INTRODUCTION TO VETERINARY TOXICOLOGY

Dr. Sindhu K.

MVSc scholar, Dept of VPT,

COVAS, Pookode.

POISON

A POISON is any substance which, when ingested, inhaled, absorbed, or when applied to, injected into, or developed with in the body, in relatively small amounts, may cause damage to body structure or disturbance of function through its chemical action.

Poison & poisonous animals have been of interest to humans since the dawn of creation.

Toxicology = the study of poisons.

Bio toxicology = the study of poisons

from living organisms.

Zoo toxicology = the study of poisonous animals.

ETYMOLOGY

TOXIN

Toxon (Greek) for bow & arrow

Toxicon poison dipped arrow

POISON

Poi to drink & becoming potare in Latin (potion)

Venomous nature derived from wen to win, & led to venus/venerate through “love potions” (venin)

I. TOXICOLOGY IN ANTIQUITY

Medicine is an ancient science.

The use of plant & animals substances

to heal disease is as old as the diseases themselves.

Early practitioners of medicine were priests or magicians/physicians, & it was commonly thought that guilty of a crime would be affected by a poison.

PREHISTORIC MAN

The historical development of toxicology began with early cave dwellers who recognized poisonous plants and animals and used their extracts for HUNTING or in warfare.

FIRST “MENTION” (3100-3000 B.C.)

Egyptian pharaoh of the 1st dynasty

United the lower & upper Egypt.

Founded Memphis as capital

Founder of many new cults & temples

Cultivated & studied effects of poisons & medicinal plants.

MESOPOTAMIA

The development of human

civilization is thought to have

originated in the fertile crescent

which is now occupied by Iraq,

Syria, Israel & Egypt, but was

known as Babylon & Assyria

historically.

Medicine had its beginnings in this

region.

The code of Hammurabi

was chiseled into stone,

providing evidence for

future generations of the

expected behavior of

physicians.

Bites & stings from venomous animals occurred & were treated with scarification, bloodletting (cut & suction), the use of incantations, & a procedure called Cupping

Cupping = use of animal horn to neutralize the poison.

EGYPTThe Egyptian civilization developed at

approximately the same time as those of Babylon & Assyria.

Writing paper was manufactured from the papyrus plant, Cyperus papyrus-sedge family- Cyperaceae, which is reed like plant that grows in shallow water.

Modern humans have learned of the prescriptions & medicine used for treating ailments through various papyri.

One Egyptian picture story depicts a puffer fish, Tetraodon sp. Which was recognized as a poisonous fish.

The Smith papyrus (1600 B.C.) lists charms for use against snakebite.

The Hearst Medical papyrus provides numerous prescriptions, some of which were prescribed for animal bites.

1ST WRITTEN RECORD (2700 B. C.)

Shen Nung Pen ts’ao ching – divine Husbandman’s material medica.

Contained list of poisonous & medicinal plants and drugs

Enlisted the effects & antidotes viz., iodine, opium, cannabis, mercury.

THE VEDAS (900 B. C.)

Hindu scriptures ATHARVA VEDA

• First Indian text dealing with medicine

• Mention of poisoning for use in warfare

I. Arrows with ducts

II. Castor bean poison

III. Poisoned nets

IV. Hook traps

ISRAEL

Ancient Hebrew people were guided in every aspect of their lives by the old Testament.

Strict dietary laws were imposed on the people, presumably to maintain health & prevent disease. Eg: trichinosis in pork.

Early Israelites were admonished not to eat items from the water that had neither fins nor scales (Deuteronomy 14:9-10). Fish with neither of these structures tend to be the most poisonous & thus should be avoided.

• One of the plagues pronounced on the Egyptians by Moses was the earliest account of red tide caused by dinoflagellates (the water turned to blood, killing all the fish– Exodus 7:19-20)

CHINA

Ancient & modern Chinese medicine rely heavily on natural products for healing disease (herbal medicine, rhinoceros horn & gall bladders).

