PHAR1001E

Who was Paracelsus?

A. A fancy dresser
B. A scientist in the 1400s who said "it's all about the dose"
C. A Latin philosopher who studied metals
D. A pope who poisoned wealthy land owners
E. A scientist who discovered Tylenol

A scientist in the 1400s who said "it's all about the dose"

What are the three major types of Toxicology?

A. Global, Probabilistic, Political
B. Political, Social, Judicial
C.Social, Deterministic, Factual
D.Environmental, Medical, Federal
E. Descriptive, Mechanistic, Regulatory

Descriptive, Mechanistic, Regulatory

The toxic effects of chemicals depends on the route of exposure; in general:

A. oral \> I.V. \> inhalation \> dermal
B. I.V. \> inhalation \> oral \> dermal
C. dermal \> oral \> inhalation \> I.V.
D. I.V. \> dermal \> oral \> inhalation
E. oral \> I.V. \> inhalation \> dermal

I.V. \> inhalation \> oral \> dermal

A patient is admitted to the Emergency Room complaining of nausea, vomiting, diarrhea and anorexia.
Which organ system is most likely involved?

A. Central Nervous System
B. Gastrointestinal System
C. Respiratory System
D. Autonomic System
E. Immune System

Gastrointestinal System

Which of the following is not a type of potential interaction between two chemicals?

A. Additive
B. Distributive
C. Antagonistic
D. Synergistic

Distributive

What is likely to be our great source of exposure to toxic compounds?

A. Our food
B. Medications we take
C. The environment
D. Our work
E. All of the above

Our food

Is water toxic?

A.Yes
B. No
C. Depends on the dose
D. Only if you can't swim E. Only for cats

Depends on the dose

Which is considered more toxic to rats?
A. Sodium Chloride
B. Nicotine
C. Ethyl Alcohol
D.Botulinum toxin
E. Morphine

Botulinum Toxin

9. Idiosyncratic reactions to drugs are:

a. Quantitatively dissimilar to those observed in most individuals
b. Qualitatively similar to those observed in most individuals
c. Genetically determined
d. All of the above

Qualitatively dissimilar to those observed in most individuals

We are exposed to a variety of chemicals every day and many of these can interact with each other. One example of such an interaction could be symbolically described as 3 + 4 \= 17. This is an example of:

a. Antagonism
b. Plagiarism
c. Synergism
d. Fascism
e. Additive Effects

Synergism

During the development of a new drug, experimental animals are often exposed to extremely high doses during toxicological testing. This is viewed as a valid method of identifying potential drug toxicity which occurs at extremely low frequency (such as the development of cancer) in humans because:

A. Drugs are often abused by humans and thus can be tested using extremely high doses.
B. Drug-drug interactions are more apparent at high doses in experimental animals.
C. Drug metabolism is often different in experimental animals as compared to
humans.
D. Drug toxicity studies would be prohibitively expensive using doses that are similar
to doses taken by humans.
E. The results of drug toxicity studies done in animals are always applicable to
humans.

Drug metabolism is often different in experimental animals as compared to
humans.

What does the "E" in ED50 stand for?

A. Effective
B. Emergency
C. Enhanced
D. Experimental
E. Exploratory

Effective

Approximately how many mg of an experimental drug would be required in a 70 kg human to give an equivalent dose of 2 mg in a 20 g mouse?

A. 7 mg
B. 70 mg
C. 700 mg
D. 7,000 mg
E. 70,000 mg

7,000 mg

Which of the following is true when describing a "threshold" dose?

A. Is the dose above which the probability of an individual responding is ~ 100%
B. Is poorly defined for acute effects
C. Is well defined for longer term effects.
D. Is the dose below which the probability of an individual responding is ~ zero
E. Is the dose at which the probability of an individual responding is ~ 50%

Is the dose below which the probability of an individual responding is ~ zero

What is the major factor that determines the slope of a dose response curve?

A. Experimental variability
B. The use of a polynomial equation to fit the data
C. Biological variability
D. Small sample sizes
E. Difficulty in measuring the Response

Biological Variability

Antibiotics are more toxic to microorganisms than to humans because of:

A. Differences in target specificity
B. Differences in biotransformation
C. Differences in absorption
D. Differences in excretion
E. Differences in administration

Differences in target specificity

The 3 major types of toxic chemicals are:

A. Endogenous chemicals as ultimate toxicants, ADP, Chemical metabolites as ultimate toxicants.
B. Parent chemicals as ultimate toxicants, ROS/RNS, Synthetic chemicals as ultimate toxicants.
C. Synthetic chemicals as ultimate toxicants, Environmental chemicals as ultimate toxicants, Chemical derivatives as ultimate toxicants.
D. Chemical metabolites as ultimate toxicants, ROS/RNS, Parent chemicals as ultimate toxicants.
E. None of the above

Parent chemicals as ultimate toxicants, ROS/RNS, Synthetic chemicals as ultimate toxicants.

