Historical Development in the Field of Toxicology

Historical Development in the Field of Toxicology And Mechanisms and Factors obligated for the Entrance of Toxi basints in the Human ashes and their malign Effects Jorge D. Rebolledo capital of South Carolina Southern University Abs folder The purpose of this paper is to make a utterly historical reference in the field of Toxicology and how this argona of science has organize starting from centuries ago until our present. It is also the intention of this paper to explain how the toxics show our be, how they argon intent and the mechanisms responsible for that. Introduction As stated by E.Monosson, rough define Toxicology as the study of toxic materials, including the clinical, industrial, economic, and legal problems associated with them. Although toxicologyas a formally recognized scientific disciplineis comparatively b be-ass (with major developments in the mid-1900s), the science itself is thousands of yrs old. Consider the potential results of wee trial and error expe riences of hunter-gatherers for whom identifying a toxic plant or zoology was a life or death situation. any(prenominal) of the most pestiferous cognitive contents cognise today argon naturally produced chemics including ricin from castor beans or tetrodotoxin from the puffer fish.Early human strains c beful observations of such plants or animals with toxic characteristics as frogs, containing cur ar, were put to use non totally for avoidance of toxic substances moreover for weaponry as well. Many naturally-derived poisons were likely employ for hunt down, as medicinal (the Egyptians were certified of many such toxic substances as lead, opium and hemlock as early as 1500 BCE). Use extended eventually to political insobrietys as practiced, for example, by the early Greeks and Romans. With time, poisons became widely used and with great sophistication.Notable poisoning victims implicate Socrates, Cleopatra, and Claudius. One of the more interesting stories resulting fro m a combination of twain ancient history and current toxicological research, is the story of King Mithridates, fagot of Pontus (120-63 BC) who according to toxicology legend was so afraid that he might be a casualty of political poisoning, is said to restrain concocted a potion from a great number of herbs for his own consumption. It is believed he understood that by overpowering belittled totalitys of potential poisons, he might protect himself from any manque pois iodinr.That is, he believed in the effectiveness of hormesis. App arently, his plans worked so well that he gained a notice for himself as one so mighty he could not be eraseed. Unfortunately, it is said that when circumstances were such that he desired to kill himself, he was unable to do so by ingesting poison and had to be run by dint of by a sword instead. Whether or not the story is true, it has led current day scientists to speculate upon the ingredients of his potion. It is believed that whatever herbs t hat he whitethorn throw away used, for example, St. Johns Wort could truly postulate contri aloneed to detoxification of some otherwise poisons. fresh studies cook demonstrated that St. Johns Wort (often used as an herbal remedy) wad accession the metabolism or tell apartdown of certain drugs and chemicals. This early story of toxicology relates a genuinely important conceptthat all animals have some kind of intrinsic ability for detoxifying a number of naturally-occurring toxi potts in undersized doses (so that, in some chemises depressive dis foundly doses of chemicals may lane through the body without make believe harm. From this we derive the concept of a chemical threshold), and that these processes can be adapted by painting to other chemicals.The question go ons as to how ace animals, including humans, are at detoxifying many of the red-hoter industrial chemicals or mixtures of industrial or industrial and natural chemicals. Additionally, it is well known that in some cases, detoxification of chemicals can produce even more toxic compounds. Pre-industrial Toxicology As declared by E. Monosson, as humans sought to better understand natural compounds that were both beneficial and harmful to them, there was very puny if any light(a) understanding of the fundamental chemical nature of substances.That is, there was no liaison between the ex piece of ground and essence of a poisonous plant or animal and any one particular chemical that might cause toxicity. In fact, an awareness of chemistry in its modern form did not occur until around the mid to late 1600s. Paracelsus, a physician from the sixteenth part century and one of the early Fathers of Toxicology believed that all matter was composed of trinity ancient bodies (sulfur, salt, and mercury). Yet, Paracelsus also coined the now famous maxim of the newly emerging discipline of toxicology All substances are poisons, there is none which is not a poison.The right dose contrastive iates a poison from a remedy. (Paracelsus, 1493-1541) This phrase and Paracelsus name are committed to memory by hundreds of new toxicology students each year and has become the motto of