Toxicology What is toxicology? The study of the effects of poisons. Poisonous substances are produced by plants, animals, or bacteria. Phytotoxins Zootoxins Bacteriotoxins Toxicant - the specific poisonous chemical. Xenobiotic - man-made substance and/or produced by but not normally found in the body.

Introduction Toxicology is arguably the oldest scientific discipline, as the earliest humans had to recognize which plants were safe to eat. Most exposure of humans to chemicals is via naturally occurring compounds consumed from food plants. Humans are exposed to chemicals both inadvertently and deliberately.

You Know ? 92% of all poisonings happen at home. The household products implicated in most poisonings are: cleaning solutions, fuels, medicines, and other materials such as glue and cosmetics. Certain animals secrete a xenobiotic poison called venom, usually injected with a bite or a sting, and others animals harbor infectious bacteria. Some household plants are poisonous to humans and animals.

History 2700 B.C. - Chinese journals: plant and fish poisons 1900-1200 B.C. - Egyptian documents that had directions for collection, preparation, and administration of more than 800 medicinal and poisonous recipes. 800 B.C. - India - Hindu medicine includes notes on poisons and antidotes. 50-100 A.D. - Greek physicians classified over 600 plant, animal, and mineral poisons.

History 50- 400 A.D. - Romans used poisons for executions and assassinations. The philosopher, Socrates, was executed using hemlock for teaching radical ideas to youths. Avicenna (A.D. 980-1036) Islamic authority on poisons and antidotes. 1200 A.D. - Spanish rabbi Maimonides writes first-aid book for poisonings, Poisons and Their Antidotes

History Swiss physician Paracelsus (1493-1541) credited with being “the father of modern toxicology.” “All substances are poisons: there is none which is not a poison. The right dose differentiates a poison from a remedy.”

The Dose Makes the Poison An apparently nontoxic chemical can be toxic at high doses. (Too much of a good thing can be bad). Highly toxic chemicals can be life saving when given in appropriate doses. (Poisons are not harmful at a sufficiently low dose).

Lethal Doses Approximate Lethal Doses of Common Chemicals (Calculated for a 160 lb. human from data on rats) Chemical Lethal Dose Sugar (sucrose) 3 quarts Alcohol (ethyl alcohol) 3 quarts Salt (sodium chloride) 1 quart Herbicide (2, 4-D) one half cup Arsenic (arsenic acid) 1-2 teaspoons Nicotine one half teaspoon Food poison (botulism) microscopic Source: Marczewski, A.E., and Kamrin, M. Toxicology for the citizen, Retrieved August 17, 2000 from the World Wide Web: www.iet.msu.edu/toxconcepts/toxconcepts.htm.

History Italian physician Ramazzini (1713) published “De Morbis Artificum” (Diseases of Workers) describing "asthma" in bakers, miners, farmers, gilders, tinsmiths, glass-workers, tanners, millers, grain-sifters, stonecutters, ragmen, runners, riders, porters, and professors. Ramazzini outlined health hazards of the dusts, fumes, or gases that such workers inhaled. The bakers and horse riders described by Ramazzini would today probably be diagnosed as suffering from allergen-induced asthma. The lung diseases suffered by most of the other workers would now be classified as "pneumoconiosis," a group of dust-related chronic diseases.

History Spanish physician Orfila (1815) established toxicology as a distinct scientific discipline.

History 20th Century Paul Ehrlich –developed staining procedures to observe cell and tissues and pioneered the understanding of how toxicants influence living organisms.

History 20th Century Rachel Carson - alarmed public about dangers of pesticides in the environment.

Occupational and Environmental Toxicology Environmental toxicants (air and water pollutants) are substances harmful to the environment and to humans. Environmental toxicants are both natural and man made. Public perception that man-made ones are more serious than natural ones - Reality: both are serious. 5,000,000 yearly deaths worldwide due to bacterial toxicants (Salmonella, E. coli)

Occupational and Environmental Toxicology Many examples of diseases associated with specific occupations were recorded in antiquity, but they were not considered serious because the health of the workers was not a societal concern. - Paracelsus - Miner’s Disease (1533) - Hill & Pott (1761 &1775) - Radium dial painters, “aniline dye” workers (1900) - Shoe salesmen (1950s) - Industrial chemical workers (1940-present)

Occupational and Environmental Toxicology - Paracelsus - Miner’s Disease (1533) came from inhaling metal vapors, foundation for the field of chemotherapy. - Hill (1761) linked tobacco (snuff) to cancer. - Pott (1775) linked scrotal cancer and soot (benzo(a)pyrene) in chimney sweeps.

