April 2003

1. Landau, Mark, et al. Changes in nerve conduction velocity across the elbow due to experimental error. Muscle and Nerve. 26: 838-840. (2002).

One diagnostic criterion for ulnar nerve mononeuropathy at the elbow (UNE) is a decrease in across-elbow nerve conduction velocity (NCV) > 10 m/s compared to the forearm segment. Distance and latency measurement errors are an inherent part of NCV calculations. Twenty electromyographers measured the latencies of stored ulnar compound muscle action potentials and measured the forearm and across-elbow distances along the ulnar nerve. Based on previously published equations, experimental error in NCV was calculated for various NCV’s. The mean distances and standard deviations for the forearm and elbow segments were 212.5 ± 2.1mm and 86.7 ± 4.2mm, respectively. For an NCV of 55 m/s, a difference of 14 m/s between the two segments can occur from measurement error alone. Distance measurements about the elbow are fraught with interobserver errors rendering the resultant NCV of that segment of limited value as a sole criterion for the diagnosis of UNE.

The effects of chronic mercury intoxication on urinary markers in workers from northeast Algeria were investigated. Workmen were chosen from highly and moderately mercury-exposed factories, while controls were selected from a non-exposed site. The number of proteinuria cases was higher in the highly exposed subjects, although the nature (glomerular or tubular) of proteinuria remains unclear. However, it appears difficult to assess the degree of renal disturbance among the different exposure levels, such as the amount of excreted proteins, which have not clearly reflected the kidney lesion severity. The results also reveal that urine acidity increased progressively with increased levels of exposure, while a remarkable inverse relationship between urinary pH and urinary Hg in the highly exposed workers has been recorded. Furthermore, the significant differences in blood and urinary mercury concentrations of the three sites reflect the dose-response relationships.

3. Iregren A, Andersson M, Nylen P. Color vision and occupational chemical exposures: I. An overview of tests and effects. NeuroToxicology. 23: 719-733 (2002).

The paper presets a summary of the literature published until December 2000 on effects from some industrial chemical exposures on color perception, as well as short descriptions of the tests applied. Several different tests have been used to study acquired alterations of color vision. These changes are frequently found in the blue-yellow axis. Many of the tests were originally designed to detect congenital alterations in the red-green axis, and thus have relatively low sensitivity when studying chemically induced deficits in color perception. At present, the Lanthony D15-desaturated panel seems most suitable to applications in industrial settings, since it is clearly the most sensitive and easily administered test. Color vision seems to be a physiological function very sensitive to several chemicals. The potency of industrial chemicals to induce color vision deficiencies has often been investigated during the last two decades. The chemicals most frequently studied are different solvents and mercury. Pronounced effects on color perception have been reported following chronic exposure to organic solvents such as styrene, carbon disulphide, perchloroethylene, n-hexane and solvent mixtures, and to organic as well as inorganic mercury. The effect of occupational toluene exposure seems not as well established, since only slight effects and several negative studies have been reported. For some of these compounds the effect on color vision has been further established through the finding of clear dose-effect relationships. In a few cases, even acute exposure situations, e.g. exposure to toluene for a few hours or acute alcohol intake, seem to affect color perception. Follow-up studies are needed to investigate the possible reversibility of effects in relation to discontinued or reduced exposures.

4. Iregren A, Andersson M, Nylen P. Color vision and occupational chemical exposures II. Visual functions in non-exposed subjects. NeuroToxicology. 23: 735-745 (2002).

This paper presents data on visual functions (visual acuity, contrast sensitivity, and several tests of color vision) in a group of 199 non-exposed healthy subjects with an even distribution over the age range 18-65 years, and sex. Although subjects with obvious congenital color vision deficiencies were removed from the analyses (four males), females were superior to males on several of the color vision tests applied. Age influenced visual acuity and contrast sensitivity, while color discrimination was less affected. Correlations between functions of the right and the left eye in the individual subjects were rather low, ranging from 0.40 to 0.73. Correlations between visual acuity and contrast sensitivity on the one hand and color discrimination on the other hand were still lower (r<0.20). These low correlations between functions in the two eyes support the need for testing each eye separately.

5. Polizzi S, et al. Neurotoxic effects of aluminum among foundry workers and Alzheimer’s disease. NeuroToxicology. 23: 761-774 (2002).

In a cross-sectional case-control study conducted in northern Italy, 64 former aluminum dust-exposed workers were compared with 32 unexposed controls from other companies matched for age, professional training, economic status, educational and clinical features. The findings lead the authors to suggest a possible role of the inhalation of aluminum dust in pre-clinical mild cognitive disorder which might prelude Alzheimer’s disease (AD) or AD-like neurological deterioration. The investigation involved a standardized occupational and medical history with particular attention to exposure and symptoms, assessments of neurotoxic metals in serum: aluminum, copper and zinc, and in blood: manganese, lead, and iron. Cognitive functions were assessed by the MMSE, the Clock Drawing Test, and auditory evoked Event-Related Potential (ERP-300). To detect early signs of mild cognitive impairment, the time required to solve the MMSE and CDT were also measured. Significantly higher internal doses of Al in serum, and Fe in blood, were found in the ex-employees compared to the control group. The neuropsychological tests showed a significant difference in the latency of ERP-300, MMSE score, MMSE-time, CDT score and CDT-time between the exposed and the control population. P300 latency was found to correlate positively with serum Al and MMSE-time. Serum Al has significant effects on all tests: a negative relationship was observed between internal Al concentrations, MMSE score and CDT score; a positive relationship was found between internal Al concentrations, MMSE-time and CDT-time. All the potential confounders such as age, height, weight, blood pressure, schooling years, alcohol, coffee consumption and smoking habit were taken into account. These findings suggest a role of Al in early neurotoxic effects that can be detected at a pre-clinical stage by P300, MMSE, MMSE-time, CDT-time, and CDT score, considering a 10 µg/L cut-off level of serum Al, in Al foundry workers with concomitant high blood levels of Fe. The authors raise the question whether pre-clinical detection of Al neurotoxicity and consequent early treatment might help to prevent or retard the onset of AD or AD-like pathologies.

Evidence discussed in this review article lends strong support in favor of an etiologic role of environmental factors in Parkinson’s disease. First, thanks to the discovery of MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrohydropyridine), it is now clear that, by targeting the nigrostriatal system, neurotoxicants can reproduce the neurochemical and pathological features of idiopathic parkinsonism. The sequence of toxic events triggered by MPTP has also provided us with intriguing clues concerning mechanisms of toxicant selectivity and nigrostriatal vulnerability. Relevant examples are i) the role of the plasma membrane dopamine transporter in facilitating the access of potentially toxic species into dopaminergic neurons; ii) the vulnerability of the nigrostriatal system to failure of mitochondrial energy metabolism; and iii) the contribution of inflammatory processes to tissue lesioning. Epidemiological and experimental data suggest the potential involvement of specific agents as neurotoxicants (e.g. pesticides) or neuroprotective compounds (e.g. tobacco products) in the pathogenesis of nigrostriatal degeneration, further supporting a relationship between the environment and Parkinson’s disease. A likely scenario that emerges from our current knowledge is that neurodegeneration results from multiple events and interactive mechanisms. These may include i) the synergistic action of endogenous and exogenous toxins (e.g. the ability of the pesticide diethyldithiocarbamate to promote the toxicity of other compounds); ii) the interactions of toxic agents with endogenous elements (e.g. the protein a-synuclein); iii) the tissue response to an initial toxic insult; and, last but not least, iv) the effects of environmental factors on the background of genetic predisposition and aging.

A case is described of an experimental physicist who developed parkinsonism, apparently as delayed toxic effect of long exposure to vapors of methanol in the laboratory. Clinical and magnetic resonance imaging (MRI) supported the diagnosis, after exclusion of hereditary diseases and primary degenerative diseases. Screening for heavy metals in urine and plasma ceruloplasmin was negative. This case illustrates the neurotoxic delayed effect of long-term exposure to methanol with no episodes of acute intoxication. The setting of a research laboratory with prolonged exposure to mixed single crystals and inhalation of methanol vapors may exist in other academic and hi-tech environments, and pose the risk of similar delayed toxic influences.

8. Sickles D, Stone J, Friedman M. Fast axonal transport: A site of acrylamide neurotoxicity? NeuroToxicology. 23: 223-251 (2002).

The cellular and molecular site and mode of action of acrylamide (ACR) leading to neurotoxicity has been investigated for four decades, without resolution. Although fast axonal transport compromise has been the central theme for several hypotheses, the results of many studies appear contradictory. Our analysis of the literature suggests that differing experimental designs and parameters of measurement are responsible for these discrepancies. Further investigation has demonstrated consistent inhibition of the quantity of bi-directional fast transport following single ACR exposures. Repeated compromise in fast anterograde transport occurs with each exposure. Modification of neurofilaments, microtubules, energy-generating metabolic enzymes and motor proteins are evaluated as potential sites of action causing the changes in fast transport. Supportive and contradictory data to the hypothesis that deficient delivery of fast-transported proteins to the axon causes, or contributes to, neurotoxicity are critically summarized. A hypothesis of ACR action is presented as a framework for future investigations.

9. Merlevede K, Theys P, and Van Hees J. Diagnosis of ulnar neuropathy: a new approach. Muscle and Nerve. 23: 478-481 (2000).

