A REVIEW ON NEUROTOXICITY

About Authors:
Yogesh Yaduwanshi*, Gireesh Mehta, Jitendra Shakyawal, Surya Pratap, Sanjay Singh, Mahaveer Kabra
Department of Pharmacology,
Kota College of Pharmacy, Kota,
Rajasthan India
*yogeshyaduwanshi24@gmail.com

Abstract:
Chemicals are an integral part of our daily lives and are responsible for substantially improving them. Yet chemicals can also endanger our health, even our survival. This report focuses on neurotoxic substances, those chemicals that adversely affect the nervous system. Included among such substances are industrial chemicals, pesticides, therapeutic drugs, abused drugs, foods, food additives, cosmetic ingredients, and naturally occurring substances. Whether a substance causes an adverse health effect depends on many factors, including the toxicity of the substance, the extent of exposure, and an individual's age and state of health. Minimizing public health risks requires knowledge about the properties and mechanisms of action of potentially toxic substances to which humans may be exposed. The assessment includes discussion of industrial chemicals, pesticides, therapeutic drugs, substance drugs, foods, food additives, cosmetic ingredients, and such naturally occurring substances as lead and mercury. It does not include radioactive chemicals, nicotine, alcohol, biological and chemical warfare agents, microbial, plant, and animal toxins, and physical agents such as noise.

Reference Id: PHARMATUTOR-ART-1979

INTRODUCTION
The nervous system comprises the brain, the spinal cord, and a vast array of nerves that control major body functions. Movement, thought, vision, hearing, speech, heart function, respiration, and numerous other physiological processes are controlled by this complex network of nerve processes, transmitters, hormones, receptors, and channels. Although every major body system can be adversely affected by toxic substances, the nervous system is particularly vulnerable to them. Unlike many other types of cells, nerves have a limited capacity to regenerate¹.

Many toxic substances can alter the normal activity of the nervous system. Some produce effects that occur almost immediately and last for a period of several hours: examples include a drug that prevents seizures, an alcoholic beverage, and fumes from a can of paint. The effects of other neurotoxic substances may appear only after repeated exposures over weeks or even years, for example, regularly breathing the fumes of a solvent in the workplace or eating food or drinking water contaminated with lead. Some substances can permanently damage the nervous system after a single exposure: certain organophosphorous pesticides. Other substances, including abused drugs such as heroin and cocaine, may lead to addiction, a long-term adverse alteration of nervous system function. Many neurotoxic sub-stances can cause death when absorbed, inhaled, or ingested in sufficiently large quantities. A substance may be safe and beneficial at one concentration but neurotoxic at another. For example, vitamins A and B6 are required in the diet in trace amounts, yet both cause neurotoxic effects in large doses⁵⁰. In other cases, a substance that is known to be neurotoxic may confer benefits that are viewed as outweighing the adverse effects. For example, thousands of individuals suffering from schizophrenia have been able to live relatively normal lives because of the beneficial effects of the antipsychotic drugs. However, chronic use of prescribed doses of some of these drugs may give rise to tardive dyskinesia-involuntary movements of the face, tongue, and limbs-side-effects so severe that they may incapacitate the patient².

The elderly are more susceptible to certain neurotoxic substances because decline in structure and function of the nervous system with age limits its ability to respond to or compensate for toxic effects³. In addition, decreased liver and kidney function and increases susceptibility to toxic substances. Aging may also reveal adverse effects masked at a younger age. Persons who are chronically ill, especially those suffering from neurological or psychiatric disorders, are at risk because neurotoxic substances may exacerbate existing problems. Also, many elderly Americans take multiple drugs that may interact to adversely affect nervous system function. Common adverse effects include depression, confusion, and loss of memory, shaking and twitching, dizziness, and impaired thought processes.

EFFECT AND CAUSE OF NEUROTOXICITY
Office of Technology Assessment (OTA) defines neurotoxicity or a neurotoxic effect as an adverse change in the structure or function of the nervous system following exposure to a chemical agent.