Medical practitioners recognized scale less fish as being toxic & 1st report of ciguatera toxicosis was described from ingestion of yellowtail tuna (ca A.D. 700)

GREECE (500 B.C TO A.D. 500)

Modern medicine had its genesis in the Greek civilization, from 500 B.C to A.D. 500.

Medicine became separated from myth, magic, & religion.

• Homer (600 B.C.) Odysseus obtains poison for his arrows

HIPPOCRATES (460 – 355 B.C).

The father of medicine.

Introduced principles of clinical toxicology related to bioavailability of toxicants.

knew of the toxicity of sea urchin spines.

Oath to ‘not poison’.

“to please no one will I prescribe a deadly drug nor give advice which may cause his death”.

ARISTOTLE (384 – 322 B.C.)

Aristotle (384 – 322 B.C.) knew of the stinging of jellyfish.

Alexander the great forbade his troops to eat fish, presumably because of concern for toxicity.

THEOPHRASTUS (370-286 B. C.)

Born in Eresus, on the island of Lesbos.

Student of Aristotle.

Authored De Historia Plantarum.

Included numerous references to poison plants.

Considered as “The Father of Botany”.

SOCRATES (469 – 399 B.C.)

Was a classical Greek (Athenian) philosopher credited as one of the founders of Western philosophy.

Execution/Suicide death of by hemlock (Conium maculatum).

The term, "Socratic paradox" can also refer to a self-referential paradox, originating in Socrates' utterance, as “I know that I know nothing”.

• No one desires evil.

• No one errs or does wrong willingly or knowingly.

• Virtue—all virtue—is knowledge.

• Virtue is sufficient for happiness.

DEMOSTHENES (385 – 322 B. C.)

Demosthenes was a prominent Greek statesman and orator of ancient Athens.

His famous saying – “ All speech is vain & empty unless it be accompanied by action.”

Suicide by poisoned pen.

NICANDER (197 – 130 B. C.)

Nicander of Colophon (2nd century B.C.), Greek poet, physician and grammarian, was born at Claros (Ahmetbeyli in modern Turkey), near Colophon, where his family held the hereditary priesthood of Apollo. He flourished under Attalus III of Pergamum.

He wrote a number of works both in prose and verse, of which two survive complete. The longest, Theriaca, is a hexameter poem (958 lines) on the nature of venomous animals and the wounds which they inflict.

The other, Alexipharmaca, consists of 630 hexameters treating of poisons and their antidotes.

The works of Nicander were praised by Cicero (De oratore, i. 16), imitated by Ovid and Lucan, and frequently quoted by Pliny and other writers

(e. g. Tertullian in De Scorpiace, I, 1).

ALEXIPHARMACA: THE WORKS OF NICANDER

CLEOPATRA (LATE 69 BC – AUGUST 12, 30 BC)

Cleopatra VII Philopator , known to history as Cleopatra,

was the last active pharaoh of Ancient Egypt,

only shortly survived by her son, Caesarion as pharaoh.

The ancient sources, particularly the Roman ones, are in general agreement that Cleopatra killed herself by inducing an Egyptian cobra to bite her.

 The oldest source is Strabo, says that there are two stories: that she applied a toxic ointment, or that she was bitten by an asp on her breast.

Several Roman poets, writing within ten years of the event, all mention bites by two asps, as does Florus, a historian, some 150 years later.

Velleius, sixty years after the event, also refers to an asp.

MITHRIDATES (120 – 63 B.C.)

The king of Pontus, Mithridates VI,

was one of the 1st to advance the art & science of poisons & antidotes.

He experimented to attempt development of a universal antidote, including numerous substances in his concoctions, which were called “mithridates”.

Even today, the term “mithridates” or “shotgun treatment” is used to describe a situation in which multiple drugs are prescribed, in the hope that one of the drugs will be effective against the ailment suffered by the patient.

Mithridates philosophy was followed for many centuries in treating all kinds of diseases, including poisoning & envenomination.

FIRST POISON LAW: CIRCA 82 B. C.

Dictator Lucius Cornelius Sulla – Lex Cornelia.

Growing conspiracy to kill men for profit.

Provisions for both the poisoner and the provider of the poison.

