Ch 1- Dose-Response Relationships Flashcards
(81 cards)
1
Q
Single vs. repeat dose graph
A
2
Q
the characteristic of exposure and the spectrum of toxic effects come together as
A
dose-response relationship
3
Q
two types of dose response relationships
A
individual dose-response relationship quantal dose-response relationship
4
Q
A continuous variables can be converted to quantal responses if desired
A
5
Q
describes the response of and individual organism to varying doses of a chemical
A
individual dose relationship
6
Q
characterizes the distribution of individual responses to different does in a population of individual organisms
A
quantal dose relationship
7
Q
what is the caveat when using dose reponse curves from a population
A
Subtle effects at low doses may be masked by more evident responses at higher doses
8
Q
Individual/ graded dose-response curve
A
Dose response curves against log 10 scale of conc. gives straight line for most of the individual (graded) and quantal dose response curves
9
Q
bell shaped curve (for quantal responses)
A
normal frequency distribution
10
Q
What do 1, 2 and 3 SD mean in a normally distributed population?
A
- the mean ±1 SD = 68.3% of the population
- the mean ±2 SD =95.5% of the population
- the mean ±3 SD = 99.7% of the population
11
Q
the reason for normal distribution
A
differences in susceptibility to chemicals among individuals
12
Q
animals responding to the left end of the curve are
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hypersusceptible
13
Q
animals responding to the right end of the curve are
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resistant
14
Q
A widely used statistical approach for estimating the response of a population to a toxic exposure is
A
“effective dose” (ED).
15
Q
the minimally ED of any chemical that evokes a stated all or none response is the ___which cannot be determined experimentally
A
threshold dose
16
Q
units of NED (normal equivalent deviations) are converted by the addition of five to the value to avoid negative numbers
A
probit units (probability units)
Probit units = NED + 5
17
Q
- 50% response means NED = 0
- 84.1% response means NED = +1
- a 50% response becomes a probit of 5,
A
18
Q
whats should allometry take into acoount while scaling (importatn)
A
PK differences bw species (PBPK)
19
Q
50% of the population will show an effect from a chemical
A
ED50
20
Q
50% of the population will show a toxic dose from a chemical
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TD50
21
Q
50% of the population will die from exposure to a chemical
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LD50
22
Q
the “graded” dose relationship in an individual over the entire dose range is actually
A
U-shaped
23
Q
the region of the dose response relationship for essential nutrients is commonly referred to as
A
deficiency
24
Q
there is considerable evidence to suggest that some nonnuritional toxic substances may also impart beneficial or stimulatory effects at low doses but that at high doses they produce adverse effects
A
hormesis
25
Hormesis was first described for
radiation effefcts
26
factors to consider when talking about the threshold concept
test population size time periods endpoints ED01 vs NOAEC
27
important assumptions for generating proper dose-response curves
effects are caused by dosed chemical magnitude of response is actually related to dose response can be quantified reliable
28
Slope of a DR cruve at _low doses_ may be a lot _different than slope at high doses. Wh?_
Due to dispositional differences
29
Whata re some of the reasons for inflection in the shapre of the DR crv?
* Saturation of biotransformation pathways or receptors
* depletion of intracellular cofactors (Eg: NAPQI)
30
Mechanisms to explain non monotonic responses
* upregulation of some receptors at low concentrations, with downregulation of the same receptors at higher levels
* integration of 2 or more monotonic dose–response
crvs.
* do not understand all interconnected molecular pathways that work in concert
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Assumption in arriving at a DR crv.
1. Response is due to chemical administered
2. Magintude of response is dose dependent
3. There is a quantifiable method of measuring and expressing toxicity
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three assumptions that cover "magnitude of response is actually related to the dose"
* there is a target site that the chemical interacts with
* response is related to concentration at target site
* concentration at target site is dependent dose administered
33
A given chemical may have a 'family' of dose–
response relationships
34
Establishing DR relationship early on based on mechanistic data is difficult. Why?
