Midterm part 2 (Q16-end) Flashcards
- What is meant by “mechanism of toxicity”
• Toxic compounds have the chemical character that causes it to interfere with critical physiological functions. This is a property that is unique to the toxicant and cell component it is affecting. It requires a toxicant-receptor concept and it must exceed the threshold to cause toxicity.
• Effects can be pharmacologic (inhibitory), genotoxic (mutations), or pathologic (destruction of cellular structures/tissues)
o All of which depend on the specific toxic substance, the route of exposure, and its concentration being above the threshold level
• Steps required for toxicity: Exposure, uptake, reach site of action, toxic compound must have specific property making it able to react with site of action (receptor interaction)
• Exposure routes (ingestion, inhalation, dermal) refer back to exposure routes
• Uptake, must get access across membrane barrier (membrane is lipid bilayer, low water solubility favored, water soluble compounds through pores or by active transport)
• The liver degrades toxins to polar metabolites which are filtered and excreted by the kidneys, there is a balance between the distribution to the site of action for toxins and the metabolism/excretion of these toxins (toxins must get to the site of action at a concentration that is capable of disruption the function)
• Toxic agent: refers generally to a material or factor than can be harmful to biological systems
• Toxicity: the degree to which something is poisonous
• Toxic substance: a material that has toxic properties
• Toxicant: a toxic substance that is man-made or result from human activity
• Toxin: usually refers to a toxic substance made by living organisms
- Know the mechanism of toxicity for organophosphorus pesticides
• Acetylcholinesterase inhibition – prevents AChE from degrading ACh → results in too much ACh in the body and overstimulation of the nervous system
- Know the mechanism of toxicity for cyanide
- Mitochondria use glucose to convert it to ATP via enzymes.
- Cyanide deactivates enzymes that carryout the electron transport chain
- Inhibits mitochondria and stops energy production, cell dies
- Know the function of the following cellular organelles:
a. Nucleus: control center of the cell that contains DNA, which is the genetic material used for the synthesis of RNA (to make proteins: DNA is transcribed to make RNA which is translated to make proteins, which are modified in the ER and packaged and sent out by the Golgi to different cellular/extracellular compartments where they are needed)
b. Mitochondrion: “Power house” of the cell where it extracts and processes energy from food sources (glucose) via oxidative phosphorylation and the electron transport chain. Energy is stored as ATP, which is the form generally needed to drive many other biochemical reactions throughout the body.
c. Ribosomes: Site of protein synthesis (by RNA) and can be located on the ER or “free floating” within the cytoplasm of the cell.
- Describe the role of DNA/RNA and amino acids in the synthesis of protein.
• Within DNA are genes that encode a protein, which are the “workhorses” of the cell and carry out all the functions necessary to sustain the body.
• To express a gene, you need to manufacture its corresponding protein, and this process has two major steps.
o Step 1: the information in DNA is transferred to a messenger RNA (mRNA) via transcription. During transcription, the DNA of a gene serves as a template for complementary base-pairing, and an enzyme called RNA polymerase II catalyzes the formation of a pre-mRNA molecule, which is then processed to form mature mRNA. The resulting mRNA is a single-stranded copy of the gene, which next must be translated into a protein molecule.
o Step 2: Translation- the mRNA is “read” according to the genetic code, which relates the DNA sequence to the amino acid sequence in proteins. Each group of three base pairs in mRNA constitutes a codon, and each codon specifies a particular amino acid. The mRNA sequence is thus used as a template to assemble—in order—the chain of amino acids that form a protein.
o Translation occurs on the ribosomes, which can be attached to the endoplasmic reticulum (RER), or free floating within the cytoplasm. From the ribosome, the protein that is assembled moves inside the ER where it undergoes modification (addition of chemical groups), which specifies each proteins specific function. From the ER, the modified protein will travel to the Golgi apparatus where it is “packaged” and sent out into the rest of the cell or can be sent out of the cell, to “work” at another site in the body.
