Chapter 2: Principles of Toxicology

Ebers Papyrus

his writings contain formulations for hemlock, aconite (arrow poison), opium, and various metals used as poisons

Hippocrates

stated that the appearance of disease in human populations is influenced by the quality of air, water and food, the topography of the land, and general living habits

Socrates

his influence on toxicology was because of his death. He was sentenced to die by drinking hemlock which comes from a plant that has several toxic alkaloids. (poison your neuromuscular junctions)

Homer

his writings that mentioned tokkicon, or arrow poison.

Paracelsus

reintroduced the use of inorganic salts, metals and minerals in medicine. Emphasized the importance of dosing in distinguishing between toxicity and treatment.

Paul Muller

In 1942 discovered the potent toxic effects on insects of DDT

Rachel Carson

In 1962 her studies led to the ban on Dichlorodiphenyltrichloroethane (DDT). Wrote that there is a continued use of DDT without limitations, the chemicals would damage the environment.

The Black Death

(1331-1770) was an infection spread mostly to humans by infected fleas with the bacterium Y. pestis that traveled on rodents. Killed millions of Europeans during the Middle Ages.

U.S Prohibition of 1919-1933

illegalized the manufacture, transportation, and sale of alcohol to minimize the harmful effects of alcohol.

First Posion Control Centers

In 1953, Edward Press, M.D., and Gdalman developed the first formal poison control center in Chicago.

Journal of Toxicology and Applied Pharmacology

In 1959, the first volume was published and contains original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products.

Society of Toxicology

Founded in 1961 and is a professional/scholarly organization of scientists from academic institutions, government, and industry representing the scientists who practice toxicology in the US and abroad.

U.S EPA

created in 1970, by President Richard Nixon to protect human health and the environment.

Love Canal Disaster

1978, the OXY organization used the abandoned Love Canal to dispose over 21,000 tons of hazardous chemicals. The drums leaked and contaminated soil and groundwater.

Bhophal Disaster

On December 3 1984, more than 40 tons of methyl isocyanate gas leaked from a pesticide plant in Bhopal, India, immediately killing at least 3,800 people

Chernobyl Accident

On April 26, 1986,a reactor at the nuclear power plant at Chernobyl, Ukraine, went out of control leading to an explosion and radiation release into the atmosphere.

What is posion?

substance that causes injury/death

Paracelsus definition of Poison

• all substances are poisons

• There is none which is not a poison

• The right dose differentiates a poison and a remedy

Define Pathogens

Disease causing organisms such as bacteria, viruses and parasites

Define Morbidity

illness

Define Mortality

death

Define Antidotes

agents that prevent diseases

Define Hazardous

dangerous

Define Allergens

substances that activate immune system

Define Toxicants

substances that produce adverse biological effects of any nature (chemcial or physical). Effects may be of various types (acute, chronic, etc.)

Define Toxins

specific proteins produced by living organisms (mushrrom or tetanus toxin). Most exhibit immediate effects.

Define Poisons

toxicants that cause immediate death or illness when experienced in very small amounts.

What is Tocicology a branch of and what does it study?

It is a branch of Biology, Chemistry, and Medicine (Pharmacology) concerened with study of adverse effects of chemical. It also studies harmful effects of chemcial, biological, and physical agents in biological systems that establishes how much damage it cause.

What is the primary focus of a Toxicologist?

the adverse effects of chemical agents

What do Toxicologists do?

• Assesment of acute/chronic exposure to chemical agents

• Recognition/identification/quantification of hazards from occuptional exposure of pollutants (air/water/food/drugs/environment)

• Development of agents selectively toxic to microorganizms (antibiotics), insects, weeds, and fungi

• Development of Antidotes

• Development of treatment regimens

What does the Science and Art part of Toxicology involve?

The Science part involves observation and datta colection while the Art allows for prediction of hazards when there’s no/little information availble.

Define Quantitative Aspect

Any substance can be toxic at some dose level and harmless at lower doses

What type of toxicant is Vinyl Chloride?

It is a potent hepatoxicant at high doses and a carcinogen at low chronic doses (multiple exposures)

What is Asprin?

is a safe drug but can cause ulcers on chronic exposure

What is an example of Qualitative Aspect?

Carbon Tetrachloride is a potent hepato-toxicant in many species but harmless in chicken because the carbon teteachloride has to be metablized to a more toxic metabolite to be toxic & the enzymes that does that, are not present in the chicken.

Biochemical Toxicology

biochemical / molecular events, enzymes, reactive metabolites, interaction of xenobiotics, molecular biology, gene expression

Behavorial Toxicology

CNS, PNS, endocrine system

Nutritional Toxicology

effect of diet

Carcinogenic Toxicology

events leading to cancer

Teratogenic Toxicology

effect on development

Mutagenic Toxicology

effect on genetic material

Organ Toxicology

neuro- , hepato-, nephrotoxicity etc.

