Term
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Definition
| the study of the adverse effects of chemicals or physical agents on living organisms |
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Term
| What forms can adverse effects take (time frame)? |
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Definition
| many - immediate death, subtle changes that aren't realized for months or years |
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Term
| What parts of the body can adverse effects affect? |
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Definition
| many - can be an organ, a type of cell, of a specific biochemical |
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Term
| What things were used to poison enemies or for state executions around 1500 BC? |
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Definition
| hemlock, opium, arrow poisons, and certain metals |
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Term
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Definition
| *focused on the primary toxic agent as a chemical entity*determined that specific chemicals were actually responsible for the toxicity of a plant or animal poison*documented that the body's response to a toxin depended on the dose received |
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Term
| Who was the 1st person to look at a dose-response relationship? |
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Definition
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Term
| What did Catherine de Medici do? |
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Definition
| took food to the poor laced with different toxic agents and made notes on how they died, how fast, what organs were affected, etc |
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Term
| What did Orfila do (~1800 AD)? |
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Definition
| *made the first systematic correlation between the chemical and biological properties of poisons *demonstrated the effects of poisons on specific organs by analyzing autopsy materials for poisons and their associated tissue damage * the father of forensic tox |
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Term
| When were anesthetics and disinfectants 1st used? |
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Definition
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Term
| What was the Wiley Bill and when was it introduced? |
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Definition
| it was the 1st of the US pure food and drug laws - in response to patent medicines - cure alls that were being sold in the streets - a lot of these were mostly alcohol and people had adverse effects |
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Term
| When was prohibition and what was discovered during this time? |
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Definition
| 1920 - the neurotoxicity of products of bootleg liquor |
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Term
| What was used to treat syphillis in the early 20th century? |
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Definition
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Term
| When was there a major push in Germany and the US to make antibiotics? |
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Definition
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Term
| When was the cytochrome p450 family of proteins discovered? |
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Definition
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Term
| What does Rubella cause and where and when was this discovered? |
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Definition
| heart and eye malformations and mental retardation in children whose mothers had rubella |
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Term
| What does FIFRA stand for and what was the significance of it? |
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Definition
| federal insecticide, fungicide, and rodenticide act - (1947) it was the 1st time in US history that there was regulation on something that wasn't specifically in food or drugs |
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Term
| What is the FDCA? What was the Delaney clause? |
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Definition
| food, drug, and cosmetic act - 1950 - any chemical found to be carcinogenic in lab animals or humans could not be added to the US food supply |
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Term
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Definition
| 1960 - a sleep aid that was later prescribed to women to relieve nausea during pregnancy - horrific limb defects - 1st time people realized that the placenta didn't protect against everything and started the advent of developmental tox testing (esp in multiple species) |
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Term
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Definition
| an herbicide used in the Vietnam war that contained dioxin - caused many health problems to the people exposed to it |
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Term
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Definition
| a utopic community in NY that was built on a hazardous waste dump site - the chemicals leached out and caused problems |
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Term
| What 2 types of research did Love Canal drive? |
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Definition
| research into mechanisms of actions of individual chemicals and mixtures of chemicals |
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Term
| What is the Superfund Bill? |
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Definition
| a law inspired by the Love Canal that says you have to have a plan for diposal when you make a chemical |
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Term
| Does toxicology only study chemicals? |
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Definition
| no - it can be adverse effects of viruses, bacteria, etc |
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Term
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Definition
| a general term for a foreign substance taken into the body - they can produce beneficial effects or toxic effects |
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Term
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Definition
| substances that are produced by or are by-products of human activities |
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Term
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Definition
| substances produced by biological systems - plants, animals, bacteria, and fungi |
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Term
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Definition
| anything that cacn produce an adverse biological effect - can be chemical, physical, or biological in form |
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Term
| What are examples of chemical, physical, or biological toxic agents? |
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Definition
| chem- cyanide, phys - radiation, bio- snake venom |
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Term
| Is a disease due to a biological organism classified as a toxic agent? Give an example. |
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Definition
| no - i.e. organisms that invade and multiply and produce their effects by biological activity, like a virus that damages cell membranes resulting in cell death |
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Term
| What are the 2 classes of toxic substances? |
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Definition
| systemic or organ toxicants/toxins |
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Term
| What is a systemic toxin? Give an example. |
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Definition
| one that affects the entire body or many organs rather than a specific site - KCN affects virtually every cell and organ b/c it interferes with the cell's ability to utilize O2 |
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Term
| What is an organ toxicant? |
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Definition
| one that affects an organ without damaging the body as a whole |
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Term
| What are 2 examples of a specific organ toxicant? |
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Definition
| benzene - primarily toxic to blood forming tissues - lead - CNS, kidney, and hematopoeitic systems |
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Term
| What are the 4 ways that body cells can be classified (give examples)? |
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Definition
| basic structure (cuboidal), tissue type (connective tissue), germinal cells (ova and sperm), and somatic cells (non-reproductive cells in the body) |
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Term
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Definition
| cellular, biochemical, molecular mechanisms exert toxic effects on living organisms. Data that they get is used in risk assessment |
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Term
| Give 2 examples of how mechanistic tox is used. |
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Definition
| organophosphates are toxic to people – they can predict toxicity of these from other species * it was thought that saccharin was toxic, but they figured out that the toxic mech was that it formed crystals in urine, causing bladder cancer, but in humans it can’t b/c you can’t eat enough to get crystals |
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Term
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Definition
| toxicity testing, safety evaluation and regulatory requirements – pharmaceutical companies, industries – preliminary tests are in rodents, then non-rodent species |
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Term
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Definition
| decides on the basis of descriptive and mechanistic data whether a drug or chemical poses a low risk so can be marketed for a stated purpose. They make regulatory decisions. They look at other animals as well as humans. |
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Term
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Definition
| medicolegal aspects of harmful effects of chemicals in humans and animals, establish cause of death (postmortem investigations) |
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Term
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Definition
| Medical science concerned with disease caused by or associated with toxic substances. They treat patients poisoned with drugs or other chemicals develop new techniques of treatment. |
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Term
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Definition
| concerned with chemical pollutants in the environment that can affect biological organisms. |
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Term
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Definition
| studies the impact of toxic substances on population dynamics in ecosystems |
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Term
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Definition
| studies the adverse effects on developing organisms. Developmental toxicologists also look at chemicals or other agents that affect conception, prenatal development as well as postnatal development. |
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Term
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Definition
| study of occurrence of adverse effects on the male and female reproductive systems that may result from exposure to chemicals or physical agents. |
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Term
| What has to happen in order for a substance to be toxic? |
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Definition
| the reagent or its metabolites have to reach an appropriate site in the body at a concentration and for a length of time sufficient to produce a toxic response |
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Term
| What is the most important influence on whether a substance is toxic or not? |
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Definition
|
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Term
| What are some ways that toxins can affect cells directly? |
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Definition
