NEUROTOXICOLOGY
1526--0046/01 $15.00 + .00
NEUROTOXIC
EXPOSURE AND
OLFACTORY
IMPAIRMENT
Richard L. Doty, PhD, and Lloyd Hastings, PhD
Normal functioning of the olfactory system is a prerequisite for the
detection of several chemical environmental hazards (e.g., spoiled foods,
leaking natural gas,smoke and various airborne pollutants), and for the full
appreciation of foods, beverages,flowers, perfumes, spices, the seashore,
the mountains, and the seasonsof the year.Distortions or loss of smell function can adversely influence food preferences, food intake, and appetite,
and in some casescan lead to significant psychological depression. It is
thus no wonder that dysfunction of olfaction is of considerable concern to
persons who experience it, particularly those dependent on this sensefor
their livelihood or safety (e.g., cooks, homemakers, plumbers, fire fighters,
perfumers, fragrance sales persons, wine merchants, coffee or tea tasters,
food and beveragedistributors, and employees of numerous chemical, gas,
and public works industries).
Although smell dysfunction secondary to toxic exposure is generally
less common than smell dysfunction caused by a number of other causes
(e.g., upper respiratory infections, head trauma, chronic rhinitis or rhinosinusitis), it nonetheless exists. In addition to directly damaging the olfactory mucosa, some toxins may, in fact, induce upper respiratory inflammatory responsesor infections that produce such damage, as well as enter the
central nervous system (CNS) and causedamage to CNS structures. Olfactory loss can occur as a result of exposure to toxins in general air pollution
and in workplace situations, where litigation becomes a consideration.
Most casesof toxin-related olfactory loss do not get referred to specialized centers such as ours for evaluation. In fact, smell function is rarely
From the Smell and TasteCenter and Department of Otorhinolaryngology: Head and Neck
Surgery, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania
CLINICS IN OCCUPATIONAL
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1 .NUMBER
3 .AUGUST
AND ENVIRONMENTAL
2001
MEDICINE
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DOTY
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assessedquantitatively by local medical personnel, despite the availability
of accurate, easy-to-use, and inexpensive tests for this purpose. unfortunately, there continues to be a paucity of quantitative researchinvestigating
toxin-related effects on the senseof smell, and most reports of such effects
are mainly anecdotal in nature.
In this article, we first describe basic elements of nasal airflow and
the peripheral anatomy of the human olfactory system.* We then discuss
common methods for quantitatively evaluating smell function, and subsequently present an overview of the types of toxic agents that reportedly
alter such function. Included are studies of toxic metals (e.g., cadmium,
mercury), irritant gases(e.g., 502, formaldehyde), and solvents (e.g., acetone). Although the emphasis of the review is on humans, a listing of toxic
agents known to damage the olfactory epithelia of rodents is provided,
and data from animal studies are discussed when they relate to findings
from human studies.
PERIPHERAL
OLFACTORY
SYSTEM
ANATOMY
Most toxic agents adversely influence olfaction by directly damaging
the olfactory neuroepithelium, which is located in the upper recessesof
the nasal chambers, lining the cribriform plate and sectors of the superior
turbinate, superior septum, and middle turbinate (Fig. 1). Although most
of this epithelium is positioned away from the main airsteam and, hence,
is thought to be protected to some degree from inhaled vapors, xenobiotics
still readily reach this vulnerable region. As noted by Swift and Proctor;oo
under conditions of normal resting inspiration (0.15-0.25Lis), air passes
at a vertical angle upwards through the anterior naris at a velocity of 2 to
3 meters per second. At this point, from 10% to 15% of the airstream is
shunted toward the olfactory cleft. At the termination of the vestibule (i.e.,
the ostium internum, the most narrow and restrictive portion of the entire
airway), the main airstream changes direction from vertical to horizontal. At this transition point, the airstream reaches hurricane-force velocities (12-18 ml s) before exiting the area and returning to speeds less than
4 meters per second. The highly nonlaminar (turbulent) flow that develops after the ostium intemum results in increased contact with the blood
swollen turbinates, thereby warming, cleansing, and humidifying the major portion of the airstream.
*In addition to the main olfactory system (cranial nerve I), the reader should be aware
that other specialized neural systems are present in the nose. These include (1) trigeminal
afferents responsible, for example, for the coolnessof menthol vapors and irritative responses
to volatile chemicals24;(2) a rudimentary and nonfunctional vomeronasal organ near the base
of the septum9,!02;and (3) the poorly understood nervus terminalis or terminal nerve (CN 0).
CN 0, a highly conserved neural plexus that ramifies throughout the nasal epithelium, is
distinguished by ganglia at n.odal points and a high gonadotropin content.96
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The olfactory epithelium begins to lose its homogeneity soon after
birth. Indeed, as early as the first few weeks of life, metaplastic islands of
respiratory-like epithelia begin to appear within its borders, presumably as
a result of insults from environmental viruses, bacteria, and toxins.76These
islands increasein extent and number throughout life. Surprisingly, in part
becauseof the cumulative metaplasia and the age-related heterogeneity of
the epithelium, the exact size of the olfactory epithelium in humans is still
not well established, and there is suggestion that it may extend, in adults,
further onto the middle turbinate than previously believed.
