In this essay we will discuss about Essay on Toxicology:- 1. Introduction to Toxicology 2. Definition of Toxicology 3. Earlier Developments 4. Relationship to other Sciences 5. Scope 6. Environmental Toxicology 7. Language 8. Portals of Entry of a Toxin 9. Distribution of a Toxin 10. Metabolism of a Toxin 11. Sites of Action of a Toxin 12. Excretion of Toxin 13. Nature of Toxic Effects 14. Modern Toxicology.
- Introduction to Toxicology
- Definition of Toxicology
- Earlier Developments in Toxicology
- Relationship of Toxicology to other Sciences
- Scope of Toxicology
- Environmental Toxicology
- Language of Toxicology
- Portals of Entry of a Toxin
- Distribution of a Toxin
- Metabolism of a Toxin
- Sites of Action of a Toxin
- Excretion of Toxin
- Nature of Toxic Effects
- Modern Toxicology
Essay # 1. Introduction to Toxicology:
Science of Toxicology, deals with the study of interactions between chemicals and biological systems in order to quantitatively determine the adverse effects in living organisms and investigate the nature, incidence, mechanism of production, factors influencing their development and reversibility of such adverse effects. In formal terms, it appears to be a young science, however, it was conceptualized by a physician known as Paracelsus. Borzellaca (2000) honoured Paracelsus as herald of modern toxicology.
Paracelsus, Philippus Theophrastus Aureolus Bombastus von Hohenheim, the “father of Chemistry and the reformer of “materia medica”, the “Luther of Medicine”, the “godfather of modern chemotherapy”, the founder of medicinal chemistry, the founder of modern toxicology, a contemporary of Leonardo da Vinci, Martin Luther, and Nicholas Copernicus, was born near or in the village of Einsiedeln near Zurich, Switzerland on 10 or 14 November, 1493. Paracelsus studied at a number of Universities in Europe & conferred doctorate in 1516 from the University of Ferrara. It was at this time that he assumed the name Paracelsus (Para- beside, beyond and celsus- a famous Roman physician).
Paracelsus discounted the humoral theory of Galen who postulated that balance amongst four humors in the body (blood, phlegm, yellow and black bile) is essential for health. Paracelsus believed in three humors- salt (representing stability), sulfur (representing combustibility) and mercury (representing liquidity).
He defined disease as a separation of one humor from the other two. He propounded the principle of simplitude meaning that “a poison in the body will be cured by a similar poison”. He introduced chemistry into medicine. He extended his interest in chemistry and biology to what we now consider toxicology. Basic tenets of Paracelsianism were summed up by Temkin and Coworkers (1996).
Since then, toxicological developments have witnessed new heights. War and prospects of war played a great role in the development of toxicology. In “world war I”, a variety of chemicals were used in the battlefields of France. Occupational toxicology originated in 19th century as a product of industrial revolution.
Development of chemical and pharmaceutical industries in 19th and 20th century gave birth to regulatory toxicology. Increasing concerns for consumer and environmental health during last three decades brought toxicology to the age of Science. World War II offered stimulus to the evolution of Environmental Toxicology.
Essay # 2. Definition of Toxicology:
Toxicology can be defined quite simply as the branch of science dealing with poisons. Broadly speaking, a poison is any substance causing harmful effects in an organism to which it is administered, either deliberately or by accident. Clearly, this effect is closely related since any substance, at a low enough dose, is without effect, while many, if not most, substances have deleterious effects at some higher dose.
Much of toxicology deals with compounds exogenous to the normal metabolism of the organism. Such compounds are referred to as foreign compounds or more recently, as xenobiotics. However, many compounds endogenous to the organism e.g., metabolic intermediates such as glutamate, and hormones such as thyroxine, are toxic when administered in unnaturally high doses.
Similarly, trace elements such as selenium, which are essential in the diet in low concentrations, are frequently toxic at higher levels. Whether the harmful effects of physical phenomena such as irradiation, sound, temperature, and humidity are included in toxicology, appear to be largely dependent on the preference of the writer, it is convenient, however, to include them under the broad definition of toxicology.
The method of assessing toxic effects is another parameter of considerable complexity. Acute toxicity, usually measured as mortality and expressed as the LD50– the dose required to kill 50% of a population of the organism in question under specified conditions- is probably the simplest measure of toxicity.
Even so, reproducibility of LD50 values is highly dependent upon the extent to which many variables are controlled. These include the age, sex, and physiological condition of the animals, their diet, the environmental temperature and humidity, and the method of administering the toxicant.
