As Cd Pb Fe

Toxicity by Heavy Metals

Dr. Maha Farid, Hg
MBBCh, MS, PhD.
Dept. Of Forensic Medicine and Clinical Toxicology
Faculty of Medicine
Helwan University

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 1

 Objectives
■ Recognize the common characteristics of heavy metal toxicity.

■ Understand the mechanisms of toxicity by heavy metals.

■ Distinguish the sources of exposure to heavy metals in the environment.

■ Identify the clinical presentations caused by exposure to toxic doses of heavy

metals.

■ Acknowledge the main outlines of managing patients exposed to toxic doses of

heavy metals.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 2

 Heavy Metals
■ Surrounded by heavy metals every where.
■ They are heavy atomic weight or high-density (5 g/cm3) metallic elements.
■ They are toxic at low concentrations.
■ Examples are:
– Arsenic: herbicides and insecticides.
– Mercury: contaminated fish and seafood.
– Lead: battery industry, smelters, pottery, old paints and pigments
– Iron: iron containing medications.
– Cadmium: paints and cigarette smoking.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 3

Int. J. Environ. Res. Public Health 2019, 16(22), 4446;

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 4

Common Characteristics of Toxicity
■ Double action
▪ Local: irritation of the GIT mucosa/respiratory epithelium.

▪ Remote: Parenchymatous organs such as liver, kidneys and heart.

■ Symptoms and signs appear after a latent period following exposure.

■ Cumulative toxic effect: acute and chronic forms of toxicity.

■ Great affinity to keratin tissues.

■ Resistant to putrefaction in post-mortem examination.

■ Causes peripheral neuritis (sensory, motor or both).

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 5

 Common Characteristics of Toxicity (cont.)
■ Biotransformation:
– Renal excretion.
– Gastrointestinal re-excretion.
– Affect the (-SH) in enzymes of oxidation/reduction → General protoplasmic poisons.
■ Management:
– Stomach wash.
– General antidotes: Sodium thiosulfate, tannin, charcoal.
– Specific antidotes: Chelating agents (DMSA, EDTA, BAL, Penicillamine).
■ Detection:
– Atomic Absorption Spectrometry.
– Reinsch’s Test: Soluble Inorganic salts of mercury, arsenic and antimony.
– Marsh’s Test: Organic compounds of arsenic and antimony.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 6

 Mechanism of Action:

SH
SH
SH
Cell SH
Pb2+
enzyme

Apoptosis
Cell damage
O2
ROS H2O ↑ ROS

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 7

 Chelation Therapy
SH

SH
SH Chelator SH
SH
Pb2+ Cell SH
enzyme

Apoptosis
Cell damage
O2
ROS H2O ↑ ROS

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 8

Heavy Metals Cycle in the Environment

M., Oves & Khan, Mohammad & Zaidi, Almas & Ahmad, Ees. (2012). Soil Contamination, Nutritive Value, and Human Health Risk Assessment of Heavy Metals: An Overview. 10.1007/978-3-
7091-0730-0_1.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 9

Occupations associated with HMT

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 10

Industries associated with HMT

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 11

 Mode of Toxicity
■ Accidental
– Very common in the environment.
– Occupational toxicity.
– Cumulative effect.
■ Suicidal
– Easy access (pesticides, environmental products).
– Cheap and flavorless.
■ Homicidal
– Long latent period.
– Odorless and flavorless.
– Different colors: (mixed with different kinds of food).

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 12

Arsenic Toxicity
■ Acute Toxicity:
– Large dose ex. Homicidal or suicidal.
■ Chronic Toxicity:
– Small repetitive doses ex. Occupational exposure.

Mechanism of Action:
• Local: Irritation of epithelium or mucosa depending on the route of exposure.
• Remote: Affects the parenchymatous organs and skin.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 13

Arsenic Salts

Kwan, Stanley S.K.. “The role of ASK1 in arsenic trioxide-induced cell death.” (2013).

