Understanding the hazards of nanomaterials
A summary of what is currently understood about the toxicological properties of nanomaterials
The scientific community still does not have a good understanding of all of the health effects likely to arise from exposure to different types of engineered nanomaterials. Knowledge gaps exist in key areas that are essential for predicting health risks such as routes of exposure, the way nanomaterials are taken up into the body, the way nanomaterials are transported once inside the body and the ways in which nanomaterials interact with the body's biological systems. Although work is underway that will help to fill these knowledge gaps, the range of nanomaterials for which comprehensive hazard data are available and will be available in the foreseeable future is very narrow. Given the wide diversity of nanomaterials and observations that different nanoforms with the same chemical composition can have different toxicological properties, it likely that new approaches that do not rely on conventional toxicity testing approaches will need to be found to assess the hazards of nanomaterials.
In vitro methods and in silico approaches are potential alternative sources of hazard information. At present, it is not clear how findings from in vitro studies relate to potential effects in humans. Often the doses that are used in these studies far exceed the doses that would be obtained from workplace exposure. Also, an in vitro test may not replicate the changes a nanomaterial will undergo during its passage from the point of entry into the body to the target site. It is therefore difficult to draw general conclusions from in vitro data. It is also not clear if the structure activity relationships that are used by computer models to predict toxicological behaviour are applicable to nanomaterials. Further work is required in this area.
Routes of nanomaterial exposure
For inhaled engineered nanomaterials, the target site most likely to be affected is the lungs. There is evidence that inhaled nanomaterials have the potential to initiate inflammatory responses. However, the factors that determine the severity of the response are not fully understood. Also the longer term health consequences for repeated exposure are in many cases unknown. Epidemiological studies looking at the health effects of exposure to ambient air pollution have suggested that in addition to effects in the lungs, people inhaling air that contains high levels of particles with sizes in the ultrafine range (this includes particles that fall within the Commission definition of a nanoparticle) are more likely to suffer from diseases of the cardiovascular system. However, the relevance of this finding to workers exposed to nanomaterials at work is unclear.
In addition to inhalation, there is the potential for nanomaterials to contact the skin and gastrointestinal tract as a result of workplace exposure. With the exception of nanomaterials that are used in cosmetic products there have been few investigations into the effects of nanomaterials on the skin. Any effects that do arise as a result of skin contact are expected to be site of contact effects. Research looking at the skin absorption potential for nanomaterials has suggested that if there is any absorption across the skin the amounts that are absorbed will be low.
There is no information that will enable general conclusions to be drawn about the fate of nanomaterials that enter the gastrointestinal tract as a result of workplace exposure.
It is important to understand the physical characteristics and the chemical composition of a nanomaterial before you begin to work with it since this information will be a key element of your risk assessment. If you have good information on the physical and chemical characteristics of the nanomaterials that you are using, this will help you to determine how similar or different it is to other nanomaterials.
When trying to assess the hazards of nanomaterials, it may be tempting to refer to information that is available for apparently similar materials. All comparisons of biological/toxicological data between nanomaterials need to be supported by a detailed physical characterisation of both materials demonstrating the similarities and differences between the materials. In the absence of an adequate assessment of the physical characteristics, general conclusions drawn on nanoparticles which may have similar chemical compositions but, in fact, have different sizes, shapes, crystal structures, surface coatings, and surface reactivity characteristics may be misleading. In general, we do not recommend that you rely on hazard information for “similar” nanomaterials in your risk assessment unless you have good data to confirm that this approach is appropriate.
Characterisation information for engineered nanomaterials should be available from manufacturers or suppliers along with a safety data sheet. If this information is not available you could ask the manufacturers or suppliers to provide this information.
Physicochemical determinants of toxicity
The following physical and chemical properties are likely to be important in determining the hazardous potential of engineered nanomaterials. This list is not exhaustive. Future research may identify other physical or chemical properties that are important.