Chronic toxicity may be manifested in a variety of ways – carcinomas, cataracts, peptic ulcers, and reproductive effects, to name only a few. Furthermore, compounds may have different effects at different doses. Vinyl chloride, a potent hepatotoxic at high doses, is a carcinogen with a very long latent period at low doses.
Most drugs have therapeutic effects at low doses but are toxic at higher levels. The relatively nontoxic acetylsalicylic acid (aspirin) is a useful analgesic at low doses, is toxic at high doses, and may cause peptic ulcers with chronic use.
Considerable variation also exists in the toxic effects of the same compound administered to different animals, or even to the same animal by different routes. The insecticide Malathion has a low toxicity to mammals, whereas it is toxic enough to insects to be a widely used commercial insecticide. The route of entry of toxicants into the animal body is frequently oral, in the food or drinking water in the case of many chronic environmental contaminants such as lead or insecticide residues, or directly as in the case of accidental or deliberate acute poisoning.
Other routes for non-experimental poisoning include dermal absorption and pulmonary absorption. The above routes of administration are all used experimentally, and in addition, several types of injection are also common -intravenous, intraperitoneal, intramuscular, and subcutaneous. The toxicity of many compounds varies tenfold or greater depending upon the method of administration.
Essay # 3. Earlier Developments in Toxicology:
Soon the nature and magnitude of toxic effects were studied. Factors viz.- physicochemical properties of the substance, its bioconversion, the conditions of exposure, and the presence of bio-protective mechanisms subsequently dominated the scene.
Morphological and biochemical injury produced by a toxin was classified as inflammation, necrosis, enzyme inhibition, biochemical uncoupling, lethal synthesis, lipid peroxidation, covalent binding, receptive interaction, immune mediated hypersensitive reactions, genotoxicity, developmental and reproductive toxicity and pharmacological effects.
In 1848, Blake in the United States published his opinion that the biological activity of a salt was due to its basic or its acidic component and not to be whole salt; as with lead nitrate it was the lead moiety and not the acetate or nitrate part. This was, for 1st time, a daring thought, because it was not until 1884 Arrhenius introduced his theory of electrolytic dissociation.
The Scottish authors Crum Brown and Fraser (1869) made a major discovery. They wrote, “there can be no reasonable doubt that a relation exists between the physiological action of a substance and its chemical composition and constitution”, understanding by the latter term, the mutual relations of the atoms in the substance.
This discovery was the first to show structure-action relationship at the turn of present century. Ernest Overton and Hans Meyer independently put forward a, “Lipoid theory of cellular Depression”. This stated that chemically inert substances exert depressant properties on cells (particularly those of central nervous system) that are rich in lipids and that higher the partition coefficients, the greater the depressant action.
The idea that drugs act upon receptors began with John Langley in (1878) in Cambridge. Later, Langley coined the term ‘receptive substances’. Paul Ehrlich was already using the term receptor in Germany. In his Noble prize address Ehrlich outlined the receptor as a small chemically defined area, which was normally occupied with the cell’s nutrition and metabolism but which could take up specific antigens or drugs instead.
First the idea of receptor was received with skepticism because of repeated failure to isolate any such substance. However, the idea of receptors became more firmly established by the work of Alfred Clark who showed that combination of drug with a receptor quantitatively followed the law of mass action. He summed up his work in a monograph, a few years before his death in 1941.
The period of Second World War (1939-1944) was a turning point in the study of structure action relationship.
There was a period when dose response relationships were highly predominant. Development of physiology and biochemistry also influenced the growth of toxicology. Metabolism of substances was conveniently classified as phase – I and phase – II reactions.
Concept of QSAR:
The concept of QSAR (quantitative structure activity relationships) was applied to study the toxicity of inorganic cations. While molecules of organic compounds reflect their properties as a whole, the inorganic compounds dissociate in various degrees and properties have thus to be attributed to anions, cations or un-dissociated molecules.
Inorganic cations can form complexes with inorganic or organic ligands contributing new properties to the complex. Components of this system (cations, anions, un-dissociated molecules) could mutually influence each other depending upon the ratio amongst components. Quantitative relationships between a chemical structure of the complex and the biological activity formed a new line of action in toxicology.
QSAR studies generated the concept of molecular connectivity in order to characterize the organic biologically effective substances. The index of connectivity is deduced from the numeric evaluation of the extent of branching of chemical bonds in the section of the molecule. There exists a correlation between the connectivity index and toxicity of cations.
Essay # 4. Relationship of Toxicology to other Sciences:
Toxicology is frequently said to be a branch of pharmacology, a science that deals primarily with the therapeutic effects of exogenous substances and with all the chemical and biochemical ramifications involved in those effects. Since the therapeutic dose range of pharmacological compounds is usually quite small, and most of these compounds are toxic at higher doses, it may be more appropriate to consider pharmacology a branch of toxicology.
