General Neurology
Metal neurotoxicity
Nov. 05, 2024
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Occupational neurotoxicology: metals …
- Updated 07.15.2024
- Expires For CME 07.15.2027
Occupational neurotoxicology: metals
Introduction
Overview
This article reviews occupational neurotoxic metal poisoning, particularly concerning the following metals and metal compounds: lead, tetraethyl lead, mercury, organomercury (dimethylmercury), manganese, thallium, tin, organotin, zinc, and arsenic. The review includes metal production and use, circumstances of occupational poisoning, metal metabolism and clinical neurotoxicology, clinical manifestations of metal neurotoxicity, methods of limiting exposure (including respirator requirements where available), exposure limits set by governmental and professional organizations, biologic monitoring, and OSHA compliance schemes (where applicable).
Key points
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• The most important occupational exposures to neurotoxic metals, in terms of frequency and severity of neurologic impairment, are poisonings from lead, mercury, and manganese, with only occasional reports of neurotoxic occupational poisonings from organomercury, thallium, zinc, organotin compounds, or arsenicals. | |
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• The predominant neurologic manifestations of occupational lead poisoning are lead encephalopathy (acute and chronic forms) and lead palsy. | |
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• The most common neurologic manifestation of inorganic mercury poisoning (although often not the first) is a bilateral intention tremor (although a minimal rest component was noted in some cases). | |
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• Neurologic manifestations of inorganic mercury poisoning may also include impaired cognition and neurobehavioral symptoms or erethism (eg, mood swings, irritability, irascibility, excitability, nervousness, timidity, shyness, loss of confidence, depression, moroseness), disturbances of smell and taste, constricted visual fields or blindness, incoordination or ataxia, impaired motor speed, and slowed nerve conduction. | |
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• Manganese is recognized to cause an unusual extrapyramidal syndrome with atypical parkinsonism and often with dystonic features. |
Description
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• Almost two thirds (63%) of adults with very high blood lead levels (BLL 40 µg/dL or higher) have an occupational source of lead. | |
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• Lead in an occupational setting is absorbed primarily via the respiratory route, whereas gastrointestinal absorption is the primary route in nonoccupational settings; transdermal absorption of inorganic lead is negligible. | |
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• Lead is excreted very slowly from the body (with a half-life of about 10 years) primarily by renal and gastrointestinal routes (both unabsorbed lead and gastrointestinal net excretion). | |
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• Lead acts as a cellular toxin, in part by inhibiting mitochondrial respiration. | |
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• Around the world, the most common source of occupational inorganic mercury poisoning is now artisanal and small-scale gold mining. | |
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• The main source of manganese uptake in occupational manganese poisoning (manganism) is inhalation of manganese dust or fumes. The primary target organs of toxicity are the lungs and the brain. | |
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• Most cases of recognized zinc-induced copper deficiency have been either (1) self-induced, (2) related to bariatric surgery or hemodialysis, or (3) iatrogenic (eg, with intentional prescription of zinc to decrease copper levels in Wilson disease). | |
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• Zinc interferes with copper absorption and metabolism. | |
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• Few recent reports are available concerning neurotoxic aspects of occupational thallium poisoning. | |
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• Reports of occupational arsenic poisoning after the 19th century are rare from the United States and Europe, and few concern arsenic neurotoxicity, such as arsenical neuropathy. |
Lead
Lead production. Six lead mines in Missouri, plus five mines in Alaska, Idaho, and Washington, produce lead as a principal product or byproduct, but nearly all lead mine production in the United States has been exported since the last primary lead smelter closed in 2013 (334); 12 secondary refineries in 10 states account for almost all the secondary lead produced.
Lead use. The lead-acid battery industry accounts for the vast majority (about 93%) of U.S. lead consumption (334). Lead-acid batteries are used as starting-lighting-ignition batteries for automobiles, as industrial-type batteries for standby power for computer and telecommunications networks, and for motive power (334).
Lead consumption is declining in the United States for several reasons: (1) a decline in automobile production, (2) increased use of lithium-ion batteries, (3) substitution by plastics for lead in cable covering and cans, (4) use of tin instead of lead in solder for potable water systems, (5) increased use of lead-free solders in the electronics industry, (6) a switch to flat-panel displays that do not require lead shielding, and (7) use of steel and zinc as substitutes for lead in wheel weights (334).
Occupational lead poisoning. Lead exposures historically have been high in mining, ore crushing and sampling, and the smelting and refining of metals where accumulations of ground lead ore cover the floor and machinery surfaces, still finer dust clings to the walls and all projecting surfaces, and lead fumes are dispersed into the ambient air of the workspace (182; 183).
Engineering controls mitigate this somewhat (eg, flared ventilation hoods), but gaps are common where lead ore dust or lead fumes are dispersed in the work areas. Personal protective equipment helps minimize exposure but is often circumvented (eg, removing respirators for convenience because of fogging of the viewing surface or to eat or smoke). Eating and smoking in work areas greatly increases potential lead exposure, in part because of the repetitive hand-to-mouth behavior and the likelihood of contamination of hands or surfaces in the work area.
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Industrial plant employee using PPE in an electric-storage battery plant
Employee in an electric-storage battery plant is cutting the lugs off lead battery plates. Note that the worker was using personal protective equipment consisting of a cap, minimal eye protection, and coveralls. The machine its...
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Industrial plant employees using PPE in a storage battery manufacturing plant
Industrial plant employees in a storage battery manufacturing plant, who were using personal protective equipment (PPE) consisting of caps, coveralls, and respirators. (Source: CDC/Barbara Jenkins, NIOSH, 1950. Public Health Im...
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Industrial plant employees using PPE while packaging lead arsenate (1)
Female employees packaging lead arsenate, which is the lead salt, or ester of arsenic acid. Note that all workers were using personal protective equipment (PPE), which included a cap, a face mask, eye protection, and coveralls ...
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Industrial plant employees using PPE while packaging lead arsenate (2)
Female employees packaging lead arsenate, which is the lead salt, or ester of arsenic acid. Note that all workers were using personal protective equipment (PPE), which included a cap, a face mask, eye protection, and coveralls ...
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Industrial plant employees using minimal PPE while cleaning lead plates
Four industrial plant employees cleaning lead plates in an electric storage battery factory. Note, that while at their workstations, all the workers were using only minimal personal protective equipment (PPE), consisting of dus...
Other, often unrecognized or underappreciated exposure risks involve professional users (eg, police) and employees of indoor firing ranges (60; 76; 78; 28), foundry workers (183; 284), workers manufacturing batteries (183; 284), workers involved in recycling lead or directly working with lead compounds, and workers manufacturing pottery (183; 150).
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Woman working with unfired clay tiles in a pottery factory with exhaust ventilation
Woman working as a remover attends unfired clay tiles on a conveyor equipped with exhaust ventilation in a West Virginia pottery factory. (Source: CDC/Barbara Jenkins, NIOSH, 1936. Flinn RH. Neal PA, Reinhart WH, Dallavalle JM....
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Woman fettling greenware in a pottery factory under uncontrolled conditions
Woman fettling (trimming) greenware (unfired clayware) in a West Virginia pottery factory under uncontrolled conditions. Note the dust produced in the operation. (Source: CDC/Barbara Jenkins, NIOSH, 1936. Flinn RH. Neal PA, Rei...
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Railroad car unloader shovels finely ground quartz while investigator collects dust samples
A railroad car unloader shovels finely ground quartz into a wheelbarrow at a West Virginia pottery factory, while a US Public Health Service investigator collects dust samples in his breathing zone with an impringer. (Source: C...
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Woman fettling unfired clayware over down-draft ventilation in a pottery factory
Woman fettling (trimming) greenware (unfired clayware) over down-draft ventilation in a West Virginia pottery factory. Note the dust produced in this operation. (Source: CDC/Barbara Jenkins, NIOSH, 1936. Flinn RH. Neal PA, Rein...
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Women applying glaze using a spray machine in a West Virginia pottery factory
(Source: CDC/Barbara Jenkins, NIOSH, 1936. Flinn RH. Neal PA, Reinhart WH, Dallavalle JM. Fulton WB, Dooley AE. Chronic manganese poisoning in an ore-crushing mill. Public Health Bulletin 1940;247:1-77. Public Health Image Libr...
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Men at work at glazing tubs in the glaze dipping room of a West Virginia pottery factory
The lunchbox in the foreground was one piece of evidence that they brought food to this room and ate while working. (Source: CDC/Barbara Jenkins, NIOSH, 1936. Flinn RH. Neal PA, Reinhart WH, Dallavalle JM. Fulton WB, Dooley AE....
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Woman attending to clayware in a sandblasting machine with an enclosed operation and exhaust ventilation
The woman attends bisqueware (once-fired clayware) in a sandblasting machine with an enclosed operation and exhaust ventilation, in a West Virginia pottery factory. (Source: CDC/Barbara Jenkins, NIOSH, 1936. Flinn RH. Neal PA, ...
