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Neuropsychological Toxicology

The following material is taken from:  Hartman, David.  Neuropsychological Toxicology:  Identification and Assessment of Human Neurotoxic Syndromes.  Second Edition. 1995.  Plenum Press:  New York.  ISBN 0-306-44922-6

Neuropsychological Toxicology

David Hartman

The influence of neurotoxic substances on behavior is the end product of biochemical, structural, and functional interactions on the human organism (Spencer, 1990b).

Injury to nervous system components may accumulate for months, or even years, and may not be apparent, except in the context of specialized neuropsychological or neurological tests, until it blossoms into a clinical syndrome many months or years later (Caine, 1991; Reuhl, 1991). Most of the evidence for neurotoxin-caused human neurodegenerative diseases is inferential, rather than direct causal, with inferences made from the observed similarity of certain neurotoxic effects to well-known degenerative diseases.

Spencer (1990a) suggests that three types of alterations in neural function are responsible for neurotoxic damage: (1) alterations of the excitable membrane, (2) interference with neurotransmitter systems, and (3) structural breakdown of the dendrite, perikaryon, or axon. For example, lead, thallium, and triethyltin may produce neurotoxic damage by interfering with or destroying the myelin sheath (Williams & Burson, 1985).

Anoxia (lack of oxygen) is a frequent mechanism of neurotoxic interference with normal cell operation, neurons are especially sensitive to oxygen deprivation and need as much as ten times the oxygen of nearby glial cells (Ruscak, Ruscakova, & Hager, 1968). Cell death can occur within minutes, either by decreasing the amount of oxygen carried in the blood, slowing the blood flow, or by blocking the utilization of oxygen. Norton (1986) described three types of anoxia resulting from neurotoxic exposure:

    •    Anoxic anoxia: from inadequate oxygen supply in the presence of adequate blood flow. Carbon monoxide poisoning is a common example, since oxygen is preferentially replaced in the hemoglobin molecule by unusable CO.
    •    Ischemic anoxia: any loss of oxygen caused by decrease in arterial blood flow. Any substance capable of causing hypotension or interfering with cardiac function may indirectly cause nervous system damage via ischemic anoxia. Cyanide's capability of causing hypotension is an example.
    •    Cytotoxic anoxia: the result of direct interference with cell metabolism while oxygen and blood supply remain normal. Cyanide is also a culprit in cytotoxic anoxia, causing damage to both gray and white matter. 

Each type of anoxia is capable of gradually increasing cellular damage, via loss of mitochondrial granules and edema. Cerebral edema, in turn, further worsens hypoxia (lack of oxygen) and results in accumulation of lactate, ammonia, and inorganic phosphates.

The propensity of many neurotoxic materials to be lipophilic ("fat-loving" or tending to accumulate in fatty tissues) puts the brain at special risk since lipids (fats) comprise 50% of the dry weight of the brain, compared with 6–20% of other body organs (Cooper, Bloom, & Roth, 1982). In addition, the unique structural properties of the nervous system make it especially vulnerable to neurotoxic insult.

Selective Vulnerability of the Nervous System to Neurotoxic Damage (Neurotoxicity, 1990):
1.    Unlike other cells, neurons normally cannot regenerate when lost; neurotoxic damage to the brain or spinal cord, therefore, is usually permanent.
 
2.    Nerve cell loss and other degenerative changes in the nervous system occur progressively in the second half of life and thus toxic damage may interact synergistically with aging effects.

3.    Many neurotoxic materials cross the blood–brain barrier.


4.    Certain regions of the brain and nerves are directly exposed to chemicals in the blood.


5.    The architecture of nerve cells, with their long axon processes, exposes vast amounts of surface area to toxic interference or degradation.


6.    The nervous system is highly dependent on a delicate electrochemical balance for proper communication. Any chemical capable of disrupting this balance can disrupt nervous system function.


7.    Neurological, behavior, and other body functions may be profoundly disrupted by impairment or damage to even minor areas of the nervous system.

Neurotoxic damage varies with substance and exposure, with disruptions capable of occurring at any point along the biochemical and structural apparatus of the cell. Some substances interfere with intracellular biochemistry, causing changes in cell acidity, protein synthesis, or fluid dynamics. Others appear to selectively damage myelinated axons, interfering with neurotransmission. Damage may occur at specific sites in the cell or to the overall cell structure.

•    Synaptic Damage from Neurotoxicants

In the synapse, degradation of neurotransmission can occur at any level of presynaptic process, including synthesis, storage, release, and termination of neurotransmitters (Atchison, 1989). 

Neurotoxicants may also affect the nerve on the receptor end of the synapse, including transmitter binding to the receptor cell, "activation of the receptor associated ionic channel, and degradation of chemical transmitter" (Atchison, 1989, p. 393). Lead has a direct effect on synaptic action by presynaptic block of the end-plate potential and may also interfere with enzyme inhibition at several sites (Goetz, 1985).

•    Cellular Damage from Neurotoxicants

Central Nervous System (CNS) and the Peripheral Nervous System (PNS)
structures appear to be differentially sensitive to toxic damage (O'Callaghan,1989).

Human studies, while not as detailed as animal studies, have, however, suggested the existence of similar cellular damage. For example, Rosenberg, Spitz, Filley, Davis, and Schaumberg (1988) performed magnetic resonance imaging (MRI) scans of 11 chronic toluene abusers. Three subjects had abnormal MRIs with "diffuse cerebral, cerebellar, and brainstem atrophy (shrinking)" that ranged in severity from mild to marked. Ventricular dilation was also seen, and other MRI findings suggested severe white matter damage. No improvement was observed on repeated MRI scans over an 18-month follow-up period, suggesting that toluene-induced physical injury to the brain may be irreversible.

Lead and mercury impair the functions of brain astrocytes (a star-shaped neuroglial cell) which control ionic and amino acid concentrations, brain energy metabolism, and cell volume (Ronnback & Hansson, 1992). Both lead and mercury have been shown to inhibit astroglial capacity to take up glutamate, causing secondary decrease in other neurotransmitters and corresponding increase in patient report of fatigue and loss of alertness (Rannback & Hansson, 1992).

Subcellular components are also differentially sensitive to neurotoxic damage. Nissl substance (concerned with protein synthesis and metabolism), a structure with high ribosome content, has been shown to be destroyed by methylmercury. The small numbers of ribosomes in cerebellar and cerebrocortical neurons may explain why those areas are so easily affected by mercury poisoning. Chronic heroin intoxication has also been shown to affect Nissl substance in primate studies (Hirano & Llena, 1980). This suggests that Nissl substance-damaging neurotoxicants may affect the cell's ability to synthesize protein and thus regenerate or repair itself. Other structures of the cell known to be differentially affected by neurotoxicants include mitochondria (LSD-25, heroin), neurofibrils (aluminum, colchicine, vinca alkaloids) and the synapse (glutamate, organic mercury) (Hirano & Llena, 1980).

Damage to various components of white matter have also been tied to specific neurotoxins, including acrylamide, alcohol, triethyltin, n-hexane,  methyl n-butyl ketone, 2,5-hexanedione, arsenic, carbon disulfide, and  tri-ortho-cresyl phosphate (Hirano & Llena, 1980). White matter is vulnerable to  a variety of neurotoxicity-related effects, including ischemia, with ensuing  demyelination or direct toxic injury to the underlying axon.