Conventional electrodiagnosis used to detect an ulnar neuropathy at the elbow depends on accurate determination of ulnar nerve length across this segment. We present a new approach, using the difference in latency of the compound nerve action potentials (CNAPs) of the ulnar and median nerves elicited by stimulation at the wrist and recorded 10 cm above the elbow. Sixty normal controls were examined in order to determine the normal upper limit (1.4ms) of the difference in CNAP latency of the ulnar and the median nerves (Dlat index). Values obtained in 10 patients with ulnar nerve lesions are discussed. This test was shown to be both sensitive and specific, was independent of ulnar nerve length, and was easy to perform.

10. Swash M. What does the neurologist expect from clinical neurophysiology? Muscle and Nerve Supplement. 11: S134-S138. (2002).

The future role of clinical neurophysiology is considered in the light of its achievements. It is argued that there is a need to develop methods for specific diagnosis, especially in neuropathies. There is also an unmet requirement for the development of techniques for the predication of treatment outcomes and for the measurement of changes during the natural history of neuromuscular disorders and their treatment. These issues are not addressed by currently available clinical test methods.

11. Carter N, et al. EUROQUEST – A questionnaire for solvent related symptoms: Factor structure, item analysis and predictive validity. NeuroToxicology. 23: 711-717. (2002).

The study evaluates the factor structure and predictive validity of the symptom questionnaire EUROQUEST (EQ) that had been developed with the goal of simplifying the evaluation of health effects associated with long-term solvent exposure. The EQ was added to the normal evaluation procedures for 118 male patients with suspected solvent-induced toxic encephalopathy (TE) referred to seven Swedish clinics of occupational medicine during an 18-month period. EQ was also completed by 239 males from a random sample of 400 Swedish males aged 25-64 years selected from the general population, and a sample of 559 occupationally active male spray painters aged 25-64 years. Factor and item analyses of EQ responses were performed. Ordinary least square regression analysis was used to evaluate sensitivity and correlation to evaluate the specificity of EQ and the separate components. Questions concerning memory and concentration symptoms alone showed better sensitivity than the other five EQ dimensions singly or combined for the entire EQ and for a subset of questions approximating Q16, a widely used organic solvent symptom screening questionnaire. However, the diagnosis of TE required information in addition to exposure and responses to EQ and Q16-like questions. The results indicate that the subset of EQ questions concerning memory and concentration might replace the more cumbersome EQ and less sensitive Q16 in screening for TE, although none of the screening instruments alone replaces current clinical diagnostic procedures.

12. Book Reviews.

Muscle and Nerve. October 2000. pp. 1612-13.

Occupational and Environmental Neurotoxicology, by R.G. Feldman. Philadelphia; Lippincott-Raven, 1998.

The review by John Wald, MD, portrays Feldman’s text as an excellent clinical resource for the physician working in neurotoxicology. An encyclopedic review of the twenty most frequently encountered neurotoxins, including exposure sources, metabolism, clinical neurophysiologic/neuropsychometric findings, diagnostic methods, prevention, and treatment. The illustrative use of tables, MR images, and references are among the strengths of this resource.

A Short History of Neurology: The British Contribution 1660-1910. Edited by F. Clifford Rose. Oxford: Butterworth-Heinemann, 1999.

Michael Aminoff, MD, describes this book as a compilation of essays from various authors contributing to the meeting held at the Medical Society of London in 1998. He criticizes the book for being neither brief, nor a true account of the British contribution to neurology. Insufficient references and lack of cohesiveness are other weaknesses. However, many essays are enjoyable and perhaps stimulating to those interested in the history of neurology/neurosciences.

Neurology in Clinical Practice (3rd ed). Edited by Walter G Bradley et al. Boston: Butterworth-Heineman, 2000.

John Engstrom, MD, claims this book to be an invaluable reference to the clinician or physician in training. A user-friendly, well-organized, comprehensive resource, the book is divided into three sections. The first 35 chapters present the signs and symptoms of neurologic disease. The next 18 chapters discuss the use of laboratory investigations and the utility of subspecialty consults to neurology. The last section discusses specific neurologic diseases. An associated website, http//www.nicp.com, provides text references, updates, links to related sites, and a discussion forum. Engstrom concludes that the text is an essential part of every medical library.

Muscle and Nerve. December 2001. pp 1897-98.

Experimental and Clinical Neurotoxicology (2nd ed). Edited by P.S. Spencer. New York: Oxford University Press, 2000.

Dr. Michael Aminoff claims this text is an invaluable resource in those interested in neurotoxicology. Introduced by a discussion of neurobiological principles in relation to medicine, the book is comprised of an alphabetical listing of neurotoxic chemicals, a summary of their biological/clinical effects, and a rating of the strength of association between them. Two appendices are provided. The first is an alphabetical list of each compound and its neurotoxicological rating. The second lists specific neurological disorders and their associated neurotoxins.

Neurologic Catastrophes in the Emergency Department, by EFM Wijdicks. Boston: Butterworth-Heinemann, 1999.

As reviewed by Dr. J. Hemphill, the book is a valuable resource for the assessment, triage, and acute management of critically ill neurologic patients. Wijdicks, the director of the Neurological/Neurosurgical Intensive Care Unit at St. Mary’s Hospital and Mayo Medical Center, provides an informative, user-friendly reference for physicians ranging from emergency to neurosurgical specialties. The first section describes evolving catastrophies in the neuroaxis. The second section outlines catastrophic neurological disorders due to specific causes. The book is well organized with highlights of important points and is claimed to be an excellent text for physicians of many specialties.

13. Landrian, Philip. A Year of Passage. American Jo of Industrial Medicine 38: 483-484 (2000).

A letter from the editor pays homage to three leading figures in the field of occupational/industrial medicine who passed on in 1999. David Platt, director of the NIEHS from 1971-1990, supported the training of scientists, conducted important toxicological studies, and founded a network of university centers in environmental health. He advanced science and the careers of young scientists both nationally and abroad. John Goldsmith was a reknowned environmental epidemiologist with expertise in air pollution, biostatistics, and respiratory disease. He served as president of the ISEE, as a consultant to the WHO and the NIEHS, and on the faculty of medicine at Ben-Gurion University of the Negev in Israel. Janusz A. Indulski was a leading figure in occupational medicine in Poland, having founded the Lodz Medical Academy, the School of Public Health at Lodz, and the Polish Society of Social Medicine. He founded the Polish Journal of Occupational Medicine, and acted as director of the Polish Institute of Occupational Medicine, a consultant to the WHO and to governments of multiple countries on topics of occupational and environmental health. Successors to these three leaders carry on their legacy, several of whom now serve on the board of the American Jo of Industrial Medicine: Lynn Gloldman, Gegory Wagner, David Goldsmith, Maureen Hatch, Anne Golden, Franklin Mirer, and Sylvia Johnson.

1. Xiao J, and Levin S. The diagnosis and management of solvent-related disorders. American Jo of Industrial Medicine. 37: 44-61 (2000).

Xiao and Levin provide a valuable review of occupational/industrial exposure to organic solvents, discussing both the acute and chronic effects upon health. This includes CV, CNS and PNS systems, renal and liver function, skin, mucous membranes, reproductive organs and development. Specific attention is given to benzene, toluene, xylene, styrene, n-hexane, trichloroethylene, tetrachloroethylene, trichloroethane, carbon disulfide, methyl ethyl ketone, and methyl-n-butyl ketone. With support from the current literature, chemical structure, industrial use, metabolism, symptoms of exposure, pathological changes, acute and chronic health effects, treatment and management are presented. Suggestions for biological/environmental monitoring and worker protection are provided. Emphasis is placed upon intervention by industrial hygienists and worker/employee education in exposure reduction techniques.

2. Herbert R, Gerr F, and Dropkin J. Clinical evaluation and management of work-related carpal tunnel syndrome. American Journal of Industrial Medicine. 37: 62-74 (2000).

This well documented article presents the clinician with a cohesive review of the etiology, diagnosis and treatment of work-related carpal tunnel syndrome (WRCTS), one of the most costly and disabling occupational musculoskeletal disorders. Key aspects of the medical history, physical exam, and laboratory evaluation are outlined. Patients may present with pain, numbness and/or tingling in the distribution of the median nerve, and weakness of the APB in advanced cases. Electrodiagnostic studies are the gold standard test for CTS. Prolonged distal motor or sensory latencies of the median nerve, slowing of the median sensory conduction velocity, and denervation of the APB are suggestive of CTS. Risk factors include forceful, repetitive, or vibratory movements of the hands, as well as systemic illness such as collagen vascular disease or renal failure. The literature supports a positive surgical outcome for severe CTS cases, while mild to moderate cases may be more effectively treated with conservative methods. WRCTS cases show poor outcomes for recovery in comparison to non-occupational cases. Emphasis is placed upon early workplace intervention and application of ergodynamic modifications. Such intervention is key to healing and faster return-to-work rates. Engineering and administrative controls must be instigated to reduce worker exposure to inciting movements. The high cost and burden of CTS in the workplace validate the need for future research and intervention in this area.