The mature olfactory epithelium is comprised of at least six distinct
cell types (Fig. 2).53The first, the bipolarsensoryreceptorneuron,reportedly
numbers approximately 6 million in the adult, exceeding the number of
receptor cells in any other sensory system except vision.74The olfactory receptors are located on the ciliated dendritic ends of thesecells whose axons
coalesceinto 30 to 50 "olfactory fila," which are ensheathedby Schwannlike cells. The ma traverse the cribriform plate of the ethmoid bone to enter
the anterior cranial fossa and collectively constitute cranial nerve I. The
secondcell type, the microvillar cell,is located near the surface of the epithelium and projects microvillae into the mucus. These cells, whose function
is unknown, are said to number approximately 600,000in the adult. The
third cell type, the supporting or sustentacularcell, also projects microvillae
into the mucus. These cells are believed to (1) insulate the receptor cells
from one another, (2) contribute to and regulate the local ionic composition of the mucus, (3) deactivate odorants, and (4) aid in protecting the
epithelium from damage from foreign agents,47As noted in detail later in
this article, the supporting cells contain several xenobiotic-metabolizing
enzymes, a feature shared with the cells that line the Bowman'sglands and
ducts.65The latter glands provide most of the mucus in the region of the
olfactory epithelium. The fifth and six cell types are the globose(light) basal
cell and horizontal (dark) basalcell. These cells are located near the basement membrane from which the other cell types arise. It is believed that
globose cells can give rise to both neurons and non-neural cells when the
olfactory epithelium is damaged, expressing a rare multipotency for stem
cells.53Although continuous neurogenesis occurs in the basal sectors of
the neuroepithelium, long-lived receptor cells have been identified, and
both endogenous and exogenous factors promote receptor cell death or
replenishment from the progenitor stem cells.68The olfactory ensheathing
cells, which form the bundles of axons that comprise the olfactory fila,
play an important role in guiding regenerating axons to their bulbar targets and have unique properties useful in repair or regeneration of both
central and peripheral nerves. For example, they enhance remyelination
and axonal conduction in demyelinated spinal tract nerves and in severed rat sciatic nerves;10exhibiting both Schwann cell-like and astrocytelike properties.55
NEUROTOXIC
EXPOSURE
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OLFACTORY
IMPAIRMENT
551
Figure 2. Low-power electron micrograph of a longitudinal section through a biopsy specimen
of human olfactory mucosa taken from the nasal septum (Original magnification x 670). Four
of the major cell types are indicated: ciliated olfactory receptors (c), microvillar cells (m),
supporting or sustentacular cells (5), and basal cells (b). The arrows point to ciliated olfactory
knobs of the bipolar receptor cells. d = degenerating cells; bs = base of the supporting cells;
Ip = lamina propria; n = nerve bundle. From Moran DT, Rowley JC Ill, Jafek BW, et al: The
fine structure of the olfactory mucosa in man. J Neurocytol11 :721, 1982; with permission.)
The receptor cell cilia differ from the cilia of the respiratory epithelium
in being longer and lacking dynein arms (and therefore intrinsic motility). In some cases,specialized proteins (odorant binding proteins) aid in
the transport of odorants through the mucus. Approximately 1000 types
of odorant receptors are now believed to exist.15Most olfactory receptors appear to be linked to the stimulatory guanine nucleotide-binding
protein Go1f.57
When stimulated, they activate the enzyme adenylate cyclase
to produce the secondme~sengeradenosinemonophosphate (cAMP)67and
552
DOTY
& HASTINGS
subsequent events related to depolarization of the cell membrane and signal propagation. In the few rodent species that have been evaluated, the
olfactory receptors are topographically organized into four strip-like zones
that roughly parallel the dorsal-ventral axis of the cribriform plate.109
METHODS OF EVALUATING OLFACTORY FUNCTION
An astute physician of yesteryear tested the senseof smell by asking a
patient to identify several crude odorants, such as coffee grounds, cloves,
or perfume placed under the nose, perhaps testing one side at a time by
closing the contralateral naris with a finger. This qualitative approach to
smell testing, however, was unreliable, was easily faked by malingerers,
and provided no information on the relative degreeof dysfunction. Importantly, it often led to the wrong conclusions,becausepersons have difficulty
accurately identifying an odor without being presented with alternatives.
Fortunately, advances in the technology of psychophysical measurement and the proliferation of easy-to-useand commercially available tests
of olfactory function now make it possible for toxicologists and others to accurately and quantitatively assessthe ability to smell.29With the exception
of dysosmia and phantosmia (whose diagnoses are based solely on patient
report), quantitative psychophysical testing allows for the assignment of
patients to specific sensory diagnostic categories.The following categories
are widely accepted:Anosmia:inability to detect qualitative olfactory sensations (i.e., absenceof smell function); partial anosmia:ability to perceive
some, but not all, odors; hyposmiaor microsmia:decreased sensitivity to
odors; hyperosmia:abnormally acute smell function; dysosmia(sometimes
termed cacosmiaor parosmia): distorted or perverted smell perception to
odor stimulation); phantosmia:a dysosmic sensation perceived in the absence of an odor stimulus (also known as olfactory hallucination); and
agnosia(olfactory):inability to recognize an odor sensation, even though
olfactory processing, language, and general intellectual functions are essentially intact, as in some stroke patients. Olfactory dysfunction can also
be classified into bilateral or unilateral categories (sometimes termed binasal or uninasal). In most cases,bilateral test scoresreflect the better functioning of the two sides of the nose. Although presbyosmia is sometimes
used to describe smell loss causedby aging, this term does not distinguish
between anosmia and hyposmia and implies that it is age per se, that is
causing the age-related deficit.
The most popular quantitative olfactory tests are those of odor identification, discrimination, memory, and detection. Self-administered tests
that use microencapsulation technology (i.e., "scratch and sniff" odorants)
are the most widely used, including the 40-odor University of Pennsylvania Smell Identification Test (UPSIT; known commercially as the Smell
NEUROTOXIC
EXPOSURE
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OLFACTORY
IMPAIRMENT
553
Identification Test [SIT]),25,29,33
the 12-odor Brief-Smell Identification Test
(B-SIT; also known as the Cross-Cultural Smell Identification Test),30the
3-odor Pocket Smell Test (PST),31and the 12-item Odor Memory Test
(OMT) (Sensonics,Inc., Haddon Heights, NJ).31The UPSIT (which has ageand gender-basednorms that allow for a determination of an individual's
percentile rank relative to peers) has been administered to over 200,000
people in Europe and North America and is available in English, Spanish,
French, and German language versions (Fig. 3).25,34
Threshold testshave also becomepopular for assessingolfactory function, in part because of their intuitive appeal, their commercial availability!' 26,106
and practical considerations (i.e.,need for establishing at what
concentration a given chemical elicits a noticeable odor). Accurate threshold testing is time consuming and more complicated than what would appear on the surface, however, even though the measurement of olfactory
Figure 3. The four booklets of the 40-odorant University of Pennsylvania Smell Identification
Test (UPSIT; commercially known as the Smell Identification Test). Each page of each 10-page
booklet contains a microencapsulated odorant that is released by means of a pencil tip, and a
multiple-choice question as to which of four possibilities smells most like the odorant. Forcedchoice answers are recorded on columns on the last page of the test. (Courtesy of Sensonics,
Inc., Haddon Heights, NJ 08035 USA. Copyright 2000, Sensonics, Inc., with permission.)
