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101 Cards in this Set
- Front
- Back
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Are all chemicals potentially toxic?
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Yes, the dose makes the poison
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What are toxicants?
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toxic substances that are man-made or result from human activity
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What are toxins?
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Usually refers to a toxic substance made by living organisms including reptiles, insects, plants, and microorganisms.
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What did concern with chemicals in the environment originally arise from?
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Occupational exposures
-Increased production of synthetic chemicals--dies, plastics, solvents, etc. -Roughly 100,000 different synthetic chemicals are not he global market |
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What is exposure?
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Any condition which provides an opportunity for an external environmental agent to enter the body through various transport mechanisms
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What is the distinction between exposure and dose?
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Exposure is "outside" the body
Dose is "inside" the body |
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What is an agent?
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Any chemical, biological, or physical material capable of eliciting a biological response
-different than the vector carrier (air, soil, water, food) |
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What is a dose?
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The amount of agent actually deposited within the body (i.e. internal dose).
-typically, the distinction between exposure and does is blurred, although in reality significantly different doses and biological effect can result from the same exposure depending on the route of entry. |
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What is a response?
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change in structure or function resulting in morbidity or mortality; the initial response is always molecular.
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What is the exposure-response paradigm?
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Exposure-->Dose-->Response
Source-->Hose-->Adverse Health Effect Air, Water, Food, Soil-->Humans-->Disease |
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Where does exposure begin?
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IN UTERO
-cord blood analysis found protein differences in children from mothers who smoke and from those that don't smoke. |
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What are the challenges in obtaining dose-resonse relationships?
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-Characterization of exposure or dose
-Assessment of Response -Selection of dose-response model to fit the observed data; particularly important in cancer risk assessment |
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What are the problems associated with quantitatively characterizing the association between previous exposure to an environmental agent and subsequent development of disease?
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-frequently "stuck" with exposure-response relationships.
-association versus cause and effect -plausible biologic mechanism (one prerequisite for cause and effect) |
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What is acute versus delayed onset?
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-latent period confounds many epidemiologic studies.
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What's the difference between short-term and delayed onset?
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irreversibility
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What is spontaneous incidence?
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-function of age
-tease out agent-produced component from background -100's of causes of "nonspecific" effects |
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What is toxicokinetics?
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What we do to the chemical
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What is toxicodynamics?
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response (what chemical does to us)
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What are the susceptibility factors?
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-Internal Dose
-Biologically Effective dose (react with molecule and elicit a response) -Early Biological Effects -Altered Structure/Function |
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What are the toxicokinetics?
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Absorption
Distribution Excretion Biotransformation |
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What is toxicokinetics (long definition).
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Toxicokinetics is the quantification of the time course of toxicants in the body during the processes of absorption, distribution, biotransformation, and excretion or clearance of toxicants. In other words, toxicokinetics is a reflection of how the body handles toxicants as indicated by the plasma concentration of that xenobiotic at various time points.
-The end result of these toxicokinetic processes is a biologically effective dose of the toxicant. |
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What is toxicodynamics?
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Refers to the molecular, biochemical and physiological effects of toxicants or their metabolites in biological systems.
-These effects are the result of the interaction of the biologically effective dose of the ultimate (active) form of the toxicant with a molecular target |
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What are the types of transport?
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-Simple diffusion
-Facillitated diffusion -Active transport -Pinocytosis/receptor mediated uptake -Filtration |
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What do both passive mediated (facilitated) and active mediated transport involve the use of?
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CARRIER PROTEINS
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Active transport uses what as an energy source for the carrier?
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ATP
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What is the distribution pattern of chemicals following different routes of entry?
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Bloodstream- Intravenous
Lungs- Inhalation Gastrointestinal- ingestion (oral route) Skin- Dermal |
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What is the major difference between a non-neural and a brain capillary?
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Things can leave a non-neural capillary with greater ease because there is no astrocytes blocking the passageways
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What are the excretion pathways?
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-Respiratory excretion
(mucocilliary clearance) -Gastrointestinal excretion (biliary excretion, entero-hepatic circulation) -urinary excretion (glomerular filtration, trans-tubular secretion) |
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What are the other routs of excretion?