Toxicology is clearly related to the two applied biology-medicine and agriculture. In the former, clinical diagnosis and treatment of poisoning as well as the management of toxic side effects are areas of significance, while in the latter the development of agricultural biocides such as insecticides, herbicides, nematicides, and fungicides is of great importance.
The detection and management of the off-target effects of such compounds is also an area of increasing importance that is essential to their continued use. Toxicology may also be considered an area of fundamental biology since the adaptation of organisms to toxic environments has important implications for ecology and evolution.
The tools of chemistry and chemical biology since the adaptation of organisms to and progress in toxicology are closely related to the development of new methodology. Those of chemistry provide analytical methods for toxic compounds, particularly for forensic toxicology and residue analysis, and those of biochemistry provide the techniques to investigate the metabolism and mode of action of toxic compounds.
On the other hand, studies of the chemistry of toxic compounds have contributed to fundamental organic chemistry, and studies of the enzymes involved in detoxication and toxic action have contributed to our basic knowledge of biochemistry.
Toxicology in the most general sense may be one of the oldest practised sciences. From his earliest beginnings, man must have been aware of numerous toxins such as snake venoms and those of poisonous plants. From the earliest written records it is clear that the ancients had considerable knowledge of poisons.
The Greeks made use of hemlock as a method of execution, more particularly, the Romans made much use of poisons for political and other assassinations. Indeed, it was Dioscorides, a Greek at the court of Nero, who made the earliest known attempt to classify poisons.
Although poisoning has enjoyed a considerable vogue at many times and places, the scientific study of toxicology can probably be dated from Paracelsus, who in the sixteenth century, put forward the necessity for experimentation and included much in his range of interests that would today be classified as toxicology.
The modem study of toxicology is usually dated from the Spaniard, Orfila (1787- 1853), who, at the University of Paris, identified toxicology as a separate science. Among his many contributions, he devised chemical methods for the detection of poisons and stressed the value of chemical analysis to provide legal evidence. He was also the author, in 1815, of the first book devoted entirely to the toxic effects of chemicals.
Toxicology can be subdivided in a variety of ways. Loomis refers to the three “basic” subdivisions as environmental, economic, and forensic. Environmental toxicology is further divided into such areas as pollution, residues, and industrial hygiene; economic toxicology is said to be devoted to the development of drugs, food additives, and pesticides; and forensic toxicology is concerned with diagnosis, therapy, and medicolegal considerations. Clearly, these categories are not mutually exclusive; for example, the off target effects of pesticides are considered to be environmental, while the development of pesticides is economic.
Environmental toxicology is the most rapidly growing branch of science. Public concern over environmental pollutants and their possible chronic effects, particularly carcinogenicity, has given rise, in the United States, to new research and regulatory agencies and recently to the Toxic Substances Control Act.
Similar developments are also taking place in many other countries. The range of environmental-pollutants is enormous, including industrial and domestic effluents, combustion products of fossil fuels, agricultural chemicals, and many other compounds that may be found in food, air, and water. Such compounds as food additives and cosmetics are also being subjected to the same scrutiny.
Other sub-specialties are frequently mentioned that do not fit into the above divisions. Behavioral toxicology, an area of increasing importance, could be involved in any of these and is usually treated as a separate sub-speciality. Analytical toxicology provides the methods used in essentially every branch of the subject, while biochemical toxicology, provides the fundamental basis for all branches of toxicology.
Like any other specialized field, environmental health has its own language. Some of the terms may need a few words of introduction.
Toxic, a central concept simply means capable of causing illness. The types of illnesses caused by environmental toxins are conventionally divided into acute and chronic. Acute illness are those which appear soon after exposure to a toxic compound, last for a relatively short time, and then resolve themselves, even if the resolution is in death.
The term sub-acute is also occasionally used to describe disorders with subtle symptoms that are not immediately obvious without special tests. Lead workers, for example, often appear to be much healthier than a thorough medical examination reveals them to be Chronic illnesses, by contrast, that may appear years or even decades after exposure, and which may “remain”, unresolved, for the victim’s lifetime.
There are three special kinds of toxic hazards that have special relevance to environmental health: carcinogens, mutagens and teratogens. As most of us know, a carcinogenic substance is one that causes cancer. A mutagenic substance is one that causes changes in the genetic material of a cell. Spontaneous, natural mutations occur in our body cells all the time; the vast majority of them cause no damage, and even when they do it is usually limited to the lifetime of the cell they occur in.
