Metal neurotoxicity …

Jonathan S Rutchik MD MPH

General Neurology

Updated 11.05.2024
Released 02.11.2004
Expires For CME 11.05.2027

Metal neurotoxicity

Author: Jonathan S Rutchik MD MPH

See Contributor Disclosures

Editor: Matthew Lorincz MD PhD

Metal neurotoxicity

In This Article

Quick Link

Introduction

Overview

This article aims to inform the reader of neurologic conditions associated with occupational or environmental exposures to heavy metals, such as lead and manganese. Metals are commonly found in the environment and in the workplace. These may be implicated in the development of neurologic symptoms, examination findings, or a diagnosis. Some metals, depending on the method and duration of exposure, may be the sole cause of a condition whereas others may contribute to the cause or accelerate a neurologic diagnosis. In some cases, halting exposures may lead to reversibility of a condition; however, stabilization or further deterioration may occur.

Key points

	• Neurotoxic illness is often a diagnosis of exclusion after considering other more common presentations for a condition.
	• Metals exist in both an inorganic and organic species, having different properties for absorption and toxicology.
	• Treatment may differ. Chelation is typically reserved for acute exposures that lead to dramatic consequences; otherwise, supportive measures are recommended.
	• Conditions resulting from metal exposure may mimic routine neurologic disease, such as encephalopathy (eg, altered mental state), movement disorders (eg, tremor), neuropathy (eg, tingling or numbness in hands and feet), or seizures.
	• There are no specific diagnostic tests to determine neurotoxic illness, and the most important item may be the occupational or environmental history.

Historical note and terminology

Consideration of neurologic disorders secondary to occupational or environmental exposure first became notable from case reports. These consisted of workers who were exposed to high doses of substances either by inhalation or accidental ingestion and began to develop irreparable neurologic damage. Some of these reports originated in industries where heavy metals exposure was common. However, few of the earlier studies report evidence of biological exposure indices or pathology to identify a corresponding dose that led to such a result.

Epidemiological studies have shown that occupational exposure to high doses of aluminum, arsenic, lead, mercury, or manganese as well as thallium and tin have led to persistent clinical neurologic or neuropsychological abnormalities. These studies have also shown that if symptoms are identified early and proper treatment and removal from exposure is provided, neurologic and/or psychological function can remain stable or actually improve despite the earlier exposures. This is particularly notable with peripheral neurotoxicity.

Martinez-Hernandez and colleagues conducted a comprehensive review of how exposure to both essential and nonessential metals affect the brain, particularly through the activation of microglia (92). Microglia, the immune cells of the central nervous system, can be activated into different phenotypes (M1 and M2), leading to inflammatory or neuroprotective responses. Metal toxicity, particularly from elements such as manganese, iron, copper, zinc, cobalt, lead, aluminum, and cadmium, disrupts microglial function, contributing to neurodegenerative processes like Alzheimer and Parkinson disease.

As individuals age, cognitive function does also decline placing them at risk of developing neurodegenerative brain diseases; however, in a cross-sectional study conducted by Sasaki and Carpenter, they noted that exposure to some neurotoxic metals (ie, cadmium, lead, arsenic, and tungsten) significantly contribute to cognitive decline (132).

More controversy surrounds whether low-level chronic exposures to heavy metals, either in the workplace or the environment, could be responsible for neurodegenerative illness such as Alzheimer disease-type dementia, Parkinson disease, or amyotrophic lateral sclerosis. The neurologic, occupational, and environmental medical literature includes various papers assessing neurologic and neuropsychological function in workers with low-level chronic exposure. For example, there is a growing body of literature focusing on manganese exposure in welders, miners, and steel cutters with central neurologic sequelae. In some studies, researchers have assessed subclinical endpoints because workers have nonspecific symptoms or no symptoms. These studies help to develop evidence that certain clinical features are consistent with occupational or environmental neurologic changes and, if exposure continues, may lead to frank clinical and possibly irreversible health effects. Halting exposures and early recognition of these problems may prevent such outcomes.

Patients with Alzheimer disease or nonspecific dementias have been involved in case-control studies to assess occupational and environmental exposures. These have revealed small relative risk values for certain exposures and Alzheimer disease.

In fact, Alzheimer disease is largely influenced by environmental factors, such as harmful metals, pesticides, and air pollution, with only 5% of cases directly inherited. Long-term exposure to these toxins contributes to the development of Alzheimer disease by causing oxidative stress, neuroinflammation, and mitochondrial dysfunction. Studies have shown that these environmental pollutants alter key signaling pathways, leading to increased expression of harmful molecules like GSK-3beta and TNF-alpha and reduced levels of neurotrophins (37).

In light of the supporting research, occupational and environmental exposures to heavy metals must be considered when diagnosing peripheral neuropathy, dementia, or a movement disorder. This requires taking an accurate work and exposure history of patients in order to determine if such a possibility exists. Therefore, it is extremely important to gain an understanding and working knowledge of these types of exposures so as to make the correct diagnosis.

The term “heavy metal” (formerly included in this title) is no longer used because there is no clear distinction between “heavy” or “nonheavy” metals on the periodic table. Also, there is no clear distinction between the terms “toxic” and “nontoxic” as well as the term “essential” because many metals may become toxic with a high enough dose.

This article discusses seven heavy metals (aluminum, arsenic, lead, manganese, mercury, thallium, and tin), their uses, and occupational exposure pathways and reviews the various studies that evaluate exposures to heavy metals and corresponding health effects.

These metals are utilized in many industrial processes throughout the world. Table 1 describes their industrial uses and some of the possibilities for non-occupational exposures.

Table 1. Industrial Uses of Heavy Metals

Compound	Industrial uses	Non-occupational exposure
Aluminum (Al)	Aluminum refinery, aluminum recycling, aluminum powder factory, welding	• Dialysis-associated exposure • Drinking water and food
Arsenic (As)	Pesticides, pigments, antifouling paint, electroplating, smelters, semiconductors, logging, alloy manufacturing, aniline color manufacturing, brass and bronze manufacturing, carpentry, ceramic manufacturing, drug manufacturing, enameling, fireworks manufacturing, gold and silver refining, lead shot manufacturing, painting, petroleum refining, printing, textile printing	• Seafood • Environmental waste
Lead (Pb)	Soldering and welding, lead shot/bullets, distilling of illicit whiskey, insecticides, automotive/storage batteries, lead-based paints and sprays, lead-stained glass, lead pipes and plumbing, production of plastics, mixing crystal glass mass, repairing automobile radiators, wire plating, cable makers, automobile repair and factory workers, ship repair, lead glass blowing, sheet metal production, brass and bronze works, canning, leather making and tanning, tile making, jewelry making, pottery glazers	• Pica (ingestion) from lead paint in infants • Drinking wine from leaded crystal glasses • Environmental waste (eg, air pollution from smelting operations, metal and battery recycling)
Manganese (Mn)	Silicon, carbon and sulfur products, mines, metallurgical fabrication, welding, alloy manufacturing, textile bleaching, leather tanning, electroplating. Ingredient in potassium permanganate, fungicides, germicides, and antiseptics. Used in production of dry cell batteries, glass, matches, fireworks, fertilizers, animal feed, paints, and varnishes. Organic compounds such as the fungicide Maneb (manganese ethylene bis dithiocarbamate) and the antiknock gasoline additive MMT (methyl cyclopentadienyl manganese tricarbonyl)	• Anti-knock gasoline additive MMT (methyl cyclopentadienyl manganese tricarbonyl) • Essential nutrient found in wheat, rice, teas, nuts, meats, poultry • Environmental waste (eg, air pollution from smelting operations, pesticide runoff)
Mercury (Hg)	Scientific instruments, electrical equipment, amalgams, electroplating, photography, felt making, taxidermy, textiles, pigments, chloralkali industry.	• Ingestion of pesticide residues as in Minamata Bay and Iraq
Thallium (Tl)	Rodenticides, fungicides, mercury and silver alloys, lens manufacturing, photoelectric cells, infrared optical instruments	• Cigarettes • Ingestion of fish and shellfish
Tin (Sn)	Coating for lead and zinc, prevents corrosion, reducing agent, solder for pipes and electric circuits, bearing alloys, window glass, tin foil, conductive coatings, mordant in printing processes, magnets, superconductors	• Ingestion of foods from unlacquered cans, tin foil, tin flavorings found in jarred foods.

Clinical manifestations

Presentation and course

General considerations. The reader should be aware that associating exposure to clinical presentation is a difficult task and that this is a process that may require frequent reassessment after a first visit. Patients may have reversible syndromes that improve after exposures end; they may have severe symptoms after a high-level, short-term exposure that may or may not improve; they may have a neurodegenerative disease that presents early; or they may have additional or atypical features. Often these manifestations are difficult to differentiate from idiopathic syndromes. In fact, most manifestations of encephalopathy or neuropathy that may be secondary to an exposure are nonspecific for a metal or, in fact, similar to those of a patient without an exposure and with a well-known etiology for a disorder. Specific instances, however, will be discussed in each metal subsection.

Deficits in concentration, attention, and memory are consistent with dementia from either an occupational or environmental source. Speech is less commonly affected. Abnormal neuropsychological test results in these domains will usually improve or remain stable after a period of months to years after exposure has ceased.

Clinical syndromes associated with metal poisoning often present with concomitant symptoms referable to other aspects of the nervous system and other organs systems. For example, arsenic toxicity commonly presents with hair and nail changes and liver and kidney disease as well as a mixed sensory-motor toxic neuropathy. Lead exposure may lead to an axonal motor, and even more commonly sensory, neuropathy as well as renal disease, hypertension, gout, infertility, and seizures when the exposure doses are high. Lead exposure is hypothesized to have a role in pathogenesis in some patients with motor neuron disease. Manganese is associated with movement and psychological disorders. Mercury is associated with pulmonary and renal dysfunction, color vision changes, and toxic neuropathy. Thallium is associated with neuropathy and hair loss. Tin is associated with seizures.

A detailed occupational and environmental history is crucial. This should include specific aspects of the patient’s employment, their use of personal protective equipment, and contact with specific chemicals if applicable. Patients may not know what chemicals they use but usually know what their company does or manufactures. Ask specific questions and, if possible, request documents, such as Safety Data Sheets (SDS). Questions about the use of specific natural remedies (eg, herbal supplements), recreational drug use, and routine household products as well the sources of residential water supply are also important.

Table 2 provides a detailed guideline for evaluation of a patient with neurotoxic illness. Taking an accurate exposure history requires a thorough evaluation of a patient’s occupational history. To evaluate whether there is a possibility of occupational or environmental exposures, it is extremely important to pay attention to small details such as those discussed below.

Lastly the reader is alerted to the fact that often neurologists are asked to opine on causation by legal representation, regarding whether an exposure is the cause of, or a contribution to a cause of, a neurologic condition. Methods described below and the literature presented in this chapter may be helpful in this very complex exercise. It is important to identify the difference between general and specific causation. General causation suggests that the agent may cause the illness or disease whereas specific causation suggests that the dose and duration and individual conditions of the specific patient’s exposure could cause this presentation of neurologic illness. General causation usually requires a detailed review of neuroepidemiology and case series whereas specific causation may require identifying (through review of case reports, regulations, biological exposure indices, and industrial hygiene and laboratory reports) that the quotient of dose and duration is sufficient to cause the diagnosis. Another important differentiation is to consider the legal arena in which these questions are asked of the neurologist. Although most states outline workers’ compensation laws supporting 1% causation to an injury or illness, personal injury thresholds may be 50% or have other language that must be used in an opinion, for example, “more likely than not,” and “with a reasonable degree of medical certainty.” The neurologist is alerted to clarify this prior to starting this exercise.

Table 2. Algorithm for the Clinical Assessment of Neurotoxic Illness

(1) Begin the evaluation with a chief complaint or complaints. Consider when these began and how they relate to an exposure.

(2) Take a thorough medical history that includes an occupational and environmental history to consider all sources of exposure to all possible agents. List details of all jobs and job tasks within the jobs and when each symptom and medical problem began. Consider social history including alcohol, smoking and drug intake. Consider exposures both in the workplace and outside including solvents and pesticides as well as other gases such as carbon monoxide or mold.

(3) Consider a review of systems and how eating, bowel movements, sexual activity, sleep, and emotional status varied during exposure incidents.

(4) List medical complaints on a timeline and relate each to exposure dates, duration, and intensity. Consider other occupational, environmental, and drug exposures. Include vitamin supplements, hobbies, and traditional practices.

(5) Include birth history, pregnancy, and extensive family history to uncover any genetic or congenital diseases.

(6) Consider how symptoms change as they relate to exposures. How often are there flare ups? Are the symptoms persistent or do they improve?

(7) Find out if colleagues or coworkers exist with similar complaints or exposures and what ages and medical histories they have, if possible.

(8) List all potential sources of exposure, including place of origin, form, and how they are used.

(9) Obtain Safety Data Sheets and scientific data on each chemical agent.

(10) Perform neurologic examination. A general medical examination including an assessment of the autonomic system, hair, teeth, nails, skin color, and lymph system is important. Are there objective neurologic signs or other systemic findings?

(11) Arrange for objective testing: neurophysiological, neuropsychological, and imaging tests.

(12) Arrange for serum and biological monitoring when appropriate. Consult Agency for Toxic Substance and Disease Registry (ATSDR) literature regarding biological exposure indices (BEIs) for urine, blood, and expired air. Discuss with a licensed industrial hygienist.

(13) Review regulatory information for each chemical. What have the Occupational Safety and Health Administration (OSHA), Environmental Protection Agency (EPA), The National Institute of Occupational Safety and Health (NIOSH), The American Congress of Governmental Industrial Hygienists (ACGIH), and other international organizations such as the World Health Organization (WHO) or the International Agency on Cancer Research (IARC) published as safe exposure levels?

(14) Consider contacting an industrial hygienist for air and water sampling. American Industrial Hygiene Association is one source: www.aiha.org.

(15) Consider removal from exposure.

(16) Consider whether exposure and problem may be consistent chronologically. Firstly, did the exposure precede the complaint or dysfunction?

(17) Exclude all other common causes of diagnosis. Are the findings consistent with a primary neurologic or other medical condition? Are the findings explained by other historical or familial factors; other exposures, illnesses, or stressors? Could the exposure have brought on a condition earlier than normally expected?

(18) Search literature for epidemiological and case studies and series that describe an association between exposure and dysfunction.

(19) Consider whether dose and duration of exposure are consistent with the described dysfunction? Focus on details of the literature.

(20) Determine the proposed mechanism for the exposure-induced dysfunction?

(21) Estimate functional status, medical treatment options, and consultation necessary for support.

(22) Re-evaluate by examination and positive neurologic neuropsychological tests. Do the results remain consistent?

Laboratory findings, tests, and imaging. Once a toxic exposure is suspected, various studies may be used to assist in confirmation of a diagnosis. Studies appropriate for a particular metal exposure are discussed in later sections of this article. A battery of tests may be conducted to screen for a reversible cause. Below is a brief description of tests that can be used for diagnosis of toxic exposures.

(1) Blood and urine studies should be performed relatively soon after exposure to provide evidence of absorption. Timing is of utmost importance, as the rate of clearance from the body varies for each metal. A complete blood count with indices and reticulocyte count may reveal forms of anemia characteristic to a particular metal. A complete screen will assess electrolytes, blood urea nitrogen, creatinine, glucose, and calcium and will assist in narrowing the diagnosis.

(2) Organic versus inorganic forms of metals must be differentiated; organic arsenic, for example, from shellfish consumption may contaminate results for toxic inorganic arsenic exposure. Patients should refrain from eating seafood for 24 hours before laboratory specimens are obtained. Arsenic blood reflects only the last 2 to 4 hours of exposure and urine reflects the last 24 hours, urine is a more reliable source for evidence of arsenic exposure. Organic arsenic is significantly less toxic than inorganic arsenic.

(3) Hair samples may contain absorbed metal such as arsenic, mercury, or manganese. Environmental contaminants must be screened for. This method of biological exposure indices may be able to assess historical exposure of up to one year. Blood is normally used to assess for acute exposures, and urine is used for acute and subacute exposures.

(4) A standard neuropsychological test battery should be conducted to reveal specific deficits. Neurocognitive deficits in the domains of attention, memory, executive functioning, verbal intelligence, concept formation, and complex cognitive tasks may be associated with metal exposure. Motor effects on tests such as finger tapping, pegboard testing, digit symbol testing, and manual dexterity are noted for certain types of metal exposures.

(5) Electromyography (EMG) and nerve conduction velocity (NCV) test results may be helpful for determining specific characteristics of a neuropathy, such as axonal versus demyelination or motor versus sensory. Furthermore, laboratory testing to rule out other common causes of neuropathy is important. These include fasting blood glucose, HA1C, glucose tolerance testing, thyroid function, liver function, HIV, RF, ANA, HIV, Lyme’s titers, SPEP, IPEP, B12, ESR, chemistries, and complete blood count as well as other tests that may be implicated with neuropathy. Questions in a history pertaining to alcohol and drugs as well as other exposures to pesticides or solvents would be important.

(6) Electroencephalogram (EEG) studies may show diffuse slowing. This may be nonspecific but suggests a central nervous system effect. The seizure activity associated with some metals may be visualized with EEG.

(7) X-ray fluorescence (XRF) is a test, used infrequently, to assess the bone stores of lead and, thereby, may give valuable insight to chronic exposures. Although acute exposures may be measured by blood lead, and zinc eryrocyte protoporphyrin measures subacute exposure to lead, chronic exposure is best measured by XRF as greater than 90% of lead is sequestered in bone. Blood lead may be a more accurate measure of body burden.

(8) MRI, SPECT, and PET imaging of the brain may illustrate gross structural changes or patterns characteristic to a particular metal, such as hyperintensities in white matter due to aluminum exposure. MRI also facilitates narrowing a differential diagnosis as hydrocephalus, cerebrovascular disease, demyelination, atrophy, or mass lesions may be visualized and thereby ruled in or out as causes for dementia.

(9) Neuroimaging and neuropsychological studies should be repeated 6 and 12 months after the exposure ended to monitor the condition.

