Options for Occupational Health Surveillance

of Workers Potentially Exposed to Engineered

Nanoparticles: State of the Science
Paul A. Schulte, PhD
Douglas Trout, MD
Ralph D. Zumwalde, MS
Eileen Kuempel, PhD
Charles L. Geraci, PhD
Vincent Castranova, PhD
Diane J. Mundt, PhD
Kenneth A. Mundt, PhD
William E. Halperin, MD
Objective: Health authorities, employers, and worker representatives
are increasingly faced with making decisions about occupational health
surveillance of workers potentially exposed to engineered nanoparticles.
This article was developed to identify options that can be considered.
Methods: The published scientific literature on health effects from
engineered and incidental nanoparticles and the principles of occupa-
tional health surveillance were reviewed to describe possible options and
the evidence base for them. Results: Various options for occupational
health surveillance were identified. The options ranged from no action
targeted to nanotechnology workers to an approach that includes
documentation of the presence of engineered nanoparticles, identifica-
tion of potentially exposed workers, and general and targeted medical
testing. Conclusions: Although the first priority should be to implement
appropriate primary preventive measures, additional efforts to monitor
employee health may be warranted. Continued research is needed, and
the collection of such information for exposure registries may be useful
for future epidemiologic studies. (J Occup Environ Med. 2008;50:
517526)
T
he question of what type of occupa-
tional health surveillance is appropri-
ate for workers potentially exposed
to engineered nanoparticles is of in-
creasing importance. This is because
of a growing, but not definitive, body
of evidence for potential health haz-
ards of some types of engineered nano-
particles and the fact that increasing
numbers of workers are currently han-
dling them.
19
These exposures can
occur in research laboratories, and in
operations where engineered nano-
particles are manufactured, used, and
disposed.
4
The development and pro-
liferation of new engineered nano-
particles can be expected to continue
to outpace health researchers ability
to evaluate the potential health con-
sequences. Consequently, health au-
thorities, employers, occupational
health professionals, and workers are
faced with determining appropriate
strategies for occupational health
surveillance in the face of uncer-
tainty about the exposure and hazard
from handling engineered nanopar-
ticles. The current dearth of regula-
tory clarity further contributes to the
ambiguity surrounding what devel-
opers and producers of engineered
nanoparticles should consider doing
to assure that their employees are
protected. Although implementing
appropriate engineering controls, us-
ing effective personal protective
equipment, and establishing safe
handling procedures are paramount,
additional efforts to monitor em-
ployee health may be warranted in
the near future. In this article, we
characterize the range of action options
From the National Institute for Occupational Safety and Health (Drs Schulte, Trout, Kuempel,
Geraci, and Castranova, and Mr Zumwalde), Centers for Disease Control and Prevention, Cincinnati,
Ohio; ENVIRON International Corporation (Dr Mundt), Amherst, Mass; and University of Medicine
and Dentistry of New Jersey (Dr Halperin), NJ.
The findings and conclusions in this report are those of the authors and do not necessarily represent
the views of the National Institute for Occupational Safety and Health.
Address correspondence to: Paul A. Schulte, PhD, National Institute for Occupational Safety and
Health, Centers for Disease Control and Prevention, 4676 Columbia Parkway, MS-C14, Cincinnati, OH
45226-1998; E-mail: pas4@cdc.gov.
Copyright 2008 by American College of Occupational and Environmental Medicine
DOI: 10.1097/JOM.0b013e31816515f7
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Volume 50, Number 5, May 2008 517
on a continuum of hazard and medical
surveillance. For each action, we de-
scribe the scientific evidence base or
rationale and implications. Because
the body of evidence for potential
hazard related to occupational expo-
sure to engineered nanoparticles is
continually changing, decisions
about the need for and type of occu-
pational health surveillance are
likely to evolve over time.
Occupational Health Surveillance
Occupational health surveillance
is the ongoing systematic collection,
analysis, and dissemination of expo-
sure and health data on groups of
workers for the purpose of early
detection of disease and injury as
well as trends or patterns of occurrence
presumably leading to prevention of
subsequent disease. Occupational
health surveillance can help define
the magnitude and scope of occu-
pational health issues among
groups of workers and guide efforts
to improve worker safety and
health and monitor progress. The
general term occupational health
surveillance includes hazard and
medical surveillance; integration of
hazard and medical surveillance is
key to an effective occupational
health surveillance program.