- Understand factors controlling/favoring transport across cellular membranes
• Diffusion – molecules move from an area of high concentration to one of low concentration with no energy required.
o Low water-solubility
o Diffusion is a form of passive transport (no energy required)
• Active Transport –When moving against a concentration gradient, or in situations where you need to move a polar substance across a non-polar membrane, you need ATP and also membrane proteins to do this.
o Water-soluble compounds
- Understand the function of the following organs:
a. Liver- Primary site of metabolism and detoxification.
• It filters blood and regulates the metabolism of toxins or other chemicals in the blood and makes substances more polar by adding a hydroxyl group so that the kidney can excrete them.
• Sensitive to toxic compounds such as chlorinated hydrocarbons (free radicals), alcohols (necrosis of cells/tissues).
b. Kidneys-filters and excrete metabolized polar compounds from the blood.
• Non-polar metabolites are reabsorbed into the blood
• Heavy metals can cause necrosis and affect reabsorption of glucose and release proteins into urine
c. Heart-circulation of blood (toxins in blood)
d. Brain-integrates signals, controls basic bodily functions, important for hormonal balance.
• Synaptic cleft for signal transduction is where some toxins work.
o Organophosphorous pesticides inhibit acetylcholine-esterase within the synaptic cleft that inhibits the degradation of NT, resulting in a prolonged signal (over-excitability)
e. Lungs-breathing, intake of O2 and other potential toxins in the air
• High surface area-high exposure rate
• Lipid soluble favored (low water soluble)
• High VP favored
- Understand the function and sensitivity of the following systems to toxic chemicals:
a. Respiratory system: inhaled chemicals are absorbed into the blood rapidly due to a high surface area of alveoli and surfactant. Blood from the lungs bypasses the liver on its “first round” throughout the body and therefore toxins that are inhaled have the potential to “hit hard” on the body. The respiratory system is very sensitive to inhaled toxic chemicals for this reason.
• High surface area-high exposure rate
• Lipid soluble favored (low water soluble)
• High VP favored
b. Nervous system: the collection of nerves transmits signals between different parts of the body. If toxins can cross the blood-brain barrier, it can greatly affect the brain and nervous system.
- Understand the process by which chemicals are metabolized and excreted from the body
- The liver is the major site of metabolism in the body; generally makes nonpolar compounds more polar and therefore more excrete-able
- Primary metabolism adds hydroxyl group.
- Secondary metabolism adds a bigger, water-soluble molecule to make the compounds even more polar.
- The polar compounds can be filtered out more easily by the kidney and excreted in the urine.
- The goal of metabolism is to increase the polarity of a chemical so that it is more easily excreted by the kidney. Metabolic enzymes, occurring at highest levels in the liver, biochemically perform the initial conversion from a non-polar to a more polar chemical through a process called “primary metabolism”. The clearest example of primary metabolism is the addition of a hydroxyl group to a portion of a molecule where only a carbon-hydrogen bond previously existed. In “secondary” metabolism, or metabolism by “conjugation” a larger very water soluble chemical, such glucuronic acid, is attached (with aid of an enzyme) to the compound that has undergoing primary metabolism, resulting a compound that is very much more water soluble. In this example, the new compound would be called a “glucuronide conjugate” of the first compound. Because glucuronic acid contains many OH groups, the conjugate is much more soluble than the primary metabolized compound, and therefore is much more likely/easily excreted by the kidney. You might consider the analogy of Kow. The conjugate would have a much lower Kow than the primary metabolite. It would therefore have a much lower likelihood of being reabsorbed into blood while it is passing through the kidney. (Recall that the kidney reabsorbs lipid soluble compounds back into the blood, so the more lipid soluble, the more likely for reabsorption, and less likely for excretion with urine.
