Peripheral Neuropathies
Toxic peripheral neuropathies
Jun. 11, 2026
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Occupational neurotoxicology: metals …
- Updated 12.02.2025
- Released 12.02.2025
- Expires For CME 12.02.2028
Occupational neurotoxicology: overview
Introduction
Overview
This overview article outlines some of the history of occupational medicine and industrial hygiene concerning neurotoxic substances, the United States Occupational Safety and Health Act of 1970, various types of safety monitoring thresholds for occupational exposures, neurologic occupational sentinel health events, occupational controls to limit or prevent occupational exposures, heuristics for recognizing neurotoxic disease, and suggestions for taking an occupational exposure history. This article will not cover medicolegal aspects of occupational neurotoxicology, para-occupational (“take home”) poisoning, or industrial environmental contamination.
Key points
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• The Occupational Safety and Health Act of 1970 is a U.S. labor law governing occupational health and safety in the private sector and federal government in the United States. Its main goal is to ensure employers provide employees with a safe working environment free from recognized hazards, such as exposure to toxic chemicals, excessive noise levels, mechanical dangers, heat or cold stress, or unsanitary conditions. | |
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• Under the Occupational Health and Safety Act, employers must identify and rectify safety and health problems. Employers must first attempt to eliminate or reduce hazards by making feasible changes in working conditions rather than relying solely on personal protective equipment. | |
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• According to the National Institute for Occupational Safety and Health, a sentinel health event is a “preventable disease, disability, or untimely death whose occurrence serves as a warning signal that the quality of preventive or therapeutic medical care may need to be improved.” A sentinel health event (occupational) is a sentinel health event that is occupationally related and whose occurrence may (1) provide the impetus for epidemiologic or industrial hygiene studies or (2) serve as a warning signal that materials substitution, engineering control, personal protection, or medical care may be required.” | |
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• The neurologic conditions associated with occupational exposures, as outlined by the National Institute for Occupational Safety and Health, focus on encephalopathies, parkinsonism and other movement disorders, cerebellar ataxia, and peripheral neuropathy. | |
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• A hierarchy of occupational controls is used to implement feasible and effective control solutions, resulting in inherently safer systems where the risk of illness or injury has been substantially reduced. Although elimination and substitution are the most effective means of reducing hazards, they are typically the most difficult to implement in an existing process because they often require major changes in equipment and procedures. Engineering controls are favored over administrative and personal protective equipment for controlling worker exposures because they remove the hazard at the source before these hazards contact the worker. | |
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• Neurotoxicity often manifests with nonfocal nervous system pathology that mimics metabolic, degenerative, nutritional, and demyelinating diseases. | |
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• Clinical laboratory tests are of limited use for most occupational neurotoxic exposures because (1) specific tests do not exist for most neurotoxins, (2) neurotoxins are often not retained in the body, and (3) resulting biochemical or metabolic abnormalities are typically nonspecific. | |
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• Many neurotoxins have a stereotyped presentation with a strong dose-response relationship; thus, knowledgeable clinicians can recognize the manifestations of the responsible toxin. | |
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• Multiple neurologic syndromes may develop from a single toxin, depending on dose and duration of exposure. | |
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• Most clinical neurotoxic presentations closely follow exposure and generally improve with removal of the toxin. Neurotoxic chemicals rarely have prolonged storage in the body and rarely produce devastating late-onset effects. | |
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• A focused occupational exposure history is the cornerstone of the neurotoxicology clinical evaluation. |
Historical note and terminology
Disorders of miners and smelters. Disorders of some miners and smelters have been recognized since antiquity, especially those related to lead and mercury. Artistic images of mining and smelting carry many similarities from the 16th to the early 20th centuries although the images progress from woodcuts to copper plate printing to other forms of representation and reproduction, including photography by the late 19th century.
Bernardino Ramazzini. The first comprehensive treatise on the diseases of workers, De Morbis Artificum Diatriba (Dissertation on Workers' Diseases, 1700) was written by Italian physician Bernardino Ramazzini (1633-1714) (115; 116; 78; 186; 07; 182; 152; 58; 60; 61; 62; 63; 64; 65; 25; 66; 144; 175; 142; 03; 148; 49; 147; 146). In 54 chapters, Ramazzini reported on the health risks of workers in more than one hundred occupations, including neurologic disorders of miners and smelters and writer's cramp among scriveners (scribes) (03).
Occupational lead poisoning
Early lead mining and smelting. Lead mining probably predated the Bronze or Iron Ages, with the earliest recorded lead mine in Turkey about 6500 BCE. Only a few datable objects made of metallic lead have been discovered from before the 4th millennium BCE, all originating from northern Mesopotamia and eastern Anatolia. These include a lead bracelet from the Yarim Tepe archaeological site in Iraq, dated to c. 5,700 BCE, which suggests that lead smelting may have begun even before copper smelting. Another artifact made from smelted lead in the late 5th millennium BCE (ca. 4300-4000 BCE) was discovered in the Ashalim Cave in the northern Negev desert, Israel (196).
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Lead object on a wooden shaft in situ at Ashalim Cave in the northern Negev desert, Israel
Radiocarbon dating of the shaft placed the object within the Late Chalcolithic period, in the late 5th millennium BCE (ca. 4300-4000 BCE). (Source: Yahalom-Mack N, Langgut D, Dvir O, et al. The earliest lead object in the levan...
Greek philosopher Theophrastus of Eresos (c. 371 BCE - c. 287 BCE), the successor to Aristotle in the Peripatetic school, described a method of preparing white lead in his brief work, “On Stones or History of Stones” (c. 300 BCE).
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Lead is placed in earthen vessels over sharp vinegar, and after it has acquired some thickness of a sort of rust, which it commonly does in about ten days, they open the vessels and scrape it off, as it were, in a sort of foulness; they then place the lead over vinegar again, repeating over and over again the same method of scraping it till it has wholly dissolved. What has been scraped off, they then beat to powder and boil for a long time, and what at last subsides to the bottom of the vessel is ceruse. (Theophrastus, quoted by Holley) (97). |
Lead paints. Lead white (basic lead carbonate) was used in paints from antiquity into the 20th century. Portrait of a Woman (Egyptian, 2nd century) in the U.S. National Gallery of Art is an early documented instance of using lead white, as shown by macroscale multimodal imaging, including x-ray fluorescence (48). Later artists continued to use lead white because of its opacity and silky smoothness when applied with oils. Flemish artist Sir Peter Paul Rubens (1577-1640) and other Dutch artists mixed lead white with chalk for use in a priming technique that provided a better base for other paints (39; 76). Another lead-based pigment that was commonly used was red lead or minium (Lead[II,IV] oxide), a bright red or orange inorganic compound with the formula Pb3O4. Lead began to be used in residential paint during colonial times and reached its peak around 1925. In 1978, the U.S. Federal Government finally banned consumer use of lead-based paint, but some states banned it even earlier.