•    Neurochemical Damage from Neurotoxicants

A wide range of clinical syndromes are better understood by the damage they exert on neurochemical tracts than on structure in the way that neuropsychologists typically think of the term (e.g., lobes, sulci, hemisphere). Parkinson's disease is a case in point, both as an example of the interaction between neurochemistry, structural neuropathology, and neuropsychology, as well as for its possible role in chronic neurotoxic exposure.

Parkinson's disease is a clinical syndrome where dopaminergic neurons from the pigmented nuclei of the substantia nigra and locus coeruleus become selectively and severely damaged. These nuclei project to the striatum, the limbic system (nucleus accumbens, olfactory tubercle, and amygdala) as well as the frontal cortex (Cote & Crutcher, 1985). Among other symptoms, Parkinson's "profoundly disrupts" the motor act control mechanisms of the prefrontal cortex (Goldman-Rakic, 1987). Without understanding the cognitive neurochemistry of Parkinson's, the neuropsychologist is left to explain a diffuse and apparently unconnected set of deficits, including impaired voluntary movement, flattened affect, and eventual dementia. By linking Parkinson's to specific correlates of neurochemical lesion, however, the relationship of behavior to brain damage is far more consistent and interpretable.

Goldman-Rakic (1987) and others have argued that catecholamine impairments in dopamine and norepinephrine systems may explain a variety of behavioral disorders. In particular, the relationship between parkinsonism and neurotoxic exposure was made graphically and gruesomely clear with the discovery that an incorrectly distilled analogue of heroin (MPTP) produced "instant" and irreversible parkinsonism in drug abusers; in some individuals with a rapidity that left them "frozen" with the syringe still hanging from a vein. Manganese and other neurotoxic substances are also known to create parkinsonian states in exposed individuals, perhaps by the oxidation of dopamine that is in turn capable of producing injurious free radicals and quinones (Langston, 1988; Langston & Irwin, 1986). 

Recent evidence suggests that many common neurotoxins act on brain neurochemistry to produce neurotoxic abnormalities that result in cognitive, affective, or behavioral impairments. For example, many common solvents "recognize dopamine as a selectively vulnerable target suggest[ing] that dopamine depletion… may have a role in solvent toxicity to the CNS" (Mutti & Franchini, 1987, p. 722)

Many pesticides inhibit the normal degradation of neurotransmitters as a principal neurotoxic effect. For example, organophosphates and carbamates inhibit (possibly irreversibly) the enzyme acetylcholinesterase, whose function would ordinarily be to break down acetylcholine. The toxic effects of these pesticides, then, are the result of the overstimulation of the cholinergic system by an excess amount of acetylcholine. Disorders of other neurochemical pathways have also been implicated in organophosphate pesticide exposure, including noncholinergic systems involving biogenic amines, glutamic acid, -y-aminobutyric acid, cyclic nucleotides and others. These systems "may play important roles in the initiation, continuation and disappearance of organophosphorus cholinesterase inhibitor-induced neurotoxicity" (Ho, 1988, p. 151). 

TABLE 1.3. Nervous System Loci for Selected Neurotoxins

Cortical gray matter              Subthalamus          Schwann cells
Azide                                          Azide                           Acrylamide
Barbiturate                                Carbon monoxide       Carbon disulfide
Carbon disulfide                       Manganese                  DDT
Cyanide                                   Internal capsule        Iminodipropionitrile
Lead                                          Azide                             Isoniazide
Mercury                                     Carbon monoxide        Lead
Methyl bromide                      Corpus callosum      Vinca alkaloids
Nitrogen trichloride                  Azide                          Sensory N. thalamus
Hippocampus                        Carbon monoxide       Acetylpyridine
Acetylpyridine                           Cyanide                       Glutamate
Azide                                         Hexachlorophene        Lead
Barbiturate                                Isoniazide                     Mercury (organic)
Carbon monoxide                    Lead                           Anterior horn
Cyanide                                    Malononitrile                Carbon disulfide
Caudate/putamen                Triethyltin                      Cyanide
Barbiturate                               Optic chiasm             Iminodipropionitrile
Carbon disulfide                      Barbiturate                  Isoniazide
Cyanide                                    Carbon monoxide      Lead
Malononitrile                            Cyanide                       Vinca alkaloids
Manganese                              Hexachlorophene       Hypothal. Vent. N.
Nitrogen trichloride                  Isoniazid                     Glutamate
Globus pallidus                     Lead                           Gold thioglucose
Carbon monoxide                   Malononitrile             Mammillary bodies
Cyanide                                   Triethyltin                     Nitrogen trichloride
Gold thioglucose                                                       Tegmentum
Manganese                                                                  Azide
Methyl bromide                                                            Cyanide
                                                                                       Nitrogen trichloride
Northon (1986) and Hartman (1991)
 

TABLE 1.9. Occupations at Risk

Occupational group                      Substances

Agricultural

Farm labor                                          Herbicides, insecticides, solvents, pesticides,                                          mercury. pesticide manufacturing and distribution
Blue-collar
Degreasers                                        Trichloroethylene
Steel                                                    Lead, other metals, solvents
Textile (rayon)                                    Carbon disulfide, solvents
Painters                                              Lead, toluene, xylene, other solvents
Printers                                               Lead, methanol, methylene chloride. toluene,                                               trichloroethylene, other solvents

Petroleum industry                        Oil, gas, solvents
Plastics workers                                Formaldehyde, styrene
Battery manufacturing                       Lead, mercury
Lumber production                            Pentachlorophenol, wood preservatives
Rubber, plastics                                Solvents
Electrical                                            Polychlorinated biphenyls, solvents
Transportation workers                    Lead (in gasoline), carbon monoxide, solvents
Trucking and distribution 
of industrial products
Professional occupations
Operating room technicians           Anesthetic gases
Pathologists                                     Solvents
Anesthesiologists                            Anesthetic gases
Dentists and dental hygienists       Mercury, anesthetic gases
Hospital personnel                          Alcohols, anesthetic gases, ethylene oxide cold                                                                  sterilization 
Service occupations
Gas stations                                    Gasoline, solvents
Dry cleaners                                    Perchloroethylene, trichloroethylene

Technical
Electronics workers                       Lead, methyl ethyl ketone, methylene chloride, tin.                                                             trichloroethylene, glycol etherxylene, chloroform, freon, arsine
Laboratory workers                       Solvents, mercury, ethylene oxide

White-collar
Office workers                               Solvents, "sick building" effects

Other
Hobbyists                                       Lead, toluene, glues, solvents

ALUMINUM

Aluminum was discovered to be a CNS neurotoxin in the late 1800s and is of scientific value in this capacity; its oxide or hydroxide applied to the cortex of animal subjects produces a useful research model for studies of focal epilepsy (Ward, 1972).

Individuals at Risk

Common routes of aluminum accumulation include industrial exposure as well as ingestion of processed food (e.g., pickles), with the average diet containing about 22 mg/day of aluminum (Shore & Wyatt, 1983). Despite such continuous environmental exposure, most individuals with normal renal function appear able to clear aluminum effectively. An exception may be patients with Alzheimer's disease (AD).  Patients with impaired kidney function or chronic renal failure may be especially vulnerable to aluminum neurotoxicity as well. 

Dialysis Dementia

Clinically, some end-stage renal disease (ESRD) patients develop what appears to be a form of aluminum encephalopathy. Exposure to aluminum occurs via aluminum-containing dialysate and, probably somewhat less often, the chronic ingestion of aluminum-containing antacids, the latter being a usual concomitant of ESRD therapy. The disorder has been termed "dialysis dementia" and shows a rapid progression from personality changes to global intellectual impairment, accompanied by seizures, gait problems, asterixis, dysarthria, apraxia, and myoclonus. Abnormal EEG or CT may be found (Sedman et al., 1984). Since not all dialysis patients who take large quantities of antacids develop dialysis dementia, unspecified individual differences may interact with aluminum ingestion to produce the disease.

