HEAVY METALS AND HEAVY METAL ANTAGONISTS

Metals - major fraction of Periodic Table

- wide range of effects

1. Physical states - solids, liquids, gases aerosols

2. Elements - indestructible

3. Electrophyllic cations - react with ligands reversible complexes molecular mimicry

4. Oxidation States affects toxicity

5. Organometallic compounds differ from inorganic

6. Essential versus non-essential

LEAD

Environmental

1. Combustion of tetramethyl in gasoline

2. Persistent lead-based paint (children with Pica)

3. Improperly glazed earthenware

4. Lead piping (acid rain)

5. Solder in food containers

6. Moonshine whiskey

7. Automobile battery casing

Occupational

1. Smelters (air concentration may exceed 1000g/m3)

2. Storage battery manufacture (50% total U.S. consumption)

3. Welding and cutting lead-painted structures

4. Automobile radiator repair

5. Production of lead-based paints (6% total U.S. consumption)

6. Frequent use of firearms

Total U.S. Annual Consumption 1.3 x 106 metric tons

"Never use water which has stood in a lead pipe over night"

"Water boiled in galvanized iron becomes poisonous, and cold water passed through zinc lined pipes should never be taken from hot water pipes".

"Never keep vinegar or yeast in stone crocks or jugs; their acid attacks the glazing, which is said to be poisonous".

 From a Cook Book published in 1890, Bell and Co, Philadelphia and Chicago

1. Absorption:

Gastrointestinal Tract 8% absorbed (adult)

50% absorbed (children)

Ca++, Fe++ decrease absorption

Respiratory Tract Particle size

Chemical form

Skin Does occur at high exposures

Lipid soluble, volatile

Well absorbed in lung, across skin

Crosses blood-brain barrier

Metabolized to trialkyl Pb

(ALK)3PB+ is toxic species

1. Acute - (high dose, single or short exposure)

a. Nausea, vomiting, abdominal pain

b. Kidney injury (shock)

c. CNS - Insomnia, irritability, anxiety, encephalopathy

2. Chronic

a. Hematologic effects - primary effect on heme synthesis

3. Other effects:

Miscarriages and stillbirths

Lead line (dental hygiene)

Ashen facial color

Renal tumors in animals

1. Symptomatology

2. History of Exposure

3. Blood - lead concentration versus effect

4. Urine

ALA and coproporphryn

CaEDTA Test*

5. X-rays of long bones

*Children

24 hr urine collection

Abnormal urine 500 g/24 hr or 1 g Pb/mg CaNa2 EDTA = blood Pb approx. 55 g/dl

Adults

1 dose, i.v. CaNa2 EDTA

Abnormal urine Pb 350-600 g/24 hr.

Calcium disodium ethylenadiamine tetraacetate (CaNa2EDTA)

Forms soluble filterable complex with Pb++

Excreted in urine

Protocol: Adultsa - i.v. drip 5 hours, twice daily

total daily dose 1 - 2 g for adults, 4-5 days

Childrenb-CaNa2-EDTA + BAL

Kidney injury

loss of zinc

aTreatment when blood 80g Pb/dl

bTreatment when blood 60g Pb/dl

 A. Chemical Form

 Tetramethyl and tetraethyl lead

Tetramethyl lead

 B. Source of Human Exposure and Use

Manufacturing

 Added to gasoline as antiknock (sniffing)

 Exhaust gases contain inorganic lead

 C. Uptake,

 D. Signs and Symptoms of Toxicity

 CNS damage

 Insomnia, irritability, anxiety , encephalopathy

Additional Readings

 MAJOR PHYSICAL AND CHEMICAL FORMS OF MERCURY

 INORGANIC

Hgo Hg2++ Hg++

 Metallic Mercurous Mercuric

 ORGANIC

 C6H5Hg+ CH3Hg+

 Phenyl Mercuric Methyl Mercuric

 Human Exposure

 Mercury Vapor

a. Environmental - unimportant

b. Occupational - main source

Electrical equipment, paints, thermometers, dental, laboratory

c. Amalgam fillings

main source of background exposure-

Additional Readings

    Consumer Update: Dental Amalgams

    Dental Amalgam Use and Benefits

Mercury Salts

 a. Monovalent (mercurous)

Medical uses (small)

 b. Divalent (mercuric)

 Past uses - felt hat industry

 Current - mercury batteries

 ORGANIC

1. Methylmercury important

a. Environmental - main source is fish

 Biomethylation

Hg (all forms) --> Hg++ --> CH3Hg and CH3HgCH3

Bioaccumulation in aquatic food chains

 b. Industrial, agricultural

* By-product of plastic industry

* Fungicide in seed grain (also ethylHg)

* Misuse of treated grain (developing countries)

2. Other organic mercurial

virtually disappeared

Phenyl mercurials and other mercurials

 well absorbed from G.I. rapidly broken down to Hg++ distribution approaches that of Hg++ excretion via urine and feces (mainly Hg++)

D. Signs and Symptoms of Poisoning

Acute Mercury Poisoning

1. Local Effects

Oral ingestion (chiefly inorganic salts) gastrointestinal: pain, vomiting, diarrhea,

hemorrhage

Inhalation: Pneumonitis, metal fume fever (HgO)

