Michael H. Dong MPH, DrPA, PhD

1. Toxicologic Side of Epidemiology (5th 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 toxicologic side of epidemiology. • Study the toxicologic relevance through three historical epidemics. • Learn the impact of toxicology, which is dynamic and case-dependent.

4. Performance Objectives • Able to describe the epidemiologic course of the three historical events presented. • To characterize the toxicologic side of these courses and events. • To outline the purpose as well as the principles of presenting the three historical epidemics.

5. Three Case Studies for Toxicologic Side of Epidemiology: 1. Pellagra 2. Thalidomide 3. AIDS/HIV

6. Pellagra:History and Clinical Manifestations • A nutritional disease caused by deficiency of niacin; in the old days related to poor corn diet. • Clinical manifestations: dermatitis, diarrhea, dementia, and death. • First reported in 1735, by a Spanish physician named Don Gaspar Casal.

7. Pellagra: The Epidemiology • Recognized as a nutritional disease in 1913, when over 30,000 cases with a mortality rate of 40% already occurring in South Carolina alone. • Socioeconomic prides prevented earlier Spanish from accepting the poverty reality; obsession with infectious disease in medical community also ignored a classic proof that pellagra is not contagious.

8. Pellagra: The Toxicologic Side • Dietary studies in orphanages showed that the lack of a nutritional factor was responsible for the disease. • Niacin as pellagra-preventative factor was identified in 1935, through the induction of black tongue in dogs (an animal disease having syndrome comparable to human pellagra).

9. Pellagra: The Impact of Toxicology • That niacin is a pellagra-preventative factor is important to the prevention of pellagra. • That nicotinic acid, nicotinamide, and tryptophan are biochemically related to one another also has a great impact on the prevention.

10. Pellagra: The Lesson • Nutritional toxicology includes the effects of dietary deficiency. • A disease like pellagra could be caused in part by political world’s resistance on accepting poverty as the culprit. • It could also be caused by medical community’s obsession with infectious disease or other beliefs, until certain toxicologic facts become available.

11. Thalidomide: History and Manifestations • It is a tranquilizer and a notorious human teratogen. • It can cause fetal phocomelia and amelia if taken during pregnancy. • Causal association was established in 1960-1961. • Today it is used for leprosy treatment and as an immunosuppressant drug.

12. Thalidomide: The Epidemiology • The drug as the notorious human teratogen was implicated primarily by results of three epidemiologic studies. • Two studies in Germany: Lenz and Knapp (1962); Weicher et al. (1962). • One study in Australia: McBride (1963). • All showed much higher incidence when taking thalidomide during pregnancy.

13. Thalidomide: The Toxicologic Side • Animal studies showed thalidomide’s teratogenicity to be specific to species, to their tissues, and to time of exposure. • These animal studies are critical not only for elucidation of mechanism of teratogenicity, but also because such toxicity could be related functionally to a chemical’s structure.

14. Thalidomide: The Impact of Toxicology • Helping refine regulatory requirements for developmental testing. • No longer treating genetic inheritance as a primary causal explanation for birth defects. • Now tremendous increase in research on xenobiotic teratogens.

15. Thalidomide: The Lesson • More stringent preclinical testing protocols are needed. • Such protocols could have prevented the thalidomide tragedy and the like. • Chemically-induced cases without characteristic appearance could escape attention, unless preclinical toxicity data are available to lend support.

16. AIDS/HIV: History and Clinical Manifestations • Global epidemic of one of the most devastating of all diseases. • AIDS is a medical condition in which the immune system suffers a progressive and often fatal failure; initially caused by HIV infection. • Occurring as early as in 1950s in Africa, the first report of 31 AIDS-like cases was published in the USA in 1981.

17. AIDS/HIV: The Epidemiology • Spread rapidly from a few cases in the USA in 1981, and now worldwide. • As of 1997, the reported cases reached 1.7 million; of these, 50% were from Americas and 35% from Africa. • The major route of HIV transmission involves sexual contact by homosexuals (60-65%), followed by needle sharing among drug users (25-30%).

18. AIDS/HIV: The Toxicologic Side • AIDS is caused by infection of HIV, which was identified in patients by Galo and Montagnier in 1983-1984. • The causal evidence satisfies essentially all Koch’s postulates for identifying an infectious disease agent. • Rapid self reproduction of HIV on the T4 white blood cells, but with a fatal slow effect on the immune system.

19. AIDS/HIV: The Impact of Toxicology • Enlightens us about the long average (8 years) incubation of AIDS, or shorter by nutrition, stress; and about such toxic responses as weight loss, skin rashes, lack of resistance to infection, etc. • Enables us to develop antiviral drugs to reduce the viral load, and drugs that can delay certain fatal opportunistic infections.

20. AIDS/HIV: The Lesson • AIDS/HIV infection continues to rise worldwide and rapidly. • The major route of HIV transmission is sexual contact with HIV-positive partners, followed by sharing needles among drug users. • For cure and prevention, social choice apparently has opted to conducting more toxicologic research, rather than relying on changes in lifestyle.

21. Overview of Next LectureEpidemiologic Side of Toxicology • Through three toxicologic cases, to spotlight the importance as well as the relevance of epidemiology to toxicologic investigation. • Also to reemphasize the somewhat arbitrary distinction between the two (toxicologic vs. epidemiologic) sides.