toxicology. Interestingly, if one takes Paracelsus at sheath value, it appears that in this cite he was referring to substances which served as potential remedies but could be poisonous if interpreted in luxuriously enough submersions. Most of us are aware of the fact that overdosing can turn remedies to poisons, even with such apparently guiltless drugs as aspirin and Tylenol.Another branch on the toxicology family tree that substantial in the sixteenth century, along with the study of drugs and the use of chemicals in hunting and war off the beaten track(predicate)e, was occupational toxicology. As humans learned how to re excise and exploit such materials as coal, and metals and other minerals, occupational scenes to these chemical substances (and chemicals produced incidentally) resulte d. Scientists eventually recognized the linkages among illnesses and exposures to these compounds. many of the first reports of occupational illness, or diseases caused by activities related to specific occupations, can be found in literature from the mid- to late-1500s. Early occupational observations hold the ill effects from lead mining and madness caused by mercury exposure (for example, the saying mad as a hatter was attributed to the uncouth use of mercury in the hat felting process). Later, in the 1700s, Bernardino Ramazzini is credited with take to light diseases of tradesmen, including silicosis in stone workers and lead poisoning.In the late 1700s, Sir Percival Potts make one of the more famous observations in toxicology, linking an occupational exposure (in this case soot in chimney sweeps) to cancer of the scrotum. At this point we have discussed the pre-Industrial Revolution developments in toxicology, that were primarily devoted to the study of such naturally-occurr ing toxicants as the polyaromatic compounds contained in soot and heavy metals, and such toxins as botulinum toxin produced by the bacterium Clostridium botulinum. Toxicology and the Chemical and Industrial RevolutionThe chemical/Industrial Revolution of the mid-19th century released many naturally-occurring chemicals into the environment in unprecedented amounts. Also, it produced and released new substances unlike any that had knowed in the natural world. With the production and use of these chemicals, and the make to protect humans from the toxic effects of industrial chemicals, toxicology eventually evolved to include its modern day branches pharmacology, pesticide toxicology, general toxicology, and occupational toxicology.Towards the mid-late 20th century, environmental toxicology was real to specifically visit the effects on both humans and wildlife of chemicals released into the environment. A notable difference among the branches of toxicology is that pharmacology, pest icides and even occupational toxicology primarily have center on the effects of comparatively postgraduate submergences of single chemicals. This compares to the relatively low submergings of several different chemicals or chemical mixtures that are relevant to environmental toxicology. The chemicals considered by the earlier branches of toxicology were, and are, a known quantity.That is, the research was designed to address questions about specific, well-characterized chemicals, exposure conditions, and even concentration ranges rather than complex chemical mixtures. For example, pharmacologists might work with a particular active ingredient (e. g. , salicylic caustic or aspirin), and be confident about the course of exposure (oral) and the concentration or dose. This is seldom the case in environmental toxicology, and hazardous absquatulate assessment and cleanup in particular, where chemicals often are present in mixtures, routes of exposure may vary (for example, from ora l to dermal to inhalation).Significantly, exposure concentrations invoke difficult to determine. Mechanisms and Factors Responsible for the Entrance of Toxicants in the Human body and their Harmful Effects density of toxicants density is the process whereby toxicants gain entrance to the body. Ingested and inhaled materials, nonetheless, are considered outside the body until they target the cubicleular barriers of the GI nerve tract or the respiratory outline. To exert an effect on inwrought organs a toxicant must be intent, although such local toxicity as irritation, may occur.Absorption varies greatly with specific chemicals and with the route of exposure. For skin, oral or respiratory exposure, the exposure dose (or, outside dose) is usually lone(prenominal) a fraction of the inattentive dose (that is, the internal dose). For substances injected or implanted straight into the body, exposure dose is the same as the absorbed or internal dose. Several factors travel th e likelihood that a foreign chemical or, xenobiotic, bequeath be absorbed. According to E. Monosson, the most important are Route of exposure Concentration of the substance at the site of contact Chemical and physiologic properties of the substance The relative roles of concentration and properties of the substance vary with the route of exposure. In some cases, a high percentage of a substance