Sunday, December 31, 2006

Nano Research Needs Assessment - A SUMMARY OF FINDINGS

Here is a review of the lterature. It was written by me and does not represent the views of ICON, Rice U, U South Carolina, or the NSF.

Aitken, R. J., Creely, K. S., & Tran, C. L., Research Report 274 - Nanoparticles: An occupational hygiene review, Edinburgh, Scotland: Institute of Occupational Medicine, http://www.hse.gov.uk/research/rrpdf/rr274.pdf, 2004.

This study examines routes, sources, levels of exposure, control measures, and numbers exposed. It concludes all processes give rise to exposure (by inhalation, dermal, and ingestion) during recovery, powder handling and product processing. Control approaches and methods for exposure from inhalation are available and should be effective in nanoparticles processes. However, for dermal and ingestion exposure, controls methods based on personal protective equipment may not be as effective. They add there is only very limited information about exposure, though information from powder handling processes indicates that exposures may be significant. The report concludes knowledge gaps in terms of nomenclature, methods by which particles surface area can be assessed in the workplace, and information to judge whether exposure to various forms of nanoparticles is occurring at significant levels in production processes. The report calls for a better understanding on the levels of exposure which may be acceptable and an effective strategy for collecting, storing and disseminating information for risk assessment including the development of appropriate databases.

Allianz Group and OECD, Small size that matter: Opportunities and risks of nanotechnologies,
http://www.allianz.com/en/index.html, 2005.

This report notes the exposure to manufactured nanoparticles is mainly concentrated on workers in nanotechnology research and companies and exposure of the general public originating from dedicated industrial processes is marginal. However, it is inevitable that in the future manufactured nanoparticles will be released gradually and accidentally into the environment.

In addition, it reports almost all safety concerns that have been raised about nanotechnologies are related to free rather than fixed engineered nanoparticles. In most applications nanoparticles will be embedded in the final produce and therefore not come into direct contact with workers, consumers or the environment. They are unlikely to raise concerns because of their immobilization. It is unlikely that engineered nanoparticles that are bound in a matrix or somehow fixed in a product are released. Manipulations like grinding or cutting do not necessarily release nanoparticles, but rather more likely particles of larger size in which the nanoparticles are still bound.

The report warns that certain applications such as environmental remediation with the help of nanoparticles could lead to the deliberate introduction of nanoparticles into the environment. This is an area which will probably lead to the most significant releases in terms of quantity of nanoparticles in the coming years.

The report caution that existing knowledge on nanoparticles and human health is quite limited and it will be necessary to generate and establish new data in the future, esp. since additional parameters like size, shape or surface properties will come into play. The same reason that makes nanoparticles technologically interesting leads to the fact that they represent a new category of (potentially) toxic substances.

The report also notes that explosibility of nanopowders has so far not received much attention in the public debate on health and safety risks of nanotechnologies.

Ata, M., Negami, Y., Ishibashi, K., & Sekiya, M., Public Recommendations from “Research Project on Facilitation of Public Acceptance of Nanotechnology”, Tokyo, National Institute of Advanced Science and Technology (AIST), http://www.coloradonanotechnology.org/image/Ethics%20and%20Social/Public%20Acceptance%20of%20Nano%20in%20Japan%5B1%5D.pdf, 31 March 2006.

This report emphasizes the importance of trust between stakeholders and notes the uncertainties existing in terms of the physico-chemical behavior and biodynamics of nanomaterials. Noting novel characteristics of nanomaterials, the report calls for a timely impact assessment for short-, medium- and long-term exposures. It recommends research into the presence of nanomaterials in the environment, their intake by organisms, and detection and measurements technologies to measure these. It calls for more research into the interactions between nanomaterials and living tissue and constituents. It also calls for the compilation of databases which are user-friendly esp. for those conducting risk assessments and preparing MSDS and GHS (Globally Harmonized System of Classification and Labeling of Chemicals) reports.

It calls on nanotechnology companies to conduct their own voluntary assessments of nanomaterials as well as exposure assessments and biological impact assessments based on in vivo tests that examine bioaccumulation and chronic effects.

It calls on government to summarize hazard information that reflect the actual presence and state of nanomaterials and to make the information public, to establish an interdisciplinary center to provide information on nanomaterials production and trade activities, and to create a database to incorporate basic knowledge on ethical and social dimensions, biological and environment impacts, and behavior of nanomaterials.

It mentions an interesting challenge related to risk management from a Japanese perspective where the work for risk kiken carries an implicit negative valence and contributes to an unarticulated uneasiness about nanotechnology risks in the minds of the general public. As such, it calls for the verification and management of aspects relating to risk in the form of studies and research about risk management.