PEDANIUS DIOSCORIDES (A.D. 50 - 100)

• was a physician, pharmacologist and botanist, the author of De Materia Medica—a 5-volume encyclopedia about herbal medicine and related medicinal substances (a pharmacopeia), which served the medical profession for 1600 years.

• Classified poisons for 1st time into plants, minerals / animal poisons.

• He described treatment for various marine animal intoxications, including the stingray & “sea vipers”.

AQUA TOFFANA

Arsenic containing perfumes were prepared by lady named Toffana

Such cosmetics are termed Aqua toffana, were used to kill the foes.

ARUM MACULATUM

Arum or Cuckoo-Pint

Ancient physicians called this plant the Drakontaia Mikre/ “small dragon” because central stalk resembles a serpant.

According to Dioscorides, its shape revealed its purpose as an antidote for snakebite.

Rubbing one’s hands with Arum root was supposed to make one unbiteable.

PLINY THE ELDER (A.D. 29 - 79)

wrote the classic Naturalis Historcia, a comprehensive encyclopedia of the natural world, which was the natural history “bible” until the Renaissance.

Pliny wrote one section devoted to De Venenalis Marinus (marine poisons).

NERO (37 – 68 A. D.)

Mother (Agrippina) consults with skilled poisoner (Locusta) to poison Emperor Claudius such that her son from a previous marriage (Nero), seize power & cleverly poisoned step-brother Brittanicus.

Used slaves as food tasters to differentiate poisonous mushrooms from edible ones.

GALEN (129 – 199 A. D.)

Claudius Galen of Pergamum

Greek physician, Philosopher

Believed therapeutics should be in the hands of physicians rather than herbalists

Galena : a remedy/anti-dote for poison

ISLAMIC COUNTRIES

Moslem countries provided little original contribution to the field of toxicology until a Persian by the name of Geber ibn Hajan (ca. A.D. 750 - 760) wrote a long treatise on poisons, including venoms & their antidotes.

II. MEDIEVAL PERIODThe collapse of the Roman empire

ushered in a period of intellectual stagnation(Dark Ages).

Many of us have the impression that nothing was accomplished in the science during this time; but in reality, the printing press & gun powder, among other things, were invented during dark ages.

A few physicians wrote about venomous animals, but little original toxicologic thought arose in this era.

MOSES BEN MAIMON (1135-1204 AD)

was a preeminent medieval Spanish, Sephardic Jewish philosopher, astronomer and one of the most prolific and influential Torah scholars and physicians of the Middle Ages.

Wrote a book “Poisons and Their Antidotes” describing the treatment of poisoning from insects, snakes & mad dogs.

With the Renaissance came the age of scientific inquiry, & numerous naturalists, physicians, missionaries, explorers, & historians began to document the prevalence of intoxication of humans by animals & plants.

EARLY RENAISSANCE

Little was known about the nature of the venoms/poisons.The provincialism of European & Mediterranean country writers was overcome as explorers returned from far-flung expeditions with factual & fanciful tales of the tropical region of the world.

Captain James Cook of H.M.S. Resolution nearly died of tetradotoxin poisoning after consuming fish in New Caledonia.

CATHERINE DE MEDICI

In France, a lady along with Marchioness de Brinvillers used the most effective poisons on sick & poor people in the name of treating them & killed several people!!

Catherine was given the tittle of ‘La Voisine’

Later she was convicted of many poisonings including over 2000 infants.

CARL VON LINNE (LINNAEUS)

The Swedish naturalist, made a monumental contribution to biology & toxicology.

He introduced the system of binomial naming & classification of plants & animals, Systema Naturae, 1758.

His system enabled scientists from around the world to communicate about plants & animals without having to know all the local, common names.

PARACELSUS (1493 - 1541)

Famous German physician who distinguished a poison from a remedy.

He gave the great statement “All substances are poisons; there is none which is not poison. The right dose differentiates a poison & a remedy”.

This statement laid the foundation of the modern concept of the ‘dose-response relationship’ & the ‘therapeutic index’ developed later.

IV. MODERN ERA OF TOXICOLOGY

Relatively young science based on the scientific works carried out by numerous dedicated researchers & scientists.

