Toxic Materials

Amjad Fayyad Khadr

Toxic materials

• Toxic materials are substances that may cause harm to an individual if it enters the body.

‘Heavy metal’

• A metal having an atomic weight greater than sodium, a density greater than 5 g/cm3

• Some notion of toxicity

• Usually includes lead, cadmium and mercury

• Many others may variably be added to list

Heavy metal poisoning can be acute or chronic and may be caused by the following:

• Lead الرصاص

• Mercury. الزئبق

• Iron.الحديد

• Cadmium.الكادميوم

• Thallium.الثاليوم

• Bismuth.البزموت

• Arsenic الزرنيخ(technically not a true metal but a semi-metal - ie non-metal with some metallic properties).

The metals may enter the body by:

• Ingestion.

• Inhalation.

• Absorption through the skin or mucous membranes.

They are then stored in the soft tissues of the body. The heavy metals once absorbed, compete with other ions and bind to proteins, leading to impaired enzymatic activity resulting in damage to many organs throughout the body.

Epidemiology

• The most common cause of heavy metal poisoning is lead. The incidence of lead poisoning has been falling steadily in affluent countries, due to removal of lead from paint, petrol and food cans

• Lead poisoning remains a problem, however, in older housing where lead water pipes and lead paint may still be present. In housing such as this, there is a particular risk to children and the American Centre for Disease Control and Prevention recognised this and recommended screening of children in areas considered to pose a threat from this hazard, in order to prevent the children from developing neurological damage

Epidemiology

• Other sources of lead poisoning are occupations (eg, smelting, battery manufacture), traditional remedies, or occasionally foreign bodies (lead weights)

• Mercury can be found in the elemental state (dental amalgam, thermometers), inorganic (industrial processes) and organic compounds (pesticides, wood preservatives, some medicines, and contaminated fish)

Epidemiology

• Ingestion of disc batteries by children can also lead to heavy metal poisoning amongst other problems. These batteries can contain varying amounts of metals including mercury, manganese and cadmium.

• Poisoning from other heavy metals most often occurs in individuals regularly exposed to the metals in their work environment.

• Criminal poisoning with lead has been reported.

Presentation

• The presentation will depend on the age of the individual, the metal absorbed, and whether this was the result of acute exposure - eg, vapour inhalation, or exposure over a more prolonged period of time.

Differential diagnosis

• The differential diagnosis will depend on the symptoms and signs displayed, but may include causes of encephalopathy, dementia, substance abuse and causes of vomiting and diarrhoea.

Investigations

Investigation of any person in whom a diagnosis of heavy metal poisoning is a possibility may include: • Full history - including occupational history, age of house and water

supply if known. • Examination. • FBC and film - basophilic stippling with lead and arsenic poisoning,

normochromic or microcytic anaemia with lead toxicity. • Blood levels for lead and mercury. • 24-hour urine collection - mercury and arsenic levels. • Long bone X-ray in children - horizontal metaphyseal lines ('lead

bands' caused by failure of the bones to remodel, not seen in adults).

• CXR - may show radiodense pulmonary emboli following injection of mercury.

Management

• Current advice on the management of any form of heavy metal poisoning may be obtained from the UK National Poisons Information Service or TOXBASE.

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) 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

Lead Poisoning

• Description

• Epidemiology

• Presentation

• Differential diagnosis

• Investigations

• Management

• Complications

Description

• Lead accumulates slowly in the body and even low doses can eventually lead to poisoning. 95% of lead in body is deposited in the bones and teeth while 99% of lead in blood is associated with erythrocytes.

• Lead also depresses haem synthesis and shortens the life span of erythrocytes, causing a hypochromic microcytic anaemia.

• Steroid production is also impaired. • Acute poisoning is mainly related to occupational

inhalation and foreign body ingestion. Chronic poisoning may be either environmental or occupational.