Regulatory agencies and occupational exposure limits. Metals such as those discussed in this article are among the thousands of chemicals regulated in the United States by The Occupational Safety and Health Administration (OSHA). This governmental agency is under the jurisdiction of The United States Department of Labor. OSHA sets enforceable permissible exposure limits (PELs) to protect workers against the health effects of exposure to hazardous substances. These are enforceable exposure limits for which a worker may be exposed over an 8-hour time-weighted average (TWA) and are based on various research data. Other US agencies like The National Institute of Occupational Safety and Health (NIOSH) and The American Congress of Governmental Industrial Hygienists (ACGIH) have published suggested exposure limits called relative exposure limits (REL) and threshold limit values (TLV), respectively. These are based on an 8-hour TWA, a 15-minute short-term exposure limit (STEL), and a ceiling limit, at which exposure should not occur (NIOSH website; ACGIH website).

In addition, the Environmental Protection Agency (EPA) has published reference doses (RfDs), and The Agency for Toxic Substances and Disease Registry (ATSDR) has published minimum risk levels (MRLs) for “an estimate of daily human exposure to a hazardous substance that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration of exposure.” Minimum risk levels are listed for both oral and inhalation exposures; durations may be acute, intermediate, and chronic for each (EPA website; ATSDR website).

These different types of exposure limits for various metals are provided in detail on the website of the corresponding agency. These can be used for reference when diagnosing occupational exposures for a patient. They also provide more detailed information on heavy metals and additional research data.

Table 3 provides an example of the permissible exposure limits that have been developed by the corresponding agencies for the following metals.

Table 3. Permissible and Recommended Exposure Limits, Threshold Limit Values/Time-Weighted Average, and Biological Exposure Indices

Compound	OSHA: PEL TWA	NIOSH REL: TWA; IDLH	ACGIH: TLV; STEL	ACGIH: Biological exposure indices
Aluminum (Al)	15 mg/m3 (total) 5 mg/m3 (resp)	10 mg/m3 (total) 5 mg/m3 (resp) ND	10 mg/m3, ND	None
Arsenic (As): (inorganic)	0.01 mg/m3; 0.005 mg/m3 (Action level)	0.002 mg/m3 (C); 5.0 mg/m3 (IDHL)	0.01 mg/m3, ND	End of work week Inorg as in urine: 35 µg/g Creatinine
Arsenic (As): (organic)	0.5 mg/m3	ND	ND	None
Lead (Pb): (inorganic)	0.05 mg/m3; 0.03 mg/m3 (Action level)	0.05 mg/m3; 100 (mg/m3 (IDHL)	0.05 v; ND	30 µg/100 ml (blood)
Lead (Pb): (organic)	0.05 mg/m3 (General skin) 0.1 mg/m3 (Construction)	0.1 mg/m3 (skin); 40 mg/m3 (as Pb)	0.05 mg/m3	None
Manganese (Mg)	5.0 mg/m3 (C)	1.0 mg/m3; 3.0 mg/m3 (STEL); 500 mg/m3	0.02 mg/m3 (elemental); 0.1 mg/m3 (Mn cyclopentadiene tricarbonyl)	None
Mercury (Hg): Aryl elemental and inorganic	0.1 mg/m3 (General or maritime) 0.1 mg/m3 (TWA) 0.1 mg/m3 (C)	0.05 mg/m3 0.1 mg/m3 (C) 10 mg/m3 (IDHL)	0.1 mg/m3 (skin); 0.025 mg/m3 (skin); ND	Preshift inorg Hg in U: 35 µg/g Cr End of shift at end of work week total inorg Hg in blood: 15 µg/L
Mercury (Hg): (organic)	0.01 mg/m3; 0.04 mg/m3 (C)	0.01 mg/m3; 0.03 mg/m3 (STEL); 10 mg/m3 (IDHL)	0.01 mg/m3 (skin); 0.03 mg/m3 (C)	None
Thallium (Tl)	0.1 mg/m3 (skin)	0.1 mg/m3; 15 mg/m3 (IDHL)	0.1 mg/m3 (skin)	None
Tin (Sn): Organic; Inorganic (except oxides)	0.1 mg/m3 (organic); 2 mg/m3 (inorganic)	0.1 mg/m3 (TWA); 25 mg/m3 (IDHL); 2 mg/m3 (TWA)	0.1 mg/m3 (TLV); 0.2 mg/m3 (STEL); 2 mg/m3 (TLV)	None
C: ceiling; should never be exceeded Ca: level for carcinogenicity ND: not determined IDLH: Immediate Danger to Life or Health

Aluminum (Al)

Points for the clinician. Aluminum may be implicated in dialysis encephalopathy dementia in renal failure patients, depression and balance problems from short-term occupational exposures, and welder-induced neuropsychological impairments. Electroencephalogram (EEG) changes have been noted in those with aluminum toxicity secondary to uremia and occupational sources. Also, environmental exposures to food and water and also from aluminum preservatives in vaccinations, have been implicated with amyotrophic lateral sclerosis (ALS) and Alzheimer disease-type dementia. There are no specific examination findings that implicate aluminum with a clinical presentation. Biological exposure indices for urine and blood are not often assessed except for comparison to nonexposed populations. Some papers associate serum and urine levels with toxicity, however. Deferoxamine chelation may provide urine levels helpful to determine toxicity and may be correlative with EEG abnormalities. MRI has revealed white matter hyperintensities after high short-term exposures. Neuropathology has identified intracytoplasmic argyrophilic inclusions as characteristic of dialysis-associated encephalopathy.

Background and sources of exposure. Aluminum is a trivalent trace element that occurs in aluminum silicate, oxide, or halide. It is mined from the impure ore, bauxite (which contains aluminum oxide), water, and iron. The weathering of soil contributes to aluminum being found in air samples, and, in acidic settings (ie, acid rain), aluminum, being very soluble, may be found at increased concentrations in water systems. Metallic aluminum, however, does not occur in nature; it occurs only secondary to electrolytic processing of the oxide from the ore. Aluminum is found in many products, such as cosmetics, surgical bone cement, antacids, and anti-inflammatory creams.

Occupational sources include dust and vapors from mining, welding, smelting, and foundry and fabrication work as well as chemical manufacturing plants that use organoaluminums as catalysts. Aluminum is commonly found in drinking water and teas and is used in leaveners and anti-adherents in the baking industry. Aluminum is also found in antacids and antiperspirants. Welders are vulnerable to exposure-related dementia, as are miners exposed to “McIntyre powder,” a dust consisting of finely ground aluminum oxides once used as a prophylactic agent against silicotic lung disease.

Acute occupational and environmental exposures. A common syndrome in which aluminum may be implicated is known in intensive care units as dialysis encephalopathy. Aluminum has been found in dialysis water and is part of the oral aluminum-containing phosphate binding gels used to control blood phosphorus levels. Clinical manifestations start with fatigue, drowsiness, and disturbances of concentration, cognition, and mentation. Impairment of speech and coordination, myoclonus, personality changes, and dementia follow, with progression to seizures and death over periods of 1 to 15 years. When compared to control subjects who were comparably dialyzed, patients with encephalopathy associated with dialysis had substantially higher aluminum levels in plasma and brain. The signs and symptoms were exacerbated by the dialysis. Diagnosis of dialysis dementia is also based on exclusion of other possible factors that may cause similar symptoms.

Patients with dialysis encephalopathy who had elevated aluminum levels were found to have myoclonus, asterixis, and lower extremity weakness as well as memory impairment, suggesting early aluminum exposure-associated dysfunction.

Studies in the late 1970s and 1980s established that in uremic patients with dialysis encephalopathy, the severity of characteristic EEG changes (bilateral spike waves activity and increased frontal slowing) are correlative with serum aluminum levels (63).

Chronic occupational and environmental exposures. Welders, smelter workers, and metal workers are populations with chronic aluminum exposure and potential neurophysiological or neuropsychological effects. Some patients have presented with incoordination, balance problems, intention tremor and spastic paraparesis after years of exposure, leading to the syndrome called “potroom palsy” (86). Three years of exposure increased these workers’ chances of having these neurologic consequences as well as depression but not dementia. A cross-sectional study conducted by Sim and colleagues did not, however, find significant neurologic differences in current and former aluminum potroom workers in respects to tremor or balance (141). Three areas of significant increase between potroom workers and controls were found: incoordination (OR 10.6, 95% CI 2.11 - ∞), difficulty buttoning (OR 6.16, 95% CI 1.16 - ∞), and depression (OR 6.16, 95% CI 1.16 - ∞).

Vlasak and colleagues conducted a meta-analysis of occupational aluminum exposure on cognitive performance (151). The study analyzed data from 18 studies, involving 2476 participants, with an average aluminum blood plasma level of 6.19 μg/L in the control group and 12.28 μg/L in the exposed group. Results showed that workers exposed to aluminum performed worse in processing speed, working memory, attention, and reaction time compared to controls, whereas no significant differences were found in visuospatial ability, visual attention, or task switching. The study suggests that aluminum levels in blood plasma may be a useful biomarker for long-term exposure and its cognitive effects. These findings contribute to understanding the risks of aluminum exposure and its potential link to neurodegenerative diseases.

Dose-dependent EEG pattern abnormalities (decreased alpha, increased theta and delta in the frontal areas) were noted in welders with mean urine aluminum concentration of 76 µg/L and mean exposure duration of four years. Concurring evidence from a meta-analysis of nine studies revealed that exposures leading to urinary aluminum concentrations below 135 µg/L, with mean duration of 4.9 to 19.2 years, have an impact on cognitive performance (97).

Aluminum has also been used as a prophylactic agent against silicosis disease in miners. However, through this route of occupational exposure, a study demonstrated a dose-response relationship between exposure to aluminum and impairment of cognitive function (123).

Aluminum neurotoxicity has also been reported in cases of an intravenous drug user who was heating and injecting oral methadone solution in an aluminum-containing cooking utensil (50), and in a patient following reconstructive otoneurosurgery with aluminum-containing cement (122).

Aluminum and Alzheimer disease. Aluminum exposure has been implicated in the etiology of Alzheimer disease. Higher levels of aluminum have been found in the brain of patients with Alzheimer disease. Aluminum was detected in the central core of senile plaques and in neurons with neurofibrillary tangles, a diagnostic hallmark of Alzheimer disease (112). In animal studies, neurofibrillary tangles and learning and memory deficits are induced by administration of aluminum via intracranial injection through enteral or systemic routes. Dialysis patients with elevated blood aluminum levels may develop increased staining for amyloid precursor protein in the brain (48; 124).

In humans, a cross-sectional case-control study of former aluminum dust-exposed workers found that exposed workers had preclinical mild cognitive disorders that may herald future Alzheimer-like pathologies (114).

In a study conducted within England and Wales, aluminum concentrations in water supplies were assessed, and the prevalence for dementias was compared to CT scanning units that served these areas. The risk of all dementias was found to be 1.5 times higher in districts where the mean aluminum concentration was greater than 0.11 mg/L compared to districts with less than 0.01 mg/L (93). Similar associations between aluminum in drinking water and Alzheimer disease were demonstrated in studies in other countries, but negative studies are reported as well. Furthermore, serum and urine aluminum content and urine aluminum to creatinine ratios of nursing home residents with dementia compared to nursing home residents without dementia was not found to be correlative in both high and low aluminum in water areas (158). The same type of retrospective studies have demonstrated no clear correlation between the prevalence of dementia and the use of aluminum-containing products, including aluminum-containing antiperspirants and antacids, or occupational exposure to aluminum (60; 58).

Alasfar and Isaifan reported on an incident that occurred on July 6, 1988, in Cameford, United Kingdom, where a reported 20 tons of aluminum sulfate, destined to a tank at the Lowermoor Water Treatment Works, was accidentally discharged into the drinking water supply, raising the aluminum concentration to 500 times the allowable limit based on the European Union Legislation (02). Residents, numbering 20,000, were exposed to these high levels of aluminum as a result. In the years that followed, residents were documented to have decreased intellectual function, and a study done by Rondeau and colleagues found that increased risk of Alzheimer disease and dementia were associated with exposures of greater than or equal to 0.1 mg/L aluminum level in drinking water (127). Cases were further noted as in a 49-year-old male, who, after six years of exposure, began to suffer from memory loss, and five years later suffered from increased memory loss, myoclonic jerks, dysphasia, and hallucinations. He died at age 69, and an analysis of his brain revealed neurodegenerative diseases, including Alzheimer disease and elevated aluminum levels in the occipital cortex of the brain. Additional cases were identified, including a 60-year-old male, suffering from epilepsy and mental problems, who later died, but was also noted to have had levels of aluminum identified in the occipital lobes, temporal lobes, and hippocampal tissue of the brain. Further research by Mirza and colleagues examined brain tissue in 12 individuals (five males, seven females, ages 42 to 86) and found aluminum in all tissue samples (99).

Epidemiological studies pertaining to aluminum and Alzheimer disease before June 2003 were reviewed by Santibanez (130). From this meta-analysis, no support was found for the hypothesis that aluminum is associated with the development of Alzheimer disease. A review of this topic by Tomljenovic in The Journal of Alzheimers Disease Research, mentions that several misconceptions about aluminum bioavailability have misled scientists regarding the significance of aluminum in the pathogenesis of Alzheimer disease (148). However, he noted that out of all bioavailable factors considered, aluminum is the only one that has been experimentally shown to trigger all major histopathological events associated with Alzheimer disease, which is likely the result of lifelong low-level exposure to a neurointoxicant, and that aluminum is the third most abundant element on earth. He cites aluminum in processed foods and in vaccines as a significant source to the human population. He also mentions that neurotoxicity increases with aging relative to clearance. He writes that immediate steps should be taken to lessen human exposure to aluminum, which may be the single most aggravating and avoidable factor related to Alzheimer disease. In 2016, Maya and colleagues also reviewed aluminum and neurotoxicity (95). It is clear that neuroscientists have many etiologic entities to focus on to further our knowledge base on this large topic.

Aluminum and amyotrophic lateral sclerosis. Elevated aluminum levels have been found in subjects with amyotrophic lateral sclerosis-parkinsonism dementia complex of Guam. In addition, animal studies have found induction of spinal neuronal degeneration after injection with aluminum (53; 52). In these patients, the soil and drinking water of Southern Guam has been mentioned as a source of aluminum as it has been noted to have low calcium and magnesium and high aluminum and manganese.

A second cluster of amyotrophic lateral sclerosis in Gulf War veterans implicates aluminum hydroxide in anthrax vaccines as etiologic (137). In an experimental study, authors performed subcutaneous injection of aluminum hydroxide in mice and identified significantly amplified apoptosis of motor neurons and disruption of motor functions as well as diminished spatial memory capacity in mice.

Aluminum has been also implicated in cases of amyotrophic lateral sclerosis in the Kii peninsula of Japan. A low calcium/magnesium and high aluminum diet has been proposed as the source of the problem as it induced tau-related neuronal degeneration in mice cerebrum, hippocampus, and brainstem as well as spinal cord of mice who were fed such a diet (72).

Laboratory findings, biological exposure indices, imaging, and pathology. No biological exposure indices (BEI) assessment is specific for aluminum exposures as per OSHA, NIOSH or ACGIH.

However, minor symptoms and subtle deficits in psychomotor function were observed in persons without renal failure with mean serum aluminum levels of 59 µg/L and urine of 330 µg/L. It has been noted that blood or urine aluminum levels don’t always correlate with symptoms (142).

Deferoxamine infusion test (DIT) is a method of assessing total body burden of aluminum in patients with chronic renal failure. A post-infusion rise in serum aluminum of greater than 125 µg/L would be considered a positive test.

When aluminum neurotoxicity is highly suspected in patients who have normal blood and urine aluminum level and negative DIT, evaluating the aluminum deposition level in bone biopsy samples will be helpful (05).

A brain MRI of a potroom worker exposed to aluminum revealed multiple hyperintensities in the white matter (160). Neuropathological assessment noted intracytoplasmic argyrophilic inclusions in the choroid plexus epithelia, neurons, and cortical glia, which are also characteristic of dialysis-associated encephalopathy (122).

Treatment. For aluminum neurotoxicity, partial improvement occurred after nine months of chelation treatment with deferoxamine, which also led to reversible renal dysfunction (50).

For patients receiving dialyses with elevated aluminum, treatment of the dialysate water and avoidance of oral aluminum-containing phosphate-binding gels decreases the incidence of dementia; however, retention of aluminum is increased in persons with renal insufficiency (04).

Supportive measures are recommended. For those with routine occupational exposure to aluminum, yearly physical examinations and testing of serum and urine aluminum levels are recommended.

Arsenic (As)

Points for the clinician. Intoxication is associated with multiorgan dysfunction, including skin and gastrointestinal, renal, and cardiac systems as well as the peripheral and central nervous system. Patients who have experienced acute exposure (eg, purposeful poisoning or incidental occupational or environmental exposure as with contaminated drinking water) may present with hyperkeratotic skin lesions and gastrointestinal disturbances along with stupor and painful progressive neuropathy that may appear similar to Guillain-Barré syndrome. Neuropathies may initially be segmental demyelinating but more commonly progress to have axonal features. Chronic exposures may lead to peripheral neuropathy and encephalopathy, revealed by neuropsychological abnormalities on testing. Urine arsenic assessment for active occupational and environmental exposures reflects those over a 24-hour period, but care must be taken to separate inorganic (potentially toxic) from organic (non-toxic) exposures, as in seafood. Hair may be unreliable for environmental exposures. Early chelation may be helpful in mild intoxication but has not been found to be helpful in severe poisonings.

Background and sources of exposure. Arsenic has been used for homicidal and suicidal purposes for many years. Most famously is the debate of Napoleon Bonaparte’s death being caused by arsenic poisoning. Arsenic has also been used for medicinal purposes, such as for psoriasis, anemia, rheumatism, and syphilis. Today, exposure mainly comes from industrial sources, copper smelting, insecticides and rodenticides, and wood preservatives. It is also applied to glassware, marine plants, and pigments as well as food additives to promote growth in farm animals. Although absorption occurs via inhalation and skin, it is best absorbed by ingestion. Arsine gas is used in the production of microchips in the semiconductor industry. Large-scale application has made arsenic a common contaminant in soil, ground water, and food. Toxicity depends on the chemical form. The most toxic is arsine gas followed by trivalent arsenites, which is 60 times as toxic as pentavalent arsenate. Organic arsenic is non-toxic and may result from ingestion of mollusks, crustaceans, or fish. Arsenic trioxide is used to treat acute promyelocytic leukemia.