Broadly defined, any substance is considered to have neurotoxic potential if it adversely affects any of the structural or functional components of the nervous system. At the molecular level, a substance might interfere with protein synthesis in certain nerve cells, leading to reduced production of a neurotransmitter and brain dysfunction. Substances that adversely affect sensory or motor functions disrupt learning and memory processes, or cause detrimental behavioral effects are neurotoxic. Exposure of children to lead, for example, leads to deficits in I.Q. and poor academic achievement⁴.

Neurotoxic substances can cause a variety of adverse health effects, ranging from impairment of muscular movement to disruption of vision and hearing, to memory loss and hallucinations. Some substances can cause paralysis and death. Some of the most frequently re-ported neurobehavioral effects of exposure to toxic substances are described hereunder⁵.

1. Motor effects:

Convulsions
Weakness tremor
Twitching lack of coordination
Paralysis
Reflex abnormalities
Activity changes

2. Sensory effects:

Equilibrium changes
Vision disorders
Pain disorders
Tactile disorders
Auditory disorders

3. Mood and personality effects:

Sleep disturbances
Excitability
Depression
Irritability
Restlessness
Nervousness
Tension
Delirium
Hallucinations

4. Cognitive effects:

Memory problems
Confusion
Speech impairment
Learning impairment

5. General effects:

Loss of appetite
Depression of neuronal activity
Narcosis
Stupor
Fatigue
Nerve damage

Neurotoxicity has been an important public health concern for many years, and incidents of human poisoning have occurred periodically throughout the world for centuries. Some of the major incidents are indicated in table. The neurotoxicity of heavy metals, widely distributed in the soil of the Earth's surface, has been recorded in fable and fact for many centuries⁶.

Table 1: Selected Major Neurotoxicity Incidents
Year(s)	Location	Substance	Comments
400 B.C.	Rome	Lead	Hippocrates recognizes lead toxicity in the mining industry⁷.
1930s	United States (Southeast)	TOCP	Compound often added to lubricating oils contaminates “Ginger-Jake,” an alcoholic beverage; more than 5,000 paralyzed 20,000 to 100,000 affected⁸.
1932	United States (California)	Thallium	Barley laced with thallium sulfate, used as a rodenticide, is stolen and used to make tortillas; 13 family members hospitalized with neurological symptoms; 6 deaths⁸.
1946	—	Tetraethyl lead	More than 25 individuals suffer neurological effects after cleaning gasoline tanks⁹.
1950s	Japan (Minamata)	Mercury	Hundreds ingest fish and shellfish contaminated with mercury from chemical plant; 121 poisoned, 46 deaths, many infants with serious nervous system damage⁸.
1950s	Morocco	Manganese	150 ore miners suffer chronic manganese intoxication involving severe neurobehavioral problems⁸.
1956	Turkey	HCB	Hexachlorobenzene, a seed grain fungicide, leads to poisoning of 3,000 to 4,000; 10 percent mortality rate¹⁰.
1956-1977	Japan	Clioquinol	Drug used to treat travelers’ diarrhea found to cause neuropathy; as many as 10,000 affected over two decades⁸.
1960	Iraq	Mercury	Mercury used as fungicide to treat seed grain used in bread; more than 1,000 people affected¹¹.
1964	Japan	Mercury	Methylmercury affects 646⁸.
1968	Japan	PCBs	Polychlorinated biphenyls leaked into rice oil, 1,665 people affected¹¹.
1971	United States	Hexachlorophene	After years of bathing infants in 3 percent hexachlorophene, the disinfectant is found to be toxic to the nervous system and other systems⁷.
1971	Iraq	Mercury	Mercury used as fungicide to treat seed grain is used in bread; more than 5,000 severe poisonings, 450 hospital deaths, effects on many infants exposed prenatally not documented ¹¹.
1973	United States (Ohio)	MnBK	Fabric production plant employees exposed to solvent; more than 80 workers suffer polyneuropathy, 180 have less severe effects¹.
1977	United States (California)	Dichloropropene (Telone II)	24 individuals hospitalized after exposure to pesticide Telone following traffic accident ¹⁰.
1979-1980	United States (Lancaster, TX)	BHMH (Lucel-7)	Seven employees at plastic bathtub manufacturing plant experience serious neurological problems following exposure to BHMH ⁸.
1980s	United States	MPTP	Impurity in synthesis of illicit drug found to cause symptoms identical to those of Parkinson’s disease¹¹.
1985	United States and Canada	Aldicarb	More than 1,000 individuals in California and other Western States and British Columbia experience neuromuscular and cardiac problems following ingestion of melons contaminated with the pesticide aldicarb ¹².
1987	Canada	Domoic acid	Ingestion of mussels contaminated with domoic acid causes 129 illnesses and 2 deaths. Symptoms include memory loss, disorientation, and seizures¹³.

