**3. Solvents**

Solvents used in industry as degreasing agents, adjuvants, thinners, and cleaners are widespread. N-Hexane, carbon disulfide, ethylene oxide are widely used solvents [57]. Adhesives containing n-hexane are also widely used in the manufacture of leather goods [58]. Repeated occupational exposure of solvents can be both inhalation and skin contact. While the hexane concentration limit of organ damage through prolonged or repeated exposure is suggested as 5%, the organic solvents used in the adhesives may contain a higher percentage of n-hexane [59]. The toxic effects of organic solvents can be considered a public health problem even though regulations have been made that reduce usage limits [60]. The organic solvent syndrome is the mildest form of chronic exposure. Irritability, fatigue, and reversible difficulty to concentrate are the related symptoms [61]. The neurotoxicity of solvents may occur in both the peripheral nervous system and central nervous system [62].

### **3.1 N-hexane**

The molecular mechanisms of peripheral neuropathy induced by hexane exposure have been investigated in several studies. ɣ-diketone 2,5-hexanedione, which is a neurotoxin, is the metabolite of n-hexane. ɣ-diketone 2,5-hexanedione is the cause of sensory or sensory-motor peripheral neuropathy [63–66]. According to the suggested mechanism, the accused metabolite reacts with amino groups of proteins, including neuroproteins. Lysine-rich neuroproteins are especially vulnerable, including microtubule-associated proteins required for axonal transport. Disruption of axonal transport causes consecutive degenerative changes resulting in localized demyelination and remyelination, with initial changes in the most extensive and most prolonged axons in peripheral nerves and the spinal cord, with similar changes in shorter nerve fibers at a later stage. It results in distal symmetrical sensorimotor neuropathy supported by central-peripheral distal axonopathy [63].

Detailed neurological and neuropsychological examinations are recommended to confirming the clinical findings of central and peripheral nervous system dysfunctions in case of suspicion of toxication. Sensory abnormalities such as insensitivity to pinprick and touch, impaired two-point discrimination, changes in sensation to position, vibration, or temperature, diminished deep tendon reflexes are common neurological findings. Peripheral neuropathy is characterized by symmetrical progressive distal sensory and motor impairment [61, 62, 64]. Nerve conduction studies and electromyography should be performed to confirm peripheral neuropathy. It is reported that severe exposure and affected patients may develop muscle atrophy and foot drop [62]. Typical electrophysiological findings increase in distal latencies, slowing of nerve conduction velocities, conduction block with temporal dispersion, and the slowing down of transmission in electromyography in subjects with severe neuropathy [58, 62]. Neuroimaging Cranial magnetic resonance imaging (MRI) should be performed to detect the atrophic changes in the frontal lobes and cerebellum and white-matter lesions described after exposure to certain solvents [67, 68]. It is reported that acute, lowdose exposures might be related to specific changes in test performance, which improve after withdrawal from exposure. However, chronic exposure can also be associated with permanent cognitive changes [67].

#### **3.2 Carbon disulfide**

Carbon disulfide (CS2) is an organic solvent used for various industrial purposes, such as an insecticide, fresh fruit conservation, disinfectant against insects [69]. CS2 is a significant metabolite of the drug disulfiram used as a dissuasive for alcohol abuse. The occupational CS2 exposure can be by inhalation and skin contact. It is known that the highest degree of exposure is in the viscose rayon industry [70]. Exposure to carbon disulfide is likely to occur for the general population by inhaling contaminated ambient air, eating vegetables and fruits, or other food products containing carbon disulfide [69]. Since carbon disulfide has lipophilic nature, the distribution of C.S. 2 is easily in organs such as the brain and liver. C.S. 2 is metabolized to thiocarbamates in these organs, and it is considered that dithiocarbamates can take part in neurotoxic effects [71].

According to acute or sub-acute high-level exposures of CS2 can lead to unconsciousness, hallucinations, emotional lability, extrapyramidal signs, and polyneuropathy [69, 70]. It is reported that exposure of 200 to 500 ppm may cause death [69]. Peripheral neuropathy and extrapyramidal signs have been reported following chronic occupational low-level exposures. In low level (10 to 40 ppm) exposure, peripheral neuropathy may be asymptomatic and detected only electrophysiologically. As the concentration of CS 2 increases (20 to 60 ppm), a progressive sensorimotor distal asymmetrical polyneuropathy appears [72].