Epidemiology

• Incidence – Lead poisoning is a lot less common than it used to be with

less use in petrol, paints or cosmetics and generally improved housing. The effect of long-term elevated lead levels on children is of particular concern and can lead to a reduction of IQ and to disruptive behavior.

– Children under the age of three are particularly at risk because ingestion of foreign material is more likely at this age.

– in adults, lead poisoning is mostly occupation-related. The occupations mainly involved are the smelting, refining, alloying and casting industry (19.1%), the lead battery industry (18.2%) and the scrap industry (7.4%).

Epidemiology

• Risk factors – Occupations involving contact with lead. – Children chewing lead-painted items or ingesting fishing weights, bullets or

contaminated soil. – Deliberate ingestion (pica) is occasionally seen in adults as part of a psychiatric

condition.[6] – Use of various imported tonics, alternative medication[7] and cosmetics

containing lead. – Associated iron deficiency - increases lead absorption from the gastrointestinal

(GI) tract. – Poor/old housing (lead paint or pipes). – Use of lead-containing folk remedies.[8] – Age - compared to an adult, a child can absorb twice as much lead from the GI

tract. – One study reports the emergence of lead poisoning in a pregnant woman

years after exposure - presumably due to increased reabsorption of lead from the skeletal system.

Presentation

• Acute poisoning The severity of symptoms often correlates with blood levels and at high levels the following may be seen: – Abdominal pain - moderate-to-severe, usually diffuse

but may be colicky. – Vomiting. – Encephalopathy - more common in children,

characterised by seizures, mania, delirium and coma, death.

– Jaundice (due to hepatitis). – Lethargy (due to haemolytic anaemia).

Presentation

• Chronic poisoning – Mild abdominal pain. – Constipation. – Aggression. – Antisocial behaviour. – Headaches. – Hearing loss. – Subfertility. – Foot drop - due to motor peripheral neuropathy. – Wrist drop - this is a late sign. – Carpal tunnel syndrome. – Gout. – Autonomic dysfunction.

Signs

• There are no pathognomonic signs but the following may be seen: – A blue discoloration of gum margins. – Mild anaemia. – Behavioural abnormalities (more marked in children) -

irritability, restlessness, sleeplessness. – Cognitive dysfunction. – Impaired fine-motor co-ordination or subtle visual-

spatial impairment. – Chronic distal motor neuropathy with decreased

reflexes and weakness of extensor muscles in adults

Differential diagnosis

• This depends on the presentation. Diagnosis may be difficult in the UK where lead poisoning is a relative rarity but the condition should be on the list in patients presenting with diffuse abdominal pain.

• Other conditions which may need to be considered include:

Differential diagnosis

• Acute confusional states. • Acute memory loss. • Epilepsy. • Encephalopathies. • Frontal lobe syndromes. • Depression. • Attention deficit hyperactivity disorder. • Learning disorder. • Developmental delay. • Language disorder. • Autism or pervasive developmental disorder. • Organic solvent poisoning. • Other heavy metal poisoning. • Radial mononeuropathy and other peripheral neuropathies. • Diabetic neuropathy. • Anaemias, acute and chronic. • Constipation. • Guillain-Barré syndrome.

Investigations

Laboratory tests

• Whole blood lead levels:

– <10 μg/dL - normal.

– >10 μg/dL - may cause impaired cognitive development in children.

– >45 μg/dL - GI symptoms in adults and children.

– >70 μg/dL - high risk of acute CNS symptoms.

– >100 μg/dL - may be life-threatening.

Laboratory tests

• It has been considered for many years that levels of 10 μg/dL have the potential to affect physical and mental development in children. Studies suggest that levels even lower than this can be unsafe.

• FBC - basophilic stippling of erythrocytes may be seen and features of a microcytic hypochromic anaemia such as a low MCV may be present. Sideroblasts may be seen.

• Renal function tests to detect renal complications and uric acid levels to detect gout may also be advisable.

• Nerve conduction tests should be considered if neuropathy is suspected.

• Psychometric testing should be considered if clinically indicated.

