Toxicology

“What is there thatis not poison?  All things are poison and nothing without poison. Solely, the dose determines that a thing is not a poison” Paracelsus (1493-1541)

Toxicology can be defined as that branch of science that deals with poisons, and a poison can be defined as any substance that causes a harmful effect when administered,  either by accident or design, to a living organism. By convention, toxicology also includes the study of harmful effects caused by physical phenomena, such as radiation of various kinds and noise. In practice, however, many complications exist beyond these simple definitions, both in bringing more precise meaning to what constitutes a poison and to the measurement of toxic effects. Broader definitions of toxicology, such as “the study of the detection, occurrence, properties, effects, and regulation of toxic substances,” although more descriptive, do not resolve the difficulties. Toxicity itself can rarely, if ever, be defined as a single molecular event but is, rather, a cascade of events starting with exposure, proceeding through distribution and metabolism, and ending with interaction with cellular macromolecules (usually DNA or protein) and the expression of a toxic end point

Toxicology is the study of the adverse effects of xenobiotics, which basically are foreign substances in the body.  Professionals that study and perform toxicology-related work are called toxicologists, however, their specific job titles may vary.  Toxicologists are scientists that study the health effects of exposure to substances and the mechanisms associated with exposure to those substances.  A toxicology professional may work for industry (such as a pharmaceutical company, or chemical company), the government, or colleges and universities.

The relationship between dose and its effects on the exposed organism is of high significance in toxicology. The chief criterion regarding the toxicity of a chemical is the dose, i.e. the amount of exposure to the substance.

All substances are toxic under the right conditions. The term LD50 refers to the dose of a toxic substance that kills 50 percent of a test population (typically rats or other surrogates when the test concerns human toxicity).

LD50 estimations in animals are no longer required for regulatory submissions as a part of pre-clinical development package.

The conventional relationship (more exposure equals higher risk) has been challenged in the study of endocrine disruptors.

There are various specialized subdisciplines within the field of toxicology that concern diverse chemical and biological aspects of this area.

The literal meaning of the term toxicology is “ the study of poisons.” The root word toxic entered the English language around 1655 from the Late Latin word toxicus (which meant poisonous), itself derived from toxikón, an ancient Greek term for poisons into which arrows were dipped. The early history of toxicology focused on the understanding and uses of different poisons, and even today most people tend to think of poisons as a deadly potion that when ingested causes almost immediate harm or death. As toxicology has evolved into a modern science, however, it has expanded to encompass all forms of adverse health effects that substances might produce, not just acutely harmful or lethal effects.

The following definitions reflect this expanded scope of the science of toxicology:

Toxic— having the characteristic of producing an undesirable or adverse health effect.

Toxicity — any toxic (adverse) effect that a chemical or physical agent might produce within a living
organism.

Toxicology — the science that deals with the study of the adverse effects (toxicities) chemicals or physical agents may produce in living organisms under specific conditions of exposure. It is a science that attempts to qualitatively identify all the hazards (i.e., organ toxicities) associated with a substance, as well as to quantitatively determine the exposure conditions under which those hazards/toxicities are induced. Toxicology is the science that experimentally investigates the occurrence, nature, incidence, mechanism, and risk factors for the adverse effects of toxic substances.

As these def initions  indicate,  the  toxic  responses  that f orm  the  study of   toxicology  span  a broad biologic and physiologic spectrum. Effects of interest may range from something relatively minor such as irritation or tearing, to a more serious response like acute and reversible liver or kidney damage, to an even more serious and permanent disability such as cirrhosis of the liver or liver cancer. Given this broad range of potentially adverse effects to consider, it is perhaps useful for those unfamiliar with toxicology to define some additional terms.

Exposure — to cause an adverse effect, a toxicant must first come in contact with an organism. The means by which an organism comes in contact with the substance is the route of exposure (e.g., in the air, water, soil, food, medication) for that chemical.

Dose — the total amount of a toxicant administered to an organism at specific time intervals. The quantity can be further defined in terms of quantity per unit body weight or per body surface area.

Internal/absorbed dose — the actual quantity of a toxicant that is absorbed into the organism and distributed systemically throughout the body.

Delivered/effective/target organ dose — the amount of toxicant reaching the organ (known as the target organ) that is adversely affected by the toxicant.