There is no clear evidence for a step change in hazardous properties relating to the specific dimensions of a particle. However, it has been reported that particles with dimensions below 20 - 30 nm are less thermodynamically stable and undergo dramatic changes in their crystalline structure compared to larger particles with the same chemical composition . These changes will influence the way these very small particles interact with their environment and biological media. Consequently it is harder to predict their toxicological behaviour based on information obtained for larger sized particles, including those at the nano scale, even where the chemical composition is the same.
The size cut-off of 100 nm that has been used within the Commission definition has been chosen because many of the specified effects of nanomaterials occur with particles with dimensions in the range 1 – 100 nm. Also this ensures consistency with definitions that are used elsewhere. It should not be assumed that a particle that has no dimensions below 100 nm is free from hazard and it should not be assumed that a particle that has at least one dimension that is below 100 nm is highly hazardous. There will be a wide variation in the hazard potential of nano-sized particles just as there is a wide variation in the hazard potential of other substances.
When nanomaterials are released, in nearly all situations they will rapidly form aggregates and agglomerates so that exposure in practice is to a much larger secondary particle than a nano-sized primary particle. The size of aggregates/ agglomerates will influence the residence time of the material in workroom air and may reduce the potential for a nanomaterial to be inhaled. The aggregation/agglomeration behaviour of nanomaterials is heavily influenced by the external environment i.e. workroom air, dispersion media, etc. It is therefore useful to understand the aggregation/agglomeration behaviour in the environment for which the risk assessment is being conducted.
Aggregates/agglomerates of nanoparticles are not necessarily stable and when the external environment changes e.g. the transition from workroom air to inhaled air, the aggregation/agglomeration state may change. So although a nanomaterial may be present in comparatively large aggregates/ agglomerates in the workroom air, there is the potential for disaggregation and disagglomeration to occur within the respiratory tract allowing smaller primary particles to penetrate to the deep lung. For this reason, although the aggregation/agglomeration state may reduce the potential to inhale a nanomaterial, it should not be assumed that nanomaterials that are exclusively present in workroom air as large aggregates/agglomerates will retain this state once inhaled. A precautionary assumption is that any nanomaterial that is inhaled has the potential to penetrate to the deep lung.
Many, but not all, of the toxic effects of particulate materials are mediated by events that take place at the particle surface. As the size of a particle decreases, the surface area to mass ratio increases. Therefore, any effects that are caused as a result of interactions at the particle surface are likely to be enhanced for nanomaterials compared to larger particles. This is one reason why nano-sized particles appear to be more potent than larger sized particles with the same chemical composition when doses are compared on the basis of mass. When doses are compared on the basis of total surface area, the apparent difference in toxicological potency is often not seen. This has led the scientific community to recommend that exposures and doses in toxicity studies for nanomaterials should be expressed in terms of surface area as well as mass.
There is very little experience with the use of surface area to express exposures and doses. The majority of the hazard data that is currently available will have been obtained from studies using mass to express dose. In this situation, a dose-response relationship for a larger particle that is expressed in terms of mass may underestimate the dose-response relationship for a nanomaterial, even though the chemical composition may be the same. For this reason, it is not appropriate to extrapolate dose-response relationships and no-effect levels that have been obtained from studies with larger particle sizes to nanomaterials unless there is scientific evidence to demonstrate that the extrapolation is valid.
There is evidence that the shape of a nanomaterial can influence its toxicity. This has been demonstrated most coherently for certain high aspect ratio nanomaterials (HARN). High aspect ratio means that one or two of the three dimensions of a particle are much smaller than the other dimension(s). Fibres are a classic example of high aspect ratio materials. The World Health Organisation (WHO) defines a respirable fibre as an object with length greater than 5µm, a width less than 3µm and a length to width ratio (aspect ratio) greater than 3:1 . Where any of these dimensions is in the nanoscale, a particle that has an aspect ratio greater than 3:1 would be considered a HARN. Platelet like structures where only one dimension falls within the nano size range are also considered to be HARN.