Chemical Industry Vision 2020 Technology Partnership, Joint NNI-Chl CBAN (National Nanotechnology Initiative-Chemical Industry Consultative Board for Advancing Nanotechnology) and SRC CWG5 (Semiconductor Research Corporation Consultative Working Group #5) - Nanotechnology Research Needs Recommendations, http://www.chemicalvision2020.org/pdfs/chem-semi%20ESH%20recommendations.pdf, 2005.

It recognized the challenge of the best metrics for nanoscale particle toxicity and lists: mass, size of primary particle, the degree or proportion of aggregates and agglomerates, aerodynamic size, number concentration, surface area, chemical composition (identity, impurities, surface characteristics), shape and structure, dissolution/durability characteristics, and the presence, nature, purity, effects, stability, influence of additives, shells and coatings. It highlights number and surface area a critical dosimetrics and calls for chemical characterization at or near the atomic level is likely to be necessary for assessment of nanoscale particles.

Noting the limiting information on exposure monitoring esp. the absence of standardized sampling and analytical techniques to quantify exposures to unbound nanoscale –particles and the uncertainty as to what parameter(s) or characteristic(s) should be measure to quantify exposure and which measured parameter will be most effective in determining and predicting toxic effects, it recommends the developing of monitoring technologies.

Noting a need to develop standardized risk assessment methodologies for both occupation and non-occupation health risks and underlining particle surface are and surface chemistry as two relevant variables, it recommends the development of exposure assessment methodologies.

Noting limitations of current in vitro data and the intricate pharmacokinetics that occurs in the body but is absent in cell cultures, it recommends developing a screening /prioritizing strategy for the hazard identification of nanoscale materials with the highest EHS concerns based on the production volume, potential for occupation, consumer, and environmental exposure, physico-chemical properties indicative of potential toxicity, validation of available in vitro and short-term toxicity assays for the testing of nanoscale materials.

Finally, noting public perception is dependent on communication mechanisms and this perception can help or hinder development of the technology, it recommends non-technical web-based outreach, non-technical summaries of significant research findings, public outreach and review of EHS related research, and databases and multi-stakeholder partnerships (referencing ICON in the last two recommendations). It also calls for internationally coordinated communications and ongoing public opinion monitoring.

DEFRA Nanotechnology Research Co-ordination Group, Characterising the potential risks posed by engineered nanoparticles, London: Department of Environment, Food and Rural Affairs (DEFRA), http://www.defra.gov.uk/environment/nanotech/research/reports/progress-report061019.pdf, October 2006.

This report identifies information on the size distribution, shape, surface area, solubility, and surface charge of nanoparticles as fundamental to understanding both toxicological and eco-toxicological properties. It calls for new measurement principles, methods, and protocols sensitive to surface chemistry, total surface area, surface curvature and defect density and calls for rapid methods of measurement. It adds concern for a measurement method for nanoparticles within a specific matrix. For example, it calls for new methods based on the special chemical and spectroscopic properties of nanotubes especially sensitive to length or aspect rations.

It asks whether dose response relationships are influenced by variables such as size, number, and shape, whether nanoparticles influence the fate, behavior, and eco-toxicity of other substances present in the environment, whether nanoform substances within environmental matrices are more persistent, bioaccumulative or toxic, and what factors influence agglomeration and other aspects of fate and behavior.

It calls for reliable reference materials to enable comparison of findings esp. regarding physico-chemical measurement and instrument calibrations. It also calls for this library divided into two types: one to represent materials in high-volume industrial production and another for materials designed to answer specific toxicological questions, such as nanotube length. The reference materials and both libraries need to be prioritized. The report adds concerns regarding the fire and explosive potential of nanoparticles, esp. nano-powders.

In terms of sources, it identifies the following: occupational exposure, deliberate environmental releases, unintentional environmental releases, exposure from consumer products, and exposure from medical products. It emphasizes the importance of life cycle analysis in terms of quantifying the amount of exposure with the life cycle which will involve a detailed study of environmental fate and behavior through environmental compartments, such as sewers, groundwater, surface water, and air from unintentional release on disposal, degradation, partitioning and potential remobilization of nanoparticles, efficacy of current treatment and disposal systems for managing nanoparticles, and the impact of nanoparticles on biological treatment systems and ecological end-points. It calls for addressing a fundamental knowledge gap on the fate and behavior of nanoparticles in soil and water as well as effects on groundwater and soil micro-organisms, animals and plants, esp. in the context of remediation.

