**Abstract**

Neurotoxicity may develop with exposure to various substances such as antibiotics, chemotherapeutics, heavy metals, and solvents. Some plants and fungi are also known to be neurotoxic. Neurotoxicity can develop acutely within hours, or it can develop as a result of exposure for years. Neurotoxicity can be presented with central or peripheral nervous system findings such as neurobehavioral symptoms, extrapyramidal signs, peripheral neuropathy. Peripheral nerve fibers are affected in different ways by neurotoxicant injury. The pattern of injury depends on the target structure involved. The focus of this chapter includes signs, symptoms, pathophysiology, and treatment options of neurotoxicity.

**Keywords:** neurodegeneration, neuropathy, neurotoxic, mechanisms of neurotoxicity, chemicals

### **1. Introduction**

The direct or indirect effects of chemical or physical agents that disrupt the function or structure of the nervous system of humans or animals are called neurotoxicants [1]. Neurotoxicity can be presented with central or peripheral nervous system findings such as neurobehavioral symptoms, extrapyramidal signs, and peripheral neuropathy. Peripheral nerve fibers are affected distinctly by neurotoxicant injury. Mild or severe polyneuropathy involves the peripheral nerves, affecting the myelinated, thinly myelinated, and unmyelinated fibers. A wide variety of etiological factors can cause polyneuropathy. In addition to frequent causes such as diabetes mellitus, alcohol abuse, the peripheral nervous system is vulnerable to several rare conditions [2]. Toxic peripheral neuropathies are caused by various chemicals, a basic form of acquired polyneuropathy [3]. Neurotoxicity may develop when exposed to heavy metals, solvents chemotherapeutics, monomers, gases and pesticides. The focus of this chapter includes signs, symptoms, pathophysiology, and treatment options of several neurotoxic agents that cause peripheral neuropathy.

#### **2. Heavy metals**

Heavy metals are naturally occurring elements with a high weight and a density at least five times greater than water [4]. In other words, any toxic metal can be defined as heavy metal, regardless of its atomic weight or density [5]. The industrial activities of the modern world have caused a massive rise in human exposure to

heavy metals, and heavy metals have harmful effects on human health [6]. Heavy metals' contamination of water and air is an environmental threat, and hundreds of millions of people are being exposed worldwide. The concentration of heavy metals in water supplies, air, and food is evaluated in this respect [7, 8].

Heavy metals such as arsenic (As), lead (Pb), mercury (Hg), aluminum (Al), and cadmium (Cd) do not have any particular role in an organism and can be toxic even at low levels [9]. On the contrary, it has been reported that some of these heavy metals such as iron, magnesium, selenium, copper, zinc, cobalt, nickel, molybdenum, chromium, and manganese are essential nutrients that have functional roles for various diverse biochemical and physiological functions in the body [10]. However, in over adequate amounts, they may cause toxicities. Acute and chronic toxic effects of heavy metals have an impact on different organs of the human body. In addition to the nervous system disorders, gastrointestinal and kidney dysfunction, skin lesions, vascular damage, immune system dysfunction, birth malformations, and cancer are examples of the complications of heavy metals toxic effects [8, 11, 12].

#### **2.1 Lead**

*Lead* is a toxic heavy metal in different sources such as contaminated drinking water, battery manufacture, cosmetics, leaded gasoline, lead-based paint, cans, glazed ceramics, traditional herbal medicine products, water pipes, jewelry, tobacco smoke, and electronic cigarettes, and toys. Lead exposure can be considered a public health concern, especially in early childhood, because children have increased hand-to-mouth activity, so they are more at risk [13, 14]. While the half-life of Pb in the bloodstream is about 35 days, it is stored in bones for approximately 30 years [15, 16]. Oxidative stress, alterations in membrane biophysics, dysregulation of cell signaling, and the impairment of neurotransmission are considered the complex underlying mechanisms of lead-induced neurotoxicity [17].

One of the most critical endpoints of Pb toxication is neurological effects. Pb toxication frequently causes neuropathy in adults, while encephalopathy is mainly seen in children. Exposure to high Pb levels causes encephalopathy with signs such as hyperirritability, cerebellar findings, seizures, unconsciousness, and coma. It is reported that exposure to low Pb levels has been associated with impaired cognitive and intellectual function in children [18, 19]. In occupational exposure, it is reported that neurological signs and symptoms include weakness, forgetfulness, irritability, headache, impotence, decreased libido, vertiginous symptoms, and paresthesia in Pb exposure workers. Moreover, increased prevalence and severity of white matter lesions, changes in nerve conduction velocity, and alterations of somatosensory evoked potentials were documented [18, 19].