In neurological examination, findings include; paresthesia and dysesthesia tend to occur in a 'stocking and glove' distribution, loss of ankle and patellar reflexes, and diminished pain, touch, and vibration sensation in the distal lower limbs. In

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

some cases, recovery may be slow and incomplete, possibly because of residual axonal damage [73].

There is no typical clinical profile and routine laboratory tests, including cerebrospinal fluid (CSF) examination. Nevertheless, CSF should be performed for differential diagnosis. Nerve conduction studies and electromyography should be performed to confirm peripheral neuropathy. It is reported that long-term exposure and a cumulative dose of CS2 exposure are related to electrophysiological findings [74]. In the electrophysiological examination, reduced motor and sensory amplitudes, slightly slowed motor conduction velocities prolonged distal latencies are reported in exposed patients with neuropathy symptoms. In the same patient group, needle EMG revealed chronic, length-dependent denervation with decreased recruitment, large motor units, and fibrillation potentials [75].

### **3.3 Ethylene oxide (EO)**

Ethylene oxide is a powerful sterilizer for medical materials and antiseptic for furs and some foods. It is a gas at room temperature. The occupational EO exposure can be by inhalation. Since EO is a water-soluble substance, it can quickly spread to all organs shortly after inhalation exposure [72]. EO is a potent alkylating agent and can interact with all cellular components, including DNA [76].

The principal neurotoxicant effect of EO is polyneuropathy. EO-related distal symmetrical axonal polyneuropathy has been reported in several cases reports in the 1980s, and Ohnishi et al. established an experimental model of EO neuropathy [77–80]. Kuzuhara et al. showed axonal degeneration with mild changes of the myelin sheath in sural nerve biopsies [79]. Neurotoxic effects may develop in both intermittent high doses and chronic prolonged low-dose exposure [72]. Gross et al. reported four cases who had occupational EO exposure. One of the cases had encephalopathy syndrome, and three of them had polyneuropathy [80]. In clinically symptomatic cases, distal extremity numbness and weakness, diminished sensation in the feet and hands can be initial symptoms. However, some of the cases can be asymptomatic. The electrophysiological examination reported reduced motor and sensory amplitudes and mildly slowed motor and sensory nerve conduction velocities [80, 81]. Gradual improvement of neurotoxicant effects was found associated with withdrawal from exposure [81].

## **4. Medications and peripheral nervous system toxicity**

Antineoplastic drugs' most frequent and sometimes serious complication is chemotherapy-induced peripheral neuropathy (CIPN). The estimated prevalence of CIPN is 19–85% [82]. Compared to other peripheral neuropathies, such as painful diabetic polyneuropathy, patients with CIPN are likely to develop more severe symptoms, suffering from pain affecting both feet and hands, with faster progression. The high prevalence of CIPN among patients with cancer poses a serious problem for both patients and doctors administering the treatment. Due to the CIPN and related symptoms, sometimes it may be necessary to interrupt, stop, or reduce the dose of drugs, limiting the treatment's efficacy [83].

Platinum analogs (Cisplatin, oxaliplatin), taxanes (Paclitaxel), vinca alkaloids, and proteasome inhibitors (bortezomib) are the most commonly preferred antineoplastic medications. These are successfully used as first-line treatment for several solid and blood cancers, such as breast, lung, colorectal, gastric cancers, and multiple myeloma [84]. Although these antineoplastic medications have different chemical structures and mechanisms, chemotherapy-induced peripheral neurotoxicity (CIPN) is one of their common side effects. The occurrence of CIPN varies according to the chemotherapeutic drugs, dose, duration of exposure, and method of assessment [85]. The highest rate of CIPN is reported in platinum analogs (70–100%), taxanes (11–87%), thalidomide, and its analogs (20–60%), and ixabepilone (60–65%) [86].

#### **4.1 Platinum analogs; cisplatin, carboplatin, oxaliplatin**

Platinum analogs interact with DNA, forming platinum-DNA compounds and cause apoptotic cell death. Most platinum analogs cause some degree of neurotoxicity. Dorsal root ganglion (Drg) is considered to be the primary target of neurotoxicity. It has been shown that platinum analogs cause apoptosis in dorsal root ganglia and morphological changes in the nucleus in-vitro [84]. Because of the lack of blood–brain barrier protection and be vascularized by fenestrated capillaries, the nuclei of Drg neurons are vulnerable to chemically-induced damages [87]. Platinum analogs induced peripheral neuropathy is a sensory neuronopathy caused by direct damage to Drg neurons, leading to an anterograde axonal degeneration. According to sensory neuronopathy, altered touch sensation, paresthesia in the distal extremities, tingling, altered touch sensation, proprioceptive loss, areflexia, and sensory ataxia occur. Patients frequently experience painful sensations, including spontaneous burning, electric shock-like pain, along with mechanical or thermal allodynia or hyperalgesia. Neuropathic pain symptoms have been reported, often even after treatment discontinuation [88, 89].

