Visalli's Toxicology Exam Review PDF

Visalli- Toxicology Exam review- we will be in b556 100 questions ~50 from Visalli- a few more questions form lect. 1 ~50 from Labib *Random All M/C questions 2 hours SHOW THE GREEN SCREEN @THE END, TO THE INSTRUCTORS Lecture 1: History: know Paracelsus and his principles and how they formed the fou...

Visalli- Toxicology Exam review- we will be in b556 100 questions ~50 from Visalli- a few more questions form lect. 1 ~50 from Labib *Random All M/C questions 2 hours SHOW THE GREEN SCREEN @THE END, TO THE INSTRUCTORS Lecture 1: History: know Paracelsus and his principles and how they formed the foundation of toxicology: Paracelsus: German physician-alchemist and son of a physician. *Formulated views that remain a major part of modern toxicology, pharmacology and therapeutics. Principles: These principles lead to the notion of dose-response relationships in toxicology: 1- Experimentation is essential in examining the response to chemicals 2- One should make distinction between the therapeutic and toxic properties of chemicals 3- These properties are sometimes not always distinguishable except by: dose 4- One can determine a degree of specificity of chemicals and their therapeutic or toxic effects. “THE DOSE MAKES THE POISON* Toxicology definition: The study of toxins: The science that deals with the adverse effects of chemicals on living systems. Slide 22: different ways to classify toxicology: 1- Descriptive toxicology: What is causing the toxicity? 2- Mechanistic toxicology: Why? 3- Analytical toxicology: How much does someone need to be exposed to have a toxic effect? Slide 23: different organ systems that are targeted: Neuro-toxicity, Genetic Toxicology, Reproductive Toxicology, Immuno-toxicology, and Endocrine Toxicology. Slide 25: Poison: Any agent capable of producing an adverse response in a biological system. Slide 28: types of toxic responses: *Most important thing to know is that for toxins to produce a response: the chemical must get to the site of action to produce an effect. 1- Local: local effect @ site of contact. Ex: lungs, GI tract. 2- Systemic: An effect that is distant from the exposure site. Ex: Lungs, Kidneys, CNS. 3- Sometimes both local and systemic 4- Immediate: From minutes to hours after a single exposure. 5- Delayed: From days to years after the exposure occurs ex: carcinogens to manifest in cells. 6- Sometimes both Immediate and delayed Slide 29: Types of Toxic responses: Reversible or Irreversible: *It all depends on the tissue, length of exposure and the magnitude of the toxin. REVERSIBLE TOXIC RESPONSE: occurs in tissues that rapidly regenerate like: Liver, blood cells and intestinal mucosa. IRREVERSIBLE TOXIC RESPONSE: CNS damage, carcinogenesis (damage to the DNA in uncontrolled cell population that doesn’t stop growing), mutagenesis, teratagenesis. Slide 30: Factors influencing toxicity: (Think about Versed in the dental field) Be familiar with what factors can affect toxicity: 1- Dosage 2- Route of exposure, the difference in species: SWEET N’ LOW- causes bladder tumors in rats but not in humans b/c our physiology is different. 3- AGE 4- SEX (MALE VS. FEMALE) 5- Ability to be absorbed 6- Metabolism (biotransformation- how fast) 7- Distribution within the body- where it goes. 8- Excretion 9- Presence of other chemicals. Slide 31: Know Bioavailability, how much and how easily the compound can get through- How soluble it is: water solubility) Bioavailability: A term that can be used to test the transmembrane movement potential- using KOW = [T]OCTANOL / [T]WATER 2 3 If the KOW is 10 to 10 that indicates a GOOD/OK chemical for absorption (Log KOW = 2 to 3) One way that you can make a substance available is by IV injection- this passes the absorption phase and cell membrane. Sometimes the absorption phase can lose product in the process, so IV injection is 100% bioavailable. A substance with GOOD bioavailability has a decent/ “OK” water solubility and fat solubility. Slide 33: 3 phases of Toxicology: 1- Exposure phase- It’s what happens when someone is exposed to a toxin- the main factors are: Time and frequency of the exposure: ex: acute, subchronic, chronic etc. and the route of administration: oral, lung, skin and injection. 