mammalian toxicology: history & principles

Mammalian Toxicology: Mammalian Toxicology: History & PrinciplesHistory & Principles

Lecture 1, Fall 2006Lecture 1, Fall 2006

History and Scope of History and Scope of Toxicology: How we got hereToxicology: How we got here

ToxicologyToxicology: The study of adverse : The study of adverse effects of xenobiotics.effects of xenobiotics.

XenobioticsXenobiotics: From the Greek : From the Greek xeno (xeno (ξένοξένο) for “foreign” and ) for “foreign” and bios (bios (βίοςβίος) for “life”.) for “life”.

This discipline actually has its This discipline actually has its roots in the ancient art of roots in the ancient art of poisoning.poisoning.

Now its scope is much broader.Now its scope is much broader.

History and Scope of History and Scope of Toxicology: Different BranchesToxicology: Different Branches

Biomedical:Biomedical:– Mechanisms of actionsMechanisms of actions– Effects of exposureEffects of exposure– Understanding biological responses Understanding biological responses

through model toxic compoundsthrough model toxic compounds Public Health:Public Health:

– Recognition and identification of Recognition and identification of hazardshazards

– Occupational exposureOccupational exposure– Development and use of pesticidesDevelopment and use of pesticides

History and Scope of History and Scope of Toxicology: Different BranchesToxicology: Different Branches

Regulatory:Regulatory:– Development of exposure standardsDevelopment of exposure standards– Detection methodsDetection methods

Environmental:Environmental:– Chemical effects on plants, animals Chemical effects on plants, animals

& ecosystems& ecosystems Clinical:Clinical:

– Development of antidotes & Development of antidotes & treatmentstreatments

– Recognition of exposureRecognition of exposure

History and Scope of Toxicology: History and Scope of Toxicology: How we got hereHow we got here

Toxicology, like other disciplines, Toxicology, like other disciplines, is a mixture of science, art & is a mixture of science, art & creative thinkingcreative thinking– ScienceScience: The observational and : The observational and

data-gathering phase.data-gathering phase.

History and Scope of Toxicology: History and Scope of Toxicology: How we got hereHow we got here

– ArtArt: Utilization of the data to : Utilization of the data to predict outcomes in humans based predict outcomes in humans based on on in vitro in vitro and and in vivo in vivo studies.studies.

– Creative ThinkingCreative Thinking: Determining the : Determining the next hypothesis and how to design next hypothesis and how to design experiments to actually answer the experiments to actually answer the questions posed.questions posed.

History and Scope of History and Scope of Toxicology: How we got hereToxicology: How we got here

It is important to note that facts are It is important to note that facts are different from predictions.different from predictions.

Facts have been proven; predictions Facts have been proven; predictions are based on probabilities.are based on probabilities. They They don’t have equal value, in terms of don’t have equal value, in terms of scientific weight.scientific weight.

Toxicologists need to be careful Toxicologists need to be careful when talking to the public to make when talking to the public to make sure they don’t confuse the two!sure they don’t confuse the two!

History of Toxicology—AntiquityHistory of Toxicology—Antiquity

Humans have a long history of Humans have a long history of using poisonsusing poisons– Hemlock (Greek capital punishment), Hemlock (Greek capital punishment),

made famous by death of Socrates.made famous by death of Socrates. MilestonesMilestones

– Dioscorides—Greek physician who Dioscorides—Greek physician who classified poisons for Nero. He classified poisons for Nero. He included descriptions and drawings. included descriptions and drawings. This was a standard text for 1600 This was a standard text for 1600 years!years!


Toxicology during this time, Toxicology during this time, however, mainly focused on however, mainly focused on poisoning (suicide, state-poisoning (suicide, state-sanctioned & personal usage…)sanctioned & personal usage…)

This knowledge also lead to This knowledge also lead to antidotes.antidotes.– EmeticsEmetics ( (εμμετικόςεμμετικός)—Agent to )—Agent to

induce vomiting following induce vomiting following poisoningspoisonings


King Mithridates VI of Pontus—King Mithridates VI of Pontus—Experimented on criminals and Experimented on criminals and himself.himself.– He would drink a poison cock-tail He would drink a poison cock-tail

(36 ingredients!) to prevent (36 ingredients!) to prevent political enemies from being able to political enemies from being able to poison him.poison him.

– When ultimately captured, he had When ultimately captured, he had to resort to using his sword.to resort to using his sword.


