Nano-TiO2--feasibility and challenges for human health risk assessment based on open literature.

This study aims at investigating feasibility and challenges associated with conducting a human health risk assessment for nano-titanium-dioxide (nano-TiO2) based on the open literature by following an approach similar to a classical regulatory risk assessment. Gaps in the available data set, both in relation to exposures and hazard, do not allow reaching any definite conclusions that could be used for regulatory decision-making. Results show that repeated inhalation in the workplace and possibly consumer inhalation may cause risks. Also short-term inhalation following spray applications may cause risks. Main future work should focus on generating occupational and consumer inhalation exposure data, as well as toxicity data on absorption following inhalation, repeated dermal contact, and contact with damaged skin. Also relevant seems further information on possible neurotoxicity and genotoxicity/carcinogenicity, as well as establishing a No Observed Adverse Effect Level (NOAEL) for acute inhalation of nano-TiO2.

Analysis of currently available data for characterising the risk of engineered nanomaterials to the environment and human health--lessons learned from four case studies.

Production volumes and the use of engineered nanomaterials in many innovative products are continuously increasing, however little is known about their potential risk for the environment and human health. We have reviewed publicly available hazard and exposure data for both, the environment and human health and attempted to carry out a basic risk assessment appraisal for four types of nanomaterials: fullerenes, carbon nanotubes, metals, and metal oxides (ENRHES project 2009(1)). This paper presents a summary of the results of the basic environmental and human health risk assessments of these case studies, highlighting the cross cutting issues and conclusions about fate and behaviour, exposure, hazard and methodological considerations. The risk assessment methodology being the basis for our case studies was that of a regulatory risk assessment under REACH (ECHA, 2008(2)), with modifications to adapt to the limited available data. If possible, environmental no-effect concentrations and human no-effect levels were established from relevant studies by applying assessment factors in line with the REACH guidance and compared to available exposure data to discuss possible risks. When the data did not allow a quantitative assessment, the risk was assessed qualitatively, e.g. for the environment by evaluating the information in the literature to describe the potential to enter the environment and to reach the potential ecological targets. Results indicate that the main risk for the environment is expected from metals and metal oxides, especially for algae and Daphnia, due to exposure to both, particles and ions. The main risks for human health may arise from chronic occupational inhalation exposure, especially during the activities of high particle release and uncontrolled exposure. The information on consumer and environmental exposure of humans is too scarce to attempt a quantitative risk characterisation. It is recognised that the currently available database for both, hazard and exposure is limited and there are high uncertainties in any conclusion on a possible risk. The results should therefore not be used for any regulatory decision making. Likewise, it is recognised that the REACH guidance was developed without considering the specific behaviour and the mode of action of nanomaterials and further work in the generation of data but also in the development of methodologies is required.

European experience in chemicals management: integrating science into policy.

The European Union (EU) adopted the first legislation on chemicals management in 1967 with the Dangerous Substances Directive (DSD). Over time the underlying concepts evolved: from hazard identification over risk assessment to safety assessment. In 1981 a premarketing notification scheme was introduced. Approximately 10 years later a risk assessment program started for existing substances following a data collection and prioritization exercise. Integration of science into EU chemicals legislation occurred via several technical committees managed by the European Chemicals Bureau (ECB) and resulted in the Technical Guidance Document on Risk Assessment (TGD), which harmonized the risk assessment methodology. The TGD was revised several times to adapt to scientific developments. The revision process, and the risk assessments for new and existing substances, led to scientific research on chemical risk assessment and thus increased in complexity. The new EU chemicals policy REACH (Registration, Evaluation, Authorization and Restriction of CHemicals) builds on previous experiences and aims to further enhance health and safety. REACH places the burden of proof for chemical safety on industry focusing on managing risks. REACH formalizes the precautionary principle. Furthermore, it underlines a continued scientific underpinning in its implementation, also via stakeholder involvement, and a focus on aligning with international fora.

Review of carbon nanotubes toxicity and exposure--appraisal of human health risk assessment based on open literature.

Carbon nanotubes (CNTs) possess many unique electronic and mechanical properties and are thus interesting for numerous novel industrial and biomedical applications. As the level of production and use of these materials increases, so too does the potential risk to human health. This study aims to investigate the feasibility and challenges associated with conducting a human health risk assessment for carbon nanotubes based on the open literature, utilising an approach similar to that of a classical regulatory risk assessment. Results indicate that the main risks for humans arise from chronic occupational inhalation, especially during activities involving high CNT release and uncontrolled exposure. It is not yet possible to draw definitive conclusions with regards the potential risk for long, straight multi-walled carbon nanotubes to pose a similar risk as asbestos by inducing mesothelioma. The genotoxic potential of CNTs is currently inconclusive and could be either primary or secondary. Possible systemic effects of CNTs would be either dependent on absorption and distribution of CNTs to sensitive organs or could be induced through the release of inflammatory mediators. In conclusion, gaps in the data set in relation to both exposure and hazard do not allow any definite conclusions suitable for regulatory decision-making. In order to enable a full human health risk assessment, future work should focus on the generation of reliable occupational, environmental and consumer exposure data. Data on toxicokinetics and studies investigating effects of chronic exposure under conditions relevant for human exposure should also be prioritised.

