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CHRONIC FATIGUE SYNDROME, FIBROMYALGIA SYNDROME
MULTIPLE CHEMICAL SENSITIVITY & GULF WAR SYNDROME
Chronic Fatigue Syndrome (CFS), also known as Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS),
Fibromyalgia Syndrome (FMS), Multiple Chemical Sensitivity (MCS), and Gulf War Syndrome (GWS) share many of
same symptoms, as described below, and often occur together, but they do differ greatly only in the methods used for
their diagnosis and treatment.
Which of these diagnoses a person receives usually depends on the type of specialist he or she sees. CFS is most
likely to be diagnosed by infectious disease specialists, FMS by rheumatologists, MCS by occupational and
environmental medicine physicians, and GWS by physicians in Veterans' Affairs hospitals.
COMPARISON OF PATIENTS WITH CHRONIC FATIGUE SYNDROME, FIBROMYALGIA, AND MULTIPLE CHEMICAL SENSITIVITIES.
Dedra Buchwald; Deborah Garrity.
Author's Abstract: COPYRIGHT American Medical Association 1994
Background: Chronic fatigue syndrome (CFS), fibromyalgia (FM), and multiple chemical sensitivities (MCS) are conditions associated with fatigue and a variety of other symptoms that appear to share many clinical and demographic features. Our objectives were to describe the similarities and differences among patients with CFS, FM, and MCS. Additional objectives were to determine how frequently patients with MCS and FM met the criteria for CFS and if they differed in their health locus of control. Methods: Demographic, clinical and psychosocial measures were prospectively collected in 90 patients, 30 each with CFS, FM, and MCS.
Patients were recruited from a university-based referral clinic devoted to the evaluation and treatment of chronic fatigue and three private practices. Variables included demographic features, symptoms characteristic of each condition, psychological complaints, a measure of health locus of control, and information on health care use. Results: Overall, the three patient groups were remarkably similar in demographic characteristics and the presence of specific symptoms. Patients with CFS and FM frequently reported symptoms compatible with MCS. Likewise, 70% of patients with FM and 30% of those with MCS met the criteria for CFS. Health care use was substantial among patients with CFS, FM, and MCS, with an average of 22.1, 39.7, and 23.3 visits, respectively, to a medical provider during the prior year. Health locus of control did not differ among the three populations. Conclusions: In general, demographic and clinical factors and health locus of control do not clearly distinguish patients with CFS, FM, and MCS. Symptoms typical of each disorder are prevalent in the other two conditions. (Arch Intern Med. 1994;154:2049-2053)
CFS is defined by the Centers for Disease Control as persistent or relapsing fatigue lasting greater than six
months that occurs in combination with at least four of the following eight symptoms: 1) short term memory loss,
2) sore throat, 3) tender cervical or axillary lymph nodes, 4) muscle pain, 5) joint pain without swelling or
redness, 6) headaches, 7) unrefreshing sleep, or 8) postexertional malaise that lasts more than 24 hours. CFS
may develop at any age but usually starts in mid-life, often in conjunction with a flu-like illness, and is diagnosed
more frequently in women. Numerous biochemical abnormalities have been identified in CFS patients but none
as yet are considered diagnostic. And although many different treatments are available that appear to help with
some CFS symptoms, no lasting cure has been found.
FMS is characterized primarily by widespread chronic muscle and joint pain that is usually associated with
disrupted sleep, chronic fatigue, cognitive problems, and many other variable symptoms. According to the
American College of Rheumatology, FMS affects about 3% of the population and, like CFS and MCS, is much more
common in women. It is easily diagnosed with a brief physical exam that involves the testing of 18 pressure (or
tender) points. Treatments focus on relieving pain, avoiding stress, improving sleep and correcting hormonal
imbalances. FMS also may be initiated by infection or chemical exposure.
MCS, like CFS, is diagnosed primarily by the patient's history. It also is characterized by many diverse symptoms
affecting multiple organs (such as the central nervous system and the respiratory system) that wax and wane in
response to previously tolerated levels of chemical exposure. These exposures may be either inhaled (like
perfume), ingested (like food, alcohol and medications), or absorbed through skin contact (like cosmetics).
Other common exposures that aggravate MCS symptoms include fresh paint, new carpet, solvents, pesticides, diesel
exhaust and poor indoor air quality known as in tight "sick" buildings syndrome.
A 1994 study found that 70% of patients with FMS and 30% of those with MCS met the strict 1988 criteria for CFS.
Up to 67% of those with CFS and/or FMS reported a worsening of symptoms following exposure to air pollution,
cigarette smoke, solvent fumes or perfumes. Post exertional fatigue, however, was significantly more common in
patients with CFS and FMS than in patients with MCS. This and other studies document the substantial overlap of
commonly reported symptoms among CFS, FMS and MCS patients.
Journal of A1lergy and Clinical immunology: April 1997, 990422
ABSTRACTS
The Journal of Allergy and Clinical Immunology Official Publication of the American Academy of Allergy, Asthma and Immunology
April 1997, volume 99 number 4
Copyright by Mosby-Year Book, Inc.
Panic response to sodium lactate infusion in patients with multiple chemical sensitivity syndrome
Karen E. Binkley, MD, and Stan Kutcher, MDb
Toronto, Ontario, and Halifax, Nova Scotia, Canada
Background:Many patients who are first seen with what has been called multiple chemical sensitivity syndrome (MCS) experience symptoms suggestive of panic disorder including chest tightness, shortness of breath, palpitations, paresthesias, lightheadedness, and mental confusion. Although such patients are often convinced that these symptoms reflect toxic effects of environmental "chemicals," direct evidence of this is lacking . To the contrary, a previous study has shown that some of these individuals exhibit hyperventilation responses on exposure to non noxious stimuli, and it has been suggested that the resulting hypocarbia accounts for their symptoms. We postulated that some patients with self-identified MCS had an underlying condition similar to panic disorder and would therefore demonstrate similar responses to provocative challenges, such as sodium lactate infusion.
Methods: Patients referred to an allergy and clinical immunology service for evaluation of "chemical sensitivity" were investigated to rule out underlying medical conditions, including asthma, as a cause of their symptoms and were enrolled for study after giving informed consent. After a standardized psychiatric assessment was performed, patients underwent single-blind intravenous infusions of normal saline solution placebo) and sodium lactate (which reproduces symptoms in individuals with underlying panic disorder). All patients were referred for independent psychiatric assessment.
Results: The standardized psychiatric assessment identified four of five patients as meeting DSM III-R diagnostic criteria for panic disorder along with other depressive and/or anxiety-related disorders. All five patients with self-identified chemical sensitivity exhibited a positive symptomatic response to sodium lactate compared with placebo infusion. Independent psychiatric assessment confirmed the diagnosis of panic disorder on the basis of DSM III-R criteria in each of the five patients.
Conclusions: These results suggest that MCS may have a neurobiologic basis similar, if not identical, to that of panic disorder.We speculate that treatments with demonstrated efficacy in panic disorder may also be of benefit in MCS, and conversely, treatments that reinforce anticipatory anxiety and avoidance behavior in patients with MCS may be detrimental
(J Allergy Clin Immunol 1997;99:4.)
GWS is less well defined and refers to the cluster of undiagnosed symptoms of unknown cause that have been reported by over 10% of the US veterans involved in the 1991 war against Iraq (more than 80,000 troops to date).
Although studies published by the Department of Defense, Department of Veterans' Affairs, the National Institute
of Medicine, and the Centers for Disease Control have failed to identify a "unique syndrome," the symptoms most
commonly reported by ill veterans--including chronic fatigue, muscle and joint pain, sleep disturbances, and
neurocognitive problems--are almost identical to those seen in CFS, FMS and MCS. Some independent
researchers attribute the symptoms of GWS to pesticide (methyl mercury) and chemical weapons exposures, while others report finding a mycoplasma infection that can be treated, although not cured, with long-term use of antibiotics.
Summers (1994) has proposed that set of unexplained symptoms in PGW veterans (skin rashes, chronic fatigue, headaches, sore joints, hair loss, irritability, insomnia, diarrhea, and depression) are related to mercury toxicity as result of installation of dental amalgams just prior to or immediately after service in PGW. This hipotesis asserts that installation of these amalgams resulted in clinically evident elemental mercury toxicity that continues as patients have ongoing exposure to mercury.
It is clear that the placement of dental amalgams results in systemic exposure to mercury (Gross and Harrisson, 1989;
Researchers suggest that Gulf War veterans and others who meet the diagnostic criteria for more than one
of CFS, FMS and/or MCS may all be suffering from dental amalgam poisoning but as yet not undefined common
syndrome. Summers et al. 1993). It is also clear that significant exposure to elemental mercury results in toxic syndrome with complex clinical presentation (Wyngaarden et al. 1992.) At the same time, relatively few human studies of adverse effects of amalgams have been done. Interest in diminishing elemental mercury exposure has resulted in proposals in Sweden, Denmark and Germany for restrictions on the use of mercury - containing dental amalgams.
To date, the hypothesis of unexplained symptoms in PGW veterans associated with the recent installation of dental amalgams has not been directly investigated to the best of our knowledge.
All, for example, seem to share heightened sensitivity to a diverse range of stresses, from physical exertion and infection to environmental exposures. In addition to chemical sensitivity, they often also report heightened sensitivity to bright lights, loud noises, hot and/or cold weather, and/or being touched. Until further research clarifies the nature of this overlap, however, the majority of physicians, insurers, attorneys and support groups continue to regard CFS, FMS, MCS and GWS for legal claims are trying to define as separate and distinct conditions.
Neurophysiological Effects of Flickering Light in Patients with
Perceived Electrical Hypersensitivity.
JOEM 39:1 (January 1997), pp 15-22
Monica Sanstrm, Bsc, Eugene Lyskov MD PhD, Andr Berglund,
Sviatoslav Medvedev MD PhD, Kjell Hansson Mild PhD,
An increasing number of people (in Sweden) are claiming that they are hypersensitive to electricity.
These patients suffer from skin as well as neurological symptoms when they are near computer monitors, fluorescent tubes, or other electrical appliances. Provocation studies with electromagnetic fields emitted from these appliances have, with only one exception, all been negative, indicating that there are other factors in the office environment that can effect the autonomic and/or central nervous system, resulting in the symptoms reported. Flickering light is one such factor and was therefore chosen as the exposure parameter in this study.
Ten patients complaining of electrical hypersensitivity and the same number of healthy voluntary control subjects were exposed to amplitude-modulated light. The sensitivity of the brain to this type of visual stimulation was tested by means of objective electrophysiological methods such as electroetinography and visual evoked potential. A higher amplitude of brain cortical responses at all frequencies of stimulation was found when comparing patients with the control subjects, whereas no differences in retinal responses were revealed.
Correspondence:
Kjell Hansson Mild, PhD
National Institute
Box 7654, S-907
13 Ume, Sweden
THE RELATIONSHIP OF COMPUTER VISION SYNDROME
TO MUSCULOSKELETAL DISORDERS
Many individuals who work at a computer video display terminal (VDT) report a high level of job-related complaints and symptoms, including ocular discomfort, muscular strain, and stress. Surveys of computer workers show that eye and vision problems are the most frequently reported health-related problems, generally occurring in 70 to 75 percent of computer workers.1-3 The complex of eye and vision problems related to near work experienced during computer use has been termed "computer vision syndrome".4
The elements of working at a computer which make it visually demanding include frequent saccadic eye movements (ocular motility) and continuous eye focusing (accommodation) and alignment (vergence) demands. Problems occur when the visual demands of the task exceed the visual abilities of the individual to comfortably perform the task.
Eye movements, eye focusing, and eye alignment processes involve repetitious muscular activity. The movement of each of the eyes is controlled by six extraocular muscles5 that are responsible for proper alignment of the eyes when viewing objects such as the computer screen. The ability of the eyes to change focus is controlled by the ciliary muscle, which exerts a force on the internal lens of the eye.6 In many respects, many computer related vision problems can be considered a form of musculoskeletal disorder, commonly referred to as cumulative trauma disorder (CTD) or repetitive stress injuries (RSI).7 The relationship between computer related vision problems and RSI include:
Symptoms are work related and associated with repetitive activity -- The development of computer vision syndrome is related to the unique aspects of the task. Working at a computer is more visually demanding than doing other standard office work such as reading printed documents. Aspects of the design of the computer video display such as screen resolution and contrast, image refresh rates and flicker, and screen glare, as well as working distances and angles all may contribute to worker symptoms.8,9
In order to accomplish specific computer related tasks, frequent eye movements from work documents to the computer screen, or from the screen to the keyboard and back again, are used. In addition, as the object being viewed changes, so does the need for a change in eye focusing to maintain a clear image. These changes occur repeatedly during computer work. The flexibility of the lens within the eye gradually decreases with age resulting in a condition called presbyopia, which affects most people after about age 40. As a result, individuals are unable to adequately focus on close work and computer screens without a proper spectacle lens correction.10
Problems are related to disorders of muscles, tendons, bones, or nerves -- Ocular motility, accommodative and vergence disorders are due to problems with the neuromuscular control mechanisms of these functions.
Problems occur or are aggravated by repeated movements -- The visual symptoms that occur from working at a computer are the result of repeatedly stressing some aspect of the eyes or visual system. Asthenopia and visual symptoms result from the task difficulty and duration stressing the accommodative and eye coordination systems.
Eye-related symptoms and the underlying vision condition may be aggravated and/or precipitated by repeated work at a computer. This is not dissimilar from other types of RSIs in which a part of the human physiology functions properly with normal activity, but breaks down and causes symptoms when strained or stressed.
A lengthy period of time is required for the problems to develop and for the individual to recover -- Although vision disorders may occur as localized fatigue and subside after discontinuance of work, they often return the next day when work is resumed. Unlike other forms of localized fatigue, the visual system is not able to adapt to the conditions that cause the fatigue so that it no longer occurs with regular exposure. Some vision problems may become more significant over time.11
Many aspects of computer vision syndrome meet the same criteria used to define cumulative trauma disorders or repetitive stress injuries. Because of the impact of computer vision syndrome on worker comfort and productivity, the American Optometric Association believes more attention needs to be given to reducing the impact of computer related vision problems in the workplace and to providing appropriate eye and vision care for workers who use computers on a regular basis.
Chronic fatigue syndrome is dismissed by many quacks passing for medical doctors in political fight for financial turf and is being as being deliberately assessed as merely not existing ever objectively confirmed bogus medical label known as psychosomatic; that is if you have it, it's only in your head, since such quack usually following the business association's (AMA) recommendations is not intelligent enough to make by himself any sound correlation and provide any sound diagnosis.
In deed there is growing evidence that AMA attracts poorly educated doctors who are trying to gain credentials as medical doctors while conning the patients. The best qualified doctors are withdrawing membership from this business organization trying to claim monopoly on medical practice and diagnosis. AMA was involved in embarrassing scandals for last decades involving Sun corporation, ZANTAC and Helocobacter Pylori, and treatment and diagnosis of known as Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS), Fibromyalgia Syndrome (FMS), Multiple Chemical Sensitivity (MCS), and Gulf War Syndrome (GWS) well known to be caused by neurotoxicity of dental amalgam.
AMA attracted aggressive management with mediocre medical education, and lack of scientific or intellectual capacity, while manipulated by big Insurance and pharmaceutical industry financial support which are nothing else as buying the influence in exchange for loyalty and some deliberately intimidating the researchers as reported in:.
England Journal of Medicine - April 17, 1997 - Volume 336, Number 16
The Messenger under Attack - Intimidation of Researchers by Special-Interest Groups Attacks on health researchers are not new. Pierre Louis, for example, was vilified nearly two centuries ago for suggesting that bloodletting was an ineffectual therapy.(1) In an open society such as ours, controversy is common and often socially useful. The fact that scientists are sometimes challenged by special-interest groups should be no surprise. However, with widening media coverage of health research, growing public interest in health hazards, and expanding research on the outcomes of clinical care, such attacks may become more frequent and acrimonious. The huge financial implications of many research studies invite vigorous attack.
In Marcia Angell's recent Shattuck Lecture, she argued that litigation, fear, bias, and greed interfere with scientific efforts to answer questions of importance to public health and that an antiscientific social attitude encourages premature or ill-informed political and legal solutions to medical questions.(2) She noted that intimidation may cause investigators and institutions with access to critical sources of data to shy away from conducting research on controversial topics. Studies of health hazards are illustrative of this problem. Media and courtroom approaches rapidly overshadowed clinical and epidemiologic studies of the potential adverse effects of breast implants.(2,3) The lead industry hobbled the work of Needleman and colleagues on the health risks of low-level lead exposure and intimidated others through coordinated attacks at scientific meetings and skillful manipulation of the procedures for investigating scientific misconduct.(4,5,6) The National Rifle Association and its allies, angered by studies funded by the National Center for Injury Prevention and Control, part of the Centers for Disease Control and Prevention, that demonstrated the risks to family members posed by guns in the home, tried to eliminate the agency that provided the funding.(7)
Such attacks often focus on "hot-button" policy issues (chemical exposure, firearm injuries) or on data relevant to large disability or liability claims (breast implants). Three recent experiences involving our institutions illustrate how vituperative such attacks may be and the range of tactics employed. Such episodes warrant close scrutiny, because intimidation of investigators and funding agencies by powerful constituencies may inhibit important research on health risks and rational approaches to cost-effective health care.
Copyright © 1997 by the Massachusetts Medical Society
Individual Differences in Neural Sensitization and the Role of Context in Illness from Low-level Environmental Chemical Exposures
Iris R. Bell,1,2,5 Gary E. Schwartz,1,2,3 Carol M. Baldwin,2,4 Elizabeth E. Hardin,1 Nancy G. Klimas,6,7 John P.
Kline,2 Roberto Patarca,6 and Zhi-Ying Song2
Departments of 1Psychiatry, 2Psychology, and 3Neurology, and 4Division of Respiratory Sciences, University of Arizona,
Tucson, Arizona; 5Department of Psychiatry, Tucson Veterans Affairs Medical Center, Tucson, Arizona, 6Department of
Medicine (Immunology), University of Miami School of Medicine, Miami, Florida; 7Miami Veterans Affairs Medical Center,
Miami, Florida
Abstract
This paper summarizes the clinical phenomenology of multiple chemical sensitivity (MCS), outlines the concepts and evidence for the olfactory-limbic, neural sensitization model for MCS, and discusses experimental design implications of the model for exposure-related research. Neural sensitization is the progressive amplification of responsivity by the passage of time between repeated, intermittent exposures. Initiation of sensitization may require single toxic or multiple subtoxic exposures, but subsequent elicitation of sensitized responses can involve low or nontoxic levels. Thus, neural sensitization could account for the ability of low levels of environmental chemicals to elicit clinically severe, adverse reactions in MCS.
Different forms of sensitization include limbic kindling of seizures (compare temporal lobe epilepsy and simple partial seizures) and time-dependent sensitization of behavioral, neurochemical, immunological, and endocrinological variables.
Sensitized dysfunction of the limbic and mesolimbic systems could account in part for many of the cognitive, affective, and somatic symptoms in MCS. Derealization (an alteration in perception making familiar objects or people seem unfamiliar or unreal) is a common MCS symptom and has been linked with limbic dysfunction in clinical neuroscience research.
Sensitization is distinct from, but interactive with, other neurobiological learning and memory processes such as
conditioning and habituation (compare adaptation or tolerance). In previous studies, hypotheses for MCS involving
sensitization, conditioning, and habituation (adaptation) have often been considered in isolation from one another. To design more appropriate chemical exposure studies, it may be important to integrate the various theoretical models and empirical approaches to MCS with the larger scientific literature on individual differences in these potentially interactive phenomena. (1997)
***
Neurogenic Inflammation: With Additional Discussion of Central and
Perceptual Integration of Non neurogenic Inflammation
Rebecca Bascom,1 William J. Meggs,2 Mark Frampton,3 Kenneth Hudnell,4 Kaye Killburn,5 Gerd Kobal,6
Michelle Medinsky,7 and William Rea8
1 Environmental and Airway Diseases Research Facility, University of Maryland School of Medicine, Baltimore, Maryland
2 Department of Emergency Medicine, East Carolina University, Greenville, North Carolina
3 Department of Pulmonary and Critical Care, University of Rochester School of Medicine, Rochester, New York
4 U. S. Environmental Protection Agency, Research Triangle Park, North Carolina
5 University of Southern California, Los Angeles, California
6 Department of Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany
7 Chemical Industry Institute of Technology, Research Triangle Park, North Carolina
8 Environmental Health Center, Dallas, Texas
Abstract
The Working Group on Neurogenic Inflammation proposed 11 testable hypotheses in the three domains of neurogenic inflammation, perceptual and central integration, and nonneurogenic inflammation. The working group selected the term people reporting chemical sensitivity (PRCS) to identify the primary subject group. In the domain of neurogenic inflammation, testable hypotheses included: PRCS have an increased density of c-fiber neurons in symptomatic tissues;
PRCS produce greater quantities of neuropeptides and prostanoids than nonsensitive subjects in response to exposure to low-level capsaicin or irritant chemicals; PRCS have an increased and prolonged response to exogenously administered c-fiber activators such as capsaicin; PRCS demonstrate augmentation of central autonomic reflexes following exposure to agents that produce c-fiber stimulation; PRCS have decreased quantities of neutral endopeptidase in their mucosa; exogenous neuropeptide challenge reproduces symptoms of PRCS. In the domain of perceptual and central integration, testable hypotheses included: PRCS have alterations in adaptation, habituation, cortical representation, perception, cognition, and hedonics compared to controls; the qualitative and quantitative interactions between trigeminal and olfactory systems are altered in PRCS; higher integration of sensory inputs is altered in PRCS. In the domain of nonneurogenic inflammation, testable hypotheses included: increased inflammation is present in PRCS in symptomatic tissues and is associated with a heightened neurosensory response; PRCS show an augmented inflammatory response to chemical exposure. The working group recommended that studies be initiated in these areas. -- (1997)
***
Testing the Neural Sensitization and Kindling Hypothesis for Illness from Low Levels of Environmental Chemicals
Iris R. Bell,1 John Rossi III,2 Mary E. Gilbert,3 Gerd Kobal,4 Lisa A. Morrow,5 David B. Newlin,6 Barbara A.