554
DOTY
& HASTINGS
thresholds seemsstraightforward and regulatory agenciesand others frequently report "the threshold value" for a given chemical. Thus, there are
several types of olfactory thresholds, including detection thresholds, identification thresholds, and differential thresholds. Even within a threshold
class, there are a variety of procedures for presenting the stimuli and operationally defining the threshold, all of which have an effect on the final
threshold value. For example, the number of trials used, the use or nonuse
of forced-choice trials, the magnitude of the stimulus steps,and the nature
of the dilution medium all have an effect on the threshold measure.28,3l,81
Importantly, the empirically defined threshold value is a function of the
human observer, being influenced by factors such as the subject's age and
general health.21Even when the number of molecules entering the nose
is known, further dilution of the stimulus occurs in the nose, making it
impossible to specify the exact number of molecules reaching the olfactory
receptors. This number depends on such variables as the size of the sniff,
the size of the nose,the size and shape of the nasal turbinates, the thickness
of the mucus, and numerous other idiosyncratic parameters. Fortunately,
from a practical perspective, the olfactory system is very sensitive to the
first few molecules it receives, minimizing the effect of such variables on
the threshold measure.
The lowest concentration of an odorant that an individual can reliably
detect (usually defined as that concentration where detection is midway
between chanceand perfect detection) is termed his or her detectionor absolute threshold.At very low concentrations, no odor quality can be discerned,
only that something is present that differs from air or the comparison diluent blank or blanks. In modern olfactory detection threshold testing, the
subject is required to report which of two or more stimuli (i.e., an odorant
and one or more blanks) smells strongest, rather than to simply indicate
whether an odor is perceived or not. Such "forced-choice" procedures are
less confounded by response biases (e.g., the conservatism or liberalism
in reporting the presence of an odor under uncertain conditions) than
nonforced-choice procedures. In addition, they are more reliable and produce lower threshold values.31The instructions given to a subjectare critical
in measuring a detection threshold, becauseif the subject is instructed to
report which stimulus produces an odor, rather than which stimulus is
stronger, a spuriously higher threshold value may result (odor quality is
present only at higher perithreshold concentrations).
The recognitionthresholdis defined as the lowest concentration where
odor quality is reliably discerned. Unfortunately, it is nearly impossible
to control criterion biases in recognition threshold measurement. Thus, in
a forced-choice situation, guessesare rarely randomly distributed among
alternatives, potentially leading to a spuriously low recognition threshold for the preferred alternative. A classic example of this problem comes
from taste psychophysics, where some subjectsreport "sour" much more
NEUROTOXIC EXPOSURE AND OLFACTORY IMPAIRMENT
555
frequently than the other primary qualities in the absence of a clearly
discernible stimulus, resulting in a spuriously low sour-taste recognition
threshold measure.113
A third type of threshold is the differential threshold,the smallest
amount by which a stimulus must be changed to make it perceptibly
stronger or weaker. The size of the increment in odorant concentration (~I)
required to produce a "just noticable difference" increasesas the comparison concentration {1) increases,with the ratio approximating a constant
(i.e., ~I/I = C). This phenomenon was described by Weber in 1834 and
was termed "Weber's Law" by Fechner in 1860.40Although differential
thresholds have been measured in olfaction, they have received little practical application.
Two types of psychophysical detection threshold procedures have received the most use in the last two decades:the ascending method of limits procedure (AML) and the single staircase procedure (55).23,28
In the
AML procedure, odorants are presented sequentially from low to high
concentrations, and the point of transition between detection and no detection is estimated. In the 55 method, the concentration of the stimulus
is increased after trials on which a subject fails to detect the stimulus and
decreasedafter trials where correct detection occurs. An average of the updown transitions ("reversals") is used to estimate the threshold value. In
both the AML and 55 procedures, the direction of initial stimulus presentation is made from weak to strong in an effort to reduce potential adaptation effects of prior stimulation. The stability or reliability of a threshold
measure is predictably related to the number of trials presented. Hence,
procedures with more trials focused in the perithreshold region, such as
the 55 procedure, produce less variable and more reliable measures than
simple AML procedures.31
For the most part, when an individual has a high threshold (i.e., is less
sensitive) to one compound, he or she has high thresholds to other compounds as well. This is because most odors depend on the activation of
more than one type of receptor and becauseodorants often share common
subsetsof receptor types. Becausethe various types of receptors are interspersed irregularly throughout the epithelium, damage to one region of
the epithelium influences the perception to many, indeed probably most,
odorants. Theoretically, the degree to which different odors are altered by
subtotal damage to the epithelium could vary idiosyncratically, depending on the extent to which each odorant depends on common or disparate
receptor types, the relative frequenciesof such receptor types, and the number of receptor types activated by each odorant. Nonetheless, as a general
rule, detection threshold sensitivity to one compound is correlated to that
of other compounds, thus explaining why a detection threshold measure
to a single chemical can typically be used clinically to establish the degree
of overall olfactory functi.on.
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OOTY & HASnNGS
Although there is suggestion that tests of identification or discrimination are more sensitive than tests of odor threshold to lesions in the
central olfactory pathways; lesions of the olfactory epithelium can also influence odor identification and discrimination test scores. Furthermore,
some studies have found that central brain lesions can, indeed, influence odor detection thresholds. Hence, one cannot reliably infer the locus of the underlying neuropathology from psychophysical test results.
Indeed, it is not even clear whether or to what degree many nominally
disparate olfactory tests actually measure dissimilar perceptual attributes.