The toxic side effects of drugs are very often due to what's called primary pharmacology?

A. True
B. False
C. It depends on the drug
D. Most drugs do not have side effects

False - secondary pharmacology

What are typical attributes of target molecules?

A. DNA, proteins, cell membranes
B. soluble, reversible, irreversible
C. enzymatic, metabolic, absorbed
D. ADME, ROS/RNS, parent chemicals
E. reactive, accessible, important to the cell

DNA, Proteins, Cell Membranes

What does ADME stand for?

A. Accessible, drug, metabolite, enzyme
B. ATP, dose, modified, effective
C. Absorbed, delivered, multiple, energy
D. Additive, delivery, multiplied, enhanced
E. None of the above

None of the above: Absorption, Distribution, Metabolism, Excretion

What is a common target that chemicals interact with to cause toxicity?

A. ATP
B. DNA
C. Cell organelles
D. EDCs
E. Endothelial cells

DNA

What did the orange ladder in the room represent?

A. DNA
B. A Cell membrane
C. ROS/RNS
D. A Transcription factor
E. ATP

Transcription factor

Binding to plasma proteins, distribution to storage sites such as adipose tissue, and export from the cells are examples of:

A. Moving chemicals away from the target
B. Moving chemicals toward the target
C. Moving chemicals into the liver
D. Moving chemicals into the cell nucleus
E. All of the above

Away from the target

EDCs can cause toxicity by:

A. Causing mutations
B. Altering gene transcription.
C. Altering ADME.
D. Altering Chemical exposure
E. None of the above

Altering gene transcription

ROS/RNS can cause toxicity by:

A. Damaging cell membranes
B. Interfering with EDCs
C. Increasing chemical metabolism
D. Decreasing chemical metabolism
E. Blocking transcription factors

Damaging cell membranes

Why does high calcium inside a cell cause toxicity?

A. It can block ATP synthesis
B. It can block transcription factors
C. It inhibits signal transduction
D. It can directly oxidize membrane lipids
E. It can block protein repair by proteases

Block ATP Synthesis

Mechanistically, EDCs can cause toxicity in humans and animals because exposure can:

A. Be below the threshold dose
B. Be less than the therapeutic index
C. Prevent normal signaling
D. All of the above
E. Depends on the dose

Prevent normal signaling

Where is most ROS/RNS produced in a cell?

A. In the nucleus
B. In the mitochondria
C. In the cell membrane
D. In the cytoplasm
E. None of the above

In the mitochondria

What does mPTP stand for?

A. Membrane permeability transition pore
B. Mitochondrial permanent transition phase
C. Membrane permanent transduction pore
D. Mitochondrial partial transduction particle
E. None of the above

None - Mitochondrial Permeability Transition Pore

There are 3 critical biochemical processes that must be regulated in all cells in order to avoid cell toxicity and/or cell death:

A. DNA, Sodium, Chloride
B. ATP, Ca, ROS/RNS
C. Apoptosis, Necrosis, mPTP
D. Transcription, Signal Transduction, Mitosis
E. All of the above

ATP, Ca, ROS/RNS

Which of the following is responsible for propagating an electrical signal between 2 or more nerve cells:

A. Neurotransmitters
B. The myelin sheath
C. The synaptic cleft
D. All of the above
E. None of the above

All of the above

Cyanide (used to kill millions of people in WWII and used in gas chambers) causes toxicity by:

A. Blocking ligand activated transcription factors B. Blocking signal transduction pathways
C. Blocking Apoptosis
D. Blocking ATP synthesis in mitochondria
E. Blocking Ca from leaving the cell

Blocking signal transduction pathways

Some EDCs can bind to ligand activated transcription factors (inside the cell) as well as receptor molecules on the outside of the cell in order to cause toxicity.

A. True
B. False
C. I'm sick of the EDC nonsense!
D. Will this be on the exam?
E. Will the exam questions be this easy?

True

Severely damaged and/or aggregated proteins are repaired by:

A. Vitamin E
B. Proteases
C. Vitamin C
D. Heat shock proteins
E. All of the above

Proteases

Why is fibrosis detrimental to tissues?

A. It can compress DNA and proteins in the cell
B. It can compress other cells within the tissue or organ
C. It causes greater fluidity in the tissue
D. It causes bleeding
E. All of the above

It can compress other cells within the tissue or organ

How do ligand activated transcription factors alter cell growth?