Analytical Toxicology

identification and assay of toxicants

Toxicity Testing

use of live animals in long- and short-term studies

Toxicologic Pathology

changes in subcellular, cellular, tissue and organ morphology

Structure-Activity Study

chemical and physical property versus prediction of toxicity

Biomathmematics and Statistics

data analysis

Epidemiology

study of toxicity as it occurs in populations

Clinical Toxicology

diagnosis and treatment of poisoning

Veterinary Toxicology

diagnosis and treatment of poisoning in animals

Forensics Toxicology

medico-legal aspects

Enviromental Toxicology

movement of toxicants in the environment

Industrial Toxicology

dealing with work environment

Chemical uses and Classes of Toxicants

• Argricultural

• Clinical

• Drugs of abuse

• Food additives

• Inustrial

• Naturally occuring

• Combustion products

What are the areas of Toxicology?

Descriptive- Animal testing, effects in humans, insects etc.

Mechanistic- mechanisims of toxic effects. Results in useful deveolping tests for assessments

Regulatory- risk assessment; involves various agencies

FDA

(Food and Drug Administration) – enforces laws according to Food, Drug and Cosmetics Act

EPA

(Environmental Protection Agency) – regulates most other chemicals by the following ACTS of EPA

FIFRA

Federal Insecticide, Fungicide, Rodenticide Act

TSCA

Toxic Substance Conservation Act

RCRA

Resource Conservation and Recovery Act

SDWA

Safe Water Drinking Act

OSHA

(Occupational Safety and Health Administration) – ensures healthy condition at workplaces

CPSC

(Consumer Product Safety Commission) – ensures protection of consumers from hazards of household products

DOT

(Department of Transportation) – ensures the materials transported across check points are safe

ATSDR

(Agency for Toxic Substances and Disease Registry) provides health-based information for use in the cleanup of chemical waste disposal sites

CDC

(Centers for Disease Control and Prevention) promotes health and quality of life by preventing and controlling disease, injury, and disability

Routes of entry

GI tract-ingestion by oral

Pulmonary- inhaltion by lungs

Dermal- topical (spill on skin) by skin

Parenteral- subcutaneous, intradermal and intraperitoneal

Put the different ways of entry in order of Descending Toxicity

Intravenus > Inhalation > Intraperitoneal > Subcutaneous > Intramuscular > Intradermal > Oral > Topical

Therapeutic vs. Side Effects

side effects could be desired or undesired

Local vs. Systemic Effects

Local means effect on site of exposure (ingestion of caustic substances or inhalation of irritable substances). Systemic requires absorption and then distribution to target sites. (Tetramethyl lead should reach CNS for its effects)

Immediate vs. Delayed Toxicity

Rapid versus long term effect – example – vaginal / uterine cancer in utero in daughters of mothers who used DES (diethyl stilbestrol) to avoid miscarriages.

Reversible vs. Irreversible Toxicity

Most effects in liver are reversible because of tissue regeneration. Most CNS and carcinogenic effects are irreversible

Allergic Reactions

Hypersensitivity to chemicals called allergens – exposure leads to release of antibodies, histamines etc..

Idiosyncratic Reactions

Genetically determined abnormal reactions – example – allergy to nitrites

Name the interactions of Chemicals when exposed Simultaneously

• Additive Effect- simple addition (2+3=5)- combined effect is equal to sum of 2; example - inhibition of acetylcholinesterase by organophosphates

• Synergistic Effect- combined effects is much more than sum (2+2=20) – example – carbon tetrachloride + ethanol – both hepatotoxicants (both synergized much more than just 2 chemicals)

• Potentiation Effect- One potentiates the effect of the other (0+2 = 10) ; basically if 2 chemicals mixed and one makes the other much more harmful than it would be on its own– example – isopropanol (a non-hepatotoxicant) + carbon tetrachloride.

• Antagonism- Chemicals here interfere with each other (4+6 = 8 or 4+4 = 0)

Functional Antagonism

Chemicals here produce opposite physiological effects

Example- Barbiturates (sleep inducers) decrease BP and epinephrine (vasoconstrictor) increases BP

Chemical Antagonism or Inactivation

Produces a less toxic substance

Example- Chelation – Dimercaprol and EDTA chelate (remove) metals such as Ar, Hg, Pb etc.

Dispositional Antagonism

Disposition includes absorption, biotransformation, distribution and excretion of a chemical agent. In this type of antagonism, a metabolite of parent compound reaches the target site

Receptor Antagonism

Two chemicals bind to same receptor and produce less effect. Receptor antagonists are often called blockers

Examples:

Naloxone is used to treat respiratory depression by morphine

Oxygen is used to treat carbon monoxide poisoning

Atropine is used to treat organophosphate poisoning

Define Chemical Tolerance

a state of decreased responsiveness to toxic effect of chemicals:

Dispositional Tolerance- Less amount of toxicant reaches target site; example-Carbon tetrachloride (CCl4) produces tolerance by decreased formation of trichloromethyl radical .CCl3

Decreased Responsiveness of Tissue- not completely

Individual or Graded D-R Relationship

a dose-related increase in the severity of the response (increase in effect with increasing dose)

Example- increase in the inhibition of acetylcholinesterase by increased doses of organophosphates

Quantal D-R Relationship

D-R relationship in a population; At a given dose, an individual in a population is classified as either a “responder” or a “nonresponder”. measured by LD₅₀

What are the different types of D-R?