Since such data is not available early on
35
What is the work around to DR based on mechanistic data
use 'effects based biomarkers'
## Footnote
eg: alteration of ASTs, ALTs for liver damage
36
the ratio of the dose required to produce a toxic effect to the dose needed to elicit the desired therapeutic response
therapeutic index (TD50/ED50)
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the larger the ratio the \_\_\_\_the relative safety
greater
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use the ED99 for the desired effect and the TD1 for the undesired effect
Margin of Safety (MOS) (TD1/ED99)
39
When is MoS (margin of safety useful and NOT useful
USEFUL: in case of single administration of chemicals
NOT USEFUL:
* chemicals with no ED (i,.e not beneficial)
* chemicals where threre repeat exposure
40
a chemical produces injury to one kind of living matter without harming another form of life even though the two may exist in intimate contact
selective toxicity
41
Whats are the reasons for selective toxicity?
1. chemical is equally toxic to both economic and uneconomic cells but _ACCUMULATES_ mainly in the uneconomic cells (due to diffrences in the transport, biotrasnformation etc.)
2. reacts specifically with a _cytological or a biochemical feature in the uneconimic part_ that is absent from or does not play role in the economic form
* eg: some insecticides toxic to specific pests due to increased SA/unit wt
* use of radioactive iodine in the treatment of hyperthyroidism (since thyroid cells accumulate Iodine)
* diff bw plant and animal cells, bw bacteria with cell wall vs. human cells
42
what is a reason for the difference in susceptibility to AFB1 between mice (very resistant) vs. rats (very susceptible)?
differences in the expression of a particular form of _glutathione S -transferase_ (mGSTA3-3) [which has high catalytic efficiency towards AFB1-epoxide]
43
Whats are some of the other examples of species differnce selective toxicity?
* development of renal tumors from exposure to 2,3,5-trimethylpentane and d -limonene in male rats
* the production of liver tumors from “peroxisomal proliferators” such as the antilipidemic drug clofibrate
* the production of liver tumors from solvent trichloroethylene
* induction of nasal carcinomas in rats after inhalation exposure to formaldehyde
44
generally the first toxicity test performed on a new chemical is
acute toxicity
45
LD50 is not a very useful metric. Why?
* It measures motality as an edn point
* It can be influenced by other factors like strain, age, and weight, type of feed, caging, pretrial fasting time, method of administration, volume etc.
46
5 objectives of acute toxicity
1. provide estimate for intrinsic toxicity of a substance 2. provide information on target organs 3. identify species differences and susceptible species 4. establish the reversibility of the toxic response 5. provide information that will assists the design and dose selection for longer term studies
47
performed to obtain information on the toxicity of a chemical after repeated administration
subacute toxicity
48
Whata re some of the sensitization tests?
1. Draize test,
2. the open epicutaneous test,
3. the Buehler test,
4. Freund’s complete adjuvant test,
5. the optimization test, the split adjuvant test,
6. the guinea pig maximization
49
How is a sensitization test generally carried out (in guinea pigs most common)?
* Test chemical is administered to the shaved skin topically, intradermally, or both (may include the use of adjuvant to enhance the sensitivity)
* Multiple administrations are generally given over a period of 2 to 4 weeks.
* Approximately 2-3 weeks after the last treatment, the animals are challenged with a nonirritating concentration of the test substance
50
common duration for subchronic testing
90 days
51
what is the general procedure for a subchronic test?
* Give 3 to 4 different doses of the chemicals to animals in diet (rats use 10 animals/sex; dogs -3/4 animals/sex)
* Clinical chemistry and histopathology are performed after either 14 or 28 days of exposure
52
what are some of the objectives of subchronic test?
* Characterize NOAEL
* Further characterizespecific organ or organs affected by the test compound after repeated administration
* Obtain LOAEL
53
What are the regulatory implications of finding NOAEL and LOAEL?
EPA to to calculate the r*eference dose (RfD*), which may be used to establish regulatory values for “acceptable” pollutant levels
Find *benchmark dose (* an alternative to NOAEL)
54
What is benchmark dodse used for ?
