Heavy Metal Toxicitychanif.lecture.ub.ac.id/files/2019/09/Heavy_Metals_rev_TX.pdf · ‘Heavy metal’ A metal having an atomic weight greater than sodium, a density greater than

Heavy Metal Toxicity

Scott Phillips, MD, FACP, FACMT, FAACT Marci Balge, RN, MSN, COHN-S

Mercury Arsenic Lead

This educational module was produced by Scott Phillips MD, FACP, FACMT, FAACT and Marci Balge, RN, MSN, COHN-S for The University of Texas Health Science Center at San Antonio (UTHSCSA) Environmental Medicine Education Program and South Texas Environmental Education and Research Program (STEER-San Antonio/Laredo/Harlingen,Texas) Administrative support was provided by the Association of Occupational and Environmental Clinics through funding to UTHSCSA by the Agency for Toxic Substances and Disease Registry (ATSDR), U.S. Department of Health and Human Services. Use of this program must include acknowledgement of the authors, UTHSCSA and the funding support. For information about other educational modules contact the UTHSCSA STEER office, Mail Code 7796, 7703 Floyd Curl Drive, San Antonio, Texas 78229-3900,(210)567-7407.

Definitions

‘Metals’ originally included only gold, silver, copper, iron, lead, and tin. Dense, malleable, lustrous

Conduct heat and electricity, cations

Many other elements since added to the list with some of these characteristics

‘Metalloids’ are elements with features intermediate between metals and non-metals. Example: arsenic

Periodic Table

‘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

Acute single exposures

blood

urine

time

Metal levels

exposure

Case Presentation

15-month old boy was treated with ampicillin for abdominal pain and diarrhea. The problem continued and the parent gave the child multiple doses of a Central American “home remedy” called azarcon. The child developed seizures. PE BP 103/68, P 94, RR 22, Tmax 98 F. Exam: listless, with poor motor tone. No neck stiffness, the heart, lungs and abdomen were unremarkable. Sz re-occurred. WBC 9.6 no anemia, Plts Nl, Lytes nl, UA nl Spinal tap was nl, with elevated opening pressure, cerebral edema was found on Cat Scan of the Head.

Case (cont)

The child was intubated, given lorazepam, fosphenatoin and phenobarbital without control of the Sz. An x-ray reveled a radiopaque image in the GI tract.

The child expired, despite aggressive supportive care.

What is azarcon?

Azarcon

Azarcon is a folk remedy that contains 85-96% lead tetroxide

Other lead containing remedies include Greta.

Case (cont.)

The child was found to have a blood lead level of 124 ug/dl., and died from lead encephalopathy.

Lead

Lead Paint

The use of lead in residential paint was banned in 1977

Lead-containing pigments still are used for outdoor paint products because of their bright colors and weather resistant properties

Tetraethyl and tetramethyl lead are still used as additives in gasoline in several countries

Sources of Exposure

Soil and dust

Paint chips

Contaminated water

Parents lead-related occupation

Folk remedies

Congenital exposure

Pica

Developmental delay

Toxicocokinetics and Toxicoynamics

Absorption: Lungs: depends on size particle

GI: Adults: 20-30%

Children: as much as 50% of dietary lead

Inadequate intake of iron, calcium, and total calories are associated with higher lead levels

Skin: Inorganic lead is not absorbed

Organic lead is well absorbed

Lead is carried bound to the RBC

Pharmacokinetics and Pharmacoynamics

Distributed extensively throughout tissues: bone, teeth, liver, lung, kidney, brain, and spleen

Body lead storage: bones- can constitute a source of remobilization and continued toxicity after the exposure has ceased

Lead crosses the BBB and concentrates in the gray matter

Lead crosses the placenta

Excretion: Kidneys. The excretion increases with increasing

body stores (30g-200 g/day)

Feces

Clinical Manifestation

Acute toxicity

Acute encephalopathy, renal failure and severe GI symptoms

Chronic and Long Term Toxicity- Pathophysiology

Lead has affinity for SH groups and is toxic to zinc-dependent enzyme systems

Heme synthesis: hemoglobin, cytochromes

Steroid metabolism and membrane integrity

Interference in vitamin D synthesis in renal tubular cells (conversion of 1-hydroxyvitamin D to 1,25-hydroxyvitamin D)

Mitochondrion

Copro* Uropor PBG

ALA* Copro-0 Copro

Protoporphyrin IX*

Heme Cytoch-C

Bilirubin + Fe

ALA-D

Pb

Pb

Pb

Ferro-C

4Fe++

ALA-S

Heme Oxidase (microsomal)

Pb

Glycine Succinyl-Coa

Pb

ALA- aminolevulinic acid

in plasma and urine COPRO- coprorphyrinogen in urine Protoporphyrin accumulates in the RBC

