MAMMALIAN TOXICOLOGY

(Biology 666, 3 credit lecture, Spring 2002)

(3 credit Online, Spring 2003, 2005, 2007...)

Kenneth L. Campbell

Professor of Biology

M-3-322

Office Hours: W 10:00 - 1:00, and by arrangement

phone: 617-287-6676

fax: 617-287-6650

e-mail: kenneth.campbell@umb.edu

website: http://kcampbell.bio.umb.edu

Lectures: M & W 2:00 - 3:30 PM

Room: [per schedule]

Prerequisites:

General and Organic Chemistry plus General Biology and at least one advanced course in Cell Biology, Biochemistry, or Physiology; or Permission of the Instructor.

Course Description:

Mammalian Toxicology (Biology 666) is a 3 credit graduate course offered to students with appropriate prerequisites in chemistry and biology. In its first offering, the course will be given as a computer-assisted lecture with two classroom meetings per week. In subsequent offerings, the course will be offered online with two or three classroom meetings during the term.

This course provides a background in principles of toxicology as they are applied to mammalian systems. Coverage will include: basic concepts in evaluation of poisons and their commonalities with evaluations of drugs and hormones; toxicant exposure routes, uptake, sites and mechanisms of action, storage, metabolism, activation, and clearance; toxicant roles in carcinogenesis, development, endocrine, and reproductive functions; exploration of the role of diet, lifestyle, and concurrent exposures; methods of toxicant evaluation with emphasis on multigeneration and high throughput testing; and environmental and medical implications of toxicant or toxin exposures on individual and ecological health.

The course will cover basic tenets of toxicology but will also underline the similarities and commonalities of this science with those of endocrinology and pharmacology. It will emphasize the integrative nature of these disciplines and will feature the applied nature of toxicology as an investigative and regulatory science.

Course resources will include a major text but will also draw heavily on Internet resources and original papers. Case studies may be used to cover parts of the material and active discussion will be encouraged through the use of a threaded discussion and one or more writing assignments. Development of Web-based resources will be an aim in projects associated with this class.

Specific Goals:

1.	Learn the basic framework of testing and evaluation that forms the foundation of toxicology.

2.	Explore the commonalities and links between toxicology, endocrinology, and pharmacology.

3.	Demonstrate how toxicology integrates and synthesizes the knowledge gleaned from a spectrum of other disciplines and applies it to investigating the nature of and risks associated with exposure to toxicants and toxins.

4.	Investigate the problems of health and the environment encountered in mammalian systems as a result of exposure to xenobiotics.

5.	Apply the knowledge base to help uncover the existing gaps in knowledge of mammalian toxicology.

Course Evaluation:

Students will be graded on two in-class, closed book exams given as a mid-term (25%) and a final (25%). Participation in class, the online threaded discussion, and peer critiquing of student projects will constitute 15% of the grade. A writing project involving exploration of a topic jointly chosen with the instructor will constitute 35% of the grade. The project will be submitted as an .HTML compatible document that explores a gap or questionable aspect of current toxicological practice or a topic that will not be covered fully within the context of the course, e.g., appropriateness for classifying toxicants as initiators, promotors, or progressors of carcinogenesis; current knowledge of the impact of phytoestrogens on apoptosis within the rat endometrium; or the molecular relatedness of P450 enzymes involved in Type I metabolism across multiple species as ascertained using online molecular databases. This document can use figures, models, and tables as well as a narrative argument to make or illustrate points. It should incorporate standard references for all texts and journal articles cited as well as complete URLs for Internet or Web resources. No materials should be copied or reproduced without alteration in production of this document. The penultimate version of the project should be submitted electronically one month prior to the end of the term. This will be critiqued by the instructor and at least two student peers. The final version of the project will be due at the time of the final and must be submitted electronically. The documents may be added to the course Website at the end of the term including appropriate information on their authorship. During the term, Website access to the threaded discussion or to critiques of the writing project will require use of a password to be distributed at the beginning of the term. Communications with the instructor may occur in person, via e-mail, or via links within the course web pages.

Students are expected to take in-class exams on the dates scheduled. Should there be an unavoidable problem, the Instructor may, at their discretion provide a makeup exam or a second project. Attendance and participation during in class lectures is expected. For the Online course, an expectation is that a total of at least 3 hours per week will be spent interacting with material posted on the Website. In both situations, prior reading of assigned materials and familiarity with linked Internet sites is expected prior to scheduled meeting times.

