Lecture 9: Metal toxicity part II

Question 1

Lead

Answer 1

is found in ores with other metals. It can be mined but is often a byproduct of smelting other metals.

It’s dense and malleable (shape in into various forms) , and is the heaviest non-radioactive metal.

Question 2

What is Pb used for?

Answer 2

• Humans have been using Pb for a long time
• Used as a malleable metal since at least 6500 BC in Turkey
• The Romans used a lot of Pb to make all their plumbing and much of their dishware. They even added powdered Pb to wine as a sweetener.

• Kohl is a mixture of lead sulfide and other resins that is used as a mascara developed in Egypt ~3100 BC.
– It is still used today in some cultures… but not all preparations have Pb in them.
• But Pb can still show up in make up.

Question 3

What is route of exposure to lead?

Answer 3

from food or what we drink

Question 4

What is the limit set by Health canada for lead?

Answer 4

Limit set by Health Canada is 10 μg/g

Question 5

Explain how lead was used in gasoline

Answer 5

A lot of lead was used in gasoline
– Early automobiles used ethanol as an anti-knocking agent (allowed engine to run smoother and quieter) in gasoline. Could not patent this, so wasn’t profitable for corporations.

In 1921, Thomas Midgley at General Motors showed that tetraethyl lead (TEL) could replace ethanol in this function. This was patented.
– DuPont chemical owned 30% of GM and made the compound.
– They just named it ‘ethyl’ because issues with lead toxicity was already publicly known.

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.

Question 6

tetraethyl lead (TEL)

Answer 6

replaced ethanol in gasoline as an anti knocking agent
This was patented.
They just named it ‘ethyl’ because issues with lead toxicity was already publicly known.

Question 7

What did research in 1979 show?

Answer 7

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…

Question 8

what kind of toxicant can lead be called?

Answer 8

teratogen

Exposure to Pb in utero and in childhood can lower IQ due to neurotoxicity.

Question 9

What has happened since Pb has be phased out?

Answer 9

Pb in the air has decreased.

Question 10

What are Other sources of Pb that we still encounter?

Answer 10

1. Old paint
   • Lead 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%
2. Old piping
   • Lead was used as pipes and as solder joints for brass piping
   • Lead pipes phased out in the 1950s, lead solder joints in 1989
3. Batteries
   • 88% of lead now used is in batteries
4. Glass and ceramics
5. Ammunition
6. Solder (electronics)
7. Soil and food (main exposure source)

Question 11

Explain how Pb can be found in ammunition and cause toxic effects

Answer 11

At a high enough level lead can be detected in animals
if you go shoot an animal and don’t properly get rid of all the shells/ lead in the bullets we can eat it
if animals are picking it up from the environment and its accumulating in their muscle tissue which is what we eat that is another source of lead toxicity

Question 12

Describe the study of bald eagles

Answer 12

Researchers found evidence of chronic and acute lead poisoning in bald eagles. Acute poisoning may be associated with lead ammunition during the hunting season.
bald eagles also eat other animals

Question 13

What was compared in the bald eagles to determine acute and chronic exposure?

Answer 13

compared lead levels in the blood which is more indicative of acute exposure
compared lead levels in bones which indicates chronic exposure bc it takes Pb longer to accumulate in the bones

Question 14

Describe the Flint water crisis

Question 15

Trihalomethanes

Answer 15

disinfectant by product; formed by reaction of chlorine (added to disinfect water) with organic matter

Question 16

orthophosphates

Answer 16

are added to water to reduce the amount of lead leaching into it from pipes

Question 17

What happened to fertility rates in Flint Michigan?

Answer 17

very dramatic drop in fertility rates after switching to lead pipes

Question 18

How to identify lead pipes vs copper pipes

Answer 18

lead water pipes; are usually a dull gray colour
you can confirm its a lead pipe by scratching the pipe and it will leave a shiny silver mark

copper pipes; usually bronze bright or dark orange colour
- scratching with a coin will leave a faint bronze coloured mark

Question 19

What is the amount of allowable lead in drinking water?

Answer 19

0.005 mg/L

Question 20

Describe how Pb gets absorbed in the body?

Answer 20

• Because Pb2+ has similarities to calcium (Ca2+), anybody who is taking up a lot of calcium can absorb lead more efficiently in the GI tract
• Growing children absorb 50% of ingested lead (because of growing bones and such)
• Adults who are well nourished with sufficient calcium levels only take up 10% and retain 5%

Question 21

Describe how Pb gets distributed in the body

Answer 21

• Again because of Ca2+ similarities, Pb is primarily stored in bones and teeth (half life 20 years)
• We can test our teeth to estimate the Pb exposure we had as children
• Pb 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)

Question 22

How does Pb cause neurotoxic affects?

