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Saturday, May 8, 2021

Nervous system

From Wikipedia, the free encyclopedia
 
Nervous system
TE-Nervous system diagram.svg
The human nervous system
Details
Identifiers
Latinsystema nervosum
MeSHD009420
TA98A14.0.00.000
FMA7157

In biology, the nervous system is a highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes that impact the body, then works in tandem with the endocrine system to respond to such events. Nervous tissue first arose in wormlike organisms about 550 to 600 million years ago. In vertebrates it consists of two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain and spinal cord. The PNS consists mainly of nerves, which are enclosed bundles of the long fibers or axons, that connect the CNS to every other part of the body. Nerves that transmit signals from the brain are called motor or efferent nerves, while those nerves that transmit information from the body to the CNS are called sensory or afferent. Spinal nerves serve both functions and are called mixed nerves. The PNS is divided into three separate subsystems, the somatic, autonomic, and enteric nervous systems. Somatic nerves mediate voluntary movement. The autonomic nervous system is further subdivided into the sympathetic and the parasympathetic nervous systems. The sympathetic nervous system is activated in cases of emergencies to mobilize energy, while the parasympathetic nervous system is activated when organisms are in a relaxed state. The enteric nervous system functions to control the gastrointestinal system. Both autonomic and enteric nervous systems function involuntarily. Nerves that exit from the cranium are called cranial nerves while those exiting from the spinal cord are called spinal nerves.

At the cellular level, the nervous system is defined by the presence of a special type of cell, called the neuron, also known as a "nerve cell". Neurons have special structures that allow them to send signals rapidly and precisely to other cells. They send these signals in the form of electrochemical waves traveling along thin fibers called axons, which cause chemicals called neurotransmitters to be released at junctions called synapses. A cell that receives a synaptic signal from a neuron may be excited, inhibited, or otherwise modulated. The connections between neurons can form neural pathways, neural circuits, and larger networks that generate an organism's perception of the world and determine its behavior. Along with neurons, the nervous system contains other specialized cells called glial cells (or simply glia), which provide structural and metabolic support.

Nervous systems are found in most multicellular animals, but vary greatly in complexity. The only multicellular animals that have no nervous system at all are sponges, placozoans, and mesozoans, which have very simple body plans. The nervous systems of the radially symmetric organisms ctenophores (comb jellies) and cnidarians (which include anemones, hydras, corals and jellyfish) consist of a diffuse nerve net. All other animal species, with the exception of a few types of worm, have a nervous system containing a brain, a central cord (or two cords running in parallel), and nerves radiating from the brain and central cord. The size of the nervous system ranges from a few hundred cells in the simplest worms, to around 300 billion cells in African elephants.

The central nervous system functions to send signals from one cell to others, or from one part of the body to others and to receive feedback. Malfunction of the nervous system can occur as a result of genetic defects, physical damage due to trauma or toxicity, infection, or simply senesence. The medical specialty of neurology studies disorders of the nervous system and looks for interventions that can prevent or treat them. In the peripheral nervous system, the most common problem is the failure of nerve conduction, which can be due to different causes including diabetic neuropathy and demyelinating disorders such as multiple sclerosis and amyotrophic lateral sclerosis. Neuroscience is the field of science that focuses on the study of the nervous system.

Diagram showing the major divisions of the vertebrate nervous system.

Structure

The nervous system derives its name from nerves, which are cylindrical bundles of fibers (the axons of neurons), that emanate from the brain and spinal cord, and branch repeatedly to innervate every part of the body. Nerves are large enough to have been recognized by the ancient Egyptians, Greeks, and Romans, but their internal structure was not understood until it became possible to examine them using a microscope. The author Michael Nikoletseas wrote:

"It is difficult to believe that until approximately year 1900 it was not known that neurons are the basic units of the brain (Santiago Ramón y Cajal). Equally surprising is the fact that the concept of chemical transmission in the brain was not known until around 1930 (Henry Hallett Dale and Otto Loewi). We began to understand the basic electrical phenomenon that neurons use in order to communicate among themselves, the action potential, in the 1950s (Alan Lloyd Hodgkin, Andrew Huxley and John Eccles). It was in the 1960s that we became aware of how basic neuronal networks code stimuli and thus basic concepts are possible (David H. Hubel and Torsten Wiesel). The molecular revolution swept across US universities in the 1980s. It was in the 1990s that molecular mechanisms of behavioral phenomena became widely known (Eric Richard Kandel)."

A microscopic examination shows that nerves consist primarily of axons, along with different membranes that wrap around them and segregate them into fascicles. The neurons that give rise to nerves do not lie entirely within the nerves themselves—their cell bodies reside within the brain, spinal cord, or peripheral ganglia.

All animals more advanced than sponges have nervous systems. However, even sponges, unicellular animals, and non-animals such as slime molds have cell-to-cell signalling mechanisms that are precursors to those of neurons. In radially symmetric animals such as the jellyfish and hydra, the nervous system consists of a nerve net, a diffuse network of isolated cells. In bilaterian animals, which make up the great majority of existing species, the nervous system has a common structure that originated early in the Ediacaran period, over 550 million years ago.

Cells

The nervous system contains two main categories or types of cells: neurons and glial cells.

Neurons

Structure of a typical neuron
Neuron

The nervous system is defined by the presence of a special type of cell—the neuron (sometimes called "neurone" or "nerve cell"). Neurons can be distinguished from other cells in a number of ways, but their most fundamental property is that they communicate with other cells via synapses, which are membrane-to-membrane junctions containing molecular machinery that allows rapid transmission of signals, either electrical or chemical. Many types of neuron possess an axon, a protoplasmic protrusion that can extend to distant parts of the body and make thousands of synaptic contacts; axons typically extend throughout the body in bundles called nerves.

Even in the nervous system of a single species such as humans, hundreds of different types of neurons exist, with a wide variety of morphologies and functions. These include sensory neurons that transmute physical stimuli such as light and sound into neural signals, and motor neurons that transmute neural signals into activation of muscles or glands; however in many species the great majority of neurons participate in the formation of centralized structures (the brain and ganglia) and they receive all of their input from other neurons and send their output to other neurons.

Glial cells

Glial cells (named from the Greek for "glue") are non-neuronal cells that provide support and nutrition, maintain homeostasis, form myelin, and participate in signal transmission in the nervous system. In the human brain, it is estimated that the total number of glia roughly equals the number of neurons, although the proportions vary in different brain areas. Among the most important functions of glial cells are to support neurons and hold them in place; to supply nutrients to neurons; to insulate neurons electrically; to destroy pathogens and remove dead neurons; and to provide guidance cues directing the axons of neurons to their targets. A very important type of glial cell (oligodendrocytes in the central nervous system, and Schwann cells in the peripheral nervous system) generates layers of a fatty substance called myelin that wraps around axons and provides electrical insulation which allows them to transmit action potentials much more rapidly and efficiently. Recent findings indicate that glial cells, such as microglia and astrocytes, serve as important resident immune cells within the central nervous system.

Anatomy in vertebrates

Horizontal section of the head of an adult female, showing skin, skull, and brain with grey matter (brown in this image) and underlying white matter

The nervous system of vertebrates (including humans) is divided into the central nervous system (CNS) and the peripheral nervous system (PNS).

The (CNS) is the major division, and consists of the brain and the spinal cord. The spinal canal contains the spinal cord, while the cranial cavity contains the brain. The CNS is enclosed and protected by the meninges, a three-layered system of membranes, including a tough, leathery outer layer called the dura mater. The brain is also protected by the skull, and the spinal cord by the vertebrae.

The peripheral nervous system (PNS) is a collective term for the nervous system structures that do not lie within the CNS. The large majority of the axon bundles called nerves are considered to belong to the PNS, even when the cell bodies of the neurons to which they belong reside within the brain or spinal cord. The PNS is divided into somatic and visceral parts. The somatic part consists of the nerves that innervate the skin, joints, and muscles. The cell bodies of somatic sensory neurons lie in dorsal root ganglia of the spinal cord. The visceral part, also known as the autonomic nervous system, contains neurons that innervate the internal organs, blood vessels, and glands. The autonomic nervous system itself consists of two parts: the sympathetic nervous system and the parasympathetic nervous system. Some authors also include sensory neurons whose cell bodies lie in the periphery (for senses such as hearing) as part of the PNS; others, however, omit them.

The vertebrate nervous system can also be divided into areas called gray matter and white matter. Gray matter (which is only gray in preserved tissue, and is better described as pink or light brown in living tissue) contains a high proportion of cell bodies of neurons. White matter is composed mainly of myelinated axons, and takes its color from the myelin. White matter includes all of the nerves, and much of the interior of the brain and spinal cord. Gray matter is found in clusters of neurons in the brain and spinal cord, and in cortical layers that line their surfaces. There is an anatomical convention that a cluster of neurons in the brain or spinal cord is called a nucleus, whereas a cluster of neurons in the periphery is called a ganglion. There are, however, a few exceptions to this rule, notably including the part of the forebrain called the basal ganglia.

Comparative anatomy and evolution

Neural precursors in sponges

Sponges have no cells connected to each other by synaptic junctions, that is, no neurons, and therefore no nervous system. They do, however, have homologs of many genes that play key roles in synaptic function. Recent studies have shown that sponge cells express a group of proteins that cluster together to form a structure resembling a postsynaptic density (the signal-receiving part of a synapse). However, the function of this structure is currently unclear. Although sponge cells do not show synaptic transmission, they do communicate with each other via calcium waves and other impulses, which mediate some simple actions such as whole-body contraction.