Activate different gene expression in nucleus, producing a protein

How do EDC's such as Bisphenol A cause toxicity in human and animals?

Binding to ligand activated estrogen receptors that regulate transcription, binding to estrogen receptors associated wit the cell membrane that promote calcium mobilization and intracellular signaling, Inapproriate

3 Critical processes that must be regulated in all cells if they are to survive?

1. Regulation of ATP levels.
2. Regulation of intracellular Ca
3. Limit over production of ROS/RNS

How does Cyanide cause toxicity?

Blocks ATP synthesis

Why does high calcium inside a cell cause toxicity?

Blocks ATP synth.
Increases formation of ROS/RNS that cause cell membrane damage
Blocks electrical signaling in nerve cells

Where is most ROS/RNS produced in a cell?

Mitochondria

What does mPTP stand for?

Mitochondrial permeability transition pore

What are the differences between acute and chronic exposure?

Acute - Less than 24 hour exposure, usually a single administration but can be more continuous inhalation
Chronic - repeated exposure for more than 3 months

What is Toxicology?

Science of poisons, the science that defines safety limits of chemicals, the science that attempt to understand the mechanistic between the dose and adverse effects in humans and ecosystems.

What is likely to be our great source of exposure to toxic chemicals?

Food

Is Tylenol toxic?

Yes, like everything it depends on the dose.

The 4 major types of toxic chemicals are what?

Parent chemicals, chemical metabolites, ROS/RNS

What is secondary pharmacology and how is it related to the toxicity of drugs?

Toxic side effects of drugs - off target based toxicity

What are typical attributes of target molecules?

Reactive, accessible, important to the cell

What does ADME stand for?

Absorption, Distribution, Metabolism, Excretion

What are major types of molecular repair we talked about in class?

Molecular Repair, Cellular Repair, Tissue Repair

What is extracellular Matrix (ECM) and why is it sometimes a problem in various organs?

Leads to fibrosis, increased rigidity of tissue compromises mechanical function, fibrosis develops because ECM production does not stop and can be caused by chronic chemical exposures.

What are 3 major areas of Toxicology?

Descriptive Toxicology, Mechanistic Toxicity, Regulatory Toxicity

What are the major routes of chemical exposure?

IV \> Inhalation \> Oral \> Dermal

A patient is admitted to the Emergency Room with symptoms suggesting Central nervous system problems. What are the most common symptoms?

Body movements, headache, disturbed dreams/sleep problems, nervousness, dizziness

What are idiosyncratic reactions to drugs?

Genetically determined abnormal reactivity to a chemical. the responses is usually qualitatively similar to the observed in most individuals, but is quantitatively different.

We are exposed to a variety of chemicals every day and many of these can interact with each other. What are the major types of chemical interactions?

Additive (2 +3\=5)
Synergistic ( 2+3 \= 20)
Antagonistic (0 + 4 \=1)

Why are typical dose response curves shaped like an S?

Biological Variability

How can EDC's like DDT and BPA cause toxicity to humans and animals?

Endocrine disrupting chemical - causes inappropriate duration - parent normal signaling

Why are chemicals less easily absorbed through the skin as opposed to the other routes of exposure?

The epidermis serves as a barrier to protect from dermal exposure

What types of chemicals show a J or U shaped does response curves and why?

Vitamins, alcohol, water, food, metal, because you need a certain amount to be healthy but too much can be toxic.

What types of chemical reactions result in relatively permanent changes to the target?

1. Noncovalent/ionic
2. Covalent binding
3. Enzymatic Reactions

What happens when a protein is damaged beyond repair?

The injured cells die (apoptosis) and are replaced by new cells (proliferation)

What are heat shock proteins?

Critical for refolding proteins that were heated and deactivated

What are the different kinds of dose responses relationships

J/U shaped curves ( good for you in moderation but bad excessively)
Threshold Dose ( 0% chance of response below the threshold)
S-Shaped (normal)

What's Toxicology

1.Science of poisons
2. Science that defines safety limits of chemicals
-Local/state/Federal Regulation...many basedo n estimates (Mercury), biological variability
3. Science that attempts to understand mechanistic relationships btw dose + adverse effects in humans/ ecosystems

History of Toxicology

1. Middle ages (Poisoner...Arsenic containing cosmetics)
2. Age of Enlightenement (1400-1900)
- Paracelsus: All things poisonous...depends on dose
-Said that toxic agent was chemical entity... NOT AN ACT OF GOD
-Occupational hazards ( metalworking) starting to get recognized
-Experimental toxicology accompanied growth of organic chemistry during 19th century

