**1. Introduction**

46 Sleep Disorders

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The sleep-wake rhythms cycle coincides with the solar 24-hour schedule. Most adult subjects in nontropical areas are comfortable with 6.5 to 8.0 hours of daily sleep, taken in a single period. It is known that normal sleep consists of four to six behaviourally and electrophysiologically (EEG) defined cycles. Sleep is divided in two main types: REM (rapid eye movements) sleep and non-REM sleep. In the general population, sleep disorders are common and usually associated with some illness, psychological and social disturbances. Insomnia as the most common sleep disorder is most often the consequence of psychological disturbances. It is characterized by the inability to fall asleep quickly. Sleepwalking, night terrors and nightmares are parasomnias which often reflect significant stress or physiopathology. Restless legs syndrome and periodic limb movements are a type of motor disorders. Restless legs usually occur before sleep onset, while periodic limb movements can fragment the sleep. Transient sleep disturbances are mostly associated with variety of factors including stress, life changes, shift work, jet lag, and some acute health disorders. The most popular drugs, such as alcohol, nicotine and caffeine, can adversely affect the quality and quantity of sleep (Hornyak et al., 2006; Lee & Douglass, 2010; Pinel, 2009; Vgontzas et al., 2010).

Occupational exposure to heavy metals, such as cadmium, lead, manganese and mercury, was very frequent in the 20th century. Many epidemiological studies show that these heavy metals can cause serious functional disability among exposed workers (World Health Organization [WHO], 1980). Inorganic lead, manganese and inorganic-elemental mercury (Hg) exposure can, among others, cause neurotoxic effects with a typical, but different, clinical picture associated with sleep disorder.

Hg a silvery-white liquid metal is quite attractive and very widespread which, despite being highly toxic, was used by humans as a medicine for thousands of years. We shall discuss its neurotoxic effects and the sleep disorders it can cause at increased occupational exposure. Hg was first described by Aristotle in the 4th century A.D., and the alchemist's concept of Hg leaned on his system of natural phenomena, which dominated all of science until the 17th century. For this reason Hg was attributed with all those qualities of nature that accelerate development, growth and maturation. The famous Arabian physician Avicena, who was active in the 11th century, wrote that Hg vapours cause paralysis, tremor

Elemental Mercury Exposure and Sleep Disorder 49

the symptoms of mercury intoxication - mercurialism among pit and smeltery workers. He classifies mercurialism according to those symptoms that are the most pronounced in the disease pattern. Scopoli describes acute, sub-acute and chronic Hg intoxication appearing during work in the smelting plant and in the pit, in poorly ventilated sites with native ore where, according to our present-day knowledge (Kobal, 1994), mercury vapour concentrations were extremely high. Among the symptoms accompanying chronic intoxication, Scopoli mentions changes in some personality traits, such as bad temper, irritability and sadness, as well as sleep disorder. *"…somnus inquietus, somnia terrifica, artuum agitatio*…" are the key words which Scopoli uses (1771, p. 80). He finds that mercury intoxication is accompanied by restless sleep, terrible dreams with nightmares, sleep terrors, and strange, periodic contractile movements of the legs (Kobal & Kobal-Grum, 2010). The reputed clinical toxicologist, Adolph Kussmaul, presented in his book (1861, p. 227) an occupational clinical picture of mercurial intoxication in miners. Among the symptoms of eretism-increased irritability, he also mentions

Our observations are based on data collected from the program of health surveillance of workers exposed to Hg in the Idrija Mercury Mine. In the first 20 years following the Second World War, the number of Hg intoxicated workers was very high (ranging from 10 to 14% of workers in the mine and smelting plant). After 1975, no new cases of intoxication were observed thanks to the introduction of preventive-target medical examinations, which, after 1968, also included biological monitoring of exposure. Subjective descriptions of sleep disturbances and other potential, known, subjective troubles associated with Hg exposure were always evaluated directly by the physician during contact with intoxicated or exposed workers in the course of preventive target examinations. No polysomnographic recording was used to define the stages of sleep in intoxicated workers, or in workers with increased Hg absorption. Some disordered sleep, such as fragmentation of sleep accompanied with dreaming and awakening, as well as periodic leg contractile movements, were often observed as some important early symptoms that announced the critical absorption of Hgº vapours in miners working in the pit where native Hg ore was mined, with substantially elevated air Hgº vapour levels. During the target medical surveillance and biological monitoring of miners intermittently exposed to native Hg, the previously mentioned sleep disorder appeared in 30% of exposed miners, associated with increased urinary Hg excretion. In these miners, the urine Hg concentrations were usually within a range of 100- 400 g/L, which is, at intermittent type of exposure, associated with blood Hg levels from 60 to 260 g/L (Kobal, 1975a, 1991), which are substantially above the blood Hg level of 35 g/L usually accompanied with the earliest nonspecific symptoms (WHO, 1976). In cases of subacute mercurialism with classical signs of intoxication, such as stomatitis, limb tremor, and other known symptoms and signs, the sleep disorders were much more pronounced, and the urinary Hg excretions were very high, in some cases even over 700 g/L (Kobal, 1975b, 1991). The periodic leg movement index was not evaluated in these miners (calculated by dividing the total number of periodic leg movements by sleep time in hours). In the cases of increased Hgº absorption, the sleep disorder decreased usually in one to two months after the interruption of exposure associated with decreased urine Hg level. In the cases of Hgº intoxication, sleep disorders with terrible dreams and and periodic leg movements were much more obstinate and disappeared very slowly in association with other symptoms and clinical signs of mercurialism; the urine Hg level decreased after 3 to 6 months. A subclinical peripheral nerve function with lower motor conduction velocities of