may not be absorbed from one route whereas a low amount may be absorbed via another route. For example, very little DDT powder ordain penetrate the skin whereas a high percentage will be absorbed when it is swallowed. Due to such route-specific differences in assimilation, xenobiotics are often ranked for hazard in accordance with the route of exposure.A substance may be categorized as relatively non-toxic by one route and highly toxic via another route. The primary routes of exposure by which xenobiotics can gain entry into the body are Gastro enteral tract Key in environmental exposu re to nutrient and water contaminants and is the most important route for many pharmaceuticals. Respiratory tract Key in environmental and occupational exposure to aerial toxicants and some drugs that use this route (i. e. inhalers). Skin Also an environmental and occupational exposure route.A lot of medicines are applied to the skin directly. Other routes of exposureused primarily for specific medical purposesare Injections (IV, Subcutaneous, Intradermal, Intrathecal) basically used for medications. Implants (Hormone patches) Conjunctival instillations (Eye drops) Suppositories For a toxic to enter the body (as well as ingrain indoors, and leave the body) it must pass evadewise prison cell tissue layers (cell walls). stall membranes are formidable barriers and major body defenses that prevent foreign invaders or substances from gaining entry into body tissues.Normally, cells in solid tissues (for example, skin or mucous membranes of the lung or intestine) are so tigh tly compacted that substances cannot pass between them. Entry, therefore, requires that the xenobiotic have some capability to penetrate cell membranes. Also, the substance must cross several membranes in pitch to go from one area of the body to another. In essence, for a substance to move through one cell requires that it first move crossways the cell membrane into the cell, pass crossways the cell, and then cross the cell membrane again in order to leave the cell.This is true whether the cells are in the skin, the lining of a fallline vessel, or an internal organ (for example, the liver). In many cases, in order for a substance to reach its site of toxic action, it must pass through several membrane barriers. Cell membranes surround all body cells and are basically similar in structure. They consist of 2 layers of phospho lipid molecules logical like a sandwich and also known as phospholipid bilayer. all(prenominal) phospholipid molecule consists of a inorganic phosphate head and a lipid bobsled. The phosphate head is polar so it is hydrophilic (attracted to water).In contrast, the lipid tail is lipophilic (attracted to lipid-soluble substances). The two phospholipid layers are oriented on opposing sides of the membrane so that they are approximate mirror images of each other. The polar heads face outward and the lipid tails inward. The cell membrane is tightly packed with these phospholipid moleculesinterspersed with various proteins and cholesterol molecules. most proteins span across the entire membrane providing for the constitution of aqueous channels or pores. Some toxicants move across a membrane barrier with relative ease while others meet it difficult or impossible.Those that can cross the membrane, do so by one of two general methods either resistless transfer or facilitated channelize. Passive transfer consists of simple diffusion (or osmotic filtration) and is dormant in that there is no requirement for cellular energy or assista nce. Some toxicants cannot simply diffuse across the membrane. They require assistance that is facilitated by narrow transport mechanisms. The primary types of specialized transport mechanisms are Facilitated diffusion quick transport Endocytosis (phagocytosis and pinocytosis). Passive transfer is the most common way that xenobiotics cross cell membranes.Two factors determine the rate of passive transfer Differences in concentrations of the substance on opposite sides of the membrane (substance moves from a region of high concentration to one having a lower concentration. Diffusion will preserve until the concentration is equal on both sides of the membrane) and Ability of the substance to move either through the elflike pores in the membrane or through the lipophilic interior of the membrane. Properties of the chemical substance that affect its ability for passive transfer are Lipid solvability Molecular size phase of ionization (that is, the electrical charge of an ato m) Substances with high lipid solubility right away diffuse through the phospholipid membrane. Small water-soluble molecules can pass across a membrane through the aqueous pores, along with normal intracellular water flow. volumed water-soluble molecules usually cannot make it through the small pores, although some may diffuse through the lipid portion of the membrane, but at a slow rate. In general, highly ionized chemicals have low lipid solubility and pass with difficulty through the lipid membrane.Most aqueous pores are about 4 angstrom (A) in size and allow chemicals of molecular lading 100-200 to pass