Sorg,7 and Ronald W. Wood8
1 Departments of Psychiatry, Psychology, and Family and Community Medicine, University of Arizona, and the Tucson
Veterans Affairs Medical Center, Tucson, Arizona
2 Naval Medical Research Institute Detachment (Toxicology), Tri-Service Toxicology Consortium, Wright-Patterson Air Force
Base, Ohio
3 1 U.S. Environmental Protection Agency, Research Triangle Park, North Carolina
4 1 Department of Pharmacology and Toxicology, University of Erlangen-Nurnberg, Erlangen, Germany
5 Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
6 National Institute of Drug Abuse, Baltimore, Maryland
7 Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman,
Washington
8 Department of Environmental Medicine, New York University, New York, New York
Abstract
Sensitization in the neuroscience and pharmacology literatures is defined as progressive increase in the size of a response over repeated presentations of a stimulus. Types of sensitization include stimulant drug-induced time-dependent sensitization (TDS), an animal model related to substance abuse, and limbic kindling, an animal model for temporal lobe epilepsy. Neural sensitization (primarily nonconvulsive or subconvulsive) to the adverse properties of substances has been hypothesized to underlie the initiation and subsequent elicitation of heightened sensitivity to low levels of environmental chemicals. A corollary of the sensitization model is that individuals with illness from low-level chemicals are among the more sensitizable members of the population. The Working Group on Sensitization and Kindling identified two primary goals for a research approach to this problem: to perform controlled experiments to determine whether or not sensitization to low-level chemical exposures occurs in multiple chemical sensitivity (MCS) patients; and to use animal preparations for kindling and TDS as nonhomologous models for the initiation and elicitation of MCS. -- (1997)
***
In Reply to: MCS and poisoning by dental amalgam posted by Mai on May 31, 1999 at 20:35:44:
Psychoneuroimmunology
Nicholas Cohen,1 Howard Kehrl,2 Birgitta Berglund,3 Ann O'Leary,4 Gerald Ross,5 James Seltzer,6 and Clifford
Weisel7
1 Department of Microbiology and Immunology, University of Rochester, Rochester, New York
2 U.S. Environmental Protection Agency, Research Triangle Park, North Carolina
3 Department of Psychology, Stockholm University, Stockholm, Sweden
4 Department of Psychology, Rutgers, The State University of New Jersey, Piscataway, New Jersey
5 Environmental Health Center-Dallas, Dallas, Texas
6 6 Indoor Hygienic Technologies, San Diego, CA
7 EOHSI, Rutgers, The State University of New Jersey, Piscataway, New Jersey
Abstract
This paper develops hypotheses regarding the interactions among stress, immunity, and chemical sensitivities and gives an overview of the questions and hypotheses generated by a working group exploring the application of
psychoneuroimmunology to chemical sensitivities. Consideration is given to prospective longitudinal studies designed to find cases among at-risk exposed populations. Relevant immune parameters to be measured longitudinally and in challenge studies for patients with MCS are discussed. Immune system changes in response to the chronic stress of having MCS and as primary responses to chemical exposure also are considered. -- (1997)
***
Potential Role of Stress and Sensitization in the Development and Expression of Multiple Chemical Sensitivity
Barbara A. Sorg and Balakrishna M. Prasad
Program in Neuroscience, Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington
State University, Pullman, Washington
Abstract
Chemical sensitivity in humans may be an acquired disorder in which individuals become increasingly sensitive to chemicals in the environment. It is hypothesized that in individuals with multiple chemical sensitivity (MCS), a sensitization process has occurred that is akin to behavioral sensitization and kindling observed in rodents. In the rodent sensitization model, repeated exposure to stress or drugs of abuse enhances behavioral and neurochemical responses to subsequent stimuli (stress or drugs of abuse). Kindling is a form of sensitization in which repeated application of electrical stimuli applied to the brain at low levels culminates in the induction of full-blown seizures when the same stimulus is applied at a later time. A similar sensitization of specific limbic pathways in the brain may occur in individuals with MCS. The time-dependent nature of sensitization and kindling and the role of stress in the development of sensitization are discussed in the context of rodent models, with an emphasis on application of these models to human studies of MCS. -- (1997)
****
Hypothesis for Induction and Propagation of Chemical Sensitivity Based on Biopsy Studies
William J. Meggs
Department of Emergency Medicine, East Carolina University School of Medicine, Greenville, North Carolina
Abstract
The reactive airways dysfunction syndrome (RADS), the reactive upper airways dysfunction syndrome (RUDS), the sick building syndrome (SBS), and the multiple chemical sensitivity syndrome (MCS) are overlapping disorders in which there is an intolerance to environmental chemicals. The onset of these illnesses is often associated with an initial acute chemical exposure. To understand the pathophysiology of these conditions, a study of the nasal pathology of individuals experiencing these syndromes was undertaken. Preliminary data indicate that the nasal pathology of these disorders is characterized by defects in tight junctions between cells, desquamation of the respiratory epithelium, glandular hyperplasia, lymphocytic infiltrates, and peripheral nerve fiber proliferation. These findings suggest a model for a relationship between the chronic inflammation seen in these conditions and an individual's sensitivity to chemicals. A positive feedback loop is set up: the inflammatory response to low levels of chemical irritants is enhanced due to the observed changes in the epithelium, and the epithelial changes are propagated by the inflammatory response to the chemicals. This model, combined with the concept of neurogenic switching, has the potential to explain many aspects of RADS, RUDS, SBS, and MCS in a unified way. --
Environ Health Perspect 105(Suppl 2):473-478 (1997)
***
Empirical Approaches for the Investigation of Toxicant-induced Loss of Tolerance
Claudia Miller,1 Nicholas Ashford,2 Richard Doty,3 Mary Lamielle,4 David Otto,5 Alice Rahill,6 and Lance
Wallace7
1 Department of Family Practice, University of Texas Health Science Center at San Antonio, San Antonio, Texas
2 Center for Technology, Policy and Industrial Development, Massachusetts Institute of Technology, Boston, Massachusetts
3 Department of Otorhinolaryngology: Head and Neck Surgery, University of Pennsylvania Medical Center, Philadelphia,
Pennsylvania
4 National Center for Environmental Health Strategies, Voorhees, New Jersey
5 U.S. Environmental Protection Agency, Research Triangle Park, North Carolina
6 Department of Environmental Medicine, University of Rochester, Rochester, New York
7 Office of Research and Development, U.S. Environmental Protection Agency, Warrenton, Virginia
Abstract
It has been hypothesized that sensitivity to low-level chemical exposures develops in two steps: initiation by an acute or chronic chemical exposure, followed by triggering of symptoms by low levels of previously tolerated chemical inhalants, foods, or drugs. The Working Group on Toxicant-induced Loss of Tolerance has formulated a series of research questions to test this hypothesis: Do some individuals experience sensitivity to chemicals at levels of exposure unexplained by classical toxicological thresholds and dose-response relationships, and outside normally expected variation in the population? Do chemically sensitive subjects exhibit masking that may interfere with the reproducibility of their responses to chemical challenges? Does chemical sensitivity develop because of acute, intermittent, or continuous exposure to certain substances?
If so, what substances are most likely to initiate this process? An experimental approach for testing directly the relationship between patients' reported symptoms and specific exposures was outlined in response to the first question, which was felt to be a key question. Double-blind, placebo-controlled challenges performed in an environmentally controlled hospital facility (environmental medical unit) coupled with rigorous documentation of both objective and subjective responses are necessary to answer this question and to help elucidate the nature and origins of chemical sensitivity. -- (1997)
Summers (1994) has proposed that set of unexplained symptoms in PGW veterans (skin rashes, chronic fatigue, headaches, sore joints, hair loss, irritability, insomnia, diarrhea, and depression) are related to mercury toxicity as result of of dental amalgams. This hipotesis asserts that installation of these amalgams resulted in clinically evident elemental mercury toxicity that continues as patients have ongoing exposure to mercury.
It is clear that the placement of dental amalgams results in systemic exposure to mercury (Gross and Harrisson, 1989; Summers et al. 1993). It is also clear that significant exposure to elemental mercury results in toxic syndrome with complex clinical presentation (Wyngaarden et al. 1992.)
The most extensive episodes of mercury (Hg) poisoning have resulted from contamination of bread accidently made from cereal grains treated with alkyl-mercury fungicides labeled for agricultural use only. The grain was accidently ordered to be treated with methyl mercury due to typo error. When arrived to late for farming some decided to use it instead of grain for fluor.
These incidents have occurred in Iraq, Pakistan, Guatemala, and on a limited scale, in other countries. The largest of these episodes occurred in Iraq, 1971-72. It involved some 50,000 cases of severe illnesses and 5000 deaths.
The mean methyl mercury (also present in fungicides and herbicites) content of wheat was found to be 7.9 mg/kg (3.7-14.9 mg/kg). In the most severely affected group of the population, the highest daily intake of Hg was about 130 mcg/kg; The average period of consumption ranged from 43-68 days.
MULTIPLE CHEMICAL SENSITIVITY SYNDROME: A Clinical Perspective.
I. Case Definition, Theories of Pathogenesis, and Research Needs
Abstract
Sparks-PJ; Daniell-W; Black-DW; Kipen-HM; Altman-LC; Simon-GE; Terr-AI
Source: Journal of Occupational Medicine, Vol. 36, No. 7, pages 718-730.
Abstract: Disease definition, theories of pathogenesis, and research needs related to the multiple chemical sensitivity syndrome (MCS) were discussed. The most acceptable definition recognized four aspects: MCS was acquired in relation to some documentable environmental exposure; symptoms involved more than one organ;
symptoms were elicited on exposure to very low levels of chemicals; and manifestations were subjective, with no objective evidence of organ damage. Theories on the
etiology of MCS fell into four groups: physical or psychophysiological reactions to chemicals; precipitation by low level environmental chemical exposure, but with an underlying psychological stress; chemical exposure not the cause, and the symptoms misdiagnosed psychological or physical disease; and simply a belief system instilled by certain practitioners, the media, or society, and was culturally shaped. Physiological and psychophysiological mechanisms, and problems associated with theories that implied an immune system disturbance were discussed in detail, with examples from both human and animal studies. The role of conditioned responses seemed important.
Repeated exposures and associated kindling of brain neurons resulted in amplification of reactivity in animals, but was not supported or refuted by studies in humans.
Examples of odor induced panic disorder in predisposing persons, symptoms of depression and anxiety induced by chemical exposure, and possible relationships with MCS were addressed. The actual pathologic significance of central neurophysiological functions induced in MCS patients was unclear. MCS with cacosmia as a manifestation was discussed. Psychological stress seemed to play a role in the subjective sensitivity to odors from chemical exposure. Cases of illness misdiagnosed as MCS were discussed. Fear of potential harm from chemical exposure seemed to play a role. The predominance of women MCS sufferers was addressed within the framework of a culturally shaped illness belief system of increased concern over the health effects of exposure to man made chemicals.
Clinical Research Testing
by Prof. Garth L. Nicolson and Dr. Marwan Nasralla
CHRONIC FATIGUE SYNDROME, GULF WAR ILLNESS, FIBROMYALGIA AND ARTHRITIS
Research indicates that a rather large subset of patients with Chronic Fatigue Syndrome, Gulf War Illness, Fibromyalgia and Arthritis have in common that they have one or more chronic infections. These chronic infections are very important, we feel, in determining their clinical problems.
The Institute for Molecular Medicine has found that in a sizable portion of such patients the chronic infections can be identified, and once identified, these chronic infections can be treated.
This has allowed, in most cases, patients with these infections to experience significant clinical benefits.
The Institute has recently begun a new program of research that is aimed at helping hundreds of thousands of patients that suffer from chronic illnesses. The tests that we employ are research tests for investigational use. They are not routine tests that can be conducted by any clinical laboratory, although we have assisted clinical laboratories in the performance of these tests and we will be training Department of Defense personnel in performing similar tests. The tests that we perform are considered ‘molecular tests' that use state-of-the-art molecular biologic procedures that have not been available for the length of time required and other criteria to be certified by the FDA for routine testing. By joining our ‘Friends of the Institute' program, individuals can request that we test their blood in our research program for the presence of chronic infections. Please consult, if necessary, with your physician on the use of investigational tests for assisting in the diagnosis of illnesses.
Neurotoxicity: Identifying and Controlling Poisons of the Nervous System
U.S. Office of Technology Assessment
April 1990
OTA-BA-436
NTIS order #PB90-252511 (361 pages)
Extraordinary developments in the neuroscience in recent years have been paralleled by a growing congressional interest in their policy implications. The designation of the 1990s by the 101st Congress as the "Decade of the Brain" is one indication of the promise shown by scientific advances for treating diseases of the nervous system and for increased general
understanding of the human mind. Other advances, however, have led us to the disturbing realization that many commonly used chemicals can adversely affect the human nervous system. Concern about this issue provided the motivation for hearings held in October 1985 on ‘‘Neurotoxins in the Home and in the Workplace' by the Subcommittee on Investigations
and Oversight of the House Committee on Science and Technology.
Another result of heightened congressional interest was a request that OTA undertake a series of assessments on major public policy issues related to the neuroscience. Requesting committees included the House Committees on Science, Space, and Technology; Energy and Commerce; Appropriations; and Veterans' Affairs; and the Senate Subcommittee on Science, Technology, and Space of the Committee on Commerce, Science, and Transportation. In addition, the Senate Committee on Environment and Public Works recently requested a study of the noncancer health risks posed by toxic substances. This Report, the first of the neuroscience series, discusses the risks posed by neurotoxic substances—substances that can adversely affect the nervous system—and evaluates the Federal research and regulatory programs now in place to address these risks.
One finding of this Report is that considerably more research and testing are necessary to determine which substances have neurotoxic potential. Neurotoxic effects can often go unrecognized because symptoms are varied and may not appear for months or even years.
Adverse effects range from impaired movement, anxiety, and confusion to memory loss, convulsions, and death.
Another important finding is the need for greater public awareness. Neurotoxic chemicals constitute a major public health threat; the social and economic consequences of excessive exposure to them are potentially very large. Minimizing exposure requires action not just by regulatory and other public officials, but also by individual citizens who can take steps to avoid these substances both at home and in the workplace.
Many individuals and institutions contributed their time and expertise to the project.
Scientists and regulatory officials in several Federal agencies and experts in academia and industry served on the project's advisory panel, in workshop groups, and as reviewers. OTA gratefully acknowledges the assistance of these contributors. As with all OTA assessments, however, responsibility for the content of the Report is OTA's alone and does not necessarily constitute the consensus or endorsement of the advisory panel or the Technology Assessment Board.
Scope of This Study
This study examines many, but not all, of the classes of neurotoxic substances. The assessment includes discussion of industrial chemicals, pesticides, therapeutic drugs, substance drugs, foods, food additives, cosmetic ingredients, and such naturally occurring substances as lead and mercury. It does not include radioactive chemicals, nicotine (from
cigarette smoke), alcohol (ethanol), biological and chemical warfare agents, microbial, plant, and animal toxins, and physical agents such as noise.
WHAT IS NEUROTOXICITY?
The nervous system comprises the brain, the spinal cord, and a vast array of nerves that control major body functions. Movement, thought, vision, hearing, speech, heart function, respiration, and numerous other physiological processes are controlled by this complex network of nerve processes, transmitters, hormones, receptors, and channels.
Although every major body system can be adversely affected by toxic substances, the nervous system is particularly vulnerable to them. Unlike many other types of cells, nerves have a limited capacity to regenerate. Also, many toxic substances have an affinity for lipids, fat-like substances that make up about 50 percent of the dry weight of the brain, compared to 6 to 20 percent of other organs.
Many toxic substances can alter the normal activity of the nervous system. Some produce effects that occur almost immediately and last for a period of several hours: examples include a drug that prevents seizures, an alcoholic beverage, and fumes from a can of paint. The effects of other neurotoxic substances may appear only after repeated exposures over weeks or even years, for example, regularly breathing the fumes of a solvent in the workplace or eating food or drinking water contaminated with
lead. Some substances can permanently damage the nervous system after a single exposure: certain organophosphorous pesticides and metal compounds such as trimethyl tin are examples. Other substances, including abused drugs such as heroin and cocaine, may lead to addiction, a long-term adverse alteration of nervous system function. Many neurotoxic substances can cause death when absorbed, inhaled, or ingested in sufficiently large quantities.
Care must be taken in labeling a substance neurotoxic because factors such as dose and intended effects must be taken into consideration. A substance may be safe and beneficial atone concentration but neurotoxic at another. For example, vitamins A and B6 are required in the diet in trace amounts, yet both cause neurotoxic effects in large doses. In other cases, a substance that is known to be neurotoxic may confer benefits that are viewed as outweighing the adverse effects. For example,
thousands of individuals suffering from schizophrenia have been able to live relatively normal lives because of the beneficial effects of the antipsychotic drugs. However, chronic use of prescribed doses of some of these drugs may give rise to tardive dyskinesia-involuntary movements of the face, tongue, and limbs—side-effects so severe that they may incapacitate the patient.
Another factor that complicates efforts to evaluate neurotoxicity is the potential additive effects of toxic substances. For example, independent exposure to two toxic substances may lead to no observable adverse effects, but simultaneous exposure could result in damage to the nervous system. In addition, the body has an effective but limited capacity for detoxifying many chemical agents. Some chemicals thought to be relatively nontoxic may cause adverse effects if exposure occurs after the body's detoxifying systems have been saturated. Such situations might occur following chronic exposure to a complex mixture of chemicals in the workplace or to chemicals at hazardous waste sites.
Broadly defined, any substance is considered to have neurotoxic potential if it adversely affects any of the structural or functional components of the nervous system. At the molecular level, a substance might interfere with protein synthesis in certain nerve cells, leading to reduced production of a neurotransmitter and brain dysfunction. At the cellular level, a substance might alter the flow of ions (charged molecules such as sodium and potassium) across the cell membrane, thereby perturbing
the transmission of information between nerve cells.
Substances that adversely affect sensory or motor functions, disrupt learning and memory processes, or cause detrimental behavioral effects are neurotoxic, even if the underlying molecular and cellular effects on the nervous system have not been identified. Exposure of children to lead, for example, leads to deficits in I.Q. and poor academic achievement. Behavioral effects are sometimes the earliest signs of exposure to neurotoxic substances. In addition, there is evidence that the adverse
effects of some toxic substance-induced neurodegenerative diseases may not become apparent until years after exposure.
For the purposes of this study, the Office of Technology Assessment (OTA) defines neurotoxicity or a neurotoxic effect as an adverse change in the structure or function of the nervous system following exposure to a chemical agent. This is the definition currently used for regulatory purposes by EPA (50 FR 188). However, as the preceding discussion illustrates, this definition should be used in conjunction with information on the intended use of the substance, the degree of toxicity, and the dose
or extent of exposure of humans or other organisms.
The definition hinges on interpretation of the word "adverse," and there is disagreement among scientists as to what constitutes "adverse change." The nature and degree of impairment, the duration of effects (especially irreversible effects), and the age of onset of effects are among the many neurobehavioral toxicity of only a small percentage of these has been reviewed. Indeed, the National Academy of Sciences evaluated a representative sample of cosmetics in 1984 (focusing on publicly available documents) and found that none had undergone adequate testing to identify potential neurobehavioral effects.
The consequences of inadequate toxicity testing are illustrated by the AETT incident. In 1955, AETT (acetylethyl tetramethyl tetralin) was introduced into fragrances; years later it was found to cause degeneration of neurons in the brains of rats and marked behavioral changes in rats, including irritability and aggressiveness. In 1978, it was voluntarily withdrawn from use by the fragrance industry. Its effects on humans through two decades of use will probably never be known.
FDA lacks the authority to require premarket testing of cosmetics. The agency may initiate an investigation, however, if a basis is presented for doubting a particular product's safety. The regulation of cosmetics is discussed further in chapter.
Organophosphorous and carbamate insecticides are the most neurotoxic classes of pesticides used in
the United States and are the most common causes of agricultural poisoning. They pose a significant threat to a substantial portion of the 4 to 5 million Americans who work in agriculture. At the biochemical level, they may affect humans in the same manner that they affect the insects for which they are intended-through inhibition of the enzyme that breaks down the neurotransmitter acetylcholine. The acute health effects of organophosphorous and carbamate insecticides include hyperactivity, neuromuscular paralysis, visual problems, breathing difficulty, restlessness, weakness,
dizziness, and possibly convulsions. The organochlorine class of pesticides is also very toxic because
these substances accumulate in the body and cause persistent overstimulation of the central nervous system.
Acute or subacute intoxication from organo-chlorines produces excitability, apprehension, dizzines headache, disorientation, confusion, loss of balance, weakness, muscle twitching, tremors, convulsions, and coma.