In lead toxicity, motor-predominant polyneuropathy, which causes the development of wrist-drop, may present. Additionally, because of secondary to autonomic nerve involvement, constipation may accompany [20]. After forbidden the usage of leaded gasoline, changes in lead mining practices, and the abandonment of lead-based paint, human exposure to the primary sources of Pb decreased. So the incidence of overt lead toxicity induced polyneuropathy decreased [21].

#### **2.2 Arcenic (As)**

Arsenic is an environmental toxin, and this heavy metal is widely distributed to the earth. Hundreds of millions of people consume inorganic contaminated tube well water [22, 23]. Burning the charcoal and metal foundry activities are known to cause atmospheric deposition of As. Excessive pesticides and fertilizers and mining use cause soil contamination with As [24, 25]. While As often exists in the world

#### *Neurotoxic Agents and Peripheral Neuropathy DOI: http://dx.doi.org/10.5772/intechopen.101103*

crust in the trivalent atomic state (inorganic) with other heavy metals such as Pd, iron, copper, it is generally oxidized to pentavalent form in the soil and water. It is reduced to in trivalent atomic state in low oxygen situations, such as deep seawater [26]. Inorganic As is more potent and has been implicated in neurotoxic effects. The inorganic form should be distinguished from the non-neurotoxic organic As found in some fish and shellfish [21].

It is reported that traditional folk medicines can be the other sources of As [27, 28]. Some herbal medicines commercially available have been reported to contain heavy metals such as lead, mercury, and arsenic. Using these products may cause heavy metal toxicity and secondary peripheral neuropathy [26]. As causes various adverse effects on human health such as carcinogenic and non-carcinogenic [26].

The exact metabolic pathways of As are yet to be proved. However, oxidative methylation and glutathione conjugation are the primary pathways suggested [29]. The primary mechanism in As-induced neurological pathologies has been suggested oxidative stress with Vitro and in vivo studies [9]. While exposure to high levels of As induces primarily central nervous system findings, exposure to low levels causes primarily peripheral nervous system findings [18].

Single high dose exposure to As may lead to severe gastrointestinal and systemic symptoms such as nausea, diarrhea, vomiting, pain, dehydration, and weakness. It is usually the result of suicide- homicide or accidental poisoning. If the patient survives acute poisoning with As, neurological symptoms such as light-headedness, weakness, delirium, encephalopathy, and peripheral neuropathy develop [30].

Chronic neurological symptoms of As exposure are delirium, encephalopathy, and also peripheral neuropathy. In neuropsychological tests, while psychomotor speed and attentive processes were mildly impaired, verbal learning and memory were severely impaired [31, 32]. It is known that peripheral neuropathy may last for several years or even life-long, but on the other hand, in severe cases, diffuse sensorimotor polyradiculoneuropathy may be seen, similar to the Guillan–Barré syndrome. At the same time, chronic As exposure can cause painless sensorypredominant peripheral neuropathy [32].

The diagnosis of arsenic toxicity can be made by demonstrating high urinary and increased arsenic levels in the nails and hairs. Serum arsenic level estimation is not recommended because of the rapid clearance of arsenic. There is no gold standard specific treatment for chronic arsenic toxicity. For acute arsenic toxicity treatment, chelating agents such as BAL, D-penicillamine, and meso-2,3-dimercaptosuccinic acid are mainly used [33].

#### **2.3 Mercury (Hg)**

Mercury is heavy metal in the air, water, and soil in three chemical forms; metallic/elemental, inorganic, and organic Hg (methyl mercury and ethyl mercury). The elemental Hg is liquid at room temperature and can evaporate quickly. The vapor form of Hg is more dangerous and can is readily absorbed from the lungs (80%) and distributed throughout the body [8]. A wide variety of fields in that Hg have been used, such as gold mining, fluorescent light bulbs production, ingredients of antiaging creams, fungicides to protect plants against infections, and protection in multidose vials of vaccines [34, 35].

In the middle of the 1950s, around 200.000 people have affected by the consumption of organic Hg-contaminated fish in Minamata Bay, Japan. Because of chronic Hg toxicity, neurological signs and symptoms occurred, such as ataxia, weakness, numbness, disturbance in speech, chewing, and swallowing. Infants born with severe developmental disabilities from the poisoned pregnant women were reported. After that, the illness was called Minamata disease [36].

It is reported that organic mercury influences the dorsal root and trigeminal ganglia and causes paresthesia, usually just before causing widespread CNS dysfunction [20]. In nerve conduction studies, motor abnormalities were much more frequently reported than sensory abnormalities. Most frequently, findings were prolonged latencies and reduced amplitudes in both motor and sensory nerves. Nevertheless, interestingly, those abnormalities were shown more often in upper extremities, not lower extremities, a finding that differs from expectations [37]. Electromyography (EMG) was less frequently performed in the studies but reported results were always abnormal. The most frequently reported EMG findings (fibrillations, positive waves) were suggestive of active denervation and also reinnervation (prolonged motor unit potential duration, polyphasic motor unit potential durations) [38]. Electromyography (EMG) was less frequently performed in the studies but reported results were always abnormal. The most frequently reported EMG findings (fibrillations, positive waves) were suggestive of active denervation and also reinnervation (prolonged motor unit potential duration, polyphasic motor unit potential durations) [20].

