(coal, gasoline etc) Metal refining. Welding ... not

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Pb Toxicity

• Leaded gasoline, paint, pb pipes
• Pb affects nervous system, Heam biosynthesis and
  Kidney
• Children are at high risk
• Poor blood brain barrier
• Absorb 30-40 of ingested Pb ( PbCa)
• Decreased iq tests at very low levels of Pb
• 10-20ug/dL

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Nervous system affectsAdults

• Adult have well developed BB barrier absorb 7 of
  ingested Pb and it affects primarily the
  periferal nervous system
• Destroys myelin coating on nerves ( insulation
  like a wire) affects the conduction velocity of
  nerves( segmental demyelination, widening of
  nodes of ranvier)

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Nervous system effects in Children

• Inorganic Pb goes to the CNS and decreases IQ
  test scores and other subtle effects.
• Children absorb more Pb because of Ca and growth
  phase
• Most important effects on CNS and they occur at
  low levels in children( why Pb was banned from
  gasoline)

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Effect On Heam Biosynthesis

• ALA dehydratase is the rate Limiting enzyme in
  the biosynthesis of Haem
• Enzyme has Fe binding site and it is very
  sensitive to inhibition by Pb
• Inhibition by Pb results in porphyrin buildup in
  the blood and in the urine ( depending upon the
  degree of inhibition urine may be brown or black)
• Inhibition of ALA dehydatase may be used as a
  biomarker of Pb exposure

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Renal effects of Pb

• Usually in adults results in a fanconi syndrome
  and leakage of phosphate and other nutrients in
  the urine
• Effects are reversible if stop Pb exposure as are
  the effects of Pb on nerve conduction and Heam
  biosynthesis

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Blood levels and toxicity

• Pb blood levels indicate relatively recent
  exposure ( range from 1-20 ug/dL, with gt20
  dangerous for children, gt50 adult toxicity)
• Pb redistributes to the bone and behaves Like Ca
  ( Ca and phosphate mobilization can mobilize Pb,
  results in episodes of toxicity)
• Half life of Pb in bone maybe 10 years and can
  cause formation of pb lines in bones

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Treatment of Pb Poisoning

• Treat symptoms and try to lower Pb levels in
  blood and urine. Renal. Nueral and Haem effects
  are reversible
• Chelating agents
• EDTA ( iv)
• DMCA ( oral)

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Other toxicities of Pb

• Carcinogenic in rats at high doses induces renal
  cancers ( may be due to Pb inclusion bodies)
• Slightly mutagenic binds to S, and O groups very
  similar to Ca and antagonizes Ca action
• Teratogenic

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Arsenic

• Ancient poison with medicinal uses in treatment
  of syphilis and psyriasis
• Current usage in premyeolocytic leukemia
  treatment ( causes cancer cells to differentiate
  and undergo apoptosis)
• Natural sources Of As in drinking water and in
  coal have caused massive poisonings in Bangladesh
  and in China

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Intake of As

• Well absorbed at all sites of entry (ingestion is
  usually the most important way we get exposed to
  As)
• Shell fish have high levels of As ( clams,
  muscles) but it is not bioavailable
• Drinking water standards are now 50 ppb and are
  going to be lowered to 5 ppb one of the lowest
  level for any toxic chemical
• Vermont and New Hampshire have high levels of As
  in their drinking water

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Distribution of As

• Following ingestion As accumulates at very high
  levels in hair, skin and nails. ( due to
  sulphydryl containing protein keratin)
• Also penetrates to most other organs
• Two forms of As ( trivalent arsenite and
  pentavalent arsenate)
• Arseante looks like Phosphate but is converted by
  reduction in the body to arsenite

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Major Toxicity of As

• Skin and Lung Cancer ( skin cancer by ingestion
  and lung cancer by inhalation)
• Well established human carcinogen but poor animal
  models for cancer induction
• UV plus As works in hairless mice
• Damages the capilleries and causes skin rashes
  and dark looking skin
• Liver and Renal toxicity as well

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Enhancement of UVR-induced Skin Tumorigenesis by
Sodium Arsenite (Tumor Yield)
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UVR Arsenite
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Tumor Yield (tumors/mouse)
4
2
UVR alone
0
5
10
15
20
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0
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Elapsed Time (Weeks)
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Mechanism of As toxicity

• Trivalent As binds to Lipoic Acid and inhibits
  glycolysis
• Pentavalent As which looks like phosphate
  uncouples oxidative phosphorylation in the
  mitochondria and destoys aerobic ATP formation
• Arsine gas AsH3 garlic odor very toxic

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Effect of As on Cell SignallingMechanism of
Carcinogenesis

• As causes cancer at low concentrations ( lt1uM)
  and is usually at nM levels in blood
• It has been postulated that it may deplete SAM
  but mole for mole this is not possible
• Most likely explanation is that it affects
  signalling pathways and causes a build up of
  Cyclin D1 which increases cell proliferation in
  the skin

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Treatment of As poisoning

• Acute and chronic Toxic effects are treated with
  Dimercaprol (BAL)
• One does develop tolerance to As exposure in fact
  certain populations in South America can
  tolerated very High levels of As in the drinking
  water ( levels that would produced severe toxic
  responses if we drank this water.

