Lecture 6: Metal Toxicity Flashcards
what are the five major toxic metals?
arsenic (as)
cadmium (cd)
mercury (hg)
nickel (ni)
leab (pb)
what are four of the 8 essential metals?
iron (fe)
copper (cu)
zinc (zn)
selenium (se)
when people refer to heavy metals what are they referring to?
the atomic weight
this term is not really used anymore!
____ are naturally occurring elements that can be introduced to humans and the
environment through industrial, agricultural, and medical activities
Metals
why do metals differ from many toxicants?
they’re natural and do not break down quickly in the body or environment
plus many are essential for cell function!
what kind of dose response curve would Zinc make?
U-shaped, toxic at low and high doses, because its essential for cell function!
what are the toxic effects of metals?
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.
___, ___, and ____ can replace Zn in some physiological processes
Cd, Cu, Ni
which affects protein function, etc.
what are two examples of medicinal metals?
platinum (Pt) and bismuth (Bi)
_______: 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…
bismuth subsalicylate
T/F: metal can be very toxic to organisms depending on the metal
true! some are super toxic, others are essential and medicinal
Pb and Cd are examples of…
major toxic metals
Zn and Cu are examples of…
essential metals
Uranium (U) is an example of…
minor toxic metals from technology
Arsenic (As) is an example of…
toxic metalloids
Fluoride (Se) is an example of…
non-metallic elemental toxicants
______ compounds have been effective for cancer chemotherapy
* Also gallium and titanium compounds can be used.
Platinum
____ can be used in antacids
Al, Aluminum hydroxide
_____ is used in pepto bismol
bismuth (Bi)
____ has been used in treating rheumatoid arthritis.
* “gold salts”
Gold, Au
_____ used for bipolar disorder
Lithium (Li)
T/F: the route of exposure, dose, and duration and
frequency of exposure are critical factors that determine
the relative toxicity of metals
true!!!!
what are the three other important factors that contribute to metal toxicity
Age - Younger and older individuals more sensitive to metal toxicity
* Children can absorb some metals in the GI tract better (e.g., Pb)
Sex – Always a potential factor and may be linked to lifestyle,
location, etc.
Genetics
* May include an increased capacity for biotransformation, reduced
absorption, increased excretion
* Protection during any part of the toxicant disposition
why are younger and older people more sensitive to metal toxicity?
less developed liver and kidneys
what are the four types of proteins that influence the disposition of metals in the body?
- non-specific binding to proteins (albumin and hemoglobin)
- methallothioneins
- tranferrin
- ferritin
_________ 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
Metallothioneins
______ 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
_______ 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
Ferritin
why is ferritin important for locking up Fe in our cells?
Fe is a vital growth factor for bacteria, without it we can starve infiltrated bacteria!
what are the 4 forms of Mercury?
inorganic
Hg0
Hg1+
Hg2+
what are the two forms of organic mercury?
methylmercury
dimethylmercury
_____ 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
Mercury
what are the four uses of mercury (Hg)?
- mixed with other metals to form amalgams
- mixed with silver for dental fillings, used to extract gold and solver from ore - thermometers and other gauges
- mercury tilt switches
- Hg gas in fluorescent lightbulbs
in _____, Canadian
government ratified a UN treaty to limit Hg use
2015
_____ disposition:
- Vapor absorbed via inhalation (~80%)
- High lipid solubility
- Readily distributed to all tissues
- Can cross blood brain barrier
- Gets converted to Hg2+ enzymatically
- Liquid not easily absorbed in GI tract
Hg^0, liquid and vapor
what are the toxic effects of Hg^0?
high doses inhaled causes acute bronchitis
neurotoxic: causes tremors, erethism (memory loss, increased excitability, insomnia, depression, and shyness)
Hg was used to treat what major European disease brought over from the Americas?
syphilis
the europeans had no resistance, they used mercury ointments, injections, vapours, and sweat baths
mercury poisoning can cause increased salivation, which they thought expelled the disease
______ disposition:
- Not easily absorbed in GI tract (10%)
- Poorer lipid solubility relative to H0
- Does not effectively cross the blood
brain barrier or placenta
- Gets conjugated to free cysteine and
accumulates in the kidney
Hg^1+ and Hg^2+, mercury salts
what are the toxic effects of mercury salts?