Radio-imaging

• Plain X-ray may show transverse lines in tubular bones. These are actually areas of arrested bone growth and may persist a long time after exposure ends. They are not seen in the early phase of exposure.

• Plain abdominal X-rays may show radio-opaque flecks in cases of suspected lead foreign body ingestion (eg pica in children).

• X-ray fluorescence works by detecting specific emissions from tissues when bombarded with X-rays. It is a sensitive method of detecting low levels of lead in the body.

• CT or MRI scan of the brain may be contributory in patients with symptoms suggestive of encephalopathy.

Management

• Severe lead poisoning (levels >60 μg/dL) due to acute ingestion may require:

– Airway maintenance.

– Management of coma and seizures.

– Intravenous (IV) drip of normal saline.

– Orogastric or nasogastric catheter and irrigation with polyethylene glycol.

Management

• Parenteral chelators such as calcium disodium edetate given intramuscularly (IM) or IV. There is a growing trend to administer it by slow IV drip. Opinions vary as to when chelation therapy should be used but it is often employed at levels of 45-60 μg/dL.

Management

• For mild lead poisoning (<45 μg/dL) it may be sufficient to detect the source of the exposure, remove the patient from it and monitor the clinical status.

• Oral chelation therapy is an option sometimes used for mild-to-moderate poisoning.

• Dimercaptosuccinic acid (DMSA, or succimer) is an alternative oral agent. There is some evidence that it can affect growth rate in children.

Management

• D-penicillamine is occasionally used but it is an unlicensed medication with adverse effects such as white cell and platelet count suppression.[16]

• Chelation therapy should be withdrawn gradually to avoid the metal leaking out of the bones and causing a rebound rise in blood levels

Complications

• Lead poisoning, with or without encephalopathy, can affect all the systems of the body.

• Hepatic, renal and neurological damage can occur.

• Chelation itself can cause problems and treated patients can develop hypertension ,raised intracranial pressure and renal failure from the chelated lead compound

Mercury poisoning

• The toxic dose for mercury compounds is about 10-50 mg/kg. Mercury is poorly absorbed from the gut and ingestion is usually harmless (unless aspiration occurs). A single dose (eg, a broken thermometer) usually causes no problems. It is only slowly absorbed through the skin but can cause contact dermatitis.

Acute poisoning:

• An acute pneumonitis (± adult respiratory distress syndrome (ARDS)).

• Flu-like symptoms.

• Irritability.

• Myalgia.

• Gastrointestinal upset.

• Subsequent peripheral neuropathy, hepatic dysfunction or renal failure may develop

Chronic poisoning:

• Irritability. • Personality changes. • Headache. • Peripheral neuropathy. • Memory problems. • Ataxia. • Coma. • Respiratory problems (pneumonitis and ARDS). • Gastrointestinal upset (abdominal pain, gingivitis and

stomatitis, nausea, vomiting). • Renal problems include acute renal failure, nephrotic

syndrome and acute tubular necrosis.

Management

• Management of inhalation of mercury should be treated with intravenous (IV) hydrocortisone to minimise pulmonary complications. Acute intakes of inorganic mercury should be treated with chelating agents such as d-penicillamine.

Iron poisoning

• Iron overdose can present with:

– Nausea ± vomiting.

– Abdominal pain and diarrhoea.

– Possible gastrointestinal bleeds.

– Serious overdose, which causes hepatocellular necrosis (jaundice, hepatic failure).

– Gastric outflow obstruction, which may be a late complication.

• Iron poisoning needs urgent treatment with emergency admission and desferrioxamine (IV) as an antidote.

