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Toxicology > Lecture 8: Metal Toxicity Part 1; Mercury > Flashcards

Lecture 8: Metal Toxicity Part 1; Mercury Flashcards

1
Q

Metals

A

are naturally occurring elements ( don’t break down quickly in the environment or the body) that can be introduced to humans and the environment through industrial, agricultural, and medical activities.

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2
Q

How do metals differ from toxicants?

A

Differ from many toxicants because most are natural and do not quickly break down in the body or environment.
– Many are essential for cell function too (i.e., Zn)- we get these from our diet

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3
Q

How do metals exert toxic effects?

A
  • Inhibit critical enzyme function.
    – Can lose or gain 1 or more electrons and form highly reactive cations – contributes to oxidative damage.
    – Can also replace other metals by binding to molecular targets.
    • Cd, Cu and Ni can replace Zn(imp in cell function) in some physiological processes
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4
Q

When talk about heavy metals…

A

they are referring to the atomic weight.

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5
Q

What kind of dose response curve would metals essential to cell function make?

A

U shaped

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6
Q

Are all metals toxic to organisms?

A

Can be very toxic to organisms depending on the metal:

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7
Q

Major toxic metals

A

(e.g., Pb, Cd)

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8
Q

Essential metals

A

(e.g., Zn, Cu)

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9
Q

Medicinal metals

A

(e. g., platinum and bismuth)

- can be remedies at small doses but at large can have adverse effects

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10
Q

Ex of medicinal metal

A

Bismuth subsalicylate
– Increase water absorption in the intestines – Can kill bacteria that cause diarrhea
– Antacid
– But….
» Can cause black stool and black tongue » And can interact with various drugs

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11
Q

Minor toxic metals from technology

A

(e.g., uranium)

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12
Q

Toxic metalloids

A

(e.g., As, antimony)

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13
Q

– Non-metallic elemental toxicants

A

(e.g., Se, fluoride)

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14
Q

Describe how metals have been used in pharmacology

A

• Platinum compounds have been effective for cancer chemotherapy
– Also gallium and titanium compounds can be used.

  • Al can be used in antacids (i.e., Aluminum hydroxide)- antidepressants
  • Bismuth.
  • Au has been used in treating rheumatoid arthritis. – “gold salts”
  • Lithium used for bipolar disorder
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15
Q

What determines relative toxicity?

A

As always, the route of exposure, dose, and duration and frequency of exposure are critical factors that determine the relative toxicity.

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16
Q

List important factors that contribute to metal toxicity

A

– Age - Younger and older individuals more sensitive to metal toxicity
• Children can absorb some metals in the GI tract better (e.g., Pb)

– Sex - However, not always clear as to why and may be linked to lifestyle, location, etc.

– Genetics
• May include an increased capacity for biotransformation, reduced
absorption, increased excretion
- anything that will change disposition of metal in the body is imp. to consider
– Protection during any part of the toxicant disposition

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17
Q

your ____being ____ to ______ of metals

A

your rarely being exposed to acutely toxic levels of metals

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18
Q

Ex of chronic exposure in wpg

A

lead pipes in wpg- we could be getting chronic exposure to lead in small doses which could lead to adverse impacts over time

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19
Q

Different types of proteins influence the disposition in the body

A
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20
Q

List proteins that bind metals and describe each

A

1) Non-specific binding to proteins (i.e., albumin- stuff can bind and be distributed that way and hemoglobin), that can move metals throughout the body.

2) Metallothioneins are specific metal-binding proteins.
– High affinity for Zn, Cd, Cu, Hg
– Can protect the cell from oxidative damage by binding to the metals to prevent them from doing their damage.
- bind to metal and keep it from damaging the cell
- bio marker
- get upregulated if being exposed to many metals

3) Transferrin binds to Fe in the plasma to help transport it across cell membranes.
– Ceruloplasmin will convert Fe to the right form to bind to transferrin.