1015
A substance may be defined as a
hazard if it has the potential to cause
harm under some set of circum-
stances. Hazard surveillance consists
of the periodic characterization of
chemical/physical hazards in the
workplace. Medical surveillance tar-
gets actual health events or a change
in a biologic function in an exposed
person or persons. Medical screening
(monitoring) is one form of medical
surveillance that is designed to detect
early signs of work-related illness by
administering tests to apparently
healthy persons to detect those with
early stages of disease or risk of
disease.
16
Occupational health surveillance
is also conducted for the purpose of
determining whether the hierarchy of
techniques for injury and illness pre-
vention are effective. These tech-
niques can be ordered by primacy
into primary, secondary, and tertiary
prevention.
4,14
Within this hierarchy
are a range of activities from premar-
ket testing for potential toxicity to
preclinical evaluation of exposed
workers; all of which are intended to
prevent long-term impairment and
disability (see Fig. 1). Occupational
health surveillance is the process by
which information resulting from
any one of these activities is col-
lected and used to support or alter
what is done at a step higher in the
hierarchy.
Critical in the discussion of occu-
pational health surveillance for
workers potentially exposed to engi-
neered nanoparticles is what triggers
the need or requirement for surveil-
lance. The standard approach to oc-
cupational health surveillance with
known hazards, that is, ones with a
documented evidence base and occu-
pational exposure limits (OELs), is
to utilize the concept of an action
level. The action level represents
some fraction of the OEL, usually
50%, which if exceeded will trigger
various preventive actions including,
in some cases, medical monitoring.
This situation generally does not oc-
cur with engineered nanoparticles
since there is no government or pro-
fessional association OELs specifi-
cally for engineered nanoparticles.
However, workers with airborne ex-
posures to the nanoscale forms of
bulk substances that have OELs will
be subject to the same medical mon-
itoring requirements as those ex-
posed to the bulk form. This is in
contrast to engineered nanoparticles
that either have no established haz-
ard database, OEL, or surveillance
guidelines.
In the absence of OELs and atten-
dant action levels for engineered
nanoparticles, occupational health
surveillance may be considered in
terms of qualitative job hazard expo-
sure analyses. This type of health
surveillance approach has been pio-
neered in the pharmaceutical indus-
try and in the United Kingdom.
17,18
Generally, these approaches are based
on some knowledge of the degree of
hazard. When this is not known, as
with many engineered nanoparticles,
various other approaches may need to
be utilized, for example, by determin-
ing whether toxicity information exists
Fig. 1. The hierarchy of occupational health prevention with examples of surveillance
feedback (Adapted from Am J Ind Med. 1996;29:321323).
518 Health Surveillance and Nanotechnology

Schulte et al
for a similar type of nanoparticle that
can be used as a surrogate for trigger-
ing action.
19
Hazard Potential of
Engineered Nanoparticles
Various factors must be consid-
ered to obtain perspective on the
hazard potential of engineered nano-
particles. First, the types and physi-
cochemical properties of engineered
nanoparticles are vast. The broad
range and combination of parameters
that can influence toxicity, such as
composition, size, shape, surface
coating, charge, attached functional
groups, solubility, contaminants, and
degree of agglomeration, may result
in nanoparticles with large differ-
ences in hazard potential. Second,
much of the scientific evidence on
the potential toxicity of engineered
nanoparticles is based on toxicologi-
cal and epidemiological studies of
certain types of microscale (microme-
ter-scale) and nanoscale (nanometer-
scale) particles, including metal ox-
ides, fumes, and combustion-derived
nanoparticles.
2,8,2022
The term ul-
trafine is frequently used in the
context of nanometer-diameter parti-
cles that have not been intentionally
produced but are the incidental prod-
ucts of processes involving combus-
tion or hot processes. The extent to
which these studies are predictive of
the potential hazard of engineered
nanoparticles will depend on the spe-
cific physicochemical properties of
the engineered particles and on the
exposure conditions.
Potential occupational health risks
associated with manufacturing and
using nanomaterials are not yet well
defined. Many engineered nanomate-
rials and devices are formed from
nanoparticles that are initially pro-
duced as aerosols or colloidal sus-
pensions. Minimal information is
currently available on the potential
for exposure, dominant exposure
routes, and material toxicity. Other
exposures in the workplace where
engineered nanoparticles are handled
(including ambient particulates) may
complicate the measurement of engi-
neered nanoparticles and confound
the association between exposures
and health outcomes that might be
reported. The epidemiological and
toxicological literature on ultrafine
or fine particles and fibers provides
information on the organ systems
and effects that may also be relevant
to clinical evaluations or medical
surveillance of workers exposed to
engineered nanoparticles. However,
engineered nanoparticles may differ
in their physicochemical properties
and may also exhibit enhanced or
unique biological effects related to
increased reactive surface area and
quantum effects.