Arsenic

Introduction

• Arsenic is common in the environment

• Sources – Groundwater

– Arsenic containing mineral ores الخامات المعدنية

– Industrial processes • Semiconductor manufacturing (gallium arsenide)

• Fossil fuels

• Wood treated with arsenic preservatives

• Metallurgy

• Smelting (copper, zinc, lead) and refining of metals and ores

• Glass manufacturing

Introduction

• Commercial products – Wood preservatives

– Pesticides المبيدات

– Herbicidesمبيدات االعشاب

– Fungicidesمبيدات الفطيرات

• Food – Seafood and fish

• Others – Antiparasitic drugs

Soil Pica

• Soil pica behavior: when children ingest large amounts of soil at a time (e.g. up to 1 teaspoon or 5,000mg)

• Children 1 to 2 years old have strongest soil pica behavior, which may occur as part of their normal exploratory behavior

• Preschool children also purposely eat soil for unknown reasons

• Some cultures promote eating soil, specifically clay, as part of a cultural practice

Toxicokinetics

• T1/2 of inorganic arsenic in the blood is 10 hrs and of organic arsenic is around 30 hours

• 2-4 weeks after the exposure ceases, most of the remaining arsenic in the body is found in keratin-rich tissues (nails, hair, skin)

Toxicokinetics

• Inorganic arsenic is converted to organic arsenic in the liver. This may represent a process of detoxification

• Renally excreted (30-50% of inorganic arsenic is excreted in about 3 days). Both forms are excreted depend on the acuteness of the exposure and dose

Pathophysiology

• Trivalent forms: – bind to sulfhydryl groups leading to inhibition of enzymatic systems

– inhibit the Krebs cycle and oxidative phosporylation. These lead to inhibition of ATP production

• Pentavalent forms – can replace the stable phosphate ester bond in ATP and produce an

arsenic ester stable bond which is not a high energy bond

• Endothelial damage, loss of capillary integrity, capillary leakage, volume loss, shock

Bodily system affected

Symptoms or signs Time of onset

Systemic Thirst Hypovolemia, Hypotension

Minutes Minutes to hours

Gastrointestinal Garlic or metallic taste Burning mucosa Nausea and vomiting Diarrhea Abdominal pain Hematemesis Hematochezia, melena Rice-water stools

Immediate Immediate Minutes Minutes to hours Minutes to hours Minutes to hours Hours Hours

Hematopoietic system

Hemolysis Hematuria Lymphopenia Pancytopenia

Minutes to hours Minutes to hours Several weeks Several weeks

Pulmonary (primarily in inhalational exposures)

Cough Dyspnea Chest Pain Pulmonary edema

Immediate Minutes to hours Minutes to hours Minutes to hours

Liver Jaundice Fatty degeneration Central necrosis

Days Days Days

Kidneys Proteinuria Hematuria Acute renal failure

Hours to days Hours to days Hours to days

Manifestations of acute arsenic poisoning

Palmer Keratosis

Biological Monitoring

• Urinary arsenic measurement – Spot sample (mcg/L)

– Timed urine collection (mcg/24 hours)

• Normal values – Spot urine= ~10 mcg/L (10-150 mcg/L)

– 24 hours urine collection=<25 mcg/24 hours

– Whole blood= <1mcg/L (usually is elevated in acute intoxication)

Biological Monitoring

• Ingestion of seafood may elevate urinary arsenic levels

• If urinary arsenic levels are high – Ask the patient whether he ingested seafood in the last 72 hours

– Speciation can be performed in several laboratories

Treatment of acute poisoning

• Gastric lavage

• Activated charcoal does not bind well inorganic arsenic

• Whole bowel irrigation with polyethylene glycol

• Skin decontamination in dermal exposure

Treatment of acute poisoning

• Supportive care

• Chelation therapy should be instituted promptly (minutes to hours) – BAL (British anti-Lewisite)- IM

– Succimer (DMSA)- PO

– DMPS – PO, IV

– D-Penicillamine- less effective

Carbon Monoxide (CO)

• An odorless, colorless, tasteless gas

• Results from incomplete combustion of carbon-containing fuels

– Gasoline, wood, coal, natural gas, propane, oil, and methane

• Affects 40 – 50,000 Americans annually who need to seek care

• Kills an additional 6,000 persons annually in the USA

• CO is the #1 cause of poisoning in industrialized countries

Sources of Carbon Monoxide – any combustible item

• Homes • Cigarette smoke • House fires • Automobile exhaust fumes • Worksites

– Including fumes from propane-powered equipment like forklifts

• Smoke from charcoal-fired cook stoves & ovens

What Effect Does Carbon Monoxide Have on Hemoglobin?

