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OCR for page 631
Identifying
Neurobehavioral Effects
of Automotive
Emissions and
Fuel Components
RONALD W. WOOD
New York University Medical Center
Neurobehavioral Effects and Mechanisms of Toxicity / 632
Identifying Acute Hazards / 633 Toxicity in Repeated or
Continuous Exposures / 634 Identifying Subtle
Effects / 634 Pursuing the Mechanisms of Toxicity / 636
Evaluating Whole Emissions, Fuels, and Their
Components / 638
Whole Emissions and Their Photochemical
By-products / 638 Carbon Monoxide / 644 Petroleum
Hydrocarbons / 646 Methanol / 647 Metals and Inorganic
Compounds / 648
Conclusions / 649
Summary / 650
Summary of Research Recommendations / 651
Air Pollution, the Automobile, and Public Health. (it) 1988 by the Health Effects
Institute. National Academy Press, Washington, D.C.
631
OCR for page 632
632
Identifying Neurobehavioral Effects
The automobile can be regarded as a mixed
blessing. Although it has become a neces-
sary part of daily life, the changes poten-
tially induced by automotive emissions are
not necessarily welcomed. Among these
are adverse neurobehavioral effects that
range in severity from the annoyance pro-
voked by unpleasant odors and the eye
irritants to overt behavioral and neurolog-
ical dysfunction.
Airborne contaminants can alter behav-
ior and the functions of the nervous system
in a variety of ways. Chemicals can damage
the structure of the nervous system di-
rectly, or can alter behavior and nervous
system function without pathological
changes by affecting neurotransm~tter sys-
tems, perturbing membranes, or altering
cellular metabolism. Since behavior de-
pends upon a wide variety of nervous sys-
tem functions, behavioral changes can
sometimes provide early indications of ad-
verse effects on other organ systems.
Automotive emissions can also alter be-
havior by stimulating sensory systems.
These stimuli may be unpleasant events
that alter the conduct of daily life, or may
serve as important discriminative or warn
, .
ing stimu. At.
The neurobehavioral toxicity of the
chemicals involved in automotive technol-
ogy is not well understood. Emissions may
not produce obvious effects at concentra-
tions commonly found in the environment;
moreover, some individuals may be ex-
posed occupationally to higher levels. A1-
though people are exposed to the chemicals
in automotive emissions environmentally
as well as occupationally, and although
studies of such people offer unique oppor
. . . . . . .
tunes, it Is Inappropriate to re .y entire By
on these exposures to detect neurotoxicity,
especially when suitable techniques exist
. .
using anlma. .s.
In this chapter, methods are described for
the detection of adverse neurobehavioral
effects of automotive emissions, and rec-
ommendations for research in this area are
offered. First, ways are described of identi-
fying, in laboratory animals, the adverse
neurobehavioral effects of hazardous sub-
stances following acute exposures and re-
peated exposures, of characterizing subtle
effects, and of determining mechanisms of
. .
tOXlClty.
Second, a review is provided of what is
currently known about the neurobehav-
ioral toxicity of automotive emissions and
fuel constituents. Third, recommendations
are offered on how to proceed with a
program to address this class of health
effects. Although there is reason to suspect
that many emissions and fuel constituents
are hazardous, little information is available
for most. To address this large group of
chemicals, a committee should select the
substances to test and the order of testing.
For the substances about which some
knowledge exists, focused recommenda-
tions are offered for detailed evaluation of
their hazards. These include whole emis-
sions, carbon monoxide (CO), petroleum
hydrocarbons, methanol, and metals and
their compounds.
Neurobehavioral Effects
and Mechanisms of Toxicity
The behavioral and neurological sciences
have made extraordinary progress in the
past 25 years. Although further progress
will continue to yield new methods, in
areas ranging from the subcellular to the
behavioral levels of analysis, adequate
methods are now available to explore the
neurobehavioral effects of automotive
emissions and fuel components.
Various approaches to neurobehavioral
hazard identification have been recom-
mended over the years by a variety of
experts. Although no single comprehensive
approach has yet been formalized, a re-
sponsible screening effort should include:
~ identification of the acute hazards of
chemicals this includes seeking evidence
of mortality, morbidity, and morphologi-
cal changes (as in any acute toxicity evalu-
ation), but with particular emphasis ac-
corded behavioral function, learned as well
as unlearned;
~ characterization of their toxicity in
repeated or continuous exposures this
provides an opportunity to characterize
OCR for page 633
Ronald W. Wood
633
toxicity that is delayed or cumulative, to
observe the development of tolerance (or
reverse tolerance), and to characterize the
reversibility of adverse effects; and
· detailed study of mechanisms of injury
and special impairments this includes ini-
tial screening for subtle sensory or percep-
tual impairments, affective disorders, or
cognitive and intellectual dysfunction, and
appropriate specialized evaluations using
refined neuropathological, neurochemical,
and neurophysiological techniques.
The U. S. Environmental Protection
Agency (EPA) has issued a series of test
guidelines that are appropriate for use in
acute and chronic neurobehavioral toxicity
evaluation. These include guidelines for the
examination of neuropathology (U.S. Envi-
ronmental Protection Agency 1985c), motor
activity (U. S. Environmental Protection
Agency 1985b), schedule-controlled behav-
ior (U.S. Environmental Protection Agency
1985f), and a functional observation battery
(U. S. Environmental Protection Agency
1985a).
Identifying Acute Hazards
It is important to determine the acute ef-
fects of chemicals on behavior and nervous
system function. Acute performance im-
pairment can increase accident proneness
and lower work efficiency; thus there can
be serious consequences of even small
lapses of coordination, vigilance, or visual
sensitivity in operators of all types of trans-
portation machinery. Irritation and sensory
effects perhaps the most common com-
plaints elicited by automotive emissions-
reduce the perceived quality of life, cause
people to change their lifestyles (by allocat-
ing their time to less distressful activities),
and Incapacitate sensitive individuals.
Hence, even apparently reversible adverse
effects are of concern. In fact, acute but
reversible effects may well be the ones of
most concern (see discussion in Whole
Emissions and Their Photochemical By-
products), and information about them,
therefore, is of particular importance when
describing acceptable limits of exposure.
With care, it is possible to design and
conduct statistically valid experiments to
accurately estimate the pollutant concentra-
tions that produce small but consistent ad-
verse effects (Wood and Colotla 1986;
Wood and Cox 1986~.
~. . .
· 1 .