3. Davis L, Wellman H, and Punnett L. Surveillance of work-related carpal tunnel syndrome in Massachusetts, 1992-1997: A report from the Massachusetts Sentinel Event Notification System for Occupational Risks (SENSOR). American Journal of Industrial Medicine. 39: 58-71 (2001).

The MA Dept of Health instituted a study to identify occupations and industries with high incidence of work-related carpal tunnel syndrome (WRCTS). Data from 1992-97 were drawn from the surveillance study and were evaluated for frequency and distribution of cases. In addition to targeting worksites with high incidence of WRCTS, the study sought to evaluate the effectiveness of the MDPH surveillance system in targeting specific worksites for intervention. Strengths of the study include the identification of cases through both workers’ compensation records (WC) and physician reports (PR) to the MDPH, rather than reliance upon a single source. Cases identified from PR and WC were compared with respect to demographics and employment characteristics. Overall, 4800 new cases were identified, at a rate of 4 cases per 10 000 workers. A high proportion was under 25 y.o., and female. The largest number and rate of WRCTS cases were identified in the manufacturing sector. High rates were also seen in technical/administrative operations using video display units. The combined use of PR and WC reports identified far more cases in MA than had been indicated by either system alone. The study is limited by underreporting by both workers and physicians. High numbers of reported cases for a given worksite reflect either a high prevalence of risk factors, or simply better reporting rates. While physician reports help identify establishments where intervention is needed, WC reports are more reliable for targeting specific occupations and industries. Future research is needed to identify factors influencing reporting rates. Improvements in reporting will allow for more accurate assessment of the costs incurred by WRCTS upon society

4. Spinner R, and Kline D. Surgery for peripheral nerve and brachial plexus injuries or other nerve lesions. Muscle and Nerve. 23: 680-695. (2000).

This neurosurgical review from Louisiana State University Medical Center provides the clinician with a clearly-outlined approach to the patient with nerve injury. In a succinct, yet comprehensive manner, the authors describe key aspects of the clinical evaluation and appropriate electrodiagnostic/radiographic studies including EMG, NCS, x-ray, CT myelogram, and MRI, for various cases. Valuable diagnostic questions are provided. A discussion of surgical versus conservative treatment includes timing factors, contraindications to surgery, and details of operative procedures. Early surgery is advised for open lacerations involving clean nerve transactions. A delay is suggested for bluntly transected nerves, or lesions-in-continuity. Advanced microsurgical techniques and introperative electrophysiologic measures such as nerve action potentials (NAP) have led to more accurate diagnoses and positive surgical outcomes. The operative procedures discussed include internal and external neurolysis, split repair, end-to-end epineurial repair, graft repair and nerve transfers. An algorithm for surgical management of nerve injury, tables, diagrams, and photos of surgical procedures are excellent supplements to the text. Post-operative management and results are outlined, with specific attention to nerve entrapments, peripheral nerve tumors, injection injuries, obstetric palsies and pain syndromes. Optimisation of surgical outcomes depends upon accurate evaluation, with identification of the pattern of deficit, type of lesion, and severity. Improved imaging (MR neurography) may reduce the need for future exploratory surgery. Research into the neurobiology of nerve injury and regeneration will foster treatments with less scarring and more rapid, effective healing. Neurotrophic factors and fibroblast products play will play important roles in regenerative techniques. Outcome studies of current nerve and muscle transfer procedures are recommended.

5. Moorhead J, and Suruda A. Occipital lobe meningioma in a patient with multiple chemical sensitivities. American Journal of Industrial Medicine. 37: 443-446. (2000).

This is a case report of a 59 year old female custodial worker presenting to an occupational health clinic with longstanding multiple chemical sensitivities (MCS), a left visual field deficit and papilledema. Her symptoms manifested upon exposure to low level chemical odors particularly cleaning products, and included headache, visual and auditory problems, dermatitis, musculolskeletal pain, fatigue and weakness, all progressing over a 12 year period. MRI revealed a 6 cm right occipital lobe tumor. Following surgical resection of the meningioma her visual deficit and multiple symptoms continued to manifest upon exposure to a variety of normally harmless odors. The case closely fits the working definition of MCS proposed by Cullen: gradually progressive multisystem symptoms, particularly neurological and psychiatric, but often respiratory or GI, in response to a low dose environmental exposure, with no underlying cause identifiable upon evaluation. The authors present plausible explanations for the patient’s symptoms. Mass lesions and increased ICP may cause headache, global neurological deficits, mental and psychiatric problems. The concepts of kindling and time-dependent sensitisation are proposed mechanisms for the patient’s increased sensitivity to cleaning compounds over time, potentially triggering a physiologically conditioned response. The case is a reminder that patients with MCS must be closely evaluated for treatable intracranial lesions affecting olfaction. This patient’s multisystem symptoms persisted following removal of the tumor, suggesting a conditioned response or psychological etiology was at hand.

6. Osterber K, et al. A comparison of neuropsychological tests for the assessment of chronic toxic encephalopathy. American Journal of Industrial Medicine. 38: 666-680 (2000).

The aim of this study was to evaluate if the current test battery for detection of solvent-induced toxic encephalopathy (TE) can be improved by utilization of new tests for complex attention and frontal lobe function. Assessment of the sensitivity and specificity of the test battery was another goal. From 1995-96, this Swedish study investigated 2 groups of men previously diagnosed with TE (5 years daily occupational solvent exposure with subsequent cognitive and emotional symptoms) and a reference group. All TE subjects were classified at 2A or 2B according to prior test outcomes. All had irreversible mixed symptoms, while only 2B suffered cognitive reduction. The three groups were examined with both traditional TE tests and the newer tests for complex attention and frontal lobe function. Results showed most new tests to be less sensitive to TE than many traditional tests. Compilation of an optimised test battery including both traditional and newer tests resulted in a sensitivity and specificity of 0.7. The authors discuss sensitivity and specificity of each traditional test, reproducibility of test profiles and strategies for clinical differentiation between 2A and 2B subjects. Because of the variability in functional domains affected in TE, variation in cognitive performance across tests is to be expected. Clinicians are reminded that no test profile is diagnostic of TE and, therefore, clinical evaluation with the optimised test battery, combining various traditional and newer tests, is recommended.

7. Fairfield K, and Fletcher R. Vitamins for chronic disease prevention in adults. JAMA. 287: 3116-3126 (2002).

Using data obtained form a Medline search, the authors conducted a review of nine clinically important vitamins. Dietary sources, biological activity, deficiency syndromes, relation to chronic disease, and toxic effects are discussed. While vitamin deficiency is not prevalent in North America, sub-optimal intake is, and has been linked to elevated risk for chronic disease such as cancer, CHD, and osteoporosis. Certain groups are at increased risk for insufficient vitamin intake or absorption, including the elderly, vegetarians, pregnant women, hospitalised patients, and those affected by alcoholism or malabsorption. While supplementation is useful, care must be taken to avoid an overdose of fat-soluble vitamins. Sub-optimal levels of vitamins B6, B12 and folate may lead to elevated homocysteine levels, and therefore increased risk for CHD. Both B6 and B12 are required for nervous system function. Low folate is also associated with aberrant DNA synthesis and neural tube defects. Vitamin E and lycopene supplementation may decrease risk of prostate cancer. Vitamin D, in association with calcium, has been shown to decrease fracture incidence. It is the responsibility of the physician to inquire about a patient’s knowledge surrounding vitamins and use of supplements, and to counsel patients about dietary sources of vitamins. Scientific evidence for the benefits of vitamin supplementation is not well established and much information has been derived from observational studies.

8. Fletcher R, and Fairfield K. Vitamins for chronic disease prevention in adults. JAMA. 287: 3127-3129. (2002).

The authors present the clinician with a discussion of vitamin supplementation in the general population. Sub-optimal levels of vitamin intake are very prevalent in the United States, and present risk factors for chronic disease. Supplementation has been shown to reduce the rate of clinical events. Folate supplementation during pregnancy is associated with decreased neural tube defects, and vitamin D with calcium supplementation has been shown to reduce fracture incidence. The authors present three options for correction of sub-optimal vitamin intake. First, physicians are advised to counsel patients about dietary improvements, as food provides the most bioavailable source of vitamins. Second, is the addition of vitamins to commercial foods. Third, is vitamin supplementation. All adults are recommended to take a single multivitamin per day. Supplemental folate, B6, B12, and vitamin D help prevent cardiovascular disease, cancer and osteoporosis. Additional B12 and D are recommended for the elderly, and folate for women who may become pregnant. Over-supplementation of vitamin A and iron are possible in certain populations. Readily available multivitamins are inexpensive and generally equivalent across brands. The authors discourage commercial testing for vitamin deficiencies in the general population, but rather encourage physicians to ask patients about vitamin use and to be aware of a patient’s potential fear that physicians may disapprove of supplementation. Websites providing links to evidence-based information regarding vitamin supplementation are cited.