Answer 22

Mostly based upon the ability of Pb2+ to act like Ca2+ in neurons

Question 23

At high doses Pb:

Answer 23

• High doses enough to trigger apoptosis and necrosis in neuronal cells

• Triggers the ‘high intracellular Ca2+’ response
• Inhibits ATP production in the mitochondria
• Inhibits superoxide dismutase activity, exacerbating ROS generation

Question 24

At low doses Pb:

Answer 24

Low doses can interfere with all sorts of neuronal functions

• Inhibits neurotransmission between neurons
• Decrease in neuron growth and development in the young

Question 25

Describe how Pb affects neuronal function

Answer 25

1. Ca2+ movement across the nerve axon is part of the transmission of the signal
2. This causes a release of neurotransmitters into the synaptic cleft to propagate the signal to the next neuron

Internal Pb2+ dampens the signal and fewer neurotransmitters are released

• if lead is in the system it can interfere with the electrochemical gradient
• having to much near neurons can interfere with ability to release neurotransmitters

Question 26

Heme biosynthesis

Answer 26

• Lead inhibits many steps in heme biosynthesis (especially ALA dehydrogenase
and ferrochelatase)
• Can result in anemia (insufficient functioning red blood cells to carry O2)

Question 27

Heme

Answer 27

involves in binding O2 and distributing it thru the body

Question 28

Carcinogenicity

Answer 28

Inorganic Pb compounds were reclassified in 2006 as probably carcinogenic to humans.

Answer 29

– The compound Manganese (Mn2+) was then used as an additive to gasoline.
• Actually, Methylcyclopentadienyl manganese tricarbonyl (MMT) was added
– Produced by the company Afton Chemical Corporation (Afton), formerly known as the Ethyl Corporation…
– This led to increases in atmospheric Mn2+ and Mn2+ in our aquatic systems, and it is a known neurotoxin…
– Now new additives are being used even though MMT is still used in small amounts.

Question 30

Arsenic

Answer 30

Many valence states (3+ and 5+ most common, 3+ being the most toxic).
Usually conjugated with other elements.
usually a natural environmental contaminant

Question 31

How are people exposed to arsenic?

Answer 31

most are exposed through drinking water sources

Question 32

dermatitis

Answer 32

caused by chronic exposure to As (but most often on feet and hands)

Question 33

What are the uses of arsenic?

Answer 33

1. Some industrial chemical synthesis uses.
2. A component of CCA(Copper,cadmiumand arsenic) treated wood.
   - Not commonly used anymore
3. Older use as a pesticide.
4. Often 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.

Question 34

Disposition of arsenic

Answer 34

• Arsenic salts readily absorbed because they
  have similarities to phosphate (PO4-).
• Gets methylated in liver to methyl-As, which is not as toxic as free As.
• Methyl-As excreted by kidneys.

Question 35

Acute effects of Arsenic

Answer 35

• Mitochondrial respiration poisoning.
• AsO43- interferes with ATP synthase. Also inhibits
pyruvate dehydrogenase (entry into the TCA cycle).
• Death from cardiovascular failure due to insufficient ATP.
• AsO43- replaces S in thiol groups and inhibits protein functions.
• Also necrosis of GI tract leading to internal bleeding.

Question 36

Chronic effects of arsenic

Answer 36

• Liver injury.
• Cardiovascular disease.
• Neurological disorders and impaired cognitive
development in children.
• Skin cancer.
Arsenic-induced skin lesions.

Question 37

How does As damage DNA

Answer 37

The biotransformation of arsenic generates ROS, which can damage DNA in two ways:
a.) direct strand breakage
b.) oxidizing guanine base pairs to form 8-hydroxyguanine
When repaired these types of DNA damage can induce mutations.

Question 38

How is As carcinogenic

Answer 38

• Fatal skin cancers are the most common mode of lethality for chronic As poisoning
• Also cancers of liver, lung, bladder
• messing with methylation of the genome to much of SAM is donating methyl groups to AS

Question 39

Epigenetic factors

Answer 39

can control whether genes are expressed or not independent of the genetic sequence. Many are dependent on S-adenosyl methionine (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.

Question 40

Arsenic is a ___________ of ___mining.

Answer 40

Arsenic is a major contaminant of gold mining.

Question 41

What are common routes of exposure for Cu in humans

Answer 41

Food, beverages (often the containers) and drinking water (Cu in pipes) are common routes of exposure for Cu in humans

Question 42

Where is copper produced?

Answer 42

Produced in industrial and mining activities as well.
• Common pollutant in aquatic systems, highly toxic to aquatic organisms.
– One of the concerns of the proposed pebble mine in Alaska.
– Potentially impact the Bristol Bay sockeye salmon fishery
• Annually brings in ~$300 million, employs ~11000 people, feeds millions

Question 43

Describe how copper is lethal to fish

Answer 43

Can be very acutely lethal for fish with LC50’s in fresh water as low as in the μg/L range.
Can have dramatic sub- lethal effects as can impair olfaction in fish… So the fish can’t “smell” (olfaction needed for migration and for avoiding predators – really important for salmon)