Heavy Metal Toxicity

Mechanism of Action

• Most common route of exposure is oral – secondary is inhalation of fumes

• Toxicity is expressed biologically because of their ability to bind to one or more ligands of biologic enzyme systems which then inactivates the enzyme system

One of the few poisons that we have a chemical antidote for:

Chelating Agents

• Chemical antidotes - chemically inactivate the poison

• Compete with enzyme systems for the metals

• Reverse the metals toxic effects

• Enhance the excretion of the metal

• The chelate formed is a stable compound

• Chelates are water soluble

• Chelates are excreted by the kidneys

Chelating Agents, cont.

How effective these chelating agents are depends upon:

• 1) the affinity of the chelator for the metal• 2) distribution of the chelator to the parts of the

body where the metal is• 3) ability of the chelator to mobilize the metal

from the body once the chelate is formed

Chelating Agents, cont.

Properties of the ideal chelating agent:• 1) greater affinity for the metal than for ligands of

tissues• 2) high water solubility• 3) can penetrate into tissues• 4) resistant to metabolic degradation by the body • 5) forms a tight stable bond with the metal which

is non toxic to the body

Chelating Agents, cont.

Properties of the ideal chelating agent, cont.• 6) be readily excreted unchanged• 7) low affinity for calcium• 8) minimal inherent toxicity• 9) be absorbed readily when given orally

Chelating Agents, cont.

• No drug has a single effect, drugs are two edged swords.

• Examples of a chelating agent:– calcium disodium EDTA - can cause renal

problems, fever, dermatitis, used to treat lead toxicity

Heavy Metals

Heavy Metal Toxicity• Uncommon yet clinically significant condition yet if

unrecognized can be fatal• Lead is most significant of the heavy metals• Study by National Health and Nutrition Examination

Survey found that 0.4& of people aged 1 year and older had blood levels of lead of 25mcg/dL or higher.

• Higher incidence in African Americans• History is the most critical aspect in diagnosing • Children absorb more from the GIT than do adults

(50% verses 10%) and childhood plumbism affects more than 2 million preschoolers

Lead toxicity• The fall of the Roman empire was due to the fact they

used lead for pipes to carry water and for drinking goblets and utensils.

• Sources - used in the past in medicines (sugar of lead), insecticides, pesticides, gasoline (tetraethyl lead), batteries, paints, manufacturing, automobile exhaust.

• Lead poisoning is probably the most important chronic environmental illness affecting modern children.

• The organ of greatest concern is the developing brain which last well into early adulthood.

Lead toxicity• Mortality today is rare.• Mounting evidence suggests that lead poisoning in

children produces long term problems with learning, intelligence and earning power.

• Adults with lead poisoning have problems with depression, aggressive behavior and antisocial behavior.

• Males with lead poisoning have lower sperm counts, women have an increase in miscarriages and smaller babies

Lead Toxicity, cont.

Clinical features, plumbism:

Acute intoxication: not common• colic• metallic taste to mouth• vomiting, diarrhea or constipation• increased thirst• hemolysis, hemoglobinuria• oliguria• paresis and paresthesias

Lead Toxicity, cont.

Chronic lead intoxication - much more common

• Burtonian line - dark gray bluish black line on the gingival margin (H2S + Pb = PbS)

• Basophilic stippling (clumping of RNA)• Anemia• Colic, diarrhea, vomiting• Skeletal muscle weakness• Increase uric acid in blood• Headache, confusion, insomnia • Lead palsy (wrist drop and foot drop)

Lead Toxicity, cont.• Consider lead poisoning whenever a small child

presents with peculiar symptoms that do not match any one particular disease entity.

• Especially:– irritability

– sleeplessness

– poor appetite

– headaches

– if parents use folk remedies or their parents work in a lead-related occupation

Lead Toxicity, cont.