Thus, in one study, nine nominally different olfactory tests (e.g., tests of
odor identification, discrimination, detection, memory, and suprathreshold intensity and pleasantnessperception) were administered to 97 health
individuals representing both sexesand a wide range of ages.35A principal components analysis performed on the correlation matrix among the
tests revealed four meaningful components. The first received strong primary loadings from most of the olfactory test measures (including tests
of odor identification, discrimination, and threshold), whereas the second
was composed of primary loadings from intensity ratings given to a set of
suprathreshold odorant concentrations. The third and fourth components
had primary loadings that reflected, respectively, mean suprathreshold
pleasantnessratings and a response bias measure derived from a yes/no
odor identification signal detection task. The results of this study suggest
that, at least in healthy subjects spanning a wide age range, several nominally distinct tests of olfactory function are measuring a common source of
variance.
LOSS OR ALTERATION OF OLFACTORY FUNCTION
FROM CHEMICAL EXPOSURE
The medical and toxicologic literature is replete with reports of smell
loss or distortion in humans after acute or chronic exposure to a number
of volatile chemicals. Becausea detailed assessmentof all of these reports
is impossible within the scope of this article, we briefly summarize data
in this section from two major reviews that have appeared on this topic
and focus on compounds for which more sound empirically-based data
are available.
Naus77listed several early and mainly European studies of smell dysfunction after workplace exposure to airborne agents.Most of thesestudies
used some form of odor threshold task and reported adverse effects on
the ability to smell dusts and heavy metals (e.g., spices, flour, cotton,
lead, coal, mercury, cadmium, coke, grain, SiO2, tobacco, paper, cement,
ashes} and industrial volatile chemicals (e.g., perfumes, menthol, carbonic disulfide, benzene,,dichloromethane, pentachlorophenolate, ammonia,
NEUROTOXIC
EXPOSURE
AND
OLFACTORY
IMPAIRMENT
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bromine, trichloroethylene, nitrous gases,acids). In the reviewed studies,
Naus further sought associations between the presence of hyposmia and
factors such as cigarette smoking and duration of exposure.Unfortunately,
the studies examined were heterogeneous in terms of methods, and their
means for assessing olfactory function were non-forced-choice, thereby
confounding the examinee's response criterion with the measure of sensory sensitivity.29Importantly, many of thesestudies, as well asNaus' own
analyses, did not use control groups or take into account such basic confounding as the association of age with duration of chemical exposure.
Age alone is known to be associatedwith decreasesin olfactory function.32
Be as it may, Naus' pioneering review mustered convincing evidence for
toxin-induced hyposmia in several industrial settings.
More recently, Amoore3listed more than 120different compounds and
industrial processesreported to adversely affect olfactory function, a number of which were mentioned by Naus. More than 75 of the studies cited
by Amoore examined the relationship between exposure and olfactory
dysfunction. Most were case reports or case series, however, and quantitative assessmentof function was the exception, rather than the rule.
Furthermore, becauseof the general lack of good industrial hygiene practices during much of the period reviewed, reported exposure levels were
mainly rough estimates. Compounds listed by Amoore for which there is
at least some empirical basis for adverse influences on smell function are
listed in Table 1.
In addition to losses of smell function, perversions of the sense of
smell or untoward irritative effects can result from some toxic exposures.
For example, Emmet38 described the case of a pipe fitter exposed to
tetrahydrofuran-containing pipe cement who complained of a constant
unpleasant smell (parosmia); recovery occurred after removal of exposure
to the pipe cement. Shusterman and SheedylOldescribed a woman exposed to chloramine gas who complained of a "stinging" in the nasopharynx in response to common household odors from which she eventually
recovered.
EMPIRICAL STUDIES OF VOLATILE TOXIC
EXPOSURES ON HUMAN OLFACTORY FUNCTION
Severalclassesof chemicalshave been clearly implicated in altering the
ability to smell, as noted in detail below. Although some studies have not
used statistical techniques to unconfound age with duration of exposure,
the frequency of the reports and the magnitude of the effectsare so large for
most of the toxins evaluated that age confounding is likely inconsequential.
The largest group of these studies has focused on workers exposed to
cadmium and nickel.
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Table 1. SUBSTANCES OR INDUSTRIAL PROCESSES THAT REPORTEDLY
ADVERSELY ALTER THE SENSE OF SMELL AND FOR WHICH THERE IS
REASONABLE SUPPORTIVE SCIENTIFIC DATA
Metallic compounds
Cadmium compounds
Cadmium oxide
Chromate salts
Nickel hydroxide
Zinc chromate
Metaltirgical processes
Chromium plating
Lead smelting
Magnet production
Mercury (chronic intoxication)
Nickel plating
Nickel refining (electroivtic)
Silver plating
Steel production
Zinc production
Nonmetallic inorganic compounds
Ammonia
Carbon disulfide
Carbon monoxide
Chlorine
Hydrazine
Nitrogen dioxide
Sulfur dioxide
Fluorides
Organic compounds
Acetone
Acetophenone
Benzene
Benzine
Butyl acetate
Chloromethanes
Ethyl acetate
Menthol
Pentachlorophenol
Trichloroethylene
Dusts
Cement
Chemicals
Hardwoods
Lime
Printing
Silicosis
Manufacturing processes
Acids
Asphalt
Cutting oils
Fragrances
Lead paints
Paprika
Spices
Tobacco
Varnishes
Wastewater (refinery)
Adaptedfrom Amoore JE: Effects of chemical exposure on olfaction in humans. In Barrow CD (ed):
Toxicology of the Nasal Passages.Washington, DC, Hemisphere Publishing, 1986,pp 155-190.
Cadmium
and Nickel
Cadmium is a highly toxic trace metal involved, often along with
nickel, in several manufacturing processes.The National Institute for Occupational Safety and Health estimatesthat 100,000Americans are exposed
occupationally to cadmium fumes or dust in industries such as electroplating and battery manufacturing. Industrial exposure to cadmium has long
been suspected as having adverse effects on the human ability to smell,
and empirical studies of cadmium's effects on smell date back to the late
1940sand early 1950s.1n1952,BaaderBreviewed the effectsof chronic cadmium poisoning on the nasal mucosa, noting edema, rhinitis, and general
atrophy in selected cases.
