HISTORY OF TOXICOLOGY

HISTORY OF TOXICOLOGY

            Since antiquity humans have been aware of and used various animal venoms and poisonous plants. However, a large percentage of knowledge about toxicity has accumulated only in the past three decades.

            The Ebers Papyrus from Egypt (1500 B.C.) is the earliest medical record of pharmacopoea and poisons, with some 800 recipes, many identified as poisons including, hemlock, aconitine, opium, and various metals. Hippocrates (400 B.C.) is credited with the foundation and documentation of formal medicine. In his Airs, Foods and Waters, he described the importance of environmental quality and of understanding the exposures expected based upon geography, climate, diet and occupation. He recognized the concept of poisons.

            Socrates (470 - 399 B.C.) was executed by (self) poisoning with hemlock. Poisoning due to plant toxins and animal venoms was well known to the ancients - learned presumably first by accident but cultivated for political and nefarious purposes. Poisoning became an occupational hazard of political life for Kings, Popes and others.

            In the 4th century B.C. there was an epidemic of poisonings and conspiracies of spouse poisoners existed for three hundred years until the Roman emperor Silla enacted the first law against poisoning. Nero was an devotee of arsenic - having poisoned Claudius to reach the throne and after repeated attempts finally killing Britannicus by the same method.

            In the Middle Ages poisoning was an accepted fact of life, a common way of eliminating political contenders, spouses and competition. An Italian lady named Toffana marketed arsenic laden liquid, "Agua Toffana", cosmetics and beauty aids. Soon a local club of wealthy married women became a club of eligible wealthy widows. She was executed in Naples in 1709.

            The families of the Borgias - (especially Cesar and Lucretia, children of Pope Alexander VI), and the Medicis - (notably Catherine, 1519-1589, who was to become the Queen of France) were both proficient poisoners. Catherine, shown here on the, left marketed her poisons and experimented her wares on the unsuspecting destitute and ill in the guise of a good Samaritan. She carefully noted dose, route, rapidity of onset, and symptom complexes.

            In France in the 1600’s, an infamous poisoner, Catherine Deshayes, known as La Voisin, developed a major industry in poisons and may have been responsible for well over possibly thousands of deaths of spouses and children. Her products became a popular method of population control. She was burned at the stake in 1680.

            Theophrastus Bombastus von Hohenheim Paracelsus an itinerant and iconoclastic medical educator (1493 - 1541) is identified as a pioneer in toxicology as a field of study having stated: "DOSIS SOLA FACIT VENENUM" or "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy." Paracelsus laid the groundwork for experimental toxicology stating:

1. Experimentation is necessary to note responses to toxins.
2. There must be a distinction between toxic and therapeutic properties.
3. These properties may be indistinguishable except by dose.
4. One can determine dose ranges and sites of action for therapeutic and toxic effects.

            Paracelsus studied medicine both from the accepted Galenic texts and from the lay practitioners he sought out, barbers and midwives. He antagonized the medical establishment by breaking with tradition both in questioning Galenic tradition and by teaching in the local vernacular instead of Latin. He recommended that natural substances used as remedies be purified and concentrated by alchemy to enhance potency and efficacy. He also sought specific therapeutic agents for specific diseases, (even the Galenic concept of specific diseases or syndromes was revolutionary given the concept of disease reflecting an individuals’ balance of the Four Humours). Paracelsus introduced mercury as a treatment for syphilis. He was denounced for using poison to treat a disease. Mercury became and remained the therapy of choice for syphilis for next 300 years - until Ehrlich discovered an arsphenamine (Salvarsan).

French hatters in 17th century were recognized as going mad as a result of use of mercuric nitrate in felting of fur; hence the term "mad as a hatter." Felting is the process of physically binding fibres of hair with each other through raising tiny barbs present on the hairs’ shafts. Mercury salts raise these barbs through reacting with sulfhydryl, (-SH), moieties which abound in keratinized tissues.