Effective Dose (ED)- therapeutic

Toxic Dose (TD)- liver injury

Lethal Dose (LD)- mortality

What are the assumptions in deriving D-R Relationship?

• Response is due to chemical administration- response observed after chemical administration (NOAEL= no observed adverese effect level)

• Response is in fact related to dose- there’s a molecular receptor for chemical. Concentration of chemical at target is related to dose

• Prescence of a precise quantifiable method- Organophosphates vs inhibition of acetylchlinesterase. indirect measures changes in liver enzyme

List 5 things about LD₅₀

• expresses toxicity

• is the statistically derived single dose of a substance that is expected to cause death in 50% of exposed individuals

• CANNOT be defined in terms of an S-shaped curve

• Probit Curve ( a linear D-R relationship) is used for calculation of LD₅₀

• Probit curve 50% mortality = to 5 Probit Units

What is LC₅₀

values for water and air

What are LC₅₀ and LD₅₀ influenced by?

Species, gender, strain, age, temp., prior exposure to other chemicals, crowding, and diet. Values can be used too see cancer or liver injury (doesn’t always involve mortalit)

Which is more toxic, Botulinum toxin, Ethyl Alcohol, or Sodium Chloride?

Botulinum Toxin > Sodium Chloride > Ethyl Alcohol

What is the ratio of LD₅₀: ED₅₀ (Therapeutic Index Ratio)

TI= LD₅₀/ ED₅₀

Formula for Margin of Safety (MS)

MS= LD₁/ ED₉₉

Define Potency and Efficacy?

Potency is the capacity of a chemical to kill at lower dose and Efficacy is to kill at any dose

What is the difference between Uneconomic forms and Economic forms?

Uneconomic forms are living forms that get injured/killed while Economic forms are living forms that are protected (Ex. parasites and hosts)

What are two factors that are part of Species Differences in Selectively Toxic chemicals?

Differential distrubution/ biotransformation/excretion- Example: effectiveness of ¹³¹I is due to its ability to reach thyroid gland alone

Surface area effects- Mammals have larger surface area than insects (less quantity is required for insects for chemicals to affect)

What are two factors that are part of Individual Differences in Selectively Toxic chemicals?

Cytotoxicity-being toxic to cells (Ex1. plants have photosynthetic properties that when targeted kill only plants. Ex2. Penicillin kills bacteria but relatively non-toxic to humans)

Biochemical Difference- Example: bacteria don’t absorb folic acid but syntehsize it from p-aminobenzoic acid. Mammals don’t synthesize folic acid but absorb it. Sulfonamid mimics p-aminobenzoic acid and no folic acid is made in bacteria

What are the 2 main principles of descriptive of Animal Toxicity testing?

• Toxicity test are not designed to show that a chemical is safe but to characterize the toxic effects a chemical can produce

• There no set toxicology test that are to be performed on every chemical intended for commerce. (must deveolp method to determine toxicity)

What are the 6 descriptive animal toxicity tests?

• Acute lethality- LD₅₀ or LC₅₀ values are determined after various routes of administration

• Skin and Eye Irritation-how much irritation happening in skin (degree of irritation)

• Sensitization- chemical administered topically or intradermally over a period of 2-4 weeks to evalute deeclopment of erythema (how sensitive the skin is)

• Subacute (repeated dose study)- typically for 14 days

• Subchronic- exposure last for 90 days (done with 2 species & 3 doses)

• Chronic- exposure is long term (6 months to 2 years) to determine cumulative/carcinogenic effect

Define NOAEL and LOAEL

NOAL- highest data point at which there wasn’t an observed toxic or adverse effect

LOAEL- lowest data point at which there was an observed toxic or adverse effect

What are chemicals present in the air & where are they coming from?

chemicals: CO₂, oxides of N & S, Hydrocarbons, particulates

Where: transportation, industries, electric generators, heating homes/buildings, Benzo[a]pyrene from combustion of automobile, pollution (reaction between UV and acrolein or formaldhyde)

What are chemicals present in the water & where are they coming from?

Chemicals: hydrocarbons (HC), organophosphates, carbamates, chlorinated HC, fertilizers, perticides, PCB, TCDD. Low halogenated HC (chloroform, dichloromethane, CCl₄) formed in water purification

Location: Run off from urban areas, sewage, reineries, chemical plats, drinking water

What are chemicals present in the food & where are they coming from?

where/chemicals:

• Bacterial toxins- exotxin from Clostridium botulini

• Mycotoxins (aflatoxins) from Aspergillus flavus

• Plant alkaloids, animal toxins, PCBs