9,22
Inhalation is generally considered
the primary route of occupational
exposure to nanoparticles. Once in-
haled, a substantial proportion of
nanoparticles are likely to deposit in
the human respiratory tract (30%
90%, depending on breathing rate
and particle size).
23
Nanoparticles
readily reach the deep lung, and the
alveolar region is the primary site of
deposition for nanoparticle sizes in
the 10 to 100 nm range, whereas
head and thoracic deposition pre-
dominate for nanoparticles less than
10 nm. Deposition increases with
exercise and in individuals with
chronic obstructive pulmonary dis-
ease.
2325
Other potential routes of
exposure include passing through the
skin and ingestion. Size and charge
of particles appear to influence both
dermal penetration and gastrointesti-
nal absorption.
2631
Exposures to some types of
nanoscale particles (eg, generated
from combustion or hot processes)
have been associated with adverse
health effects in humans. For ex-
ample, diesel exhaust has been as-
sociated with eye and respiratory
irritation,
32
endothelial dysfunction
(impaired vasodilation) with mild
systemic inflammation,
33
and lung
cancer,
34
while welding fume ex-
posure has been associated with
metal fume fever, susceptibility to
pulmonary infection, obstructive
lung disease, and possible neurologic
changes.
35,36
Cardiovascular system
effects, including markers of blood
coagulation and systemic inflamma-
tion, have been observed in experi-
mental studies of human volunteers
inhaling a low concentration of car-
bon nanoparticles.
24,25,37,38
In the
general population, particulate air
pollution (a mixture that includes
combustion-derived ultrafine parti-
cles) has been associated with in-
creased morbidity and mortality
from adverse respiratory and car-
diovascular effects, primarily
among susceptible populations
such as the elderly or infirm.
3943
No epidemiological studies of oc-
cupational cohorts exposed to engi-
neered nanoparticles have been
published.
In experimental animal studies with
ultrafine and nanoscale particles, the
large surface area of the particles has
been shown to play a key role in
adverse lung effects, including inflam-
mation and tumorigenesis, as does the
surface reactivity, crystallinity, and
biopersistence of the particles in the
lung.
4449
Adverse lung responses ob-
served in humans occupationally ex-
posed to fine and ultrafine particles are
similar to those observed in experi-
mental studies with rodents.
34,50
Translocation is considered more
likely for nanosized particles than for
fine particles. In rodents, nanopar-
ticles have been found to translocate
from the respiratory tract to other
organs, including brain, liver, kidney,
and spleen,
5153
and the rate appears to
depend on the physicochemical prop-
erties of the nanoparticles (eg, size,
chemical composition, shape, and
charge).
5457
In experimental studies
of human volunteers, low-dose,
short-term inhalation of radiolabeled
carbon nanoparticles (Technegas)
showed that most of the deposited
nanoparticles remained in the lungs
up to 2 days after exposure.
58,59
These studies did not find evidence
for the rapid translocation of nano-
particles to the blood circulation or
accumulation in the liver, as had
been reported earlier (possibly due to
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Volume 50, Number 5, May 2008 519
instability of the radiolabel-nanopar-
ticle complex).
60
Studies of carbon nanotubes in
rodents have shown early-onset of
pulmonary fibrosis, granulomas, and
oxidative stress in the lungs and car-
diovascular system.
5,61 67
Metal
nanoparticles, including cobalt and
nickel caused greater lung inflamma-
tion and injury in rats than microme-
ter-sized particles.
68,69
Liver, kidney,
and spleen were target organs of
copper nanoparticles in mice ex-
posed by oral gavage, causing acute
toxicity, while micrometer-sized
copper did not.
70
As observed in
animal studies with various types of
nanoparticles, contaminants associ-
ated with specific nanoparticles (eg,
metals used as catalysts) may pose a
health risk to workers.