ARSENIC

Arsenic is a principal element in many insecticides, weedkillers, and fungicides. Arsenic is found in wood preservatives, animal feed additives, and riot control gas (Morton & Caron, 1989). 

PNS Effects

Peripheral neuropathy is a principal finding associated with inorganic arsenic intoxication. Schaumburg, Spencer, and Thomas (1983) report different profiles of neurotoxic damage, depending on the level of exposure.

CNS Effects

Bleecker and Bolla-Wilson (1985) speculate that CNS effects of arsenic may be similar to those found in thiamine deficiency, since arsenic prevents the transformation of thiamine into acetyl-CoA and succinyl-CoA. 

Burns, Cantor and Holder found that individuals who displayed arsenic related hyperkeratosis and or polyneuropathy showed psychomotor slowing, moderately impaired latency of recall, long term memory impairment, emotional abnormalities, slowed recognition of perceptual figures, and greater variability in auditory P300. 

Emotional Effects

Organic arsenic-containing compounds may cause rapidly developing CNS symptoms, with progression from drowsiness to confusion and stupor. Organic psychosis resembling paranoid schizophrenia is a common result of organic arsenic intoxication and delirium may follow (Windebank et al., 1984). Fluctuating mental state, agitation, and emotional lability have been noted (Beckett, Moore, Keogh, & Bleecker, 1986).

COPPER

Structural damage from copper toxicity includes "neuronal degeneration, spongy focal change in cortex, corpus striatum and central myelin" (Feldman, 1982a, p. 150). The basal ganglia and cerebellum are said to be particularly affected (Bornstein, McLean, & Ho, 1985). Generalized brain atrophy may or may not be present. Cirrhosis of the liver and deposits of excess copper around the cornea, Wilson’s Disease, (Kayser–Fleischer rings) are also present in some degree.

Neurological symptoms of Wilson's disease include choreic movement, parkinsonian-like rigidity, and masked facies. Dementia and death within 4–5 years can result if copper is not chelated from the body. 

Initial testing reveals abnormal motor functioning with intact IQ, while more advanced cases exhibit intellectual dysfunction, and the possibility of dementia in the late stage of the illness. Psychological abnormalities may also accompany Wilson's disease, and a 1985 review of case studies concluded that affective and behavioral or personality changes are the most common sequelae, with two less common profiles showing schizophreniclike or cognitive deterioration (Dening, 1985).

Emotional complaints included high perceived stress, with a very low threshold of annoyance or irritation, and occasional outbursts of violent rage.

LEAD

Lead has no known biological benefit and, like all nonessential heavy metals, it is hazardous to living matter (Niklowitz, 1980, p. 27). The toxic effects of lead have been known almost as long as it has been mined. Two thousand years ago, Dioscorides wrote that lead "makes the mind give way" (Major, 1931).

Both Benjamin Franklin and Charles Dickens wrote about the deleterious effects of lead (Needleman, 1993). The United States, however, was particularly slow in adopting lead regulations, and even in 1921, when the White Lead Convention proposed control of leaded paint and was ratified by 13 countries, the United States declined to join the signatories. The country was a large consumer and producer of leaded paint and the lead industry controlled dissemination of research funding and information related to lead through the late 1960s, when federally sponsored funding for lead research became available (Mushak, 1992).  In humans, lead is accumulated via inhalation and ingestion. 

Neuropathology

Several mechanisms of lead-related neurotoxic damage have been proposed and the subject remains under investigation. Lead may compete with calcium, sodium, and/or magnesium in neurotransmission. Direct and indirect effects on nerve cell mitochondria, inhibiting phosphorylation, have been suggested (Silbergeld, 1982). 

Evidence from primate and other mammalian studies indicates that "the brain has low uptake but tenacious retention of lead" (Leggett, 1993, p. 606).

Neurophysiological Effects

High-level childhood lead poisoning more often presents with CNS neuropsychological symptoms than peripheral neuropathy. Childhood peripheral neuropathies, when they do occur, involve the legs more than the arms, whereas in adults the reverse is true (Windebank et al., 1984). Hearing loss and impairment of postural sway may also be found.

Evidence has steadily accrued that ingestion of lead in childhood produces neurotoxic sequelae at both clinical and subclinical levels. Several studies show neuropsychological impairment to be associated with subclinical blood lead levels in children (e.g., Rutter, 1980). Hunter, Urbanowicz, Yule, and Lansdown (1985) found a small but significant slowing in reaction time in children with lead levels of 5–26 g/ dl (mean = 11.85 g/dl). David, Grad, McGann, and Kolton (1982) found a significant negative correlation between supposedly "nontoxic" mean blood levels of 25 g/dl and mental retardation that could not otherwise be explained by other factors. Yule, Lansdown, Millar, and Urbanowicz (1981) studied 141 children with blood levels from 7 to 33 g/dl and found significant impairments in general intelligence and several achievement test scores (reading and spelling) that remained after social class had been partialed out.

Lead assays of shed teeth have also correlated with neuropsychological dysfunction. For example, Needleman et al. (1979) found WISC-R Full Scale IQs to be significantly lower by about 45 points between high- and low-lead groups. High-tooth-lead children also performed significantly more poorly on all subtests of the Seashore Rhythm Test, suggesting auditory processing dysfunction, and on a reaction time measure, suggesting impaired vigilance or attention. Winneke, Hrdina, and Brockhaus (1982) found impaired problem-solving and perceptual-motor integration in children with high lead dentine levels, although they also warn against confounding variables of "socio-hereditary background" in these types of studies (Winneke et al., 1983). 

Personality and conduct-related variables may also be correlated with lead levels in shed teeth. Bellinger, Leviton, Allred, and Raboniwitz (1994) found that tooth lead level was significantly associated with total problem behavior ratings of eight year old children on a teacher rating form of the Child Behavior Profile.

Association of hyperactivity with lead has been noted (David, Hoffman, Clark, Grad, & Swerd, 1983) and replicated with a nondisadvantaged group of children (Gittelman & Eskenazi, 1983). Another study examined a total of about 1000 children and found that high lead levels were associated with impaired Verbal and Full Scale IQ on the WISC, especially in the Information, Comprehension, and Vocabulary subtests in a group of children matched for parent social status, sex, school, and neighborhood. The high-lead group also made significantly more errors on the Bender Visual Motor Gestalt and had poorer ratings in a behavioral rating scale (Hansen, Trillingsgaard, Beese, Lyngbye, & Grandjean, 1985). Similar deficits in other visuospatial tasks have also been found (Maracek, Shapiro, Burke, Katz, & Hediger, 1983). Such dysfunctions may be cumulative, and with repeated exposure the risk of permanent brain damage approaches certainty (Niklowitz, 1979).

Evidence for lead-related central auditory processing dysfunction can be found in Dietrich, Succop, Berger, and Keith (1992), who found that prenatal, neonatal, and postnatal blood lead levels were associated with increased difficulty perceiving speech in the presence of background noise, irrespective of IQ or hearing acuity. Primate experiments suggest that lead exposure either delays speech structure development, or alternatively causes compensation and reorganization of neural mechanisms in response to lead-mediated nerve damage (Otto & Fox, 1993).