9. Booker, Susan. Optimism pervades Parkinson’s conference. Environmental Health Perspectives. 109 (12). (2001).

This article presents a synopsis of the information presented during the 2001 conference in Colorado, sponsored by the University of Arkansas for Medical Sciences and the NIEHS. The multifaceted aspects of Parkinson’s disease (PD) are outlined. Progression of tremor and impaired gait, balance, co-ordination, and proprioception occur most often after age 55. Symptoms manifest when deterioration of the substantia nigral cells has led to 80% depletion of dopamine, the neurotransmitter responsible for smooth motor control by the motor cortex. Risk factors for PD include viral infections, high levels of dietary fat, depression, head trauma, elevated iron levels, and exposure to hydrocarbon solvents, Mn, Pb, Cu, Fe, and pesticides such as paraquat, heptachlor or maneb. The existence of Lewy bodies has not yet been determined to be a cause, or effect, of PD. Future research is directed at identification of specific gene mutations common to the PD phenotype and defining the role of the Lewy body. There is a call for the combined expertise of epidemiologists, geneticists, and those working in the basic sciences. Future funding should be directed towards identifying pathological symptoms of PD, gene profiling, and outlining the cellular mechanisms of neurodegeneration. The late onset of PD and lack of PD registries, diagnostic tests, or biomarkers pose difficulties to epidemiological studies. A promising nested case-control study is currently examining aspects of PD among farmers potentially exposed to pesticides, metals and Nocardia. Twenty-four PD-related projects are currently supported by the NIEHS. A consortium has been established to study the gene-environment interaction in PD, and is intended to facilitate communication between clinicians, geneticists, epidemiologists, and researchers, and support translation of lab discoveries to the clinic.

November 2002

1. Bast-Patterson R, Skaug V, Ellingsen D, and Thomassen Y. Neurobehavioral performance in aluminum welders. American Journal of Industrial Medicine. 37 : 184-192 (2000).

This cross-sectional study of 20 aluminum workers (mean exposure 8.1 years) and 20 controls examined possible neuromotor/behavioral effects of aluminum exposure. Prior studies have shown impaired motor function, neuropsychiatric symptoms, and delayed reaction times. Current exposure was assessed by sampling of air within respiratory protection devices and urinary Al levels. Testing included screening for neurological symptoms, memory and attention, hand steadiness and reaction times. Welders reported significantly more symptoms than controls. No clinically significant tremor was apparent in either group. Welders performed significantly better than controls in tests for hand steadiness and reaction times. However, there was a significant association between duration of exposure and impaired performance in tremor tests, as well as longer reaction times and Al in air. Results indicate welders are not clinically impaired in steadiness or reaction time. The high performance of welders may be attributable to a job-related training effect or selection of steady-handed workers to the welding profession. 

2. Lo B, et al. Discussing religious and spiritual issues at the end of life. JAMA 287 (6) :749-754 (2002).

A patient’s spiritual issues and religious concerns may become heightened near the end of life and affect their medical decisions about life-sustaining interventions. Communication of these concerns to the physician is of great importance to relieving patient distress and improving understanding between the patient and physician. This article presents physicians with valuable guidelines for addressing, and responding to, a patient or family members about such concerns. Three case scenarios are analyzed. Emphasis is placed on respectfully helping patients think through medical decisions, empathetic listening, posing of open-ended questions, and providing a supportive environment in which patients may find comfort and closure near the end of life. 

3. Kirkey K, et al. Occupational categories at risk for parkinson’s disease. American Jo of Industrial Medicine 39 : 564-571 ( 2001).

Previous studies have indicated that exposure to certain metals, herbicides and pesticides may lead to neurochemical changes and neuronal death in the substantia nigra, leading to development of Parkinson’s Disease. This population-based case-control study examined the relationship between PD and a range of occupations and industries. Subjects included 144 cases and 464 controls receiving primary care within the Henry Ford Health System between 1991-1994. Occupational histories were obtained by structured interviews and classified into 1 of 9 broad categories. Strengths of the study included the detailed method of job history classification for both cases and controls, and the use of well-defined coding systems. Results indicated an increased risk of PD with work experience in agriculture, fishing and forestry occupations, while experience in a service occupation was negatively associated with PD. This is the first case-control study to identify an inverse relationship between ever-working in the service industry and PD. Future studies should focus on validation of this protective effect among various populations, as well as the elevated risk of PD associated with agricultural industries. Attention to potential environmental exposures and common lifestyle factors within each occupational category is warranted. 

4. Manzo L, et al. Assessing effects of neurotoxic pollutants by biochemical markers. Environmental Research 85 : 31-36 (2001).

This article reviews the efficacy and limitations of current neurotoxicity biomarkers. Toxic biochemical changes often occur at the cellular/subcellular level before overt nervous system disease manifests. These changes may serve as markers of neurotoxicity in exposed populations. Complexity of nervous system functions, the multistage nature of neurotoxic events, and inaccessibility of target tissues pose obstacles to the use of biomarkers. However, new techniques have been established to assess exposure, effect and susceptibility to neurotoxic disease. Surrogate markers for nervous tissue are found in peripheral tissues. Presently, ALAD, AchE, and MAO are used as biomarkers of exposure to lead, organophosphates, and Mn/styrene respectively. The use of peripheral biomarkers is limited to agents whose mechanism of action is known, and is based upon the assumption that peripheral tissues have the same pharmacological properties as nervous system targets, and therefore are affected by neurotoxins in a similar way. This must be validated by mechanistic studies. Differences in dose-response and adaptation may occur. Markers detecting early neurotoxic changes may be effective as tools for identifying subclinical disease states and initial neurotoxic effects. Their development could play a critical role in occupational and preventative medicine. In combination with neurobehavioral and physiological assays, biochemical markers may lead to more precise human neurotoxicity assessment, especially in chronic, low dose exposures. 

5. Apostoli P, Lucchini R, Alessio L. Are current biomarkers suitable for the assessment of manganese exposure in individual workers ? American Jo of Industrial Medicine 37 : 283-290 (2000).

The rising industrial and agriculture use of Mn has given rise to heightened interest in the chronic effects of low-dose exposure. To assess health effects, a precise means of quantifying Mn exposure is required. Currently estimates of external and internal dose are based upon airborne [Mn] and whole blood/ urine [Mn] respectively. This study examined the relationship between airborne Mn levels and Mn in blood and urine in a group of Italian feroalloy workers. Biological and environmental monitoring of Mn was conducted among 94 exposed workers and 87 controls, and a cumulative exposure index (CEI) was calculated. Generally blood Mn for subjects was twice that of controls, and urine Mn was five times as high. Blood Mn reflected total body burden and was linearly related to Mn in air. No association between CEI and Mn levels were observed. Mn B and MnU may effectively indicate exposure on a group basis, but due to high variability, are not suitable as biomarkers of individual exposure. Further research with attention to precise analytical techniques is required to determine more accurate biomarkers for Mn exposure. 

6. Dietz M, et al. Results of magnetic resonance imaging in long-term manganese dioxide-exposed workers. Environmental Research 85 : 37-40 (2001).

A cross-sectional study of 11 battery factory workers (mean 10 yrs exposure) and 11 controls was conducted to assess the relationship between Mn exposure and pallidus signal intensity on MRI, neurophysilogical and motor performance, and biological levels of Mn. Exposure was assessed via ambient air monitoring and biomonitoring of hair, blood and urine. A cumulative exposure index as calculated. Subjects underwent standardized interviews and clinical exams with neuophysiological testing. MRI evaluation allowed for calculation of the Pallidal Index (PI), the ratio of signal intensity in the global pallidus to subcortical frontal white matter multiplied by 100. Exposed subjects had higher mean blood Mn, with no significant signs of Parkinsonism or neurophysiological deficits. However, significantly increased signal intensity in the globus pallidus was observed, and is proposed to be due to paramagnetic properties of Mn. There was a positive correlation between CEI and blood Mn, as well as CEI and PI, for males only. Controlling for gender differences, future studies must focus on determining normal values for PI, and the health outcomes of elevated PI levels including Parkinsonism and neurotoxic effects. PI in T1-weighted MRI studies was found to be an effective marker of Mn exposure. 

7. Kishi R, et al. Effects of low-level occupational exposure to styrene on color vision : dose relation with a urinary metabolite. Environmental research. 85 : 25-30 (2001).

This study examined the threshold effects of chronic styrene exposure on color vision. Mandelic acid in urine served as the biomarker of exposure for 105 styrene workers (mean exposure 6.2 years) and 117 controls. Work history, solvent exposure, alcohol and drug use data were obtained via standardized questionnaires. Color vision was assessed by Lanthony desaturated panel D-15 testing and a color confusion index (CCI) was calculated. A significant difference was observed in the CCI between both medium and high exposure groups and their age-matched controls. A dose-effect relationship was apparent for urinary mandelic acid and impaired color vision, particularly in the blue-yellow range. The threshold value for increased risk of color vision loss appears to be .1-.2 g/L. Color vision testing is recommended before and after occupational styrene exposure to facilitate detection of early toxic effects. 

8. Noonan C, et al. Occupational exposure to magnetic fields in case-referent studies of neurodegenerative diseases. Scandinavian Jo of Work and Environmental Health 28 (1) : 42-48.

This study examined the relationship between occupational magnetic field exposure and Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. Case referent sets were created from death certificates for males in Colorado between the years of 1987-1996. These were analyzed according to three methods of exposure assessment : electrical vs non-electrical occupations ; a tiered grouping of potential magnetic field exposure based upon job title and industry ; and estimates of mean magnetic field exposure values from a job-exposure matrix. While there were no consistent observations of elevated risk for either Alzheimer’s disease or ALS, PD did show a positive association to magnetic field exposure with all 3 assessment methods. The study is limited by variations in definitions of high exposure job titles between the three exposure assessment methods, and the inherent inaccuracy of data obtained from death certificates. Furthermore, no duration of exposure was documented. The authors conclude that findings for an association between magnetic field exposure and neurodegenerative disease are sensitive to the method of exposure assessment used. The positive association between magnetic exposure and PD requires verification in future studies. 