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

History of Toxicology—Middle History of Toxicology—Middle AgesAges

Maimonides—Concept of Maimonides—Concept of bioavailabilitybioavailability: Based on the forms : Based on the forms of toxicant, or what one of toxicant, or what one eats/drinks before ingestion, the eats/drinks before ingestion, the chemical can be more or less chemical can be more or less readily available in the body.readily available in the body.– Milk, butter and cream could delay Milk, butter and cream could delay

intestinal absorption (due to the fat intestinal absorption (due to the fat content)content)

– Full stomach also delays absorptionFull stomach also delays absorption


The poisoner, in Renaissance The poisoner, in Renaissance Italy, was an integral part of Italy, was an integral part of society.society.– Toffana—Woman who sold arsenic-Toffana—Woman who sold arsenic-

laced cosmeticslaced cosmetics– Hieronyma Spara—Provided Hieronyma Spara—Provided

‘services’ to local young soon-to-be ‘services’ to local young soon-to-be widows.widows.


Catherine de Medici—Systematic study Catherine de Medici—Systematic study of the effects of poisons in the sick of the effects of poisons in the sick and poor to make sure the correct and poor to make sure the correct concoction was delivered to her concoction was delivered to her ‘customers’.‘customers’.– Noted the following:Noted the following:

Rapidity of the toxic response (Rapidity of the toxic response (onset of actiononset of action)) Effectiveness of the compound (Effectiveness of the compound (potencypotency)) Degree and specificity of response (Degree and specificity of response (site of site of

actionaction)) Complaints of victims (Complaints of victims (clinical signs and clinical signs and

symptomssymptoms))

History of Toxicology—Age of History of Toxicology—Age of EnlightenmentEnlightenment

The age of Paracelsus (1493-The age of Paracelsus (1493-1541)—Responsible for the most 1541)—Responsible for the most famous saying in all of famous saying in all of toxicology:toxicology:

All substances are poisons; All substances are poisons; there is none which is not a there is none which is not a poison. The right dose poison. The right dose differentiates a poison from a differentiates a poison from a remedy.remedy.


Paracelsus focused on the Paracelsus focused on the importance of the ‘importance of the ‘toxicontoxicon’—a ’—a primary toxic agent and a single primary toxic agent and a single chemical entity.chemical entity.

This was in contrast to previous This was in contrast to previous schools of thought that included schools of thought that included the concept of mixtures.the concept of mixtures.


Fundamental contributionsFundamental contributions::– Experimentation is essential in the Experimentation is essential in the

examination of responses.examination of responses.– There is a difference between the There is a difference between the

therapeutic and toxic properties.therapeutic and toxic properties.– The above are not easily The above are not easily

determined, except by dose.determined, except by dose.– It is possible to ascertain a degree It is possible to ascertain a degree

of specificity of chemicals and their of specificity of chemicals and their therapeutic or toxic effects.therapeutic or toxic effects.


Seminal texts:Seminal texts:– On the Miners’ Sickness and other On the Miners’ Sickness and other

Diseases of MinersDiseases of Miners (1567) by (1567) by ParacelsusParacelsusIncluded treatment and Included treatment and prevention prevention

strategiesstrategies– Discourse on the Diseases of Discourse on the Diseases of

WorkersWorkers (1700) by Bernardino (1700) by Bernardino RamazziniRamazziniSet the standard for occupational Set the standard for occupational

medicine.medicine.Also included information about Also included information about

miners, midwives, printers, weavers miners, midwives, printers, weavers and potters.and potters.


Major developments:Major developments:– 1775—Role of soot in scrotal cancer 1775—Role of soot in scrotal cancer

in chimney sweeps (due to in chimney sweeps (due to polyaromatic hydrocarbons)polyaromatic hydrocarbons)

– 1825—Synthesis of phosgene and 1825—Synthesis of phosgene and mustard gas (chemical warfare)mustard gas (chemical warfare)

– 1880—Boom in organic chemical 1880—Boom in organic chemical synthesis led to over 10,000 new synthesis led to over 10,000 new compounds (no industry testing for compounds (no industry testing for toxicity)toxicity)


Major developments:Major developments:– Orfila (1787-1853): Introduced the Orfila (1787-1853): Introduced the

use of autopsy material to use of autopsy material to toxicology to provide legal proof of toxicology to provide legal proof of poisoning.poisoning.

– Magendie (1783-1885): Detailed the Magendie (1783-1885): Detailed the absorption and distribution of absorption and distribution of various compounds in the body.various compounds in the body.