66,67
Continuum of Occupational
Health Surveillance
Like the techniques of prevention
shown in Figure 1, occupational
health surveillance efforts can also
be ordered in a continuum. Because
there is a lack of definitive evi-
dence regarding specific health ef-
fects associated with nanoparticle
exposures, and because engineered
nanoparticles are highly heteroge-
neous, it is difficult to identify an
appropriate evidence-based occupa-
tional health surveillance strategy for
workers handling nanomaterials. It
may be that hazard surveillance
rather than medical surveillance is
more appropriate to initiate at this
time, given the lack of knowledge
regarding specific health outcomes
in humans. A continuum of hazard
and medical surveillance is shown in
Figure 2, ranging from no targeted
hazard or medical surveillance action
to targeted medical surveillance of
workers handling nanoparticles. Tar-
geted medical surveillance refers to
medical surveillance for specific bi-
ologic changes known to be linked to
exposure to specific engineered
nanoparticles. Generally, each action
in the continuum builds on the con-
duct of the previous actions.
No Targeted Action (ie, No
Specific Occupational
Surveillance Related to
Engineered Nanoparticles)
A decision to take no targeted
action for workers potentially ex-
posed to engineered nanoparticles
may be influenced by whether or not
there are other medical surveillance
programs in place for these workers.
These programs are established
because of existing hazardous sub-
stances in the workplace rather than
exposure to engineered nanopar-
ticles. Clearly, there is extensive
medical surveillance conducted in
various workplaces where known
hazardous materials are manufac-
tured or used. Over 30 Occupational
Safety and Health Administration
(OSHA) standards and hundreds of
National Institute for Occupational
Safety and Health (NIOSH) guid-
ance documents recommend medical
surveillance for various occupational
hazards. Additionally, three types of
medical surveillance that might also
be occurring in a workplace pertain
to the assessment of the workers abil-
ity to wear or use required respiratory
or other personal protective equip-
ment, and medical examination per-
taining to job placement and medical
examination as part of emergency
medical care after a work-related ex-
posure or incident. So the option at
one end of the continuum is no new
action in addition to what already is
occurring, or, if there is no other
medical surveillance occurring in a
given workplace, then nothing new
related to medical surveillance
would be implemented.
Hazard surveillance may follow
a similar logic as medical surveil-
lance.
13
Employers, as part of their
due diligence and in adherence to
occupational safety and health and
environmental laws, are obligated to
make a determination as to whether
regulated materials are present in the
workplace. This is a rudimentary
form of hazard surveillance. The no
action option involves doing noth-
ing beyond this rudimentary effort.
Whether pertaining to hazard or
health surveillance, a no action
determination should be the product
of active evaluation that is well doc-
umented, and should not be equated
with inaction. In most cases no
action will pertain to no additional
medical or hazard surveillance for
workers potentially exposed to engi-
neered nanoparticles.
Document the Presence of
Engineered Nanomaterials
The presence of free (unbound)
engineered nanomaterials in work-
places where they are produced or
purchased should be obvious to em-
ployers since they are the result of
intentional efforts. This second option
for action on the continuum includes
identifying and recording where in the
Fig. 2. Continuum of hazard and medical surveillance and related research approaches for
nanoparticle workers.
520 Health Surveillance and Nanotechnology

Schulte et al
workplace and production process
engineered nanomaterials are han-
dled (eg, producing nanomaterials as
powders or slurries/suspensions/
solutions), including storage and dis-
posal.
71
The information that would
be useful to record can be gathered
based on existing management
knowledge of processes and job
tasks, including
What nanomaterials are being
manufactured or handled
Where in the workplace exposure
might occur
When these nanomaterials are
made or used
How the nanomaterials are pro-
duced or used.
Special consideration should be
given to processing equipment break-
down and the need for and frequency
of major routine maintenance.
Less clear are situations where
engineered nanoparticles are aggre-
gated, agglomerated or even embed-
ded in materials, such as composites,
and hence are not free or unbound.
71
The question is whether these engi-
neered nanoparticles can be released
and inhaled or come into contact
with the skin. The answer may be
yes if the nanomaterial is subject
to manipulation through kinetic pro-
cesses that result in generating air-
borne nanomaterial or free unbound
engineered nanoparticles. There is
limited information currently avail-
able to evaluate the extent to which
such release actually occurs.
Identify Workers Potentially
Exposed to Nanoparticles
Identification of workers poten-
tially exposed to engineered nano-
particles is the next higher action
option on the continuum. Given the
uncertainty about the hazards of en-
gineered nanoparticles it has been
suggested that a broad definition ini-
tially be used to identify workers
potentially exposed to nanoparticles
and that such a definition be refined
as more reliable information on ex-
posures and health effects become
available.