Radiata

Jellyfish, comb jellies, and related animals have diffuse nerve nets rather than a central nervous system. In most jellyfish the nerve net is spread more or less evenly across the body; in comb jellies it is concentrated near the mouth. The nerve nets consist of sensory neurons, which pick up chemical, tactile, and visual signals; motor neurons, which can activate contractions of the body wall; and intermediate neurons, which detect patterns of activity in the sensory neurons and, in response, send signals to groups of motor neurons. In some cases groups of intermediate neurons are clustered into discrete ganglia.

The development of the nervous system in radiata is relatively unstructured. Unlike bilaterians, radiata only have two primordial cell layers, endoderm and ectoderm. Neurons are generated from a special set of ectodermal precursor cells, which also serve as precursors for every other ectodermal cell type.

Bilateria

A rod-shaped body contains a digestive system running from the mouth at one end to the anus at the other. Alongside the digestive system is a nerve cord with a brain at the end, near to the mouth.
Nervous system of a bilaterian animal, in the form of a nerve cord with segmental enlargements, and a "brain" at the front

The vast majority of existing animals are bilaterians, meaning animals with left and right sides that are approximate mirror images of each other. All bilateria are thought to have descended from a common wormlike ancestor that appeared in the Ediacaran period, 550–600 million years ago. The fundamental bilaterian body form is a tube with a hollow gut cavity running from mouth to anus, and a nerve cord with an enlargement (a "ganglion") for each body segment, with an especially large ganglion at the front, called the "brain".

Area of the human body surface innervated by each spinal nerve

Even mammals, including humans, show the segmented bilaterian body plan at the level of the nervous system. The spinal cord contains a series of segmental ganglia, each giving rise to motor and sensory nerves that innervate a portion of the body surface and underlying musculature. On the limbs, the layout of the innervation pattern is complex, but on the trunk it gives rise to a series of narrow bands. The top three segments belong to the brain, giving rise to the forebrain, midbrain, and hindbrain.

Bilaterians can be divided, based on events that occur very early in embryonic development, into two groups (superphyla) called protostomes and deuterostomes. Deuterostomes include vertebrates as well as echinoderms, hemichordates (mainly acorn worms), and Xenoturbellidans. Protostomes, the more diverse group, include arthropods, molluscs, and numerous types of worms. There is a basic difference between the two groups in the placement of the nervous system within the body: protostomes possess a nerve cord on the ventral (usually bottom) side of the body, whereas in deuterostomes the nerve cord is on the dorsal (usually top) side. In fact, numerous aspects of the body are inverted between the two groups, including the expression patterns of several genes that show dorsal-to-ventral gradients. Most anatomists now consider that the bodies of protostomes and deuterostomes are "flipped over" with respect to each other, a hypothesis that was first proposed by Geoffroy Saint-Hilaire for insects in comparison to vertebrates. Thus insects, for example, have nerve cords that run along the ventral midline of the body, while all vertebrates have spinal cords that run along the dorsal midline.

Worms

Earthworm nervous system. Top: side view of the front of the worm. Bottom: nervous system in isolation, viewed from above

Worms are the simplest bilaterian animals, and reveal the basic structure of the bilaterian nervous system in the most straightforward way. As an example, earthworms have dual nerve cords running along the length of the body and merging at the tail and the mouth. These nerve cords are connected by transverse nerves like the rungs of a ladder. These transverse nerves help coordinate the two sides of the animal. Two ganglia at the head (the "nerve ring") end function similar to a simple brain. Photoreceptors on the animal's eyespots provide sensory information on light and dark.

The nervous system of one very small roundworm, the nematode Caenorhabditis elegans, has been completely mapped out in a connectome including its synapses. Every neuron and its cellular lineage has been recorded and most, if not all, of the neural connections are known. In this species, the nervous system is sexually dimorphic; the nervous systems of the two sexes, males and female hermaphrodites, have different numbers of neurons and groups of neurons that perform sex-specific functions. In C. elegans, males have exactly 383 neurons, while hermaphrodites have exactly 302 neurons.

Arthropods

Internal anatomy of a spider, showing the nervous system in blue

Arthropods, such as insects and crustaceans, have a nervous system made up of a series of ganglia, connected by a ventral nerve cord made up of two parallel connectives running along the length of the belly. Typically, each body segment has one ganglion on each side, though some ganglia are fused to form the brain and other large ganglia. The head segment contains the brain, also known as the supraesophageal ganglion. In the insect nervous system, the brain is anatomically divided into the protocerebrum, deutocerebrum, and tritocerebrum. Immediately behind the brain is the subesophageal ganglion, which is composed of three pairs of fused ganglia. It controls the mouthparts, the salivary glands and certain muscles. Many arthropods have well-developed sensory organs, including compound eyes for vision and antennae for olfaction and pheromone sensation. The sensory information from these organs is processed by the brain.

In insects, many neurons have cell bodies that are positioned at the edge of the brain and are electrically passive—the cell bodies serve only to provide metabolic support and do not participate in signalling. A protoplasmic fiber runs from the cell body and branches profusely, with some parts transmitting signals and other parts receiving signals. Thus, most parts of the insect brain have passive cell bodies arranged around the periphery, while the neural signal processing takes place in a tangle of protoplasmic fibers called neuropil, in the interior.

"Identified" neurons

A neuron is called identified if it has properties that distinguish it from every other neuron in the same animal—properties such as location, neurotransmitter, gene expression pattern, and connectivity—and if every individual organism belonging to the same species has one and only one neuron with the same set of properties. In vertebrate nervous systems very few neurons are "identified" in this sense—in humans, there are believed to be none—but in simpler nervous systems, some or all neurons may be thus unique. In the roundworm C. elegans, whose nervous system is the most thoroughly described of any animal's, every neuron in the body is uniquely identifiable, with the same location and the same connections in every individual worm. One notable consequence of this fact is that the form of the C. elegans nervous system is completely specified by the genome, with no experience-dependent plasticity.

The brains of many molluscs and insects also contain substantial numbers of identified neurons. In vertebrates, the best known identified neurons are the gigantic Mauthner cells of fish. Every fish has two Mauthner cells, in the bottom part of the brainstem, one on the left side and one on the right. Each Mauthner cell has an axon that crosses over, innervating neurons at the same brain level and then travelling down through the spinal cord, making numerous connections as it goes. The synapses generated by a Mauthner cell are so powerful that a single action potential gives rise to a major behavioral response: within milliseconds the fish curves its body into a C-shape, then straightens, thereby propelling itself rapidly forward. Functionally this is a fast escape response, triggered most easily by a strong sound wave or pressure wave impinging on the lateral line organ of the fish. Mauthner cells are not the only identified neurons in fish—there are about 20 more types, including pairs of "Mauthner cell analogs" in each spinal segmental nucleus. Although a Mauthner cell is capable of bringing about an escape response individually, in the context of ordinary behavior other types of cells usually contribute to shaping the amplitude and direction of the response.

Mauthner cells have been described as command neurons. A command neuron is a special type of identified neuron, defined as a neuron that is capable of driving a specific behavior individually. Such neurons appear most commonly in the fast escape systems of various species—the squid giant axon and squid giant synapse, used for pioneering experiments in neurophysiology because of their enormous size, both participate in the fast escape circuit of the squid. The concept of a command neuron has, however, become controversial, because of studies showing that some neurons that initially appeared to fit the description were really only capable of evoking a response in a limited set of circumstances.

Function

At the most basic level, the function of the nervous system is to send signals from one cell to others, or from one part of the body to others. There are multiple ways that a cell can send signals to other cells. One is by releasing chemicals called hormones into the internal circulation, so that they can diffuse to distant sites. In contrast to this "broadcast" mode of signaling, the nervous system provides "point-to-point" signals—neurons project their axons to specific target areas and make synaptic connections with specific target cells. Thus, neural signaling is capable of a much higher level of specificity than hormonal signaling. It is also much faster: the fastest nerve signals travel at speeds that exceed 100 meters per second.

At a more integrative level, the primary function of the nervous system is to control the body. It does this by extracting information from the environment using sensory receptors, sending signals that encode this information into the central nervous system, processing the information to determine an appropriate response, and sending output signals to muscles or glands to activate the response. The evolution of a complex nervous system has made it possible for various animal species to have advanced perception abilities such as vision, complex social interactions, rapid coordination of organ systems, and integrated processing of concurrent signals. In humans, the sophistication of the nervous system makes it possible to have language, abstract representation of concepts, transmission of culture, and many other features of human society that would not exist without the human brain.

Neurons and synapses

Major elements in synaptic transmission. An electrochemical wave called an action potential travels along the axon of a neuron. When the wave reaches a synapse, it provokes release of a small amount of neurotransmitter molecules, which bind to chemical receptor molecules in the membrane of the target cell.

Most neurons send signals via their axons, although some types are capable of dendrite-to-dendrite communication. (In fact, the types of neurons called amacrine cells have no axons, and communicate only via their dendrites.) Neural signals propagate along an axon in the form of electrochemical waves called action potentials, which produce cell-to-cell signals at points where axon terminals make synaptic contact with other cells.