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Macroscale multimodal imaging revealed the use of lead white in ancient painting production technology in Greco-Roman Egypt
X-ray fluorescence elemental maps of the sum of the K or L lines for Iron (Fe), Lead (Pb), Calcium (Ca), Potassium (K), and copper (Cu). X-ray fluorescence is the emission of characteristic "secondary" (or fluorescent) x-rays f...
Late 19th-century occupational medicine and lead poisoning. By the late 19th century, physicians in Great Britain and the United States developed specialized expertise in occupational medicine and industrial hygiene and had a fairly good understanding of the clinical manifestations of lead poisoning; these included Scottish physician Sir Thomas Oliver (1853-1942), English physician Sir George Hare Philipson (1836-1918), English neurologist Sir William Gowers (1845-1915), and American neurologist James Hendrie Lloyd (1853-1932) (135; 81; 118). Oliver presented the 1891 Goulstonian Lectures on “Lead poisoning in its acute and chronic forms,” which he illustrated with color images of various aspects of lead poisoning from occupational exposures to white lead or red lead, including lead lines on the gums, wrist drop and other manifestations of lead neuropathy, a rare example of progressive muscular atrophy in chronic lead poisoning, and various manifestations of toxic optic neuropathy and optic disc edema progressing to optic atrophy (135). Oliver also presented histological sections of the gum with a blue lead line, the large intestine, showing a deposit of lead in the mucous membrane, the posterior interosseous nerve from a case of lead poisoning showing an increase of connective tissue, and the lead-related pathology of the liver and kidneys (not shown) (135). Lloyd and Gowers similarly provided images of wrist drop as a common presentation of lead neuropathy, and Lloyd also presented a case with progressive muscular atrophy (81; 118).
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Blue lead line on gums and a blue patch on the inside of the cheek, opposite the lower incisors and canines
(right). Rachael H, at age 35 years. (Source: Oliver T. Lead poisoning in its acute and chronic forms: The Goulstonian Lectures, delivered in the Royal College of Physicians, March 1891. Edinburgh and London: Young J. Pentland,...
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Lead poisoning with extensive paralysis of the muscles of the arms, shoulders, back, and legs (1)
Case of English physician George Hare Philipson (1836-1918), professor of Medicine at Durham University. (Source: Oliver T. Lead poisoning in its acute and chronic forms: The Goulstonian Lectures, delivered in the Royal College...
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Lead poisoning with extensive paralysis of the muscles of the arms, shoulders, back, and legs (2)
Case of English physician George Hare Philipson (1836-1918), professor of Medicine at Durham University. The patient recovered. (Source: Oliver T. Lead poisoning in its acute and chronic forms: The Goulstonian Lectures, deliver...
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Transverse section of posterior interosseous nerve from a case of lead poisoning showing increased connective tissue
The posterior interosseous nerve (also called the dorsal interosseous nerve) is the continuation of the deep branch of the radial nerve after it penetrates the supinator muscle. It carries fibers from the C7 and C8 spinal roots...
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Optic nerve and retina from a case of acute lead poisoning with encephalopathy
Case of Barbara R. The optic nerve has been cut at an angle. (Source: Oliver T. Lead poisoning in its acute and chronic forms: The Goulstonian Lectures, delivered in the Royal College of Physicians, March 1891. Edinburgh and Lo...
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Section of large intestine showing a deposit of lead in the mucous membrane
(x 250) Case of Barbara R. (Source: Oliver T. Lead poisoning in its acute and chronic forms: The Goulstonian Lectures, delivered in the Royal College of Physicians, March 1891. Edinburgh and London: Young J. Pentland, 1891. Pub...
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Worker in a white-lead factory with progressive muscular atrophy due to long exposure to white lead (1)
Anterior view. “He has extensive muscular atrophy, involving the muscles of the arms and shoulders, and also, to a less extent, those of the legs. The arms are wellnigh powerless. The muscles have not lost their electro-irritab...
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Lead neuropathy with wrist drop but preservation of the supinator longus muscle
"The most characteristic (form of lead neuropathy) is the paralysis of the extensors of the hands, producing the well-known wrist-drop. The muscles supplied by the musculo-spiral (radial) nerve are the ones to suffer, although ...
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Worker in a white-lead factory with progressive muscular atrophy due to long exposure to white lead (2)
Posterior view. “He has extensive muscular atrophy, involving the muscles of the arms and shoulders, and also, to a less extent, those of the legs. The arms are wellnigh powerless. The muscles have not lost their electro-irrita...
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 (Centers for Disease Control and Prevention 2014) |
Especially in underdeveloped countries, artisanal and small-scale lead mining and gold ore processing are major sources of lead exposure to miners and their families (Douine et al 2025b; Nota et al 2025).
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). In addition, the Environmental Protection Agency requires facilities to report lead emissions to the Toxics Release Inventory, presenting a potential tool for identifying at-risk worksites, although corporate noncompliance is common (Abasilim et al 2025). 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. Elevated lead levels are correlated with significantly decreased hemoglobin and hematocrit values (Memon et al 2024). 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 an 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 the level requiring medical removal (see A above) | Every 2 months |
(3) Employees removed from exposure to lead because of an elevated blood lead level of 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 time the 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 (Anonymous 1928d; 150; Nriagu 1990; Kovarik 1993; Markowitz and Rosner 2000; Needleman 2000; Seyferth 2003a; Seyferth 2003b; Kovarik 2005; Mielke 2018), and the risks had been minimalized by government after its use was already established (Anonymous 1930; 150). 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 (US Geological Survey 2020).
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 (US Geological Survey 2020). Some button-type batteries, cleansers, fireworks, folk medicines, grandfather clocks, pesticides, and skin-lightening creams and soaps may still contain mercury (US Geological Survey 2020).
The leading domestic end users of mercury in the United States are the chlorine-caustic soda (chloralkali), dental, electronics, and fluorescent-lighting manufacturing industries (US Geological Survey 2020). 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 (US Geological Survey 2020).