| cell replacement, like fibrosis*damage to enzyme systems* disruption of protein synthesis* production of reactive chemicals in cells* DNA damage |
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Term
| What are some of the ways that xenobiotics act indirectly on cells? |
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Definition
| modification of an essential biochemical function* interference with nutrition* alteration of a physiological mechanism |
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Term
| How are toxic effects categorized? |
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Definition
| by the site of the toxic effect - 1 site, specific target organ, multiple sites - systemic toxicity |
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Term
| What are undesirable effects of therapeutics called? |
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Definition
| side effects - usually a therapeutic has 1 main effect |
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Term
| What is an allergic reaction? |
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Definition
| undesired effect - immunological adverse reaction - usually have to be sensitized, initially you don't get a reaction - it's hard to get population based data on this b/c it such an individual thing |
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Term
| What is an idiosyncratic reaction |
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Definition
| a reaction you have specifically b/c of genetic predisposition |
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Term
| What are the two time classifications of undesired effects? |
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Definition
| immediate or delayed response |
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Term
| Give examples where toxicity can be reversed and irreversible. |
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Definition
| reversible - liver cells can repair and regenerate * irreversible - CNS |
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Term
| What is the difference between local and systemic toxicity? |
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Definition
| systemic gets into the blood stream and affects all parts of the body |
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Term
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Definition
| toxicity that occurs almost immediately after exposure (hours/days) |
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Term
| What is an acute exposure? |
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Definition
| a single dose or a series of doses received within a 24 hour period |
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Term
| What is the main concern in acute exposure? |
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Definition
|
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Term
| What are 2 examples of acute toxicity? |
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Definition
| 1989- 5000 people die and 30,000 disabled due to methyl isocyanate exposure from an industrial accident in India * a lot of people die every year from CO from heaters |
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Term
| What else can happen besides death in acute exposure? |
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Definition
| non lethal effects like convulsions and respiratory irritation |
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Term
| What does subchronic toxicity result from? |
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Definition
| exposure to a toxicant for several weeks or months - common human exposure pattern for pharmaceuticals and environmental agents |
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Term
| What are 2 examples on subchronic toxicity |
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Definition
| ingestion of coumadin for several weeks can cause unusual bleeding * workplace exposure to lead over several weeks can result in anemia |
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Term
| What does chronic toxicity mean? |
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Definition
| cumulative damage to specific organ systems - takes many months or years to become a recognizable clinical disease |
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Term
| Why is it hard to recognize chronic toxicity sometimes? |
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Definition
| damage due to subclinical individual exposures may do unnoticed * the damage builds up from repeated exposures or long-term continual exposure until the damage exceeds the threshold for chronic toxicity |
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Term
| What happens in chronic toxicity? |
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Definition
| the damage builds up and becomes so severe that the organ can no longer function properly |
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Term
| What are 4 examples of chronic toxicity? |
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Definition
| cirrhosis in alcoholics (50% or more of your liver is connective tissue) * lead exposure over several years = kidney disease * chronic bronchitis in cigarette smokers * black lung disease (pulmonary fibrosis) in coal miners |
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Term
| What are the 2 stages of carcinogenicity? |
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Definition
| initiation - a normal cell undergoes irreversible changes (original damage) * promotion - initiated cells are stimulated to progress to cancer and overgrow **not all initiated cells become cancer |
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Term
| What role do chemicals have in carcinogenesis? |
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Definition
| they can act as initiators or promoters |
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Term
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Definition
| an uncontrolled growth of cells - a tumor |
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Term
| What are the characteristics of a benign tumor? |
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Definition
| grow at the site of origin * no metastasis * generally treatable |
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Term
| What are the characteristics of a malignant tumor? |
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Definition
| defined as cancer - invasive, metastasized, more difficult to treat and often cause death |
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Term
| What are the 3 basic types of developmental tox? |
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Definition
| embryolethality - failure to conceive, spontaneous abortion, stillbirth * embryotoxicity - growth retardation, delayed growth of a specific organ system * teratogenicity - irreversible conditions that leave permanent birth defects |
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Term
| What does genetic toxicity result from? |
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Definition
| damage to DNA and altered genetic expression |
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Term
|
Definition
| the process of damaging DNA and altering genetic expression |
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Term
|
Definition
| an agent that damages DNA |
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Term
|
Definition
| the genetic change that comes from altered DNA |
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Term
|
Definition
| a change in DNA sequence within a gene |
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Term
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Definition
| changes in chromosome structure |
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Term
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Definition
| decrease or increase in the number of chromosomes |
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Term
| How does the form of the agent affect toxicity? |
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Definition
| some metals have different forms - i.e. Hg or MeHg that affect systems differently |
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Term
| What does innate activity of a chemical mean? |
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Definition
| how active the chemical is - some chemicals bind right away and cause damage immediately, some cause damage later - i.e. HCN binds to cytochrome C and shuts down cells immediately, nicotine does damage much more slowly |
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Term
| How does dosage affect toxicity? |
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Definition
| the more you give, the closer together the dose, the more toxic the agent - if the agent can be at least partially eliminated before the next dose it won't be as toxic |
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Term
| How does exposure route affect toxicity? |
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Definition
| critical - if it enters portal circulation (like when you eat something), the liver can detox a lot of it - if it gets into the system 1st, like with inhalation, it can be more toxic |
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Term
| How does species affect toxicity? |
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Definition
| Different species may be sensitive to different things - that's why you test in multiple species |
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Term
| What effect does age have on the toxicity of a compound? |
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Definition
| young and old are more susceptible b/c repair mech. aren't as effective - immune system-wise, in the young it isn't as developed and in the old its function is decreased - young also have fewer storage depots for toxins |
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Term
| Why can something affect the fetus but not the mother? |
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Definition
| the fetus may not have the detox systems yet to deal with it and has fewer storage depots |
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Term
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Definition
| yes - for some things males are more sensitive to females |
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Term
| Give an example of how sex influences toxicity. |
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Definition
| male rats are 10x more sensitive to DDT than females |
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Term
| What does a compound have to be able to do to be toxic? |
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Definition
| be absorbed - if you can't absorb it, you can't be affected by it |
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Term
| What factors affect a compound's ability to be absorbed? |
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Definition
| chemical structure and how lipophilic it is |
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Term
| Does metabolism affect toxicity? |
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Definition
|
|
Term
| How does distribution in the body affect toxicity? |
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Definition
| if it can get into the cells it can be toxic - so things that are lipid soluble get into cells |
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Term
| What is the primary excretion organ? |
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Definition
|
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Term
| What are more minor excretion systems? |
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Definition
| GI tract, lungs, sweat, tears, and milk |
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Term
| Can the presence of other chemicals affect a compound's toxicity? |
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Definition
| yes - they can make them more or less toxic |
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Term
| Why is studying the effects of chemical interactions important? |
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Definition
| b/c humans are usually exposed to several chemicals at 1 time, not individual chemicals, esp in medical treatments or environmental exposures |
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Term
| What are some examples of multiple compound exposures? |
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Definition
