**5. Tests to detect neurotoxicity/Neurotoxicology screenings**

While substances that lead to neurotoxic effects can be found by routine toxicity screening testings (e.g., chronic, acute, developmental/reproductive toxicity), specific standards exist to further evaluate compounds' potential neurotoxicity. The requirements established by the USEPA (the United States Environmental Protection Agency) are based on a functional observational battery, motor health assessments, and neuropathological examinations. Similarly, the OECD

#### *Neurotoxicity, Types, Clinical Manifestations, Diagnosis and Treatment DOI: http://dx.doi.org/10.5772/intechopen.101737*

(Organization for Economic Cooperation and Development) criteria emphasize clinical results, practical test findings (e.g., motor activity, sensory response to stimuli), and neuropathology. These batteries are intended to provide a Tier 1 screening for neurotoxicity, with positive findings necessitating additional testing (Tier 2), which may involve specialized behavioral tests in addition to electrophysiological and neurochemical data. Examples include memory and learning tests, nerve conduction velocity measurements, and biochemical tests linked to neurotransmission or indices of cell integrity or function. Specific recommendations for developmental neurotoxicity (DNT) testing have also been created in the United States of America and Europe. The mother is exposed to the test drugs from prenatal day 6 to postnatal day 10 or 21, ensuring exposure both in utero and via maternal milk. The examinations cover developmental milestones and reflexes, motor activity, hearing testing, learning and memory tests, and neuropathology. DNT has been demonstrated to be exceedingly practical and beneficial in detecting substances and agents that have the potential to cause developmental neurotoxicity during neurotoxicity testing. However, additional effort is needed to improve these tests, either because they are susceptible and generate a significant proportion of false positives or because they are insufficiently sensitive and thorough [8–11].

Additionally, concerns have been expressed about historical control data, toxicokinetic parameters, toxicity mediated by the mother versus direct effects, test selection, and their analysis and interpretation. Toxicologists have increasingly recognized the need for acceptable and accurate alternatives to conventional animal testing in recent years, highlighting the issues associated with rising costs and time requirements for toxicity assessment tests, the growing number of chemicals being developed, and commercializing the demand in response to recent legislation and efforts to reduce the number of animals used in toxicity testing. This, combined with efforts in the field of developmental neurotoxicity, has resulted in the development of alternative models, either using mammalian cells *in vitro* or nonmammalian model systems (using zebrafish), that may serve as valuable tools for neurotoxicity and developmental neurotoxicity testing, particularly for screening. These alternative tests should be utilized as Tier 1 testing for drugs and agents with an uncertain DNT potential. Given the complexity of the nervous system and the range of possible neurotoxic outcomes, developing a single test that covers the entire spectrum of neurotoxicity is challenging. Rather than that, a battery of tests should be explored that includes some *in vitro* experiments with mammalian cells and one or two tests using nonmammalian models. This can be augmented by applying computational approaches and procedures to develop a quantitative structure–activity relationship. Additionally, novel methodologies that are a component of "omics" technology can be applied in these endeavors. Alternative models for DNT must strive to reproduce a large number of events that occur *in vivo*, and given the complexity of the central nervous system (CNS), the approach for DNT is significantly more extensive than for other toxicity target organs [11–15].

## **6. Long-term effects of neurotoxicity/developmental neurotoxicity**

Neurotoxic effects linked with developmental exposure during pregnancy, nursing, early childhood, and adolescence are frequently documented following a brief period of exposure. Nonetheless, evidence indicates that the insalubrious effects of toxicants may take months, if not years, to manifest clinically. The "silent" phase refers to the time period during which an individual may display no signs or symptoms of poisoning. Silent toxicity is a term that refers to continuing