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 (Mackenzie and Kyle 1984; Branches et al 1993; Aks et al 1995; Camara Vde et al 1997; Counter et al 1997; Counter et al 2002; Counter et al 2006; Boischio and Cernichiari 1998; de Kom et al 1998; Donoghue 1998; Malecki 1998; Malm 1998; Appleton et al 1999; Harada et al 1999; Harada et al 2001; Drasch et al 2001; Drasch et al 2007; Crompton et al 2002; Formigli et al 2002; Kazantzis 2002; Santos et al 2002a; Santos et al 2002b; Bose-O'Reilly et al 2003; Bose-O'Reilly et al 2008; Bose-O'Reilly et al 2010a; Bose-O'Reilly et al 2010b; Bose-O'Reilly et al 2017; Campbell et al 2003; Gochfeld 2003; Eisler 2004; German Human Biomonitoring Commission 2004; Silva et al 2004; Garcia-Sanchez et al 2006; Rojas et al 2006; Spiegel et al 2006; Spiegel et al 2009; Corbett et al 2007; Peplow and Augustine 2007; Risher and De Rosa 2007; da Costa et al 2008; Berzas Nevado et al 2010; Oosthuizen et al 2010; Olivero-Verbel et al 2011; Tomicic et al 2011; Gardner 2012; Robledo 2012; Plumlee et al 2013; Saunders et al 2013; Wade 2013; Ford and Beyer 2014; Marinho et al 2014; Motts et al 2014; Bortey-Sam et al 2015; Ceccatto et al 2016; Doering et al 2016; Fraser 2016; Nakazawa et al 2016; Noble et al 2016; Obiri et al 2016; Malek et al 2017; Steckling et al 2017a; Steckling et al 2017b; Da Silva-Junior et al 2018; Kumar et al 2018; Nemery and Banza Lubaba Nkulu 2018; Pateda et al 2018; Peregrina-Chavez et al 2018; Schutzmeier et al 2018; Alcala-Orozco et al 2019; Junaidi et al 2019; Tsang et al 2019; Vianna et al 2019; Diringer et al 2020; Freire et al 2020; Khan and Abbas 2020; Kolipinski et al 2020; Wanyana et al 2020; Watson et al 2020; Hazelhoff et al 2021; Saalidong and Aram 2022; Waack et al 2022; Douine et al 2023; Douine et al 2025a; George et al 2023; Reboucas et al 2024).
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 (Swenson et al 2011). 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 (Steckling et al 2017b). 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 (Steckling et al 2017b). 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 (Steckling et al 2017b).
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; Branches et al 1993; Malm 1998; Harada et al 2001; Counter et al 2002; Counter et al 2002; Counter et al 2006; Kazantzis 2002; Santos et al 2002; Garcia-Sanchez et al 2006; Peplow and Augustine 2007; Berzas Nevado et al 2010; Gardner 2012; Wade 2013; Fraser 2016; Alcala-Orozco et al 2019; Watson et al 2020; Reboucas et al 2024), Africa (Harada et al 1999; Spiegel et al 2006; Spiegel 2009; Bose-O'Reilly et al 2008; Bose-O'Reilly et al 2010b; Oosthuizen et al 2010; Tomicic et al 2011; Wanyana et al 2020; Saalidong and Aram 2022), Indonesia (Bose-O'Reilly et al 2008; Bose-O'Reilly et al 2010a; Nakazawa et al 2016; Pateda et al 2018; Junaidi et al 2019), and the Philippines (Appleton et al 1999; Drasch et al 2001). 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 (The Global Initiative Against Transnational Organized Crime 2016). Small numbers of cases of inhalational mercury toxicity from artisanal gold extraction continue to occur in the United States (Noble et al 2016; Waack et al 2022).
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 (Drasch et al 2001; Wade 2013). Mercury-contaminated slurry is also typically discarded directly into waterways (Wade 2013). 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) (Wade 2013; Marinho et al 2014; Kolipinski et al 2020; Reboucas et al 2024).
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 (US Geological Survey 2020). 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 (Beasley et al 2014; Cappelletti et al 2019; Krakowiak et al 2023; Majdanik et al 2023), 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 (Schutte et al 1994).
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 (Pazderova et al 1974; Nierenberg et al 1998).
As a result of a single tragic case in 1998 (Endicott 1998; Nierenberg et al 1998), OSHA issued a Hazard Information Bulletin (Occupational Safety and Health Administration 1998). 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 (US Geological Survey 2020). Manganese ore is consumed mainly by eight firms with plants in the East and Midwest (US Geological Survey 2020). Most ore consumption is related to steel production, either directly in pig iron manufacture or indirectly through upgrading the ore to ferroalloys (US Geological Survey 2020). Additional quantities of ore are used in the production of dry cell batteries, in fertilizers and animal feed, and as a brick colorant (US Geological Survey 2020).
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 (Smith et al 2007; Rolle-McFarland et al 2018; Karyakina et al 2022; Nossa et al 2024). 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 (Smith et al 2007). 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) (Rolle-McFarland et al 2018). Toenail manganese levels are not a suitable proxy for brain manganese levels or metabolic changes (Nossa et al 2024).
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) (Hoffman et al 1988; Hassan et al 2000; Irving et al 2003; Rowin and Lewis 2005; Carroll et al 2017; Cathcart and Sofronescu 2017; Dolcourt et al 2019; Almeida et al 2020; Amisha et al 2021; Stagg et al 2024), (2) related to bariatric surgery (Spinazzi et al 2007; Griffith et al 2009; Choi and Strum 2010; Draine and Simmons 2020) or hemodialysis (Nishime et al 2020; Munie and Pintavorn 2021), or (3) iatrogenic (eg, with intentional prescription of zinc to decrease copper levels in Wilson disease) (Foubert-Samier et al 2009; Horvath et al 2010; Duncan et al 2016a; Duncan et al 2016b; Duncan et al 2023; Wu et al 2020; Chevalier et al 2023).
Zinc interferes with copper absorption and metabolism (Van Campen and Scaife 1967; Fischer et al 1984; L'Abbe and Fischer 1984; Festa et al 1985; Lee et al 1989; Kumar et al 2003). 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 (Kumar et al 2003). Zinc also induces hepatic metallothioneins that bind copper in a sequestered form (Lee et al 1989), and zinc further interferes with the function of copper-containing metalloenzymes (L'Abbe and Fischer 1984; Festa et al 1985).
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 (US Geological Survey 2020). 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 (US Geological Survey 2020). 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 (Zhao et al 2008; Kemnic and Coleman 2024):
(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 Krebs’ 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
The main source of occupational exposure to arsenic is through air contaminated with inorganic arsenic in mines, arsenic or copper smelter industries, and chemical factories (Bidu et al 2024).
Arsenic trioxide and arsenic metal have not been produced in the United States since 1985 (US Geological Survey 2020). Arsenic trioxide is primarily used for production of arsenic acid for the chromated copper arsenide preservatives used in pressure-treated lumber (US Geological Survey 2020). 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 (US Geological Survey 2020). 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 (US Geological Survey 2020).
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 (US Geological Survey 2020). China is also the leading world producer of arsenic metal and supplies about 90% of United States imports (US Geological Survey 2020).
Most reports of occupational arsenic poisoning concern non-nervous-system cancers, arsenic-induced dermatologic toxicity, and arsenic-induced leukopenia (Bidu et al 2024; Sassano et al 2024). 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.
In September 1976, an explosion of an ammonia-washing column at the petrochemical plant in Manfredonia, Italy, released 39 tons of arsenic into the atmosphere, contaminating the plant and the surrounding neighborhoods (Di Staso et al 2024). A 45-year follow-up of 1772 exposed workers contributing 67,743 person-years found that survival was significantly shortened among contract workers, compared to the reference category (plastic area workers). Accounting for latency greater than 20 years, higher mortality rates for lung cancer were observed among workers residing in Manfredonia who were more exposed to arsenic during the clean-up activities. More exposed workers lost 5 years of life on average. The mortality rates of residents in Manfredonia were also higher than those of workers residing elsewhere.