| hospital patients on the average get 6 drugs per day * gasoline vapors have 40-50 compounds * home flu treatment includes aspirin, antihistamines, and cough syrup * drinking water can contain pesticides, heavy metals, and solvents * air often contains hundreds of chemicals - i.e. cigarette smoke |
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Term
| How do xenobiotics act in the presence of other xenobiotics? |
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Definition
| they can act independently, most of the time the presence of 1 affects the toxicity of the other - the combination can be more or less toxic than individual components |
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Term
| What is interaction (chemical)? |
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Definition
| the effect that 1 chemical has on the toxic effect of another one |
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Term
| What is an additive interaction? |
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Definition
| combination that is the sum of the expected individual exposures - 1+1=2 |
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Term
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Definition
| 1 chemical by itself is toxic - combined with another it's even more toxic - 1+2 = 10 |
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Term
| What is 1 example of a synergistic interaction |
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Definition
| carbon tetrachloride and ethanol - do more liver damage together than the sum of each individually |
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Term
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Definition
| 1 chem. doesn't have a toxic effect, but when it's added to another chem, it becomes toxic - 0+2=10 |
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Term
| What is an example of potentiation? |
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Definition
| isopropanol isn't toxic, but when carbon tetrachloride is present (which is) - isoprop increases the hepatotoxicity of carbon tet |
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Term
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Definition
| the exposure of 1 chemical results in the reduction of the toxicity of the other - i.e. 2+4 = 3 |
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Term
| How can interactions be classified? (4) |
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Definition
| by their chemical and biological interactions - chem reactions between chemicals * modification in absorption, metab, or excretion * reactions at binding sites and receptors *physiological changes |
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Term
| Give 3 examples of additive effects. |
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Definition
| 2 CNS depressants taken at the same time (alcohol and tranquilizers) * organophosphate pesticides - 2 is equal to the toxicity of each individually (interferes with nerve conduction) * chlorinated insecticides and halogenated solvents are both toxic to liver |
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Term
| What are 3 examples of synergistic interactions? |
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Definition
| cigarette smoke and radon gets you a significantly higher risk of cancer * asbestos and cigarette smoke gives you a greater risk of lung cancer * ethanol and carbon tet = more liver toxicity |
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Term
| Give an example besides carbon tet and isopropanol of potentiation. |
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Definition
| warfarin is normally 2% active b/c it's bound to plasma albumin - drugs that compete for binding sites on albumin raise the % of warfarin that is free to 4%, which can cause a fatal hemorrhage |
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Term
| What is the basis for most antidotes? |
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Definition
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Term
| Give an example of physiological antagonism. |
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Definition
| a severe drop in blood pressure due to a barbiturate OD can be reversed by a vasopressor, which increases blood pressure |
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Term
| Give an example of chemical antagonism. |
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Definition
| mercury toxicity can be reduced by chelation with dimercaptol |
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Term
| Give an example of disposition antagonism |
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Definition
| swallowed poison is absorbed by charcoal introduced into the stomach |
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Term
| Give an example of receptor antagonism. |
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Definition
| CO poisoning is treated with O2 b/c that displaces CO from hemoglobin receptors |
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Term
| What is the most common type of drug interaction? |
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Definition
|
|
Term
|
Definition
| the amount of a substance administered at one time |
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Term
| What, besides dose, are the parameters needed to characterize exposure to xenobiotics? |
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Definition
| number of doses, frequency of doses, and total time period of the treatment |
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Term
| What is the exposure of dose? |
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Definition
| the amount of xenobiotic encountered in the environment |
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Term
| What is the absorbed dose? |
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Definition
| the actual amount of the exposed dose that enters the body |
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Term
| What is the administered dose? |
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Definition
| the quantity administered usually orally or by injection |
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Term
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Definition
| the sum of the individual doses |
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Term
| What does fractionating a total dose do to toxicity? |
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Definition
| usually decreases the possibility that it will be toxic - i.e. 30 mg strychnine is fatal, 10 doses of 3mg of strychnine is not |
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Term
| What is the standard unit of dose? What is usually used? |
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Definition
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|
Term
| What do you relate to the clinical and toxic effects of a dose? |
|
Definition
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|
Term
| What is the best comparison unit for dose? What if time is a factor? |
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Definition
| mg/kg body weight * mg/kg/day |
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|
Term
| What is the rule in the dose-response relationship? |
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Definition
| the higher the dose, the more severe the response |
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Term
| What 3 things does a dose response relationship deermine/establish? |
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Definition
| establishes causality that the chemical has induced the observed effect * est. the lowest dose where an induced effect occurs (threshold) * det. the rate at which injury builds up - the slope of the dose response |
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Term
| What is a quantal response? |
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Definition
| the response of a population to a dose, so people that have severe effects at low doses are susceptible and people that have minimal effects are resistant |
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Term
| What shape does a quantal response graph have? What does a large standard deviation indicate? |
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Definition
| bell shaped - indicates great variability in the population |
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Term
| What shape does a dose response curve usually have? |
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Definition
|
|
Term
| What is the threshold dose? |
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Definition
| the point on the curve at which a toxic effect first appears |
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Term
| What's happening in the body when you reach the threshold dose? |
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Definition
| the body's ability to detox a xenobiotic or repair damage caused by it has been exceeded |
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Term
| Define the slope of a dose-response curve. |
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Definition
| the percent of the population responding per unit change in dose |
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Term
| What does a steeper slope indicate? A flatter one? |
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Definition
| a small increase in dose will cause a big effect - flatter slope means that you can change the dose and not see as big of an effect |
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Term
| What is the typical use of a dose-response curve (what do you want to establish)? |
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Definition
| LD50 - the dose that is expected to be lethal to 50% of the population - use these curves to derive dose estimates |
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Term
| What does the effective dose indicate? |
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Definition
| the effectiveness of a substance - usually a beneficial effect, like the dose needed to relieve pain for a % of the population |
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Term
| What is selective toxicity? |
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Definition
| when an agent can be lethal to 1 species without harming another, even if the two are in close proximity |
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Term
| Give an example of how a difference in species can make a huge difference in the toxicity of a xenobiotic. |
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Definition
| aflatoxin at 10,000 ppb doesn't cause liver tumors in mice, but 15ppb does in rats |
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Term
| What is the therapeutic index? |
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Definition
| relative safety of a drug - it's used to compare the therapeutically effective dose to the toxic dose - LD50/ED50 - the higher the number, the safer - like if a drug had an LD of 200mg and an ED50 of 20 mg, the TI would be 10 |
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Term
| What is the margin of safety? |
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Definition
| the ratio of the dose that is just lethal to the dose that is 99% effective - LD1/ED99 - if MOS is less than 1, you have to use a lot of caution in prescribing the drug |
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Term
| Why can low doses be effective without producing toxicity? Why not prescribe higher doses? |
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Definition
| differences in slopes and threshold doses - the potential benefit is offset by the potential increase in toxicity |
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Term
| What are the 2 principles that animal testing is based on? |
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Definition
| the effects produced by a compound in laboratory animals are applicable to humans * the exposure of experimental animals to high doses of toxic agents is a necessary and valid method of discovering possible hazards in humans b/c the incidence of an effects in a population is greater as the dose or exposure increases |
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Term
| What is the purpose of descriptive animal toxicity tests? |
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Definition
| to characterize the toxic effects a chemical can produce |
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Term
| What does the type of toxic test conducted on an animal depend on? |
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Definition