But in rare cases the cell may continue to grow and divide after a mutagen has altered its basic genetic structure, and if this mutation is passed on to succeeding generations via egg or sperm, it may cause birth defects, inherited diseases, mental deficiency, increased susceptibility to disease, and a host of other abnormalities and disorders. If the mutated genes are recessive, it may take more than one generation for these effects to show up.
Mutagenicity and carcinogenicity are related in some way, but were not yet sure just how. Radiation is probably the best-known example of a mutagenic environmental hazard.
Contamination is measured in terms of the concentration of a substance in the environment, and there are a number of different conventions governing the measurement of concentration. The most common system makes use of metric units, particularly the milligram (one-thousandth of a gram, abbreviated mg) and the microgram (one million of a gram, abbreviated Ì g). Occasionally, in very refined, ultrasensitive measurements, nanograms (one-billionth of a gram), picograms (one- trillionth of a gram), and even smaller units may be used.
Obviously, a contaminant concentration of one milligram per kilogram is the same as one part of contaminant per million parts of non-contaminant, or 1 ppm, and this alternative method of indicating relative concentrations is also widely used, particularly for air pollutants, food additives, and pesticides residues. The terms ppm and ppb (parts per billion) are common- ppt (parts per trillion) appears only rarely.
Exposure is a way of saying that the contamination in the environment has passed into an organism; a human being is exposed to a toxic compound if some amount of it has entered his or her body. Exposure does not mean that a person has merely been in the proximity of a toxic substance.
For example, if you walk past a drum bearing a warning label and containing a toxin, you are not necessarily exposed to whatever it contains. But if the drum leaks its contents into the air or soil, and pollutes the air you breathe or the water you drink, you probably will be exposed to its contents.
Like illnesses, exposures may also be subdivided into acute and chronic types. Acute exposures are those that occur over short periods of time, often to high concentrations of a hazardous substance. Chronic exposures, which are much more common among the general public, involve longer periods of time and for the most part, lower concentrations. Dose is the term for measuring exposures.
Basically, the dose a person exposed to a toxic substance receives is dependent on its concentration in the immediate environment and the duration of the exposure. However, because the interaction of human beings and the environment is a complex, constantly changing process, numerous other factors may also play a part in determining dose.
Dose can be a function of weather conditions, the persistence and solubility of the toxic substance in the biosphere, the size of its molecules or particulates, the presence of other compounds in the environment that it may react with, the age and overall health of the exposed individual, whether the substance is inhaled, swallowed, or absorbed through the skin, and the effectiveness of the body’s natural defenses in detoxifying the substance and eliminating it from the body.
Some substances, like asbestos, become virtually permanent contaminants in the body once they have penetrated far enough into the lungs or other organs. Others, such as methanol, are metabolized and excreted from the body in a matter of hours at most.
The tendency for some substances to collect in the tissues of a living organism and stay there is known as bioaccumulation. Their tendency to move up the food chain as one species consumes another, becoming ever more concentrated as they go, is called biomagnification.
Traditionally a threshold was a measurable level of exposure to a toxic substance below which there would probably be no adverse health effect and above which there probably would be. The setting of safety standards for the work site as well as the general environment often involves the assumption that approximate thresholds can be determined, monitored and enforced for the toxin in question.
But this assumption has been subjected to various criticisms in the past few decades. First, it is often pointed out that, whether we can measure it or not, it is entirely possible that every molecule of every substance we take into our bodies has some effect on us. It may not be a detectable effect and it may not be harmful or long lasting, but it is an effect.
Thus, this argument goes, the concept of a specific cutoff point below which a substance is treated as though it didn’t exist and above which it is considered harmful is misleading. Far more appropriate, proponents of this view argue, is the assumption that these substances have a range of effects, beginning at once end with those that are imperceptibly molecular and extending to the catastrophically toxic, ultimately fatal effect at the other end of the spectrum.
An LD50 is customarily expressed in terms of milligrams per kilogram of body weight. Thus, a substance whose LD50 is 2 mg/kg is five times as toxic as one whose LD50 is 10 mg/kg. In general, substances with LD50 values below 50 mg/kg are considered highly toxic. Those with values between 50 and 500 mg/kg are considered moderately toxic, and those with values above 500 mg/kg are regarded as less toxic.
The principal portals of entry are the skin, the gastrointestinal tract, and the lungs. The fact is stressed that in all cases the toxicant must pass through a number of biological membranes before it can be distributed throughout the body and that uptake depends on the nature of the membranes as well as the physical properties of the toxicant.
The structure of cell membranes, basically bimolecular lipid leaflets with associated proteins, and their various modifications are presented in some detail since their nature is responsible for the fact that lipophilicity is the most important determinant of the rate of uptake of exogenous molecules. Active transport, pinocytosis etc. are much less common than diffusion across the lipid membranes.