Synapses may be electrical or chemical. Electrical synapses make direct electrical connections between neurons, but chemical synapses are much more common, and much more diverse in function. At a chemical synapse, the cell that sends signals is called presynaptic, and the cell that receives signals is called postsynaptic. Both the presynaptic and postsynaptic areas are full of molecular machinery that carries out the signalling process. The presynaptic area contains large numbers of tiny spherical vessels called synaptic vesicles, packed with neurotransmitter chemicals. When the presynaptic terminal is electrically stimulated, an array of molecules embedded in the membrane are activated, and cause the contents of the vesicles to be released into the narrow space between the presynaptic and postsynaptic membranes, called the synaptic cleft. The neurotransmitter then binds to receptors embedded in the postsynaptic membrane, causing them to enter an activated state. Depending on the type of receptor, the resulting effect on the postsynaptic cell may be excitatory, inhibitory, or modulatory in more complex ways. For example, release of the neurotransmitter acetylcholine at a synaptic contact between a motor neuron and a muscle cell induces rapid contraction of the muscle cell. The entire synaptic transmission process takes only a fraction of a millisecond, although the effects on the postsynaptic cell may last much longer (even indefinitely, in cases where the synaptic signal leads to the formation of a memory trace).

Structure of a typical chemical synapse

There are literally hundreds of different types of synapses. In fact, there are over a hundred known neurotransmitters, and many of them have multiple types of receptors. Many synapses use more than one neurotransmitter—a common arrangement is for a synapse to use one fast-acting small-molecule neurotransmitter such as glutamate or GABA, along with one or more peptide neurotransmitters that play slower-acting modulatory roles. Molecular neuroscientists generally divide receptors into two broad groups: chemically gated ion channels and second messenger systems. When a chemically gated ion channel is activated, it forms a passage that allows specific types of ions to flow across the membrane. Depending on the type of ion, the effect on the target cell may be excitatory or inhibitory. When a second messenger system is activated, it starts a cascade of molecular interactions inside the target cell, which may ultimately produce a wide variety of complex effects, such as increasing or decreasing the sensitivity of the cell to stimuli, or even altering gene transcription.

According to a rule called Dale's principle, which has only a few known exceptions, a neuron releases the same neurotransmitters at all of its synapses. This does not mean, though, that a neuron exerts the same effect on all of its targets, because the effect of a synapse depends not on the neurotransmitter, but on the receptors that it activates. Because different targets can (and frequently do) use different types of receptors, it is possible for a neuron to have excitatory effects on one set of target cells, inhibitory effects on others, and complex modulatory effects on others still. Nevertheless, it happens that the two most widely used neurotransmitters, glutamate and GABA, each have largely consistent effects. Glutamate has several widely occurring types of receptors, but all of them are excitatory or modulatory. Similarly, GABA has several widely occurring receptor types, but all of them are inhibitory. Because of this consistency, glutamatergic cells are frequently referred to as "excitatory neurons", and GABAergic cells as "inhibitory neurons". Strictly speaking, this is an abuse of terminology—it is the receptors that are excitatory and inhibitory, not the neurons—but it is commonly seen even in scholarly publications.

One very important subset of synapses are capable of forming memory traces by means of long-lasting activity-dependent changes in synaptic strength. The best-known form of neural memory is a process called long-term potentiation (abbreviated LTP), which operates at synapses that use the neurotransmitter glutamate acting on a special type of receptor known as the NMDA receptor. The NMDA receptor has an "associative" property: if the two cells involved in the synapse are both activated at approximately the same time, a channel opens that permits calcium to flow into the target cell. The calcium entry initiates a second messenger cascade that ultimately leads to an increase in the number of glutamate receptors in the target cell, thereby increasing the effective strength of the synapse. This change in strength can last for weeks or longer. Since the discovery of LTP in 1973, many other types of synaptic memory traces have been found, involving increases or decreases in synaptic strength that are induced by varying conditions, and last for variable periods of time. The reward system, that reinforces desired behaviour for example, depends on a variant form of LTP that is conditioned on an extra input coming from a reward-signalling pathway that uses dopamine as neurotransmitter. All these forms of synaptic modifiability, taken collectively, give rise to neural plasticity, that is, to a capability for the nervous system to adapt itself to variations in the environment.

Neural circuits and systems

The basic neuronal function of sending signals to other cells includes a capability for neurons to exchange signals with each other. Networks formed by interconnected groups of neurons are capable of a wide variety of functions, including feature detection, pattern generation and timing, and there are seen to be countless types of information processing possible. Warren McCulloch and Walter Pitts showed in 1943 that even artificial neural networks formed from a greatly simplified mathematical abstraction of a neuron are capable of universal computation.

Illustration of pain pathway, from René Descartes's Treatise of Man

Historically, for many years the predominant view of the function of the nervous system was as a stimulus-response associator. In this conception, neural processing begins with stimuli that activate sensory neurons, producing signals that propagate through chains of connections in the spinal cord and brain, giving rise eventually to activation of motor neurons and thereby to muscle contraction, i.e., to overt responses. Descartes believed that all of the behaviors of animals, and most of the behaviors of humans, could be explained in terms of stimulus-response circuits, although he also believed that higher cognitive functions such as language were not capable of being explained mechanistically. Charles Sherrington, in his influential 1906 book The Integrative Action of the Nervous System, developed the concept of stimulus-response mechanisms in much more detail, and Behaviorism, the school of thought that dominated Psychology through the middle of the 20th century, attempted to explain every aspect of human behavior in stimulus-response terms.

However, experimental studies of electrophysiology, beginning in the early 20th century and reaching high productivity by the 1940s, showed that the nervous system contains many mechanisms for maintaining cell excitability and generating patterns of activity intrinsically, without requiring an external stimulus. Neurons were found to be capable of producing regular sequences of action potentials, or sequences of bursts, even in complete isolation. When intrinsically active neurons are connected to each other in complex circuits, the possibilities for generating intricate temporal patterns become far more extensive. A modern conception views the function of the nervous system partly in terms of stimulus-response chains, and partly in terms of intrinsically generated activity patterns—both types of activity interact with each other to generate the full repertoire of behavior.

Reflexes and other stimulus-response circuits

Simplified schema of basic nervous system function: signals are picked up by sensory receptors and sent to the spinal cord and brain, where processing occurs that results in signals sent back to the spinal cord and then out to motor neurons

The simplest type of neural circuit is a reflex arc, which begins with a sensory input and ends with a motor output, passing through a sequence of neurons connected in series. This can be shown in the "withdrawal reflex" causing a hand to jerk back after a hot stove is touched. The circuit begins with sensory receptors in the skin that are activated by harmful levels of heat: a special type of molecular structure embedded in the membrane causes heat to change the electrical field across the membrane. If the change in electrical potential is large enough to pass the given threshold, it evokes an action potential, which is transmitted along the axon of the receptor cell, into the spinal cord. There the axon makes excitatory synaptic contacts with other cells, some of which project (send axonal output) to the same region of the spinal cord, others projecting into the brain. One target is a set of spinal interneurons that project to motor neurons controlling the arm muscles. The interneurons excite the motor neurons, and if the excitation is strong enough, some of the motor neurons generate action potentials, which travel down their axons to the point where they make excitatory synaptic contacts with muscle cells. The excitatory signals induce contraction of the muscle cells, which causes the joint angles in the arm to change, pulling the arm away.

In reality, this straightforward schema is subject to numerous complications. Although for the simplest reflexes there are short neural paths from sensory neuron to motor neuron, there are also other nearby neurons that participate in the circuit and modulate the response. Furthermore, there are projections from the brain to the spinal cord that are capable of enhancing or inhibiting the reflex.

Although the simplest reflexes may be mediated by circuits lying entirely within the spinal cord, more complex responses rely on signal processing in the brain. For example, when an object in the periphery of the visual field moves, and a person looks toward it many stages of signal processing are initiated. The initial sensory response, in the retina of the eye, and the final motor response, in the oculomotor nuclei of the brain stem, are not all that different from those in a simple reflex, but the intermediate stages are completely different. Instead of a one or two step chain of processing, the visual signals pass through perhaps a dozen stages of integration, involving the thalamus, cerebral cortex, basal ganglia, superior colliculus, cerebellum, and several brainstem nuclei. These areas perform signal-processing functions that include feature detection, perceptual analysis, memory recall, decision-making, and motor planning.

Feature detection is the ability to extract biologically relevant information from combinations of sensory signals. In the visual system, for example, sensory receptors in the retina of the eye are only individually capable of detecting "points of light" in the outside world. Second-level visual neurons receive input from groups of primary receptors, higher-level neurons receive input from groups of second-level neurons, and so on, forming a hierarchy of processing stages. At each stage, important information is extracted from the signal ensemble and unimportant information is discarded. By the end of the process, input signals representing "points of light" have been transformed into a neural representation of objects in the surrounding world and their properties. The most sophisticated sensory processing occurs inside the brain, but complex feature extraction also takes place in the spinal cord and in peripheral sensory organs such as the retina.

Intrinsic pattern generation

Although stimulus-response mechanisms are the easiest to understand, the nervous system is also capable of controlling the body in ways that do not require an external stimulus, by means of internally generated rhythms of activity. Because of the variety of voltage-sensitive ion channels that can be embedded in the membrane of a neuron, many types of neurons are capable, even in isolation, of generating rhythmic sequences of action potentials, or rhythmic alternations between high-rate bursting and quiescence. When neurons that are intrinsically rhythmic are connected to each other by excitatory or inhibitory synapses, the resulting networks are capable of a wide variety of dynamical behaviors, including attractor dynamics, periodicity, and even chaos. A network of neurons that uses its internal structure to generate temporally structured output, without requiring a corresponding temporally structured stimulus, is called a central pattern generator.

