Week 2 - POP + metals Flashcards by Emmanuelle Poirier

T or F : Default uncertainty value of 100 to convert NOAEL to ADI/TDI can often not be applied for metals when defining safe levels of intake (Upper levels or ULs), since the resulting levels may then be lower than the dietary needs, the RDI and EAR

true, since there are some metals that are essential.

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What does RDA stands for ?

Recommended/ reference daily intake (or amount if RDA)

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What does EAR stands for

Estimated average requirement

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What is one way that the body regulates the toxicity of metals ?

with the expression of metal chelators like metallothionein

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What are the examples of chelators seen in class

Metallothionein
Ethylene-diamino-tetra-acetic acid (EDTA)
Dimercaptopropanol (britis anti-lewisite (BAL)

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What are chelators ?

Compounds capable of binding to toxic metal ions to form complex structures which are easily excreted from the body

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How does chelators bind the metals to reduce their toxicity ?

They do it by having a oxidizable group either : thiol(R-SH), carboxy(R-COOH) or amino(R-NH2)

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How does British Anti-Lewisite (BAL) works ?

it binds the arsenic based chemicals like lewisite (warfare agent which blocks pyruvate oxidation) and so they put it in masks to bind the arsenic and make it not toxic and so you won’t get neurological problems observed with arsenic.

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How does metallothionein works to reduce the toxicity of metals ?

It works by having a lot of cystein in the protein which contains sulfur groups (SH) which bind metals.

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___ ions are captured by methallothionein reduces the transfer to embryos. This is also why there is an increase in cellular expression in mothers carying

zinc

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What are the factors influencing the bioavailability of metals

Solubility of salts
Valency (oxidized vs reduced)
The presence of other ions (competition for uptake)
Lipophilicity
Food in the GIT

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What are the toxic metals seen in the lecture ?

Methylmercury
Lead
Cadmium
Arsenic

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Mercury is a problem because it is a _____ toxin

neuro (developmental)

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What is the mechanism of action of methyl mercury ?

inhibit the glutamate uptake by the astrocytes
inhibits the glutamate re-uptake by the synaptic vesicles
this leads to the cells being too stimulated by the NMDA receptor and so too much calcium leads to elevated levels of ROS and then cell death.

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T or F: the mercury in food can come from illegal mining sites, coal plants and volcanoes

true and it will bioaccumulate in the food because it is rapidely converted into the highly bioavailable form (methyl-mercury)

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T or F : High fish consumers, which might include pregnant women, may exceed the TWI by up to approximately six-fold. Unborn children constitute the most vulnerable group.

true

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how do we know the calculated TWI for methylmercury is very protective

it was calculated based on neurotoxicity in the most vulnerable population (7 y/o)

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What is the effect of long term exposure to lead on humans ?

lead : results in problems with long term neural excitation and memory storage because of the formation of ROS and the disturbance of calcium homeostasis

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T or F : the absorption of lead is 4 fold higher in children than in adults

true because it has a similar structure as calcium and so absorption of calcium being increased in children leads to higher bioavailability of lead

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What is the half life of lead ?

it accumulates in the bones since it is similar to calcium which increases the half life to 10-30 years. in the blood the t1/2 is 30 days.

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What are the toxicity mechanisms of lead ?

will lead to anemia
Can accumulate in the bones
Can lead to a demyeliation (neurotoxicity)

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T or F : lead poisoning can occur in illegal gold mining sites

true

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T or F ; lead can lead to anemia

true, it is due to the inhibition of the heme synthesis

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T or F : Cadmium high blood levels were linked to reduced intelligence (lower IQ)

false, it is for lead and by banning its use in petrol the blood levels decreased

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\_\_\_\_\_, ___ and ____ were the most important contributors to lead exposure in the general European population

Cereals, vegetables and tap water

T or F : Lead is a very high concern for children and adults

true, the MOE ranged from 0.16 and 0.45 for 1-3 y/o

What are the target organs (and resulting conditions after exposure) of cadmium

Nephrotoxicity (kidneys) Osteoporosis (bones)

T or F. : cadmium is a very persistant metal

very persistant chemical metal and can stay there for a decade in your body. The most of it is in the kidney (t1/2 is 10 years)

T or F ; the methallothionein binds cadmium

true, when it is saturated is when you can have sever kidney damage

What are the mechanisms of toxicity of cadmium ?

1. Induces the Nrf2 pathway and so ROS production 2. It is stored in the kidney (proximal tubule dysfunction) with methallothionin and leads to calcium loss through urine and so bone loss

The Kamioka mine that lead to higher levels in the Jinzu river gave information on the ____ toxicity

cadmium

Why is cadmium a concern in europe ?

The mean exposure for adults across Europe is close to, or slightly exceeding, the TWI.

What are the two good markers for kidney function which also lead to the calculation of the BMDL10 and BMDL5

beta-2-microglobullin (B2M) Creatinine

We are exposed to arsenic via : ___ and \_\_\_

environment and water

What is the target organ of the toxicity of arsenic and the resulting condition

skin is the target organ and so can lead to cancer

T or F : it is very hard to study the effect of arsenic on humans because we have a high uptake and it metabolised and excreted

true. So it is hard to extrapolate the data of the toxicology from the animals to the humans and so we do not have suitable basis for the risk characterisation

Incident in bangladesh from contaminated water lead us to have more information on the acute effect of ____ on the skin

arsenic

What is the proposed mechanism of toxicity of arsenic ?

1. Leads to genomic instability because of the decrease in the global DNA methylation (cancer risk is increased)

What are the food source containing arsenic ?

