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Introduction to Toxicology Principles
Michael A. Trush, PhD
Johns Hopkins University
Section A
What Is Toxicology?
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Definitions
! Toxicology is the study of poisons
- It developed at a time in history when agents where commonly
being used to poison “enemies”
- Lead to the development of antidotes
! Poisons are chemical/physical agents which produce adverse
responses in biological organisms
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Poison
“What is there that is not
poison? All things are poison and
nothing without poison. Solely
the dose determines that a
thing is not a poison”
— Paracelsus (1493–1541)
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We Are Exposed to Chemicals on a Daily Basis
! Some chemicals are intended for human use and exposure while
others are not (drugs vs environmental chemicals)
! All chemicals are potentially toxic; the dose makes the poison
! There are variations in the response (i.e., susceptibility) of humans
to chemicals
- Responses are determined in large part by our genetics and the
age of exposure
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Drug Toxicity: A Public Health Issue
! In the late 1950s and early 1960s, more than 10,000 children in 46
countries were born with deformities —such as phocomelia—as a
consequence of thalidomide use
! The impact in the United States was minimized when the
pharmacologist Frances Oldham Kelsey refused Food and Drug
Administration (FDA) approval for an application from Richardson
Merrell to market thalidomide, saying more study was needed
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Drug Toxicity : A Public Health Issue
! In 1953, published research showed that diethylstilbesterol (DES)
did not prevent miscarriages or premature births
! However, DES continued to be prescribed until 1971
- In that year, the FDA issued a Drug Bulletin advising physicians
to stop prescribing DES to pregnant women
- The FDA warning was based on a study published in 1971 that
identified DES as a cause of a rare vaginal cancer in girls and
young women who had been exposed to DES before birth (in the
womb)
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Drug Toxicity Remains a Major Public Health Issue
! In the United States alone, it is estimated that adverse drug
reactions affect nearly two million patients and kill about 100,000
people each year
! Acetaminophen is the most common cause of acute liver failure in
the United States and the United Kingdom
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Chemicals in Our Environment
! Concern from chemicals in the environment originally arose from
occupational exposures
! Increased production of synthetic organic chemicals—dyes, plastics,
solvents, etc.
- 1935: less than 0.15 billion kilograms
- 1995: more than 150 billion kilograms
- More than a thousand-fold in the United States alone
! Roughly 100,000 different synthetic chemicals are on the global
market
- Many others are emitted as by-products of their production,
use, or disposal
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Environmental Chemicals in Us
This image has been removed due to copyright.
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Everyday Exposures to Chemicals Occur in the Home
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Exposure Begins in Utero
! A report by the Environmental Working Group on tests of 10 samples
of umbilical cord blood taken by the American Red Cross found an
average of 287 contaminants in the blood
- Including mercury, fire retardants, pesticides, and the Teflon
chemical PFOA
! Cord blood analysis revealed protein changes in children from
mothers who smoked from those who didn’t smoke
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Exposure Begins in Utero
! Animal studies have shown that in utero exposure leads to the
development of changes in adulthood, including disease (Fetal Basis
of Adult Disease)
! Mechanism appears to be related to changes in gene expression
through epigenetic modification
- Epigenetic modifications are different from gene mutations
! Both epigenetic modifications and gene mutations result in altered
gene expression
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What Comes after Exposure?
! Clearly we are being exposed to chemicals that pose a potential risk
to our health
! Exposure in of itself is not sufficient to cause toxicity
- What comes after exposure?
! How do we determine if a chemical poses a risk to our health?
! What have classic toxicants taught us?
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