Internal pattern generation operates on a wide range of time scales, from milliseconds to hours or longer. One of the most important types of temporal pattern is circadian rhythmicity—that is, rhythmicity with a period of approximately 24 hours. All animals that have been studied show circadian fluctuations in neural activity, which control circadian alternations in behavior such as the sleep-wake cycle. Experimental studies dating from the 1990s have shown that circadian rhythms are generated by a "genetic clock" consisting of a special set of genes whose expression level rises and falls over the course of the day. Animals as diverse as insects and vertebrates share a similar genetic clock system. The circadian clock is influenced by light but continues to operate even when light levels are held constant and no other external time-of-day cues are available. The clock genes are expressed in many parts of the nervous system as well as many peripheral organs, but in mammals, all of these "tissue clocks" are kept in synchrony by signals that emanate from a master timekeeper in a tiny part of the brain called the suprachiasmatic nucleus.

Mirror neurons

A mirror neuron is a neuron that fires both when an animal acts and when the animal observes the same action performed by another. Thus, the neuron "mirrors" the behavior of the other, as though the observer were itself acting. Such neurons have been directly observed in primate species. Birds have been shown to have imitative resonance behaviors and neurological evidence suggests the presence of some form of mirroring system. In humans, brain activity consistent with that of mirror neurons has been found in the premotor cortex, the supplementary motor area, the primary somatosensory cortex and the inferior parietal cortex. The function of the mirror system is a subject of much speculation. Many researchers in cognitive neuroscience and cognitive psychology consider that this system provides the physiological mechanism for the perception/action coupling. They argue that mirror neurons may be important for understanding the actions of other people, and for learning new skills by imitation. Some researchers also speculate that mirror systems may simulate observed actions, and thus contribute to theory of mind skills, while others relate mirror neurons to language abilities. However, to date, no widely accepted neural or computational models have been put forward to describe how mirror neuron activity supports cognitive functions such as imitation. There are neuroscientists who caution that the claims being made for the role of mirror neurons are not supported by adequate research.

Development

In vertebrates, landmarks of embryonic neural development include the birth and differentiation of neurons from stem cell precursors, the migration of immature neurons from their birthplaces in the embryo to their final positions, outgrowth of axons from neurons and guidance of the motile growth cone through the embryo towards postsynaptic partners, the generation of synapses between these axons and their postsynaptic partners, and finally the lifelong changes in synapses which are thought to underlie learning and memory.

All bilaterian animals at an early stage of development form a gastrula, which is polarized, with one end called the animal pole and the other the vegetal pole. The gastrula has the shape of a disk with three layers of cells, an inner layer called the endoderm, which gives rise to the lining of most internal organs, a middle layer called the mesoderm, which gives rise to the bones and muscles, and an outer layer called the ectoderm, which gives rise to the skin and nervous system.

Four stages in the development of the neural tube
in the human embryo

In vertebrates, the first sign of the nervous system is the appearance of a thin strip of cells along the center of the back, called the neural plate. The inner portion of the neural plate (along the midline) is destined to become the central nervous system (CNS), the outer portion the peripheral nervous system (PNS). As development proceeds, a fold called the neural groove appears along the midline. This fold deepens, and then closes up at the top. At this point the future CNS appears as a cylindrical structure called the neural tube, whereas the future PNS appears as two strips of tissue called the neural crest, running lengthwise above the neural tube. The sequence of stages from neural plate to neural tube and neural crest is known as neurulation.

In the early 20th century, a set of famous experiments by Hans Spemann and Hilde Mangold showed that the formation of nervous tissue is "induced" by signals from a group of mesodermal cells called the organizer region. For decades, though, the nature of neural induction defeated every attempt to figure it out, until finally it was resolved by genetic approaches in the 1990s. Induction of neural tissue requires inhibition of the gene for a so-called bone morphogenetic protein, or BMP. Specifically the protein BMP4 appears to be involved. Two proteins called Noggin and Chordin, both secreted by the mesoderm, are capable of inhibiting BMP4 and thereby inducing ectoderm to turn into neural tissue. It appears that a similar molecular mechanism is involved for widely disparate types of animals, including arthropods as well as vertebrates. In some animals, however, another type of molecule called Fibroblast Growth Factor or FGF may also play an important role in induction.

Induction of neural tissues causes formation of neural precursor cells, called neuroblasts. In drosophila, neuroblasts divide asymmetrically, so that one product is a "ganglion mother cell" (GMC), and the other is a neuroblast. A GMC divides once, to give rise to either a pair of neurons or a pair of glial cells. In all, a neuroblast is capable of generating an indefinite number of neurons or glia.

As shown in a 2008 study, one factor common to all bilateral organisms (including humans) is a family of secreted signaling molecules called neurotrophins which regulate the growth and survival of neurons. Zhu et al. identified DNT1, the first neurotrophin found in flies. DNT1 shares structural similarity with all known neurotrophins and is a key factor in the fate of neurons in Drosophila. Because neurotrophins have now been identified in both vertebrate and invertebrates, this evidence suggests that neurotrophins were present in an ancestor common to bilateral organisms and may represent a common mechanism for nervous system formation.

Pathology

Layers protecting the brain and spinal cord.

The central nervous system is protected by major physical and chemical barriers. Physically, the brain and spinal cord are surrounded by tough meningeal membranes, and enclosed in the bones of the skull and vertebral column, which combine to form a strong physical shield. Chemically, the brain and spinal cord are isolated by the blood–brain barrier, which prevents most types of chemicals from moving from the bloodstream into the interior of the CNS. These protections make the CNS less susceptible in many ways than the PNS; the flip side, however, is that damage to the CNS tends to have more serious consequences.

Although nerves tend to lie deep under the skin except in a few places such as the ulnar nerve near the elbow joint, they are still relatively exposed to physical damage, which can cause pain, loss of sensation, or loss of muscle control. Damage to nerves can also be caused by swelling or bruises at places where a nerve passes through a tight bony channel, as happens in carpal tunnel syndrome. If a nerve is completely transected, it will often regenerate, but for long nerves this process may take months to complete. In addition to physical damage, peripheral neuropathy may be caused by many other medical problems, including genetic conditions, metabolic conditions such as diabetes, inflammatory conditions such as Guillain–Barré syndrome, vitamin deficiency, infectious diseases such as leprosy or shingles, or poisoning by toxins such as heavy metals. Many cases have no cause that can be identified, and are referred to as idiopathic. It is also possible for nerves to lose function temporarily, resulting in numbness as stiffness—common causes include mechanical pressure, a drop in temperature, or chemical interactions with local anesthetic drugs such as lidocaine.

Physical damage to the spinal cord may result in loss of sensation or movement. If an injury to the spine produces nothing worse than swelling, the symptoms may be transient, but if nerve fibers in the spine are actually destroyed, the loss of function is usually permanent. Experimental studies have shown that spinal nerve fibers attempt to regrow in the same way as nerve fibers, but in the spinal cord, tissue destruction usually produces scar tissue that cannot be penetrated by the regrowing nerves.

Endocrine disruptor

From Wikipedia, the free encyclopedia
 
A comparison of the structures of the natural estrogen hormone estradiol (left) and one of the nonyl-phenols (right), a xenoestrogen endocrine disruptor

Endocrine disruptors, sometimes also referred to as hormonally active agents, endocrine disrupting chemicals, or endocrine disrupting compounds are chemicals that can interfere with endocrine (or hormonal) systems. These disruptions can cause cancerous tumors, birth defects, and other developmental disorders. Found in many household and industrial products, endocrine disruptors "interfere with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for development, behavior, fertility, and maintenance of homeostasis (normal cell metabolism)."

Any system in the body controlled by hormones can be derailed by hormone disruptors. Specifically, endocrine disruptors may be associated with the development of learning disabilities, severe attention deficit disorder, cognitive and brain development problems; deformations of the body (including limbs); breast cancer, prostate cancer, thyroid and other cancers; sexual development problems such as feminizing of males or masculinizing effects on females, etc.

There has been controversy over endocrine disruptors, with some groups calling for swift action by regulators to remove them from the market, and regulators and other scientists calling for further study. Some endocrine disruptors have been identified and removed from the market (for example, a drug called diethylstilbestrol), but it is uncertain whether some endocrine disruptors on the market actually harm humans and wildlife at the doses to which wildlife and humans are exposed. Additionally, a key scientific paper, published in 1996 in the journal Science, which helped launch the movement of those opposed to endocrine disruptors, was retracted and its author found to have committed scientific misconduct.

Studies in cells and laboratory animals have shown that EDCs can cause adverse biological effects in animals, and low-level exposures may also cause similar effects in human beings. EDCs in the environment may also be related to reproductive and infertility problems in wildlife and bans and restrictions on their use has been associated with a reduction in health problems and the recovery of some wildlife populations.

History

The term endocrine disruptor was coined at the Wingspread Conference Center in Wisconsin, in 1991. One of the early papers on the phenomenon was by Theo Colborn in 1993. In this paper, she stated that environmental chemicals disrupt the development of the endocrine system, and that effects of exposure during development are often permanent. Although the endocrine disruption has been disputed by some, work sessions from 1992 to 1999 have generated consensus statements from scientists regarding the hazard from endocrine disruptors, particularly in wildlife and also in humans.

The Endocrine Society released a scientific statement outlining mechanisms and effects of endocrine disruptors on “male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology,” and showing how experimental and epidemiological studies converge with human clinical observations “to implicate EDCs as a significant concern to public health.” The statement noted that it is difficult to show that endocrine disruptors cause human diseases, and it recommended that the precautionary principle should be followed. A concurrent statement expresses policy concerns.