Occupational lead poisoning continues to be a significant problem in the United States (04; 05; 28; 59; 60; 61; 63; 64; 65; 66; 67; 68; 69; 70; 71; 72; 73; 74; 75; 77; 79; 80; 81; 82; 83; 84; 85; 86; 87; 181; 201; 349) and other countries (62). Almost two thirds (63%) of adults with very high blood lead levels (BLL 40 µg/dL or higher) have an occupational source of lead, almost one half (32%) have an unknown exposure source, and only 5% have a nonoccupational source (87). Occupational lead poisoning almost always involves inorganic lead.
Although adult blood lead levels have generally declined over the past 30 years, the most recent figures indicate that 20 per 100,000 adults have blood lead levels (BLLs) of at least 10 μg/dL, whereas five per 100,000 adults have BLLs of at least 25 μg/dL (83; 85; 04; 05). Some states have higher rates of adults with elevated blood levels; these include Alabama, Alaska, Iowa, Kansas, Missouri, New Hampshire, New Jersey, New York, North Carolina, Ohio, Pennsylvania, Rhode Island, Wisconsin, and Wyoming, but some others that would likely be among states with higher than average rates did not participate in the Adult Blood Lead Epidemiology and Surveillance (ABLE) program or did not submit data on the number of adults exceeding the stated thresholds. These numbers primarily reflect occupational exposures in the mining and manufacturing sectors.
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US national prevalence rate of reported cases of elevated blood lead levels by year (1994-2012)
National prevalence rate of reported cases of elevated blood lead levels (BLLs), by year (State Adult Blood Epidemiology and Surveillance Programs, United States, 1994-2012).
Notes:
(1) All cases = all report... -
US national prevalence rate of reported cases of elevated blood lead levels for adults, by year (1994-2013)
National prevalence rate of reported cases of elevated blood lead levels (BLLs) for adults, by year (State Adult Blood Epidemiology and Surveillance Programs, United States, 1994-2013).
Notes:
(1) Rates are p... -
US national prevalence rate of adults with elevated blood lead levels by state (2012)
Prevalence rate of adults with elevated blood lead levels (BLLs) 10 μg/dL or higher, by state (State Adult Blood Lead Epidemiology and Surveillance programs, United States, 2012).
Notes:
(1) Rate per 100,000 employe... -
Mean annual rate by state of adults with blood lead levels 25 µg/dL or higher in 25 states, 1998-2001
Mean annual rate by state of adults with blood lead levels 25 µg/dL or higher reported by 25 Adult Blood Lead Epidemiology and Surveillance (ABLES) Program states, 1998-2001.
Note: Nebraska 2 years of data; South ...
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Mean annual rate by state of adults with blood lead levels 40 µg/dL or higher in 25 states, 1998-2001
Mean annual rate by state of adults with blood lead levels 40 µg/dL or higher reported by 25 Adult Blood Lead Epidemiology and Surveillance (ABLES) Program states, 1998-2001.
Note: Nebraska 2 years of data; South ...
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Mean annual rate by state for adults in 20 states with blood lead levels 25 µg/dL or higher, 1998-2001 vs. 1994-2007
Mean annual rate by state for adults with blood lead levels 25 µg/dL or higher in 20 Adult Blood Lead Epidemiology and Surveillance (ABLES) Program states reporting data for 2 or more years in each period.
Note: S...
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Mean annual rate by state for adults in 20 states with blood lead levels 40 µg/dL or higher, 1998-2001 vs. 1994-2007
Mean annual rate by state for adults with blood lead levels 40 µg/dL or higher in 20 Adult Blood Lead Epidemiology and Surveillance (ABLES) Program states reporting data for 2 or more years in each period.
Note: S...
The Adult Blood Lead Epidemiology and Surveillance (ABLES) Program identified 11,536 adults with at least one very high blood lead level in the United States over the 10-year interval from 2002 to 2011; of these, 2,210 (19%) had persistently high blood lead levels in 2 or more years in that interval (87). Blood lead levels are shown for four of these individuals: three with occupational sources for lead exposure and one with a nonoccupational exposure source (87). Of the three with occupational exposures, one was responsible for recycling grit and steel from bridge painting, one worked in construction and painting, and one worked in battery manufacturing.
Occupations associated with very high blood levels in the United States are shown in Table 1.
Table 1. Occupations Associated with Very High Blood Levels in the United States
• Lead ore and zinc ore mining (87) |
Metabolism. Lead in an occupational setting is absorbed primarily via the respiratory route, whereas gastrointestinal absorption is the primary route in nonoccupational settings; transdermal absorption of inorganic lead is negligible. At least 95% of circulating lead is bound to erythrocytes. At a steady state, about 90% of the lead body burden is bound to bone. Although inorganic lead does pass the blood-brain barrier, the concentration of lead in the central nervous system remains comparatively low.
Lead is excreted very slowly from the body (with a half-life of about 10 years), primarily by renal and gastrointestinal routes (both unabsorbed lead and gastrointestinal net excretion). Renal excretion is predominantly (and possibly exclusively) by glomerular filtration. Gastrointestinal excretion includes (1) active secretion or passive loss from salivary glands, the pancreas, and the intestinal wall; (2) shedding of epithelial cells; and (3) biliary excretion.
Lead acts as a cellular toxin, in part by inhibiting mitochondrial respiration.
Occupational exposure limits. The Occupational Safety and Health Administration requires that industries limit airborne lead levels to 50 µg/m3 without reliance or respirator protection through a combination of engineering, work practice, and other administrative controls (Table 2). While these controls are being implemented, respirators must be used to meet the 50 µg/m3 exposure limit (Tables 3 and 4). The action level at which an employer must begin specific compliance activities, including blood lead testing for exposed workers, is 30 µg/m3.
Table 2. Exposure Limits for Inorganic Lead
OSHA PEL | NIOSH REL | ACGIH TLV | CAL/OSHA PEL | ||||
Action level | 30 μg/m3 | Action level | 30 μg/m3 | ||||
PEL-TWA | 50 μg/m3 | REL-TWA | 50 μg/m3 | TLV-TWA | 50 μg/m3 | PEL-TWA | 50 μg/m3 |
Skin notation | no | Skin notation | no | Skin notation | no | Skin notation | no |
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Table 3. OSHA Respirator Requirements (General Industry Lead Standard)
Airborne concentration or condition of use | Required respirator |
0.5 mg/m3 or less (10 X PEL) | Half-mask* air-purifying respirator equipped with high-efficiency filters.** |
2.5 mg/m3 or less (50 X PEL) | Full-facepiece air-purifying respirator with high-efficiency filters.** |
50 mg/m3 or less (1000 X PEL) | (1) Any powered air-purifying respirator with high-efficiency filters**; or |
100 mg/m3 or less (2000 X PEL) | Supplied-air respirators with full facepiece, hood, helmet, or suit, operated in positive-pressure mode. |
More than 100 mg/m3, unknown concentration, or firefighting | Full-facepiece, self-contained breathing apparatus operated in positive-pressure mode. |
Abbreviations: PEL, permissible exposure level (OSHA) | |
Table 4. OSHA Respirator Requirements (Construction Lead Standard)
Airborne concentration or condition of use | Required respirator |
0.5 mg/m3 or lower | (1) Half-mask* air-purifying respirator with high-efficiency filters**; or |
1.25 mg/m3 or lower | (1) Loose-fitting hood- or helmet-powered air-purifying respirator with high-efficiency filters**; or |
2.5 mg/m3 or lower | (1) Full-facepiece air-purifying respirator with high-efficiency filters**; |
50 mg/m3 or lower | Half-mask-* supplied air respirator operated in pressure-demand or other positive-pressure mode. |
100 mg/m3 or lower | Full-facepiece-supplied air respirator operated in pressure-demand or other positive-pressure mode (eg, type CE abrasive blasting respirators operated in a continuous-flow mode). |
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Biologic monitoring. The U.S. OSHA standard for biologic monitoring of workers requires that both blood lead levels and zinc protoporphyrin be monitored on a regular basis (Table 5). The lead level in whole blood provides a direct measure of recent exposure, whereas zinc protoporphyrin and hemoglobin serve as measures of the biochemical effect of exposure. Zinc protoporphyrin is an indicator of average exposure to lead over the last 3 to 4 months but does not reflect recent or acute lead exposure because it does not change quickly when the source of lead exposure is removed. Erythrocyte protoporphyrin accumulates in red blood cells when insufficient iron is present for proper heme synthesis; a small percentage of erythrocyte protoporphyrin is unbound and can be measured as free erythrocyte protoporphyrin, with the remaining erythrocyte protoporphyrin (about 90%) measured as zinc protoporphyrin. Although OSHA does not set limits for zinc protoporphyrin or hemoglobin (which may fluctuate for reasons other than lead exposure), a zinc protoporphyrin of 500 µg/dL can be considered the highest permissible level for a worker with a blood lead level of 50 µg/dL. Confirmed hemoglobin levels less than 11.0 g/dL for men and less than 10.0 g/dL for women warrant investigation.
