Module 1: General Principles

> Lecture 1: Absorption, Distribution, and Excretion (Trush)

Describe the characteristics of the various types of cellular transport

Identify the major routes of exposure and excretion of xenobiotics

State factors which affect the distribution and excretion of xenobiotics

Illustrate how consideration of PBPK modeling to estimate the level of exposure to a reactive metabolite can be used to improve the risk assessment
process

> Lecture 2: Xenobiotic Biotransformation (Trush)

Distinguish the differences between Phase I and Phase II reactions

Recognize the enzymes involved in this process and identify factors that affect this process

Recognize that one of the possible consequences of biotransformation is the conversion of xenobiotics to reactive intermediates, and that depending
upon their chemical nature, these intermediates can modify molecular targets through different mechanisms

> Lecture 3: Environmental Carcinogenesis (Kensler)

Describe the role of the environment in carcinogenesis

Discuss the multistage nature of the carcinogenic process

Relate experimental findings to humans

Apply knowledge to prevention strategies

> Lecture 4: Cancer Biomarkers and Susceptibility Factors (Kensler)

Relate the selection of biomarkers to the toxicological paradigm

Discuss analytical approaches used for measuring biomarkers of exposure to environmental carcinogens

Describe the criteria for selecting useful biomarkers for human studies

Assess the contributions of inter-individual variability in biotransformation and DNA repair to risk of cancer

Summarize the uses of biomarkers in public health research

> Lecture 5: Elements of Risk Assessment (Yager)

Describe the main components of the risk assessment process

Identify the fundamental differences in determining risk for exposure to non-carcinogens and to carcinogens

Module 2: Case Studies

> Lecture 6: Hepato and Renal Toxicology (Yager)

Describe the cellular composition and basic structure of the hepatic acinus and kidney nephron.

Describe the main functions of the liver and kidney.

Describe the mechanisms of hepatic toxicity caused by ethanol and carbon tetrachloride.

Describe the mechanisms responsible for xenobiotic-xenobiotic interactions and give specific examples.

Describe the process of lipid peroxidation.

Describe the mechanisms of hepatic and renal toxicity caused by chloroform.

Discuss the animal hepatic and renal carcinogenicity data for chloroform and describe its use for determination of very safe doses in the risk
assessment for human exposure.

Discuss the importance of considering the route of exposure and predictions derived from PBPK modeling in determinations of the very safe dose
level for human exposure.

> Lecture 7: Reproductive and Developmental Toxicology (Yager)

Describe the basic structures and cellular composition of the testis and ovary.

Describe the concept of "windows of susceptibility" or "toxic windows" for developmental toxicity.

Discuss the reproductive and developmental toxicity in humans of 3 chemicals, 1,2-dibromo-3-chloropropane, diethylstilbestrol and thalidomide.

Discuss the mechanisms of these toxicities and factors that my influence the extent of toxicity that can occur upon exposure.

Evaluate reproductive toxicity data in light of the possible mechanisms causing the adverse effects.

Better interpret the potential significance of the findings to possible adverse health effects to exposed humans.

> Lecture 8: Persistent Organic Pollutants (POPs) and Dioxins (Trush)

Recognize and differentiate between the various types of compounds classified as POPs

Identify sources of dioxins

Diagram routes of dioxin exposure to humans

Describe toxicological manifestations of dioxins

Explain why the Ah receptor (AhR) is a critical target in the mechanism of dioxin toxicity

Describe mechanisms by which dioxin could disrupt the endocrine system

> Lecture 9: Neurotoxicology (Guilarte)

Describe features of the nervous system that influence its vulnerability to neurotoxicants.

Identify structural and molecular targets of neurotoxicants.

Understand the rationale for the increased vulnerability of the developing central nervous system to neurotoxic insult.

Describe mechanisms of action for specific neurotoxicants discussed in the lecture.

> Lecture 10: Immunotoxicology (Trush)

Describe various ways chemicals affect the immune system.

Explain the organs, cells, and cytokines involved in the immune system.

Describe how cells of the immune system respond to antigen.

Describe how activation of the immune system can result in pathology.

Explain through case study examples how chemical exposures result in hypersensitivity in people.