2. Systemic Effects

Shock Kidney (inorganic salts) CNS: lethargy, (shock related effects) Metallic taste, sore gums, salivation

Diagnosis

1. Mercury vapor

symptoms history of exposure urine Hg concentration-normal less than 20 g/l Tremors > 500 g/l

2. Methylmercury

neurological signs and symptoms early diagnosis difficult

dietary history blood normal less than 20 g/l symptoms 200 g/l

hair normal about 1 g/g (adult) symptoms 50 g/g (adult)

3. Inorganic salts

signs and symptoms history elevated urine concentrationTherapy

1. Dimercaprol (British Anti-Lewisite. 2,3dimercaptopropanol)

effective for protection of kidney (Hg++) ineffective from protection of brain (CH3Hg+) cannot be given orally side effects

2. Pencillamine

given orally effective for HgO, less so for CH3Hg+ some side effects

3. Dimercaptosuccinic acid (DMSA), new agent

given orally probably effective for CH3Hg+, Hgo, Hg++ low toxicity

4. Polythiol resion CH3Hg+ only

A. Chemical Forms

Cadmium does not form organometallics

One oxidation state

B. Sources of Human Exposure

Environmental

1. Coal and fossil fuels

2. Cereal crops (superphosphate fertilizers)

Shellfish

3. Cigarette smoking

4. Waste incineration

Occupational

1. Lead and zinc smelters

2. Pigments

3. Electroplating

4. Cadmium-nickel batteries

Signs and Symptoms of Poisoning

1. Acute Poisoning

a. Oral - local irritant effects on G.I.

- nausea, vomiting, diarrhea

b. Inhalation - local irritant effects

- death due to pulmonary edema

2. Chronic Poisoning

a. Lung

1. emphysema inhibits alpha-antitrypsin

2. cancer (in animals)

b. Kidney

1. Critical organ for cadmium

2. Effects above 200 g Cd/g, tubular

damage

3. Urinary B2 microglobin

(blood=urine=10 g/l)

3. Bone

Itai Itai disease (ouch ouch disease)

4. Cardiovasular

Possible cause of hypertension

Diagnosis

a. Emphysema (occupational exposure)

b. Signs of kidney tubular damage

c. Urinary cadmium

d. History of exposure

Reference values

a. blood 1 g/l (non-smokers)

b. urine 0.5 -1 g/l

c. hair external contamination

F. Therapy

a. No effective chelating agents

- counter indicated

b. Vitamin D used for Itai Itai disease

Summary

Cumulative poison

No effective chelating agents

B. Sources of Human Exposure

Environmental

1. All routes: air, water, food, beverage,

Drinking water - mainly inorganic

Food - marine fish, crustaceans-mainly

organic

Beverage - wine (as pesticides)

Occupational

1. Inhalation - main route

2. Industries:

a. Smelters of copper, gold, lead ores

b. Vintners

c. Production of pesticides

Other

1. Drugs:

Fowlers solution

Antiparasitic drugs

C. Absorption, Biotransformation, Distribution, Excretion

1. Absorption

a. Gastrointestinal - Soluble forms well absorbed

Depends on solubility

b. Inhalation - AsH3 well absorbed

Particulate forms of inorganic

2. Biotransformation

Inorganic --> methylated forms

As3+ --> As5+ --> As3+

3. Distribution

a. Initially liver and kidney

b. Later - highests hair, nails, skin

c. Crosses placenta

4. Elimination

a. Mainly via kidneys in man

b. Large individual variation

c. Partly in methylated form in urine

d. Organic eliminated faster than inorganic

e. Both forms have short half times (hours)

D. Signs and Symptoms of Poisoning

1. Inorganic more toxic than organic

2. AsH3 extremely toxic

3. As3+ reacts with thiols (lipoic acid)

Alpha lipoic acid is an essential cofactor for the enzyme pyruvate dehydrogenase. Thus arsenic inhibits this enzyme leading to a blockade of energy metabolism and to the accumulation in plasma of pyruvic acid.

Signs and Symptoms of Poisoning (Cont'd)

Acute Poisoning

1. Rice-water stools As3+

2. Shock As3+, AsH3

3. Hemolysis AsH3

Chronic Poisoning

1. Local - inhalation perforation of septum

Systemic:

many tissues involved

skin, liver, cardiovascular, nervous system

a. Early Signs

1. Diarrhea

2. Skin pigmentation, hyperkeratosis

3. Edema

4. Garlic odor of breath

b. Progression

1. Dermatitis and keratosis of skin

2. Enlarged liver

3. Kidney damage

4. Peripheral neuritis, encephalopathy

5. Aplastic anemia

c. Late effects

1. Cancer of skin and lung As3+

2. Teratogenic in animals As3+

E. Diagnosis

1. Often difficult - early signs non-specific

2. History of exposure

3. Indicator media not very useful

        Blood - normal values <10 g/l

        Urine - normal values 10-30 g/l

        Hair - normal values 0.3-0.5 mg/kg