Acute occupational and environmental exposures. Acute arsenic poisoning occurs after accidental ingestions of pesticides or insecticides and, less commonly, ingestion for the purpose of suicide. Excess salivation, vomiting, and diarrhea as well as abdominal pain may result from small amounts of exposure and may resolve when exposure ceases.

Authors have reported that patients with these symptoms should be considered to have arsenic toxicity. Also, acute psychosis, a diffuse skin rash, and toxic cardiomyopathy as well as seizures may be associated with poisonings. A lethal dose, 100 to 300 mg or 0.6 mg/kg/day, may be the result of inorganic arsenic ingestion.

Hematological manifestations and renal dysfunction have also been reported in acute industrial exposures.

Acute exposure of significant intensity may lead to peripheral neuropathy. The most common is an axonal dying back neuropathy, but syndromes resembling Guillain-Barré and requiring ventilation have been reported. Some have reported segmental progressive demyelinating neuropathy, which later has progressed to a dying back axonal neuropathy. Desquamating skin rash and persistent vomiting and weight loss along with leukopenia and hematuria have occurred in some patients with arsenic intoxication and neuropathy.

One hundred and four workers at a copper-smelting factory in Fuxin, China presented to a local hospital with complaints of malaise, nausea, vomiting, diarrhea, and abdominal pain, which was assumed to be food poisoning (163). An investigation was launched, and the patients were subsequently diagnosed with subacute arsenic poisoning caused by leakage of arsenic-containing waste from a drainpipe in the copper-smelting factory. Eighty-three (79.8%) of the patients experienced gastrointestinal symptoms, and 72 (69.2%) had leucopenia. After 17 days of admission, 45 (43.3%) patients developed peripheral neuropathy, and 25 (24%) of these patients showed a decrease in motor and sensory nerve conduction velocity and stocking-glove distribution numbness. All 104 patients were placed on chelation therapy with 250 mg dimercaptopropanesulfonic acid (DMPS) per day intravenously until urinary arsenic excretion dropped to a normal range (0.005 to 0.05 mg/L). Within seven weeks, values of all lab tests in the 104 patients were normal, and all recovered from peripheral neuropathy symptoms in 40 weeks.

In four patients with a single dose of arsenic exposure due to accidental or suicidal ingestion, symptoms began 10 days to 3 weeks after exposure. The disorder progressed to a maximum sensory and motor affliction within 4 to 5 weeks. Motor conduction velocities and marked abnormal sensory nerve action potentials were noted (81; 40).

Briefly contaminated sources of municipal drinking water and beer have been reported culprits for arsenic toxicity and deemed responsible for neurologic symptoms and for abnormalities found on EMG and nerve conduction velocity tests.

Chronic occupational and environmental exposures. Multisystem disease is common with chronic arsenic toxicity. A significant body of literature has outlined skin, gastrointestinal, cardiovascular, respiratory, genitourinary, endocrine, and hematological illness as well as malignancy disease associated with arsenic in different populations of patients (121).

Studies have shown that chronic exposure to arsenic at concentrations as low as 10 to 50 ppb in drinking water causes peripheral neuropathy. It has been further noted that the resulting impairment is predominantly found in the sensory fibers more so than in the motor fibers (100). Furthermore, Mochizuki and colleagues found that residents with exposure to arsenic containing drinking water at concentrations of 10 ppb or more reported subjective complaints of feelings of weakness and chronic numbness, whereas those with arsenic containing drinking water concentrations of 50 ppb or more showed objective findings of sensory disturbances to pain, vibration, and 2-point discrimination (combined sensation) (100). These findings were not supported by electrodiagnostic studies; however, it has been reported that abnormal nerve conduction studies are not always seen in subjects with chronic exposure to arsenic. Mochizuki and colleagues concluded that arsenic in drinking water should be less than 10 ppb to ensure human health.

Neurobehavioral studies have also shown an association between abnormal results and chronic exposures to arsenic. Exposures to arsenic in drinking water in India and Pakistan have also been implicated in an increased prevalence of cerebrovascular disease and infarction (31).

A study conducted by Carroll and colleagues looked at chronic low-level exposure to inorganic arsenic in American Indian tribes and communities in the western United States (Arizona, Oklahoma, North Dakota, and South Dakota) (29). This cohort study, drawn from participants of the Strong Heart Study (largest epidemiological study conducted with American Indian communities), included 928 participants, using data on arsenic species in urine samples collected at baseline (1989-1991). Neuropsychological testing was administered during follow-up examinations between 2009 and 2013. Results showed that the sum of inorganic and methylated arsenic species in urine was associated with limited fine motor functioning and processing speed, a decrease of 0.10 (95% CI -0.20, -0.01) on finger tap test in the dominant hand, and a 0.13 (95% CI -0.29, -0.04) decrease on finger tap test in the nondominant hand. It was further noted that a 10% increase in urine arsenic was associated with a 0.15 (95% CI -0.29, 0.00) decrease on the Wechsler Adult Intelligence Scale-Fourth Edition Coding Subtest. Other neuropsychological functioning, however, was not found (29).

Arsenic exposure has been implicated also with Alzheimer disease because it has been associated with hyperphosphorylation of protein tau and over transcription of amyloid precursor protein consistent with the amyloid hypothesis for Alzheimer disease. It has also been implicated in the vascular and brain inflammatory hypotheses of Alzheimer disease. Lastly, arsenic and its metabolites generate free radicals, which fits the hypothesis of oxidative stress leading to Alzheimer disease (56).

Laboratory findings, biological exposure indices, imaging, and pathology. Urine inorganic arsenic is a better marker for exposure than blood arsenic because blood reflects only the past 2 to 4 hours of exposure whereas urine reflects the past 24 hours.

Hair analysis may be helpful, but environmental arsenic may adhere to the hair and make analysis unreliable. Hair arsenic analysis has been utilized also for cumulative exposure but is not considered a reliable method.

Differentiating organic arsenic (resulting from seafoods) from inorganic arsenic (resulting from other exposures) is important because the inorganic form is more toxic, and the organic form is benign. Communication with lab personnel is necessary. Furthermore, refraining from eating seafood for 24 hours is required prior to these laboratory tests.

Urine arsenic was assessed in a population in Argentina due to a massive epidemic of 718 people. Those will urine arsenic greater than 75 µg/dl were noted to have an increased incidence of systemic symptoms (128).

The American Conference of Governmental Industrial Hygienists (ACGIH) has recommended urinary concentrations at the end of a work week should not exceed 50 mg/g creatinine.

No brain imaging has been reported for patients with arsenic exposure.

No brain pathology has been described as a consequence for arsenic exposure or toxicity.

Sural nerve pathology has identified large fiber axonal degeneration in patients with significant neuropathy (94).

Treatment. British anti-Lewisite was reported ineffective in preventing neuropathy when given a few hours after arsenic exposure in a small series of patients.

Chelation therapy with DMSA over five days reduced blood arsenic and increased urinary arsenic excretion, but the patient was left with painful paresthesias resistant to tricyclics and antiepileptics. Some functional impairment was noted (94).

Case reports of chronic occupational exposure to arsenic describe delirium and encephalopathy that improved with time (12; 21; 102).

Lead (Pb)

Points for the clinician. High-dose acute exposures to lead may present with a spectrum of neurologic symptoms that range from chronic headaches to refractory seizures and cognitive changes that may be reversible. Long-term chronic lead exposure is associated with a syndrome that includes gastrointestinal pain, renal dysfunction, hypertension, peripheral neuropathy and brain atrophy. Wrist drop, a textbook-described effect of lead intoxication, is rare. Motor demyelination neuropathy may occur as an effect of high-dose lead exposures and may be reversible whereas sensorimotor axonal neuropathies are likely with low-level chronic exposures and may be less amenable to improvement. Laboratory testing revealing anemia with basophilic stippling on a CBC and differential may be specific for lead intoxication. Gingival lead lines may be present. MRI has revealed an association between frontal and parietal brain volume loss and cumulative lead exposure.

Background and sources of exposure. Lead is a ubiquitous bluish gray metal that is known to produce acute and chronic neurologic and systemic symptoms in humans. Lead ores are often found as conglomerates with other ores, such as silver, zinc, copper, and irons. Lead exists in both inorganic (acetates, oxides, chlorides, chlorates in Pb+2 and +4) and organic (tetraethyl, tetramethyl from Pb+4) forms. Exposures to lead occur by various means, including occupational exposures, consumption of food or products contaminated with or containing inorganic lead, and exposure to inorganic lead released from consumer products such as paints and toys. Organic lead exposure mainly comes from gasoline and atmospheric fallout from industrial sources. Organic lead exposure mainly comes from atmospheric fallout from industrial sources. Historically, organic lead was used as an additive to gasoline, thus, proving to be a significant exposure source before its use was eliminated.

Occupational sources for inorganic lead include many industries, such as mining, painting, automotive, and glass manufacturing. In recent centuries, mining of lead has increased surface soil concentrations. Manufacturing of lead-containing products (gasoline, food containers, and paints) has decreased in order to reduce health hazards. Lead gasoline was prohibited in the United States in 1995. Lead in food containers has been reduced from 47% to 0.9%.

Acute occupational and environmental exposures. In adults, high-level acute exposures are clearly associated with severe neurologic syndromes, including seizures, peripheral neuropathy, and encephalopathy.

Acute symptoms that result from high-level exposures, documented by elevated blood lead levels, include nonspecific subjective symptoms but may lead to attention and memory difficulties. Seizures refractive to antiepileptics may be a consequence of acute lead exposure along with other neurocognitive symptoms. EEG may reveal diffuse slowing. Neurologic symptoms are accompanied by basophilic stippling and anemia, gingival lead lines, and other systemic problems, such as hypertension and renal colic.

Encephalopathy following acute exposure in children is a serious consequence. Oral intake of inorganic lead in paint chips and soil is the main route of exposure. A blood lead level greater than 70 µg/dL in children represents an acute medical emergency. Chelation therapy should be administered. Chelation in acute settings may be useful where blood lead levels are high for adults and children. This is based on case reports and not placebo-controlled case studies.

A review study by Ortega and colleagues looked at the cognitive impact of lead exposure throughout the different stages of life (110). Significant cognitive and developmental impacts were seen in children between the ages 2 to 12 years. Negative impacts included language development, increases in depression, aggressive behaviors, sleep difficulties, IQ decreases by up to 15 points, and cognitive dysfunction. Blood lead levels for this group ranged from 2 to 246 µg/dL.

They further reviewed impacts to adults in ages ranging from 22 to 71 years old, which noted poor executive functioning, decreased reaction time, increased depression, anger, and fatigue, as well as short-time memory difficulties. In this group, blood lead levels ranged from 0.88 to 128.3 µg/dL.

Chronic occupational and environmental exposures. It has been proposed that chronic lead exposure causes endoneural edema, Schwann cell damage, and neural fiber degeneration, leading to peripheral neuropathy.

Classically, the neuromuscular involvement associated with lead poisoning has been reportedly purely motor. A typical patient with lead neuropathy presents with symmetric distal upper limb weakness and wasting, selectively radial palsy. The symptoms develop insidiously from subclinical stages to clinically overt signs and symptoms. Neuropathic features develop only when lead levels exceeded 70 μg/dL. At lead levels this high, other organ involvement such as bone marrow suppression, gastrointestinal disturbance, proteinuria, hypertension, and gout are almost invariably observed in addition to neuropathy (41; 139).

In 2006, Thomson and Parry summarized that motor neuropathy is mainly secondary to short-term exposure to high lead concentrations, and prognosis is good with termination of exposure (147). Distal sensory and motor neuropathy, after many years of exposure, evolves more slowly and recovers less certainly. Lead intoxication in humans causes axonal degeneration, but in other species causes primary demyelination.

Because there is a generally weak relationship between the development of lead neuropathy and blood lead levels, at least for the subacute motor neuropathy, it is speculated that the metabolic basis for the neuropathy is interference with porphyrin metabolism.

Workers have been evaluated for neuropathy with occupational exposure to lead. Mild sensory and autonomic neuropathy features were found to be more common than motor neuropathy classically attributed to lead. Lifetime integrated blood lead (IBL) and lifetime weighted-average blood lead (TWA), two measures of chronic lead exposure, were also associated with impairment of large and small myelinated sensory nerve fibers.

Most of the studies on the cognitive effects of lead were conducted in populations with occupational exposures to lead. Although cases with elevated blood lead levels are routinely documented in workers from many industries, such as metal workers, welders, and construction workers, the prevalence of blood lead levels in adults and children has decreased by significant margins since these measurements were first recorded.

Many studies have been conducted to examine the relationship of various measurements of exposure to lead, both occupational and environmental, and impairment of cognitive and neuropsychiatric functions as measured by standardized tests (17). Chronic neurocognitive effects are often concurrent with peripheral neuropathy, hypertension, and impotence. Many papers show that performance on neuropsychological testing of attention, visuospatial functioning, and memory is impaired. One paper reported that a reversibility of function may occur when blood lead level is maintained below 40 µg/dl (83).

Furthermore, a case-control study conducted in the United States detailed how individuals in the highest quartile of lifetime lead exposure had twice the risk for the development of Parkinson disease compared to those in the lowest quartile (116).

A 2019 epidemiological study looked at cases of children in a slum area of Mumbai that presented with neurologic complaints, convulsions, and drowsiness. It was found that the families of these children were primarily involved in the smelting of lead for artificial jewelry. The mean blood lead level in the children was 42.6 µg/dL. Results of this study focused on the need, on the part of the clinician, for in-depth inquiry into occupational and environmental exposure in cases presenting with unexplained neurotoxicity (55).

Although many papers document neuropsychological impairment from chronic low-level exposure, controversy surrounds whether low-level, long-term exposure is responsible for dementia (09; 10).

White and colleagues evaluated 18 adults exposed to inorganic lead 50 years earlier (when under the age of 4 years) with evidence of blood lead levels greater than 60 µg/ml as children and compared them to age-matched controls (161). Those exposed had neurocognitive deficits that were found to impede their ability to learn new information.

Hanninen and colleagues confirmed that those with evidence of high past and low present lead levels have neuropsychological decrements that are long-lasting or permanent. Also, the authors noted that a history of elevated blood lead levels is a more accurate predictor of neuropsychological effects than bone lead (62).

Lead encephalopathy has also been reported in those whose exposure ended years ago but who continue to have elevated blood lead levels.

Mobilization of stored lead in bone is identified as the culprit in cases where no new exogenous source of inorganic lead is found. In vivo lead measurements of long bones such as around the knee joint can be made with x-ray fluorescence instrumentation. The concentration of lead in bone is associated with a decrease in hematocrit and hemoglobin levels in patients with low blood lead levels (65). Peak tibial lead, an extrapolated value from current values using year from last exposure, was consistently associated with impaired performance in the modalities of manual dexterity, executive ability, verbal intelligence, and verbal memory (145).

Reduction of lead levels appears to improve peripheral nervous system dysfunction as well as return EEG to normal, yet neuropsychological impairments have often been persistent after occupational exposures.

Lead and Alzheimer disease. Prince hypothesized that occurrence of Alzheimer disease may be related to exposure to lead early in life. The hypothesis was based on the observation that a higher prevalence of Alzheimer disease coincided with higher levels of environmental lead in urban areas and developed countries (115). No apparent association between occupational exposure to lead and an increased risk for Alzheimer disease was found in a case-control study performed in the VA system (136). Neurofibrillary tangles, a pathological feature of Alzheimer disease, were reported in cases of childhood lead encephalopathy (107). In animals, neurofibrillary tangles can be induced by systemic administration of lead. From a meta-analysis of 11 studies, no association was found between occupational lead exposure and Alzheimer disease (59).

A study in the journal Movement Disorders reported that patients with Parkinson disease with higher levels of cumulative exposure to lead, as measured by tibial bone lead, were associated with worse cognitive function. The authors opined that this was an example of how community level exposure may manifest itself in chronic diseases of older age. Information about exposures was not gathered in this study (159).

Patients who were found to have elevated tibial bone lead were associated with worse global composite scores encompassing cognitive testing.

Between 2016 and 2017, a case-control study was performed on patients with cognitive impairment referred to the Neurological Clinic of Birjand with control patients matched by age and sex (44). In the Alzheimer disease group, it was found that the average blood lead level was 22.22 +/- 28.57 ug/dL, significantly higher in the patients than in the controls. The unadjusted odds ratio was 1.05 (95% CI 1.01-1.09; p = 0.01) for blood lead level patients compared to the controls.

Lead and amyotrophic lateral sclerosis. It has long been hypothesized that lead (Pb) exposure is associated with amyotrophic lateral sclerosis. Some studies have found associations between amyotrophic lateral sclerosis and blood- and bone-lead levels and still others have only found associations between amyotrophic lateral sclerosis and blood-lead levels (68). Researching the association between amyotrophic lateral sclerosis and blood- and bone-lead levels, researchers conducted a case-control study of United States veterans between the years 2003-2007 to examine this association and to analyze the influence on the association of bone turnover and genetic factors related to lead toxicokinetics. Results showed that a doubling of blood-lead was associated with a 1.9-fold increased risk of amyotrophic lateral sclerosis (95% CI 1.3-2.7) after adjustment for age and bone reabsorption C-terminal telopeptides of type 1 collagen (CTX) (43). Further adjustment for smoking (ever/never) and the measurement of plasma procollagen type 1 amino-terminal peptide (PINP) did not alter the results. Results of this study compounded on earlier studies by accounting for bone turnover in confirming the association between elevated blood-lead levels and an increased risk of amyotrophic lateral sclerosis. Even with this strong association between lead exposure and risk of amyotrophic lateral sclerosis, the mechanisms relating to lead neurotoxicity and amyotrophic lateral sclerosis are still unclear (43).

Another study revealed that the risk of developing amyotrophic lateral sclerosis among individuals with a history of occupational exposure to lead was almost doubled on the basis of nine case controls studies with specific lead exposure information reviewed in a meta-analysis by Wang and colleagues (155). It was mentioned that due to a reduction of lead pollution and a reduction of lead content in lead-containing products, lead might not account for a large number of amyotrophic lateral sclerosis cases presently.

Lead and children. Exposure to lead is well known to adversely affect children’s developing brains. The issue of child exposure will not be discussed at great length in this article.

