Medical Pharmacology Topics   

Toxicology: CO and Metals

Carbon Monoxide

In the US, 3,500 to 4,000 people are killed annualy by exposure to carbon monoxide, 2/3 during fires. Carbon monoxide causes more accidental poisoning in the US than any other chemical. It can be generated from many areas of a house or appliances:

• car running in attached garage
• clogged chimeney
• corroded or disconected water heater flue
• gas or wood-burning fireplace
• cracked furnance exchange
• improperly installed kitchen range or vent
• operating a grill indoors or in the garage
• portable paraffin or gas heaters

Inhaled carbon monoxide combines with hemoglobin instead of oxygen, forming carboxyhemoglobin (COHb). The afinity between CO and hemoglobin is 200 fold stronger than hemoglobin's affinity for oxygen. The strong bonding readily displaces oxygen and makes CO elimination more difficult.

Early symptoms include malaise, flu-like symptoms, hyperactivity, anxyety, agitation, insomnia, nervousness, gidyness, headache, dyzzyness, vertigo, lightheadedness, nausea, vomiting, skin lsions, blisters, erythema, and flushed skin (rare). Late symptoms are acidosis, metabolic cyanosis, arrhythmias, irregular heart beat, palpitations, dysrhythmias, lethargy, stupor, coma, hypotension and pulmonary edema,

CoHb levels in smokers is usually 5-10%, but may be as high as 15% in heavy smokers.

Oxygen administration at 100% sea level will reduce COHb levels by more than 50% in one hour. Higher oxygen pressures will achieve faster recovery: 3 atm induces 50% reduction in 30 minutes. Hyperbaric oxygen is recomended due to high fetal hemoglobin affinity for CO.

After treatment, rebound in serum COHb levels may occur due to release of CO from myoglobin, the main extravascular store of CO. CO binding tomyogobin contributes to the muscle weakness and myocardial depression.

Lead

Since lead can be a developmental toxin, young children and the fetus are especially at risk of lead exposure, even at low levels around 10 ug/dL. Adults need to be exposed at much higher doses to be toxic. For children, the primary source of exposure is lead paint, an maybe water from leaded pipes or were lead solder was used. Auro emisions use to be a major source when gasoline contained lead or in contries were it still does. Ocuppational exposures can occur for plumbers, miners (silver), firing range instructures, brudge construction workers and gas station attendant (when gasolin was leaded). Broader environmental exposure may occur were lead-containing waste has been dump, ex. led-containing paint chips and painted wood after building renovation. Other sources inlude folk remedies, moonshine wiskey, and some pottery.

Lead enters the body by ingestion or inhalation, and distributes primarily to three compartments: blood (t1/2 ~ 36 days), soft tissue (t1/2 ~ 40 days), and mineralizing tissues (bone and teeth, t1/2 ~ 10,000 days). Mineralizing tissue contains 95% of lead in the body, which may be movilized in time of stress and increase blood levels. Normally the body contains a small amount of lead, that is accumulated and released constantly.

Lead affects primarily the peripheral and central nervous systems. It also affects blood cells, and vitamin and calcium metabolisms. In the patway foe heme biosynthesis, lead prevents production ofthe precursor porphobilinogen and the integration of iron into protopophyrin. Porphobilinogen synthesis is prevented by inhibiting aminolevulinic acid (ALA) synthetase and ALA dehydrase. Heme assembly is prevented by inhibition of ferrochelatase.

Neurologic effects include permanent neurologic deficits, lower IQ scores, decreased hearing acuity, behavioural changes, fatigue, impaired concentration, and peripheral neuropathy. Hemolitic effects include hemolitic anemia on acute expesure and interference with erythropoiesis at chronic esposure. Anemia is not an early sign of lead poisoning. Lead is considered aprobable human carcinogen since is causes kidney cancer in rodents.

The first signs of lead poisoning in children are subtle neurobehavioural problems, changes in classroom behaviour and social; interaction, and speech/hearing impediments. Lead is more harmful to children under 6 years old, especially those that ingest paint chips. The best screening method is to measure blood lead levels. Asymptomatic patients and those under 25 ug/dL require only removal from the soure of contamination. Patients with lead levels above 45 ug/dL should undergo chelation therapy, using mostly CaNaEDTA, but also dimercaprol (BAL), penicilamine, or dimercaptosuccinic acid (DMSA).

Mercury

Mercury is found at high conentrations in the environment naturally in some areas, in others due to pollution. Sources of mercury include burning of fossil fuels, latex paint (before 1990), some medicines (folk remedies, antisyphilitic, antiseptics, antiparasitics), preservative in eye drops and nasal sprays, and dental silver amalgams. People at risk of mercury poisoning includes workers using mercury or mercyry products, household members of these wrkers, and individuals consuming contaminated fish. Children, infants and fetuses are at greater risk, especially children atracted to liquid mercury as a curiosity.

There are three forms of mercury with different toxicological profiles: elemantal, inorganic and organic. The chemical form determines its pharmacokinetics, thus its toxicity to different organs. In general, mercury is more toxic to the CNS and kidneys. The mechanism of action is unclear, probably by altering the structure and function of proteins since it binds to sulphydryl groups.