Most cases of organic lead intoxication are the result of exposure to leaded gasoline.

General Symptoms of Inorganic Lead Intoxication. Neurotoxic reactions to inorganic lead usually occur in the context of a systemic illness with classic symptoms. These include "abdominal pain, constipation, anemia and neuropathy." Gout may also be present (Windebank et al., 1984, pp. 213—245).  Lead exposure is associated with hearing impairment. Schwartz and Otto (1991) found increased risk of elevated hearing thresholds at all four reference frequencies (500, 1000, 2000, and 4000 Hz). 

Neuropsychological Effects

Subjective Complaint. As is the case with neurological effects, lead-induced changes in neuropsychological function are not well correlated with subjective complaint.

Cognitive Effects. Neuropsychological functions shown to be deleteriously affected by lead include visual intelligence and visuomotor functions (Hknninen, Hernberg, et al., 1978), general intelligence (Grandjean, Arnvig, & Beckmann, 1978), choice reaction time (Stollery, Broadbent, Banks, & Lee, 1991), and memory, "particularly in learning new material" (Feldman, Ricks, & Baker, 1980). Williamson and Teo (1986), using an information processing model of memory, found significant lead-related decrements in sensory storage memory (brief tachistoscopic presentation of letter pairs), Sternberg-type short-term memory scanning, and a paired associate learning task. In combination with lowered critical flicker fusion thresholds, the authors interpreted their results as consistent with arousal deficit and/or degradation of retinal or visual pathway input.

Reductions in psychomotor speed and dexterity (e.g., Williamson & Teo, 1986; Repko, Corum, Jones, & Garcia, 1978) have been cited in many studies, perhaps related to either reduced nerve conduction velocities or damage to the motor areas of the cortex (Hknninen, 1982). Matsumoto et al. (1993) found that lead workers' tapping speed decreased with higher blood lead levels.

Emotional Effects. Lead-induced emotional alterations include depression, confusion, anger, fatigue, and tension (Baker, Feldman, White, & Harley, 1983). These symptoms have been observed both in chronically exposed patients, as well as in individuals with lead exposure histories of 2 weeks to 8 months (Bleeker et a/., 1982, p. 255). 

Lead has no known biological benefit and, like all nonessential heavy metals, it is hazardous to living matter (Niklowitz, 1980, p. 27). The toxic effects of lead have been known almost as long as it has been mined. Two thousand years ago, Dioscorides wrote that lead "makes the mind give way" (Major, 1931).

Both Benjamin Franklin and Charles Dickens wrote about the deleterious effects of lead (Needleman, 1993). The United States, however, was particularly slow in adopting lead regulations, and even in 1921, when the White Lead Convention proposed control of leaded paint and was ratified by 13 countries, the United States declined to join the signatories. The country was a large consumer and producer of leaded paint and the lead industry controlled dissemination of research funding and information related to lead through the late 1960s, when federally sponsored funding for lead research became available (Mushak, 1992).

In humans, lead is accumulated via inhalation and ingestion. 

Neuropathology

Several mechanisms of lead-related neurotoxic damage have been proposed and the subject remains under investigation. Lead may compete with calcium, sodium, and/or magnesium in neurotransmission. Direct and indirect effects on nerve cell mitochondria, inhibiting phosphorylation, have been suggested (Silbergeld, 1982). 

Evidence from primate and other mammalian studies indicates that "the brain has low uptake but tenacious retention of lead" (Leggett, 1993, p. 606).

Neurophysiological Effects

High-level childhood lead poisoning more often presents with CNS neuropsychological symptoms than peripheral neuropathy. Childhood peripheral neuropathies, when they do occur, involve the legs more than the arms, whereas in adults the reverse is true (Windebank et al., 1984). Hearing loss and impairment of postural sway may also be found.

Evidence has steadily accrued that ingestion of lead in childhood produces neurotoxic sequelae at both clinical and subclinical levels. Several studies show neuropsychological impairment to be associated with subclinical blood lead levels in children (e.g., Rutter, 1980). Hunter, Urbanowicz, Yule, and Lansdown (1985) found a small but significant slowing in reaction time in children with lead levels of 5–26 g/ dl (mean = 11.85 g/dl). David, Grad, McGann, and Kolton (1982) found a significant negative correlation between supposedly "nontoxic" mean blood levels of 25 g/dl and mental retardation that could not otherwise be explained by other factors. Yule, Lansdown, Millar, and Urbanowicz (1981) studied 141 children with blood levels from 7 to 33 g/dl and found significant impairments in general intelligence and several achievement test scores (reading and spelling) that remained after social class had been partialed out.

Lead assays of shed teeth have also correlated with neuropsychological dysfunction. For example, Needleman et al. (1979) found WISC-R Full Scale IQs to be significantly lower by about 45 points between high- and low-lead groups. High-tooth-lead children also performed significantly more poorly on all subtests of the Seashore Rhythm Test, suggesting auditory processing dysfunction, and on a reaction time measure, suggesting impaired vigilance or attention. Winneke, Hrdina, and Brockhaus (1982) found impaired problem-solving and perceptual-motor integration in children with high lead dentine levels, although they also warn against confounding variables of "socio-hereditary background" in these types of studies (Winneke et al., 1983). 

Personality and conduct-related variables may also be correlated with lead levels in shed teeth. Bellinger, Leviton, Allred, and Raboniwitz (1994) found that tooth lead level was significantly associated with total problem behavior ratings of eight year old children on a teacher rating form of the Child Behavior Profile.

Association of hyperactivity with lead has been noted (David, Hoffman, Clark, Grad, & Swerd, 1983) and replicated with a nondisadvantaged group of children (Gittelman & Eskenazi, 1983). Another study examined a total of about 1000 children and found that high lead levels were associated with impaired Verbal and Full Scale IQ on the WISC, especially in the Information, Comprehension, and Vocabulary subtests in a group of children matched for parent social status, sex, school, and neighborhood. The high-lead group also made significantly more errors on the Bender Visual Motor Gestalt and had poorer ratings in a behavioral rating scale (Hansen, Trillingsgaard, Beese, Lyngbye, & Grandjean, 1985). Similar deficits in other visuospatial tasks have also been found (Maracek, Shapiro, Burke, Katz, & Hediger, 1983). Such dysfunctions may be cumulative, and with repeated exposure the risk of permanent brain damage approaches certainty (Niklowitz, 1979).

Evidence for lead-related central auditory processing dysfunction can be found in Dietrich, Succop, Berger, and Keith (1992), who found that prenatal, neonatal, and postnatal blood lead levels were associated with increased difficulty perceiving speech in the presence of background noise, irrespective of IQ or hearing acuity. Primate experiments suggest that lead exposure either delays speech structure development, or alternatively causes compensation and reorganization of neural mechanisms in response to lead-mediated nerve damage (Otto & Fox, 1993).

Most cases of organic lead intoxication are the result of exposure to leaded gasoline.

General Symptoms of Inorganic Lead Intoxication. Neurotoxic reactions to inorganic lead usually occur in the context of a systemic illness with classic symptoms. These include "abdominal pain, constipation, anemia and neuropathy." Gout may also be present (Windebank et al., 1984, pp. 213—245).
Lead exposure is associated with hearing impairment. Schwartz and Otto (1991) found increased risk of elevated hearing thresholds at all four reference frequencies (500, 1000, 2000, and 4000 Hz). 

Neuropsychological Effects

Subjective Complaint. As is the case with neurological effects, lead-induced changes in neuropsychological function are not well correlated with subjective complaint.