Paracelsus:

1. Experimentation is essential in the examination of response to chemicals
2. Distinction btw terapeutic and toxic properties of chemicals
3. Therapeutic vs. toxic based on DOSE

The Jungl

1. Led to Pure food and Drug Act--\> Eventually FDA.. National Safety ocuncil 1911, Division of industrial Hygein

Modern Toxicology

1. WWII: increase in drug pesticides, increased demand to understand mechanisms\-- Silent spring and Agent Orange increase public awareness, and need for guidelines

Types of Toxicology

1. Descriptive (animal/environment toxicity testing
-Identify Quantify chemicals in tissues/food/air/soil/water
-Toxicity testing in experimentla models (how toxic it is to SOMETHING)
-Data used to evaluate risk
2. Mechanistic Toxicology: Mechanisms by which chemicals cause toxicity
-Links descriptive tox, to Regulatory tox
3. Regulatory Tox: Assessment of risk based on descriptive + mechanistic studies
-Variety of Local state and federal agencies

Toxicity Classes

Super toxic (

Route of Exposure

1. Inhalation
2.Oral Ingestion--\> Goes to Small intestine (Portal Vein/artery/liver)
3. Liver --\> Heart

Dermal Absorption

1. Skin protects from UV microbe/dehydration
-Feel touch/pain/temp
-Makes Vitamin D
-Regulates temperature (sweat/vasodilation)
2. Acts as Barrier: epidermis, keratinocytes, melanocytes,

Toxic Effects of chemicals depends on routeo f exposure:

IV \> Inhalation \> Oral \> Dermal

Acute exposure:

Duration of Exposure

1. Subacute

Toxic Effects and Examples:

1. CNS/ Somatomotor--\> Headache, disturbed dreams, poor sleep, perspiration, nervousness, diziness
2. Respiratory: Constriction of chest, cough, wheezing
Ocular: Pain on accomodation, dimness, lacrimation, conjuctival injection
3. Gastrointestinal: Anorexia, nausea, vomiting, diarrhea
4. Genera: Acute- temperature, skin texture/color, cardiovascular, jaundice
Chronic: food intake, body weight, tumor, disease, sleep time

Types of effects on Immune System

1. Immunoenhancement: Hypersensitivity, autoimmunity (Penicillin)
2. Immunosuppression: Immunosuppressive drugs, AIDS drugs, drugs of abuse (cannnabinoids, cocaine, heroin, ethanol
3. Idiosyncratic reacitons: Genetically determined abnormal reactivity to a chemical, qualitatively similar to observed...but is QUANTITATIVELY different (rextreme sensitivity, or extreme insensititvity
4. REversible vs. Irreversible: Liver damage vs. CNS damage

Interactinos of Chemicals

1. Additive: MOST COMMON (2+3 \= 5), Ibuprophen and naproxen
2. Syngergistic (2+3\=20) ethanol/tylenol
Antagonistic (0+4\=1)...basis for many antidotes... ethanol for antifreeze toxicity

Types of Responses to LD

1. Lethality,
Short attention, headache, nausea, hyperactive, vomit, numb, sweat, heart rate increase
dilated pupils
loss balance, unconsciousness

Responses

LD50 (lethal dose
TD50 (toxic dose)
ED50 (effective dose)

Threshold Dose

Dose below which probability of individual responding is 0,
-Well defined for acute effects, not for longer term

Assumptions of Dose-response relationship

Response due to chemical administered (placebo effect)
-Receptor site for drug to interact
-Type or response/ degree of response are related to concentration of the chemical at the receptor site

Variation in toxic response-selective toxicity

1. Selective Toxicity: Toxic to plants but not humans...etc (animals, organs, tissues)
-Basis for most drugs: Herbicices, antibiotics, cancer
-Thalidomide
-Species difference important in risk and drug safety assessment

Descriptive animal toxicity tests within Pharmaceutical industry:

1. Toxic effects produced by chemical in lab animals ARE APPLICABLE to humans...generally true bc of DOSE per kg
2. Exposure of animlas to high doses is valid method of discovering possible hazards inhumans
- For low frequency diseases, like cancer (0.01% incidence--\> 25000 people) to test would need 30,000 rats for several years
-Not economically feasible

3 Main types of chemicals:

1. Parent Xenobiotic (Xenobiotic\= foreign chemical)
2. Xenobiotic metabolites
3. Reactive oxygen/ RNS (nitrogen)

Mechanisms of Toxicity:

