Michael H. Dong

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Epidemiologic Side of Toxicology (6th of 10
Lectures onToxicologic Epidemiology)

• Michael H. Dong
• MPH, DrPA, PhD

readings
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Taken in the early 90s, when desktop computers
were still a luxury.
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• 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.

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• 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.

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Three Case Studies for the Epidemiologic Side of
Toxicology 1. Jamaica Ginger Epidemic 2.
London Smog of 1952 3. Multistage Model of
Carcinogenesis
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• 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.

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• 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.

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• 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.

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• 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. EPAs development of a
  regulatory guideline specifically for testing
  delayed neurotoxicity.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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).

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• 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.

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• 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.

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• 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.