Ch 1-General Tox Principles (contd.) Flashcards
A toxic substance produced by biological systems is specifically as a… A. Toxicant B. Toxin C. Xenobiotic D. Poison
B. Toxin (differentiaiton b/w toxin and toxicant not always easy eg: arsenic)
A newly formed hapten complex usually stimulates the formation of a significant amount of antibodies in…. A. 1-2 minutes B. 1-2 hours C. 1-2 days D. 1-2 weeks
D. 1-2 weeks
Prolonged muscle relaxation in response to succinylcholine is an example of a/an…. A. IGE-mediated allergic reaction B. Idiosyncratic reaction C. Immune complex reaction D. Reaction related to a genetic increase in liver enzyme activity
Normally succinylcholine is broken down by butyrylcholinesterase/ pseudocholinesterase. SNPs cause reduced expression of butyrylcholinesterase
B. idiosyncratic reaction
Increased production of methemoglobin is due to a decrease in activity of…. A. Cytochrome P450 2B6 B. NADH cytochrome b5 reductase C. Cytochrome oxidase D. Cytochrome a3
B. NADH cytochrome b5 reductase
Excessive sensitivity to nitries and a few othe chemicals ( which can oxidize Hb to methHb and therfore lead to reduced O2 carrying capacity) is an example of
idiosyncratic reaction
Most recently recognized plausible cause for idiosyncratic reactions
Genetic polymorphisms
(also polymorphisms in immune genes like those of MHC)
Whats is the reason for idiosyncratic reaction to nitrites in some individuals?
deficiency in NADH-cytochrome b5 reductase activity (inherited autosomal recessive disorder)
The most common target organ of toxicity is the… A. Heart B. Lungs C. CNS D. Skin
C. CNS
The organs least involved in systemic toxicity are… A. Brain and peripheral nerves B. Muscle and bone C. Liver and kidney D. Hematopoietic system and lungs
B. Muscle and bone
If 2 organophosphate insecticides are absorbed into an organism, the results will be… A. An additive effect B. A synergistic effect C. Potentiation of effect D. Subtraction of effect
A. An additive effect
If ethanol and carbon tetrachloride are chronically absorbed into an organism, the result will be…. A. An additive effect B. A synergistic effect C. Potentiation of effect D. Subtraction of effect
B. A synergistic effect (due to acetone a metabolite of EToH?)
If isopropyl alcohol and carbon tetrachloride are chronically absorbed into an organism, the effect on the liver will be…. A. An additive effect B. A synergistic effect C. Potentiation of effect D. Subtraction of effect
C. Potentiation of effect (due to acetone a metabolite of IPA)
The treatment of strychnine-induced convulsions by diazepam is an example of… A. Chemical antagonism B. Dispositional antagonism C. Receptor antagonism D. Functional antagonism
D. Functional/ Physiological antagonism (2 drugs hit 2 different targets and cancel out the effect of each other)
eg:
- glucagon, glucocorticoids vs. insulin
- fall in BP with barbiturates vs. increase increase in BP via intravenous vasopressor such as norepinephrine or metaraminol
- convulsant vs. anitconvulsant (eg: benzodiazepines (eg, diazepam)
The use of antitoxin in the treatment of snakebites is an example of… A. Dispositional antagonism B. Chemical antagonism C. Receptor antagonism D. Functional antagonism
B. Chemical antagonism (chemical chelation/neutralization)
Eg:
1) Protamine sulfate (low MW) binds heaprin (anti-coagulant)
2) Caclium sodium edetate complex with Arsenic/Lead
3) DMSA( Succimer) chelates with metal ions such as arsenic, mercury, and lead
The use of charcoal to prevent the absorption of diazepam is an example of… A. Dispositional antagonism B. Chemical antagonism C. Receptor antagonism D. Functional antagonism
A. Dispositional antagonism / Physical antagonism
Eg:
- charcoal adsorb alkaloids
- ipecac syrup
- increased excretion of a chemical by administration of an osmotic diuretic or alteration of the pH
Note on functional antagonism
In some cases :
1) Parent cmpd. toxic—— metabolite less toxic
2) In some other cases: metabolite more toxic ——-parent cmpd. less toxic
In case of (2) have an inhibitor of microsomal enzyme activity (SKF-525A or piperonyl butoxide)
Types of receptor antagonism (called BLOCKERS)
Competitive (reversible at high concentrations OR irreversible)
COMPETITIVE (Antag competes to bind to the same active site as agonist)
Non competitive (irreversible)
Competitive REVERSIBLE receptor antagonism
forms weak bonds
effects overcome by increasing conc. of agonist
graph of COMPETITIVE receptor antagonism
Competitive IRREVERSIBLE receptor antagonism
- forms strong covalent bonds
- CANNOT be reversed at high concs. of agonist
Eg: dibenamine and norepinephrine at α1 adrenergic receptors
NONCOMPETITIVE receptor antagonism
binds to a site other than the agonist binding site
but this prevents receptor activation by agonist
Eg: Flumazenil (GABA receptor antag) comptes to bind to GABA receptor. Benzodiazepines (act as GABA receptor agonist) also binds to GABA receptor.