Table 5. U.S. OSHA Blood Lead Level Compliance Scheme
(A) Blood lead level requiring employee medical removal. (Level must be confirmed with a second follow-up blood lead level test within 2 weeks of the first report.) | 60 µg/dL or higher or average of last three blood samples or all blood samples over previous 6 months (whichever is over a longer time period) is 50 µg/dL or higher unless last blood sample is 40 µg/dL or lower |
(B) Frequency at which employees exposed to action level of lead (30 µg/m3 time-weighted average) must have blood lead level and zinc protoporphyrin checked: | |
(1) Last blood lead level lower than 40 µg/dL | Every 6 months |
(2) Last blood lead level between 40 µg/dL and level requiring medical removal (see A above) | Every 2 months |
(3) Employees removed from exposure to lead because of an elevated blood lead level 60 µg/dL or higher | Every 1 month |
(C) Permissible airborne exposure limit for workers removed from work due to an elevated blood lead level (without regard to respirator protection) | 30 µg/m 3- to 8-hour time-weighted average |
(D) Blood lead level confirmed with a second blood analysis, at which employee may return to work | Lower than 40 µg/dL |
Organolead (tetraethyl and tetramethyl lead)
Tetraethyllead (tetraethyl lead; TEL; Pb[C2H5]4), and to a lesser extent tetramethyl lead, was used as a fuel additive for much of the 20th century, first being mixed with gasoline beginning in the 1920s as an “antiknock agent” (ie, a gasoline additive that raised the temperature and pressure at which auto-ignition occurs, thus preventing early ignition -- knocking -- before the correctly timed spark). “Leaded gasoline” had an increased octane rating (a measure of a fuel's ability to resist knocking) that allowed engine compression to be raised substantially, improving vehicle performance and fuel economy. Many countries began phasing out the use of tetraethyllead in automotive fuel in the 1970s because of its contribution to environmental lead contamination and its negative impact on brain health, particularly in children, even though this had been opposed and effectively delayed by industry (15; 286; 253; 215; 237; 247; 305; 306; 216; 241), and the risks had been minimalized by government after its use was already established (21; 286). Since 2011, leaded gasoline has been banned in every country as an automobile fuel, although it is still used in certain grades of aviation fuel.
Inorganic mercury
Mercury production. Mercury has not been produced as a principal mineral commodity in the United States since 1992, although mercury is recovered as a byproduct from processing gold-silver ore at several mines in Nevada, and secondary, or recycled, mercury is recovered from batteries, compact and traditional fluorescent lamps, dental amalgam, medical devices, and thermostats, as well as mercury-contaminated soils (334).
Mercury use. Domestic mercury consumption has been declining in the United States for several reasons: (1) reduced use of conventional fluorescent tubes and compact fluorescent bulbs with conversion to LED lighting; (2) substitution of nonmercury-containing products in control, dental, and measuring applications; (3) conversion to nonmercury technology for chloralkali production; and (4) discontinuation of mercury use in most batteries and paints manufactured in the United States (334). Some button-type batteries, cleansers, fireworks, folk medicines, grandfather clocks, pesticides, and skin-lightening creams and soaps may still contain mercury (334).
The leading domestic end users of mercury in the United States are the chlorine-caustic soda (chloralkali), dental, electronics, and fluorescent-lighting manufacturing industries (334). Only two mercury cell chloralkali plants still operate in the United States. Beginning January 1, 2013, the export of elemental mercury from the United States was banned (with some exceptions) under the Mercury Export Ban Act of 2008, and effective January 1, 2020, exports of five additional mercury compounds were banned (334).
Table 6. Work Environments With Risk of Mercury Exposure
• Facilities where electrical equipment is manufactured |
Around the world, the most common source of occupational inorganic mercury poisoning is now artisanal and small-scale gold mining (230; 43; 03; 49; 107; 105; 106; 33; 116; 121; 233; 235; 23; 185; 186; 125; 124; 111; 153; 208; 294; 295; 40; 36; 37; 38; 39; 50; 170; 136; 167; 312; 162; 282; 315; 316; 103; 267; 277; 112; 29; 261; 260; 330; 164; 280; 271; 297; 342; 152; 236; 244; 35; 58; 118; 157; 246; 252; 255; 234; 320; 321; 113; 218; 248; 264; 268; 301; 07; 204; 332; 336; 117; 158; 211; 214; 346; 348; 189; 291; 341; 122; 166; 274).
The rapid escalation of gold prices has spurred a new gold rush in developing countries, particularly using artisanal and small-scale gold mining, ie, mining activities that use rudimentary methods to extract and process minerals and metals on a small scale (325). Globally, 14 to 19 million people, typically the poorest and most marginalized, work in artisanal and small-scale gold mining, which produces about 20% of global gold output--the world's largest anthropogenic source of mercury emissions (321). Based on human biomonitoring data, between 25% and 33% of these miners--3.3-6.5 million people globally--suffer from moderate chronic metallic mercury vapor intoxication (321). The resulting global burden of mercury poisoning from artisanal and small-scale gold mining is estimated to range from 1.22 to 2.39 million disability-adjusted life years (321).
Since the 1990s, the most severe problems with mercury poisoning related to artisanal and small-scale gold mining have been in South America's Amazon River Basin (Bolivia, Brazil, Colombia, Ecuador, Guyana, Peru, Suriname, and Venezuela) (Boischio and Cernichiari 1993; 43; 235; 186; 105; 105; 106; 208; 294; 162; 267; 29; 164; 342; 157; 07; 348; 274), Africa (185; 315; 316; 36; 38; 261; 330; 346; 291), Indonesia (36; 37; 246; 264; 204), and the Philippines (23; 125). Most artisanal and small-scale miners in the Amazon work illegally, often in protected areas where mining is prohibited. In Colombia and Venezuela, where organized crime is strongly linked to illegal gold mining, narco-terrorist and guerilla groups have extorted miners to finance their operations (329). Small numbers of cases of inhalational mercury toxicity from artisanal gold extraction continue to occur in the United States (252; 341).
Miners use liquid mercury to separate the gold from either refined ore (concentrate amalgamation) or whole ore without concentration (whole-ore amalgamation, which requires greater quantities of mercury), forming a mercury-gold amalgam. The amalgam is then heated to burn off the mercury, leaving purified gold behind; since at least the 1990s, this is typically done in the open with a blow torch for artisanal and small-scale gold mining (125; 342). Mercury-contaminated slurry is also typically discarded directly into waterways (342). This mercury-dependent gold extraction process exposes miners and their families to harmful mercury vapor and methylmercury (formed from inorganic mercury by the action of microbes that live in aquatic systems and then is bioaccumulated through the food chain) (342; 236; 214; 274).
Release into the environment. Mercury continues to be released to the environment from numerous sources, including (1) mercury-containing car switches (when automobiles produced prior to 2003 are scrapped without recovering them for recycling), (2) coal-fired powerplant emissions, (3) incineration of mercury-containing medical devices, and (4) from naturally occurring sources (334). In many developing countries, mercury used in the recovery of gold in artisanal and small-scale gold mining is burned off with blow torches into the atmosphere or is dumped into waterways.
Occupational mercury poisoning. Occupational mercury poisoning is almost always caused by inhaling mercury vapor and dust of mercury compounds. Skin contact and gastrointestinal absorption are not significant contributors to the absorption of metallic mercury, whereas methyl mercury is almost completely absorbed from the gastrointestinal tract. Some inorganic mercury compounds are nevertheless extremely toxic and corrosive; for example, as little as 1 to 4 gm of mercuric chloride (mercury[II] chloride; mercury bichloride; mercury dichloride; corrosive sublimate; HgCl2) is fatal with corrosive injury of the gastrointestinal tract, acute renal failure, and circulatory collapse (27; 52; 217; 231), whereas mercurous chloride (mercury[I] chloride or calomel, Hg2Cl2) is comparatively harmless and was used as a laxative and as a treatment for syphilis from the 17th to late 19th century.
Occupational exposure limits. Exposure limits for inorganic mercury are provided in Table 7, and NIOSH respirator recommendations based on airborne concentration of mercury vapor or condition of use are provided in Table 8.