Mostly kidney damage leading to kidney failure in high
doses
- Can non-specifically bind to –SH groups on proteins
- Limited neurotoxic effects
_____ disposition:
- Readily absorbed in GI tract
- Rapidly distributed throughout body,
can accumulate in the brain (10% of
total absorbed)
- Can also bind thiol-containing (–SH
groups) molecules like cysteine and
mimic methionine (an essential amino
acid)
organic mercury (methylmercury, MeHg)
what are the toxic effects of methylmercury?
Very neurotoxic. Causes paresthesia (numbness),
ataxia (lack of coordinating muscle movement),
blindness. Can progress to coma then death.
Children and fetuses are particularly vulnerable
how does MeHg cause neurotoxicity?
causes ROS generation
glutathione generation
High intracellular Ca2+ levels
mitochondrial damage
… which all lead to apoptosis or necrosis in nerve cells
Astrocytes are particularly targeted by MeHg… why is this such a problem?
- surround neurons and hold them in place
- supply nutrients and oxygen to neurons
- insulate one neuron from another
- destroy pathogens and remove dead neurons
what is the proposed mechanism for the targeting of astrocytes by MeHg?
that it inhibits membrane ion transporters, and thus
the ability of the astrocytes to ionoregulate.
This causes them to swell and burst.
what are the two main industrial sources of Hg in the environment?
burning coal and pulping paper
what is the natural source of Hg in the env?
volcanoes
why does Hg biomagnify in fish?
because bigger fish eat smaller fish… and we often eat the biggest fish!
____ gets converted to Hg2+ naturally, bacteria in sediment take up Hg2+ and convert it to ____
Hg0
methylmercury (MeHg)
which disease was named after a historical mass mercury exposure?
minamata disease
what happened in Minamata?
Chemical factory in Japan dumped
inorganic mercury salts into the bay.
Converted to MeHg by bacteria,
biomagnification in fish.
The Minamata residents eat a lot of
fish.
Because the conversion to MeHg
wasn’t understood yet, it was
originally thought to be a new
disease.
what are the symptoms of Minamata disease?
Symptoms:
- Central and peripheral nervous
system degeneration
- Tingling and numbness of limbs
- Impaired motor function
- Impaired vision and speech
in which Canadian province was there a Minamata disease outbreak?
Ontario (near Dryden)
what happened to cause the Ontario Minamata disease?
First Nations communities were impacted by consuming methylmercury
contaminated fish in the late 1960s (2 communities near Dryden).
Mercury contamination was from dumping waste from pulping mills. Over 9000
kg of mercury from 1962 to 1970!
mercury contaminated fish in Ontario in the 1960s… when were provincial officials told about the contamination of the paper mill
1990s, and they kept it secret for decades!!
what happened with the mass mercury exposure in Iraq?
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 and distribution
too late into the growing cycle, which led to it
being consumed instead of being planted.
6,530 patients were admitted to hospital with
poisoning, and 459 deaths were reported
what are the health canada recommendations for fish consumption?
no more than 150g per week of top predator fish (tuna, shark, swordfish, etc.)
what affects mercury levels in Manitoban fish?
dams! water held behind them can accumulate bacteria turning inorganic mercury to organic methylmercury
T/F: Piscivorous fish in Lake Winnipeg have higher Hg levels than ones
that eat invertebrates
true! because Hg bioaccumulates!
what is the latin word for lead?
plumbum
what is atomic number and charge of lead (Pb)?
82
Pb2+
_____ is found in ores with other metals. It can be mined but is often a byproduct
of smelting other metals
Lead
_____ is dense and malleable (used since at least 6500 BC), and is the heaviest non-
radioactive metal
lead
what is the limit set by Health Canada for lead? what can it still be found in?
10 µg/g, still found in some cosmetics!
why was a lot of lead used in gasoline?
Early automobiles used ethanol as an anti-knocking agent in gasoline.
Could not patent this, so wasn’t profitable for corporations.
In 1921, General Motors showed that tetraethyl lead (TEL) could replace
ethanol in this function. This was patented.
by 1936, 90% of all gasoline sold had TEL in it.
in 1972, the EPA indicated that TEL was to be phased out of gasoline. Ethyl
corporation promptly sued, but lost.