The insect, with its waxy epicuticle and plants, with a waxy cuticle and a stomatal system represent important special examples of entry of a toxin.
Various factors responsible for the distribution of toxicants throughout the body need discussion. This is primarily concerned with the binding of toxicants to blood proteins particularly lipoproteins. Lipoproteins are an important class of protein, particularly in the vascular fluids.
They vary in molecular weight from 200,000 to 10,000,00 and the lipid content varies from 4% to 95%, being composed of triglycerides, phospholipids, and free and esterified cholesterol. Although they are classified into groups based on their flotation constants, each group is, in fact, a mixture of many similar lipoproteins.
The nature and importance of various types of ligand-protein interactions are assessed, including covalent binding, ionic binding, hydrogen bonding, Vander Waals forces, and hydrophobic interactions. Many of the same binding forces are also important in toxicant receptor interactions.
It deals with the mathematical approach to the distribution of toxicants, or toxicokinetics. It provides a simplified, but still mathematically rigorous, treatment of distribution data, including both analysis and the formulation of mathematical models.
The majority of xenobiotics that enter the body do so because they are lipophilic. The metabolism of xenobiotics, which is carried out by a wide range of relatively nonspecific enzymes, serves to increase their water solubility and make possible their elimination from the body. This process consists of two phases. In phase I, a reactive polar group is introduced into the molecule, rendering it a suitable substrate for phase II reactions.
Phase I reactions include the well-known cytochrome P450 -dependent mixed-function oxidations as well as reductions, hydrolyses, etc. Phase II reactions include all the conjugation reactions in which a polar group on the toxicant is combined with an endogenous compound such as glucuronic acid, glutathione etc. to form a highly water- soluble conjugate that can be eliminated from the body.
It should be pointed out at this early stage that these metabolic reactions are not all detoxications since many foreign compounds are metabolized to highly reactive products that are responsible for their toxic effect. These include the activation of carcinogens and hepatotoxic cants.
Although the liver is the most studied organ with regard to xenobiotic metabolism, several other organs are known to be active in this respect, although neither the specific activity nor the range of substrates metabolized is as large as in the liver.
These organs include the lungs and the gastrointestinal tract, as one might expect of organs that are important site for the entry of xenobiotic into the body, and to a lesser extent, the other important portal of entry, the skin. Other organs, such as the kidney, may also be important sites for xenobiotic metabolism.
Because toxicants are both activated and inactivated metabolically, physiological factors affecting metabolic rates can have dramatic effects on the expression of toxicity. These effects, including age, sex, pregnancy, and diet need to be considered.
Comparative toxicology is of considerable importance from the point of view of selectivity, resistance to toxic action, and environmental studies of toxicants, as well as of some academic importance from the evolutionary viewpoint.
Although only a few generalizations can be made on the basis of phylogenetic relationships, there have been many comparisons between species of toxicological interest.
Foreign compounds can be substrates, inhibitors, inducers of the enzymes that metabolize them and, not infrequently, serve in more than one of these roles. Since the enzymes in question are nonspecific, numerous interactions between foreign compounds are possible.
These may be synergistic or antagonistic and may have a profound effect on the expression of toxicity. Depending upon the compounds and the enzymes involved in a particular interaction, the effect can be an increase or a decrease in either acute or chronic toxicity. The basic principles of such interactions are summarized.
The cell type that has been studied most intensively in biochemical toxicology is the hepatocyte, the cell that forms the bulk of the liver. These cells are highly active metabolically, both in normal intermediary metabolism and in reactions involving xenobiotics. The principal cell organelles shown in the diagram play of important sole in biochemical toxicology.
The nucleus, the chromosomes that contain DNA responsible for most of the proteins synthesized in the cell, is the site for the primary reaction of carcinogenesis, since carcinogens react with DNA. Depending upon the toxicant, the organ, and the cell type involved, similar reactions are involved in mutagenesis and teratogenesis. The nuclear envelope has recently been shown to have an active aryl hydrocarbon hydroxylase system.
Mitochondria are the site of electron transport and oxidative phosphorylation pathways that provide sites for the action of many acute toxicants.
The endoplasmic reticulum exists in two forms- rough, which is associated with protein synthesis, and while both rough and smooth are active in the oxidation of xenobiotics, the latter usually has the highest specific activity. After, disruption of the cells, followed by differential centrifugation, the two types are isolated as rough and smooth microsomes.