Acute tOXlClty testing requires evaluation
of function and morphology, and can
have outcomes that are positive or negative
with respect to either. Thus the possible
outcomes can be expressed in array form
as:
No Effect
Effect
Morphology
No Effect Erect
A B
C D
Morphological changes (outcomes B or
D) are clearly of immediate concern. How-
ever, many chemicals can produce observ-
able functional changes without any mor-
phological correlates (outcome C). Lead,
for example, is an automotive emission that
produces functional impairments in hu-
mans and animals without marked neuro-
pathological changes. Consequently, a
complete safety evaluation requires func-
tional tests at levels of exposure so low that
they do not produce detectable morpholog-
ical changes.
Examinations of conditioned behavior
can be constructed to detect impairment of
a variety of functions. Evaluation of func-
tion may, however, fail to warn of mor-
phological changes in the nervous system
(outcome B) until the loss of"functional
reserve" is sufficiently great (outcome D).
Challenges with pharmacological agents
may be useful in such situations to unmask
silent damage (outcome A or B).
Behavioral tests detect performance dis-
ruptions that are indirect results of effects
on other systems, just as a disinclination
to dance might precede the onset of diar-
rhea (Dews 1975~. Thus motor activity or
food and water consumption can be
changed by chemicals that do not enter the
central nervous system, and without con-
comitant changes in body weight (Evans et
al. 1986~. Irritation is another possible in-
direct manifestation of toxic impairment,
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634
Identifying Neurobehavioral Effects
and is discussed further under Whole Emis-
sions and Their Photochemical By-prod-
ucts. There are important gaps in our
knowledge of the relationship between ex-
posure and the acute behavioral changes it
produces.
Toxicity in Repeated or Continuous
Exposures
After acute toxicity has been examined,
repeated exposure experiments should be
undertaken, typically 28- or 90-day sub-
chronic exposures with routine examina-
tion of neuropathology, measurement of
motor activity (preferably in the home
cage), and routine use of functional obser-
vational batteries. With the insights af-
forded by the acute toxicity experiments,
repeated-exposure experiments can be tai-
lored to further characterize those effects
and to yield improved sensitivity. For ex-
ample, special histological studies might be
indicated; examining learned behavior in
detail can provide important insights into
the nature of toxic impairment (Laties and
Wood 1986~.
Such repeated-exposure experiments be-
come particularly important if acute studies
indicate the potential for irreversible toxic-
ity. In such cases, for example, tolerance
may play an important role, and the re-
peated administration of other compounds
or reference substances as probes may dem-
onstrate a forward or reverse tolerance.
The mechanism of tolerance may then be
revealed with an appropriate design, such
as taking concurrent blood level and behav-
ioral measurements or using satellite groups
of animals for tissue-level determinations
of whether tolerance results from an in-
crease in metabolism or elimination of the
toxic substance. In some cases, the mecha-
nism of tolerance may be behavioral, and
may depend only on an animal's opportu-
nity to respond in the presence of the
material. The observations of Kane and
Alarie (1977) with formaldehyde and acro-
lein illustrate how the context of previous
experience with the toxicant can affect bi-
ological response (see Conditioned Re-
sponses to Exposure).
Identifying Subtle Effects
Many sensory and perceptual deficits, af-
fective disorders, and cognitive and intel-
lectual dysfunctions are sufficiently subtle
that they can be missed in routine acute and
subchronic studies.
Sensory and Perceptual Deficits. There is
a recognized need for rapid screening pro-
cedures (National Institutes of Health
1977), as well as comprehensive studies of
the complex functions of sensory systems.
Vision. Toxic effects on this highly
complex sensory system are easily missed,
especially when studies are undertaken
with . rodents. For example, experiments
with rodents do not reveal the profound
restriction of visual fields produced by
methylmercury in humans and nonhuman
primates. Carbon disulfide can produce se-
lective impairment of the discrimination of
coarser features of visual stimuli, leaving
the discrimination of fine features unim-
paired (Merigan et al. 1985b). Carbon di-
sulfide also affects color vision and hue
discrimination (Raitta et al. 1981), an effect
that can only be observed in experimental
animals having color vision.
Agents that produce peripheral neuropa-
thies (for example, hexacarbons) are likely
to affect vision. Measurement of visual
function in primates apparently provides a
very sensitive index of central nervous sys-
tem injury (Eskin et al. 1985; Merigan et al.
1985a). Appropriate studies in primates as
well as rodents might support the inference
of a defensible safety factor from rodent
data on peripheral neuropathy. However,
inferences about other compounds (for ex-
ample, those with a cortical distribution of
injury) are much more problematic, and
reveal functional deficits only with detailed
evaluation.
Audition. In most species, the inner ear
is difficult to remove from the surrounding
bone, so its pathologies are rarely uncov-
ered. Lesions may be missed if specific
functional evaluations are not performed.
Toluene, whose toxicity has been the focus
of much study for years, offers an excellent
illustration. It was only recently that Pryor
OCR for page 635
Ronald W. Wood
635
and coworkers (1984a,b) and Rebert and
colleagues (1983) documented a selective
high-frequency hearing loss following in-
tense toluene exposure. They discovered
this damage using a pole-climb avoidance
test that required animals to jump on a pole
to avoid shock in response to a warning
stimulus; they varied the characteristics of the
tone to demonstrate the frequency-specific
loss. Techniques have also been developed
that do not rely on training, for example, the
inhibition of noise-elicited startle by barely
detectable sounds (Hoffman and Ison 1980;
Young and Fechter 1983~.
The loss of sensation can readily be de-
tected using psychophysical procedures
with animals, but detecting the loss of
, . . ..
perception poses a more Cult prob-
lem. Some chemicals produce no impair-
ment of hearing for pure tones, but pro-
duce profound impairment of"perceptual
speed." Thus methylmercury poisoning
does not alter "hearing" per se, but does
impair language comprehension in such a
way that individuals function only when
spoken to extremely slowly.
Recommendation 1. Quick and sim-
ple tests of sensory impairment should be
developed that can be used for screening in
conjunction with functional observation
batteries. At the same time, psychophysical
procedures that are more comprehensive
should be developed; these should be di-
rected at specific sensory and perceptual im-
pairments, for example impairment of com-
plex auditory and visual discriminations.
Olfaction, Gustation, Somesthesis, and Pro-
prioception. Toxic effects on these func-
tions might be detected following high
doses of chemicals, albeit with great uncer-
tainty. Experiments could be designed to
assess these end points in detail. The tech-
nologies are readily available, but knowing
when best to use them can be a problem,
except for chemicals that affect or react
with the olfactory mucosa (and potentially
the olfactory nerve and bulb), such as oxi-
dants, aldehydes, and large particles.