| the structural analog of the chemical, the eventual use of the chemical, and the toxic effects of the chemical |
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Term
| What are the goals of an acute toxicity test? |
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Definition
| to quantitatively estimate acute toxicity (LD50) *identify the target organ * obtain clinical information * establish if there is a reversibility of the toxic response * provide dose-range guidance for other studies |
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Term
| In acute tox study, how many routes of exposure? How many species? What clinical signs are taken? What is determined? |
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Definition
| 1 or more * 1 or more - usually mouse and rat, sometimes dog and rabbit * daily signs- lethargy, appetite, behavior, morbidity * # of animals to die in a 14 day period after a single dose |
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Term
| How long is an inhalation acute tox test done for? What about dermal studies? |
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Definition
| 4 hours inhalation * 24 hours dermal - rabbits, skin is shaved, drug applied, plastic dressing |
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Term
| Describe the Draize Irritation Test. |
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Definition
| done in rabbits - the skin is shaved and drug is applied to 1 intact and 2 abraded areas and covered for 4 areas - look for erythema (redness), eschar (scabs), and edema (swelling) |
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Term
| How are sensitization studies done? |
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Definition
| the test compound is applied topically or intradermally to the shaved skin of guinea pigs * the substance stays on for 2-4 weeks and reapplied 2-3 weeks after removal with a non-irritation concentration - redness is evaluated |
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Term
| What is the goal of a subacute study? How long is it? |
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Definition
| to obtain info on the toxicity of a chemical with repeated exposures * 14 days |
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Term
| What are the dosages used in subacute studies? Method of delivery? Animals used and number? Housing? Tests? |
|
Definition
| 3-4 different dosages + control* mixing in feed * rats - 10/sex/dose, dogs - 3-4/sex/dose * housed individually, uniquely identified * clinical chemistries, histopath, hematology |
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Term
| What is the goal of a subchronic study? |
|
Definition
| establish NOAEL and LOAEL * ID and characterize specific organs or organ systems affected by test substance after repeated exposures |
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|
Term
| What is the protocol for a subchronic study? How long? Routes? Animals? Dosages? Tests (things noted)? |
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Definition
| 90 days * route is the intended exposure * 2 species rat/dog FDA; mouse/dog EPA *10-20 rats/sex/dose*4-6 dogs/sex/dose , all hosued individually* 3 doses + control* clinical signs 2x/day, deaths and necropsy, hematology, pathology |
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Term
| What is the goal of a chronic study? |
|
Definition
| to determine the carcinogenicity and cumulative potential of a substance |
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|
Term
| What is a major factor to consider in a chronic study? |
|
Definition
| having enough animals survive to the end - you sometimes double the number of animals at the beginning to ensure that enough survive at the end |
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|
Term
| What is the highest dose used in a chronic study? |
|
Definition
| the MTD - maximum tolerable dose - the dose that suppressed weight gain in the subchronic study |
|
|
Term
| What is the time frame of a chronic study? |
|
Definition
| rodents - 6mo to 2 years, non-rodent - 1 year *human exposure is a determining factor - if real exposure is short, 6 mo may be sufficient like antimicrobials |
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|
Term
| What is developmental toxicology? |
|
Definition
| the study of adverse effects to the developing organism, from prior to conception (either parent), prenatal development, or postnatally until puberty that may result from a chemical or physical agent |
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Term
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Definition
| the study of defects induced during the development between conception and birth |
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Term
| What is reproductive toxicology? |
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Definition
| the study of adverse effects on male and female reproductive system that may result from the exposure to chemical or physical agents. |
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Term
| What are the goals of segment I developmental testing? |
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Definition
| general fertility and reproductive performance |
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Term
| What is the protocol in a segment I test - animals, doses, dose time, endpoints? |
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Definition
1 species – rat - 20 rats/sex/dose – 2-3 doses and control *
Males dosed with chemical 60 days prior to mating (catch all stages of spermatogenesis)*
Females dosed 14 days prior to mating *
Chemical given throughout gestation and lactation *Endpoints -
% females that become pregnant,
# stillborn/live births,
weight, growth, survival of offspring during 1st 3 weeks of life |
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Term
| What are the goals of a developmental segment II test? |
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Definition
| to determine the teratogenic potential of a drug to disrupt embryonic and/or fetal development |
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Term
| What is the protocol in a segment II test - animals, doses, dose time, endpoints? |
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Definition
2 species – rodent and non-rodent (usually rabbit) - 12 rabbits/dose; 24/rats or mice/dose *
3 dosages and control *
Exposure during organogenesis; 7-19 rabbits or 7-17 rodents *
Fetuses removed one day before estimated time of delivery *
Uterus excised and weighed; examined for live, dead, or resorbed fetuses; examined for gross malformations *
Fetuses weighed; ½ examined for skeletal malformations; ½ examined for soft tissue abnormalities |
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Term
| What is the goal of a developmental segment III test? |
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Definition
| multigeneration study to determine effects of chemicals or agents on reproductive system |
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Term
| What is the protocol for a segment III test - animals, dosages, and generations? |
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Definition
Rats -
25 rats/sex/dose *
3 dosages and control *
Test substance given shortly after weaning (30-40 days old); mate at 140 days – this is the F0 generation – these guys get dosed throughout breeding, pregnancy, and lactation -->
F1 generation exposed in utero and via lactation and feed *
When F1 is140 days old – pick 25/sex mated (test substance administration continued) *
F2 generation – continued administration of test chemical, exposed in utero and via lactation |
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Term
| What endpoints are evaluated in a segment III test? |
|
Definition
% F1 and F2 litters examined immediately after dosing *
Determine % F0 and F1 pregnant, * # pregnancies to full term, litter size* # still born/# live births *
Viability counts, pup weights recorded at birth and days 4, 7, 14, 21 |
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Term
| What is a fertility index? |
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Definition
| % mating resulting in pregnancy |
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Term
| What is the gestation index? |
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Definition
| % pregnancies resulting in live births |
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Term
| What is the viability index? |
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Definition
| % animals survive >14 days |
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Term
| What is the lactation index? |
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Definition
| % animals alive at 4 days to survive to 21 days |
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Term
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Definition
| international commision on harmonization |
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Term
| What is the role of the ICH? |
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Definition
| provides flexible guidelines to address 5 stages of development |
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Term
| What are the 5 stages of development? |
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Definition
Stage A – pre-mating and conception *
Stage B – conception to implantation *
Stage C – Implantation to closure of hard palate*
Stage D – Closure of hard palate to end of pregnancy *
Stage E – birth to weaning |
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Term
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Definition
| the ability of chemicals to cause changes in the genetic material that allows changes to be transmitted during cell division |
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Term
| Why is mutagenesis testing often used to screen for potential carcinogens? |
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Definition
| b/c the initiating events of cancer are thought to be mutagenic ones |
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Term
| What is the microscopic test for mutagenicity? |
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Definition
| analysis of bone marrow smears of animals exposed to the test compound |
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Term
| How do you do a dominant lethal test? |
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Definition
| some chemicals aren't compatible with normal development - use rats - the males are given a single dose, mated with 2 untreated females and the # of live fetuses and corpora lutea are determined |
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Term
| What does an Ames test look for? |
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Definition
| the number of reverse mutations in salmonella that are caused by exposure to a test chemical |
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Term
| How do you do an Ames test? |
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Definition
| get salmonella that are missing phosphoribosyl ATP synthetase, which is required for histidine synthesis - these can't grow on media that lack histidine - add test chemical and rat liver microsomes to the media (liver enzymes biotransform the chemical, sometimes necessary to make toxic byproducts) - if a back mutation occurs, the salmonella will grow on the plate and exposure to the chemical is what did it |
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Term
| What are 5 practical reasons to study the mechanisms of toxicology? |
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Definition
Provides basis for interpretation of descriptive toxicity data *
Estimating probability that a chemical causes harmful effects *
Establishes procedures to prevent or antagonize toxic effects *
Design drugs and industrial chemicals that are less hazardous *
Develop pesticides more selectively toxic to target organisms |
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Term
| What are 2 theoretical reasons to study mechanisms of toxicology? |
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Definition
Understanding of pathologic conditions – cancer , Parkinson’s disease *
Better understanding of physiologic and biochemical processes -neurotransmitters, DNA repair |
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Term
| What are the 4 steps in the development of toxicity? |
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Definition
| 1. Target delivery 2. interaction 3.cellular dysfunction 4. repair mechanisms/dysrepair |
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Term