Table 7. Exposure Limits for Inorganic Mercury*
OSHA PEL | NIOSH REL | ACGIH TLV | CAL/OSHA PEL | ||||
PEL-TWA | 0.1 mg/m3 | REL-TWA | 0.05 mg/m3 | TLV-TWA | 0.025 mg/m³ | PEL-TWA | 0.025 mg/m³ |
PEL-C | REL-C | 0.1 mg/m3 | TLV-C | PEL-C | 0.1 mg/ m³ | ||
IDLH | 10 mg/m3 | ||||||
Skin notation | Yes | Skin notation | Yes | Skin notation | Yes | Skin notation | Yes |
Abbreviations and definitions: ACGIH, American Conference of Governmental Industrial Hygienists; C, ceiling; CAL/OSHA, California Division of Occupational Safety and Health; IDLH, immediately dangerous to life or health; NIOSH, National Institute for Occupational Safety and Health; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limits; REL, recommended exposure limit; STEL, short-term exposure limit; TLV, threshold limit values (airborne concentrations of chemical substances at which it is believed that nearly all workers may be repeatedly exposed, day after day, over a working lifetime, without adverse effects); TWA, time-weighted average. | |||||||
Table 8. Respirator Recommendations (CDC/NIOSH)
Airborne Concentration or Condition of Use | Recommended Respirator |
Up to 1 mg/m3 | • (APF = 10) Any chemical cartridge respirator with cartridge(s) providing protection against the compound of concern. An ESLI is required. |
Up to 2.5 mg/m3 | • (APF = 25) Any supplied-air respirator operated in a continuous-flow mode. |
Up to 5 mg/m3 | • (APF = 50) Any chemical cartridge respirator with a full facepiece and cartridge(s) providing protection against the compound of concern. An ESLI is required. |
Up to 10 mg/m3 | • (APF = 1000) Any supplied-air respirator operated in a pressure-demand or other positive-pressure mode. |
Emergency or planned entry into unknown concentrations or IDLH conditions | • (APF = 10,000) Any self-contained breathing apparatus with a full facepiece that is operated in a pressure-demand or other positive-pressure mode. |
Escape | • (APF = 50) Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern. |
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Biological monitoring. Clinical signs are essential for diagnosis, particularly (1) neurobehavioral changes, (2) intention tremor, and (3) gum changes. A determination of urinary mercury levels, preferably a 24-hour collection, should be made, although the correlation between urinary mercury levels and clinical manifestations is poor. Special mercury-free bottles and stoppers must be used to collect blood and urine specimens.
Interpretation guidelines for urinary mercury levels (μg/L) in workers exposed to inorganic mercury vapor are as follows: normal < 10 μg/L; increased mercury absorption > 50 μg/L; warning level > 100 μg/L; hazardous level (remove from further exposure) > 200 μg/L; symptomatic poisoning likely > 300 μg/L (300).
Organic mercury
Most exposures to organic mercury are environmental rather than directly occupational, but occupational cases do occur.
Dimethyl mercury poisoning. Until 1998, dimethylmercury was the common calibration standard for 199Hg NMR spectroscopy. However, dimethylmercury is extremely toxic, and even an accidental, brief exposure can be fatal. Several deaths were reported among laboratory technicians who synthesized the compound (266; 250).
As a result of a single tragic case in 1998 (140; 250), OSHA issued a Hazard Information Bulletin (256). OSHA guidelines include the following:
• Consider the use of less hazardous substances as alternatives. | |
• Employees must wear impervious gloves and a face shield at least 8 inches in length and work under a hood when handling this chemical. Latex, neoprene, and butyl gloves do not provide adequate protection for direct contact with dimethylmercury (dimethylmercury migrates through plastics and rubber). Silver Shield laminate gloves are impermeable to dimethylmercury for at least 4 hours. Silver Shield gloves should be worn under an outer glove that is resistant to abrasion and tears. The vial containing the dimethylmercury should be clamped and the contents drawn up by means of a glass syringe and cannula. Gloves should be removed and disposed of in a manner that precludes re-entry of this material back into the workplace. All gloves that may have been in contact with dimethylmercury should be considered contaminated and not reused. | |
• Employees using organometallic compounds must be appropriately trained and aware of the toxic properties of these compounds. | |
• All spills or even suspected contact with this material must be reported immediately to the employer, and medical attention should be sought as soon as possible. Because of the high vapor pressure, dimethylmercury evaporates rapidly, and nearby workers can be quickly exposed to levels above the PEL of 0.01 mg/m3. | |
• Emergency showers and eyewash facilities must be provided within the immediate work area for emergency use in case of eye or skin contact. | |
• Medical surveillance consisting of periodic blood and urine testing of all individuals who work with this chemical on a routine or frequent basis should be provided by a physician experienced in occupational medicine. |
Manganese
Manganese ore containing 20% or more manganese has not been produced domestically in the United States since 1970 (334). Manganese ore is consumed mainly by eight firms with plants in the East and Midwest (334). Most ore consumption is related to steel production, either directly in pig iron manufacture or indirectly through upgrading the ore to ferroalloys (334). Additional quantities of ore are used in the production of dry cell batteries, in fertilizers and animal feed, and as a brick colorant (334).
The main source of manganese uptake in occupational manganese poisoning (manganism) is the inhalation of manganese dust or fumes. The primary target organs of toxicity are the lungs and the brain.
Biomarkers. The relationships between manganese biomarkers--including biomarkers in blood, plasma, serum, erythrocytes, urine, bone, toenails, fingernails, hair, and saliva--and both external manganese exposure indices and neurofunctional impairments are limited and inconsistent (313; 283; 207). Laboratory biomarkers of manganese exposure have not been proven to be useful, in part because there is a complex and limited relationship between exposure and blood manganese levels that may depend on exposure attributes and the latency of blood sampling relative to exposure; in particular, plasma and urine manganese levels appear to be of little utility as exposure biomarkers (313). Although one study reported a statistically significant association between a Cumulative Exposure Index for manganese with bone manganese levels, this was not clinically useful as the correlation was only moderate (ρ=0.44) (283).
Occupational exposure limits. Exposure limits for manganese are given in Table 9. What is distinctive about available exposure limits for manganese compared to other neurotoxic metals is the wide disparity from different sources. OSHA does not even provide a permissible exposure level time-weighted average but only a high ceiling level. In 2012, the American Conference of Governmental Industrial Hygienists recommended a 10-fold reduction in the current threshold limit value time-weighted average (TLV-TWA) for inhaled manganese particles measured over an 8-hour shift from 0.2 mg/m3 to 0.02 mg/m3. The National Institute for Occupational Safety and Health recommended exposure limit is now two orders of magnitude higher than the threshold limit value of the American Conference of Governmental Industrial Hygienists (ACGIH). Given the dramatic permanent neurotoxic damage caused by manganese, it would seem prudent to use the most stringent exposure limits, those of the ACGIH.
Table 9. Exposure Limits for Manganese
OSHA PEL | NIOSH REL | ACGIH TLV | CAL/OSHA PEL | ||||
PEL-TWA | REL-TWA | 1 mg/m³ | TLV-TWA | 0.02 mg/m³ (respirable particulate matter); 0.1 mg/m³ (inhalable particulate matter)* | PEL-TWA | 0.2 mg/m³ | |
PEL-STEL | REL-STEL | 3 mg/m³ | TLV-STEL | PEL-STEL | 3 mg/m³ | ||
PEL-C | 5 mg/m³ | REL-C | TLV-C | PEL-C | |||
Skin notation | no | Skin notation | no | Skin notation | no | Skin notation | no |
Abbreviations and definitions: ACGIH, American Conference of Governmental Industrial Hygienists; action level, level at which an employer must begin specific compliance activities, including blood lead testing for exposed workers; C, ceiling; CAL/OSHA, California Division of Occupational Safety and Health; NIOSH, National Institute for Occupational Safety and Health; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limits; REL, recommended exposure limit; STEL, short-term exposure limit (the acceptable average exposure over a short period of time, usually 15 minutes that should not be exceeded at any time during a workday); TLV, threshold limit values (airborne concentrations of chemical substances at which it is believed that nearly all workers may be repeatedly exposed, day after day, over a working lifetime, without adverse effects); TWA, time-weighted average. | |||||||
Zinc
Most cases of recognized zinc-induced copper deficiency have been either (1) self-induced (eg, coin swallowing, overuse of zinc supplements, use of zinc-laden over-the-counter products, or use of zinc-laden denture adhesives) (194; 188; 200; 290; 53; 57; 119; 08; 09; 319), (2) related to bariatric surgery (317; 175; 95; 123) or hemodialysis (251; 245), or (3) iatrogenic (eg, with intentional prescription of zinc to decrease copper levels in Wilson disease) (156; 195; 127; 129; 128; 352; 94).
