The vulnerability of the nervous system to both temporary changes and permanent damage from a wide variety of agents is increasingly evident. For thousands of years humans have searched out agents that affect the nervous system. Many people today are regular users of alcohol, caffeine, or other agents designed to affect the nervous system. Industrialization ushered in an era of rapid development of new chemicals, often accompanied by human exposure that we learned, sometimes through tragic experience, can irreparably damage the nervous system. No one can reach his or her full genetic potential with a damaged nervous system. As a consequence, neurotoxicology developed as a discipline in the 1970s to advance our understanding of the effects of chemicals on the nervous system.
Neurotoxicity or a neurotoxic effect: an adverse change in the chemistry, structure, or function of the nervous system following exposure to a chemical or physical agent
Voluntarily and involuntarily, we are exposed to a range of chemicals that affect the nervous system. We spend billions of dollars every year voluntarily purchasing chemicals such as caffeine, alcohol, and nicotine to influence our nervous system. Most stores and many industries are dependent on our desire to influence our nervous system. Many of us are familiar with the undesirable effects of too much caffeine or alcohol, which is a form of neurotoxicity. Fortunately, we quickly recover from the neurotoxic effects of caffeine or alcohol and learn to manage our consumption of these chemicals to minimize the undesirable effects and maximize the desirable effects. In this sense, many of us are experienced neurotoxicologists.
Voluntary consumption of drugs that our society has classified as illegal is also common. These drugs range from the active ingredient of the easily cultivated marijuana plant to chemicals produced in illicit laboratories. Billions of dollars are spent on the purchase of illegal drugs and in turn billions more are spent on trying to stop their manufacture and purchase. The direct and indirect costs to our society of the "war on drugs" are enormous.
A range of legal drugs is sold by the pharmaceutical industry to treat illnesses of the nervous system. Advances in our understanding of the structure and function of the nervous system has accelerated the development of chemicals for treating diseases such as Parkinson's syndrome, Alzheimer's disease, and mild depression. The treatment of mild depression with drugs like Prozac is a billion-dollar industry. However, some drugs may produce undesirable nervous system side effects that can limit their utility in disease treatment. The anticancer drugs vincristine and cisplatin damage sensory nerves in the fingers and the antibiotic gentomycin can affect hearing.
We are also involuntarily exposed to chemicals, compounds, or even physical agents that can damage the nervous system. The science of neurotoxicology has largely focused on understanding the adverse effects of agents on the nervous system. This research has shown that the nervous system, particularly the developing nervous system, is vulnerable to permanent damage by a number of agents. For example, even low levels of lead exposure will permanently damage the nervous system of young children, reducing their ability to learn and perform well in school, and ultimately affecting their performance and quality of life as adults. Alcohol, while having a predictable effect on the pregnant mother, can be disastrous for the nervous system of the developing infant. Many workers are exposed to agents such as solvents or pesticides that can transiently affect the nervous system or even cause permanent damage. Physical agents such as noise and heat can also adversely affect the nervous system or degrade performance. Many people, including construction workers who routinely use hearing protection devices, are a testament to the awareness that excessive exposure to loud noise will permanently damage hearing.
A more formal definition of neurotoxicity or a neurotoxic effect is as an adverse change in the chemistry, structure, or function of the nervous system following exposure to a chemical or physical agent. An important part of this definition is that the effect may produce either structural change in the nervous system, such as gross cell loss, or functional changes that may be related to subtle changes in nerve cell communication. Even minor changes in the structure or function of the nervous system may have profound consequences for neurological, behavioral, and related body functions. Often the very young and elderly are more susceptible to neurotoxic effects. Lead is a good example of a compound that at high levels of exposure can cause actual nerve cell damage but at low levels, particularly in children, can cause functional losses such as decreased learning and memory.
Defining and testing for neurotoxicity is difficult because there is no one easy-to-define measure. Neurotoxicology effects can be divided into five areas (Table 17.1).