1. Industrial Chemicals:
Thousands of chemicals are produced by industry, and new substances are constantly entering the marketplace. Organic solvents are a class of industrial chemicals that have the potential for significant human exposure. This is due in large part to their volatility; that is, in the presence of air they change rapidly from liquids to gases, which may be readily inhaled. Their fat volubility and other chemical properties make many solvents neurotoxic in varying degrees. Exposures may be accidental, as often occurs in the industrial or household setting, or deliberate, as in glue-sniffing, a common form of inhalant abuse. Many solvents, including ethers, hydrocarbons, ketones, alcohols, and combinations of these, have caused neurological and behavioral often unaware of the permanent damage that this problems in the workplace. For example, in 1973, workers at a fabric production plant in the United States were discovered to have neuropathies, or degeneration of nerve fibers. These workers had been regularly exposed to methyl-n-butyl ketone (MnBK), a dye solvent and cleaning agent introduced to the plant the previous year²⁵. Subsequent laboratory studies implicated MnBK as the causative agent. Solvents are commonly used in glues, cements, and paints. The fumes of toluene-based spray paints, various solvents, and modeling cements are some-times inhaled as intoxicants. Inhalant abuse, an important public health problem¹⁴, can cause severe degeneration and permanent loss of nerve cells. About one in five high school students has tried inhalants¹⁵.

2. Pesticides:
Pesticides are one of the most commonly encountered classes of neurotoxic substances. In this report "pesticide" is used as a generic term and includes insecticides (used to control insects), fungicides (for blight and mildew), rodenticides (for rodents such as rats, mice, and gophers), and herbicides (to control weeds), among others. More than 1 billion pounds of pesticides are used annually in the United States alone.

These active ingredients are combined with so-called inert substances to make thousands of different pesticide formulations. The organophosphorous insecticides, which account for about 40 percent of the pesticides registered in the United States, have neurotoxic properties¹⁶, as do other classes of pesticides, including the carbamate and organochlorine insecticides. Because of the biochemical similarities between the insect and human nervous systems, insecticides can adversely affect humans as well, Organophosphorous and carbamate insecticides inhibit acetylcholinesterase, an enzyme responsible for inactivating the neurotransmitter acetylcholine (a common chemical messenger in the nervous system) after it has been released by stimulation of a nerve cell. Consequently, these pesticides cause acetylcholine to accumulate in the synapses (or points of contact) between nerves and muscles. This leads to over-stimulation of many nerves, including those that control muscle movement, some organ systems, and thought and emotional processes.

Acute human poisoning from organophosphorous insecticides can cause muscle weakness, paralysis, disorientation, convulsions, and death. Of particular concern are the delayed neurotoxic effects of some of the organophosphorous insecticides. Some of these compounds cause degeneration of nerve processes in the limbs, leading to changes in sensation, muscular weakness, and lack of coordination¹⁷.