Zinc interferes with copper absorption and metabolism (335; 148; 225; 147; 228; 221). Zinc blocks copper absorption by inducing intestinal metallothionein, which binds copper. Metallothionein is a family of cysteine-rich, low molecular-weight proteins that are localized to the membrane of the Golgi apparatus. Metallothionein has the capacity to bind both physiological (eg, zinc, copper, selenium) and xenobiotic (such as cadmium, mercury, silver, arsenic, lead) heavy metals through the thiol group of its cysteine residues, but it has a higher binding affinity for copper than for zinc. When intestinal mucosa cells slough into the bowel lumen, the metallothionein-bound copper is excreted in the stool. Oral intake of zinc exceeding the minimum daily requirements for zinc (approximately 15 mg/day) can deplete total body copper stores, but this may take years (221). Zinc also induces hepatic metallothioneins that bind copper in a sequestered form (228), and zinc further interferes with the function of copper-containing metalloenzymes (225; 147).
Occupational exposure limits. Occupational exposure limits for zinc are shown in Table 10.
Table 10. Exposure Limits for Zinc
OSHA PEL | NIOSH REL | ACGIH TLV | CAL/OSHA PEL | ||||
PEL-TWA | 5 mg/m3 | REL-TWA | 5 mg/m3 | TLV-TWA | 5 mg/m³ | PEL-TWA | 5 mg/m³ |
PEL-STEL | REL-STEL | 10 mg/m3 | TLV- STEL | 10 mg/m³ (respirable particulate matter) | PEL-STEL | 10 mg/ m³ | |
Skin notation | No | Skin notation | No | Skin notation | No | Skin notation | No |
| |||||||
Thallium
Thallium is a heavy metal used in the manufacture of electronic components, optical lenses (for infrared detection and transmission equipment), semiconductor materials for wireless communications, alloys, gamma radiation detection equipment (scintillometer), imitation jewelry, artist's paints, low-temperature thermometers, and green fireworks (334). Thallium is also used as an additive in glass to increase its refractive index and density, a catalyst for organic compound synthesis, and a component in high-density liquids for gravity separation of minerals (334). Trace amounts of radioactive thallium-201 are used for medical purposes in cardiovascular imaging.
Occupational thallium exposure may occur at smelters in the maintenance and cleaning of ducts and flues. Criminal and unintentional thallium poisonings are still reported.
Thallium neurotoxicity. The mechanisms of thallium neurotoxicity are unclear but are probably multifactorial (354; 210):
(1) Thallium is structurally similar to potassium but is more strongly associated with the sodium-potassium ATPase channel (with 10-fold greater affinity than potassium). Tissues with high potassium concentrations accumulate large concentrations of thallium, causing early stimulation, followed by inhibition of potassium-dependent processes. | |
(2) Intracellularly, thallium interferes with the function of enzymes by binding sulfhydryl groups. Inhibiting pyruvate kinase and succinate dehydrogenase disrupts the Kreb’s cycle and glucose metabolism, with resultant decreased ATP production, swelling, and vacuolization due to impairment of the sodium-potassium ATPase. Thallium’s high affinity for disulfide bonds also disrupts cysteine residue cross-linking, causing a reduction in keratin formation. | |
(3) Thallium-induced riboflavin sequestration and inhibition of flavin adenine dinucleotide disrupts the electron transport chain and decreases ATP production. Secondary riboflavin deficiency can itself cause dermatitis, alopecia, Mees’ lines, and neuropathy. | |
(4) Thallium damages ribosomes and thereby impairs protein synthesis. | |
(5) Thallium causes degeneration of myelin in the central and peripheral nervous systems by an unknown mechanism. |
Occupational exposure limits. Occupational exposure limits for thallium are shown in Table 11.
Table 11. Exposure Limits for Thallium*
OSHA PEL | NIOSH REL | ACGIH TLV | CAL/OSHA PEL | ||||
PEL-TWA | 0.1 mg/m3 | REL-TWA | 0.1 mg/m3 | TLV-TWA | 0.1 mg/m3 | PEL-TWA | 0.2 mg/m³ |
Skin notation | Yes | Skin notation | Yes | Skin notation | Yes | Skin notation | Yes |
Abbreviations and definitions: ACGIH, American Conference of Governmental Industrial Hygienists; action level, level at which an employer must begin specific compliance activities, including blood lead testing for exposed workers; C, ceiling; CAL/OSHA, California Division of Occupational Safety and Health; NIOSH, National Institute for Occupational Safety and Health; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limits; REL, recommended exposure limit; STEL, short-term exposure limit (the acceptable average exposure over a short period of time, usually 15 minutes that should not be exceeded at any time during a workday); TLV, threshold limit values (airborne concentrations of chemical substances at which it is believed that nearly all workers may be repeatedly exposed, day after day, over a working lifetime, without adverse effects); TWA, time-weighted average. | |||||||
Tin and organotin compounds
Organotin compounds are widely used in the industrial preparation of polyvinylchloride plastics, as fungicides and pesticides on crops, as slimicides in industrial water systems, as wood preservatives, and as marine antifouling agents.
Occupational exposure limits. Occupational exposure limits for tin and organotin compounds are shown in Tables 12 and 13. Note the order-of-magnitude lower thresholds for organotin compounds than for inorganic tin.
Table 12. Exposure Limits for Inorganic Tin Compounds (Except Oxides)
OSHA PEL | NIOSH REL | ACGIH TLV | CAL/OSHA PEL | ||||
PEL-TWA | 2 mg/m3 | REL-TWA | 2 mg/m3 | TLV-TWA | 2 mg/m3 (inhalable particulate matter) | PEL-TWA | 2 mg/m³ |
Skin notation | no | Skin notation | no | Skin notation | no | Skin notation | no |
| |||||||
Table 13. Exposure Limits for Organic Tin Compounds
OSHA PEL | NIOSH REL | ACGIH TLV | CAL/OSHA PEL | ||||
PEL-TWA | 0.1 mg/m3 | REL-TWA | 0.1 mg/m3 | TLV-TWA | 0.1 mg/m3 (inhalable particulate matter) | PEL-TWA | 0.1 mg/m³ |
PEL-STEL | REL-STEL | TLV-STEL | 0.2 mg/m³ | PEL-STEL | 0.2 mg/m³ | ||
Skin notation | No | Skin notation | Yes | Skin notation | Yes | Skin notation | Yes |
| |||||||
Arsenic
Arsenic trioxide and arsenic metal have not been produced in the United States since 1985 (334). Arsenic trioxide is primarily used for production of arsenic acid for the chromated copper arsenide preservatives used in pressure-treated lumber (334). Arsenic metal is used to strengthen the grids in lead-acid storage batteries, as an antifriction additive for bearings, to harden lead shot, and in clip-on wheel weights (334). Arsenic compounds are used in herbicides and insecticides. High-purity (99.9999%) arsenic metal is used to produce gallium arsenide, indium-arsenide, and indium-gallium-arsenide semiconductors used in biomedical, communications, computer, electronics, and photovoltaic applications (334).
China and Morocco are the leading global producers of arsenic trioxide, accounting for about 90% of estimated world production and almost all United States imports (334). China is also the leading world producer of arsenic metal and supplies about 90% of United States imports (334).
Most reports of occupational arsenic poisoning concern non-nervous-system cancers and arsenic-induced dermatologic toxicity. Reports of occupational arsenic poisoning after the 19th century are rare from the United States and Europe, and few concern arsenic neurotoxicity, such as arsenical neuropathy.
Occupational exposure limits. Occupational exposure limits for arsenic are shown in Table 14.