Changes in olfactory sensitivity may or
may not be reversible, and they can alter
behavior and quality of life without the
affected individual's being aware of it. Peo-
ple with injuries to their sense of smell
complain of burning their food while cook-
ing, or of having bouts of food poisoning
from eating undetected spoiled food. These
effects, as well as the techniques for study-
ing them, have been reviewed (Wood
1982~. Olfactory psychophysics is a highly
developed research area in which trained
observers (human or animal) are used to
establish thresholds for detection of odors
or for the detection of differences in inten-
sity of odor (Cain and Moskowitz 1974;
Moulton et al. 1975~. Pursuing research in
this area on human subjects could bear
fruit. Neurophysiological techniques can
detect acute alteration of nasopalatine nerve
function following 1-fur exposures to form-
aldehyde or ozone (03) (Kulle and Cooper
1975~.
Odor preference studies with animals are
readily done but offer little predictive util-
ity for human preferences. Subjective re-
sponses to environmental odors have been
studied in humans (see, for example, Turk
et al. 1974) including work on diesel odor
(Springer 1974~.
Recommendation 2. Studies of olfac-
tory sensitivity following aldehyde and ox-
idant exposures should be undertaken in
humans and rodents.
Affective Disorders. Exposure to some
chemicals can produce apparently aberrant
"affective" or "emotional" behavior in an-
imals. Normally docile strains of rats ex-
posed to inorganic mercury vapor and
housed in groups have been observed to
spontaneously assume aggressive postures
in the home cage (Beliles et al. 1968~.
Inorganic mercury vapor is well known for
its early production of a "neurotic" syn-
drome in humans. Other chemicals may
exaggerate startle responses to sudden
stimulation, or make animals very difficult
to handle. Carbon disulfide can make dogs
extremely aggressive (Lewey 1941~; its ef-
fects on humans range from the induction
of affective disorders to suicide (Wood
1981b). These effects, some of which can be
OCR for page 636
636
Identifying Neurobehavioral Effects
detected only by a careful observer, have
received insufficient attention (National In-
stitutes of Health 1977~. Procedures that
rely on conditioned behavior to detect af-
fective changes produced by toxic chemi-
cals have yet to be put to use; avoidance or
punishment procedures should be well
suited for this purpose.
Recommendation 3. Behavioral mod-
els of affective disorders should be devel-
oped. The models should be calibrated
with reference substances, drugs as well as
toxicants, before their application to test
chemicals or mixtures.
Cognitive and Intellectual Dysfunction.
Short of epidemiologic investigations, the
only practical way to study the impairment
of normal cognitive or intellectual func-
tioning resulting from the intake of chem-
icals is to undertake conditioning experi-
ments with animals (National Institutes of
Health 1977; Laties 1982~. Studying simple
performances in well-trained animals can
provide useful information, but the find-
ings may not necessarily be associated with
learning impairments. More complex per-
formances conditioned explicitly to exam-
ine learning can provide us with insight
into the likelihood of injury to this impor-
tant function.
The repeated-acquisition technique has
been used considerably as a model of learn-
ing impairment (Thompson and Moersch-
baecher 1978~. This procedure requires an
animal to perform two tasks, both requir-
ing the animal to respond in a particular
sequence. For one task, the response se-
quence is constant from day to day, so that
performance of a well-learned task is mea-
sured; for the second task, the sequence is
changed daily. The animal "learns to learn"
a new sequence every day, so that acquisi-
tion of a response pattern can be studied
repeatedly. Toxicants and psychoactive
drugs disrupt this acquisition of new re-
sponse sequences. A variety of other pro-
cedures could also be used to model other
aspects of intellectual functioning, includ-
ing alternation procedures, conditional dis-
criminations, and respondent conditioning
procedures, to name a few.
Recommendation 4. Existing proce-
dures should be used to examine whether
toxicants of concern impair learning, mem-
ory, cognition, and intellectual functioning.
Pursuing the Mechanisms of Toxicity
The detection of toxicity in either acute or
subchronic tests will generate questions
that should be pursued, since the conclusive
demonstration of physiological or bio-
chemical mechanisms of action can be
enormously important.
Neurochemical Evaluation. Normal be-
havioral activities of animals (Sparber and
Tilson 1972) as well as adverse behavioral
effects of exposure result in neurochemical
changes. It is therefore difficult to interpret
the significance of acute neurochemical
changes without correlated functional ob-
servations. If large numbers of false posi-
tives are acceptable, then routine neuro-
chemical evaluation may be desirable as a
screening test; otherwise, such use of neu-
rochemical tests is likely to be a poor allo-
cation ot resources.
Neurochemical evaluations can be very
useful as adjuncts to other tests and to
determine mechanisms of toxicity. Manga-
nese (Mn) is an example where such studies
could be especially useful, because Mn is
likely to have specific interactions with
neurochemical substrates. Furthermore,
Prolonged or irreversible changes in neuro-
transm~tter (or neuromodulator) levels,
turnover rates, or receptor numbers, which
might be suspected following the observa-
tion of other forms of toxicity, are always
important. Several good examples exist in
the literature on sympathomimetic amines.
Repeated amphetamine administration can
produce behavioral changes and death in
animals, in the absence of obvious pathol-
ogy. Amphetamine-like drugs can also
produce long-lasting reductions in dopa-
mine and serotonin, and a decreased num-
ber of uptake sites in brain (Ricaurte et al.
1985~. The changes found would not be
obvious in a first-pass neuropathological
examination. However, the destruction of
some receptor populations could be dem-
onstrated histochemically (using Fink
OCR for page 637
Ronald W. Wood
637
Heimer silver stains), after the identifica-
tion of neurochemical changes.
There probably will not be tests for
neurobehavioral toxicity comparable to in
vitro tests for mutagenicity (that is, the
Ames test). A high rate of false positives
could be expected from most such test
systems; an effect in the test tube does not
mean that an effect will necessarily occur in
viva, because the agent may not reach the
site of action. False negatives might occur
less frequently, but be of greater concern.
However, nerve culture techniques will
assist in clarifying the mechanisms of neu-
rotoxicity (Veronesi et al. 1980~.