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milk
sweat hair nails saliva |
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How can the processes associated with toxicokinetics be quantified?
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HALF LIVES
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How are half lives determined?
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serial blood analysis of the chemical
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What is a biological half life?
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the time required for some measure of the amount of a chemical in the body (for example, body burden, tissue concentration) to decrease by 1/2 its value at the beginning of the observational interval
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What are xenobiotics?
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foreign--and potentially toxic--compounds
-they are usually lipophilic (fat soluble) |
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How does biotransformation and bioactivation work?
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the body readily excretes water soluble compounds. So the body transforms (enzymatically alters) xenobiotics (via phase I and phase II reactions) to try to make them more water soluble. Sometimes these transformations make the resulting compound more toxic (the compound is bioactivated)
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What are phase I reactions?
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Enzymatic reactions that add or expose functional groups to xenobiotics such as- OH, -SH, -NH2 or -COOH
-Functional groups are analogous to having a trailer hitch on a vehicle. They both allow a coupling process to occur |
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What are phase II reactions?
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Enzymatic reactions that result in the conjugation of large water-soluble, charged (polar) biomolecules to xenobiotics
-For these reactions to occur, a functional group (i.e. hitch) must be present on either rthe parent compound or its phase I product |
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What is the Truck-Hitch-Trailer paradigm?
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Truck: foreign chemical (xenobiotic); lipophilic, not charged, not water soluble, poorly excitable
Hitch (Phase I): still lipophilic, possibly reactive, poorly water soluble, poorly excretable, catalyzed by P450s Trailer (Phase II): not lipophilic, usually not reactive, water soluble products, excitable, catalyzed by transferases. |
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What is the primary Phase I enzyme?
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cytochrome P-450 (mixed function oxidase)
-can metabolize many xenobiotics -can catalyze many types of reactions (broad substrate specificity) -widely distributed amongst tissues -exists in multiple forms (determined by many genes) -levels can be increased by exposure to chemicals in food, water, or air (induction) |
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What are the 4 primary Phase II enzymes?
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These 4 primary enzymes attach
glucoronyltransferase->glucuronic acid sulfotransferase->sulfate glutathione-S-Transferase--> gluathione (GSH) Acetyltransferase--> AcetylCoA |
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What is bioactivation?
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The dark side of biotransformation
The generation of biologically reactive intermediates that may occur during biotransformation. The toxicity of most organic molecules is due to bioactivation. |
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What is the chemical nature of reactive intermediates?
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Chemicals prefer to be electronically neutral.
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What are electrophiles?
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-Electron deficient
-Have a positive charge: look for negative charge -DNA, proteins, and glutathione have a negative charge |
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What are free radicals?
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--odd or unpaired electrons
-can act as electrophiles-- covalent bonding -can abstract hydrogen from target molecules -can activate molecular oxygen |
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What is the first principle of toxicology?
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Molecular targets concept: The toxic action of ac hemical is a consequence of the physical/chemical interaction of the active form of that chemical with a molecular target within the living organism
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What are markers of biologically-effective dose?
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(Assessment of the interaction fo the active form of toxicants with their molecular targets.
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What are examples of biologically-effective dose?
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-DNA adducts (cellular DNA, urine)
-Protein adducts (hemoglobin, albumin) |
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What is the second principle of toxicology?
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Dose-Response Concept
The magnitude of the toxic effect be will be a function of the concentration of altered molecualr targets which, in turn, is related to the concentration of the active form of the toxicant (biologically effective dose) at the site where the molecular targets are located |
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What are examples of the second principle of toxicology?
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-Carbon monoxide and hemoglobin (CO can replace oxygen in its complex; its binding is so strong that minute levels in the atmosphere can block oxygen transport.)
-Dioxin and the Ah receptor -Human paraquat exposure can result in lung toxicity due to its accumulation in lung cells |
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What is the primary molecular target for cancer?
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DNA
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What are the effects of toxicodynamics?
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Result of the interaction of the biologically effective dose of the ultimate (active) form of the toxicant with a molecular target.
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What are the causes of cancer?
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Breathing
Eating Drinking Radiation Sex Doctors Parents |
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What causes carcinogenesis?