1. Delivery from site of exposure to target
2. Reacion of chemical w/ target
3. Injury
4. Repair

Delivery: From site of exposure to the Target

1. Absorption
2. Distribution
3. Metabolism- physical/chem properties enable many chemicals to be absorbed into our cells (ability to cross cell membranes).. the elimination of many chemicals dependso n metabolism to more water soluble compounds
4. Excretion- Chemicals are water solube or can be metabolized to water soluble compounds, can be eliminatedi n bile or urine
-Some chemicals metabolizedi n liver cells to make more water soluble

Distribution: Mechanisms moving chemical to the target

1. Porosity of capillary endothelium
2. Size/solubility of chemical
3. Specialized membrane trnasport (Lead)

Dsitrubition: Mechanisms moving chemical AWAY

1. Size/ LIPID SOLUBILITY of chemical
2. BIND TO PLASMA proteins
3. Specialized barriers: blood-brain
4. Distrubtion to STORAGE SITES (adipose tissue)
5. Export from cells

Reaction of Chemical w/ Target Molecule

1. Attributes of Target Molecules: Will react w/ chemical, is ACCESSIBLE to chemical, is IMPORTANT to cell
-DNA , proteins, cell membranes
2. Reaction Types: Reversible (Noncovalaent/ionic) + Permanent Binding (Covalent) very damaging , Enzymatic reactions (Snake venoms)
3. Outcomes: Loss of function of target /Destruction (ROS/RNS destruction of CELL MEMBRANES)

Injury: Type of injury caused by chemical depends on what the target does

1. WHAT DOES THE TARGET DO
2. CHEmical can cause change in Cell Signaling: Cell growth/ death
-Changes Gene expressions through changes in gene TRANSCRIPTION (Most often) due to altered TRANSCRIPTION FACTOR regulation
-Changes SIGNAL TRANSDUCTION: binds to membrane receptors cause cell to grow/die... CHEMICAL DOESNT GO INSIDE CELL
-Estradiol
-Changes in ongoing function of specialized cells (neuronal/muscle cells) ( ion cahnnel blockers)
3. Chemical can cause changes in Cell MAintenance: Synthesis of ATP, Ca regulation, Protein synthesis
-Cells must maintain structural/functional integrity, assemble membrane/organelles produce ATP
-3 CRITICAL processes in ALL CELLS to avoid toxicity/cell death
-Regulation of ATP levels
-Regulation of intracellular Ca2+
-Limit overproduction of ROS/RNS

Estradiol

1. Promotes formation of female secondary sex characteristics
2. EDC's \= Endocrine Disrupting Chemicals

Bisphenol A (BPA)

1. EDC
2. is IMPLICATED in prostate/breast cancer, early onset of puberty, decline in semen quality, increased incidence of type 2 diabetes, obesity, neurobehavioral problems (ADHD)
3. Bind to Ligand activated estrogen receptors that regulate transcription, Receptors more sensitive to BPA than ligand activated transcription factors
4. Bind to estrogen receptors associated w/ cell membrane that promote signal TRANSDUCTION

Regulation of ATP levels
Regulation intracellular Ca2+

1. Chemicals that cause ATP depletion: Ethanol, Hydrogen peroxide, Cyanide, Carbon Monoxide
2. Calcium plays pivitol role in physiology/biochemistry of all cell types
-Plays role in Signal transduction pathways (Cellgrowth/death)
-Neurotransmitter relase from neurons
-Electrical transmission in Nerve cells
-Contraction of muscle cells

Why is high [Ca] toxic in cells

1. Increased Ca in mitcohondria blocks ATP synthesis
2. Increase formation of ROS/RNS and that causes cell membrane damage
3. Increased Ca blocks electrical signaling in nerve cells

Limit Over Production of ROS and RNS:

1. Some chemicals can generate ROS/RNS but it's rare
2. Overproduction of ROS and RNS can be due to high levels of calcium since calcium activates enzymes that generate ROS and/or RNS
3. Production of ATP in mitochondria produces most of the ROS/RNS in our cells. There are enzymes in our cells which metabolize ROS/RNS to less toxic compounds
-ROS/RNS produced in mitchondrai cause LIPID/MEMBRANE damage (protein damage too)

Relationship btw ATP, Ca2+ and ROS/RNS

If ATP decreases--\> Ca2+ increases --\> RON/RNS increases
- Mitochondrial Permeability Transition Pore (MPTP)
Cell survival in a few mitochondria
-Apoptosis in more mitochondria (Controlled cell death)
-Necrosis in ALL mitochondria (Un-controlled Cell death)

Step 4: Repair

1. Delivery
2. Reaction
3. Injury
4. Repair:
- Molecular Repair,
-Cellular Repair
- Tissue Repair
-When Repair Fails