Although lower intelligence quotient scores are found in children exposed to inorganic lead, many of these results are not statistically significant. A meta-analysis done by Needleman and Gatsonis in 1990 did find data from 24 studies suggesting that children’s IQ scores are inversely related to lead-body burden (106). The specific threshold for lead-induced alterations for intelligence test scores is not yet known. However, a decrement in IQ testing occurred in a cohort whose mean blood lead was 7 µg/dl (13). In another study where socioeconomic status was lower, IQ deficits of 7 points were found in a group with a mean blood lead level of more than 20 µg/dl (38).

Laboratory findings, biological exposure indices, imaging, and pathology. Blood lead has been a useful marker for lead exposure but is suspected to be representative of acute exposure. Zinc erythrocyte protoporphyrin, ZPP, is a marker for chronic lead exposure.

Occupational studies show that impairment, as measured by neuropsychological testing, occurs in asymptomatic individuals when blood lead levels, or ZPP, is elevated. ZPP is a marker for chronic lead exposure. A biological exposure index, a level below which has been deemed safe, was published by the American Congress of Government Industrial Hygienists (ACGIH) for blood ZPP to be 100 µg/ml. Baker and colleagues showed similar findings for a blood lead level of 50 µg/ml (09; 10). Other studies have found no statistically significant neuropsychological impairments with elevated blood lead or ZPP. Lucchini and colleagues assessed a group of 66 workers with mean blood lead of 27.5 µg/ml and 86 controls with mean blood lead of 8 µg/dl and found differences in neurotoxic symptom reporting and visual contrast sensitivity but none regarding neuropsychological testing (87).

Tibial lead has been described as a measure of retained cumulative dose. X-ray florescence is a technique used in research. Schwartz and colleagues assessed blood and tibia lead in occupational-exposed individuals in Korea (135). The authors found that test scores of executive abilities, manual dexterity, and peripheral vibration thresholds declined in association with blood lead levels at baseline and tibia lead over the next year.

Biological exposure indices have been measured in patients with chronic lead exposures. Cumulative lead exposure in former organolead workers was assessed with MRI. Higher tibial lead measured by XRF was significantly related to smaller total brain volume as well as frontal and total gray matter volume and parietal white matter volume, supportive of the theory that cumulative lead dose is associated with persistent brain lesions and neurodegeneration (144).

Effects of environmental exposure from lead on cognitive function have also been assessed in population studies. These studies show that low level of exposure to lead can be associated with cognitive impairment in the older population. Patients with blood lead above 8 µg/dl were found to perform significantly lower in memory, psychomotor speed, attention, and mental flexibility tests, independent of other risk factors for dementia (103). Other studies have also supported that small elevations in blood lead may result in neuropsychological decrements in older populations.

Shin and colleagues evaluated Baltimore, Maryland residents aged 50 to 70 years and compared blood lead to tibial bone lead via XRF and neurocognitive endpoints (138). They found that higher tibial bone lead was associated with worse cognitive function. Hair analysis of lead seldom provides exposure information of clinical value beyond that taken from history and measurement of blood lead.

Treatment. Before chelation therapy, prevention of lead exposure and clearance of any gastrointestinal lead should be confirmed. Avoidance of exposures should be continued for weeks. Chelation is not recommended for asymptomatic individuals. A review of medical management of lead exposure in adults was done by Kosnett and colleagues in 2007 (76).

Chelation therapy is recommended for blood lead levels greater than 50 µg/dL with significant symptoms or signs of lead toxicity. Removal from the workplace is recommended more commonly and specifically for blood lead levels above 30 µg/dL or if two successive concentrations over a 4-week interval are greater than 20 µg/dL. If blood lead level does not fall below 10 µg/dL after control measures are taken, removal is recommended to reduce risk of long-term health consequences.

Other sources recommend that chelation can be possibly considered for blood lead levels between 50 and 79 µg/dL, strongly considered for levels of 80 to 99 µg/dL, and recommended for levels above 100 µg/dL.

Recommendations by the American Occupational and Environmental Clinics (AOEC) mention that oral chelation has supplanted parenteral methods. This document recommends contacting the AOEC to reach clinicians familiar with chelation at http://www.aoec.org. Succimer, an oral preparation at a dose of 10 mg/kg three times daily for five days and then twice daily for another two weeks is recommended and often effective in lowering the blood lead level. Gastrointestinal upset is common.

Other chelating agents such as Calcium EDTA (versenate) and dimercaprol (British anti-Lewisite) may be complicated by cardiac sequelae and renal dysfunction.

Dimercaprol is often used with severe lead toxicity or encephalopathy, recommended at 50 mg/m2 intramuscularly every 4 hours for 5 days. Peanut oil may be a component of this injection and, thus, allergy must first be confirmed. CaEDTA may be used in conjunction with British anti-Lewisite dosed 1 to 1.5 g/m2 intravenous infusion daily for five days. Intramuscular dosing may be possible. Hydration and good renal function is required. Urine should be monitored for other minerals when using this agent (51).

Chelation has been found to improve some patients’ level of function. Patients have reported subjective improvement of cognitive problems that have been substantiated with improvement on neuropsychological testing.

Manganese (Mn)

Points for the clinician. Short-term, high-dose exposure to manganese may lead to irritation including headaches along with pulmonary symptoms. Chronic exposures may lead to extrapyramidal effects and neurobehavioral effects. Manganese miners presented with psychosis and atypical parkinsonism. For welders with manganese exposure, controversy arises as to whether chronic exposure may lead to an atypical form of parkinsonism or something similar to idiopathic Parkinson disease with an earlier age of onset or both. MRI findings may include basal ganglia changes, and PET scan assessment may reveal abnormalities consistent with either presynaptic or postsynaptic parkinsonism. Blood manganese levels are appropriate to be measured during active work but may not be correlative to MRI findings or toxicity.

Background and sources of exposure. Manganese occurs in degrees of varying purity and states of oxidation. It is often found combined with other chemicals, such as silicon, carbon, and sulfur. Manganese is an important essential trace element necessary for normal development. Deficiencies are associated with skeletal deformities, sterility, and neonatal death. Divalent manganese acts as an antioxidant scavenger of superoxide radicals; trivalent manganese produces reactive oxygen species, autoxidation of dopamine, and neurotoxic byproducts.

Manganese is mined from the earth; thus, miners have occupational risks. Other industries such as welding, alloy manufacturing, chemical production, textile bleaching, electroplating, and leather tanning have exposures to manganese. It is also an ingredient in certain fungicides, MANEB, and in the production of matches, glassware, dry-cell batteries, fireworks, and varnishes as well as MMT, a component of gasoline used as an antiknock agent and smoke inhibitor for fuel oil. Manganese is also a component of many foods, such as rice, tea, nuts, meats, and poultry or may be present because of residues from pesticides.

Occupational exposures to manganese have been documented in many industries, most notably in the welding and mining industries. Workers, such as welders, exposed to inhaled manganese are believed to be at the highest risk of developing manganese-related neurologic disease. Other workers who are commonly exposed to inhaled manganese include mechanics, forgery workers, and chemical production workers.

Several neurologic health effects have been associated with exposure to elevated levels of manganese. Exposures may occur via dermal contact, ingestion, or inhalation. Each route varies in its rate of absorption. Ingestion may lead to only 1% to 5% absorption whereas inhalation is much higher but varies depending on the solubility and size of the particles inhaled (88). Of particular interest are the neurologic effects on workers exposed to levels at or below the current regulatory level of 0.2 mg/m³ over an 8-hour period. Also, literature has focused on those who live in geographical locations with elevated manganese in ground water and their risks of neurologic illness.

Historical accounts of workers exposed to elevated levels of manganese have described a wide range of neurologic conditions including mood disturbances, weakness, sleep-disturbances, and movement disorders, some of which are clinically similar to parkinsonism. These symptoms, together with confirmed exposure to manganese, may be referred to as manganism or manganese-induced neurotoxicity. For those with movement disorders, nomenclature may be improved by using the term manganese-induced movement disorder.

Acute occupational and environmental exposures. In 2007, a study of 49 welders employed in the construction of the San Francisco Bay Bridge found 11 cases of what was referred to as manganism. These workers were confined to small spaces for up to two years with minimal protection and poor ventilation. Results identified symptoms including sleep disturbance, mood changes, bradykinesia, headaches, sexual dysfunction, olfaction loss, muscular rigidity, tremors, hallucinations, slurred speech, postural instability, monotonous voice, and facial masking. This study strongly suggested that “neuropsychological features contribute in a dose-effect related way to the portrait of manganism usually characterized by tremor, loss in balance, diminished cognitive performance, and signs and symptoms of parkinsonism” (25).

Chronic occupational and environmental exposures. Manganese encephalopathy, along with other neurologic findings, is also found in workers with chronic liver failure. Manganese psychosis may be the initial manifestation of the clinical syndrome. Clinical features include emotional outbursts, compulsive laughter, and hallucinations along with impaired neuropsychological function. Motor disturbances become the primary problem as the psychosis subsides with time. Neuropsychological testing shows motor effects on tests such as finger tapping, pegboard testing, and digit symbol testing and reaction time; attention and memory are also decreased. Language is spared, except in children who may exhibit persistent language impairments.

A correlation between exposure levels represented by a cumulative exposure index and the development of cognitive effects was noted by authors using neurobehavioral testing. Furthermore, a 2020 paper examining receptor for advanced glycation end products (RAGE), specifically those with altered glucose metabolism compounded with manganese and cadmium exposure, can induce neurodegeneration (80).

There is a growing body of literature describing the neurologic impacts to communities exposed to chronic low-level exposures to manganese. In the Valcamonica region of Italy, three ferroalloy plants operated from 1902 to 2001. Italian researchers Lucchini and colleagues examined pediatric and the elderly residents and found that adolescents between the ages of 11 to 14 years showed significant impairment in motor coordination, hand dexterity, and odor identification associated with manganese in soil, as well as increased tremor associated with manganese in the blood and in the hair (91). Elderly residents between the ages of 65 to 70 years also showed a significant impairment in motor and odor discrimination (90).

MRI was investigated in children exposed to manganese in drinking water who did not have clinical effects, and it revealed lower signal intensity in the globus pallidus (in contrast to occupational exposure to manganese, which reveals high signal), which correlated with poorer motor performance on behavioral testing (39). Hypointensities were opined to be related to the different pathways and levels of exposure.

In a community in Ohio, residents with a long-term exposure history to manganese-air emissions from a ferroalloy plant were assessed with the United Parkinson’s Disease Rating Scale (UPDRS) and tested for motor efficiency and mood against a control group in a similar Ohio town. The exposed group reported more generalized anxiety on the Symptom Checklist-90-Revised test compared to that of the control group. Anxiety scores were related to poorer performance on UPDRS tests (24).

These populations were assessed to tremor by the same authors and were found to have associations with air manganese (23). Low psychomotor speed was also found to be associated with increased manganese levels in air.

These and several other studies are showing that even low-level occupational and environmental exposures to manganese are associated with parkinsonism and motor and cognitive dysfunction, further suggesting that regulatory limits for manganese exposure should be revisited (06).

An emerging health risk with regards to parkinsonism is through occupational exposures to mixed heavy metals in electronic waste (e-waste), which frequently contains a variety of heavy metals, including manganese, copper, iron, and cadmium. Much of the electronic waste disposed of is transported overseas to countries in Africa, Asia, and South America, where environmental regulations to protect against occupational exposures to these products is often lacking. There is a critical gap in our understanding of the neurotoxicological issues that may arise in workers involved in electronic waste; specifically, there is a lack of important exposure assessments of both the work environment and the workers themselves. As workers are not exposed to just one metal, it is necessary to evaluate how these metals interact with one another to elicit neurologic impacts and delineate the biological pathways that may underlie neurotoxicity (30).

A case study of a 40-year-old male working as a tea seller noted presenting symptoms of gradual onset of bilateral, asymmetric hyperkinetic movement disorder with multi-domain cognitive impairment, dysarthria, and generalized rigidity. MRI of the brain was suggestive of paramagnetic substance deposition, which was found to be manganese. Clinical investigation resulted in a diagnosis of acquired hypermagnesemia due to a significant overconsumption of manganese containing black tea on a daily basis. Following chelation therapy, he had complete resolution of chorea, dysarthria, and partial amelioration of rigidity, as well as improvement in cognitive decline and behavioral abnormalities (54).

Manganese and Alzheimer disease. Manganese exposure has also been considered an etiology for Alzheimer disease; however, no difference has been noted in patients when measured for CSF manganese or brain manganese when compared to controls.

Manganese, welding, and movement disorders. The striking similarities between manganism and parkinsonism led many researchers to believe that manganese exposure may place individuals at an increased risk of developing parkinsonism (125). Similarities of rigidity, bradykinesia, and tremor between the extrapyramidal syndrome associated with manganese toxicity, and the typical features of Parkinson disease suggest a possible etiological role for manganese. Authors prior to 1994 described manganese-induced neurotoxicity as clinically indistinguishable to Parkinson disease and reported that some of their patients had hemi-parkinsonism and levodopa responsiveness and were progressive (42; 143; 66; 67; 154). Olanow wrote an editorial 10 years later and reviewed animal studies in which monkeys were intravenously infused with manganese, which lead to striatal pathology supportive of a distinctly separate entity for manganese-induced movement disorder (MIMD) (109).

Jankovic wrote an editorial in Neurology in 2005 that discussed this topic (69). He mentioned an early appearance of hypokinetic, hypophonic dysarthria and early gait and balance abnormalities along with dystonia and hyperreflexia and extensor plantar responses as clinical characteristics. He described that the onset of symptoms was weeks or months after toxic manganese exposure. Findings were noted to be bilateral, simultaneous, and symmetric along with early personality changes and emotional labiality. Also, he mentioned visual and auditory hallucinations and a low amplitude rapid postural tremor. He cited a poor response to levodopa and an initial rapid progression followed by stabilization.

Some authors then reported cases and series that supported that manganese-induced movement disorder is a separate entity, post-synaptic parkinsonism, with different characteristics; and others presented cases that were similar to presynaptic Parkinson disease. Although many papers have been published supporting that manganese-induced neurotoxicity may present with a syndrome similar to idiopathic Parkinson disease, a consensus is not clear on whether the presentation of a manganese-induced movement disorder is always symmetrical and atypical, the deficit is always post synaptic, and the response to levodopa is always absent. PET scans have been reported to reveal both post- and presynaptic abnormalities in welders with parkinsonism, depending on their presentation. Conservatives believe that the manganese exposure is simply coincidental to these patients’ evolving generic form of Parkinson disease.

In 2001, Racette and colleagues reported that welders with Parkinson disease were similar to controls in all features except that they were younger (118). In fact, 18- FDOPA PET scans of two of these welders were consistent with Parkinson disease with globus pallidal hypometabolism, consistent with presynaptic pathology. Racette and colleagues then published a population study of more than 1400 Alabama welder litigants and calculated the prevalence for Parkinson disease to be greater than 10 (120). They used a study by Schoenberg in Copiah County, Mississippi as controls, which created some controversy (134). Racette has since also published more rigorous studies supporting the idea that the prevalence of Parkinson disease is increased in welders (117).

A number of other population studies have supported an increased prevalence of Parkinson disease in those exposed to manganese. Strict constructionists have criticized many of these papers. A number of papers have reported no association between occupational exposure to manganese and welders with Parkinson disease.

Andruska and Racette clarified this discussion in 2015 by identifying three myths: (1) the features of manganese-induced parkinsonism are easily distinguishable from other causes of parkinsonism, (2) manganese neurotoxicity is distinguishable from Parkinson disease by normal dopaminergic function on molecular imaging of the striatum, (3) and the neuropathology of manganese neurotoxicity is well described and unique from Parkinson disease (06).

Racette and colleagues looked to determine whether the parkinsonian phenotype prevalent in welders was progressive and whether progression was related to exposure of manganese-containing welding fume (119). Racette and associates observed an annual change in UPDRS3 of 0.24 (95% CI 0.10-0.38) for each mg Mn/m³-year of exposure. Exposures were most strongly associated with progression of upper limb bradykinesia, upper and lower limb rigidity, and impairment of speech and facial expression. This association was most frequently seen in those welders performing flux core arc welding in confined spaces or in those welders with baseline examinations within five years of their first welding experience.

Manganese, welding, and neuropathology. Differences in the pathology were initially described between Parkinson disease and manganese-induced movement disorder (a presynaptic dopamine deficiency syndrome), based on lesions in the substantia nigra zona compacta of the midbrain for Parkinson disease versus a postsynaptic dopamine deficiency syndrome due to lesions in the basal ganglia for manganese-induced movement disorders (164).

Lewy bodies have been described as pathognomonic for Parkinson disease but have also been identified in the zona compacta of the substantia nigra for a patient with suspected manganism (14). In this patient, however, it is reported that Parkinsonian symptoms began 10 years after his work ended. With this in mind, however, the literature editorializes that there is no single Parkinson disease and that pathology is not the gold standard for the diagnosis. This stems from the fact that genetic mutations have been uncovered that cause Parkinson disease but present in various clinical forms (156; 157; 74; 78).

Laboratory findings, biological exposure indices, imaging, and pathology. A patient with an elevated blood manganese level may have a hyperintensity in the basal ganglia that may be reversible if the blood manganese lowers. However, a positive MRI does not necessarily support neurotoxicity but only absorption of manganese and distribution to that location.

In idiopathic Parkinson disease, an MRI may reveal substantia nigra abnormalities. Patients with manganese exposure may have elevated blood manganese levels and abnormalities in the globus pallidus, which may normalize with reduced exposures (27). In a cross-sectional study conducted on smelting workers in China who were exposed to elevated concentrations of airborne manganese, results showed intensified MRI signals in the absence of clinical symptoms (70).

It was concluded that the MRI may be a useful tool in early diagnosis of manganese exposure. In 2005, Halatek and colleagues conducted a study to assess whether it is possible to use neurophysiological tests for the detection of early effects of exposure to low manganese concentrations (61). The subclinical effects were revealed in neurologic endpoints and abnormal results of neurophysiological tests, visual-evoked potentials, and EEG. This confirmed that these tests could be used for the detection of the early effects of exposure to low manganese concentration.