Readings:

Chapters in assigned texts will be indicated within the syllabus. These provide some background for the lectures or weekly meetings. These will be supplemented by readings in other texts, journal articles, or Web documents. Whenever possible, these will be drawn from sources that are accessible through the Internet or in every science library. In other instances, I will have a copy in my office or available in the Biology Offices.

Required Text:

Casarett & Doull's Toxicology: The Basic Science of Poisons, 6th Ed. C.D. Klaassen. McGraw-
Hill:New York, NY. 2001. 1236 pp. ISBN 0-07-134721-6.

Supplemental Texts:

(Readings may be drawn from these. However, they are listed here as a source for more extended reading, not necessarily for acquisition in association with this course.)

Silent Spring. R. Carson. Fawcett Crest: New York, NY. 1970. [Many other editions are available.]

Our Stolen Future. T. Colburn, D. Dumanoski, J.P. Myers. Penguin Books: New York, NY. 1997.

Hormonally Active Agents in the Environment. Committee on Hormonally Active Agents in the Environment, Board on Environmental Studies and Toxicology, Commission on Life Sciences, National Research Council. National Academy Press: Washington, D.C. 1999.

Endocrine and Hormonal Toxicology. P.W. Harvey, K.C. Rush, A. Cockburn. John Wiley & Sons Ltd.: Chichester, UK. 1999.

Casarett & Doull's Toxicology: The Basic Science of Poisons, 5th Ed: Companion Handbook. C.D. Klaassen, J.B. Watkins III. McGraw-Hill: New York, NY. 1999.

Generations at Risk: Reproductive Health and the Environment. T. Schettler, G. Solomon, M. Valenti, A. Huddle. The MIT Press: Cambridge, MA. 1999.

Toxicology for the Next Millennium. R.J. Isfort, J. Lederberg. Annals of the New York Academy of Sciences, Volume 919. New York Academy of Sciences: New York, NY. 2000.

Hormonal Chaos: The Scientific and Social Origins of the Environmental Endocrine Hypothesis. S. Krimsky. Johns Hopkins University Press: Baltimore, MD. 2000.

Pills, Potions, Poisons: How Drugs Work. T. Stone, G. Darlington. Oxford University Press: Oxford, UK. 2000.

Introduction to Biochemical Toxicology, 3rd Ed., E. Hodgson, R.C. Smart. John Wiley & Sons, Inc.: New York, NY. 2001.

Toxicology Secrets: Questions You Will Be Asked ... on Rounds, in the Ed, on Bedside Oral Exams.

L.J. Ling, R.F. Clark, T.B. Erickson, J.H. Trestrail III. Hanley and Belfus, Inc.: Philadelphia, PA. 2001.