| How does tetrodotoxin cause toxicity? |
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Definition
| it gets ingested, then acts on Na gated channels of motoneurons (steps 1&2), it blocks the Na channels, leading to muscle paralysis and there is no repair (steps 3 & 4) |
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Term
| When does toxicity occur? |
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Definition
| when cellular dysfunction exceeds the cells' repair mechanisms or when the repair mech malfunctions |
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Term
| What counteracts absorption? |
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Definition
| presystemic elimination (1st pass metabolism) |
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Term
| What counteracts distribution toward the target of a toxicant? |
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Definition
| distribution away from the target |
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Term
| What counteracts reabsorption? |
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Definition
|
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Term
| What counteracts toxication? |
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Definition
|
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Term
| What does the toxic effect depend on? |
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Definition
| the concentration of the ultimate toxicant that is at the site of action |
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Term
| What is the ultimate toxicant? |
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Definition
| the chemical that reacts with the target molecule or alters the biological environment where the result is toxicity |
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Term
| What can the ultimate toxicant be? |
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Definition
| the original chemical that the person is exposed to or a metabolite, or ROS/RNS generated |
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Term
| What facilitates accumulation of a toxicant? |
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Definition
| absorption, distribution to site of action, and reabsorption and toxification. |
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Term
| What facilitates anti-absorption? |
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Definition
| presystemic elimination, distribution away from site of action, excretion and detoxification. |
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Term
| What is the definition of absorption? |
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Definition
| the transfer of a chemical from the site of exposure, through the skin, mucosa of alimentary and respiratory tracts, to the systemic circulation |
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Term
| What 4 things does the rate of absorption relate to? |
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Definition
Concentration of the chemical at the absorbing site *
Area of exposed surface *
Characteristics of the epithelial layer (thickness of the stratum corneum) *
Lipid solubility – lipid soluble substances are absorbed more readily than water soluble ones |
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Term
| What does 1st pass elimination do? |
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Definition
| prevents the toxicant from entering systemic circulation as a toxicant |
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Term
| What are major sites of 1st pass elimination? |
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Definition
|
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Term
| Can toxicants injure 1st pass elimination organs? |
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Definition
| yes - i.e. paraquat and ethanol |
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Term
| What does a toxicant have to do in terms of absorption to be toxic? |
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Definition
| you have to absorb enough, fast enough - If fraction absorbed and rate of absorption low, chemical may never attain high enough concentration at the site of action to be toxic. |
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Term
| Is distribution in a tissue or a target organ more toxic? |
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Definition
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Term
| What 3 layers does a toxicant have to pass through to be absorbed by a target organ? |
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Definition
| outer membrane of the skin/lungs/GI, capillary endothelium, and the cells of the target organ or tissue |
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Term
| What are some features of passive transport - energy requirements, size and type of molecules, and rate? |
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Definition
No energy required *
Small [600mw], hydrophilic through aqueous pores *
Hydrophobic diffuse across lipid domains *
Rate of transport correlates with lipid solubility |
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Term
| What are some features of active transport - energy requirements, movement, transport systems? |
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Definition
Requires energy *
Movement against concentration or electrochemical gradient *
Selective transport system |
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Term
| What is the P glycoprotein system - what is it also known as and what does it do? |
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Definition
| mdr [multi-drug resistant] – exudes chemicals from GI cells, brain endothelium, liver, and kidney cells, and helps protect fetus |
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Term
| What does the mrp stand for and do? |
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Definition
| multi-resistant drug protein – also exudes, phase II conjugates are faves |
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Term
| What does oct do and stand for? |
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Definition
| organic cation transport system – imp in renal and hepatic uptake of xenobiotics |
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Term
| What does oat do and stand for? |
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Definition
| organic anion transport system – imp in the renal uptake of anions |
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Term
| What do nt, dmt, and pept do and stand for? |
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Definition
nt – nucleotide transport system *
dmt – divalent metal transport system *
pept – peptide transport system *
All work in GI absorption of nucleotides, divalent metals, and peptides |
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Term
| What do phagocytosis and pinocytosis do? |
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Definition
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Term
| What is a characteristic and an example of facilitated transport? |
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Definition
| no energy required, metabolic poisons don’t interfere – i.e. transport of glucose in the intestines |
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Term
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Definition
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Term
| What are parenteral routes? |
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Definition
|
|
Term
| What is the most important site of toxicant absorption? Where does absorption take place in this site? |
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Definition
| GI tract - all along the GI tract |
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Term
| What influences rate of absorption in the GI tract? |
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Definition
| surface area and blood flow |
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Term
| How do most toxicants enter the GI tract? |
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Definition
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Term
| What types of transport systems are in the GI tract? |
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Definition
| transporters for nutrients and electrolytes as well as P glycoprotein system that moves chemicals back into the lumen so they can be eliminated |
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Term
| What determines the amount of chemicals that enter systemic circulation from the GI tract? |
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Definition
| depends on the amount absorbed into the GI mucosa, biotransformation by GI mucosal cells, and extraction into bile by the liver. |
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Term
| What are absorption differences of the GI tract of different species due to? |
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Definition
| differences in anatomy and gut flora |
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Term
| What is absorbed by the lungs? |
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Definition
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|
Term
| What is the role of the nose in toxicant absorption? |
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Definition
| acts like a "scrubber" - things that are very water soluble can dissolve in the mucosa and never reach the lungs |
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Term
| What happens eventually to gases in the lungs after they're inhaled? |
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Definition
| they reach equilibrium in the blood and the alveolar space - the rate of transfer of gas from the alveolar space to the blood equals the rate of removal by blood from the alveolar space |
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Term
| What are the major characteristics that affect absorption of aerosols? |
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Definition
| size and water solubility |
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Term
| How are particles >5um, 2-5um, and <1um dealt with in the respiratory system? |
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Definition
>5 Nasopharynx – can be removed by wiping nose, sneezing. Moved by cilia. Aerosols this size can be inhaled through the nose and swallowed. Soluble particles may dissolve in mucosa or absorbed through nasal epithelium into the blood. *
2-5 Tracheobronchiolar region. Moved out by cilia; may be swallowed andabsorbed by GI tract. *
<1 Alveolar sacs – absorbed into blood or cleared through lymphatics after being scavenged by alveolar macrophages. |
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Term
| How are toxicants physically removed from the lungs? |
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Definition
| particles get deposited on the fluid layer, get aspirated from ciliated epithelium or tracheobronchal region, get transported to the mouth, and get swallowed |
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Term
| Is the skin a good site of absorption for toxicants? |
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Definition
| no if it's intact, although moist skin absorbs better than dry |
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Term
| What has to happen for a toxicant to be absorbed through the skin? |
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Definition
| must pass through the epidermis, sweat gland, sebaceous gland, or hair follicles. |
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Term
| What is the biggest barrier in skin? |
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Definition
|
|
Term
| What mechanism is used by toxicants entering through the skin? |
|
Definition
|
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Term
| What are the absorption rates for IP, SQ, IM, and IV methods? |
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Definition
Intraperitoneal - rapid absorption because of the large number of vessels in the peritoneal cavity.*
Subcutaneous – slower rate of absorption but directly from tissue into systemic circulation *
Intramuscular - also goes directly into systemic circulation, also a little slow *
Intravenous – directly into bloodstream [not absorbed] |
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Term
| What can happen if you give a drug IP? |
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Definition
| it gets into the portal system and may be completely extracted and biotransformed, then excreted into the bile |