Table 14. Exposure Limits for Arsenic
OSHA PEL | NIOSH REL | ACGIH TLV | CAL/OSHA PEL | ||||
Action level | 5 μg/m3 | Action level | 5 μg/m3 | ||||
PEL-TWA | 10 μg/m3 | REL-TWA | TLV-TWA | PEL-TWA | 10 μg/m3 | ||
PEL-STEL | REL-STEL | TLV-STEL | PEL-STEL | ||||
PEL-C | REL-C | 2 μg/m3 | TLV-C | PEL-C | |||
Skin notation | no | Skin notation | no | Skin notation | no | Skin notation | no |
Abbreviations and definitions: ACGIH, American Conference of Governmental Industrial Hygienists; action level, level at which an employer must begin specific compliance activities for exposed workers; C, ceiling; CAL/OSHA, California Division of Occupational Safety and Health; NIOSH, National Institute for Occupational Safety and Health; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limits; REL, recommended exposure limit; STEL, short-term exposure limit (the acceptable average exposure over a short period of time, usually 15 minutes that should not be exceeded at any time during a workday); TLV, threshold limit values (airborne concentrations of chemical substances at which it is believed that nearly all workers may be repeatedly exposed, day after day, over a working lifetime, without adverse effects); TWA, time-weighted average. | |||||||
Clinical applications
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• The predominant neurologic manifestations of lead poisoning are lead encephalopathy (acute and chronic forms) and lead palsy. | |
|
• Acute lead encephalopathy (usually with blood lead levels exceeding 100 μg/dL) is variably manifest as headache, insomnia, fatigue, memory loss, depression, irritability, restlessness, confusion, altered level of consciousness, and seizures. | |
|
• Severe cases of lead encephalopathy develop cerebral edema, often with headache and persistent and forceful vomiting, and progress rapidly from apathy to stupor to coma, often with intractable seizures (or status epilepticus), and ultimately death. | |
|
• Lead neuropathy or lead palsy is a motor neuropathy, typically affecting predominantly extensor muscles (often unilaterally), without associated sensory involvement. | |
|
• The most common neurologic manifestation of inorganic mercury poisoning (although often not the first) is a bilateral intention tremor (although a minimal rest component was noted in some cases). Neurologic manifestations may also include impaired cognition, neurobehavioral symptoms or erethism (eg, mood swings, irritability, irascibility, excitability, nervousness, timidity, shyness, loss of confidence, depression, moroseness), disturbances of smell and taste, constricted visual fields or blindness, possibly disturbances of the extraocular muscles, incoordination or ataxia, impaired motor speed, and slowed nerve conduction. | |
|
• Manganese is recognized to cause an unusual extrapyramidal syndrome with atypical parkinsonism and often with dystonic features. | |
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• The pathophysiology of zinc-induced myeloneuropathy elaborated as resulting from secondary copper deficiency. | |
|
• Acute thallium poisoning is primarily characterized by gastrointestinal, neurologic, and dermatological symptoms, whereas neurologic findings predominate with chronic exposure. |
Occupational lead poisoning
Lead has neurologic, hematologic, gastrointestinal, renal, and cardiovascular effects. The predominant neurologic manifestations of lead poisoning are lead encephalopathy (acute and chronic forms) and lead palsy. Acute lead encephalopathy (usually with blood lead levels exceeding 100 μg/dL) is variably manifest as headache, insomnia, fatigue, memory loss, depression, irritability, restlessness, confusion, altered level of consciousness, and seizures. Severe cases develop cerebral edema, often with headache and persistent and forceful vomiting, and progress rapidly from apathy to stupor to coma, often with intractable seizures (or status epilepticus), and ultimately death. Pathologically acute lead encephalopathy is characterized by vasogenic cerebral edema, with petechial hemorrhages, cerebellar and cerebral cortical damage, partial loss of myelin, and associated astrocytic reaction. On MRI, patients with acute lead encephalopathy may demonstrate hyperintensity in the white matter and basal ganglia that may diminish after chelation therapy; with chronic lead poisoning, progressive atrophy may develop in the frontal gray matter and the anterior cingulate cortex. The prognosis of acute lead encephalopathy is often poor, with a mortality of at least 5% even with prompt chelation therapy and permanent brain damage in at least 25% of survivors. Residual neurologic impairment can include dementia, blindness, or more subtle abnormalities (eg, poor learning ability and behavioral abnormalities such as aggressiveness, hostility, and destructive behavior).
Lead neuropathy or lead palsy is a motor neuropathy, typically affecting predominantly extensor muscles (often unilaterally), without associated sensory involvement. Before frank lead palsy develops, affected individuals often report muscle aches and tenderness, increased fatiguability, and sometimes a fine tremor. Because the most heavily used muscles are most often affected, the typical presentation is a wrist drop of the dominant hand. Other muscles of the upper extremities, extensors of the lower extremities, and the extraocular muscles are involved less often. The responsible lesion generally involves the motor neurons peripherally, although the lesion may sometimes involve the anterior horn cells. The prognosis of lead neuropathy is generally poor, although some milder cases may be healed with chelation therapy.
Toxic optic neuritis may occur but is uncommon, especially in adults.
Further lead exposure after clinically evident central or peripheral nervous system involvement. The hematologic effects of lead poisoning result from inhibition of hemoglobin synthesis and a shortened life span of circulating erythrocytes. Hematologic effects include anemia (often microcytic and hypochromic initially, but often normochromic and normocytic in the chronic stage) with reticulocytosis and basophilic stippling of erythrocytes.
Gastrointestinal effects include anorexia, digestive disturbances, postprandial epigastric discomfort, and constipation or diarrhea. With blood lead levels exceeding 100 μg/dL, frequent colicky abdominal pain and severe constipation are likely, with classic lead colic typical with blood lead levels exceeding 150 μg/dL. Lead colic is characterized by “sharp onset and recurrent spasms in which the patient writhes in pain, retracts his legs spasmodically to his abdomen, groans, clenches his hands, grits his teeth, with beads of sweat on his brow” (209).
Heavy and prolonged lead exposure (usually of at least 10-year's duration) may cause a progressive and irreversible renal disease, typically accompanied by hypertension. Lead nephropathy causes damage to the proximal tubules and, in severe cases, can cause Fanconi syndrome (ie, aminoaciduria, glucosuria, and hyperphosphaturia with hypophosphatemia) and saturnine gout (because of impaired excretion of urates).
Occupational organolead (tetraethyl and tetramethyl lead) poisoning
Workers involved in manufacturing tetraethyllead were at risk of acute lead poisoning involving encephalopathy, neuropathy, and toxic myoclonus, typically via inhalation (11; 12; 13; 14; 16; 17; 18; 19; 20; 101; 102; 142; 56; 279; 26; 100; 96; 333; 254; 353; 239; 340; 243; 130; 355) but occasionally from occupational accidents with inhalational and transdermal exposure and profound neurologic consequences after even brief exposure (168). To a lesser degree, individuals chronically exposed to car exhaust (eg, traffic policemen in large cities) also had higher lead exposures (263).
Tetraethyllead also caused acute non-occupational lead poisoning (especially encephalopathy and neuropathy) from recreational inhalant abuse, such as gasoline (petrol) sniffing or “huffing” (32; 278; 161; 287; 104; 131; 155; 205; 45; 46; 327; 47). Althopugh gasoline sniffing still carries severe health risks, including death, the risk of acute lead poisoning from recreational gasoline sniffing in the late 20th century has been eliminated with the removal of tetraethyllead from gasoline.
Ingestion was a rare route of tetraethyllead toxicity. An adolescent who unintentionally ingested a fuel stabilizer containing 80% to 90% tetraethyllead developed severe neurologic manifestations, including agitation, hallucinations, weakness, and tremor (350). He ultimately required endotracheal intubation and a propofol infusion, chelation, baclofen, and nutrition provided through a gastrostomy tube. The patient slowly recovered and, after 2 months, had near-resolution of symptoms with residual slurred speech and a slight limp.
Occupational inorganic mercury poisoning
Acute mercury poisoning from inhalation of high concentrations of mercury vapor or dust can manifest within hours to several days of exposure with irritation of eyes and skin, hypersalivation (ptyalism), gingivitis, stomatitis, metallic taste, headache, insomnia, irritability, indecision, lassitude (weakness, exhaustion), coughing and dyspnea due to acute pneumonitis and bronchitis or bronchiolitis, chest tightness or pain, gastroenteritis (abdominal pain, nausea, vomiting, diarrhea), and albuminuria or proteinuria. A dark “mercury line” may form on the inflamed gums due to accumulation of mercury sulfide, the teeth may loosen, and ulcers may develop on the oral mucous membranes. More severe cases develop tremor and neurobehavioral symptoms (erethism) (326); the neurobehavioral manifestations of erythrism are now considered to include anxiety, excessive timidity, diffidence, increasing shyness, loss of self-confidence, and an explosive loss of temper when criticized (345).
Chronic mercury poisoning presents with a similar range of clinical manifestations. The mouth may show generalized inflammation, with tender gingivitis and stomatitis, loose teeth, and discolored gums with bluish or black dots along the gum line. The salivary glands may swell. Either hypersalivation or a dry mouth may occur. There may also be nasal irritation, epistaxis, anorexia, facial pallor, anemia, excessive perspiration, discoloration of the cornea and lens (mercurialentis; hydrargyrosis lentis) (24), and decrements in glomerular function and renal tubular injury (02). The most common neurologic manifestation (although often not the first) is a tremor (262; 90; 91; 141; 144; 06; 89; 249; 347; 171). The tremor is predominantly a bilateral intention tremor (90; 91; 144; 171), “completely subsiding during sleep, hardly noticeable at rest, and triggered by voluntary use of the affected muscle” (144). The hands were most affected by mercurial tremor, but the eyelids, head, and tongue could also manifest mercurial tremor, with secondary effects on speech (171). Although predominantly an intention tremor, a minimal rest component was noted in some cases (171). Neurologic manifestations may also include impaired cognition, neurobehavioral symptoms or erethism (eg, mood swings, irritability, irascibility, excitability, nervousness, timidity, shyness, loss of confidence, depression, moroseness), disturbances of smell and taste, constricted visual fields or blindness, possibly disturbances of the extraocular muscles, incoordination or ataxia, impaired motor speed, and slowed nerve conduction (02).