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Exogenous: chemicals, radiation, viruses
Endogenous: Hormunes, immune dysfunction Inherited mutations (susceptibilities) |
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How does cancer arise?
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Accumulation of genetic damage
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What is susceptibility?
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refers to something that has responsiveness and sensitivity; susceptibility genes confer a higher than normal risk associated with some pathology
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What is the gene-environment interaction?
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The interaction between specific environmental exposures and a specific gene (or genes) and their subsequent impact on human health
-Inherited genes: don not cause cancer necessarily but can be triggered by the environment. |
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What is the role of epidemiology in environmental roles in human cancer?
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-there are large differences in tumor incidences within populations of a single country
-Migrant populations assume the cancer incidence of their new environment within one or two generations -cancer rates with a population can change rapidly |
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What is Ramazzini (1713)?
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noted that nuns exhibited a higher frequency of breast cancer than other women; attributed it to celibate life
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What is Hill (1761)?
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associated the use of tobacco snuff with cancer of the nasal passages
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What is Pott (1775)?
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noted the occurrence of soot-related cancer in chimney sweeps
-young boys had high scrotal cancer; shower 1-2 times a week lowered exposure and occurrence |
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What is Unna (1984)?
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associated sunlight exposure with skin cancer
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What is Rehn (1895)?
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associated occupational exposure to aromatic amine dyes with bladder cancer
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What is Ichikawa (1915)?
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first experimental production of tumors in animals (application of coal tars to ears of rabbit)
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What are physical carcinogenic agents?
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-X-Rays (breasts, leukemia's)
-Ultraviolet light: skin: non-melanoma and melanoma -Asbestos: lung-mesothelioma, pleural lining of the long; bronchogenic cancer with cigarette smoking |
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What are biological carcinogenic agents?
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Viruses (RNA tumor viruses); DNA tumor viruses
-Bacteria |
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What are chemical carcinogenic agents?
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Inorganic: Arsenic, cadmium, chromium, nickel
Organic: polycyclic aromatic hydrocarbons, heterocyclic amines, aflatoxin, nitrosamines Hormones: DES, ethinyl estradiol (pregnant-> daughter gets uterine cancer), estradiol, tamoxifen (birth control) |
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What is multistage carcinogenesis?
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Carcinogen--Exposure--Initiation--Promotion (selected growth)--Conversion--Progression--Give off cells that spread to other organs
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Once it hits stage three (progression), what happens?
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It starts to spread to lymph nodes and reaches blood stream
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What are the mechanisms of chemical carcinogenesis?
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-Activation of carcinogens to electrophiles by biotransformation
(molecular target: DNA). DNA repair processes; gene targets: cellular and proto-oncogenes, and tumor suppressor genes -Multistage carcinogenesis |
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How are heterocyclic amines produced?
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By cooking meats
carcinogenic to breasts, colon and prostate |
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What is a DNA adduct?
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a piece of DNA covalently bonded to a (cancer-causing) chemical. This process could be the start of a cancerous cell, or carcinogenesis. DNA adducts in scientific experiments are used as biomarkers of exposure[1] and as such are themselves measured to reflect quantitatively, for comparison, the amount of carcinogen exposure to the subject organism, i.e. rats or other living animals.[
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What are the different types of repair?
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-base excision repair
-nucleotide excision repair |
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What are the causes of DNA repair defects?
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-Increase sensitivity to carcinogens (get from your parents)
-Xeroderma pigmentosum (failure to repair UV damage to DNA) -Ataxia telangiectasis (failure in repair or replication of double-strand breaks in DNA. |
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What are examples of genotoxicity?
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mutagenesis: occurence of "point" or "gene-locus" mutation (base pairs), substitution, and small deletions or additions
-clastogenesis: occurrence of chromosomal breaks resultin in gain, loss, or rearrangement of pieces of chromosome -aneuplodization: gain or loss of one or more chromosomes |
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What are the 2 main classes of genes that get damaged/mutated?
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gain of function: (proto-oncogenes and oncogenes): protooncogenes are important regulators of many normal aspects of cell growth; purpose of promoting carcinogenesis. mutated proto-ongogene=oncogene
-Loss of function (tumor suppressor genes): lsos of ability to regulate growth; most commonly mutated tumor suppressor gene is p53 |
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What is the p53 tumor suppressor gene?