In terms of human toxicology, it calls for identifying potential target organs/tissues for assessment, inter and intracellular transport or localization, oxidative stress and inflammatory effects and genotoxicity and research to understand deposition, distribution, toxicity, pathogenicity and translocation potential and pathways (toxico-kinetics) for nanoparticles, esp. interaction with tissue to tissue barriers including blood-brain and placental. It also recommends research to understand dermal uptake, penetration and toxicity in the skin. The report underlines the importance of discovering what controls the toxicity of representative nanoparticles (a structure/activity paradigm for nanoparticles toxicity) to extrapolate from studies on well characterized nanoparticles (it noted problems regarding batch to batch variation and recommends a central bank for samples) to possible effects of new particles. It offers a plan in three tiers: detailed characterization, in vitro studies, and in vivo studies.

It calls for improved methods of collection and characterization of airborne nanoparticles. It calls for learning whether nanoparticles that are present in final food (to be ingested) are comparable with those used to product the risk assessment. It calls for an international group to develop a control banding approach to exposure control.

Finally, it calls for building public value into new technologies before they reach the market.

Federal Institute for Occupation Safety and Health (BAuA Bundesanstalt für Arbeitsschutz under Arbeitsmedizin, Federal Institute for Risk Assessment (BfR Bundesinstitut für Riskobewertung), & Federal Environment Agency (UBA Umwelt Bundes Amt), Nanotechnology: Health and Environmental Risks of Nanoparticles – Research Strategy – Draft, Berlin, Germany: BfR, http://www.baua.de/nn_47716/sid_B0AA05CB8FF8141A55EAC94DDDFCC809/nsc_true/de/Themen-von-A-Z/Gefahrstoffe/Nanotechnologie/pdf/draft-research-strategy.pdf, August 2006.

Noting the toxicological and eco-toxicological risks from nanotechnologies, esp. insoluble and poorly soluble nanoparticles, cannot be assessed, it calls for research to close the knowledge gaps. It calls for the research to be structured, to develop the measurement technologies, to record information on exposure and effects, to promote risk related test and assessment strategies, to identify elements of a test strategy, to move substances of particular importance to center stage, and to ensure suitability of data for regulatory questions.

This mission would be effectuated if companies voluntarily report schemes for production and create exposure categories to allow priority setting. Companies need to develop, test, and standardize measure methods and record exposure to consumers and the environment. Measurement methods for quantification and characterization are currently in the development stage and far from routine. Companies’ goals would include examining exposure scenarios and life cycle analyses to adapt them if necessary. Reliable data about the distribution of nanoproducts is needed and the report underscores the problem with products marketed as “nano” without containing nanoscale ingredients.

Exposure to the environment should increase given the growing use of synthetic nanoparticles. Research to determine how stable and long-lived forms are, under what conditions they disintegrate or agglomerate, solubility in water or body fluids, as well as how they interact with other nanoparticles, chemicals and surfaces or are degraded and how their properties change are in order. This is especially valid for nanoparticles intentionally released to control pests or to decontaminate soil or water or to remove inorganic or organic impurities. Research must attend to bioaccumulation and biomagnifications as well as the influence of agglomeration on bioavailability to better understand accumulation and persistence. In addition, quantitative methods are needed that allow the detection of nanoparticles in various body compartments. Also noted was the scarce number of studies on the effects of nanoparticles on terrestrial systems.

Importantly, one of the goals should be to establish substance classes for nanoparticles so that not all nanoparticles would have to be examined extensively and to do this we must elucidate the mechanism of toxicity, for example the degree of systematic availability of nanoparticles after dermal exposure as well as a mutagenic potential of a widespread nanoscale substance such as nanoparticles of zinc oxide. The report recommends nanoparticles with similar toxicity to be compiled in groups in order to examine one representative substance in this group for purposes of generalization. Compiling nanoparticles into classes with similar effects and suitable reference sized would be prudent.

There is further need to standardize imaging methods in the reproducible manner and to determine distribution in the organism in kinetic studies. Work should be done to establish what information is needed to assess the validity and comparability of nanostudies (such as stipulation of characterization, impurities, etc.). Standardized test guidelines and an appropriate test and assessment strategy may be in order to be used in research into and assessment of health risks. As such, the report recommends a larger number of physico-chemically exactly characterized nanoparticles should be examined with validated screening tests which look at various endpoints of toxicity in order to be able to assess the influence of physico-chemical properties of toxicological properties.

The report underlines the importance of co-ordinated and effective research for economics and in order the place recommendations on a sound basis. Noting no concrete strategy to date to facilitate a comprehensive risks assessment, it calls for a screening strategy of nanomaterials encompassing physico-chemical properties (particle size and distribution, solubility, agglomeration state, shape, crystal structure, surface, surface chemistry and charge as well as porosity). As these parameters can influence toxicity, their determination would be a major precondition for the interpretation of experimental studies.

One of the recommendations is for a join nano discourse platform.