Compounds of intrinsic toxicity and active metabolites produced in the body ultimately arrive either at a site of action or an excretory organ. Although almost any organ can show the effects of toxicity, some are more easily affected than others by particular classes of toxicants, and some have been studied in greater detail than others. In all cases, however, toxicant-receptor interactions are important. Acute toxicants tend to affect either oxidative metabolism, the synapses of the nervous system, or the neuromuscular junction. Toxic effects on the central nervous have been widely studied.
The commonest modes of chronic toxicity involve interaction with nucleic acids, causing carcinogenesis or reproductive effects. Although specific organ damage is known for several toxicants, the central role of the liver in studies of toxic action is acknowledged.
While toxicants can be classified in many ways, based either on natural distribution, commercial use patterns, or chemistry, only two such groups viz.- metals and pesticides.
Many metabolic pathways are affected by toxicants. They include glycolysis, the tricarboxylic acid cycle, the pentose cycle, the electron transport system and oxidative phosphorylation, nucleic acid synthesis, protein synthesis, and many others, as well as such specialized systems as photosynthesis in plants. In vivo testing for chronic toxicity in animals and short-term mutagenicity tests are both somewhat remote from a strictly biochemical treatment of the mechanisms involved in toxicology.
Either the un-metabolized toxicants or their metabolic products are ultimately excreted, the latter usually as conjugated products resulting from phase II reactions. The two primary routes of excretion (the urinary system and the biliary system), minor routes also (such as the lungs, sweat glands, sebaceous glands, hair, feathers, and nails) and sex related routes (such as milk, eggs, and fetus) constitute the routes of excretion.
The nature and magnitude of a toxic effect depend on many factors, amongst which are the physicochemical properties of the substance, its bioconversion, the conditions of exposure, and the presence of bio-protective mechanisms. The last factor includes physiological mechanisms such as adaptive enzyme – induction, DNA repair mechanisms and phagocytosis.
Some of the frequently encountered types of morphological and biochemical injury constituting a toxic response are listed below. They may take the form of tissue pathology, aberrant growth processes, altered or aberrant biochemical pathways or extreme physiological responses.
Inflammation is a frequent local response to irritant chemicals or may be a component of systemic tissue injury. The inflammatory response may be acute with irritant or tissue damaging materials, or chronic with repetitive exposure to irritants or the presence of insoluble particulate material. Fibrosis may occur as a consequence of the inflammatory process.
Necrosis, used to describe circumscribed death of tissues or cells, may result from a variety of pathological processes induced by chemical injury, e.g. corrosion, severe hypoxia, membrane damage, reactive metabolite binding, inhibition of protein synthesis and chromosome injury.
With certain substances, differing patterns of zonal necrosis may be seen. In the liver, for example, galactosamine produces diffuse necrosis of the lobules, acetominophen (paracetamol) mainly centrilobular necrosis and certain organic, arsenicals peripheral lobular necrosis.
Enzyme Inhibition by chemicals may inhibit biologically vital pathways, producing impairment of normal function. The induction of toxicity may be due to accumulation of substrate or to deficiency of product or function.
For example, organophosphate anticholinesterases produce toxicity by – accumulation of acetylcholine at cholinergic synapses and neuromuscular junctions. Cyanide inhibits cytochrome oxidase and interferes with mitochondrial oxygen transport, producing cytotoxic hypoxia.
Biochemical uncoupling agents interfere with the synthesis of high- enephosphate molecules, but electron transport continues resulting in excess liberation of energy a heat. Thus, uncoupling produces increased oxygen consumption and hyperthermia. Examples of uncoupling agents are dinitrophenol and pentachlorophenol.
Lethal synthesis occurs when foreign substances of close structural similarity to normal biological substrates become incorporated into biochemical pathways and are then metabolized to a toxic product. A classical example is fluoroacetate, which becomes incorporated in the Kreb’s cycle as fluoroacetyl coenzyme A, which combines with oxaloacetate to form fluorocitrate. The latter inhibits aconitase, blocking the tricarboxylic acid various system toxicity.
Lipid peroxidation in biological membranes by free radicals starts a chain of events causing cellular dysfunction and death. The complex series of events includes oxidation of fatty acids to lipid hydro-peroxides which undergo degradation to various products, including toxic aldehydes. The generation of organic radicals during peroxidation results in a self-propagating reaction.
Carbontetrachloride, for example, is activated by a hepatic cytochrome P450-dependent mono-oxygenase system to the trichloromethyl and trichloromethyl peroxy radicals; that covalently bind with macromolcules and the latter initiates the process of lipid peroxidation leading to hepatic centrilobular necrosis. The zonal necrosis is possibly related to high cytochrome P450 activity in centrilobular hepatocytes.
Covalent binding of electrophilic reactive metabolites to nucleophilic macromolecules may have a role in certain genotoxic, carcinogenic, teratogenic and immunosuppressive events. Important cellular defence mechanisms exist to moderate these reactions, and toxicity may not be initiated.