What scientific and epidemiological data there are suggest pesticide poisoning prevails despite existing protective measures. The Environmental Protection Agency (EPA) is aware of the shortcomings of the protections currently in effect for farmworkers and others who work with pesticides. The Agency has proposed regulations to improve them, but critics have already deemed the proposals inadequate. EPA claims to be restricted by the Federal
Insecticide, Fungicide, and Rodenticide Act, which grants the Agency only limited regulatory power. Inadequate funding has also contributed substantially to the weaknesses of Agency programs.
The possible occurrence of neurobehavioral disorders after chronic low-level exposure or acute poisoning deserves further study. Neuropsychological assessments of occupational groups have yielded inconsistent results, perhaps reflecting differences in the type and scope of tests used. Few studies have had an adequate follow-up to assess the length of impairment. Field studies have not provided sufficient data on levels of pesticides in children's blood or duration of exposure to understand dose-response relationships, nor have most studies controlled for age,
education, or other potential confounding factors. Few or no studies have examined exposed workers prospectively, subgroups of women or aging workers, interactions between pesticides, or interactions between pesticides and pharmacological agents (including ethanol and common medications).
Organic Solvents in the Workplace
Organic solvents and mixtures of solvents with other organic solvents or other toxic substances are widely used in the workplace. Millions of workers come into contact with solvents every day through inhalation or contact with the skin, Some solvents profoundly affect the nervous system. Acute exposure to organic solvents can affect an individual's manual dexterity, response speed, coordination, and balance. Chronic exposure of workers may lead to reduced function of the peripheral nerves and such adverse neurobehavioral effects as fatigue, irritability, loss of memory, sustained changes in personality or mood, and decreased ability to learn and concentrate.
The National Institute for Occupational Safety and Health (NIOSH) recommends that employers inform and educate workers about the materials to which they are exposed, potential health risks involved, and work practices designed to minimize exposure to these substances. NIOSH also recommends that employers assess the conditions under which workers may be exposed to solvents, develop monitoring programs to evaluate the extent of exposure, establish medical surveillance for adverse health effects resulting from exposure, and routinely examine the effectiveness of control methods being employed.
The Occupational Safety and Health Administration has recently updated the permissible exposure limits for approximately 428 substances, including many solvents. The new ruling established lower exposure limits for approximately 212 substances already regulated by the agency. Permissible exposure limits are established for the first time for another 168 substances, while existing limits for 25 substances are reaffirmed. This marks the first time in 17 years that a new set of exposure standards has been established. For many companies, meeting the new standards may require stricter engineering controls or more frequent use of respirators and other personal protective devices, or both. Continued education of workers, improved methods of preventing exposure, and plans or
procedures to maintain compliance with the new ruling are required.
TOXIC SUBSTANCES AND NEUROLOGICAL AND PSYCHIATRIC DISORDERS
Concerns about the effects of neurotoxic substances on public health have increased recently because of new evidence that some neurological or psychiatric disorders may be caused or exacerbated by toxic agents in the environment. A noted case in point is Parkinson's disease. Researchers recently discovered that exposure to small amounts of the toxic substance MPTP can cause Parkinson-like symptoms (20). Exposure to small quantities over a period of days to a few weeks leads to the muscle
weakness and rigidity that is characteristic of Parkinson's disease.
Because of this finding, the possibility that toxic chemicals might be causative agents in some cases of Parkinson's disease is being actively considered by researchers. Some recent findings support this hypothesis. For example, it has been reported that in cases in which Parkinson's disease afflicts several members of a family, the onset of the disease tends to cluster in time. Normally, if a disorder has a purely genetic basis, onset of symptoms occurs at similar ages, not at similar times. Evidence that
Parkinson's disease does not occur more frequently in identical than fraternal twins also argues against a hereditary determinant of the disorder . A recent epidemiological study revealed that between 1962 and 1984, U.S. mortality rates for Parkinson's disease substantially increased in individuals over the age of 75 (figure 2-2). Environmental factors appear to have played a significant role in the increase (23). The relative roles of hereditary and environmental factors in triggering Parkinson's disease remain to be determined.
Evidence for a substantial increase in the incidence of motor neuron disease (MND), primarily amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, in the United States has also recently been reported (22). This disease is characterized by the progressive degeneration of certain nerve cells that control muscular movement. MND is a relatively rare disease, and its cause has eluded researchers for more than a century. Recent data indicate that between 1962 and 1984, the MND
mortality rate for white men and women in older age groups rose substantially (figure 2-3). The increase is thought to be largely due to environmental factors.
In Reply to: Poisoning by dental amalgam - Gulf War Illness posted by MAi on May 31, 1999 at 20:40:08:
TOXIC SUBSTANCES AND NEUROLOGICAL AND PSYCHIATRIC DISORDERS
Concerns about the effects of neurotoxic substances on public health have increased recently because of new evidence that some neurological or psychiatric disorders may be caused or exacerbated by toxic agents in the environment. A noted case in point is Parkinson's disease. Researchers recently discovered that exposure to small amounts of the toxic substance MPTP can cause Parkinson-like symptoms (20). Exposure to small quantities over a period of days to a few weeks leads to the muscle
weakness and rigidity that is characteristic of Parkinson's disease.
Because of this finding, the possibility that toxic chemicals might be causative agents in some cases of Parkinson's disease is being actively considered by researchers. Some recent findings support this hypothesis. For example, it has been reported that in cases in which Parkinson's disease afflicts several members of a family, the onset of the disease tends to cluster in time. Normally, if a disorder has a purely genetic basis, onset of symptoms occurs at similar ages, not at similar times. Evidence that
Parkinson's disease does not occur more frequently in identical than fraternal twins also argues against a hereditary determinant of the disorder . A recent epidemiological study revealed that between 1962 and 1984, U.S. mortality rates for Parkinson's disease substantially increased in individuals over the age of 75 (figure 2-2). Environmental factors appear to have played a significant role in the increase (23). The relative roles of hereditary and environmental factors in triggering Parkinson's disease remain to be determined.
Evidence for a substantial increase in the incidence of motor neuron disease (MND), primarily amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, in the United States has also recently been reported (22). This disease is characterized by the progressive degeneration of certain nerve cells that control muscular movement. MND is a relatively rare disease, and its cause has eluded researchers for more than a century. Recent data indicate that between 1962 and 1984, the MND
mortality rate for white men and women in older age groups rose substantially (figure 2-3). The increase is thought to be largely due to environmental factors.
Naturally occurring toxic substances can also affect the nervous system. An unusual combination of the neurodegenerative disorders ALS, Parkinson's disease, and Alzheimer's disease endemic to Guam (known as Guam ALS-Parkinson's dementia) puzzled investigators for many years because of the correlation between incidence of the disease and preference for traditional foods. During food short-ages, residents of the island ate flour made from the false sago palm, a member of the neurotoxic cycad family. The cycad contains one or more naturally occurring toxic substances that appear to cause a neuromuscular disease in cattle and trigger slow degeneration of neurons, As old age approaches and natural brain cell death accelerates, the effects of the degeneration become apparent and the neurological symptoms appear, This possible link between a naturally occurring compound and a neurodegenerative disease has stimulated the search for other toxic substances that may trigger related neurological and psychiatric disorders. This work and that of others led to the hypothesis that Alzheimer's disease, Parkinson's disease, and ALS could be due in part to damage to specific regions of the central nervous system caused by environmental agents and that the damage may not become apparent until several decades after exposure.
Aluminum and silicon, Toxicology is concerned with the adverse effects of natural or synthetic chemicals on the biochemical, physiological, and behavioral processes of living organisms. Because of the large number of chemicals in commerce and the wide variety of effects they may cause, toxicology is a broad science and toxicologists tend to specialize in one or more areas
of the field. Biochemical toxicologists study the effects of toxic chemicals at the molecular and cellular levels. Regulatory toxicologists evaluate the risks posed by these substances and recommend actions that can be taken to reduce human exposure and environmental contamination. Clinical toxicologists examine the effects of drugs and toxic chemicals on human health and develop treatments to mitigate adverse effects. Behavioral toxicologists are concerned with the effects of toxic substances on
animal and human behavior. Environmental toxicologists address the effects of pollutants on plants and animals, including humans.
Neurotoxicology is concerned with the adverse effects of chemicals on the nervous system. Research in this field involves examining the modes by which neurotoxic substances enter the body, the effects of these substances on the various components of the nervous system, the biochemical and physiological mechanisms by which these effects occur, the prevention of damage to the nervous system, and the treatment of neurological and psychiatric disorders associated with exposure to toxic substances. Although scientists have made tremendous progress in understanding the nervous system, there is still much to learn about its function under both normal and abnormal circumstances.
OVERVIEW OF TOXICOLOGICAL PRINCIPLES
In order for a toxic substance to cause adverse health effects, it, or its metabolic products, must
enter the body and reach the target organ(s) at a sufficient concentration and for a sufficient length of
time to produce a biological response. Chemicals differ in toxicity, with some being toxic in very
small quantities and others having little effect at even very high doses. This relationship between
exposure to a toxic substance and the extent of injury or illness resulting from it is called the "dose-response" relationship. In addition to dose, other critical variables determining toxicity are the properties of the chemical (e.g., its volubility), the means of exposure (through the lungs, stomach, or skin, the health and age of the exposed individual, and the susceptibility of the target organ or tissues.
Absorption,Distribution, Biotransformation, and Excretion
Toxic substances normally enter the body through the lungs (inhalation), the skin (absorption), or the gastrointestinal tract (ingestion). In the industrial setting, most exposures occur through inhalation or absorption. After the substance enters the blood-stream, it is partitioned into body tissues, where it may act on target organs or tissues. For various reasons, including insolubility, some substances are not distributed through the body. Ultimately, toxic substances are eliminated from the bloodstream through accumulation in various sites in the body and through biotransformation and excretion.
Sites of accumulation of toxic substances mayor may not be the primary sites of toxic action. Carbon monoxide, for example, reaches its highest concentration in red blood cells, where it competes successfully with oxygen for binding sites in hemoglobin;
it then causes widespread brain damage when these red blood cells fail to supply an adequate amount of oxygen to the brain. Lead, a potent neurotoxic substance, is found in highest concentrations in bone but exerts its most serious effects on the brain. The liver and kidney are major sites of accumulation of toxic substances, probably because of their large blood capacities and their roles in eliminating toxic substances from the body. Lipophilic toxic chemicals (i.e., chemicals soluble in fat-like materials; also termed hydrophobic) tend to accumulate in lipid-rich areas such as body fat. The brain may be particularly vulnerable to these toxic substances since 50 percent of the dry weight of the brain is lipid, compared to 6 to 20 percent of other organs of the body.
The body has a number of ways to detoxify foreign substances. The liver is the principal organ involved in detoxification, but other organs such as the kidney, the intestine, and the lung also play major roles. In fact, nearly every tissue tested has some capacity for detoxification; these capacities, however, are often limited to particular types of compounds. Adverse effects may occur when the quantity of the substance ingested overwhelms detoxification mechanisms, when an injury or illness
has compromised the body's capabilities for detoxification, or when no mechanism is available to modify or remove the particular substance.
Before excretion, a substance may undergo bio-transformation, the biochemical process by which it is converted into new chemical compounds which are often more easily excreted. This process usually changes lipophilic compounds to compounds which are more hydrophilic (water soluble) and therefore more easily excreted. Although biotransformation normally aids in the detoxification of substances, it sometimes results in compounds that are more toxic.
Therefore, when analyzing neurotoxic substances and the health risks they pose, it is important to remember that the compound originally ingested or absorbed by an organism may not be the toxic substance that eventually acts on the nervous system.
Excretion of toxic chemicals from the body occurs through a variety of routes. Many substances are removed by the kidney and excreted through the urine. The liver is effective in detoxifying and removing substances that enter the body through the gastrointestinal tract. Some toxic substances, such as lead and mercury, are excreted from the liver into the bile and then into the small intestine, bypassing the blood and the kidneys.
Toxic substances are more easily removed from the body if they are hydrophilic or if they can be biotransformed into a more hydrophilic compound.
Lipophilic toxic substances are removed from the body through a number of mechanisms; these include excretion in feces and bile, excretion of water-soluble metabolizes in the urine, expiration into the air, and excretion through the skin.
Interaction of Multiple Toxic Substances
The health effects of toxic substances are frequently examined with the assumption of a single chemical acting alone on a particular organ or type of tissue. Such an analysis has limitations, however.
In some cases, an individual may be exposed to multiple chemicals that act on different organs and tissue types, and one cannot assume that the effect of these substances combined is the same as the combined effects of separate exposures. Chemical interactions may take place between substances.
Sometimes the effects are additive (i.e., the combined effects are equal to the sum of the effects of each of the substances individually); at other times, the effects may be synergistic (i.e., the combined adverse effects exceed the sum of the individual effects).
A substance that is not toxic may increase the toxicity of another substance through a process called potentiation. More rarely, two toxic chemicals may result in no adverse effect when present together, a phenomenon called antagonism. Synergism, potentiation, and antagonism must be taken into account when examining exposure to complex mixtures of toxic substances such as those found in contaminated drinking water, smoke from an industrial fire, and fumes from a hazardous waste site.
THE NERVOUS SYSTEM
The fundamental unit of the nervous system is the nerve cell, or neuron. While neurons have many of the same structures found in every cell of the body, they are unique in that they have axons and dendrites, extensions of the neuron along which
nerve impulses travel, and in that they synthesize and secrete neurotransmitters, specialized chemical messengers that interact with receptors of other neurons in the communication process.
Certain nerve cells are specialized to respond to particular stimuli. For example, chemoreceptors in the mouth and nose send information about taste and smell to the brain. Cutaneous receptors in the skin are involved in the sensation of heat, cold, and touch. Similarly, the rods and cones of the eye sense light.
Glial cells appear to perform functions which support neurons- i. e., supplying nutrition, structural support, and insulation. Certain glial cells, for example, produce myelin, a fatty substance that covers the axons of many neurons throughout the body and acts as insulation. Electrical information in the form of nerve impulses travels along the axons and dendrites of
neurons. The impulses are generated by a rapidly changing flow of charged ions, primarily sodium and potassium, through channels in the nerve cell membrane. The insulating myelin sheath surrounding many nerves allows the electrical impulses (action potentials) to travel farther and faster than they otherwise could. Impulses generally travel away from the cell body of the neuron along axons and interact with the dendrites of other neurons. The point of interaction between adjacent nerve cells is called the synapse. Here, neurotransmitters stored in vesicles in the axon terminal are released by electrical impulses, travel across the synaptic cleft, and bind to receptors on adjacent nerve cells, triggering biochemical events that lead to electrical excitation or inhibition. Information may also be transmitted from nerves to muscle fibers; in this case the point of interaction is called the neuromuscular junction.
Neurotransmitters are chemical messengers that can be subdivided into two categories: the classical neurotransmitters and the neuropeptides. Classical neurotransmitters include serotonin, dopamine, acetylcholine, and norepinephrine; the neuropeptides include endorphin, enkephalin, substance P, and vasopressin. Classical neurotransmitters are typically secreted by one neuron into the synaptic cleft, where they interact with receptors on the surface of the adjacent cell. Neuropeptides, on the other hand, may act over long distances, traveling through the bloodstream to receptors on other nerve cells or in other tissues. Binding of a transmitter to a receptor triggers a series of biochemical events that ultimately affect the electrical activity, or excitability, of the neuron. Depending on the type of transmitter released and the type of receptors, the effect of the chemical interaction is either to inhibit or to stimulate the electrical activity of the adjacent cell.
When multiple neurons impinge on a single neuron, that neuron integrates the inputs, resulting in a net excitation or inhibition. 2
The nervous system is anatomically separated into two major divisions: the central nervous system and the peripheral nervous system. The central nervous system encompasses the brain and spinal cord, while the peripheral nervous system encompasses the nerves that travel to and from the spinal cord, sense organs, glands, blood vessels, and muscles.
The brain is composed of between 10 billion and 100 billion cells organized into vast networks of interacting axons and dendrites which comprise on the order of 10 connections (17). The brain and spinal cord control vital functions of the body (including vision, hearing, speech, learning, memory, and muscular movements) through these complex networks and through a wide variety of neurotransmitters.
Information from sensory receptors is sent to the spinal cord and brain, where it is translated and integrated with other information. Sometimes the sensory information leads to muscular movement— for example, if one touches a hot stove. This reflex circuit involves both sensory neurons, which sense the heat and send the information to the spinal cord, and motor neurons, which send instructions to the muscles.
Most of the central nervous system is partially protected by the blood-brain barrier, a layer of tightly juxtaposed cells in blood vessel walls that allow some substances to pass from blood to neural tissue while keeping others out. This selective barrier protects much of the nervous system from substances that are either not necessary for metabolic functions or that may be damaging. Smaller compounds and compounds that are soluble in lipids tend to cross the barrier more easily, while larger compounds and substances which are soluble in water may be kept out. In addition, some compounds cross the barrier with the help of carrier proteins which bind specifically to them. Drugs intended to act directly on the nervous system must therefore be designed in such a way as to pass through the blood-brain barrier into the brain. Most tranquilizers, narcotics, and anesthetics readily traverse the barrier.
Development and Aging
The first signs of the nervous system are exhibited around the 10th to 14th day of fetal development, when a flat sheet of around 125,000 cells forms from the outer layer of the ball of undifferentiated embryonic cells. The sheet then rolls into a tube, called the neural tube, which will eventually develop into the spinal cord and brain. Over the next 2 months these cells multiply, migrate, and begin differentiating into specific types of neurons and glia. The mechanism by which the undifferentiated embryo develops is unknown; however, embryologists believe that the cells' chemical environments
play large roles in these determinations.
At approximately the 20th week, the neurons begin to extend axons and dendrites, initiating development of the nervous system's complex network of synaptic contacts. The nervous system is not fully developed until sometime during infancy.
However, small modifications in the network do appear to take place even in the adult nervous system.
The nervous system undergoes major changes with aging. At the tissue and cellular level, the aging process results in nerve cell loss, neurofibrillary tangles (abnormal accumulation of certain filamentous proteins), and neuritic plaques (abnormal clusters of proteins and other substances near synapses).
Neurons have a very limited capacity to regenerate; thus, as cells die, the complex neuronal circuitry of the brain becomes impaired. Aging is also accompanied by alterations in neurotransmitter concentration and the enzymes involved in the synthesis of these transmitters. Some neurons gradually lose their insulating myelin sheath, slowing conduction of electrical impulses along the axons.
Some-components of the nervous system appear to age differently than others. In a healthy person, for example, intellectual abilities such as memory, vocabulary retention, and comprehension seem to be maintained at least until the mid-70s, while motor skills, coordination, and sensory functions gradually become impaired . Specific areas of the brain may age at different rates. The locus ceruleus and the substantial nigra, two discrete areas of the brain, undergo a period of cell loss between the ages of 30 and 50, with the decline in cell number slowing thereafter. Between the ages of 20 and 80, the number of cells in the cerebral cortex may be reduced by half. In contrast, the Purkinje cells of the cerebellum decline in a linear fashion throughout life, while other clusters of cells are maintained at the same levels regardless of age.
EFFECTS OF TOXIC SUBSTANCES
ON THE NERVOUS SYSTEM
Structural Changes
Toxic substances can alter both the structure and the function of cells. Structural alterations include
changes in the morphology of the cell and the subcellular structures within it, and destruction of groups of cells. The long axons of some neurons, the inability of neurons to regenerate, and the nervous system's dependency on a delicate electrochemical balance for the proper communication of information make the system especially vulnerable to the effects of toxic chemicals.
When a toxic substance enters the human body, it can affect the biochemistry and physiology of neurons and glia in a variety of ways. The cells may swell, their internal contents may become more acidic, and biochemical processes such as protein synthesis and neurotransmitter secretion may be inhibited. Often these changes result from anoxia— i.e., oxygen deprivation. Neurons require relatively large quantities of oxygen because of their high metabolic rate and are therefore more vulnerable
than other cells to anoxia.
At the morphological level, toxic substances seem to act selectively on the various components of the nervous system, damaging the neuronal bodies (neuropathy), axons (axonopathy), and myelin sheaths (myelinopathy). A common type of structural change induced by toxic substances on axons is central-peripheral distal axonopathy (CPDA).
Degeneration of this type usually begins at the end of the axon and proceeds toward the cell body, hence it is often referred to as the "dying-back" process.
Some organophosphorous insecticides can cause this type of damage after a single exposure; how-ever, for the majority of chemicals producing these effect, continuous or prolonged intermittent exposure is necessary. Thousands of people were paralyzed during Prohibition after ingesting a popular alcohol substitute contaminated with an organophosphorous chemical.
Toxic substances often cause a slow degeneration of the nerve cell body or axon that may result in permanent neuronal damage. Acute carbon monoxide poisoning, for example, can produce a delayed, progressive deterioration of portions of the nervous system that may lead to psychosis and death over a period of weeks.
Functional Changes
Toxic chemicals can induce functional changes that involve modifications of motor and sensory activities, emotional states, and integrative capabilities such as learning and memory. Numerous sensory systems can be adversely affected, including sight, hearing, and touch and pain sensation. These effects may be caused by destruction of the myelin sheath that surrounds neurons (a process known as demyelination), damage to the neuron itself, or damage to the neurotransmitter system.