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. | |||||||
Occupational inorganic mercury poisoning. The expression “mad as a hatter” was commonly used in Britain and its colonies by the 1820s, as indicated by its usage in English literature from that time. For example, the June 1829 issue of Blackwood's Edinburgh Magazine presented an odd playlike scene by an anonymous author (presumably William Blackwood) in which the character Odoherty says, “Mad as a hatter. Hand me a segar” (05; p. 729). Eight years later, the Nova Scotian politician and author Thomas Chandler Haliburton (1796-1865) wrote in “The Clockmaker” (1837), “And with that, he turned right round, and sat down to his map, and never said another word, lookin' as mad as a hatter the whole blessed time” (83; p. 64). Similarly, in the novel “The History of Pendennis” (1848-1850) by British author William Makepeace Thackeray (1811-1863), a character says, “We were talking about it at mess, yesterday, and chaffing Derby Oaks—until he was as mad as a hatter” (Thackary 1849; p. 117). These examples, though, suggest irritability or irascibility rather than insanity or derangement. Even older terms like “mad as a March hare” and “mad as a wet hen” suggest that the expression “mad as a hatter” was simply a variation on an existing theme.
Many have speculated that “mad as a hatter” refers to the symptoms of mercury poisoning. So-called “hatters’ shakes” (ie, tremor) was a common manifestation of chronic mercury poisoning occurring in workers exposed to mercury in the manufacture of felt hats. Other features of mercury toxicity in these workers included mental and behavioral changes and stomatitis.
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Canadian voyageurs supplied the beaver pelts that were used in the manufacturing of beaver-hair top hats from Canada-produced pelts
From Charles Knight's Pictorial Gallery of the Arts, England, 1858. William Barclay Parsons Collection, New York Public Library Archives. (Public domain. Edited by Dr. Douglas J Lanska.)
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) (Atkinson and von Sallmann 1946), and decrements in glomerular function and renal tubular injury (Agency for Toxic Substances and Disease Registry 2022). The most common neurologic manifestation (although often not the first) is a tremor (Orr 1866; Charcot 1888; Charcot 1889; Eschner 1910; Fawer et al 1983; Albers et al 1988; Chapman et al 1990; Netterstrom et al 1996; Wastensson et al 2006; Goetz 2010; 21). The tremor is predominantly a bilateral intention tremor (Charcot 1888; Charcot 1889; Fawer et al 1983; Goetz 2010), “completely subsiding during sleep, hardly noticeable at rest, and triggered by voluntary use of the affected muscle” (Fawer et al 1983). The hands were most affected by mercurial tremor, but the eyelids, head, and tongue could also manifest mercurial tremor, with secondary effects on speech (Goetz 2010). Although predominantly an intention tremor, a minimal rest component was noted in some cases (Goetz 2010). 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 (Agency for Toxic Substances and Disease Registry 2022).
In some cases, it may not be straightforward to decide whether occupational or nonoccupational exposures are responsible for elevated mercury levels. For example, in two asymptomatic dental workers who had elevated urinary mercury levels (37 and 25.6 mcg/L) during routine health screenings, with normal previous mercury tests and no symptoms or abnormal findings identified on clinical examination, mercury exposure occurred both occupationally through amalgam contact and nonoccupationally via unregulated facial creams and seafood consumption (Chuthong et al 2025).
Dimercaprol and penicillamine have been used to treat occupational mercury poisoning (21; 22).
For exposures through airborne mercury vapor, it is essential to evaluate and monitor workers for mercury exposure and safeguard employees using a hierarchy of controls (Shi et al 2025). Controls should include providing training tailored to the individual workers, changing work practices to reduce mercury exposure, and improving the ventilation system (Shi et al 2025).
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) (Endicott 1998; Nierenberg et al 1998). 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 (Couper 1837a; Couper 1837b; von Jaksch 1901; von Jaksch 1910; von Jaksch 1913; Emden 1901; Emden 1922; Friedel 1903; Seiffer 1904; Casamajor 1913; Casamajor 1916; Seelert 1913; Drinker 1919a; Edsall and Drinker 1919; Edsall et al 1919; Charles 1922; Davis and Huey 1922; Gayle 1925; Hamilton 1929; Canavan et al 1934; Lee 2000; Blanc 2018; Hicham et al 2020). Couper reported five stereotyped cases in workers grinding “manganese peroxide” [sic, manganese dioxide; there is no oxygen-oxygen peroxide bond] (Couper 1837): “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. (Couper 1837b; 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 (Anonymous 1940; Flinn et al 1940; Rodier 1955; Mena et al 1967; Emara et al 1971; Cook et al 1974; 160; Huang et al 1989; Huang et al 1998; Hochberg et al 1996; Miranda et al 2015). 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”) (Abdel-Naby and Hassanein 1965; Bouchard et al 2007; Guilarte 2013; Bouabid et al 2016). 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 peculiarly slow, labored, high-stepped, and somewhat stiff-legged gait, later called hähnentritt (cock walk) (Edsall et al 1919), sometimes attributed to von Jaksch (von Jaksch 1901; von Jaksch 1910), 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 (Fairhall and Neal 1943; Huang et al 1997; Kim et al 1998; Cherian et al 2022).
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 (Rodier 1955) (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.” (Rodier 1955; 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 (Shinotoh et al 1997; Olanow 2004; 108), although, uncommonly, some affected individuals can achieve modest benefit (Rosenstock et al 1971). 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 (Calne et al 1994; Olanow 2004; Guilarte 2010; Guilarte and Gonzales 2015; 108). 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 (Sikk et al 2011; Iqbal et al 2012; 42; Edmondson et al 2019; Habrat et al 2021); 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 (Perl and Olanow 2007). 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 (Olanow et al 1996).
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 (de Bie et al 2007; Sanotsky et al 2007; Sanotsky et al 2020; Selikhova et al 2008; Stepens et al 2008; Stepens et al 2014; Colosimo and Guidi 2009; Sikk et al 2010; Sikk et al 2011; Iqbal et al 2012; Fudalej et al 2013; Bonnet et al 2014; Poniatowska et al 2014; Dolgan et al 2015; Janocha-Litwin et al 2015; Sikk and Taba 2015; Kałwa 2020; Habrat et al 2021; Majewski et al 2024). 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 (Stepens et al 2008). 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” (Schlockow 1875). 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” (Schlockow 1875; Schlockow 1879; Anonymous 1887). 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 (Phillips 1882).
Zinc-induced myelopathy was a recognized problem in the late 19th century with chronic therapeutic use of zinc salts (Hare 1894; Cerna 1895) and in zinc smelter workers exposed to zinc fumes (Schlockow 1875; Schlockow 1879; Lanska and Remler 2014). 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 (Schlockow 1875, 1879; Lanska and Remler 2014). 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 (Rosenau 1917; Garcia-Vargas et al 2014).