4) Ferritin is a primary cellular storage site for Fe.
– Can sequester Fe in the cell if necessary (bacterial infection!)
– But also binds Cd, Zn, beryllium, Aluminum
- protein complex
- sequesters iron within the cell during infection cells can upregulate ferritin which sequesters iron and keep bacteria from getting it and causes bacteria to die

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21
Q

What are the different forms of mercury?

A

Inorganic: Hg0, Hg1+, Hg2+
- inorganic is less of an issue

Organic mercury:
methylmercury,- big one to worry about, accumulates in food chain and we consume
dimethylmercury- lab invented

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22
Q

Where can Mercury be found?

A

is also found in ores, but is rare (only a few major mines worldwide).
It is liquid at room temperature… which is why it was named after the Roman god of swiftness.

23
Q

What are the uses of Hg?

A 
1. Readily mixes with other metals (to form amalgams)
• Mixed with silver for dental
fillings
• Used to extract gold and silver
from ore
• Still used today by ‘artisanal
miners’ who produce 25% of global gold
  1. Thermometers and other gauges
  2. Mercury (tilt) switches
  3. Hg gas in fluorescent lightbulbs
24
Q

What did the harper government do in 2015?

A

In 2015, the Harper government ratified a UN treaty to limit Hg use.

25
Q

Mercury disposition

A

route of exposure is important

-

26
Q

Mercury liquid and vapor (H0)

A
  • Vapor absorbed via inhalation (80% inhaled)
  • Readily distributed in tissues
  • Gets converted to Hg2+ enzymatically
  • Liquid barely absorbed in GI tract
27
Q

Mercury salts (Hg1+ and Hg2+)

A
  • Barely absorbed in GI tract (10%)

- Gets conjugated to free cysteine and accumulates in the kidney

28
Q

What is the fastest way to get mercury in the body?

A

vapor- much more efficient way to get in the body than liquid

29
Q

What was mercury used to treat?

A

Mercury was used to treat syphilis.

Syphilis was the only disease that was passed from the Americas to Europe. Europeans had no resistance.

The only ‘cure’ at the time was mercury ointments, injections, breathing Hg0 vapors, and sweat baths.

They also forced patients to drink it. One of the symptoms is excessive saliva. Thus the expression ‘frothing at the mouth’ crazy… because late-stage syphilis messed with your mind.

30
Q

Describe the toxic effects of Mercury liquid and vapor (H0)

A
  • High doses inhaled can cause acute bronchitis that can be lethal
  • Neurotoxic: can cause tremors and erethism (memory loss,
    increased excitability, insomnia, depression, and shyness)
  • vapor- can get into our bodies fast which then gets converted to salt form
31
Q

Toxic effects of Mercury salts (Hg+1 and Hg+2)

A
  • Mostly kidney damage leading to kidney failure in high doses
  • Can non-specifically bind to –SH groups on proteins
  • Limited neurotoxic effects
32
Q 
Toxic effects of 
Organic mercury (methylmercury and dimethylmercury)
A

Very neurotoxic. Causes paresthesia (numbness), ataxia (lack of coordinating muscle movement), blindness

  • Children and fetuses are particularly vulnerable
  • methylmercury; attacks nerve cells, most commonly exposed to, readily exposed and most toxic effects
33
Q

How does MeHg cause neurotoxicity?

A

In cell cultures, MeHg causes ROS generation, glutathione reduction, and high intracellular Ca2+ levels, and mitochondrial damage (ATP)

All of this leads to apoptosis or necrosis in nerve cells.
- to many mitochondria die

Astrocytes are particularly targeted

Another proposed mechanism is that MeHg inhibits membrane ion transporters, and thus the ability of the astrocytes to ionoregulator(regulate ion balance)
This causes them to swell and burst.

34
Q

Ebselen

A

is a powerful antioxidant that protects the mitochondria and cells from oxidative damage

35
Q

Minamata disease

A

Historical mass mercury exposure:
- didn’t understand connection between dumping mercury and mercury toxic environments

Chemical factory in Japan dumped inorganic mercury salts into the bay

Converted to MeHg by bacteria, biomagnification in fish.

The Minamata residents, as is common in Japan, eat a lot of fish!