2- Toxicokinetic phase: “What your body is doing to the toxin”: a. ABSORPTION b. DISTRIBUTION c. METABOLISM d. EXCRETION 3- Toxicodynamic phase: “What the toxin is doing to your body” SLIDE 36: DIFF. WAYS YOU CAN BE EXPOSED (routes and sites of exposure): INGESTION (GI TRACT) INHALATION (LUNGS) DERMAL/TOPICAL (SKIN) INJECTION (IV, IM, IP, SC) *TYPICAL EFFECTIVENESS OF ROUTE: IV > INHALATION > IP > IM (intramuscular)> SC (subcutaneous)>ORAL>TOPICAL Slide 37- slide 41: 3 major types of exposure: 1- ACUTE (SHORT)- High dose over short amount of time (single dose in ~24 hours). 2- SUBCHRONIC (MEDIUM)- repeated exposure for weeks to months (~3 months- ex: in a workplace/factory working with the toxin every day). 3- CHRONIC (LONG)- takes months to years to become recognizable. Ex: liver damage in alcoholics, lung cancer in cigarette smokers. Toxicokinetics: (slide 43/44): know what is involved with absorption phase: Everything needs to go through the absorption phase except IV. Site of absorption: GI Tract, dermal (pretty effective barrier), lungs (inhale) Typically, the charged molecules do not cross the membranes well Things that govern transmembrane movement: o Lipid-water solubility [BIOAVIALBILITY]: KOW o Ionization of the molecule (pKa) o Functional groups o Molecular size and conformation- ex: Planar (flat) molecules cross a lot better. Slide 45/46: Distribution (factors that affect distribution): Distribution has 4 fates: 1- Site of action, 2- storage, 3- metabolism, 4- excretion. 3 barriers: BBB, Placental and Mammary It occurs in the blood (fast moving) and the lymph (slow moving immune system) *FACTORS AFFECTING DISTRIBUTION: 1- Tissue affinity for the toxin 2- The amount of blood flow (ex: the kidneys receive ~20% of blood flow, which means that it can have high exposure to the toxicity) 3: protein binding 4: It’s route of administration 5: It’s rate of metabolism *Redistribution: Enterohepatic recirculation (when we have bile acids/salts released into GI tract that gets reabsorbed/reused). Slide 47: Metabolism: know the difference of both phases. PHASE I: CONVERTING THE FUNCTIONAL GROUPS OF THE TOXIN TO MAKE IT MORE WATER SOLUBLE (MORE POLAR) FOR THE BODY TO EXCRETE IT. PHASE II: CONJUGATION REACTIONS: link a molecule to the toxin/drug. Slide 48-54: interaction of toxins (know the difference) Interaction of toxicants: means that the presence of other chemicals may add to the toxicity, decrease toxicity, or increase toxicity of some xenobiotic (toxin). 4 types of interactions: 1- ADDITIVITY- MOST COMMON TYPE OF DRUG INTERACTION A COMBINATION OF TWO OR MORE CHEMICALS IS THE SUM OF THE EXPECTED INDIVIDUAL RESPONSES. EX: TWO CNS DEPRESSANTS TAKEN SIMULTANEOUSLY EX: TRANQUILIZER ADMINISTRATION DURING ALCOHOL EXPOSURE 2- ANTAGONISM EXPOSURE TO ONE TOXIN/CHEMICAL= A REDUCTION IN THE EFFECT OF THE OTHER TOXIN/CHEMICAL (OFTEN WILL BE THE DESIRABLE EFECT IN TOXICOLOGY AS THIS IS THE BASIS FOR MOST ANTIDOTES) a. EX: ANTIDOTES (Antivenom/ Antitoxin) given for snake bites. b. EX: CO POISONING THAT IS BEING TREATED WITH O2- WHICH IS CAUSING DISPLACEMENT OF THE CO FROM THE HEMOGLOBIN RECEPTORS. 3- POTENTIATION WHEN A CHEMICIAL THAT DOES NOT HAVE A SPECIFIC TOXIC EFFECT, MAKES ANOTHER CHEMICAL MORE TOXIC (INCREASES Its EFFECT) EX: HEPATOXICITY (LIVER TOXIXITY) OF CARBON TETRACHLORIDE IS GREATLY ENHANCED BY THE PRESCENCE OF ISOPROPANOL (WHICH IS A NON-HEPATOTOXIC). 