9. Goodman M, et al. Neurobehavioral testing in workers occupationally exposed to lead: a systematic review and meta-analysis of publications. Occupational and Environmental Medicine. 59 : 217-223.

The blood concentration at which lead toxicity manifests has not yet been determined. This meta-analysis of occupational studies evaluated the association between results of neurobehavioral testing and moderate blood lead levels. A Medline search produced 22 studies meeting inclusive criteria, including blood Pb concentrations less than 70µg/dl. Results indicated that available data is inconsistent and provides inconclusive information on the neurobehavioral effects of moderate Pb exposure. Studies provided inadequate cumulative exposure/absorption data, and poor adjustments for age and pre-exposure intellectual function. A lack of uniform testing methods also existed. Meta-analysis results are very sensitive to changes in inclusion criteria and statistical methods. Prospective studies are required to compare neurobehavioral function before and after lead exposure. In determining occupational health regulations, the quality of scientific data for individual studies is more valuable than a pooled analysis of many studies. 

10. Araki S, Sato H, Yokoyama K, Murata K. Subclinical neurophysiological effects of lead : A review of peripheral, central, and autonomic nervous system effects in lead workers. American Jo of Industrial Medicine. 37 : 193-204 (2000).

This article presents an overview of 102 articles examining the subclinical effects of occupational lead exposure. Assessment of PNS effects focused on nerve conduction velocity (NCV)and distribution of NCV’s (DCV). Somatosensory, visual, and brainstem auditory evoked potentials served as measures of PNS function to CNS targets. Event-related potentials (P300) reflected cognitive function. ECG R-R interval (CVRR) variability was a useful assessment of ANS function. Vestibulo-cerebellar system effects were evaluated by posturography. Results indicate slowing of NCVs at lead levels as low as 30-40 µg/dL, and possible effects on the P300 latency, postural balance, and CVRR at similar levels. At 40-50 µg/dL, effects on DCV, somatosensory, visual, and brainstem auditory evoked potentials may occur. Children are more susceptible to lead toxicity than adults, and may develop deficits at lower doses. Cognitive function is particularly susceptible to lead toxicity at low exposure levels. Subclinical effects of lead on the nervous system have shown reversibility (chelation with CaEDTA). Zinc and copper may antagonize lead toxicity. Results show lead simultaneously affects peripheral, central, and autonomic nervous systems. Follow-up studies are required to determine the precise relationships between blood lead levels and neurophysiologic effects. 

11. Robinson L. Traumatic injury to peripheral nerves. Muscle and Nerve. 23 : 863-873 (2000).

Robinson comprehensively outlines the epidemiology and classification schemes for peripheral nerve injury, including the effects of each type of injury on associated muscles and nerves. The appropriate use and optimal timing of electrodiagnostic studies are discussed. Using ECG, CNAP, F and H waves, and SNAP measures, the degree of injury severity, prognosis and surgical necessity may be determined. Such measures are also useful in localization of pathology in cases of mixed injuries. Electrodiagnostic changes specific to each type of nerve injury are presented. Mechanisms of recovery are discussed in relation to determinants of prognosis, treatment, and surgical intervention. 

12. Storzbach D, et al. Neurobehavioral deficits in Persian Gulf veterans : Additional evidence from a population-based study. Environmental Research. 85 : 1-13 (2001).

The Portland Environmental Hazards Research Center undertook a population-based study to examine unexplained Gulf War symptoms such as problems with memory and attention, fatigue, and muscle pain. Cases (239) were drawn from veterans reporting symptoms and compared with 112 non-symptomatic GW veteran controls. A prior interim study showed a significant difference between cases and controls and identified a distinct subgroup of very slow responders in the Oregon Dual Task Procedures (ODTP) test. This study examined a larger sample of veterans to determine if the bimodal distribution identified in the interim study continued to exist, and to determine if “slow ODTP” veterans constitute a subgroup distinct from other GW vets with unexplained symptoms. Subjects completed mail-in surveys, clinical exams, and a battery of psychological and neurobehavioral tests. The slow ODTP group performed significantly worse in neurobehavioral testing than other cases and controls. Deficits in memory, attention, and response speed were identified. These results confirm that a bimodal distribution of cases exists and provided significant evidence that the majority of cases reporting behavioral symptoms had no objective evidence of neurobehavioral deficits. However, the larger group did show significantly elevated levels of psychological distress. The majority of significant differences between cases and controls in neurobehavioral performance are due to the presence of a small ODTP subgroup. This may represent a group at the lower end of health status prior to the GW experience. Further research should focus on this group, rather than all symptomatic veterans, to identify why neurobehavioral differences are present between cases and controls. This group provides the opportunity to discover the etiology of cognitive complaints, possibly involving neurotoxic exposures during the war. Studies should include brain imaging, EEG, and comprehensive neuropsychological exam.  

1. Zhou W, Liang Y, Christiani D. Utility of the WHO Neurobehavioral Core Test Battery in Chinese Workers-A Meta-Analysis. Environmental Research. Section A 88: 94-102,2002.

A meta-analysis assessing the efficacy of the WHO NCTB, summarizing measures of the tests, and aiming to determine the most sensitive subtests for specific exposure agents. Widespread use of NCTB in China made this an appropriate resource base. Following database searches and screening, 39 cross-sectional studies met inclusion criteria. Summary effect measure was estimated using the fixed-effect model. All subtests were found to be sensitive for detection of neurotoxic effects of occupational/environmental agents, yet specific subtests showed higher sensitivity for neurobehavioral changes induced by a given exposure agent. For Hg exposure, the Benton Visual Retention Test was most sensitive; for Pb exposure, Pursuit Aiming II and Profile Mood States showed highest sensitivity, and for organic solvent exposure, Digit Span, Pursuit Aiming II, and Digit Symbol were most sensitive. These subtests may not represent primary neurotoxic targets. Further study is required to clarify the relation between exposure and subtest results. Results may be valuable in streamlining test batteries for a given toxic exposure. The analysis is limited by application to a single ethnic group. 

2. Lotti M. Low-level exposures to organophosphorous esters and peripheral nerve function. Muscle and Nerve. 25: 492-504, 2002.

A critical review of studies examining the association of chronic low dose OPE exposure to development of peripheral neuropathy. In contrast to prior studies, recent data suggests peripheral neuropathy may develop in the absence of a preceding cholinergic toxicity, if low-level OPE exposure is experienced. An outline of the neurotoxic effects of severe OPE exposure is provided, including the cholinergic syndrome, intermediate syndrome, and organophosphate-induced delayed polyneuropathy (OPIDP). Considerable data from recent studies suggests peripheral neuropathy develops post low level OPE exposure. However, a lack of exposure data, mild or inconsistent changes in PNF, and small/poorly selected sample groups lead the authors to believe the data is inconclusive. Classic OPIDP provides the only available experimental model for comparison. The mechanism of low-level OPE induced peripheral neuropathy is unclear, as is the significance of the variety of findings in the reviewed studies. The authors claim some individuals may experience sensory deficits differing from the OPIDP pattern, but conclude there is no evidence that prolonged low-level exposure to OPE's leads to peripheral nerve dysfunction in humans. 

3. Hwang K, Lee B, Bressier J, Bolla K, Stewart W, Schwartz B. Protein Kinase C activity and the relations between blood lead and neurobehavioral function in lead workers. Environmental Health Perspectives. 110 (2): 133-138, 2002.

This study provides insight to the mechanism of lead toxicity in humans. It aims to determine if PKC activity is associated with neurobehavioral function, or if it acts as an effect modifier between blood lead levels and neurobehavioral test function. The cross-sectional study of 212 Korean current lead workers involved measurements of blood lead, PKC activity, and neurobehavioral function PKC activity was assessed by levels of phosphorylation of 3 erythrocyte membrane proteins, using an in-vitro back phosphorylation assay. The WHO NCTB test battery and several other tests measured neurobehavioral function. Controlled for confounding variables, results indicated elevated blood levels were associated with impaired performance in tests of psychomotor and executive functions and manual dexterity, only in subjects with lower in-vitro back phosphorylation levels, corresponding to higher in-vivo PKC activity. In-vivo PKC activity was not directly associated with decrements in neurobehavioral performance in humans with current occupational lead exposure. Yet it did modify the relationship between blood lead and neurobehavioral test scores. The authors suggest individuals with higher PKC activity may be at higher risk for neurotoxic effects of lead. This is the first study providing evidence that PKC does play a role in the lead toxicity. Limitations of the study include reliance upon a single lead biomarker (blood ), and extrapolation of information about PKC function in erythrocytes to its function in nervous tissue, though no direct studies provide evidence for this. 

4. Chouaniere D, Wild P, Fontana J, Hery M, Fournier M, Baudin V, Subra I, Rousselle D, Toamin J, Saurin S, Ardiot M. Neurobehavioral disturbances arising from occupational toluene exposure. American Journal of Industrial Medicine. 41: 77-88 (2002).