Since the 1980s, Cisplatin has been used to treat testicular, ovarian, and small cell lung cancers. Cisplatin administration induced severe toxicity, especially to the kidneys and nervous system [90]. Cisplatin causes primarily sensory neuropathy, characterized by distal parenthesis, progressing to proprioceptive loss, areflexia, and sensory ataxia [88]. Symptoms arise after cumulative doses above 300 mg/ m2. Severe symptoms related to neuropathy have been reported to occur three to six months post-treatment cessation [91]. Electrophysiological studies have typically shown marked reduction in sensory action potential amplitudes with relative preservation of conduction velocity, indicative of axonal loss [84, 91]. Motor and autonomic symptoms and signs are infrequent but may occur in severe cases. Treatment with platinum analogs has been rarely associated with acute inflammatory demyelinating polyradiculoneuritis in patients with solid tumors [92].

Carboplatin is known to be less toxic, with neuropathy observed in 13–42% of patients. At the same time, carboplatin may induce mild neurotoxicity in quarter patients, with moderate to severe neurotoxicity in 5% of patients [93]. Peripheric neurotoxic side effects are common with high doses (800–1600 mg/m2) [94]. Electrophysiological studies reveal a reduction in compound sensory and motor amplitudes. Experimental studies have reported that at very high doses (10–15 mg/kg), carboplatin induces neurotoxicity and associated platinum deposition in the dorsal root ganglion, similar to Cisplatin [84].

Oxaliplatin has been effectively used as a first-line therapy against colorectal cancer. Its neurotoxicity may develop both acute and chronic. Acute and rapidly reversible peripheral neuropathy occurs in approximately 65–98% of patients within hours of drug infusion at a dose ranging 85–130 mg/m2 and may last up to one week. In 12 cycles of chemotherapy received, symptoms may persist up to 21 days or longer. Myelotoxicity and enteric and peripheral neuropathy may be induced by chemotherapy with oxaliplatin [95]. Cold-induced neuropathic symptoms are the most important difference in the clinical presentation between oxaliplatin and cisplatin-induced neuropathy [96]. Chronic peripheral neuropathy occurs in approximately 50–70% of patients, described as a pure sensory, axonal

neuropathy [95]. Patients frequently experience distal paresthesia, sensory ataxia, jaw pain, leg cramps. Electrophysiological studies of oxaliplatin-induced peripheral neuropathy reduce the sensory action potentials with preserved motor amplitudes and conduction velocities. However, spontaneous activity can be obvious, suggesting an immediate effect of the drug on the axonal excitability rather than structural damage [84, 97].

## **4.2 Taxanes; paclitaxel**

Paclitaxel, docetaxel, cabazitaxel are the class of taxanes that act on microtubules, interfering with the normal cycling of microtubule depolymerization and polymerization. The incidence of CIPN according to taxanes may be very high (11 to 87%), and the highest rates are reported for Paclitaxel [98]. Neuropathy caused by taxanes usually emerges as a dominant sensory neuropathy with the stocking-and-glove distribution. The manifestations are paresthesias, dysesthesias, numbness, altered proprioception, and loss of dexterity predominantly in the toes and fingers. Motor and autonomic involvement are infrequent [99]. Neurological symptoms and findings are dose-dependent and tend to improve after stopping the treatment. However, some patients experience symptoms up to 1–3 years and sometimes lifelong after the therapy [100]. Microtubule disruption, mitochondrial dysfunction, axonal degeneration, altered calcium homeostasis, altered expression and function of ion channels, production of pro-inflammatory cytokines are the suggested underlying mechanisms of CIPN [101, 102].

*Paclitaxel* is a microtubule-binding antineoplastic drug commonly used to treat various solid tumors like lung, breast, and ovarian cancer. Paclitaxel is highly potent against proliferating neoplastic cells, but neurons not dividing cells are vulnerable to Paclitaxel. The treatment with paclitaxel affects the peripheral nervous system and primarily causes sensory axonal polyneuropathy [103]. Peripheral nerves biopsies have revealed a pathology of axonal degeneration, secondary demyelination, and, in cases of severe neuropathy, nerve fiber loss has also been observed [104].