Endocrine disrupting compounds encompass a variety of chemical classes, including drugs, pesticides, compounds used in the plastics industry and in consumer products, industrial by-products and pollutants, and even some naturally produced botanical chemicals. Some are pervasive and widely dispersed in the environment and may bioaccumulate. Some are persistent organic pollutants (POPs), and can be transported long distances across national boundaries and have been found in virtually all regions of the world, and may even concentrate near the North Pole, due to weather patterns and cold conditions. Others are rapidly degraded in the environment or human body or may be present for only short periods of time. Health effects attributed to endocrine disrupting compounds include a range of reproductive problems (reduced fertility, male and female reproductive tract abnormalities, and skewed male/female sex ratios, loss of fetus, menstrual problems); changes in hormone levels; early puberty; brain and behavior problems; impaired immune functions; and various cancers.

One example of the consequences of the exposure of developing animals, including humans, to hormonally active agents is the case of the drug diethylstilbestrol (DES), a nonsteroidal estrogen and not an environmental pollutant. Prior to its ban in the early 1970s, doctors prescribed DES to as many as five million pregnant women to block spontaneous abortion, an off-label use of this medication prior to 1947. It was discovered after the children went through puberty that DES affected the development of the reproductive system and caused vaginal cancer. The relevance of the DES saga to the risks of exposure to endocrine disruptors is questionable, as the doses involved are much higher in these individuals than in those due to environmental exposures.

Aquatic life subjected to endocrine disruptors in an urban effluent have experienced decreased levels of serotonin and increased feminization.

In 2013 the WHO and the United Nations Environment Programme released a study, the most comprehensive report on EDCs to date, calling for more research to fully understand the associations between EDCs and the risks to health of human and animal life. The team pointed to wide gaps in knowledge and called for more research to obtain a fuller picture of the health and environmental impacts of endocrine disruptors. To improve global knowledge the team has recommended:

  • Testing: known EDCs are only the 'tip of the iceberg' and more comprehensive testing methods are required to identify other possible endocrine disruptors, their sources, and routes of exposure.
  • Research: more scientific evidence is needed to identify the effects of mixtures of EDCs on humans and wildlife (mainly from industrial by-products) to which humans and wildlife are increasingly exposed.
  • Reporting: many sources of EDCs are not known because of insufficient reporting and information on chemicals in products, materials and goods.
  • Collaboration: more data sharing between scientists and between countries can fill gaps in data, primarily in developing countries and emerging economies.

Endocrine system

Endocrine systems are found in most varieties of animals. The endocrine system consists of glands that secrete hormones, and receptors that detect and react to the hormones.

Hormones travel throughout the body and act as chemical messengers. Hormones interface with cells that contain matching receptors in or on their surfaces. The hormone binds with the receptor, much like a key would fit into a lock. The endocrine system regulates adjustments through slower internal processes, using hormones as messengers. The endocrine system secretes hormones in response to environmental stimuli and to orchestrate developmental and reproductive changes. The adjustments brought on by the endocrine system are biochemical, changing the cell's internal and external chemistry to bring about a long term change in the body. These systems work together to maintain the proper functioning of the body through its entire life cycle. Sex steroids such as estrogens and androgens, as well as thyroid hormones, are subject to feedback regulation, which tends to limit the sensitivity of these glands.

Hormones work at very small doses (part per billion ranges). Endocrine disruption can thereby also occur from low-dose exposure to exogenous hormones or hormonally active chemicals such as bisphenol A. These chemical can bind to receptors for other hormonally mediated processes. Furthermore, since endogenous hormones are already present in the body in biologically active concentrations, additional exposure to relatively small amounts of exogenous hormonally active substances can disrupt the proper functioning of the body's endocrine system. Thus, an endocrine disruptor can elicit adverse effects at much lower doses than a toxicity, acting through a different mechanism.

The timing of exposure is also critical. Most critical stages of development occur in utero, where the fertilized egg divides, rapidly developing every structure of a fully formed baby, including much of the wiring in the brain. Interfering with the hormonal communication in utero can have profound effects both structurally and toward brain development. Depending on the stage of reproductive development, interference with hormonal signaling can result in irreversible effects not seen in adults exposed to the same dose for the same length of time. Experiments with animals have identified critical developmental time points in utero and days after birth when exposure to chemicals that interfere with or mimic hormones have adverse effects that persist into adulthood. Disruption of thyroid function early in development may be the cause of abnormal sexual development in both males and females early motor development impairment, and learning disabilities.

There are studies of cell cultures, laboratory animals, wildlife, and accidentally exposed humans that show that environmental chemicals cause a wide range of reproductive, developmental, growth, and behavior effects, and so while "endocrine disruption in humans by pollutant chemicals remains largely undemonstrated, the underlying science is sound and the potential for such effects is real." While compounds that produce estrogenic, androgenic, antiandrogenic, and antithyroid actions have been studied, less is known about interactions with other hormones.

The interrelationships between exposures to chemicals and health effects are rather complex. It is hard to definitively link a particular chemical with a specific health effect, and exposed adults may not show any ill effects. But, fetuses and embryos, whose growth and development are highly controlled by the endocrine system, are more vulnerable to exposure and may suffer overt or subtle lifelong health and/or reproductive abnormalities. Prebirth exposure, in some cases, can lead to permanent alterations and adult diseases.

Some in the scientific community are concerned that exposure to endocrine disruptors in the womb or early in life may be associated with neurodevelopmental disorders including reduced IQ, ADHD, and autism. Certain cancers and uterine abnormalities in women are associated with exposure to Diethylstilbestrol (DES) in the womb due to DES used as a medical treatment.

In another case, phthalates in pregnant women’s urine was linked to subtle, but specific, genital changes in their male infants – a shorter, more female-like anogenital distance and associated incomplete descent of testes and a smaller scrotum and penis. The science behind this study has been questioned by phthalate industry consultants. As of June 2008, there are only five studies of anogenital distance in humans, and one researcher has stated "Whether AGD measures in humans relate to clinically important outcomes, however, remains to be determined, as does its utility as a measure of androgen action in epidemiologic studies."

Effects on levels of the body's own hormones

While the fact that there are chemical differences between endocrine disruptors and endogenous hormones have sometimes been cited as an argument for endocrine disruptors affecting only some (not all) of the traits that are affected by hormones, toxicology research shows that many of the effects of endocrine disruptors target the aspects of hormone effects that make one hormone regulate the production and/or degradation of the body's own hormones. These regulation effects are intertwined so that a hormone that is level affected by another hormone in turn affects the levels of multiple other hormones produced by the body itself, leaving no endogenous hormones or traits affected by them unaffected by endocrine disruptors. Endocrine disruptors have the potential to mimic or antagonize natural hormones, these chemicals can exert their effects by acting through interaction with nuclear receptors, the aryl hydrocarbon receptor or membrane bound receptors.

U-shaped dose-response curve

Most toxicants, including endocrine disruptors, have been claimed to follow a U-shaped dose response curve. This means that very low and very high levels have more effects than mid-level exposure to a toxicant. Endocrine disrupting effects have been noted in animals exposed to environmentally relevant levels of some chemicals. For example, a common flame retardant, BDE-47, affects the reproductive system and thyroid gland of female rats in doses of the order of those to which humans are exposed. Low concentrations of endocrine disruptors can also have synergistic effects in amphibians, but it is not clear that this is an effect mediated through the endocrine system.

Critics have argued that data suggest that the amounts of chemicals in the environment are too low to cause an effect. A consensus statement by the Learning and Developmental Disabilities Initiative argued that "The very low-dose effects of endocrine disruptors cannot be predicted from high-dose studies, which contradicts the standard 'dose makes the poison' rule of toxicology. Nontraditional dose-response curves are referred to as nonmonotonic dose response curves."

The dosage objection could also be overcome if low concentrations of different endocrine disruptors are synergistic. This paper was published in Science in June 1996, and was one reason for the passage of the Food Quality Protection Act of 1996. The results could not be confirmed with the same and alternative methodologies, and the original paper was retracted, with Arnold found to have committed scientific misconduct by the United States Office of Research Integrity.

It has been claimed that Tamoxifen and some phthalates have fundamentally different (and harmful) effects on the body at low doses than at high doses.

Routes of exposure

Food is a major mechanism by which people are exposed to pollutants. Diet is thought to account for up to 90% of a person's PCB and DDT body burden. In a study of 32 different common food products from three grocery stores in Dallas, fish and other animal products were found to be contaminated with PBDE. Since these compounds are fat soluble, it is likely they are accumulating from the environment in the fatty tissue of animals we eat. Some suspect fish consumption is a major source of many environmental contaminants. Indeed, both wild and farmed salmon from all over the world have been shown to contain a variety of man-made organic compounds.

With the increase in household products containing pollutants and the decrease in the quality of building ventilation, indoor air has become a significant source of pollutant exposure. Residents living in homes with wood floors treated in the 1960s with PCB-based wood finish have a much higher body burden than the general population. A study of indoor house dust and dryer lint of 16 homes found high levels of all 22 different PBDE congeners tested for in all samples. Recent studies suggest that contaminated house dust, not food, may be the major source of PBDE in our bodies. One study estimated that ingestion of house dust accounts for up to 82% of our PBDE body burden.

It has been shown that contaminated house dust is a primary source of lead in young children's bodies. It may be that babies and toddlers ingest more contaminated house dust than the adults they live with, and therefore have much higher levels of pollutants in their systems.

