Metal Compounds Toxicity of Various Metal Compounds.

Metal Compounds

Toxicity of Various Metal Compounds

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.

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.

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

INDIVIDUAL METALS

Mercury

Three Forms of MercuryElemental, Inorganic, Organic Hgo (elemental mercury) Hg+ (mercurous inorganic

mercury) Hg++ (mercuric inorganic

mercury) Methylmercury and

dimethylmercury (organic forms)

Global Sources and Distribution of Mercury The major natural source of

mercury is the natural degassing of the earth’s crust – Volcanic Activity.

  Human Activity Source: Fossil

fuels (especially coal) may contain as much as 1 ppm of mercury.

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.

Sources (Continued) Methylation of mercury is

accomplished by anaerobic bacteria in the aquatic environment.

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%).

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.

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.

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

Toxicity Mercury vapor and methylmercury

affect the CNS  Inorganic mercury affects kidney  Toxicity occurs at much lower

levels in the fetus than in adults.

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.

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.

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.

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.

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.

Human Exposure To Methlymercury Minamata Japan

Iraq

Seychelle Islands

INDIVIDUAL METALS

Arsenic

Forms of Arsenic Found as As+3 or As+5

The most common As+3 inorganic forms are arsenic trioxide, sodium arsenite, and arsenic trichloride.

The most common As+5 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.

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.

Toxicokinetics Exposure is through inhalation,

drinking water, and soil Almost complete absorption from

G.I. Tract

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.

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).

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.

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.

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.

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.

Cancer Effects (Continued) Several studies suggest that As +3

compounds are capable of producing chromosome breaks.

Individual Metals

Lead

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

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

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.

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

Distribution > 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

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

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

Heme Synthesis Inhibition Pb inhibits heme synthesis at

several key points in pathway Aminolaevulinate synthetase Aminolaevulinate dehydrase Ferrochelatase Haem oxidase Coproporphyronogen oxidase

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.

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

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.

Individual Metals

Cadmium

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

Absorption Airborne exposure in workplace Shellfish accumulate Cd from

water Cigarette smoke Oral absorption is low Inhalation absorption is high

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

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

Toxicity (Continued) Carcinogen

Lung cancer Testicular cancer Prostate cancer

Individual Metals

Tin

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

Individual Metals

Selenium

General Issues Selenium is a required metal for

humans at low doses Selenium can be toxic at high

doses Embyotoxic and teratogenic to

animals