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EMERGING RESEARCH FRONTS - 2008

Günter Oberdörster, Eva Oberdörster, and Jan Oberdörster talk with ScienceWatch.com and answer a few questions about this month's Emerging Research Front Paper in the Multidisciplinary field. The authors have also sent along images of their work.
Günter Oberdörste Article: Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles
Authors: Oberdorster, G;Oberdorster, E;Oberdorster, J
Journal: ENVIRON HEALTH PERSPECT, 113 (7): 823-839 JUL 2005
Addresses: Univ Rochester, Dept Environm Med, 575 Elmwood Ave,MRBx Bldg,Box 850, Rochester, NY 14642 USA.
Univ Rochester, Dept Environm Med, Rochester, NY 14642 USA.
So Methodist Univ, Dept Biol, Dallas, TX 75275 USA.
Bayer Cropsci, Dept Toxicol, Res Triangle Pk, NC USA.

 Why do you think your paper is highly cited?

This paper is a comprehensive—and we think balanced—review of the then fledging and now maturing discipline of nanotoxicology, which we defined as "the science of engineered nanostructures and nanodevices that deals with their effects in living organisms" or more generally, the science dealing with "the safety evaluation of engineered nanostructures and nanodevices." Publication in Environmental Health Perspectives, an open-access journal with worldwide distribution, helped to draw attention to an important scientific and public health problem. In this review we raised a number of questions about nanomaterials (<100 nm in at least one of three dimensions), more specifically engineered nanoparticles (NPs), ranging from route of exposure to mode of action, to risk assessment (human and environmental).

Eva Oberdörster

Jan Oberdörster

At the time of publication, nanotechnology had become highly visible, being viewed by many as a new industrial revolution with promises of numerous benefits for society. However, concerns were being raised about potential negative impacts on humans and the environment. Many of the questions raised in our review are currently being addressed in an ever-increasing number of laboratories. For example: Do NPs induce adverse effects (i.e., can a hazard be identified)? If so, what are the dose–response relationships (i.e., how can the hazard be characterized)? What do we know about occupational/environmental levels in different media, (i.e., is there any exposure)? Do all or only some NPs pose a risk, and if so, how can this risk be characterized so that appropriate risk-management decisions can be made?

We also addressed the question as to what degree the nanoform of a substance increases systemic uptake via the lung, GI tract, or skin by asking: "What are the translocation pathways and which physico-chemical properties determine how many NPs that enter blood and lymph circulation will distribute throughout the body, reach the bone marrow, sequester effectively in the liver, or cross the blood–brain barrier and/or the placenta?"

We raised the equally important question about retention kinetics and elimination/clearance pathways in the organism. The question of translocation is of particular relevance in light of the presently ongoing popular press dominated discussion as to whether inhaled carbon nanotubes can reach the lining of lungs and thorax (visceral and parietal pleura) from their portal of entry, and cause a malignant form of cancer. Regarding release into the environment, we need to know: Do NPs spread and affect species that are important in food chain dynamics? And completely unknown yet, what, if any, are the long-term consequences of human and environmental exposure to NPs?

  Does it describe a new discovery, methodology, or synthesis of knowledge?

We attempted to write a thorough review of the state-of-the-science of nanotoxicology stipulating the interdisciplinary nature of this field. We also included some of our newest data, such as the translocation of inhaled nanoparticles to the brain via the olfactory nerve, but especially data in the area of environmental impacts, which had primarily been presented at scientific symposia and workshops prior to our review paper. We pointed out the lack of knowledge in many areas of nanotoxicology, and, as described above, raised a number of important questions that remain mostly unanswered.

  Would you summarize the significance of your paper in layman's terms?

 
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NPs are both of anthropogenic (engineered and incidental) and natural origins, and are defined as particles less than 100 nm in size. Because NPs are being used in an increasing number of consumer applications (e.g., cosmetics, sporting equipment, clothing, and delivery systems for pharmaceuticals), there is potential for human and environmental exposure. However, the important difference between NPs firmly embedded in a matrix vs. potential for significant exposures to airborne individual NPs needs to be recognized.

A key characteristic of NPs is their propensity to cross cell membranes and barriers, in contrast to larger particles—thus in principle any tissue in a living organism can be targeted. However, translocation rates in general appear to be very low, but they could be manipulated by altering physico-chemical properties of NPs. Accordingly, one of our questions addressed the role of NP surface properties in terms of their bioavailability and toxicity. The latest research has verified that surface properties are critical—and, moreover, that surface properties change as NPs move through various biological compartments (e.g., from the respiratory tract through blood and lymph to secondary organs).

