Toxicological Risk Assessment
26 important questions on Toxicological Risk Assessment
What is the mayor difference in toxicological and microbiological risk assessment?
On what should your hazard identification be based?
What is an invivo and a invitro test?
In vitro is not on animals
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What are the different kind of animal test that can be performed?
- Acut test (single dose toxicity)
- Short term (sub-acute) test (28 days)
- Semi-chronic test (90 days)
- Chronic test (6-12 months) (also carciogenicity).
What are the minimal requirements for testing a food ingredient?
- In vitro genotoxicity
- In vivo semi-chronic (90 days) tests
- In vivo repdroductive and developmental toxicity tests
- Chronic toxicity/carcinogenicity test
Why is acute toxicity not required?
What are the test you need to perform in order to see if your ingredient is genotoxic?
- bacterial and/or mammalian cell mutation tests (Ames, tk-assay)
- mammalian cell micronucleus test
In vivo follow up:
- mammalian erythrocyte or bone marrow micronucleus test
- transgenic rodent somatic and germ cell gene mutation assays
- in vivo Comet assay
Is a compound seen as genotoxic when the in vitro test is positive and then invivo test is negative?
How does the ames test with Salmonella typhimurium go?
How does the mouse lymphoma thymide kinase (tk) assay go?
- You have a mouse lymphoma cells in which you only have one intact koppy of the tk gene.
- Under the toxic conditions only that one cell with the intact tk gene can grow.
- However when there are mutations more cells will be able to grow.
What do the large and the small colonies stand for in the mouse lymphoma thymidin kinase assay?
The small colonies are chromosome damage.
What happens in a micronucleus assay?
If you see this micro-nucleus it is a strong indication you have a genotoxic compound
What is a commet assay?
Cels are put on a glass plate and if the DNA is damaged you will have smaller particles and they will diffuse faster then large particles. So if the DNA is damaged you will get a tail.
What is do you do after you realize your compound is not genotoxic?
You wand a dose response curve for the target organ.
Why is a dose response curve essential in your risk assessment?
- you need it in order to prove taht your chemical is causing the adverse health effect. If you dont get a dose responce curve it is not the case.
- You need to get the NOAEL or the BMDL
What are the experiments done in order to find the critical effect and the target organ?
Macroscopic evaluation:
- external picture,
- position and weight of body organs,
- edema,
- tumors,
- haemorrhages,
- inflammations
Histopathology (to see if organs are dammaged):
- light microscopy (especially important for kidneys)
- histochemistry
Biochemical tests:
- microsomal enzymes,
- cholinesterase, etc.
Analytical chemical tests:
- amount of dosed substance or its metabolites
What are the negative points of animal testing?
- ethical considerations
- time consuming and expensive
- high to low dose extrapolation
- in diet compound in complex food matrix
- animal to human extrapolation
If you wand to reduce animal testing, on what should you work?
What might be a possible in vitro reproductive-toxicity test?
The nice thing is that you test it on human cels.
Compute models can recalculate it to a daily intake of human effect.
What are the effect you should know of the dose response curve?
- Still based on animal experiments
- Should focus on target organ and critical effect
- Proves that adverse effect is due to the compound tested
- route of administration
- Defines NOAEL, LOAEL, Benchmark dose (lower confidence limit) = BMD(L)10
- To be used as Point of Departure for defining safe levels (ADI, TDI) and risk assessment (MOE)
What is the difference between TDI and ADI?
TDI = Tolerable Daily Intake for unavoidable contaminants like dioxins, mycotoxins, heavy metals
How do you do a risk assessment for a non-genotoxic chemical?
They have to be divided by 100 since there is a inter species and a inter individual difference.
From this division the ADI or TDI is obtained.
And then you have to see that if the expected daily intake (EDI) is under the ADI or TDI
What are the disadvantages of the NOAEL?
- NOAEL dependent on sample size more dose groups, more animals lower
- NOAELs; better experimental designs are penalized
- NOAEL limited to experimental dose
- NOAEL differ across studies
- Only one experimental data point is used
All in all less testing is rewarded because you get a higher NOAEL. This is not good!
What is the bench Mark Dose approach?
(Statistical lower confidence limit of) the dose corresponding to a small increase in effect over background level BMDL BMD BMR NOAEL
How do you do a risk hazard assessment for genotoxic compounds?
There are 2 different products.
The genotoxics that can be avoidable and the ones that are not avoidable.
The ones that are avoidable are NOT allowed. So you can use a genotoxic chemical.
The ones that are not avoidable can have 3 values:
- ALARA: As Low As Reasonable Achievable
- Virtural safe dose (VSD)
- Margin of Exposure (MOE) approach
What is a DALY?
It are the disability adjusted life years.
DALY = YLL + YLD
YLL: number of life years lost (deaths)
YLD = number of years with illness or disability
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