General Neurology
Metal neurotoxicity
Nov. 05, 2024
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- Updated 07.01.2024
- Expires For CME 07.01.2027
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) (113; 114; 76; 183; 07; 179; 150; 56; 58; 59; 60; 61; 62; 63; 24; 64; 142; 172; 140; 03; 146; 47; 145; 144). 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 (194).
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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) (95). |
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 (46). 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 (37; 74). 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) (133; 79; 116). 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 (133). 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) (133). 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 (79; 116).
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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...
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” (81; p. 64). Similarly, in the novel “The History of Pendennis” (1848-1850) by British author William Makepeace Thackery (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” (Thackery 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.)
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 (71). 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 (187).
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. (29; 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. (29; 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 (187). 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; 155).
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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. (80; p. 10) |
English fantasy novelist Terence Hanbury (“TH” or “Tim”) White (1906-1964) wrote in a memoir of musings and recollections in 1936 (193):
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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. (193; 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 (137), 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. (137; 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. (136; 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 (187).
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 (122; 51; 08; 55; 77; 123; 38; 66; 04; 128; 188; 36; 173; 178; 17; 30; 111). 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 (83; 86; 148). In addition to reports on various toxins (85), 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) (84; 87; 86; 88).
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 (149).
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