In the mid-1970s, the American public became acutely aware of the threat to human health posed by neurotoxic substances when a number of workers at a chemical plant in Hopewell, Virginia, were exposed to the insecticide chlordecone (a chlorinated hydrocarbon marketed as Kepone). A previously unidentified neurological disorder resulted, characterized by tremors, muscle weakness, slurred speech, lack of coordination, and other symptoms. The symptoms appeared from 5 days to 8 months after onset of exposure to large amounts of the insecticide and remained in several of the workers for months after cessation of exposure and closing of the plant. This incident illustrates the difficulty physicians’ face in diagnosing poisoning episodes¹⁸.

Affected workers reported that the overt signs of poisoning were preceded by a feeling of ''nervousness, ' a symptom that might not lead a physician to suspect exposure to a neurotoxic substance.

Because of their widespread use, pesticides are dispersed in low concentrations throughout the environment, including the Nation's food and water supplies. Between 1982 and 1985, the Food and Drug Administration (FDA) detected pesticide residues in 48 percent of more than two dozen frequently consumed fruits and vegetables¹⁹. However, OTA recently found that FDA's analytical methods detect only about one-half of the pesticides that contaminate fruits and vegetables²⁰. Use of pesticides has been so widespread that measurable levels are frequently found in human tissues. DDT, for example, was banned a number of years ago, yet nearly everyone born since the mid-1940s has measurable levels of this pesticide or it metabolizes in their fatty tissues²⁹. Some scientists believe that the levels of the persistent pesticides present in humans pose no risk; others think there is cause for concern and that more research is needed to evaluate the public health risk of chronic, low-level exposures. The possible effects on the developing nervous system of chronic exposure to pesticides are of particular concern.

Exposure to agricultural pesticides is highest among mixers, loaders, applicators, farmworkers, and farmers. Poisonings are a particular problem in developing countries, where the misuse of pesticides is relatively common.

3. Therapeutic Drugs:
Therapeutic drugs often alter the function, and less often the structure, of the nervous system. Generally, this alteration is desirable, as, for example, in the case of the tranquilizing effects of a drug to treat anxiety or the mood-lifting effects of a drug to treat depression. But such drugs can have undesirable effects on the brain also. As mentioned earlier, some drugs that effectively control the symptoms of schizophrenia may also severely affect neuromuscular function. Drugs that are used to treat illnesses or health problems unassociated with the nervous system (e.g., some anticancer drugs) may have neurotoxic side-effects. Often, the adverse effects of drugs are poorly documented or may go undetected.

Of particular concern are the effects of therapeutic drugs on the developing fetus. Most prescription drugs given to pregnant women have not been tested for potential effects on the fetus, nor have over-the-counter drugs been evaluated for use during pregnancy¹⁴. Physicians normally exert particular caution in prescribing drugs for pregnant women. The Federal Food, Drug, and Cosmetic Act require that drugs be both safe and effective. Some persons assert that FDA does not require adequate neurotoxicity testing of prescription drugs and that neurotoxic concern are not being adequately ad-dressed in the FDA review and regulatory process. Others suggest that FDA moves too slowly in approving drugs and that regulation are overly burdensome. However, FDA officials believe that current testing and evaluation procedures adequately address neurotoxicological concerns²¹.

The reported adverse effects of drugs listed in the Physicians Desk Reference²² and similar publications illustrate that many prescription drugs, especially psychoactive drugs, have neurotoxic side-effects of varying significance. Some adverse effects are an accepted consequence of drug therapy. When a drug has been properly tested for neurotoxic effects, doctor and patient can make informed decisions about using it. However, inadequate testing for neurotoxicity exposes the public to unnecessary risk.