It was further reported by Pyatha and colleagues investigating Mn-induced Parkinson disease that positron emission tomography (PET) and single-photon emission computed tomography (SPECT) examinations of Parkinson disease patients’ dopaminergic neurons revealed a gradual loss of dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) (116). Pyatha and colleagues continued by noting Mn halts dopamine reuptake by mobilizing DAT receptors from the cell structure to intracellular compartments, prompting dopamine-generated cell toxicity.

The ACGIH has not established a biological exposure index for workers with manganese exposure. A correlation has been mentioned between urine manganese and mean air concentrations at work. The rapid clearance of manganese in blood limits its usefulness as a biomarker of toxicity. Also, blood manganese is influenced by body burden and may not reflect immediate exposure. Blood manganese has, however, been used in medical monitoring for manganese exposure. Reference ranges vary in laboratories. Many neurophysiology papers have correlated blood manganese with neurologic endpoints such as tremor at levels above noted at whole blood levels of 10 µg/l (125). Environmental manganese exposure from industrial pollution was found to lead to no difference in blood manganese when comparing a paired non-exposed town (126). Plasma-manganese was deemed a promising biomarker of current exposure to manganese in welders from a study of the Bay bridge welders. Authors commented that their results lend biological plausibility to proposed change of the manganese TLV-TWA of 20 mg by ACGIH (presently 0.2 mg/m3 or 200 µg/m3, see Table 3 above).

Hair has been used to measure manganese to confirm exposure, but results vary with degree of pigmentation of hair shaft. A paper in 1995 by Sierra and colleagues found elevated manganese in hair samples in automotive mechanics exposed to methyl cyclopentadienyl manganese tricarbonyl, MMT an antiknock additive in gasoline (140). Hair was also used as one of many biomarkers to measure exposure to manganese from environmental sources in Italy. Manganese H (MnH) was in fact associated with tremor, measured by a device called the “Tremor 7.0” of Danish Products Developments-DPD. Other studies correlated MnH with cognitive deficits, but these have been criticized for their methods. (91).

Rutchik and Ratner looked at age of onset of parkinsonism, noting that Mn exposed welders with parkinsonisms show an increase of misfolded α-synuclein in their serum exosomes (129). In their review, they found the data support the hypothesis that “exposure to Mn via welding fumes acts as a disease modifying factor in [Parkinson’s disease],” and thus, contribute to a younger age of onset of Parkinson disease. They concluded that “observations in welders and welders helpers that future studies employing serum exosomal α-synuclein as a biomarker of Mn effect should be designed to assess for the interactions between age at onset of Parkinson disease and exposure to Mn.”

Lucchini and Tieu examined the neurotoxic effects of manganese (Mn) exposure, particularly its role in inducing parkinsonism and potentially contributing to Parkinson disease (89). Occupational exposure to manganese, especially in industries like welding and mining, has been associated with an increased prevalence of parkinsonism, with exposure levels often exceeding the safety threshold of 20 to 25 ng/m³ in airborne particles. Long-term, low-level manganese exposure can extend manganese deposition to areas like the basal ganglia, including the substantia nigra, a brain region affected in Parkinson disease, which may explain the observed overlap between manganese-induced parkinsonism and idiopathic Parkinson disease. The review concludes that controlling manganese exposure is crucial for preventing its potential contribution to neurodegenerative diseases, highlighting the need for further research on low-level chronic exposure and its long-term effects.

Manganese toxicity has been treated with Ca EDTA with mixed results. Although manganese excretion does result, it is unclear if neurotoxicological consequences are improved. (64).

Levodopa has been noted to treat welders with what resembled idiopathic Parkinson disease (75) and reported ineffective in those with atypical Parkinsonism.

Para-aminosalicylic acid has also been used in Chinese patients with reported success but has not been replicated (71). This same group reported that Para-aminosalicylic acid may be helpful as a chelator as it reduced levels of copper and iron resulting from manganese exposure in Sprague Dawley rats (165).

Mercury (Hg)

Points for the clinician. Acute health effects for mercury exposure are different depending on the type of mercury--organic, inorganic, or vapor. These effects may range from paresthesias to death. Neuropsychological consequences, specifically visual-spatial and short-term memory problems, sparing language, may be secondary to low-level exposures, occupational or environmental, to all three forms of mercury. Renal abnormalities may coexist with neurologic consequences. Tremor, color vision changes, and peripheral neuropathy have been associated with occupational exposures to inorganic mercury whereas visual-field deficits and occipital lobe pathology have been associated with environmental exposures to organic mercury. MRI findings such as frontoparietal white matter changes and atrophy may be consistent with mercury exposure. Studies have found that a significant number of patients exhibiting symptoms of idiopathic axonal neuropathy are the result of increased blood mercury levels (79). Blood mercury testing is the best method to assess recent inorganic or elemental mercury exposure and can differentiate organic versus inorganic species. Nerve conduction velocity (NCV) results attributed to elemental mercury include low-amplitude sensory responses and normal or borderline-low amplitude motor responses. Distal latencies may be slightly prolonged, which is consistent with loss of large myelinated axons. EMG needle examination may show chronic neurogenic changes, most notable in the intrinsic foot muscles (84). Serial urine testing is appropriate for industrial assessment. Chelation is recommended for cases of high-level acute exposures.

Background and sources of exposure. Mercury is extracted from cinnabar ore, HgS, and exists in three oxidative states: Hg0 (zero valent, elemental or metallic mercury), two forms of inorganic mercury (Hg+1 [univalent, mercurous mercury, Hg2Cl2] and Hg+2 [divalent, mercuric mercury, HgCl2]), and organic mercury such as methyl mercury, which is an extremely toxic form.

Cross-sectional studies have focused on neurobehavioral effects in fluorescent lamp and thermometer workers exposed to elemental mercury vapors, chloralkali workers with exposure to mercuric chloride, and outbreaks of methyl mercury poisoning in Japan in the 1950s (113), Iraq in the 1970s (11), and the United States (113). Neurophysiological testing, EEG, EP, and EMG as well as tremometer have been used to assess patients exposed to various states of mercury. “The Mad Hatter” in the play, Alice in Wonderland is thought to be suffering from the effects of mercury from the felt hat that he was wearing.

Another study reviewed the electronic records of newly seen patients with neuropathy between July 2013 to June 2014 (n = 147). Of those evaluated, 37 had idiopathic axonal neuropathy (IAN), 19 had diabetic neuropathy, 32 had chronic inflammatory demyelinating neuropathy, and 37 had small-fiber axonal neuropathy. Blood mercury levels were elevated in 18% of patients with idiopathic axonal neuropathy and 9% in patients with small-fiber axonal neuropathy, as compared with none with chronic inflammatory demyelinating neuropathy or diabetic neuropathy. Findings were statistically significant between idiopathic axonal neuropathy and chronic inflammatory demyelinating neuropathy (p = 0.02) (79).

Acute occupational and environmental exposures. Cultural and ritual use of metallic mercury may lead to acute, high levels of mercury vapor exposure. Professional gilders use a mix of liquid mercury with gold powder to create a blend of gold to be applied to shrines. This process results in a substantial release of mercury vapor leaving the gold to cover the desired surface. Three men, working with this mixture for 6 to 8 hours a day for approximately 20 to 50 days, presented with neuropsychiatric disorders after returning home. Symptoms included anxiety, memory weakness, insomnia, depression, weight loss, persistent cough, and dyspnea. Urine mercury levels ranged from 326 to 760 ug/L. Chest x-ray, NCV, and EMG were normal. Following chelation therapy, the patients recovered clinically, and urine mercury concentrations declined to nontoxic levels (< 25 ug/L) (150).

Acute exposure to inorganic mercury from ingestion has led to persistent CNS symptoms after respiratory, gastrointestinal, and urological symptoms resolved. In some, encephalopathy has resulted secondary to renal failure. Ingestion of a laxative with mercurous chloride, pork with methyl mercury after hogs ingested contaminated feed grain, and fish in Japan have led to these untoward effects. (35; 20).

Inhalation exposure to mercury vapor in occupational and environmental settings has led to flu-like symptoms with neurologic presentations. Chelation has improved some patients’ conditions. Residents of a building where silver recovery from amalgams was taking place in the basement using a furnace led to a number of deaths. A Guillain-Barré-like syndrome was reported in three children who lived in a home where elemental mercury was spilled. One child recovered after chelation. Tremors and myoclonus were noted in workers with short-term exposure to mercury vapor who were working with metal pipes of a mercury cathode used as a catalyst to produce chlorine. Neurologic symptoms persisted documented by neuropsychological testing.

In another pediatric case study, a 14-year-old boy was seen at a rheumatology clinic with severe back and extremity pain, weight loss, and weakness. Initial labs and MRI were all normal, but EMG showed mild neurogenic involvement on L2-S1. Clinical investigation discovered he had played with a bottle of mercury on a construction site two months prior. During follow-up, blood mercury levels were found to be significantly high, and he was treated with dimercaptosuccinic aside (DMSA), with reduction in complaints over the following months (73).

A chemist, Dr. Karen Wetterhahn, experienced a rapidly progressive neurologic syndrome that began five months after exposure and included cognitive impairment that led to coma and death one year after dermal exposure to dimethylmercury. Her problem went undiagnosed until late in the course of her illness. This case emphasized the risk of experimentation with this dangerous chemical (19).

Chronic occupational and environmental exposures. Peripheral neuropathy is a significant effect of both inorganic and organic mercury exposure. Please refer to the article on mercury neuropathy for a more comprehensive review of this topic. Most literature describing these cases is from the chloralkali industry where inorganic mercury is used.

The two most famous environmental disasters of mercury toxicity were in Japan and Iraq. In Japan, residents ingested contaminated fish, and clinical manifestations included difficulty with concentration, memory loss, depression, intellectual deterioration, and, in some, coma and death (146). Cerebellar signs were first noted, and 2500 residents were affected. Constriction of visual fields, sensory disturbances, muscle atrophy, and cognitive disturbances were the most prominent symptoms; deafness was also reported. Symptoms worsened over 3 to 10 years. Prenatal exposure led to brain damage. In Iraq, neurocognitive symptoms appeared weeks to months after intake of food accidentally made from grain treated with methylmercury (32). These grains were intended for planting and not eating. Some victims have no untoward effects even though they had ingested lethal doses. A number of cases of mental retardation following exposure in pregnant females during critical developmental periods were noted.

Chronic occupational inhalation exposures to vapors of elemental mercury occur in thermometer factory workers, jewelers, dentists, gold miners, and chloralkali workers. Reports of symptoms of blurred vision, weakness, memory loss, and irrational behavior as well as headache and cognitive challenges are noted in various papers (152; 149; 07; 161). Examination findings have included visual field abnormalities, nystagmus, tremor, cerebellar signs, diminished reflexes, and sensory loss. Nerve conduction velocity tests have revealed peripheral neuropathy, and MRI changes have indicated diffuse and focal white matter disease; neuropsychological abnormalities are documented. Language and long-term memory are typically unaffected.

Study data of artisanal small-scale gold miners from the Philippines, Mongolia, Tanzania, Zimbabwe, and Indonesia were assessed for mercury exposure and body burden. Health assessments were pooled, and urine, blood, and hair samples were analyzed for mercury (N = 1252). Results showed mean mercury concentrations in all exposed groups were elevated above threshold limits. Amalgam burners, miners who smelt the mercury-gold mixture and vaporize off the mercury, showed the highest levels. Researchers concluded that chronic mercury intoxication with tremor, ataxia, and other neurologic symptoms, along with a raised body burden of mercury, was clinically diagnosed in artisanal small-scale mining areas (22).

Biernat and colleagues compared tremor resulting from mercury vapor exposure to that of Parkinson disease and essential tremor (16). Tremor was noted to be more intense in a high-frequency window, 6.6 to 10 Hz, compared to those with Parkinson disease who had more intensity noted in the lower frequency window, 3 to 6.5 Hz whereas those patients tested with essential tremor had intensity noted in both windows. Mercury in urine did not correlate with intensity of tremor in the high frequencies, however.

A review of several studies that included more than 3000 workers chronically exposed to mercury between the years 1950 to 2015 found that urine mercury levels from less than 50 ug/L to greater than 200 ug/L showed increased frequency in tremor, impaired coordination, abnormal reflexes on physical examination, and reduced neurobehavioral tests of tremor, manual dexterity, and motor speed (47). The data suggest that response thresholds of urine mercury levels are about 275 ug/L for physical exam findings and about 20 ug/L for neurobehavioral outcomes.

Environmental exposure to fish contaminated with mercury in the Amazon has reportedly led to neurobehavioral effects (57). In widespread informal gold mining in the Amazon Basin, mercury is used to capture the gold particles as amalgam. Releases of mercury to the environment have resulted in the contamination of freshwater fish with methylmercury. Neuropsychological tests of motor function, attention, and visuospatial performance showed decrements associated with the hair-mercury concentrations.

In a review of the literature, Panzenhagen and colleagues looked at studies of the effects of methylmercury (MeHg) on neurodevelopmental biomarkers (111). Their investigation revealed that studies on populations with significant mercury exposure, such as those who consume large quantities of fish from mercury-contaminated waters, show increased risks of developmental delays, cognitive impairments, and neurobehavioral deficits in children. These include reduced IQ, attention deficits, and impaired fine motor skills. Studies further showed that even low levels of prenatal exposure to mercury can result in long-term developmental and neuropsychological consequences, including learning disabilities and behavioral disorders. These effects may persist throughout life, as the developing brain is particularly susceptible to the disruptive effects of toxic agents.

A 2019 Norwegian literature review of dentists and dental personnel exposed to mercury in the occupational setting was done to evaluate the relevance between mercury exposure in the dental industry and idiopathic disturbances in motor functions, cognitive skills, and affective reactions, as well as dose-response relationships (18). This study looked at dentists, dental assistants, and dental students from various countries. In multiple studies reviewed, neuropsychological effects in attention, psychomotor speed, cognitive flexibility, visual memory, short-term memory, visual memory, and visuomotor coordination were noted. In another study of neuropsychological performances in low-level mercury-exposed female dental workers, results showed that even chronic subtoxic levels of inorganic mercury can cause mild modifications in the short-term nonverbal recall, generally increased distress, psychoticism, and anxiety. In all, these researchers concluded that dental workers exposed to chronic, low levels of metallic mercury resulted in a significant occurrence of neurologic and sensory symptoms. Of these, memory loss was noted as potentially the most important.

Santos-Sacramento and colleagues conducted a systematic review of mercury’s neurotoxic impact on individuals in the Amazon with exposures to mercury within three river basins (Tapajos, Rocantins, and Madeira) (131). Their findings showed mercury body burden was two to 10 times higher than recommended with neurologic deficits noted in cognitive function, vision, motor function, somatosensory, and emotional deficits.

Pyatha and colleagues did also report that patients exposed to mercury through dental amalgam fillings are at a six-fold increased risk for the development of Parkinson disease compared to nonexposed patients (116).

Mercury and Alzheimer disease. Patients with Alzheimer disease were assessed for mercury concentrations in the brain. Although elevated blood mercury was found in patients with Alzheimer disease compared to controls, a number of authors have concluded that there does not appear to be a neurotoxic factor in the pathogenesis of Alzheimer disease (133). Authors postulated that this difference may be a release of mercury from brain tissue with neuronal death.

Inconsistencies in the literature for blood urine, hair, nails and CSF for mercury was acknowledged in a review of the literature by Mutter and colleagues in 2010; the authors also noted that inorganic mercury in vitro and in animal models reproduces all pathological changes seen in Alzheimer disease (104). This paper hypothesized that mercury’s high affinity for selenium and selenoproteins may lead to neurodegenerative disorders via disruption of redox regulation or that it may play a role as a co-factor in the development of Alzheimer disease.

Laboratory findings, biological exposure indices, imaging, and pathology. Blood plasma concentration of mercury is the best method of assessing the recent exposure to inorganic and elemental mercury. The plasma to red blood cell (RBC) ratio can differentiate the organic or inorganic type of mercury in the blood. A ratio of 1:1 indicates the inorganic mercury exposure because it is equally distributed between plasma and RBC. A ratio of 1:10 suggests an organic source of mercury exposure. Serial urine mercury levels may be appropriate in industrial settings and in large populations; however, the severity of intoxication cannot be ascertained by a given individual from a random sample.

A 24-hour urine mercury test is the best method to assess recent inorganic mercury exposures whereas a blood mercury test better assesses recent organic mercury exposure. Albers in 1988 found that those with urine mercury levels above 850 µg/l had a two to three times higher chance of detectable peripheral neuropathy (03). Associations between mercury and neuropathy have been reported in occupational exposures with urine mercury levels in the range of 500 µg/l or greater, however. Franzblau and colleagues have been critical of these conclusions (49). Dose as measured by urine mercury levels of greater than 50 µg/l was associated with impaired neuropsychological performance in chloralkali workers (98).

Urine mercury levels have been documented in the general population in the United States by NHANES and based on a spot urine, the mean mercury level among women 16 to 49 years of age was 1.55 µg/l based on 1748 individuals (96). NHANES data combined with that from the U.S. Department of Agriculture’s Food Intakes Converted to Retail Commodities Database (FICRCD) examined 49 different food and environmental metal exposure. Using the results from blood and urinary biomarkers, researchers estimated that 4.5% of the variation of mercury among children and 10.5% among adults is explained by diet. A previously unrecognized association between rice consumption and mercury exposure was found (36).

The United States Environmental Protection Agency, the World Health Organization (WHO), and Health Canada have revised their mercury intake guidelines. Because nearly all fish and shellfish contain traces of mercury, recommendations are provided for pregnant women, nursing mothers, and young children for selecting and eating fish and shellfish. Recommendations are summarized for women who are or may become pregnant and young children so that they can be confident to enjoy the benefits but limit the harmful risks of mercury toxicity. Advice includes: (1) do not eat shark, swordfish, king mackerel, or tilefish because they contain high levels of mercury and (2) eat up to 12 ounces (two average meals) a week of a variety of fish and shellfish that are lower in mercury. Five of the most commonly eaten fish that are low in mercury are shrimp, canned light tuna, salmon, pollock, and catfish. Another commonly eaten fish, albacore (“white”) tuna, has more mercury than canned light tuna. So, when choosing your two meals of fish and shellfish, you may eat up to 6 ounces (one average meal) of albacore tuna per week. Check local advisories about the safety of fish caught by family and friends in your local lakes, rivers, and coastal areas. If no advice is available, eat up to 6 ounces (one average meal) per week of fish you catch from local waters, but don’t consume any other fish during that week.

