Mammalian Toxicology: History & Principles

Mammalian Toxicology: History & Principles Lecture 1, Fall 2006

History and Scope of Toxicology: How we got here • Toxicology: The study of adverse effects of xenobiotics. • Xenobiotics: From the Greek xeno (ξένο) for “foreign” and bios (βίος) for “life”. • This discipline actually has its roots in the ancient art of poisoning. • Now its scope is much broader.

History and Scope of Toxicology: Different Branches • Biomedical: • Mechanisms of actions • Effects of exposure • Understanding biological responses through model toxic compounds • Public Health: • Recognition and identification of hazards • Occupational exposure • Development and use of pesticides

History and Scope of Toxicology: Different Branches • Regulatory: • Development of exposure standards • Detection methods • Environmental: • Chemical effects on plants, animals & ecosystems • Clinical: • Development of antidotes & treatments • Recognition of exposure

History and Scope of Toxicology: How we got here • Toxicology, like other disciplines, is a mixture of science, art & creative thinking • Science: The observational and data-gathering phase.

History and Scope of Toxicology: How we got here • Art: Utilization of the data to predict outcomes in humans based on in vitro and in vivo studies. • Creative Thinking: Determining the next hypothesis and how to design experiments to actually answer the questions posed.

History and Scope of Toxicology: How we got here • It is important to note that facts are different from predictions. • Facts have been proven; predictions are based on probabilities. They don’t have equal value, in terms of scientific weight. • Toxicologists need to be careful when talking to the public to make sure they don’t confuse the two!

History of Toxicology—Antiquity • Humans have a long history of using poisons • Hemlock (Greek capital punishment), made famous by death of Socrates. • Milestones • Dioscorides—Greek physician who classified poisons for Nero. He included descriptions and drawings. This was a standard text for 1600 years!

History of Toxicology—Antiquity • Toxicology during this time, however, mainly focused on poisoning (suicide, state-sanctioned & personal usage…) • This knowledge also lead to antidotes. • Emetics (εμμετικός)—Agent to induce vomiting following poisonings

History of Toxicology—Antiquity • King Mithridates VI of Pontus—Experimented on criminals and himself. • He would drink a poison cock-tail (36 ingredients!) to prevent political enemies from being able to poison him. • When ultimately captured, he had to resort to using his sword.

History of Toxicology—Antiquity • Poisonings were so rampant in Rome, a law was enacted in 82BC. It made poisoning illegal, and later extended to careless dispensers of drugs (an early regulatory effort!)

History of Toxicology—Middle Ages • Maimonides—Concept of bioavailability: Based on the forms of toxicant, or what one eats/drinks before ingestion, the chemical can be more or less readily available in the body. • Milk, butter and cream could delay intestinal absorption (due to the fat content) • Full stomach also delays absorption

History of Toxicology—Middle Ages • The poisoner, in Renaissance Italy, was an integral part of society. • Toffana—Woman who sold arsenic-laced cosmetics • Hieronyma Spara—Provided ‘services’ to local young soon-to-be widows.

History of Toxicology—Middle Ages • Catherine de Medici—Systematic study of the effects of poisons in the sick and poor to make sure the correct concoction was delivered to her ‘customers’. • Noted the following: • Rapidity of the toxic response (onset of action) • Effectiveness of the compound (potency) • Degree and specificity of response (site of action) • Complaints of victims (clinical signs and symptoms)

History of Toxicology—Age of Enlightenment • The age of Paracelsus (1493-1541)—Responsible for the most famous saying in all of toxicology: • All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.

History of Toxicology—Age of Enlightenment • Paracelsus focused on the importance of the ‘toxicon’—a primary toxic agent and a single chemical entity. • This was in contrast to previous schools of thought that included the concept of mixtures.

History of Toxicology—Age of Enlightenment • Fundamental contributions: • Experimentation is essential in the examination of responses. • There is a difference between the therapeutic and toxic properties. • The above are not easily determined, except by dose. • It is possible to ascertain a degree of specificity of chemicals and their therapeutic or toxic effects.

History of Toxicology—Age of Enlightenment • Seminal texts: • On the Miners’ Sickness and other Diseases of Miners (1567) by Paracelsus • Included treatment and prevention strategies • Discourse on the Diseases of Workers (1700) by Bernardino Ramazzini • Set the standard for occupational medicine. • Also included information about miners, midwives, printers, weavers and potters.

History of Toxicology—Age of Enlightenment • Major developments: • 1775—Role of soot in scrotal cancer in chimney sweeps (due to polyaromatic hydrocarbons) • 1825—Synthesis of phosgene and mustard gas (chemical warfare) • 1880—Boom in organic chemical synthesis led to over 10,000 new compounds (no industry testing for toxicity)

History of Toxicology—Age of Enlightenment • Major developments: • Orfila (1787-1853): Introduced the use of autopsy material to toxicology to provide legal proof of poisoning. • Magendie (1783-1885): Detailed the absorption and distribution of various compounds in the body.

Modern Toxicology • Toxicologists must understand aspects of biology, chemistry and metabolism. • They tend to function as detectives who must utilize many clues. • Initial growth in the field spurred by need to explain deaths occurring after administration of ether, chloroform and carbonic acid in iatrogenic deaths. • Iatrogenic: From the Greek iatros (ιατρός) for doctor

Modern Toxicology • 1890s-1900s • Discovery of vital amines (vitamins) led to the wide-spread usage of bioassays to determine whether these new chemicals were beneficial. • Development of neurotoxicity field due to the production of bootleg liquor by-products (methanol & lead). • Toxicology of metals due to the production of ‘the bomb’.

Modern Toxicology • Post World War II • Discovery of organophosphates (OPs) as cholinesterase inhibitors. • Today used as non-bioaccumulating pesticides • Production of quinine as an antimalarial. • Based on derivative of chincona bark • First use of non-human primates • Discovery of mixed-function oxidases (MFOs) • Prelude to latter work on P450s

Modern Toxicology • Two major discoveries (1948): • Paper chromatography for chemical separation. • Use of blood and urine for testing presence of various chemical metabolites (biomarkers).

Modern Toxicology • Formalization of the experimental program for the testing of food, drug and cosmetic safety in 1955. • Updated by the FDA in 1982. • Basically states that any chemical found to be carcinogenic in lab animals or humans cannot be added to the US food supply.

Modern Toxicology • Toxicology and Applied Pharmacology started around 1958—First journal dedicated to toxicology. • Textbook of Toxicology published in 1959. • Society of Toxicology (SOT) founded in 1965.

Modern Toxicology • Major events in the 1960s: • Thalidomide babies • Silent Spring by Rachel Carson • Highlighted the ecological effects of pesticide usage • Equipment available for detecting parts per billion (ppb) • Genetic assays for point mutations (Ames assay)

Modern Toxicology • In the 1970s: • “Discovery” of Love Canal as a major dumping site for toxic chemicals. • Push for toxicology to consider exposures to complex mixtures. • Recall that this shift had already taken place once—move from mixtures to the toxicon. Now a movement back to mixtures.

Currently • Now a unique and separate discipline • Offered at many graduate schools • “Surprisingly, courses in toxicology are now being offered in several liberal arts undergraduate schools as part of their biology and chemistry curricula.” (p 10)

Possible Short Research Topics

Mammalian Toxicology: History & Principles