Acute exposure — exposure over a brief period of time (generally less than 24 h). Often it is considered to be a single exposure (or dose) but may consist of repeated exposures within a short time period.

Subacute exposure — resembles acute exposure except that the exposure duration is greater, from several days to one month.

Subchronic exposure — exposures repeated or spread over an intermediate time range. For animal testing, this time range is generally considered to be 1–3 months.

Chronic exposure — exposures (either repeated or continuous) over a long (greater than 3 months) period of time. With animal testing this exposure often continues for the majority of the experimental animal’s life, and within occupational settings it is generally considered to be for a number of years.

Acute toxicity — an adverse or undesirable effect that is manifested within a relatively short time
interval ranging from almost immediately to within several days following exposure (or
dosing). An example would be chemical asphyxiation from exposure to a high concentration
of carbon monoxide (CO).

Chronic toxicity — a permanent or lasting adverse effect that is manifested after exposure to a toxicant. An example would be the development of silicosis following a long-term exposure to silica in workplaces such as foundries.

Local toxicity — an adverse or undesirable effect that is manifested at the toxicant’s site of contact with the organism. Examples include an acid’s ability to cause burning of the eyes, upper respiratory tract irritation, and skin burns.

Systemic toxicity — an adverse or undesirable effect that can be seen throughout the organism or in an organ with selective vulnerability distant from the point of entry of the toxicant (i.e., toxicant requires absorption and distribution within the organism to produce the toxic effect). Examples would be adverse effects on the kidney or central nervous system resulting from the chronic ingestion of mercury.

Reversible toxicity — an adverse or undesirable effect that can be reversed once exposure is stopped. Reversibility of toxicity depends on a number of factors, including the extent of exposure (time and amount of toxicant) and the ability of the affected tissue to repair or regenerate. An example includes hepatic toxicity from acute acetaminophen exposure and liver regeneration.

Delayed or latent toxicity — an adverse or undesirable effect appearing long after the initiation and/or cessation of exposure to the toxicant. An example is cervical cancer during adulthood resulting from in utero exposure to diethylstilbestrol (DES).

Allergic reaction—a reaction to a toxicant caused by an altered state of the normal immune response. The outcome of the exposure can be immediate (anaphylaxis) or delayed (cell-mediated).

Idiosyncratic reaction — a response to a toxicant occurring at exposure levels much lower than those generally required to cause the same effect in most individuals within the population. This response is genetically determined, and a good example would be sensitivity to nitrates due to deficiency in NADH (reduced-form nicotinamide adenine dinucleotide phosphate)– methemoglobin reductase.

Mechanism of toxicity — the necessary biologic interactions by which a toxicant exerts its toxic effect on an organism. An example is carbon monoxide (CO) asphyxiation due to the bindingof CO to hemoglobin, thus preventing the transport of oxygen within the blood.

Toxicant — any substance that causes a harmful (or adverse) effect when in contact with a living organism at a sufficiently high concentration.

Toxin — any toxicant produced by an organism (floral or faunal, including bacteria); that is, naturally produced toxicants. An example would be the pyrethrins, which are natural pesticides produced by pyrethrum flowers (i.e., certain chrysanthemums) that serve as the model for the man made insecticide class pyrethroids.

Hazard — the qualitative nature of the adverse or undesirable effect (i.e., the type of adverse effect) resulting from exposure to a particular toxicant or physical agent. For example, asphyxiation
is the hazard from acute exposures to carbon monoxide (CO).

Safety — the measure or mathematical probability that a specific exposure situation or dose will not produce a toxic effect.

Risk — the measure or probability that a specific exposure situation or dose will produce a toxic effect.

Risk assessment — the process by which the potential (or probability of) adverse health effects of exposure are characterized.

The Toxicological Paradigm

Toxicokinetics is the quantitation of the time course of  toxicants in the body during the processes of absorption, distribution, biotransformation, and excretion or clearance of toxicants. In other words,

toxicokinetics is a reflection of how the body handles toxicants as indicated  by the plasma concentration of that xenobiotic at various time points.Š The end result of these toxicokinetic processes is a biologically effective dose of the toxicant.

Toxicodynamics refers to the molecular, biochemical, and physiological effects of toxicants or their metabolites in biological systems. These effects are result of the interaction of the biologically effective dose of the ultimate (active) form of the toxicant with a molecular target.

Modes of Toxic Action.