Neurological and Behavioral Effects of Exposure to Toxic Substances
Convulsions, weakness, tremor, twitching, lack of coordination, unsteadiness, paralysis, reflex abnormalities, activity changes
Equilibrium changes, vision disorders, pain disorders, tactile disorders, auditory disorders
Memory problems, confusion, speech impairment, learning impairment
Mood and personality effects
Sleep disturbances, excitability, depression, irritability, restlessness, nervousness, tension, delirium, hallucinations
Loss of appetite, depression of neuronal activity, narcosis, stupor, fatigue, nerve damage
Adapted from W.K. Anger (1986)
Caffeine is the most widely consumed stimulant drug in the world. It occurs naturally in coffee, tea, and the cola nut and is added to many soft drinks. Many of us consume coffee and soda drinks because of the desirable stimulatory effects produced by caffeine; many of us have consumed too much caffeine and felt the consequences. The undesirable effects of caffeine—the agitation, the inability to concentrate, the mild tremors, and the general unpleasantness—are a form of neurotoxicity. Literally your brain, and more specifically, the adenosine receptors in your brain, has too much caffeine. These effects are a reversible form of neurotoxicity as we metabolize caffeine quickly. By experience we have learned how to moderate our caffeine consumption to avoid the unpleasant side effects. A great deal of money is made from the neuroactive and physiological effects of caffeine. You can learn more about this fascinating drug in the chapter on caffeine.
The decision to use lead as a gasoline additive resulted in one of the greatest public health disasters of the 20th century. Lead from the tail pipes of cars settled as dust over wide areas and was most prevalent in high-traffic areas along city streets. Going from hand to mouth, the lead from cars and some additional lead from old lead-based paint were ingested by young children. In the 1970s and 1980s, researchers demonstrated that even low levels of lead exposure damaged the nervous system of children, confirming what the Greeks knew 2000 years ago: that "Lead makes the mind give way" (Dioscorides). Exposure of the developing nervous system to lead causes irreversible harm, degrading the learning and memory capabilities of the child and resulting in a lifetime of deficit. While lead was banned from most paint and removed from gasoline, it still remains a threat to many children living in older homes with lead paint or near areas contaminated with lead. Lead is still turning up in children's toys, jewelry, PVC plastics (as a stabilizer), and other products accessible to children. Lead is an example of a neurotoxic agent that causes permanent, irreversible damage to the developing nervous system, robbing children of their genetic potential. You can learn more about developmental effects of lead in chapter 8.
Prozac (fluoxetine hydrochloride)
Prozac, produced by the pharmaceutical company Eli Lilly and Company, was first approved for the treatment of depression in Belgium in 1986. A year later, in 1987, it was approved for use in the United States. It is now approved for use in over 90 countries and used by more than 40 million people worldwide. Needless to say it is a very profitable drug.
Prozac is commonly prescribed for treatment of mild depression, which is not uncommon as we make our way through the dramas and disappointments of life. Prozac, similar to many neuroactive chemicals, has a remarkably specific effect on one neurotransmitter. Typically, a neurotransmitter is released from one cell to communicate across a very small gap and picked up by a neuroreceptor on another cell. Once the neurotransmitter has performed its function of communicating with the other, it is either degraded or taken back up by the releasing cell to be reused. Prozac functions by blocking this reuptake, thus leaving more neurotransmitter within the cell gap to continue stimulating the receiving cell. Prozac selectively inhibits the reuptake of the neurotransmitter serotonin. The increased availability of serotonin appears to reduce the symptoms of depression. A range of drugs, including the well-known hallucinogen LSD, acts through serotonin.
MPTP and Parkinson's disease
In the early 1980s, MPTP or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was accidentally produced as a contaminant of a new compound that clandestine chemists created in their search for a synthetic heroine. Tragically, drug users exposed to MPTP developed tremors and a lack of muscle control that was very similar to symptoms of Parkinson's disease. Parkinson's disease is usually a slow-developing disease associated with the natural process of aging and the dying of cells in the brain. Further study revealed that MPTP attacked cells in a specific area of the brain that produces the neurotransmitter dopamine, the very same cells implicated in Parkinson's disease. This was the first time that a compound was clearly implicated in causing Parkinson's-like disease. Researchers immediately began searching for other compounds that might cause Parkinson's disease or interact with the aging processes to accelerate the onset of the disease. A number of studies have examined the association of exposure to some pesticides with an increase in Parkinson's disease. Researchers now use MPTP to develop animal models for finding new treatments for Parkinson's disease and to better understand the underlying progression of the disease.