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 14

 Manifestations of Arsenic Toxicity

Muhammad Shahid, Camille Dumat, Nabeel Khan Niazi, Sana Khalid et Natasha, « Global scale arsenic pollution : increase the scientific knowledge to reduce human exposure », Vertigo - la revue électronique en
sciences de l'environnement [En ligne], Hors-série 31 | septembre 2018.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 15

 Dermatopathology of Chronic Arsenic Toxicity
(a) Palms and fingers: Punctate and
diffuse keratosis.

(b) Palms and fingers: Punctate

keratosis on right hand and
Bowen’s carcinoma on the left
hand.

(c) Dorsum of foot: Diffuse and

punctate pigmentation.

(d) Sole: Severe punctate keratosis.

(e) Chest: Diffuse pigmentation and

punctate leukoderma.

(f) Forehead: Multiple Bowen’s

disease.
Hossain K., Hasibuzzaman M.M., Himeno S. (2019) Characteristics and Health Effects of Arsenic Exposure in Bangladesh. In: Yamauchi H., Sun G. (eds) Arsenic Contamination in Asia.
Current Topics in Environmental Health and Preventive Medicine. Springer, Singapore.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 16

 Dermatopathology of Chronic Arsenic Toxicity

Iatrogenic induced Mees’ lines following cancer Chronic Arsenic poisoning causing Mees’ lines in the nail.
chemotherapy with Arsenic trioxide.

Bagic, Anto & Lupu, V & Kessler, C & Tornatore, Carlo. (2006). Iatrogenic arsenic induced Mees' lines. Postgraduate medical journal. 82. 515. 10.1136/pgmj.2006.045229.
Heavy Metal Poisoning: Clinical Presentations and Pathophysiology - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Arsenic-poisoning-and-Mees-lines-
Courtesy-of-R-Pascuzzi-MD-Indianapolis-IN_fig1_7212503.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 17

 Mercury Toxicity
■ Mode of Toxicity:
– Accidental:
• Acute: irritation and severe pain.
• Chronic: CNS presentation.
■ Compounds:
– Organic salts: pesticides, embalming → Seafood (NOT for pregnant women and infants).

– Inorganic salts: cosmetics, disinfectants, explosive devices.

– Metallic Mercury: dental amalgam, thermometers, vapor lamps.

■ Mechanism of Action
– Local: Irritation of epithelium or mucosa (contact dermatitis, corrosive like action).
– Remote: Affects the parenchymatous organs (liver and kidneys) and CNS.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 18

Metallic Mercury

Thermometers

Dental fillings (amalgam)

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 19

Methylmercury
■ Easy Absorption.
■ Bioaccumulation.
■ Biomagnification.
■ 1950s, Minamata Japan.

https://www.sfei.org/calendar_events/4326#sthash.NfPZjZGN.dpbs

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 20

Ethyl mercury (Thimerosal)

https://www.cdc.gov/vaccinesafety/concerns/thimerosal/index.html

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 21

Manifestations of Mercury Toxicity

https://www.alignable.com/oroville-ca/forum/do-you-know-what-heavy-metals-are-and-how-to-remove-them-from-our

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 22

Manifestations of Hg
Toxicity
Pink Disease:
■ Common in Children.

■ Hypersensitivity or idiosyncrasy .

■ Acrodynia: swollen, erythematous and desquamated skin of the

extremities associated with paresthesia.

■ Other manifestations: irritability, excessive salivation, tachycardia

and hypertension.

■ Differential Diagnosis: Kawasaki Disease. Pink ladies: mercury poisoning in twin girls
Michael Weinstein, Stacey Bernstein
CMAJ Jan 2003, 168 (2) 201;
12/8/2020 Toxicity by Heavy Metals_MF, PhD. 23
Manifestations of Hg
Toxicity
Mercurial Erethism:
Mental disorder with behavioral patterns:
– Mood changes.
– Irritability.
– Shyness and not wanting to work under observation.
– Depression.
– Explosive anger episode alternating with apathy.
– Loss of memory.
– Insomnia and sleep disorders.

Toxicity by Heavy Metals_MF, PhD. 12/8/2020 24

Manifestations of Hg
Toxicity
Mercury Gingivitis:
– Mercury re-excreted in saliva.

– Excessive salivation.

– Swollen painful bleeding gums.

– Grey linear pigmentation of the gums.

– Loss of teeth.