MRI studies were obtained in thermometer workers with cognitive impairment and significant exposures. Cortical atrophy and punctate white matter changes were noted in the frontal and parietal lobes (162).

Treatment. Treatment for mercury neurotoxicity includes supportive therapy as well as chelation agents that have been mentioned for metals above, including lead, British anti-Lewisite (BAL), penicillamine (DPCN), and succimer (DMSA). These have been used in cases where dramatic neurotoxicity is confirmed from mercury. Side effects have previously been mentioned and include hypersensitivity, renal effects, and aplastic anemia. Some of these contain thiol units, which compete with groups on proteins for the binding effects of mercury, removing them from general circulation. Hemodialysis may also be used in cases where renal function is compromised. L-cysteine may significantly improve the ability of hemodialysis to remove circulating mercury (153). DMSA and DMPS are found to be less toxic and more efficient than BAL in the treatment of heavy metal poisoning, and they are available in capsules for oral use (01). Additionally, DMSA taken orally has been approved by the U.S. Federal Drug Administration (FDA) for the treatment of mercury poisoning (105).

A consensus paper regarding out-of-hospital management was published in 2008 (28).

Chelation with oral 2,3 dimercapto 1 propanesulfonate (DMPS) has been dramatically helpful in individual and case series. Bradberry reported reversal of neurologic damage with a 5-day course of DMPS chelation in a jeweler who presented with a 1-year progressive neurologic syndrome after five years of exposure to mercury vapor (26). In 2011, Liu and colleagues reported 92 cases of occupational and non-occupational mercury exposure, mainly through respiratory tract, digestive tract, and skin absorption (85). Diverse neurologic presentation has been detected in these subjects. After starting sodium DMPS therapy, the neurologic symptoms were gradually alleviated within 3 months.

Thallium (Tl)

Points for the clinician. The rare presentation of thallium toxicity from rodenticide ingestion or occupational inhalation exposure includes alopecia, ataxia, seizures, motor neuropathy, brain edema, and gastroenterological, cardiac, and neurologic sequelae. Urine thallium has been reported in these cases. Blood thallium represents very recent exposures. Hair testing may be helpful to rule out chronic exposures. Prussian blue sequesters heavy metal ions and acts as an antidote. The Centers for Disease Control warns readers that signs of hair loss and painful neuropathy should prompt clinical considerations of thallium poisoning.

Background and sources of exposure. Thallium is a rare element found in rock formations containing feldspar and mica. It is present in trace amounts and exists in oxidative states, Tl+1 (thallous) and Tl+3 (thallic). Thallium was used on a large-scale as a rodenticide and insecticide. Incidents of toxicity led to the ban of thallium-based rodenticides in North America in the 1970s; however, worldwide use is increasing. Thallium is used in manufacturing electronic devices, switches, and closures, primarily in the semiconductor industry. It is also used in the manufacture of special glass and for certain medical procedures. Toxicity results from incidental ingestions because it is odorless, colorless, and tasteless and is popular as a homicidal agent. Skin contact, inhalation, or snorting a powder mistaken for cocaine has been described.

Acute and chronic occupational and environmental exposures. Clinical symptoms of thallium exposure have been reported to include vomiting, diarrhea, temporary hair loss, and even death (ATSDR ToxFAQs 1995).

Neurotoxicological sequelae have been reported in those with accidental ingestions in the workplace, intentional poisonings, and occupational inhalation from those handling raw materials. Seizures, transient loss of consciousness, and persistent flaccid paralysis as well as peripheral neuropathy and cerebellar ataxia have been reported from short-term exposures. An important clinical feature differentiating thallium neuropathy from other toxic neuropathies is the coexisting alopecia presenting in the second week after acute intoxication (84). Abdominal pain, diarrhea, and tingling in all four extremities have been commonly reported acutely, even from low-level exposures. In one case with severe sensorimotor neuropathy, an autonomic neuropathy with tachycardia followed but a complete remission was reported. Another case reported choreiform movements of the right arm and leg, ataxia, and a mental status change. EEG revealed left lateralizing slowing, and the patient’s condition responded to levodopa. Chronic exposures have led to optic neuritis. Research on a group of occupationally exposed workers revealed that abnormal electroretinograms were noted preclinically (108). EMG has been known to reveal mild motor changes.

Zhu and colleagues present a case of attempted murder by acute thallium poisoning in a 45-year-old woman (166). The patient presented with an 8-day history of pain and weakness in the bilateral arms and legs, as well as gastrointestinal symptoms. The patient exhibited albuminocytological dissociation in the CSF, which is typically seen in Guillain-Barré syndrome. Diagnostic tests revealed elevated thallium levels in the blood at 0.6 μg/mL and in the urine at 8.0 μg/mL, whereas the thallium concentration in the CSF was 0.0028 μg/mL. Symptoms included alopecia and vision impairment that progressively worsened. Despite treatment with Prussian blue and other interventions, her visual impairment persisted, although her limb weakness and sensory symptoms improved over time.

A 2019 article reported on a 42-year-old female in a coma due to severe thallium poisoning. On admission to the ICU, she was on her 44th day of coma, and blood and urine thallium concentrations were recorded at 380.0 and 2580.0 ng/mL, respectively. She was diagnosed with toxic encephalopathy induced by thallium poisoning. She was subsequently treated with Prussian blue (6600 mg/d for 15 days) combined with plasma exchange and other supportive treatments. By the 13th day, thallium concentrations in blood had decreased to 0 ng/mL, and she gradually regained consciousness. Recovery was slow, but after 37 months, she had mostly recovered (82).

Laboratory findings, biological exposure indices, imaging, and pathology. Medical tests are available to measure levels of thallium in blood, urine, and hair. The most reliable diagnostic procedure is a 24-hour urine test. Urinary thallium concentrations are representative of inhalation or dietary thallium. Exposures causing less than 5 µg/l of urinary thallium are unlikely to cause adverse health effects as unexposed population have been reported to have around 1 µg/l. Concentrations of 5 to 500 µg/l may possibly cause effects; those above 500 µg/l have been associated with clinical poisoning. Blood tests are not dependable because thallium stays in the blood only a short time. Retrospective monitoring is possible with hair.

Treatment. Avoidance of exposure is the sole prevention of toxicity from thallium. Accidental ingestion in children of candy like pesticide pellets results from mistaken identity of the poison. Those with routine occupational exposure should be periodically evaluated and screened.

Once toxicity is acknowledged, prevention of further exposure is the first step. Gastric lavage is important if ingestion has recently occurred because absorption occurs within 24 hours. Enhanced fecal elimination requires gastric lavage as soon as possible, forced diuresis of 8 to 12 liters/24 hours should continue until urine thallium is lower than 1 mg/24 hours. Most cases present after this window of time, and this enhancement of elimination then is the primary focus of treatment. As constipation would hinder this, a laxative is often initiated. Prevention of absorption is instigated with activated charcoal or oral Prussian blue, leading to forced diuresis and hemodialysis.

Prussian blue should be administered twice daily (10 g suspended in 100 ml 15% mannitol as a laxative, if necessary, through a duodenal tube) until urinary thallium excretion is lower than 0.5 mg/24 hours; and intermittent hemoperfusion should be conducted, using activated charcoal adsorbents, in the early phase of intoxication (up to 48 hours after ingestion). Using Prussian blue alone, the half-life was three days, but when forced diuresis was added, half-life was 2 days; combined with hemoperfusion, the half-life was 1.4 days.

Intravenous administration of potassium may also be indicated as it has a positive effect on urinary excretion. Care must be taken, however, because this may mobilize thallium faster than it can be eliminated.

Tin (Sn)

Points for the clinician. Occupational and accidental exposures to organic tin cause significant neurotoxicity. Trimethyltin (TMT) may cause mental status change with persistent neuropsychological and EEG abnormalities. Accidental triethyltin (TET) exposure may lead to death secondary to brain edema. In survivors, persistent EEG, MRI, and neuropsychological changes are common. Potassium alteration is often noted. Urine organotin is used to assess occupational exposures. MRI changes include persistent leukoencephalopathy.

Background and sources of exposure. Tin is obtained from cassiterite (SnO2) and teallite, which are mined in the United States but more so in other parts of the world. Reclamation of tin scrap metal from cans and containers accounts for 25% of the tin used in the United States. Tin exists in two oxidative states, +2 and +4, as well as bivalent and quadrivalent inorganic compounds, named either stannous tin or stannic tin. Inorganic tin salts are less toxic than organotins. These vary in toxicity due to chemical structure. Occupational exposure risks exist for research chemists. Triphenyltin (TPhT) is used as a molluscide, antifouling agent, fungicide, and rodent repellent, and neurotoxic health effects have been reported from accidental exposures. Trimethyltin(TMT) and triethyltin (TET) are associated with neurotoxicity and have been used to study mechanisms of neuronal degeneration and hippocampal neurobehavioral functions in animals, such as memory and dementia and cerebral edema, cerebral myelinopathy, and neurodegeneration.

Acute occupational and environmental exposures. Severe acute exposure causes irreversible behavioral impairments. Some case reports have documented clinical presentations.

Occupational short-term, high level TMT exposure presents with memory deficits, confusion, inappropriate affect, and disorientation along with persistent neuropsychological effects. EEG slowing as well as low-voltage spikes and theta have been reported. Liver function has been reported to become abnormal during high-level exposures but has recovered when chelation has been used. Axonal neuropathy has also been documented with both motor and sensory amplitude loss. Dimethyltin (DMT), thought to be less toxic than TMT has been known to be methylated in vivo, increasing toxicity. TMT may also lead to acute renal failure, resulting in urinary elevation of potassium.

Chronic occupational and environmental exposures. Neurologic sequelae have been reported from both TMT and TET. Association of symptoms and urine organotin has been inconsistent but seems to depend on severity. Severe exposures to TMT have been chronicled, resulting in neurologic and psychiatric symptoms, such as headache, tinnitus, defective hearing, changing disorientation, depression, and aggressiveness symptoms. Seizures and sensory neuropathy along with laboratory findings including low levels of serum potassium, leucocytosis, and elevated transaminases has been noted. Treatment has not been effective. Long-term prognosis for those with severe consequences has been deemed poor. Besser in 1987 reported cases that also had significant hearing loss and cerebellar syndromes with gaze-evoked nystagmus and ataxia. In these cases, severity of symptoms did, in fact, correlate with urine organotin between day 4 and 10 (15).

TET neurotoxicity most famously occurred when 100 people died in France in the 1950s. Two hundred others fell ill when an antibacterial skin agent was prepared with the incorrect salt--in some, a lethal dose of TET. Four days after use, many developed headache and were found to have elevated intracranial pressure. Some had changes in consciousness and seizures with EEG changes. Slow improvement occurred in some. Those who perished were found to have significant brain edema.

Laboratory findings, biological exposure indices, imaging, and pathology. Because of the aforementioned alterations in potassium and liver function as well as changes noted in neutrophils reported by Colosio in 1991, complete blood count and chemistries are appropriate in this evaluation (33). Excess urinary organotin would suggest excess body burden and severity of symptoms correlated with the maximal urinary excretion (46).

Urine organotin determinations can be performed using atomic absorption spectroscopy after toluol extraction. Patients with persistent clinical features secondary to organotin have been found to have urine organotins greater than 400 ppb. Baseline urine and blood levels are appropriate for those who commonly work with these agents. Brain edema has been noted in those who have suffered fatalities from TET exposure (34).

Necropsy in cases of death from TMT found changes in the temporal cortex, basal ganglia, and pontine nuclei (15; 77).

Treatment. Importantly, baseline blood and urine levels should be determined for workers at risk for exposure in the workplace. For those with abnormal urine and blood who have health effects from exposure, reducing body burden of tin is the first item of treatment. If skin or mouth is the avenue of exposure, washing with water to remove the salts is indicated. Ingested tins can be diluted by this method as well.

D- penicillamine has been used but has not been shown to improve patients’ outcomes with severe neurologic effects from organotin exposure. A combination of D-penicillamine and dimercaprol was not shown to increase urinary excretion of urine organotin. D-penicillamine and plasmapheresis was used following exposure in severely compromised patients who did survive, suggesting its effectiveness (15).

Treating seizures may be an issue, and carbamazepine and valproic acid treatment should be instituted and possibly continued prophylactically if re-exposure to TMT is likely as TMT selectively effects hippocampal neurons and may incite limbic seizures, proven to be effectively treated by these anti-seizure agents.

For those with TET exposure, prevention of cerebral edema and herniation must be instituted urgently. Restriction of water intake may be sufficient if no clinical symptoms are present after a confirmed exposure. Osmotic diuretics or may be indicated if symptoms are present.

Prognosis and complications

Recovery from the neurologic conditions caused by metal neurotoxicity varies greatly. Following removal from the source, neuropsychological function often improves or remains stable. However, some exposures, such as childhood lead exposure, are known to cause lasting or permanent deficits. Abstention from cigarettes, recreational drugs, and alcohol is strongly advised, as these substances exacerbate the effects of heavy metal toxicity.

Clinical vignette

Case 1. Lead neuropathy, movement disorder and dementia. A 57-year-old man worked for 20 years coating wire. He had frequently used his bare hands to dip wire in an acid bath and then a tub of molten lead. These tubs were heated and gave off fumes and smoke. He did not use a mask and often ate and drank while using his dominant hand to dip and thread wire. He often complained of chronic stomach problems and had noted a metallic taste in his mouth, abdominal cramps, difficulty swallowing, and nausea for three years.

Over a period of time, his family noted that he had become more withdrawn and would become forgetful. His gait became stiff and hesitant, and writing became difficult. His speech was hesitant. Exam revealed rigidity of all extremities, left greater than right, and increased reflexes without pathological reflexes. At rest, he had a flexed dystonic posture of all four limbs but no tremor. A blood lead level of 160 µg/ml (normal is less than 30 for occupationally exposed workers) was noted as was a hematocrit of 45%. He had no chronic diseases. Atrophy was noted in the left bicep and deltoid, and some fasciculations were noted. EMG revealed denervation in both upper and lower extremity muscles. Atrophy of the interossei was present, yet motor nerve conduction velocities were normal for both ulnar nerves.

CaEDTA infusion was given over 3 days at 25 mg/kg. A urine lead level was 640 µg/L; a second collection was 1560 µg/L; and a third was 1080 µg/L. Two years later he was asymptomatic and was able to again serve as a church treasurer. Muscle tone returned to normal (45).

Case 2. Chronic mercury exposure and dementia. A 48-year-old man was exposed to vapors from elemental mercury for 3.5 years in a thermometer factory. He often vacuumed mercury off the floor, disassembled machines, and operated a crusher that separated broken glass for reuse. At one point he sought medical attention when he suffered from a laceration at work. He explained to the physician that he had symptoms during the past 2 to 3 years including blurred vision, eye pain, weakness, memory loss, and irrational behavior. An elevated urine mercury was measured at 690 µg/L. Chelation with penicillamine was started, and he was removed from his job. Follow-up urine mercury was 17 µg/L. Five months later, he had a neurologic exam that revealed nystagmus, tremor, diminished reflexes, and diminished sensation to pain. Nerve conduction studies revealed mild peripheral neuropathy. MRI revealed diffuse and focal white matter disease that did not resemble multiple sclerosis. Neuropsychological testing revealed deficits in attention and executive function including preservation on all tasks. Facial matching and memory tests were abnormal (162).

Prevention

Prevention of exposures in the workplace is extremely important. OSHA provides specific health and safety standards and guidelines that can be used to prevent occupational exposure to chemicals and related toxic exposures. Many options can be used for prevention depending on the situation. They can range from specific equipment usage to worker education. However, the effectiveness of these options can vary widely and must be chosen accordingly.

Substitution of a less or nonhazardous chemical is the most effective protective measure. However, the risk and benefits of substituting a less hazardous chemical for one with better chemical properties and less costliness for the process is a decision reserved for management. Engineering controls and devices are another option for a company. These include ventilation systems, ergonomic changes, safer tools, and the isolation of areas for dangerous exposures. It also includes scheduled maintenance of machinery to ensure its proper and safe functioning. Job re-design and work practice alternatives are a third option. This may reduce stress on the job, improve work hours, or arrange for rotation in schedules. Work practices directed at the workers are less effective because they do not reduce the absolute potential for exposure.

Education and advice about work hazards is essential but not always successful in reducing accidents and exposures. For example, the proper use of personal protective equipment can be very effective. However, use of such equipment commonly results in limited protection for individual workers because these garments may not fit properly or may be uncomfortable to wear. As a result, noncompliance may be a major problem, leading to dangerous situations for the workers.

Another important option, but a less effective one, is to conduct preplacement medical examinations. These can be used to identify those workers with risk factors for certain medical conditions and reduce their exposures by reassigning work. Screening and surveillance is categorized as a secondary prevention option because these processes are aimed at identifying or documenting early adverse health effects. If appropriate to the situation, using a combination of different options should be considered and can provide the best prevention measure.

Differential diagnosis

Etiologies of neurologic conditions are diverse. These include tumors, infection, and autoimmune disease as well as other toxic or metabolic syndromes, vascular conditions, and idiopathic neurodegenerative diseases or congenital diseases. For example, other causes of memory loss are Korsakoff syndrome or bilateral temporal lobe damage resulting from anoxia, encephalitis, head trauma, or surgical procedures. In such instances, other cognitive functions are intact, whereas in dementia they are not. The reader is referred to the article on dementia and other neurologic diagnoses for information on the differential diagnosis and the standard of care.

A diagnosis of occupationally or environmentally induced neurologic illness or injury is determined at only after all other causes of these neurologic conditions are considered. The diagnosis of a heavy metal dementia, movement disorder, neuropathy, or other neurologic disease is made through a careful history, physical exam, and use of appropriate tests. This includes obtaining exposure data, estimating the dose and duration of exposure, and comparing this dose with those that are published by regulatory agencies. Comparison of these data to available research from individual, group, or animal data can help identify the specific health effects related to chemical exposures that a patient may be experiencing. Conducting this type of risk assessment is part of the algorithm when considering exposure as a possible etiology. In addition, working with a board-certified occupational and environmental physician, toxicologist, industrial hygienist, or risk-assessment scientist is recommended when managing such a patient.