On the other hand, biochemical tests can
contribute to identifying particular kinds of
neurotoxicity. Assays for neurotoxic ester-
ase induction in the brain and the spinal
cord have been useful for the identification
of neuropathic organophosphates, and an
EPA test guideline has been written for this
purpose (U. S. Environmental Protection
Agency 1985d). Glial fibrillary acidic pro-
tein assays reflect the astrocytic response to
central nervous system injury, and may be
useful as a screening technique (Brock and
O'Callaghan 1987~.
chemical assays may be able to help steer
the process of chemical synthesis; thus if a
test indicates possible toxicity for a chemi-
cal being developed, further synthesis work
might be directed toward developing less
toxic alternatives.
Neuropathological Examinations. Neu-
ropathological examinations should be in-
cluded in toxicity assessment; frequently,
the same animals can be used for behavioral
testing and Neuropathological examination.
Subsequent studies of mechanisms of tox-
icity, of special systems, or of chronic
effects may require the study of satellite
groups because immersion tissue fixation
and routine staining procedures are inade-
quate for the description of some types of
nervous system injury. For example, histo-
chemical techniques (fluorescence, metal
stains, Golgi) and immunohistochemistry
can provide insights into the mechanisms
underlying the neurotoxic effects of certain
chemicals. Such techniques are not rou-
tinely used for hazard identification.
Furthermore, bio
Special procedures are sometimes re-
quired for some classes of injuries; for
example, techniques to examine axoplas-
mic transport. Most such techniques are
incompatible with routine toxicologic eval-
uation. Similarly, nerve teasing and elec-
tron microscopy can demonstrate subtle
neuropathies. Both are extremely labor in-
tensive. Neuropathological studies can use
special chemicals for studies of the mecha-
nisms of toxic injury. The description of the
role of fly diketones in the production of
hexacarbon neuropathies offers a good exam-
ple; subsequent studies of 3,tdimethyl-2,5-
hexanedione have examined accelerated pyr-
role formation and its role in potential
neurofilament cross-linking (Anthony et al.
1983a,b).
Neurophysiological Examinations. Peri-
pheral nerve conduction velocity is used
clinically to assess peripheral nerve function
in humans. In animals, hind limb weak-
ness, gait disturbance, and peripheral neu-
ropathology provide adequate sensitivity
for hazard identification, given that the
exposure concentrations contemplated are
high enough to induce frank peripheral
neuropathy. Measurement of peripheral
nerve conduction velocity may be useful
for the detection of demyelination, and the
U. S. Environmental Protection Agency
(1985e) has promulgated a test standard for
this purpose. However, it may not detect
axonopathies. Most important, the reversi-
bility of peripheral nerve impairments need
not imply the reversibility of central ner-
vous system injury.
Evoked-potential studies might be cost-
e~ective for some classes of sensory effects,
especially to determine low-level effects.
Brainstem auditory evoked responses are
useful in detecting hearing loss; the sensi-
tivity of these procedures is comparable to
that for behavioral procedures (Rebert et al.
1983). Flash-evoked responses are less infor-
mative about injuries to the visual system
than are counterphase spatial-frequency re-
versal experiments. More advanced proce-
dures are available to characterize the inter-
play of structural and functional alterations
produced by toxicants. By simultaneous
measurement throughout a brain structure, it
OCR for page 638
638
Identifying Neurobehavioral Effects
should be possible to describe the pathophys
1 r
1ologlca progression or 1nJury.
Evaluating Whole Emissions,
Fuels, and Their Components
Although it is possible to study whole
emissions directly as complex mixtures,
this is usually not the most fruitful course
to pursue. The difficulties encountered in
studying such complex mixtures are pro-
found, because the myriad interactions pos-
sible among the reactive components of
automotive emissions may result simulta-
neously in potentiation of, and protection
against, adverse effects. The study of mix-
tures should not preclude the continued
evaluation of the toxicity of individual
components of mixtures, especially since
the reduction or elimination of a single
component could have major health im-
pacts. We learn relatively little from the
study of a single idiosyncratic mixture or
simulated automotive emission; indeed, in
such studies, the data collected on the ref-
erence substance used to calibrate the sen-
sitivity of the experiment may well consti-
tute a greater scientific contribution than
the data from the mixture (Laties 1973;
Horvath and Frantik 1974~.
More information about the behavioral
effects of carcinogenic emissions is needed.
When testing for carcinogenesis, pollutant
doses and concentrations are usually
maximum tolerated doses; those that typi-
cally produce behavioral effects are often
much lower. Thus, under ambient condi-
tions of exposure, the behavioral, rather
than the carcinogenic, effects of carcino-
genic components of emissions may be the
principal effects of concern; these effects
might include malaise or performance deg-
radation.
Whole Emissions and Their
Photochemical By-products
Air pollution episodes alter human behav-
ior. Weather reports in certain metropoli-
tan areas regularly include air quality
reports, and the elderly, those with respi
ratory problems, and athletes modify their
behavior accordingly. The description of
atmospheric conditions (even an erroneous
prediction) may change the activities peo-
ple engage in; for example, in a form of
conditioned avoidance behavior, the
heightened probability of chest discomfort
in a smog alert may lead an athlete to
change his or her training regimen. During
the 1984 Olympics in Los Angeles, concern
about the potential effects of automotive
emissions and photochemical products on
performance and health prompted recom-
mendations for the siting of athletic com-
netitions and for traffic control, as well as
for training and competition schedules
(McCafferty 1981).
Even if individuals cannot articulate the
association between verbal warnings about
air quality and discomfort during exercise,
they may nevertheless avoid the circum-
stances in which unpleasant sensations oc-
cur~ without directly attributing their
avoidance to atmospheric quality. The ex-
tent to which unpleasant or uncomfortable
sensations alter the behavior patterns of
dally llle has not been recognized.
Nervous system function can be directly
affected by constituents of whole emis-
sions, such as CO. Emissions can also
produce effects mediated by less direct
mechanisms. Functional disturbances that
. . .
Occur in response to emissions may ae
conditionable in and of themselves, as one
might condition a dog to salivate following
the ringing of a bell; the evidence for such
conditioning will be discussed later.
Eye Irritation. Eye irritation is the most
frequent complaint evoked by emission
exposure. Numerous studies have docu-
mented the increasing frequency of com
. . . . .
P alnts Wit n increasing contaminant con-
centrations. In a report on O3 and other
photochemical oxidants, the National
Academy of Sciences (1977a, p. 430) as-
serted "For the two most prevalent symp-
toms related to photochemical-oxidant ex
. . . . .
posurc- eye irritation anc ~ ~ .acrlmatlon no
method of quantification has been devel-
oped. Eye irritation, although real, is a
subjective response of the subject, and no
measurement, other than the complaint it
OCR for page 639
Ronald W. Wood
639
self, has yet been developed...." In an-
other report on pollutants, the National
Academy of Sciences (1976) stated that the
first uncomfortable reactions are usually
felt in the eye tissues. That report examined
several studies of eye irritation, including
one by Schuck and collaborators (1966~.