Ramazzini (1633 - 1714) physician and professor of medicine at Modena and Padova, Italy, is regarded as the founder figure in Occupational Medicine. His text, De Moribus Artificium Diatriba in 1713 described diseases associated with 52 trades including mercury poisoning among mirror makers, miner's pneumoconiosis, lead-poisoning of potters and printers, silicosis of stonemasons, breast cancer in nuns, etc.

Orfila (1787 - 1853) has been identified as the founder of toxicology - Spanish physician who first described the systematic correlation between the chemical and biological attributes of poisons. He was a pioneer in chemistry and jurisprudence (he introduced the need for chemical analysis as proof of lethal intoxication). He worked on the detection of metallic and plant derived poisons and his work led to the use of autopsy material for detecting accidental and intentional poisonings.

Sir Percival Potts (1714 - 1788) was an English surgeon who first described a high incidence of scrotal cancer in chimney sweeps. This resulted from accumulation of coal soot in the skin folds of the scrotum and perineum. The finding of this association resulted in one the first documented legislations aimed at decreasing occupational disease.

            Rudolf Peters (1929-) developed 2,3-dimercaptopropanol, also known as dimercaprol or British anti-Lewisite (BAL) - antidote to the arsenic containing war gas blistering agent, Lewisite, (dichloro-[2-chlorovinyl]-arsine). BAL acts as a source of sulfhydryl groups which chelate with arsenic and a variety of toxic heavy metals.

Paul Muller - a Swiss chemist is credited with the discovery in 1939 of DDT, dichlorodiphenyltrichloroethane, a synthetic biologically and environmentally persistent organochlorine insecticide. DDT was widely used in agriculture and as a vector control agent for vector borne diseases, (malaria, yellow fever, typhus and sleeping sickness in particular). DDT is recognized as the single synthetic chemical with the greatest impact upon public health as a result of vector control. In 1972 a ban was placed upon DDT because of it’s bioaccumulation and devastating effects upon the reproduction of raptors, predatory birds at the top of the food chain. DDT was/is a remarkably safe insecticide from the point of view of acute mammalian toxicity.

German chemists, Willy Lange and Gerhard Schrader developed organophosphorus insecticides in the 1930’s. These agents were initially adopted by the Ministry of Defense as agents of war or nerve gases. Subsequent to the ban on DDT use, these much more acutely toxic agents began to replace DDT with a resultant trade off between DDT’s environmental threat and the organophosphates’ human toxicity threat.

Harriet Hardy was an Occupational Physician and community activist in the first half of the 20th century who recognized and strived to eliminate community and industrial lung diseases from beryllium dust from the fluorescent bulb industry. She coined the phrase: "Industrial toxins do not stop at the factory gates."

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. By 1500 BC, written evidence indicated that hemlock, opium, arrow poisons, and certain metals were used to poison enemies or for state executions.

With time, poisons became widely used—and with great sophistication. Notable poisoning victims include Socrates, Cleopatra, and Claudius. By the time of the Renaissance and the Age of Enlightenment, certain concepts fundamental to toxicology began to take shape. Noteworthy in this regard were the studies of Paracelsus (~1500AD) and Orfila (~1800 AD).

Paracelsus determined that specific chemicals were actually responsible for the toxicity of a plant or animal poison. He also documented that the body's response to those chemicals depended on the dose received. His studies revealed that small doses of a substance might be harmless or beneficial whereas larger doses could be toxic. This is now known as the dose-response relationship, a major concept of toxicology. Paracelsus is often quoted for his statement: "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy."

Orfila, a Spanish physician, is often referred to as the founder of toxicology. It was Orfila who first established a systematic correlation between the chemical and biological properties of poisons of the time. He demonstrated effects of poisons on specific organs by analyzing autopsy materials for poisons and their associated tissue damage.

The 20th century is marked by an advanced level of understanding of toxicology. DNA (the molecule of life) and various biochemicals that maintain body functions were discovered. Our level of knowledge of toxic effects on organs and cells is now being revealed at the molecular level. It is recognized that virtually all toxic effects are caused by changes in specific cellular molecules and biochemicals.