Three sensory systems are uniquely constructed to monitor contact with environmental substances: olfaction (smell), taste (sweet, salty, sour, and bitter perception), and the common chemical sense (detection of irritation or pungency). Because they require stimulation by chemicals, they are termed “chemosensory” systems. Olfactory disorders consist of temporary or permanent: complete or partial smell loss (anosmia or hyposmia) and parosmias (perverted smells dysosmia or phantom smells phantosmia) (Mott and Leopold 1991; Mott, Grushka and Sessle 1993). After chemical exposures, some individuals describe a heightened sensitivity to chemical stimuli (hyperosmia). Flavour is the sensory experience generated by the interaction of the smell, taste and irritating components of food and beverages, as well as texture and temperature. Because most flavour is derived from the smell, or aroma, of ingestants, damage to the smell system is often reported as a problem with “taste”.

Chemosensory complaints are frequent in occupational settings and may result from a normal sensory system’s perceiving environmental chemicals. Conversely, they may also indicate an injured system: requisite contact with chemical substances renders these sensory systems uniquely vulnerable to damage. In the occupational setting, these systems can also be damaged by trauma to the head and agents other than chemicals (e.g., radiation). Pollutant-related environmental odours can exacerbate underlying medical conditions (e.g., asthma, rhinitis), precipitate development of odour aversions, or cause a stress-related type of illness. Malodors have been demonstrated to decrease complex task performance (Shusterman 1992).

Early identification of workers with olfactory loss is essential. Certain occupations, such as the culinary arts, wine making and the perfume industry, require a good sense of smell as a prerequisite. Many other occupations require normal olfaction for either good job performance or self-protection. For example, parents or day care workers generally rely on smell to determine children’s hygiene needs. Firefighters need to detect chemicals and smoke. Any worker with ongoing exposure to chemicals is at increased risk if olfactory ability is poor.

Olfaction provides an early warning system to many harmful environmental substances. Once this ability is lost, workers may not be aware of dangerous exposures until the concentration of the agent is high enough to be irritating, damaging to respiratory tissues or lethal. Prompt detection can prevent further olfactory damage through treatment of inflammation and reduction of subsequent exposure. Lastly, if loss is permanent and severe, it may be considered a disability requiring new job training and/or compensation.

Anatomy and Physiology

Olfaction

The primary olfactory receptors are located in patches of tissue, termed olfactory neuroepithelium, at the most superior portion of the nasal cavities (Mott and Leopold 1991). Unlike other sensory systems, the receptor is the nerve. One portion of an olfactory receptor cell is sent to the surface of the nasal lining, and the other end connects directly via a long axon to one of two olfactory bulbs in the brain. From here, the information travels to many other areas of the brain. Odorants are volatile chemicals that must contact the olfactory receptor for smell perception to occur. Odorant molecules are trapped by and then diffuse through mucus to attach to cilia at the ends of the olfactory receptor cells. It is not yet known how we are able to detect more than ten thousand odorants, discriminate from as many as 5,000, and judge varying odorant intensities. Recently, a multigene family was discovered that codes for odorant receptors on primary olfactory nerves (Ressler, Sullivan and Buck 1994). This has allowed investigation of how odours are detected and how the smell system is organized. Each neuron may respond broadly to high concentrations of a variety of odorants, but will respond to only one or a few odorants at low concentrations. Once stimulated, surface receptor proteins activate intracellular processes that translate sensory information into an electrical signal (transduction). It is not known what terminates the sensory signal despite continued odorant exposure. Soluble odorant binding proteins have been found, but their role is undetermined. Proteins that metabolize odorants may be involved or carrier proteins may transport odorants either away from the olfactory cilia or toward a catalytic site within the olfactory cells.

The portions of the olfactory receptors connecting directly to the brain are fine nerve filaments that travel through a plate of bone. The location and delicate structure of these filaments render them vulnerable to shear injury from blows to the head. Also, because the olfactory receptor is a nerve, physically contacts odorants, and connects directly to the brain, substances entering the olfactory cells can travel along the axon into the brain. Because of continued exposure to agents damaging to the olfactory receptor cells, olfactory ability might be lost early in the lifespan if it were not for a critical attribute: olfactory receptor nerves are capable of regeneration and may be replaced, provided the tissue has not been completely destroyed. If the damage to the system is more centrally located, however, the nerves can not be restored.