Hett, A., Swiss Re, Nanotechnology – Small matter, many unknowns, Zurich, Switzerland: Swiss Reinsurance Company, www.swissre.com, 2004.

This report has surely been eclipsed by others, but it was one of the first to raise concerns over translocation and transportation beyond the lungs, over dermal exposure, over the impact of coatings on exposure and toxicity, over the importance of mass and surface area ratios, over the production of free radicals and oxidative stress, over soil, plants, and groundwater exposure, over the inadequacy of current workplace health and safety technologies, over the inadequacy of MSDS, etc. Under a challenge for research is the straightforward statement: Toxicological studies cannot simply be carried out on certain particles and the findings compulsorily applied to all other nanoparticles.

ICF International, Characterizing the Environmental, Health, and Safety Implications of Nanotechnology: Where Should the Federal Government Go from Here? Fairfax, VA: ICF International, http://www.icfi.com/markets/environment/doc_files/nanotechnology.pdf, December 2006.

ICF claims to have created a strategic research framework to inform priority risk management and enhance a sustained nanotechnology EHS function. They add three elements into the mix: reverse engineer priority risk management decisions, provide a voice to “orphan” risk issues, and establish a multi-agency Federal Nanotechnology EHS Research Council.

They call for 10% of government spending allocated to EHS research and warn that neither the NEHI nor the NNI per se is empowered to set or fix research priorities. They are pragmatists and claim research is valuable only to the extent it informs risk management decisions and most valuable when it informs risk management decisions in areas of greatest EHS concern.

They reference the Board on Environmental Studies and Toxicology (BEST) at the National Research Council that reviewed EPA’s airborne particulate matters program from 1998 to 2002 as a model for NanoEHS Research Assessment.

They call for a new interagency oversight group and call for it to close monitor pre-market notifications under TSCA, professional literature and industry conferences, and close collaboration with European and Asian regulators.

They call for strict scheduling of scientific findings from EHS grants, interim deliverables, and opening of all grants to all potential researchers whether in academia or in industry.

They call for a central location for interested stakeholders to easily access the details and the results of EHS research on nanotechnology. In addition to managing the hub, the team of librarians would be responsible for producing newsletters, holding workshops, and working directly with policymakers, updating them as research results are received.

They call for the research agenda to anticipate the commercialization of specific nanomaterials and continuously adapt the research focus to those nanomaterials that emerge from the laboratories.

Lux Research, Taking Action on Nanotech Environmental Health, and Safety Risks, May 2006.

The report observed exposure can be difficult to predict and measure and studies arrive at contradictory results and, importantly, even the safest nanomaterials could become a liability since risk is perceived and made the relevant notation that studies on hazard far outnumber studies on exposure by ten to one in both 2005 and 2006. It notes nanomaterials are complex and variables such as size distribution, surface chemistry, coating, surface charge, crystal structure, etc. can affect a material’s toxicity or exposure potential and warns analogies to existing materials are not sufficiently accurate to predict their actual toxicity. It also noted the effectiveness of engineering controls, such as filters, etc. remains uncertain.

Maynard, A., Nanotechnology: A Research Strategy for Addressing Risk, Washington, DC: Project on Emerging Nanotechnologies, Woodrow Wilson International Center for Scholars, http://www.nanotechproject.org/67, July, 2006.

Maynard begins with the thesis that federal funding of safety research is inadequate and calls for focused research on nanomaterials in use or close to commercialization, identifying and measuring exposure and release, evaluating toxicity, controlling release, and developing best practices. He warns most of the risk research is focused disproportionately on carbon and on human exposure in the lungs. He calls for research on exposure in the gastrointestinal tract due to likely applications in the food and nutritional supplements industries. He calls for full and effective international collaboration and co-ordination. On p. 26 he offers a table regarding nanotechnology risks research areas that need addressing. He appeals for research to determine how to collect, sort, and use the vast and diverse amount of data being generated on engineered nanomaterials that is relevant in determining risk. Because we may not have the luxury of researching every aspect of nanomaterials toxicity, some strategic action plan addressing research priorities needs to be established and offers a 10-year nanotechnology risk research prioritization on p. 29. He equivocates over the capabilities of the Heath Effects Institute to function effectively in the area and ends by opting for a new Nanotechnology Effects Institute. He also summons NSET’s Nanotechnology Environmental and Health Implications (NEHI) to oversee an appropriate strategic framework.

Nanotechnology Workgroup, EPA’s (U.S. Environmental Protection Agency) Science Policy Council, Nanotechnology White Paper: External Review Draft, Washington, DC: Science Policy Council, http://es.epa.gov/ncer/nano/publications/whitepaper12022005.pdf, 2 December 2005.

