Introduction to Toxicology

Toxicology

• Toxicology studies the adverse effects of chemicals or physical agents on living organisms and the underlying mechanisms.
• Paracelsus, the father of toxicology, stated in the 1500s that "All substances are poisons; there is none that is not a poison. The right dose differentiates a poison from a treatment."
• Key principles of toxicology include chemical form, routes and sites of exposure, duration and frequency of exposure, and dose-response effects.

Toxicity

• The term "toxicity" describes the nature of an adverse effect produced and the necessary conditions for its production.
• A substance must contact a body surface such as skin, eye, or mucosa of the alimentary or respiratory tract before toxicity can develop.
• "Toxic" relates to poisonous or deadly effects on the body.
• A "toxicant" refers to toxic substances produced by or are a by-product of human-made activities.
• A "toxin" refers to toxic substances produced naturally.

History

• From 50-400 AD Roman used poisons for executions and assassinations.
• The philosopher Socrates was executed via hemlock for teaching radical ideas to youths.
• Avicenna (980-1036 AD), an Islamic authority, wrote on poisons and antidotes.
• In 1200 AD, Spanish rabbi Maimonides wrote the first-aid book for poisonings called "Poisons and Their Antidotes".

Toxicity vs. Hazard

• Toxicity: The ability of a substance to have an adverse health effect.
• Hazard: The probability that a concentration will occur at that site in the body.
• Chemicals can have the same toxicity but different hazards.
• Chemicals with warning properties may present a lesser degree of hazard.

Toxicology Study

• Toxicology studies how toxicants enter the organism, how they affect the organism, and how they are eliminated from the organism.
• The right dose differentiates a poison from a remedy.
• All substances are toxic if taken in the wrong quantities.
• There are no harmless substances, only harmless ways of using substances.
• 8.3% of all deaths are due to environmental exposure to certain chemicals annually (2016-17 UNO data).
• Major contributors include indoor smoke from solid fuel, outdoor air pollution, secondhand smoke, occupational particulates, chemicals in acute poisonings, and pesticides in self-poisonings.

How Toxicants Enter an Organism

• Environmental exposure to selected chemicals causes 8.3% of all deaths each year (2016-2017).
• Major contributors to this statistic are indoor smoke from solid fuel use, outdoor air pollution and second-hand smoke, occupational particulates, chemicals used in acute poisonings, and pesticides used in self-poisonings.
• Toxicants can enter an organism through ingestion, inhalation, injection, or dermal absorption.
• Ingestion occurs when toxicants enter through the mouth or stomach, then into the blood, and can controlled by enforcing rules on eating, drinking, and smoking.
• Inhalation occurs when toxicants enter through the mouth or nose, then into the blood, and can be controlled by using ventilation, respirators, and other personal protection equipment.
• Injection occurs when toxicants enter through cuts in the skin, then into the blood, and can controlled by wearing proper protective clothing.
• Dermal absorption occurs when toxicants enter through the skin, then into the blood, and can controlled by wearing proper protective clothing.
• The greatest threats in industry from the four routes of entry are exposure through the inhalation and dermal routes.
• The gastrointestinal (GI) tract plays a key role in toxicants entering the body through ingestion, and food or drink is the usual mechanism of exposure.
• Airborne particles (solid or liquid) can lodge in the mucous of the upper respiratory tract and be swallowed.
• The rate and selectivity of absorption by the GI tract depends on the chemical type and its molecular weight, molecule size and shape, acidity, susceptibility to attack by intestinal flora, and rate of movement through the GI tract.
• Skin plays an important role in dermal absorption and injection.

Skin Layers

• Stratum corneum is the top of the five layers making epidermis and is composed of keratinized dead cells with lipids
• The skin sheds and replaces every two weeks and depending on the part of the body its thickness is 0.05 mm to 1.5 mm.
• Most chemicals are not readily absorbed by the skin, however, some chemicals have remarkable skin permeability.
• The respiratory system plays a significant role in toxicants entering the body through inhalation.
• The main function of the respiratory system is to exchange oxygen and carbon dioxide between the blood and inhaled air.
• The gastrointestinal (GI) tract, skin, and respiratory system all play significant roles in how toxicants enter the body.

Respiratory Tract

• The upper respiratory system - nose, sinuses, mouth, pharynx (section between the mouth and esophagus), larynx (the voice box), and trachea or windpipe.
• The lower respiratory system - the lungs and smaller structures, including the bronchi and alveoli.
• Bronchi tubes carry fresh air from the trachea through branching tubes to alveoli.
• Alveoli are small, blind air sacs where gas exchange occurs with blood.
• Upper and lower respiratory tracts respond differently to toxicants.
• The upper respiratory tract is impacted most by water-soluble toxicants.
• Harmful materials react or dissolve in mucous to create acids and bases.
• Upper respiratory toxicants - hydrogen halides (hydrogen chloride, hydrogen bromide), oxides (nitrogen oxides, sulfur oxides, sodium oxide), and hydroxides (ammonium hydroxide, sodium dusts, potassium hydroxides).
• Lower respiratory toxicants - monomers (such as acrylonitrile), halides (fluorine, chlorine, bromine), and other substances such as hydrogen sulfide, phosgene, methyl cyanide, acrolein, asbestos dust, silica, etc.

Effects of Toxicants

• Acute exposure is a one-time event with rapid material absorption, sudden and severe effects, and a critical period for death/survival.
• Chronic exposure is small doses over a long time with a rate of intake larger than the rate of elimination, and material remains in tissue.

Irreversible Effects

• Carcinogen causes cancer.
• Mutagen causes chromosome damage.
• Reproductive hazard damages the reproductive system.
• Teratogen causes birth defects.