Modern ToxicologyModern Toxicology

Toxicologists must understand Toxicologists must understand aspects of biology, chemistry and aspects of biology, chemistry and metabolism.metabolism.– They tend to function as detectives who They tend to function as detectives who

must utilize many clues.must utilize many clues. Initial growth in the field spurred by Initial growth in the field spurred by

need to explain deaths occurring need to explain deaths occurring after administration of ether, after administration of ether, chloroform and carbonic acid in chloroform and carbonic acid in iatrogenic deaths. iatrogenic deaths.

IatrogenicIatrogenic: From the Greek iatros (: From the Greek iatros (ιατρόςιατρός) for ) for doctordoctor


1890s-1900s1890s-1900s– Discovery of vital amines (vitamins) led to Discovery of vital amines (vitamins) led to

the wide-spread usage of bioassays to the wide-spread usage of bioassays to determine whether these new chemicals determine whether these new chemicals were beneficial.were beneficial.

– Development of neurotoxicity field due to Development of neurotoxicity field due to the production of bootleg liquor by-the production of bootleg liquor by-products (methanol & lead).products (methanol & lead).

– Toxicology of metals due to the Toxicology of metals due to the production of ‘the bomb’.production of ‘the bomb’.


Post World War IIPost World War II– Discovery of organophosphates (OPs) as Discovery of organophosphates (OPs) as

cholinesterase inhibitorscholinesterase inhibitors..– Today used as non-bioaccumulating Today used as non-bioaccumulating

pesticidespesticides Production of quinine as an Production of quinine as an

antimalarial.antimalarial.– Based on derivative of chincona barkBased on derivative of chincona bark– First use of non-human primatesFirst use of non-human primates

Discovery of Discovery of mixed-function oxidases mixed-function oxidases (MFOs)(MFOs)– Prelude to latter work on Prelude to latter work on P450sP450s


Two major discoveries (1948):Two major discoveries (1948):– Paper chromatography for chemical Paper chromatography for chemical

separation.separation.– Use of blood and urine for testing Use of blood and urine for testing

presence of various chemical presence of various chemical metabolites (metabolites (biomarkersbiomarkers).).


Formalization of the experimental Formalization of the experimental program for the testing of food, program for the testing of food, drug and cosmetic safety in 1955.drug and cosmetic safety in 1955.– Updated by the FDA in 1982.Updated by the FDA in 1982.– Basically states that any chemical Basically states that any chemical

found to be carcinogenic in lab found to be carcinogenic in lab animals or humans cannot be added animals or humans cannot be added to the US food supply.to the US food supply.


Toxicology and Applied Toxicology and Applied PharmacologyPharmacology started around started around 1958—First journal dedicated to 1958—First journal dedicated to toxicology.toxicology.

Textbook of ToxicologyTextbook of Toxicology published in 1959.published in 1959.

Society of Toxicology (SOT) Society of Toxicology (SOT) founded in 1965.founded in 1965.


Major events in the 1960s:Major events in the 1960s:– Thalidomide babiesThalidomide babies– Silent SpringSilent Spring by Rachel Carson by Rachel Carson

Highlighted the ecological effects of Highlighted the ecological effects of pesticide usagepesticide usage

– Equipment available for detecting Equipment available for detecting parts per billion (ppb)parts per billion (ppb)

– Genetic assays for point mutations Genetic assays for point mutations (Ames assay)(Ames assay)


In the 1970s:In the 1970s:– ““Discovery” of Love Canal as a Discovery” of Love Canal as a

major dumping site for toxic major dumping site for toxic chemicals.chemicals.

– Push for toxicology to consider Push for toxicology to consider exposures to complex mixtures. exposures to complex mixtures. Recall that this shift had already taken Recall that this shift had already taken

place once—move from mixtures to the place once—move from mixtures to the toxicon. Now a movement back to toxicon. Now a movement back to mixtures.mixtures.

CurrentlyCurrently

Now a unique and separate Now a unique and separate disciplinediscipline– Offered at many graduate schoolsOffered at many graduate schools– ““Surprisingly, courses in toxicology Surprisingly, courses in toxicology

are now being offered in several are now being offered in several liberal arts undergraduate schools liberal arts undergraduate schools as part of their biology and as part of their biology and chemistry curricula.” (p 10)chemistry curricula.” (p 10)

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mammalian toxicology: history & principles

Documents

scope of toxicology

long history

history principleslecture

mammalian toxicology

different branchesregulatory

different branchesbiomedical

chemical effects

poisoning suicide