"restless sleep, terrible dreams and frighten awakenings".

and frequent limb spasms. In Columbus' time began to be used to treat syphilis. The use of its compounds was still widespread in the United States in the 19th century, and was among others also used to treat depression (Goldwater, 1972). The popularity of Hg at the time was considerable, for even President Abraham Lincoln found relief for his health problems in a pharmacy-prepared drug called "blue pills", which contained elementary Hg (Hirschhorn et al., 2001). Various, mostly organic Hg compounds were still widely used in the 20th century, and even to a smaller extent today (Clarkson & Magos, 2006).

The Roman historian Pliny speaks of the first occupational Hg intoxications *– hydrargyrismis*, or mercurialism, in slaves who mined and smelted Hg ore for several centuries in the Sisapo-Almaden mine. Occupational exposure to Hg did not receive any noticeable attention until the 15th century, when Ulrich Ellenenborg described occupational exposure for the first time in his book, which was published posthumously in 1524. In a very extensive work entitled »The morbis artificum diatribe« (1700), Bernardo Ramazzini presented several occupational illnesses, among which he also described occupational intoxications with Hg vapours (Goldwater, 1972). In the 16th century, several physicians described the symptoms and signs of Hg intoxication in miners of the Idrija Mercury Mine, the most famous among them being Theophrastus von Hohenheim, otherwise known as Paracelsus, and Pierandreia Mattioli, a reputed botanist and physician who worked in the town of Gorica at the time (1544).

In his book *Von der Bergsucht und anderen Krankheiten*, published in 1527, Paracelsus described the serious condition of sick miners whom he had met during his visit to the Idrija Mine: "All the people who live there are deformed and paralyzed, asthmatic and benumbed, without any hope of ever getting well" (Lesky, 1956, p. 8). Hg intoxication in mercury miners of the Idrija Mercury Mine was well-described by Joannes Antonius Scopoli, the first physician appointed to the Idrija Mercury Mine in 1754. Along with the symptoms of Hg intoxication observed in miners, he also described their personality traits as well the characteristics of sleep disorders that usually appear in Hg intoxication. Sleep disorders were also mentioned in the monographs on inorganic mercury published by WHO (1976, 1991) and the Agency for Toxic Substances and Disease Registry [ATSDR] (1999).

The observations of J. A. Scopoli in the 18th century, our observations of workers exposed to Hg in the Idrija Mercury Mine, as well as certain biochemical interactions of Hg in central nervous system (CNS) that were studied by many researchers in the late 20th and early 21st centuries, help to throw light on those biochemical effects of Hg in CNS that could hypothetically disturb the regulation of sleep and cause the sleep disorders occurring in occupational intoxications or increased Hg absorption in exposed miners and smelters. In this chapter, we shall briefly present the subjective characteristics of sleep disorder observed in occupational Hg intoxication and increased absorption, the interaction of Hg in the body and its toxic effects in the CNS, the basic neurobiological and biochemical characteristics of sleep-wake cycles and, finally, its hypothetical interactions with Hg.

#### **2. Sleep disorder in occupational exposure to Hg vapours**

J. A. Scopoli presented his knowledge on occupational Hg exposure of miners and smelters in the Idrija Mercury Mine in his book entitled DE HYDRARGYRO IDRIENSI *TENTAMINA Phisico – Chimico – Medica*, which was printed in Venice in 1761, and reprinted in 1771. In the third part of this book, *De Morbis Fossorum Hydrargyri*, he presents an in-depth description of

and frequent limb spasms. In Columbus' time began to be used to treat syphilis. The use of its compounds was still widespread in the United States in the 19th century, and was among others also used to treat depression (Goldwater, 1972). The popularity of Hg at the time was considerable, for even President Abraham Lincoln found relief for his health problems in a pharmacy-prepared drug called "blue pills", which contained elementary Hg (Hirschhorn et al., 2001). Various, mostly organic Hg compounds were still widely used in the 20th