Common chemical sense

The common chemical sense is initiated by stimulation of mucosal, multiple, free nerve endings of the fifth (trigeminal) cranial nerve. It perceives the irritating properties of inhaled substances and triggers reflexes designed to limit exposure to dangerous agents: sneezing, mucus secretion, reduction of breathing rate or even breath-holding. Strong warning cues compel removal from the irritation as soon as possible. Although the pungency of substances vary, generally the odour of the substance is detected before irritation becomes apparent (Ruth 1986). Once irritation is detected, however, small increases in concentration enhance irritation more than odorant appreciation. Pungency may be evoked through either physical or chemical interactions with receptors (Cometto-Muñiz and Cain 1991). The warning properties of gases or vapours tend to correlate with their water solubilities (Shusterman 1992). Anosmics appear to require higher concentrations of pungent chemicals for detection (Cometto-Muñiz and Cain 1994), but thresholds of detection are not elevated as one ages (Stevens and Cain 1986).

Tolerance and adaptation

Perception of chemicals can be altered by previous encounters. Tolerance develops when exposure reduces the response to subsequent exposures. Adaptation occurs when a constant or rapidly repeated stimulus elicits a diminishing response. For example, short-term solvent exposure markedly, but temporarily, reduces solvent detection ability (Gagnon, Mergler and Lapare 1994). Adaptation can also occur when there has been prolonged exposure at low concentrations or rapidly, with some chemicals, when extremely high concentrations are present. The latter can lead to rapid and reversible olfactory “paralysis”. Nasal pungency typically shows less adaptation and development of tolerance than olfactory sensations. Mixtures of chemicals can also alter perceived intensities. Generally, when odorants are mixed, perceived odorant intensity is less than would be expected from adding the two intensities together (hypoadditivity). Nasal pungency, however, generally shows additivity with exposure to multiple chemicals, and summation of irritation over time (Cometto-Muñiz and Cain 1994). With odorants and irritants in the same mixture, the odour is always perceived as less intense. Because of tolerance, adaptation, and hypoadditivity, one must be careful to avoid relying on these sensory systems to gauge the concentration of chemicals in the environment.

Olfactory Disorders

General concepts

Olfaction is disrupted when odorants can not reach olfactory receptors, or when olfactory tissue is damaged. Swelling within the nose from rhinitis, sinusitis or polyps can preclude odorant accessibility. Damage can occur with: inflammation in the nasal cavities; destruction of the olfactory neuroepithelium by various agents; trauma to the head; and transmittal of agents via the olfactory nerves to the brain with subsequent injury to the smell portion of the central nervous system. Occupational settings contain varying amounts of potentially damaging agents and conditions (Amoore 1986; Cometto-Muñiz and Cain 1991; Shusterman 1992; Schiffman and Nagle 1992). Recently published data from 712,000 National Geographic Smell Survey respondents suggests that factory work impairs smell; male and female factory workers reported poorer senses of smell and demonstrated decreased olfaction on testing (Corwin, Loury and Gilbert 1995). Specifically, chemical exposures and head trauma were more frequently reported than by workers in other occupational settings.

When an occupational olfactory disorder is suspected, identification of the offending agent can be difficult. Current knowledge is largely derived from small series and case reports. It is of importance that few studies mention examination of the nose and sinuses. Most rely on patient history for olfactory status, rather than testing of the olfactory system. An additional complicating factor is the high prevalence of non-occupationally related olfactory disturbances in the general population, mostly due to viral infections, allergies, nasal polyps, sinusitis or head trauma. Some of these, however, are also more common in the work environment and will be discussed in detail here.

Rhinitis, sinusitis and polyposis

Individuals with olfactory disturbance must first be assessed for rhinitis, nasal polyps and sinusitis. It is estimated that 20% of the United States population, for example, has upper airway allergies. Environmental exposures can be unrelated, cause inflammation or exacerbate an underlying disorder. Rhinitis is associated with olfactory loss in occupational settings (Welch, Birchall and Stafford 1995). Some chemicals, such as isocyanates, acid anhydrides, platinum salts and reactive dyes (Coleman, Holliday and Dearman 1994), and metals (Nemery 1990) can be allergenic. There is also considerable evidence that chemicals and particles increase sensitivity to nonchemical allergens (Rusznak, Devalia and Davies 1994). Toxic agents alter the permeability of the nasal mucosa and allow greater penetration of allergens and enhanced symptoms, making it difficult to discriminate between rhinitis due to allergies and that due to exposure to toxic or particulate substances. If inflammation and/or obstruction in the nose or sinuses is demonstrated, return of normal olfactory function is possible with treatment. Options include topical corticosteroid sprays, systemic antihistamines and decongestants, antibiotics and polypectomy/sinus surgery. If inflammation or obstruction is not present or treatment does not secure improvement in olfactory function, olfactory tissue may have sustained permanent damage. Irrespective of cause, the individual must be protected from future contact with the offending substance or further injury to the olfactory system could occur.