Lewis Carroll’s Alice's Adventures in Wonderland (1865). The Hatter character in Alice's Adventures in Wonderland (1865) is commonly referred to as the “Mad Hatter” under the assumption that his presumed insanity was attributable to occupational exposure to inorganic mercury in the process of making felt hats (73). However, the author, Lewis Carroll—the pen name or nom de plume of English author Charles Luttwidge Dodgson (1832-1898)--simply referred to the character as the Hatter without directly designating him as “mad.” Nevertheless, the Hatter's profession is suggestive, and there are numerous allusions to the Hatter's madness in the text; indeed, the Cheshire Cat assured Alice that the Hatter is mad (p. 90), and the chapter in which the Hatter appears was titled “A Mad Tea-Party.” Although Carroll's Hatter character appeared to be insane, it is less clear whether his clinical manifestations match those of inorganic mercury poisoning, a point that has been debated for decades (190).
The Hatter does not appear in Carroll's original manuscript version of the story, titled Alice’s Adventures Underground, which was written between 1862 and 1864; instead, the Hatter was added, along with the rest of the “Mad Tea Party,” for the print edition, which was published in 1866 (Carroll found a first printing in 1865 to be unsatisfactory).
Carroll's Hatter character was forgetful, “anxious,” and tremulous, and his behavior was certainly peculiar, asking riddles with no answers and reciting nonsensical rhymes.
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Alice felt dreadfully puzzled [by the Hatter]. The Hatter’s remark seems to her to have no sort of meaning in it, and yet it was certainly English. (Caroll 1869; p. 100) | ||
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“Take off your hat,” the King said to the Hatter. | ||
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“It isn’t mine,” said the Hatter. | ||
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“Stolen!” the King exclaimed, turning to the jury, who instantly made a memorandum of the fact. | ||
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“I keep them to sell,” the Hatter added as an explanation: “I’ve none of my own. I’m a hatter.” | ||
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Here the Queen put on her spectacles, and began staring at the Hatter, who turned pale and fidgeted. | ||
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“Give your evidence,” said the King; “and don’t be nervous, or I’ll have you executed on the spot.” | ||
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This did not seem to encourage the witness at all; he kept shifting from one foot to the other, looking uneasily at the Queen, and in his confusion he bit a large piece out of his teacup instead of the bread-and-butter. (30; p. 168) | ||
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[The Queen] said to one of the officers of the court, “Bring me the list of the singers in the last concert!” on which the wretched Hatter trembled so, that he shook both his shoes off.” | ||
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“Give your evidence,” the King repeated angrily, “or I’ll have you executed, whether you’re nervous or not.” | ||
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“I’m a poor man, your Majesty,” the Hatter began in a trembling voice… | ||
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“But what did the Dormouse say?” one of the jury asked. | ||
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“That I can’t remember,” said the Hatter. (30; pp 170-1) | ||
In any case, Carroll’s model for the Hatter was probably not a mercury-poisoned hatmaker, but possibly an Oxford cabinet-maker and furniture dealer named Theophilus Carter (1824-1904), who was known locally as “the mad hatter” because of his eccentricity and because always wore a top hat (190). Reverend W. Gordon Baille noted that,
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...all Oxford called him ‘The Mad Hatter,’ and surely his friends, or enemies, must have chaffed him about it. He would stand at the door of his furniture shop in the High, sometimes in an apron, always with a top-hat at the back of his head, which, with a well-developed nose and a somewhat receding chin, made him an easy target for the caricaturist. The story went that Mr. Dodgson (“Lewis Carroll”), thinking T.C. had imposed upon him, took this revenge. (12; p. 10) |
Theophilus Carter, inspiration for the Hatter in Lewis Carroll's “Alice's Adventures in Wonderland”
Theophilus Carter (1824-1904), ca 1894, an eccentric British furniture dealer thought to be an inspiration for the illustration by Sir John Tenniel (1820-1914) of the Hatter in Lewis Carroll's "Alice's Adventures in Wonderland"...
Attendees of “The Great Exhibition of the Works of Industry of All Nations” in 1851 in Hyde Park in London recalled 80 years later seeing as children “with much pleas[ur]e an alarm clock bed” made by Carter, “which tipped up and threw the occupant out at the appointed time” (06; 157).
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[Theophilus Carter] was the doubtless unconscious model for the Mad Hatter in “Through the Looking Glass,” as depicted by Tenniel, who was brought down to Oxford by the author, as I have heard, on purpose to see him. The likeness was unmistakable. (82; p. 10) |
English fantasy novelist Terence Hanbury (“TH” or “Tim”) White (1906-1964) wrote in a memoir of musings and recollections in 1936 (195):
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I think of the Mad Hatter of Shireham, who lived first on bran, water and turnip tops (at a cost of 3/4 d. a week) and finally on a simple diet of dock leaves and grass… He had a sackcloth suit, built his own hut, preached, meditated, saw “visions of the Paradise of God” while digging his parsnips, was an astrologer, a doctor with 120 patients, and a witch. He was imprisoned at Clerkenwell, without any food at all, until a dog, on a kind thought, brought him a bit of bread. He was a haberdasher of hats at Butterbury, but he would pray behind the counter. He sold everything to give to the poor, after he had been a soldier, a vegetarian, a Quaker, a hermit, an author, a haberdasher, a doctor, and a wise man. Eventually they called him The Mad Hatter; and he gave birth of a hero of Alice in Wonderland. (195; p. 54) |
Mercurial erethism. The symptoms of mercury poisoning were described during the eighteenth century when mercurial ointments were used in the treatment of syphilis: “A night with Venus followed by a lifetime with Mercury.” Physicians then considered the toxic signs of iatrogenic mercury poisoning (eg, excessive salivation and gingivitis) as desirable indications that their patients were receiving therapeutic doses of mercury.
The term erethism was used by John Pearson in 1800 to encompass the manifestations of mercury poisoning (139), but during the latter part of the nineteenth century, its use was restricted to mean certain neurobehavioral symptoms of the disease.
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The morbid condition of the system that supervenes on these occasions, during a mercurial course [of treatment], and which tends to a fatal issue, is a state which, in a former work (Pearson 1888), I have denominated Erethismus;* and is characterized by great depression of strength, a sense of anxiety about the praecordia, frequent sighing, trembling, partial or universal, a small quick pulse, sometimes vomiting, a pale contracted countenance, a sense of coldness; but the tongue is seldom furred, nor are the vital or natural functions much disordered. When these symptoms are present, a sudden and violent exertion of the animal power will sometimes prove fatal; for instance, walking hastily across the ward; rising up suddenly in the bed to take food or drink; or slightly struggling with some of their fellow patients, are among the circumstances which have commonly preceded the sudden death of those afflicted with the mercurial Erethismus. To prevent the dangerous consequences of this diseased state, the patient ought to discontinue the use of Mercury; nor is this rule to be deviated from, whatever may be the stage, or extent, or violence of the venereal symptoms. (139; pp 131-2) |
Pearson had used the word “erethismus” in his textbook on surgery, where he wrote that,
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ERETHISMUS is characterized by a depression of strength. ... The presence of ERETHISMUS depends on the continued application of the REMOTE cause. ... ERETHISMUS is marked by a small, quick, and often unequal pulse. ... ERETHISMUS is a symptomatick affection, where the motions of the System do not appear to be directed to any determinate end. (138; pp. 25-6) |
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 (190).