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Term
| What happens during distribution? |
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Definition
| the toxicant exits the blood and enters the extracellular space and may penetrate into the cells. |
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Term
| What does distribution depend on? |
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Definition
the rate and flow of blood and rate of diffusion and affinity of xenobiotic for various tissues *
[If the substance is lipophilic, enters the cells easily; if hydrophilic (or highly ionized) then the xenobiotics are restricted to extracellular space unless membrane carriers are available.] |
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Term
| What 4 things can enhance distribution? |
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Definition
| membrane transport, porosity of the capillary epithelium, accumulation in cell organelles, and reversible intracellular binding |
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Term
| What 5 things can reduce distribution? |
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Definition
| binding to plasma proteins, specialized barriers, distribution to storage sites, association with intracellular binding proteins, and export from the cell |
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Term
| What does the concentration of toxicant in the blood depend mainly on? |
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Definition
| the volume of distribution in the body |
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Term
| What happens if toxicants don't cross cell membranes readily? |
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Definition
| their distribution is restricted |
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Term
| If toxicants pass rapidly through cell membranes, what happens? |
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Definition
| they are distributed throughout the whole body |
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|
Term
| Why do some toxicants accumulate in certain parts of the body? |
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Definition
| protein binding, active transport, or high solubility in lipids |
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Term
| Is storage of toxicants protective? |
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Definition
| yes, but as unbound toxicant is eliminated, stored toxicant is released - can be problematic |
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Term
| What are 4 major storage depots for toxicants? |
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Definition
| plasma proteins, kidney and liver, fat, and bone |
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Term
| Why is the blood brain barrier less permeable than other parts of the body? |
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Definition
Capillary endothelial cells are tightly joined *
Brain capillary endothelial cells contain ATP dependent mdr [P glycoprotein] *
Capillaries in the CNS are surrounded by glial processes (astrocytes) *
Protein concentration in the interstitial fluid of CNS is much lower than in other body fluids limiting movement of water |
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Term
| What kind of toxicants equilibrate rapidly within the brain? |
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Definition
|
|
Term
| How do toxicants enter the brain? |
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Definition
| through a carrier mediated process |
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|
Term
| What determines the rate of entry into the CNS? |
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Definition
| lipid solubility and degree of ionization - the more lipid soluble, the easier it penetrates - ionization reduces the rate of penetration |
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Term
| What types of things can cross the placenta? |
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Definition
| chemicals, viruses (rubella), antibodies, cellular pathogens (syphilis), RBC |
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Term
| What protects the fetus from a lot of toxicants? |
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Definition
Anatomically toxic agents have to cross many layers of cells (6 at the most) *
The placenta contains active transport systems, biotransformation enzymes that protect fetus from some xenobiotics.*
Fetuses have little fat so do no accumulate lipophilic chemicals |
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Term
|
Definition
| the removal of xenobiotics from blood and their return to the external environment. |
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Term
| What types of compounds to the kidneys and liver remove? Why (4 reasons)? |
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Definition
highly hydrophilic, ionized chemicals *Renal glomeruli – only compounds dissolved in plasma can be filtered.*
Transporters in hepatocytes and renal proximal tubular cells are specialized for secretion of highly hydrophilic, ionized organic acids and bases.*
Only hydrophilic chemicals are soluble in aqueous bile and urine.*
Lipid-soluble compounds are reabsorbed by transcellular diffusion. |
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Term
| How heavy can compounds be to be filtered by glomeruli? |
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Definition
|
|
Term
| What does the degree of plasma protein binding reflect? |
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Definition
|
|
Term
| Where are transport systems located in the kidneys? Which transport systems are there? |
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Definition
| in the basolateral membranes of the proximal convoluted tubules – oct, mdr, mrp. |
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Term
| Why are xenobiotics eliminated more slowly in newborns? |
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Definition
| the kidneys aren't completely developed at birth |
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Term
| What is eliminated in the feces? |
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Definition
|
|
Term
| Describe biliary excretion (GI absorption-->feces) |
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Definition
Blood from the GI tract passes through the liver before reaching the general circulation. *
Liver removes toxic agents from blood after absorption from GI tract. *
The liver can extract compounds from the blood and prevent distribution to other parts of the body.*
Xenobiotics entering the intestines with bile may be excreted with feces |
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Term
| What are the 3 classes of biliary excretion based on? |
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Definition
| the ration of the concentration in the bile vs plasma concentration |
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Term
| What are the 3 classes of biliary excretion (give examples)? |
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Definition
Class A: ratio nearly 1
Na, K, glucose, mercury, cobalt *
Class B: ratio >1 (10-1000)
Lead, arsenic, bile acids, bilirubin
Class C: ratio <1 *
Insulin, albumin, zinc, gold |
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Term
| What class of biliary excretion do most compounds that are rapidly excreted in bile belong to? |
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Definition
| class B - the amount in bile is 10-1000x greater than that in the plasma |
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Term
| Are there specialized transport mechanisms for exhalation excretion? |
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Definition
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Term
| How are things excreted by exhalation? What is elimination inversely proportional to - give examples. |
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Definition
Elimination is by simple diffusion *
Elimination of gases are inversely proportional to the rate of absorption*
Ethylene – low solubility ; rapidly eliminated *
Chloroform – high solubility; slowly eliminated |
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Term
| What are 2 concerns about excretion of toxicants in milk? What are some examples of things that are eliminated in milk? |
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Definition
Toxicants may be passed from mother to child *
Compounds can be passed from cows to people via dairy products *
DDT, polychlorinated and polybrominated biphenyls are know to occur in milk |
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|
Term
| How are chemicals reabsorped in the kidneys? |
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Definition
| Renal tubules → across tubular cells → peritubular capillaries |
|
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Term
| How does reabsorption slow urine flow? |
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Definition
| Reabsorption increases the intratubular concentration |
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Term
| Other than kidneys, what other type of cells are good at reabsorption? |
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Definition
|
|
Term
| What 4 things are commonly formed when a xenobiotic is made toxic? |
|
Definition
electrophiles [positively charged – react with nucleophiles] *
Free radicals [chemical species with highly reactive unpaired electrons] *
Nucleophiles [negatively charged molecules] *
Redox-active reactants [molecules that can donate or accept electrons] |
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|
Term
|
Definition
biotransformations that eliminate the
ultimate toxicant or prevent its formation |
|
|
Term
| What are the most common target molecules for toxicants? |
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Definition
| nucleic acids, membranes and proteins |
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|
Term
| What is a common 1st target for a toxicant? |
|
Definition
| the enzyme responsible for their production or adjacent intracellular structures |
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|
Term
| What are the 5 types of reactions that toxicants undergo? |
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Definition
| ionic* covalent- practically irreversible - permanently alters endogenous molecules,* enymatic reactions with target proteins, * hydrogen abstraction - taking H from endogenous compounds - creates radicals, * electron transfer |
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|
Term
| Name 5 ways that toxicants can interfere with target molecules. |
|
Definition
blocking neurotransmitter receptors or ion channels *
Inhibit enzymes *
Interaction with toxicant may change conformation of protein thereby impairing function *
Interfere with the template function of DNA *
Interfere with protein moieties causing impaired maintenance of cell’s energy and metabolic homeostasis. |
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|
Term
| Name 3 ways that toxicants can alter the microenvironment of a target to cause toxicity. |
|
Definition
Chemicals that alter Hydrogen ion concentration in aqueous biophase *
Solvents and detergents that physiochemically alter the lipid phase of cell membranes and destroy transmembrane solute gradients.*
Xenobiotics can cause harm by occupying a site or space. |
|
|
Term
| What are the 2 target functions that toxicants can affect? |
|
Definition
| cell regulation and cell maintenance |
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|
Term
| What 3 things can happen if a toxicant affects gene expression? |
|
Definition
| inappropriate cell division-->neoplasm, teratogenesis *inappropriate apoptosis (get tissue involution) * inappropriate protein synthesis (eg peroxisome proliferation) |
|
|
Term
| What can happen if a toxicant affects ongoing cell function? |
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Definition
| eg inappropriate muscular activity - tremors, convulsions, etc |
|
|
Term
| What can be affected if a toxicant impairs a cell's internal maintenance? |
|
Definition
| impaired ATP synthesis, Ca regulation, protein synthesis, microtubular fnc, etc, which can all lead to cell death |
|
|
Term
| What can happen if a toxicant impairs a cell's external maintenance? |
|
Definition
| impaired function of integrated systems - like hemostasis, which could result in bleeding |
|
|
Term
| Where can a toxicant act to dysregulate gene expression and which is the most common? |