Consumer goods are another potential source of exposure to endocrine disruptors. An analysis of the composition of 42 household cleaning and personal care products versus 43 "chemical free" products has been performed. The products contained 55 different chemical compounds: 50 were found in the 42 conventional samples representing 170 product types, while 41 were detected in 43 "chemical free" samples representing 39 product types. Parabens, a class of chemicals that has been associated with reproductive-tract issues, were detected in seven of the "chemical free" products, including three sunscreens that did not list parabens on the label. Vinyl products such as shower curtains were found to contain more than 10% by weight of the compound DEHP, which when present in dust has been associated with asthma and wheezing in children. The risk of exposure to EDCs increases as products, both conventional and "chemical free," are used in combination. "If a consumer used the alternative surface cleaner, tub and tile cleaner, laundry detergent, bar soap, shampoo and conditioner, facial cleanser and lotion, and toothpaste [he or she] would potentially be exposed to at least 19 compounds: 2 parabens, 3 phthalates, MEA, DEA, 5 alkylphenols, and 7 fragrances."

An analysis of the endocrine disrupting chemicals in Old Order Mennonite women in mid-pregnancy determined that they have much lower levels in their systems than the general population. Mennonites eat mostly fresh, unprocessed foods, farm without pesticides, and use few or no cosmetics or personal care products. One woman who had reported using hairspray and perfume had high levels of monoethyl phthalate, while the other women all had levels below detection. Three women who reported being in a car or truck within 48 hours of providing a urine sample had higher levels of diethylhexyl phthalate which is found in polyvinyl chloride, and is used in car interiors.

Additives added to plastics during manufacturing may leach into the environment after the plastic item is discarded; additives in microplastics in the ocean leach into ocean water and in plastics in landfills may escape and leach into the soil and then into groundwater.

Types

All people are exposed to chemicals with estrogenic effects in their everyday life, because endocrine disrupting chemicals are found in low doses in thousands of products. Chemicals commonly detected in people include DDT, polychlorinated biphenyls (PCB's), bisphenol A (BPA), polybrominated diphenyl ethers (PBDE's), and a variety of phthalates. In fact, almost all plastic products, including those advertised as "BPA free", have been found to leach endocrine-disrupting chemicals. In a 2011, study it was found that some "BPA-free" products released more endocrine active chemicals than the BPA-containing products. Other forms of endocrine disruptors are phytoestrogens (plant hormones).

Xenoestrogens

Xenoestrogens are a type of xenohormone that imitates estrogen. Synthetic xenoestrogens include widely used industrial compounds, such as PCBs, BPA and phthalates, which have estrogenic effects on a living organism.

Alkylphenols

Alkylphenols are xenoestrogens. The European Union has implemented sales and use restrictions on certain applications in which nonylphenols are used because of their alleged "toxicity, persistence, and the liability to bioaccumulate" but the United States Environmental Protections Agency (EPA) has taken a slower approach to make sure that action is based on "sound science".

The long-chain alkylphenols are used extensively as precursors to the detergents, as additives for fuels and lubricants, polymers, and as components in phenolic resins. These compounds are also used as building block chemicals that are also used in making fragrances, thermoplastic elastomers, antioxidants, oil field chemicals and fire retardant materials. Through the downstream use in making alkylphenolic resins, alkylphenols are also found in tires, adhesives, coatings, carbonless copy paper and high performance rubber products. They have been used in industry for over 40 years.

Certain alkylphenols are degradation products from nonionic detergents. Nonylphenol is considered to be a low-level endocrine disruptor owing to its tendency to mimic estrogen.

Bisphenol A (BPA)

Bisphenol A chemical structure

Bisphenol A is commonly found in plastic bottles, plastic food containers, dental materials, and the linings of metal food and infant formula cans. Another exposure comes from receipt paper commonly used at grocery stores and restaurants, because today the paper is commonly coated with a BPA containing clay for printing purposes.

BPA is a known endocrine disruptor, and numerous studies have found that laboratory animals exposed to low levels of it have elevated rates of diabetes, mammary and prostate cancers, decreased sperm count, reproductive problems, early puberty, obesity, and neurological problems. Early developmental stages appear to be the period of greatest sensitivity to its effects, and some studies have linked prenatal exposure to later physical and neurological difficulties. Regulatory bodies have determined safety levels for humans, but those safety levels are currently being questioned or are under review as a result of new scientific studies. A 2011 cross-sectional study that investigated the number of chemicals pregnant women are exposed to in the U.S. found BPA in 96% of women. In 2010 the World Health Organization expert panel recommended no new regulations limiting or banning the use of bisphenol A, stating that "initiation of public health measures would be premature."

In August 2008, the U.S. FDA issued a draft reassessment, reconfirming their initial opinion that, based on scientific evidence, it is safe. However, in October 2008, FDA's advisory Science Board concluded that the Agency's assessment was "flawed" and hadn't proven the chemical to be safe for formula-fed infants. In January 2010, the FDA issued a report indicating that, due to findings of recent studies that used novel approaches in testing for subtle effects, both the National Toxicology Program at the National Institutes of Health as well as the FDA have some level of concern regarding the possible effects of BPA on the brain and behavior of fetuses, infants and younger children. In 2012 the FDA did ban the use of BPA in baby bottles, however the Environmental Working Group called the ban "purely cosmetic". In a statement they said, “If the agency truly wants to prevent people from being exposed to this toxic chemical associated with a variety of serious and chronic conditions it should ban its use in cans of infant formula, food and beverages." The Natural Resources Defense Council called the move inadequate saying, the FDA needs to ban BPA from all food packaging. In a statement a FDA spokesman said the agency's action was not based on safety concerns and that "the agency continues to support the safety of BPA for use in products that hold food."

A program initiated by NIEHS, NTP, and the U.S. Food and Drug Administration (named CLARITY-BPA) found no effect of chronic exposure to BPA on rats and the FDA considers currently authorized uses of BPA to be safe for consumers.

Bisphenol S (BPS) and Bisphenol F (BPF)

Bisphenol S and Bisphenol F are analogs of bisphenol A. They are commonly found in thermal receipts, plastics, and household dust.

Traces of BPS have also been found in personal care products. It is more presently being used because of the ban of BPA. BPS is used in place of BPA in “BPA free” items. However BPS and BPF have been shown to be as much of an endocrine disruptor as BPA.

DDT

DDT Chemical structure

Dichlorodiphenyltrichloroethane (DDT) was first used as a pesticide against Colorado potato beetles on crops beginning in 1936. An increase in the incidence of malaria, epidemic typhus, dysentery, and typhoid fever led to its use against the mosquitoes, lice, and houseflies that carried these diseases. Before World War II, pyrethrum, an extract of a flower from Japan, had been used to control these insects and the diseases they can spread. During World War II, Japan stopped exporting pyrethrum, forcing the search for an alternative. Fearing an epidemic outbreak of typhus, every British and American soldier was issued DDT, who used it to routinely dust beds, tents, and barracks all over the world.

DDT was approved for general, non-military use after the war ended. It became used worldwide to increase monoculture crop yields that were threatened by pest infestation, and to reduce the spread of malaria which had a high mortality rate in many parts of the world. Its use for agricultural purposes has since been prohibited by national legislation of most countries, while its use as a control against malaria vectors is permitted, as specifically stated by the Stockholm Convention on Persistent Organic Pollutants

As early as 1946, the harmful effects of DDT on bird, beneficial insects, fish, and marine invertebrates were seen in the environment. The most infamous example of these effects were seen in the eggshells of large predatory birds, which did not develop to be thick enough to support the adult bird sitting on them. Further studies found DDT in high concentrations in carnivores all over the world, the result of biomagnification through the food chain. Twenty years after its widespread use, DDT was found trapped in ice samples taken from Antarctic snow, suggesting wind and water are another means of environmental transport. Recent studies show the historical record of DDT deposition on remote glaciers in the Himalayas.

More than sixty years ago when biologists began to study the effects of DDT on laboratory animals, it was discovered that DDT interfered with reproductive development. Recent studies suggest DDT may inhibit the proper development of female reproductive organs that adversely affects reproduction into maturity. Additional studies suggest that a marked decrease in fertility in adult males may be due to DDT exposure. Most recently, it has been suggested that exposure to DDT in utero can increase a child's risk of childhood obesity. DDT is still used as anti-malarial insecticide in Africa and parts of Southeast Asia in limited quantities.

Polychlorinated biphenyls

Polychlorinated biphenyls (PCBs) are a class of chlorinated compounds used as industrial coolants and lubricants. PCBs are created by heating benzene, a byproduct of gasoline refining, with chlorine. They were first manufactured commercially by the Swann Chemical Company in 1927. In 1933, the health effects of direct PCB exposure was seen in those who worked with the chemicals at the manufacturing facility in Alabama. In 1935, Monsanto acquired the company, taking over US production and licensing PCB manufacturing technology internationally.

General Electric was one of the largest US companies to incorporate PCBs into manufactured equipment. Between 1952 and 1977, the New York GE plant had dumped more than 500,000 pounds of PCB waste into the Hudson River. PCBs were first discovered in the environment far from its industrial use by scientists in Sweden studying DDT.

The effects of acute exposure to PCBs were well known within the companies who used Monsanto's PCB formulation who saw the effects on their workers who came into contact with it regularly. Direct skin contact results in a severe acne-like condition called chloracne. Exposure increases the risk of skin cancer, liver cancer, and brain cancer. Monsanto tried for years to downplay the health problems related to PCB exposure in order to continue sales.