Cognitive Effects. Neuropsychological functions shown to be deleteriously affected by lead include visual intelligence and visuomotor functions (Hknninen, Hernberg, et al., 1978), general intelligence (Grandjean, Arnvig, & Beckmann, 1978), choice reaction time (Stollery, Broadbent, Banks, & Lee, 1991), and memory, "particularly in learning new material" (Feldman, Ricks, & Baker, 1980). Williamson and Teo (1986), using an information processing model of memory, found significant lead-related decrements in sensory storage memory (brief tachistoscopic presentation of letter pairs), Sternberg-type short-term memory scanning, and a paired associate learning task. In combination with lowered critical flicker fusion thresholds, the authors interpreted their results as consistent with arousal deficit and/or degradation of retinal or visual pathway input.

Reductions in psychomotor speed and dexterity (e.g., Williamson & Teo, 1986; Repko, Corum, Jones, & Garcia, 1978) have been cited in many studies, perhaps related to either reduced nerve conduction velocities or damage to the motor areas of the cortex (Hknninen, 1982). Matsumoto et al. (1993) found that lead workers' tapping speed decreased with higher blood lead levels.

Emotional Effects. Lead-induced emotional alterations include depression, confusion, anger, fatigue, and tension (Baker, Feldman, White, & Harley, 1983). These symptoms have been observed both in chronically exposed patients, as well as in individuals with lead exposure histories of 2 weeks to 8 months (Bleeker et a/., 1982, p. 255). 

MANGANESE

Although required as a nutritional trace element, manganese is neurotoxic in large amounts. Customary route of exposure is via inhalation, which can result in serious neurological disturbance. Thousands of workers are said to have developed manganese neurotoxicity (Politis, Schaumburg, & Spencer, 1980). Manganese miners, welders, and workers in dry-cell battery plants are primary exposure victims (Grandjean, 1983, p. 335). Other occupations where manganese is used include steel alloy plants, and factories that produce ceramics, matches, glass, dyes, fertilizers, welding rods, oxidizing solutions, animal food additives, germicides and antiseptics (Katz, 1985). Poor ventilation systems in worksites where manganese is present increase the risk for neurotoxic exposure (Wang, Huang, et al., 1989).

Neurological and Neuropsychological Aspects

Manganese poisoning is thought to occur in three stages. The initial manifestations of manganese intoxication last approximately 13 months and include sleepiness, poor coordination, ataxia, and impaired speech (Baker, 1983a) as well as other more psychiatric-seeming symptoms, including asthenia, anorexia, insomnia, hallucinations, "mental excitement, aggressive behavior and incoherent talk" (Chandra, 1983; Politis et al., 1980; Cawte, 1985). This latter set of early symptoms has led to the term "manganese mania." Arousal, judgment, and memory deficits have also been reported (Rosenstock, Simons, & Meyer, 1971).

The second stage of manganese intoxication is characterized by greater numbers of neurological symptoms, including abnormal gait, expressionless facies, speech disorder, clumsiness, and sleepiness. 

In "third stage" severe cases, the syndrome is called "manganism" and presents with "parkinsonian-like" symptoms of "asthenia, staggering gait, muscular hypertonia and hypokinesia, and tremor" (Grandjean, 1983, p. 335). Frontal lobe dysfunction, dementia, and emotional lability have also been reported to occur at this final stage (Cawte, 1985).

MERCURY

Mercury miners are at obvious risk for poisoning and intoxications. Kishi, Doi, et al. (1993) surveyed a cohort of 76 ex-mercury miners from Hokkaido, Japan, who had worked in a mine that opened in 1939 and closed in 1970. The survey was conducted approximately 18 years after exposure had ceased. Exposures were high at over 1.0 mg/m' and many of the miners had a history of overt intoxication, with exposure of more than 100 times the present Japanese TLV. While there was a decrease in symptoms 18 years after exposure, prevalence of hand tremor, headache, and slurred speech was higher in the poisoned group than controls. For example, 72% of miners with a history of intoxication reported tremors. Neuropsychological testing of workers showed that performance in tests of grip strength, eye—hand coordination, color reading, block design, and digit span were significantly impaired relative to controls in a matched pair analysis.

Occupations where the volatility of mercury causes risk to workers include those that employ or manufacture barometers or mercury vapor lamps. Also at risk are technicians who prepare dental amalgams, and possibly dentists themselves.

When dentintists in Singapore were compared with controls with no exposure to mercury, dentists had a higher aggressive mood scores and scored significantly more poorly on a variety of neuropsychological measures, including Trails A&B, Symbol Digit, Digit Span, and WMS Verbal and Visual Memory (immediate and delayed recall). Neuropsychological impairments and emotional changes were related to cumulative exposure to mercury vapor (Ngim, Foo, Boley, & Jeyaratnam, 1992).

Other occupational groups at risk for mercury exposure include felt-makers [“mad as a hat”], photoengravers, and photographers (Feldman, 1982b). Industrial workers who manufacture electrical switches and batteries, those using mercuric salts in plating operations, tanners and embalmers are also at risk. Employees who produce or apply organic mercury compounds as pesticides, fungicides, disinfectants, or wood preservatives may also be endangered (Feldman, 1982b; Hamilton, 1985).

Nonoccupational Exposure

Mercury vapor exposure is not limited to the workplace. The most common and controversial nonoccupational mercury exposure occurs via implants of dental amalgam to correct the effects of dental caries. Approximately 100 million amalgam fillings are implanted each year by dentists in the United States (Fung & Molvar, 1992). Amalgam is a metallic alloy, usually composed of 25–35% silver, 15–30% tin, 2–30% copper, and other metals which are then mixed with between 40 and 54% mercury. An additional concern is that mercury may be converted by common mouth bacteria (e.g., Streptococcus sanguis, S. mutans, or S. mitiors) to methylmercury in the mouth. Chewing with recently implanted amalgam fillings increases mercury vapor levels 4–15 times resting state, and 3 times OSHA safety levels (Gay, Cos, & Reinhardt, 1979; Svare et al., 1981; Wolff, Osborne, & Hanson, 1983). Mercury levels from fillings continue to be detectable for as long as 1 year after amalgam implant, albeit below current safety levels (8.5–15 ng) (Fung, Molvar, Strom, Schneider, & Carlson, 1991). Individuals with many fillings (more than 36 restored surfaces) absorb more than 10–12 g of mercury per day, double that of individuals without significant amalgam expo-sure. Brain and kidney concentrations of mercury are significantly higher in autopsied individuals with amalgam fillings, than in those with amalgam restoration (Nylander, Frieberg, & Lind, 1987). The neurotoxic effects of this long-term body burden of mercury are largely unknown, although relatively few cases of overt allergic response are known and no cases of mercury neurotoxicity from this route have yet entered the literature (Fung et al., 1991; Fung & Molvar, 1992). Removing old amalgam, or careless dental techniques, may also expose patients to elevated levels of mercury vapor.

Wolff et al. (1983) warn that "patients [with amalgam fillings] could receive a chronic low level exposure to elemental Hg for many years.... It is generally agreed that if amalgam was introduced today as a restorative material, they [sic) would never pass F.D.A. approval" (p. 203). Mercury from amalgam fillings may cross the placenta in pregnant women, and may be especially dangerous to the fetus under typical conditions of chronic, low dose exposure. "Experimental evidence suggests that it would be prudent to avoid placing dental `silver' amalgam fillings in pregnant women" (Lorscheider & Vimy, 1990, p. 1579).