|
Definition
| binding to the promotor region, transcription factors (most common) or other factors in the initiation complex |
|
|
Term
| What are the 2 types of transcription factors that get interfered with and how does this work? |
|
Definition
signal – activated – signal interacts w/receptor, gets amplified, interacts with TF - outside the cell *
ligand – just attaches to TF and attaches directly – is already in the nucleus |
|
|
Term
| Name 1 example of a toxicant acting on ligand-activated transcription factors. |
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Definition
| cortisol is the endogenous ligand and glucocorticoid receptors are the TF - dexamethasone is exogenous and can cause apoptosis of lymphocytes and cleft palate |
|
|
Term
| What are 2 examples of what can happen when there is dysregulation of signal transduction with proliferative effects? |
|
Definition
Promote mitosis and tumor formation *
Increase kinase activity or decrease phosphatase activity - the signal was supposed to get turned off but it doesn't |
|
|
Term
| If a xenobiotic interfered with thyroid hormone metabolism (increased elimination, inhibits production), what can happen? |
|
Definition
| thyroid tissue can proliferate to share the increased workload - get tumors or goiters |
|
|
Term
| What is the basic mechanism associated with drug overdose, pesticides, etc? |
|
Definition
| altered regulation of neural and/or muscular activity |
|
|
Term
| How can toxicants alter synaptic levels of neurotransmitters? |
|
Definition
| interfere with synthesis, storage, release, or removal from the receptor |
|
|
Term
| What types of chemicals interact directly with neurotransmitter receptors? |
|
Definition
Agonist *
Antagonists *
Activators *
Inhibitors *
Agonist/activators mimic *
Antagonists/inhibitors block |
|
|
Term
| Give 1 example of a an agonist/antagonist - receptor, where it's located, agonist and effect, antagonist and effect. |
|
Definition
| GABA receptor - CNS neurons - agonist - sedatives like barbiturates -->neuronal inhibition, sedation* antagonist- picrotoxin -->neuronal activation, tremors |
|
|
Term
| What 3 biochemical disorders are initiated when a toxicant is causing death? |
|
Definition
ATP depletion *
Sustained rise in intracellular CA++ *
Overproduction of ROS and RNS (reactive nitrogen species) |
|
|
Term
| What is oxidative phosphorylation? |
|
Definition
| the process of phosphorylating ADP-> ATP that couples the oxidation of hydrogen into water |
|
|
Term
| Where are the places that a toxicant could mess up oxidative phosphorylation? |
|
Definition
| cytochromes - e- gets passed down, must have someplace to go * receptor for O2 at the end * ATP synthase - without this, you get no ATP |
|
|
Term
| What are the 5 classes of substances that interfere with oxidative phosphorylation? |
|
Definition
| A - interferes with the delivery of of H to the ETC -i.e. arsenite * B - inhibits transport of e along the ETC - i.e. cyanide * C - interferes with O2 delivery to the terminal acceptor - CO * D - inhibits activity of ATP synthase - DDT * E - causes mitochondrial DNA damage, impairs transcription of key mitochondrial proteins - prolonged use of EtOH, anti-virals |
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|
Term
| What is the normal concentration of Ca in the cell compared to outside? Where is Ca found in the cell? |
|
Definition
| Ca is about 1000x less inside the cell- it's actively pumped from the cytosol into the mitochondrion and ER |
|
|
Term
| How do toxicants induce a rise in Ca in the cytoplasm? |
|
Definition
| by either inhibiting Ca++ out of or promoting Ca++ into the cytoplasm – either can’t get out or comes in too fast |
|
|
Term
| What 4 things can a sustained rise of intracellular Ca cause? |
|
Definition
1. Depletion of energy reserves by inhibiting ATPase used in oxidative phosphorylation – disrupts membrane potential in the inner membrane where ATP synth takes place - Mitochondrial Ca uptake dissipates membrane potential so inhibits ATP synthesis
2. Destruction of microfilaments - disassemble - increases the likelihood of membrane ruprure
3. Activation of hydrolytic enzymes - degrade proteins, phospholipids, nucleic acids which will cause membrane break down
4. Generation of ROS, RNS -Excess ROS and RNS transition metal redox cycles – Fe, Cu, Mn, Cr, Ni |
|
|
Term
| What is mitochondrial permeability transition (MPT)? |
|
Definition
| an abrupt increase in the mitochondrial inner membrane permeability - caused by the opening of a pore that can let a lot of things in |
|
|
Term
| What can cause mitochondrial permeability transport? |
|
Definition
Mitochondrial uptake of Ca++ *
Decreased membrane potential *
Generation of ROS, RNS *
Depletion of ATP *
Accumulation inorganic phosphate/free fatty acids/lysophosphatids |
|
|
Term
| What is the result of mitochondrial permeability transport to the cell? |
|
Definition
Free influx into matrix of protons *
Rapid dissipation of membrane potential *
Cease ATP synthesis *
Influx water cause mitochondrial swelling * mitochondria start reversing their ATP process - breaking it down rather than making it |
|
|
Term
| What can mitochondrial permeability transport ultimately lead to (2)? What are some examples of things that can cause MPT? |
|
Definition
| apoptosis and necrosis - snake venom, detergents, CCl4, chloroform |
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|
Term
| What is necrosis and why is it bad? |
|
Definition
| the cell swelling and bursting - can cause inflammation and possible infection - can damage surrounding tissue |
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|
Term
| What is apoptosis and why is it not bad? |
|
Definition
| programmed cell death - cellular contents are packaged into apoptotic bodies, so cell contents don't set off inflammation - they get eaten by phagocytes - no surrounding tissue damage or inflammation - there's also replacement cells ready to go, like in the GI tract |
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|
Term
| What is a major gene involved in apoptosis? |
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Definition
|
|
Term
| What is the relationship between a toxicant dose and apoptosis/necrosis? |
|
Definition
| at low concentrations, it causes apoptosis, at higher ones, it causes necrosis |
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Term
| How are ATP and MPT determining factors as to whether a cell undergoes apoptosis or necrosis? |
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Definition
If few mitochondria develop MPT it’s called a pro-apoptotic signal – can be reversed and you’ll have a healthy cell *
If more mitochondria develop MPT then cytochrome C released causing caspase and activation of apoptosis – there’s a diagram in the book on this – once it’s gotten to this point, ATP can’t be formed *
If most of the mitochondria develop MPT the ATP is depleted preventing execution of ATP requiring apoptotic program - necrosis |
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Term
| What does molecular repair involve? |
|
Definition
| Hydrolytic removal of molecule’s damaged units and insertion of newly synthesized unit |
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Term
| Why is nuclear DNA stable? Why is mitochondrial DNA unstable? |
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Definition
| Nuclear DNA is stable because of chromatin packaging (histones) and nuclear DNA has several repair mechanisms * Mitochondrial DNA no histones and lacks efficient repair mechanisms |
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|
Term
| How does nuclear DNA repair itself? |
|
Definition
| Excise mismatched nucleotides – proofreading – polymerase comes back in and ligates the correct one in |
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Term
| Can mature neurons repair themselves? How does the CNS deal with damage? |
|
Definition
| no - can't undergo mitosis - there are a lot of reserve cells to compensate for damage |
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|
Term
| Can peripheral neurons with axonal damage be repaired? |
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Definition
| yes, but it requires macrophages and Schwann cells – may take a long time |
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Term
| How do macrophages and Schwann cells help repair damaged peripheral neuron axons? |
|
Definition
Macrophages remove debris and produce growth factors and cytokines that activate Schwann cells *
Schwann cells proliferate then transdifferentiate into growth supporting function – go with the growing axon and chemotactically guide it to its target |
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|
Term
| What can initiate apoptosis? Why can it be helpful? |
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Definition
| cell injury - might interrupt necrosis by eliminating cells with potentially mutagenic DNA |
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Term
| What types of cells undergo a lot of apoptosis? What types don't? |
|
Definition
tissue is made-up of constantly renewing cells -
Bone marrow, respiratory, GI tract, skin *lessened in tissues that contain non-replicating and non-replaceable cells
Neurons, cardiac muscle cells, female germ cells |
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|
Term
| When does replacement of cells happen? |
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Definition
|
|
Term
| How does replacement of lost cells in tissues happen? |
|
Definition
| Cells adjacent to damaged area enter the cell division cycle (go from G0 to mitosis) |
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Term
| What happens genetically when tissues need to be repaired? |
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Definition
| Genetic expression is reprogrammed so that DNA synthesis and mitosis gain priority over specialized cellular activities |
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|
Term
| What initiates the regeneration process in tissue repair? |
|
Definition
| the release of chemical mediators from damaged cells - Cell migration contributes to the restitution of certain tissues |
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Term
| Can the extracellular matrix be repaired? |
|
Definition
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|
Term
| How does repair of the extracellular matrix happen? |
|
Definition
| PDGF and TGF-beta released from platelets accumulating and degranulating at the site of injury - these activate stellate cells (type of stem cells), which can make GAGs, fibers, proteins, etc |
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Term
| Describe the inflammation process. cells involved, what is secreted, etc |
|
Definition
Tissue damage *
Macrophage secrete cytokines *
Cytokines stimulate stromal cells *
Capillaries become permeable *
WBC migrate into injured tissue *
Macrophages and WBC recruited to damaged site may undergo respiratory burst – releases O2, which forms ROS that kill the bacteria *
Produce free radicals, activated enzymes *
Damage adjacent tissue *
Not the best outcome b/c of tissue damage |
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|
Term
|
Definition
| when damage overwhelms the repair mechanism (consumes enzymes or cofactors needed for repair) *Toxicant-induced injury adversely affects repair process itself – may not be that it’s used up, just that the whole process was inactivated * Some types of toxic injury cannot be repaired effectively – xenobiotics covalently bound to proteins – very hard to break these bonds and reverse it |
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|
Term
| At what levels of damage does dysrepair happen? |
|
Definition
| molecular, cellular, and tissue levels |
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|
Term
| When does tissue necrosis happen? |
|
Definition
| when molecular mechanisms inefficient or if the molecular damage is not readily reversible |
|
|
Term
| What 2 mechanisms are there to counteract necrosis? |
|
Definition
Progression to necrosis intercepted by 2 repair mechanisms – apoptosis and cell proliferation *
Apoptosis counteracts progression of toxic injury by preventing necrosis and inflammation *
Rapid and complete restoration of injured tissue prevents necrosis |
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|
Term
| What is fibrosis? Why is it bad? |
|
Definition
| Pathological condition that is characterized by excessive deposition of an ECM of abnormal composition – takes the place of cells – see this a lot in liver – the fibers don’t do anything, so you’re losing function – get enough fibers, the organ is affected and won’t function properly |
