Transcript Toxicology and Epidemiology (1st of 10 lectures on toxicological

Epidemiologic Side
of Toxicology
(6th of 10 Lectures on
Toxicologic Epidemiology)
Michael H. Dong
MPH, DrPA, PhD
readings
Taken in the early ’90s, when desktop computers were still a luxury.
Learning Objectives
• Appreciate the importance of the
epidemiologic side of toxicology.
• Study the epidemiologic relevance
through three historical events.
• Learn the impact of epidemiology,
which is dynamic, case-dependent,
and often tremendous.
Performance Objectives
• Able to describe the toxicologic
course of the three historical events
presented.
• To characterize the epidemiologic
side of these courses and events.
• To outline the purpose as well as
the principles of presenting the
three toxicologic events.
Three Case Studies for
the Epidemiologic Side
of Toxicology:
1. Jamaica Ginger Epidemic
2. London Smog of 1952
3. Multistage Model of
Carcinogenesis
Ginger Paralysis:
Syndrome & Cause
• Characterized by ataxia, muscular
weakness, unsteady gait, flaccid
paralysis of the legs.
• Also known as jake leg, wrist drop,
and foot drop.
• Caused by exposure to TOCP, with
delayed onset of 1 to 3 weeks.
Ginger Paralysis: History
and Toxicity
• The syndrome known for a century;
and later, as ginger paralysis due to
its first major episode in the USA.
• TOCP is the most toxic isomer of
TCP; both, like some other OP, can
induce delayed neurotoxicity.
• The initial effects likely involve the
inhibition of neurotoxic esterase.
Ginger Paralysis: The
Epidemiologic Side
• 20,000 cases reported in the USA in
1930, related to consumption of illegal
alcohol contaminated with TOCP.
• 10,000 cases reported in Morocco in
1959, related to consumption of food
cooked in oil contaminated with TOCP.
• The association was initiated by two
Oklahoma doctors: Miles and Goldfain.
Ginger Paralysis: The
Impact of Epidemiology
• It was the first major epidemic that
enabled Smith et al. to focus on
TOCP as the prime suspect.
• A large number of toxicology
studies were hence launched, along
with U.S. EPA’s development of a
regulatory guideline specifically for
testing delayed neurotoxicity.
Ginger Paralysis: The
Lesson (and Speculation)
•Despite the Jamaica ginger episode,
there were still numerous outbreaks
involving cooking oil contaminated
with TOCP.
•Delayed neurotoxicity is extremely
specific to chemical structure.
•It was epidemiologic evidence that
advanced the toxicology of TOCP.
London Smog: History
& the Epidemic
• 4,000 premature deaths, with most
being elderly or having preexisting
diseases, from breathing heavily
polluted air in London in 1952.
• Smog is a mixture of smoke and fog,
now also involving the equally irritating
photochemical air pollution.
• Air pollution is predictable, and was
recognized back in the Roman period.
London Smog: Toxicity
of the Air Pollutants
• Sulfur dioxide is an upper airway
irritant.
• Carbon dioxide is a potent asphyxiant.
• Nitrogen dioxide causes severe
irritation of the innermost parts of the
lungs.
• Ozone is a reactive and toxic form of
elemental oxygen.
London Smog:
Other
Pollutants & Newer Problems
• Other pollutants: suspended particulate
matter (e.g., black smoke); and volatile
organic compounds (e.g., petroleum
benzene as an exhaust product).
• 1.6 million people may now be at risk
from poor air quality in urban areas
throughout the world.
• There are also areas everywhere filled
with traffic-generated pollutants.
London Smog: The
Impact of Epidemiology
• The 1952 incident led to the passage of
the British Clean Air Act of 1956.
• More epidemiologic studies have since
been conducted to cope with air
pollution problems and episodes.
• Also more studies on long-term toxic
effects and on photochemical formation.
London Smog: The
Lesson
• The older winter smog problem in
London and worldwide is now
being replaced with summer smogs
from photochemical formation.
• The adverse health effects of the
winter or summer air pollutants
cannot be investigated using classic
toxicology studies alone.
Multistage Model: The
Course of Carcinogenesis
• Carcinogenesis is the biochemical
process characterizing the progression
of normal cells to neoplastic and later
into tumor cells.
• Multistage model is a quantitative as
well as a mechanistic theory used to
characterize this biochemical process.
• Two of the stages basic to the model are
presumably initiation and promotion.
Multistage Model: The
Underlying Theories
• In addition to being an initiator or a
promoter, an agent initially can be a
precarcinogen and later be transformed
into a harmful ultimate carcinogen.
• Initiation is usually irreversible, of short
duration, and invisible, whereas
promotion has the opposite effects.
• As an outgrowth of the challenge to the
single stage and the multicell theories.
Multistage Model: The
Epidemiologic Side
• The single stage model and the multicell
model were found to be incompatible
with epidemiologic data.
• Although the multistage model is based
on a single cell theory, its development
was driven by epidemiologic data that
many cancer incidences increased with
the 5th or 6th power of age (that also
implicating latency period).
Multistage Model: The
Relevance and Impact
• Gaining wide acceptance due to the
strong evidence that cancer is a single
cell in origin.
• Useful as a quantitative tool in the
cohort analysis of tumors induced by
chemicals.
• Found for the large part successful in
describing many experimental and
epidemiologic data.
Multistage Model: The
Lesson & Its Utilities
• Leading to the use of more proper
mitigation measures; and to the
adoption by regulatory agencies for
cancer risk assessment.
• Toxicologists using animal studies,
without this epidemiology-based
theory, would likely fail to elucidate
or make fuller use of the mechanistic
process of carcinogenesis.
Overview of Next Lectures
Human Exposure
Assessment I & II
• Human exposure assessment is one of
the key components in the health risk
assessment.
• Lecture 7 (Assessment I) will cover the
direct measurement methods.
• Lecture 8 (Assessment II) will focus on
the indirect measurement methods.