We pointed out that a careful evaluation of exposure–dose–response relationships is critical to the proper risk assessment of NPs. Risk is defined as the product of exposure and hazard (toxicity) of a chemical. It follows that, if an agent is hazardous (i.e., highly toxic), but there is no exposure, then there is no risk. For NPs, this includes not only questions about the dosemetric—mass, number, or surface of the NPs as discussed in our review—but most important, also the relevance of appropriate dose levels for a meaningful interpretation of results. Unfortunately, the terms "hazard" and "risk" are often misunderstood as meaning the same. As we pointed out, identifying a significant toxicity of NPs only with extremely high unrealistic doses—high dose toxicity can readily be demonstrated with any NP—is most often meaningless if doses or exposures under relevant in vivo conditions are many orders of magnitude lower.

  How did you become involved in this research and were any particular problems encountered along the way?

With respect to NPs, it was our finding in the late 1980s and early 1990s that TiO2 and Al2O3 NPs are significantly more inflammatory on a mass basis in the lung than their larger counterparts. Since then we (Günter Oberdörster) started to work on effects of ambient ultrafine particles (UFPs) which are of the same small size as NPs (i.e., <100 nm), and that gave rise to the ultrafine particle hypothesis. This hypothesis, that it was possible for tiny particles with such small masses to induce significant effects, was received with sound skepticism. Because UFPs are in the size range of engineered nanoparticles, shifting to nano-toxicology was a natural progression.

"Failure to implement precautionary measures at workplaces with NP exposures may result in unwelcome surprises of serious organ injuries.."

Günter Oberdörster’s two children followed their father's scientific footsteps. Jan Oberdörster's area of expertise is in drug development and risk assessment and Eva Oberdörster's is in ecotoxicology. The 2005 review paper, therefore, was an intrafamily affair, combining expertise in mammalian toxicology, environmental toxicology, and risk assessment.

  Where do you see your research leading in the future?

First, a cautionary note: Despite the hype about perceived and real risks of nanomaterials (certainly making news stories more exciting), fortunately to date engineered NPs have not been associated with any specific disease, which of course should not be taken as assurance that there will not be any. Urgently needed are data to perform an appropriate risk assessment on NPs so that results of many high-dose studies identifying a significant hazard can be put into perspective. Essential for this are better estimates and knowledge about human and environmental exposures; information about NP biokinetics in the organism and in the environment; development and validation of simple high-throughput toxicity assays to characterize hazard with predictive power for in vivo effects; and unraveling mechanisms underlying such effects.

Important aspects for future research include the identification of susceptible subgroups, a lesson learned from epidemiological studies with ambient ultrafine and fine particles; and evaluating whether NPs may have a role in the induction or exacerbation of specific disease processes. Also very important but most difficult is toxicity assessment following chronic NP exposure. While most NPs are unlikely to pose a significant health risk, some likely will because of the vast diversity of their physico-chemical properties. Accordingly, it will be critical to identify these more toxic NPs.

  Do you foresee any social or political implications for your research?

As consumers are already purchasing nanotechnology-enabled devices—cosmetics, health supplements, sporting equipment and clothing, to name a few, there is potential for widespread exposure although, as pointed out before, in cases where NPs are firmly embedded in a solid matrix exposure of the consumer is essentially zero, unless there is release during physical destruction (e.g., waste disposal). The question remains as to the level of exposure and corresponding NP bioavailability. Workplace exposures at manufacturing sites may pose the greatest risk, and—until we know better—avoiding such exposures through wearing personal protective equipment and installing appropriate preventive engineering controls at the workplace will be key.

Failure to implement precautionary measures at workplaces with NP exposures may result in unwelcome surprises of serious organ injuries. Assessing the safety of engineered NPs has become a global issue, and governmental agencies, industry, NGOs, research alliances, and consortia of various countries and regions have started to work together in a collaborative and cooperative process to engage in research with the goal to come up with science-based regulations of NPs.

Günter Oberdörster, D.V.M., Ph.D.
Professor of Toxicology
University of Rochester
Department of Environmental Medicine
Rochester, NY, USA

Eva Oberdörster, Ph.D.
Senior Lecturer
Department of Biology
Southern Methodist University
Dallas, Texas, USA

Jan Oberdörster, Ph.D., D.A.B.T.
Manager
Toxicology Department
Drug Safety Evaluation
Pharmaceutical Research and Development
Bristol-Myers Squibb Company
Syracuse, NY, USA

Keywords: nanotoxicology, ultrafine particles, biokinetics, nanomaterials, nanoparticles, NPs, nanosized particles, nanostructures, nanodevices, retention kinetics, elimination/clearance pathways, inhaled carbon nanotubes, visceral and parietal pleura, food chain dynamics, drug development, mammalian toxicology, environmental toxicology, NP bioavailability

  



2008 : June 2008 : Günter Oberdörster, Eva Oberdörster, and Jan Oberdörster