This report established challenges for the EPA especially pollution prevention, sustainable resource consumption, and product stewardship involving collaborative research in areas such as chemical identification and characterization, fate, detection and analysis, potential releases and human exposure, effects assessment, and environmental technology applications. It recommends the EPA engage in case studies to identify information gaps to help map areas of research to inform risk assessments on nanomaterials in addition to determining whether current exposure assessment processes are adequate. Research questions call for identifying unique chemical and physical characteristics, determining whether characteristics vary among different types of particles, resolving how these properties affect reactivity, toxicity, and so forth, ascertaining how this research should be used, establishing testing methods to evaluate hazard and exposure, verifying which nanomaterials are now on the market and what new types can be expected to be developed, and uncovering how manufacturing processes may alter the characteristics of nanomaterials. The report highlights measurement challenges associated with nanoparticle mass/mass concentrations, surface area, particle count concentration, size, physical structure (morphology), and chemical composition and what alternative metrics to measuring exposure may need to be designed. The report calls for fate research, especially in terms of transport and deposition and degradation and bioaccumulation, not only for free nanoparticles but also for matrix bound nanoparticles. Questions involving aggregation, sorption, and agglomeration were also asked. The report adds exposure scenarios involving industrial accidents, natural disasters, and malevolent activities, such as terrorism to more traditional exposure considerations. In terms of exposure, the report asks whether sensitive populations (endangered species, children, asthmatics, etc.) are especially vulnerable. The report asks whether current technologies are capable of reducing or eliminating exposure to nanomaterials. Finally, the report calls for more research on the EHS considerations of nanomaterials.

Nel, A., et al, “Toxic potential of materials at the nanolevel,” Science, 331, www.sciencemag.org, 3 February 2006.

These researchers warn that some nanoparticles regularly travel throughout the body, deposit in target organs, penetrate cell membranes, lodge in mitochondria, and may trigger injurious responses. They note the combination of size, surface area, and unique physico-chemical properties of the materials can generate adverse biological effects by increasing the number of material interactions that could lead to toxicological effects and that some nanoparticles may exert their toxic effects as aggregates or through the release of toxic chemicals. In addition, they note that shape, aggregation, surface coating, and solubility may produce physico-chemical and transport properties. They add the presence of impurities, such as metals, could affect toxicity as well as surface coating.

They add: several nanomaterials characteristics can culminate in reactive oxygen species (ROS) generation which they claim is the best-developed paradigm for nanoparticles toxicity (Table 2, p. 626).

They add that a direct relationship may exist between surface area, ROS-generating capability, and pro-inflammatory effect of nanoparticles in the lung, several types of nanoparticles target mitochondria directly, and other forms of injury include protein denaturation, membrane damage, DNA damage, immune reactivity, and the formation of foreign body granulomas.

They also note, modification of fullerene surfaces yields nanoparticles with biologically useful antioxidant activity and that throughout uptake and transport, nanomaterials will encounter defenses that eliminate, sequester, or dissolve nanoparticles such as cell and tissue antioxidant defenses.

In addition, they note methods to detect airborne nanoparticles, such as personal monitoring devices, need to be developed. In the interim, they recommend standard hygiene procedures and to move ahead as new information becomes available. New data should be used to develop MSDS that inform workers and consumers of possible nanomaterials hazards.

The report claims it remains too early to draw meaningful conclusions about the inherent dangers of engineered nanomaterials. It remains to be determined whether the unique physico-chemical properties of nanomaterials will introduce new mechanisms in injury and whether these will result in new pathology. Due to the wide range of nanoparticles in use and under development, it is important to establish which materials should be tested first and how to perform this testing. Nanomaterials that are new commercializations and are produced in large quantities as freely dispersible nanoparticles, with the potential of substantial exposure in humans and the environment should probably be given preference.

The goal of the predictive approach would be to develop a series of toxicity assays that can limit the demand for in vivo studies, both from a cost as well as an animal-use perspective.

NIOSH (National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention), Strategy Plan for NIOSH Nanotechnology Research: Filling the Knowledge Gaps – Draft, Washington, DC: Centers for Disease Control and Prevention,
http://www.cdc.gov/niosh/topics/nanotech/strat_plan.html, 28, September 2005.