The Roman historian Pliny speaks of the first occupational Hg intoxications *– hydrargyrismis*, or mercurialism, in slaves who mined and smelted Hg ore for several centuries in the Sisapo-Almaden mine. Occupational exposure to Hg did not receive any noticeable attention until the 15th century, when Ulrich Ellenenborg described occupational exposure for the first time in his book, which was published posthumously in 1524. In a very extensive work entitled »The morbis artificum diatribe« (1700), Bernardo Ramazzini presented several occupational illnesses, among which he also described occupational intoxications with Hg vapours (Goldwater, 1972). In the 16th century, several physicians described the symptoms and signs of Hg intoxication in miners of the Idrija Mercury Mine, the most famous among them being Theophrastus von Hohenheim, otherwise known as Paracelsus, and Pierandreia Mattioli, a reputed botanist and physician who worked in the

In his book *Von der Bergsucht und anderen Krankheiten*, published in 1527, Paracelsus described the serious condition of sick miners whom he had met during his visit to the Idrija Mine: "All the people who live there are deformed and paralyzed, asthmatic and benumbed, without any hope of ever getting well" (Lesky, 1956, p. 8). Hg intoxication in mercury miners of the Idrija Mercury Mine was well-described by Joannes Antonius Scopoli, the first physician appointed to the Idrija Mercury Mine in 1754. Along with the symptoms of Hg intoxication observed in miners, he also described their personality traits as well the characteristics of sleep disorders that usually appear in Hg intoxication. Sleep disorders were also mentioned in the monographs on inorganic mercury published by WHO (1976,

The observations of J. A. Scopoli in the 18th century, our observations of workers exposed to Hg in the Idrija Mercury Mine, as well as certain biochemical interactions of Hg in central nervous system (CNS) that were studied by many researchers in the late 20th and early 21st centuries, help to throw light on those biochemical effects of Hg in CNS that could hypothetically disturb the regulation of sleep and cause the sleep disorders occurring in occupational intoxications or increased Hg absorption in exposed miners and smelters. In this chapter, we shall briefly present the subjective characteristics of sleep disorder observed in occupational Hg intoxication and increased absorption, the interaction of Hg in the body and its toxic effects in the CNS, the basic neurobiological and biochemical characteristics of sleep-wake cycles and, finally, its hypothetical interactions with Hg.

J. A. Scopoli presented his knowledge on occupational Hg exposure of miners and smelters in the Idrija Mercury Mine in his book entitled DE HYDRARGYRO IDRIENSI *TENTAMINA Phisico – Chimico – Medica*, which was printed in Venice in 1761, and reprinted in 1771. In the third part of this book, *De Morbis Fossorum Hydrargyri*, he presents an in-depth description of

1991) and the Agency for Toxic Substances and Disease Registry [ATSDR] (1999).

**2. Sleep disorder in occupational exposure to Hg vapours** 

century, and even to a smaller extent today (Clarkson & Magos, 2006).

town of Gorica at the time (1544).

the symptoms of mercury intoxication - mercurialism among pit and smeltery workers. He classifies mercurialism according to those symptoms that are the most pronounced in the disease pattern. Scopoli describes acute, sub-acute and chronic Hg intoxication appearing during work in the smelting plant and in the pit, in poorly ventilated sites with native ore where, according to our present-day knowledge (Kobal, 1994), mercury vapour concentrations were extremely high. Among the symptoms accompanying chronic intoxication, Scopoli mentions changes in some personality traits, such as bad temper, irritability and sadness, as well as sleep disorder. *"…somnus inquietus, somnia terrifica, artuum agitatio*…" are the key words which Scopoli uses (1771, p. 80). He finds that mercury intoxication is accompanied by restless sleep, terrible dreams with nightmares, sleep terrors, and strange, periodic contractile movements of the legs (Kobal & Kobal-Grum, 2010). The reputed clinical toxicologist, Adolph Kussmaul, presented in his book (1861, p. 227) an occupational clinical picture of mercurial intoxication in miners. Among the symptoms of eretism-increased irritability, he also mentions