The possibility of amalgam toxicity has prompted the Dental Products Panel of the U.S. Food and Drug Administration to consider opening the issue for further regulatory study. While studies of amalgam exposure on neuropsychological function have not yet been conducted, known toxic effects of mercury and recent toxicological findings strongly indicate the need for this avenue of investigation.

It has been suggested that routine eating of mercury-containing fish constitutes a greater source of daily mercury exposure than amalgam. Thimerosal contact lens disinfection solutions also contain mercury and may likewise constitute another source of daily exposure to mercury. Neither has been investigated for their relationships to neurological disorders or neuropsychological impairments (Fungi & Molvar, 1992).

Neurotoxic exposure to mercury has also occurred in home accidents. Spilled mercury sinks into floor cracks and carpeting and may be difficult to see or remove. Attempts to take up the metal via a vacuum cleaner may actually propel the metal through the vacuum and expel it as an aerosol, facilitating its spread.

Neuropathology—Methylmercury 

The methylated form of mercury is a far more potent CNS poison than mercury in its inorganic state (Weiss, 1978). Methylmercury is almost completely absorbed from the gastrointestinal tract. By contrast, less than 15% of inorganic mercury is retained (World Health Organization 1976). Methylmercury intoxications cause symptoms of toxic encephalopathy, either early symptoms of poisoning that include weakness, unusual taste in the mouth, gum hemorrhage, sleep disturbances, and sometimes auditory and visual hallucinations (Koloyanova & El Batawi, 1991). 

In addition, chronic exposure to methylmercury produces systemic CNS damage, including constriction of visual fields, ataxia, dysarthria, partial deafness, tremor, and intellectual impairment (Windebank et al., 1984). Feldman (1982b) reports one case of methylmercury poisoning where members of a family ate pork from animals accidentally fed seed grain treated with methylmercury fungicide. Several individuals developed initial symptoms of ataxia, agitation, decreased visual acuity and stupor. Evaluation 10 years later showed blindness, ataxia, retardation, choreoathetosis, myoclonic jerks, and abnormal EEGs.

Intellectual disturbance from mercury intoxication has been found to occur in tests of visuospatial abilities, visual memory, nonverbal abstraction, cognitive efficiency, and reaction time (Angotzi et al., 1982). Block Design, Digit Symbol, and Raven's Progressive Matrices appear to be sensitive indicators of toxic effects, as are Digit Span and tests of visual memory (Hanninen, 1982; Soleo et al., 1990). Lowered eye—hand coordination and decreased finger tapping scores are significantly correlated with urinary mercury levels (Langolf, Chaffin, Henderson, & Whittle, 1978), as are foot tapping scores (Chaffin & Miller, 1974). Mercury exposure increases test fatigue, and decreases initial learning of word associations.

The emotional dysfunction called "erethism" is also thought to be a very common emotional abnormality related to mercury exposure. This syndrome, derived from the French and Greek word "to irritate," represents an unusual and morbid level of overactivity of the "mental powers or passions" (Oxford English Dictionary, 1971, p. 890). In current use the term also connotes symptoms of avoidant, irritable, and overly sensitive interpersonal behavior, depression, lassitude, and fatigue (Hanninen, 1982, p. 167). 

Hanninen's (1982) review concluded that mercury-induced neuropsychological abnormalities fell into three major groups: (1) motor system abnormalities (e.g., fine motor tremor), (2) intellectual impairment (gradual and progressive deterioration of memory, concentration, and logical reasoning), and (3) emotional disability. Occupational studies of mercury exposure have found support

SELENIUM

Selenium and compounds (as Se)

Selenium is found in industrial settings as a result of mining or processing selenium-containing minerals including copper, lead, zinc pyrite, roasting lime, and cement. Selenium is used commercially in the production of glass and ceramics, and other substances including steel, rubber, brass, paint and ink pigment, and photoelectric materials (Katz, 1985).

In very small doses, selenium is an essential trace element in the human diet. In larger amounts from voluntary or industrial exposure, selenium has been associated with neurotoxic effects, including headache, vertigo, convulsions, and a motor neuron disease similar to amyotrophic lateral sclerosis, a disease reported in four ranchers who grazed their cattle in high-selenium soil and ate meat with
high selenium content (Goetz, 1985). Neurotoxic symptoms may be expected as secondary features of systemic pulmonary or hepatic disease stemming from selenium exposure. Exposure to hydrogen selenide may cause pulmonary edema or obstructive pulmonary disease. The lowest level of daily selenium intake estimated to be dangerous is 500 \s.g (World Health Organization, 1977). There
are no neuropsychological studies of selenium intoxication.

ZINC

Zinc is a common metal, found in sheet metal, batteries, and various alloys. Three neurological syndromes have been linked to toxic exposure. Oral ingestion of zinc chloride or of acidic foods stored in galvanized containers has been fatal, with survivors showing residual neurological symptoms of dyspnea, weakness, muscle spasm, and lethargy (Goetz, 1985). Inhalation of zinc vapor may produce neurological and psychiatric symptomatology, including irritability, "upper extremity coarse intention tremor, incoordination and ataxia" (Brazier's disease) (Goetz, 1985, p. 57). Neuropsychological tests of zinc toxicity have not been performed. Exposure to zinc phosphide has produced symptoms of irritability, psychomotor stimulation, drowsiness, and stupor. Egyptian workers exposed to
zinc phosphide reported memory impairment, decreased attentional capacity,  psychomotor hyperactivity, and rapid fatigue. EEG abnormality was present in 17.4 of the sample (Amr et al., 1993).

CAFFEINE

Caffeine is said to be the most widely used psychoactive substance in the world. Caffeine increases plasma catecholamines in humans, and also affects central norepinephrine and central dopamine turnover (Stoner, Skirboll, Werkman, & Hommer, 1988). Performance-enhancing effects of caffeinated beverages have been assumed to provoke tolerance. However, a recent, large-scale survey suggested that psychomotor and cognitive effects of drinking coffee or tea may outweigh tolerance effects. Jarvis (1993) reviewed the relationship between cognitive performance and habitual coffee and tea consumption in a cross section of 9003 British adults. After controlling for social, age, health, and demographic variables, significant trends for better performance as a function of higher coffee intake were observed on choice reaction time, incidental verbal memory, and visuospatial reasoning. Compared to coffee teetotalers, individuals who drank more than six cups of coffee per day were faster by 6% in simple reaction time, 4% in choice reaction time, and 4—5% better in memory and visuospatial tasks. Improved performance in reaction times did not occur at the price of increased error rate. Tea drinkers showed somewhat weaker improvements in cognitive function. The largest improvements appeared to occur in the oldest subjects. Survey results must be considered tentative since coffee and tea consumption information was obtained without determining type of coffee or tea (instant, ground decaffeinated) or strength. The author correctly suggests the need for a follow-up study utilizing blood levels of caffeine at the time of testing. Most commonly used pesticides, including the chlorinated hydrocarbons (e.g., DDT), the organophosphates (e.g., Malathion, Diazinon, Ronnel), and the carbamates (e.g., Baygon, Maneb, Sevin, Zineb), are lethal to insects via neurotoxic action (Morgan, 1982). Studies using higher mammals have also demonstrated pesticide neurotoxicity (e.g., Vandekar, Plestina, & Wilhelm, 1971; Aldridge & Johnson, 1971; DuBois, 1971). It is not surprising, therefore, that neurotoxic effects of pesticides are also found in human exposure victims, and that both cognitive and emotional functions are affected. 