To calculate;
reference dose (RfD)
or derived no-effect level (DNEL)
or acceptable daily intake (ADI).
55
use to establish regulatory values for acceptable pollutant levels
reference dose
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What is benchmark dose?
A dose that produces a predetermined change in an adverse effect?
57
uses all the experimental data to fit 1 or more dose-response curves
benchmark dose
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performed similarly to subchronic studies except that the period of exposure is longer than three months
chronic toxicity
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dose that suppresses body weight gain slightly
maximum tolerable dose
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chronic exposure can occur if :
* rate of absorption \> rate of elimination
* chemical produces irreversible toxic effects
* there is insufficient time for the system to recover from the toxic damage
61
Half life is also called
DT50
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Sigmoid DR curve forms straight line when converted to probit units
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probit transformation is an adjustment of quantal data to an assume normal population distribution
64
what is the premise that makes it necessary to use very high doses to treat animals?
statistical and experimental limitations
65
What is the caveat of using high doses in animals to extrapolate to humans?
Problem is the responses at high doses do not occur at low doses
66
Why is using a high dose in animals a valid method?
Because it is not possible to have a really large group of animals that would be able to detect low incidence of tumors above the background
67
What is the approach to dose selection (maximum dose) for non genotoxic pharmaceuticals for oncogenicity studies (laid out in ICH 1C)?
1. Allow for a margin of safety over the human therapeutic exposure
2. Dose selected should be well tolerated with good survival
3. Permit data interpretation in the context of clinical use
68
What is the maximum dose (need NOT go beyond this) for non genotoixic chemcials (as per ICH guidelines)?
* Need not exceed **1500 mg/kg per day** where there is no evidence of genotoxicity
OR
* where maximum recommended **human dose does not exceed 500 mg per day**
69
What is benchmark rate (BMR)?
The rate at which there is a change in the adverse effect (generally 5-10%)
70
In oncogenicty studies one has to document level of tutmors (benign and malignant) above the controls
71
When do increase in tumors above control gp sill not raise a 'red flag'?
* If _control gp_ has _extremely low incidence of tumor_ (relative to historical data).
* If there is _lack of dose response_ for the test substance
Control gp should be matched with treated ert age, diet, caging conditioins etc.
72
what are some of the general lessions to be learned from NTP 2 yr rodent carcinogenicity study
1. Gender differences in tumor incidence
2. species differences
3. background incidence occurs even in controls
4. differnece rates iof incidence despite controlling for diet, caging, environment etc.
73
* Wistar rats -used to test chemicals that may have the testis as a target organ
* Sprague–Dawley rats used to test chemicals that have estrogenic potential
74
What is a developmental neurotoxicity
(DNT) developed by Irwin that can be used in neurotoxicity testing?
functional observational battery (FOB)
75
What are soem of the parameters measuered in DNT?
auditory startle,
learning and memory function,
changes in motor activity
methods to measure cognitive impact on weanlings
76
what is the tiered approach to immunotoxicity testing by ICH?
Initially test for immunotox potential using a Combination of :
1. standard tox testing with
2. biological properties of the chemical
3. structural similarities to known immunomodulators
4. disposition
5. hematological changes (eg: effects on WBCs, immunoglobulin changes)
77
As per the tiered approach for immunotox tesing what should be done should inital test indicates +ve results?
Follow-up with detailed _'functional'_ immune tox tests
eg:
T-cell-dependent antibody response or
natural killer cell activity
immunophenotyping
78
Who postulated the theory that environment also plays a role in the expression of genes?
Conrad Waddington in 1930s
79
what are some of the challenges to using Omics apparoches to risk assessment
1. Omics (transient , dynamic and provide snapshot) vs. traditional (end point)
2. is the change observed a direct effect of a toxicant or it is a compensatory mechanism?
But can help in class prediction and contribute to 3Rs in toxicology
80
What are some of the challenges to using Proteomics?
1. proteins (copies) in a cell cannot be amplified ;ike the transcriptome
2. Detection of some proteins is more challenging
81
what is the challenge of using bioinformatics in risk assesment
Large # of "false positives" from large data