• Hemoglobin molecules each contain four oxygen binding sites

• Carbon monoxide binds to hemoglobin • This binding reduces the ability of blood to

carry oxygen to organs • Hemoglobin occupied by CO is called

carboxyhemoglobin • Body systems most affected are the

cardiovascular and central nervous systems

Effects of Carbon Monoxide

• Oxygen cannot be transported because the CO binds more readily to hemoglobin (Hgb) displacing oxygen and forming carboxyhemoglobin

• Premature release of O2 prior to reaching distal tissue leads to hypoxia at the cellular level

• Inflammatory response is initiated due to poor and inadequate tissue perfusion

• Myocardial depression from CO exposure

– Dysrhythmias, myocardial ischemia, MI • Vasodilation – from increased release of nitric oxide;

worsening tissue perfusion and leading to syncope

Half-life of Carbon Monoxide

• Half-life – time required for half the quantity of a drug or other substance to be metabolized or eliminated

• CO half-life on 21% room air O2 – 4 - 6 hours

• CO half-life on 100% O2 – 80 minutes

• CO half-life with hyperbaric O2 – 22 minutes

Expected Carboxyhemoglobin Levels

• Non-smokers – 5%

• Smokers – up to 10%

– 5 – 6% for a 1 pack per day smoker

– 7 - 9% for a 2-3 pack per day smoker

– Up to 20% reported for cigar smokers

Presentation

Low-level poisoning • Early features • Low-level exposure may produce no abnormal

physical signs. Symptoms are likely to be mild and may include nausea, subjective weakness, headache and poor concentration/memory. Carbon monoxide poisoning is likely to be suspected in circumstances where exposure to a source has taken place and symptoms improve when the patient has been removed from the source.

Late features

• Some patients develop later symptoms perhaps after several weeks of apparent recovery from the incident. This late stage is more common in those aged over 40 Neurological or neuropsychiatric features including disorientation, apathy, mutism, irritability, inability to concentrate, personality change, Parkinsonism and parietal lobe lesions. Memory loss is thought to be a late feature, but the link with carbon monoxide poisoning has been challenged

• Encephalopathy develops 2-6 weeks after the initial acute intoxication. Urinary incontinence and/or faecal incontinence and disturbance of gait are common

Chronic poisoning

• This is often unsuspected and unrecognized and features may appear nonspecific, eg headache, nausea and flu-like symptoms. They are most common in winter as that is when fires are used and ventilation is restricted. It should be suspected if more than one person in a household has such symptoms that do not appear to be due to a viral infection. There may be black, sooty marks near a fire.

Chronic poisoning

• Headache occurs in 90%.

• Nausea and vomiting occurs in 50%.

• Vertigo occurs in 50%.

• Alteration in consciousness occurs in 30%.

• A subjective feeling of weakness occurs in 20%

High-level poisoning

The above symptoms may be more severe. In addition there may be: – Personality change. – Poor performance on the mini mental state examination. – Tachycardia and tachypnoea. – Dizziness and ataxia. – Angina, hypotension, arrhythmias. – Agitation, seizures, impairment of consciousness and respiratory

failure. – Cerebral oedema and metabolic acidosis may develop. – Less common features include skin blisters, rhabdomyolysis, acute

renal failure,pulmonary oedema, myocardial infarction, retinal haemorrhages, cortical blindness.

– The classical cherry red coloration is rarely seen in life although it may be seen on the postmortem slab.

Investigations

• The GP will need to refer the patient to hospital for investigation and management if applicable.

