MOLECULAR MECHANISMS OF ENVIRONMENTAL TOXINS
BSCI 273
Fall 2004
COURSE SYLLABUS
Professor Wallace M. LeStourgeon
w.m.lestourgeon@vanderbilt.edu
Office (Biological Sciences Bldg 5269) Phone (2-2588)
Introduction: Course rationale.
The fundamental problem: The earth is 4.57 billion years old. While bipedal primates have existed for
4-6 million years, until about 4000 BC, modern primates (humans) existed in small dispersed groups
probably rarely exceeding a few thousand individuals. In the past 200 years (a hiccup in geological
time) the human population has entered an exponential growth phase.
In 1650, about 500 million humans inhabited the earth. In the following 200 years the population
doubled to 1 billion. The population doubled to 2 billion between 1850 and 1930 and again to 4
billion by 1975. Today there are about 6,177,607,223 humans on the planet and this number is
increasing at a rate of 3 people per second or about 95 million each year. Y6B occurred October 12,
1999. 95 million new people each year corresponds to more than eleven new New York cities per
year. By 2050 nine billion people will inhabit the earth. At no time in earth’s history has a single
species so dominated the biosphere. More importantly, we now move mountains, redirects rivers,
farms desserts and rain forests, and alters atmospheric chemistry on a global scale.
Human Population Growth
5
2000
000
4
3
P opul ation
(B illi ons)
2
The Plague
8000BC
4000BC 3000BC 1000BC
0
AD 1000
1
AD 2000
In the ascent of mankind, an inescapable fact of social development is that economic growth is directly
proportional to and therefore encourages population growth. This is the major reason our borders
have been open to immigrants for the past 20 years. Modern cultures do not know how to uncouple
economic growth from population growth nor can they change the basic elements of human behavior
that fuel the engine for economic growth. We are motivated by our egos, misguided values, and greed
to acquire wealth far beyond our personal needs (yachts, 5000 sq.ft. homes, etc).
As the current inhabitants of space ship Earth, we are motivated to understand the biological problems
arising from high population density due to the severity of its consequences. For example: As a result
of human activity, in the last 30 years the atmospheric CO2 concentration has increased more than
11%. Microbubbles in the Greenland ice cap demonstrate that CO2 concentrations were stable for
many thousands of years (at 280 ppm) until about 1800. In 1957 [CO2] was 315 ppm and today it is
362 ppm. Fossil fuel combustion alone now adds over 6 billion metric tons of CO2 annually to the
atmosphere. Of equal significance, human activities now fix nitrogen from the atmosphere at a rate
near 100 million metric tons per year. It is estimated that in 1940 human activities fixed almost no
nitrogen and that half of all the nitrogen ever fixed by human activities has occurred since 1980.
Ultimately, CO2 - and nitrous oxide (N2O)-induced earth warming (the green house effect) will limit
human population growth through land and food crop loss. The preceding two decades were back to
back the warmest decades in recorded history.
Toxic environments limit population growth through many mechanisms: In addition to humaninduced atmospheric alterations, until the early 1940’s organic compounds with covalently bound
halogen (chlorine, fluorine, bromine) were exceedingly rare on the earth’s surface (some
environmentalists argue that, “God knew better than to link chlorine to a benzene ring”). Today these
compounds are the most abundant of all man made molecules (type and amount). In the United States,
the concentration of chlorocarbons and flame retardants in normal human breast milk is so high that it
can not (based on EPA guidelines) be sold in stores for human consumption. In the past 20 years
halogenated hydrocarbons are alone responsible for a 10% depletion of atmospheric ozone (O3). This
chemical activity may limit population growth because released chlorine, fluorine, bromine (and
nitrous oxide) act as never-ending cyclical catalysts. While we often hear of increased cancer due to
UV irradiation, the population-limiting effect of ozone depletion (enhanced UV irradiation) will
actually be due to the loss of plant and animal life.
A classic means of limiting population growth is shortened life span. Today, in industrialized
countries, one man in two will be diagnosed with cancer in his lifetime and this “age-independent”
incidence continues to increase. At this writing, one in eight women will develop breast cancer alone.
Without question, more than 98% of all human cancers result from chemical-induced somatic
mutations in the genes that regulate the cell cycle (oncogenes). Interestingly, the “cause” of cancer
was deduced in the 1950s as was its increase in incidence. Today, the general public is completely
unaware of the 50% cancer incidence rate, and that 98% of all cancers are caused by mutagens in the
environment. The first convincing evidence for cancers environmental etiology was seen in the
acquisition of local cancer incidence rates by immigrants. Today, unequivocal evidence that 98% of all
cancers are caused by environmental mutagens, has come from our ability to identify the mutated
oncogenes in an individuals cancerous cells and compare them to the same genes in neighboring
normal cells . We often hear that today, humans are living longer than ever. This is false. Humans
have no greater life span potential today than a 5 thousand years ago (probably less). “”Longevity”
(the average age at death for a population group) has increased in the past 50 years but this is entirely
due to antibiotics and better diagnostic procedures.
