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.
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?
Figure
1:
+enlarge
Figure
2:
Figure
3:
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