Toxicity by Heavy Metals_MF, PhD. 12/8/2020 25

Lead Toxicity
Inorganic:
• Metallic lead:
o Alloys with other metals such as copper and tin.
o Used in battery manufacturing and electronics.
o Very toxic in both gas and solid forms.
• Lead salts:
o Oxides soluble in water containing ammonia and weak acids.
o Used in paints and pigments: colored substances.
Organic Lead:
o Gasoline: tetra-ethyl lead increases fuel efficiency.
o Insecticides: lead arsenate.
o Medical remedies: Lead acetate or subacetate (ecbolic).
12/8/2020 Toxicity by Heavy Metals_MF, PhD. 26
Lead Toxicity
Mechanism of Action
• Local: Irritation of epithelium, mucosa or skin.
• Remote: Affects the parenchymatous organs (liver and kidneys), CNS and bones.

Routes of Toxicity
• Oral : Most common, soluble lead compounds ex. Lead subacetate.
• Inhalation: Lead fumes.
• Contact: Tetra-ethyl lead only absorbed through the skin.
• Tissue Absorption: Following unremoved retained lead bullets or shots in the body.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 27

Lead Toxicity

Distribution in the body

• Follows the Ca2+ metabolism in the body.

• Stored in the epiphysis of long bones.

• Deposition of lead into the bones:

✓ Alkalis, Vit D and Ca2+ rich diet.

• Mobilization of lead from the bones:

✓ Ammonium Chloride, iodides and PTH.

Toxicity by Heavy Metals_MF, PhD. 12/8/2020 28

Lead Toxicity

Acute Lead poisoning Chronic Lead poisoning

■ Overdose: ■ Household exposure
• lead-containing traditional medical ■ Industrial exposure
remedies .
■ Absorption from retained shots or bullets.
• large amounts of lead salts.
■ Sudden de-leading.
■ Exposure to contaminated air with lead.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 29

Manifestations of Lead Toxicity

https://chewingthesfat.com/flinth2o/leadpoisoning.html

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 30

 Complications of Chronic Lead Poisoning
Plumbism
■ Mental Retardation in young children.

■ Peripheral Neuritis: mainly motor, affect extensor muscles.

■ Demyelination of axis cylinders of the peripheral nerves.
■ Wrist Drop and/or ankle drop.

■ Optic Nerve Atrophy.

■ Burton’s line: Blue-purplish line in the gums around the teeth.

■ Reaction between lead and Sulphur ions produced by the oral bacteria.

■ Anemia: Basophilic stippling of the red blood cells.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 31
12/8/2020 Toxicity by Heavy Metals_MF, PhD. 32
Helmich F, Lock G N Engl J Med. 2018 Nov 8;379(19):e35. doi:
10.1056/NEJMicm1801693.

Warang, P., Colah, R.B., & Kedar, P.S. (2017). Lead Poisoning Induced Severe Hemolytic Anemia, Basophilic
Stippling,Mimicking Erythrocyte Pyrimidine 5'-nucleotidase Deficiency in BetaThalassemia Minor.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 33

 Iron Toxicity
■ Most commonly accidental toxicity.

■ In children → large doses of iron pills (mistaken for

candy).

■ Fatal iron poisoning > fatal aspirin poisoning.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 34

 Iron Toxicity
■ Mechanism of Action:
• Local:
• Corrosive effect on the GIT mucosa → coagulative necrosis.
• Cause of death: bleeding and shock.

• Remote:
• Increase capillary permeability → loss of plasma → ↓ blood volume → hypovolemic shock.
• Cellular Hypoxia → Acidosis.
• Hepatotoxicity: direct toxic effect on the mitochondria of the liver.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 35

 Phases of Acute Iron Toxicity
■ Stage I: Local GIT manifestations (1/2- 6hrs).
▪ Corrosive effects on stomach and duodenum → bloody diarrheal, hematemesis.

■ Stage II: Quiescent stage (6- 24hrs).

▪ Apparent recovery: compensation of the GIT manifestations.

■ Stage III: Systematic Toxicity (12- 24hrs).

▪ Hypovolemia and Acidosis → pallor, cold extremities, tachycardia and tachypnea and hypotension.
▪ Direct toxic effect of iron on the cardiac muscles.