through. Exceptions are membranes of capillaries and kidney glomeruli that have relatively vast pores (about 40A) that allow molecules up to a molecular angle of about 50,000 (molecules slightly smaller than albumen which has a molecular weight of 60,000) to pass through. Facilitated diffusion is similar to simple diffusion in that it does not require energy and follows a concentration gradient. The difference is that it is a carrier-mediated transport mechanism.The results are similar to passive transport but faster and heart-to-heart of moving orotundr molecules that have difficulty diffusing through the membrane without a carrier. Examples are the transport of sugar and amino acids into red blood cells (RBCs), and into the central nervous system (CNS). Some substances are unable to move with diffusion, unable to dissolve in the lipid layer, and are too life-size to pass through the aqueous channels. For some of these substances, active transport processes go in which movement through the membrane may be against the concentration gradient they move from low to higher concentrations.Cellular energy from adenosine triphosphate (ADP) is need in order to accomplish this. The transported substance can move from one side of the membrane to the other side by this energy process. officious transport is important in the transport of xenobiotics into t he liver, kidney, and central nervous system and for maintenance of electrolyte and nutrient balance. Many large molecules and particles cannot enter cells via passive or active mechanisms. However, some may enter, by a process known as endocytosis. In endocytosis, the cell surrounds the substance with a section of its cell wall.This engulfed substance and section of membrane then separates from the membrane and moves into the interior of the cell. The two main forms of endocytosis are phagocytosis and pinocytosis. In phagocytosis (cell eating), large particles suspended in the extracellular fluid are engulfed and either transported into cells or are destroyed within the cell. This is a very important process for lung phagocytes and certain liver and lien cells. Pinocytosis (cell drinking) is a similar process but involves the engulfing of liquids or very small particles that are in suspension within the extracellular fluid.Gastro enteral packet The fuck uptrointestinal tract (GI tract, the major portion of the alimentary canal) can be viewed as a tube going through the body. Its contents are considered exterior to the body until absorbed. Salivary glands, the liver, and the pancreas are considered accessory glands of the GI tract as they have ducts entering the GI tract and secrete enzymes and other substances. For foreign substances to enter the body, they must pass through the gastrointestinal mucosa, cut through several membranes before entering the blood stream.Substances must be absorbed from the gastrointestinal tract in order to exert a general toxic effect, although local gastrointestinal damage may occur. Absorption can occur at any turn out along the entire gastrointestinal tract. However, the degree of intentness is strongly site dependent. Three main factors affect engrossment within the various sites of the gastrointestinal tract Type of cells at the specific site Period of time that the substance remains at the site pH of wear or int estinal contents at the site.Under normal conditions, xenobiotics are scummyly absorbed within the speak and esophagus, delinquent mainly to the very short time that a substance resides within these portions of the gastrointestinal tract. There are some notable exceptions. For example, nicotine readily penetrates the mouth mucosa. Also, nitroglycerin is placed under the tongue (sublingual) for immediate absorption and treatment of heart conditions. The sublingual mucosa under the tongue and in some other areas of the mouth is thin and highly vascularized so that some substances will be rapidly absorbed.The yield, having high acidity (pH 1-3), is a probatory site for absorption of weak organic acids, which exist in a diffusible, nonionized and lipid-soluble form. In contrast, weak bases will be highly ionized and therefore are absorbed poorly. Chemically, the acidic stomach may break down some substances. For this undercoat those substances must be administered in jelly capsul es or coated tablets, that can pass through the acidic stomach into the intestine before they dissolve and release their contents. Another determinant that affects the amount of a substance that will be absorbed in the stomach is the presence of food.Food ingested at the same time as the xenobiotic may result in a considerable difference in absorption of the xenobiotic. For example, the LD50 for Dimethline (a respiratory stimulant) in rats is 30 mg/kg (or 30 part per million) when ingested along with food, but only 12 mg/kg when it is administered to desist rats. The greatest absorption of chemicals, as with nutrients, takes place in the intestine, particularly in the small intestine (see Figure 9). The intestine has a large come in area consisting of outward projections of the thin (one-cell thick) mucosa into