Michael H. Dong MPH, DrPA, PhD

1. Epidemiologic Side of Toxicology (6th of 10 Lectures onToxicologic Epidemiology) Michael H. Dong MPH, DrPA, PhD readings

2. Taken in the early ’90s, when desktop computers were still a luxury.

3. 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.

4. 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.

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

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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).

19. 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.

20. 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.

21. Overview of Next LecturesHuman 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.