Occupational dimethylmercury poisoning
In 1998, a case of accidental dimethylmercury poisoning was reported in a professor of chemistry at Dartmouth University, Karen Wetterhahn (1948-1997) (140; 250). Her research focused on the biological toxicity of heavy metals. She handled dimethylmercury on only 1 day, in August 1996, while wearing latex gloves and working under a ventilated hood designed to prevent exposure to chemical fumes. Unfortunately, she spilled one or two drops of dimethylmercury from the tip of a pipette onto her latex-gloved hand, which led to rapid, progressive neurologic dysfunction and death.
Approximately 3 months after the incident, she began experiencing brief episodes of abdominal discomfort and developed significant weight loss. Distinctive neurologic symptoms, including loss of balance and slurred speech, appeared in January 1997, 5 months after the accident. Examination showed moderate upper-extremity dysmetria, ataxia, a wide-based gait, and mild “scanning speech.” Despite chelation therapy with succimer, she experienced rapid deterioration. Three weeks after the first neurologic symptoms appeared, she lapsed into a nearly vegetative state punctuated by periods of extreme agitation. She was removed from life support less than a year after her exposure. Autopsy disclosed extensive damage involving (1) the cerebral cortex, especially the calcarine area, with necrosis of neurons and gliosis, and (2) the cerebellum, with extensive neuronal loss.
Occupational manganese poisoning (manganism)
The first report of manganese neurotoxicity was by Couper in 1837, but subsequent reports did not occur until the beginning of the 20th century, more than 60 years later (108; 109; 337; 338; 339; 138; 139; 159; 303; 54; 55; 302; 126; 126; 134; 92; 114; 165; 184; 51; 229; 31; 191). Couper reported five stereotyped cases in workers grinding “manganese peroxide” [sic, manganese dioxide; there is no oxygen-oxygen peroxide bond] (108): “Their skin is constantly covered with a layer of the oxide, and the air which they breathe is impregnated with a multitude of molecules of this oxide which are introduced into their lungs by respiration.” In describing the manifestations in one worker who had previously been healthy, Couper highlighted progressive neurologic symptoms that developed over a period of several months:
The weakening of muscle contractility was much greater in the lower extremities; it was such that the patient's legs wobbled, and he leaned forward when he wanted to try to walk; the arms were weak in a small expanse; the patient complained while speaking; he couldn't be heard by anyone at a short distance like he used to; the other sensations and those of the intelligence had lost nothing; the muscles of the face had the same appearances as those of paralytics; saliva came out of the mouth, especially when speaking; no tremor of any other part of the body; no colic, no constipation, no disturbance in the digestive functions. (109; translation by Dr. Douglas J Lanska) |
The patient's symptoms progressed while he worked grinding manganese ore but stabilized when he left for another country; nevertheless, his neurologic impairment persisted for years but gradually improved when he was not grinding manganese ore: “It was not until the end of 6 years that this patient felt well-being.”
Several other important clinical and occupational studies were published in the mid-20th century (22; 151; 281; 240; 137; 99; 296; 198; 197; 193; 242). Now, manganese is recognized to cause an unusual extrapyramidal syndrome with atypical parkinsonism and often with dystonic features. Clinical manifestations develop after a variable latent period of several months to as long as 10 years, likely as a function of the amount of manganese dust inhaled and individual susceptibility. Early neurobehavioral symptoms, developing within the first several months of exposure, include insomnia or somnolence, apathy, asthenia or lassitude, and a combination of aggressiveness and excitement (labeled “manganese psychosis”) (01; 42; 177; 41). Other early symptoms include headache, myalgias and muscle cramps, decreased libido and impotence, increased salivation (ptyalism), diaphoresis, altered speech, clumsiness, and paresthesia. As the disease progresses, parkinsonian features become more apparent, including hypophonic, monotonous speech and an expressionless facial appearance (masked facies). The gait develops a festinating character with markedly impaired postural stability; attempting quick turns or walking backward results in falls, and even balancing in place becomes impossible. Individuals with advanced manganism have a peculiar slow, labored, high-stepped and somewhat stiff-legged gait, later called hähnentritt (cock walk) (134), sometimes attributed to von Jaksch (337; 338), but neither of von Jaksch's reports used this terminology. In any case, this peculiar gait has since been noted by others, even if it occurs in a minority of reported cases (143; 196; 212; 93).
In 1955, Rodier published an excellent study of manganism in Moroccan miners, with a detailed clinical description divided into three stages: a prodromal period, an intermediate phase, and an established phase (281) (Table 15).
Table 15. Clinical Course of Manganism in 115 Moroccan Miners Exposed to Manganese
Prodromal period | ||
• Asthenia | ||
Intermediate phase | ||
• Alterations of speech (70%) | ||
- Voice becomes monotonous, lacking modulation | ||
• “Masque manganique”: facial expression is at once jovial and fixed, giving the individual a “dazed appearance” (65%) | ||
- Spasmodic laughter “mostly evoked by trivialities and quite disproportionate to the events or emotions provoking it” (47%) | ||
• Movements clumsy, slow, and uncertain (82%) | ||
- Climbing or descending ladders | ||
• Loss of arm swing while walking (frequency unstated) | ||
Established phase | ||
• Alterations of speech may progress to mutism “The patient starts with his trunk bent forward as though he were trying to drag his feet from the ground. The steps are short and hesitant. He moves with legs spread apart and knees stretched [extended]. Sometimes the feet seem to be flung forward, the toe describing a half-circle at each step. Eventually the patient is able to progress normally by putting his feet flat on the ground. In the majority of cases purchase is obtained with the ball of the foot, and this is the gait named “Hahnetrett” [sic, Hähnen tritt or cock walk] or “pas du coq” [sic, marche du coq] ... Only rarely is the contact made along the external border of the foot. Some patients are able to progress only when supported by another [person] or with a stick. The staggering so often seen does not appear to be of cerebellar origin but rather due to hypertonia which, slowing down the automatic movements conserving balance, obliges the patient to walk with straddled legs. Walking backwards is impossible, the patient who attempts it fall backwards at once or after a few steps. Climbing up or descending a ladder has long since been abandoned... Ther half-turn becomes progressively more difficult, the patient achieving it by little steps, very slowly. In certain cases it becomes impossible, the sick man losing his balance and falling.” (281; p24) | ||
• Impaired mobility | ||
- Voluntary gestures carried out very slowly and often decomposed into component movements | ||
• Postural instability: | ||
- Widened stance: “It is often impossible to maintain balance standing upright with feet together” (even with eyes open) | ||
• Tremor (action tremor, not a rest tremor): “Usually they affect the upper limbs, less often the legs, and are of moderate amplitude and frequency, rhythmic, and regular. Exceptionally generalized shaking may involve the whole body and affect arms and legs equally.” | ||
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The manganese-induced extrapyramidal disorder does not respond much, if at all, to l-dopa in most cases (308; 258; 224), although uncommonly, some affected individuals can achieve modest benefit (285). Other clinical distinguishing features in manganism compared with Parkinson disease include a straddling stance (very wide base), a strong propensity to fall backward, more frequent dystonia, more action tremor, and less resting tremor (48; 258; 176; 178; 224). MRI in manganism shows hyperintense signals in the medial and lateral part of the globus pallidus, putamen, and, to a lesser extend, in part of thalamic nuclei, substantia nigra, dentate nucleus, and pontine tegmentum (309; 199; 110; 132; 180); these changes may gradually disappear in the absence of continued exposure. The neuropathology of the manganese-induced extrapyramidal disorder is quite distinct from that of Parkinson disease; it is characterized by damage to the globus pallidus (particularly the internal segment) with sparing of the substantia nigra pars compacta and the absence of Lewy bodies (269). Similarly, in experimental manganese intoxication in the rhesus monkey, manganese primarily damages the globus pallidus and the substantia nigra pars reticularis and relatively spares the nigrostriatal dopaminergic system (259).
Since around 2007, an outbreak of manganese-induced parkinsonism associated with methcathinone (alpha-methylamino-propiophenone or ephedrone) abuse has been identified in Russia and Eastern Europe, particularly Estonia, Latvia, Poland, and Ukraine. This syndrome recapitulates the clinical, radiologic, and pathologic findings of occupational manganism, especially the most severe forms of this condition (115; 293; 292; 304; 322; 323; 97; 311; 309; 199; 160; 34; 272; 120; 202; 310; 206; 180; 232). Methcathinone is a monoamine alkaloid and psychoactive stimulant that is used as a recreational drug due to its potent stimulant and euphoric effects; methcathinone is addictive, with both physical and psychological withdrawal occurring if its use is discontinued after prolonged or high-dosage administration. Methcathinone can be illicitly manufactured by oxidation of ephedrine and pseudoephedrine contained in various pharmaceutical products for colds and allergies. In Russia and Eastern Europe, an intravenous preparation is produced by potassium permanganate oxidation in the presence of acetic acid, whereas in North America, powder for inhalation or nasal insufflation is made by chromate oxidation in the presence of sulfuric acid (322). The use of potassium permanganate (KMnO4) in preparation followed by intravenous injection in Russia and Eastern Europe is responsible for delivering very high doses of manganese directly into the bloodstream.
