Principles  of Toxicology: A Clinical Review

 

Salma Shaheen*, Safia Sultana, Mohammed Nayeem Uddin, Abdul Saleem Mohammad

Department of Pharmacy, Nizam Institute of Pharmacy, Deshmukhi (V), Pochampally (M), Behind Mount Opera, Yadadri (Dist)-508284, Telangana, India.

 

ABSTRACT:

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. In short, it is the study of toxic kinetics and toxic dynamic. Poison is a quantitative concept, almost any substance being harmful at some doses but, at the same time, being without harmful effect at some lower dose. Between these two limits there is a range of possible effects, from subtle long-term chronic toxicity to immediate lethality. Vinyl chloride may be taken as an example. It is a potent hepatotoxic at high doses, a carcinogen with a long latent period at lower doses, and apparently without effect at very low doses. The measurement of toxicity is also complex. Toxicity may be acute or chronic, and may vary from one organ to another as well as with age, genetics, gender, diet, physiological condition, or the health status of the organism. Exposure of humans and other organisms to toxicants may result from many activities: intentional ingestion, occupational exposure, environmental exposure, as well as accidental and intentional (suicidal or homicidal) poisoning. The toxicity of a particular compound may vary with the portal of entry into the body, whether through the alimentary canal, the lungs, or the skin. The initial approach to a person who has been poisoned should be to assess the airway, breathing, and circulation, and to take a thorough history. Less than 1 per cent of poisonings are fatal; therefore, management in most cases is supportive unless a specific antidote is available. Treatment for poisoning depends on the type of exposure (e.g., ingestion, inhalation), the specific toxin (poisonous substance), and the severity of the person's condition.Childhood poisoning that involves a foreign object (e.g., small toy, battery) may require surgery to remove the object. This review article gives you an overall view on toxicity, its principles, management and treatment.

 

 

 

INTRODUCTION:

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.

 

Toxicology can be defined as the branch of science that deals with poisons its managementand the practice of diagnosing and treating exposures to toxins and toxicants. A poison can be defined as any substance that causes a harmful effect when administered, either by accident or design, to a living organism. 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. 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.Toxicology isa discipline,overlappingwith biology, chemistry, pharmacology, medicine, and nursing⁽¹⁾.

 

The relationship between dose and its effects on the exposed organism is of high significance in toxicology. 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⁽²⁾. This sequence may be mitigated by excretion and repair. It is to the complications, and to the science behind them and their resolution, that this article is dedicated, particularly to the how and why certain substances cause disruptions in biologic systems that result in toxic effects^(3,6). Taken together, these difficulties and their resolution circumscribe the perimeter of the science of toxicology⁽⁴⁾.

 

The study of toxicology serves society in many ways, not only to protect humans and the environment from the deleterious effects of toxicants but also to facilitate the development of more selective toxicants such as anticancer and other clinical drugs and pesticides⁽⁵⁾. Poison is a quantitative concept, almost any substance being harmful at some doses but, at the same time, being without harmful effect at some lower dose. Clinical drugs are even more poignant examples because, although therapeutic and highly beneficial at some doses, they are not without deleterious side effects and may be lethal at higher doses. Aspirin (acetylsalicylic acid), for example, is a relatively safe drug at recommended doses and is taken by millions of people worldwide^(3,5). At the same time, chronic use can cause deleterious effects on the gastric mucosa, and it is fatal at a dose of about 0.2 to 0.5 g/kg⁽⁶⁾.

 

Poisons are substances that cause disturbances in organisms, usually by chemical reaction or other activity on the molecularscale, when an organism absorbs a sufficient quantity⁽⁷⁾.The fields of medicine (particularly veterinary) and zoology often distinguish a poison from a toxin, and from a venom. Poisons are toxins produced by organisms in nature, and venoms are toxins injected by a bite or sting (this is exclusive to animals). The difference between venom and other poisons is the delivery method. Industry, agriculture, and other sectors use poisons for reasons other than their toxicity^(7,9). Pesticides are one group of substances whose toxicity to various insects and other animals deemed to be pests (e.g., rats and cockroaches) is their prime purpose⁽⁸⁾.

