1. Scott Phillips, MD, FACP, FACMT, FAACT Marci Balge, RN, MSN, COHN-S
Heavy Metal Toxicity
Scott Phillips, MD, FACP, FACMT, FAACT
Marci Balge, RN, MSN, COHN-S
Arsenic
Lead
Mercury

2. 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 ,(210)

3. 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

4. Periodic Table

5. ‘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

6. Acute single exposures
urine
blood
Metal levels
time
exposure

7. 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.

8. 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?

9. Azarcon Azarcon is a folk remedy that contains 85-96% lead tetroxide
Other lead containing remedies include Greta.

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

11. Lead

12. 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

13. Sources of Exposure Soil and dust Paint chips Contaminated water
Parents lead-related occupation
Folk remedies
Congenital exposure
Pica
Developmental delay

14. 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

15. Pharmacokinetics and Pharmacoynamics
Distributed extensively throughout tissues: bone, teeth, liver, lung, kidney, brain, and spleen

16. Lead crosses the BBB and concentrates in the gray matter
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 (30g-200 g/day)
Feces

17. Clinical Manifestation
Acute toxicity
Acute encephalopathy, renal failure and severe GI symptoms

18. 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)

19. Mitochondrion Copro* Uropor PBG ALA* Copro-0 Copro Protoporphyrin IX*
Heme
Cytoch-C
Bilirubin + Fe
ALA-D Pb
Ferro-C
4Fe++
ALA-S
Oxidase
(microsomal)
Glycine
Succinyl-Coa
ALA- aminolevulinic acid
 in plasma and urine
COPRO- coprorphyrinogen
 in urine
Protoporphyrin
 accumulates in the RBC

20. 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

21. Range of Lead-induced Health Effects in Adults and Children
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

22. Childhood Lead Poisoning
Childhood lead poisoning is now defined as a blood lead level of 10 g/dl

23. 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

24. 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

25. 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

26. Treatment Environmental inspection/hazard reduction
Nutritional supplementation
Chelation therapy

27. Nutritional Supplementation
Iron supplementation
Calcium supplementation – calcium rich foods
Phosphorus supplementation
Frequent food consumption- regular meals + snacks

28. Chelation Therapy BLL > 70 g/dl or encephalopathy
Hospital admission
Administration of a parenteral chelator
BLL > 45 g/dl- oral chelator
BLL g/dl- if these levels persist despite environmental intervention

29. Arsenic

30. 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

31. Introduction Commercial products Food Others Wood preservatives
Pesticides
Herbicides
Fungicides
Food
Seafood and fish
Others
Antiparasitic drugs
Folk remedies

32. 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

33. 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)

34. 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

35. Pathophysiology Trivalent forms: Pentavalent 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

36. Manifestations of acute arsenic poisoning
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
Hours
Hematopoietic system
Hemolysis
Hematuria
Lymphopenia
Pancytopenia
Several weeks
Pulmonary
(primarily in inhalational exposures)
Cough
Dyspnea
Chest Pain
Pulmonary edema
Liver
Jaundice
Fatty degeneration
Central necrosis
Days
Kidneys
Proteinuria
Acute renal failure
Hours to days

38. Palmer Keratosis

39. Biological Monitoring
Urinary arsenic measurement
Spot sample (mcg/L)
Timed urine collection (mcg/24 hours)
Normal values
Spot urine= ~10 mcg/L ( mcg/L)
24 hours urine collection=<25 mcg/24 hours
Whole blood= <1mcg/L (usually is elevated in acute intoxication)

40. 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

41. 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

42. 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

43. Cadmium

44. What is Cadmium? Cadmium is used in batteries
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

45. 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

46. 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

47. 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

48. 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.

49. 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

50. 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

51. 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

52. 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

53. 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

54. 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

55. 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

56. Evaluation Inhalation Chronic exposure Chest radiograph Renal tests
Serum electrolytes, BUN, serum and urinary creatinine, serum creatinine, cadmium in blood & urine, urinary protein
Other tests – CBC & LFTs

57. 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

58. Indirect Biologic Indicators
Urinary ß2-microglobulin – evaluate urine levels > 300 g/g creatinine
Urinary RBP
Urinary metallothionein (MT)

59. 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

60. Mercury

61. 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.

62. 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

63. 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.

64. 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.

65. 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.

66. 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.

67. 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.

68. Questions?