TOX- Toxicological Tests and Endpoints of Toxicity 1

drraythe's version from 2018-03-11 01:39

Masures of things

Question Answer
what is Clinical toxicology?treating a patient with an intoxication
Veterinary public health is/what does it do?assessing the safety of animal derived foods and the likelihood of an undesirable exposure of humans (drug residues, contaminants in the food chain)
what is Environmental toxicologythe exposure of humans and animals to hazardous compounds in the environment
what is Occupational toxicology?working with animals, their feed, their medication and disease control (pesticides)
if we are looking at the lethality of a substance, we are looking at ___ toxacute
explain acute toxicity (lethality) in Experimental toxicologyThis is Single dose toxicity testing and determines the LD50. It Serves as the start of cumulative dose-effect curves and gives us a yes/no response.Traditional 1st classification and dose-range finding
explain acute toxicity (lethality) in Clinical toxicologyThis is A toxic effect that is directly related to exposure-- such as the "chocolate dog!" we are generally looking at pharmacological active substances at a high dose: interaction with a target (enzyme, receptor) (animal ingests something, see symptoms after a period of time)
This is Chemical toxicity: ranking based on acute toxicity. What is it useful for, what is the downside of it?Used for occupational exposure assessment: PSDS (Personnel Screening Data Sheet). Unfortunately, System is not harmonized - figures vary between countries
What can we learn from LD50 values? Describe the trends seen here Looking at oral MALE vs FEMALE mouse, we see there is a larger variability in the female mouse's response... This might mean there is interaction with estrogen (Oxidative stress is influenced by an animal’s estrogen level-- which means that antioxidant therapy might be able to help since the females tolerated it slightly better and there was more variation depending on their cycle. Vit E repairs cell membrane and selenium inc cellular antioxidant defense). Then if you compare The ORAL versus the IP mice, you see that it takes a much LOWER dose for the IP route to be lethal- meaning the drug has poor oral bioavailability comparatively. Then you can compare the MOUSE IP to the RAT, and the species difference in LD50 means there is a difference in phase II biotransformation (mice have a stronger phase II biotransformation so tolerate better than rats- aka mice need higher dose needed to kill a mouse bc of more phase II biotransformation in mouse). Hamster needs a WAY WAY higher dose than mouse or rat to kill it- must have the best/most optimum phase II biotransformation.
Acute toxicity (LD50 vs TC50)--> what IS LD50 and TC50? What kinda tests are these?LD50 (lethal dose in 50% of subjects-- remember this only shows the ACUTE TOX AT A SINGLE DOSE) TC50 is the Toxic concentration (so when 50% of the subjects are showing toxic effects from a particular concentration in their tissue/plasma/whatever) ... These are DESCRIPTIVE TESTS which are used for finding the dose/concentration range
Acute toxicity (LD50 vs TC50)--> what animals would we use (in vivo) to test this out?Rodents (rats/mice/hamsters), Chickens (cheapest to use)
Acute toxicity (LD50 vs TC50)--> how do you go about testing these in VITRO as opposed to VIVO?Have to do Concentration dependent toxicity testing in different cell-types. Look at Direct cytotoxicity (dead cells) of.... Fibroblast type cells, HepG2 cells (liver derived), Neuro 2A cells (neuroblastoma), Caco cells (colon carcinoma)
If we are looking at repetitive doses, what kinda tox are we looking at?subacute (this is 90day rodent assay!)
Subacute toxicity - repetitive dose--> how do we assess this in Experimental toxicology?They will have a Defined protocol, where they do 7-10 repetitive doses to different dosage groups (often diff routes used). They then use Clinical observation, Clin path, and post mortem (gross) pathology to determine Substance characterization (does it accumulate? does it only lead to nephrotoxic or does it lead to hepatotox too?)
Subacute toxicity - repetitive dose--> how do we assess this in Clinical toxicology?Not defined, but common in daily practice as the time between 1st exposure, onset of clinical symptoms and reporting. (usually just circumstantial). (animal eats something, doesn't immediately show adverse effects, might take some time... or take up particular compound over prolonged amount of time. usually between 1st exposure and onset of clinical signs)
***90 days toxicity testing in rats--> what are the two major things we get out of a study like this?Defines NO(A)EL and Defines LOEL (Most important study. Mandatory for all compounds in our life pretty much)
***what is NO(A)EL?in (mg/kg BW): the tested dose without any effect (no-observable (adverse) effect level)... ***Provides basis for ADI* (acceptable daily intake) (result of toxicological testing: most sensitive endpoint in the most sensitive laboratory animal species)
what is LOEL?the lowest dose that induces a measurable effect: lowest observable effect level