The report identifies knowledge gaps and calls for them to be addressed in a transparent and credible product that coincides with the development of this new technology and outlines a strategic plan for addressing knowledge gaps concerning worker exposures, health risks from such exposures, and development of control and preventive technologies. It calls for measurement technologies for workplace air, the development and validation of methods of exposure assessment, and predictive animal models to develop hazard identification, dose-response, and risk assessment information. In addition, it adds a call regarding the application of nanotechnology products to prevent work-related injuries and illnesses, such as sensors and communication devices for real-time occupational safety and health management. It calls for best practice research and the evaluation of control banding as a hazard-based approach to risk assessment and control. Figure 2 on p. 12 offers a linear model depicting its goals. Appendix A lists ten issues, eight of which are issue specific: (1) exposure and dose (fate, exposure, internal dose); (2) acute and chronic toxicity (properties such as size, shape, surface area, solubility, chemical properties, and trace components), predictive modeling, and dose metrics; (3) epidemiology and surveillance (call for new epidemiological studies and integrating nano-safety issues into existing surveillance mechanisms); (4) risk assessment (whether current exposure-response data may be used in hazard identification or quantitative risk assessment); (5) measurement (evaluate current methods for airborne mass concentration to determine if they may function as a interim approach as well as develop new methods); (6) control (engineering, control banding, and substitute materials); (7) safety (other hazards such as explosive potential); (8) communication and education. It makes four recommendations next: evaluate current mass-based exposure limits for airborne particulates, implement criteria based on classification to determine new standards for toxicity testing for new, engineered, and existing nanoparticles, evaluate a revision of mass-based requirements under TSCA (high-production volume), and update the MSDS system. A research agenda and a reiteration of recommendations are found in Appendix B. Appendix D includes a project for a web-based nano-information library (A. Miller, SRL) and another assessing the utility of control banding (T. J. Lentz).

NSTC (Nanoscale Science, Engineering, and Technology Subcommittee, Committee on Technology), The National Nanotechnology Initiative: Environmental, Health, and Safety Research Needs for Engineered Nanoscale Materials, Washington, DC; National Science and Technology Council, http://www.mos.org/automedia/subsite/forum/pdf/research_needs.pdf, September 2006.

The document was created to inform federal government research, risk assessment, and risk management activities in nanotechnology. Chapters 2-6 address the assessment and management of EHS risks of nanomaterials. While underlining the important of life cycle exposure potential (esp. recycling and disposal), it notes the exposure potential for some nanomaterials will be very limited to non-existent and notes the dosimetry link between hazard and exposure. It warns that potentials for different nanomaterials cannot easily be generalized and calls for tiered testing approaches including increased computational modeling. Figure 1, p. 6 presents an influence diagram for nanomaterials properties relevant to evaluation of hazard.

Chapter 2 reviews standards development for instrumentation and metrology to characterize the properties of nanomaterials and to measure and control exposures to same. Variables of interest include purity, particle size and distribution, shape, crystal structure, composition, surface area, surface chemistry, surface charge, surface activity, and porosity and calls for efforts to develop measurement methods, reference data, and standards. It references NIOSH’s web-based Nanoparticle Information Library as a starting point. It underlines issues associated with batch to batch variations and the effects of modifications such as coatings challenging methods for standardization and characterization and underlines the lack of information on current production levels.

Chapter 3 begins by noting how changes to surface chemistry may affect biocompatibility and toxicity and the complex physiological response can influence effects by size and composition, purity of material following synthesis, type and degree of surface modifications; the inclusion of a surfactant or vehicle; the binding of biological molecules to the material following exposure; the types of cells and organs exposed and degradation characteristics. These are further complicated by multiple routes of exposure and status factors (age, socioeconomic status, etc.) of the exposed populations. It notes a need to standardized dosing protocols for in vitro testing and identifies four classes of nanoscale materials under focus: metal oxides, fluorescent crystalline semiconductors, fullerenes, and carbon nanotubes. It calls for a better understanding of absorption and transport throughout the body and long-term effects of implantable nanomaterials (such as wear debris and degradation) and the integration of data into predictive physiology-based, pharmacokinetic models of toxicity as well as integrative databases of engineered nanomaterials properties and effects. It underlines research needs to determine relationships between properties and uptake via lungs, skins, and digestive tract, exposure/measurement metrics, methods to quantify and characterize exposure, and technologies to detect and measure particle size, surface area, and biochemical status within an organism.

Chapter 4 addresses transport such as attachment to dust, pollen, and other particulates, presence in wastewater streams and runoff from manufacturing, and intentional releases for purpose of remediation. It notes programs are needed to study the influences of aging or degrading nanomaterials in reactive environments, such as waste treatment plants. It calls for evaluation of testing schemes and protocols, understanding of bioaccumulation and toxicity in aquatic systems, sampling and analytical methods in diverse environmental media such as soil, sediments, and plant and animal matrices, and understanding the transformation of nanomaterials (i.e., oxidation, exposure to sunlight, etc.). It offers a possible research approach focusing on major classes of commercial products likely to be released in the environment.