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most frequently found to be mutated in human tumors. mutation of the gene rsults in a p53 protein with an altered strucutre and function.
-p53 protein binds to dna and regulates the expression of cell cycle-related genes. Wild type protein blocks cell cycle progression while mutant protein promotes cell proliferation |
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What is epigenetic and what are the drivers?
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Epigenetic is in addition to changes in genetic sequence.
Known or suspected drivers include many agents, including heavy metals, pesticides, diesal exhaust, tobacco smoke, polycyclic aromatic hydrocarbons, hormones, radioactivity. |
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What is the methylation?
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one epigenetic mechanism for repressing transcription
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What does initiation of multistage carcinogenesis include?
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somatic cell mutation of dna
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What does promotion of multistage carcinogenesis include?
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clonal expansion of initiated cells; benign
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What does progression of multistage carcinogenesis include?
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evolution of neoplastic phenotype; malignant
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In initation, what happens if you are exposed minimally?
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You won't get tumor
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How do we prevent cancer?
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prevention + protection
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What does prevention include?
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elimintion of carcinogenic influences (industrial carcinogens, cigarette smoking, radiation, UV radiation)
-knowledge of identity of carcinogen is essential |
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What does protection include?
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measures designed to interrupt the carcinogenic process without specific efforts to identify or eliminate carcinogenic influences (e.g. dietary measures)
-Knowledge of identity of carcinogen is desirable (5 helpings of fruits and vegetables) |
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The aflatoxin-DNA adduct is unstable and excreted in...
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URINE
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What vegetable will shun cancer the most?
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BROCOLLI via detoxication enzymes (cruciferae family of veggies)
Amazing: same amount in sprout as the whole head. |
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Environmental factors may contribute to how many of all human cancers?
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3/4
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What classes can be carcinogenic?
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chemicals, viruses, and radiation
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What are the vectors/routes of exposure?
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Water, Air, Food, Soil
routes of exposure: GI tract, skin, lungs |
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How many pounds of air do we inhale a day?
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35 lbs
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What is the third leading cause of death in the US?
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lung cancer
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What's the fourth leading cause in the US?
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Chronic Obstructive Pulmonary Disease (COPD)
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What is the most common chronic illness in children?
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asthma (leading cause of hospital admissions)
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What is COPD?
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lungs->tubes of air bronchioles-> air sacs where gas exchange occurs->oxygen goes into the blood (RBCs), carbon dioxide is exhaled
-In COPD, destruction of airways (caused by tobacco smoke) with less of a capacity to breathe. |
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What are examples of catastrophic air pollution?
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1911 in London--1150 died from coal smoke (smoke + fog= smog)
1952 in London-4000 died from smog 1948- Donora (20 died, 6000 died from smog from steel mill, zing smelter and sulfuric acid plant) |
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What is the London Killer Smog of 1952?
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Smoke went up, sulfur dioxide went up, deaths went up
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What are the economic costs of air pollution?
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$71 billion annually from criteria air pollution
-We lose productivity and agriculutre -Lose 71 billion dollars |
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What are natural air pollutants?
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volcanic ash, radioactivity, pollen dust, smoke from fires
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What are man-made air pollutants?
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gaseous
-derived from combustion processes -hydrocarbons -oxides of sulfur and nitrogen compounds -Particulate matter (solid or aqueous particles) -Smallest can remain suspended but some can penetrate respiratory tract |
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What are the classification of air pollutants?!?!
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1. "Criteria Pollutants" (Caps)
-ubiquitous (wide-spread) -not very toxic-not carcinogenic -Particulate matter (PM), sulfur dioxide, nitrogen dioxide, ozone, carbon monoxide, lead 2. Hazardous air pollutants (Haps) -limited sources and more industry specific -considered more toxic and more carcinogenic -188 chemicals (benzene, formaldehyde, many don't target lung directly). |
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What are criteria pollutants and where do they come from?
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Emitted from mobile and stationary sources
omnipresent-> greatest threat to human health -presuppostion: don't consider these cancerous -They come from transport, stationary sources, industrial processe, and waste disposal |
