LECTURE 1B: Introduction to Toxicology + Poisons

Define toxicology

• The study of harmful effects of drugs, chemicals + poisons on biological systems

What can toxicological studies determine and help evaluate? What do they for the most part deal with?

• Toxicological studies can 

  • DETERMINE the adverse effects of chemical agents upon subcellular, systemic, physiological or behavioral processes in an individual organism 

  • OR can help evaluate their impact on large populations

• Principally (For the most part) deals with understanding the potential hazards of poisons, toxins, drugs of abuse, negative effects of medications, + health ramifications of environmental pollutants

What are the 5 major fields of toxicology?

• Environmental toxicology - air, water, soil

• Consumer toxicology - foods, cosmetics, drugs

• Clinical toxicology - prescription medication

• Forensic toxicology - investigation of death, poisoning + drug use

• Analytical toxicology - quantitative + qualitative analysis of poisons

Why is Paracelsus important? What did Paracelsus’ studies reveal? Define dose-response relationship

• (1493 - 1541

• Swiss physician + alchemist

• His studies revealed that

  • Small doses of a substance might be harmless or beneficial, whereas larger doses could be toxic 👈

  • This is known as the dose-response relationship, a major concept of toxicology 

Why is Mathieu Orfila important? What did he develop?

• 1787 - 1853

• The ‘father of toxicology’

• Lead the way towards the establishment of the scientific foundation of modern toxicology

• Studied the biological & chemical characteristics of multiple toxic substances 

• Developed & applied methods of chemical analysis of postmortem materials to determine whether the death was caused by a toxic substance 👈

• In 1813 he wrote the first paper on the detection of poison + its effect on animals

• Was the first to identify arsenic in the human body

Why is Alexander Gettler important? What did he do.publish?

1883-1968)

The first U.S. toxicologist

Worked for the Office of Chief Medical Examiner of the City of New York (OCME) between 1918 and 1959

Published “The Toxicology of Cyanide,” in the American Journal of the Medical Sciences

He is considered the first to publish significant research on the effects of cyanide in the human body 👈

Still referenced in current day

Define toxicant

• Substances producing undesirable/toxic biological effects

• May be chemical, physical, or biological in nature

• Used when talking about toxic substances produced by or are a by-product of human activities

Define toxic

• Venoms are produced by living organisms

• Usually are proteins/peptides in origin

• Injected unto another biological system via bite or sting (natural/biological substance)

Define poison

• Produced by organic (living) or inorganic (nonliving) things

• May be natural or synthetic (man-made/created in a laboratory)

• Requires small quantities; immediate effects are observed

What is Xenobiotic? (important)

• A substance that is foreign to the body or to an ecological system

  • EX) drugs, pesticides, food additives, + pollutants

• May produce beneficial effects (pharmaceuticals) or they may be toxic (mold)

What 3 factors influence exposure to Xenobiotics?

• Number of doses

• Frequency

• Total treatment period

What are the 4 types of exposures to Xenobiotics? Define them

1. Exposure Dose

   • Amount of xenobiotic found in environment (ppm)

2. Administered Dose

   • Quantity given usually orally or by injection; or inhaled. If present in gaseous form (not that a dose taken orally may not necessarily be totally absorbed)

3. Absorbed Dose (or internal Dose)

   • Amount of a substance that entered the body (via the skin, eyes, lungs, or digestive tract) + was taken up by organs or specific tissues

4. Total Dose

   • Sum of all individual doses

What is the significance of poison?

• Poisoning is a significant problem in the United States

• Leading cause of unintentional injury death, surpassing car accident mortality

• Fatal and nonfatal poisonings overwhelmingly occur among adults = largely attributed to the opioid epidemic in the United States

  • 41% of poisoning exposures involve children 5 years of age or younger

  • 92% of nonfatal poisonings and 98% of fatalities are adults > 19 years of age

What are 3 ways poison can get into the body? What is important to know about doses and poisons? (important)

• Poisons have many ways to get into the body: can be swallowed, inhaled, or absorbed through the skin

  • Some substances are toxic in small doses, but other usually harmless substances can be poisonous if encountered in large enough amounts 👈

  • Poisoning can occur in almost any setting, from any substance + in any form (liquid, solid or gas)

What can a toxicologist do when evaluating factors to determine if a chemical is harmful? (important)

• Several factors need to be considered to determine if exposure to a chemical/drug/toxin might be harmful

• A toxicologist can help evaluate these factors

  • Investigate whether a specific chemical/drug/toxin is the cause of harm (or death) to an individual, group of people, or other living species (eg, dogs, farm animals)

  • Help establish mode of injury/death

  • Identify where the exposure occurred + institute ways to mitigate further danger

Explain the graph - Governed by the principles of: Absorption, Distribution, Metabolism + Excretion (ADME)? Identify the factors that affect toxicity

How Do We Measure the Toxicity of a Substance? Define LD50 and LC50 (important)

• What is LD₅₀? 

