The Human Nervous System is the Most Sensitive to Environmental Toxins

 

By

 

Kaye H. Kilburn

 

from Approach to a Consensus for the Basis of Regulation of Environmental Chemicals, (eds) J. D. Arcos, et al. Special Issue of Environmental Carcinogenesis Reviews Part C of Journal of Environmental Sciences and Health, Marcel Dekker, Inc. (1991)

 

Every school child is taught that the human nervous system evolved to apprehend and perceive the environment. It registers, and discriminates with great sensitivity, light, color, sound, vibration, touch, pain, position, odor, and taste. Could this capacity be it's Achilles heel? Sensitivity may be its undoing.

We have accepted the fact that other organs are highly sensitive to environmental toxins, such as the lung to asbestos and Isocyanates, the liver to carbon tetrachloride and vinly chloride, the kidney to cadmium and phenacetic, and the skin to methacrylate and urushiol. However, intuition and history favor the brain and nervous system for sensitivity. If this is true, why has it escaped our attention until recently?

Perception of damage to the brain and nervous system may be masked by its wonderful redundancy. Such effective damage control is carried out by substituting function and redirecting impulses so that until reserves are nearly gone, only a slowing of response may be seen. And because slowing is regarded as an ordinary manifestation of aging, the damage is concealed. Even considerable slowing may be overlooked in clinical neurological evaluations, which are only qualitative and at best measure one subject's nervous system against that of another, making fine estimates of time impossible.

Quantative measurements focused on speed appear to be the key to the appraisal of many subtle changes in function, elusive until recently. Just as spirometry measures the speed of expiratory airflow from the lung, reaction time, speed of the sway-movement, and blink speed (for example) measure the time needed to perform diverse functions. Ideal comparisons would be to follow up an individual across time or across an episode of exposure, which may be brief or prolonged. Short of such ideal, but very rare cases, comparisons between populations exposed to an agent or situation or to a site, such as a workplace or neighborhood, require controls.

In a world increasingly polluted, finding a group of human subjects to compare to may be a most difficult problem.

Although the origins of neurotoxicology are lost in prehistory, systematic observations of palsy and colic from lead were made by Benjamin Franklin and of erethism (irritation), tremor, and cachexia in mirror silverers exposed to mercury in amalgams by Ramazzini and by Kussmaul, and immortalized in "hatters shakes" and madness by Lewis Carroll. Remarkably, despite this long history, the focusing on neurotoxins and their targets in the brain has been belated, and there has been an apparent lack of a unifying body of concepts concerning their detection and mechanisms of action.

As a first step toward rectifying these deficiencies, I suggest that we reexamine the significance of the fact that the human nervous system, with its special sensory endings, is a highly evolved apparatus for apprehending and perceiving the environment. However, this sensitivity may be its very undoing. The intuitive hypothesis has been advanced that among the systems of living organisms, the nervous system is, in fact, the most liable to damage from environmental toxins.

Damage may be masked against detection, however, because subtle dysfunction is often concealed by the nervous system's remarkable redundancy and ability to substitute function, or it is simply overlooked in clinical evaluations which are usually only quantative. Unless various functions are appraised quantitatively, dysfunction may be attributed to anxiety, tension, aging or a deficient endowment of intelligence.

The Critical keys are quantitative measurements of diverse functions which can be compared to past performance, to predicted scores, or to the behavior of unexposed individuals or populations. The menu of the variety of measurements spreads subtly from the affective and symptomatic, through cognitive functions which require the subject's cooperation such as recall and fund of information, to the measurement of unconscious or automatic functions which have previously been in the sphere of the neurophysiologist.

Symptoms of altered affective states or mood are common in every day experience, particularly fatigue, headache, irritability and depression. The application of quantitative methods such as the Minnesota multi-phasic personality inventory (MMPI) or the profile of mood states (POMS) to the appraisal of affective states and the correlation of these with the outcome of psychological tests for cognitive functions, such as perceptual motor speed, sensory motor reaction time, verbal and visual-spatial memory and design analysis, have begun to provide insight into their relations with cognitive and neurological functions.

Based on profound and prolonged neurobehavioral impairment in individuals such as on the battlefield or as prisoners of war or other ordeals, "post traumatic stress" has been advanced as an explanation for dysfunction. This thesis has also been offered to explain the effects of occupational or environmental exposure to neurotoxins such as organophosphate pesticide over-dose or exposure to trichloroethylene in well water. Although some affected subjects display anger or appear outraged, more often they appear apathetic or depressed. To argue that affective disorders derange neurobeyhavioral function begs the question, mistakes an outcome for a cause and ignores the mind-body unity which is remarkably well demonstrated in the integration of the human nervous system.

Although the human mind has many facets, the integrative position argues that affective disorders which we characterize as confusion, tension-anxiety, depression, anger, fatigue and absence or vigor in the profile of mood states, arise form the apprehension by the damaged but still perceptive brain of its disordered function. Thus, affective disorders are the outcome of toxic encephalopathy and not its imitators by adversely affecting testing. Such damage appears analogous to the situation after massive localized brain damage from vascular accidents (strokes), when all these affective states may ensue together, and depression and/or confusion are frequently obvious on even casual observation.