Occupational and Environmental Toxicology Industrial chemical workers (1940-present) Workers typically are exposed to a greater number of carcinogens for longer periods of time. Occupations with high risk of cancer : Health care workers, pharmaceutical and laboratory workers, refinery workers, rubber workers, furniture makers, and pesticide workers.

1961 - Society of Toxicology Modern Toxicology 1961 - Society of Toxicology 1970s - EPA, FDA, and NIOSH

Toxicology Terms Toxicity - The adverse effects that a chemical may produce. Dose - The amount of a chemical that gains access to the body.

Toxicology Terms Exposure – Contact providing opportunity of obtaining a poisonous dose. Hazard – The likelihood that the toxicity will be expressed.

Threshold Effects for Dose Dose-Response Relationships Is there such a thing as a ‘safe’ dose?? Agent A Agent B Response “NOEL” (No Observable Effect Level) Dose

Fundamental Rules of Toxicology Exposure must first occur for the chemical to present a risk. The magnitude of risk is proportional to both the potency of the chemical and the extent of exposure. “The dose makes the poison” (amount of chemical at the target site determines toxicity).

Exposure Concepts Different toxic responses may arise from different: Routes of exposure. Frequencies of exposure. Duration of exposure (acute vs. chronic).

Routes of Environmental Exposure Ingestion (water and food) Absorption (through skin) Injection (bite, puncture, or cut) Inhalation (air)

Chemicals, Chemicals Everywhere Everything in the environment is made of chemicals. Both naturally occurring and synthetic substances are chemical in nature. People are exposed to chemicals by eating or swallowing them,breathing them, or absorbing them through the skin or mucosa. People can protect themselves by blocking these routes of exposure.

Duration & Frequency of Exposure Duration and frequency are also important components of exposure and contribute to dose. Acute exposure - less than 24 hours; usually entails a single exposure Repeated exposures are classified as: Subacute - repeated for up to 30 days Subchronic - repeated for 30-90 days Chronic -repeated for over 90 days

Exposure to chemicals may come from many sources: Exposure Concepts Exposure to chemicals may come from many sources: Environmental Occupational Therapeutic Dietary Accidental Deliberate

Children & Poisons

Individual Responses Can Be Different The variety of responses among organisms that get the same dose of chemical is due to individual susceptibility. Dose and individual susceptibility play roles in all situations involving chemicals, including those making medicine and caffeine.

Introduction to Xenobiotics *Recall: Foreign chemicals are synthesized within the body are termed xenobiotics (Gr.Xenos meaning “strange”)* Xenobiotics may be naturally occurring chemicals produced by plants, microorganisms, or animals (including humans). Xenobiotics may also be synthetic chemicals produced by humans. Poisons are xenobiotics, but not all xenobiotics are poisonous.

How Does the Body Prevent the Actions of Xenobiotics ? 1) Redistribution 2) Excretion – (primarily water soluble compounds) - kidney and liver 3) Metabolism – the major mechanism for terminating xenobiotic activity, and is frequently the single most important determinant of the duration and intensity of toxic responses to a xenobiotic. - LIVER, kidney, lung, GI, and others Note: 1) and 2) are highly dependent upon 3)

Xenobiotics at Work TOXICOKINETICS Xenobiotic Excretion

General Scheme of Xenobiotic Metabolism Lipophilic Hydrophilic (parent compound) (metabolite) Metabolism Decrease biological activity 2) Increase excretability Phase I Phase II (oxidative) (synthetic) Metabolites Metabolites size ionization water solubility Increase excretability Bioactivation Detoxification polarity functionality Detoxification

How Xenobiotics Cause Toxicity Some xenobiotics cause toxicity by disrupting normal cell functions: Bind and damage proteins (structural, enzymes) Bind and damage DNA (mutations) Bind and damage lipids React in the cell with oxygen to form “free radicals” which damage lipid, protein, and DNA

Types of Toxic Effects Death - arsenic, cyanide Organ Damage - ozone, lead Mutagenesis - UV light Carcinogenesis - benzene, asbestos Teratogenesis - thalidomide

Target Organ Toxicity Central Nervous System – lead Immune System - isocyanates Liver - ethanol, acetaminophen Respiratory Tract - tobacco smoke, asbestos, ozone Eye - UV light (sunlight) Kidney - metals Skin - UV light, gold, nickel Reproductive System – dibromochloropropane

Mechanistic Toxicology How do chemicals cause their toxic effects?