Those investigators conducted eye-only
exposures, and permitted subjects to turn a
knob that adjusted the position of a pointer
on a scale to indicate the eye irritation
intensity experienced at any instant during
the 5-min exposure. Concurrently, the rate
of eye blinking was measured. Orderly
functional relationships to exposure
emerged from this study, demonstrating
the value of such experiments. Comparable
studies were undertaken more recently
with formaldehyde and sidestream ciga-
rette smoke (Weber-Tschopp et al. 1977~.
Studies are most frequently performed
by having questionnaires completed by
members of exposed populations (for ex-
ample, Heuss and Glasson 1968; Hagberg
et al. 1985), or by exposing panelists to test
atmospheres, measuring the elapsed time to
a complaint, and eliciting a subjective rat-
ing (Bender et al. 1983~. Such scaling stud-
ies could profit from better utilization of
psychophysical scaling procedures devel-
oped for the study of odorants (Cain and
Moskowitz 1974~.
The development of procedures to assay
eye irritancy in animals would be desirable.
In vitro tests designed to replace the Draize
test (instillation of chemicals into the eye of
a rabbit) are currently being validated, but
neither in vitro tests nor the Draize test can
directly address the subjective response to
low-level sensory irritation. Blink rate
measurements are useful, but with repeated
experience in the test situation. animals
. . . .
. .
may learn to close their eyes to avow
exposure. Procedures that permit animals
to terminate but not to avoid graded con-
centrations of irritants are discussed in
some detail below. These latter procedures
give the animal the opportunity to control
the unpleasant stimulation, unlike tech-
niques that require measurement of struc-
tural changes following instillation of the
material into the eye. Another potential
advantage of these procedures is that the
cornea is served by the trigeminal nerve,
and stimulation of this nerve decreases res-
piratory and heart rate. These physiological
changes are of interest per se and may yield
sensitivity comparable to behavioral mea-
surements without training the subject. In
any circumstance, the sensitivity of these
tissues to irritants may permit the identifi-
cation of the threshold for aversive stimu
lation.
Recommendation 5. Quantitative pro-
cedures should be developed using eye-
only exposures to provide estimates of
aversiveness derived from behavior under
the control of irritant stimulation, and from
measuring blink, heart, and respiratory
rates.
Behavioral Effects. Wheel Running. Sev-
eral experiments describing the effects of
whole emissions on animal behavior pro-
vide leads for further work. Boche and
Quilligan (1960) accustomed mice to run-
ning wheels, and then put one in a cham-
ber with filtered air, and another in a
smog-like mixture of O3 and gasoline. The
mice were moved from one chamber to the
other every day (three 1-day exposures in
each chamber), permitted to rest for a
week, and then subjected to the same proc-
ess at a higher smog concentration (figure
1~. Although there was no assessment of
running in the exposure chamber in the
absence of smog, a concentration-related
reduction in running was observed. This
set the stage for a series of experiments
demonstrating the utility of behavior for
the study of emissions and photochemical
products.
Gage (1979) exposed mice in running
wheels to emissions from an automobile
engine burning unleaded gasoline. The ex-
haust from the engine under lean tuning
suppressed running in proportion to expo-
sure concentration. The exhaust of an op-
timally tuned engine had no effect. Ultra-
violet irradiation of the exhaust simulated
photochemical smog, which suppressed
running to a greater extent than nonirradia-
ted exhaust. Activity returned to normal
several days after the termination of irradi-
ated exhaust exposure. However, termina
OCR for page 640
640
Identifying Neurobehavioral Effects
E ° o cr) rat co us Cot co a, cat ~ tD co to
m ~ arc t~ ~ CO tr) t£ ~Us U) ~ ~ rat ~ a)
Q O O O O O O O O
Z ^
44 E ° ~ o, a, ,~ u, ~cut _ to us co a) co
~ a, CO ~ CO CD CO - O C\l C\l C~J ~ ~ ~ N
X Q - - - - - C\i C~J
1 -~:~-.o~~;8.8,,°;8~ ~ ,,
104
At
o
t; 103
Is
lo2
o LAB AIR
o PURIFIED AIR
· SMOG
MOUSE 5
MOUSE 6
,
0 5 10
o~.c,.o ·o
O .'o-~_O a. O
° 1 'o_0~°
1.11
1;4
I ~I ~1 ~1 1
15 20 25
DAYS
Figure 1. Spontaneous wheel-turning activity of two C57 black male mice in
different environments. The total oxidant and O3 determinations are shown at the
top of the graph for each day of exposure to synthetic air pollutant mixture of O3
and gasoline. (Adapted from Boche and Quilligan 1960.)
lion of nonirradiated exhaust produced re-
bound hyperactivity (figure 2, upper right
panel). This study was not the first report
of exhaust-induced hyperactivity (Hueter
et al. 1966; Emik and Plata 1969; Stinson
and Loosli 1979~. These studies could have
been improved by more complete report-
ing of the effects across time, and of their
relationship to concentration.
Several investigators have used wheel
running to examine biological effects of
smog constituents (see, for example, the
review by Murphy 1964~. Murphy and
colleagues (1964) observed a 46 percent
reduction in activity following a 6-fur ex-
posure to 0.2 ppm 03, and a 20 percent
reduction following exposure to 7.7 ppm
nitrogen dioxide (NOT. Campbell and co-
workers (1970) demonstrated that peroxy-
acetyl nitrate, a constituent of photochem-
ical air pollution, depressed running in pro-
portion to the exposure concentration.
Emik and Plata (1969) and Emik et al.
(1971) set mice in wheel-running cages
between the lanes of the Hollywood free-
way and demonstrated an association be-
tween oxidant concentration and depressed
running.
Because humans complain following ex-
ercise in 03, Tepper and colleagues (1982)
undertook a detailed analysis of the tempo-
ral patterning of wheel-running behavior
that revealed disruption during 6 hr of
exposure to 0.12 ppm 03, the current
ambient air quality standard. Low concen-
trations increased the duration and number
of pauses, but did not change the speed at
which the animal ran, or the length of an
individual running burst. Unlike the effects
on learned behavior described below
(Weiss et al. 1981), effects were obvious in
the first hour at lower concentrations, and
performances declined throughout expo-
sure.