Carbon nanotubes (CNTs)Carbon nanotubes (CNTs)
There is evidence that HARNs with the following characteristics:
- are thinner than 3 µm,
- are longer than 10-20 µm,
- are biopersistent,
- do not dissolve/break into shorter fibres
May be retained within the narrow space surrounding the lungs - the ‘pleural cavity’ - for long periods of time.
It is known that long fibres that are retained in the pleural cavity can cause persistent inflammation, which may lead to diseases such as lung cancer, HSE’s advice is to take a precautionary risk management approach when there is the potential for workers to inhale nanomaterials with these characteristics.
If you are uncertain about the hazardous properties of the nanomaterials that you are using, precautionary control measures aimed at preventing exposure should be followed.
There is an increasing body of evidence that HARN with the characteristics identified in box 1 have the potential to cause serious adverse effects . Carbon nanotubes (CNTs) are an example of a diverse group of HARN. Some CNTs exist as long, straight fibres and in the absence of evidence to the contrary, it should be assumed that these types of CNTs have the properties identified in box 1. Other types of CNTs have a more tangled structure and exist as low density ‘fluffy’ bundles of nanotubes. For these CNTs, no evidence has so far emerged to indicate that they represent a hazard for the pleural cavity. However, they may still have the potential to cause inflammation in the lungs. It is currently not possible to make statements about the potential long term health consequences of repeated exposure to tangled CNTs.
The situation is similar for other structures that may be considered as HARN such as thin plate-like particles. Their aerodynamic behaviour is likely to result in penetration to the deep lung. There is no information to indicate how easily plate-like particles will be cleared from the lungs, but it is possible that their shape and size may prevent effective clearance. In this situation there is the potential for inflammatory reactions to occur in the deep lung. The long term health consequences of exposure to plate-like particles are not known. Much more research is needed into these particle types to understand the level of hazard that they represent.
There is no information to indicate how the shape of nanomaterials that are not HARN may influence their toxicological properties, but it will be useful to obtain information on particle shape to inform future scientific investigations into the importance of this parameter for non-HARN nanomaterials.
The surface charge of a particle can influence the adsorption of ions, contaminants, the interaction of the particle with biomolecules, uptake into cells and the way the cells react when exposed to the particle. The zeta potential of a particle is a measure of its surface charge. Recent research has identified that certain metal and metal oxide nanoparticles that are known to be inflammogenic also have a high positive zeta potential . This suggests that this parameter may be a useful predictor of certain types of toxicological effects. Further research is required to fully understand the relationship between zeta potential and toxicological effect, but it may be useful to obtain information on this property so that you can use it in future to inform your risk assessment.
Surface chemistry/surface modification
This is a broad and non-specific term. It includes elements of solubility equilibrium, catalytic properties, surface charge, surface adsorption and desorption of molecules in solution. These properties are functions of the atomic or molecular composition and the physical surface structure. Chemical purity, functionalisation and surface coating are also important aspects that could affect surface chemistry.
Surface modification has been found to enhance or reduce the toxicity of CNTs depending on the modification that is employed . This has also been observed with titanium dioxide (TiO2). Based on the information currently available, it is very difficult to predict the effect that a specific surface modification may have on hazard. However, functionalisation and surface modification are important issues to consider when deciding if the hazard information that is available is relevant to your material.
Some elements have been identified as carcinogens, mutagens, reproductive toxicants (collectively referred to as CMRs) or have the potential to cause asthma. It is reasonable to assume that a nanoparticle containing an element(s) that has these hazardous properties also has the potential to exhibit these hazards.
The presence of reactive metals is thought to be responsible for the toxicity of complex particulate mixtures such as welding fume. A nanomaterial that contained a significant proportion of such metals (e.g. large amounts of catalyst residues in CNTs) could pose a greater hazard to health than a similar material with no or low amounts of reactive metals.