Receptor interaction at a cellular or macromolecular level, with specific chemical structures may modify the normal biological effect mediated by the receptor, these may be excitatory or inhibitory. An important example is effects on Ca channels.
Immune-mediated hypersensitivity reactions by antigenic materials are particularly important considerations for skin and lung resulting in allergic contact dermatitis and asthma, respectively.
Immunosuppression by xenobiotics may have important repercussions in increased susceptibility to infective agents and certain aspects of tumorigenesis.
Neoplasia, resulting from aberration of tissue growth and control mechanisms of cell division, and resulting in abnormal proliferation and growth, is a major consideration in repeated exposure to xenobiotics.
The terms tumorigenesis and oncogenesis are general words used to describe the development of neoplasms; the word carcinogenesis should be restricted specifically to malignant neoplasms. In experimental and epidemiological situations, oncogenesis may be exhibited as an increase in specific types of neoplasm, the occurrence of rare, or unique neoplasms or a decreased latency to detection of neoplasm.
The preceding description of the nature and scope of biochemical toxicology should make it clear that the biochemistry of toxic action is a many-faceted subject, covering, all aspects from the initial environmental contact with a toxicant to its ultimate excretion back into the environment.
Essay # 14. Modern Toxicology:
In recent years, toxicology has developed from an activity relying principally on the tools of classical pathology to observe and classify harmful effects so as to become a discipline of increasing ability to explain the effects of toxic compounds in molecular and mechanistic terms.
Over the last several years, it has become apparent that many environmental toxicants exert their effects by the action or disruption of specific signaling pathways, ultimately resulting in alterations in gene expression. With the completion of the human genome project and the advent of many powerful new technologies, there has been a revolution in our understanding of these mechanisms at molecular level.
Toxicant-induced alterations in gene expression depend on receptors. Four receptors namely the Ah receptor (AhR, the constitutive Androstone Receptor (CAR), the Pregnane X Receptor (PXR), and the peroxisome Proliferator Activated Receptor (PPAR) mediate the toxicity of four broad classes of chemicals.
In contrast to these specific receptor mechanisms, metals exert their toxicity through both stress response pathways and specific metal responsive transcription factors. Role of tissue selective transcription factors on the expression of xenobiotic metabolizing enzymes is now being investigated in several laboratories.
Recent developments show that toxicology is not merely a study of the effects of a variety of poisons in animals, plants and man but a multidisciplinary science embracing pathology, pharmacology, cell biology, biochemistry and public health.
While dwelling with the subject for about three decades, I could witness the sustained progress made by science of toxicology. Earlier developments got smoothly integrated into modern concepts of toxicology. This communication is an attempt to review the present status of toxicology.
It is broadly defined as gene and protein expression technology that addresses pertinent issues of toxicology. The term genome has been traditionally used to define the haploid set of chromosomes in the nuclei of multicellular organisms. The study of genome is referred as genomics. The patterns by which genes and their protein products act in concert to affect function is known as functional genomics.
Certain environmental stimuli will perturb the normal cellular functions of proteins and cause changes in gene expression. These kinds of environmental factors can also lead to the pathology of disease. Often the development of disease will be the result of complex mix of factors including inherent genetic susceptibility and a series of environmental changes or challenges.
The term proteome was coined in 1994 by Mark Wilkins. It refers to total protein repertoire able to be expressed from a given genome. A proteome of a cell, tissue, or organ is not only different, it can express differently under particular set of conditions. Thus toxicogenomics appear challenging.
ii. Metabonomic Technology:
Toxicants by definition, disrupt the normal composition and flux of endogenous biochemical in, or through, key intermediate cellular metabolic pathways. These disruptions, either directly or indirectly, alter the blood that percolates through the target tissues. The diagnostic utility of any one trace biomolecule is limited by the number of variables affecting its concentration in situ and by the common biochemical processes disrupted by toxicants.
However, if a significant member of trace molecules is monitored, the overall pattern or “fingerprint” produced may be more consistent and protective than any other marker. This comprehensive information can be obtained from high field nuclear magnetic resonance (NMR) spectroscopy coupled with pattern recognition technology.
Magic angle spinning NMR technology enables similar information to be garnered from tissues as well. Temporal evaluation of metabolic consequences of toxicity, coupled with genomic and proteomic technologies and metabolomics permit complete assessment of toxicity from genotype through phenotype.
Pharmacogenetics, a term originally coined in the 1950s may now be viewed as the study of correlations between an individual’s genotype and the same individuals’ ability to metabolize an administered drug or compound.