***WHAT TEST DETERMINES NO(A)EL?90 days toxicity testing in rats
explain the process of doing a 90 days toxicity testing in rats(Most important study. Mandatory for all compounds in our life pretty much. Determines how safe a compound is) 90 days = ⅛ of the life span of the animal-- at least 3 different doses (male and female groups). Daily exposure will/should induce all possible toxic effects. Generally oral application (can't do IM for 90d straight- SQ might work) (in drug-testing. Application according to the intended clinical use where possible). It is an extended protocol: daily clinical (including behavioral studies when appropriate), urine and blood sampling, total (histo-) pathology. In the end of the study, we are able to determine the NO(A)EL (no-observable (adverse) effect level) and the Defines LOEL (lowest observable effect level)
90 days rodent toxicity test--> for Regulatory toxicology, what will we use this for/look at?Determines NOAEL and Determines ADI (acceptable daily intake) (for people- Concentration in a food material that doesn’t cause an adverse effect when used over the entire lifespan )
90 days rodent toxicity test--> for Veterinary toxicology, what will we use this for/look at?look at Qualitative information: Steepness of the dose response curve (NOAEL - LOEL) (is it very safe or not so safe?), Organ-specific effects (target structures), Reversibility of the effects (and prognosis) (obv is reversible, better prognosis), and ADI minus MRL (Acceptable daily intake – mean residue level)
explain how we can get AI (acceptable daily intake) from our toxicological testingbasically did the 90 day rodent assay and other tox testing, and then account for the uncertainty/safety factor (<--aka not everyone is the same so we need to account for this) to get ADI. It is an equation: ADI= (NO(A)EL in mg/kg TIMES the bodyweight of the average human aka 65 kg..... and then you divide that all by the Uncertainty factor (which is 10*10 aka 100)
what is MRL/ how do we determine it/ why do we need itMax residue level- use this to determine a withdrawal time (a recommendation). It is almost identical to the ADI (acceptable daily intake) calculation but includes the food factor-- which is obv how much we eat. Its established in the high consumer.
Explain the UF/uncertainty factor and what it meansuncertainty factor 10 * 10 = 100 (10 is extrapolation laboratory animal to human and the other 10 is variation in human population) (previously SF-safety factor). taking into account the extrapolation from laboratory animal to human and the variability within the human population. (use a UF > 100 in all cases were results of toxicity studies give rise to concern) (this is your wiggle room because everyone isnt the same)
what is the body weight in the ADI/MRL calculations?65kgs-- the average HUMAN body weight (because we are doing all this testing for human safety and it's the ADI for humans)
what is the FF/food factor/ why do we care?This is the extra piece of information we need to determine the MRL from the ADI. It is Reflecting the consumption of a certain food (milk, meat or eggs) (based on a "high consumer" amount of that food)
Adjustment for interspecies differences--> explain how we determine what is good for people from ANIMAL studies, and when how it is good for people when people are all so differentThis uncertainty is covered by the Composite uncertainty factor (CUF 100)... we get the 100 from 10 times 10, where the first ten is a factor of interspecies differences, and the other ten is Inter-individual differences. We got these numbers (10s) from toxicodynamic and toxicokinetic studies/factors.
**what calculation defines the withdrawal period for us?THE MRL [ (NOAELxBW)/(UFxFF) ] (mrl is defined by the ADI)
what is with withdrawal period-- and how do we determine it?It is a recommendation to avoid undesirable residues (And we determine it from the MRL calculation)
You can shorten the calculation of MRL to...ADI:FF (: can mean divided by)
What is the true risk of drug residues?--> Substances that do not meet these criteria can not be licensed for use in (food producing) animals (3 situations)(1) VMPs (vet. medicinal product) are not licensed if they induce chronic (or non-linear) dose-dependent effects (carcinogenicity) (2) Pesticides are tested by the same criteria (and more tests on environmental toxicology and tolerance levels are established: see vegetables) (3) Natural toxins generally do not meet these criteria!
(thing in kirks review, idk) what should we remember about the UF?UF= Uncertain CUMULATIVE????**** <--doesn't make sense but remember this!

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