Because folks didn’t understand the conversion to MeHg yet, they originally thought it was a new disease.
- slow process of getting rid of MeHg from environment

36
Q

What happens when inorganic mercury goes into the environment?

A
  • when inorganic mercury goes into the environment certain type of bacteria that live in anoxic conditions can convert inorganic Hg to MeHg
    zooplankton pick up methylmercury small fish eat these big fish we eat them (goes up food chain)
37
Q

anoxic

A

low O2 conditions

38
Q

Symptoms of Minamata disease

A
  • Central and peripheral nervous system degeneration
  • Tingling and numbness of limbs - Impaired motor function
  • Impaired vision and speech
39
Q

Describe Iraq mass mercury exposures

A
  • Iraq in 1971 was undergoing drought and famine.
  • Grain shipped as aid to be planted was coated in methylmercury to prevent fungal growth… colored with pink dye to show toxicity.
  • Not labelled in the right language though… it was consumed instead of being planted.
  • 6,530 patients were admitted to hospital with poisoning, and 459 deaths were reported.

Bags labelled in Spanish. Coated grain was died pink to indicate toxic Hg levels

  • this was a rare occasion of acute toxicity
40
Q

ontario Minamata disease

A

• First Nations communities were impacted by consuming methylmercury contaminated fish in the late 1960s (2 communities in Dryden).

• Mercury contamination was from dumping waste from pulping mills. Over 9000 kg of mercury from 1962 to 1970!
- Mg was left behind and never taken of

41
Q

What are some Hg Sources in the Environment?

A

Main industrial sources: Burning coal and pulping paper

Natural sources: Volcanoes

42
Q
A

Hg0 gets oxidized into Hg2+ naturally.
Bacteria in sediment take up Hg2+ and can methylate it into methylmercury (MeHg)

i.e., MeHg biomagnifies in fish because bigger fish eat the smaller fish. We often eat the top predator fish (e.g., tuna, walleye

43
Q
A

bigger is in fish that eat other fish will have high methylmercury than fish that don’t eat other fish

44
Q
A

you can predict how safe a fish is to eat depending on their diet

45
Q

Methylmercury

A

is lipophilic

- accumulates in muscle in tissue

46
Q

Hg accumulation in fish

A

Health Canada recommendations for “fish” consumption:
- No more than 150 g per week of top predator fish (tuna, shark, swordfish, etc.).
Pregnant women no more than 150 g per month. - Acanoftunacanbeupto~120g…

47
Q

What happens when you cook lipophilic things?

A

if things are lipophilic and you cook it, it can decrease lipophilic compounds in tissue

48
Q

What type of fish is better to eat?

A

better to eat smaller fish

49
Q

Describe category 3 level

A
  • the more effort it takes to get to a place to fish for them there is less fishing pressure do they live longer in those areas
  • if they live longer= grow longer= accumulate more Hg over time
  • so you get big fish that eat smaller fish resulting in them accumulating Hg
50
Q

atmospheric disposition

A
  • this is why we find evidence of Hg everywhere
  • a non- point source of pollution
  • can’t pin point source of pollution
  • this is a big issue when it goes into atmosphere and can be distributed everywhere
  • biggest issue of when it enters aquatic systems gets converted to methyl mercury and accumulates up the food chain and reaches us when we eat fish or eat other animals that eat fish
51
Q

Walleye

A

in the city of wpg they eat other fish and can accumulate higher levels of mercury at smaller size

outside of wpg they have to grow bigger than fish in the city of Wpg to accumulate same amount of Hg bc its a bigger issue in Wpg

52
Q

Northern pike

A

eat lots of small fish

53
Q

Organic mercury (methylmercury)

A

Readily absorbed in the GI tract

  • rapidly distributed throughout the body, can accumulate in the brain (10% is absorbed)
  • big issue for young children and developing fetuses
  • most common in our body
54
Q

Astrocytes

A

They…
• surround neurons and hold them in place
- supply nutrients and oxygen to neurons
- insulate one neuron from another
- destroy pathogens and remove dead neurons

Toxicology (13 decks)

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