The detrimental health effects of PCB exposure to humans became undeniable when two separate incidents of contaminated cooking oil poisoned thousands of residents in Japan (Yushō disease, 1968) and Taiwan (Yu-cheng disease, 1979), leading to a worldwide ban on PCB use in 1977. Recent studies show the endocrine interference of certain PCB congeners is toxic to the liver and thyroid, increases childhood obesity in children exposed prenatally, and may increase the risk of developing diabetes.

PCBs in the environment may also be related to reproductive and infertility problems in wildlife. In Alaska, it is thought that they may contribute to reproductive defects, infertility and antler malformation in some deer populations. Declines in the populations of otters and sea lions may also be partially due to their exposure to PCBs, the insecticide DDT, other persistent organic pollutants. Bans and restrictions on the use of EDCs have been associated with a reduction in health problems and the recovery of some wildlife populations.

Polybrominated diphenyl ethers

Polybrominated diphenyl ethers (PBDEs) are a class of compounds found in flame retardants used in plastic cases of televisions and computers, electronics, carpets, lighting, bedding, clothing, car components, foam cushions and other textiles. Potential health concern: PBDE's are structurally very similar to Polychlorinated biphenyls (PCBs), and have similar neurotoxic effects. Research has correlated halogenated hydrocarbons, such as PCBs, with neurotoxicity. PBDEs are similar in chemical structure to PCBs, and it has been suggested that PBDEs act by the same mechanism as PCBs.

In the 1930s and 1940s, the plastics industry developed technologies to create a variety of plastics with broad applications. Once World War II began, the US military used these new plastic materials to improve weapons, protect equipment, and to replace heavy components in aircraft and vehicles. After WWII, manufacturers saw the potential plastics could have in many industries, and plastics were incorporated into new consumer product designs. Plastics began to replace wood and metal in existing products as well, and today plastics are the most widely used manufacturing materials.

By the 1960s, all homes were wired with electricity and had numerous electrical appliances. Cotton had been the dominant textile used to produce home furnishings, but now home furnishings were composed of mostly synthetic materials. More than 500 billion cigarettes were consumed each year in the 1960s, as compared to less than 3 billion per year in the beginning of the twentieth century. When combined with high density living, the potential for home fires was higher in the 1960s than it had ever been in the US. By the late 1970s, approximately 6000 people in the US died each year in home fires.

In 1972, in response to this situation, the National Commission on Fire Prevention and Control was created to study the fire problem in the US. In 1973 they published their findings in America Burning, a 192-page report that made recommendations to increase fire prevention. Most of the recommendations dealt with fire prevention education and improved building engineering, such as the installation of fire sprinklers and smoke detectors. The Commission expected that with the recommendations, a 5% reduction in fire losses could be expected each year, halving the annual losses within 14 years.

Historically, treatments with alum and borax were used to reduce the flammability of fabric and wood, as far back as Roman times. Since it is a non-absorbent material once created, flame retardant chemicals are added to plastic during the polymerization reaction when it is formed. Organic compounds based on halogens like bromine and chlorine are used as the flame retardant additive in plastics, and in fabric based textiles as well. The widespread use of brominated flame retardants may be due to the push from Great Lakes Chemical Corporation (GLCC) to profit from its huge investment in bromine. In 1992, the world market consumed approximately 150,000 tonnes of bromine-based flame retardants, and GLCC produced 30% of the world supply.

PBDEs have the potential to disrupt thyroid hormone balance and contribute to a variety of neurological and developmental deficits, including low intelligence and learning disabilities. Many of the most common PBDE's were banned in the European Union in 2006. Studies with rodents have suggested that even brief exposure to PBDEs can cause developmental and behavior problems in juvenile rodents and exposure interferes with proper thyroid hormone regulation.

Phthalates

Phthalates are found in some soft toys, flooring, medical equipment, cosmetics and air fresheners. They are of potential health concern because they are known to disrupt the endocrine system of animals, and some research has implicated them in the rise of birth defects of the male reproductive system.

Although an expert panel has concluded that there is "insufficient evidence" that they can harm the reproductive system of infants, California, Washington state and Europe have banned them from toys. One phthalate, bis(2-ethylhexyl) phthalate (DEHP), used in medical tubing, catheters and blood bags, may harm sexual development in male infants. In 2002, the Food and Drug Administration released a public report which cautioned against exposing male babies to DEHP. Although there are no direct human studies the FDA report states: "Exposure to DEHP has produced a range of adverse effects in laboratory animals, but of greatest concern are effects on the development of the male reproductive system and production of normal sperm in young animals. In view of the available animal data, precautions should be taken to limit the exposure of the developing male to DEHP". Similarly, phthalates may play a causal role in disrupting masculine neurological development when exposed prenatally.

Dibutyl phthalate (DBP) has also disrupted insulin and glucagon signaling in animal models.

Perfluorooctanoic acid

PFOA exerts hormonal effects including alteration of thyroid hormone levels. Blood serum levels of PFOA were associated with an increased time to pregnancy — or "infertility" — in a 2009 study. PFOA exposure is associated with decreased semen quality. PFOA appeared to act as an endocrine disruptor by a potential mechanism on breast maturation in young girls. A C8 Science Panel status report noted an association between exposure in girls and a later onset of puberty.

Other suspected endocrine disruptors

Some other examples of putative EDCs are polychlorinated dibenzo-dioxins (PCDDs) and -furans (PCDFs), polycyclic aromatic hydrocarbons (PAHs), phenol derivatives and a number of pesticides (most prominent being organochlorine insecticides like endosulfan, kepone (chlordecone) and DDT and its derivatives, the herbicide atrazine, and the fungicide vinclozolin), the contraceptive 17-alpha ethinylestradiol, as well as naturally occurring phytoestrogens such as genistein and mycoestrogens such as zearalenone.

The molting in crustaceans is an endocrine-controlled process. In the marine penaeid shrimp Litopenaeus vannamei, exposure to endosulfan resulted increased susceptibility to acute toxicity and increased mortalities in the postmolt stage of the shrimp.

Many sunscreens contain oxybenzone, a chemical blocker that provides broad-spectrum UV coverage, yet is subject to a lot of controversy due its potential estrogenic effect in humans.

Tributyltin (TBT) are organotin compounds that for 40 years TBT was used as a biocide in anti-fouling paint, commonly known as bottom paint. TBT has been shown to impact invertebrate and vertebrate development, disrupting the endocrine system, resulting in masculinization, lower survival rates, as well as many health problems in mammals.

Temporal trends of body burden

Since being banned, the average human body burdens of DDT and PCB have been declining. Since their ban in 1972, the PCB body burden in 2009 is one-hundredth of what it was in the early 1980s. On the other hand, monitoring programs of European breast milk samples have shown that PBDE levels are increasing. An analysis of PBDE content in breast milk samples from Europe, Canada, and the US shows that levels are 40 times higher for North American women than for Swedish women, and that levels in North America are doubling every two to six years.

It has been discussed that the long-term slow decline in average body temperature observed since the beginning of the industrial revolution may result from disrupted thyroid hormone signalling.

Animal models

Because endocrine disruptors affect complex metabolic, reproductive, and neuroendocrine systems, they cannot be modeled in in vitro cell based assay. Consequently animal models are important for access the risk of endocrine disrupting chemicals.

Mice

There are multiple lines of genetically engineered mice used for lab studies, in this case the lines can be used as population-based genetic foundations. For instance, there is a population that is named Multi-parent and can be a Collaborative Cross (CC) or Diversity Outbred (DO). These mice while both from the same 8 founder strains, have distinct differences.

The 8 founder strains, combine strains that are wild-derived (with high genetic diversity) and historically significant biomedical research bred strains. Each genetically differential line is important in EDCs response and also almost all biological processes and traits.

The CC population consists of 83 inbred mouse strains that over many generations in labs came from the 8 founder strains. These inbred mice have recombinant genomes that are developed to ensure every strain is equally related, this eradicates population structure and can result in false positives with qualitative trait locus (QTL) mapping.

While DO mice have the identical alleles to the CC mice population. There are two major differences in these mice; 1) every individual is unique allowing for hundreds of individuals to be applied in one mapping study. Making DO mice an extremely useful tool for determining genetic relationships. 2) The catch is that DO individuals cannot be reproduced.

Transgenic

These rodents mainly mice have been bred by inserting other genes from another organism to make transgenic lines (thousands of lines) of rodents. The most recent tool used to do this is CRISPR/Cas9 which allows this process to be done more efficiently.

Genes may be manipulated in a particular cell populations if done under the correct conditions. For Endocrine disrupting chemical (EDC) research these rodents have become an important tool to the point where they can produce humanized mouse models. Additionally scientists use gene knockout lines of mice in order to study how certain mechanisms work when impacted by EDC’s. Transgenic rodents are an important tool for studies involving the mechanisms that are impacted by EDC but take a long time to produce and are expensive. Additionally, the genes aimed at for knockout are not always successfully targeted resulting in incomplete knockout of a gene or off-target expression.

Social Models

Experiments (gene by environment) with these relatively new rodent models may, be able to discover if there are mechanisms that EDCs could impact in the social decline in autism spectrum disorder (ASD) and other behavioral disorders. This is because prairie and pine voles are socially monogamous making them a better model for human social behaviors and development in relation to EDCs. Additionally the prairie vole genome has been sequenced making it feasible to do the experiments mentioned above. These voles can be compared to montane and meadow voles who are socially promiscuous and solitary, when looking at how different species have various forms of development and social brain structure. Both monogamous and promiscuous mice species have been used in these types of experiments, for more information studies can expand on this topic. More complex models that have systems that are as close as possible to humans are being looked at. Looking back at more common rodent models for instance the common ASD mouse are helpful but do not fully encompass what a model of the human social behaviors needs to. But these rodents will always just be models and this is important to keep in mind.

