funding to the PneumoNP project, SetLance SRL had the opportunity to develop a new formulation of M33 that enhances its antimicrobial activity.

The new formulation of M33 fights Gram-negative bacteria in three steps. First of all, the M33 binds with the lipopolysaccharides (LPS) on the outer membrane of bacteria. Then, the molecule forms a helix and finally disrupts the membrane provoking cytoplasm leaking. The peptide enabled up to 80% of mices to survive Pseudomonas Aeruginosa-based lung infections. Beyond these encouraging results, toxicity to the new M33 formulation seems to be much lower than antimicrobial peptides currently used in clinical practice like colistin [2].

Lately, SetLance scaled-up the synthesis route and is now able to produce several hundred milligrams per batch. The molecule is robust enough for industrial production. We may expect this drug to go on clinical development and validation at the beginning of 2018.

[1] http://www.erswhitebook.org/chapters/acute-lower-respiratory-infections/pneumonia/
[2] Ceccherini et al., Antimicrobial activity of levofloxacin-M33 peptide conjugation or combination, Chem Med Comm. 2016; Brunetti et al., In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate. Scientific Reports 2016

I believe all the references are open access.

Brief final comment

The only element linking these news bits together is that they concern the lungs.

Introducing the LIFE project NanoMONITOR

I believe LIFE in the project title refers to life cycle. Here’s more from a June 9, 2016 news item from Nanowerk (Note: A link has been removed),

The newly started European Commission LIFE project NanoMONITOR addresses the challenges of supporting the risk assessment of nanomaterials under REACH by development of a real-time information and monitoring system. At the project’s kickoff meeting held on the 19th January 2016 in Valencia (Spain) participants discussed how this goal could be achieved.

Despite the growing number of engineered nanomaterials (ENMs) already available on the market and in contract to their benefits the use, production, and disposal of ENMs raises concerns about their environmental impact.

A REACH Centre June 8, 2016 press release, which originated the news item, expands on the theme,

Within this context, the overall aim of LIFE NanoMONITOR is to improve the use of environmental monitoring data to support the implementation of REACH regulation and promote the protection of human health and the environment when dealing with ENMs. Within the EU REACH Regulation, a chemical safety assessment report, including risk characterisation ratio (RCR), must be provided for any registered ENMs. In order to address these objectives, the project partners have developed a rigorous methodology encompassing the following aims:

  • Develop a novel software application to support the acquisition, management and processing of data on the concentration of ENMs.
  • Develop an on-line environmental monitoring database (EMD) to support the sharing of information.
  • Design and develop a proven monitoring station prototype for continuous monitoring of particles below 100 nm in air (PM0.1).
  • Design and develop standardized sampling and data analysis procedures to ensure the quality, comparability and reliability of the monitoring data used for risk assessment.
  • Support the calculation of the predicted environmental concentration (PEC) of ENMs in the context of REACH.

Throughout the project’s kick off meeting, participants discussed the status of the research area, project goals, and expectations of the different stakeholders with respect to the project outcome.

The project has made this graphic available,

LIFE_NanoMONITOR

You can find the LIFE project NanoMONITOR website here.