SCHEDULE FOR MAMMALIAN TOXICOLOGY

Biology 666, Spring 2002

#	Day	Date	Topic	Text Readingsa
1	M	01/ 28	Organization, passwords, e-mail addresses, overview of course, projects. Definition and derivation of toxicology and sister sciences endocrinology and pharmacology.	C 1, 2
2	W	01/30	Modes of exposure, elimination, bioavailability, partition	C 3, 5, 7
3	M	02/04	Intercellular chemical communication: hormone, receptor, transducer, effector; agonist, antagonist	C 3
End of Add/Drop
4	W	02/06	Interconnections of transduction mechanisms	C 3
5	M	02/11	Organismal regulation, feedback circuits	C 20, 21
6	W	02/13	Cell cycle controls: current models	C 3
M	02/18	President's Day Holiday
7	W	02/20	Cell death: necrosis, apoptosis	C 3, 10, 18, 20
8	M	02/25	Neural and immune function overview	C 3, 12, 16, 19
9	W	02/27	Biochemistry of toxicant metabolism, enterohepatic circulation	C 5, 6, 7, 13
10	M	03/04	Gamete production in mammals	C 9, 20
11	W	03/06	Gestation in mammals	C 10, 20
12	M	03/11	Mid-Term Exam
13	W	03/13	Finalization of Writing Project Choices.	--
03/16-24	Spring Break
14	M	03/25	Physiologic dose-response; derivation of mono- and multiphasic forms	C 2, 21
15	W	03/27	Mammalian toxicity testing: in vivo, in vitro, multigeneration	C 2, 8, 9, 10, 20
16	M	04/01	Molecular methods, high throughput testing	C 9, 31
17	W	04/03	Stress and dose interactions	C 10
F	04/05	Course Withdrawal Deadline
18	M	04/08	Diet as modulator or mode of exposure	C 10
19	W	04/10	Developmental status/age and toxicity	C 10, 29
M	04/15	Patriot's Day Holiday
20	W	04/17	Project Drafts Due. Predispositions to toxic risk	C 4, 9
21	M	04/22	Moderators of toxic risk	C 4, 9
22	W	04/24	Carcinogenesis : Are the toxicity models correct?	C 8, 9, 25
23	M	04/29	Discussion of Draft Projects	--
24	W	05/01	Discussion of Draft Projects	--
25	M	05/06	Adequacy of models for developmental toxicity	C 10, 29
26	W	05/08	Steroid disruptors: estrogen, androgen, progestin, corticoid	C 20, 21, 29
27	M	05/13	Thyroid, retinoid and other disruptors	C 10, 20, 21
28	W	05/15	Final Projects Due. Summary Discussion.
05/20-24	Final Exam Period/ Final Exam
a Readings in Casarett & Doull's Toxicology: The Basic Science of Poisons, 6th Ed., Klaassen, 2001, McGraw-Hill: New York, NY, are shown in this table. Additional suggested readings are given in the list that follows.

Additional Readings:

Session 1. Introduction

Paracelcius

Koch's Postulates

Session 2. Exposure/Elimination

Routes: Pharmacology Review

Bound vs Free & Albumin Bound

Binding Proteins

Ekins models

Session 3. Intercellular Communication

Receptors, Check from Mendelson bibliography in Griffin & Ojeda

Effectors, Review of intercellular communications

Session 4. Interconnections of transduction mechanisms

Session 5. Organismal regulation

Session 6. Cell cycle controls

Weinberg's papers

Session 7. Cell death

Review of Cellular Pathology

Review of Apoptosis

Session 8. Neural and immune function

Review of neural function and action potentials

Review of soluble immunity

Review of cellular immunity

Session 9. Toxicant metabolism

Review of phase I and phase II metabolism

P450s

Web URLs/Documents on steroid metabolism

Nebert

Search on Human Genome Map

Session 10. Gamete production

Review of folliculogenesis and oogenesis

Review of spermatogenesis

Session 11. Gestation

Review of Fertilization

Review of Nidation

Review of Embryogenesis

Review of Organogenesis

Review of Sex Deteremination

Review of Parturition

Session 14. Dose-responses

Monphasic vs biphasic e.g.,GH, corticoids, phytoestrogens, vitamin A

Session 15. Toxicity testing

Review of acute testing

Review of chronic testing

Session 16. Analytical methods

High throughput testing: Chip technique limitations & possibilities

Schena, M., DNA Microarrays: A Practical Approach, Oxford University Press:New York, 1999.

PCR

Sequencing

Human Genome

Transgenics

Microbial Strains

Microtiter Screens of Cells

Microcircuit implants

Alza minipumps

Multiplexed Immunoassays/Chemical Assays

Session 17. Stress/dose interactions

Review of impact of stress on endocrine system

Stress impact on immune system

Stress impact on neural system

Stress impact on digestive system

Session 18. Diet

Gut transit impacts (Britte)

Fiber components

Lipid components

Protein and carbohydrate components

Micronutrients

Session 19. Development and age

Review

Science 2001, Epigenetics Issue

Session 20. Predispositions to toxic risk

BRCA 1 Review

Metabolic

Ecological

Female Alcohol dehydrogenase paper

Session 21. Moderators of toxic risk

Coexposures, medications

Nebert

Gilbert

Insect toxicity

Genetic/Enzymatic makeup

Session 22. Carcinogenesis models

Weinberg's papers

Vogelstein

Session 25. Developmental toxicity models

Importance of maternal exposure

Exposure of mother vs fetus

Importance of timing

Acute vs chronic or delayed exposures

Session 26. Steroid disruptors

Spearow, Science, 2000

Soto

Session 27. Other hormone disruptors

Thyroid function, PCBs, PBBs

Retinoid mimics

Protein hormone mimics??