Alice Hamilton. American physician and research scientist Alice Hamilton (1869-1970) is best known as a pioneer in the field of industrial toxicology and leading authority in the field of occupational health (124; 53; 08; 57; 79; 125; 40; 68; 04; 130; 191; 38; 176; 181; 17; 31; 113). Hamilton received her medical training at the University of Michigan Medical School, became a professor of pathology at the Woman's Medical School of Northwestern University in 1897, and, in 1919, became the first woman appointed to the faculty of Harvard University. Hamilton, an authority on lead poisoning, opposed the introduction of leaded gasoline in the 1920s (85; 88; 150). In addition to reports on various toxins (87), Hamilton wrote a series of monographs on occupational medicine and industrial toxicology: “Hygiene of the printing trades” (1917), “Industrial poisons in the United States” (1925), and “Industrial toxicology (c1945) (86; 89; 88; 90).
Division/Bureau of Labor Standards. The Bureau of Labor Standards was an agency of the U.S. Department of Labor from 1934 until 1971. The unit was formed as the Division of Labor Standards in November 1934 and was renamed the Bureau of Labor Standards in 1948. Formation of this agency led to competition with the Division of Industrial Hygiene of the U.S. Public Health Service because the Department of Labor actively advocated for labor unions' efforts to improve work conditions, whereas the Public Health Service championed the non-partisan provision of scientific data (151).
Description
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• The Occupational Safety and Health Act of 1970 is a U.S. labor law governing occupational health and safety in the private sector and federal government in the United States. Its main goal is to ensure employers provide employees with a safe working environment free from recognized hazards, such as exposure to toxic chemicals, excessive noise levels, mechanical dangers, heat or cold stress, or unsanitary conditions. | |
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• Under the Occupational Health and Safety Act, employers must identify and rectify safety and health problems. | |
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• Employers must first attempt to eliminate or reduce hazards by making feasible changes in working conditions rather than relying solely on personal protective equipment. | |
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• The American Conference of Governmental Industrial Hygienists determines and publishes threshold limit values annually. |
The United States Occupational Safety and Health Act of 1970. The Occupational Safety and Health Act of 1970 is a U.S. labor law governing occupational health and safety in the private sector and federal government in the United States. Its main goal is to ensure employers provide employees with a safe working environment free from recognized hazards, such as exposure to toxic chemicals, excessive noise levels, mechanical dangers, heat or cold stress, or unsanitary conditions. The Act created the Occupational Safety and Health Administration and the National Institute for Occupational Safety and Health in 1971, when the Occupational Health and Safety Act became effective. OSHA incorporated much of what had been the original Bureau of Labor Standards. The Occupational Safety and Health Act does not cover the self-employed, immediate family members of farm employers, or workplace hazards regulated by another federal agency.
Under the Occupational Health and Safety Act, employers must identify and rectify safety and health problems. Employers must first attempt to eliminate or reduce hazards by making feasible changes in working conditions (eg, switching to safer chemicals, enclosing processes to trap harmful fumes, or using ventilation systems to clean the air) rather than relying solely on personal protective equipment. Employers are also obligated to: (1) inform workers about chemical hazards through training, labels, alarms, color-coded systems, and chemical information sheets (ie, safety data sheet, material safety data sheet, or product safety data sheet); (2) provide safety training to workers in a language and vocabulary they can understand; (3) keep accurate records of work-related injuries and illnesses; (4) perform tests in the workplace (eg, air sampling) when required by Occupational Health and Safety Act standards; (5) provide the required personal protective equipment at no cost to workers; and (6) provide hearing examinations or other medical tests when required by Occupational Health and Safety Act standards.
Permissible exposure limits. OSHA established a series of 8-hour, time-weighted average permissible exposure limits where “time-weighted average is the employee's average airborne exposure in any 8-hour work shift of a 40-hour work week which shall not be exceeded” (as defined in 29 CFR 1910.1000 in the Federal Register 1992; 57[114]:26539, 26556, 26572, 26573 and 26590).
Threshold limit values and biological exposure indices. The American Conference of Governmental Industrial Hygienists determines and publishes threshold limit values annually. Threshold limit values “refer to airborne concentrations of chemical substances and represent conditions under which it is believed that nearly all workers may be repeatedly exposed ... without adverse health effects.” Four categories of threshold limit values are specified: time-weighted average (TLV-TWA), short-term exposure limit (TLV-STEL), surface limit (TLV-SL), and ceiling (TLV-C). The TLV-TWA is the level at which nearly all workers may be repeatedly exposed for a conventional 8-hour workday and a 40-hour workweek without adverse effects. The TLV-STEL is a 15-minute time-weighted average exposure that should not be exceeded at any time during a workday, regardless of whether the 8-hour time-weighted average is within the TLV-TWA. The TLV-SL is the concentration on workplace equipment and facility surfaces that is not likely to result in adverse effects following direct or indirect contact. Finally, the TLV-C is the concentration that should not be exceeded during any part of the working exposure. If any of these threshold limit value types are exceeded, a potential hazard from that substance is presumed to exist. Threshold limit values are expressed in ppm, mg/m3, or mg/100 cm2.
Biological exposure indices are guidance values for evaluating biological monitoring results below which nearly all workers should not experience adverse health effects; the specimens used for biological monitoring are urine, blood, or exhaled air. Biological exposure indices generally represent the levels of monitored chemicals or metabolites that are most likely to be observed in specimens collected from healthy workers exposed to industrial chemicals to the same extent as workers with inhalation exposure at the TLV-TWA. However, in some cases, biological monitoring is desirable because of the potential for significant absorption via a route of entry other than respiratory (usually the skin). In addition, some biological exposure indices predict health effects better than air levels. Biological exposure indices may be based on the monitored chemicals, metabolites, or characteristic reversible biochemical changes induced by the monitored chemicals. Biological exposure indices determinants provide an index of an individual’s uptake of a chemical by all routes.
Biological monitoring is important for many occupational exposures to ensure safety for all workers. Although air monitoring to determine the threshold limit value indicates the potential inhalation exposure of an individual or group, the actual absorbed dose for individuals within a workgroup may be different (eg, because of other routes of exposure, usually dermal). In addition, individual differences in physiological makeup (age, gender, pregnancy status), health status (eg, medications and disease states), occupational exposure factors (eg, effectiveness of personal protective devices, work-rate intensity and duration, temperature and humidity), and non-occupational exposure factors (eg, personal hygiene, smoking, alcohol and drug intake) may impact the risks of exposure, even within threshold limit values.