Sensory changes are often reported as numbness or a tingling sensation. Methyl mercury is one chemical that is extremely toxic to the visual, sensory, and motor systems. Several episodes of large-scale human intoxication by this organic heavy metal have been described. In recent years, tests have been developed to detect sensory changes, particularly in visual and auditory functions resulting from exposure to toxic substances.
Organophosphorous and carbamate insecticides can induce functional changes by inhibiting acetylcholinesterase, an enzyme that breaks down the neurotransmitter acetylcholine. The functionalchanges include hyperactivity, neuromuscular paralysis, weakness, vomiting, diarrhea, and dizziness, with more severe cases exhibiting convulsions, coma, or death.
The onset and duration of symptoms depend on the inherent toxicity of the insecticide, the dose, the route of exposure, and preexisting health conditions.
Some organophosphorous pesticides can produce delayed and persistent neuropathy by damaging neurons in the spinal cord and peripheral nervous system; in these cases, the resulting muscle weakness may progress to paralysis .
Motor and sensory functions are closely linked within the nervous system. Body movements, for example, involve complex feedback interactions between motor and sensory neurons to allow smooth, controlled movements. Consequently, damage to sensory systems can indirectly affect certain motor functions. Some toxic substances affect motor neurons directly; others damage both sensory and motor neurons (a condition termed mixed neuropathy).
Neurophysiological tests are available to monitor the conduction velocity of impulses along nerve axons, and various neurological tests can be used to detect muscle weakness and lack of control of muscular movements.
Toxic substances often affect the higher functions of the nervous system such as learning, memory, and mood. Exposure to inorganic lead can lead to mental retardation in children; at lower levels of exposure, however, it may manifest itself as a shortened attention span or a learning disability.
Various tests are available to detect impairment of these processes, some of which are described in chapter 5.
Behavioral Effects
Behavioral changes may be the first indications of damage to the nervous system. An individual exposed to a toxic substance may initially experience vague feelings of anxiety or nervousness.
These feelings may progress to depression, difficulty in sleeping, memory loss, confusion, loss of appetite, or speech impairment. In severe cases, a person may exhibit bizarre behavior, delirium, hallucinations, convulsions, or even death.
Often, behavioral toxicological testing can detect an impairment for which investigators have not yet found a physiological or biochemical mechanism.
Exposure to neurotoxic chemicals during pregnancy may not produce obvious symptoms of behavioral toxicity until long after the exposure has ceased. This phenomenon has given rise to the field of behavioral teratology. An issue of particular concern to neurotoxicologists is the latency of some neurotoxic effects. One explanation for latent, or "silent," damage is that at younger ages the brain may be able to compensate for some adverse effects.
With age, this ability to compensate diminishes, and the damage inflicted early in life may become apparent (19, 25). It has been proposed that exposure to toxic substances may trigger biochemical events that may later contribute to the cause of certain neurological diseases such as Parkinson's disease, amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease), or Alzheimer's disease. This hypothesis, sometimes referred to as the environmental hypothesis, has recently been the subject of increased
interest following the MPTP incident (see box 3-C) and the Guam-ALS episode (19). (See ch. 2).
Susceptibility to neurotoxic Substances
Everyone is susceptible to the adverse effects of neurotoxic substances, but individuals in certain age groups and persons with certain health problems may be particularly at risk. The developing nervous system is especially vulnerable to certain toxic substances. Its cells are actively growing, dividing, migrating, and making synaptic connections, and the blood-brain barrier is not yet fully developed.
During the first weeks of prenatal development, toxic substances may interrupt closure of the neural tube, leading to such birth defects as spina bifida (a defect in which the vertebral column is exposed) and anencephaly (the absence of all or part of the brain). During later development, the risks of exposure have diminished for many components of the nervous system; however, the cerebrum and cerebellum, major portions of the brain responsible for functions such as sight and movement, remain particularly vulnerable (15, 22).
Factors such as dose of the toxic substance and nutritional deficiencies in the mother also influence the extent of damage. Ethanol (alcohol), cocaine, antibiotics, and steroids, for example, can all adversely affect the fetal nervous system (18). Since few drugs have been adequately evaluated for effects on the developing fetus, physicians are advised to exert special care in prescribing drugs to pregnant women.
As the structure and function of the nervous system decline with age, individuals become more susceptible to the effects of many neurotoxic substances. Adverse effects that might have been masked at a younger age by a vital, healthy nervous
system may become apparent. Those suffering from neurological disorders are at greater risk because toxic chemicals may exacerbate existing problems.
Persons suffering from multiple sclerosis or neuromuscular disorders, for example, are vulnerable Neurobiology and toxicology are rapidly expanding scientific fields that cut across many disciplines.
A brief chapter can only touch on some of the general scientific principles underlying neurotoxicology, which lies at the intersection of these two fields. The interested reader may wish to consult any of several textbooks or nontechnical books for further information.
SUMMARY AND CONCLUSIONS
The complexity of the nervous system has made the field of neurotoxicology one of the most demanding disciplines in toxicology. In the last decade, neurotoxicologists have been able to differentiate the effects of many chemicals in terms of where they act and the symptoms they produce, but in most cases they have not yet been able to determine the mechanisms of action. Very few suspected neurotoxic chemicals have been evaluated in the laboratory and even fewer have been tested
thoroughly. These chemicals act at many levels of the nervous system and exert their effects in a variety of ways, with consequences ranging from mild sensations of tingling in the extremities to severe mental retardation, loss of sensory function, and death. The chemicals may be particularly toxic to susceptible populations such as the unborn, the young, the sick, and the elderly. In order to safeguard human populations against the potentially damaging effects of these chemicals, it is necessary to study the consequences of prolonged low-level exposures as well as the effects of neurotoxic chemicals on sensitive populations.
**
In Reply to: Re: Poisoning by dental amalgam - Gulf War Illness posted by MAI on May 31, 1999 at 20:43:14:
Industrial Exposure and Control Technologies for OSHA
Regulated Hazardous Substances
U.S. Department of Labor
2Elizabeth Dole, S
Secretary March 1989
Volume II of II
Substances K-Z and Indices
Occupational Safety and Heath Administration John A. Pendergrass, Assistant Secretary
HEALTH EFFECTS
Effects of exposure may be delayed. [USCG, 19851 Acute poisoning may result from inhalation of vapors of elemental mercury. If poisoning occurs by inhalation of fumes of metallic mercury, the syndrome is characterized by pneumonitis, lethargy or restlessness, fever, tachypnea, cough, chest pain, cyanosis, diarrhea & vomiting; atelectasisd emphysema, hemorrhage & pneumothorax often follow. Systemic effects of the poison start within a few hours & may last for days; death may ensue. Systemic signs of acute poisoning by elemental mercury include those referable to CNS.
[GOODMAN. PHARN BASIS THERAP 6TH ED 19801
The condition is characterized by metallic taste, nausea, abdominal pain, vomiting, diarrhea, headache, & sometimes albuminuria. After few days, salivary glands swell, stomatitis & gingivitis develop, & a dark line of mercury sulfide forms on inflamed gums. Teeth may loosen, & ulcers may form on lips & cheeks. In milder cases, recovery occurs within 10-14 days, but in others, poisoning of chronic type may ensue. Some of acute cases have resulted from exposure concentration of 1.2 to 8.5 ml Hg~cu m. [PATTY. INDUS HYG & TOX 3RD ED VOLZA,2B,2C 1981-82]
If poisoning occurs by fumes of metallic mercury, the syndrome is characterized by pneumonitls, lethargy or restlessness, fever, tachypnea, cough, chest pain, cyanosis, diarrhea and vomiting; atelectasis, emphysema, hemorrhage and pneumothorax often follow. Systemic effects of the poison start within a few hours and may last for days; death may ensue. Systemic signs of acute poisoning by elemental mercury include those referable to the CNS. ~GO0DMAN. PHARN BASIS THERAP 6TH ED 19801
Slightly elevated temperature, shallow respiration, general malaise, & pleuritic chest pain, with shortness of breath for 24 hr. Pulmonary function may be reduced.
The most consistent & pronounced effects of chronic exposure to elemental mercury vapor are on CNS. Effects are neurological & psychiatric. Common symptoms include depression, irritability, exaggerated response to stimulation (erethism), excessive shyness, insomnia, emotional instability, forgetfulness, Confusion, & vasomotor disturbances such as excessive perspiration & uncontrolled blushing. Tremors are also common; these are exaggerated when task is required but minimal when patient is at rest or asleep. A fine trembling of fingers, eyelids, lips, & tongue may be interrupted intermittently by coarse shaking movements. Erethism & tremors may be reversible.[GOODMAN. PHARN BASIS THERAP 6TH ED 19801
Exposure of humans to mercury vapor causes cough, chest pain and dyspnea, leading to bronchitis and pneumonitis. [NIOSH OSHA. OCCUPAT HEALTH GUIDE CHEM HAZARDS. 1981
Humans exposed occupationally to metallic mercury compound or Hg amalgams had significantly increased occurrence of lymphocytic aneuploidy but not structural chromosome aberrations relative to controls. Metallic mercury or Hg amalgams [NAT1L RESEARCH COUNCIL CANADA; EFFECT OF MERCURY IN THE CANADIAN ENVIRONMENT P.115 (1979) NRCC NO. 167391
Severe nephrotic changes have not been described in patients exposed only to mercury vapor. In patients exposed to combination of mercury dust & vapor, such changes have been reported. An increased frequency of aneuploidy in lymphocytes from mercury vapor exposed workers are reported. [FRIBERG. HDBK TOX OF METALS 1979 1
Brain is critical organ in humans for chronic mercury vapor exposure; in severe cases, spongeous degeneration of brain cortex can occur as a late sequela to past exposure. Renal protelnuria has been described following exposure to mercury vapor. Other reported effects from elemental mercury are contact dermatitis from mercury amalgam fillings & mercury sensitivity occurring among dental students. [PATTY. INDUS HYG & TOX 3RD ED VO~2A,2B,2C 1981-821
Exposed to mercury man developed a syndrome resembling amyotrophic lateral sclerosis.
The syndrome disappeared when urinary mercury returned to normal. [ADAM CR ET AL; JAMA H AM MED ASSOC 250: 642-3 (1983) AS CITED IN USEPA; MERCURY HEALTH EFFECTS UPDATE P.5-S (1984) EPA 6O0~8-84-0i9FI
Investigators studied the excretion of specific proteins and enzymes in urine samples of 87 control workers (mean urinary mercury in the range of 3.3 to 4.6 mcg Hg~g~creatinine, based upon three separate visits) and In 105 exposed workers (mean urinary mercury In the range of 63 to 71 mcg Hg~g~creatinine, based upon three separate visits). The range of individual values was 0.4 to 275 mcg Hg~ g/creatinine. The corresponding mean blood mercury values were 5 and 17.5 mcg Hg~l, respectively. Highly significant correlations were found between blood and urinary mercury concentration. Urinary gamma glutamyl transferase correlated with urinary mercury levels in the exposed group. The prevalence of greater than normal activities of the enzymes, N-acetyl-beta-glucosaminldase and gamma glutamyl transferase, appeared to increase when the mercury concentration in urine exceeded 100 mcg Hg~g/creatlnine, but there was no evidence of a dose-response relationship over the full range of mercury concentration. [STaNDARD ND ET AL; INT ARCH OCCUP ENVIRON HEALTH 6: 480-3 (1983) AS CITED IN USEPA; MERCURY HEALTH EFFECTS UPDATE P.5-8 (1984) EPA 600/8-84-019F]
Aneuploldy and other chromosomal aberrations have been observed in lymphocytes from whole blood cultures of exposed to mercury, including people working with mercury amalgams, some dentists demonstrated severe Parkinson's symptoms. [USEPA; MERCURY HEALTH EFFECTS UPDATE (1984) EPA 600/8-84-019F1
Carcinogenicity: NTP: no IARC: no Z List: no OSHA REG: no. Effects of overexposure: Inhalation of vapors may cause coughing, chest pains, nausea and vomiting. Chronic effects of overexposure may include kidney and/or liver damage. Chronic effects of overexposure may include central nervous system depression. Chronic effects of mercury poisoning include a buildup of the metal in the brain, liver and kidneys. Symptoms include headache, tremors, loose teeth, loss of appetite, blisters on the skin and impaired memory. Target organs: eyes, skin, respiratory system, central nervous system, kidneys.
Medical conditions generally aggravated by exposure identified as routes of entry: dental amalgam, inhalation, absorption, eye contact, skin contact.
The most consistent and pronounced effects of chronic exposure to elemental mercury vapor are on the CNS. Effects are neurological and psychiatric. Common symptoms include depression, irritability, exaggerated response to stimulation (erethism), excessive shyness, Insomnia, emotional instability, forgetfulness, confusion, and vasomotor disturbances such as excessive perspiration and uncontrolled blushing. Tremors are also common; these are exaggerated when task is required but minimal when patient is at rest or asleep. A fine trembling of fingers, eyelids, lips, and tongue may be Interrupted intermittently by coarse shaking movements. Erethism and tremors are reversible. [GOODMAN. PHARM BASIS THERAP 6TH ED 19801 Acute intoxication from inhaling mercury vapor in high concentrations used to be common among those who extracted mercury from its ores. The condition is characterized by metallic taste, nausea, abdominal pain, vomiting, diarrhea, headache, and sometimes albuminurla. After a few days, salivary glands swell, stomatitis and gingivitis develop, and a dark line of mercury sulfide forms on Inflamed gums. Teeth may loosen, and ulcers may form on lips and cheeks. In milder cases, recovery occurs within 10-14 days, but in others, poisoning of chronic type may ensue. Some acute cases have resulted from exposure concentrations of 1.2 to 8.5 ml Hg~m3. [PATTY. INDUS HYG & TOX 3RD ED VOL2A,2B,2C 1981-82]
It is still not known to what degree renal damage may occur in connection with chronic exposure to mercury vapor. Severe nephrotic changes have not been described in patients exposed only to mercury vapor. In patients exposed to combination of mercury dust and vapor, such changes have been reported. An increased frequency of aneuploidy in lymphocytes from mercury vapor exposed workers is reported. [FRIBERG. HDBK lOX OF METALS 1979
Brain is critical organ in humans for chronic mercury vapor exposure; in severe cases, spongeous degeneration of brain cortex can occur as a late sequela to past exposure. Renal proteinuria has been described following exposure to mercury vapor. Other reported effects from elemental mercury are contact dermatitis from mercury amalgam fillings and mercury sensitivity occurring among dental students. [PATTY. INDUS HYG & TOX 3RD ED VOL2A,ZB,2C 1981-821
The man exposed to mercury vapors developed a syndrome resembling amyotrophic lateral sclerosis. [ADAM CR El AL; JAMA H AM MED ASSOC 250: 642-3 (1983) AS CITED IN USEPA; MERCURY HEALTH EFFECTS UPDATE P.S-S (1984) EPA 600~8-84-019FJ
Investigators were able to confirm an increased prevalence of albuminuria in workers exposed to mercury vapor. The median (range) mercury levels in urine for controls were 1.3 (0.6-4.7) and for exposed were 71 (9.9-286) mg Hg~g creatinine (creatinine Is proportional to the lean body mass, and therefore does not change greatly for a given individual or for groups of workers having roughly similar body weights). Observations on psychomotor performance indicated that decrement in performance was found in mercury-exposed workers but occurred independently from the presence of proteinuria. [ROELS H ET AL; INT ARCH OCCUP ENVIRON HEALTH SO: 77-93 (1982) AS CITED IN USEPA; MERCURY HEALTH EFFECTS UPDATE P.5-7 (1984) EPA 600/8-84-019F1
Investigators studied the excretion of specific proteins and enzymes in urine samples of 87 control workers (mean urinary mercury in the range of 3.3 to 4.6 mg Hg~g~creatinine, based upon three separate visits) and in 105 exposed workers (mean urinary mercury in the range of 63 to 71 mg Hg/g~creatinine, based upon three separate visits). The range of individual values was 0.4 to 275 mg Hg/g/creatinine. The corresponding mean blood mercury values were 5 and 17.5 mg Hg/l, respectively. Highly significant correlations were found between blood and urinary mercury concentration. Urinary gamma glutamyl transferase correlated with urinary mercury levels in the exposed group. The prevalence of greater than normal activities of the enzymes, N-acetyl-beta-glucosaminidase and gamma glutamyl transferase, appeared to increase when the mercury concentration in urine exceeded 100 mg Hg/g/creatinine, but there was no evidence of a dose-response relationship over the full range of mercury concentrations. [STONDARD ND ET AL; INT ARCH OCCUP ENVIRON HEALTH 6: 480-3 (1983) AS CITED IN USEPA; MERCURY HEALTH EFFECTS UPDATE P.5-8 (1984) EPA 6O0~8-84-019F]
Aneuploidy and other chromosomal aberrations have been observed in lymphocytes from whole blood cultures of workers occupationally exposed to mercury, including people working with mercury amalgams. [USEPA; MERCURY HEALTH EFFECTS UPDATE P.5-Il (1984) EPA 6OO~8-84-O19F1
Exposure of humans to mercury vapor in concentrations of 1.2 to 8.5 mg/m3 causes cough, chest pain and dyspnea, leading to bronchitis and pneumonitis. [NIOSH OSHA. OCCUPAT HEALTH GUIDE CHEM HAZARDS. 1981]
Humans exposed occupationally to metallic mercury compounds or Hg amalgams had significantly increased occurrence of lymphocytic aneuploidy but not structural chromosome aberrations relative to controls. [NAT'L RESEARCH COUNCIL CANADA; EFFECT OF MERCURY IN THE CANADIAN ENVIRONMENT P.115 (1979) NRCC NO. 167391
The case of a 25-year-old woman with previous metallic mercury skin deposits treated by excision of the affected area and oral administration of 125 mg penicillamine 2 times~day, is reported. Symptoms of metallic mercury intoxication were not shown. Biopsy of the lumps produced a salmon pink fluid containing globules of metallic mercury. [GROUNDS RH; J R SOC MED 77:611-13 1984)]
Mercury affect health
The nervous system is very sensitive to all forms of mercury. Methylmercury and metal vapors are more harmful than other forms, because more mercury in these forms reaches the brain. Exposure to high levels of metallic, inorganic, or organic mercury can permanently damage the brain, kidneys, and developing fetus. Effects on brain functioning may result in irritability, shyness, tremors, changes in vision or hearing, and memory problems.
Short-term exposure to high levels of metallic mercury vapors may cause effects including lung damage, nausea, vomiting, diarrhea, increases in blood pressure or heart rate, skin rashes, and eye irritation.
There are inadequate human cancer data available for all forms of mercury. Mercuric chloride has caused increases in several types of tumors in rats and mice, while methylmercury increased kidney tumors in male mice. The EPA has determined that mercuric chloride and methyl mercury are possible human carcinogens.
Mercury affect on children:
Very young children are more sensitive to mercury than adults. Mercury in the mother's body passes to the fetus and can pass to a nursing infant through breast milk.
The case of an 8-month-old girl with acute mercury vapor intoxication successfully treated with oxygen, intravenous injections of nafcillin sodium (100 mg~kg~day) and chloramphenicol sodium succinate (100 mg~kg~day) is reported. [JAFFE KM ET AL; AM J DIS CHILD 137: 749-51 (1983)1
Mercury's harmful effects that may be passed from the mother to the developing fetus include brain damage, mental retardation, and incoordination, blindness, seizures, and an inability to speak. Children poisoned by mercury may develop problems of their nervous and digestive systems and kidney damage.
Tests are available to measure mercury levels in the body. Blood tests are not reliable, urine samples are used to test for exposure to metallic mercury and to inorganic forms of mercury. Mercury in in scalp hair is measured to determine exposure to methylmercury.
Source of Information
Agency for Toxic Substances and Disease Registry (ATSDR). 1999. Toxicological profile for mercury. Atlanta, GA:
U.S. Department of Health and Human Services, Public Health Service.
In Reply to: Poisoning by dental amalgam posted by Industrial Exposure and Control Technologies for OSHA on May 31, 1999 at 20:46:17:
Introduction and Overview
Howard Kipen and Nancy Fiedler
University of Medicine and Dentistry of New Jersey--Robert Wood Johnson Medical School, Piscataway,
New Jersey
-- Environ Health Perspect 105(Suppl 2):405407 (1997)
Multiple chemical sensitivity (MCS) or environmental illness has been the subject of numerous conferences (1,2),
several research papers (3), and much controversy. What is the purpose of yet another workshop on this topic?
Patients report that low-level chemical exposures are making them ill, yet these reports of illness are not well
supported by the knowledge bases of toxicology or medicine. If MCS is not classical toxicity, perhaps the next
logical assumption is that this illness has more to do with the individual susceptibility than with chemical toxicity.
But what are the mechanisms for this clinical phenomenon and how can we begin to test objectively the
interaction of susceptibility factors, chemical exposures, and illness? This was the purpose of our workshop.
Unlike previous conferences, this conference was conducted as a workshop in which experienced MCS clinicians
who could document patient characteristics worked with experimental investigators from scientific disciplines
related to MCS to develop experimental approaches. This supplement is a compilation of papers given by invited
speakers, both clinical and methodologic, along with assigned commentaries in response to some of the papers.
These papers reflect the background and the diversity of opinion that exists in this area of inquiry.
The paper by Fiedler and Kipen (3) is an overview of published studies that have characterized patients with
chemical sensitivity and highlights differences in case definition and subject selection criteria between studies.