It’s the outcome of rational thinking, experimentation, relationship between dose & therapeutics as compared with toxic, and response to chemicals.

FRIEDRICH SERTURNER (1783-1841)

German pharmacologist who isolated the specific narcotic substance from opium & named it morphine after Morpheus, the Roman god of sleep.

Its isolation allowed physicians to prescribe painkiller's in regulated dose.

M. J. B. ORFILA (1787-1853)

Spanish physician considered as ‘Father of Toxicology’.

He established toxicology as a discipline distinct from others & defined toxicology as the study of poisons.

In 1813, he published the results of many toxicological experiments under the tittle of “toxicologic Generale”

He advocated the necessity of chemical analysis for medicolegal cases.

Orfila became very proficient in the chemistry of crime scene investigation & was an early promoter of chemical evidence in the courtroom.

FATHER OF TOXICOLOGY

FRANCOIS MAGENDIE (1783-1855)

A pioneer French experimental physiologist & toxicologist who researched the different motor functions of the body in relation to the spine, as well as nerves within it.

He also described the effects & uses of morphine, emetine, quinine, strychnine, & other alkaloids, for which he is also called the “Father of Experimental Pharmacology”.

19TH CENTURY

Scientific disciplines began to proliferate viz., chemistry, physiology, pharmacology & toxicology.

Scientific meetings provided a forum for expounding theories, & professional publications spread information throughout the world.

Biologists studied natural history of plant & animals.

Anatomists dissected & described the venom apparatus.

Biochemists studied venoms & poisons, & much was learned in the 19th century about chemical structure and pharmacologic effects.

Textbooks on toxicology were published in German, French, Japanese, English & other languages.

Toxicology became a required course in most medical & veterinary schools

• The field of toxicology became so broad that scientists began to narrow their fields of interest further: into plant poisoning, marine biotechnology, or pesticide toxicology.

• Scientists of the 20th century continued & intensified the study of poisons.

JAMES MARSH 1832Developed the first chemical

test for identifying arsenic, called Marsh test.

Hugo Reinsch 1842Developed a series of tests for

detecting arsenic & mercury.

THEODORE G. WORMLEY (1869)

Wrote the 1st American book -‘Microchemistry of poisons’ , dedicated to poisons.

LOUIS LEWIN (1854-1929)

A German scientist who took up the task of classifying drugs & plants in accordance to their psychological effects.

He also published many articles & books dealing with toxicology of methyl alcohol, ethyl alcohol, chloroform, opium, & other chemicals.

His important publications are;

Toxicologist’s view of world history.

A text book of toxicology.

FDA, 1930.

• Food & Drug Administration was founded to regulate the content and safety of consumer drugs & foods.

PAUL HERMANN MULLER (1899-1965)

He discovered the insecticidal properties of DDT in 1939 & along with his team introduced other chlorinated hydrocarbon insecticides.

He was awarded the Nobel prize in physiology/medicine in 1948 for his discovery of “the high efficiency of DDT as a contact poison against several arthropods”.

GERHARD SCHRADER (1903-1990)A German chemist who accidentally

developed the toxic nerve agents viz., sarin, tabun, soman, cyclosarin while attempting to develop new insecticides.

Schrader & his team, thus, introduced a new class of synthetic insecticides, the organophosphorous insecticides & defined the structural requirements for insecticidal activity of anticholinesterase compounds.

He is also called the “Father of the nerve agents”

K. K. CHEN (1934)

• Demonstrated antagonist effect of sodium nitrite & sodium thiosulphate in cyanide poisoning.

R. A. PETERS, L. A. STOCKEN, & R. H. S. THOMPSON. (1945)

• Developed dimercaprol as an antidote to arsenic containing war gases {lewisite}.

was first marketed in 1957 in West Germany under the trade-name Contergan. The German drug company Chemie Grünenthal (now Grünenthal) developed

and sold the drug. Primarily prescribed as a sedative or hypnotic, thalidomide also claimed to cure

“anxiety, insomnia, gastritis, and tension". Afterwards, it was used against nausea and to alleviate morning sickness in

pregnant women. Thalidomide became an over the counter drug in Germany on October 1, 1957. Shortly after the drug was sold in Germany, between 5,000 and 7,000 infants

were born with phocomelia (malformation of the limbs). Only 40% of these children survived. Throughout the world, about 10,000 cases were reported of infants with

phocomelia due to thalidomide.