General Signs and Symptoms of Lead Toxicity

Fatigue

Irritability

Lethargy

Paresthesis

Myalgias

Abdominal pain

Tremor

Headache

Vomiting

Weight loss

Constipation

Loss of libido

Motor neuropathy

Encephalopathy

Cerebral edema

Seizures

Coma

Severe abdominal cramping

Epiphyseal lead lines in children (growth arrest)

Renal failure

Blood lead levels

Adults Children

10 g/dL

Hypertension may occur •Crosses placenta

•Impairment IQ, growth •Partial inhibition of heme synthesis

20 g/dL Inhibition of heme synthesis Increased erythrocyte protoporphyrin

Beginning impairment of nerve conduction velocity

30 g/dL •Systolic hypertension •Impaired hearing()

Impaired vitamin D metabolism

40 g/dL •Infertility in males •Renal effects •Neuropathy •Fatigue, headache, abd pain

Hemoglobin synthesis inhibition

50 g/dL Anemia, GI sx, headache, tremor

Colicky abd pain, neuropathy

100 g/dL Lethargy, seizures, encephalopathy

Encephalopathy, anemia, nephropathy, seizures

Range of Lead-induced Health Effects in Adults and Children

Childhood Lead Poisoning

Childhood lead poisoning is now defined as a blood lead level of 10 g/dl

The average lead level of American children is 2 g/dl

8.9% of American children have lead poisoning

Lead intoxication is more prevalent in minority groups and among those living in the northeast

Neurotoxicity of Lead in Childhood

Mental retardation in severe lead intoxication

5 points in IQ for every 10 g/dl in blood lead level- population based studies

Other adverse developmental outcomes: Aggression

Hyperactivity

Antisocial behaviors

Learning disability- impairment in memory, auditory processing, and visual-motor integration. The IQ is normal. These effects has been demonstrated with blood lead levels as low as 6 g/dl

Diagnosis

Evaluation of clinical symptoms and signs

CBC

Serum iron levels, TIBC, ferritin

Abdominal radiographs (for recent ingestion of lead-containing material)

Whole blood lead level

X-ray fluorescence (XRF)- to asses body burden

Treatment

Environmental inspection/hazard reduction

Nutritional supplementation

Chelation therapy

Nutritional Supplementation

Iron supplementation

Calcium supplementation – calcium rich foods

Phosphorus supplementation

Frequent food consumption- regular meals + snacks

Chelation Therapy

BLL > 70 g/dl or encephalopathy

Hospital admission

Administration of a parenteral chelator

BLL > 45 g/dl- oral chelator

BLL 25-45 g/dl- if these levels persist despite environmental intervention

Arsenic

Introduction

Arsenic is common in the environment

Sources Groundwater

Arsenic containing mineral ores

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

Herbicides

Fungicides

Food Seafood and fish

Others Antiparasitic drugs

Folk remedies

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 (biomethylation to monomethyl arsonic- MMA or DMA) 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

Methylated derivatives determination in the urine. These levels are not influenced by the presence of organic arsenic from marine origin

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

Cadmium

What is Cadmium? A metal most often encountered in earth’s crust combined with

chlorine (cadmium chloride), oxygen (cadmium oxide), or sulfur (cadmium sulfide)

Exists as small particles in air, result of smelting, soldering or other high temp. industrial processes

By-product of smelting of zinc, lead, copper ores

Used mainly in metal plating, producing

pigments, batteries, plastics and as a

neutron absorbent in nuclear reactors

Cadmium is used in batteries

Cadmium and Smelters/Mine

Sites

Cadmium is a by-product of smelters

Has been a concern at the Summitville mine site in Colorado

Photo of Smelter

Exposure Sources - Tobacco

Tobacco smoke (a one pack a day smoker absorbs roughly 5 to 10 times the amount absorbed from the average daily diet)

Tobacco smoke is an important source of cadmium exposure

Exposure Sources – By Mouth

Foods (only a small amount is absorbed)

Itai Itai disease (cadmium contamination + diet low in calcium & vitamin D)

Cadmium a component of chuifong tokwan, sold illegally as a miracle herb

Low levels are found in grains, cereals, leafy vegetables, and other basic foodstuffs

Biologic Fate Cadmium has no known beneficial function in

the human body

Is transported in the blood bound to metallothionein

Greatest concentrations found in kidneys & liver

Urinary excretion is slow

Biologic half-life may be up to 30 yrs.

Why Is Cadmium a Health Hazard?

