Is oxidative stress the principal mode of toxicity for metal oxide nanoparticles?

Manufactured nanoparticles (NPs) can be defined as very small materials purposefully produced by human activity with at least one dimension between 1 and 100 nm (i.e. they are larger than most chemical products but much smaller than biological cells). They are currently of tremendous scientific, technological and economic importance, having a wide range of applications or potential applications in environmental technologies, medical and health applications (e.g. drug delivery vehicles, diagnostics, antibiotics), computing, cosmetics and elsewhere. Global research and development was valued at approximately £10 billion in 2006 and international nanotechnology markets are expected to be valued at trillions of dollars in the next decade. Given this huge and growing importance, concern is warranted because (1) discharges into the environment are now occurring and will grow at increasing rates as the nanotechnology industry increases, (2) significant adverse effects on human and environmental health have been shown to occur and yet there remains great uncertainty as to the type of damage that they may cause and whether this can lead to adverse health effects at exposure levels likely to be achieved in the environment. We seek to ensure responsible development of these hugely beneficial products. This is vital to ensure that industry and government (and ultimately the general public) are informed of the possible risks of NPs, so that these risks can be minimised and a large scale public backlash, such as occurred for genetically modified organisms, is prevented. Metal oxide NPs, especially TiO2 and CeO2, are amongst the most widely used NPs in consumer goods and it is almost certain that these NPs are present in the environment despite our lack of methods to measure concentrations under realistic conditions. There is evidence that both of these materials can lead to damage of biological cells and that this is caused by their ability to produce highly damaging forms of oxygen (called reactive oxygen species). However, there is very little information on whether such damage can occur in whole organisms, particularly in the freshwater environment, which is likely to be a major source of exposure. There is also very little information on whether other modes of toxicity are important. We wish to test the hypothesis that such 'oxidative damage' can occur in intact cells of freshwater algae and of the water flea, Daphnia magna. We will use several state-of-the-art molecular technologies (called 'omics' techniques) to obtain a comprehensive assessment of such oxidative damage as well as an assessment of potential alternative responses (as yet unidentified) in these organisms that may impact on their health. Health will also be measured in relation to growth and reproduction of these organisms. The NPs to be used will be synthesised and well characterised in relation to physical and chemical features prior to, and after, the exposure studies, including assessments of uptake into the organisms and an assessment of the relative importance of different routes of uptake. We will thus determine the nature and potency of the potential damage and risks posed by specific characteristics of the NPs to organisms in the environment, enabling targeted analyses for safety assessment screening to be developed, and provide the knowledge to reduce uncertainty in risk prediction for different species, including humans.