The nervous system can be divided into the central nervous system (CNS), which includes the brain and spinal cord, and the peripheral nervous system (PNS), which carries information to and from the CNS. The PNS is the information highway while the CNS is the coordinating center. Sensory information such as touch or pain is transmitted to the CNS by the nerves of the PNS. For example, if we touch something hot the CNS will then command, through the PNS, to move those muscles that will withdraw us from the pain, in the case of something hot. The CNS also communicates with a number of glands and organs through the PNS. In addition to the basic functions of keeping us alive, the brain is responsible for our thinking, reasoning, and emotions.
The brain is incredibly complex. It is estimated to contain between 10 billion and 100 billion cells that form approximately 1015 connections; this is a huge number, 100 million times more than the 42 million transistors on a state-of-the-art microprocessor chip. The information-processing capabilities of the brain are enormous. The nervous system starts developing early in gestation and continues to grow and change, particularly in the first few years of infancy and childhood. During development, the brain organizes into separate but interconnected areas that control different functions. For example, the area of the brain that processes visual information is located in the back of your head. During development, cells from the eyes must connect with cells of the optic nerve to move information to the visual processing center of the brain. This complex dance of one cell looking for a partner in another area of the brain is one reason the brain is so sensitive to disruption by a range of compounds.
The peripheral nerves undergo many similar challenges. Think of the longest nerves in your body that run from the bottom of your spinal cord to your toes. These very long cells must be able to connect, grow, and communicate with the right cells of the spinal cord, which in turn must communicate with the cells of the brain.
Cells of the Nervous System
The nervous system consists of cells called neurons (Figure 17.1), that are responsible for the majority of information transfers in the central and peripheral nervous systems and supporting cells. In the PNS, the neurons can be very long. For example, consider the information that must be sent to and from your fingers or toes to sense touch or pain or move the muscles. The neurons have a cell body and a long connecting structure called an axon. To increase the transmission speed along the axon, another cell, a Schwann cell, wraps the axon to provide a form of insulation and facilitate the movement of electrical signals. The Schwann cells literally wrap themselves around the long axon, forming multiple layers similar to tree rings. As will be discussed below these cells are susceptible to damage because of the long axon and the energy requirements of the cell.
In the CNS, glial cells aid in the communication between densely packed neurons. These cells also play a big part in forming the blood-brain barrier. The blood-brain barrier keeps some classes of chemicals from entering the brain, which can make it very difficult to treat diseases of the brain. However, some chemicals, such as caffeine, readily enter the brain, as do many other neuroactive compounds. Compounds essential for function are actively transported across this barrier.
Transmission of Information in the Nervous System
Nerve cells communicate by the release of chemicals (neurotransmitters) into the space between the cells (Figure 17.2). The neurotransmitter is typically stored in a small packet (synaptic vesicle) and then released in response to a signal that is transmitted down the cell axon. In the example in Figure 17.2, dopamine, an important neurotransmitter involved in movement disorders related to Parkinson's disease, is released into the gap (synaptic cleft) and reacts with specific receptors on the adjacent cell. This in turn causes a reaction in the adjacent cell. Dopamine in the gap can either be broken down or absorbed into the releasing cell and repackaged for future use.
In Parkinson's disease the dopamine-releasing cells are damaged or die, thus reducing the release of dopamine. Loss of the dopamine neurotransmitter contributes to the movement disorders associated with Parkinson's disease. Typically, the loss of dopamine-producing cells in a very specific location in the brain does not become evident until old age, and for a long time Parkinson's disease was thought of as strictly age related. In the 1970s this concept was changed when chemists produced a designer drug meant to mimic common narcotics; the drug had an impurity that resulted in Parkinson's-like syndrome in young people never thought to be susceptible to Parkinson's disease. A specific compound, MPTP, was found to cause the death of the dopamine-producing cells in the same area of the brain. While the consequence to the individuals was tragic, MPTP has proven to be a very important research tool for understanding this disease as well as developing new treatments.
There is no simple or correct way to examine the causes of neurotoxicity. I have divided them into three overlapping areas: neurotransmitter/receptor effects, which are often transient; damage to the peripheral nerves, which is often permanent; and damage to the developing nervous system, which is almost always permanent.