We summarize the peer-reviewed literature on the psychiatric, neuropsychologic, immunologic, and olfactory
function of patients reported to have chemical sensitivity, and offers suggestions for subject selection and
experimental approaches based upon the limited published experience with individuals who have this syndrome.
The series of clinical papers offers a summary of patient characteristics from both the research that has directly
evaluated patients with chemical sensitivities and from clinical experience. The purpose of these talks and
papers was to provide background to those researchers with limited previous access or knowledge of MCS.
Ross (4), and Ziem and McTamney (5) describe case studies of patients who are unable to tolerate low-level
chemical exposures. Ziem and McTamney (5) further describe the use of various clinical tests for diagnosing
chemical sensitivity.
The patients discussed by these authors are good examples of the heterogeneity in exposure history and illness
presentation among patients to whom the term chemically sensitive is applied. The tests and theories described,
although different from those noted by Kipen and Fiedler (3), represent the breadth of clinical approaches and
laboratory analyses used to characterize these patients, and challenge experimentalists looking for a
homogeneous subject pool characterized by standardized methodology.
Kehrl (6) comments on the clinical surveys and emphasizes the inherent difficulties in using inadequately
standardized laboratory assays or assays that are not validated for the conditions they are used to assess.
The next group of papers discusses divergent models to account for chemical sensitivity. Each model has a
different experimental approach, and it is the use of these models that is the subject of the working groups.
Miller's model of chemical sensitivity proposes that MCS is explained by a loss in the ability to tolerate
chemicals, which results after an exposure (7). Subsequently, low-level exposures trigger symptoms. This is an
expansion and development of the concept of adaptation proposed by Rea (8), with less emphasis on putative
metabolic explanations.
Miller further explains that the only method by which these responses to exposures can be detected is by
removing patients from all exposures for 3 to 5 days (deadaptation) and then exposing them to single chemicals.
This paradigm provides substantial theoretical and logistical challenges for the design of experiments. MacPhail
(9) comments on the model proposed by Miller, and notes that large interindividual differences commonly are
found in animal studies, and that we should not be surprised that some individuals are more sensitive than others:
"Variation in sensitivity has rarely been the focus of research, because scientists have been generally preoccupied
with measures of central tendency." He recommends an approach that examines conditioning of adverse effects
of airborne chemicals to provide a rigorous laboratory model for some aspects of MCS.
Bell et al. (10) review and present hypotheses suggesting that chemical sensitivity may be a neural sensitization
phenomenon exemplified by time-dependent sensitization or limbic kindling. That is, patients become chemically
sensitive following one toxic exposure or repeated low-level exposures separated in time. Subsequent responses
may be triggered by very low-level exposures. Bell points out that sensitization is distinct from but interactive
with other neurobiological learning and memory processes such as conditioning and habituation, both of which
are emphasized in various other discussions in the monograph.
Sorg and Prasad (11) wonder whether nonelectrical kindling can occur. Sorg and Prasad examine the potential
involvement of stress and temporal changes in the development of MCS from the perspective of behavioral
sensitization and kindling in rodents. One model involves cross-sensitization between stress and drugs of abuse in
looking for enhancement of response over time.
Meggs (12), on the other hand, suggests that chemical sensitivity results through a process of neurogenic
inflammation.
He describes preliminary results from a study of nasal pathology in MCS as well as other patients in which
defects in tight junctions, mucosal desquamation, glandular hyperplasia, lymphocytic infiltrates, and peripheral
nerve fiber proliferation have been found. He describes how this inflammation suggests a model in which a
positive feedback loop is set up between the inflammatory response to low-level irritants and the epithelial
changes propagated by the inflammation, and that multi-organ symptoms can then be explained by the concept of
neurogenic switching.
Lehrer (13) discusses analogies from the behavioral literature to propose hypotheses and strategies for exploring
the contribution of psychological factors to MCS. Hypotheses are based on concepts of individual response
stereotypy, situational response specificity, classical conditioning and psychophysiologic arousal in response to
odor cues as models for chemical sensitivity. These strategies are tightly connected to the experimental
psychology literature, and suggest immediately testable approaches.
Benignus (14) provides a brief and cautionary commentary to respect the canon of parsimony in generating
theoretical constructs to explain MCS. He suggests careful work to connect explanatory hypotheses to the body
of accessible scientific literature and compares the approaches of Rea (8) and Lehrer (13).
The final series of papers focus on experimental methods and dependent variables that could be employed in
experimental studies suggested by the previous models.
Weiss (15) suggests that scepticism about MCS stems, in part, from a lack of supporting experimental data.
Because of the apparent broad variations in sensitivity and the need to establish reproducibility, he strongly
favors the single-subject design, emphasizing repeat observations on individual subjects combined with
appropriate time series statistical tests.
Wetherell (16) comments from a perspective of psychopharmacology research and emphasizes good study design
as the key to meaningful results when looking at neurobehavioral end points. Cognitive and psychomotor tests are
examined from a perspective of sensitivity, reliability, and validity, and the Latin Square design is proposed as a
way to resolve design issues. Difficulties with placebos are discussed.
Newlin (17) describes a behaviorgenetic approach modeled after research on substance abuse to explore both the
epidemiology and genetics of MCS. Opportunities to use twin registers and comparisons or contrasts with
addiction are examined.
Eissenberg and Griffiths (18) describe elegant and well-developed protocols for assessing interindividual
differences in sensitivity to or tolerance of caffeine. Although not the most prominent or challenging problem
cited by MCS subjects, such intolerance is frequently reported and can be evaluated without developing new
testing procedures, as inhalation studies would require. Thus, a window can be opened on the phenomenology of
unusual sensitivity of some individuals to doses of agents usually well-tolerated by the rest of the population.
These manuscripts provide a rich insight into the wealth of clinical observation and scientific challenges offered
by MCS. While two presenters were not able to submit papers for publication, we refer the interested reader to
reviews to supplement this volume [Bascom (19) and Ader et al. (20)].
Following the plenary talks and commentaries, all presenters also participated in one of five working groups. The
papers from these working groups reflect a synthesis of research questions, experimental approaches, and
methods to test hypotheses generated by the proposed model of MCS (2125). Each group was composed of both
individuals who had experience with MCS patients and researchers who had developed research methods
relevant to the model under discussion.
To summarize, these papers represent a rich source of hypotheses. The workshop brought together clinicians and
researchers from divergent backgrounds and although controversies arose, their interactions produced many ideas
and suggestions. We hope they will be of use to the research community as we endeavor to understand chemical
sensitivities.
References
1. Rest KM, ed. Proceedings of the Association of Occupational and Environmental Clinics (AOEC) Workshop
on Multiple Chemical Sensitivity. Toxicol Ind Health 8:1257 (1992).
2. Mitchell Fl, ed. Proceedings of the Conference on Low-level Exposure to Chemicals and Neurobiologic
Sensitivity. Toxicol Ind Health 10:253669 (1994).
3. Fiedler N, Kipen H. Chemical Sensitivity: The Scientific Literature. Environ Health Perspect 105(Suppl
2):409415 (1997).
4. Ross GH. Clinical characteristics of chemical sensitivity: an illustrative case history of asthma and MCS.
Environ Health Perspect 105(Suppl 2):437441 (1997).
5. Ziem G, McTamney J. Profile of patients with chemical injury and sensitivity. Environ Health Perspect
105(Suppl 2):417436 (1997).
6. Kehrl H. Commentary. Laboratory testing of the patient with multiple chemical sensitivity (MCS). Environ
Health Perspect 105(Suppl 2):443444 (1997).
7. Miller C. Toxicant-induced loss of tolerance on emerging theory of disease? Environ Health Perspect
105(Suppl 2):445453 (1997).
8. Rea WJ. Chemical Sensitivity. Dallas, TX:Lewis Publications, 1992.
9. MacPhail R. Commentary. Evolving concepts of chemical sensitivity. Environ Health Perspect 105(Suppl 2):
455456 (1997).
10. Bell I, Schwartz GE, Baldwin CM, Hardin EE, Klimas NG, Kline JP, Patarca R, Song Z-Y. Individual
difference in neural sensitization and the role of context in illness from low-level environmental chemical
exposures. Environ Health Perspect 105(Suppl 2):457466 (1997).
11. Sorg BA, Prasad BM. Potential role of stress and sensitization in the development and expression of
multiple chemical sensitivity. Environ Health Perspect 105(Suppl 2):467471 (1997).
12. Meggs WJ. Hypothesis for induction and propagation of chemical sensitivity based on biopsy studies.
Environ Health Perspect 105(Suppl 2):473478 (1997).
13. Lehrer P. Psychology hypotheses regarding multiple chemical sensitivity syndrome.
Environ Health Perspect 105(Suppl 2):479483 (1997).
14. Benignus VA. Commentary. Systematic considerations in the area of multiple chemical sensitivity. Environ
Health Perspect 105(Suppl 2):485 (1997).
15. Weiss B. Experimental strategies for research on multiple chemical sensitivity. Environ Health Perspect
105(Suppl 2):487494 (1997).
16. Wetherell A. Cognitive and psychomotor performance tests and experiment design in multiple chemical
sensitivity. Environ Health Perspect 105(Suppl 2):495503 (1997).
17. Newlin DB. A behavior genetic approach to multiple chemical sensitivity.
Environ Health Perspect 105(Suppl 2):505508 (1997).
18. Eissenberg T, Griffiths RR. Human drug discrimination and multiple chemical sensitivity: caffeine
exposure as an experimental model. Environ Health Perspect 105(Suppl 2):509513 (1997).
19. Bascom R. Differential responsiveness to irritant mixtures. An NY Acad Sciences 641:225-247 (1992).
20. Ader R, Cohen N, Felten D. Psychoneuroimmunology: interactions between the nervous system and the
immune system. Lancet 345:99-103 (1995).
21. Miller CS, Ashford N, Doty R, Lamielle M, Otto D, Rahill A, Wallace. Working Group Report 1: Empirical
approaches for the investigation of toxicant-induced loss of tolerance.
Environ Health Perspect 105(Suppl 2):515519 (1997).
22. Siegel S, Kreutzer R. Working Group Report 2: Pavlovian conditioning and multiple chemical sensitivity.
Environ Health Perspect 105(Suppl 2):521526 (1997).
23. Cohen N, Kehrl H, Berglund B, O'Leary A, Ross G, Seltzer J, Weisel C. Working Group Report 3:
Psychoneuroimmunology. Environ Health Perspect 105(Suppl 2):527529 (1997).
24. Bascom R, Meggs W, Frampton M, Hudnell K, Killburn K, Kobal G, Medinsky M, Rea W. Working Group
Report 4: Neurogenic inflammation: with additional discussion of central and perceptual integration and
nonneurogenic inflammation. Environ Health Perspect 105(Suppl 2):531537 (1997).
25. Bell IR, Rossi J III, Gilbert ME, Kobal G, Morrow LA, Newlin DB, Sorg BA, Wood RW. Working Group
Report 5: Testing the neural sensitization and kindling hypothesis for illness from low levels of environmental
chemicals. Environ Health Perspect 105(Suppl 2):539547 (1997).
Manuscript received at EHP 27 December 1996; manuscript accepted 27 December 1996.
Address correspondence to Dr. N. Fiedler, UMDNJRobert Wood Johnson Medical School, Environmental and
Occupational Health Sciences Institute, 681 Frelinghuysen Road, Room 210, Piscataway, New Jersey 08855.
Telephone: (908) 445-0190. Fax: (908) 445-0127. E-mail: nfiedler@eohsi.rutgers.edu
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Chemical Sensitivity: The Scientific Literature
Nancy Fiedler and Howard Kipen
University of Medicine and Dentistry of New JerseyRobert Wood Johnson Medical School, Piscataway, New
Jersey
Abstract
This article provides an overview of the scientific literature in which chemically sensitive patients have been
directly evaluated. For that purpose, consideration of various case definitions is offered along with summaries of
subjects' demographic profiles, exposure characteristics, and symptom profiles across studies. Controlled
investigations of chemically sensitive subjects without other organic illnesses are reviewed. To date, psychiatric,
personality, cognitive/neurologic, immunologic, and olfactory studies have been conducted comparing subjects
with primary chemical sensitivity to various control groups. Thus far, the most consistent finding is that
chemically sensitive patients have a higher rate of psychiatric disorders across studies and relative to diverse
comparison groups. However, since these studies are cross-sectional, causality cannot be implied.
Demonstrating the role of low-level chemical exposure in a controlled environment has yet to be undertaken with
this patient group and is crucial to the understanding of this phenomenon.
-- Environ Health Perspect 105 (Suppl 2):409415 (1997)
This paper is based on a presentation at the Conference on Experimental Approaches to Chemical Sensitivity
held 2022 September 1995 in Princeton, New Jersey. Manuscript received at EHP 6 March 1996;
manuscript accepted 13 August 1996.
This work was supported by grants from the Hazardous Substance Management Research Center, a National
Science Foundation, Industry/University Cooperative Center; the New Jersey Commission on Science and
Technology; and National Institute of Environmental Health Sciences Superfund Basic Research Program, grant
ES-91-02.
Address correspondence to:
Dr. N. Fiedler, UMDNJ-Robert Wood Johnson Medical School, Environmental and Health Sciences Institute,
681 Frelinghuysen Road, Room 210, Piscataway, NJ 08855. Telephone: (908) 445-0190. Fax: (908) 445-0173.
E-mail: nfiedler@eohsi.rutgers.edu
Abbreviations used: EEG, electroencephalogram; EMG, electromyogram; MCS, multiple chemical sensitivity;
MEK, methyl ethyl ketone; MMPI-2, Minnesota Multiphasic Personality Inventory; PEA, phenyl ethyl alcohol;
PET, positron emission tomography; PYR, pyridine; SPECT, single photon emission computed tomography.
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
The Assessment of Neurobehavioral Toxicity: SGOMSEC Joint Report
Nancy Fiedler(1), Robert G. Feldman(2), Joseph Jacobson(3), Alice Rahill(4), and Anthony Wetherell(5), (1)
UMDNJ-Robert Wood Johnson Medical School, Environmental and Occupational Health Sciences Institute,
Piscataway, New Jersey; (2) Department of Neurology, Boston University School of Medicine, Boston,
Massachusetts;
(3) Wayne State University, Psychology Department, Detroit, Michigan; (4) Department of Occupational
Medicine, University of Rochester, Rochester, New York; (5) Human Factors Group, Chemical and Biological
Defense Establishment, Porton Down Salisbury, United Kingdom
Exposure to neurobehavioral toxicants is a problem of international scope. Although many different procedures
are available for the assessment of human behavioral function, performance tests are displacing traditional
diagnostic tests for ascertaining the consequences of exposure to neurotoxic chemicals. Performance testing
includes variables such as attention and concentration, sensory function, motor control, spatial relations,
visuomotor coordination, memory, and affect. Special tests have also been devised for evaluating child
development. One of the salient needs in these efforts is the construction of databases allowing access to
normative data. – Environ Health Perspect 104(Suppl 2):179-191 (1996)
This paper was prepared as background for the Workshop on Risk Assessment Methodology for Neurobehavioral
Toxicity convened by the Scientific Group on Methodologies for the Safety Evaluation of Chemicals
(SGOMSEC) held 12-17 June 1994 in Rochester, New York. Manuscript received 1 February 1995;
manuscript accepted 17 December 1995.
Address correspondence to:
Dr. Nancy Fiedler, Environmental and Occupational Health Sciences Institute, 681 Frelinghuysen Road, Room
210, Piscataway, NJ 08855. Telephone: (908) 445-0190. Fax: (908) 445-0173.
E-mail: nfiedler@eohsi.rutgers.edu
Abbreviations used: CNS, central nervous system; PNS, peripheral nervous system; IQ, intelligence quotient; NF,
number facility; WAIS-R, Wechsler Adult Intelligence Scale-Revised;
WMS-R, Wechsler Memory Scale-Revised; CVLT, California Verbal Learning Test; NBAS, Neonatal
Behavioral Assessment Scale; WPPSI, Wechsler Preschool and Primary Scale of Intelligence; WISC, Wechsler
Intelligence Scale for Children; PCBs, polychlorinated biphenyls; CPT, continuous performance test;
RT, reaction time.
Introduction
Exposure to neurobehavioral toxicants in the environment is an urgent international problem. The problems range
from the catastrophic effects of industrial accidents such as Bhopal to ubiquitous background environmental
exposures to chemicals such as lead. While it is expected that high-level exposures occur only in developing
nations, such exposures continue to occur in the most technologically advanced countries in the world. For
example, despite widespread knowledge of the deleterious effects of inorganic lead on the nervous system, cases
of lead poisoning (i.e., >80 mg/dl in blood) have been documented within the construction trades in this decade
(1). The neurobehavioral effects of acute high-level exposures are well known. For example, the overt clinical
manifestations of acute pesticide or lead poisoning can be easily recognize. Patients presenting with acute
delirium and convulsions accompanied by high blood lead levels do not require neurobehavioral testing to
document the adverse health effects due to exposure. Further, neurobehavioral tests were not required to
document the nervous system effects in Bhopal. However, for less catastrophic exposures,
neurobehavioral assessment plays an important role in determining the functional impact of neurotoxic exposure.
Why is the assessment of the behavioral impact of neurotoxicants important? Unlike other chemicals such as
carcinogens, for which no evidence of excessive exposure may be seen for years, exposure to neurotoxicants may
impact an individual's functioning directly. Thus, entire subsets of a population may experience a reduced level of
function in response to the effects of acute or chronic exposures. Neurobehavioral tests provide a systematic
method for documenting behaviors that are essential for optimal functioning in a technologically complex society.
Weiss (2) illustrated this point in the case of chronic low-level lead exposure. For example, suppose that
background lead exposure at relatively low levels (10 mg/dl blood lead) reduces scores by 5 points (5%) on a
standard intelligence test.
Translated into population terms, such a shift means that, in a population of 100 million, only 990 thousand
individuals, rather than 2.3 million, will score above 130 (that is, in the upper ranges of intellectual function).
There would be a corresponding inflation of the proportion of the population scoring below 70. The only way in
which this impact could be known is through the use of standardized neurobehavioral tests.
On an acute basis, accident rates may increase on the job or in the community due to the transitory effects of
exposure.
Also, acute exposures may have a differential effect on subsets of the exposed population based on individual
differences in susceptibility. For example, individuals reported to suffer from multiple chemical sensitivities (3)
experience acute neurobehavioral symptoms in response to low-level environmental exposures such as solvents in
perfumes and cleaning products. Neurobehavioral tests can document the extent of functional impairment due to
acute exposures.
Recognition that a significant neurotoxic exposure has occurred can grow out of a suspicion that a hazard exists
or from complaints and observations of changes in individuals. Suspicion that a hazard exists can arise from
routine surveillance (monitoring of urine or other biological samples) or an industrial accident. Complaints may
be initiated by individuals who perceive changes in their own cognitive, motor, or affective function. Over time,
such individuals may come to be recognized as having been subjected to a common occupational or residential
exposure, often referred to as a cluster.
Complaints may also consist of reports by parents that infants or children are failing to develop at the expected
rate (developmental delay) or observations by health care workers of an increased incidence in particular
functional deficits among the client they serve. In public health terms, neurobehavioral assessment provides a
useful methodology for the regulator to detect and characterize health effects at primary, secondary, and tertiary
levels of prevention. At the level of primary prevention, a neurotoxic exposure may occur at what are regarded as
background levels and individuals may not appear symptomatic. Neurobehavioral testing can provide a
systematic evaluation of subclinical effects. Childhood lead exposure provides a good example of the utility of
these methods for detection of an effect at this level of prevention.
No cases are evident; lead's neurotoxic impact is revealed by a population shift in IQ scores. For secondary
prevention, exposure to a neurotoxic agent may be documented and individuals appear symptomatic.
Neurobehavioral tests are important to systematically establish the objective impact on behavioral function.
Documentation of behavioral dysfunction at this level can help prevent morbidity or permanent dysfunction.
Finally, at the tertiary prevention level, acute high-level or chronic exposure to neurotoxic agents may occur, and
individuals may show symptoms of behavioral dysfunction (e.g., poor concentration or memory).
Neurobehavioral assessment will provide a standardized evaluation of the level of disability and can be used
prospectively to track the effects of intervention, such as removal
from exposure or the permanence of impairment. Examples of the utility of neurobehavioral assessment for
tertiary prevention are clearly presented in the literature on organic solvents and lead (4). The purpose of this
paper is 4-fold: a) to discuss the situations or problems for which neurobehavioral assessment techniques are
useful;
b) to outline the functional aspects of behavior that should be included in an assessment;
c) to provide guidelines for the use of the various methods available; and
d) to discuss the advantages and disadvantages of these methods.
Special consideration will be given to the sensitivity of these methods for detecting and characterizing effects at
each level of prevention. Neurobehavioral methods for assessment of child development will also be reviewed.
Targets of Neurotoxic Effects
Behavior is the outcome of multiple mechanisms within the central nervous system (CNS); its expression may be
internal (subjective state) or externally observable by others. In humans emotional responses to stress, learning
processes, and innovative problem-solving techniques are expected activities of the intact nervous system. The
CNS is vulnerable to the actions of environmental factors that include physical conditions (trauma, temperature),
as well as chemical factors.
Exposure to chemicals may result in neurobehavioral effects depending on the particular chemical, the
circumstances of exposure, the duration and intensity of the exposure, and the susceptibility of the organism.