the lumen of the intestine (the villi).This large surface area facilitates diffusion of substances across the cell membranes of the intestinal mucosa. Since the intestinal pH is near neutral (pH 5-8), both weak bases and weak acids are nonionized and are usually readily absorbed by passive diffusion. Lipid soluble, small molecules effectively enter the body from the intestine by passive diffusion. In adjunct to passive diffusion, facilitated and active transport mechanisms exist to move certain substances across the intestinal cells into the body, including such essential nutrients as glucose, amino acids and calcium.Also, strong acids, strong bases, large molecules, and metals (and some important toxins) are transported by these mechanisms. For example, lead, thallium, and paraquat (herbicide) are toxicants that are transported across the intestinal wall by active transport systems. The high degree of absorption of ingested xenobiotics is also due to the slow movement of substances through the intestinal tract. This slow passage increases the length of time that a compound is available for absorption at the intestinal membrane barrier. Intestinal microflora and gastrointestinal enzymes can affect the toxicity of ingested substances.Some ingested substances may be only poorly absorbed but they may be biotransformed within the gastrointestinal tract. In some cases, their biotransformed products may be absorbed and be more toxic than the ingested substance. An important example is the formation of carcinogenic nitrosamines from non-carcinogenic amines by intestinal flora. Very little absorption takes place in the colon and rectum. As a general rule, if a xenobiotic has not been absorbed after passing through the stomach or small intestine, very little further absorption will occur.However, there are some exceptions, as some medicines may be administered as rectal suppositories with significant absorption. An example, is Anusol (hydrocortisone preparation) used for treatment of local inflammation which is partially absorbed (about 25%). Respiratory Tract Many environmental and occupational agents as well as some pharmaceuticals are inhaled and enter the respiratory tract. Absorption can occur at any place within the hurrying respiratory tract. However, the amount of a particular xenobiotic that can be absorbed at a specific location is highly dependent upon its bodily form and solubility.There are three basic regions to the respiratory tract Nasopharyngeal region Tracheobronchial region Pulmonary region By far the most important site for absorption is the pulmonary region consisting of the very small stockways (bronchioles) and the alveolar sacs of the lung. The alveolar region has a very large surface area (about 50 times that of the skin). In addition, the alveoli consist of only a single layer of cells with very thin membranes that separate the inhaled air from the blood stream. Oxygen, carbon dioxide and other gases pass readily through this membrane.In contrast to absorption via the gastrointestinal tract or through the skin, gases and particles, which are water-soluble (and thus blood soluble) , will be absorbed more efficiently from the lung alveoli. Water-soluble gases and liquid aerosols can pass through the alveolar cell membrane by simple passive diffusion. In addition to solubility, the ability to be absorbed is highly dependent on the physiologic form of the agent (that is, whether the agent is a gas/vapor or a particle). The physical form determines penetration into the deep lung.A gas or vapor can be inhaled deep into the lung and if it has high solubility in the blood, it is almost completely absorbed in one respiration. Absorption through the alveolar membrane is by passive diffusion, following the concentration gradient. As the agent dissolves in the circulating blood, it is taken away so that the amount that is absorbed and enters the body may be quite large. The only way to increase the amount absorbed is to increase the rate and erudition of breathing. This is known as ventilation-limitation.For blood-soluble gases, equilibrium between the concentration o f the agent in the inhaled air and that in the blood is difficult to achieve. Inhaled gases or vapors, which have poor solubility in the blood, have quite limited capacity for absorption. The reason for this is that the blood can become quickly saturated. Once saturated, blood will not be able to accept the gas and it will remain in the inhaled air and then exhaled. The only way to increase absorption would be to increase the rate of blood supply to the lung.This is known as flow-limitation. Equilibrium between blood and the air is reached more quickly for relatively insoluble gases than for soluble gases. The absorption of airborne particles is usually quite different from that of gases or vapors. The absorption of solid particles, regardless of solubility, is dependent upon particle size. Large particles (5 M) are generally deposited in the nasopharyngeal region ((head airways region) with little absorption. Particles 2-5 M can penetrate into the tracheobronchial region. Very smal l particles (