  • Lethal Dose (single oral dose; for solids)

  • The amount of a material, given all at once, which causes the death of 50% of the test population

  • Normally expressed as milligrams of substance per kilogram of animal body weight (mg/kg)

• What is LC₅₀?

  • Lethal concentration (short exposure; for gases/liquids)

  • Concentration dose in environment required to kill 50% of a test population

  • Normally expressed as milligrams of substance per liter of air or water (mg/L or parts per million, or PPM)

What are substances with an LD50 of less than 100mg/kg/body weight called? What does a Higher LD50 and Lower LD50 mean in regards to toxicity?

• Substances with an LD₅₀ of < 100 mg/kg/body weight are called poisons

• Higher LD₅₀ = Decreasing toxicity (15,000mg/kg)

  Lower LD₅₀ = Increasing toxicity (5mg/kg)

How do we calculate LD50 values? important

Step 1: Convert weight in pounds to kilograms. Use the following conversion factor: 2.2 lb = 1 kg

Step 2: Find the LD50 of Vitamin D3 from the chart (it is 37 mg/kg)

Step 3: Therefore, the lethal dose for 50% of 165 lb (75kg) adults is (weight of adult in kg x LD50)

What is a Dose-Response Curve? Included image

• Shows the relationship between the amount of a substance consumed or exposed to + its effect on a biological system

What is NOAEL?

No Observed Adverse Effect Level (NOAEL)

Highest dose at which no toxic or negative effects are seen

What is Chemical Potency? What does it describe?

• A measure of the capacity of a chemical substance/drug/toxic agent to exert an effect, described in terms of the relationship between the dose used and the magnitude of the resulting effect

• Simply put: chemical potency describes the intensity of effect produced by a specific chemical substance/drug/toxic agent dose (the amount of drug required to produce an observed response)

• For instance, if 5 milligrams of Drug A relieves pain as effectively as 10 milligrams of Drug B, Drug A is said to be twice (2X) as potent as Drug B 

• Drug A is “MORE STRONGER” than Drug B

What is Chemical Efficacy?

• Efficacy is the capacity for a chemical/drug/toxic substance to produce an effect (biological change, which can be either beneficial or harmful)

• (ability of a drug to reach its maximal effect or response)

• Drug A would be considered a better blood pressure-lowering agent than Drug B

• Drug A does it job more efficiently/quicker than Drug B

What happens when you combine drugs/poisons with different potencies? (4). Define additive response, synergistic response, potentiated response, and antagonistic response

• Additive response: 

  • a combination of two or more chemicals is the sum of the expected individual responses

• Synergistic response: 

  • exposure to one chemical causes a dramatic increase in the effect of another chemical

• Potentiated response: 

  • exposure to one chemical results in the other chemical producing an effect greater than if given alone

• Antagonistic response: 

  • a combination to one chemical results in a reduction in the effect of the other chemical

Key takeaways

• All substances can be a poison

  • This is dependent on the dose, which makes a poison

    • The dose, in turn, determines the resulting response

• The extent of the effect of poison/or drug is dependent upon the concentration (amount) of the substance at its site of action (where in the body the poison takes effect) over time

  • This is known as Absorption, Distribution, Metabolism & Excretion

    • This is abbreviated by toxicologists as ADME

      • Individual biological/genetic variations in an organism will affect ADME
        

• Every drug/poison has its own characteristics that make it uniquely suited to do its job

  • Knowing the LD50 is a good measure for determining the toxicity/lethality of a substance

  • How strong + how well a poison works is a function of two main factors: potency + efficacy, respectively

    • Poisons/drugs can be combined to make their efficacy stronger or, in some cases, unchanged, or less than when they are given individually!