Patient management:

• Acute intoxication - induce vomiting, give cathartics, give proteins to delay absorption (milk, egg whites), chelating agents

• Chronic toxicity - give chelating agents

Iron Toxicity• Seen mostly in children, 40, 000 exposures/yr.

• Toxic doses: – 20-60 mg/kg of elemental iron is potentially toxic– 60-120 mg/kg is toxic but not usually fatal– > 120 mg/kg is potentially fatal

• Only 10% of ingested iron is absorbed

• Most iron tablets contain 10-30% elemental iron by weight

Iron Toxicity, cont.• Sources - dietary supplements

Clinical features: • toxicity develops when serum iron levels exceed the iron

binding capacity of transferrin in the blood• body is poorly equipped to handle excessive amounts of

iron - can eliminate only very small amounts/day

• free iron damages tissues by direct corrosive effects, free iron is a potent vasodilators, directly injures blood vessels, causes hepatocellualr death, coagulation disturbances, and metabolic acidosis

Iron Toxicity, cont.Clinical presentation of acute toxicity- 4 Stages• Stage I - 30 min. to 6 hrs. post ingestion

Acute GI corrosive effects of iron, nausea,

abdominal pain, vomiting, and diarrhea,

hematemesis, hematochezia and melena.

Most patients with mild to moderate toxicity do not progress beyond this phase.

• Stage II - 6-24 hours post ingestionsometimes called the latent or quiescent period

transient resolution of patient’s GI signs

Iron Toxicity, cont.

• Stage III - 12-48 hours post ingestionrecurrence of GI hemorrhage, hematemesis,

melena and bowel perforation may be seen

acute circulatory shock, metabolic acidosis,respiratory distress syndrome

death is common is this stage

• Stage IV - 4-6 weeks post ingestiongastric outlet obstruction or pyloric stenosis

as a result of gastric scarring, vomiting

Iron Toxicity, cont.

Chronic toxicity: • pigmented hepatic cirrhosis, diabetes mellitus,

hyperpigmentation of the skin, hemosiderosis• hemochromatosis

Treatment:• induce vomiting • activated charcoal is of no value• transport• chelators

Mercury Toxicity

• Hg (Gr. - hydrargyros - water silver)• Used throughout the centuries, as early as 1500

BC in Egypt• Drugs (antisyphilitic agents (18th century),

diuretics, cathartics, topical salves), batteries, paint, shell fish, neon lamps, thermometers, industry (“mad as a hatter”, 1800’s), BP cuffs, wood preservatives

• Dental amalgam fillings (50% mercury, 35% silver, 13% tin, 2% copper with a trace of zinc)

Mercury Toxicity

• 1998 AAPCC documented 4039 exposures• Of these 1039 were in children > 6 years and

1385 in persons > 19years, with 3 deaths.• Mercury toxicity is usually misdiagnosed

because of the insidious onset, nonspecific signs and symptoms, and lack of knowledge by medical profession.

Mercury Toxicity, cont.

• Recent environmental exposures:– 1960 Minamata Bay, Japan

– Mercury contaminated fish in Canada

– Methylmercury treated grain in Iraq (1970) and in US 1996

– Beauty cream products from Mexico.

– Mercury contamination of tuna - currently a problem

– prior to 1990 many paints contained mercury as an anti mildew agent

Mercury Toxicity, cont.• Only metal which is liquid at room temp.• Exists in nature in 3 major forms: Mercury in any form

is toxic - difference lies in how it is absorbed, signs and symptoms, and response to treatment.– organic (methyl mercury) – mecuric salts - is highly toxic and corrosive– elemental - as a vapor can penetrate the CNS

• All forms of mercury are toxic to the fetus, but methylmercury most readily passes through the placenta and maternal exposure can lead to spontaneous abortion or retardation.

Mercury Toxicity, cont.Elemental mercury - quicksilver• Vaporizes easily at room temperature• Causes: amalgams, manometers, thermometers, etc. • 80% absorbed through inhalation, not absorbed well by

GIT.• Lipid soluble and passes rapidly into blood stream• See acute pulmonary symptoms, fever, chills, dyspnea,

lethargy, confusion, (in elderly can be misdiagnosed as Parkinson or Alzheimer’s disease).