Tests originally developed to study alcoholism, to select recruits for pilot training, to explore the effects of aging, and to estimate educable children for school placement, are used together with other tests that have been developed to measure toxicity of materials at work, for assessing effects of environmental toxins on the human nervous system.

It would be remiss to proceed further without crediting David Wechsler's contributions in devising two standard instruments. One is an immediate learning (recall and memory) scale and the other is an adult intelligence scale(1,2). Wechsler cautioned that "the information obtained from intelligence tests is relevant to the extent that establishes and reflects whatever it is one finds in overall capacity for intelligent behavior." The tests used to measure intelligence served primarily as a means to an end. "In this respect, the tests do not differ essentially from devices employed by physicists to measure heat by the use of thermometers or thermoelectric couples."

Wechsler combined 11 tests in his WAIS(2) and standardized each. The verbal scale included information, digit span, vocabulary, arithmetic, comprehension, and similarities. The performance scale included picture completion, picture arrangement, block design, object assembly, and digit symbol. Essentially, these were pencil and paper tests suited for literate and language-aware individuals. Others, such as Cattell, deliberately avoided language and literacy in devising "Culture Fair," which consists of four groups of designs: logical series, maximal difference, design completing, and definition establishment and application, for estimating human intelligence(3).

The application of tests to environmental or occupational groups should follow Wechsler's suggestions that the abilities measured broadly characterize human behavior, and that intelligence is multi-phasic and multi-determined with a judgment of overall competency, and finally, that test scores and competency in coping effectively with the environment are not necessarily closely related. Testing the conscious level, nevertheless, requires cooperation, is strongly dependent on understanding language and on capacity to handle numbers, and is also somewhat sensitive to attitude and feeling states.

Attempts to reduce the influence of intelligence, vigilance, cooperation, and feeling states on the final integrative assessment, and to encompass other CNS processes, led to the measurement of automatic neurophysiological functions. Examples include: Nerve conduction, the blink reflex, body balance, visual and auditory evoked potentials, and peripheral vibration and temperature senses. Traditionally these measurements have been restricted to specialized laboratories and have required such large investments of time per subject that they have seldom been employed for epidemiological or even clinical studies. Their use has been limited to confirmation rather than detection. This is a pity, because there is evidence that balance is reversibly affected by ethanol(4), that blink, particularly the initial motor response, is reduced by trichloroethylene(5), that nerve conduction is reduced by lead(6), and that the visual evoked potential, the responses to flash versus pattern are significantly changed in aluminum intoxication(7).

All of these methods broaden the clinical neurologists' qualitative estimates with quantitative ones for detecting subtle differences across time or delays in function induced by exposures. Investigator certainty or "comfort" is greatest when the automatic or neurophysiological tests show abnormality or dysfunction in concert with the ones requiring subject cooperation, and that these also keep track with affective appraisal scores and symptoms.

Clearly, the first application of testing for the affecting-symptomatic area, the conscious-cooperative-cognitive area and the subconscious-automatic neuro-physiological one, is to understand a single patient and relate his impairment or dysfunction to toxic exposures.

Application beyond this subject to many individuals in a group is an epidemiological survey. Sensitivity, i.e., the ability to detect effects, is frequently greater in an epidemiological survey because small differences when compared to suitable populations may be significant while the individual must be looked at in terms of 95% confidence intervals or deviations from his measured or estimated prior level of function.

One among the critical issues is how to estimate previous levels of function when they are unavailable. For some rests, years of school completed is a sensitive predictor; in others, age is a major determinant. Balance exemplifies a function with a U-shaped curve with age, showing improvement during growth and development, a plateau during adulthood and progressive impairment in advanced age. Poor balance also relates to frailty and occurs typically in the eighth or ninth decade of life(8). Subjects exposed to either occupational or environmental chemicals can be studied using these methods.

Workers breathe and contact chemicals and metals while employed for perhaps 40 hours a week. "Environmental neighbors" usually receive diluted doses down-stream or down-wind from industrial processes or their dump sites but for up to 168 hours per week. Although studies or painters with exposure to lead and solvents and rayon workers exposed to carbon disulfide have produced quantitative data to explore these problems, it is now clear that chemicals in dumps, chemical exposure during hazardous material clean-up particularly with the use of ingenious disposal methods such as incineration and injection into exhausted petroleum wells, offer new challenges involving mixtures of chemicals. Chemical waste may be defined functionally, as mixtures too expensive to refine, provided they can be conveniently "lost." Thus, the toxic clean-up workers, the HAZMAT teams, the well-head injectors and perhaps firemen, above all others, are at greatest risk.