May or May not be Reversible

• Dermatotoxic affects skin.
• Hemotoxic affects blood.
• Hepatotoxic affects the liver.
• Nephrotoxic affects the kidneys.
• Neurotoxic affects the nervous system.
• Pulmonotoxic affects lungs.

Elimination of Toxins

• Toxicants are eliminated or rendered inactive through excretion, detoxification, and storage.
• Excretion occurs through the kidneys, liver, lungs, or other routes.
• Detoxification changes the chemical into something less harmful using biotransformation.
• Storage occurs in fatty tissue.
• The kidney are the dominant means of excretion in the human body, extracting toxicants from the bloodstream and excreting them with urine.
• Toxicants that are ingested into the digestive tract are frequently excreted by the liver.
• The lungs serve as a method for eliminating substances particularly volatile ones and are found in chloroform and alcohol which are partially excreted.
• Other excretion routes include the skin (via sweat), hair, and nails which are usually minor compared to the liver, kidneys, and lungs.
• The liver is the dominant organ for detoxification via biotransformation which occurs by the chemical agents transformed by reaction into either harmless or less harmful substances.
• Biotransformation reactions also occur in the blood, intestinal tract wall, skin, kidneys, and other organs.
• Storage involves depositing the chemical agent mostly in the fatty areas of the organism but also in the bones, blood, liver, and kidney.
• Storage creates a future problem if the organism's food supply is reduced and fatty deposits are metabolized; the chemical agents stored will be released into the bloodstream.

Toxicological Studies

• A primary goal is to quantify the effects of a suspect toxicant on a target organism.
• For most toxicological studies, animals are used to extrapolate results to humans.
• Once the effects of a suspect are quantified, procedures are established to ensure proper handling.
• Before a toxicological study, the toxicant, target/test organism, effects/response to be monitored, dose range, and period of the test must be identified.
• Toxicants must be identified by chemical composition and state because each state enters through a different route and requires a different study.
• No ethical way exists to get human volunteers.
• The field uses "model" systems of rats, cats, dogs, or rabbits.
• Ethical concerns hinder the production of new chemicals.

Dose vs Response

• Biological organisms exhibit varied responses to the same dose of a toxicant.
• Individual characteristics including age, gender, weight, diet, and general health influence the responses.
• The threshold dose suggests a dose or exposure level below which harmful or adverse effects are not seen in a population.
• The amount of chemical entering, or dose, is measured by mg of chemical/kg of body weight. Factors that impact the dose include environmental concentration, toxicant properties, exposure frequency and length, and the exposure pathway.
• A Gaussian or normal distribution represents the biological response to exposure to a toxicant.
• In these distributions, the standard deviation and mean characterize the shape and location.
• With less standard deviation, the distribution becomes more pronounced around the mean value.
• The response interval within 1 standard deviation of the mean represents 68% of individuals affected.
• A response interval of 2 standard deviations represents 95.5% of the total individuals affected.
• The area under the entire curve represents 100% of the individuals affected.

Dose vs Response Tests

• Tests are given to a "large" population, that receives the same dose in dose/body mass, and number or fraction of individuals that have a response is found.
• Tests are repeated using different doses until an average response is found and plotted versus logarithm of dose to form a sigmoid shaped curve.
• Lethal dose (LD) is the dose that causes death.
• Effective dose (ED) is the dose in which the response to chemical is minor and reversible.
• Toxic dose (TD) is where the response is toxic and undesirable, not lethal, but irreversible
• ED50 is a dose at which 50% of the population therapeutically respond.
• TD50 is a dose at which 50% of the population experiences toxicity.
• LD50 is a dose at which 50% of the population dies.
• Mathematical modeling has been advocated to assist in developing a dose-response relationship particularly when extrapolation to low doses is necessary.

Key Concepts of Predictive Models

• Threshold versus non-threshold mechanism.
• Independent versus synergistic action.
• The particular nature of inoculum.
• The models should also represent the conditional events: the probability of infection given exposure, the probability of acute illness given infection and the probability of mortality given acute illness.
• A threshold exists if there is no effect below a certain level, but above that level the effect becomes certain.
• Attempts to assign numerical values typically are unsuccessful.
• A non-threshold mechanism implies how low the dose, always, has a nonzero probability of infection and illness.
  • The probability increases with the dose.
• The probability of illness depends on the host damage resulting in clinical symptoms and pathogens developing beyond a certain minimum number.
• If no effect occurs below exposure, there is a threshold of certainty.
• Unsuccessful attempts have defined numerical value in the test with minimal infectious dose.
• A relationship of the mean probability, "p," is independent of number of pathogens.
• The hypothesis of synergism postulates that increased pathogen, increases the size of the dose.

Threshold Limit Values

• The American Conference of Governmental Industrial Hygiene (ACGIH) established threshold doses called threshold limit values for many chemical agents.
• The TLV refers to airborne concentrations where adverse effects are not expected during a worker's lifetime and only occur during normal working hours (eight hours per day, five days per week).
• The TLV was formerly called the Maximum Allowable Concentration (MAC).
• Three types of TLVs exist : TLV-TWA, TLV-STEL, and TLV-C.
• Occupational Safety and Health Administration OSHA defined their own permissible exposure level (PEL). The PEL values follow the TLV-TWA of ACGIH closely.
• STEL = Short Term Exposure Limit.
• TWA = Time Weighted Average.
• C = Ceiling.

TLV Types

• TLV-TWA: Time- weighted average nearly all workers can be exposed, without adverse effect.
• TLV-STEL: Short-term exposure which is the maximum concentration to which worker can expose for 15 minutes without suffering.
  • Includes narcosis, chronic and irreversible issues, and irritation.
• TVL-C: The concentration that should not be exceeded immediately