Because human behaviors change routinely in normal conditions to adapt to actual and perceived conditions, the
definition of normal or baseline parameters of behavior is difficult. Consequently, it becomes even more
important to have methods for detecting changes in neurobehavior when they are the outcome of chemical
exposure or conditions other than ordinary life experiences.
Peripheral Nervous System
The central nervous system comprises the brain and spinal cord. The components of the peripheral nervous
system (PNS) lie outside these structures and include the spinal and cranial nerves. Motor and sensory symptoms
can arise from damage to peripheral nerves. Clinical manifestations of toxic peripheral neuropathies begin with
complaints of numbness or tingling, usually in the feet before the fingers because the longer nerve fibers are
affected first. Damage may progess to the less distal portions of a nerve as the exposure continues. Even after
ending exposure to chemicals capable of inducing neuropathy, there will be further progression of neurologic
impairment followed by a plateau and a very slow or gradual recovery of function in some instances. Nerve
damage is often irreversible, however.
In Reply to: Re: Poisoning by dental amalgam posted by Multiple chemical sensitivity (MCS) on May 31, 1999 at 20:51:06:
Targets of Neurotoxic Effects
Behavior is the outcome of multiple mechanisms within the central nervous system (CNS); its expression may be
internal (subjective state) or externally observable by others. In humans emotional responses to stress, learning
processes, and innovative problem-solving techniques are expected activities of the intact nervous system. The
CNS is vulnerable to the actions of environmental factors that include physical conditions (trauma, temperature),
as well as chemical factors.
Exposure to chemicals may result in neurobehavioral effects depending on the particular chemical, the
circumstances of exposure, the duration and intensity of the exposure, and the susceptibility of the organism.
Because human behaviors change routinely in normal conditions to adapt to actual and perceived conditions, the
definition of normal or baseline parameters of behavior is difficult. Consequently, it becomes even more
important to have methods for detecting changes in neurobehavior when they are the outcome of chemical
exposure or conditions other than ordinary life experiences.
Peripheral Nervous System
The central nervous system comprises the brain and spinal cord. The components of the peripheral nervous
system (PNS) lie outside these structures and include the spinal and cranial nerves. Motor and sensory symptoms
can arise from damage to peripheral nerves. Clinical manifestations of toxic peripheral neuropathies begin with
complaints of numbness or tingling, usually in the feet before the fingers because the longer nerve fibers are
affected first. Damage may progess to the less distal portions of a nerve as the exposure continues. Even after
ending exposure to chemicals capable of inducing neuropathy, there will be further progression of neurologic
impairment followed by a plateau and a very slow or gradual recovery of function in some instances. Nerve
damage is often irreversible, however.
Central Nervous System
The central nervous system is vulnerable to neurotoxic effects at lower levels of exposure than the peripheral
nervous system. In fact, depending upon the particular neurotoxicant, an individual may be unaware of any
relationship between symptoms and exposure. Such a patient may exhibit behavioral changes recognized only by
his family or co-workers.
Neurobehavioral effects of exposure to neurotoxicants usually precede other symptoms, including those of
peripheral neuropathy. Symptoms such as poor attention, drowsiness, memory problems, mood changes, and
impaired fine motor performance may interfere with job tasks resulting in costly injuries and lost productivity.
Neurotoxic effects on the central nervous system must be differentiated from effects induced by other
neurological disorders. Behavioral effects in humans can be acute or insidious and chronic in their emergence.
Attention has been focused on the need to identify neurotoxic effects of the brain as early as possible to avoid
permanent damage by continuing exposure.
Carefully selected neuropsychological testing provides standardized procedures for evaluating specific aspects of
behavioral function arising from damage to various areas of the brain.
Application of Neurobehavioral Methods
Historically, four approaches have been used to evaluate neurobehavioral function: the clinical neurological
examination, self-report checklists, performance tests, and neuropsychological tests. Primary prevention is the
concern when an exposure has occurred, but individuals are generally asymptomatic and the nature and degree of
neurobehavioral impairment are unknown. When this occurs, computerized performance tests and self-report
checklists may be most appropriate because they are the most sensitive in detecting relatively subtle effects.
Where secondary prevention is the concern because there is some overt evidence of neurobehavioral dysfunction,
such as health complaints from individuals or exposed groups, both performance tests and traditional
neuropsychological assessments will be useful. When clear evidence of behavioral dysfunction due to exposure is
available, administration of a neurological examination together with a neuropsychological test battery can
estimate the nature and degree of impairment.
In the case of primary and secondary prevention in which the degree of impairment is more subtle, it is usually
not possible to link dysfunction to exposure in the individual case. In some instances when individuals are
routinely exposed to hazardous chemicals, administration of performance tests and self-report checklists at the
beginning of the exposure (e.g., prior to employment) and at regular intervals thereafter can provide a useful
baseline against which neurobehavioral changes can be evaluated. In the absence of such a baseline,
neurobehavioral effects can be ascertained only by comparing level of function to established norms or by
comparing a group of exposed individuals with nonexposed controls. Unfortunately, published norms do not
exist for performance tests. Therefore, most primary prevention studies, designed to detect subtle effects of
exposure, must rely on comparisons with an appropriate control group or on changes from baseline relative to
controls to detect such effects. Many of the neuropsychological tests, on the other hand, have established norms.
However, established norms will not necessarily be relevant for evaluating effects in the exposed population,
which may differ from the normative sample in ethnic and cultural background, educational level, age, etc. Also,
even in the case in which symptomatic individuals are being evaluated (i.e., secondary prevention), effects may be
relatively subtle and may not fall within the impaired range on standard neuropsychological tests. Therefore,
comparison with an appropriate control group will be necessary.
Ideally, if neurobehavioral testing were to become a standard method for monitoring exposure-related effects in
the workplace, it would be introduced before exposure and provide baselines for subsequent evaluations.
Selecting appropriate controls in the absence of historical data is difficult but essential. In general, controls
should be as similar as possible to exposed individuals in ethnic background, socioeconomic status, educational
attainment, occupation, age, and gender. A matching procedure can be used to ensure that for each exposed
subject a control similar in these background characterisitics is also evaluated. To enhance sensitivity, a 2:1 or
3:1 ratio of subjects to controls is desirable. It is never feasible to match on all the relevant background
characteristics, however. Any characteristic in which the exposed and control subjects differ other than the
exposure itself is considered a potential confounding variable. For example, if more exposed subjects than
controls are chronic alcoholics, any observed differences in neurobehavioral function between the two groups
may well be due to differences in incidence of alcoholism rather than to exposure. Therefore, even if the
exposed and control subjects are matched on certain critical background characterisitics, it is important to assess
other potential confounding variables as well. When between-group differences are found on such variables, they
can be controlled statistically in all analyses comparing the performance of exposed subjects with that of controls.
A detailed discussion about the selection of and statistical control for potential confounders can be found in
Jacobson and Jacobson (5). Finally, the evaluation, in which tertiary prevention is the assessment level, most
closely resembles a traditional clinical evaluation of brain injury. A neurological examination will be most useful
in this situation in which overt symptoms of frank dysfunction can guide the inquiry. Also, one would expect
significant discrepancies in performance on standardized neuropsychological tests. Thus, comparison with
normative values for the individual case as well as for groups of individuals should reveal significant
discrepancies (e.g., 2 standard deviations below the mean) from expected values for individuals of similar
demographic composition. As for the other examples, appropriate controls must be selected for group
comparisons.
Test Methods Neurological Assessment
The neurotoxicant-exposed individual is at risk for developing changes in locomotor, peripheral, sensory, and
neurobehavioral functions involving perceptual, cognitive, and communications skills. Levels of toxic effect
determine severity of impairment or disability. Although possibly detectable as subclinical manifestations on
sensitive neurologic tests, earliest effects following exposure may be unrecognized by the subject. For example, a
metabolic change could be measured in a blood or urine test or with electronically determined nerve conduction
velocity studies while the patient has no symptoms and an examiner cannot detect abnormalities on clinical
examination even with specially designed tests. In the case of secondary or tertiary prevention situations, the
patient will report neurologic complaints such as an unusual sensation in the extremities (e.g., neuropathy) or a
change in mood. At this level, formal clinical neurologic tests may be able to identify indications of a physiologic
effect. Diagnosis of toxic peripheral neuropathy is made by testing perception of sensations of pain, temperature,
vibration, and joint position. Each of these modalities, if intact, will indicate the preservation of function in the
various sizes of nerve fibers.
As outlined by Feldman and White (6), the examination would begin with a clinical interview, which would
include a detailed description of the symptoms and functional changes that have been noted and their time of
onset, duration, and intensity. To aid in determining whether the presenting complaint is related to a chemical
exposure, detailed information should also be obtained regarding any exposure to chemicals in the workplace,
home or hobbies, as well as any genetic and/or congenital factors that might provide alternative explanations for
the complaint [see Feldman and White (6); Table 3].
Normal motor function can be defined as the ability of a person to initiate, sustain, and effectively perform
desired movement of a part or all of the body with speed, accuracy, and strength. Automatic motor behaviors are
completed without conscious awareness, using reflex pathways and adaptive mechanisms that adjust to variables
in resistance to the intended motor activity from gravity or other obstacles. Weakness is perceived by an affected
person as the need to exert more than usual effort to accomplish an action previously done without additional
effort. Qualitative assessment of strength by grip tests, weight lifts, or other measures that require overcoming
known resistance data about one aspect of motor functioning. Other techniques are necessary to record tremor
and coordination and to evaluate postural control (7). Walking pattern, a common clinically observable motor
response, can be quantified by measuring the distance between foot positioning at rest and between foot
placement while walking. The axial posture, flexed or erect, is an important indication of the ability of
spinal-central reflexes to maintain the posture. This function uses spinal cord posterior columns as pathways of
conduction potential and vibration sensation to inform the brain where the patient's feet are, and to send
instructions from cerebellum and cerebral motor systems (extrapyramidal) to regulate a balance between the
agonist and antagonist musculature.
Reduced sensation, demonstrated bilaterally in a symmetrical stocking and glove pattern, and hypoactive tendon
reflexes in the ankles and knees indicate peripheral neuropathy on neurological exam. Electrophysiological
methods are available to document the ability of a peripheral nerve to conduct an evoked nerve impulse and to
measure its amplitude and speed of conduction. Therefore, neurotoxic effects on the peripheral nervous system
can be ascertained in individual cases or in groups of exposed persons.
Sensory systems contribute to the ability to move with coordination and finesse. Thus, impairment in tactile,
visual, and auditory systems, as well as the vibratory and point position sensations will produce unsteadiness of
gait (ataxia) and poor coordination. Motor functions cannot be expressed independently of the sensory systems
with which they function.
Feldman and White (6) summarized the basic neurologic examinations used to detect nervous system function.
In addition, they describe the common electrophysiologic techniques used to obtain evidence of disturbances in
brain functions (i.e., electroencephalogram, evoked potentials, and imaging) and peripheral nerves. It emphasized
that electrophysiological tests may be applied differentially, depending on techniques and recording conditions,
instrumentation, and methods of data collection and interpretation. Conventional methods (8-10) have been well
described. The results of all these techniques are not specific to any particular neurotoxicant. The changes reflect
only the physiologic process and whether or not they are affected.
Performance Testing
Performance tests are designed to assess whether an individual can do a designated job. They can be sensitive,
reliable, cheap, and quick and easy to administer and have their main application when considering groups of
people at the primary prevention level of public health. Performance tests may also prove useful at the secondary
level, but they are not normally considered at the tertiary level unless some particular type of performance is at
issue. However, it is important to remember that while performance tests may show acceptable content and
construct validity (that is, they are internally consistent and can be placed in the context of accepted theories or
models of performance), they can be deficient in criterion validity [the degree to which they actually reflect
real-life situations (11)].
Performance tests are not normally diagnostic, although some can differentiate, for example, between colds and
influenza (12). Thus, they will not normally aid in identifying chemicals.
Performance tests make no claim to reveal effects on any brain areas, transmitter systems, or even on the nervous
system itself. Performance is usually affected directly by an agent's effects on the CNS, but it can also be
affected indirectly through a subject's awareness of peripheral effects, real or imagined. One of the main
advantages of performance tests is that they can measure the basic factors that compose real-life performance.
Thus, they have breadth of application, i.e., they can be applied in various combinations to build a picture of any
real-life task. The main disadvantage is that they cannot be applied to any one real-life task in any depth. If this
is what is needed, then it would perhaps be better to use simulators or to measure performance on the job itself.
However, simulators or adequate performance measures are not always available. There is actually a small
number of basic performance test designs, but there are so many variations of each that it is not possible to
describe them all. Some tests have been devised as parts of test batteries or collected together into batteries, but
there are very few standardized batteries such as are found in neuropsychological testing.
This is because the very process of standardization tends to reduce the tests' sensitivity. The lack of
standardization means that it is difficult to compare results between laboratories, but this is not normally an
issue at the primary public health level. What is important here is to determine whether any changes have
occurred that might be caused by exposure to a chemical, and this can be achieved by proper use of performance
tests as part of a controlled design.
In very general terms, sensitivity can be increased by making the test more difficult. With some tests, this can
easily be done, e.g., mathematical processing tests can contain more difficult problems to solve. With other tests,
increasing difficulty can only be done by introducing other aspects of performance. For example, in vigilance or
attention tests, the subject searches for a named stimulus such as a specified digit among sequences of random
digits. This can be made more difficult by asking the subject to search for certain strings of digits, but this then
begins to involve short-term memory.
Regarding standardization, some attempts have been made, but the resulting batteries have usually failed to
achieve general acceptance, mostly on the grounds of reduced sensitivity. One notable exception is the AGARD
STRES Battery (13,14) that, after a somewhat slow start, now seems to be gaining acceptance. The basic form
of the battery takes 25 to 30 min to administer and could be considered a first step in the investigation of any
performance effects of suspected exposure (15). Before describing performance tests, however, it is appropriate
to mention some of the principles of their use. General Procedural Aspects. Performance tests are usually of
short duration, such as 3 to 5 min, although they can be as long as required. For example, some people run
vigilance tests for several hours to duplicate the kind of context, such as air traffic control, in which vigilance
behavior is paramount. The scores obtained are variations on, or derivations from, measures of speed and
accuracy. There are two ways of testing: let the subjects complete the test and see how long they take, or
impose some time limit and see how far they get. The former is the more sensitive, but is not normally possible
since time is almost always limited. The test may be administered using paper-and-pencil methods or purpose-
built equipment, although most are now administered using personal computers.
This increases the precision, reliability, and consistency of the test but can introduce problems of validity. The
performance psychologist and the computer programmer should be aware of this. Performance tests, because of
their sheer number and variety, do not have norms and must be compared with some standard or control. This
can be achieved in two main ways. One method is to compare scores with those obtained earlier from the same
subjects. The advantage is that the subjects serve as their own controls; the disadvantage is that they might have
changed in various ways, other than having been exposed, between the two tests. Thus, any difference in test
results could be due to a variety of causes other than exposure to chemicals. Because exposure is not normally
anticipated, preexposure control results are not normally available.
The other method is to compare test subjects' scores with those of another group of people identical in all respects
except that they have not been exposed. This sounds easy, but it is actually very difficult to achieve. For example,
if all the workers in an area or factory might have been exposed, then no control group from the same area or
factory might be available. Here, the investigator must find the best comparison possible from other areas, and
often the best is not very good. The control group may differ from the test group in many ways, including their
inherent abilities and levels of knowledge, experience, and skill. For example, if the test group naturally happens
to be worse than the control group at one or more of the tests, then its scores will be worse and could be
interpreted erroneously as an effect of chemical exposure. Despite this great disadvantage, this form of control is
the one that most often has to be used, and it is important that very great care is taken to match the test and
control groups as carefully as possible.
When such control groups are used in experiments, it is vital that neither the subjects nor the experimenters know
which group has been given which treatment. This is called a double blind procedure and ensures that there is no
bias.
Double blind procedures are not possible in cases of suspected exposure to chemicals, but it is important that the
investigators remain unaware of the groups' identities as far as possible so that they remain free from any bias.
Learning is a considerable problem with performance tests. It will occur when any test has to be completed more
than once, e.g., to check the progress of an illness, or when subjects' test scores are compared with previously
obtained scores. Performance will improve with practice, which could mask any performance impairment, and
lead an investigator to the erroneous conclusion that all is well. Learning cannot be overcome, but it can be
minimized by proper test design, prior training, and proper study design. With regard to test design, subjects
can and do learn the items on the test. Thus, when they have to repeat a test, their results will reflect less of the
function that the test is supposed to measure and more their memory of the items on previous tests. With
psychomotor tests such as reaction time, tracking, or manual dexterity, this must be tolerated. With cognitive
tests such as mathematical, verbal, or spatial processing, the items are often randomized or pseudorandomized to
produce the same, or at least similar, degrees of difficulty.
Memory tests suffer from particular learning problems, which is not surprising since they are designed to
measure learning. An example of the sort of problem that can arise is with word lists. Subjects commonly offer
words they learned on one test when asked to recall words presented in later tests. This can be a serious problem
when tests are repeated frequently, e.g., to monitor the time-course of effect.
With regard to training, subjects should be given instructions on how to do the test and at least allowed to
practice until they are sure of what to do. Repeated training is advisable, up to even as many as four trials, until
a performance plateau has been established. When not enough time is available for extended training, the effects
of practice should be analyzed. With regard to design, the performance of test subjects must be compared with
that of control subjects after the same amounts of practice, i.e., first test with first test, nth test with nth test. A
drop in performance can be interpreted as evidence of impairment, given that the design criteria have been
satisfied. The lack of an expected improvement in performance is sometimes interpreted as impaired learning,
but cautiously, since absence of evidence is not evidence of absence.
Classification.
Performance tests are based on four main theories or models of performance: factor analysis, general information
processing, multiple resource/resource strategy, and stage processing. In practice, tests based on factor analysis
and resource models are very similar in appearance. They tend to be phenomenological in that they measure
various skills that humans exhibit, e.g., reaction time, verbal ability, and tracking. Processing stage tests take a
more functional approach--that of dissecting the processing stages that occur in all types of performance, e.g.,
detection, discrimination, recognition, identification, decision, response selection and response execution.
Phenomenological tests can indicate what types of performance are affected; processing stage tests can show
which stages are affected. Most performance psychologists use both types of tests, but phenomenological ones
predominate.
Several taxonomies have been proposed for phenomenological tests; one of the simplest is into sensory, cognitive,
and motor functions. One of the most practical taxonomies is in terms of seven functional areas: a) attention
(detection of rapidly or frequently occurring events), b) vigilance (detection of infrequent or uncertain events), c)
simple information processing such as coding, d) complex information processing such as logical reasoning and
spatial reasoning, e) memory, f) simple psychomotor skills such as tapping, aiming, or simple reaction time, and
g) complex psychomotor skills such as manual dexterity or tracking. Sometimes sensation is considered a
separate area as are psychophysical tests (e.g., flicker fusion, EEGs), although these might be considered to lie
more in the province of neurology.
Regarding test nomenclature, a point to remember is that tests may not always measure what they purport to
measure.
The name of a test reflects what the designer or user thinks is the function measured, but all tests involve all
functions to some degree. For example, a memory test involves not only memory but also perception and motor
functions, and all tests involve working or short-term memory. These contaminating functions may be minimal
but they are still there, and some tests may be better measures of the contaminating function than of the function
they claim to measure.
The main types of performance tests, with some of their main variations, are described below. There is some
overlap with neuropsychological tests since they cover similar functional domains and, in some cases, the same
tests are used in both neuropsychology and performance fields. All of the tests have been used successfully to
study the effects of various stressors, mainly drugs.
Attention/Vigilance are considered together since, in practical terms, they differ only with respect to the
frequency of stimulus presentation. All of the tests present signals embedded in noise for the subject to detect.
The number, frequency, and complexity of the signals can be varied with the amount, type, and degree of
similarity of the noise.
These parameters are often manipulated to vary the difficulty or sensitivity or to match more closely a particular
real life skill that might be at issue. Attention tests with frequent stimuli tend to last 3 to 5 min. Vigilance tests
can last longer if the stimuli are so infrequent that more time is needed to present enough target stimuli to provide
a realistic assessment.
One of the simplest tests is letter cancellation in which subjects are presented with sheets of paper full of random
letters and they have to strike out certain letters. The difficulty can be varied, for example, by altering the size,
font, or number of letters or the number of targets versus the total number.
There are several versions presented by computer. Most present sequences of letters or digits, and subjects have
to detect given targets. Sensitivity may be varied by changing the rate of presentation and the complexity of the
targets.
For example, rates of presentation can vary from one every few seconds to two or more per second; targets may
be single alphanumeric characters or groups of characters. One of the most difficult and sensitive versions of the
test presents digits at a rate of 100 per min, and the targets are triads of odd or even digits.
Mathematical Processing. The ability to perform simple arithmetic has been identified as a discrete factor in
factor analytical studies (16), and mathematical processing tests have been used to study the effects of several
drugs and effects of exposure to methyl chloride (17).
Mathematical processing tests vary in their complexity and sensitivity. One of the first of these tests was the
paper and pencil Number Facility (NF) test (16). It consisted of 90 questions, each consisting of three one- or
two-digit numbers.
Subjects had to complete as many questions as possible in 3 min and write the answers in boxes. The test was
standardized on U.S. servicemen and was widely used throughout the 1960s as a sensitive, reliable, and valid
measure of mathematical processing. Twenty equivalent forms were produced for repetitive testing, although
now the test may be administered using computers, which can produce as many equivalent forms as needed or
generate items as required.