"restless sleep, terrible dreams and frighten awakenings". Our observations are based on data collected from the program of health surveillance of workers exposed to Hg in the Idrija Mercury Mine. In the first 20 years following the Second World War, the number of Hg intoxicated workers was very high (ranging from 10 to 14% of workers in the mine and smelting plant). After 1975, no new cases of intoxication were observed thanks to the introduction of preventive-target medical examinations, which, after 1968, also included biological monitoring of exposure. Subjective descriptions of sleep disturbances and other potential, known, subjective troubles associated with Hg exposure were always evaluated directly by the physician during contact with intoxicated or exposed workers in the course of preventive target examinations. No polysomnographic recording was used to define the stages of sleep in intoxicated workers, or in workers with increased Hg absorption. Some disordered sleep, such as fragmentation of sleep accompanied with dreaming and awakening, as well as periodic leg contractile movements, were often observed as some important early symptoms that announced the critical absorption of Hgº vapours in miners working in the pit where native Hg ore was mined, with substantially elevated air Hgº vapour levels. During the target medical surveillance and biological monitoring of miners intermittently exposed to native Hg, the previously mentioned sleep disorder appeared in 30% of exposed miners, associated with increased urinary Hg excretion. In these miners, the urine Hg concentrations were usually within a range of 100- 400 g/L, which is, at intermittent type of exposure, associated with blood Hg levels from 60 to 260 g/L (Kobal, 1975a, 1991), which are substantially above the blood Hg level of 35 g/L usually accompanied with the earliest nonspecific symptoms (WHO, 1976). In cases of subacute mercurialism with classical signs of intoxication, such as stomatitis, limb tremor, and other known symptoms and signs, the sleep disorders were much more pronounced, and the urinary Hg excretions were very high, in some cases even over 700 g/L (Kobal, 1975b, 1991). The periodic leg movement index was not evaluated in these miners (calculated by dividing the total number of periodic leg movements by sleep time in hours). In the cases of increased Hgº absorption, the sleep disorder decreased usually in one to two months after the interruption of exposure associated with decreased urine Hg level. In the cases of Hgº intoxication, sleep disorders with terrible dreams and and periodic leg movements were much more obstinate and disappeared very slowly in association with other symptoms and clinical signs of mercurialism; the urine Hg level decreased after 3 to 6 months. A subclinical peripheral nerve function with lower motor conduction velocities of

Elemental Mercury Exposure and Sleep Disorder 51

Hg mercury concentration (*r*=0.68, *p* < 0.001), which, in such types of exposure, allows use of

Table 1. Total Hg concentration in autopsy samples (homogenised tissue) of pituitary gland, pineal gland, hippocampus, nucleus dentatus and cereballar cortex (ng/g fresh weight) in ex-miners of the Idrija Mercury Mine and controls (data adapted by Falnoga et al., 2000).

Various Hg species, as Hg°, methyl-Hg ore ethyl-Hg, accumulates in the central nervous system (CNS) and has extremely neurotoxic effects, including the appearance of well-known clinical symptoms and signs. In case of occupational exposure to Hg°, the most frequent symptoms and signs include "erethism", increased irritability, depression and other neurobehavioral changes, sleep disturbances, oral disturbances, gingivitis and stomatitis with excessive salivation, intentional tremor, peripheral neuropathy (lower sensor and motor conduction velocities), and renal impairment. In vitro and in vivo studies showed that Hg can stimulate free radical generation as a catalyst in Fenton-type reactions and through some other mechanisms, and can promote oxidative stress, peroxidation of lipids and DNA bases, disturbances in cell membrane permeation and calcium homeostasis in cells, impairment and even apoptosis of monocytes, T cells, glial cells and neurons, disturb the functioning of neurotransmitters, and cause immune disorders (Aschner, 2000; ATSDR, 1999; Castoldi et al., 2001; Clarkson & Magos, 2006; Kobal et al., 2004; Kobal-Grum et al., 2006; Lund et al., 1993;

Various Hg species presynaptically blocks sodium and calcium channels and thus inhibits the uptake of some neurotransmitters, especially *glutamate* into astrocytes, which increases their extracellular concentration, thus increasing the sensitivity of neighbouring neurons for *stimulating excitotoxic effects* (Aschner et al., 2007; Brookes, 1996; Castoldi et al., 2001; Sirois & Atchison, 1991; Trotti et al., 1997). Many studies reviewed by Mottet et al. in 1997 showed

Magos, 1997; Pollard & Hultman, 1997; Schara et al., 2001; WHO, 1991).

**3.2.1 Interaction with neurotransmitters** 

urine Hg as a biological indicator of recent exposure (Kobal, 1991).

**3.2 Toxic effects of Hg**

the median nerve and lower sensory conduction velocities of the ulnar nerve was observed in the subgroup of miners with long-term intermittent exposure and increased Hgº absorption (urine Hg excretion > 100g/L). In contrast to sleep disorder, these subclinical pripheral nerve function changes usually persist many years after the cessation of exposure (Gabrovec-Nahlik et al., 1977; Kobal et al., 2004), which is also in agreement with some other observations (Albers et al., 1982).

As already mentioned above, sleep disorders were also mentioned in the monographs on inorganic-elemental mercury published by WHO (1976, 1991) and ATSDR (1999), which place them among the symptoms of erethism. However, no disorders of sleep structure or any possible neurobiological or biochemical mechanisms and EEG changes that could accompany sleep disorders in intoxicated subjects exposed to Hgº are described in these monographs.
