Metal Compounds

1
Metal Compounds

• Toxicity of Various Metal Compounds

2
General Issues

• About 80 of the 105 elements in the periodic
  table are regarded as metals fewer than 30 have
  been reported to produce toxicity.
•  Metals are distributed naturally in the
  environment by both geologic and biologic cycles.
•  A critical determinant of the metabolism and
  toxic behavior of a metal is its biological
  half-life. The half-life of cadmium and lead are
  20 to 30 years whereas for metals such as
  arsenic, cobalt, and chromium it is a few hours
  to a few days.

3
General Issues (Continued)

• Cellular targets for toxicity are specific
  biochemical processes (enzymes) and/or membranes
  of cells and organelles.
•  Alkyl compounds (organic compounds) are lipid
  soluble and pass readily across biological
  membranes, and they are only slowly dealkylated
  to inorganic salts. Hence their excretion tends
  to be slower than inorganic forms and the pattern
  of toxicity tends to be different from inorganic
  forms.
•  Ex. Methylmercury is primarily a neurotoxin
  while mercuric chloride is toxic to the kidneys.

4
General Issues (Continued)

• FACTORS INFLUENCING THE TOXICITY OF METALS
• Interactions with essential metals
• Formation of metal-protein complexes
• Age and stage of development
• Lifestyle factors
• Chemical form or speciation
• Immune status of host

5
INDIVIDUAL METALS

• Mercury

6
Three Forms of MercuryElemental, Inorganic,
Organic

• Hgo (elemental mercury)
• Hg (mercurous inorganic mercury)
• Hg (mercuric inorganic mercury)
• Methylmercury and dimethylmercury (organic forms)

7
Global Sources and Distribution of Mercury

• The major natural source of mercury is the
  natural degassing of the earths crust Volcanic
  Activity.
•  
• Human Activity Source Fossil fuels (especially
  coal) may contain as much as 1 ppm of mercury.

8
Sources (Continued)

• Metallic mercury in the atmosphere represents the
  major pathway of global transport of mercury.
  Metallic mercury may be oxidized to mono or
  divalent mercury in the presence of organic
  matter.
• Residence time of Hg vapor in the air is 0.4 to
  3.0 years, global distribution. Hg is removed
  from air by dry and wet deposition so therefore
  it is deposited onto land and water by rain.

9
Sources (Continued)

• Methylation of mercury is accomplished by
  anaerobic bacteria in the aquatic environment.

10
Toxicokinetics

• Metallic mercury volatilizes to mercury vapor and
  most human exposure to metallic mercury is by
  inhalation. This vapor is lipid soluble.
• G.I. tract absorption of inorganic mercury salts
  from food is low (7 15) whereas absorption of
  methylmercury from G.I. tract is high (90 95).

11
Toxicokinetics (Continued)

• The kidney contains the greatest of mercury
  following exposure to inorganic mercury and
  mercury vapor, whereas organic mercury has a
  greater affinity for the brain.
• Excretion is mainly by the biliary route with
  enterohepatic recirculation in the case of
  methylmercury.

12
Toxicokinetics (Continued)

• Methylmercury, can cross the placenta to the
  fetus and additional mercury exposure can occur
  during nursing since methylmercury is also found
  in milk at 5 of maternal blood.
• Biological half-life is about 70 days for
  methylmercury and about 40 days for inorganic
  forms.

13
Cellular Targets

• has a particular affinity for compounds
  containing sulfhydryl groups
• affects enzyme systems in microsomes and
  mitochondria
• becomes localized in lysosomes of kidney cells

14
Toxicity

• Mercury vapor and methylmercury affect the CNS
•  
• Inorganic mercury affects kidney
•  
• Toxicity occurs at much lower levels in the fetus
  than in adults.

15
Mercury In Fish

• Methylmercury is produced both in the sediment
  and in the water column by methylation of Hg by
  microbes.
• Fish obtain methylmercury from their diet and, to
  a much lesser extent, from the water passed over
  the gills. Diet accounts for 90 of uptake.
• Assimilation efficiency for dietary uptake is 65
  80 or greater. 7 12 assimilation
  efficiency across gills.