Acute poisoning is exposure to a poison on one occasion or during a short period of time. Symptoms develop in close relation to the exposure⁽⁹⁾. Absorption of a poison is necessary for systemic poisoning. In contrast, substances that destroy tissue but do not absorb, such as lye, are classified as corrosives rather than poisons. Furthermore, many common household medications are not labelled with skull and crossbones, although they can cause severe illness or even death. In the medical sense, poisoning can be caused by less dangerous substances than those legally classified as a poison⁽¹⁰⁾.

 

Chronic poisoning is long-term repeated or continuous exposure to a poison where symptoms do not occur immediately or after each exposure. The patient gradually becomes ill, or becomes ill after a long latent period. Chronic poisoning most commonly occurs following exposure to poisons that bioaccumulate⁽⁵⁾, or are biomagnified⁽¹¹⁾, such as mercury, gadolinium, and lead.

 

Much of the early history of toxicology has been lost and in much that has survived toxicology is of almost incidental importance in manuscripts dealing primarily with medicine. Some, however, deal more specifically with toxic action or with the use of poisons for judicial execution, suicide or political assassination⁽¹²⁾. Regardless of the paucity of the early record, and given the need for people to avoid toxic animals and plants, toxicology must rank as one of the oldest practical sciences. The Egyptian papyrus⁽¹³⁾, Ebers, dating from about 1500 BC, must rank as the earliest surviving pharmacopeia, and the surviving medical works of Hippocrates, Aristotle, etc.There were some important developments during the eighteenth century. Probably the best known is the publication of Ramazini’s Diseases of Workers in 1700, which led to his recognition as the father of occupational medicine. The correlation between the occupation of chimney sweeps and scrotal cancer by Percival Pott in 1775 is almost as well known, although it was foreshadowed by Hill’s correlation of nasal cancer and snuff use in 1761^(10,14). Poisons were defined by different toxicologist in different ways.

 

“Poison: Any substance, either taken internally or applied externally, thatis injuriousto health or dangerous to life.Or Any substance that, when relatively small amounts are injested ,inhaled, or absorbed, or applied to, injected into, or developed within the body, has chemical action that causes damage to structure or disturbance of function, producing symptoms, illness, or death.”

 

CHARACTERISTICS OF “IDEAL” POISONS:

There are certain characteristics to an “ideal” poison, and homicidal Poisoners ⁽¹³⁾ will select their murderous compounds to encompass as many of these characteristics as possible. What follows are some of the characteristics of such an ideal homicidal poison⁽¹⁵⁾:

• It should be odourless, tasteless, and colourless. This allows administration to the intended victim without any warning signs that the victim can detect by the normal bodily senses of smell, taste, and sight.

 

• It should be readily soluble, preferably in water. This allows easy administration in normal foods and drinks of which the victim may partake⁽¹⁶⁾.

 

• It should have a delayed onset of action. This allows a time period in which the poisoner can attempt to create an alibi^[14].

 

• It should be undetectable, and certainly the more exotic the poison the more likely that it will not be detected in more routine toxicological analyses⁽¹⁷⁾.

 

• It should have a low-dose lethality, which means less of the toxic material needs to be administered in the dose. It is much easier to administer a pinch of a substance, rather than a pound.

 

• It should be easily obtained, but not traceable, so that it will leave no investigative trail that would lead to the poisoner⁽¹⁸⁾.

 

• It should be found as a naturally occurring substance in the environment of the burial place.

 

The heavy metals ⁽¹⁹⁾ (e.g., arsenic, antimony, mercury, lead) are elements or elemental compounds and are as toxic today as they were when first created millions of years ago. These compounds tend to remain detectable many years after a victim’s burial^(13,20), which is advantageous for law enforcement investigators.