72
The broad definition
will, by intent, be overly broad in
terms of identification of a group that
is at risk of exposure. The Depart-
ment of Energy, for example, defines
a worker potentially exposed to en-
gineered nanoparticles as one who
handles engineered nanoscale par-
ticles that have the potential to
become dispersed in air;
is routinely exposed (spends a sig-
nificant amount of time in an area
in which engineered nanoparticles
have the potential to be dispersed
in the air);
works on equipment that might be
contaminated with materials that
could foreseeably release engi-
neered nanoparticles during ser-
vicing or maintenance.
72
The purpose for identifying and
recording such information in a sys-
tematic mannersuch as in a data-
baseis 3-fold. First, such records
can be used to determine whether or
not workers with potential exposure
will need to have appropriate train-
ing in the safe handling and disposal
of materials, proper maintenance of
equipment, and use of personal pro-
tective equipment. Second, such
records will be available if there is a
need to establish exposure regis-
tries or participate in epidemiologic
or health surveillance studies.
73,74
Third, should new information about
health effects trigger the need for
medical monitoring, a roster of po-
tentially at risk workers will be
available.
As more information becomes
available about appropriate metrics
and instrumentation for airborne-
engineered nanoparticles, there will
be a need for quantitative rather than
qualitative assessments of exposure
to engineered nanoparticles for indi-
vidual workers. Such information
will allow for assessment of the ef-
fectiveness of controls, adherence
with exposure recommendations and
standards, and could serve to help set
action levels to trigger medical sur-
veillance. At present it is not known
what exposure metrics and particle
characteristics (eg, mass, surface
area, particle count, shape, aerody-
namic diameters) are best for expo-
sure assessment; however, particle
count, surface area and mass are pres-
ently considered to be most useful.
19
Whether monitoring biological
markers of exposure will be useful to
supplement exposure assessment is
not known. Before such action would
be warranted more information is
needed on biotransformation of par-
ticles and toxicokinetics, given the
potential invasiveness and some-
times complicated logistical issues
surrounding biomonitoring.
General Medical Monitoring
Baseline and periodic routine non-
specific medical monitoring is the
next action in the occupational health
continuum. It may take place apart
from or in conjunction with one of
the previous actions. If such medical
monitoring is provided it would
likely either be provided to all work-
ers in a facility or to some subset of
workers potentially exposed to engi-
neered nanoparticles. The utility of
nonspecific medical monitoring is
limited because the health endpoints
that may be linked to engineered
nanoparticle are not well known or
confirmed at this time. Nonetheless,
general medical monitoring may
serve as an early warning system for
possible, yet to be determined, health
effects linked to exposure. This de-
termination will require that the data
be continually analyzed on a group
basis and if possible, linked to expo-
sure and compared with appropriate
comparison population rates. The
limitation of this monitoring ap-
proach is that it may identify health
effects unrelated to exposure to en-
gineered nanoparticles and in some
cases false positives, all of which
will require follow-up and diagnostic
evaluation. It also may give moni-
tored employees a false sense that
such procedures would be sensitive
to any health risk associated with
exposure to engineered nanopar-
ticles. This needs to be balanced
against a reasonable assurance that
periodic examination affords that no
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Volume 50, Number 5, May 2008 521
obvious or easily detected health ef-
fects are present.
In some worksites, workers will be
monitored through existing programs
if they work in areas with both reg-
ulated hazards (or hazards which
may not be regulated but for which
well-accepted medical monitoring
procedures exist) and engineered
nanoparticles. This medical monitor-
ing, which is conducted due to the
exposure to the regulated hazards,
may have the effect of collecting
baseline health information for
workers. If medical data were in-
cluded, medical history and lifestyle
information (eg, tobacco and alcohol
use, exercise frequency) would also
be useful to record in such baseline
data.
Targeted Medical Testing for
Workers Exposed to
Engineered Nanoparticles
If specific hazards of engineered
nanoparticles are identified and
characterized then it could be pos-
sible to detect preclinical changes
through medical testing and/or
modify exposure potential through
risk management interventions.
Medical monitoring is not meant as
the primary means for protecting
workers but rather as a secondary
prevention effort, after risk manage-
ment efforts (eg, engineering con-
trols and use of personal protection
equipment) have been implement-
ed.