This includes the consideration, at the fundamental level of organ, cell and molecular function, of all events leading to toxicity in vivo: uptake, distribution, metabolism, mode of action, and excretion. The term mechanism of toxic action is now more generally used to describe an important molecular event

in the cascade of events leading from exposure to toxicity, such as the inhibition of acetylcholinesterase in the toxicity of organophosphorus and carbamate insecticides. Important aspects include the following:

1. Biochemical and molecular toxicology consider events at the biochemical and molecular levels, including enzymes that metabolize xenobiotics, generation of reactive intermediates, interaction of xenobiotics or their metabolites with macromolecules, gene expression in metabolism and modes of action, and signaling pathways in toxic action.

2. Behavioral toxicology deals with the effects of toxicants on animal and human behavior, which is the final integrated expression of nervous function in the intact animal. This involves both the peripheral and central nervous systems, as well as effects mediated by other organ systems, such as the endocrine glands.

3. Nutritional toxicology deals with the effects of diet on the expression of toxicity and with the mechanisms of these effects.

4. Carcinogenesis includes the chemical, biochemical, and molecular events that lead to the large number of effects on cell growth collectively known as cancer.

5. Teratogenesis includes the chemical, biochemical, and molecular events that lead to deleterious effects on development.

6. Mutagenesis is concerned with toxic effects on the genetic material and the inheritance of these effects.

7. Organ toxicity considers effects at the level of organ function (neurotoxicity, hepatotoxicity, nephrotoxicity, etc.).

Applied Toxicology.

This includes the various aspects of toxicology as they apply in the field or the development of new methodology or new selective toxicants for early application in the field setting.

1. Clinical toxicology is the diagnosis and treatment of human poisoning.

2. Veterinary toxicology is the diagnosis and treatment of poisoning in animals other than humans, particularly livestock and companion animals, but not excluding feral species. Other important concerns of veterinary toxicology are the transmission of toxins to the human population in meat, fish, milk, and other foodstuffs and the care and ethical treatment of experimental animals.

3. Forensic toxicology concerns the medicolegal aspects, including detection of poisons in clinical and other samples.

4. Environmental toxicology is concerned with the movement of toxicants and their metabolites and degradation products in the environment and in food chains and with the effect of such contaminants on individuals and, especially, populations. Because of the large number of industrial chemicals and possibilities for exposure, as well as the mosaic of overlapping laws that govern such exposure, this

area of applied toxicology is well developed.

5. Industrial toxicology is a specific area of environmental toxicology that deals with the work environment and constitutes a significant part of industrial hygiene.

Types of Toxicology

• Mechanistic Toxicology - It focuses on understanding specific chemical, biochemical and molecular mechanisms by which toxicants have their effects. 

• Descriptive toxicology -gives information about the toxicity of drugs, foods, and other products.  It is often perform experiments in a pharmaceutical or academic setting.

• Regulatory toxicology - use scientific data to decide how to protect humans and animals from excessive risk. Set standards for “safe” exposure.

• Forensic toxicology - It is the application of toxicology to the law that uses chemical analysis to determine the cause and circumstances of death in a postmortem investigation.

• Clinical toxicology - concerns diseases (usually human) caused by or uniquely associated with toxicants.

• Reproductive toxicology - studies the occurrence of adverse effects of toxicant exposure on the male or female reproductive system.

• Developmental toxicology - studies life-long adverse effects of toxicant arising from exposures:
  •  before conception
  •  during prenatal development
  •  postnatally to puberty

• Occupational toxicology - focuses on toxicological hazards occurring in workplace, with objective of preventing adverse effects in workers.

• Environmental toxicology - study the effects of pollutants on organisms, populations, ecosystems, and the biosphere.

Classification of Toxic Agents:

Toxic substances are classified into the following:

A.  Heavy Metals

Metals differ from other toxic substances in that they are neither created nor destroyed by humans. Their use by humans plays an important role in determining their potential for health effects. Their effect on health could occur through at least two mechanisms: first, by increasing the presence of heavy metals in air, water, soil, and food, and second, by changing the structure of the chemical. For example, chromium III can be converted to or from chromium VI, the more toxic form of the metal.

B.  Solvents and Vapors

Nearly everyone is exposed to solvents. Occupational exposures can range from the use of “white-out” by administrative personnel, to the use of chemicals by technicians in a nail salon. When a solvent evaporates, the vapors may also pose a threat to the exposed population.