The diagnosis is often a diagnosis of exclusion. Although some neurotoxins may lead to a diagnosis that also involves other organs, some may mimic a routine neurologic diagnosis, and no specific features are apparent, often making this process challenging.

References

01: Aaseth J, Skaug MA, Cao Y, Andersen O. Chelation in metal intoxication--Principles and paradigms. J Trace Elem Med Biol 2015;31:260-6. PMID 25457281
02: Alasfar R, Isaifan R. Aluminum environmental pollution: the silent killer. Environ Sci Pollut Res 2021;28(33):44587-97. PMID 34196863
03: Albers JW, Kallenbach LR, Fine LJ, et al. Neurological abnormalities associated with remote occupational elemental mercury exposure. Ann Neurol 1988;24(5):651-9. PMID 2849369
04: Alfrey AC, LeGendre GR, Kaehny WD. The dialysis encephalopathy syndrome. Possible aluminum intoxication. N Engl J Med 1976;294(4):184-8. PMID 1244532
05: Andrade LG, Garcia FD, Silva VS, et al. Dialysis encephalopathy secondary to aluminum toxicity, diagnosed by bone biopsy. Nephrol Dial Transplant 2005;20(11):2581. PMID 16105866
06: Andruska KM, Racette AB. Neuromythology of manganism. Curr Epidemiol Rep 2015;2(2):143-8. PMID 26046010
07: Anger WK. Worksite behavioral research. Results, sensitive methods, test batteries and the transition from laboratory data to human health. Neurotoxicology 1990;11(4):627-717. PMID 2087287
08: ATSDR. Agency for Toxic Substance and Disease Registry. ToxFAQs for Thallium. Available at: ATSDR Toxic Substances Portal - Thallium. 1995.
09: Baker EL, Feldman RG, White RA, et al. Occupational lead neurotoxicity: a behavioural and electrophysiological evaluation. Study design and year one results. Br J Ind Med 1984;41(3):352-61. PMID 6743583
10: Baker EL, White RF, Pothier LJ, et al. Occupational lead neurotoxicity: improvement in behavioural effects after reduction of exposure. Br J Ind Med 1985;42(8):507-16. PMID 4016002
11: Bakir F, Damluji SF, Amin-Zaki L. Methylmercury poisoning in Iraq. Science 1973;181(96):230-41. PMID 4719063
12: Beckett WS, Moor JL, Keogh JP, Bleeker ML. Acute encephalopathy due to occupational exposure to arsenic. British J Ind Med 1986;43(1):66-7. PMID 3947565
13: Bellinger D, Sloman J, Leviton A. Lower level lead exposure and children's cognitive function in the preschool years. Pediatrics 1991;87:219-27. PMID 1987535
14: Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 1973;20(4):415-55. PMID 4272516
15: Besser R, Kramer G, Thumler R, Bohl J, Gutmann L, Hopf HC. Acute trimethyltin limbic-cerebellar syndrome. Neurology 1987;37(6):945-50. PMID 3587645
16: Biernat H, Ellias SA, Wermuth L, et al. Tremor frequency patterns in mercury vapor exposure compared with early Parkinson’s disease and essential tremor. Neurotoxicology 1999;20:6:945-52. PMID 10693975
17: Bilinska M, Brzezowska D, Koszewicz M, Antonowicz-Juchniewicz J, Modrzycka T. Subclinical lead neuropathy. Pol Merkuriusz Lek 2004;17(99):244-7. PMID 15628050
18: Bjorklund G, Hilt B, Dadar M, Lindh U, Aaseth J. Neurotoxic effects of mercury exposure in dental personnel. Basic Clin Pharmacol Toxicol 2019;124(5):568-74. PMID 30589214
19: Blayney MB. The need for empirically derived permeation data for personal protective equipment: the death of Dr. Karen E Wetterhahn. Appl Occup Environ Hyg 2001;16(2):233-6. PMID 11217716
20: Bluhm RE, Bobbitt RG, Welch LW, Wood AJ, Bonfiglio JF, Sarzen C, Heath AJ, Branch RA. Elemental mercury vapour toxicity, treatment, and prognosis after acute, intensive exposure in chloralkali plant workers. Part I: History, neuropsychological findings and chelator effects. Hum Exp Toxicol 1992;11:201-10 PMID 1352115
21: Bolla-Wilson K, Bleecker ML. Neuropsychological impairment following inorganic arsenic exposure. J Occup Med 1987;29:500-3. PMID 3612324
22: Bose-O’Reilly S, Bernaudat L, Siebert U, Roider G, Nowak D, Drasch G. Signs and symptoms of mercury-exposed gold miners. Intl J Occ Med Environ Health 2017;30(2):249-69. PMID 28366955
23: Bowler RM, Beseler CL, Gocheva VV, et al. Environmental exposure to manganese in air: Associations with tremor and motor function. Sci Total Environ 2016;541:646-54. PMID 26437342
24: Bowler RM, Harris M, Gocheva V, et al. Anxiety affecting parkinsonian outcome and motor efficiency in adults of an Ohio community with environmental airborne manganese exposure. Int J Hyg Environ Health 2012;215(3):393-405. PMID 22112744
25: Bowler RM, Nakagawa S, Drezgic M, et al. Sequelae of fume exposure in confined space welding: a neurological and neuropsychological case series. Neurotoxicology 2007;28(2):298-311. PMID 17169432
26: Bradberry SM, Sheehan TM, Barraclough CR, Vale JA. DMPS can reverse the features of severe mercury vapor induced neurological damage. Clin Tox 2009;47(9):894-8. PMID 19852623
27: Calne DB, Chu NS, Huang CC, Lu CS, Olanow W. Manganese and idiopathic parkinsonism. Neurology 1994;44:1583-5. PMID 7936278
28: Caravati EM, Erdman AR, Christianson G, et al. Elemental mercury exposure: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2008;46(1):1-21. PMID 18167033
29: Carroll CR, Noonan C, Garroutte EM, Navas-Acien A, Verney SP, Buchwald D. Low-level inorganic arsenic and neuropsychological functioning in American Indian elders. Environ Res 2017;156:74-9. PMID 28334644
30: Caudle WM. Occupational metal exposure and parkinsonism. In Aschner M, Costa LG, eds. Neurotoxicity of metals, advances in neurobiology 18. Springer International Publishing AG, 2017:143-58.
31: Chiou HY, Huang WI, Su CL, Chang SF, Hsu YH, Chen CJ. Dose response relationship between prevalence of cerebrovascular disease and ingested inorganic arsenic. Stroke 1997;28:1717-23. PMID 9303014
32: Clarkson TW. Mercury: major issues in environmental health. Environ Health Perspect 1993;100:31-8. PMID 8354179
33: Colosio C, Tomasini M, Cairoli S, et al. Occupational triphenyltin acetate poisoning: a case report. Br J Ind Med 1991;48(2):136-9. PMID 1825604
34: Cossa P, Duplay, Fischgold, et al. [Toxic brain diseases caused by stalinon; anatomo-clinical and electroencephalographic aspects]. [Article in English, French] Rev Neurol (Paris) 1958;98(2):97-108. PMID 13568430
35: Davis LE, Wands JR, Weiss SA, Price DL, Girling EF. Central nervous system intoxication from mercurous chloride laxatives. Quantitative, histochemical, and ultrastructural studies. Arch Neurol 1974;30:428-31. PMID 4827059
36: Davis MA, Gilbert-Diamond D, Karagas MR, et al. A dietary-wide association study (DWAS) of environmental metal exposure in US children and adults. PLoS One 2014;9(9):e104768. PMID 25198543
37: Dhapola R, Sharma P, Kumari S, Bhatti JS, HariKrishnaReddy D. Environmental toxins and Alzheimer's disease: a comprehensive analysis of pathogenic mechanisms and therapeutic modulation. Mol Neurobiol 2024;61(6):3657-77. PMID 38006469
38: Dietrich KN, Berger OG, Succop PA, Hammond PB, Bornschein RL. The developmental consequences of low to moderate prenatal and postnatal lead exposure: intellectual attainment in the Cincinnati Lead Study Cohort following school entry. Neurotoxicol Teratol 1993;15(1):37-44. PMID 8459787
39: Dion LA, Bouchard MF, Sauve S, et al. MRI pallidal signal in children exposed to manganese in drinking water. Neurotoxicology 2016;53:124-31. PMID 26801245
40: Donofrio PD, Wilbourn AJ, Albers JW, Rogers L, Salanga V, Greenberg HS. Acute arsenic intoxication presenting as Guillain-Barré-like syndrome. Muscle Nerve 1987;10(2):114-20. PMID 3029587
41: Dsouza HS, Dsouza SA, Menezes G, Thuppil V. Evaluation and treatment of wrist drop in a patient due to lead poisoning: case report. Ind Health 2009;47(6):677-80. PMID 19996545
42: Emara AM, el-Ghawabi SH, Madkour Ol, el-Samra GH. Chronic manganese poisoning in the dry battery industry. British J Ind Med 1971;28(1):78-82. PMID 5101169
43: Fang F, Kwee L, Allen K, et al. Association between blood lead and the risk of amyotrophic lateral sclerosis. Am J Epidemiol 2010;171(10):1126-33. PMID 20406759
44: Fathabadi B, Dehghanifiroozabadi M, Aaseth J, et al. Comparison of blood lead levels in patients with Alheimer’s disease and healthy people. Am J Alzheimers Dis Other Demen 2018;33(8):541-7. PMID 30134734
45: Feldman RG, Hayes MK, Younes R, Aldrich FD. Lead neuropathy in adults and children. Arch Neurol 1977;34(8):481-8. PMID 889480
46: Feldman RG, White RF, Eritator II. Trimethyltin encephalopathy. Arch Neurol 1993;50(12):1320-4. PMID 8257310
47: Fields CA, Borak J, Louis ED. Mercury-induced and sensory neurotoxicity: systemic review of workers currently exposed to mercury vapor. Crit Rev Toxicol 2017;47(10):815-48. PMID 28722535
48: Flendrig JA, Kruis H, Das HA. Letter: Aluminum and dialysis dementia. Lancet 1976;1(7971):1235. PMID 58273
49: Franzblau A, d'Arcy H, Ishak MB, et al. Low-level mercury exposure and peripheral nerve function. Neurotoxicology 2012;33(3):299-306. PMID 22370089
50: Friesen MS, Purssell RA, Gair RD. Aluminum toxicity following IV use of oral methadone solution. Clin Toxicol (Phila) 2006;44(3):307-14. PMID 16749550
51: Garman RF. Lead II: Neurotoxicity. In Dobbs MR, editor. Clinical Neurotoxicology. Philadelphia: Saunders, 2009.
52: Garruto RM, Strong MJ, Yanagihara R. Experimental models of aluminum-induced motor neuron degeneration. Adv Neurol 1991;56:327-40. PMID 1853766
53: Garruto RM, Swyt C, Fiori CE, Yanagihara R, Gajdusek DC. Intraneuronal deposition of calcium and aluminium in amyotrophic lateral sclerosis of Guam. Lancet 1985;2(8468):1353. PMID 2866399
54: Ghosh R, Dubey S, Chatterjee S, Ghosh M, Ray BK, Benito-Leon J. Hypermanganesemia induced chorea and cognitive decline in a tea seller. Tremor Other Hyperkinet Mov (NY) 2020;10:45. PMID 33178484
55: Goel A, Chowgule RV. Outbreak investigation of lead neurotoxicity in children from artificial jewelry cottage industry. Environ Health Prev Med 2019;24(1):30. PMID 31077132
56: Gong G, Oʼbryant SE. The arsenic exposure hypothesis for Alzheimer’s disease. Alzheimer Dis Assoc Disord 2010;24:4. PMID 20473132
57: Grandjean P, White RF, Nielsen A, Cleary D, de Oliveira Santos EC. Methylmercury neurotoxicity in Amazonian children downstream from gold mining. Environ Health Perspect 1999;107(7):587-91. PMID 10379006
58: Graves AB, Rosner D, Echeverria D, Mortimer JA, Larson EB. Occupational exposures to solvents and aluminum and estimated risk of Alzheimer. Occup Environ Med 1998;55(9):627-33. PMID 9861186
59: Graves AB, van Duijn CM, Chandra V, et al. Occupational exposures to solvents and lead as risk factors for Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group. Int J Epidemiol 1991;20 Suppl 2:S58-61. PMID 1833355
60: Graves AB, White E, Koepsell TD, Reifler BV, van Belle G, Larson EB. The association between aluminum-containing products and Alzheimer's disease. J Clin Epidemiol 1990;43(1):35-44. PMID 2319278
61: Halatek T, Sinczuk-Walczak H, Szymczak M, Rydzynski K. Neurological and respiratory symptoms in shipyard welders exposed to manganese. Int J Occup Med Environ Health 2005;18(3):265-74. PMID 16411566
62: Hanninen H, Aitio A, Kovala T, et al. Occupational exposure to lead and neuropsychological function. Occup Environ Med 1998;55(3):202-9. PMID 9624272
63: Hanninen H, Matikainen E, Kovala T, Valkonen S, Riihimaki V. Internal load of aluminum and the central nervous system function of aluminum welders. Scand J Work Environ Health 1994;20(4):279-85. PMID 7801073
64: Herrero Hernandez E, Discalzi G, Valentini C, et al. Follow-up of patients affected by manganese-induced Parkinsonism after treatment with CaNa2EDTA. Neurotoxicology 2006;27(3):333-9. PMID 16271769
65: Hu H, Watanabe H, Payton M, Korrick S, Rotnitzky A. The relationship between bone lead and hemoglobin. JAMA 1994;272(19):1512-7. PMID 7966843
66: Huang CC, Chu NS, Lu CS, et al. Chronic manganese intoxication. Arch Neurol 1989;46(10):1104-6. PMID 2803069
67: Huang CC, Lu CS, Chu NS, et al. Progression after chronic manganese exposure. Neurology 1993;43(8):1479-83. PMID 8351000
68: Ingre C, Roos P, Piehl F, Kamel F, Fang F. Risk factors for amyotrophic lateral sclerosis. Clin Epidemiol 2015;7:181-93. PMID 25709501
69: Jankovic J. Searching for a relationship between manganese and welding and Parkinson’s disease. Neurology 2005;64(12):2021-8. PMID 15985567
70: Jiang Y, Zheng W, Long L, et al. Brain magnetic resonance imaging and manganese concentrations in red blood cells of smelting workers: search for biomarkers of manganese exposure. Neurotoxicology 2007;28(1):126-35. PMID 16978697
71: Jiang YM, Mo XA, Du FQ, et al. Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study. J Occup Environ Med 2006;48(6):644-9. PMID 16766929
72: Kihira T, Yoshida S, Yase Y, Ono S, Kondo T. Chronic low-Ca/Mg high-Al diet induces neuronal loss. Neuropathology 2002;22(3):171-9. PMID 12416556
73: Kisaarslan AP, Sozeri B, Bastug F, et al. Elemental mercury intoxication in seven patients admitted to a pediatric rheumatology clinic. Turk J Pediatr 2019;61(5):786-90. PMID 32105014
74: Klein C, Schlossmacher MG. Parkinsons disease, 10 years after its genetic revolution: multiple clues to a complex disorder. Neurology 2007;69(22):2093-104. PMID 17761553
75: Koller WC, Lyons KE, Truly W. Effect of levodopa treatment for parkinsonism in welders: A double-blind study. Neurology 2004;62(5):730-3. PMID 15007122
76: Kosnett MJ, Wedeen RP, Rothenberg SJ, et al. Recommendations for medical management of adult lead exposure. Environ Health Perspect 2007;115(3):463-71. PMID 17431500
77: Kreyberg S, Torvik A, Bjorneboe A, Wiik-Larsen W, Jacobsen D. Trimethyltin poisoning: report of a case with postmortem examination. Clin Neuropathol 1992;11(5):256-9. PMID 1424320
78: Lang AE. The progression of Parkinson disease: a hypothesis. Neurology 2007;68(12):948-52. PMID 17372132
79: Latov N, Kumar G, Vo ML, et al. Elevated blood mercury levels in idiopathic axonal neuropathy. JAMA Neurol 2015;72(4):474-5. PMID 25867721
80: Lawes M, Pinkas A, Frohlich BA, Iroegbu JD, Ijomone O, Aschner M. Metal-induced neurotoxicity in a RAGE-expressing C. elegans model. Neurotoxicology 2020;80:71-5. PMID 32621835
81: LeQuesne PM, McLeod JG. Peripheral neuropathy following a single exposure to arsenic. J Neurol Sci 1977;32:437-51. PMID 196051
82: Lin G, Yuan L, Bai L, Liu Y, Wang Y, Qiu Z. Successful treatment of a patient with severe thallium poisoning in a coma using Prussian blue and plasma exchange: a care report. Medicine 2019;98(8):e14629. PMID 30813198
83: Lindgren KN, Ford DP, Bleecker ML. Pattern of blood lead levels over working lifetime and neuropsychological performance. Arch Environ Health 2003;58(6):373-9. PMID 14992313
84: Little AA, Albers JW. Clinical description of toxic neuropathies. Handb Clin Neurol 2015;131:253-96. PMID 26563794
85: Liu XL, Wang HB, Sun CW, et al. [The clinical analysis of mercury poisoning in 92 cases]. Zhonghua Nei Ke Za Zhi 2011;50(8):687-9. PMID 22093564
86: Longstreth WT, Rosenstock L, Heyer NJ. Potroom palsy. Neurologic disorder in three aluminum smelter workers. Arch Int Med 1985;145(11):1972-5. PMID 4062445
87: Lucchini R, Albini E, Cortesi I, et al. Assessment of neurobehavioral performance as a function of current and cumulative occupational lead exposure. Neurotoxicology 2000;21(5):805-11. PMID 11130286
88: Lucchini R, Selis L, Folli D, et al. Neurobehavioral effects of manganese in workers from a ferroalloy plant after temporary cessation of exposure. Scand J Work Environ Health 1995;21(2):143-9. PMID 7618060
89: Lucchini R, Tieu K. Manganese-induced parkinsonism: evidence from epidemiological and experimental studies. Biomolecules 2023;13(8):1190. PMID 37627255
90: Lucchini RG, Guazzetti S, Zoni S, et al. Neurofunctional dopaminergic impairment in elderly after lifetime exposure to manganese. Neurotoxicology 2014;45:309-17. PMID 24881811
91: Lucchini RG, Guazzetti S, Zoni S, et al. Tremor, olfactory and motor changes in Italian adolescents exposed to historical ferro-manganese emission. Neurotoxicology 2012;33(4):687-96. PMID 22322213
92: Martinez-Hernandez MI, Acosta-Saavedra LC, Hernández-Kelly LC, Loaeza-Loaeza J, Ortega A. Microglial activation in metal neurotoxicity: impact in neurodegenerative diseases. Biomed Res Int 2023;2023:7389508. PMID 36760476
93: Martyn CN, Barker DJ, Osmond C, Harris EC, Edwardson JA, Lacey RF. Geographical relation between Alzheimer's disease and aluminum in drinking water. Lancet 1989;1(8629):59-62. PMID 2562879
94: Mathew L, Vale A, Adcock JE. Arsenical peripheral neuropathy. Practical Neurol 2010;10:34-8. PMID 20130295
95: Maya S, Prakash T, Madhu KD, Goli D. Multifaceted effects of aluminium in neurodegenerative diseases: A review. Biomed Pharmacother 2016;83:746-54. PMID 27479193
96: McDowell MA, Dillon CF, Osterloh J, et al. Hair mercury levels in U.S. children and women of childbearing age: reference range data from NHANES 1999-2000. Environ Health Perspect 2004;112(11):1165-71. PMID 15289161
97: Meyer-Baron M, Schäper M, Knapp G, van Thriel C. Occupational aluminum exposure: evidence in support of its neurobehavioral impact. Neurotoxicology 2007;28(6):1068-78. PMID 17692380
98: Miller JM. Subclinical psychomotor and neuromuscular changes in workers exposed to inorganic mercury. Am Ind Hyg Assoc J 1975;36(10):725-33. PMID 1180206
99: Mirza A, King A, Troakes C, Exley C. Aluminum in brain tissue in familial Alzheimer’s disease. J Trace Elem Med Biol 2017;40:30-6. PMID 28159219
100: Mochizuki H, Phyu KP, Aung MN, et al. Peripheral neuropathy induced by drinking water contaminated with low-dose arsenic in Myanmar. Environ Health Prev Med 2019;24(1):23. PMID 31014238
101: Mochizuki H. Arsenic neurotoxicity in humans. Int J Mol Sci 2019;20(14). PMID 31336801
102: Morton WE, Caron GA. Encephalopathy: an uncommon manifestation of workplace arsenic poisoning. Am J Ind Med 1989;15(1):1-5. PMID 2929604
103: Muldoon SB, Cauley JA, Kuller LH, et al. Effects of blood lead levels on cognitive function of older women. Neuroepidemiology 1996;15(2):62-72. PMID 8684585
104: Mutter J, Curth A, Naumann J, Deth R, Walach H. Does inorganic mercury play a role in Alzheimer's disease. A systematic review and an integrated molecular mechanism. J Alzheimers Dis 2010;22(2):357-74. PMID 20847438
105: Mutter J, Yeter D. Kawasaki’s disease, acrodynia, and mercury. Curr Med Chem 2008;15(28):3000-10. PMID 19075648
106: Needleman HL, Gatsonis CA. Low-level lead exposure and the IQ of children: a meta-analysis of modern studies. JAMA 1990;263(5):673-8. PMID 2136923
107: Niklowitz WJ, Mandybur TI. Neurofibrillary changes following childhood lead encephalopathy. J Neuropathol Exp Neurol 1975;34(5):445-55. PMID 1176997
108: Nordentoft T, Andersen EB, Mogensen PH. Initial sensorimotor and delayed autonomic neuropathy in acute thallium poisoning. Neurotoxicology 1998;19(3):421. PMID 9621348
109: Olanow CW. Manganese-induced parkinsonism and Parkinson's disease. Ann N Y Acad Sci 2004;1012:209-23. PMID 15105268
110: Ortega DR, Gonzalez Equivel DF, Ayala TB, et al. Cognitive Impairment Induced by Lead Exposure during Lifespan: Mechanisms of Lead Neurotixicity. Toxics 2021. 9,23. PMID 33525464
111: Panzenhagen AC, Petry FDS, Alves-Teixeira A, et al. Biomarkers of methylmercury neurotoxicity and neurodevelopmental features: a systematic review. Food Chem Toxicol 2024;191:114851. PMID 38986832
112: Perl DP, Brody AR. Alzheimer's disease: x ray spectrometric evidence of aluminum accumulation in neurofibrillary tangle bearing neurons. Science 1980;208(4441):297-9. PMID 7367858
113: Pierce PE, Thompson JF, Likosky WH, Nickey LN, Barthel WF, Hinman AR. Alkyl mercury poisoning in humans: report of an outbreak. JAMA 1972;220(11):1439-42. PMID 5067577
114: Polizzi S, Pira E, Ferrara M, et al. Neurotoxic effects of aluminum among foundry workers and Alzheimer's disease. Neurotoxicology 2002;23(6):761-74. PMID 12520766
115: Prince M. Is chronic low level lead exposure in early life an etiological factor in Alzheimer's disease? Epidemiology 1998;9(6):618-21. PMID 9799170
116: Pyatha S, Kim H, Lee D, Kim K. Association between heavy metal exposure and Parkinson’s disease: a review of the mechanisms related to oxidative stress. Antioxidants 2022;11(12):2467. PMID 36552676
117: Racette BA, Criswell SR, Lundin JI, et al. Increased risk of parkinsonism associated with welding exposure. Neurotoxicology 2012;33(5):1356-61. PMID 22975422
118: Racette BA, McGee-Minnich L, Moerlein SM, Mink JW, Videen TO, Perlmutter JS. Welding-related parkinsonism: clinical features, treatment, and pathophysiology. Neurology 2001;56(1):8-13. PMID 11148228
119: Racette BA, Searles Nielsen S, Criswell SR, et al. Dose-dependent progression of parkinsonism in manganese-exposed welders. Neurology 2017;88:344-51. PMID 28031394
120: Racette BA, Tabbal SD, Jennings D, Good L, Perlmutter JS, Evanoff B. Prevalence of parkinsonism and relationship to exposure in a large sample of Alabama welders. Neurology 2005;64(2):230-5. PMID 15668418
121: Ratnaike RN. Acute and chronic arsenic toxicity. Postgrad Med J 2003;79(933):391-6. PMID 12897217
122: Reusche E, Koch V, Lindner B, Harrison AP, Friedrich HJ. Alzheimer morphology is not increased in dialysis-associated encephalopathy and long-term hemodialysis. Acta Neuropathol 2001;101(3):211-6. PMID 11307619
123: Rifat SL, Eastwood MR, McLachlan DR, Corey PN. Effect of exposure of miners to aluminium powder. Lancet 1990;336(8724):1162-5. PMID 1978033
124: Rodella LF, Ricci F, Borsani E, et al. Aluminum exposure induces Alzheimer-like histopathological alterations in mouse brain. Histol Histopathol 2008;23(4):433-9. PMID 18228200
125: Roels H, Lauwerys R, Buchet JP, et al. Epidemiological survey among workers exposed to manganese: effects on lung, central nervous system, and some biological indices. Am J Ind Med 1987;11(3):307-27. PMID 3578289
126: Roels HA, Bowler RM, Kim Y, et al. Manganese exposure and cognitive deficits: a growing concern for manganese neurotoxicity. Neurotoxicology 2012;33(4):872-80. PMID 22498092
127: Rondeau V, Jacqmin-Gadda H, Commenges D, Dartigues JF. Aluminum and silica in drinking water and the risk of Alzheimer’s disease or cognitive decline: finding from 15-year follow-up of the PAQUID Cohort. Am J of Epidemiol 2009;169(4):489-96. PMID 19064650
128: Roses OE, García Fernández JC, Villaamil EC. Mass poisoning by sodium arsenite. J Toxicol Clin Toxicol 1991;29(2):209-13. PMID 2051508
129: Rutchik J, Ratner MH. Should age at onset of parkinsonism be the end point of interest in investigations of the link between exosomal α-synuclein and manganese exposure in welders? J Occ Environ Med 2019;61(12):530-1. PMID 31568106
130: Santibanez M, Bolumar F, Garcia AM. Occupational risk factors in Alzheimer: a review assessing the quality of published epidemiological studies. Occup Environ Med 2007;64(11):723-32. PMID 17525096
131: Santos-Sacramento L, Arrifano GP, Lopez-Araujo A, et al. Human neurotoxicity of mercury in the Amazon: a scoping review with insights and critical considerations. Exotox Environ Saf 2021;208:111686. PMID 33396018
132: Sasaki N, Carpenter D. Associations between metal exposures and cognitive function in older adults. Int J Environ Res Public Health 2022;19(4):2327. PMID 35206515
133: Saxe SR, Wekstein MW, Kryscio RJ. Alzheimer's disease, dental amalgam and mercury. J Am Dent Assoc 1999;130(2):191-9. PMID 10036842
134: Schoenberg BS, Anderson DW, Haerer AF. Prevalence of Parkinson’s disease in the biracial population of Copial County, Mississippi. Neurology. 1985;35:841-5. PMID 4000484
135: Schwartz BS, Lee BK, Bandeen-Roche K, et al. Occupational lead exposure and longitudinal decline in neurobehavioral test scores. Epidemiology 2005;16(1):106-13. PMID 15613953
136: Shalat SL, Seltzer B, Baker EL. Occupational risk factors and Alzheimer's disease: a case control study. J Occup Med 1988;30(12):934-6. PMID 3230443
137: Shaw CA, Petrik MS. Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration. J Inorg Biochem 2009;103:1555-62. PMID 19740540
138: Shih RA, Glass TA, Bandeen-Roche K, et al. Environmental lead exposure and cognitive function in community-dwelling older adults. Neurology 2006;67:1556-62. PMID 16971698
139: Shobha N, Taly AB, Sinha S, Venkatesh T. Radial neuropathy due to occupational lead exposure: phenotypic and electrophysiological characteristics of five patients. Ann Indian Acad Neurol 2009;12(2):111. PMID 20142857
140: Sierra P, Loranger S, Kennedy G, Zayed J. Occupational and environmental exposure of automobile mechanics and nonautomotive workers to airborne manganese arising from the combustion of methylcyclopentadienyl manganese tricarbonyl (MMT). Am Ind Hyg Assoc J 1995;56(7):713-6. PMID 7618609
141: Sim M, Dick R, Russo J, et al. Are aluminium potroom workers at increased risk of neurological disorders? Occup Environ Med 1997;54(4):229-35. PMID 9166127
142: Sjögren B, Elinder CG. Proposal of a dose-response relationship between aluminium welding fume exposure and effect on the central nervous system. Med Lav 1992;83(5):484-8. PMID 1297062
143: Smyth LT, Ruhf RC, Whitman NE, Dugan T. Clinical manganism and exposure to manganese in the production and processing of ferromanganese alloy. J Occup Med 1973;15(2):101-9. PMID 4631080
144: Stewart WF, Schwartz BS, Davatzikos C, et al. Past adult lead exposure is linked to neurodegeneration measured by brain MRI. Neurology 2006;66(10):1476-84. PMID 16717205
145: Stewart WF, Schwartz BS, Simon D, Bolla KI, Todd AC, Links J. Neurobehavioral function and tibial and chelatable lead levels in 543 former organolead workers. Neurology 1999;52(8):1610-7. PMID 10331686
146: Tamashiro H, Arakaki M, Akagi H, Futatsuka M, Roht LH. Mortality and survival for Minimata disease. Int J Epidemiol 1985;14(4):582-8. PMID 4086144
147: Thomson RM, Parry GJ. Neuropathies associated with excessive exposure to lead. Muscle Nerve 2006;33(6):732-41. PMID 16477615
148: Tomljenovic L. Aluminum and Alzheimer's disease: after a century of controversy, is there a plausible link. J Alzheimers Dis 2011;23(4):567-98. PMID 21157018
149: Triebig G, Schaller KH. Neurotoxic effects in mercury-exposed workers. Neurobehav Toxicol Teratol 1982;4(6):717-20. PMID 7170033
150: Vahabzadeh M, Balali-Mood M. Occupational metallic mercury poisoning in gilders. Int J Occup Environ Med 2016;7(2):116-22. PMID 27112720
151: Vlasak T, Dujlovic T, Barth A. Aluminum exposure and cognitive performance: a meta-analysis. Sci Total Environ 2024;906:167453. PMID 37777128
152: Vroom FQ, Greer M. Mercury vapour intoxication. Brain 1972;95(2):305-18. PMID 4144038
153: Wallace DR, Lienemann E, Hood AN, et al. Clinical aspects of mercury toxicity. In: Dobbs MR, editor. Clinical Neurotoxicology. Saunders, 2009: 251-7.
154: Wang JD, Huang CC, Hwang YH, et al. Manganese induced parkinsonism: an outbreak due to an unrepaired ventilation control system in a ferromanganese smelter. British J Ind Med 1989;46:856-9. PMID 2611159
155: Wang MD, Gomex J, Cashman NR, Little J, Krewski D. A meta-analysis of observations studies of the association between chronic occupational exposure to lead and amyotrophic lateral sclerosis. J Occup Environ Med 2014;56(12):1235-42. PMID 25479292
156: Weiner W. A differential diagnosis of Parkinsonism. Rev Neurol Dis 2005;2(3):124-31. PMID 16400311
157: Weiner W. There is no Parkinson’s disease. Arch Neurol 2008;65(6):705-8. PMID 18541790
158: Wettstein A, Aeppli J, Gautschi K, Peters M. Failure to find a relationship between mnestic skills of octogenarians and aluminum in drinking water. Int Arch Occup Environ Health 1991;63(2):97-103. PMID 1889888
159: Weuve J, Press DZ, Grodstein F, Wright RO, Hu H, Weisskopf MG. Cumulative exposure to lead and cognition in persons with Parkinson’s disease. Mov Disord 2013;28(2):176-82. PMID 23143985
160: White DM, Longstreth WT, Rosenstock L, Claypoole KH, Brodkin CA, Townes BD. Neurologic syndrome in 25 workers from an aluminum smelting plant. Arch Int Med 1992;152(7):1443-8. PMID 1627023
161: White RF, Diamond R, Proctor S, et al. Residual cognitive deficits 50 years after lead poisoning during childhood. Br J Ind Med 1993a;50(7):613-22. PMID 8343422
162: White RF, Feldman RG, Moss MB, Proctor SP. Magnetic resonance imaging (MRI), neurobehavioral testing, and toxic encephalopathy: two cases. Environ Res 1993b;61(1):117-23. PMID 8472665
163: Xu Y, Wang Y, Zheng Q, et al. Clinical manifestations and arsenic methylation after a rare subacute arsenic poisoning accident. Toxicol Sci 2008;103(2):278-84. PMID 18308700
164: Yamada M, Ohno S, Okayasu I, et al. Chronic manganese poisoning: a neuopathological study with determination of manganese distribution in the brain. Acta Neuropathol (Berl) 1986;70:273-8. PMID 3766127
165: Zheng W, Jiang YM, Zhang Y, Jiang W, Wang X, Cowan DM. Chelation therapy of manganese intoxication with para-aminosalicylic acid (PAS) in Sprague-Dawley rats. Neurotoxicology 2009;30(2):240-8. PMID 19150464
166: Zhu J, Meng P, Han X, Yang S. Painful sensory motor neuropathy with albuminocytological dissociation of the cerebrospinal fluid as the presenting features of acute thallium poisoning. J Clin Neurol 2023;19(6):624-6. PMID 37901901