75
The rationale for specific med-
ical surveillance of workers exposed
to nanoparticles is based on the re-
sults of a needs assessment.
10
A
primary determination from a needs
assessment involves some assess-
ment of risk, which is the potential or
probability of a hazardous material
under certain exposure scenarios to
cause harm.
Risk may be thought of as a com-
bination of hazard and exposure. For
example, workers producing a sub-
stance with known toxicity but never
exposed might be judged as not at
risk from that substance. A compo-
nent of determining this risk, how-
ever, may involve the presence or
absence of controls (engineering, ad-
ministrative, personal protection) in
the workplace and whether the expo-
sure is being controlled successfully.
Further, even if low, the probability
of a process failure, operator error, or
industrial accident could result in
some potential risk. If the potential
exists for residual riskthat is, the
workers are at some risk of harm
based on the hazard and exposure
concentration, medical surveillance
may be warranted. Targeted medical
testing data, analyzed on a group
basis, can assist in detecting patterns
and trends, and linking with expo-
sure.
14,16
If known or anticipated
biological changes linked to expo-
sure to engineered nanoparticles can
be identified, then medical testing
can serve to identify sentinel
events.
76,77
On the basis of the toxicological
studies summarized above, prelimi-
nary findings of research on exposure
to engineered nanoparticles and previ-
ous research of ultrafine particles, the
most likely target organ systems will
include the respiratory and circula-
tory systems, although skin exposure
may also occur.
1,79,20,22
Medical
tests that include an evaluation of the
respiratory system could help to in-
dicate changes in pulmonary func-
tion or early indicators of fibrosis.
Although not widely validated, ex-
haled nitrous oxide or isoprostanes
have been used as noninvasive mark-
ers of pulmonary inflammation.
7880
Additionally, the National Institute
of Occupational Health in South Af-
rica is conducting a biomarker study
of gold miners.
81
They are monitor-
ing blood levels of several antioxi-
dant enzymes, cytokines, and total
antioxidant levels. They report that
decreases in red cell glutathione
and serum Clara cell proteins were
associated with silica exposure.
Also, tests that are indicative of
inflammatory response in pulmo-
nary and circulatory systems might
be useful.
5,62,65
None of these tests
are validated for use in asymptom-
atic workers. Beyond the respiratory
and circulatory systems, the impact
of engineered nanoparticles is poorly
understood. Nanoparticles in the
blood circulatory system could reach
many other organs and specific tests
related to early changes in organ
function may be warranted.
3
Trans-
location to the brain by nanoparticles
has been demonstrated but the sever-
ity and clinical relevance is not
known, nor is there enough informa-
tion to suggest what type of testing
could be useful to assess such ef-
fects. Criteria for medical testing for
workers have been published and
would need to be met before imple-
mentation of specific medical
screening of workers potentially ex-
posed to engineered nanopar-
ticles.
10,12,16,8284
At the present
time, it does not appear that there is
scientific and medical evidence suf-
ficient to recommend medical
screening of workers potentially ex-
posed to engineered nanoparticles.
A medical surveillance plan, like all
targeted medical surveillance plans, in-
volves adherence to recognized basic
elements that include interpretation of
the findings for workers and manage-
ment, implementation of follow-up ac-
tion, and program evaluation.
10,82
Data Collection and
Use Responsibilities
Regardless of the level of occupa-
tional health surveillance action that
may be selected; the gathering, stor-
age, and use of individual-level or
individually identifiable data carry
certain legal and ethical obligations.
Various issues are outside the scope
of this article; they include confiden-
tiality, Health Insurance Portability
and Accountability Act (HIPPA) re-
quirements, understanding of origi-
nal and intended use of surveillance
data, informed consent, and report-
ing test results, among others.
12,83,84
Less well appreciated are possible
ethical responsibilities to properly
analyze and report findings from
constructed databases.
522 Health Surveillance and Nanotechnology

Schulte et al
Future Research
In Vitro and In Vivo Studies
The basis for selecting among the
options for occupational health sur-
veillance of workers potentially ex-
posed to engineered nanoparticles is
based on knowledge of potential haz-
ards. The results from in vivo studies
involving various animal models and
in vitro studies using various testing
systems are frequently used as the
basis for that determination.