THALIDOMIDE DISASTER 1959-1960’s

RACHEL CARSON (1962)

• Started crusade against the use of DDT & published the great book “silent spring”.

LOUIS J. CASARETT & JOHN DOULL (1971)

• published the 1st modern Toxicology textbook titled “Toxicology: The basic science of poisons”.

NUCLEAR ACCIDENTS AT THREE MILE ISLAND NEAR HARRISBURG, PENNSYLVANIA. (1979)

• The accident began with failures in the non-nuclear secondary system, followed by a stuck-open pilot-operated relief valve in the primary system, which allowed large amounts of nuclear reactor coolant to escape.

• The partial meltdown resulted in the release of unknown amounts of radioactive gases and radioactive iodine into the environment.

BHOPAL GAS DISASTER, (1984)

occurred due to accidental release of methyl isocyanate killing thousands & injuring hundred’s of people.

CHERNOBYL NUCLEAR POWER PLANT ACCIDENT (1986)

Occurred in Soviet Union spreading radioactive debris over several countries.

LATTER HALF OF THE 20TH CENTURY

A noteworthy achievements led to better understandings of the ecology of poisons & venoms.

Some answers have been discovered to such puzzling questions as:

1. Why are plants & animals poisonous/venomous ?

2. What have poisons contributed to evolution ?

3. How can an understanding of poisons & venoms contribute to the management of both free-ranging wild animal populations & domestic animals ?

COEVOLUTION??

Plants & herbivorous animals (insects) coevolved in an adversarial relationship.

Plant population developed various strategies for coping with herbivores that could potentially destroy them!

Mechanical means thorns, spines, harsh outer coats of stems/leaves.

Chemical deterrents PSM’s bitter tasting, offensively odorous, poisonous or have antinutitional effects.

As plants became more efficient in producing PSM’s animals, likewise improved their own methods of coping.

The case of coevolution of plants & insects is easily demonstrated, while evidence for plant/mammal coevolution is more elusive.

Seems logical ??

1) Insects & plants have shared the earth for approximately 250 million years (Carboniferous Period, Paleozoic Era).

2) Primitive mammals have been on earth only for 100 million years (Cretaceous Period, Mesozoic Era).

The progenitors of large, wild herbivorous animals viz., cattle/horse/bison/antelope didn’t appear until 40 million years ago.All domestic animals arose from their wild counterparts less than 12,000 years ago!!!

Even though mammalian herbivores may not have coevolved with plants like insects, there is sound evidence that plant (dietary) selection is determined by the presence & quantity of PSM’s in the part of the plant consumed viz., leaves, stem, fruit & seeds.

ANIMAL TOXIN ECOLOGY

Animal toxin & venoms are used to obtain

• Food

• Deter predation

• Regulate population

• Aid in exploiting a territory

• Aid in defense against enemies.

Just as in plants, the end products of sec. metabolites are channeled to storage sites within or upon the animals body, where there is slow turnover.

The slow turnover minimizes the necessity of excessive expenditure of precious energy & chemical resources to this function.

CONCLUSIONS

Poisons & venoms have served a vital role in the evolution of plants & animals.

• The pharmacological effects of plants & animals = PSM (Plants Secondary Metabolites).

• The determining factor of whether a substance is a medicine or a poison may be a matter of dosage.

Scientists are just beginning to unravel many of the mysteries of plant/animal/animal interactions.

DISCUSSIONS

REFERENCES.

Murray E. Fowler: Veterinary Zootoxicology. (CRC press).

Sandhu H. S. & Brar R. S: Text Book of Veterinary Toxicology.

Garg S. K: Veterinary Toxicology.

Matham V. K: Essentials of Toxicology.

Wikipedia & Google images.