Head trauma

Head trauma can alter olfaction through (1) nasal injury with scarring of the olfactory neuroepithelium, (2) nasal injury with mechanical obstruction to odours, (3) shearing of the olfactory filaments, and (4) bruising or destruction of the part of the brain responsible for smell sensations (Mott and Leopold 1991). Although trauma is a risk in many occupational settings (Corwin, Loury and Gilbert 1995), exposure to certain chemicals can increase this risk.

Smell loss occurs in 5% to 30% of head trauma patients and may ensue without any other nervous system abnormalities. Nasal obstruction to odorants may be surgically correctable, unless significant intranasal scarring has occurred. Otherwise, no treatment is available for smell disorders resulting from head trauma, although spontaneous improvement is possible. Rapid initial improvement may occur as swelling subsides in the area of injury. If olfactory filaments have been sheared, regrowth and gradual improvement of smell may also occur. Although this occurs in animals within 60 days, improvements in humans have been reported as long as seven years after injury. Parosmias developing as the patient recovers from injury may indicate regrowth of olfactory tissue and herald return of some normal smell function. Parosmias occurring at the time of injury or shortly thereafter are more likely due to brain tissue damage. Damage to the brain will not repair itself and improvement in smell ability would not be expected. Injury to the frontal lobe, the portion of the brain integral to emotion and thinking, may be more frequent in head trauma patients with smell loss. The resultant changes in socialization or thinking patterns may be subtle, though harmful to family and career. Formal neuropsychiatric testing and treatment may, therefore, be indicated in some patients.

Environmental agents

Environmental agents can gain access to the olfactory system through either the bloodstream or inspired air and have been reported to cause smell loss, parosmia and hyperosmia. Responsible agents include metallic compounds, metal dusts, nonmetallic inorganic compounds, organic compounds, wood dusts and substances present in various occupational environments, such as metallurgical and manufacturing processes (Amoore 1986; Schiffman and Nagle 1992 (table 1). Injury can occur both after acute and chronic exposures and can be either reversible or irreversible, depending on the interaction between host susceptibility and the damaging agent. Important substance attributes include bioactivity, concentration, irritant capacity, length of exposure, rate of clearance and potential synergism with other chemicals. Host susceptibility varies with genetic background and age. There are gender differences in olfaction, hormonal modulation of odorant metabolism and differences in specific anosmias. Tobacco use, allergies, asthma, nutritional status, pre-existing disease (e.g., Sjogren’s syndrome), physical exertion at time of exposure, nasal airflow patterns and possibly psychosocial factors influence individual differences (Brooks 1994). Resistance of the peripheral tissue to injury and presence of functioning olfactory nerves can alter susceptibility. For example, acute, severe exposure could decimate the olfactory neuroepithelium, effectively preventing spread of the toxin centrally. Conversely, long-term, low-level exposure might allow preservation of functioning peripheral tissue and slow, but steady-transit of damaging substances into the brain. Cadmium, for example, has a half-life of 15 to 30 years in humans, and its effects might not be apparent until years after exposure (Hastings 1990).

Table 1. Agents/processes associated with olfactory abnormalities

H = hyposmia; A = anosmia; P = parosmia; ID = odour identification ability

1 = Mott and Leopold 1991. 2 = Amoore 1986. 3 = Schiffman and Nagle 1992. 4 = Naus 1985. 5 = Callendar et al. 1993.

Specific smell disturbances are as stated in the articles referenced.

Nasal passages are ventilated by 10,000 to 20,000 litres of air per day, containing varying amounts of potentially harmful agents. The upper airways almost totally absorb or clear highly reactive or soluble gases, and particles larger than 2 mm (Evans and Hastings 1992). Fortunately, a number of mechanisms exist to protect tissue damage. Nasal tissues are enriched with blood vessels, nerves, specialized cells with cilia capable of synchronous movement, and mucus-producing glands. Defensive functions include filtration and clearing of particles, scrubbing of water soluble gases, and early identification of harmful agents through olfaction and mucosal detection of irritants that can initiate an alarm and removal of the individual from further exposure (Witek 1993). Low levels of chemicals are absorbed by the mucus layer, swept away by functioning cilia (mucociliary clearance) and swallowed. Chemicals can bind to proteins or be rapidly metabolized to less damaging products. Many metabolizing enzymes reside in the nasal mucosa and olfactory tissues (Bonnefoi, Monticello and Morgan 1991; Schiffman and Nagle 1992; Evans et al. 1995). Olfactory neuroepithelium, for example, contains cytochrome P-450 enzymes which play a major role in the detoxification of foreign substances (Gresham, Molgaard and Smith 1993). This system may protect the primary olfactory cells and also detoxify substances that would otherwise enter the central nervous system through olfactory nerves. There is also some evidence that intact olfactory neuroepithelium can prevent invasion by some organisms (e.g., cryptococcus; see Lima and Vital 1994). At the level of the olfactory bulb, there may also be protective mechanisms preventing transport of toxic substances centrally. For example, it has been recently shown that the olfactory bulb contains metallothioneins, proteins which have a protective effect against toxins (Choudhuri et al. 1995).