4- SYNERGISM: SYNERGISM: EXPOSURE TO ONE CHEMICAL CAUSES A DRAMATIC INCREASE IN THE EFFECT OF ANOTHER CHEMICAL. EX: ASBESTOS AND CIGARETTE SMOKING RESULTS IN SIGNIFICANTLY GREATER RISK FOR LUNG CANCER THAN EACH INDIVIDUALLY. Slide 55- EXCRETION: routes and 56: the effect of varying elimination rate has on a target. Excretion: Very important in toxicology 1- Renal excretion: Urine 2- Non-renal excretion: Breathing, biliary, gastric secretion- secreted into stomach and eliminated into the GI tract. Slide 58: know what the DOSE/DOSAGE definitions are. Dose: The amount of a substance administered at one time Dosage: The amount per unit weight of the exposed individual. * Always the dose divided by Kg of what a person weighs. Mg/Kg- Dose/ Dosage Slide 60- LD50 (What it is and what it means) LD50: The lethal dose that killed 50% of the population- Can vary among chemicals/animals. *the lower the LD50: the more toxic the compound. Ex: ethanol: LD 50 = 10,000 vs Poison dart frogs LD 50 = 0.008 Slide 67: know what DOSE-RESPONSE CURVE is: Dose-response curve is an “S”-shaped curve that has Dose (mg) in the X-AXIS and the Response (%) on the Y-AXIS. It shows that as you increase dose of the toxic agent, your response increases. Slide 68: know Normal (Gaussian) Distribution: It is a “Bell-shaped” curve that shows a population’s response to a given dose. Not everyone will respond to the same dose in the same way. Slide 69: make sure you know how to read the dose-response curve A: DOSE-RESPONSE CURVE that is plotted on an arithmetic scale B: Same data plotted on a semi-log scale Point: To look @ two different Esterases and see the effect of each @ different doses. Outcome: Cholinesterase is MORE EASILY inhibited @ lower doses than Carboxylesterase. Slide 70: LOAEL/ NOAEL NOAEL: NO OBSERVED ADVERSE EFFECT LEVEL LOAEL: LOW ADVERSE EFFECT LEVEL Adverse effect can be seen to start here Slide 72: how to derive from LD50: Slide 73-75: shape and slope of dose-response curve and how that can tell us the toxicologic compound Toxicant A (RED): has a faster toxic effect in response with less dose than what Toxicant B (BLUE) has. Toxicant B, you need to increase the dose a lot more than toxicant A to get the same response.  This is comparing 2 different drugs/chemicals that have the same LD50 of 4.5 in a dose-response relationship with different slopes. Slide 76: know concept where if you put 2 dose response curve you can see the effective vs toxic dose SAME DRUG: RED CURVE= EFFECTIVE DOSE BLUE CURVE= TOXICITY 50-75% EFFECTIVE DOES NOT CAUSE TOXICITY 90% EFFECTIVE DOSE MAY RESULT IN A SMALL AMOUNT OF TOXICITY. Slide 77- POTENCY: A range of doses over which a chemical result in increasing responses MAXIMAL EFFICACY: The limit of the dose-response relationship. A > B (A is more potent). C < D D has a higher efficacy than C, but C is more potent at lower doses.  Slide 78-80: Therapeutic index: know how to calculate and MOS (MARGIN OF SAFETY) Therapeutic Index: is the LETHAL DOSE divided by the EFFECTIVE DOSE: LD50/ ED50 THE LARGER THE RATIO, THE GREATER THE SAFETY. MARGIN OF SAFETY (MOS): it’s the LETHAL DOSE (01) dived by the EFFECTIVE DOSE (99) MOS: LD01/ED99x MOS is more of a conservative calculation b/c it takes the slopes of the extremes. TI = LD50/ED50 = 200/20 = 10 Slide 81: vitamin dose-response curve So, for a vitamin dose-response curve, it shows that if you have insufficiency, it can be toxic to you, but if you have too much it can also be toxic to you.  Slide 83: know that animal testing is required for pharmaceutical things and all of that. The effects produced by a compound in lab animals, are applicable to humans. The exposure of lab animals to toxic agents @ high doses is necessary and valid methods of discovering hazards in humans. Know that FDA (PHARMACUTICALS) KNOW THAT EPA (PESTICIDES) Slide 88: know the concept of uncertainty factors UNCERTAINTY FACTORS: PROVIDE ANOTHER LEVEL OF SAFETY IN CALCULATING HUMAN DOSES. If chronic studies were done in the animals, then: (NOAEL/100) If prolonged ingestion studies were done in men/women: (NOAEL/10) If only short-term studies were done in the animals, then: (NOAEL/1000) Slides 90-end: tie things together (make sure you can understand) SUCCESFUL DELIVERY OF A TOXICANT IS THE FIRST STEP IN THE DEVELOPMENT OF TOXICITY.  