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Jonathan S Rutchik MD MPH

Dr. Rutchik of the University of California at San Francisco has no relevant financial relationships to disclose.
See Profile

Editor

Matthew Lorincz MD PhD

Dr. Lorincz of the University of Michigan has no relevant financial relationships to disclose.
See Profile

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: None selectively affected
Occupation groups selectively affected: See Table 1. Industrial Uses of Heavy Metals

ICD & OMIM codes

ICD-10: Mononeuropathy, unspecified: G58.9

Paraesthesia of skin: R20.2

Polyneuropathy due to other toxic agents: G62.2

Polyneuropathy, unspecified: G62.9

Toxic encephalopathy: G92
ICD-11: Mononeuropathy of unspecified site: 8C1Z

Anaesthesia of skin: MB40.3

Other specified neuropathy due to toxicity: 8D43.2Y

Polyneuropathy, unspecified: 8C0Z

Encephalopathy due to toxicity: 8D43.0

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Metal neurotoxicity

Associated Disorders

Alzheimer disease
Dementia

Differential Diagnosis

dementia due to other toxic exposures
dementia due to organic toxins
dementia due to drug overdose
dementia due to congenital or hereditary disease
age-related Alzheimer disease
- metabolic encephalopathy
- Korsakoff syndrome
- bilateral temporal lobe
- anoxia
- encephalitis
- head trauma
- surgical procedures

Also Relevant

Alzheimer disease
Arsenic neuropathy
British anti-Lewisite
Chelation therapy
Childhood lead poisoning
- Environmental and behavioral sleep disorders
- Lead neuropathy
- Mercury neuropathy
- Thallium neuropathy
- Toxic peripheral neuropathies

Metal neurotoxicity

Introduction

Overview

Key points

Historical note and terminology

Table 1. Industrial Uses of Heavy Metals

Clinical manifestations

Presentation and course

Table 2. Algorithm for the Clinical Assessment of Neurotoxic Illness

Table 3. Permissible and Recommended Exposure Limits, Threshold Limit Values/Time-Weighted Average, and Biological Exposure Indices

Aluminum (Al)

Arsenic (As)

Lead (Pb)

Manganese (Mn)

Mercury (Hg)

Thallium (Tl)

Tin (Sn)

Prognosis and complications

Clinical vignette

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Neurogenetics and genetic and genomic testing

Acute traumatic spinal cord injury

Tumors of the skull base

Toxic and nutritional deficiency optic neuropathies

Nystagmus

Third nerve palsy

Brain death/death by neurologic criteria

Outpatient rehabilitation of chronic neurologic conditions

This is an article preview.
Start a Free Account
to access the full version.