More than 63,000 chemical compounds are commonly used in the U.S. today. No information exists
on the biological effects of more than 50,000 of these chemicals and about 1,000 new chemicals per
year are waived into common use without testing for their effects on human and environmental health.
The EPAs latest Toxics Release Inventory shows that more than 23,000 industrial facilities in the US
alone release 3.2 billion pounds of known toxic pollutants into the air, soil and waterways per year.
This figure is derived from voluntary reports by only the largest corporations on just 300 or so
chemicals. Estimates of the US’ total yearly emission of toxic chemicals from all sources, legal and
illegal, are in the neighborhood of 22.5 billion pounds. The intent of the Clean Water Act enacted in
1972 was “zero discharge” of known toxic agents. In response to powerful financial concerns and a
sympathetic administration, this act has been quietly gutted by Congress during the past 3 years.
Interestingly, the voluntary consumption of pharmaceutical compounds and recreational drugs are
major culprits in the etiology of human cancer.
Limiting population growth by decreased fertility and potency. In comparison to their fathers at
the same age, today in certain industrialized areas and in farming areas where atrazine is widely used,
young males produce half as much normal sperm and this appears to be associated with decreased
libido and sexual potency in young men. Apparently related to sperm decline in humans and domestic
animals is: the early onset of puberty in females, the unprecedented increase in testicular, prostate, and
breast cancer, the production of eggs in the testes of male trout harvested from rivers near cities, and
undeveloped male genitals in reptiles of the Florida everglades. A wide variety of man made
molecules are now known to possess both estrogenic and androgenic activity.
What to do? While the mechanisms mentioned above will ultimately slow population growth, the
quality of life will be miserable by today’s standards for many generations. In order to identify the
most significant health threats that exist naturally in our environment and that arise from human
activities and high population densities, we must understand the molecular mechanisms of all
environmental toxins. In other words, how xenobiotic (foreign to life, or non-biological) compounds
act to interfere with normal biochemical processes at the cellular, organismal, and ecosystem levels.
With this knowledge we can identify those substances that must be strictly avoided and with this
knowledge we may be able to develop antidotes and strategies to minimize the effects of environmental
toxins. If all the numerous human cancers could be cured with a simple painless biochemical/genetic
therapy would we fear environmental carcinogens? Would it be fair to the animals that must exist in
increasing volumes of human waist but that can not be so treated? With knowledge, we can
objectively address these and many other questions. With knowledge we can strive to safeguard our
own health and, hopefully with knowledge, we can educate our peers in an objective manner. Herein
lies the rationale for BSCI 273.
Course Objectives: In order to understand the molecular mechanisms of action of environmental
toxins it is first necessary to identify their subcellular targets (i.e. the cellular receptors or
macromolecules that are bound by the toxic agent). Secondly it is important to understand the forces
that direct binding specificity and that determine binding affinity. With this information in hand it is
often possible to identify the metabolic pathway involved and to predict the physiological magnitude of
the toxic effect. This semester we will study the toxicology of a representative number of xenobiotic
agents. While detailed biochemical information is available for only a few of the thousands of
environmental chemicals, we often can make good predictions as to a new molecules toxicity and mode
of action by comparing its molecular structure and chemical properties to those of well characterized
molecules.
It is not an objective of this course to berate industry or industrialists. We will; however, on several
occasions consider the conflicting positions of “industrial conservatives” and “environmental
conservatives”. We will also consider examples of overt directed efforts to misinform the public in an
effort to continue the manufacture and distribution of environmental toxins (i.e., lead, pesticides,
alcohol, nicotine, formaldehyde, and many others). The adage “caveat emptor” is as valid today as in
the past. However, in the past this advice applied to a single individual. Today it applies to mankind.
These discussions will constitute the Science and Society component of the course.
Some important incidentals: There is no textbook for this course. All lectures will be PowerPoint
presentations and hard copies of each presentation will be handed out in class and posted on the
internet. During the last half of the semester original research articles, and review articles on specific
subjects will be studied. Much of the basic information presented this semester can be found in the
reference list at the end of this syllabus.
Course Grade: The course grade will be based on two hour examinations, a 6-10 page term paper and
15 minute in-class presentation, and a final examination. The paper and presentation will count as one
hour examination (22% of course grade). Regarding the paper/presentation each student in
consultation with the professor may select either a specific environmental toxin, class of toxins, or
toxicological phenomenon for detailed study (history, rationale for production, use, distribution,
toxicology, and politics). The final exam will comprise one-third of the course grade and it will be
comprehensive.
LECTURE TOPICS, READING ASSIGNMENTS AND IMPORTANT DATES
August
Wed. 25
Fri. 27
Mon. 30
Introduction, Course Objectives, The Fundamental Problem (population and greed)
The absorption, distribution, biotransformation, and elimination of chemical compounds.