Thus low concentrations of automotive
emissions or photochemical reaction prod-
ucts can impair wheel-running perform-
ance. The mechanism by which these
changes are produced should be a focus of
the research agenda because it is of interest
per se and because it contributes to risk
analysis.
OCR for page 641
Ronald W. Wood
3o[;
he
~ 20
G
co
JO
x
he
20
g
of:
:5 10
641
30-
2a
10
~_
CO Cone (ppm) I 0 1 100 1 25 1 50 1 75 1 100 1 25 1 50 1 75 1 100 1Days
Atmosphere I Air I CO I Nonirredated I Irradiated I
Exposure A O Hb~es
EM Females
Exposure B
301~
30
20
10
O Control r
O Nonirradisted, 100 ppm CO j
~ Irradiated, 100 ppm CO
i
.SS
~'a
0~s\~' /!
I 1 1 1 1 1 1 1 1
1 2 3 4 5 6 7 8 9
| ~ EXPOSED ~ |
Exposure C
1;1~!1!~!1)1'l1'-.: ,
CO Cone (ppm) 1 0 1 100 1 50 1 75 1 100 1 50 1 75 1 100 0 1 100 1 50 1 75 1 100 1 50 1 75 1 100 1
Atmosphere I Air I CO I Nonirrad~ated I Irredated I I Air I CO I Nonirredated I Irredated l
Figure 2. Mean daily activity of mice groups during emission exposure periods of the three exposure tests.
Exhaust level is described by the nominal CO concentration. During exposures A and C, engine was tuned to
factory specifications. During B. engine was optimally tuned. Upper right panel shows activity over the course
of exposure A for male and female mice exposed to concentrations indicated. (Adapted with permission from
Gage 1979.)
Mechanistic Experiments. Several mech-
anistic experiments indicate that the sup-
pression of wheel running performance
was probably not due to acute aversive-
ness of O3 Wood (1979, 1981a) developed
a procedure that permits direct behavioral
assessment of the aversive properties of
inhaled materials. Mice poked their noses
into a conical recess to terminate the deliv-
ery of an irritant, and simultaneously pro-
duced a facial shower of clean air. Tepper
and Wood (1985) demonstrated that O3
reliably maintained escape behavior, and
that its aversive properties were not depen-
dent on previous experience with irritants.
Performance was related to concentration,
OCR for page 648
648
Identifying Neurobehavioral Effects
There are a number of clinical reports of
damage to the basal ganglia, delayed motor
dysfunction resembling parkinsonism, and
gross brain injury following methanol ex-
posure (Erlanson et al. 1965; Guggenheim
et al. 1971; Aquilonius et al. 1978, 1980;
Lev and Gall 19831. This has vet to be
studied In primate models of methanol
. . .
ntoxlcatlon.
· Recommendation 17. An animal
model of methanol-induced motor disor-
ders should be developed. Such a model
would assist in determining if acidosis is a
necessary precondition for the emergence
of methanol-induced motor disorders and
if antidotes are effective.
It has been demonstrated that the expres-
sion of acidosis is mediated by a folate-
dependent metabolic pathway, and that the
inhibition of methionine synthetase (pro-
duced with nitrous oxide exposure) can
provoke methanol-induced acidosis in rats,
a normally insensitive species. Furthermore,
following a few hours of exposure to nitrous
oxide, monkeys treated with 1 g metha-
nol/kg body weight developed acidosis (Eells
et al. 1983~; this is a much lower dose than is
normally required to produce the acute syn-
drome. This observation might provide a
basis for a more sensitive model.
Recommendation 18. More sensitive
animal models of methanol toxicity should
be developed, perhaps through the manip-
ulation of folate metabolism. Repeated or
continuous exposure to low concentrations
of methanol should then be undertaken to
determine if acidosis can be produced, and
if systemic acidosis is a precondition for the
expression ot toxicity.
· Recommendation 19. Clinical trials
should be undertaken with 4-methylpyra-
zole, a new drug that is a promising meth-
anol antidote and a candidate for wide-
spread deployment in emergency facilities.
Metals and Inorganic Compounds
Lead (Pb) is the prototypical metallic auto
. . . . . . . .
motive emission; it IS instructive to review
our experience with Pb before other metals
are added to automotive fuels. The fuel
additive tetraethyllead has been responsible
for multiple deaths from neurotoxicity and
was the focus of a major public health
controversy (Rosner and Markowitz 1985~.
The neurobehavioral toxicity of Pb would
most probably have been detected had
some systematic approach to testing been
in place. Exposure increases the frequency
of conditioned behavior of rats at blood
levels of Pb below the current clinical
definition of elevated Pb burden that re-
quires further diagnostic intervention
(Cory-Slechta et al. 1985~. Morphological
changes in the brain that accompany these
functional changes have not been identi-
fied.
Another metal, manganese (Mn), how-
ever, can produce functional as well as
morphological changes. Methylcyclopen-
tadienyl manganese tricarbonyl (MMT) is a
potential gasoline additive that has anti-
knock properties. When used in diesel
fuels, Mn additives improve combustion
and reduce smoke. The chronic toxicity of
the emission product may be subtle, de-
layed, and readily confused with diseases of
other etiology. The syndrome progresses
from manic psychosis and disturbances of
speech and gait in the early phase, to dis-
turbances of speech, a fixed jovial facial
expression, clumsiness and hyperemotion-
alism in the intermediate stage, and later,
muscular hypertonic and tranquil euphoria
with memory loss and intact sensory func-
tion (Rodier 1955; Mena et al. 1967; Bar-
beau 1984~.
The National Academy of Sciences
(1973) reviewed the toxicity of Mn, ex-
pressed concern about the Mn emission
problem, and made twenty-five research
recommendations. Although Mn is not
now regulated as a hazardous pollutant,
knowledge of the health effects of Mn is
limited, especially about the relationship of
exposure concentration and duration to ef-
fects. The existing data are inadequate to
conduct a risk analysis. The risk of adverse
health effects from Mn emissions should be
characterized as unknown but not necessar-
ily unlikely. The potential injuries are great
enough to warrant further study before any
OCR for page 649
Ronald W. Wood
649
. . . . .
s~gn~cant Increase In exposure Is contem-
plated.