• Recovery is usually without sequela.• Treatment: ABC’s, O2, chelation

Mercury Toxicity, cont.

Inorganic mercury - mercurial salts• route of exposure - oral and GIT• source - disc batteries, mercurous chloride• clinical signs associated with the corrosive effects• signs and symptoms - ashen gray mucous membranes

secondary to ppt. of mecuric salts, severe abdominal pain, vomiting, hematemesis, shock, loosening of teeth, renal tubular necrosis.

• Treatment: ABC’s, chelation therapy

Mercury Toxicity, cont.

Organic Mercury - methyl mercury• Usually results from ingestion of contaminated food• Onset of symptoms usually delayed for days to weeks

post exposure• Targets enzymes and depletion of these enzymes must

occur before the onset of symptoms• Clinically see: visual disturbances, ataxia, hearing loss,

mental deterioration, muscles tremors, paralysis and even death.

Mercury Toxicity, cont.

• Thimerosal - an organic mercurial compound used as a preservative in vaccines to prevent bacterial contamination - found in diptheria-tetanus-whole cell pertussis (DTP), Haemophilus influenzae (HIB), and hepatitis B vaccines.

• July 7, 1999 - American Academy of Pediatrics and the US Public Health service issued an alert concerning thimerosal.

Mercury Toxicity, cont.

Diagnosis is based on:• patient history and clinical signs

• urinary levels of mercury (values greater than 20-25 ug/L is abnormal)

Treatment: • acute therapy - same as any poison

• chronic - chelation therapy (BAL)

Arsenic Toxicity

• Commonly found throughout the earth’s crust in the metallic state, contaminates well water

• Used in manufacture of herbicides, rodenticides (arsenic trioxide), and glass and semiconductors

• Tasteless and resembles sugar • Has been used as a therapeutic agent and as a poison for

more than 2000 years • Used as a poison for political assassinations; speculated

that Napoleon was poisoned with arsenic

Arsenic Toxicity

• 1998 - 956 non pesticide related arsenic exposures with 4 fatalities; 400 arsenic containing pesticide exposures with no fatalities

• Arsenic exposure is usually suicidal, homicidal or occupational

• Most exposures are accidental and deaths are very rare

Arsenic Toxicity, cont.Mechanism of action: • Inhibition of sulfhydryl group-containing cellular

enzymes and the replacement of phosphate molecules in “high energy” compounds

• Trivalent arsenic is a carcinogen (lung and skin cancer) and is the most toxic form

• Toxic dose ranges from 1 mg to 10 grams• Can be recovered from the hair, nails and skin

Arsenic Toxicity, cont.

Clinical presentation:

• Acute exposure – burning of the mouth and throat, nausea,

vomiting, profuse diarrhea (rice water stool), garlic like odor to breath, increased capillary permeability, shock, renal damage

Arsenic Toxicity, cont.Chronic toxicity:• skin pigmentation changes, palmar and plantar

hyperkeratosis• anorexia, GI symptoms • anemia (see pale patient with areas of increased

pigmentation and hyperemia - “Milk and Roses” complexion)

• Mee’s lines (white transverse bands in the nails)• metallic taste to the mouth • gangrene of the feet (“blackfoot disease”)• encephalopathy

Arsenic Toxicity, cont.

Diagnosis:• Urine sample provide the most reliable diagnostic

testing, >200ug/L are abnormal– use of hair or nails is generally not useful in

evaluating individual patients

Treatment:• provide support to airway, breathing and circulation• chelation therapy

Natural Chelators

• Chlorella (from algae) is a natural immune stimulant and has a high affinity for heavy metals (it contains sulfur bound amino acids and acts as a natural chelator)

• Garlic and cilantro (Chinese parsley) aid in the removal of heavy metals