The NF test proved sensitive but was fairly difficult to perform, so some people were not able to complete many
questions in the 3 min allowed. Thus, most subsequent mathematical processing tests have used addition or
subtraction of single digits. The test used in the AGARD STRES battery, for example, presents three single
digits with two operators and requires the subject to say whether the answer is greater than or less than 5.
Verbal Processing. Verbal processing is considered by some to measure the same area of function as
mathematical processing; however, the two functions are intuitively discrete and they can be affected
differentially. Several verbal processing tests have been reported in the field of experimental psychology,
but the most widely adopted as a performance test is Baddeley's Grammatical Reasoning test (18). The test
consists of several sentences, each followed by a pair of letters--AB or BA. The sentence describes which letter
comes first, and the subject has to say whether the description is true or false. Examples include "A follows
B--AB", "B does not follow A--BA", "A is preceded by B--BA".
The test is related to the ability to comprehend the structure and syntax of English and has proved sensitive to a variety of environmental stressors. However, its main disadvantage is that it is restricted to English.
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The test is related to the ability to comprehend the structure and syntax of English and has proved sensitive to a
variety of environmental stressors. However, its main disadvantage is that it is restricted to English. Attempts to
translate to other languages have met with varied success, e.g., German rarely uses the passive voice. The
AGARD STRES version of this test tried to remedy this defect by increasing the number and complexity of the
comparisons that had to be made, but the sensitivity of this version has yet to be fully assessed.
Spatial Processing. Spatial processing, like mathematical processing, has been identified as a discrete factor in
factor analytic studies, and a variety of tests have been reported to assess various subfactors such as spatial
relations, spatial orientation, and visualization. Some of these have found use as performance tests. They all use
spatial or graphic items that are impossible, or at least very difficult, to verbalize.
One is the manikin test in which a stylized picture of a human figure is shown holding an object in one hand. The
figure may be presented at any angle, forward or reversed, and the subject has to say which hand is holding the
object.
Another is the Shephard and Metzler block test (19), consisting of pairs of two-dimensional representations of
shapes produced by putting together eight cubes. In some pairs, the block shapes are the same, but one of the
pair is rotated; in other pairs, one block shape is the mirror image of the other. Subjects have to say whether the
shapes are the same.
A third is the Histogram test (20). Here, pairs of histograms are presented one histogram at a time. The first
histogram is normally presented upright, and the second is rotated normally through 90 or 270 degrees. Subjects
have to say whether the second histogram is the same as the first. This test has the advantage that the number of
bars and their lengths can be varied to change the level of difficulty.
Memory. There are perhaps more memory tests than all other performance tests combined. This is because
memory is a logical part of every aspect of human performance. Most memory tests assess short-term memory,
and most are unsuited for repetitive testing because what the subject learns on one test interferes with recall on
subsequent tests.
Sometimes this phenomenon can be used to advantage, e.g., to study perseveration, but usually it seriously
impairs the sensitivity of the test. Two tests that can be used repetitively are Wechsler's digit span test and
Sternberg's memory search test.
Wechsler's digit span test is one of the most widely used short-term memory tests, perhaps because it is easy to
use, it can be used repetitively, and it provides measures of two component memory skills labeled as rote recall
and mental manipulation. Subjects are presented with sequences of digits that they have to recall and report in the
same order immediately, and the sequences include more and more digits until the subject fails. Subjects are
usually allowed another attempt to minimize the effects of distractions, and the digit span is taken as the longest
sequence of digits that can be recalled successfully. Typically, healthy subjects can recall 6 to 8 digits. The test is
usually repeated with subjects recalling the digits in reverse order. This manipulation varies the cognitive
workload while keeping the memory load constant. In the somewhat unusual circumstance in which subjects
recall more digits backwards than forwards, a heightened arousal or motivation is postulated for the more
complex material. Although the digit span test is widely used, the literature suggests that it is of variable
sensitivity (21).
The Sternberg test presents subjects with a set of items (usually digits or letters) called the memory set followed
by a single probe item, and their responses indicate whether the probe is a member of the memory set. The test
can differentiate memory searching strategies, and the stages can be manipulated to vary their difficulty. For
example, memory searching can be affected by varying the size of the memory set, detection by varying the
figure-ground contrast of the probe items, and recognition by varying the clarity of the probe items. The test has
proved to be quite sensitive and is being used increasingly, particularly in psychopharmacology. The main
disadvantage is that the more stages that are covered the longer the test takes.
For this reason, many researchers use it simply as a short-term memory test, which seems a waste of its potential.
Simple Psychomotor Skills. Examples of simple psychomotor tests include finger tapping, aiming, simple and
choice reaction time, continuous reaction time (each response triggers the next stimulus (22), and
unidimemsional tracking.
These tests are simple in principle, but they vary widely in their style of administration such that it is rare to find
two laboratories with the same version. Despite this, the tests are generally sensitive and easy to administer.
Complex Psychomotor Skills. Complex psychomotor skills are measured by manual dexterity tests such as the
O'Connor fine finger dexterity test. For this test, subjects pick up three small pins at a time from a tray, using
only one hand, and place them in small holes. This skill has been identified as a discrete factor in factor analysis
studies, and the test has proved sensitive to a range of drug effects. Other tests under this heading include
two-dimensional tracking, which is generally of three types: pursuit, in which the subject pursues a moving target;
compensatory, where the target is stationary and the tracking device drifts; or combined compensatory/pursuit.
Various refinements have been made, e.g., where the evasive movements of the target increase as the cursor gets
closer. Generally, sensitivity increases as the tracking difficulty increases. One of the most sensitive is the
unstable tracking test in which the subject has to control a cursor that tends to accelerate away from a target.
This test originated from analyses of aircraft handling and is well-founded in human engineering theory.
Multitasking. Multitasking has proved useful in experimental psychology and performance work, and might also
prove useful in the assessment of neurotoxic chemicals. Multitasking is simply performing two (or more) tasks
concurrently.
The tasks may be chosen on the basis of a particular real-life application (e.g., vigilance and tracking are often
used) or to investigate or stretch reserve capacity, resource allocation, or time sharing functions. For this purpose,
cognitive tests are sometimes combined with motor tests such as tapping a finger at a nominal rate of once per
second. Variations in the rate of tapping can be used to reflect variations in performance load.
Neuropsychological Testing
At least 250 different tests have been used to evaluate the effects of neurotoxicants on behavior (21). Thus, when
the researcher or clinician is confronted with the task of selecting tests to evaluate reported symptoms, no single
test or battery of tests has been validated for characterization of dysfunction due to neurotoxicants. Before
selecting a test battery for assaying a suspected exposure, the relevant literature on that particular agent or
chemical class should be consulted. Specific guidance for tests to be used with the more frequent sources of
exposure can be found in publications such as White et al. (23). Although potentially useful in the evaluation of
gross impairment, traditional neuropsychological tests are less suited to characterize subtle cognitive dysfunction
since they often provide summary scores that are insensitive to the nuances of performance on the test. For
example, a total score is given for block design from the WAIS-R (24), a test frequently used to characterize the
effects of exposure. Speed of performance, motor coordination, and visuospatial skills are necessary to earn a
high score. It is impossible from this test score, however, to quantify which aspect of performance is impaired.
Likewise, performance-based tests from cognitive experimental psychology cannot offer a complete
characterization of behavioral dysfunction arising from brain injury. Thus, selection of tests from each tradition
depends on the purpose of the evaluation and the exposure situation.
Some studies have attempted to suggest patterns of performance associated with particular agents (e.g., lead vs
solvents (4); however, these patterns have not been well established.
Therefore, while it would be desirable to define specific batteries of tests suited for identified exposure situations,
the knowledge base does not allow that level of specificity. What is clear from the existing literature is that, to
adequately characterize neurobehavioral effects of a neurotoxic exposure, tests from each of the domains listed in
Table 1 should be selected. This conclusion is consistent with the World Health Organization's proposed
standardized screening battery of neurobehavioral tests (26). Specific tests wax and wane in their popularity, but
the domains to be represented are relatively consistent across studies and among clinical laboratories. Fiedler (3)
provides a description of the functional domains to be assessed and representative neuropsychological tests for
each category.
Use of a test battery that includes tests in each domain (e.g., the WHO battery) will provide an adequate initial
characterization of behavioral effects when a neurotoxic exposure of sufficient magnitude has occurred. For
example, if workers from a factory have used organic solvents routinely over several years and have symptomatic
complaints, application of these batteries to characterize the behavioral effects is advised. The literature is replete
with examples of the utility of these tests for characterizing neurobehavioral effects (27). Of course, if these tests
are applied in different cultures or languages, then consideration must be given to the impact of these
modifications on the test results. For example, normative values generated from one culture or country may not
be applicable to a different culture.
The following is a discussion of the tests commonly used to evaluate each of the functional domains. Table 1 lists
relevant strengths and weaknesses of frequently used tests from each functional category.
Evaluation of Sensory Function. While the neurologic examination involves evaluation of sensory function, such
an examination may not be possible in every situation. Therefore, before administering a battery of
neurobehavioral tests, it is important to determine that basic sensory processes, particularly of vision and
audition, are intact. Most of these tests require, at the very least, intact visual and auditory function, and tests of
motor speed and visuomotor skills require intact somatosensory function. For example, blue collar workers in the
construction trades or in farming may have hearing impairment due to noise or tactile sensory imperception due
to injuries to the hands. Clearly, these mechanical problems would account for poor performance on some
neurobehavioral tests. Therefore, it is important to know about these difficulties so that cognitive impairment is
not inferred inappropriately. Basic tests of visual acuity and hearing as well as simple tests of tactile perception
should be performed before the initiation of a neurobehavioral examination.
Overall Cognitive Ability. Unfortunately, in most exposure situations, a standardized indicator of preexposure
cognitive function is not available. Performance on all neurobehavioral tests is influenced by the individual's
overall intellectual ability. To interpret results from group studies or from an individual evaluation, an estimate of
preexposure ability must be obtained. In some situations, achievement test scores may be available from military
or school records and should be obtained. If different tests are used from one individual to the next in a group,
these scores may be converted to the same scale (e.g., T score) to allow rough comparisons between groups.
Educational level has also been used as a rough surrogate of overall cognitive ability. In the absence of an actual
test score documenting preexposure ability, many investigators and clinicians use standardized tests of verbal
skills to estimate ability. This strategy rests on the assumption that neurotoxicants do not reduce performance on
indicators of well-learned information such as vocabulary or reading ability.
The vocabulary test from the WAIS-R (24) requires that the individual define words in a free recall situation.
Other tests of vocabulary, such as the Shipley (28) are given in a multiple choice format, which reduces the
verbal expressive demands on the individual. Another frequently used group of tests to assess ability are tests of
reading such as the National Adult Reading Test-Revised (29) or the Wide Range Achievement Test-Revised,
Reading Subtest (30). These tests require that the individual pronounce a series of words of increasing difficulty.
Individuals are given credit if the words are pronounced correctly. All of these tests are heavily dependent on
language abilities. Therefore, their use in other cultures must be adapted accordingly.
Attention/Concentration. The ability to orient to a stimulus and sustain attention is the precursor to successful
performance on most neurobehavioral tasks; therefore, tests to assess this function must be included. Otherwise, a
deficit on another test such as a test of memory may be misinterpreted as a primary memory dysfunction when an
inability to sustain attention is the primary deficit. Digit span from the WAIS-R (24) is a widely used test of
auditory attention in which the individual is asked to repeat an increasing string of digits presented by an
examiner. Instructions are given to repeat the digits as they are presented and to reverse them. The
Bourdon-Wiersma (31) is another test widely used in the Scandinavian literature to assess vigilance. In this
paper and pencil test, the individual must cross out each series of four dots interspersed among a page full of
other dot configurations.
Motor Skills. The standard neurological examination includes a clinical evaluation of motor skills. However,
neurobehavioral tests provide a relatively more standardized assessment of these skills which can be related to
normative values. Grooved pegboard (32) is a simple test of fine motor coordination in which the individual
places grooved pegs in grooved holes with the dominant and nondominant hand while being timed. This task
requires some fine manipulation of the pegs to fit correctly into the grooves. Finger tapping (33) is another
simple task of motor speed in which the individual taps as quickly as possible with the index finger of the
dominant and nondominant hands. The number of taps is recorded with a mechanical counter. Although a
version of this test is available on computer (NES2) (34), the manual version requires minimal equipment and
normative values are available for its administration (25).
Finally, the Santa Ana (35) is a test applied frequently in Scandinavia that also involves placing pegs in holes on
a board while being timed.
Visuomotor Coordination. Digit symbol from the WAIS-R (24) is probably the most widely used test of
visuomotor coordination and speed within the literature on neurobehavioral assessment of neurotoxicants. In this
task, the individual is asked to record symbols associated with digits from a key that is present throughout the
task. The individual is given 90 sec and the number coded correctly during this time period is the score. A version
requiring only an oral response is available for motor-impaired individuals. Trials A and B (33) are also widely
used tasks involving visuomotor coordination and speed. The instructions are to connect numbers in sequence
(Trails A) or shift between numbers and letters in sequence (Trails B) while being timed. Speed of performance is
measured, and mistakes add to the time required to complete the task.
Visuospatial Relations. Tests of visuospatial ability may serve as indicators of overall ability but are not
recommended when exposure is suspected because they have also been sensitive to the effects of neurotoxicants.
For example, Raven's Progressive Matrices (36) is a test of visuospatial problem solving for which minimal
verbal skills are required. Block design from the WAIS-R has also been extensively used. This task involves
putting blocks together to mimic a design while being timed. Additional points are given for quick performance,
but a design must be completely correct and performed within the time limit to receive full credit. Thus, speed as
well as visuospatial ability contribute to performance.
Memory. Many tests of memory are available. Among those most frequently applied in the field of
neurobehavioral assessment are subtests from the Wechsler Memory Scale-Revised (WMS-R) (37). The Paired
Associates test from the WMS-R involves the verbal presentation of four easy and four difficult word pairs over
six separate trials. The correct answers are summed over the first three trials. The purpose of this task is to
evaluate the ability of the individual toncode verbal information. Delayed recall is also evaluated after a 30-min
delay.
This task is relatively simple compared to the California Verbal Learning Test (CVLT) (38). The latter involves
learning a list of 16 common shopping items presented verbally over five consecutive trials. Delayed recall is
evaluated after a 20-min latency by providing a recognition trial. The precursor to the CVLT, i.e., the Rey
Auditory
Verbal Learning Test (39), has been used on several occasions to evaluate the effects of neurotoxicants. In
addition to learning efficiency over the trials, the CVLT also evaluates the strategies used to encode the word list,
the effects of an interfering list on subsequent recall of the original list, and the effects of a 30 min delay on
recall. Also, recognition of the list is evaluated separately from free recall. Thus, in one test, many parameters of
verbal learning are evaluated. It is important in any evaluation of memory to include memory for visual as well
as verbal material. Tests of visual memory often involve abstract figures as stimuli that cannot be easily encoded
verbally. For example, abstract figures are presented for 10 sec in the visual reproduction test of the WMS-R.
The individual is then asked to draw them from immediate memory. Standardized scoring procedures are used to
evaluate the performance. Similarly, in the Benton Visual Retention Test (40), abstract figures are presented,
reproduced from memory, and scored with standardized procedures. Individuals are also asked to draw the
figures from memory after a 30-min delay. The Rey-Osterreith Complex Figure Test (41) follows a similar
procedure except that the figure is much more complex.
Affect/Personality. Many checklists and symptom rating scales are available to evaluate subjective ratings of
mood. As stated previously, alterations in mood are often one of the first indicators of the effects of
neurotoxicants. In selecting a measure of mood, it is important to evaluate the range of affect including symptoms
of anxiety, irritability, and depression. The Profile of Mood States (42) and the Minnesota Multiphasic
Personality Inventory-2 (43) have been used frequently to evaluate the mood changes in response to
neurotoxicants. Computerized Test Batteries.
More recently, tests from the neuropsychological tradition and cognitive experimental or performance testing
have been computerized for use in the assessment of the effects of neurotoxicants. Batteries such as NES2 (34)
and the Milan Automated Battery (44) grew out of the need to conduct studies that could be conducted efficiently
in the field.
Also, these batteries have been some of the first to bring performance testing together with traditional
neuropsychological tests for these evaluations. For example, NES2 includes reaction time and continuous
performance as a part of the battery, along with computerized versions of digit symbol and finger tapping. It is
important to remember that adaptation of the neuropsychological tests for the computer makes the test
fundamentally different so that the normative data collected on the original tests are not applicable. In keeping
with the tradition of experimental psychologists, the test parameters within the software are adjustable so that the
duration and difficulty of each component test can be altered by the administrator. Therefore, it is critical to
publish the parameters of test administration along with the results obtained. Experimental psychologists may feel
constrained by the clinical standardization and the limiting of response modalities to a keyboard, mouse, or
joystick. However, for comparison of groups, these batteries offer tests from both traditions that are easily
administered and accessible. Some general advantages of all neuropsychologic tests listed below are that these tests have normative values. As
for the use of any test, good practice demands that care be taken to insure demographic comparability of the
individual(s) tested and the normative values provided for the test. When normative values are clearly not
representative of the general U.S. population, this is listed as a weakness for the specific test. Another advantage
of the tests listed is that standard instructions for test administration are provided in the test manuals. This
reduces the variability due to differences in examiners. A universal disadvantage of these tests is that they must
be given by an examiner with some experience and training in test administration. This increases the time
involved and cost of administering a battery of these tests. However, the equipment required to give these tests is
inexpensive, readily available, and quite portable. Thus, the primary cost of testing is for personnel. Finally,
while many of these tests may be administered by a well-trained technician, interpretation of the results from an
individual or group requires the expertise of a professional trained in the use of these tests and their applications.
Developmental Assessment
Research on numerous substances, including lead, alcohol, methylmercury, and polychlorinated biphenyls (PCBs)
indicates heightened susceptibility of infants and children to neurotoxicity, particularly when exposure occurs
early in the course of development. By contrast to the effects of acute adult exposures, which are frequently
transitory, the effects of exposure during development are often more persistent. Moreover, effects of in utero
exposure on the CNS often do not become evident for several years, that is, when the affected cognitive or
behavioral system matures. In the case of industrial accidents or other acute exposures, particular attention needs
to be given to effects on offspring of women exposed during pregnancy.
Much of our knowledge of the effects of neurotoxic exposure on development comes from prospective,
longitudinal studies in which exposed infants are recruited prenatally or immediately after birth and assessed over
the course of development. Prenatally, vulnerability of a particular brain structure or region may be heightened,
particularly when exposure occurs during a period of rapid cell division or cell migration. After delivery, the
blood-brain barrier and a more highly developed drug-metabolizing capacity may provide protection not available
in utero. Because brain development and mylenation continue for several months after delivery, there may also be
heightened vulnerability during infancy. Given the unique vulnerability during early development, the cognitive
and behavioral deficits seen in adults exposed to a particular chemical may provide little indication of the types of
neurobehavioral impairment that might be expected in infants and children exposed during development.
The test used most extensively to evaluate neurobehavioral function in the newborn is the Brazelton (45)
Neonatal Behavioral Assessment Scale (NBAS). The NBAS, a 30-min examination procedure, assesses 17
reflexes and a range of behaviors including muscle tone, activity level, attention and orientation, and arousal
(46). Although sensitive to many prenatal chemical exposures, including obstetrical medication, opiates, and
PCBs (46,47), effects seen on the NBAS are often very transitory, and the test is not predictive of
neurobehavioral function during later development. No norms are available. The test used most frequently to
evaluate neurobehavioral function during infancy is the Bayley Scales of Infant Development. The Bayley,
which provides both a Mental Development Index and a Psychomotor Development Index, focuses primarily on
the rate at which the infant attains age-appropriate developmental skills. Standardized norms are available for
both the original Bayley and the recently released Bayley II. The Bayley has proven sensitive to a broad range of
prenatal exposures, including alcohol (48,49), lead (50,51), methadone (52), and PCBs (53,54).
Although predictive validity for school-age cognitive function is poor for children who perform within the normal
range (55), most neurotoxic exposures detected by the Bayley are also associated with poorer cognitive
performance at school age. Thus, the Bayley may be sufficiently sensitive to detect group differences associated
with neurotoxic exposure even if it is not sufficiently reliable to predict for individual children.
The Bayley is an apical test; successful performance on a single item usually depends on the integrity of multiple
elements of cognitive and fine motor function, as well as attention to the task and motivation to perform. The
principal advantage of apical tests is sensitivity. Because the infant's performance on a given item can be
affected by deficits in any of several domains, the Bayley is sensitive to a broad range of impairments. The
principal weakness of an apical test is lack of specificity; little information is provided about which aspects of
cognitive function have been compromised.
The Bayley grew out of a maturationist tradition (56,57) that regarded infant development as a series of
milestones programmed to emerge over time. As a result, at each age only those domains in which new behaviors
are emerging are assessed in detail. Nevertheless, given the Bayley's sensitivity, it is probably advisable to include
it in any assessment of the effects of a previously unstudied exposure.