What Do Toxicologists Do? Most toxicologists work to develop a mechanistic understanding of how chemicals affect living systems: Develop safer chemical products Develop safer drugs Determine risks for chemical exposures Develop treatments for chemical exposures Teach ( e.g. other toxicologists, graduate students, and youth)

What Do Toxicologists Do? Mechanistic toxicologists study how a chemical causes toxic effects by investigating its absorption, distribution, and excretion. They often work in academic settings or private industries and develop antidotes. Descriptive toxicologists evaluate the toxicity of drugs, foods, and other products. They often perform experiments in a pharmaceutical or academic setting. Clinical toxicologists usually are physicians or veterinarians interested in the prevention, diagnosis, and treatment of poisoning cases. They have specialized training in emergency medicine and poison management.

What Do Toxicologists Do? Forensic toxicologists study the application of toxicology to the law. They uses chemical analysis to determine the cause and circumstances of death in a postmortem investigation. Environmental toxicologists study the effects of pollutants on organisms, populations, ecosystems, and the biosphere. Regulatory toxicologists use scientific data to decide how to protect humans and animals from excessive risk. Government bureaus such as the FDA and EPA employ this type of toxicologist. ?

Regulatory Toxicology Use data from descriptive and mechanistic toxicology to perform risk assessments. Concerned with meeting requirements of regulatory agencies. Industry/government interactions.

Review Toxicology is the science that studies the harmful effects of overexposure to drugs, environmental contaminants, and naturally occurring substances found in food, water, air, and soil. Main objectives are to establish safe doses and determine mechanisms of biologic action of chemical substances. A career in toxicology involves evaluating the harmful effects and mechanisms of action of chemicals in people, other animals, and all other living things in the environment. This work may be carried out in government, private industry and consulting firms, or universities and other research settings. Toxicologists routinely use many sophisticated tools to determine how chemicals are harmful. (e.g.) computer simulations, computer chips, molecular biology, cultured cells, and genetically-engineered laboratory animals .

What Is the Risk? People can make some choices about chemical exposure; however, some exposure is controlled at a level other than an individual one. Collective groups of people, such as communities and governments, seek to control chemical exposure on a community or global level.

Animals in Research “Virtually every medical achievement of the last century has depended directly or indirectly on research in animals.” U.S. Public Health Service

Summary Toxicology is a fascinating science that makes biology and chemistry interesting and relevant. Understanding HOW (i.e. mechanism) something produces a toxic effect can lead to new ways of preventing or treating chemically-related diseases. Animal use in research is essential for medical progress. Many diseases are the result of an interaction between our genetics (individual variability) and chemicals in our environment. Toxicology provides an interesting and exciting way to apply science to important problems of social, environmental, and public health significance.

Toxicology or Environmental Health Science is a “hook” to interest your students in science and nonscience curricula.

Hook The science of toxicology provides a fantastic pedagogical opportunity to do true ‘interdisciplinary’ teaching, to make relevant many of the exciting biological discoveries that occur everyday. Whether it is exploring the wonders of the biology of DNA and heredity, or the more mundane aspects of acid-base chemistry, or the ethical, legal, and social implications of genetic testing for common diseases such as cancer or Alzheimer's -

Hook or the global ecological implications of species extinction; or social risks and benefits of genetically modified foods - or diagnosing the cause of the Mad Hatter’s strange behavior in Lewis Carol’s ‘Alice in Wonderland’ (mercury poisoning)- or the fall of the Roman Empire (lead poisoning), toxicology and environmental health science provide an interesting “hook” to make the subject matter – what ever it may be – interesting and relevant to your students.

Your Role NIEHS, SOT, and PEER feels the responsibility to help educate the next generation of citizens to better understand the world around them, and especially to understand how chemicals – man-made or natural – present both risks and benefits to society. Of course, everything we eat, drink, breathe, touch, or use is made of chemicals, so the task is LARGE! We hope to make the science of toxicology ‘less obscure’ to the public.

Your Role Risk is a part of everyday life, and one’s decisions as to the ‘acceptability’ of a particular risk is influenced by knowledge and experience. While we can’t do much about the ‘experience part’, we can try to increase the public’s knowledge about the risks and benefits of all things chemical. You play a critical role in this effort, and we can’t do it without YOU.

The power of EDUCATION

National Institute of Environmental Health Sciences Texas Rural Systemic Initiative The Center for Environmental and Rural Health Partnership for Environmental Education and Rural Health College of Education, Texas A&M University College of Veterinary Medicine at Texas A&M University