Zebrafish

The endocrine systems between mammals and fish are similar, because of this Danio rerio are a popular lab choice. The Danio rerio, or zebrafish work well as a model organism, part of which can be attributed to the fact that researchers are able to study them starting from the embryo, as the embryo is nearly transparent. Additionally, zebrafish have DNA sex markers, this allows the biologists to individually assign sex to fish, this is particularly important when studying endocrine disruptors as the disruptors can affect how, among other things, the sex organs work, so if by chance there is sperm in the ovaries later on through the testing it can then be pinned to the chemical without the chance of it being a genetic abnormality since the sex was determined by the researcher. Besides zebrafish being readily available, and easy to study through their different life stages, they have hugely similar genes to humans - 70% of human genes have a zebrafish counterpart and even more fascinatingly 84% of disease genes in humans have a zebrafish counterpart. Most importantly perhaps is the fact that the vast majority of endocrine disruptors end up in water ways, and so it is important to know how these disruptors affect fish, which arguably have intrinsic value and just happen to be model organisms as well.

The zebrafish embryos are transparent, relatively small fish (larvae are less than a few millimeters in size). This allows scientists to view the larvae (in vivo) without killing them to study how their organs develop in particular, neuro development and transport of presumed endocrine disrupting chemicals (EDC). Meaning how their development is impacted by certain chemicals. As a model, they have simple modes of endocrine disruption. Along with homologous physiological, sensory, anatomical and signal-transduction mechanism similar to mammals. Another helpful tool available to scientists is their recorded genome along with multiple transgenic lines accessible for breeding. Zebrafish and mammalian genomes when compared have prominent similarities with about 80% of human genes expressed in the fish. Additionally, this fish is also fairly inexpensive to breed and house in a lab partly due to their shorter life span and being able to house more of them, compared to mammalian models.

Directions of research

Research on endocrine disruptors is challenged by five complexities requiring special trial designs and sophisticated study protocols:

  1. The dissociation of space means that, although disruptors may act by a common pathway via hormone receptors, their impact may also be mediated by effects at the levels of transport proteins, deiodinases, degradation of hormones or modified setpoints of feedback loops (i.e. allostatic load).
  2. The dissociation of time may ensue from the fact that unwanted effects may be triggered in a small time window in the embryonal or fetal period, but consequences may ensue decades later or even in the generation of grandchildren.
  3. The dissociation of substance results from additive, multiplicative or more complex interactions of disruptors in combination that yield fundamentally different effects from that of the respective substances alone.
  4. The dissociation of dose implies that dose-effect relationships use to be nonlinear and sometimes even U-shaped, so that low or medium doses may have stronger effects than high doses.
  5. The dissociation of sex reflects the fact that effects may be different depending on whether embryos or fetuses are female or male.

Legal approach

United States

The multitude of possible endocrine disruptors are technically regulated in the United States by many laws, including: the Toxic Substances Control Act, the Food Quality Protection Act, the Food, Drug and Cosmetic Act, the Clean Water Act, the Safe Drinking Water Act, and the Clean Air Act.

The Congress of the United States has improved the evaluation and regulation process of drugs and other chemicals. The Food Quality Protection Act of 1996 and the Safe Drinking Water Act of 1996 simultaneously provided the first legislative direction requiring the EPA to address endocrine disruption through establishment of a program for screening and testing of chemical substances.

In 1998, the EPA announced the Endocrine Disruptor Screening Program by establishment of a framework for priority setting, screening and testing more than 85,000 chemicals in commerce. While the Food Quality Protection Act only required the EPA to screen pesticides for potential to produce effects similar to estrogens in humans, it also gave the EPA the authority to screen other types of chemicals and endocrine effects. Based recommendations from an advisory panel, the agency expanded the screening program to include male hormones, the thyroid system, and effects on fish and other wildlife. The basic concept behind the program is that prioritization will be based on existing information about chemical uses, production volume, structure-activity and toxicity. Screening is done by use of in vitro test systems (by examining, for instance, if an agent interacts with the estrogen receptor or the androgen receptor) and via the use of in animal models, such as development of tadpoles and uterine growth in prepubertal rodents. Full scale testing will examine effects not only in mammals (rats) but also in a number of other species (frogs, fish, birds and invertebrates). Since the theory involves the effects of these substances on a functioning system, animal testing is essential for scientific validity, but has been opposed by animal rights groups. Similarly, proof that these effects occur in humans would require human testing, and such testing also has opposition.

After failing to meet several deadlines to begin testing, the EPA finally announced that they were ready to begin the process of testing dozens of chemical entities that are suspected endocrine disruptors early in 2007, eleven years after the program was announced. When the final structure of the tests was announced there was objection to their design. Critics have charged that the entire process has been compromised by chemical company interference. In 2005, the EPA appointed a panel of experts to conduct an open peer-review of the program and its orientation. Their results found that "the long-term goals and science questions in the EDC program are appropriate", however this study was conducted over a year before the EPA announced the final structure of the screening program. The EPA is still finding it difficult to execute a credible and efficient endocrine testing program.

As of 2016, the EPA had estrogen screening results for 1,800 chemicals.

Europe

In 2013, a number of pesticides containing endocrine disrupting chemicals were in draft EU criteria to be banned. On the 2nd May, US TTIP negotiators insisted the EU drop the criteria. They stated that a risk-based approach should be taken on regulation. Later the same day Catherine Day wrote to Karl Falkenberg asking for the criteria to be removed.

The European Commission had been to set criteria by December 2013 identifying endocrine disrupting chemicals (EDCs) in thousands of products — including disinfectants, pesticides and toiletries — that have been linked to cancers, birth defects and development disorders in children. However, the body delayed the process, prompting Sweden to state that it would sue the commission in May 2014 — blaming chemical industry lobbying for the disruption.

“This delay is due to the European chemical lobby, which put pressure again on different commissioners. Hormone disrupters are becoming a huge problem. In some places in Sweden we see double-sexed fish. We have scientific reports on how this affects fertility of young boys and girls, and other serious effects,” Swedish Environment Minister Lena Ek told the AFP, noting that Denmark had also demanded action.

In November 2014, the Copenhagen-based Nordic Council of Ministers released its own independent report that estimated the impact of environmental EDCs on male reproductive health, and the resulting cost to public health systems. It concluded that EDCs likely cost health systems across the EU anywhere from 59 million to 1.18 billion Euros a year, noting that even this represented only "a fraction of the endocrine related diseases".

Environmental and human body cleanup

There is evidence that once a pollutant is no longer in use, or once its use is heavily restricted, the human body burden of that pollutant declines. Through the efforts of several large-scale monitoring programs, the most prevalent pollutants in the human population are fairly well known. The first step in reducing the body burden of these pollutants is eliminating or phasing out their production.

The second step toward lowering human body burden is awareness of and potentially labeling foods that are likely to contain high amounts of pollutants. This strategy has worked in the past - pregnant and nursing women are cautioned against eating seafood that is known to accumulate high levels of mercury. Ideally, a certification process should be in place to routinely test animal products for POP concentrations. This would help the consumer identify which foods have the highest levels of pollutants.

The most challenging aspect of this problem is discovering how to eliminate these compounds from the environment and where to focus remediation efforts. Even pollutants no longer in production persist in the environment, and bio-accumulate in the food chain. An understanding of how these chemicals, once in the environment, move through ecosystems, is essential to designing ways to isolate and remove them. Working backwards through the food chain may help to identify areas to prioritize for remediation efforts. This may be extremely challenging for contaminated fish and marine mammals that have a large habitat and who consume fish from many different areas throughout their lives.

Many persistent organic compounds, PCB, DDT and PBDE included, accumulate in river and marine sediments. Several processes are currently being used by the EPA to clean up heavily polluted areas, as outlined in their Green Remediation program.

One of the most interesting ways is the utilization of naturally occurring microbes that degrade PCB congeners to remediate contaminated areas.

There are many success stories of cleanup efforts of large heavily contaminated Superfund sites. A 10-acre (40,000 m2) landfill in Austin, Texas contaminated with illegally dumped VOCs was restored in a year to a wetland and educational park.

A US uranium enrichment site that was contaminated with uranium and PCBs was cleaned up with high tech equipment used to find the pollutants within the soil. The soil and water at a polluted wetlands site were cleaned of VOCs, PCBs and lead, native plants were installed as biological filters, and a community program was implemented to ensure ongoing monitoring of pollutant concentrations in the area. These case studies are encouraging due to the short amount of time needed to remediate the site and the high level of success achieved.

Studies suggest that bisphenol A, certain PCBs, and phthalate compounds are preferentially eliminated from the human body through sweat.

Economic effects

Human exposure may cause some health effects, such as lower IQ and adult obesity. These effects may lead to lost productivity, disability, or premature death in some people. One source estimated that, within the European Union, this economic effect might have about twice the economic impact as the effects caused by mercury and lead contamination.

The socio-economic burden of endocrine disrupting chemicals (EDC)-associated health effects for the European Union was estimated based on currently available literature and considering the uncertainties with respect to causality with EDCs and corresponding health-related costs to be in the range of €46 billion to €288 billion per year.

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