14 - Introduction to Toxicology

• Toxicology studies the adverse effects of chemicals or physical agents on living organisms
• It is known as the science of poisons

Basic Terminologies

• A toxin is a toxic substance produced by living organisms, such as rattlesnake or bee venom
• A toxicant is any chemical that can potentially produce harm, being nonspecific or affecting specific tissues or organs
• Dose dictates whether a substance is harmful; any substance can be harmful

Classification of Toxic Agents

• Toxic agents can be classified based on physical state (gas, liquid, dust), chemical stability/reactivity (explosive, flammable, oxidizer), general chemical structure (aromatic amine, halogenated hydrocarbon), and poisoning potential (extremely toxic to slightly toxic)
• Mechanisms of action include acting as an alkylating agent or cholinesterase inhibitor
• Carcinogens cause cancer, mutagens cause mutations in DNA, and teratogens cause birth defects
• Allergens cause unnecessary immune responses, neurotoxins damage the nervous system, and endocrine disruptors interfere with hormones.

Dose

• Mutations in DNA can lead to cancer, but carcinogens don't just disrupt DNA structures
• Carcinogens have a broader scope, including chemicals causing cancer without inducing DNA mutations
• The amount of a substance determines if it's beneficial or toxic
• Some substances are non-toxic until reaching certain levels
• It is the dose/amount of substance taken in that determines if it is beneficial or not

Types of Dose

• Administered dose is the amount of substance that has entered through the skin, eyes, lungs or digestive tract.
• Internal does, amount of chemical stored in body compartments.
• Dose-response relationship studies the degree of response to the amount of toxicant administered

Brief History

• Prehistoric people recognized poisonous plants/animals and used extracts for hunting/warfare
• 1500 BC: written records show hemlock, opium, arrow poisons, and metals were used to poison enemies for state executions
• c. 1198: people connected substance exposure with illness/death
• Moses Maimonides wrote about toxicology in "The Treaties of Poison and Their Antidotes"
• Renaissance & Enlightenment: fundamental toxicology concepts formed through studies by Paracelsus and Orfila
• Paracelsus (16th Century):
  • Discovered specific chemicals cause toxicity of plant or animal poison
  • The body's response depends on the dose
  • Small doses can be harmless/beneficial, larger doses can be toxic (dose-response relationship)
  • Stated all substances are poisons; the right dose differentiates a poison/remedy
• Orfila (19th Century):
  • Known as the Founder of Toxicology
  • A Spanish physician
  • Described systematic correlation between chemical and biological poison properties
  • Demonstrated poison effects on specific organs through autopsy analysis
• 20th & 21st Centuries:
  • DNA/biochemicals that maintain body functions have been discovered
  • Knowledge of toxic effects expanded to the molecular level
  • Virtually all toxic effects result from cellular molecule and biochemical changes

Areas of Toxicology

• Mechanistic Toxicology: identifies how chemicals have toxic effects with the impact on living organism's cellular, biochemical, and molecular mechanisms
• Descriptive Toxicology: uses toxicity testing for safety evaluation and regulatory requirements, establishing chemical levels that cause harm
• Regulatory Toxicology: determines if a drug/chemical poses low enough risk to be marketed and monitors certain substance effects on people and the environment
• Risk Assessment: makes sure the exposure levels of a certain chemical, is kept "as low as reasonably possible"

Frances Oldham Kelsey

• Frances Oldham Kelsey prevented US market introduction of "thalidomide", a sedative drug developed in Germany that was found to cause birth defects
• She found thalidomide data on absorption and toxicity lacking and Merell (manufacturer) had not tested on pregnant animals
• With each rejection of the drug by the FDA, news surfaced of thalidomide's adverse effects, such as nerve damaged and severe birth defects
• After 6 rejections, Merrell withdrew their application

Other Specialized Areas of Toxicology

• Forensic Toxicology: establishes cause-and-effect between a substance/drug and lethal effects
• Clinical Toxicology: concerned with diseases from short-term exposure to substances, helping clinicians understand toxic effect symptoms

Environmental Toxicology

• Environmental toxicology is a multidisciplinary study of manmade and natural chemicals' effects on health/environment, including pollutant interactions with the ecosystem

Goals of Environmental Toxicology

• Mode/site of action of a xenobiotic
• Xenobiotic: chemical foreign to an organism, external substance introduced
• Fate and transport/interaction of xenobiotic with the biosphere after release
• Effect of the xenobiotic on ecosystems

Rachel Carson & Environmental Toxicology Development

• Rachel Carson pioneered the environmental toxicology field, working for the US Fish and Wildlife Services and writing "Silent Spring (1962)"
• She observed how substances released into the environment influenced organisms' behavior/population
• National Environmental Policy Act (NEPA): passed in 1969, requiring federal agencies to assess environmental action impacts
• Environmental Protection Agency (EPA): created to enforce NEPA, issuing a partial DDT ban in 1972
• Carson asserted DDT accumulated over time, affecting genes, insects, animals consuming insects, and humans

Occupational Toxicology

• Occupational toxicology applies principles/methods to understand/manage hazards encountered at workplaces, focusing on preventing adverse worker health effects
• The goal is understanding how workers are exposed and how to protect them
• Factors include genetic characteristics, age, and nutritional status
• An occupational setting constantly interacts with workers so all existing hazards in it contribute to health disparities

Industrial Hygiene

• Industrial Hygiene is concerned anticipation, recognition, evaluation, and control of hazards present in a certain workplace
• Hierarchy of Controls from most to least effective: Elimination, Substitution, Engineering controls, Administrative Controls and PPE (personal protective equipment)