In a pioneering report on this topic, Friberg43 noted that 44% of
43 workers employed in an alkaline battery factory exposed to both
NEUROTOXIC
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cadmium-iron dust (5-15 mg/m3 of air) and nickel graphite dust (10150 mg/m3 of air) for periods ranging from 9 to 34 years complained of
decreased ability to smell. On sensory examination, approximately one
third of these workers were reportedly anosmic, although the nature of
the olfactory testing was not reported. Only 10% of 15 workers employed
in the same areas of the factory for four years or less complained of this
problem; none were apparently tested for their smell ability.
Ten years after the Friberg study, Adams and Crabtree1 found, in a
study of 106cadmium- and nickel-dust-exposed alkaline battery workers
and 84 matched normal controls that the exposed individuals performed
significantly more poorly than the controls on an odor threshold test using phenol. In this study, 27% of the exposed workers were reportedly
anosmic, compared with 5% of the controls. Although the amount of exposure to cadmium could only be roughly estimated, in some factory sites
it apparently reached levels as high as 2.76mg/m3. Approximately half of
the anosmic workers were unaware of their disorder. Despite the fact that
examination of the nasal mucosa failed to yield any relationship between
degree of irritation and olfactory dysfunction, proteinuria was positively
correlated with the presenceof anosmia.
A report of even a higher prevalence of anosmia among workers exposed to cadmium appeared four years later. Potts84reported that 64% of
70 workers exposed to cadmium dust (.6-236 mg/m3 of air) in a section
of a battery factory for 10 to 40 years were anosmic. Unfortunately, no description was made in this study as to whether or how the smell testing
was carried out.
Three studies have appeared on this topic in the more modern era. In
the first of these studies, Yin-Zeng et aP18found that 28% of individuals
who had worked five years or more in a cadmium-refining plant reported
having anosmia. No olfactory measureswere apparently taken. The average concentration of airborne cadmium was said to be comparatively low
(between 0.004and 0.187mg/m3), but still slightly above the current Occupational Safety and Health Administration Permissible Exposure Limit
of 0.005mg/m3 to which a worker may be exposed. In the second of these
studies, Rose et al91administered a butanol odor detection threshold test
and an odor discrimination test to 55 workers exposed for an average
of 12 years to cadmium fumes (from brazing refrigerator coils). Airborne
cadmium, measured for the first time 13 years after production began,
was 0.300 mg/m3. Workers with the highest body burden of cadmium,
as measured by urinalysis, exhibited moderate to severe hyposmia, but
not anosmia, on the detection threshold task, but performed normally on
the odor discrimination task. These observations led the authors to the
questionable conclusion that only peripheral, and not central, elements of
the olfactory pathway were damaged. In the third study, Sulkowski et al93
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compared the olfactory function of 73 workers involved in the production
of cadmium-nickel batteries to that of 43 nonexposed, age- and smokingmatched controls. Anosmia or hyposmia was found in 45.2%of the exposed
group and in 4.6%of the controls. Unfortunately, the Elsberg blast injection
procedure was used to assessolfactory function. This procedure has been
criticized on numerous grounds, including (1) the lack of a forced-choice
response (which results in artificially elevated threshold values), (2) the
confounding of pressure with the number of molecules in the stimulus,
(3) the introduction of a very unnatural stimulus pulse into the nose, and
(4) the production of unreliable threshold measures.58,114
Despite its shortcomings, however, this study is in accord with earlier ones in implying
that, even at low concentrations, cadmium exposure can result in loss of
smell function.
Chromium
Like cadmium, chromium is often used with nickel and other metals in
industrial situations, most notably in the manufacture of high-quality steel
alloys. Unlike cadmium, there has been relatively little researchabout the
effects of chromium on the ability to smell, even though this metal has long
been suspected as having an adverse influence. Watanabe and Fukuchil12
examined odor detection and recognition thresholds of 26 male and 7 female employees of a chromate-producing factory who had worked there
for at least sevenyears. Over half of the subjects(51.4%)were noted as having perforated nasal septa;54.5%exhibited elevated smell thresholds to the
five odorants evaluated (phenyl ethanol, cyclopentenolone, isovaleric acid,
r -undecalactone,scatol), with two reportedly being anosmic.Although the
degree of olfactory function was not related to the presence of the septal
perforations, it was related to the duration of employment in the factory.
Mercury
Although mercury exposure occurs in a number of industrial operations and reportedly produces olfactory deficits, like chromium, the data in
support of this contention are limited. In fact, the sole empirical study used
patients (mean age, 79 years) suffering from Minamata diseasedeveloped
through exposure to in utero mercury. The patients and controls were administered the UPSIT25and an odor detection threshold test using phenyl
ethyl alcohol.44The patients with Minamata diseaseexhibited greater agerelated declines in both threshold sensitivity and UPSIT scores than did
age-matched controls. In an autopsy study of patients with chronic Minamata disease,damage to the olfactory bulb and tract was found, although
no obvious changesin ~henasal epithelium were observed.44Whether this
NEUROTOXIC
EXPOSURE
AND
OLFACTORY
IMPAIRMENT
561
is becausethe mercury exposure was due to ingestion and not inhalation
is unknown.
Lead
Inorganic and organic lead can alter CNS neurotransmitters and can
produce transient or possibly permanent difficulties in attention or concentration, manual dexterity, memory, visuoconstruction, psychological
well-being, and psychomotor speed and accuracy.Whether and to what
degree this metal alters the ability to smell is not clear, although the available evidence suggeststhat occupational exposure to lead has only minor
effects, if any. Surprisingly, no studies are available on children who have
been exposed to lead, despite the fact that the pediatric population is more
sensitive to neurotoxic effects of exposure to low levels of lead.
Schwartz et a197
administered the UPSIT,along with several neuropsychological tests,to 222 employees of a tetraethyllead manufacturing plant.