Wheat bread Rice Milk and dairy products water

T or F : toddlers/children are at risk of arsenic toxicity

true, the MOE is 1.5 nd for adults about 3.

What are the persistent organic pollutants that we saw in class ?

1. Organochlorine pesticides (DDT) 2. PCBs 3. Dioxins 4. Brominated flame retardants 5. Per and polyfluoroalkylated substances (PFASs ; PFOS & PFOA

What are two of the POP we focused on in the lectures ?

1. Dioxins 2. PBCs

What are the source of dioxins ?

1. formed by natural combustion and geological processes 2. Side products of the syntehsis of chlorinated compounds

What is the structure of dioxins ?

What is the structure of PCBs

What is the source of PCBs

they do not have a natural source, but they are foun in synthetic products

The Yusho (rice oil) disease gave us more information on the toxicity of \_\_\_

PCBs, it was a rice oil contaminated with PCBs and PCDfs

What are the symptoms of PCBs toxicity

1. neurological dammage 2. immune system suppression 3. local skin infections - acne like condition - chloroacne

TCDD is a \_\_\_\_

dioxin

The chemical plant in italy (ICMESA) gave us information on the chemical \_\_\_\_

TCP

What were the long term effect of the chronic exposure to TCP in the italy chemical plant ?

1. Chloroacne 2. increase soft tissue sarcoma 3. Decreased sperm counts in boys 4 Change of the sex ratio

What is the most toxic compound in the class of PCBs/Dioxins and what is its structure

TCDD

What are the effectd of TCDD in animals ?

●Endometriosis in monkeys ●Neurobehavioral effects in monkeys ●Immune suppression in offspring rats ●Decreased sperm count in male offspring of rats ●Liver tumours in female rats at higher dose levels

What is the mode of action of TCDD ?

●Recognized human carcinogen (IARC group 1) that is non-genotoxic so threshold for carcinogenicity (action through AhR)

T or F : dioxin are able to enter in the cells

true and it will interact with other proteins to have effect on the CYP1A1 metabolism and the genes that affect physiological processes like growth, differentiation and apoptosis.

What is the initiating event of the toxic effect of dioxin ?

linkage to the AhR.

What are the two PCB categories ?

1. Coplanar : non-ortho substituted cngeners so the two phenyl rings are on the same plane, more affinity because strucutre is similar to dioxins 2. Noncoplanar : ortho substitued and so does not activate the receptor because the two phenyl rings are not on the same plane

What influences the affinity of PCB / dioxins to the AhR ?

the more planar the molecule and the more strongly it will link the AhR. So when the molecule is non ortho substituted, the stucture will be more planar and so more affinity.

PCB needs to be in the ____ to be able to bind to the AhR

co-planar

T or F : the PCB with no chlorine will be mroe co-planar and so will interact more with the AhR

true

How can we study the PCB dioxin like and dioxin mixtures

With the Toxic equivalent quotient (TEQ)

How does the TEQ approach works for the PCB dioxin like and dioxin mixtures

Every molecule is evaluated based on the invivo and invitro assessment (in vivo more weight) with TCDD and given a number which is the toxic equivalent factor (TEF). The TEF of TCDD is 1. The the TEF is multiplicated with the level found in the mixture.

What are the assumptions when we use the TEQ principle for a mixture ?

1- All effectd are mediated by the AhR 2- Effects are additives

T or F : mono-ortho are more toxic than non-ortho PBCs

false, the non-ortho (no chlorine on position 2) are more planar and so more toxic)

What is the TDI of dioxins and dioxin like PCBs ?

WHO : 1-4 pg TEQ/kg bw / day EU -SFC : 3 pg TEQ / kg bw / day

T or F ; the kinetics uncertainty factor for PCB is redued from 4 to 3.2 to be safer

true because humans are more likely to internalsie the PCBs than rats

What is the new TWI for dioxins and dioxins like PCB by EFSA based on human data ?

30.4 pg TEQ/kg bw/week

True : in 2018, after revision of the risk assessment on dioxin like pcbs data obtained from human exposure in seveso italy, EFSA revised the TWI to 2 pg TEQ / kg bw / week

true, the critical effect was the seme quality and a bigger uncertainty factor of 10 instead of 3.2 was used.

What was the critical effect used for the assessement of dioxin and dioxin like pcb by efsa ?

the effect on the semen quality

T or F : in europe, the EDI is currently exceeding the TWI set by EFSA in 2018

true, the TWI is 2 pg TEQ and the average exposure is between 0.57 and 2.54 pg TEQ / bw / day

\_\_\_\_ are a new categoy of POP

Per and polyfluoroalkylated substances (PFAS)

What are the source of PFAs ?

Grease resistant food packaging Surface active agent cooking devices

PFAs : Thermal stability and chemical stability due to \_\_\_

to very strong carbon-fluorine bonds

The assessement of PFAs is based on :

based on human epidemiological data, the risk assessmenet is still ongoing for PFAS

Toxic effects dioxins and dl-PCBs mediated via the aryl hydrocarbon receptor (AhR) ●Acute effects:

●Acute effects: chloracne

Toxic effects dioxins and dl-PCBs mediated via the aryl hydrocarbon receptor (AhR) ●Chronic effects:

developmental, reproductive toxicity: effects on sperm quality critical effect

What are the effects of PFAs on humans ?

1. higher cholesterol 2. Smaller birth weight 3. Liver damage

what is the effect of exposure to organophosphates ?

exposure to the Organophosphate pesticideswill inhibits the acetylcholine esterase which results in cramps because over stimulation of muscles. Some pesticides are more capable of doing that than others.