morphological or biochemical damage that is clinically undetected unless concealed by special techniques. Silent toxicity is comparable to carcinogenesis, in which cellular and molecular damage develop years, if not decades before clinical symptoms show. This area contains numerous instances of silent poisoning. Parkinsonismdementia, frequently referred to as Guam's disease, is the most widespread kind, with a latency of several decades between supposed yet-undefined exposures and clinical manifestations. Another case of bovine spongiform encephalopathy (mad cow disease) is a form of Creutzfeld–Jacob disease with a documented latency of decades [8, 15–19]. The time interval between the onset of clinical symptoms and exposure to a neurotoxic event can be explained by a number of factors. For example, while a specific population of neurons may be injured, the brain's plasticity may compensate for this loss temporarily. Exogenous stressors (stress, illness, chemical exposure) or the normal aging process, on the other hand, may disclose the silent toxicity. Alternatively, an organism may be capable of compensating for a specific defect. Nevertheless, persistent loss of function may eventually exhaust the brain's functional reserve and plasticity. The likelihood of such a latent period occurring between exposure and clinical manifestation occurring throughout the development stage is significantly greater. David Barker was a pioneer in establishing the possibility that many adult disorders have fetal origins. The "Barker hypothesis" is the name given to this concept. Toxic substance exposure has the potential to directly destroy or modify developmental programming, resulting in later-life functional impairments [8, 9, 19–22]. Diethylstilbestrol is the most prominent example, which may contribute to an increase in vaginal adenocarcinoma around puberty as a result of in utero exposure. Perinatal exposure of rats to the Gram (−) bacteriotoxin lipopolysaccharide causes a 30% loss in dopaminergic neurons in the substantia nigra and persistent injury to the dopaminergic system, implying that, in humans, prenatal infections occurring at a specific gestational age may result in the birth of an individual with significantly fewer dopaminergic neurons. This could be an example of developmental neurotoxicity. This may seem minor, given that Parkinson's disease does not manifest clinically until around 80% of dopaminergic neurons are lost completely. When the aging process culminates in the typical progressive loss of dopaminergic neurons, this early-life lesion may play a substantial role in an individual's development of Parkinson's disease. Exposure to some pesticides during development, such as the herbicide paraquat and the fungicide maneb, both of which act on dopaminergic neurons, has also been related to the development of Parkinson's disease later in life. Similarly, developmental exposure to the now-banned organochlorine insecticide dieldrin has been found to cause significant and long-lasting alterations in the dopaminergic system, as well as a silent dopaminergic dysfunction. Rarely, modest and mild injuries may worsen as an individual develops and ages. In this manner, the neurotoxic effects of embryonic MeHg exposure do not manifest themselves for years. Microencephaly produced by uterine exposure to methyl azoxy methanol resulted in an early loss of cognitive abilities, and the neurotoxic consequences of neonatal exposure to triethyltin, a glial neurotoxicant, were increased with age. This cannot be the case in all other situations. Nonetheless, developmental exposure appears to have irreversible neurotoxic effects, and even if they do not deteriorate with age, they have long-term ramifications, as evidenced by perinatal lead exposure [23–28].

### **7. Treatment and Prognosis**

The treatment of neurotoxicity involves terminating, eliminating, or reducing dangerous chemicals and commencing therapy to reduce symptoms and offer necessary support [2, 3].

The difficulty is that if biotoxicity or neurotoxicity is the underlying cause of the pain or sickness and the treatment plan does not include a detoxification regimen, the overall recovery will almost certainly be incomplete and take longer than necessary [2, 3].

Biotoxicity/neurotoxicity treatment protocol can also include acupuncture, herbal remedies & nutritional supplements, nutritional counseling, and prescription of medication. For example, the key factors in the initial management of acute arsenic intoxication are gut decontamination and hemodynamic stabilization in patients with suspected acute arsenic poisoning. Generally, in such neurotoxicity, rapid stabilization with fluid and electrolyte replacement in an intensive care setting is very important. Aggressive intravenous fluid replacement therapy maybe even life-saving in serious poisoning. Gastric lavage may also be useful soon after acute ingestion to prevent any further absorption. The efficacy of activated charcoal is controversial, but its administration together with a cathartic (such as sorbitol) is frequently recommended, but if profound diarrhea is present, cathartics must be withheld. Hemodialysis may be beneficial in a patient with concomitant renal failure. Chelating agents administered within hours of arsenic absorption can successfully prevent the full effects of arsenic toxicity. If patients are treated within several hours after arsenic ingestion, chelation is likely to be beneficial. Therefore, even if arsenic ingestion is only suspected but not confirmed, consultation with a clinical specialist with expertise in the treatment and management of arsenic poisoning is essential [29].

Generally, neurotoxicity has a prognosis and outcome that are determined by the extent and duration of toxic substance exposure and the extent of brain damage. In some cases, individuals die due to neurotoxins exposure, while others live but do not fully recover. The patient may recover entirely following the necessary treatment [2].

### **8. Innovations in the future**

The potential threats to human health posed by hazardous chemicals in the surrounding environment have become a significant public health concern. It is critical to have the necessary abilities, tools, and facilities to study neurotoxicity in an individual. Treatment for patients exposed to environmental neurotoxins is not yet defined, and multidisciplinary teams will be necessary to manage the most severe cases. Diagnostic indicators for neurotoxic diseases based on rapid-response biomarkers should be identified and developed more efficiently to be used by all centers. Two essential variables should be considered—the severe effect on the developing fetus and newborn, the long-term health consequences of chronic exposure to low levels of environmental neurotoxins, and the long-term health consequences of severe acute poisoning in patients.

Additionally, a conclusive study is needed to address the frequent allegation that putative neurotoxins lack a "safe" limit, owing to our inadequate understanding of the lethal synergy that can occur when multiple toxins are exposed concurrently. Additionally, significant progress is anticipated in elucidating the relationship of harmful environmental chemicals and susceptibility risk factors in progressive neurodegenerative diseases such as motor neurons, Parkinson's disease, and Alzheimer's disease [2–4].

#### **9. Conclusion**

Neurotoxicity refers to the direct or indirect effect of chemicals that disrupt the nervous system. Neurotoxins can be found naturally in the environment, and they

#### *Neurotoxicity - New Advances*

could be synthetic. Some neurotoxins act directly on neural cells; others interfere with metabolic processes on which the nervous system is primarily dependent— The effects of neurotoxicity can appear and disappear rapidly, evolve slowly over days or weeks, regress over months or years, or cause permanent deficits. Neurotoxicity is usually self-limiting after exposure ceases and rarely progressive in the absence of continued exposure. The treatment is terminating the toxins exposure and providing symptomatic treatment.