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Hg Toxicity ( Introduction)

• Three forms of Hg with very different toxicities
  ( Inorganic Hg, Organic Hg and Hg Metal)
• Hg metal ( thermometers, Mining smelting,
  electrodes for electrolysis)
• Organic Hg ( Fungicide, chemical industry)
• Inorganic Hg ( fur cutting, felt hat manufacture)

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World Wide Poisoning

• Most of the Environmental levels Of Hg come from
  natural sources ( valconos etc)
• Swordfish accumulate Hg and they had higher
  levels 100 years ago than today
• Metallic Hg ( dental fillings)
• Methyl Hg ( Minimatta bay, IraQ)

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Toxicity Of Hg

• Inorganic ( effects mainly the Kidney)
• Methyl Hg ( CNS effects sensory input loss of
  hearing, periferal vision delayed onset of
  symptoms may be related to cellular conversion of
  Methy Hg to Inorganic Hg
• Metallic Hg ( psychiatric effects, fine motor
  trembling in lips and hands, depression,
  excessive shyness withdrawal from society)

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Mechanism of toxicity

• Inorganic Hg binds to SH groups in cells and
  Inactivates enzymes ( inactivation of enzymes
  that protect the cell from oxidative stress SOD,
  Catalase)
• Methyl Hg penetrates all cells in the body
  particularly the CNS and over time inorganic Hg
  is formed
• Hg metal may also form inorganic Hg and it also
  can penetrate many strauctures

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Treatment of Hg toxicity

• Bal Or Pen for Inorganic Hg and methyl Hg
• Methyl Hg delayed onset of symptoms can confirm
  exposure by Hair measurements
• Death Of Karen Wetterhahn

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Chromate

• Chromium exposure occurs in welding, anti-rust,
  superfund sites, Cr mine tailings
• Many environmental exposures (Erin Brokovitch)
• Two forms with very different Toxicity ( Cr III
  and Cr VI)
• CrVI looks like Phosphate ( trojan horse)actively
  taken up into cells
• Cr III nutritional no upatake ( Cr picolinate)

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Toxicity of Chromate

• Contact dermitis, nose bleeding, Chrome holes in
  nose, liver damage ( since it resembles phosphate
  and sulphate it goes to all cells of the body
• Cancer
• Epidemiological studies lung cancer but can cause
  cancer in almost every cell

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Mechanism of Cr Toxicity

• CrVI is taken up into the cells by active
  transport and is converted to Cr III plus oxygen
  radicals which damage protein and DNA
• DNA damage involves actually adducts of Cr III
  bound to DNA
• DNA protein crosslinks, DNA-DNA crosslinks

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BIOMARKERS OF CHROMATE (VI) EXPOSURE AND
EFFECT 1) Cr in red blood cells (Exposure) 2)
DNA-protein crosslinks (EDTA) (Exposure and
Effect) 3) UvrABC/mapping Cr adducts with
ligation-mediated PCR (Exposure and
Effect) 4) Amino acid/GSH, Cr(III) DNA adducts
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Example of drinking water standard

• At 500 ppm CrVI induces 1-2 mice more than
  controls to develop cancer ( 1 cancer incidence)
  
• Acceptable cancer risk is 1X106- so from risk of
  .01 to risk of .000001 divide by 10,000 and you
  get 50 ppb the current drinking water standard

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Nickel

• Exposure occurs in Ni refining, plating and
  welding
• Most important toxicity is contact dermititis a
  and lung and nasal cancer
• Ni(CO)4 is a gas and the most toxic compound
  known to man causes lung injury and death no good
  antidote ( Diethyldithiocarbamate)

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Cadmium

• Batteries, Solder,electroplating
• 6-10 absorbed and stored in liver and kidney (
  very long half life in body 20 years)
• Itai Itai disease ( skeletal malformations,bone
  fractures)
• Major toxicity is Kidney damage, testicular
  cancers and Lung cancers

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Mechanism of Cd Toxicity

• Signal transduction ( many of the toxic effects
  of Cd can be attributed to cell Signalling)
• Cd interacts with Zn binding sites and can
  inactivate enzymes
• Binds to Protein SH groups

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Other Metals

• Mn ( essential but at high doses produces a
  Parkinsonian type syndrome ie difficulty walking,
  speech disturbances, and causes decrease in
  levels of brain dopamine and serotonin treat with
  L-
• dopa
• Be ( fluorescent lamps, nuclear reactor
  linings,neon signs, causes Berrylium disease a
  delayed onset ( 1-20 years) immunological lung
  injury, lung cancer, skin lesions ( delayed onset)

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Other metals Continued

• Vanadate ( catalysts ocupational exposure, may
  be essential but difference between essential
  levels and toxic levels is very small)
• Primarily nuerotoxic affects vasomoter and
  intercardiac nerves convulsion, respiratory
  problems by Inhalation 2 absorbed by ingestion
  goes to soft tissue and bone( 50)
• Mechanism involves inhibition of Phospatases