The actual amount of pesticides put into the environment is staggering. There are over 34,000 pesticides registered by the EPA. In recent years, approximately 1.1 billion pounds of pesticides were utilized in the United States alone (Lang, 1993); not appreciably different from estimates of 1.4 billion pounds in 1975 (Ecobichon & Joy, 1982). Over 4 billion pounds are applied worldwide, with the United States using 1.1 billion pounds of that total annually (Lang, 1993). Pesticides are applied to over 900,000 farms in the United States. Seventy-five percent of all cropland and seventy percent of all livestock are treated with pesticides (Lang, 1993). An estimated 340,000 workers are involved in some aspect of pesticide production in the United States (Moses, 1983). An additional estimated 2.5–2.7 million migrant or seasonal workers come into contact each year with pesticides (Moses, 1983).

Considering the EPA’s estimate that 69 million families store and use pesticides, it is perhaps not surprising that there are 60,000 to 70,000 estimated poisonings annually from organophosphates alone (Lang, 1993; Muldoon & Hodgson, 1992). The number of nonoccupational poisonings may be underestimated, as results from a South Carolina hospital survey found that half of all patients hospitalized for pesticide exposure had incurred exposure in non-workrelated situations (Schuman, Whitlock. Coldwell. & Horton. 1989).  Estimated pesticide-related illnesses in the United States alone are between 150,000 and 500,000 per year (Coye, 1985; Koloyanova & El Batawi, 1991).

PSYCHOSOMATIC DISORDERS

Psychosomatic and psychological disorders are implicit diagnostic rule-outs in any evaluation of neurotoxic exposure. These maladies neither presume nor eliminate the possibility of neurotoxic nervous system damage in that neurotoxic injury to limbic system and emotional substrates may indicate organic mood disorder. 

MULTIPLE CHEMICAL SENSITIVITY

A curious interaction between psyche and soma has come to the attention of health care workers in the phenomenon of multiple chemical sensitivity (MCS). Also known as ecological or ecologic illness, twentieth century syndrome, total allergy syndrome, or other terms (see Terr, 1989), MCS is a diagnostic disorder of uncertain etiology, but usually characterized by the following symptoms (after Cullen, 1987):

1.          Acquired in relation to documented environmental exposures, insults, or illnesses
2.          Involve more than one organ system
3.          Symptoms recur and abate in response to predictable stimuli
4.          Symptoms elicited by chemicals of diverse structure and toxicologic action
5.          Symptoms elicited by demonstrable, albeit ultra-low-level exposures
6.          Exposures far below levels known to cause damage elicit symptoms
7.          No single test explains symptoms

MCS is characterized by remission or dissipation of symptoms when expo-sure is terminated. Symptom profile resembles an acute response to a stimulus, rather than chronic Type 2A, 2B, or 3 solvent encephalopathy; disorders that are characterized by impairments independent of exposure (Fiedler, Maccia, & Kipen, 1992). Clinically, MCS symptoms tend to overlap with those of somatoform disorder, mass psychogenic poisoning, and posttraumatic stress disorder, suggesting at least a partial psychosomatic component to the disorder. In many cases, there are no observable physical correlates of the disease other than patient report. In Terr's (1986) review of 50 litigating cases, 31 had no physical or laboratory abnormalities.

Patient Profile

Patients volunteering for MCS studies are typically female Caucasians with good education and above-average socioeconomic status (e.g., Black, Rathe, & Goldstein, 1990). However, it is not clear whether this profile is confounded by self-selection biases and high cost of treatments (Mooser, 1987). Most MCS patients have an extensive history of health care with less than satisfactory results, and a "profound aversion to psychiatry" (Gots, Hamosh, Flamm, & Carr, 1993). Such patients are convinced that they are being damaged by the environment, perhaps as the result of an unusual disease process that has not yet been discovered. 

Such patients often develop a life-style, observed by Brodsky (1983) and Black et al. (1990), that is heavily involved in activities, literature, friendships, and support groups that validate their symptoms. Many are in treatment with so-called "clinical ecologists" who prescribe a variety of vitamins, "immune boosters," and other nostrums to relieve symptoms. Recommendations often include removal of all offending products from the immediate environment, resulting in expensive home renovation, building of "clean rooms" or "safe rooms," usually surrounded in ceramic tile or glass, and sometimes, moving to a supposedly less polluted area. 

Etiology of MCS: Multiple Diagnostic Possibilities

The unusual symptom constellation experienced by MCS patients eludes easy explanation. MCS syndrome has been explained as a disorder of immune regulation, biochemical imbalance, nutritional deficiency, and psychological/psychiatric abnormalities.

Immune Regulation

One explanation proposed for MCS is that it produces vasculitis of auto-immune etiology; causing environmental toxins to induce antibodies for blood vessel antigens (Terr, 1989; Rea, 1977). Another autoimmune hypothesis was proposed by McGovern, Lazaroni, Hicks, et al. (1983) to involve T-suppressor cell toxicity.

Biochemical

Some support for biochemical abnormality in MCS patients comes from Rea etal., who found elevated organic pollutants and reduced erythrocyte chromium. However, other studies have failed to find abnormalities of biochemistry in MCS patients. Another explanation was proposed by Levine and Reinhardt (1983) who view MCS as resulting from failure of human antioxidant mechanisms, leaving free radicals produced by environmental toxins to cause systemic damage.  Thus, it is not clear whether (1) this physiologically stressed population more easily experiences MCS because of increased physiological vulnerability, (2) MCS is responsible in some way for a subset of complaints, or (3) preexisting diagnoses cause the complaints attributable to MCS.

Psychological

Psychological explanations fall into five categories: (1) those that classify MCS patients as having a psychological disorder with physical symptom expression in the form of a hysterical or somatoform disorder (Kahn & Letz, 1989; Schottenfeld, 1987), (2) those resulting from severe psychologically traumatic threat of poisoning (posttraumatic stress disorder), (3) those that appear to be related to conditioning and generalization of autonomic and/or neurotoxic abnormalities, (4) MCS is an iatrogenic psychological disorder produced by physician/clinical ecologist "treatment" (Terr, in Gots et al., 1993), and (5) MCS patients represent a mixed group of psychiatric disorders with no underlying factor, except "that some person in the medical community has told them they have an environmental illness and has fostered that belief" (Black, in Gots et al., 1993, p. 73).

Schottenfeld (1987) supports a common opinion in the psychiatric community that MCS-related disorders fall under the DSM-III-R categorization of Somatoform Disorders. He also suggests that MCS patients may be a heterogeneous group, including subjects who (1) show unusual sensitivities that are not allergic or immune system-based, (2) somaticizers who exaggerate normal body symptoms, (3) somaticizers who amplify irritant symptoms, (4) primary psychiatric diagnoses, and (5) psychiatric diagnosis reactive to and exacerbated by MCS (Schottenfeld, 1987). Support for a high incidence of psychiatric disorders was found in several studies, including Stewart and Raskin (1985) who reported that all 18 patients referred to a university psychiatric clinic for MCS symptoms were found to have somatoform, psychotic, or personality disorder. Brodsky (1983) described 8 MCS patients as having long histories of somatization, undocumentable illnesses, and high health care utilization. This is further supported by Black et al. (1990) who found that lifetime prevalence of major mental disorders, especially major depression, anxiety disorders, and somatoform disorders, was significantly greater in MCS patients compared with age- and sex-matched controls. 