Biotransformation, Cytochrome P450 and first pass, and phase I and II bioactivation.
September
Wed. 1
Fri. 3
Mon. 6
Wed. 8
Fri. 10
Mon. 13
Wed. 15
Fri. 17
Mon. 20
Wed. 22
Fri. 24
Mon. 27
Wed. 29
The mechanism of action of xenobiotic compounds – Receptors, ligands, binding affinities
and specificity, binding assays.
Receptor-activated pathways and ligand-receptor interactions.
Principles of toxicology - the dose response relationship.
Chemical carcinogens - types and mechanisms - risk assessment.
Risk assessment continued.
Chemicals acting at synaptic and neuroeffector junctions. The sympathetic and
parasympathetic nervous systems.
Continued.
Neurotransmission - axonal conduction, chemical blockade and specific toxins and
pesticides.
Cholinergic transmission
Adrenergic transmission and desensitization
Chemicals that interfere with acetylcholinesterase, organophosphates and other pesticides
Test I
Heavy metals defined, environmental sources, contaminant levels
October
Fri. 1
Mon. 4
Wed. 6
Fri. 8
Mon. 11
Wed. 13
Fri. 15
Mon. 18
Wed. 20
Fri. 22
Mon. 25
Wed. 27
Fri. 29
Heavy metals: mechanisms of toxicity
DNA repair enzymes, polymerases, and tumor suppressor denaturation (heavy metal
mutagenesis)
Air pollutants, solvents.
Solvents continued.
Pesticides
Pesticides continued.
Endocrine disrupters.
Fall Break
Xenobiotics, immunotoxins, and autoimmune disease.
Autoimmune disease continued.
Mutagenic pharmaceuticals.
Test
Cell cycle controls.
November
Mon. 1
Wed. 3
Fri. 5
Mon. 8
Wed. 10
Fri. 12
Mon. 15
Wed. 17
Fri. 19
Mechanisms of chemical carcinogens.
Assays for chemical carcinogens.
Chemical carcinogens continued.
Who gets cancer, genetic polymorphisms.
Polymorphisms continued.
TBA
Film
Film
TBA
Mon. 22-Fri. 26 Thanksgiving holidays
Mon. 29 Group presentations begin
December
Wed 1 and Friday 3, Presentations Continue
Mon 6 Last class day and last presentation,
course overview, information for final exam.
Final Exam: Friday, December 17 @ 9:00 A.M.
References:
Mechanistic Toxicology. Urs A. Boelsterli. Taylor and Francis Group. London and New York, 2003
Essentials of Toxicology (Casarett and Doull’s). Curtis D. Klaassen and John B. Watkins III, eds. McGraw-Hill, 2003
Guide to Cytochromes P450 (Structure and Function). David F. V. Lewis. Taylor and Francis Group, London. 2001
Reactive Oxygen Metabolites, Chemistry and Medial Consequences. Manfred K. Eberhardt. CRC Press 2000
Principles of Biochemical Toxicology (3rd Ed.). John Timbrell. Taylor and Francis Press. 2000
Environmental Toxicology and Chemistry. Donald G. Crosby. Oxford University Press. New York 1998
Pathology of Environmental and Occupational Disease. John E. Craighead. Mosby-Year Book, Inc. St. Louis. 1995
Molecular Toxicology. P. David Joseph. Oxford University Press, New York, N.Y. 1997
Disposition of Toxic Drugs and Chemicals in Man. (4th Ed.). Baselt & Carvey, eds. Chemical Toxicology Institute, Foster
City, CA. 1995
Perspectives in Environmental Chemistry. D.L. Macalady, Oxford University Press, Inc. New York. 1998
Goodman and Gilman’s The Pharmacological Basis of Therapeutics. J.G. Hardman and Lee E. Limbird editors in chief.
Ninth Edition. McGraw-Hill. 1996
Medical Toxicology. Matthew J. Ellenhorn. Williams and Wilkins, Baltimore. 1997
Handbook of Carcinogenic Potency and Genotoxicity Databases. L.S. Gold and E. Zeiger, eds. CRC Press, New York. 1997
Origins of Human Cancer. H.H. Hiatt, J.D. Watson, J. A. Winsten, eds. Cold Spring Harbor Press. Cold Spring Harbor, N.
Y. 1977
Clinical Management of Poisoning and Drug Overdose. Second Edition. L. M. Haddad and J. F. Winchester, eds. W.B.
Saunders Co. Philadelphia 1990
Toxic Deception. D. Fagin and M. Lavelle. Birch Lane Press. 1996
Fertility on The Brink. The National Wildlife Federation, Washington D.C., 1994
Cancer at a Crossroads: A Report to Congress for the Nation. National Cancer Advisory Board. 1994
The Environmental Safety Guide: Hazardous Chemical Waste Management - Guide for Vanderbilt Personnel. Department
of Institutional Safety. Environmental Safety Section. 1994