In 1979, research was published that showed that even low doses of lead
caused developmental effects (lower IQ ratings) in exposed children. It still
took until 1982 to completely ban it
Exposure to Pb in utero and in childhood can lower IQ due to neurotoxicity… what kind of toxicant can it be called?
teratogen!
T/F: Since the phase out, Pb in the air has decreased
true!
what replaced Pb in gas after it was banned?
Manganese (Mn2+)… specifically MMT
produced by same OG corporation (Afton, formerly Ethyl)
led to increases in atmospheric Mn2+ and Mn2+ in our aquatic systems, and it is known to cause neurotoxicity
still used in small amounts!!!!
what are the 7 other sources of Pb that we encounter? what is our main exposure?
- Old paint
- Old piping
- Batteries
- Glass and ceramics
- Ammunition
- Solder in electronics
- soil and food (main exposure)
Old paint
* ______ was added to oil paints up until the
1970s (10 to 50%)
* Canada Hazardous Products Act (1976)
reduced to max. 5000 mg/kg (0.5%)
* In 2010, this was reduced to 0.009%
Lead
Old piping
* ____ was used as pipes and as solder
joints for brass piping
* ____ pipes phased out in the 1950s, _____
solder joints in 1989
Lead
Batteries
* Most _____ is now used in batteries
lead
what caused the Flint Water Crisis?
switched water supply from Lake Huron to Flint River in 2014 to cut costs, created a public health disaster
what were some of the main symptoms experienced by Flint residents? one in six Flint homes had lead levels above the EPA’s threshold
young children with high blood sugar levels soared
many women couldn’t get pregnant, had miscarriages
how to tell if you have lead vs copper pipes?
lead water pipes are a dull grey colour, if you gently scratch the surface with a coin and it leaves a shiny silver mark… its lead!
T/F: Using Pb in ammunition is
banned in a lot of places
true!
T/F: Lead weights for fishing can be an
issue in aquatic systems. Banned
for use in National Parks in
Canada.
true!
T/F: Researchers found evidence of chronic and
acute lead poisoning in bald eagles. Acute
poisoning may be associated with lead
ammunition during the hunting season
true!
____ disposition:
Absorbed through gastrointestinal tract, lungs, and skin
* Because ___ has similarities to calcium (Ca2+), anybody who is taking up
a lot of calcium can absorb ___ more efficiently in the GI tract
* Growing children absorb 50% of ingested ___ (because of growing bones and such)
* Adults who are well nourished with sufficient calcium levels only take up
10% and retain 5%
Pb2+, lead
distribution of ____:
primarily stored in bones and
teeth (half life 20 years)
We can test our teeth to estimate the ___ exposure we had as children
___ can be bound in red blood cells (half life ~25 days)
Can be stored in muscle (half life 40 days)
Readily crosses the blood brain and placental barriers (2-year half life in
brain)
lead
what are the main toxic effects of Pb on humans?
effects hemoglobin synthesis
can cause neurotoxicity
has lower dose toxicity in children
how does Pb cause neurotoxicity?
acts like Ca2+ in neurons
high doses trigger apoptosis and necrosis in neuronal cells
- inhibits ATP production, inhibits superoxide dismutase (excess ROS)
low doses can interfere with neuronal functions
- inhibit neurotransmission between neurons
- decrease neuron growth and development in young people
in normal neuronal function, Ca2+ movement across the presynaptic terminal causes a release of neurotransmitters, how does Pb2+ change this process?
dampens the signal and fewer neurotransmitters are released
what are the hematological effects of Pb?
Lead inhibits many steps in heme biosynthesis (especially the enzymes ALA
dehydratase and ferrochelatase)
Can result in anemia (insufficient functioning red blood cells to carry O2)
which two enzymes does Pb target in heme biosynthesis?
ferrochelatase
ALA dehydratase
T/F: Inorganic Pb compounds were reclassified in 2010 as probably carcinogenic to humans
false! 2006
_____ has many valence states (3+ and 5+ most common, 3+ being the most toxic).
Usually conjugated with other elements
arsenic (As)
what is the most toxic valence state of As?
