Nanoparticles: the ins and outs of breathing safely

With a growing range of advanced materials made from engineered nanoparticles, what are the potential health risks from these minute entities to our lungs and vascular system? Terry Tetley, Professor of Lung Cell Biology at Imperial College, London is leading a multi-disciplinary, nanotoxicology project to understand the effects and enable the development of safer nanomaterials.

The use of engineered nanomaterials has become widespread over the last two decades. They are very diverse, and have a wide range of applications, from aerospace composites to flameproof clothing, from medicine and cosmetics to graphite tennis rackets. They have many attractions for manufacturers; take carbon nanotubes for example, which are light, strong and excellent conductors of electricity. Nanomaterials can be synthesised into different shapes, from spheres to tubes and wires, and positively, negatively or neutrally charged to alter their surface properties and reactivity.

Nanoparticles of elements such as carbon and silver, which form the basis of such materials, measure (via the official definition at least) no more than 100 nanometres (a nanometre = 1 billionth/metre) in one dimension – approximately one thousandth of the width of a human hair. Yet their significance in our modern manufacturing world is huge.

If these particles are so minute, what is the effect on our lungs and vasculature if we inhale them? That’s the focus of a continuing series of studies that Professor Tetley has been involved in since 2006. So what prompted this line of research?

“There was no eureka moment,” she says. “My interest follows on from studies that emerged in the 1990s showing that particulate matter (PM) in ambient air pollution (PM less than 10 or less than 2.5 micrometres diameter; PM10, PM2.5) adversely affected the lungs and cardiovascular system, and the possibility that engineered nanomaterials might have similar effects was highlighted in a report by The Royal Society and Royal Academy of Engineering in 2004, Nanoscience and nanotechnologies: opportunities and uncertainties. While there was no definitive answer, the report concluded that we ought to at least anticipate potential effects, and as someone who had previously studied the effects of other inhaled toxicants, such as asbestos and cigarette smoke, I became interested in this area of research.”

While Professor Tetley’s research focuses on the effects on the lungs and vasculature, other groups are studying the effects on the rest of the body, including the brain, skin, gut and immune system, to build up a complete picture of possible effects of nano-sized material on the human body. The research initiatives in which she works (with collaborators in Europe and the USA) are particularly focused on which physical and chemical features of nanomaterials induce cellular reactivity, and which do not, so that the generation and use of these materials can be properly and safely controlled, particularly in the work place. “Ultimately, the different research groups will give their data to mathematical modellers who will use it to predict how nanoparticles will react with different parts of the body,” says Professor Tetley.

So what could the potential effects be? “The macrophages in our lungs are designed to remove unwanted particulate substances of a certain size range, through a process known as phagocytosis,” explains Professor Tetley. “But if you’re inhaling nanoparticles, they could have the ability to act rather like a protein or lipid and may by-pass the protective macrophages and enter other cells, such as the respiratory epithelium where gas exchange takes place. Moreover, when a material is broken down into nanoparticles, it is able to disperse over a much bigger surface area – rather like breaking up a single sugar cube into hundreds of grains – and therefore interact with a much larger area of the lung’s epithelial surface.”

Quite what effect the nanoparticles have on the lung cells when they get there is still not understood, but Professor Tetley says there are at least some theories. “One hypothesis is that nanoparticles, because of their size, are able to get across the epithelium [the respiratory wall of the lungs] and the endothelium [the capillary wall of the lung vasculature] into the bloodstream, although there is no evidence to suggest that this occurs to any great extent. Another hypothesis is that perhaps they simply aggravate the walls at the respiratory surface and cause inflammation, contributing to adverse effects such as cardiovascular disease, pulmonary fibrosis, emphysema and tumours. But we just don’t know – we’re still working on that.”

The methodology she is using in uncovering this mystery involves building lung models of cells from extracted human lung tissue to test nanoparticle reactivity. “We expose extracted cells, such as those from the epithelial lining and the macrophages, to the particles and investigate the responses – such as cell death or over-production of pro-inflammatory mediators,” says Professor Tetley. “Sometimes we use monocultures (a single cell type) and sometimes we put different cells together as a co-culture, to mimic the situation inside the lung more accurately.”

What is clear is that materials change their properties when they are at nanoparticle size. “As a simple model that I started working with three years ago shows, using spheres of latex, there are big differences in the reactivity of nanoparticles depending on their size and functionality,” says Professor Tetley. “Latex particles of 50 nanometres were more reactive than those of 100 nanometres. Similarly, nanoparticles given a positive charge were more cytotoxic, causing cell death and inducing oxidative stress, while the negatively-charged ones were more pro-inflammatory.”

Professor Tetley also highlights other important findings from the research so far. “We’ve made a unique discovery – that certain nanoparticles can form a pore in the epithelial cell wall – which proves that the particle is going through the cell membrane into the cytoplasm. And thanks to the wonders of hopping probe ion conductance microscopy we can watch it happen at very high resolution in real time with live cells – that’s been very exciting.”

“We’ve also found that whether nanoparticles can get into, or across, the epithelial cells depends on the property of the particular particle. Furthermore, we’ve seen that if the particle interacts with lung secretions first, this modifies the particle and can make it less toxic.”

However, the research also shows that nanoparticle interaction with lung secretions might cause problems. “Nanoparticles can absorb proteins and lipids out of the lung secretions, too,” says Professor Tetley. “This could cause some sort of deficiency at the lung surface – certain proteins and lipids (lung surfactant) are important for keeping your lungs open when you exhale, for example, so this would suggest a potential deficiency in that function. Determining whether this occurs and is therefore important is one of the major areas of our research.” There are also potential implications for the heart and cardiovascular cells. “If nanoparticles are actually absorbed into the bloodstream and reach the heart – and we don’t yet know if they do – they may have adverse effects on the cardiovasculature and heart,’ says Professor Tetley. “ Studies are in progress to investigate this possibility.”

Professor Tetley’s preliminary findings therefore suggest that some engineered nanoparticles could be highly reactive in the lungs and cardiovasculature, with other researchers showing similar things in other parts of the body.

So we would be wise, it seems, to be cautious in our use of nanoparticles. But, she argues, this doesn’t mean we should stop using them.

“We use many potentially dangerous resources every day – electricity for example – but we manage that risk by using them at a safe level or changing their form – so that we can enjoy their benefits. It is the same with engineered nanoparticles, as they have so many unique properties which enhance everyday life.”

The hope, therefore, is that the research will identify common features among nanoparticles, that cause certain effects on the lung and vasculature.

“If we could relate the physical and chemical characteristics of the particles to their reactivity, we would be able to say ‘this particle is harmful to this organ but safe for that organ’ or ‘this size nanoparticle is safe to use but this one is not.” says Professor Tetley.

“Similarly, if we were able to ‘mop up’ the nanoparticles from the lungs after use in a drug delivery spray for example, before they caused harm, then we could have the benefits of the drug treatment without the harmful side effect to the lungs.”

Nanotoxicology of this kind is a young area of science – around five years old – but already awareness of the importance of such research is growing among government agencies, health professionals and industry. “There are already some companies sponsoring research into toxicology,” says Professor Tetley, “And we would hope to build on that awareness in the future, of course.”

Whether the release of nanoparticles occurs mainly at the manufacturing stage or also through natural wear and tear of the finished product is another unknown – and revealing that secret is another hope for the future.

What the research has confirmed, however, is that it is right to anticipate the potential effects on human health, so that we can engineer our materials to provide the safe, high performance products of the future.

Click here to contact Professor Terry Tetley.

Published: Monday, 10th October 2011