Slide 97: toxin needs to hit the target molecule- and the outcomes Lecture 3: Know terms on slide 2,3,4 Tumor: A space occupying lesion that may or may not be neoplastic Neoplasm (a mass): an independent growth of tissue with abnormal regulation of gene expression (benign or malignant) Metastases: Secondary growths of cells from the primary neoplasm Cancer: a subset of malignant neoplastic lesions (neoplasms) Carcinogen: n agent that causes or induces neoplasia (dysregulated cell growth) Carcinoma: Malignant tumor arising in the epithelium- most common form of cancer, usually spreads via the lymph system. Sarcoma: Malignant tumor arising in muscle or connective tissue, usually spreads via circulation. Slide 6: carcinogens- Know that they don’t always have to be a synthetic compound, it can be other things. Ex: Hormonal- excessive production or derangement of the homeostatic mechanisms of an organism may result in neoplastic transformation- too much production of growth hormone or estrogen/testosterone. Mix of things- Tobacco smoke, diesel exhaust. DIET- Too many calories, too much alcohol etc. Slide 8: know properties of certain functional groups and why they may be a concern to carcinogenicity Carcinogenetic chemicals have functional groups that contain a NITROGEN. They interact well with DNA, and therefore have the ability to lead to cancer and disrupt. Slide 10: Know that: “Ultimate carcinogens” are highly reactive metabolites that are involved in the carcinogenic process. Mechanisms of chemical carcinogens: most often, covalent interactions of chemicals with large biological macromolecules (ex: DNA) is required to start cancer. SOME-NOT ALL parent compounds require metabolic alteration (activation) to a metabolite that is capable of covalent binding (pro-carcinogens) that is later metabolized into its carcinogenic form. Slide 11: not always is the parent molecule, but the byproduct From Benzo(a)pyrene to Benzo (a)pyrene 7,8 diol-9,10 Epoxide (the by-product) Results in the ultimate carcinogen: which covalently interacts with guanine in DNA. Slide 12: MUTAGENESIS: Structural DNA alteration and cell proliferation fixes the DNA damage. Slide 13-14-15-16: talk about diff. mechanisms of chemical carcinogenesis Summary of it in slide 17 Slide 18: mechanisms of DNA repair: know that there are mechanisms to repair DNA Repair Pathways: the damage is removes or it is reversed and the adducts are removed and new bases are inserted Tolerance Mechanisms: The damage can be by-passed and not repaired BUT the body kinda gets around it in another way. SLIDE 19: KNOW THE DIFFERENCE: BASE EXCISION REPAIR: Removal of a single altered base with an small adduct (complex)- used for smaller things. NUCLEOTIDE EXCISION REPAIR: Removal of a base with a large adduct (complex). This has the potential for mutations. Ex: Xeroderma pigmentosum: a condition in which most patients are highly sensitive to UV exposure due to the defects in nucleotide excision repair capabilities. Slide 20: know how nucleotide excision repair can lead to… It is great as a repair 99.9% of the time, BUT it can fail the more times you’re exposed to the same carcinogen. Slide 23: process of neoplastic development slide 23-31 (summary in slide 29) Initiation: Promotion: Progression: Complete carcinogen: (know the diff. steps (initiation, promotion, progression) Slide 33: know that studies are often not controlled and insufficient Epidemiology: The study of distribution and determinants of disease from observation