4. Abused Drugs:
In 1986, drug abuse in the United States led to more than 119,000 emergency room visits and 4,138 deaths²³. Many more cases go unreported. As users and their families and friends sometimes discover, substance abuse can permanently damage the nervous system. In some cases, damage is so severe as to cause personality changes, neurological disease, mental illness, or death. Persons who abuse drugs are often not aware of, or do not take seriously, the threat these substances pose to their health. Although the adverse effects of drugs are often short-lived, some effects can be prolonged or permanent. MPTP, an impurity sometimes formed during the illicit synthesis of an analog of the drug meperidine, can cause irreversible brain damage and long-term dysfunction characteristic of Parkinson's disease²⁴. LSD, a highly potent hallucinogen, can seriously affect nervous system function. Other drugs may have more subtle neurotoxic effects. The chemically sophisticated, illicit "designer drugs" can dramatically alter normal brain functions. MDMA, known on the street as "Adam' or ''ecstasy, ' is a synthetic drug that causes euphoria and hallucinations. It also causes confusion, depression, severe anxiety, blurred vision, and paranoia. Some of these effects may occur weeks after taking the drug. It was recently discovered that MDMA, at relatively high doses, causes selective degeneration of brain cells producing the neurotransmitter serotonin. Until it became illegal, MDMA was occasionally used as an adjunct to psychotherapy because of the belief that it removed barriers to communication between doctor and patient²⁵.

Phencyclidine (PCP) is another major abused drug. In 1984, it was responsible for 11,000 hospital emergency room visits and more than 225 deaths. Chronic use of PCP leads to depression, speech difficulties, and memory loss²⁶.

Cocaine (known as 'crack' in its smokable form) is currently the most frequently abused street drug in the United States. More than 22 million Americans have used cocaine at some time in their lives²⁷. In 1986, approximately 25,000 high school seniors reported that they had used cocaine in the past year and were unable to stop using it. Cocaine blocks reabsorption of the neurotransmitter dopamine into nerve cells. Feelings of euphoria are thought to be due to excess dopamine in the synapses between cells. Large concentrations of dopamine cause changes in nerve cells, making them less responsive to normal levels of the transmitter. Consequently, when individuals stop using the drug they experience depression and want to take more to feel "normal." They are then caught in the addiction cycle. Recently, it was reported that cocaine use by pregnant women alters the development of the brains of fetuses and infants ²⁸.

5. Food Additives:
Food additives serve a variety of purposes, such as to prolong shelf-life or to improve flavor, and hundreds of them are used during the preparation, manufacture, and marketing of foods. The use of these substances is regulated by FDA, which maintains a list of additives that are generally recognized as safe and may be used without specific approval. All other food additives must be approved prior to use. However, few additives have undergone neurotoxicity testing. In 1984, the NAS reported that 73 percent of the food additives it examined had not been tested for neurobehavioral toxicity. Although animal testing of food additives is required under the Federal Food, Drug, and Cosmetic Act to evaluate their safety, studies in humans are not required. Approval of drugs, however, does require human testing. Many observers believe that food additives should come under the same scrutiny as drugs, particularly because many of them are regularly ingested by millions of people²⁹.

6. Cosmetics
Some 3,400 chemicals are used as cosmetics or cosmetic ingredients in U.S. products. Indeed, the National Academy of Sciences evaluated a representative sample of cosmetics in 1984 (focusing on publicly available documents) and found that none had undergone adequate testing to identify potential neurobehavioral effects.

The consequences of inadequate toxicity testing are illustrated by the AETT incident. In 1955, AETT (acetylethyl tetramethyl tetralin) was introduced into fragrances; years later it was found to cause degeneration of neurons in the brains of rats and marked behavioral changes in rats, including irritability and aggressiveness. In 1978, it was voluntarily withdrawn from use by the fragrance industry. Its effects on humans through two decades of use will probably never be known³⁰.