The testing was performed on site, prior to or in place of a work shift, to
minimize any possible acute toxic effects and to reduce work-related fatigue. Industrial hygiene sampling data were available, and duration of
exposure to lead was estimated from personnel records and from detailed
occupational histories compiled by trained occupational medicine physicians. In this subject population, organolead production peaked in the late
1960sand early 1970s,and urine lead levels showed an upward trend from
1965through 1985,followed by a decline. Mean differencesin the test scores
were estimated by comparing the averagescoresof the moderate, high, and
highest exposure groups to those of the low exposure (reference)group and
by adjusting for the confounding influences of age,intellectual ability, race,
and alcohol consumption. No influence of lead on UPSIT scoreswas apparent, even though lead exposure was associated with decrements in a
several the neuropsychological measures.
Subsequently, Bolla et arl compared UPSIT data from a subset
(n = 190) of the aforementioned lead-exposed subjects to those from 144
solvent-exposed workers and 52 referencesubjectswho had been administered the sameset of sensoryand neuropsychological tests.Again, the overall results showed that, after adjusting for confounding variables such as
age,vocabulary score,and race, the UPSIT scoresof lead-exposed workers
did not differ significantly from those of the reference group (respective
mean scores, 36.4 and 36.9). However, when the lead-exposed workers
were divided into exposure durations of less than 11years, 11 to 17 years,
and more than 17 years, significantly lower UPSIT scoreswere noted relative to the reference group, for the 11 to 17-year exposure group, but not
for the other two groups. This effect was apparently not viewed by the authors asmeaningful, as they statein the conclusion of the article, "Olfactory
function was. ..unaffect~d by lead exposure".ll
562
DOTY
& HASTINGS
Solvents
Workers in many occupations, including painting and paint manufacturing, lumber and furniture fabrication, machining operations, equipment cleaning and degreasing, and floor and carpet laying, are exposed
over time to significant levels of solvents, such as acetone, methyl ethyl
ketone, and tetrahydrochloride, often in closed quarters. Evidence that
exposure to such solvents may influence smell ability ranges from selfreported disturbances of smell function in floor-layer workers exposed to
high levels of toluene to sophisticated case-control studies of long-term
exposure to solvents in manufacturing plants. Becauseof their lipophilicity, solvents can readily cross the nasal mucosa and penetrate underlying
cellular membranes. Such agents can also enter the bloodstream through
the nasal capillaries and can cross the blood-brain barrier, producing in
extreme cases(e.g.,in chronic glue sniffers), atrophy of central brain structures (e.g.,frontal lobes, cerebellum).52
Ahlstrom et a13found that fuel oil tank cleaners exhibit higher detection thresholds for n-butanol and fuel oil vapors than controls, whereas
this was not the case for pyridine and dimethyl disulfide. The elevated
thresholds, however, did not fall outside of the normal range. The authors
noted, for all stimuli evaluated, that the workers exhibited relatively normal perception of strong stimuli, but impaired perception of weak stimuli.
The largest decrement was found for detection of fuel oil vapor. This observation is in accord with the concept of "industrial anosmia," where
exposure to strong odors in the workplace results in a reduction in sensitivity that is confined to those particular odors. Such effects may reflect
long-term adaptation because,unlike the effects resulting from exposure
to toxic metals, they are typically reversible, disappearing after a worker
is removed for a period from the exposure area.
Schwartz et a199
evaluated the effects of chronic, low-level solvent exposure on olfactory function in 187 workers at a paint formulation plant.
As in their lead exposure research,industrial hygiene sampling data and
detailed occupational history data from personnel records were used. A
significant dose-related adverse effect of solvent exposure on UPSIT scores
was documented, but only in never-smokers.
Recently, Mergler and Beauvais7°examined detection thresholds for
toluene and phenyl ethyl methyl ethyl carbinol in five volunteers who
were experimentally exposed for seven-hour periods to either toluene,
xylene, or a mixture of thesetwo agents in an order counterbalanced using
Latin squares. A sixfold shift in the detection threshold for toluene was
found immediately after exposure to toluene, xylene, or their mixture. No
differences were found in phenyl ethyl methyl ethyl carbinol thresholds
after exposure to any of the compounds. Becausethe alterations in olfactory
function were reversi~le, the shift in detection threshold is again likely
NEUROTOXIC EXPOSURE AND OLFACTORY IMPAIRMENT
563
causedby odor adaptation, rather than by direct toxic insult to the olfactory
receptor neurons.
In contrast to the aforementioned studies, Sandmark et a194
found no
long-term influences of solvent exposure on smell function in a group of
54 painters exposed to organic solvents relative to 42 unexposed controls.
When the confounding influences of age and smoking habits were controlled for, no differences in UPSIT or pyridine threshold test scoreswere
noted between the two groups. The lack of an effect was attributed to the
low-to-moderate degree of exposure to the solvents.
Irritant
Gases
Numerous empirical studies report olfactory deficits after accidental
exposure to high concentrations of irritant gases.Such irritants as ozone
and formaldehyde are common components of both indoor and outdoor
pollution, combustion products in tobacco smoke, and exhaust from automobile and other internal combustion engines.Although chronic exposure
to low levels of irritative airborne contaminants occur in a number of neighborhoods and workplaces, it does not necessarily follow that nasal irritation, per se, translates into loss of olfactory function. Indeed, some nasal
irritants have no clear smell. Nonetheless, one would expect an association
between an odorant's irritative properties and its propensity to alter smell
function if continued irritation of the mucosa leads to necrosis and other
problems. Furthermore, a large animal literature (mainly rodent) supports
the idea that chronic exposure to several irritants can, at higher concentrations, damage the olfactory epithelia.