Exceeding protective capacities can precipitate a worsening cycle of injury. For example, loss of olfactory ability halts early warning of the hazard and allows continued exposure. Increase in nasal blood flow and blood vessel permeability causes swelling and odorant obstruction. Cilial function, necessary for both mucociliary clearance and normal smell, may be impaired. Change in clearance will increase contact time between injurious agents and nasal mucosa. Intranasal mucus abnormalities alter absorption of odorants or irritant molecules. Overpowering the ability to metabolize toxins allows tissue damage, increased absorption of toxins, and possibly enhanced systemic toxicity. Damaged epithelial tissue is more vulnerable to subsequent exposures. There are also more direct effects on olfactory receptors. Toxins can alter the turnover rate of olfactory receptor cells (normally 30 to 60 days), injure receptor cell membrane lipids, or change the internal or external environment of the receptor cells. Although regeneration can occur, damaged olfactory tissue can exhibit permanent changes of atrophy or replacement of olfactory tissue with nonsensory tissue.

The olfactory nerves provide a direct connection to the central nervous system and may serve as a route of entry for a variety of exogenous substances, including viruses, solvents and some metals (Evans and Hastings 1992). This mechanism may contribute to some of the olfactory-related dementias (Monteagudo, Cassidy and Folb 1989; Bonnefoi, Monticello and Morgan 1991) through, for example, transmittal of aluminium centrally. Intranasally, but not intraperitoneally or intracheally, applied cadmium can be detected in the ipsilateral olfactory bulb (Evans and Hastings 1992). There is further evidence that substances may be preferentially taken up by olfactory tissue irrespective of the site of initial exposure (e.g., systemic versus inhalation). Mercury, for example, has been found in high concentrations in the olfactory brain region in subjects with dental amalgams (Siblerud 1990). On electroencephalography, the olfactory bulb demonstrates sensitivity to many atmospheric pollutants, such as acetone, benzene, ammonia, formaldehyde and ozone (Bokina et al. 1976). Because of central nervous system effects of some hydrocarbon solvents, exposed individuals might not readily recognize and distance themselves from the danger, thereby prolonging exposure. Recently, Callender and colleagues (1993) obtained a 94% frequency of abnormal SPECT scans, which assess regional cerebral blood flow, in subjects with neurotoxin exposures and a high frequency of olfactory identification disorders. The location of abnormalities on SPECT scanning was consistent with distribution of toxin through olfactory pathways.

The site of injury within the olfactory system differs with various agents (Cometto-Muñiz and Cain 1991). For example, ethyl acrylate and nitroethane selectively damage olfactory tissue while the respiratory tissue within the nose is preserved (Miller et al. 1985). Formaldehyde alters the consistency, and sulphuric acid the pH of nasal mucus. Many gases, cadmium salts, dimethylamine and cigarette smoke alter ciliary function. Diethyl ether causes leakage of some molecules from the junctions between cells (Schiffman and Nagle 1992). Solvents, such as toluene, styrene and xylene change olfactory cilia; they also appear to be transmitted into the brain by the olfactory receptor (Hotz et al. 1992). Hydrogen sulphide is not only irritating to mucosa, but highly neurotoxic, effectively depriving cells of oxygen, and inducing rapid olfactory nerve paralysis (Guidotti 1994). Nickel directly damages cell membranes and also interferes with protective enzymes (Evans et al. 1995). Dissolved copper is thought to directly interfere with different stages of transduction at the olfactory receptor level (Winberg et al. 1992). Mercuric chloride selectively distributes to olfactory tissue, and may interfere with neuronal function through alteration of neurotransmitter levels (Lakshmana, Desiraju and Raju 1993). After injection into the bloodstream, pesticides are taken up by nasal mucosa (Brittebo, Hogman and Brandt 1987), and can cause nasal congestion. The garlic odour noted with organophosphorus pesticides is not due to damaged tissue, but to detection of butylmercaptan, however.