Review of fullerene toxicity and exposure--appraisal of a human health risk assessment, based on open literature.

Fullerenes have gained considerable attention due to their anti-oxidant and radical scavenging properties. Their current applications include targeted drug delivery, energy application, polymer modifications and cosmetic products. The production of fullerenes and their use in consumer products is expected to increase in future. This study aims to investigate the feasibility and challenges associated with conducting a human health risk assessment for fullerenes based on the open literature, utilising an approach similar to that of a classical regulatory risk assessment. Available data relates to different types of fullerenes (with varying size, surface chemistry, solubility, aggregation/agglomeration) and care should therefore be taken when drawing general conclusions across the parameters. Pristine fullerenes have shown low toxicity and there is probably no risks expected for humans exposed to fullerenes in the workplace under good hygiene conditions. The main concern for consumers is exposure via direct dermal application of fullerenes present in cosmetics. Available studies do not indicate a short term risk from the tested fullerene types, however no extrapolation to all fullerene types and to chronic exposure can be made. In conclusion, the current dataset on fullerenes in relation to both, human exposure and hazard is limited and does not allow reaching any definite conclusions suitable for regulatory decision making. Main future work should focus on generating occupational and consumer exposure data, as well as suitable data on toxicokinetics and potential toxic effects following repeated inhalation and dermal exposure allowing to determine a NOAEL. It seems also relevant to clarify whether certain fullerene types may potentially induce genotoxic and/or carcinogenic effects via physiologically relevant routes.

A critical review of the biological mechanisms underlying the in vivo and in vitro toxicity of carbon nanotubes: The contribution of physico-chemical characteristics.

This critical review of the available human health safety data, relating to carbon nanotubes (CNTs), was conducted in order to assess the risks associated with CNT exposure. Determining the toxicity related to CNT exploitation is of great relevance and importance due to the increased potential for human exposure to CNTs within occupational, environmental and consumer settings. When this information is combined with knowledge on the likely exposure levels of humans to CNTs, it will enable risk assessments to be conducted to assess the risks posed to human health. CNTs are a diverse group of materials and vary with regards to their wall number (single and multi-walled CNTs are evident), length, composition, and surface chemistry. The attributes of CNTs that were identified as being most likely to drive the observed toxicity have been considered, and include CNT length, metal content, tendency to aggregate/agglomerate and surface chemistry. Of particular importance, is the contribution of the fibre paradigm to CNT toxicity, whereby the length of CNTs appears to be critical to their toxic potential. Mechanistic processes that are critical to CNT toxicity will also be discussed, with the findings insinuating that CNTs can exert an oxidative response that stimulates inflammatory, genotoxic and cytotoxic consequences. Consequently, it may transpire that a common mechanism is responsible for driving CNT toxicity, despite the fact that CNTs are a diverse population of materials. The similarity of the structure of CNTs to that of asbestos has prompted concern surrounding the exposure of humans, and so the applicability of the fibre paradigm to CNTs will be evaluated. It is also necessary to determine the systemic availability of CNTs following exposure, to determine where potential targets of toxicity are, and to thereby direct in vitro investigations within the most appropriate target cells. CNTs are therefore a group of materials whose useful exploitable properties prompts their increased production and utilization within diverse applications, so that ensuring their safety is of vital importance.

Nano-silver - feasibility and challenges for human health risk assessment based on open literature.

This study aims at investigating feasibility and challenges associated with conducting a human health risk assessment for nano-silver based on the open literature by following an approach similar to a classical regulatory risk assessment. Gaps in the available data set, both in relation to exposures and hazard, do not allow reaching any definite conclusions that could be used for regulatory decision making. Results show that repeated inhalation in the workplace and possibly consumer inhalation may cause risks. Also (uncontrolled) nano-silver drug intake and burn treatment of large parts of the body with wound dressings may cause risks. Main future work should focus on generating occupational and consumer exposure data, as well as toxicity data on absorption (are particles or only ions absorbed?), information on genetoxicity, and further information on the toxicity following inhalation exposure to sizes and agglomeration states as uncounted in the workplace.

A review of the in vivo and in vitro toxicity of silver and gold particulates: particle attributes and biological mechanisms responsible for the observed toxicity.