A EURONEST study examining the neurotoxic effects of low-level toluene exposure. A cross-sectional study of 128 workers from 2 French printing plants. Neurotoxic effects were assessed by a self-administered EURONEST questionnaire investigating neurobehavioral performance, mood, neurologic and psychosomatic symptoms. A computerized NES test battery measured attention, memory, learning, and psychomotor speed. Ambient air measures of toluene were collected from both plants. Subjects with acute exposure were excluded. Adjusting for confounders, results showed impaired performance in short-term memory function . Multiple regression analysis showed significant relations between current exposure and decrements in test scores for digit span forwards and digit span backwards, equivalent to an aging factor of 25 and 14 years respectively. Other cognitive functions did not show impairment. No association was found between cumulative exposure and test performance or neurotoxic symptoms. The authors conclude current low level toluene exposure may cause early decrements in memory function. Non-participation of the most highly exposed group may underestimate the relation of toluene to impaired neurobehavioral functions. More specific cognitive function tests and long-term follow up are recommended for further study.  

1. Michalek J, Akhtar F, Arezzo J, Garabrant D, Albers J. Serum dioxin and peripheral neuropathy in veterans of Operation Ranch Hand. Neuotoxicology. 22 (4): 479-490, 2001.

This study examines the relationship of exposure to Agent Orange containing (2,3,7,8-tetrachlorodibenzo-p-dioxin) and the development of peripheral neuropathy. The subjects were veterans of Operation Ranch Hand, responsible for application of aerial herbicide in Vietnam from 1962-71. Data obtained from an ongoing Air Force study provided measurements of PNF, NCV's, and vibrotactile thresholds. Subjects were categorized to low, medium, and high exposure, relative to serum dioxin levels measured at the outset of the study. Subjects were screened for DM at each exam. Results from 1992 and 1997 indicate a consistently increased risk of peripheral neuropathy (probable and diagnosed) in the high exposure group of ORH vets, suggestive of an adverse effect. The study is limited by incomplete knowledge of dioxin exposure, confounding by the high number of vets with DM, and changes in peripheral neuropathy status between subsequent exams. 

2. Khaldoun N, Kristensen P, Al-Khatib A, Takrori F, Bjertness E. Prevalence of neuropsychiatric and mucous membrane irritation complaints among Palestinian shoe factory workers exposed to organic solvents and plastic compounds. American Journal of Industrial Medicine. 40 (2): 192-198, 2001.

A cross-sectional survey of 167 shoe workers was conducted to assess whether chronic exposure to organic solvents is associated with neuropsychiatric and mucus membrane irritation. Prevalence of self-reported health problems were compared with history of long-term occupational exposure to solvents and plastics. Prevalence ratios were obtained by Cox regression, and adverse health effects were reported within 95% CI's. Tingling limbs (PR=1.8), sore eyes (PR=1.9), and impaired breathing (PR=2.0) were related to cleaning tasks; tingling limbs (PR=1.8) and sore eyes (PR=1.7) were common to plastic work; impaired breathing (PR=1.9) was associated with varnishing. The study indicates a strong association between self-reported health complaints and exposure to organic solvents for the observed tasks. Volatile organic solvents (dichloromethane, n-hexane) and plastic compounds (isocyanates and polyvinyl chloride) may be responsible for the high prevalence of complaints. Absence of ventilation and suitable protection increased exposure levels. Underestimation of complaints is possible, due to selection of subjects by factory management, rather than by random selection. 

3. Kaufmann H, and Hinsworth R. Why do we faint? Muscle and Nerve. 24: 981-983, 2001.

An editorial discussing proposed mechanisms for vasovagal syncope. Hypotension and bradycardia leading to insufficient cerebral perfusion cause loss of consiousness and postural tone. Proposed mechanisms for hypotension include sympathetic activation of B2 adrenergic receptors, reactive hyperemia, and NO-mediated vasodilation. Causes of fainting may be of central origin (vasodilation and bradycardia in response to intense fear or emotion), or may be due to failure of normal homeostatic reflexes or overstimulation of depressor reflexes (ie. Carotid sinus syncope, valsalva-like maneuvers, micturation, orthostatic hypotension.). Complete mechanism for vasovagal syncope remains unclear. The trigger mechanism involves both central stimulation and peripheral reflexes. Fainting is related to decreased effective blood volume and the effect can be mediated by volume expansion.  

1. Grandjean P., Weihe P., Burse VW., Needham LL., Storr-Hansen E., Heinzow B., Debes F., Murata K., Simonsen H., Ellefsen P., Budtz-Jorgensen E., Keiding N., White RF.
Neurobehavioral deficits associated with PCB in 7-year-old children prenatally exposed to seafood neurotoxicants. Neurotoxicology and Teratology. 2001, 23: 305-317.

This study analyzed mercury-associated neurobehavioral dysfunctions in a cohort that had been exposed to PCBs through their normal diet of whale meat. Pre-natal exposure to PCB's was examined by analysis of cord blood and tissue from a Faroese birth cohort (1986-87) of 435 children. Cord blood showed excellent correlation to cord tissue concentrations of PCB's in 50-paired samples. Cohort children were clinically examined at 7 years old, and neuropsychological deficits were compared to PCB levels of stored cord blood samples. Of 17 neuropsychological outcomes, cord PCB concentration was associated with deficits on the Boston naming Test (basic language function), the Continuous Performance Test reaction time (attention), and possibly in the California Verbal Learning test (long term recall). Increased thresholds were seen in 2/8 frequencies on audiometry, on the left side only. PCB-associated deficits were only apparent in children with higher levels of mercury exposure. An interaction of the two neurotoxicants is possible. This cohort showed limited PCB-related neurotoxicity, with possible confounding by methylmercury exposure.

2. Dick RB., Steenland K., Drieg EF., Hines CJ.
Evaluation of acute sensory-motor effects and test sensitivity using termiticide workers exposed to chlorpyrifos. Neurotoxicology and Teratology. 2001, 23: 381-393.

Sensory and motor testing was performed on a group of termiticide workers exposed to chlorpyrifos to evaluate the acute effects of exposure and the sensitivity of the measures to detect effects. The study group consisted of 106 termiticide applicators and 52 non-exposed controls. Current exposure was determined by urinary levels of TCP (3,5,6-trichloro-2-pyridinol). The mean TCP for applicators was 200 micrograms/g creatinine. Sensory-motor tests recommended by a NIOSH-sponsored panel were employed. Tests of olfactory dysfunction, visual acuity, contrast sensitivity, color vision, vibrotactile sensitivity, tremor, manual dexterity, eye-hand co-ordination and postural stability were analyzed. Results showed minimal acute effects from exposure to pesticides using urinary TCP as a measure of current exposure. A possible sub-clinical effect involving proprioceptive and vestibular pathways is suggested by a measured effect on postural sway. Evaluation of the sensitivity of the sensory and motor tests employed, using MADD (minimal absolute detectable difference) as an indicator of effect size, showed that either a larger study group or a greater exposure effect was needed to determine a significant relationship.

3. Lauria G. MD, Sghirlanzoni A. MD, Lombardi R, and Pareyson D. MD.
Epidermal nerve fiber density in sensory ganglionopathies: clinical and neurophysiologic correlations. Muscle and Nerve. 2001, 24: 1034-1039.

The involvement of somatic unmyelinated fibers in sensory ganglionopathies was assessed by skin biopsy and quantitative sensory testing . The study group consisted of 16 patients with ganglionopathy, 16 with axonal neuropathy, and 15 normal controls. Skin biopsy was performed at the proximal thigh and distal leg. Neuropathy patients showed a greater proximodistal gradient of IENF density than controls, suggesting a loss of cutaneous innnervation in a length-dependent fashion. In contrast, ganglionopathy patients with hyperalgesic symptoms showed global rather than proximo-distal degeneration of sensory neurons. This was consistent with the clinical and neurophysiologic observations, and distinguished ganglionopathies from axonal neuropathies.

4. Molloy FM, Floeter MK, Syed NA, Sandbrink F, Culcea E, Steinberg SM, Dahut W, Pluda J, Kruger EA, Reed E, and Fig WD.
Thalidomide Neuropathy in Patients Treated for Metastatic Prostate Cancer. Muscle and Nerve. 2001, 24: 1050-1057.

A prospective study of peripheral nerve function was conducted in a cohort of 67 patients with metastatic hormone-refractory prostate cancer. The study was designed to assess the clinical and neurophysiologic features of thalidomide neuropathy and to assess the efficacy of the SNAP (sensory nerve action potential) index as a monitor for early onset. Patients were treated with thalidomide in an open-label and evaluated for induced neuropathies by neurologic exams and nerve conduction studies prior to treatment and at 3 month intervals. Average values were determined from SNAP values for the median, radial, ulnar and sural nerves in each patient. Of 67 initial patients, 55 discontinued treatment due to lack of therapeutic response; 24 remained at 3 months, 8 remained at 6 months, 4 remained at 8 months, and 3 remained at 9 months. 6 patients developed neuropathy, with clinical symptoms and a decreased SNAP index (at least 40% decline from baseline) occurring simultaneously. Older age and cumulative dose are possible contributing factors. The study concludes that poorly reversible neuropathy may be a complication of thalidomide treatment in older patients and recommends close clinical and electrophysilogic evaluations during treatment, and discontinuation of treatment as paresthesias develop. The SNAP index may be used to monitor development of peripheral neuropathy, but is not a useful tool for early detection. Limits of this study included the lack of an untreated control group, and the withdrawal of most patients from the study as their cancer progressed or neuropathic symptoms increased.