Some of the adverse effects that may arise following exposure to nanomaterials arise as a result of solubilisation of the material. It has been found that the solubility of a nanomaterial may be different to that of larger particles of the same substance. For example, nano sized silver particles have a greater tendency to release silver ions into solution compared to larger silver particles. If dissolution leads to the release of reactive or cytotoxic components, and these are released more readily from a nano form compared to larger particles, the dose-response relationship for the larger particle may underestimate the dose-response relationship for the nano form.
In some cases, where reactive or cytotoxic components are not released, enhanced dissolution will speed up the rate at which nano sized particles are cleared from e.g. the lungs. This could result in a nano form presenting a lower level of hazard compared to a larger particle depending on the type of effects that are seen with the larger particle.
It may be useful to consider information on the toxicological properties of ionic forms of elements that are present in nanomaterials to help understand which sites in the body could be affected following exposure. It is not appropriate to extrapolate dose response relationships and no-effect levels that have been obtained from studies with larger particle sizes or ionic forms to nanomaterials unless there is scientific evidence to demonstrate that the extrapolation is valid.
Other potentially relevant properties
It has been suggested that nanomaterials that have photocatalytic activity may have a greater potential to cause inflammation because the particle becomes more reactive when exposed to light.
It has also been suggested that nanomaterials that are highly acidic or alkaline could produce localised irritation at the site of contact (e.g. lungs, skin or gastrointestinal tract).
Assessing the hazards of nanomaterial
In order to conduct a risk assessment it is important to understand the hazardous properties of the material that you are using. Given the current limited availability of hazard data for most nanomaterials it will be challenging to establish the toxicological behaviour of specific nanomaterials with any degree of certainty. In most cases it will be necessary to refer to information that has been obtained for similar materials. In this case it is important to establish that the information you find is relevant for the material that you are using.
Many of the most commonly used nanomaterials have similar or the same chemical composition as larger scale particulates (often referred to as bulk materials). However, it is not clear which properties from a bulk material can be assumed to apply to a nano sized particulate. Also, given the diversity of nanomaterials that may be produced which share the same or similar chemical composition but have different physical characteristics, it is often not clear which properties of a nano sized particulate can be assumed to apply to other nano sized particulates. It is therefore important to consider sameness when you are using information from one material to establish the hazardous properties of another material.
In order to determine the similarities and differences between the material that you are working with and the material for which hazard data is available, it is important to obtain as much information as possible on the physical and chemical characteristics of both materials. The previous section identifies some physical and chemical characteristics that may be particularly relevant; future research may identify other relevant characteristics. For this reason, sameness should be assessed on the basis of all available information. It is suggested that as a minimum the following characteristics could be used to establish sameness (other characteristics may be added to this list as our understanding of the relationships between physical characteristics and hazard improves):
- Chemical composition and purity
- Primary particle size distribution with an indication of the number fraction of primary particles smaller than 100 nm
- Other particle size distributions representing possible agglomerated/aggregated forms during the uses of the nanoform
- Surface functionalisation/treatment
- Surface area
The greater the differences between the physical and chemical characteristics of your material and the physical and chemical characteristics of another material, even though they may have the same chemical composition, the greater the uncertainty in extrapolating hazard data between the two materials. It is therefore important to have information on the physical and chemical characteristics of the material that you are using to ensure that you identify hazard data for materials with similar physical and chemical characteristics. If you find hazard data, but cannot properly establish the identity and characteristics of the material that has been tested, it is unwise to assume that the results are applicable to your material.
In the absence of adequate information about the physical characteristics (size, shape, crystal structure, surface coating, surface reactivity, etc), of the particular nanomaterial you are going to work with, it is unwise to make general conclusions about its potential hazards based on ‘other’ nanoparticles which may have a similar chemical composition, unless you have good data to confirm that this approach is appropriate. Where nanomaterials have an uncertain or not clearly defined toxicology and unless, or until, sound evidence is available on the hazards from inhalation, ingestion, or absorption a precautionary approach should be taken to the risk management.