Arsenic 3+
____ is usually a natural environmental contaminant and most people are
exposed through drinking water sources
Arsenic (As)
World Health Organization (WHO) recommends a maximum of ______ of
As in drinking water
10 ppb
do hotspots of Arsenic around the world (California, Bangladesh) have more As ppb than reccomended?
yes, much more
California can be 50 ppb
Bangladesh 150 ppb
T/F: Arsenic isn’t used much anymore
true
how was arsenic used? four ways
- Some industrial chemical synthesis uses.
- A component of CCA (Copper, cadmium and
arsenic) treated wood.
- Not commonly used anymore - Older use as a pesticide.
- Used as a poison (Arsenic trioxide).
- White odorless powder that is undetectable in
food while eating it. Symptoms of poisoning
resemble food poisoning, dysentery and cholera.
_____ salts readily absorbed because they
have similarities to phosphate (PO4-).
Arsenic
what does As get methylated in the liver to?
methyl-As, not as toxic as free As
where is Methyl-As excreted?
by kidneys
Mitochondrial respiration poisoning.
* AsO4
3- interferes with ATP synthase. Also inhibits
pyruvate dehydrogenase (entry into the TCA
cycle).
* Death from cardiovascular failure due to
insufficient ATP.
* AsO4
3- replaces S in thiol groups and inhibits
protein functions.
* Also necrosis of GI tract leading to internal
bleeding.
these are all examples of the acute side effects of….
arsenic
Liver injury.
* Cardiovascular disease.
* Neurological disorders and impaired cognitive
development in children.
* Skin cancer
these are all examples of chronic side effects of…
arsenic
The biotransformation of arsenic
generates ROS, which can
damage DNA in two ways, what are they?
direct strand breakage
oxidizing guanine base pairs to form 8-hydroxyguanine
is arsenic carcinogenic?
yes!!
how is arsenic carcinogenic?
Fatal skin cancers are the most common
mode of lethality for chronic As poisoning
* Also cancers of liver, lung, bladder
______ ______ can control whether genes are expressed or not independent of the genetic
sequence. Many are dependent on _______ (SAM) to donate a methyl group to
methylate DNA and other molecules, which can affect gene expression. Methylation of As may deplete the SAM pool, which thus alters the epigenetic regulation of genes that are important in
carcinogenesis
Epigenetic factors
S-adenosyl methionine
Food, beverages (often the containers) and drinking water (___ in pipes)
are common routes of exposure for _____ in humans.
copper (Cu)
where is Cu also produced?
Produced in industrial and mining activities
____ is a common pollutant in aquatic systems, highly toxic to aquatic organisms
copper (Cu)
what metal threatens the proposed pebble mine in Alaska?
Cu
it could potentially impact the sockeye salmon fishery in Bristol Bay
55% to 75% of oral dose of ____ is absorbed from the GI tract
Cu
In mammals, major route of excretion of ____ is via feces
Cu
Biliary secretion, enterohepatic recirculation, and intestinal
reabsorption maintain ____ homeostasis
Cu
we need to keep some around for homeostasis!
T/F: Cu is not essential in small amounts
false!
Excess oral ____ intake leads to gastrointestinal distress (nausea,
vomiting, and abdominal pain)
Cu
Ingestion of large amounts of _______ can lead to liver necrosis
and death
Cu salts
_____ _______: genetic disorder characterized by excessive
accumulation of Cu in the liver, brain, kidneys, and cornea. Impaired
biliary excretion of Cu increases chances for liver failure or liver
cancer.
Wilson Disease
what are the three main mechanisms of Chronic Cu toxicity in aquatic vertebrates?
- Oxidative Stress:
Primary driver of chronic Cu toxicity.
Leads to cellular damage. - Bioenergetic Effects:
Impaired energy metabolism leads to growth and
reproductive issues. - Disruption of ion regulation:
Indirect driver of chronic toxicity.
Inhibition of sodium uptake.
____ impairs neuromast formation in
the lateral line which leads to
reduced ability to orientate in a current), causes disorientation in water
Cu
_____ induces apoptosis in olfactory
sensory system.
Impairs ability to “smell” which is
important for migrations and
avoiding predators
Cu
_____ is a major contaminant of gold mining.
Canadian companies own
mines worldwide!
As
____ is a major contaminant of coal mining.
Can lead to developmental
issues in fish
Se