## **4.3 Vinca alkaloids; vincristine**

Vinca Alkaloids are developed from the Madagascar periwinkle plant, including vincristine, vinblastine, vinorelbine, and vindesine. These drugs are commonly prescribed to treat various tumors, such as Hodgkin and non–Hodgkin lymphoma, testicular cancer, and non–small cell lung cancer [102]. Vinca alkaloids have welldocumented effects on microtubules – including binding to tubulin and inhibiting microtubule Dynamics [105].

Vincristine was approved in July 1963 by the United States Food and Drug Administration (FDA). It is one of the most common anticancer drugs used in pediatrics oncology. However, its clinical use is accompanied by severe side effects, such as peripheral neuropathy and neuropathic pain leading to treatment discontinuation. Both sensory and motor dysfunctions characterize peripheral neuropathy related to vincristine [106]. The duration and therapeutic doses received by patients directly affect the severity of symptoms. Besides sensory symptoms, patients also experienced muscle weakness and cramping. Changes in axonal transport and dorsal root ganglia resulting in Wallerian degeneration, altered ion channels activity and hyperexcitability of peripheral neurons, production of pro-inflammatory cytokines are the suggested underlying mechanisms of vincristine-induced peripheral neuropathy [101].

Vincristine use in Charcot–Marie–Tooth disease (CMT) patients has a black box warning added by the FDA. The CMT patients with the ERG2 gene mutation and

polymorphism in the CEP72 gene are associated with increased risk and severity of drug-induced neuropathy [107, 108].

There is no specific treatment for vinca alkaloid-induced peripheral neuropathy. Pyridoxine or pyridostigmine can be having a certain efficacy in vincristineinduced neuropathy. A topical capsaicin cream was demonstrated to give benefit in peripheral neuropathy. In neuropathic pain, carbamazepine, imipramine, or lignocaine can be used [101].

#### **4.4 Proteasome inhibitors; bortezomib**

*Bortezomib* is a reversible proteasome inhibitor antineoplastic drug that is successfully used against multiple myeloma and some types of solid tumors. It was first described as an inflammation inhibitor, but with its cytotoxic effects, it began to be used in cancer therapy. Bortezomib was approved in 2003 by FDA as a single agent against advanced myeloma but is now mostly used in combination therapies [109]. Although bortezomib is generally well tolerated, the most frequent limiting factor for its clinical use is a painful peripheral neuropathy side effect. Bortezomibinduced peripheral neuropathy is attributed to paresthesias, dysaesthesias, burning sensations, numbness, sensory loss, reduced proprioception, and vibratory sensation. Besides these symptoms and signs, demyelinating neuropathy may also be present. Deep tendon reflexes and autonomic innervation of the skin are reduced in patients treated with bortezomib [110]. Chronic, distal, and symmetrical sensory peripheral neuropathy is typical neuropathy induced by bortezomib.

Neuropathic pain symptoms have been reported to continue for weeks, months, or even years after treatment discontinuation.

Bortezomib-induced peripheral neuropathy is reported in approximately one-third of the patients [111]. Suggested mechanisms of bortezomib-induced peripheral neuropathy are increased sphingolipid metabolism in astrocytes, inflammation related to TNFa and IL-1, mitochondrial damage, reactive oxygen radical production, and alteration in Ca++ signaling [101].

## **5. Others**

#### **5.1 Acrylamide**

*Monomeric acrylamide* is a potent neurotoxin used in different industrial and laboratory processes. Acrylamide is readily absorbed by inhalation, ingestion, or dermal contact. The acrylamide exposure affects the central nervous system (CNS) and peripheral nervous system (PNS). Chronic and high-level exposure to this water-soluble chemical mostly causes peripheral neuropathy. The peripheral neuropathy causes impairment in the arms and legs of exposed workers. Several studies reported that short-term occupational exposure to acrylamide resulted in weakness of lower extremities, loss of deep tendon reflexes and sensations in distal limbs, and numbness preceded by skin peeling from the hands [112–114]. Moreover, it has been shown that longer exposure involved more severe symptoms, including cerebellar dysfunction followed by peripheral neuropathy. Based on numerous investigations and risk assessments, acrylamide is generated in food preparation processes involving high temperatures [115, 116]. Different pathogenetic mechanisms were hypothesized; however, the exact mechanism of action is not completely elucidated. Like other toxic neuropathies, the prognosis of neuropathy is associated with the degree of central axonal degeneration. Three important hypotheses currently considering acrylamide neurotoxicity include inhibition of kinesin-based

fast axonal transport, alteration of neurotransmitter levels, and direct inhibition of neurotransmission [117].