Chapter 5 centers of ascertaining the nature and extent of occupational exposures and the development of a protection strategy. It calls to vigilance to identify a sentinel event should it occur and the development of exposure monitoring methods and technologies. It calls for integrated exposure registries and cohort epidemiology studies. It also recognizes a need to quantify exposure to the general public from consumer products, industrial processes and products containing nanomaterials and targeting surveillance on potentially exposure groups and sensitive populations. Without any current programs to conduct surveillance on ecological health that focus on nanomaterials releases, it calls for research to quantify exposure and the development of methods to monitor environmental fate.

Chapter 6 calls for an evaluation of current risk management techniques to determine appropriateness and discussed many efforts including control banding approaches. Banding or tiered approaches to risk management of nanomaterials dominate the discussion. It calls for reducing exposure through process designs and engineering controls and notes efforts toward in situ, real-time, high-resolution measurements of nanoparticles size distributions. It calls for a review of filtration systems and particulate respirator technologies as well as development of exposure limit standards. It also recommends research on the possible hazardous character of solid wastes from nanomaterials manufacturing and whether disposal and degradation of consumer products could result in the release of nanomaterials into the environment. It identifies two additional concerns: spill containment and mitigation and explosive risk associated with nanoscale powders. It emphasizes the importance of life cycle assessments and determining the applicability of risk communication models. It concludes with identifying current existing mechanisms for reporting product problems and defects are likely to be used for nanomaterials-related products though it admits new mechanisms which provide reliable information to the public might be required.

This report has the most complete references yet published.

Oberdörster, G., et al, “Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy,” Particle and Fibre Toxicology, http://www.particleandfibretoxicology.com/content/2/1/8/abstract6 October 2005 for ILSI (International Life Sciences Institute) Research Foundation/Risk Science Institute, Principles for Characterizing the Potential Human Health Effects from Exposure to Nanomaterials: Elements of a Screening Strategy – Draft, Washington, DC:ILSI Research Foundation/Risk Science Institute, 20 May 2005.

While certain concepts of toxicity such as size may apply to all nanomaterials, traditional screening approaches may not be responsive to nanostructure-related biological activity of nanomaterials. Research gaps included: what is being made and in what quantities, exposure levels, likely routes of exposure. The routes of exposure can present unique toxicological outcomes and vary with the physico-chemical properties of the nanoparticles. Current findings indicate a need for standardized tests to get comparable results in screening nanomaterials for adverse effects. A chart on p. 6 examines the biokinetics of nano-sized particles.

The article’s authors call for a screening strategy for nanomaterials. Noting adversity would be impacted by physico-chemical characteristics of surface and core of nano-sized particles, the authors note current toxicity studies generally fail to consider these parameters. Identifying a set of characterization criteria is the challenge but would start with a minimum set of characterization parameters we consider essential. This must include characterization of as-produced or supplied materials, of administered materials, and after administration. For example, potential changes after administration might include aggregation state, physisorption or chemisorption of biomolecules and biochemically-induced changes in surface chemistry. Key characteristics would include: size distribution, agglomeration state, shape, crystal structure, chemical composition, surface area, surface chemical, surface charge, and porosity. Dose metrics would include mass, surface area, and particle number.

In terms of material characterization prioritization, three factors would include: the context within which a material is being evaluated, the importance of measuring a specific parameter within that context, and the feasibility of measuring the parameter within a specific context (see Table 2, p. 11 – Recommendations on material characterization).

There are six articulated research gaps: (1) development of viable in vivo detection techniques; (2) inexpensive real-time monitoring instruments and methods for mass concentration, surface area concentration, and size distribution; (3) standardized and well-characterized samples; (4) development of radio-labeled samples; (5) advanced surface chemistry characterization techniques; and (6) electron microscopy techniques for biologically-relevant analysis. Recommendations include: a call for independent characterization beyond what is provided by producers and suppliers and information of production, preparation, storage, heterogeneity and agglomeration states for all toxicity screening studies.

What follows is a highly articulated discussion of in vitro and in vivo testing methods. Some highlights include a call for more information on dermal penetration, exposure via the gastrointestinal tract, translocation and redistribution away from portals of entry, biopersistence of surface coatings and cores, the effect on the nervous system, the adsorptive properties of nanoparticles, esp. relating to proteins, oxidative stress and genotoxicity, and effects on different target cells and respective endpoints in vitro.

Nanomaterials most likely to present a health hazard are nanoparticles, agglomerates of nanoparticles, and particles of nanostuctured materials. While in some cases, nanomaterials will be components of larger scale products and direct exposure would be negligible. As such, significant exposure potential rests with nanoparticles readily deposited in the lungs, ingested, or on the skin. This lead to the conclusion that appropriate physico-chemical characterization of nanomaterials used in toxicity screening tests is essential.