16
Mercury In Fish (Continued)

• Feeding habits and food-chain structure
  influences methylmercury uptake in fish.
• Get biomagnification of methylmercury
  progressively increases from primary producers to
  fish. Piscivorous fish have greater than
  fish of lower trophic levels. Lake trout have a
  greater of methylmercury when forage fish
  are present versus invertebrates.
• Fish from smaller, warmer lakes also have greater
  s.

17
Mercury In Fish (Continued)

• The of methylmercury in fish increases with
  increasing age or size of fish.
• Acidic bodies of water have greater methylmercury
  production.
• Fish from newly flooded reservoirs have high s
  of methylmercury.

18
Mercury In Fish (Continued)

• Nearly all of the mercury in fish is
  methylmercury (95 99).
• The greatest amount of mercury in the body of a
  fish is found in the skeletal muscle even though
  mercury is at a lower in skeletal muscle than
  in brain.

19
Mercury In Marine Mammals

• Marine mammals store the majority of mercury in
  the inorganic forms because they have a very good
  ability to demethylate organic mercury within
  their bodies.
• Transfer to fetus is low because only
  methylmercury is able to cross the placenta.

20
Human Exposure To Methlymercury

• Minamata Japan
• Iraq
• Seychelle Islands

21
INDIVIDUAL METALS

• Arsenic

22
Forms of Arsenic

• Found as As3 or As5
• The most common As3 inorganic forms are arsenic
  trioxide, sodium arsenite, and arsenic
  trichloride.
• The most common As5 inorganic forms are arsenic
  pentoxide, lead arsenate, and calcium arsenate.
• Organic forms may be 3 or 5 As and may occur as
  methylated forms due to methylation by organisms
  in soil, fresh water, and sea water.

23
Forms (Continued)

• Trivalent forms of As are the principal toxic
  forms. Pentavalent forms generally have little
  or no effect.
• However, 5 forms can be converted to 3 forms in
  vivo.

24
Toxicokinetics

• Exposure is through inhalation, drinking water,
  and soil
• Almost complete absorption from G.I. Tract

25
Toxicokinetics (Continued)

• Excretion of inorganic forms is largly through
  the urine. Methylated forms have a longer
  half-life. Methylated forms seem to be a
  detoxification product with dimethyl-As the
  principal detox product.
• As also has a predilection for skin and is
  excreted by desquamation of skin and in sweat,
  particularly during periods of profuse sweating.

26
Toxicokinetics (Continued)

• Also concentrates in nails and hair.
• Human milk contains some As and As can be
  transferred across the placenta ( in fetal
  blood same as maternal blood).

27
Cellular Targets

• Sulfhydryl-containing proteins and enzymes
  systems are altered by exposure to As compounds.
• Affects mitochondrial enzymes. Mitochondria
  accumulate As. Succinic dehydrogenase activity
  is inhibited and oxidative phosphorylation is
  uncoupled.
• As chelates with alpha-lipoic acid forming a
  ring-like structure. Alpha-lipoic acid is an
  essential cofactor for pyruvate dehydrogenase, an
  enzyme required for energy production in the
  Krebs Cycle.

28
Cellular Targets (Continued)

• Some As forms mimic the phosphate anion in cells.
  Substitution of As for phosphate would disrupt a
  number of metabolic reactions that require
  phosphorylation.

29
Noncancer Effects

• Large doses (70 180 mg) can be fatal. Acute
  effects sensory loss in peripheral nervous
  system (degeneration of axons).
• Chronic exposure to inorganic As leads to
  neurotoxicity of both the peripheral and central
  nervous systems.
• Liver injury is also characteristic of chronic
  exposure.

30
Cancer Effects

• Skin cancer. Hyperpigmentation and
  hyperkeratosis. Basal cell carcinoma and
  squamous cell carcinomas.
• Occupational exposure to airborne As may be
  associated with lung cancer. The time period
  between initiation of exposure and occurrence of
  As-associated lung cancer is on the order of 34
  to 45 years.

31
Cancer Effects (Continued)

• Several studies suggest that As 3 compounds are
  capable of producing chromosome breaks.