RECENTS:
Concerns about the effects of neurotoxic sub-stances on public health have increased recently because of new evidence that some neurological or psychiatric disorders may be caused or exacerbated by toxic agents in the environment. A noted case in point is Parkinson's disease. Researchers recently discovered that exposure to small amounts of the toxic substance MPTP can cause Parkinson-like symptoms. Exposure to small quantities over a period of days to a few weeks leads to the muscle weakness and rigidity that is characteristic of Parkinson's disease³¹.

Because of this finding, the possibility that toxic chemicals might be causative agents in some cases of Parkinson’s disease is being actively considered by researchers. Some recent findings support this hypothesis. For example, it has been reported that in cases in which Parkinson's disease afflicts several members of a family, the onset of the disease tends to cluster in time³². Normally, if a disorder has a purely genetic basis, onset of symptoms occurs at similar ages, not at similar times. Evidence that Parkinson's disease does not occur more frequently in identical than fraternal twins also argues against a hereditary determinant of the disorder. A recent epidemiological study revealed that between 1962 and 1984, U.S. mortality rates for Parkinson's disease substantially increased in individuals over the age of 75 (figure 2.1.). Environmental factors appear to have played a significant role in the increase. The relative roles of hereditary and environmental factors in triggering Parkinson's disease remain to be determined ³³.

Evidence for a substantial increase in the incidence of motor neuron disease (MND), primarily amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, in the United States has also recently been reported. This disease is characterized by the progressive degeneration of certain nerve cells that control muscular movement. MND is a relatively rare disease, and its cause has eluded researchers for more than a century. Recent data indicate that between 1962 and 1984, the MND mortality rate for white men and women in older age groups rose substantially (figure 2.2.). The increase is thought to be largely due to environmental factors³⁴.

Naturally occurring toxic substances can also affect the nervous system. An unusual combination of the neurodegenerative disorders ALS, Parkinson's disease, and Alzheimer's disease endemic to Guam (known as Guam ALS-Parkinson's dementia) puzzled investigators for many years because of the correlation between incidence of the disease and preference for traditional foods. During food shortages, residents of the island ate flour made from the false sago palm, a member of the neurotoxic cycad family. The cycad contains one or more naturally occurring toxic substances that appear to cause a neuromuscular disease in cattle and trigger slow degeneration of neurons. As old age approaches and natural brain cell death accelerates, the effects of the degeneration become apparent and the neurological symptoms appear. This possible link between a naturally occurring compound and a neurodegenerative disease has stimulated the search for other toxic substances that may trigger related neurological and psychiatric disorders. This work and that of others led to the hypothesis that Alzheimer's disease, Parkinson's disease, and ALS could be due in part to damage to specific regions of the central nervous system caused by environmental agents and that the damage may not become apparent until several decades after exposure. Aluminum and silicon, for example, have been hypothesized to be causative agents in Alzheimer's disease; however, numerous other possible causes have been proposed, and no link between a toxic chemical and the disease has been conclusively demonstrated³⁵.

Understanding the relationship between toxic substances and biochemical and physiological neurological disease requires concerted epidemiological analyses. The extent to which toxic substances contribute to major neurological and psychiatric disorders is not known. Considerable research is needed to define the role of neurotoxic substances as causative agents³⁶.

Figure 2.1 Average Annual Parkinson's disease Mortality in the United States.

CONCLUSION:
Everyone is at risk of being adversely affected by neurotoxic substances, but individuals in certain age groups, states of health, and occupations face a greater probability of adverse effects. The developing nervous system is particularly vulnerable to some neurotoxic substances, for several reasons. It is actively growing and establishing cellular net-works, the blood-brain barrier that protects much of the adult brain and spinal cord from some toxicants has not been completely formed, and detoxification systems are not fully developed. Consequently, fetuses and children and adults are more vulnerable to the effects of certain neurotoxic substances. Cause of neurotoxicity includes various factors like industrial chemicals, pesticides, cosmetics etc. These neurotoxicities cumulate slowly and produce major health problems. Monitoring of these agents is necessary to protect the human beings.

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