Although smoking can inflame the lining of the nose and reduce smell ability, it may also confer protection from other damaging agents. Chemicals within the smoke may induce microsomal cytochrome P450 enzyme systems (Gresham, Molgaard and Smith 1993), which would accelerate metabolism of toxic chemicals before they can injure the olfactory neuroepithelium. Conversely, some drugs, for example tricyclic antidepressants and antimalarial drugs, can inhibit cytochrome P450.

Olfactory loss after exposure to wood and fibre board dusts (Innocenti et al. 1985; Holmström, Rosén and Wilhelmsson 1991; Mott and Leopold 1991) may be due to diverse mechanisms. Allergic and nonallergic rhinitis can result in obstruction to odorants or inflammation. Mucosal changes can be severe, dysplasia has been documented (Boysen and Solberg 1982) and adenocarcinoma may result, especially in the area of the ethmoid sinuses near the olfactory neuroepithelium. Carcinoma associated with hard woods may be related to a high tannin content (Innocenti et al. 1985). Inability to effectively clear nasal mucus has been reported and may be related to an increased frequency of colds (Andersen, Andersen and Solgaard 1977); resultant viral infection could further damage the olfactory system. Olfactory loss may also be due to chemicals associated with woodworking, including varnishes and stains. Medium-density fibre board contains formaldehyde, a known respiratory tissue irritant that impairs mucociliary clearance, causes olfactory loss, and is associated with a high incidence of oral, nasal and pharyngeal cancer (Council on Scientific Affairs 1989), all of which could contribute to an understanding of formaldehyde-induced olfactory losses.

Radiation therapy has been reported to cause olfactory abnormalities (Mott and Leopold 1991), but little information is available about occupational exposures. Rapidly regenerating tissue, such as olfactory receptor cells, would be expected to be vulnerable. Mice exposed to radiation in a spaceflight demonstrated smell tissue abnormalities, while the rest of the nasal lining remained normal (Schiffman and Nagle 1992).

After chemical exposures, some individuals describe a heightened sensitivity to odorants. “Multiple chemical sensitivities” or “environmental illness” are labels used to describe disorders typified by “hypersensitivity” to diverse environmental chemicals, often in low concentrations (Cullen 1987; Miller 1992; Bell 1994). Thus far, however, lower thresholds to odorants have not been demonstrated.

Non-occupational causes of olfactory problems

Ageing and smoking decrease olfactory ability. Upper respiratory viral damage, idiopathic (“unknown”), head trauma, and diseases of the nose and sinuses appear to be the four leading causes of smell problems in the United States (Mott and Leopold 1991) and must be considered as part of the differential diagnosis in any individual presenting with possible environmental exposures. Congenital inabilities to detect certain substances are common. For example, 40 to 50% of the population can not detect androsterone, a steroid found in sweat.

Testing of chemosensation

Psychophysics is the measurement of a response to an applied sensory stimulus. “Threshold” tests, tests that determine the minimum concentration that can be reliably perceived, are frequently used. Separate thresholds can be obtained for detection of odorants and identification of odorants. Suprathreshold tests assess ability of the system to function at levels above threshold and also provide useful information. Discrimination tasks, telling the difference between substances, can elicit subtle changes in sensory ability. Identification tasks may yield different results than threshold tasks in the same individual. For example, a person with central nervous system injury may be able to detect odorants at usual threshold levels, but may not be able to identify common odorants.

Summary

The nasal passages are ventilated by 10,000 to 20,000 litres of air per day, which may be contaminated by possibly hazardous materials in varying degrees. The olfactory system is especially vulnerable to damage because of requisite direct contact with volatile chemicals for odorant perception. Olfactory loss, tolerance and adaptation prevent recognition of the proximity of dangerous chemicals and may contribute to local injury or systemic toxicity. Early identification of olfactory disorders can prompt protective strategies, ensure appropriate treatment and prevent further damage. Occupational smell disorders can manifest themselves as temporary or permanent anosmia or hyposmia, as well as distorted smell perception. Identifiable causes to be considered in the occupational setting include rhinitis, sinusitis, head trauma, radiation exposure and tissue injury from metallic compounds, metal dusts, nonmetallic inorganic compounds, organic compounds, wood dusts, and substances present in metallurgical and manufacturing processes. Substances differ in their site of interference with the olfactory system. Powerful mechanisms for trapping, removing and detoxifying foreign nasal substances serve to protect olfactory function and also prevent spread of damaging agents into the brain from the olfactory system. Exceeding protective capacities can precipitate a worsening cycle of injury, ultimately leading to greater severity of impairment and extension of sites of injury, and converting temporary reversible effects into permanent damage.

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