• Direct spectrophotometric measurement of HbCO in a blood gas analyser is the gold standard, although the initial level may not correlate with severity. A bedside HbCO oximeter is now available (this is not to be confused with an oximeter which measures blood levels). Symptoms such as headaches start around 10% whilst at 50-70% seizure, coma and death may occur.

• Arterial blood gases may show a metabolic acidosis

• ECG may show myocardial ischaemia or infarction and creatine kinase or troponin levels may indicate myocardial damage.

• In severe cases other investigations may include urea and electrolytes because of metabolic acidosis, lactate dehydrogenase (LDH) for tissue damage and, in chronic severe cases, urinalysis may show both albumin and glucose.

• If there is an unexplained metabolic acidosis after an industrial fire, consider cyanide toxicity.

• Haematological investigations may be needed to exclude disseminated intravascular coagulation (DIC) and thrombotic thrombocytopenic purpura (TTP).

• Check human chorionic gonadotrophin (hCG) if pregnancy is a possibility.

• If symptoms are severe, get a chest X-ray, as pulmonary oedema may develop.

• MRI scan may show cerebral abnormalities. • Neuropsychological testing, involving assessment of

concentration, fine movements and problem solving may be useful in providing diagnostic and prognostic information

Differential diagnosis

• Acute respiratory distress syndrome • Alcohol toxicity • Altitude illness • Cluster headache • Cyanide poisoning • Depression • Diabetic ketoacidosis • Encephalitis • Gastroenteritis • Hypoglycaemia • Hypothyroidism • Labyrinthitis • Lactic acidosis • Meningitis • Methaemoglobinaemia • Migraine • Smoke inhalation • Tension headache • Alcohol toxicity • Narcotic toxicity

Management

What GPs should do If low-level exposure is suspected • Remove the person (and others) from the source and

advise them to stay away from the area until it has been ventilated.

• If a woman is pregnant arrange for urgent assessment by an obstetrician.

• Check an HbCO level to establish the diagnosis or monitor exhaled carbon monoxide level (a suitable meter may be available from a smoking cessation clinic).

• Contact the local Health Protection Unit (HPU) to arrange environmental testing and management

If a high level of CO poisoning is suspected:

• Arrange for the removal of the person (and others) from the source of the exposure.

• Check and manage airways, breathing and circulation. • Give oxygen at up to 100% (most GPs may not have this

available). • Arrange for urgent hospital transfer. • Check blood glucose whilst waiting for the ambulance

to exclude hypoglycaemia that may need to be treated urgently.

• Contact the local HPU - contact details available from the Health Protection website

What hospital doctors should do

• Give oxygen at 100% concentration. Expert evidence suggests that this reduces the half-life of HbCO . It may be required for 24 hours.

• The evidence concerning the use of hyperbaric oxygen is controversial and there is no international consensus. Although in widespread use in other countries (notably the USA), UK recommendations are that it should not be employed, as the evidence base does not support its superiority over 100% oxygen in terms of long-term clinical outcomes.

What hospital doctors should do

• Metabolic acidosis should be corrected by increasing oxygen delivery to the tissues. Sodium bicarbonate is contra-indicated.

• Give mannitol 1g/kg intravenously over 20 minutes if cerebral oedema is suspected.

• Monitor the heart rhythm for 4-6 hours.

• Measure the HbCO concentration as an emergency. HbCO of 30% indicates severe exposure but much lower concentrations do not exclude significant poisoning and the relationship between HbCO and severity of poisoning and clinical outcome is poor.

What hospital doctors should do

• If the patient is unconscious, look for extrapyramidal features and retinal haemorrhages to assess the severity of central nervous system toxicity.

• Asymptomatic patients with HbCO below 10% may be discharged although if the patient is pregnant there is concern for the fetus.

• Limit exertion for the next few weeks and if the patient is a smoker, stop smoking.

• Blood gases must be monitored with use of oxygen in chronic obstructive pulmonary disease.