Affects lungs & kidneys

2o effects on skeletal system

Binds to sulfhydryl groups, displacing other metals from metalloenzymes, disrupting those enzymes

Competes with calcium for binding sites on regulatory proteins

Lipid peroxidation has been demonstrated

Respiratory Effects Acute inhalation may mimic metal fume fever

Fever, chills & decreases in FVC and FEV1

Initial symptoms: flu-like symptoms

Later: chest pain, cough, dyspnea

Bronchospasm and hemoptysis may occur

Chronic inhalation MAY result in impairment of pulmonary function with reduction in ventilatory capacity

Renal Effects

May cause tubular and glomerular damage with resultant proteinuria

May follow chronic inhalation or ingestion

Latency period of ~10 yrs

Nephropathy is progressive & irreversible

Renal Effects Chronic exposure – progressive renal tubular

dysfunction

Toxic effects are dose related

Critical renal concentration

Decreased GFR

Chronic renal failure

Kidney stones more common

Skeletal Effects

Bone lesions occur late in severe chronic poisoning

Pseudofractures

Other effects of osteomalacia and osteoporosis

Appear to be secondary to increased urinary calcium and phosphorus losses

Signs and Symptoms - Acute

Food poisoning (ingestion)

Bronchitis (inhalation)

Interstitial pneumonitis (inhalation)

Pulmonary edema (inhalation)

A condition that mimics metal fume fever

Children who eat dirt (pica behavior) are at risk

Signs & Symptoms - Chronic

Chronic exposure may result in renal dysfunction and bone disease

Mild anemia, anosmia & yellow discoloration of the teeth may occur

Chronic exposure may effect the sense of smell

Evaluation

Inhalation

Chest radiograph

Chronic exposure

Renal tests

Serum electrolytes, BUN, serum and urinary creatinine, serum creatinine, cadmium in blood & urine, urinary protein

Other tests – CBC & LFTs

Direct Biologic Indicators

24 hour urine cadmium – reflects exposure over time an total body burden

Blood cadmium

Cadmium in hair – not reliable

No quantitative relationship between hair cadmium levels and body burden

Indirect Biologic Indicators

Urinary ß2-microglobulin – evaluate urine levels > 300 g/g creatinine

Urinary RBP

Urinary metallothionein (MT)

Treatment & Management

Acute Exposure

No proven treatment

Supportive treatment includes fluid replacement, oxygen, mechanical ventilation. With ingestion, gastric decontamination by emesis or gastric lavage soon after exposure. Activated charcoal not proven effective

Chronic – Prevent further exposure

Mercury

Mercury

Occurs in three forms (elemental, inorganic salts, and organic compounds)

Contamination results from mining, smelting, and industrial discharges. Mercury in water can be converted by bacteria to organic mercury (more toxic) in fish.

Can also be found in thermometers, dental amalgams, fluorescent light bulbs, disc batteries, electrical switches, folk remedies, chemistry sets and vaccines.

Mercury - Exposure

Elemental liquid at room temperature that volatizes readily rapid distribution in body by vapor, poor in GI

tract Inorganic

poorly absorbed in GI tract, but can be caustic dermal exposure has resulted in toxicity

Organic lipid soluble and well absorbed via GI, lungs and

skin can cross placenta and into breast milk

Elemental Mercury

At high concentrations, vapor inhalation produces acute necrotizing bronchitis, pneumonitis, and death.

Long term exposure affects CNS. Early: insomnia, forgetfulness, anorexia,

mild tremor Late: progressive tremor and erethism (red

palms, emotional lability, and memory impairment)

Salivation, excessive sweating, renal toxicity (proteinuria, or nephrotic syndrome)

Dental amalgams do not pose a health risk.

Inorganic Mercury

Gastrointestinal ulceration or perforation and hemorrhage are rapidly produced, followed by circulatory collapse.

Breakdown of mucosal barriers leads to increased absorption and distribution to kidneys (proximal tubular necrosis and anuria).

Acrodynia (Pink disease) usually from dermal exposure maculopapular rash, swollen and

painful extremities, peripheral neuropathy, hypertension, and renal tubular dysfunction.

Organic Mercury

Toxicity occurs with long term exposure and effects the CNS.

Signs progress from paresthesias to ataxia, followed by generalized weakness, visual and hearing impairment, tremor and muscle spasticity, and then coma and death.

Teratogen with large chronic exposure

Asymptomatic mothers with severely affected infants

Infants appeared normal at birth, but psychomotor retardation, blindness, deafness, and seizures developed over time.

Diagnosis and Treatment

Dx made by history and physical and lab analysis. Inorganic mercury can be measured in 24 hour urine collection; organic mercury is measured in whole blood.

The most important and effective treatment is to identify the source and end the exposure

Chelating agents (DMSA) may enhance inorganic mercury elimination. Dimercaprol may increase mercury concentration in the brain.

Mercury - Prevention

Many mercury compounds are no longer sold in the United States.

Elemental mercury spills:

Roll onto a sheet of paper and place in airtight container

Use of a vacuum cleaner should be avoided because it causes mercury to vaporize (unless it is a Hg Vac)

Consultation with environmental cleaning company is advised with large spills.

State advisories on public limit or avoid consumption of certain fish from specific bodies of water.

Questions?