5. Chislom JJ. Evolution of the Management and Prevention of Childhood Lead Poisoning:
Dependence of Advances in Public Health on Technological Advances in the Determination of Lead and Related Biochemical Indicators of Its Toxicity. Environmental Research. 2001, 86: 111-121.

A review of technological advances as the basis for improvements in the recognition and diagnosis of childhood lead poisoning, and public health activities directed at its prevention. The history is divided into three stages: Pre-dithizone era, dithizone era, and atomic absorption/electrochemical era. The pre-dithizone era depended primarily on the identification of symptoms for diagnosis and case documentation. In the 1930s the development of the dithizone procedure allowed measures of lead in blood, urine and tissues to be determined. This allowed for more accurate documentation of cases including encephalopathic, mildly symptomatic, and asymptomatic cases. The urinary UCP test and ALAU test made possible the screening of children in hospitals, and greatly facilitated the diagnosis and management of cases. The advent of chelating agents CaN2 EDTA and BAL allowed analysis of paint samples, and assisted public health activities in management. Volume capacity and the speed of analyzation improved dramatically with the development of x-ray fluorescence. Developments in the atomic absorption spectrophotometric and electrochemical era allowed advancements in lead analysis and provided a basis for improvements in the research in lead toxicity and public health steps to decrease its occurrence. Today advanced lab technology is more than adequate for screening the necessary volume of samples, yet public health procedures reach only ½ to 2/3 of high risk children.

6. Priyadarshi A, Khuder SA, Schaub EA, and Priyadarshi SS.
Environmental Risk Factors and Parkinson's Disease; A Metaanalysis. Environmental Research. 2001, 86: 122-127.

The study examines the relationship between PD and exposure to environmental factors such as living in a rural area or on a farm, well water use, farming, exposure to farm animals, and pesticides. It involved a meta-analysis of peer-reviewed case-control studies; 16 for living in rural areas, 18 for well water drinking, 11 for farming, and 14 for pesticides. All were evaluated for statistical significance, heterogeneity, and publication bias. Significant heterogeneity was detected among studies and a combined odds ratio was calculated. The meta-analysis concludes living in rural areas, drinking well water, farming and exposure to pesticides cause a small but significant increased risk for development of PD due to potential exposure to neurotoxins. The authors suggest future cohort studies be conducted for prospective evaluation of the association between environmental factors and PD, as well as studies targeting specific occupational groups; future studies must also examine composition of soil, water, pesticides and fertilizers, application processes and potential lifestyle differences of subjects.

August 2001

1. "Neuropsychological Function in Gulf War Veterans: Relationships to Self-Reported Toxicant Exposures"
White, RF, et al.
American Journal of Industrial Medicine Vol 40. pg 42-54 (2001).

Four years after the Gulf War, military personnel who had been exposed to neurotoxicants and military personnel who were not exposed to neurotoxicants were tested on several specific tests over the following domains: general intelligence, attention/executive function, motor ability, visuospatial processing, verbal and visual memory, mood, and motivation. Lower scores on neuropsychological tests were observed among the gulf-deployed group compared to the non-gulf-deployed group, in the areas of attention and executive function and mood. However, after effects for PTSD and psychological diagnoses were controlled for, only mood effects were observed at significant levels.

2. "Prospective Study of Caffeine Consumption and Risk of Parkinson's Disease in Men and Women"

Axcherio A, et al.
Annals of Neurology, Volume 50, No. 1, July 2001

The consumption of caffeine from different sources and the risk of Parkinson's disease in men and women was examined prospectively within the HPFS (Health Professionals' Follow-Up Study) and the NHS (Nurses' Health Study) cohorts. The study population was followed for 10 years in men, 16 years in women. In men, an inverse association was observed with consumption of caffeine (including coffee, noncoffee sources, and tea). The relative risk in men was 0.42. Among women, the relationship between caffeine and risk of Parkinson's was U-shaped, with the lowest risk observed at moderate intakes, 1-3 cups of coffee/day.

3. "Environmental Pesticide Exposure as a Risk Facor for Alzheimer's Disease: A Case-Control Study"

Gauthier, E, et al.
Environmental Research Section A Volume 86, pp 37-45 (2001)

After controlling for obvious confounding factors such as genetics, occupational exposure and sociodemographic factors, there appeared to be no significant risk for Alzheimer's disease with exposure to herbicides, insecticides, and pesticides. Statistical analysis with logistic regression was performed on a randomly selected elderly population from Quebec, Canada. This area is geographically isolated, so that evaluating the long-term environmental exposure is easier.

4. "Amyotrophic Lateral Sclerosis in a Battery-factory Worker Exposed to Cadmium" Bar-Sela, S, et al.

International Journal of Occupational and Environmental Health Vol 7, pp 109-112 (2001).

This is a case-control report of a 44 year old man who had nine years of heavy exposure to Cadmium from working in a nickel-cadmium battery factory. He had classic signs of cadmium toxicity and was diagnosed with ALS nine years after starting work at the factory. Cadmium perhaps causes neurotoxicity by several mechanisms suggested in this paper.

5. "Symptoms of Gulf War Veterans Possibly Exposed to Organophosphate Chemical Warfare Agents at Khamisiyah, Iraq"

McCauley LA, et al.
International Journal of Occupational and Environmental Health Vol 7, pp 79-89 (2001).

Nine years after the Gulf war in 1991, 2,918 U.S. Gulf War veterans were interviewed by telephone for symptoms past and present indicative of organophosphate chemical exposure. Veterans who were located within 50 km of a known episode of sarin/cyclosarin release (in Khamisiyah in Jan-Mar 1991) were compared with those that were outside of this 50 km radius. There was no significant difference in current symptoms experienced by the two groups. However, there was a significant different in self-reporting of symptoms as recalled by the within 50 km group within two weeks of the known chemical exposure. These symptoms are consistent with low-levels of sarin exposure.

6. "Criteria for the work relatedness of upper-extremity musculoskeletal disorders"

Scandanavian Journal of Work and Environmental Health 2001, Vol. 27, Suppl 1.

This is a practical article describing work factors that cause UEMSD. The physical factors include extreme posture, high repetitiveness, most of the day, high force, and little recovery time. None physical factors include perceived work stress, work tempo, work pressure, mental demands, and social stress. There is a four step process of making decisions as to the work relatedness of an UEMSD. There are many descriptive, practical tests described and illustrated to test for various UEMSDs.

7. "Effects on the nervous system in different groups of workers exposed to aluminium"
Iregren, A et al.

Occupational and Environmental Medicine 2001;58:453-460

Exposure to aluminium was evaluated with aluminium blood and urine levels in groups of aluminium pot room and foundry workers, aluminium welders, and aluminium flake powder producers. These groups were evaluated for neurotoxic effects at different dose levels with mood and symptom questionnaires and psychological and physiological tests. The control group was steel welders.

There was no statistical neurotoxic effect on the aluminium pot room, foundry, or flake powder producers. There was a subtle neurological effect on the aluminium welders at a urinary concentration of aluminium above 100 microgm/l.

1. Biernat H, Ellias SA, Wermuth L, Cleary D, De Oliveira Santos EC, Jorgensen PJ, Feldman RG, and Grandjean P.  Tremor Frequency Patterns in Mercury Vapor Exposure Compared with Early Parkinson's Diseaae and Essential Tremor.  Neurotoxicology  20 (6): 945-952, 1999

New instrument allows measurement of tremor intensities at different frequencies.  81 healthy controls showed higher preferred hand tremor intensity, dependant on age.  10 parkinsonian patients showed increased intensity within the lower frequencies, 3-6.5 Hz.  10 patients with essential tremor had peak frequencies in both windows, some only on one side.  63 Brazilian gold traders exposed to HG vapor showed increased intensity in the high frequency window.  Their urine mercury levels were correlated with the number of burning sessions per week, though did not correlate with intensity of tremor within the high frequency window. 

2. Viaena MK, Masschelein R, Leenders J, DeGroof M, Swerts LJVC, Roels HA.  Neurobehavioral effects of occupational exposure to cadmium: a cross sectional study.  Occ Env Med.  2000; 57: 19-27.

89 adult men, 42 exposed to Cd were given blinded standardized examination consisting of computer assisted neurobehavioral test battery.  Cd workers performed worse on visuomotor tasks, symbol digit substitution and simple reaction time to direction or location.  Complaints consistent with peripheral neuropathy, concentration and equilibrium correlated with Cd U. 

3. Arnetz., BB.  Model development and research vision for the future of multiple chemical sensitivity.  Scand J Work Env Health.  1999; 25 (6): 569-573.

A two step model for the pathophysiology of MCS is presented.  One, different environmental stressors act as initiators and the limbic system and two, other parts of the brain become sensitized and hyper reactive to environmental triggers.  Odor acts as an important trigger. 