Formaldehyde, an ubiquitous and highly reactive gas, is used in a
variety of manufacturing processesand in biology classes,hospital and
university histology departments, mortuaries, and other situations where
preservation or fixing of tissue is required. This gas is absorbed mainly in
the nose. Although exposure to formaldehyde is often alleged to decrease
olfactory acuity!03 only two human studies have reported an adverse effect of this agent on the ability to smell. In the first, workers exposed to
0.075 to 0.750 ppm formaldehyde (alone or in combination with wood
dust) showed a slight but significant elevation in detection thresholds (serial dilutions of pyridine) when compared to controls (14.2vs 15.6).5In the
second, a questionnaire administered to histology technicians regularly
exposed to 0.200 to 1.900ppm formaldehyde revealed that 68% reported
decreasedodor perception. Only 9% of the control group did SO.60
In the most extensive systematic investigation of toxic chemicals
on the human ability to smell to date, Schwartz et al98administered the
UPSIT to 731 chemical workers exposed to acrylic acid and a variety of
acrylates and methacryl~tes at levels typically below their threshold limit
564
DOTY
& HASTINGS
values. Although analysis of the cross-sectional data revealed no relationship between chemical exposure and olfactory deficits, a nested casecontrol study designed to examine cumulative effects of exposure uncovered several associations: (1) olfactory function decreasedwith increased
cumulative exposure; (2) the effects appeared to be reversible; and (3) the
highest relative risk of olfactory dysfunction occurred in workers who had
never smoked. The similarity of the latter phenomenon to that found in the
previously mentioned solvent study illustrates how ancillary factors can
determine the expression of the olfactory toxicity of some compounds.
Recently,Dalton et a12°investigated whether occupational exposure to
styrene altered smell function. Exposure histories were reconstructed using
industrial hygiene data, and the workers were tested using a battery of olfactory tests,including tests of odor identification ability, detection threshold sensitivity to phenyl ethyl alcohol and styrene, and retronasal odor perception. No significant differences were found between exposed workers
and matched controls on any of the tests,except for the styrene thresholds,
which were significantly elevated in the workers. The latter phenomenon
was interpreted as being caused by exposure-induced adaptation.
Workplace exposure to several irritants that are major components
of air pollution has also been associated with loss of olfactory function.
Harada et aP9reported that exposure to sulfur dioxide and ammonia produced an elevation in odor detection thresholds for five substancesthat
were evaluated. Several of these workers complained of olfactory dysfunction. Similarly, repeated exposure of human volunteers to 0.4 ppb of
ozone for four hours per day for four days produced initial elevations in
detection thresholds to butanol that returned to normal soon after cessation
of the exposure.85
CHEMICAL EXPOSURE AND THE MULTIPLE
CHEMICAL SENSITIVITY SYNDROME
There are proponents of the notion that a wide variety of somatic
symptoms, including hypersensitivity to odors, depression, anxiety, fatigue, general malaise, mental confusion, lightheadedness, headache, insomnia, myalgia, loss of appetite, and numbness, can be elicited by single
or multiple exposures to extremely low concentrations of several common household or industrial chemicals. Such symptoms occur without
documentable signs of medical disease.92
This unorthodox complex of apparent chemically induced symptoms was first termed "environmental
illness" or "chemical reactivity" by Randolph in the 1960s.86
Cullen19subsequently termed this complex of chemically induced symptoms multiple chemical sensitivities (MCs) and developed an operational case definition of the disorder.1~Cullen confined the definition to a subgroup of
NEUROTOXIC
EXPOSURE
AND
OLFACTORY
IMPAIRMENT
565
"environmentally sensitive" patients and set seven criteria for its definition: (1) some documentable environmental exposure(s), illness(es) or insult(s) were coincident with the onset of the problem; (2) the symptoms are
associatedwith more than one organ system; (3) the symptoms recur and
abate in response to predictable stimuli; (4) the symptoms are elicited by
chemicals of diverse classesand toxicologic modes of action; (5) the symptoms are elicited by exposures that are demonstrable (albeit of low level);
(6) the symptoms cannot be explained by a single, widely available test
of organ system function; and (7) exposures that elicit symptoms are very
low-"(i.e., many standard deviations below "average" exposuresknown
to cause adverse human response. ..generally lower than 1% of the established threshold limit values for toxicity)." Some of the agents that
have been reported to induce these symptoms include perfumes, drugs,
organic solvents, combustion exhausts, soaps, insecticides, preservatives,
cigarette smoke, fragrances, perfumes, and colognes.
Although not all patients with the putative MCS syndrome report
heightened smell sensitivity, enough have done so to catalyze two empirical studies on this topic. In both cases,no evidence of altered odor detection
threshold sensitivity was found. In the first, the detection threshold values
of 18 patients with putative MCS did not differ significantly from those
of matched controls for the solvent methyl ethyl ketone and the rose-like
smelling agent phenyl ethyl alcohol.27In the second, detection thresholds
of 23 MCS subjectsand 23 controls to phenyl ethyl alcohol also did not differ from one another.54Paradoxically, in the latter study, the MCS subjects
were inferior to normal controls in identifying and discriminating among
suprathreshold odors and exhibited smaller odor-induced event-related
potentials. Assuming the validity of these findings, this study implies that
the suprathreshold olfactory function of MCS patients is decreased,not
increased.
MECHANISMS
OF
TOXIN-INDUCED
OLFACTORY
LOSS
It should be noted that many chemicals potentially damaging to the
olfactory system activate intranasal protective reflexes,mainly through the
trigeminal nerve, that minimize their penetration into the nasal passages.**
**It is noteworthy that the reflexive depression in respiratory rate induced by exposure
to a sensory irritant (which is mainly caused by stimulation of intranasal or pharyngeal
trigeminal afferents) has been used extensively in the establishment of the OSHA Permissible
Exposure Limit (PELs)and the American Conference of Governmental Industrial Hygienist's
(ACGIH) Threshold Limit Values (TLVs). Indeed, exposure limits for approximately one
third of the compounds regulated by OSHA have been based, at least in part, on their irritant
properties. For a new irritative compound, the concentration at which it depressesrespiratory
rate by 50% is typically first established (RDso).A value of 0.03 X RDsois then calculated; for
many compounds, this value has been found to be very close to the established TLV.
566
OOTY
& HASnNGS
Such reflexive mechanismsinclude rejection responses(e.g.,sneezing,halting of inhalation}, increased engorgement of the erectile tissue in the nasal
passages,and increased mucus secretion. Unfortunately, although such
mechanisms reduce exposure to irritating chemicals to some degree, they
do not always protect the olfactory system from inhaled chemicals, particularly ones that do not active trigeminal nerve afferents or are present on
a chronic basis.