Clinical applications
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• According to the National Institute for Occupational Safety and Health (NIOSH), a sentinel health event is a “preventable disease, disability, or untimely death whose occurrence serves as a warning signal that the quality of preventive or therapeutic medical care may need to be improved.” | |
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• A sentinel health event (occupational) is a sentinel health event that is occupationally related and whose occurrence may: (1) provide the impetus for epidemiologic or industrial hygiene studies or (2) serve as a warning signal that materials substitution, engineering control, personal protection, or medical care may be required.” | |
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• The National Institute for Occupational Safety and Health developed a sentinel health event (occupational) list that encompasses disease conditions linked to the workplace for which objective documentation of an associated agent, industry, and occupation exists in the scientific literature. | |
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• The neurologic conditions associated with occupational exposures, as outlined by the National Institute for Occupational Safety and Health, focus on encephalopathies, parkinsonism and other movement disorders, cerebellar ataxia, and peripheral neuropathy. | |
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• A hierarchy of occupational controls is used to implement feasible and effective control solutions, resulting in inherently safer systems where the risk of illness or injury has been substantially reduced. | |
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• Although elimination and substitution are the most effective means of reducing hazards, they are typically the most difficult to implement in an existing process because they often require major changes in equipment and procedures. | |
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• Engineering controls are favored over administrative and personal protective equipment for controlling worker exposures because they remove the hazard at the source and before these hazards contact the worker. | |
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• Neurotoxicity often manifests with nonfocal nervous system pathology that mimics metabolic, degenerative, nutritional, and demyelinating diseases. | |
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• Clinical laboratory tests are of limited use for most occupational neurotoxic exposures because (1) specific tests do not exist for most neurotoxins, (2) neurotoxins are often not retained in the body, and (3) resulting biochemical or metabolic abnormalities are typically nonspecific. | |
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• Many neurotoxins have a stereotyped presentation with a strong dose-response relationship; thus, knowledgeable clinicians can recognize the manifestations of the responsible toxin. | |
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• Multiple neurologic syndromes may develop from a single toxin, depending on dose and duration of exposure. | |
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• Most clinical neurotoxic presentations closely follow exposure and generally improve with removal of the toxin. Neurotoxic chemicals rarely have prolonged storage in the body and rarely produce devastating late-onset effects. | |
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• A focused occupational exposure history is the cornerstone of the neurotoxicology clinical evaluation. |
Occupational sentinel health events. According to NIOSH, a sentinel health event is a “preventable disease, disability, or untimely death whose occurrence serves as a warning signal that the quality of preventive or therapeutic medical care may need to be improved” (156). A table of disease events was developed in 1976 based on the concept of a sentinel health event (155). The Joint Commission now defines a sentinel event as “a patient safety event that results in death, permanent harm, or severe temporary harm.” A sentinel health event (occupational) is occupationally related and may (1) provide the impetus for epidemiologic or industrial hygiene studies or (2) serve as a warning signal that materials substitution, engineering control, personal protection, or medical care may be required” (156). NIOSH developed an occupational sentinel health event list that encompasses disease conditions linked to the workplace for which objective documentation of an associated agent, industry, and occupation exists in the scientific literature (156). For an expanded and updated version of that list that focuses on neurologic occupational sentinel health events, see Table 1. The neurologic conditions associated with occupational exposures, as outlined by NIOSH, focus on encephalopathies, parkinsonism and other movement disorders, cerebellar ataxia, and peripheral neuropathy.
Although not the focus of this article, industry is the source of considerable morbidity and mortality for people who are not employed by industry. This occurs in two ways: (1) para-occupational (or “take home”) poisoning, for example, when workers bring home toxic substances on their bodies or clothing or when female employees transmit industrial toxic substances transplacentally to their unborn children or in breast milk to their infants and young children; and (2) environmental toxicity, for example when industries release hazardous substances into the general environment, either into the atmosphere, groundwater, or dumped on land.
Table 1. Occupational Neurologic Sentinel Events*
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Condition |
Agent |
Industries or occupations |
References |
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Encephalopathy (“toxic encephalitis”) |
Lead (acute psychosis) |
Mining, artisinal gold mining, battery, smelter, foundry workers, lead recycling, ship repair, bridge demolition and repair |
(26; 13; 80) |
|
Inorganic and organic mercury (erethism with organic mercury) |
Mining, electrolytic chlorine production, battery manufacturing, fungicide manufacturing, artisanal and small-scale gold mining |
(15; 16; 26; 56; 21; 22) | |
|
Toluene or solvents |
Chemical industry using toluene (eg, paint manufacturing) |
(09; 51; 106; 105; 184; 188) | |
|
Parkinsonism and other movement disorders (“Parkinson disease [secondary]”) |
Manganese |
Manganese mining and smelting, steel manufacturing, welding |
(160; 178; 194; 42; 94; 102; 108) |
|
Organic mercury (tremor) |
Mining, electrolytic chlorine production, battery manufacturing, fungicide manufacturing, artisanal and small-scale gold mining |
(110; 59; 162; 72; 180) | |
|
Carbon monoxide |
Internal combustion engine, paint stripping |
(77; 101; 74; 127; 119; 120; 54; 43; 121; 145; 93; 154) | |
|
Carbon disulfide |
Rayon manufacturing |
(140; 47; 179; 107; 75) | |
|
Acrylonitrile |
Manufacture acrylic fibers, plastics, and rubbers |
(163) | |
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Chlorinated hydrocarbon solvents (eg, carbon tetrachloride, trichloroethylene, and methylene chloride) |
Solvent exposure (eg, machine or engine mechanic, laboratory assistant, electronic or telecommunications worker) | ||
|
Pesticides |
Agriculture | ||
|
Cerebellar ataxia |
Toluene |
Chemical industry using toluene (eg, paint manufacturing) |
(114; 23; 161; 122; 18; 106; 105; 99; 193; 158; 45; 27; 98; 187; 198; 123; 112) |
|
Organic mercury |
Electrolytic chlorine production, battery manufacturing, fungicide manufacturing |
(26; 44; 103; 131; 172) | |
|
Peripheral neuropathy (“inflammatory and toxic neuropathy”) |
Arsenic and arsenicals (primarily sensory neuropathy) |
Pesticides, pigments, pharmaceuticals |
(96; 50; 109; 110; 84; 174; 173) |
|
Inorganic lead (motor neuropathy) |
Battery, smelter, and foundry workers |
(26; 164; 13; 56; 168; 110; 167; 185; 92; 19; 34; 35; 153; 01; 170; 14; 104; 36) | |
|
Inorganic mercury |
Dentists, chloralkali workers |
(177; 100; 169) | |
|
Organic mercury |
Chloralkali plant workers, fungicide manufacturing, battery manufacturing |
(44; 56) | |
|
Carbon disulfide |
Rayon manufacturing |
(189; 56; 141; 159) | |
|
Acrylamide |
Plastics industry, paper manufacturing |
(117; 132; 164) | |
|
N-hexane (motor neuropathy) |
Furniture refinishers, degreasing operations, shoe making, silk-screen printing |
(95; 137; 164; 149; 41; 33; 28; 111; 128; 143; 136) | |
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Methyl n-butyl ketone |
Plastic-coated-fabric workers. |
(20; 24) | |
|
Trinitrotoluene (TNT) |
Explosives manufacturing |
(91) | |
|
Carbon disulfide |
Rayon manufacturing |
(189; 56; 141; 159) | |
|
Tri-ortho-cresyl phosphate (TOCP) |
Plastics manufacturing, hydraulics, coke industry |
(129; 164) | |
|
Optic neuropathy |
Arsenic |
(126; 70; 55; 46; 134; 171; 133; 11; 71; 69) | |
|
Lead |
(10; 11; 32; 166; 197; 52) | ||
|
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Occupational controls. Controlling exposures to occupational hazards is fundamental to protecting workers. A hierarchy of occupational controls is used to implement feasible and effective control solutions, resulting in inherently safer systems where the risk of illness or injury has been substantially reduced.