This review is concerned with evaluating the toxicity associated with human exposure to silver and gold nanoparticles (NPs), due to the relative abundance of toxicity data available for these particles, when compared to other metal particulates. This has allowed knowledge on the current understanding of the field to be gained, and has demonstrated where gaps in knowledge are. It is anticipated that evaluating the hazards associated with silver and gold particles will ultimately enable risk assessments to be completed, by combining this information with knowledge on the level of human exposure. The quantity of available hazard information for metals is greatest for silver particulates, due to its widespread inclusion within a number of diverse products (including clothes and wound dressings), which primarily arises from its antibacterial behaviour. Gold has been used on numerous occasions to assess the biodistribution and cellular uptake of NPs following exposure. Inflammatory, oxidative, genotoxic, and cytotoxic consequences are associated with silver particulate exposure, and are inherently linked. The primary site of gold and silver particulate accumulation has been consistently demonstrated to be the liver, and it is therefore relevant that a number of in vitro investigations have focused on this potential target organ. However, in general there is a lack of in vivo and in vitro toxicity information that allows correlations between the findings to be made. Instead a focus on the tissue distribution of particles following exposure is evident within the available literature, which can be useful in directing appropriate in vitro experimentation by revealing potential target sites of toxicity. The experimental design has the potential to impact on the toxicological observations, and in particular the use of excessively high particle concentrations has been observed. As witnessed for other particle types, gold and silver particle sizes are influential in dictating the observed toxicity, with smaller particles exhibiting a greater response than their larger counterparts, and this is likely to be driven by differences in particle surface area, when administered at an equal-mass dose. A major obstacle, at present, is deciphering whether the responses related to silver nanoparticulate exposure derive from their small size, or particle dissolution contributes to the observed toxicity. Alternatively, a combination of both may be responsible, as the release of ions would be expected to be greater for smaller particles.

The biological mechanisms and physicochemical characteristics responsible for driving fullerene toxicity.

This review provides a comprehensive critical review of the available literature purporting to assess the toxicity of carbon fullerenes. This is required as prior to the widespread utilization and production of fullerenes, it is necessary to consider the implications of exposure for human health. Traditionally, fullerenes are formed from 60 carbon atoms, arranged in a spherical cage-like structure. However, manipulation of surface chemistry and molecular makeup has created a diverse population of fullerenes, which exhibit drastically different behaviors. The cellular processes that underlie observed fullerene toxicity will be discussed and include oxidative, genotoxic, and cytotoxic responses. The antioxidant/cytoprotective properties of fullerenes (and the attributes responsible for driving these phenomena) have been considered and encourage their utilization within the treatment of oxidant-mediated disease. A number of studies have focused on improving the water solubility of fullerenes in order to enable their exploitation within biological systems. Manipulating fullerene water solubility has included the use of surface modifications, solvents, extended stirring, and mechanical processes. However, the ability of these processes to also impact on fullerene toxicity requires assessment, especially when considering the use of solvents, which particularly appear to enhance fullerene toxicity. A number of the discussed investigations were not conducted to reveal if fullerene behavior was due to their nanoparticle dimensions but instead addressed the biocompatibility and toxicity of fullerenes. The hazards to human health, associated with fullerene exposure, are uncertain at this time, and further investigations are required to decipher such effects before an effective risk assessment can be conducted.

Identification of the mechanisms that drive the toxicity of TiO(2 )particulates: the contribution of physicochemical characteristics.

This review focuses on outlining the toxicity of titanium dioxide (TiO(2)) particulates in vitro and in vivo, in order to understand their ability to detrimentally impact on human health. Evaluating the hazards associated with TiO(2 )particles is vital as it enables risk assessments to be conducted, by combining this information with knowledge on the likely exposure levels of humans. This review has concentrated on the toxicity of TiO(2), due to the fact that the greatest number of studies by far have evaluated the toxicity of TiO(2), in comparison to other metal oxide particulates. This derives from historical reasons (whereby the size dependency of particulate toxicity was first realised for TiO(2)) and due to its widespread application within consumer products (such as sunscreens). The pulmonary and dermal hazards of TiO(2 )have been a particular focus of the available studies, due to the past use of TiO(2 )as a (negative) control when assessing the pulmonary toxicity of particulates, and due to its incorporation within consumer products such as sunscreens. Mechanistic processes that are critical to TiO(2 )particulate toxicity will also be discussed and it is apparent that, in the main, the oxidant driven inflammatory, genotoxic and cytotoxic consequences associated with TiO(2 )exposure, are inherently linked, and are evident both in vivo and in vitro. The attributes of TiO(2 )that have been identified as being most likely to drive the observed toxicity include particle size (and therefore surface area), crystallinity (and photocatalytic activity), surface chemistry, and particle aggregation/agglomeration tendency. The experimental set up also influences toxicological outcomes, so that the species (or model) used, route of exposure, experiment duration, particle concentration and light conditions are all able to influence the findings of investigations. In addition, the applicability of the observed findings for particular TiO(2 )forms, to TiO(2 )particulates in general, requires consideration. At this time it is inappropriate to consider the findings for one TiO(2 )form as being representative for TiO(2 )particulates as a whole, due to the vast number of available TiO(2 )particulate forms and large variety of potential tissue and cell targets that may be affected by exposure. Thus emphasising that the physicochemical characteristics are fundamental to their toxicity.