- Describe the potential consequences of a cellular mutation
• A cellular mutation is some change in the nucleotide sequence of an organism’s genome. Mistakes in a cells DNA that changes the RNA strand that is transcribed, and ultimately can change the 3 nucleotide codon sequence that is corresponds to a particular amino acid. If the mutation results in a change in the codon sequence, then different amino acids will be created and therefore a protein may have several effects.
o Mutations may produce a loss of function effect in the protein that it affects, where the protein synthesized will be unable to function.
o The mutation may not change the protein at all, known as a silent mutation where the nucleotide change still created the same amino acid sequence
o Gain of function mutation, where the mutation actually assists in the current function of the protein or adds additional functions, which may be harmful.
• Carcinogens: If the replication function of these cells is compromised, it becomes a pre-neoplastic cell.
- Understand the basic mechanism of chemical carcinogenesis
- Carcinogen causes a mutation in a cell that is specific for a cell that divides rapidly and in an unregulated manner, giving rise to a malignant tumor, which can metastasize and invade other tissues and organs.
- Mutations can be in a protein or group of proteins that now allows uncontrolled proliferation, or in a protein or group of proteins that are responsible for a cells natural ability to undergo apoptosis, or a programmed cell death. If cells are not dying, they can then build up and result in tumors.
- An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels. Most normal cells undergo a programmed form of rapid cell death (apoptosis). Activated oncogenes can cause those cells designated for apoptosis to survive and proliferate instead.
- Know the definition of a cancer slope factor (CSF), and how it is derived
- CSFs are used to estimate the risk of cancer associated with exposure to a carcinogenic or potentially carcinogenic substance.
- A slope factor is an upper bound, approximating a 95% confidence limit, on the increased cancer risk from a lifetime exposure to an agent by ingestion or inhalation.
- The value used to estimate the excess risk over the normal cancer incidence rates associated with a specific level of lifetime/long term exposure to a particular chemical, over the incidence of cancer normally occurring in the general population, which is generally >40%.
- It is derived by graphically/mathematically extrapolating the observed incidence of cancer at level chronic/ sub chronic exposures by test animals to low level exposures, extending toward zero, assuming a linear response.
- Direct relationship between exposure and incidence, the slope of this line is the cancer slope factor that will increase the probability of getting cancer. If the slope factor is=0.5 then you will get a 50% increase in your risk of getting cancer (above the assumed ~40% risk).
- If a slope factor = 0.1 then that means that for every specified dose, you get an increase cancer risk of 10%.
- The EPA says that it’s not acceptable to add more than 1/1,000,000 risk.
- Be able to list/describe the conservative assumptions incorporated into derivation of a cancer slope factor
- Assume humans will respond similar to test animal
- Lifetime and acute exposures are treated the same (assume an additive lifetime risk)
- The targeted precision for excess cancer incidence is 0.000001, so that you can resolve a difference between 0.400000 and 0.400001 (determine 1 in a million difference).
- Assume cancer rates observed at high dose are directly proportional to cancer rates expected at low doses –linear relationship
- Understand what a teratogen is, and the concept of phase sensitivity.
• Teratogen: a substance that can cause birth defects.
• Phase sensitivity describes the time period in which a teratogen can affect a specific developing system of the fetus.
o Different phases correspond to the development of different systems within the fetus and different phases may be more or less susceptible to different toxins
i..e. thalidomide – causes abnormalities in the appendages of newborns.
- Be able to describe what a Reference Dose is, and how it is derived.
• Reference dose is the chronic daily lifetime dose (mg/kg) that is acceptable to all members of human population at a high level of confidence; however exceeding it does not necessarily imply toxic effects.
• VERY CONSERVATIVE ESTIMATE
• It is based on animal testing and “safety factors”.
• It relies on Lowest Observed Adverse Effect Level (LOAEL) and NOAEL.
• To identify NOAEL, review toxicity data and find the most sensitive species & endpoint.
• Apply Uncertainty Factors to NOAEL, which account for the general variability (x10), extrapolating animal data for humans (x10), using subchronic data for chronic data (x10), for additional margin (x10), if using the LOAL instead of the NOAL (x10)
o Ex NOAEl = 5mg/kg day
o RfD = (5mg/kg day)/(10x10x10x10)