Although elimination and substitution are the most effective at reducing hazards, they are typically the most difficult to implement in an existing process because they often require major changes in equipment and procedures. If the process is still in design or development, eliminating and substituting hazards may be less expensive and simpler to implement.
Engineering controls are favored over administrative and personal protective equipment (PPE) for controlling worker exposures because they remove the hazard at the source, before these hazards contact the worker. Well-designed engineering controls can be highly effective in protecting workers and are independent of worker actions; for example, engineering controls that eliminate mercury fumes from workplace air are safer for workers and even protect workers who are noncompliant with PPE. The initial cost of engineering controls is often higher than the cost of administrative controls or PPE, but long-term operating costs are frequently lower.
Administrative controls (ie, rules that regulate how people work) and PPE are frequently used with existing processes where the hazards are not particularly well controlled. These methods are less effective than other measures in the hierarchy, requiring significant, sustained effort by workers; the use of PPE often gets increasingly ignored by workers over time. Administrative controls and PPE programs may be relatively inexpensive to establish but can be costly to sustain over the long term.
Recognizing neurotoxic disease
In 1987, neurologist and neuropathologist Herbert Schaumburg and neurotoxicologist Peter S Spencer outlined diagnostically helpful features of neurotoxic disease, which apply to both occupational and non-occupational settings (165):
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1. Neurotoxicity often manifests with nonfocal nervous system pathology that mimics metabolic, degenerative, nutritional, and demyelinating diseases. Consequently, neuroimaging and electrodiagnostic tests do not often identify pathognomonic findings of neurotoxicity; such tests are most useful in excluding other conditions from diagnostic consideration. | |
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2. Clinical laboratory tests are of limited use for most occupational neurotoxic exposures because (1) specific tests do not exist for most neurotoxins, (2) neurotoxins are often not retained in the body, and (3) resulting biochemical or metabolic abnormalities are typically nonspecific. | |
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3. Many neurotoxins have a stereotyped presentation with a strong dose-response relationship; thus, knowledgeable clinicians can recognize the manifestations of the responsible toxin. | |
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4. Multiple neurologic syndromes may develop from a single toxin, depending on dose and duration of exposure. An acute high-level exposure may have a neurologic presentation that differs from that resulting from chronic low-level exposure. | |
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5. Most clinical neurotoxic presentations closely follow exposure (usually during or within hours of exposure, and uncommonly several weeks after exposure) and generally improve with removal of the toxin (even if some effects are persistent). Neurotoxic chemicals rarely have prolonged storage in the body and rarely produce devastating late-onset effects. Rarely, acute exposures to neurotoxins produce the acute or subacute onset of irreversible neurologic dysfunction, either with massive overwhelming exposures or with the high susceptibility of vulnerable neurons (eg, the substantia nigra with MPTP). | |
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6. The neurotoxicity of a chemical cannot be reliably predicted by its structural formula because the biochemical mechanisms and active metabolites of many neurotoxins are unknown, and even slightly different intramolecular spacings may dramatically alter neurotoxicity. | |
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7. Neurotoxicity of one chemical may be enhanced by otherwise “innocent bystander” chemicals (as exemplified, for example, by the neurotoxic potentiation of n-hexane by the presence of methyl-ethyl ketone) (02). | |
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8. Subclinical neurotoxic disease is common. Modest declines in performance are often unnoticed or attributed to non-occupational factors. | |
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9. The relationship between neurotoxic exposure and neurotoxic disease may be obscure to affected workers because many neurotoxic conditions result from prolonged, low-level exposure, and the resultant neurotoxic diseases have an insidious onset. | |
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10. A focused occupational exposure history is the cornerstone of the neurotoxicology clinical evaluation. | |
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11. In some cases, a workplace site visit may identify or clarify the neurotoxin responsible for a neurotoxic disease. |
Taking an exposure history
Components of an exposure history are outlined in Table 2 and include occupational exposures, health and safety practices at the work site, work history, and environmental (non-occupational) exposures (67). In cooperation with NIOSH, ATSDR has developed an exposure history form to facilitate taking an exposure history.
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Exposure history form to facilitate taking an exposure history, page 1
(Source: Frank AL, Balk S, Resha K. Taking an exposure history: case studies in environmental medicine. ATSDR publication number ATSRD-HE-CS-2001-0002. Atlanta, Georgia. Agency for Toxic Substances and Disease Registry, 2000. I...
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Exposure history form to facilitate taking an exposure history, page 2
(Source: Frank AL, Balk S, Resha K. Taking an exposure history: case studies in environmental medicine. ATSDR publication number ATSRD-HE-CS-2001-0002. Atlanta, Georgia. Agency for Toxic Substances and Disease Registry, 2000. I...
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Exposure history form to facilitate taking an exposure history, page 3
(Source: Frank AL, Balk S, Resha K. Taking an exposure history: case studies in environmental medicine. ATSDR publication number ATSRD-HE-CS-2001-0002. Atlanta, Georgia. Agency for Toxic Substances and Disease Registry, 2000. I...
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Exposure history form to facilitate taking an exposure history, page 14
(Source: Frank AL, Balk S, Resha K. Taking an exposure history: case studies in environmental medicine. ATSDR publication number ATSRD-HE-CS-2001-0002. Atlanta, Georgia. Agency for Toxic Substances and Disease Registry, 2000. I...
Table 2. Components of an Exposure History
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Part 1. Exposure survey | |||
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A. Occupational exposures | |||
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• Do symptoms improve after leaving the workplace, especially on weekends and holidays? | |||
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B. Health and safety practices at the work site | |||
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• Ventilation | |||
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- Smoke or eat in the work area? | |||
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Part 2. Work history | |||
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• Description of current and previous jobs, including short-term, seasonal, and part-time employment and military service | |||
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Part 3. Environmental exposure history | |||
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• Present and previous home locations | |||
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Media
References
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Douglas J Lanska MD MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health has no relevant financial relationships to disclose.
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