The strongest, and seemingly conclusive study proving that the majority of claimed MCS patients have some form of primary psychological and/or somatoform disorder rather than a physiological or immunologic hypersensitivity disease is that of Staudenmayer, Seiner, and Buhr (1993) who subjected claimed MCS patients (including those whose diagnoses were "confirmed" by clinical ecologists) to controlled trials of chemical provocation in a specially built exposure chamber of porcelainized steel, glass, and aluminum. The chamber provided air filtered with a HEPA filter, activated charcoal, and a Purafil bed, which removed more than 90% of volatile organic compounds and atmospheric oxidants, and more than 99% of all particles from filtered air.

Patients were exposed to chemical challenges using chemicals selected by each patient as capable of eliciting symptoms, at concentrations and durations reported to induce symptoms (from 15 min to 2 h). Distinctive odors of certain substances were masked by a tolerated masking agent, e.g., peppermint, cinnamon, or anise.  Results were analyzed with a signal detection paradigm that analyzed sensitivity.  MCS patients showed only 33.3% sensitivity, 64.7% specificity, and most telling 53.4% efficiency, that is, their reaction occurred at a pure chance level.  No patient was ever discovered to have a general chemical sensitivity, although Dr. Staudenmayer has validated specific reactions to individual chemicals.

SICK BUILDING SYNDROME

Sick building syndrome (also called "tight building syndrome") is characterized by mucosal irritation of the eyes, nose, throat, and lower airway, dermatological reactions, fatigue, headache, nausea, and other nonspecific somatic and psychological symptoms. The symptom constellation is distinguished from building-related illness, which includes medical diseases related to poor indoor air quality, such as hypersensitivity pneumonitis, humidifier fever, asthma, and legionellosis (Welch, 1991). Symptoms worsen during the workday and may diminish after workers leave the building. The disorder is prevalent, with a Danish study finding office work-related mucosal irritation estimated at 44% for women and 25% for men [versus 21% women and 12% men in the general population (Valbjorn et al., 1986, cited in Skov et al., 1989)]. Morrow (1992) estimates that from 800,000 to 1.2 million commercial buildings in the United States evoke at least some sick building related symptoms, the impact of which is sufficiently severe as to cause an estimated 500,000 lost workdays each year.

Early studies suggested associations among observed symptoms and formaldehyde levels (Main et al., 1983; Olsen & Dossing, 1982), total hydrocarbon concentrations (Skov et al., 1989), smoking (Skov et al., 1987), interpersonal cooperation and stress. Some forms of sick building syndrome may be related to a combination of building design inadequacies and odorant perception. Cone and Shusterman (1991) found such a problem in an elementary school, where a combination of fireproofing odorant and poor air ventilation rates produced symptoms of head-ache, dizziness, abdominal pain, cough, runny nose, and itchy eyes. Other recent studies conclude that multifactorial explanations may best explain complaints. Bauer et al. (1992) showed that patients in sick buildings had greater distrust of authority, defensiveness, anxiety, and confusion, but psychological inventories alone did not distinguish patients with sick building symptoms from nonsymptomatic workers.

MASS PSYCHOGENIC ILLNESS

Mass psychogenic illness is usually characterized by a rapid spread of physical and psychosomatic symptoms in the context of a real or imagined environmental trigger (e.g., a chemical odor; an "invisible gas"). Behavioral contagion may affect entire communities, as occurred in a residential area of Memphis, Tennessee, where residents complained to their physicians of various maladies after false rumors surfaced that the town was built on a toxic waste dump (Schwartz, 1985). Symptoms of mass psychogenic illness are similar to those found in sick building syndrome, e.g., throat irritation, dryness or irritation of the eyes, nose, mouth, or throat, dizziness, anxiety, or fatigue.

The model individual likely to be affected has been characterized as a highly stressed female who is dissatisified with her job. Hall and Johnson (1989) showed that 33% of the variance in the characterization of a mass psychogenic illness outbreak was explained by five factors: work intensity, mental strain, home and work problems, education, and gender, in decreasing order. Ryan and Morrow (1992) suggest that individuals prone to MPI have premorbid psychological vulnerability and chronically high levels of stress.

WORKPLACE STRESS

A World Health Organization report indicates that approximately one half of the working population are unhappy with their jobs (Levi, 1989). A 1985 report estimates that 11 million workers report health-damaging levels of mental stress while at work. In 1988, 21% of all Social Security Administration Disability allowances were for mental disorders (Social Security Bulletin, 1989). 

It has been suggested that high psychosocial stress and low input into the work process may be physically and emotionally dangerous (Social Security Bulletin, 1989). Work stress may behaviorally manifest as affective disturbance or maladaptive behavior or lifestyle, including chemical dependency and/or alcohol abuse. Sauter et al. (1990) specified several avenues of questioning that can increase knowledge of psychosocial risk factors in work stress:

1.    Personal control or discretion over workload and work pace: Research indicates emotional distress results from lack of worker participation in these factors.
2.    Consistency of work schedule: Shift work and night work are more stressful than consistent work scheduling.
3.    Role ambiguity: Ambiguous role or conflictual position in the workplace has been linked to hypertension and increased heart rate.
4.    Security: Fear of forced retirement, low job security.
5.    Interpersonal relationships.
6.    Job content: Narrow, repetitive jobs are more stressful.
7.    Psychological factors: The meaning of job attributed by the individual, e.g., one person might find the job of a food server as interesting, another highly stressful and demeaning because of differing expectations.

TABLE 9.2. Diagnostic Criteria for 309.81 Posttraumatic Stress Disorder

1. The person has been exposed to a traumatic event in which both of the following  were present:

a.    the person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others

 b. the person's response involved intense fear, helplessness, or horror. Note: In children, this may be expressed instead by disorganized or agitated behavior

2. The traumatic event is persistently reexperienced in one (or more) of the following  ways:

a.  recurrent and intrusive distressing recollections of the event, including images, thoughts, or perceptions. Note: In young children, repetitive play may occur in which themes or aspects of the trauma are expressed.

b.    recurrent distressing dreams of the event. Note: In children, there may be frightening dreams without recognizable content.


c.    acting or feeling as if the traumatic event were recurring (includes a sense of reliving the experience, illusions, hallucinations, and dissociative flashback episodes, including those that occur on awakening or when intoxicated). Note: In young children, trauma-specific reenactment may occur.


d. intense psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event


e. physiological reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event.

3. Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not present before the trauma), as indicated by three (or more) of the following:

a. efforts to avoid thoughts, feelings, or conversations associated with the trauma

b. efforts to avoid activities, places, or people that arouse recollections of the trauma


c. inability to recall an important aspect of the trauma


d. markedly diminished interest or participation in significant activities


e. feeling of detachment or estrangement from others


f. restricted range of affect (e.g., unable to have loving feelings)


g. sense of a foreshortened future (e.g., does not expect to have a career, marriage, children, or a normal life span)

4. Persistent symptoms of increased arousal (not present before the trauma), as  indicated by two (or more) of the following:

a.    difficulty falling or staying alseep
b.    irritability or outbursts of anger
c.    difficulty concentrating
d.    hypervigilance
e.    exaggerated startle response

5. Duration of the disturbance (symptoms in Criteria B, C, and D) is more than 1     month.

6. The disturbance causes clinically significant distress or impairment in social,  occupational, or other important areas of functioning.

Specify if:
Acute: if duration of symptoms is less than 3 months Chronic: if duration of symptoms is 3 months or more

Specify if:
With delayed onset: if onset of symptoms is at least 6 months after the stressor.

"Reprinted with permission from American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington. DC: Author.