 

 

 

TYPES OF POISON⁽²¹⁾:

1.      Agricultural  and industrial chemicals:

Insecticides: HETP, TEPP, OMPA and Malathion, Parathion

Herbicides

Rodenticides

Plant growth regulator

Organic compounds

Inorganic compounds

 

 

 

2.      Drugs and health care products:

Painkillers

Tranquilizers and sleeping pills

Antipsychotic drugs

Cold medications

Antiseptics

Vitamins and iron pills

Antidepressants

Drugs of abuse

Cardiovascular drugs

Antiasthmatics.

 

3.      Poisons of biological origin:

Microbial toxins

Plant toxins (phytotoxins)

Animal poisons (zootoxins)

 

4.      Radiations:

Ionising radiations

Non ionising radiation.

 

MECHANISM OF TOXICITY:

This includes the consideration, at the fundamental level oforgan, 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⁽²²⁾ and carbamate insecticides. Important aspects include the following:

 

1. Biochemical and molecular toxicology⁽²³⁾ considerevents at the biochemical and molecular levels, including enzymes that metabolize xenobiotic, generation of reactive intermediates, interaction of xenobiotic or their metabolites with macromolecules,gene expression in metabolism and modes of action, and signalling pathways in toxic action.

 

2. Behavioural toxicology⁽²⁴⁾ deals with the effects of toxicants on animal and human behaviour, 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⁽²⁵⁾ 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⁽²⁴⁾.

 

5. Teratogenesis⁽²⁶⁾ 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⁽²⁷⁾.

 

7. Organ toxicity considers effects at the level of organ function (neurotoxicity, hepatotoxicity, nephrotoxicity, etc.)^(25,27).

 

 

ANTIDOTE:

An antidote is a substance which can counteract a form of poisoning Or neutralise the effects of poison. The term ultimately derives from the Greek (φάρμακον) ἀντίδοτον (pharmakon) antidoton, "(medicine) given as a remedy". Antidotes for anticoagulants are often referred to as reversalagents⁽²⁸⁾.

 

The antidotes for some particular toxins are manufactured by injecting the toxin into an animal in small doses and extracting the resulting antibodies from the host animals' blood. This results in an antivenom that can be used to counteract poison produced by certain species of snakes, spiders, and other venomous animals^(29,31). A number of venoms lack a viableantivenom, and a bite or sting from an animal producing such a toxin often results in death^(30). Some animal venoms, especially those produced by arthropods (e.g., certain spiders, scorpions, bees, etc.) are only potentially lethal when they provoke allergic reactions and induce anaphylactic shock; as such, there is no "antidote" for these venoms because it is not a form of poisoning and anaphylactic shock can be treated (e.g., by the use of epinephrine)⁽³¹⁾.

 

There are dozens of different antidotes; however, some may only counteract one particular drug, whereas others (such as charcoal) may help reduce the toxicity of numerous drugs. Most antidotes are not 100% effective, and fatalities may still occur even when an antidote has been given⁽³²⁾. Some examples of antidotes include:

 

TYPES OF ANTIDOTE^{(16,20,26,37)}:

1.      Physical/ mechanical antidote:

substances which inhibit the absorption of poison. Eg. Demulcents such as fats, oils and egg albumin, banana is the best antidote for glass poisoning, charcoal is used to absorb alkaloidal poisons.

 

2.      Chemical antidote:

substances which interact chemically with the poison to form an insoluble precipitate which is nontoxic or it oxidises the poison to its nontoxic form.

 

3.      Physiological antidote:

substances which produces the effects opposite to that of the poison without interacting chemically with it. These are the antagonist of the poisons.