Nerve cells have unique structural and physiological features that often make them more susceptible to damage from chemical agents. Cells of the central nervous system have a high metabolic rate that makes them highly dependent on glucose and oxygen, much like computer chips need lots of electrical power. Anything that disrupts the flow of glucose or energy utilization within the cell causes a loss of function and potentially long-term damage. Nerve cells, unlike muscle cells, can only work for a very short time without oxygen. The most obvious indicator of this is that we quickly loose consciousness when our brain is deprived of well-oxygenated blood. Agents like carbon monoxide reduce the availability of oxygen to the brain, quickly causing unconsciousness or even death. Cyanide, working by a very different mechanism, inhibits a cell's ability to utilize oxygen, which produces the same results. In the peripheral nervous system, the length of cells contributes to their increased susceptibility to damage from agents that disrupt the transfer of nutrients along the length of the cell. Acrylamide, for example, causes damage to the cell transport system, which results in paralysis that is first noticed in the legs.
In the majority of cases, the cells of the nervous system cannot divide and replace themselves, thus most damage is permanent. The developing nervous system exposed to lead will be damaged for a lifetime. However, peripheral nerves can grow, recovering some of the connections and functionality that results in some sensation and return of movement, usually most noticeable in the arms and legs.
Many naturally occurring compounds and an increasing number of synthesized chemicals work by influencing the effectiveness of a specific neurotransmitter. Typically neurotransmitters are released from one neuronal cell and are picked up by specific receptors in the adjacent cell, which causes the receiving cell to react. The receptor then releases the neurotransmitter into the gap between the cells. At this time the neurotransmitter must be removed either by being broken down by a specific enzyme or be taken back up by the releasing cell to be reused. A compound can influence a neurotransmitter and thus the response of the receiving cell in several ways: 1) blocking the receptor so that the neurotransmitter cannot reach the receptor and thus the receiving cell is unable to respond; 2) mimicking the neurotransmitter so that the receiving cell responds even though there is no naturally occurring neurotransmitter; 3) blocking the degradation of the neurotransmitter, thus leaving the neurotransmitter to react with another receptor; or 4) blocking the reuptake of the neurotransmitter into the releasing cell, which leaves the neurotransmitter free to react again with the receptor.
Table 17.2 provides just a few examples of different neuroactive agents and their mechanism of action. Caffeine, the most widely consumed stimulant drug in the world, works by affecting the adenosine receptor. Adenosine is a naturally occurring depressant, so caffeine works by blocking the depressive actions of adenosine, causing stimulation.
Table 17.2 Mechanism of Action of Neuroactive Agents
Blocks the adenosine receptor
Increase the neurotransmitter acetylcholine by blocking its degradation
Mimics acetylcholine, thus looks like increased acetylcholine
Increases serotonin by blocking its reuptake into neuronal cells
LSD (lysergic acid diethylamide)
Mimics serotonin, thus stimulating receptor
THC: Delta 9-tetrahydrocannabinol (Cannabis)
Relaxation, euphoria, enhancement of senses, increase in appetite and sense of time
Blocks dopamine transporter, thus increasing dopaminergic stimulation
Increases alertness and energy, euphoria, insomnia, restlessness, fear, paranoia, hallucinations
Domoic acid (shellfish)
Loss of memory
Agents acting through a specific neurotransmitter are often transient, and exposure must be repeated to continue the effect, an example is our repeated need for caffeine every morning. This is not always the case. Very potent (poisonous) nerve gases permanently block the agent responsible for degrading acetylcholine, causing death because the nervous system cannot recover.
Damage to the Peripheral Nerves
The peripheral nerves of the body communicate sensation and deliver commands from the central nervous system to move muscles from our fingers to our toes—quite a distance. Peripheral nerves are wrapped by a specialized cell to form an insulation (myelin) that aids the transmission of electrical signals along the length of the nerve cell. Agents damage the peripheral nervous system either by killing the nerve cell (neuronopathy), attacking the axon (axonopathy), or attacking the insulation that surrounds the cells (myelinopathy) (Table 17.3 and Figure 17.3). Interfering with the neurotransmitter is a form of transmission toxicity, which was discussed in more detail above.