It is instructive to consider this century's lessons from lead poisoning - which was manifested by colic and palsy in the last century - that learning deficits and behavioral problems occur in young children in whom increased lead absorption is without a threshold(9,10). In fact, dentine lead, a marker of cumulative lead dose is correlated with increased incidence of "problem behavior" in children compared to controls (who themselves consist of subjects with greatly increased body burdens as compared to pre-industrial populations). Consequent to lead poisoning in young children, a constellation of neurobehavioral disorders including hyperactivity has been called minimal brain dysfunction (MBD) or attention deficit disorder (ADD). It has been suggested that in these children, the monoaminergic systems are dysfunctional, that myelin synthesis and repair are defective, and that nervous system development is impaired. In any case, the neurotoxicity of lead appears to be irreversible(10).

Recently, exposure to high impact noise from artillery and rifle fire, well known to cause deafness, was shown in Finnish soldiers to also adversely affect balance(11). Our preliminary studies on ironworkers, men who assemble structural steel in notoriously noisy construction sites using heavy machinery including air impact hand tools, show hearing loss and impaired balance which are highly correlated (personal observation). Lead toxicity has also been associated with hearing loss(12) as has solvent exposure, illustrating that both chemical, and physical agents can adversely affect cochlear and vestibular functions of the eighth cranial nerve, and the brain which governs them.

Neurobehavioral testing of a population chronically exposed to trichloroethelene (TCE), trichloroethane, chromium and other chemicals in their well water for up to 25 years showed impairment in most domains including memory (recall), perceptual-motor speed, dexterity, balance, blink, and in recognizing logical series, differences, design completion and applying definitions in designs. Comparison to a national reference group showed that these impairments were statistically significant(13). Comparison to a similar population in the same state uncovered another well water contamination incident with TCE and other chlorinated solvents. At Woburn (MA) a cluster of leukemia cases stimulated investigations which demonstrated high prevalence of fatigue, headache, memory loss, and difficulty of concentrating(14). Specific demonstrating of prolonged R, of blink reflex response was attributed to trigeminal nerve poisoning by TCE(15).

Individual patients have shown neurobehavioral impairment from a brief, subfatal exposure to hydrogen sulfide, carbon monoxide or PCBs, and from prolonged occupational exposures to formaldehyde, styrene and epoxy resin systems (including ethyl and methyl aniline) used to make prosthetic limbs, and to mixtures of toxic chemicals injected into abandoned oil wells. Exposures ranged from single elements such as lead and aluminum - and simple compounds such as hydrogen sulfide, carbon monoxide and formaldehyde - to complex mixtures such as were found in the Livingston (LA) train derailment of cars containing 21 different chemicals to multiple industrial solvents in the ground water in Woburn (MA) and Tucson (AZ).

Firemen exposed to pyrolysis products of PCBs in a single dose superimposed upon years of repeated subclinical exposures, showed neurotoxicity months after the incident(15). Perhaps comparison of firemen in the PCB incident to firemen not in the incident concealed measurable dysfunction which would be obvious if these "control" firemen were compared to men without exposure. Quantitative expressions of neuropsychological function enhance the opportunity for finding associations with body burdens of such materials(16).

Recently, alcohol was once again identified as an added-load exposure which, for example, reinforced lead-induced cognitive dysfunction and added to workers' irrationality and behavioral problems(17). It appears that the effects of neurotoxicity may be unrecognized in an exposed population until an episode stimulates investigations which lead to demonstration of impairment.

Much remains to be done in this field. Despite its long history, some branches on its developmental tree are puny or missing. It would help to standardize the descriptive language, and not only group the tests into logical categories, but to standardize them so as to increase the comparability between the work of various investigators on the same toxic substance or of similar occupationally or environmentally exposed populations.

What is also needed, is a clear understanding of the relationships between measures of affective disorder (MMPI or POMS), symptom inventories, cognitive or perceptual testing which requires cooperation, and testing of subconscious and automatic (neurophysiological) performance. As the apparatus for these latter tests is made robust for field use, progress should accelerate. Comparisons across these axes should reveal interrelationships and map the dysfunctions of the nervous system. Quantitative comparisons should increase specificity and predictive capacity. They would improve epidemiology by providing measurements linking it to biochemical and biological markers(18). Rapid progress may be imperative in order to conserve neurobehavioral competence in the population. The field must mature far behind its substantial but somewhat incoordinate beginnings, just described.

The ultimate Hogartian picture shows that - as human discriminatory functions fall -

not only will it be impossible to find unexposed subjects for comparison, but society's resolve and ability to identify the problems and solve them will ebb.

The examples of alcohol, heroin, cocaine, marijuana, "crack," and "speed" which alter perception temporarily are disquieting. Insidious permanent loss is more so. Perhaps it is more than a historical speculation that the fall of the Roman Empire was linked to lead, ingested after it was leached from containers by wine and water.

Contributing to this nightmarish scenario is evidence that the effects of neurotixins mimic aging such that the population's brains age faster than other organs to produce, at worst, epidemic Alzheimer's disease. The economic and political implications are awesome. The realization that the effects of solvents are analogous to aging has led to an elegant method of analysis. It consists of constructing regression equations for age and specific neurophysiological or neuropsychological functions for populations exposed to potential neurotoxins and for control groups. Larger are coefficients in those exposed suggest cumulative effects from extended periods of exposure and confirm the "form frustra" of the nightmare.