32
Individual Metals

• Lead

33
General Issues

• Lead is the most ubiquitous metal
• Most susceptible populations are children,
  particularly toddlers, infants in neonatal
  period, and fetus
• There is no demonstrated biological need for lead

34
Intake of Lead

• Oral absorption
• Food
• Lead based indoor paint
• Contaminated drinking water
• Hand to mouth activity in children
• Lead-glazed pottery
• Inhalation absorption
• Lead dust from environmental sources
• Air from lead-containing industrial/auto emissions

35
Intake of Lead (Continued)

• Dietary intake has decreased dramatically since
  the 1940s (400 500 ug/day) to present (20
  ug/day) in US.
• Since the introduction of lead-free gasoline in
  US, airborne exposure from auto exhaust in
  minimal.

36
Absorption

• Adults absorb 5 to 15 of ingested lead and
  usually retain less than 5 of that absorbed
• Children absorb 40 of ingested lead and retain
  about 32 of that absorbed
• About 90 of inhaled lead is small enough to be
  retained in alveoli and get 100 absorption

37
Distribution

• gt 90 of the Pb in the blood is in the red blood
  cells (RBCs)
• One compartment is the RBC membrane
• Second compartment is hemoglobin
• Redistribution of Pb from blood to skeleton with
  half-life of 20 years
• Pb crosses placenta to fetus to match levels in
  maternal blood

38
Toxicity of Lead

• Neurotoxicity
• Significant affect on timing of cell-to-cell
  connections get modified neural circuits in
  central nervous system
• Demyelination and axon degeneration in peripheral
  nervous system
• Interference with synaptic transmissions Pb
  substitutes for Ca at synapse

39
Toxicity (Continued)

• Hematological Toxicity
• Anemia
• Fragile RBC membrane shortens RBC lifespan
• Impairment of heme synthesis
• Effects on myoglobin and CYP
• Myoglobin and CYPs also contain heme

40
Heme Synthesis Inhibition

• Pb inhibits heme synthesis at several key points
  in pathway
• Aminolaevulinate synthetase
• Aminolaevulinate dehydrase
• Ferrochelatase
• Haem oxidase
• Coproporphyronogen oxidase

41
Heme (Continued)

• Significant inhibition of amionolaevulinate
  dehydrase is detectable in people with Pb blood
  levels of 0.4 ug/ml, which results from normal
  exposure to the urban environment.

42
Toxicity (Continued)

• Renal Toxicity
• Acute exposure can cause reversible renal damage
• Chronic exposure causes permanent renal damage.
  Get impaired ATP production in mitochondria of
  proximal tube cells of nephron

43
Toxicity (Continued)

• Organic Lead (tetraethyl Pb) is lipid soluble,
  targets brain of developing fetus resulting in
  Encephalophathy
• Organic Lead does not effect heme synthesis or
  kidney.

44
Individual Metals

• Cadmium

45
General Issues

• Cadmium is a modern toxic metal industrial use
  was minor until about 60 years ago
• Use today is in electroplating, color pigments in
  paints, batteries

46
Absorption

• Airborne exposure in workplace
• Shellfish accumulate Cd from water
• Cigarette smoke
• Oral absorption is low
• Inhalation absorption is high

47
Distribution

• In blood, binds to RBCs and to plasma proteins
  (particularly albumin)
• 50 to 75 of body burden is in liver and kidneys
• Half-life is 30 years

48
Toxicity

• Pulmonary, Renal, and Bone Toxicity
• Damage to alveolar macrophages which release
  enzymes that damage alveolar basement membranes
  fibrosis
• Cd-Metallothionein Renal toxicity
• Cd-Metallothionein Reproductive Protection
• Cd replaces Ca in bone Itai-Itai disease

49
Toxicity (Continued)

• Carcinogen
• Lung cancer
• Testicular cancer
• Prostate cancer

50
Individual Metals

• Tin

51
Toxicity of Tin Compounds

• Organic tin compounds are potent neurotoxins
• These compounds are often used as anti-fouling
  paints on boats and ships
• Compounds are also involved as endocrine
  disrupting compounds

52
Individual Metals

• Selenium

53
General Issues

• Selenium is a required metal for humans at low
  doses
• Selenium can be toxic at high doses
• Embyotoxic and teratogenic to animals