Table 17.3 Peripheral Nervous System Damage
Nerve cell death
Degeneration of axon
Damage to myelin (e.g. Schwann cells)
Disruption of neurotransmission
Organophosphate pesticides, cocaine, DDT
Damage to the Developing Nervous System
The developing nervous system is more vulnerable to damage than the mature nervous system for a number of reasons. The blood-brain barrier of the central nervous system is not well developed in the very young, which allows toxic agents easy access to the nervous system. The nervous system develops through our gestation and continues changing well into our teens with cells multiplying, growing in size or length, migrating to a new location, or forming connections with other cells. During this period toxic agents may kill cells, interfere with their migration, or interfere with the cell-forming connections. Different areas of the nervous system develop at different times, so exposure to an agent such as alcohol during the fourth month of gestation will have different effects than exposure during the sixth month.
Damage to the brain can range from the severe and obvious to the very subtle and undetectable. Exposure to high levels of alcohol during gestation can cause obvious reductions the ability of a child to perform well in school and even contribute to society. More difficult to assess is the damage caused by very low levels of exposure. Low levels of exposure to alcohol or lead during development may reduce a child's IQ only slightly, by a degree that is within the normal range of variation. These more subtle changes can only be examined by comparing large groups of people, some of whom are exposed to the agent and some that are not. Group-based studies such as these were the first to show that even low levels of lead exposure during development can cause subtle decreases in IQ, thus depriving an individual of the ability to reach their full genetic potential. Any one individual would not know if their intellectual capabilities had been reduced, but on a large scale these changes have serious implications for society. Additional information is available in the lead and alcohol chapters.
Another area of concern is exposure to fat-soluble compounds such as PCBs or chlorinated pesticides. All cells contain lipids or fat; the high number of densely packed cells of the brain means that the brain is just a big ball of fat. The brain is a great storage site for fat soluble compounds can cross the blood-brain barrier. An additional concern is that these compounds can be mobilized from the fat of women breastfeeding their infants, resulting in exposure to the infant and, given the size of the infant, this exposure translates into a large dose.
Diseases of the Nervous System
Can toxic agents cause what have been classically defined as diseases of the nervous system, such as Parkinson's disease, Alzheimer's type dementia, multiple sclerosis, or amyotrophic lateral sclerosis (ALS)? The discovery that the chemical MPTP can cause a syndrome very similar to Parkinson's disease focused people's attention on the possibility that chemical agents may play a role in the onset of neurological disorders once exclusively associated with aging or just bad luck. MPTP selectively damaged the same neurons, in the same area of the brain, as those responsible for Parkinson's disease. Supporting the hypothesis that chemical agents may contribute to Parkinson's disease were data showing that the incidence of this disease was correlated with the increased use and exposure to chemicals. Additional research found that the active metabolite of MPTP that was really responsible for damaging the neurons, was very similar to the chemical structure of some pesticides. This immediately raised the question: Could pesticide exposure increase the incidence of Parkinson's disease or cause the disease to occur at an earlier age? In fact, researchers did find some correlation with pesticide exposure in farm workers and the onset of Parkinson's disease.
Exposure to metals is associated with a number of neurological disorders, so it was reasonable to ask: Could exposure to metals contribute to age-related neurological disorders? Researchers found that brain cells of many Alzheimer's patients has elevated levels of aluminum, and kidney dialysis patients could suffer from a neurological disorder related to elevated exposure to aluminum. Additional study has never found that aluminum exposure causes Alzheimer's disease; there is, however, some data supporting the possibility that exposure to mercury results in accelerated age-related decline of cognitive function.
Neurological and psychiatric disorders such as depression, hyperactivity, and manic depression have driven many pharmaceutical companies to develop neuroactive drugs to treat these conditions. This is an active area of research that will accelerate as we gain more knowledge of the underlying mechanisms of the nervous system. Early drugs used to treat psychiatric disorders often had highly undesirable side effects that often limited their long-term use or required additional drugs to manage the complications. Newer drugs are more specific and have fewer side effects.
Without a doubt the developing fetus and child are the most vulnerable to the effects of chemicals on the nervous system. Children have no control over these exposures, which can result in a lifetime of disability. The nervous system of adults is clearly affected by a range of chemicals, both those we voluntarily expose ourselves to and those in our environment.