#### **2.4 Cadmium (Cd)**

Cadmium is a highly toxic heavy metal. According to Agency for Toxic Substance and Disease Registry, Cd is the 7th most toxic heavy metal. The biological half-life of Cd is about 20–30 years in humans [39]. Cd exists naturally in unrefined rocks. Several sources of human exposure to Cd include mining works, contaminated groundwater use, commercial products (batteries, color pigments, several alloys, and Polyvinyl chloride, phosphate fertilizer) [40].

Exposure to Cd can be occurred by inhalation and also ingestion. It can accumulate into the lungs, olfactory bulb, and kidney [40]. Suggested mechanisms of Cd neurotoxicity include increased lipid peroxidation associated with oxidative stress and causing injury to the microvasculature of the brain. Experimental studies show that rats exposed to Cd, accumulation in choroid plexus, and Cadmium-related lipid peroxidation were demonstrated in brain areas such as the cerebellum and cerebral cortex [41, 42]. Cd neurotoxicity might be caused by defective neurogenesis, lead notably reduced neuronal differentiation and axonogenesis, leading to neuronal cell death [43].

Exposure to Cd causes very different neurological signs and symptoms of both the peripheral and central nervous systems. These are mental retardation, learning disabilities, behavioral pathologies [44]. Moreover, there is growing evidence about Cd-dependent neurotoxicity being one of the possible etiological factors of neurodegenerative diseases such as Alzheimer's, Parkinson's diseases, and sporadic amyotrophic lateral sclerosis [45, 46]. However, Little is known about the influence of cadmium on the peripheral nervous system. Experimental studies have shown that Cd can be a potent neurotoxicant for the peripheral nervous system. Viaene et al. investigated the influence of Cd on polyneuropathy in 13 retired, long-term Cd-exposed workers. They performed the neurological clinical examination, nerve conduction studies, and needle EMG were performed in the study. 54% of the retired Cd workers were diagnosed with polyneuropathy. The authors concluded that increased Cd body burden promotes PNP development at older age [47].

There is no consensus in the literature regarding the treatment of Cd toxicity. While clinical treatment protocols exist for the use of Ethylene Diamine Tetra Acetic Acid (EDTA), 2,3-Dimercapto-1-propane sulfonic acid (DMPS), and meso-2, 3-dimercaptosuccinic acid (DMSA), there are limited human studies. EDTA is the agent most widely accepted for clinical use. It should be noted that these chelation treatments applied during acute poisoning may aggravate damage to the renal tubules. EDTA, which has a long history of safe use, is approved by the FDA to chelation heavy metals. It should not be given faster than one gram per hour nor in dosage greater than three grams per session. Cd is also significantly present in sweat during sauna, which appears to be a moderately successful modality for reducing the body burden of Cd without risk of tubular damage [48–50].

#### **2.5 Tallium (T.I.)**

Thallium is one of the heavy metals found in the earth's crust. Tl is colorless, odorless, and tasteless, and it has been used as a pesticide and rodenticide. Although the use of T.I. in this field has been abandoned in most western countries, there are still countries where it continues to be used. Thallium has been used in a wide variety of industries fields such as electronics, lamps, jewelry, pigmentation [51].

Thallium can contaminate by skin contact, inhalation of contaminated air, or food consumption from contaminated soil or water. Suggested mechanisms of T.I. neurotoxicity include lipid peroxidation and lysosomal enzyme beta-galactosidase in brain regions [52].

Toxication of T.I. causes neurological and non-neurological disorders. Anorexia, vomiting, gastrointestinal bleeding, abdominal pain, alopecia, cardiac arrhythmias are the best-known disorders. In a dose-dependent manner, neuropsychiatric signs have been reported as following; coma, delirium, seizure, hallucination, fatigue, emotional changes, ataxia, and loss of sensation, cranial neuropathy, and polyneuropathy [51, 53, 54]. Thallium-related polyneuropathy can become evident within 1–2 days. It is reported that a painful sensory-motor polyneuropathy mimicking Guillain-Barre's syndrome occurs. In delayed admission, patients are more prone to severe polyneuropathy and other neurological disorders [51, 55].

Treatment for thallium intoxication consists of termination from exposure, supportive care, and enhanced elimination. Prussian blue is approved as an oral agent to prevent absorption of thallium. It is reported that hemodialysis combined with the usage of Prussian blue helps treat patients even delayed admission [51, 55, 56].