1,9
Al-
though such research has provided
preliminary indications of hazards
from some types of engineered nano-
particles, the heterogeneity of these
particles is large. Also, whether and
the degree to which effects seen in
various animal testing systems are
relevant to humans (especially at lev-
els to which humans are exposed)
may not be known. Nevertheless,
animal (rat) models of adverse lung
effects from inhaled poorly soluble
particles have been shown to be
consistent with the findings of
some epidemiological studies in-
cluding occupational exposures to
asbestos, silica, and diesel exhaust
particulate.
8588
Ultimately for guidance and regu-
latory purposes, it may be necessary
to determine whether broad catego-
ries of engineered nanoparticles can
be identified that are based on simi-
lar physicochemical parameters. It is
not known if particle size will be the
preeminent factor or various combi-
nations of size and other physico-
chemical parameters will be needed
to help establish risk-based catego-
ries on which to base future surveil-
lance decisions.
Epidemiologic Studies
It will be important to know
whether workers who have handled
and been exposed to engineered
nanoparticles develop adverse health
effects and disease.
19
Chronic ef-
fects, such as pulmonary malignant
and nonmalignant disease, and circu-
latory disease may take decades to
assess in worker populations. This is
because of the inherent nature of
such effects as well as the fact that
exposures, if they occur, are likely to
be quite low given the initial societal
concerns and precautions for control-
ling workplace exposures to engi-
neered nanoparticles.
1,79,75
Acute
effects may be more easily assessed
but the frequency also may be low
given the wide prevalence of work-
place exposure controls.
Epidemiologic studies of worker
populations potentially exposed to
engineered nanoparticles will be dif-
ficult to conduct for various reasons
including
1. Heterogeneity of engineered nano-
particles making it difficult to find a
sufficiently large group of workers
exposed to the same particles;
2. Dispersion of the contemporary
workforce resulting from generally
small numbers of potentially ex-
posed workers in any given facility;
3. Difficulty in identifying and re-
cruiting potentially exposed work-
ers and employers;
4. Insufficient exposure to cause
and/or latency to detect chronic
diseases;
5. Lack of exposure data and stan-
dardized exposure metrics needed
to develop comparable exposure
histories.
Despite these limitations, the es-
tablishment of formal national, or
even an international, exposure and
employee tracking registries might
be warranted. Exposure registries are
useful tools for surveillance of new
or perceived hazards since they pro-
vide documentation of who is work-
ing with which materials, when, and
where in the facility. A registry pro-
vides a structured and orderly ap-
proach to handling the problem of
identifying and maintaining commu-
nication with workers exposed to
hazardous substances,
72
utilizing a
common set of variables.
74
An expo-
sure registry is the enrollment of
persons exposed or likely to have
been exposed to occupational or en-
vironmental hazards that can serve as
a means of identifying persons for
primary or secondary preventive ef-
forts. In occupational situations,
company employee rosters are de
facto registries; however, they may
not address employees who leave a
company. Moreover, for new tech-
nologies, such as nanotechnology,
registries could be developed and
maintained by government entities;
however, there are examples of pri-
vate sector registries related to expo-
sure to commercial products.
Whether such registries would foster
potential discriminatory actions or
legal liabilities would need to be
addressed.
If sufficient numbers of workers
can be recruited with exposure to the
same engineered nanoparticles using
similar exposure metrics, it may be
useful to conduct studies to link ex-
posures with various biological
markers or other biological changes
that may be precursors to more seri-
ous health effects.
89
In the meantime,
results from in vivo and in vitro
research will continue to be the basis
for decision-making concerning oc-
cupational health surveillance.
Companies currently involved
with nanotechnology are faced with
the dilemma of balancing a desire to
expand a potentially bountiful tech-
nology with limited knowledge
about the potential hazards.
90
The
potential health risks associated with
nanotechnology are not well estab-
lished, and the perceived risks are
undetermined. As one commentator
noted: Even if studies showed every
commercially relevant nanoparticle
to be harmless in every real world
scenario, public skepticism about the
safety of nanoparticles could still
build and sharply limit their use in
products.
91
One of the earliest areas
where exposures to nanoparticles is
occurring is in the workplace
including universities and other non-
manufacturing settings.
71
In the face
of uncertainty about the hazards of
nanoparticles, a corporate or societal
response (such as implementing se-
lected exposure registries in poten-
tially high exposure sectors) may
assure the public that appropriate
efforts are being taken to identify
JOEM

Volume 50, Number 5, May 2008 523
and control exposures in a timely and
responsible manner.
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