The home, workplace, and general environment each represent unique places of possible exposure to neuroactive agents. The home contains a range of compounds that affect the nervous system: caffeine in coffee and tea, alcohol, medicines, pesticides, cleaning agents, paints, and solvents, to name just a few. Compounds such as lead or pesticides can be tracked into the home on shoes or bare feet. Working family members may bring agents such as lead home on clothing. Probably the greatest concern in workplaces is solvent exposure from cleaning agents or chemical processes. Farmers and pesticide workers can also be exposed to compounds clearly designed to affect the nervous system. The outdoor environment can contain elevated levels of a number of persistent chemicals that can adversely affect the nervous system, such as lead, mercury, and chlorinated pesticides.
Table 17.5 Exposure to Neurotoxic Compounds
children: during development from maternal exposure
children: lead in the home
mercury (in fish)
persistent environmental pollutants
As our appreciation for the subtle neurological effects and long-term consequences of exposure to compounds has increased, there has been a gradual increase in the testing requirements for new compounds. Government agencies can now require additional testing for the neurotoxic effects of a compound. However, for many compounds we know very little about their potential to cause neurotoxicity or affect the developing nervous system. In the case of lead, there is no safety factor included in the levels of concern indicated by the Center for Disease Control; the standard was based on a low level found in the general population when lead was removed from gasoline. In general, the government struggles to keep up with the ever-growing list of new chemicals and struggles to assess their potential to cause neurotoxic injury.
Many of us regularly consume compounds that affect our nervous system and are well aware of chemicals that cause neurotoxicity, so the recommendation is simple: be aware. The developing nervous system is very sensitive to neurotoxicity and exposure to the wrong chemical at the wrong time can cause a lifetime of disability. From an ethical and social perspective this vulnerability of the developing nervous represents unique challenges and responsibilities. Many of the persistent bioaccumulative toxicants are neurotoxic, which is a compelling reason for these compounds to be phased out or banned. Our expanding understanding of the nervous system, combined with the knowledge of the subtle harm that can be done, is one of the most important contributions of the toxicological sciences.
Slide Presentation and Online Material
A Small Dose of Neurotoxicology presentation material and references. Website contains presentation material related to the neurotoxic effects of chemicals.
European, Asian, and International Agencies
• Organization For Economic Co-Operation And Development (OECD). Chemical Safety. This OECD Site contains general information on chemical safety as well as specific testing guidelines for neurotoxic effects of chemicals. [accessed June 20, 2009]
• International Neurotoxicology Association (INA). Site provides links to neurotoxicology testing guidelines and other information on neurotoxicology. [accessed June 20, 2009]
• International Brain Research Organization (IBRO). "IBRO is a nonprofit international organization for neuroscientists." [accessed June 20, 2009]
North American Agencies
• US Food and Drug Administration (FDA). Neurotoxicology. Information on FDA and neurotoxicology. [accessed June 20, 2009]
• US National Institute of Health. National Institute of Neurological Disorders and Stroke (NINDS). NINDS is works to shape "the future of research and its relationship to brain diseases". [accessed June 20, 2009]
• US National Research Council. Environmental Neurotoxicology. Publication available on the web at this site. [accessed June 20, 2009]
• Society for Neuroscience (SFN). "SFN is a nonprofit membership organization of basic scientists and physicians who study the brain and nervous system." [accessed June 20, 2009]
• ALS Association (ALSA). The mission of The ALS Association is to find a cure for and improve the quality of life for those afflicted with ALS. [accessed June 20, 2009]
• Institute of Neurotoxicology & Neurological Disorders (INND). INND was founded in 1999 and focuses on education and policy issues related to neurotoxicology. [accessed June 20, 2009]
• Neurobehavioral Teratology Society (NBTS). The NBTS mission is to understand how the environment affects the health of infants and children. [accessed June 20, 2009]
Spencer, Peter S. and Herbert H. Schaumburg (Eds). Experimental and Clinical Neurotoxicology 2nd edition. New York: Oxford University Press, 2000.
Dobbs, Michael R. Clinical Neurotoxicology: Syndromes, Substances, Environments. Philadelphia: Saunders, 2009.
Harry, G. Jean, and Hugh A. Tilson. Neurotoxicology, Third Edition (Target Organ Toxicology Series). New York: Informa HealthCare 2009.
US Environmental Protection Agency "Guidelines for Neurotoxicity Risk Assessment". Federal Register 63, 93 (1998):26926-26954.