Mn is an essential trace element, but at
some higher dose it becomes toxic. The
relationship between dose and adverse ef-
fect remains unclear, despite the fact that
the toxicokinetics of Mn have received
fairly detailed attention (Dastur et al. 1971;
Newland et al. 1987~. The literature pro-
vides only limited insight into whether
increased exposure increases the severity of
effect, as well as the number of individuals
affected, or merely shortens the time to
toxicity. Children, in particular, may be at
high risk, because, as with Pb emissions,
(1) the amount of Mn in dust and soil
should increase with proximity to the emis-
sion source, (2) children put their hands
and many other things in their mouths,
(3) children become more mobile at 6
months of age, and (4) younger organisms
absorb a larger proportion of the adminis-
tered dose (Cahill et al. 1980; Rehnberg et
al. 1981~.
Most of the clinical literature consists
of effects reported following an idiosyn-
cratic exposure, rather than well-controlled
experiments. The emphasis has been on
identifying toxicity, and not on generating
an orderly dose/effect or dose/response
function. There are anecdotal reports of
delayed toxicity commencing several years
after the termination of exposure (Cook et
al. 1974~. Changes in human behavior
from exposure to Mn at levels that are 20
percent of current recommended exposure
limits have been reported by Roels et al.
(1985~.
· Recommendation 20. Should any in-
crease in Mn emissions be contemplated, an
expert committee should be formed to re-
view the neurotoxicity of Mn and the ade-
quacy of current exposure estimates, and to
consider the benefits of a chronic study in
primates. If significant exposure is contem-
plated, several experiments must be under-
taken to provide data for risk analysis that
provide close attention to neurobehavioral
function, and consequent regional neuro-
chemical assessment. Early signs of altered
dopaminergic function should be exam-
ined.
· Recommendation 21. Should any in-
crease in Mn emissions be contemplated,
kinetic studies of Mn should be under-
taken, with the emphasis on brain uptake
and the ingestion of accumulated dust by
neonates. Estimates of possible intake
should be modeled; exposure of neonatal
primates and evaluation of neurobehavioral
toxicity should be considered.
Studies of the acute toxicity of MMT
have identified seizures and Clara cell ne-
crosis as sequelae to exposure. The delayed
effects of acute or chronic low doses have
not been well characterized, and are of
interest per se; the nervous system is of
interest because of the greater access an
organic metal should have to the central
nervous system and because of the evident
neurotoxicity of Mn in primates. Organic
complexes or salts might facilitate entry
and shorten the time to toxicity.
Recommendation 22. The acute and
chronic neurobehavioral toxicity of MMT
should be more adequately characterized.
Conclusions
Determining the acute effects of chemicals
on behavior and nervous system function is
important to the evaluation of neurotoxic-
itv: acute reversible effects may be the
effects of major concern. Similarly, re-
peated or continuous exposures are needed
to characterize toxicity that is delayed or
cumulative, to observe the development of
tolerance (or reverse tolerance), and to
characterize the reversibility of adverse ef-
fects. Initial screening for subtle sensory or
perceptual impairments, affective disor-
ders, or cognitive and intellectual dysfunc-
tion needs to be conducted, and, finally,
highly focused studies may be needed to
fully characterize hazards using methods
that are dictated by the nature of the system
or function affected, such as specialized eval-
uations and refined neuropathological, neu-
rochemical, and neurophysiological tech-
n~ques.
Since the neurobehavioral toxicity of
OCR for page 650
650
Identifying Neurobehavioral Effects
many compounds present in automotive Summary
emissions is unknown, they should be
studied systematically, proceeding from
acute, then through repeated administra
tion, experiments and subchronic expo
sures, and finally to detailed characteriza
tions of injuries and mechanisms. The U.S.
Environmental Protection Agency has
promulgated guidelines for a variety of
neurobehavioral studies, including neuro
pathology (1985c), motor activity for ex
ample, wheel-runnin~ studies (1 98-c~h1
schedule-controlled
,, ~. ,
O ~ ,,
(learned) behavior
t~Ybbl), and a battery of structured func-
tional observations (1985a). Adopting such
tests and incorporating them into a more
comprehensive testing strategy is a logical
step in developing a rational approach to
answering the many unanswered questions
surrounding safety evaluation of automo-
tive emissions and their fractions.
Such a testing strategy, depending on a
network of methods and techniques, offers
several advantages. First, it reduces the
likelihood of overlooking a hazard or class
of hazards, which any single screening
method might miss.
Second, it can be structured in "tiers,"
in such a way that each tier provides es-
sential information for subsequent tiers
as well as useful information in its own
right. Such a tiered format is likely to speed
up the testing process as well as achieve
significant economies in laboratory opera-
tions that would serve to offset the po-
tential expense of an extensive screening
program. For example, acute toxicity eval-
uations may serve a dose-ranging func-
tion for subsequent repeated-exposure ex-
periments; the findings in both may later
give direction to detailed mechanistic stud-
ies.
~ Recommendation 23. The neurobe-
havioral toxicity of many constituents pres-
ent in automotive emissions is unknown
and should be studied using a tiered-testing
strategy. An expert committee should pri-
oritize the selection of compounds for a
systematic testing program, and recom-
mend specialized evaluations when appro-
priate.
This chapter has described adverse neuro-
behavioral effects of automotive emissions
and offered research recommendations to
facilitate their detailed characterization.
· Neurobehavioral toxicity has not been
evaluated thoroughly for most of the com-
pounds that are known to produce adverse
effects, nor have screening and evaluation
procedures for such toxicity been applied
systematically to the universe of chemicals
that mobile sources produce.
· To some extent, the absence of data Is
attributable to a lack of process. Those
deficits could be remedied by subscribing
to a tiered-testing strategy, with its initial
agenda of test substances prescribed by an
expert committee. The strategy will pro-
vide a disciplined approach, relying on
animal studies and supplemented by avail-
able literature, for dealing with a large
collection of chemicals with largely un-
known effects. However, many new tests,
procedures, and models need to be devel-
oped to assess the adverse health effects that
can reasonably be expected to be encoun-
tered.
· To another extent, the lack of visibil-
ity, prominence, and/or appreciation ac-
corded to neurobehavioral toxicity, even
with respect to substances where such ef-
fects are well-documented and widespread,
contribute to the data shortage. In particu-
lar, we should be immediately concerned
with:
-Sensory irritation and/or repeated and
chronic effects that may alter the quality
of life;
-Effects of CO on complex human
performances, and on special popula-
tions with exaggerated sensitivity (for
example, the fetus, the infant, and the
aged);
-Effects of petroleum hydrocarbons on
behavior, and brain structure and func-
t~on;
-Methanol hazards, should methanol
come into wider use; and
-Metallic fuel additives, especially Mn,
should that come into wider use.