Flumazenil binds to a site different from Benzodiazepine. But binding of flumazenil to GABA receptor prevents binding and activation by benzodiazepine
The use of tamoxifen in certain breast cancers is an example of… A. Dispositional antagonism B. Chemical antagonism C. Receptor antagonism D. Functional antagonism
C. Receptor antagonism
Other egs. of competitive reversible receptor antagonism:
1) Atropine and acetocholine at muscarinic acetocholine receptors
Atropine blocks the acetocholine receptor to excess ACh
2) Naloxone and Morphine ( opiod) at opiod receptors
what sis an allosteric Ag/ Ant
A drug that binds to a receptor molecule without interfering with normal agonist binding but alters the response to the normal agonist
graph of NONCOMPETITVE receptor antagonism
In some cases even if 50% of the receptors are knocked down, the remaining 50% might be sufficient to still give 100% response
Chemicals known to produce dispositional tolerances are… A. Benzene and xylene B. trichloroethylene and methyl chloride C. Paraquat and diaquat D. Carbon tetrachloride and cadmium
D. CCl4 and Cd
Due to Cd binding to metallothionein
Tolerance is due to
- reduced responsiveness
- reduced amount of toxicant (dispositional tolerance)- more is known about this than 1.
Dispositional tolerance to PB is due to
phenobarbital inducing enzy responsible for its biotranformation to inactive metab.
The most rapid exposure to a chemical would occur through which route… A. Oral B. Subcutaneous C. Inhalation D. Intramuscular
C. Inhalation
A chemical that is toxic to the brain but which is detoxified in the liver would be… A. More toxic orally than intramuscularly B. More toxic rectally than intraveniously C. More toxic via inhalation than orally D. More toxic on the skin than intraveniously
C. More toxic via inhalation than orally
The LD50 is calculated from… A. A quantal dose-response curve B. A hormesis D/R curve C. A graded D/R curve D. A log-log D/R curve
A. A quantal D/R curve
A U-shaped graded toxicity D/R curve is seen in humans with… A. Pesticides B. Sedatives C. Opiates D. Vitamins
D. Vitamins
The TD1/ED99 is called… A. Margin of safety B. Therapeutic index C. Potency ratio D. Efficacy ratio
A. Margin of safety
How is therapeutic index calculated
TD50/ED50
All of the following are reasons for selective toxicity except… A. Transport differences between cells B. Biochemical differences between cells C. Cytology of male and female neurons D. Cytology of plant cells versus animal cells
C. Cytology of male and female neurons
Hereditary differences in a single gene that occur in more than 1% of the population are referred to as… A. Significant mutations B. Dominant mutations C. Genetic polymorphisms D. Sister chromatid exchange
C. Genetic polymorphisms
Which of the following statements is true? A. Chemical carcinogens in animals are always carcinogens in humans B. A chemical that is carcinogenic in humans is carcinogenic in at least one animal species C. From a regulating perspective, carcinogens are considered to have a threshold D/R curve D. Arsenic is a carcinogen in humans and nearly all animal species tested.
B. A chemical that is carcinogenic in humans is usually carcinogenic in at least 1 animal species.
The percentage of mating resulting in pregnancy is called the… A. Fertility index B. Gestation index C. Viability index D. Survival index
A. Fertility index
The percentage of pregnancies resulting in live litters is the… A. Fertility index B. Gestation index C. Viability index D. Survival index
B. Gestation Index
whats is viability index?
percentage of animals that survive 4 days or longer
The lactation index in rats is the… A. Number of live births that breast-feed B. Number of days an animal breast-feeds C. Calories lost per day by a mother who breast-feeds D. % of live animals at 4 days that survive the 21 day lactation period
D. % of live animals at 4 days that survive the 21 day lactation period
What are the 6 stages that ICH uses to address reproductive toxicity?
1) premating and conception (stage A),
2) conception to implantation (stage B),
3) implantation to closure of the hard palate (stage C),
4) closure of the hard palate to end of pregnancy (stage D),
5) birth and weaning (stage E), and
6) weaning to sexual maturity (stage F).