Especially interesting seems to be the following call: application of mathematical and computer models to improve prioritization of data requirements and risk assessments.

Synthesis Report on the public consultation of the SCENIHR opinion on The appropriateness of existing methodologies to assess the potential risks associated with engineered and adventitious products of nanotechnologies, European Commission, Scientific Committee on Emerging and Newly Acquired Health Risks, http://ec.europa.eu/health/ph_risk/documents/synth_report.pdf, 29 September 2005.

This report calls for international coordination in the field of environmental health and safety of nanotechnology products. In the background, the report notes risks need to be assessed on a case by case basis, existing toxicological and eco-toxicological methods may not be sufficient, equipment for routine measures is inadequate, and exposure assessment methods may not be appropriate.

There seems to be some agreement screening and prioritization is a useful and pragmatic option for prioritizing nanoparticles for further risk characterization. Annex I, Committees on Toxicity, Mutagenicity and Carcinogenicity of Chemicals in Food, Consumer Products and the Environment presented a systematic tiered approach for initial toxicological studies with nanomaterials based on in vitro screening of selected materials supported by biodistribution studies to aid in the identification of cell types to study, followed by appropriate in vitro testing. It is presented as a five step process. As one respondent attested: The biggest benefit of carefully characterizing the dosed particles using an array of parameters will come for the subsequent ability to draw inferences about new particle types or for the same particle type when exposure data predict that the particles will be available to exposure in substantially different form.

The list of relevant nanoparticle features includes shape of primary and morphologies of primary particles, aggregates, and agglomerates, surface chemistry, coatings, surface/volume ratios, surface energy, absorption by other chemicals, etc. Another respondent warns that methodologies for determining correlations between nanoparticles size/shape/surface composition/bulk composition and biological effect may not easily lend themselves to a routine testing strategy unless there is also significant mechanistic research to understand the cause of these dependencies.

A respondent team notes many toxicology studies did not adequately characterize the test materials in their studies. The same team added a lack of standardized protocols prevents comparison of results and leads to scattering of research results. Another that most studies were carried out at unrealistically high mass concentrations in intratracheal instillation studies. Another called for modes of delivery in test systems to be more relevant for the exposure values. Another warned there might be a direct interference of the particles with the measure system or analytical chemicals. In general, few seem to disagree that the development of metrology of nano-products is mandatory.

It adds long-term effects on the distribution of nanoparticles in nature, in the environment (including micro-organisms) and in occupational settings are important. It calls for a better understanding of the fate, distribution, and persistence and bioaccumulation of nanoparticles in the environmental and occupational exposure on workers involved in manufacture and processing of nanoparticles. One respondent noted that long term effects on soil/water/plants/fish might be of equal relevance or more important than air concentration in the workplace.

It calls for particular attention to be given to the mode of delivery of nanoparticles to the test system to ensure that it reflects the relevant exposure scenarios which may include personal sampling devices for exposure monitoring. According to one respondent exposure evaluation needed to be closely related to persistence and mobility/immobility of the nanoparticles in the human body and in the environment. According to another, an adequate cohort study for workers should be initiated as soon as possible.

In terms of modified methodologies for risk assessment, the range of responses extended from slight modifications (business representatives) to new methodologies (academia and individual researchers). Respondents seem to agree nano-sized material may have properties which may lead to appropriate modifications of the risk assessment process. In general, there seems to be agreement that methods and equipment for exposure assessment need to be improved.

One respondent identified prioritization needs as a critical gap in knowledge. SCENIHR responded that a paradigm for nanotoxicology does not exist and underlines the need for appropriate testing methods for the novel properties of nanotechnology products. In terms of risk assessment, SCENIHR added that existing methods used for environmental exposure assessment are not necessarily appropriate for determining the distribution, partitioning and persistence of nanoparticles in the various environmental compartments.

The survey was noted by a respondent for excluding fire and explosion hazards of nanoparticles.

The survey calls for special attention given to pharmaceutical products to assess whether new guidance documents or amendments of existing guidance documents would be useful.

There is a demand to extend to scope of risk assessment to nanotechnology production and applications in the food industry.

The report also expressed concern about animal testing though some respondents suggest there are too many uncertainties to allow for reliable health risk assessment in all cases without in vivo testing.

The survey adds a call for an efficient mechanism for the information exchange internationally on nanosafety studies and notes the role of sound communication on the impacts of risks and advantages as crucial for public perception. For example, one respondent was concerned there may be a total overestimation of the actual exposure of the public from a wide range of production processes due to low production volumes of nanoparticles and since they are embedded in matrices. SCENIHR responded that while fixed nanoparticles are of less concern, during use and at the end of the product lifetime, fixed particles may be released.