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|
Term
| What is the main mediator of fibrogenesis? How does it work? |
|
Definition
TGF- is major mediator of fibrogenesis *
When repair is complete TGF- normally ceases to function; if this doesn’t stop functioning this results in overproduction of TGF- which leads to fibrosis |
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|
Term
| What are the main causes of fibrosis? |
|
Definition
| May be caused by continuous injury or defect in the regulation of TGF- |
|
|
Term
| What are the 3 main reasons you get carcinogenesis? |
|
Definition
| failure of DNA repair * failure of apoptosis to occur * failure to terminate cell proliferation |
|
|
Term
| What 2 types of damage can still result in a functional protein? |
|
Definition
| damage to coding regions that don't code for a protein and amino acid substitution |
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|
Term
| What is a pro-oncogene and what does it become when damaged? |
|
Definition
| a gene that makes a protein involved in the cell cycle - growth factors, transcription factors, etc - becomes an oncogene when damaged - get tumors |
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|
Term
| What protein is important in apoptosis? |
|
Definition
| p53 - damage this gene and you can dysregulate apoptosis |
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|
Term
| Give an example ofa chemical that causes a failure of apoptosis and subsequent tumor formation. |
|
Definition
| phenobarbital - dose for 12 months, after 6 you get tumors - no increase in mitosis, but you're having mitosis without apoptosis |
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|
Term
| What does methylation do and how does it contribute to carcinogenicity? |
|
Definition
| slows transcription - inhibits TF interaction - if you decrease methylation, you can produce tumors and clonal expansion will lead to nodules and tumor production |
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|
Term
| What happens if a chemical messes with gap junctions? |
|
Definition
| it will screw with cell communication, which facilitates invasion - phenobarbital decreases gap junction communication |
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|
Term
| How does research link to risk assessment? |
|
Definition
| Decisions about risk are made based on research and risk assessment feeds back into research b/c of uncertainties in risk |
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|
Term
|
Definition
| Systematic scientific characterization of potential adverse health effects resulting from human exposures to hazardous agents or situations |
|
|
Term
|
Definition
| the probability of an adverse outcome |
|
|
Term
| What does risk assessment require, information-wise? |
|
Definition
| Requires qualitative information and quantitative assessment, description of uncertainties in the estimates and conclusions |
|
|
Term
| What qualitative information does risk assessment require? |
|
Definition
| information about the strength of evidence and the nature of the outcomes |
|
|
Term
| What quantitative information does risk assessment require? |
|
Definition
| exposures, host susceptibility factors, potential magnitude of the risk |
|
|
Term
| What does characterization of the risk combine? |
|
Definition
| qualitative and quantitative analyses |
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|
Term
| How are actions chosen in risk management? |
|
Definition
| actions are chosen to control hazards identified in the risk assessment *Risk managers consider scientific evidence and risk estimates - statutory, engineering, economic, social and political in evaluating options and choosing among the options |
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|
Term
| What are the objectives of risk assessment (4)? |
|
Definition
| 1. Balance risks and benefits 2. Set target levels of risk 3. set priorities for program activities 4. estimate residual risks and extent of risk reduction after steps are taken to reduce risks |
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|
Term
| What are 2 examples of things that have to have risks vs benefits weighed? |
|
Definition
|
|
Term
| What are 2 examples of things that have to have target levels of risk established? |
|
Definition
| food contaminents and water pollutants |
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|
Term
| What types of agencies are heavily involved in risk management? |
|
Definition
| regulatory agencies, manufacturers, and environmental/consumer organizations |
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|
Term
| What is risk communication? |
|
Definition
| process of making information about risk assessment and risk management comprehensible to community groups, lawyers, business people, labor and environmentalists |
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|
Term
| What is a major challenge of risk assessment, management, and communication? |
|
Definition
| to work with many disciplines to demonstrate biological plausibility and clinical significance of conclusions |
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|
Term
| In assessing risk, why would you not go to an animal study first? |
|
Definition
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|
Term
| What are 2 alternative methods of getting risk data without using animals? What are their good and bad points? |
|
Definition
| Structure/activity relationships (SARs) - computerized models haven't been very useful, but 3D molecular modeling has b/c you can really study chemical interactions |
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|
Term
| What are the next steps up from computer methods of risk assessment that aren't as extensive as long-term testing? |
|
Definition
| in vitro and short-term tests - bacterial mutation assays, developmental and repro tox testing, immunotoxicity testing - a lot more short term |
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|
Term
| What is the principle behind using animal assays to assess risk? What should you do if you see something in 1 species of animal? |
|
Definition
| chemicals that cause tumors in animals cause tumors in humans * if you see something adverse in one species you test in another to make sure, but always err on the side of caution – assume if you see something in 1, you’ll see it in another |
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|
Term
| What are some indicators of chemical carcinogenicity? |
|
Definition
Increase in the number of tumors at a particular organ site –i.e. kidney tumors *
Induction of rare tumors *
Earlier induction of commonly observed tumors – identifying endpoints can be problems *
Increases in the total number of observed tumors |
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|
Term
| What are some problems of animal studies in risk assessment? |
|
Definition
Tumors may be increased only at high dose *
Even without toxicity, high dose may trigger different events than low dose exposure |
|
|
Term
| Why is epidemiological data good at identifying hazards? |
|
Definition
| it's the most convincing evidence for human risk (you're dealing with human exposure) and it looks at cause and effect |
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|
Term
| Why are epidemiological studies not the best way to identify hazards? |
|
Definition
Study is exploratory – weak hypothesis *
Exposure estimates are often crude and retrospective *
Multiple exposures – when lifetime is concerned *
Contributions from lifestyle factors *
Human are out bred – consider variation *
Detailed information on few vs large numbers of people |
|
|
Term
| What are the 3 major types of epidemiological studies? |
|
Definition
| cross-sectional, cohort, and cas-control |
|
|
Term
| What is a cross-sectional study and what is it good/bad for? |
|
Definition
| survey groups of humans to identify risk factors and disease; not useful for establishing cause and effect |
|
|
Term
| How do you do a cohort study? |
|
Definition
| evaluate individuals selected on the basis of exposure to an agent; prospective studies monitor over time individuals who are initially disease free to determine the rates disease develops |
|
|
Term
| How to you do a case-control study? |
|
Definition
| individuals selected on basis of disease status; two groups disease cases matched with disease-free cases; exposure histories of 2 groups compared ; retrospective |
|
|
Term
| How is molecular epidemiology used to study risk? |
|
Definition
| uses biomarkers of exposure and susceptibility - allows scientists to link molecular events in causative disease oathways |
|
|
Term
| What does molecular epi do that solves 2 problems in traditional epidemiology? |
|
Definition
| provides a biological basis for extrapolation across humans - great b/c they're so diverse * allows you to do more cross-species comparisons with rodent bioassay info |
|
|
Term
| What endpoints are evalutated when a threshold approach is used for risk characterization? |
|
Definition
|
|
Term
| What endpoints are assessed when a non-threshold approach is used to characterize risk? |
|
Definition
|
|
Term
| In a dose-repsonse assessment, what is the 1st step? What are the critical points to be determined? |
|
Definition
Analysis begins with critical effects to be quantitatively evaluated *
Critical effect – significant adverse biological effect that occurs at the lowest exposure level * choose data sets with adverse effects happening at the lowest levels of exposure * determine NOAEL and LOAEL |
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|
Term
| How are animal bioassays conducted in dose-response assessments? |
|
Definition
Animal bioassays are conducted with sufficient numbers of animals to detect low-level biological responses at the 10% response range *
Risk assessor should understand the biological significance of the response |
|
|
Term
| How are reference dose (RfD) and acceptable daily intake (ADI) calculated? |
|
Definition
| from NOAEL - divide by modifying factors * uncertainty factors |
|
|
Term
| What are criticisms of the NOAEL method for risk assessment? |
|
Definition
By definition NOAEL must be one of the doses used *
Once NOAEL is identified the rst of the dose-response curve is ignored *
Fewer animals larger NOAEL – produces less certainty *
Does not identify the actual responses at the NOAEL – varies with experimental design |
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|
Term
| Why is the benchmark dose method (BDM) seen as better than NOAEL for assessing risk? |
|
Definition
Takes into account the full dose-response curve *
Inclusion of a measure of variability
Use of responses in dose range *
Use of a consistent benchmark response level for RfD calculations across studies |
|
|
Term
| Decribe the principle behind statistical approach to non-threshold risk assessment. |
|
Definition
| Each individual has a tolerance level for a tet agent with the response being a variable that follows a probability distribution |
|
|
Term
| What is the mechanistic model of non-threshold approach to risk assessment? |
|
Definition
| Models based on the idea that a response in a particular unit is the result of the random occurrence of one or more biological events |
|
|
Term
| What is the hit model for cancer risk assessment (what are the assumptions)? What is a 1 hit model? |
|
Definition
Hit Models for cancer modeling (hit defined as a critical event that must occur before a toxic effect is produced assume that:
An infinitely large number of targets exist*
The organism responds with a toxic response only after a minimum number of targets have been modified *
A critical target is altered if a sufficient number of hits occur *
The probability of a hit in the low-dose range of the dose-response curve is proportional to the dose of the toxicant *
Simplest of the models is the 1 hit model is 1 hit is required for a cell to be altered. As theories of cancer has grown in complexity then multihit models have been developed |
|
|
Term
| What is determined in exposure assessment? |
|
Definition
the source, type, magnitude, duration of exposure
Goal: to determine how much reaches the target |
|
|
Term
| What are the key steps in exposure assessment? |
|
Definition
determining which exposure route are relevant for risk scenario under development *
Another key step is how time and duration are evaluated |
|
|
Term
| What causes variation in susceptibility in environmental exposures? |
|
Definition
Genetic traits *
Sex and age *
Pre-existing diseases *
Behavioral traits *
Coexisting exposures *
Medications *
Vitamins *
Protective measures |
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