rather than through controlled experimentation. It is often insufficient, rarely possible to identify a single chemical as a sole carcinogen. - There are many environmental variables - Long time interval between the exposure and the neoplasm development. Slide 37: talks about diff lifestyle factors that can be decreased to prevent cancer- and that all of these are linked to the promotion stage. *MOST METHODS OF PREVENTIONS ARE LINKED TO THE STAGE OF PROMOTION: BECAUSE THIS IS THE REVERSIBLE STAGE OF NEOPLASTIC DEVELOPMENT (BEFORE ITS TOO LATE). Passive: - Stop smoking - Better diet - Moderate alcohol intake - Avoid too much UV exposure. Active: -Modify your diet -Vaccinate against oncogenic viruses -Apply UV sunblock -Screen for certain pre-neoplastic lesions Slide 40-42?: what structure activity alerts,  Slide 42: AMES test: Ames test: AN ASSAY THAT THE FDA REQUIRES THAT ALL DRUGS NEED TO GO THROUGH. NEEDS HISTIDINE TO LIVE CONTROL (NOT A MUTAGEN): WE INCUBATED, AND WE GET COLONIES (NATURAL MUTATIONS)- WE EXPECT THEM TO DIE BC OF NO HISTIDINE. POSSIBLE MUTAGEN: PLATES IT WITHMEDIUMAND WE INCUBATE IT, WE GET A LOT OF COLONIES- SHOWED OUR SUBSTACE OF INTEREST THAT WE TINKIS A MUTAGEN, CHANGED DNA ABOVE CONTROL AMOUNTS AND CHANGED DNA IN SME TYPE OF WAY- IT HAS THE CAPABILITY OF DAMAGING DNA- HAS LIKELY ABILITY TO BE A CARCINOGEN. WITHOUT S9, HAS MINIMAL COLONIES THE ONE WITH S9 HAS SOMETHING WITH NO COLONIES, YOU KNOW THAT THE S9 IS A CARCINOGEN.  Slide 43: dominant lethal assay: LOOKING FOR THE ABILITY TO DAMAGE SEX CELLS (SPERM) AND THAT EVIDENCE LEADS TO YOU THE ABILITY TO KNOW IF THE COMPOUND IS A CARCINOGEN.  Example (in vivo):  Dominant Lethal Assay  Older assay…replaced by genetically engineered animals  Male mice exposed to carcinogen  Mated with untreated female mice  % pregnancy determined against a control population Lecture 5: Slide 4: Blood Brain Barrier definition: BBB employs toxin transporters that pump toxins back into the blood. Molecules must pass “into” cell membranes of endothelial cells in the brain rather than “between” them to gain entry to the nervous system. Slide 5 and 6*: difference/and the reason Systemic Capillaries  Intercellular gaps (spaces Brain Capillaries between cells) (fenestrations)- -Tight junctions allow certain molecules to pass through. -Lack of pinocytosis  Abundant pinocytosis- cells take -Transcellular passage of lipid- what is in the circulation and soluble compounds pinch and grab it into the cell  Transcellular passage of lipid- soluble compounds Slide 7: imp. B/c it talks about the energy requirements (know why) A lot of energy is spent on the nervous system: everything wants to be at equilibrium. The nervous system is highly dependent on ion gradient- when you have action potential fires (in order to maintain those gradients- it requires a lot of energy because ions need to be pumped against their gradient). The brain is extremely sensitive to small interruptions in the supply of O2 or Glucose. Slide 8: know what AXONAL transport is (slide 11-14 as well) know dynein and kinesin Axonal transport: moves protein products from cell body to appropriate site in the axon. Provides distal portion of the axon with the required functional and structural proteins from cell body. Kinesin: Away from cell body- Anterograde transport Dynein: towards the cell body- Retrograde transport- from terminal to cell body  Provide mechanochemical force in form of microtubule-associated ATPase and the interface between microtubules as the “track” and the vesicles as the “cargo” Neurons are elongating single cells (~3ft long), so what needs to be done is an extremely large cellular volume is required. More proteins synthesis, something may be made at one end of the cell and needs to get to the other end for the cell and needs energy for this transport. Slide 15-18: Axonal degeneration- know