Genotypic variations, often in the form of single nucleotide polymorphism (SNPs), exist for many of the enzymes that metabolize drugs/chemicals. Extensive metabolism of a drug is a general characteristic of the normal population.
Poor metabolism which typically is associated with excessive accumulation of specific drugs or active metabolic products is a recessive trait requiring a functional change, such as frame shift or splicing defect in both copies of the relevant gene.
Ultra-extensive metabolism which may have the effect of diminishing a drug, apparent efficacy in an individual, is generally an autosomal dominant state derived from a gene duplication or amplification. For example in cancer chemotherapy, several common drugs show wide polymorphism related metabolic variations with 30 fold or greater inter-individual variability.
iv. Molecular Toxicology:
Apoptosis is a natural consequence in vivo and there is now substantial evidence that apoptosis plays an important role in the toxic effects of a number of drugs and chemicals. Numerous coherent pathways regulate cell suicidal process.
Target organ toxicities, target organ apoptogenic drugs and chemicals, regulation of apoptosis at organs, cellular and subcellular and molecular levels emerges a new discipline. Since oxidative stress, caspases, caspase activated DNAse, reactive oxygen species, mitochondrial and cell cycle related events are known to modulate this process, their respective roles are under investigation in several laboratories.
In-excitable and non-excitable tissues are the direct and indirect targets of many xenobiotics that produce apoptotic and necrotic cell death. Determination of the temporal and sequential relationships between the opening of the mitochondrial permeability transition (PT) pore, mitochondrial depolarization and swelling, cytochrome C release and caspase activation during cell death are critically important.
In toxicology, understanding the role and molecular mechanisms of PT pore opening will allow the development of pharmacological and genetic strategies to prevent inappropriate apoptosis as well as to initiate and control the apoptotic process for therapeutic purposes. The current evidence suggests that the PT pore is a complex of the voltage dependent anion channel (VDAC), adenine nucleotide translocase (ANT) and cyclophilin-D (CyP-D), formed at connect sites between the inner and outer mitochondrial membranes.
v. Concept of Biomarkers:
The emergence of specific biomarkers offer the promise of being able to measure signals and/or events that reflected more accurately the biology associated with exposure, effects, and susceptibility. The 1983 NRC publication formalized human health risk assessment into a four component process namely exposure, assessment, hazard identification, dose response assessment and risk characterization.
Biological rhythms are toxicologically important because they have a positive or negative effect on all measures of normal physiological functions, and health of the individual. Circadian patterns affect the absorption of drug/toxin. Once the drug/toxin has been absorbed, it is transported to its tissue/target sites and its elimination sites. Large circadian variations have been shown in humans and rats in plasma proteins binding of a variety of drugs.
In addition, drug/toxin transport can occur by their binding to red blood cells. In general, lipophilic materials pass into blood cells more rapidly than hydrophilic materials. Circadian variation with respect to drug permeability of the blood-brain barrier is of interest. Circadian rhythms in heavy metal toxicology have been described for mercury and cadmium.
The level of liver microsomal benzene hydroxylase activity is highest at a particular time of the day. Carcinogenicity and teratogenicity of chemicals have also been found to be affected by circadian rhythms.
Circadian time structure is not routinely considered in toxicity testing in human or preclinical (rodent) models. Actually, they are not the only rhythms which modulate the outcome following drug or chemical exposure. Other cycles, such as fertility cycle and seasonal cycles markedly and reproducibly alter toxicity profiles.
In summary, considering toxicology in the absence of these three factors within the biological time structure of living animals seems to be uneconomical, misleading and unwise.
It is now well recognized that human environmental exposures are not to single chemical. Rather humans are exposed concurrently or sequentially to multiple chemicals, by various routes of exposure and from a variety of sources. The process of carcinogenesis can be modified significantly by other chemicals. The term co-carcinogenesis was initially defined as the enhancement of neoplasm induction brought about by new carcinogenic factors, which act in conjunction with an initiating carcinogen.
Whereas the additive or synergistic effects of two or more carcinogens in neoplasm production has been defined as syn-carcinogenesis. When the toxic responses grossly exceed the expected response after an ideal substantial, the process is called as superinteraction. An important example of an environmental ‘superinteraction’ is that of chlordecone (CD) and CCl4.
In this case a prior 15 days exposure to CD enhanced the acute toxicity of CCl4 in male rats by 67- fold. This physiological/biochemical framework within which extremely potent interactions could occur is important in planning screening programmes or to predict superinteractions in toxicology/pharmacology.
A brief review of studies made by the science of Toxicology from the times of its founder Paracelsus to modern times as presented in this communication might attract young workers to this wonderful discipline of science.