Animal studies suggest that the primary means by which chemicals
alter olfactory function is by direct interaction with the olfactory epithelium, where they damage the olfactory receptors and associated cells.
Agents such as dimethylamine and 3-methylfuran damage the epithelium
indirectly by producing metabolic byproducts that, in turn, damage the
mucosa}2 The speed by which restoration occurs after the sloughing off of
the epithelium depends on the concentration and speciesof the chemicals
involved. For some substances,restoration occurs in a few weeks, whereas
for others it can take months. In general, the degree of reconstitution depends on the degree of insult; poor reconstitution is expected when the
lamina propria and Bowman's glands become heavily damaged.l°B
As shown in Table 2, a variety of exogenous agents damage the olfactory membrane of rodents. Unfortunately, the degree to which such
data generalize to humans is not known. Although olfactory epithelial
tissue can be obtained in living humans via endoscopic spot biopsy, there
are sampling issues involved, and no such study has been performed in
toxin-exposed human populations. Furthermore, no cadaver study has
yet been performed in such groups. Rodents, in addition to being obligate nose breathers, possessmaxillary turbinates and an additional row
of ethmoidal turbinates, resulting in a more complex distribution of airflow patterns and nasal absorption distribution of chemicals than seen in
humans.
The limited data available suggestthat the rodent olfactory epithelium
may be more resilient than the human olfactory epithelium to toxic damage
from some agents,perhaps reflecting differences in xenobiotic metabolism.
In one study, for example, adult male rats were exposed to relatively high
levels of airborne cadmium (0.500mg/m3} for 20 weeks.l0SUnlike the situation with humans, no evidence of pathologic alterations of either the
olfactory or nasal respiratory epithelia was present, and behavioral tests
were unable to document any cadmium-related adverse effect on detection
threshold sensitivity. This is in spite of the fact that lung and cardiac toxicity were found. Although similar rodent studies (using nickel and
chromium} have found nickel-related damage to the olfactory epithelium,
behavioral deficits were not observed.39
The nasal and olfactory mucosa possess several chemical defense
mechanisms in addition to those mentioned to thwart invasion of
NEUROTOXIC
EXPOSURE
AND
OLFACTORY
IMPAIRMENT
567
xenobiotic and pathogenic agents.For example, they are capable of secreting antibodies and antimicrobial proteins, such aslactoferrin and lysozyme
to deal with inhaled pathogens.69The nasal passagesare also protected by
the presenceof phase I and phase II enzymes (i.e., cytochrome P-450s,glutathione, and related enzymes) found in concentrations that can be greater
on a per gram basis than in the liver or lungs.88The source of such agentsin
the olfactory epithelium is the supporting cells and the Bowman's glands,
ensuring their presencein the mucus of the region. In some cases,chronic
exposure to low dosesof toxic compounds induces an enzymatic metabolic
protective status so that subsequent higher exposures produce little or no
toxicity.
Some olfactory toxicants produce acute or chronic inflammation that,
in addition to limiting airflow to the olfactory region or inducing metabolic
toxins in the epithelium, can ultimately damage the epithelium. Such inflammation can also decreaseupper airway immunoglobulin A, thereby
allowing for colonization of the olfactory mucosa with pathologic bacteria
that can have adverse effects on the mucosa. In rare cases,volatile chemicals can increase mucosal cellular proliferation that can lead to neoplastic
processesthat themselves can alter the ability to smell. Increased prevalence of nasal and sinus carcinomas have been noted in workers exposed
to nickel dust, ionizing radiation, wood dust, formaldehyde, and leather
dust.64
Toxic effects of airborne chemicals on the olfactory neuroepithelium can result from the synergism of several factors. For example, because of weakened defense mechanisms, concurrent exposure to a toxic
compound during an upper respiratory infection may result in much
greater damage than exposure to either alone.48,89
Conversely, cigarette
smoking may protect against solvent-induced olfactory deficits of
chemical workers.2,98Estrogens and some other hormones may mitigate
olfactory epithelial damage produced by neurotoxins such as 3-methyl
indole.Z2
Attempts to ameliorate the dysfunction resulting from exposure to
toxic compounds are limited. In some instances, inhibition of enzymatic
pathways that produce toxins can eliminate the damaging effects of such
chemicals as dimethylamine and 3-methylfuran.88Topical steroids, which
are routinely used for alleviation of rhinitis and polyposis, may do more
than to simply increaseairway patency by shrinking inflamed tissue. Thus,
they may hasten the reconstitution of the olfactory epithelium after insult,61
although large doses may have an adverse effect.62As we increase our
understanding of the factors that regulate neurogenesis and apoptosis in
the olfactory epithelium, and of the factors involved in the guidance of
axonal propagation through the cribriform plate, new therapeutic avenues
will undoubtedly present themselves.
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DOTY
& HASTINGS
CONCLUSIONS
Although the bulk of evidence suggests that toxic chemicals influence human olfactory function by damaging the olfactory neuroepithelium, there is a dearth of information as to of whether solvents and other
agents adversely influence central olfactory structures. Clearly, studies of
the toxic effects of airborne agents on the human olfactory system are still
in their infancy, and no human biopsy or cadaver studies of even the olfactory epithelium of chemically exposedhumans have been made. Although,
at face value, the available data suggest that most industrial chemicals
do not damage the olfactory membrane at concentrations below current
threshold limit values,98few epidemiologic studies on this point have been
performed, and longitudinal data are completely lacking. As noted at the
beginning of this article, the olfactory epithelium undergoes metaplastic
changes throughout life, and the degree to which exposure to even low
levels of airborne toxins contributes to such changes is not known. Future studies are needed to establish how generalizable rodent data are to
the human condition and whether the human olfactory system is, in fact,
cumulatively damaged by intermittent exposure to environmental toxic
chemicals.
ACKNOWLEDGMENT
Supported, in part, by Grants POI DC 00161,ROl DC 04278,ROl DC 02974,and ROl
AG 27496from the National Institutes of Health, Bethesda,MD (RLD).
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Address reprint requests to
University
Richard L. Doty, PhD
Smell & Taste Center
of Pennsylvania Medical Center
Philadelphia, PA 19104-4283