[ALL COVERVERED IN SEGMENTS 1 -III]
Which of the following statements are false? A. There is good concordance between human and animal neurotoxicity assessment B. The developing nervous system is insensitive to toxicant exposure C. Monkeys can be used to test low-level effects of neurotoxicants D. In vitro cell cultures can be used in neurotoxicity testing
B. The developing nervous system is insensitive to toxicant exposure
A severe cytokine response that progressed to a systemic organ failure occurred in a phase 1 study involving the use of… A. An uncoupler of oxidative phosphorylation B. A COX2 inhibitor C. A CD28 monoclonal antibody D. A microtubule assembly inhibitor
C. A CD28 monoclonal antibody
Within the human genome, how much variability in DNA sequence exists between any 2 individuals? A. 0.01% B. 0.1% C. 0.5% D. 1.0%
B. 0.1%
Which of the following can be used to characterize a response to a toxicant? A. Proteomics B. Transcriptomics C. Metabonomics D. All of the above
D. All of the above
All of the following are true concerning animal carcinogenicity studies except… A. Historic control data is never considered B. A rodent carcinogenicity study usually takes 2 years C. It is impractical to use doses that occur in humans D. Gender differences in background tumor incidence are sometimes observed
A. Historic control data is never considered
Examples of significant conc. of a toxicant in a tissue that is not the target organ include all of the following except… A. Lead in bone B. DDT in adipose tissue C. Paraquat in lungs D. TCDD in adipose tissue
C. Paraquat in lungs
The ability of a chemical to cause skin and eye irritation is usually evaluated in a… A. Rabbit B. Rat C. Mouse D. Dog
A. Rabbit
Before a potential pharmaceutical compound can be given to humans… A. An NDA must be filed with the FDA B. An IND must be filed with the FDA C. Acute toxicity studies on 4 species must be conducted D. A 2 year dog carcinogenicity study must be complete
B. An IND must be filed with the FDA
Phase 1 clinical trials are conducted to determine all of the following except… A. Pharmacokinetics B. Safety C. Rare adverse effects D. Preliminary efficacy
C. Rare adverse effects
MTD stands for… A. Minimal tolerated dose B. Maximum total dose C. Maximum tolerated dose D. Minimum threshold dose
C. Maximum tolerated dose/ Mimimal toxic dose
The acute toxicity study in animals provides… A. An approximate lethal dose B. Information on target organs C. Info on dose selection for longer studies D. All of the above
D. All of the above
A subacute toxicity study in rats usually lasts… A. 3 days B. 14 days C. 3 months D. 6 months
B. 14 days
The period of organogenesis in rats is… A. Days 3-10 B. Days 7-17 C. Days 12-25 D. Days 17-56
B. Days 7-17
A dose of investigational drug that suppresses body weight gain slightly in a 90 day animal study is… A. LOAEL B. NOAEL C. MTD D. reference dose
C. MTD
Apart from BW what otehr paratmeter can be used by regulatory authorities to determine MTD?
physiological and pharmacokinetic parameteres (eg urinary metabolites)
A subchronic animal study required by the FDA will usually include.. A. 2 species (1 rodent, 1 non-rodent) B. both genders C. At least 3 doses (low, med, high) D. All of the above
D. All of the above
When all receptors are occupied by a toxicant and there is a maximum number of receptor-toxicant complexes formed, the response is termed… A. T1/2 B. LCmax C. Emax D. Cmax
C. Emax
Whats is Kd
The concentration of drug that binds 50% of the receptors in the system
Which of the following statements is true? A. Toxicant-receptor interactions are always reversible B. Receptors for toxicants are always enzymes C. Toxic response is related to toxicant conc. in plasma more so than the conc. at the site of action D. None of the above
D. None of the above
An increase in free drug conc. will… A. Increase the pharmacologic effect B. Decrease the toxic effect C. Decrease the amount of drug filtered at the glomerulus D. None of the above
A. Increase the pharmacologic effect
Whats are the consequences of mutations in the sperm or egg at the time of fertilization?
- may result in death during early stages of embryonic cell division.
- death of th fetus later in dev leading (abortion)
- congenitial abnormalities
Somatic mutations can pass the mutation on to other cells in the same tissue
What are the 2 most signifcant addtional mutations in Ames strains
- Mutations to enhance penetration of substances into the bacteria
- mutations to decrease the ability of the bacteria to repair DNA damage
Using Saccharomyces cerevisiae to test for mutations
identifies:
A) deletions in genetic material (due to recombination events in cell division, oxidative DNA damage
B) direct mutagenic effects,
C) alterations in fidelity of DNA repair
D) changes in cell cycle regulation
Big Blue Mosue and Muta mouse for mutation detection
E.coli lac operon inserted into animal (mice, rat) genome