4. Jones TF, Craig AS.  Hoy D, Gunter EW, Ashley DL, Barr DB, Brock JW, Schaffner W.  Mass Psychogenic Illness Attributed to Toxic Exposure at a High School.  NEJM.  2000, 342, 96-100.

A gasoline like smell in a high school was noticed on a day in November 1998.  Soon after many students and teachers noted symptoms.  After the school was evacuated, students were evaluated in the local hospital emergency room.  Five days after the school was reopened, another group of people complained of symptoms.  No cause was identified for these symptoms.  A questionnaire revealed that the symptoms reported were associated with the female sex, seeing another person ill and knowing that a classmate was ill and reported an unusual odor at the school.  The illness was attributed to mass psychogenic illness.

5. McGill C, Boyer LV, Flood TJ.  Ortega L.  Mercury cream due to Use of a Cosmetic Cream.  JOEM.  42, 1, January 2000.

Arizona Dept of Public Health assessed urine mercury of those who used a mercury containing beauty cream.  66 of 88 were found to have levels >20 ug/l, 55 people were evaluated in a clinic.  No major abnormalities were noted on physical exam.  139 days later, the Uhg means lowered from 170 ug/l to 32 ug/l at the final test.  Neuropsychiatric symptoms were frequently reported without objective signs. 

6. Letzel S, Lang CJG, Schaller KH,  Angerer J, Fuchs S, Neurndorfer B, Lehnert G.  Longitudinal study of neurotoxicity of occupational exposure to aluminum.  Neurology  2000; 54:997-1000.

Biological monitoring, neuropsychological testing and P300 potentials were measured in 32 aluminum dust exposed workers and matched controls.  Exposure ranged from 2.8- 42 years in the industry, median of 13.7 years, with median ears of exposure to Al at 12.6.  Results did not differ for the subjects versus controls.  Authors noted that chronic exposure to Al dust a the levels documented does not induce measurable cognitive decline. 

7. Marie RM, Le Biez E, Busson P, Schaffer S, Boiteau L, Dupuy B, Viader F.  Nitrous Oxide Anesthesia- Associated Myelopathy.  Arch Neurology, 2000; 57: 380-382.

Two weeks after surgery, a 69 year old man developed ascending paresthesia of the limbs, ataxia and sensory loss of all 4 limbs with absent reflexes.  Four months after the procedures, he had paraplegia, severe weakness of the upper limbs and cutaneous anesthesia sparring the head.  Pernicious anemia was initially diagnosed, after serum levels and a Schilling test.  NO exposure has been reported to cause subclinical cobalamin deficiency, it can trigger or worsen neurological consequences of this deficiency.  This should be addressed after undergoing a surgical procedure, even in the absence of hematological changes. 

December 1999

1.   Khattak S, K-Moghtader, McMartin K, Barrera M, Kennedy D, Koren G.  Pregnancy Outcome Following Gestation Exposure to Organic Solvents.  JAMA.  1999, 281,12, 1106-1109

125 pregnant woman exposed to organic solvents during their occupation where seen in their first trimester between 1987 and 1996.  Each was matched to a female with exposure to a non teratogenic agent on age, gravidity and smoking and drinking status. 
 Occurrence of major congenital malformation was the outcome measure. 
 13 major malformation occurred in the exposed group versus 1 in the non exposed group.  (RR 13.0; 95% confidence interval, 1.8-99.5)  12 occurred among 75 women who reported symptoms during their work from exposures.  None occurred in 43 asymptomatic exposed females.  More of the exposed had previous miscarriage than the controls (54/117 versus 24/125; p<.001)
Women with previous miscarriages had the same rate of major malformation than those who were not exposed. 
 The organic solvent exposed group was composed of 37 women who worked in a factory, 21 who were laboratory technicians, 16 artists, 14 in the printing industry, 13 chemists, 8 painters, 4 office workers, 3 car cleaning workers, 3 veterinary technicians, 2 orthotists, 2 funeral home service workers and 1 carpenter and 1 social worker. 
 Women with occupational exposure to organic solvents had a 13 fold risk of major malformations as well as an increased risk of miscarriages in previous pregnancies while working with organic solvents. 

2.   Feldman RG, Ratner MH, Ptak T.  Chronic Toxic Encephalopathy (CTE) in a Painter Exposed to Mixed Solvents.  Environmental Health Perspectives, 107, 5, 1999.

A  57 year old painter was exposed to various solvents for 30 years of employment developed short term memory impairment and changes in his affect which progressed until exposure ended (he could no longer perform his work duties).  Serial neuropsychological testing after exposure ceased revealed persistent cognitive problems without further progression.  MRI revealed global and symmetrical volume loss involving more white than gray matter.  Findings were deemed consistent with toxic encephalopathy.  The differential diagnosis of dementia is discussed. 

An absence of naming problems (anomia), preservation of language skills and the lack of progression of dementia is atypical for Alzheimer's disease and consistent with chronic toxic encephalopathy.  The diffuse MRI findings were consistent with other reported cases of CTE. 

3.  Buschke H, Kuslansky G, Katz M, Stewart WF, Sliwinksi MJ, Eckholdt HM.  Lipton RB.  Screening for dementia with the Memory Impairment Screen.  Neurology.  1999, 52, 231-238

TO improve screening for AD and dementia, a Memory Impairment Screen (MIS) is a 4 minute four item delay free and cued recall test of memory impairment.  The MIS uses controlled learning to ensure attention, induce specific semantic processing and optimize encoding specificity to improve detection of dementia.  Reliability was tested.  MIS had good sensitivity and sensitivity as well as PPV. 
 Each participant was presented with an 81/2" by 11" sheet of paper with four MIS items to be recalled in 24 point upper case letters.  Each item belonged to a different category.  The individual was asked to identify and name each item aloud and then asked to identify and name each item ("potato") when the tester said its category cue ("vegetable").  The sheet was then removed.  After a nonsemantic interference task (repeated counting from 1 to 20 and back) lasting approximately 2 to 3 minutes, the individual was asked for free recall of the four items in any order.  The category cues were then presented to elicit cued recall of only those items that were not retrieved by free recall.  The number of items retrieved by free recall and the number retrieved by cued recall were recorded.  The MIS score is as calculated (2 x free recall + cued recall).
 Mean MIS scores were 2.5 for dementia (including AD), 2.1 Ad only, and 7.2 for non dementia subjects.  Age for all three groups was near 80; education was 11-12 years for all three categories.

4. Gifford DR and Cummings JL.  Evaluating dementia Screening tests.  Neurology.  1999, 52, 224-227.

Review article.  Limitations for the MIS are mentioned.  Despite these.the MIS appears to be reliable and valid. 

5. Cornblath DR, Chaudry V,   Carter K, Lee D, Seysedadr M, Miernicki M, Joh T.  Total neuropathy score.  Validation and reliability score.  Neurology 1999, 53, 1660-1664.

The TNS provides a single measure to quantify neuropathy. It includes grading of symptoms, signs, nerve conduction studies, and quantitative sensory testing.  Inter and intra rater reliability was excellent (0.966 and 0.986).
Sensory symptoms, motor symptoms, autonomic symptoms, pin sensibility, vibration sensibility, strength, tendon reflexes, vibration sensation (QST vibration), sural amplitude and peroneal amplitude are rated on a 0-4 point scale. 

6. Peripquet MI, Novak V, Collins MP, Nagaraja HN, Erden S, Nash SM, Freimer ML, Sahanek Z, Kissel JT, Mendell JR.  Painful sensory neuropathy.  Neurology 1999, 53, 1641-1647.

The role of skin biopsy in establishing a diagnosis of neuropathy.  Interepidermal nerve fiber (IENF) density is tested.  Both large and small fiber neuropathy are characteristic of presentation of neuropathy.  IENF has been proposed to be able to diagnose small fiber neuropathy.  38 % of patients referred to a Neurology clinic with painful extremities had reduced IENF densities.  NCVs had been normal in these patients.   Thus IENF was more sensitive in this population of patients.  51% had abnormal NCVs and did not have IENFD.  IENF was more sensitive than quantitative sudomotor axon testing and quantitative sensory testing. 

7. Herrmann DN, Griffin JW.  Hauer P, Cronblath DR.  McARthur JC.  Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies.  Neurology 1999, 53, 1634-1640.

26 patients with neuropathic complaints were studies with NCV, distal leg skin biopsy and sural nerve biopsy.  IENF and myelinated and unmyelinated fibers in the sural nerve amplitudes were examined.    Reduced IENF was the only indicator of small fiber depletion in 23% of the cases.  It was normal in acquired demyelinating neuropathies and where clinical suspicion was low.  Distal leg IENF density may be ore sensitive than sural nerve biopsy in identifying small fiber sensory neuropathies. 

8. Kennedy WR and Said G.  Sensory nerves in skin.  Answers about painful feet.  Neurology. 1999, 53, 1614-1615. 

Review article regarding IENF density testing.  Reduced ENF occur with diabetic neuropathy, sensory neuropathy, including HIV and small fiber neuropathy among others.  ENF may be the first detectable sign of neuropathy and perhaps can detect changes over time, as during progression of disease or therapeutic trials.  The skin biopsy and the new non invasive skin blister method give the neurologist the tools make an early diagnosis of epidermal nerve damage in patients with metabolic, inherited or toxic neuropathy.