 

S.NO	Poison	Antidote
1.	Paracetamol/ acetaminophen	N-Acetylcysteine/ methionine
2.	organophosphates and carbamates	Atropine or Pralidoxime
	digoxin toxicity	Digoxin immune fab
3.	Arsenic, gold, or inorganic mercury poisoning	Dimercaprol(BAL or British anti-lewiste)
4.	Benzodiazepine	Flumazenil
5.	Drug-inducedmethemoglobinemia	Methylene blue
6.	Opioid or narcotic drugs	Naloxone
7.	Non prescription medication	NSAIDs
8.	Most poisons or unknown poisons	Activated charcoal
9.	Morphine	Caffeine
10.	Pilocarpine	Atropine
11.	Strychnine	Chloroform
12.	Copper	BAL, penicillamine
13.	Lead	BAL, EDTA, penicillamine
14.	Thallium	Prussian blue
15.	Iron	Desferrioxamine
16.	Oxalic acid	Lime
17.	Phosphorus	Copper sulphate
18.	Alkaloids	Tannins
19.	Barbiturates	Potassium permanganate
20.	Unknown poisons	Universal antidotes
21.	Warfarin	Vitamin k
22.	Beta blockers	Glucagon
23.	Cyanides	Amyl nitrite, sodium thiosulfate, sodium nitrite

 

UNIVERSAL ANTIDOTE:

A mixture of 50% activated charcoal, 25% magnesium oxide, and 25% tannic acid, formerlythought to be useful as anantidote for most types of acid, heavy metal, alkaloid, and glycosidepoisons. It is now believed that the mixture is nomore effective than activated charcoal givenwith water⁽³³⁾.

 

Ingredients	Quantity	Use
1. Powdered charcoal	2 parts	Adsorbs alkaloids
2. Magnesium oxide	1 part	Neutralize acids
3. Tannic acid	1 part	Precipitates  alkaloids

 

Activated charcoal is considered to be medicine's most powerful absorbent and as such, it readily works to absorb many toxins and poisons, rendering them harmless  ^(34,36).

 

As an antidote, activated charcoal is mainly known both for its use in drug overdoses and chemical poisonings. Charcoal acts to purify and cleanse the body due to its amazing ability to attract poisons to itself. Charcoal has a wide range of absorption. Heavy metals, viruses, bacterial and fungal toxins, etc. are all absorbed effectively. Activated charcoal often absorbs more than its own weight of injurious materials⁽³⁵⁾.

 

Internally as an antidote and remedy, charcoal works by binding drugs and poisons within the gastrointestinal tract. This allows their transfer out of the body in a harmless form. Charcoal absorbs like a sponge, and renders poisons harmless⁽³⁷⁾. It can do varied tasks because of it is amazing ability to attract other substances to its surface and hold on to them until they exit the body^(36,37).

 

The Poisoningin human beingis of two types^(25,36):

 

4.      Acute poisoning:

The symptoms of the acute poisoning appear immediately after the ingestion of poison. They increasein severity and may follow death. The poison can be detected in the ingested substance or vomit, stool and urine of the victim. The main symptoms are vomiting and diarrhoea or convulsions and coma.

 

 

5.      Chronic poisoning:

The symptoms of the chronic poisoning appear gradually over the period of time. The symptoms may disappear after removal of the victim from his surroundings. Poison can be detected in the ingested substance or stool, vomit and urine of the victim. The main symptoms are chronic ill health malaise, repeated attacks of GI irritation and increased cachexia.

 

GENERAL TREATMENT⁽³⁵⁾:

The main aim of treatment is to help the patient to stay alive by attention to respiration and circulation while he is encouraged to get rid by metabolism or excretion.

The steps involved in treatment of a case of poisoning are:

1.      Removal of unabsorbed poisons from the system

2.      Use of antidote

3.      Elimination of the absorbed poison

4.      Treatment of general symptoms

5.      Maintenance of the patient general condition.

 

CONCLUSION:

Therefore this study shows the different principles of toxicology, poisons, toxicity of different dugs, dose response relationship. Also it reveals the various antidotes and their mechanism in poisoning therapy. The use of universal antidote in different toxicities. It gives an overall view of treatment therapies for poisoning.

 

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