OCR for page 651
Ronald W. Wood
651
Summary of Research Recommendations
Although the behavioral and neurosciences have already been
used to good effect in toxicity evaluation, some areas need further
research and development effort, both to demonstrate feasibility
and to improve cost-effectiveness. Such a research effort should
include attempts to:
· Undertake testing via a tiered approach for chemicals about
which little is known (Recommendation 23) before sophisticated
and expensive procedures are used to examine candidate toxicants
for their capacity to impair learning, memory, cognition, and
intellectual functioning (Recommendation 4~.
· Develop rapid tests of sensory impairment that can be used in
conjunction with functional observation batteries, and develop
comprehensive psychophysical studies directed at specific func-
tional impairments, including impairments of complex auditory
and visual discriminations (Recommendation 1~.
· Develop animal models of affective disorders. Selected refer-
ence substances, drugs as well as toxicants, should be used to
validate these models before they are used to test uncharacterized
chemicals or mixtures (Recommendation 3~.
In addition, more specific recommendations for certain automo-
tive emissions can be made immediately. These are outlined here
according to priority and contingent upon increases in the level
of exposure to a particular emission or deployment of new tech-
nology.
HIGH PRIORITY
Recommendations Whole emissions and photochemical by-products deserve imme
6, 23 diate attention. Acute and repeated-exposure wheel-running stud
ies should be used to characterize emissions, to differentiate the
behavioral consequences of materials that affect primarily the upper
or lower airways, and to determine whether the observed effects
are attributable to alterations in irritant receptors in lung or lung
innervation, frank lung injury, or actual alterations in the periph
eral or central nervous systems. The agents responsible for rebound
hyperactivity should be determined.
Recommendation 5 Eye irritation is one of the most frequently complained-about
effects of automotive emissions and photochemical products.
Quantitative procedures should be developed using eye-only ex
posures to provide estimates of aversiveness derived from behavior
under the control of irritant stimulation, and from measurement of
blink, heart, and respiratory rates. The development and validation
of animal models would be particularly useful.
Recommendation 8 Signs and symptoms of exposure to automotive emission and
photochemical by-products, ranging from asthmatic attacks to com
OCR for page 652
652
Identifying Neurobehavioral Effects
plaints of breathing difficulties, may be conditioned to occur after
exposure to concentrations that evoke no response in naive subjects.
Experiments to define the exposure parameters that produce condi-
tioned alterations in sensitivity to airborne irritants are needed.
Recommendation 12 Prenatal exposure to CO can alter the behavior of offspring.
Such effects may be of great importance and should be studied
further with the techniques of modern developmental neurobiol
ogy.
Recommendation 14 The neurobehavioral toxicity of petroleum hydrocarbons in
unleaded automotive fuels has received virtually no serious atten
tion. Acute performance impairment should be a major focus of
investigation; acute effect determinations are also necessary to
ascertain if preventing acute effects will prevent chronic toxicity.
MEDIUM PRIORITY
Recommendation2 In humans and rodents, the reduction in olfactory sensitivity
produced by oxidants and aldehydes should be described as a
function of concentration and duration of exposure.
Recommendation 7 A model of human populations with compromised pulmonary
function should be developed, because such populations are more
sensitive than others to oxidant exposure. Experimental models of
chronic obstructive pulmonary disease should be developed that
will permit quantitative estimation of exaggerated oxidant sensi
tivity and display behavioral effects that resemble those produced
by chronic exposure to oxidants.
Recommendations The aspects of performance most susceptible to disruption by
9,10,11 CO should be identified. The relative importance of different
exposure parameters in determining the extent of behavioral im
pairment should be described. Exaggerated sensitivity in the eld
erly and those with cardiovascular or respiratory insufficiency
should be examined.
Recommendation 13 Repeated-exposure studies utilizing quantitative morphometric
neuropathology should be undertaken in experimental animals
exposed to petroleum hydrocarbons. Chronic solvent exposure
usually does not produce gross central nervous system lesions, but
rather a selective wasting syndrome that may not be evident in
measurements of gross brain weight.
Recommendation 15 A primate model of the solvent syndrome should be developed.
Repeated-acquisition procedures would be an appropriate baseline
---I ~ 1- - - - - rid - -- - - - - jar -I
for the study of learning impairment; procedures for the explicit
evaluation of memory impairment would assist in clarifying the
nature of any learning impairment observed.
CONTINGENT PRIORITY
Recommendation 16 Because methanol offers special risks to the visual functions of
OCR for page 653
Ronald W. Wood
653
primates, additional work should be performed to assist in charac-
terizing the hazards and their relationship to exposure.
Recommendation 17 An animal model of methanol-induced motor disorder should be
developed. Such a model would assist in determining if acidosis is
a necessary precondition for the emergence of methanol-induced
motor disorders, and if antidotes are effective.
Recommendation 18 More sensitive animal models of methanol toxicity should be
developed, perhaps through the manipulation of folate metabo
lism. Repeated or continuous exposure of susceptible individuals to
low concentrations of methanol should be undertaken to determine
if acidosis can be produced, and if systemic acidosis is a precondi
tion for the expression of toxicity.
Recommendation 19 Clinical trials should be undertaken with 4-methylpyrazole, a
drug that is a promising methanol antidote, and a new candidate for
widespread deployment in emergency facilities.
Recommendation 20 Should any increase in Mn emissions be contemplated, an expert
committee should be formed to review the neurotoxicity of Mn
and the adequacy of current exposure estimates, and to consider the
benefits of a chronic study in primates. If significant exposure is
contemplated, several experiments must be undertaken to provide
data for risk analysis that provide close attention to neurobehav
ioral function, and consequent regional neurochemical and neuro
pathological assessment. Early signs of altered dopaminergic func
tion should be examined.
Recommendation21 Toxicokinetic studies of Mn should be undertaken, with the
emphasis on brain uptake and the ingestion of dust by neonates.
Crawling infants ingesting Mn accumulated in dust may be of great
concern, as indicated by past experience with Pb. Estimates of
possible intake should be modeled; exposure of neonatal primates
and evaluation of neurobehavioral toxicity should be considered.
Recommendation 22 The acute neurobehavioral toxicity of any Mn additive should
also be evaluated. The delayed ejects of single, lower doses have
not been well characterized and would be of some interest per se, as
might chronic, lower-level exposure. Organic Mn compounds
should be very interesting to study in the primate.
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Representative terms from entire chapter:
automotive emissions