what happened- what the process is dependent on (ca+ etc.) AXONAL DEGENERATION: If axon is severed (axotomy) or clinically injured: the degeneration of the distal nerve with survival of the cell body occurs. The axon will swell up and fragmentation of the distal axon occurs by macrophages. Regeneration: Schwann cells then provide physical guidance to direct the re-growth of a new axon and change protein synthesis to foster a regenerative environment. PROCESS CAN BE DELAYED BY DECREASING TEMPERATURE, LOWERING EXTRACELLULAR Ca2+, OR INHIBITING PROTEOLYSIS (LYSIS OF PROTEINS).  Slide 19: what happens with the death of the neuron: If a CELL BODY is injured, a DEATH OF NEURON (Neuronopathy) process occurs. This causes the degeneration of the CELL BODY and all processes with no potential for regeneration. Slide 20-22: Myelin formation and maintenance Myelin sheath is important b/c it allows action potential to jump from one axon to another axon without going through the entire axon to get a signal. Myelin formation occurs in 2 places: CNS: Uses Oligodendrocytes PNS: Uses Schwann cells They wrap these cells around the axon progressively. Maintenance: The maintenance of myelin depends on many proteins and specific lipids. Demyelination: Loss of myelin with preservation of the axon. *Some TOXIC compounds may interfere with this complex process and result in myelopathies aka: DEMYELINATION which can cause a slowing down of the action potential. Slide 25: Neurotransmission-Intercellular signal transmission that is achieved through synapses Pre-synaptic cell: Contains vesicles of neurotransmitters Post-synaptic cell: contains the receptors *The receptor affects the ion channels or 2ns messengers, which leads to changes in response in the post-synaptic cell. This process is affected by toxins and drugs. 1- vesicles 2- action potential 3- release of neurotransmitter into synapse (space in between cells) 4- neurotransmitters bind and activate 5- seated in post-synaptic receptor 6- causes action potential to fire 7- REUPTAKE of that neurotransmitter back to the pre- synaptic cell (we don’t want them to be hanging around too much b/c then we will have too many actions occurring) slide 27: know that the developing nervous system is not in completed form and it is vulnerable to certain toxins Immature (developing) nervous system (infants) are especially vulnerable to certain toxicants because brain is not fully developed. Ex: Ethanol in alcohol can cause abnormalities in the development of neuronal processes that results in mental retardation, delayed myelination etc. Slide 28: mechanisms of neurotoxicity. Individual neurotoxic compounds have one of four targets: 1- The neuron 2- The axon 3- The myelinating cell (oligodendrocytes or Schwann cells 4- The neurotransmitter system Slide 29: know neuronopathy Neuropathy: Certain toxicants are specific for neurons. The neuron loss is irreversible, and the degeneration of all compartments occurs. The injury is often followed by apoptosis or necrosis Exposure usually results in encephalopathy with dysfunction. Slide 31: examples of toxins (focus on mechanism of action that cause it) ex: inhibition of reuptake, blocking post synaptic cell (etc.) rather than what toxin does it. Slide 34: neuronal injury Slide 36: things that just target the axon Slide 37: CNS/PNS know why they’re different CNS: CNS axons CAN’T regenerate Irreversible damage occurs PNS: Peripheral axons CAN REGENERATE Partial to complete recovery occurs Slide 38: be familiar with the mechanisms of action Slide 40: Myelinopothies: know that any swelling or separation will affect those insulating properties. Slide 44: know that this is the prominent form of neurotoxicity- -often reversible and many different ways a toxin can. (slide 45) Slide 26 *** Slide 47: know mechanism of cocaine (reuptake inhibition of neurotransmitter)