An alternative approach to infant neurobehavioral assessment is provided by certain newer tests of infant
cognitive function exemplified by the Fagan visual recognition memory test (57). In the Fagan test, infant
patterns of visual fixation to familiar and novel stimuli are used to assess recognition memory and visual
discrimination, two processes that are fundamental to intellectual function during childhood and adulthood. By
contrast to an apical test like the Bayley, the Fagan takes a "narrow band" approach and will provide an
indication of neurobehavioral deficit only if there is a neurotoxic effect on one of the specific domains of function
that it assesses. Nevertheless, the Fagan has been found to be sensitive to prenatal exposure to PCBs in human
infants (58), to methylmercury in rhesus monkeys (59), and, when scored in terms of information processing
speed, to prenatal exposure to alcohol as well (60). By contrast to the Bayley, the Fagan has been found to be
moderately predictive of intellectual function during childhood (61). Visual acuity can be assessed during infancy by means of a new procedure developed by Teller et al. (62), which
is based on infant visual fixation to vertical lines displayed at different horizontal distances on a screen. In
principle, it is similar to the Fagan test because it measures differences between the time spent gazing at the
vertical pattern compared to that spent gazing at a blank target. The density of the patterned target provides
scores related to what vision scientists term spatial contrast sensitivity. It describes the ability of the visual
system to distinguish darker from lighter arrays by specifying the width (visual angle) of the array and the depth of the dark-light difference, or contrast.
Many of the neuropsychological and performance tests originally designed for adults are also available for use
with children. Several IQ tests are available, including the McCarthy Scales of Children's Abilities and the
WPPSI (Wechsler Preschool and Primary Scale of Intelligence - Revised) for the preschool period; the Wechsler
Intelligence Scale for Children (WISC)-III for school-age children; and the Stanford-Binet and Kaufman
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Many of the neuropsychological and performance tests originally designed for adults are also available for use
with children. Several IQ tests are available, including the McCarthy Scales of Children's Abilities and the
WPPSI (Wechsler Preschool and Primary Scale of Intelligence - Revised) for the preschool period; the Wechsler
Intelligence Scale for Children (WISC)-III for school-age children; and the Stanford-Binet and Kaufman
Assessment Battery for Children, which cover both periods. The principal advantages of these tests include
standardized norms and coverage of a broad range of domains of function. Examination of effects on subtest
scores, which are frequently also normed, can provide information regarding effects on specific domains of
function. Although there is evidence suggesting that IQ tests may be culturally biased, they are predictive of
success in school and therefore provide a valid indicator of that important domain of intellectual performance
during childhood. Childhood IQ tests ave been found to be sensitive to prenatal or early childhood exposure to
lead (51,63), alcohol (64,65), and PCBs (66). Effects on school achievement can also be assessed directly by
administering standardized school achievement tests in such domains as reading, math, spelling, etc.
Neuropsychological tests available for use with children include the grooved pegboard and the Wisconsin card
sorting tests. One of the most frequently used performance tests is the continuous performance test (CPT), which
has repeatedly been found to be sensitive to the effects of prenatal exposure to alcohol (67-70). The Sternberg
memory search test can easily be used with school-age children, and a mental rotation test designed by Kail (71)
is also available, which measures RT in discriminating between mirror images of rotated letters to assess mental
manipulation of visual images.
One very important potential confounding influence in neurobehavioral assessment during childhood is quality of
intellectual stimulation and emotional support provided by parents. In some studies, chemical exposures have
been found to be so confounded with such influences that it was not possible to evaluate their effects on
intellectual development (5).
One important advantage of performance tests over IQ and school achievement is that they are markedly less
affected by socioenvironmental influences (5). Infant tests administered during the first year are also much less
likely to be confounded with social environment (5,72).
One of the principal advantages of a prospective longitudinal approach for evaluating developmental toxicity is
that it provides an opportunity to assess exposure during the potentially vulnerable prenatal and infant periods.
Retrospective studies are feasible, however, where the chemical remains have been deposited in the child's tissue
over an extended period of time.
Needleman et al.'s (73) classic retrospective study demonstrating lead neurotoxicity based on levels of lead
deposited in deciduous teeth provides a relevant example. In some cases medical records can be used to document
early exposure, as in the 1979 PCB poisoning in Taiwan, where all exposed individuals were enrolled in a
government registry (5). For some exposures, such as maternal smoking during pregnancy, parental recall can
provide reliable information, although recall for many prenatal exposures will not be accurate (5).
Summary and Recommendations As demonstrated in this chapter, a wide variety of procedures are available for
the assessment of human neurobehavioral function. The validity of performance tests for evaluating the
neurobehavioral effects of drugs is well established, but these types of tests have been used to only a limited
degree for assessing the neurotoxic effects of chemical exposures in the clinic. As performance tests are
incorporated into studies of neurotoxicity induced by chemical exposures, it would be helpful to establish a
database. This database would provide information regarding their sensitivity in this context to help
investigators select from the many tests when undertaking neurotoxicity studies.
Although traditional neuropsychological tests have been used extensively in clinical assessments of chemical
exposures, there is no centralized source of information about their validity in these studies. A database covering
the use of both types of assessments in this context would therefore be very useful.
Over time, such a database would also be useful for investigators interested in conducting metaanalyses to
integrate data from diverse studies using similar measures to investigate the neurotoxicity of a given chemical
exposure. There are probably already sufficient data for such an analysis in the neurotoxicity of organic solvents.
As indicated by several of the papers in this volume, more information is also needed about the validity of
repeated assessments using these measures to track recovery or deterioration during the period after an exposure
has occurred.
One issue that warrants increased attention is individual differences in vulnerability to exposures. We have
already reviewed some of the evidence indicating the heightened vulnerability found when exposure occurs in
utero or during infancy, and it has been suggested that vulnerability may also be increased by the process of aging
or when individuals are under stress (74). Drug studies have demonstrated individual differences in vulnerability
in women that are related to variations in hormone levels. Such differences might be expected for neurotoxic
chemicals as well, particularly those like PCBs that are known to affect hormone levels. Evidence of multiple
chemical sensitivity reviewed by Fiedler (3) also indicates the importance of increased attention to individual
differences in susceptibility.
Finally, although assessment of neurobehavioral outcome has been the principal focus of this chapter, it is critical
to recognize the importance of obtaining as concurrent and reliable an assessment of exposure as possible. For
studies of substances such as lead and PCBs, which leave detectible biological residues, this would mean
obtaining blood or other tissue samples as close to the time of exposure as possible. For others, detailed
documentation of extent of exposure (e.g., proximity to the spill) should be recorded in an official government
registry. Often government assistance can be made contingent on registration. Concurrent measures of exposure
are critical for investigating long-term consequences, which may not become evident until several years after the
fact. Wherever possible, it is important to document not only the fact of exposure but also its extent to
investigate dose-response relationships and lowest-dose thresholds at which neurotoxic effects first become
evident.
Legal cases:
1. SARCHET V. CHATER, (78 F.3d 305) (7th Cir. 1996)("...there are no laboratory tests for the presence of fibromyalgia.......but elusive and mysterious, disease, much like chronic fatigue syndrome, with which it shares a number of features. Its cause or causes are unknown, there is no cure, and, of greatest importance to disability law, its symptoms are entirely subjective...Whether or not she is disabled within the necessarily restrictive meaning of the Social Security Act and its regulations, she is unemployable...");
2. ROSE V. SHALALA, (34 F.3d 13) (1st Cir. 1994) ("...the absence of definitive diagnostic tests "for chronic fatigue syndrome" does not constitute substantial evidence to support a finding that claimant did not suffer from the syndrome");
3. SISCO V. DEP'T OF HEALTH AND HUMAN SERVICES, (10 F.3d 739)
(10th Cir. 1993) ("there is no 'dipstick' laboratory test for chronic fatigue syndrome");
4. COHEN V. SECRETARY, (964 F.2d 524) (6th Cir. 1992)
"the exact causes of chronic fatigue syndrome are still being explored");
5. LANTOW V. CHATER,(No. 95-5262) (N.D. Okla. October 8,1996) "negative test results or the absence of an objective medical test to diagnose [fibromyalgia] cannot support a conclusion that claimant does not suffer from a potentially disabling condition").
6. SHERMAN V. APFEL, (No. 97-7085) (10th Cir. 1997)
("...may not use the lack of corroborating objective medical evidence to disregard the claimant's allegations..Nonspecific malaise, anorexia, and fatigue often dominate the clinical picture, sometimes with low-grade fever and nondescript upper abdominal discomfort....the severity of plaintiff's abdominal pain, diarrhea, and nausea, it does not undermine her complaints of other nonexertional limitations, such as frequent headaches or fatigue, which plaintiff described as her most limiting symptom...")
7. PETERSON, v. CHATER, (No. 96-1906)(" So if, as the administrative law judge found, Peterson is not capable of prolonged sitting, standing, and walking, he is not capable of doing sedentary or light work-- contrary to the administrative law judge's other finding.")
8. SHERMAN, V. CALLAHAN (No. 97-7085)("fatigue does not differentiate between patients with mild or severe liver disease..Liver tests performed in May and June 1994 showed an upward trend in certain liver enzymes, and hospital records showed continued complaints of headaches, diarrhea, abdominal pain, decreased energy, depression and anxiety. Dr. Inbody diagnosed plaintiff with moderate depression and ongoing polysubstance abuse. He reported that plaintiff had severe psychosocial stressors and gave her a "global assessment of functioning" (GAF) score of forty-five, id. at 290, which meant that she had "[s]erious symptoms (e.g., suicidal ideation, severe obsessional rituals, frequent shoplifting) or any serious impairment in social, occupational or school functioning (e.g., no friends, unable to keep a job)," American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders 32... In so describing plaintiff's activities, the ALJ ignored other statements on the same forms that evidenced limitations on plaintiff's activities."
9. TIGER, v. APFEL,
("An ALJ cannot substitute his own opinion for medical opinion") So conclusively DLIR can not do so also, and can not choose from available alternatives presented by experts for hire.
10. DENISE KEHOE, Decision of NH Supreme Court,
"Dr. Daniel Kinderlehrer, a specialist in environmental medicine, who diagnosed her as "suffering from Multiple Environmental Sensitivities, with a severe Multiple Chemical Sensitivity Disorder." This diagnosis was "evident on the basis of her significant symptomology provoked by exposure to low doses of chemicals."
$$$$$$$$$$
THE SUPREME COURT OF NEW HAMPSHIRE
___________________________
Compensation Appeals Board
No. 95-316
APPEAL OF DENISE KEHOE
(New Hampshire Compensation Appeals Board)
November 13, 1996
Sullivan & Gregg, P.A., of Nashua (James H. Leary on the brief and orally), for the claimant.
Kelliher & Clougherty, of Manchester (Thomas W. Kelliher on the brief), and Elizabeth Cazden, of Manchester, by brief and orally, for the respondents, Lockheed-Sanders Company and Liberty Mutual Insurance Company.
BROCK, C.J. This is the claimant's second appeal from the New Hampshire Compensation Appeals Board's (board) denials of workers' compensation benefits. We reverse and remand for calculation of benefits.
The claimant, Denise Kehoe, worked as an assembler at the Lockheed-Sanders Company (Sanders) from August 1979 to March 1991. During those twelve years, she was regularly exposed to numerous chemicals while performing her job, including lacquer thinner, HumiSeal, isopropyl alcohol, RTV adhesive sealant, trichloroethane, and chemical adhesives such as Locktite. Many of these substances were rated by their manufacturers as posing a health hazard, with health hazard ratings as high as "three" ("four" being the most hazardous). The claimant used many of these chemicals on a daily basis, breathing their fumes as she applied them with a brush to seal joints or to clean or dissolve substances. Her work sometimes entailed heating joints previously soldered with HumiSeal (a "serious" hazard rating of "three") in order to disassemble the materials; the heated compound exposed her to additional fumes beyond those emanating from the unheated HumiSeal containers.
Prior to her employment at Sanders, the claimant did not have severe headaches or breathing difficulties. Approximately two months after commencing her employment at Sanders, the claimant began experiencing headaches at work. As time passed, her headaches worsened into migraines and additional symptoms developed, such as dizziness, sinus irritation, and muscle aches. Beginning in 1989, her tenth year at Sanders, she began experiencing breathing disorders, including bronchospasm and chronic sinus problems. By March 1991, the combination of symptoms was so debilitating that she was compelled to take a medical leave from work. Although her condition improved during her leave, her symptoms recurred during two separate visits to Sanders, and she was forced to extend her medical leave. In May 1991, her doctors advised her not to return to work. At this point, she had developed hypersensitivities to a wide variety of chemicals, including not only the chemicals she worked with at Sanders but also many household cleaners, perfumes, and other things encountered in ordinary non-work life.
During the years that the claimant was employed at Sanders, her treating physician, Dr. Alexis-Ann Bundschuh, had difficulty diagnosing her condition, in part because the symptoms accelerated in both number and degree over the years. Dr. Bundschuh referred the claimant to several specialists, including a pulmonary consultant who diagnosed her as suffering from chronic asthma, and an occupational health specialist who diagnosed her as suffering from "[b]ronchospastic airway disease reactive to nonspecific irritants with . . . sensitivity to a vast array of various at-home and at-work fumes and smells." Soon after leaving her job, the claimant also saw Dr. Daniel Kinderlehrer, a specialist in environmental medicine, who diagnosed her as "suffering from Multiple Environmental Sensitivities, with a severe Multiple Chemical Sensitivity Disorder." This diagnosis was "evident on the basis of her significant symptomology provoked by exposure to low doses of chemicals."
The claimant filed for workers' compensation benefits in 1991. Her claim was denied by a hearings officer, and the claimant appealed to the board. After a hearing, the board upheld the denial, finding that the claimant did not suffer from an occupational disease as defined in RSA 281-A:2, XIII (Supp. 1995). She appealed and we reversed, holding that multiple chemical sensitivity syndrome (MCSS) due to workplace exposure to chemicals is an occupational disease compensable under our workers' compensation statute. Appeal of Kehoe, 139 N.H. 24, 26, 648 A.2d 472, 474 (1994). We remanded to the board "for a determination of whether the claimant suffers from [MCSS] and, if she does, whether the workplace caused or contributed to the disease." Id. at 27, 648 A.2d at 474.
On remand, the board held a new hearing and again denied the claim. The board found that the claimant does suffer from MCSS, but concluded that she "failed to prove by a preponderance that the MCSS is causally related to a risk or hazard of employment at Sanders," and therefore "failed to meet her burden of proving causation." This appeal followed.
We will overturn the board's decision only for errors of law, or if we are satisfied by a clear preponderance of the evidence before us that the order is unjust or unreasonable. Appeal of Lambrou, 136 N.H. 18, 20, 609 A.2d 754, 755 (1992); RSA 541:13 (1974). The board's findings of fact will not be disturbed if they are supported by competent evidence in the record, Lambrou, 136 N.H. at 20, 609 A.2d at 755, upon which the board's decision reasonably could have been made. See Appeal of Normand, 137 N.H. 617, 619, 631 A.2d 535, 536 (1993); Town of Hudson v. Wynott, 128 N.H. 478, 483, 522 A.2d 974, 977 (1986).
To make out a claim for workers' compensation, a claimant is required to show that her injuries arose "out of and in the course of [her] employment." RSA 281-A:2, XI (Supp. 1995). To show this, the claimant must prove by a preponderance of the evidence that her work-related activities "probably caused or contributed to [her] disability." Appeal of Cote, 139 N.H. 575, 578, 660 A.2d 1090, 1093 (1995).
The test for causation has two prongs; a claimant must prove both legal causation and medical causation. Id. at 578, 660 A.2d at 1093. Legal causation entails a showing that the claimant's injury is in some way work-related, while medical causation requires a showing that the injury was actually caused by the work-related event or condition. Id. at 578-79, 660 A.2d at 1093. The board did not make clear whether it found that the claimant failed to meet her burden with respect to legal or medical causation. We hold, however, that no reasonable board could have found that the claimant failed to meet her burden of proving either legal or medical causation on the record in this case. See id. at 579-80, 660 A.2d at 1094.
"The legal causation test defines the degree of exertion that is necessary to make the injury work-connected." Appeal of Briggs, 138 N.H. 623, 628, 645 A.2d 655, 659 (1994). "The test to be used depends upon the previous health of the employee." Id. Where a claimant had a preexisting disease or condition prior to employment, she must show by a preponderance of the evidence that her employment "contribut[ed] something substantial" to her medical condition by demonstrating that the work-related conditions presented greater risks than those encountered in her non-employment activities. New Hampshire Supply Co. v. Steinberg, 119 N.H. 223, 231, 400 A.2d 1163, 1168 (1979). Where there is no preexisting condition, any work-related activity connected with the injury as a matter of medical fact would be sufficient to show legal causation. Id.
Here, although the board did not make an express finding as to whether the claimant's MCSS was a preexisting condition, the record clearly indicates that the claimant exhibited no unusual degree of headaches and experienced no respiratory or bronchial disease prior to going to work for Sanders. On the record before us, we can presume that the claimant had no preexisting condition. It is equally clear from the record that the claimant presented evidence, through expert medical witnesses and medical records, to connect her MCSS to her work environment. Although the board found this evidence unpersuasive on the ultimate issue of causation, we conclude that the board could not reasonably have found that the claimant had not met her minimal burden of establishing legal causation. See Appeal of Cote, 139 N.H. at 579, 660 A.2d at 1094.
The test for medical causation requires the claimant to establish, by a preponderance of the evidence, that the work-related activities "probably cause[d] or contribute[d] to the employee's [disabling injury] as a matter of medical fact." Bartlett Tree Experts Co. v. Johnson, 129 N.H. 703, 709, 532 A.2d 1373, 1376 (1987); see Wheeler v. School Admin. Unit 21, 130 N.H. 666, 672, 550 A.2d 980, 983 (1988). Even if the work-related activities did not directly cause or contribute to her injury, it would be sufficient to show that the activities caused the activation of her disabling symptoms. Appeal of Briand, 138 N.H. 555, 560, 644 A.2d 47, 50 (1994); see also Bothwick v. State, 119 N.H. 583, 588, 406 A.2d 462, 465 (1979) (finding medical evidence of aggravation of preexisting condition by work-related activities sufficient evidence of medical causation).
Medical causation "is a matter properly within the province of medical experts, and the board [is] required to base its findings on this issue upon the medical evidence rather than solely upon its own lay opinion." Appeal of Cote, 139 N.H. at 579-80, 660 A.2d at 1094. In the instant case, no physician who treated or evaluated the claimant expressed any doubt that work contributed to, or at a minimum aggravated, her condition. See id. at 580, 660 A.2d at 1094; Bothwick, 119 N.H. at 588, 406 A.2d at 465. "Because a claimant's treating physicians have great familiarity with [her] condition, their reports must be accorded substantial weight." Appeal of Morin, 140 N.H. 515, 519, 669 A.2d 207, 210 (1995) (quotation omitted). Dr. Albee Budnitz, a pulmonary consultant, concluded that the claimant suffered from "[a]sthmas of mixed variety[, p]robably with multiple factors as precipitants including stress, respiratory infections, some degree of allergy and certainly multiple chemical irritants the most obvious of which is T.D.I." HumiSeal contains T.D.I. Dr. Barbara O'Dea, an occupational health specialist, who was also consulted on referral, opined that although "it would be difficult to say that her chronic exposures at work initiated her basic problem," the claimant did "show[] evidence that exposures to fumes at work cause exacerbation of her underlying condition
. . . ."
Journal of Neuroscience, Vol 16, 1066-1071, Copyright © 1996 by Society for Neuroscience
ARTICLE
THE POSSIBLE ROLE OF HYDROGEN SULFIDE AS AN ENDOGENOUS NEUROMODULATOR
K Abe and H Kimura
Salk Institute for Biological Studies, San Diego, California 92138, USA.
Hydrogen sulfide (H2S), which is well known as a toxic gas, is produced endogenously from L-cysteine in mammalian tissues. H2S is present at relatively high levels in the brain, suggesting that it has a physiological function. Two other gases, nitric oxide and carbon monoxide, are also endogenously produced and have been proposed as neuronal messengers in the brain. In this work we show the following: (1) an H2S-producing enzyme, cystathionine beta-synthase (CBS), is highly expressed in the hippocampus; (2) CBS inhibitors hydroxylamine and amino-oxyacetate suppress the production of brain H2S; and (3) a CBS activator, S-adenosyl-L-methionine, enhances H2S production, indicating that CBS contributes to the production of endogenous H2S. We also show that physiological concentrations of H2S selectively enhance NMDA receptor-mediated responses and facilitate the induction of hippocampal long-term potentiation. These observations suggest that endogenous H2S functions as a neuromodulator in the brain.
In Reply to: MCS and poisoning by dental amalgam posted by Mai on May 31, 1999 at 20:35:44:
The NH&MRC have withdrawn their endorsement of the safety of Dental Amalgam since
the 18th August 1997
The Australian Dental Association thus can no longer claim support for the safety of
dental amalgam from the NH&MRC
The Australian Dental Association have no support from any scientific organization for
their claim that dental amalgam is safe.
ASOMAT urges the dissemination of this information for the welfare of the general
public.
Dental Malgam contains mercury-
Mercury is toxic-
There is no safe level of mercury exposure.
Brought to you by
Australasian Society of
Oral Medicine & Toxicology
PO Box A860 Sydney South 2000
For further information please contact
Dr Roman Lohyn 03 9650 1660 (President ASOMAT)
Dr Robert Gammal 02 9264 5195 (Secretary ASOMAT)
Return Fax to 02 9665 5043
E-mail; rgammal@zip.com.au
In Reply to: Re: MCS and poisoning by dental amalgam posted by MAI on June 08, 1999 at 19:28:37:
Thanks, MAI.
I hope Bill can archive this for us.
Walt
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