> Lecture 11: Air Toxicants (Trush)

Identify sources of exposure and describe components related to the toxicokinetics and toxicodynamics of these two agents

Recognize the human effects related to exposure to ozone or benzene

Identify sources of benzene exposure and describe components related to the toxicokinetics and toxicodynamics of benzene

Recognize the human health effects related to exposure to benzene

Be able to identify differences between different bone marrow pathologies

> Lecture 12: Food-Borne Toxicants and Prevention in Toxicology (Kensler)

Define mycotoxin and summarize sources of exposure

Evaluate the role of mycotoxins as environmental toxins impacting human health

Describe the role of metabolism in the toxicity of the mycotoxin aflatoxin

Propose means to prevent aflatoxin-induced liver cancer in high-risk populations and apply knowledge to other environmental carcinogens

> Lecture 13: Metal Toxicology (Culotta)

Discuss a broad overview of metals in the environment and heavy metal toxicity

Describe some of the ways in which we can protect ourselves from metal poisoning, both through man-made agents and natural chelators of heavy
metals

Gain a detailed understanding of two heavy metals that have an important impact on human health: mercury and cadmium

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Readings

Primary Text (required)

Essentials of Toxicology. Klaassen CD, Watkins JB III, eds. New York: McGraw-Hill, 2003.

Additional References (not required):

Casarett and Doull's Toxicology-The Basic Science of Poisons, 6th Edition. Klaassen CD, ed. New York: McGraw-Hill, 2001.

Staying Healthy in a Risky Environment: The New York University Medical Center Family Guide. Upton AC, Graber E, eds. New York: Simon and Schuster.

Environmental Medicine: Integrating a Missing Element into Medical Education. Pope AM, Rall DP, eds. Washington DC: National Academy Press

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Readings

Textbook

Essentials of Toxicology. Klaassen CD, Watkins JB III, eds. New York: McGraw-Hill, 2003.

TOPIC

READINGS

Module 1: General Principles

Lecture 1: Absorption,
Distribution, and
Excretion

Casarett and Doull's Essentials of Toxicology

Lecture 2: Xenobiotic
Biotransformation

Casarett and Doull's Essentials of Toxicology

pages 22-26, 59-70, 98-107, and 209-211.

pages 72-74, 77-97, and 25-28.

Lecture 3:
Environmental
Carcinogenesis

Casarett and Doull's Essentials of Toxicology

Chapter 8: Chemical Carcinogenesis pages 111-130
Chapter 9: Genetic Toxicology pages 131-145

Lecture 4: Cancer
Biomarkers &
Susceptibility Factors

Perera FP. Uncovering new clues to cancer risk. Scientific

American 1996;274:54.

Lecture 5: Elements of
Risk Assessment

Casarett and Doull's Essentials of Toxicology

Chapters 2, 4, 34, and self-assessment questions
Toxicity Testing for Assessment of Environmental Agents Interim Report. National Research Council of the National
Academies, Washington DC, 2006.
Toxicity Testing in the Twenty-first Century: A vision and a
Strategy. National Research Council of the National Academies,
Washington DC, 2007.
Module 2: Case Studies

Lecture 6: Hepato &

Renal Toxicology

Casarett and Doull's Essentials of Toxicology

Hepatotoxicity, Chapter 13
Renal Toxicity, Chapter 14

Lecture 7:
Reproductive and
Developmental
Toxicology

Casarett and Doull's Essentials of Toxicology

Lecture 8: Persistent
Organic Pollutants
(POPs) and Dioxins

Casarett and Doull's Essentials of Toxicology

Lecture 9:
Neurotoxicology

Casarett and Doull's Essentials of Toxicology

Chapters 10 and 20

pages 343, 297-298, and 336-338 (organochlorine compounds)

Chapter 16

Lecture 10:
Immunotoxicology

Casarett and Doull's Essentials of Toxicology

pages 176-193 and 291-293.

Lecture 11: Air

Toxicants

Casarett and Doull's Essentials of Toxicology

pages 220-232 and 407-418.

Lecture 12: FoodBorne Toxicants and

Prevention in
Toxicology

Casarett and Doull's Essentials of Toxicology

Chapter 30: Food Toxicology, pages 431-439
Kensler T, et al: Translational strategies for cancer prevention in
liver. Nature Reviews Cancer. 2003;3:321-329.

Lecture 13: Metal

Toxicology

Casarett and Doull's Essentials of Toxicology

pages 348-353 and 355-356