C.  Radiation and Radioactive Materials

Radiation is the release and propagation of energy in space or through a material medium in the form of waves, the transfer of heat or light by waves of energy, or the stream of particles from a nuclear reactor.

D.  Dioxin/FuransDioxin, (or TCDD)

It was originally discovered as a contaminant in the herbicide Agent Orange. Dioxin is also a by-product of chlorine processing in paper producing industries.

E.  Pesticides

The EPA defines pesticide as any substance or mixture of substances intended to prevent, destroy, repel, or mitigate any pest. Pesticides may also be described as any physical, chemical, or biological agent that will kill an undesirable plant or animal pest.

F. Microbial toxins

Bacteria, fungi and algae are the microorganisms typically associated with  microbial toxin production. Cholera toxin produced by Vibrio cholerae is the virulence factor responsible for the massive secretory diarrhea seen in Asiatic cholera (5 million cases each year).

G. Mushroom toxins

Several mushroom species (e.g. Amanita phalloides, A. virosa), produce a family of cyclic octapeptides called amanitins. Symptoms of intoxication appear at the end of a latent period of 6-48 hours during which the patient shows no symptoms. Death in 50-90% of the cases from progressive and irreversible liver, kidney, cardiac damage may happen 6-8 days after ingestion.

H.  Plant Toxins

Different portions of a plant may contain different concentrations of chemicals. Some chemicals made by plants can be lethal. For example, taxol, used in chemotherapy to kill cancer cells, is produced by a species of the yew plant. One of the main toxic proteins is "ricin" from the seeds of castor bean plant. Perhaps, ingestion of just one milligram of ricin can kill an adult. The main alkaloid of Aconitum plants is  aconitine, a highly toxic  diterpenoid alkaloid. Ingestion of  a few grams of roots may result in death occuring from ventricular arrhythmias, which are most likely to occur within the first 24 hours.

I.  Animal Toxins

These toxins can result from venomous or poisonous animal releases. Venomous  animals are usually defined as those that are capable of producing a poison in a highly developed gland or group of cells, and can deliver that toxin through biting or stinging. Poisonous animals are generally regarded as those whose tissues, either in part or in their whole, are toxic. Batrachotoxins are extremely potent cardiotoxic and neurotoxic steroidal alkaloids found in skin secretions from certain species of frogs (poison dart frogs). The most toxic frog is very likely the golden poison frog, Phyllobates terribilis.


 Subcategories of Toxic Substance Classifications

All of these substances may also be further classified according to their:

•  Effect on target organs (liver, kidney, hematopoietic system),
•  Use (pesticide, solvent, food additive),
•  Source of the agent (animal and plant toxins),
•  Effects (cancer mutation, liver injury),
•  Physical state (gas, dust, liquid),
•  Labeling requirements (explosive, flammable, oxidizer),
•  Chemistry (aromatic amine, halogenated hydrocarbon), or
•  Poisoning potential (extremely toxic, very toxic, slightly toxic)

General Classifications of Interest to Communities

• Air pollutants

• Occupation-relate

• Acute and chronic poisons

       All chemicals (or any chemical) may be poisonous at a given dose and through a particular route. For                example, breathing too much pure oxygen, drinking excessive amounts of water, or eating too much salt can 

cause poisoning or death.

References:

http://faculty.ksu.edu.sa/73069/Documents/Toxicology.pdf
http://www.lnt.ch/Toxicology.pdf
http://potentcompoundsafety.com/2011/06/toxicology-it.html
http://www.news-medical.net/health/Toxicology-What-is-Toxicology.aspx
http://shawnslayton.com/open/medschool/Medical%20Books%20(Misc)/Principles%20of%20Toxicology%20(good%20book).pdf

Photo credit:
http://www.cartoonstock.com/directory/d/desk.asp&docid=Y9ZYrC0C_9vooM&imgurl
http://www.istockphoto.com/stock-illustration-8345458-cartoon-doctor-with-syringe.php
http://forensictalks.blogspot.com/2010/12/friday-cartoon.html
http://www.angelfire.com/theforce/jeremysite/Cloning/animalrep.htm
http://homeopathic-treatments.com/?attachment_id=1174
http://www.medicaltox.com/practice.htm
http://www.scienceforhealthandenergy.com/consulting/environment.html