■ Stage IV: Hepatic Necrosis (24-48hs).

▪ Portal blood delivers high level of iron to the liver → hepatic necrosis and metabolic acidosis.
▪ Disturbed coagulation mechanisms and inhibition of clotting factors.

■ Stage V: Intestinal obstructions (4-6wks).

▪ Due to pyloric stenosis and gastric fibrosis.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 36

 Management
(5S)

Stabilization Of Symptomatic Stomach Wash Specific Antidote Stop Further

The Patient Treatment Chelation Therapy Exposure

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 37

Chelation Therapy
■ Iron → Defroxamine.

■ Lead → E.D.T.A.(Ethylene Diamine Tetra-acetic Acid).

D.M.S.A (DiMercapto Succinic Acid).

■ Mercury → B.A.L(British Anti Lewisite).

Penicillamine.
D.M.S.A.

■ Arsenic → B.A.L(British Anti Lewisite).

Penicillamine.
D.M.S.A.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 38

Self Learning Topics

ARSINE GAS TOXICITY.

CADMIUM TOXICITY

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 39

References
■ Olivier Pourret, Andrew Hursthouse, Int. J. Environ. Res. Public Health 2019, 16(22), 4446.
■ M., Oves & Khan, Mohammad & Zaidi, Almas & Ahmad, Ees. (2012). Soil Contamination, Nutritive Value,
and Human Health Risk Assessment of Heavy Metals: An Overview. 10.1007/978-3-7091-0730-0_1.
■ Muhammad Shahid, Camille Dumat, Nabeel Khan Niazi, Sana Khalid et Natasha, « Global scale arsenic
pollution : increase the scientific knowledge to reduce human exposure », VertigO - la revue électronique
en sciences de l'environnement [En ligne], Hors-série 31 | septembre 2018.
■ Kwan, Stanley S.K. “The role of ASK1 in arsenic trioxide-induced cell death.” (2013).
■ Hossain K., Hasibuzzaman M.M., Himeno S. (2019) Characteristics and Health Effects of Arsenic
Exposure in Bangladesh. In: Yamauchi H., Sun G. (eds) Arsenic Contamination in Asia. Current Topics in
Environmental Health and Preventive Medicine. Springer, Singapore.
■ Heavy Metal Poisoning: Clinical Presentations and Pathophysiology - Scientific Figure on ResearchGate.
Available from: https://www.researchgate.net/figure/Arsenic-poisoning-and-Mees-lines-Courtesy-of-R-
Pascuzzi-MD-Indianapolis-IN_fig1_7212503.
■ https://www.cdc.gov/vaccinesafety/concerns/thimerosal/index.html

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 40

References
■ https://www.sfei.org/calendar_events/4326#sthash.NfPZjZGN.dpbs
■ https://www.alignable.com/oroville-ca/forum/do-you-know-what-heavy-metals-are-and-how-to-remove-them-
from-our
■ Michael Weinstein, Stacey Bernstein, Pink ladies: mercury poisoning in twin girls, CMAJ Jan 2003, 168 (2) 201;
■ https://chewingthesfat.com/flinth2o/leadpoisoning.html
■ Suraj Chandrasekar, MD; Laurie M. Lomasney, MD; Nathan Derhammer, MD, Systemic Lead Toxicity
,Orthopedics. 2015;38(10):592, 644-64
■ Olivier Pourret, Andrew Hursthouse, Int. J. Environ. Res. Public Health 2019, 16(22), 4446.
■ Helmich F, Lock G N Engl J Med. 2018 Nov 8;379(19):e35. doi: 10.1056/NEJMicm1801693.
■ Warang, P., Colah, R.B., & Kedar, P.S. (2017). Lead Poisoning Induced Severe Hemolytic Anemia, Basophilic
Stippling,Mimicking Erythrocyte Pyrimidine 5'-nucleotidase Deficiency in BetaThalassemia Minor.

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 41

Take Home message

Contact:
Maha.farid@med.helwan.edu.eg

spreadshirt.com

12/8/2020 Toxicity by Heavy Metals_MF, PhD. 42