Occupational zinc poisoning
19th-century reports of zinc toxicity involved primarily acute or subacute presentations with prominent respiratory and gastrointestinal symptoms, along with transient headaches and “vertigo” (298). In workers exposed to metal fumes, acute toxicity was recognized by such terms as “spelter shakes,” “spelter chills,” “zinc chills,” “zinc fever,” “casting fever,” “smelter-worker’s arthropathy,” “brass-founder’s ague,” and “brass-workers’ disease” (298; 299; 10). Initial symptoms of malaise, back pain, and arthralgias were followed in several hours by rigors, tachycardia, chest pain, coughing, and a severe frontal headache, followed by diaphoresis. Although it was initially unclear which specific metals were responsible, zinc was later implicated. Chronic zinc toxicity was recognized by digestive problems and anemia in epileptics who chronically used oral zinc oxide (270).
Zinc-induced myelopathy was a recognized problem in the late 19th century with chronic therapeutic use of zinc salts (187; 88) and in zinc smelter workers exposed to zinc fumes (298; 299; 227). In the 1870s, Schlockow described a progressive ataxic myelopathy among 36 workers chronically exposed to zinc fumes in three smelting plants in Schoppinitz (now Szopienice) in Upper Silesia (298, 1879; 227). Throughout the 20th century, workers in zinc smelters, foundry workers, and workers involved in brass casting often had inadequate protection from zinc fumes and zinc dust (284; 163).
Zinc-induced myeloneuropathy was recently (re)discovered, and its pathophysiology elaborated as resulting from secondary copper deficiency (220; 290; 317; 314; 95; 213; 172; 53; 57; 123; 251). In addition to a myeloneuropathy, hypocupremia due to zinc products can cause sideroblastic anemia and neutropenia or pancytopenia (265; 44; 324; 149; 273; 190; 200; 351; 328; 203; 119; 343; 344; 09; 245; 223; 179; 319).
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Bone marrow biopsy sample of a 74-year-old woman showing a ringed sideroblast
Biopsy with Perls Prussian blue stain (H&E, 50x), ie, blue color staining the erythroid precursor. Abbreviation: H&E, hematoxylin, and eosin. (Source: Stagg MP, Miatech J, Majid B, Polala R. Zinc-containing over-the-cou...
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Bone marrow biopsy sample of a 74-year-old female demonstrating cytoplasmic vacuolization of myeloid precursors
(H&E, 100x). Abbreviation: H&E, hematoxylin, and eosin. (Source: Stagg MP, Miatech J, Majid B, Polala R. Zinc-containing over-the-counter product causing sideroblastic anemia and neutropenia. Cureus 2024;16(5):e59796. C...
The myeloneuropathy in such cases resembles subacute combined degeneration due to vitamin B12 deficiency with a subacute onset, slowly progressive spastic-ataxic gait difficulty, marked dorsal column deficits and Rombergism, variable weakness in legs (late), brisk muscle stretch reflexes (except variably depressed ankle jerks), variable Babinski signs, and distal paresthesias, dysesthesias, and sensory loss (226; 222; 174; 219). The prominent proprioceptive impairment, sensory disequilibrium, and Rombergism result from posterior-column dysfunction rather than from the relatively mild axonal neuropathy (174; 173).
Occupational thallium poisoning
Thallium poisoning may cause gastrointestinal, neurologic, dermatological, circulatory, and respiratory symptoms. Acute thallium poisoning is primarily characterized by gastrointestinal, neurologic, and dermatological symptoms, whereas neurologic findings predominate with chronic exposure. Gastrointestinal symptoms, including nausea, vomiting, abdominal pain, and distension, are usually the first manifestations of thallium poisoning but are nonspecific and typically attributed to other more common causes. Dermatologic manifestations include alopecia, which is often the clinical finding that leads to the recognition of heavy metal poisoning and eventually to a specific diagnosis of thallium poisoning (354). Neurologic damage following thallium poisoning can include polyneuropathy with paresthesia, dysesthesia, and hypoalgesia in the distal limbs. Thallium intoxication may also cause CNS pathology, including cranial neuropathies, ataxia, tremor, and mental disturbances, such as poor attention, anxiety, depression, altered consciousness, hallucinations, and paranoid syndromes (331). Affected individuals may develop hyperreflexia initially, followed after several weeks by hyporeflexia. In forensic poisoning, thallium neuropathy has frequently been misdiagnosed as diabetic peripheral neuropathy or Guillain-Barré syndrome. MRI in thallium-poisoned individuals may show increased signal intensity lesions in the corpus striatum on T2-weighted and FLAIR sequences. Treatment of thallium toxicity consists of initial stabilization, prevention of absorption, enhanced elimination (hemodialysis), and antidotal therapy (Prussian blue).
There are relatively few reports or discussions of occupational thallium poisoning, particularly in the last 50 years (other than a few that represented murder or attempted murder cases in work settings) (238; 135; 169; 276; 307; 192; 25; 318). Very few of these in the last 50 years were original reports associated with neurologic manifestations (192).
Hirata and colleagues in Japan reported a male worker who handled thallium-containing raw material for glass manufacturing over a period of 4 years and complained of alopecia, abdominal pain, diarrhea, and paresthesia in the extremities (192). Neurologic examination revealed signs of mild peripheral polyneuropathy. Sensory nerve conduction velocity of the median nerve was lower in the right hand than in the left hand, suggesting that conduction function in the dominant hand was reduced. The thallium content of hair, as determined by inductively coupled plasma mass spectrometry, was 20 ng/g 32 months after he had ceased glass production work; the thallium content of hair for his successor was 576 ng/g at 13 months. Those levels were high compared with the control levels. The clinical course of signs and symptoms, neurophysiological findings, and thallium content of hair supported chronic poisoning due to occupational exposure to thallium-containing dust.
Occupational organotin poisoning
Occupational neurotoxicity has been reported for organotin compounds (154; 288; 289; 30; 275; 98; 145; 146) (Table 16). Manifestations include headaches, dermatologic abnormalities, neuropsychiatric abnormalities, anorexia, seizures, blurred vision, nystagmus, hearing loss, ataxia, and neuropathy.
Table 16. Occupational Organotin Intoxication
Source | Subjects | Exposure | Clinical features | Tests |
(154) | Two chemists | Trimethyltin and dimethyltin | Headaches, impaired vigilance and memory, confusion, disorientation, insomnia, anorexia, pain, seizures (tonic-clonic) | |
(288; 289) | 12 workers with high exposure vs. 10 with low exposure | Trimethyltin | Headaches, alternating rage and depression, poor concentration, forgetfulness, disorientation, stuttering, sleep disturbance, loss of libido and motivation, fatigue, weakness, dim vision | Urine tin levels 20 to 200 parts per billion; EEG showed no specific abnormalities; slow nerve conduction velocity; neuropsychological testing showed impaired verbal memory, fine hand-eye coordination, visual motor integration, finger tap speed, and learning; emotional disturbances. |
(275; 30) | Six workers | Trimethyltin | Amnesia, disorientation, confabulation, confusion, restlessness, aggressiveness, hyperphagia, disturbed sexual behavior, seizures, blurred vision, nystagmus, hearing loss, ataxia, neuropathy, death | Urine tin 445 to 1580 parts per billion 4 to 8 days after exposure; EEG was normal except theta activity in fatal case; autopsy in fatal case showed necrosis in limbic system, pons, and cerebellum. |
(98) | One worker | Triphenyltin acetate pesticide (accidentally spilt on arm) | 12 to 24 hours after exposure: bilateral plantar pain, severe genital edema, erythematous eruption on trunk; 2 days after exposure: general malaise, dizziness, nausea, abdominal pain, hepatomegaly; next 6 months: periodic urticaria on trunk and arms | EEG showed generalized paroxysmal abnormalities and bradyrhythmia. |
(145; 146) | One chemist | Trimethyltin | Memory impairment, disorientation, depression, fatigue, insomnia, amotivation and indifference, complex partial seizures (persistent) | Acute urine tin > 52 parts per billion; serum tin 13 parts per billion, 17 days after exposure (normal, < 3.3); EEG left paroxysmal theta; MRI normal; serial neuropsychological assessments over 4-year period revealed residual memory impairments. |
Media
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Douglas J Lanska MD MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
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