Elemental mercury (Hg, quicksilver) is well absobed when inhaled (80%) but not when ingested (0.01%), and affects mostly the CNS. Mercuric salts (Hg) are absorbed in the GI tract (10%) and are more toxic than mercurous salts (Hg). They do not cross the blood brain barrier, and their toxicity is mostly on the kidney. Elemental mercury may be converted to methyl mercury (HgCH3) in the environment, which is readiliy absorbed by inhalatio, dermal contact and ingestion (90%). Methylmercury has toxic effects on the blood and CNS.

Elemental and methyl mercury may cause irreversible CNS damage and affect the development of the nervous system. Symptoms may not manifest until months after exposure. Early symptoms are malaise, blurred vision and hearing loss. The mechanism may involve alteration of neirutransmssion but is not clear. In the developing nervous system, mercury will affect neuronal migration and cell division, and children may be born with mental retardation, blindness, cerebral palsy or deafness.

The renal toxicity of mercury is seen more with its organic and phenylmercury compounds. These accumulate in the kidney, increasing the permability of the tubular epithelium, leading to increased proteinuria and acute proximal tubular necrosis.

Mercury can be meaured in blood, urine and hair. The half life in blood is 3 days, after that it is only detected accurately in urine. In unexposed adults, blood mercury rarely exceeds 1.5 ug/dL. 5.0 ug/dL is considered the threshold for toxicity. Urine especimens ar collected as 1st morning void and analyzed by atomic absorption. Urinary levels lower than 20 ug/dL are normal. At 20-100 ug/dL some subtle toxicity may be seen: irritability, depression, memory loss, minor tremor, disturbed kidney function. At 500-1000 ug/dL in urin more significant symptoms are seen: kidney inflammation, swolen gums, significant ttremor and nervous system disturbances.

Inorganic and elemental mercury poisoning is treated by chelation, expecially using dimercaptol or DMSA. Chelation therapy is contraindicated for organic mercury poisoning because it may increase mercury levels in the brain. Only supportive care is indicated for methyl mercury poisoning.

Arsenic

People at risk of arsenic poisoning are workers that handle arsenic, people that drink ground water frim areas naturally high in arsenic, and and less commonly murder or suicide victims. Ingested arsenic is well absorbed (60-90%), and it may also enter the body by inhalation or dermal absorption (minor). Arsenic crosses the placentaand once absorbed is rapidly cleared except for tissues with high levels of keratin (skin, hair, nails). It is methylated to less toxic forms in the liver and excreted in the urine within a few days.

Like mercury, arsenic tragets sulphydril groups in proteins. It seems to affect all organs, although GI effects are seen primarily after ingestion. Arsenic may cauyse hepatic necrosis, increased liver enzymes, renal necrosis and failure, cardiovascular changes, dermal toxicity respiratory effects and neurologic effects. There is a strong association with lung and skin cancer in humans.

Acute cardiovascular effects of arsenic include vasodilation, cardiomyopathy, ventricular tachycardia and hypovolemic shock. Chronic effects are due to peripheral vascular insuficiency: gangrene of the extremities (blackfoot disease), fibrous thickening of arterioles and myocardial hyperthrophy. The chronic cardiovascular effects are common with groundwater exposure.Inhalation of arsenic vapors irritates the respiratory mucosa. Lung cancer is common in smelters exposed to arsenic trioxide.

Neurologic effects include peripheral neuropathy (common), weakness, oaralysis, and encephalopathy. In children, hearingg loss, mental retardation snd epilepsy may occur. Recovery from neurological damage cause by arsenic is slow and not complete.

Dermal effects of arsenic are seen when drnking water leves are 400 ppb or higher. Patchy pigmenttion can be found anywere in the body, but primarily in eyelids, neck and temple. These are dark brown patches with scatytered pale spots like "raindrops on a dusty road". Squamous or basal cell cancer my occur after 30-40 years of chronic exposure. Hyperkeratosis of palms and soles (small elevations 0.4-1 cm in diameter) may remain morphologically bening or develop into preneoplastic lesions.

A acute lethal dose of arsenic is between 50 and 300 mg. Symptoms are gastrointestinal, neurologic, cardiovascular and other. GI symptoms include severe abdominal pain, nausea, vomiting, and bloody diarrhea. Neurologica symptoms include lightheadness, headache, weakness, lethargy, delirium, convulsions and coma. Cardiovascular sysmptoms include hypotension, shock, ventricular arrhythmia and pul;monary edema. Other symptoms and signs include hematuria, proteinuria, elevated liver enzymes, garlic odor in breath and delayed appearance of Mees lines.

Signs and symptoms of chronic exposure to arsenic include skin lesions, peripheral neurophathy, skin hyperpigmentation, hyperkeratosis, anemia and lung and skin cancers.

Arsenic is measured most accurately in the urine. Normal urinary levels are around 50 ug/L, anything above 200 ug/L is abnormal. Fish and shelfish contain arsenobetaine and arsenocholilne, non toxic methylated forms of arsenic that may confound urinary tests (total usinary arsenic will go down to normal 24 hours after a fush/shelfish meal). The usine test can be specified to separate inorganic and methylated arsenic values. Indirect indicators of arsenic exposure are liver function, kidney function and cardiovascular function.

Acute arsenic toxicity is treated by performing gastric lavage and chelation therapy. Dimercaprol and DMSA are the preferrect chelating agents. Chronic toxicity is adressed by removing from exposure and trating the symptoms.

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