17 Lead as a colorant or to add weight to food, folk medicines, herbal remedies, illicit drugs and cosmetics: these uses of lead are probably banned in most jurisdictions, yet examples abound because poverty has not been eradicated and lead is the cheapest pigment or weight that can be added, as it is so easily retrieved.
Proposed MOA for arsenic and examples of biochemical effects that result from this action.
Toxicity of Heavy Metals
• Most common heavy metals
toxicity: lead (Pb), mercury (Hg),
cadmium (Cd) and arsenic (As)
• They are mainly produced by
industrial activities, and deposit
slowly in the surrounding water
• Toxicity may occur through ingestion,
inhalation or dermal exposure
• Toxicity is either acute or chronic
• Metallic taste if ingested except arsenic
which is tasteless
• Can cause both local & systemic effects
• Most metals cause diarrhea except lead
which causes constipation
• The antidotes are called chelators
• The most common metallic poison.
• Occurs in organic and inorganic forms.
• Absorption of ingested lead in children is
much more than in adults (50% children&
10% in adults).
• Probably the most important chronic
environmental illness affecting children.
• In children, probably no organ system is
immune to the effects of lead poisoning.
• Developing brain is the most risky organ to be affected.
1- Occupational: More than 900 occupations. Parents
may bring lead dust.
2- Some cosmetics and folk remedies.
3- Water & Food contamination: lead pipes or storage
tanks, and eating contaminated food.
4- Foreign body ingestion: several reports have
documented cases of childhood lead poisoning
resulting from the ingestion of lead-based foreign
5- Retained bullet
6- Illegally manufactured alcohols
7- Inhalation of lead from motor vehicle
LEAD AS A COLORANT OR TO ADD
WEIGHT TO FOOD
• Lead has a high affinity for SH groups. It is therefore particularly
toxic to multiple enzyme systems.
• Many of lead’s toxic effects also result from its inhibition of
cellular function requiring calcium.
• Lead binds to calcium-activated proteins 105 times than Ca2+
• Pb2+ and Ca2+ compete at the plasma membrane for transport
systems, which affect their entry or exit (ie, Ca2+ channels and
the Ca2+ pump.)
• Intracellular Ca2+ is buffered by proteins, endoplasmic
reticulum, and mitochondria; Pb2+ disturbs this intracellular
• Pb2+ interacts with a number of Ca2+-dependent effector
mechanisms, such as calmodulin (Ca2+ binding protein,
which couples to several enzymes, eg, phosphodiesterase,
• Hypochromic Microcytic
• More in children
•Inhibition of heme synthesis:
•a) Inhibits conversion of DALA to porphobilinogen.
•b) Inhibits conversion of coproporphyrinogen III to
•c) Blocks incorporation of iron into protoporphyrin to
form heme. Protoporphyrin accumulates in RBCs and
chelate zinc. EP reflects chronic lead exposure.
ENZYMES INVOLVED IN THE INHIBITION OF HEME SYNTHESIS
• Increase of RBC fragility
• Erythropoietin deficiency: from the toxic
effects of lead on renal tubules.
• Inhibition of 5-pyrimidine nucleotidase:
aggregation of ribosomes, appearing as
basophilic stippling of RBCs (not specific to
Inhibition of 5-
stippling of RBCs
(not specific to
• Acute toxicity may cause renal colic.
• Acute toxicity may cause direct tubular
damage (Fanconi-like syndrome)
• Chronic toxicity may cause chronic
• Alters rennin-angiotensin system and
may cause hypertension.
• Alters uric acid excretion resulting in
hyperuricemia and gout
• Direct effect on CNS causing lead
encephalopathy especially in children.
• Delayed or reversed development,
permanent learning disabilities.
• Children below 3 Y are at the greatest
risk (brains are rapidly developing).
• DALA is thought to be neurotoxic by
interfering with GABA.
• Chronic lead exposure affects peripheral
nerves mainly the motor (radial nerve)
D- Reproductive System Effects
• Abortion, stillbirth, neurodevelopmental problems.
• May cause decreased sperm count, and increased
number of abnormal sperms.
E- Bone Effects
• Triggers hypermineralization (reflected in
metaphyseal & growth plate densities (lead lines).
• They reflect bone growth arrest and not deposition.
Their width is related to the duration of exposure.
• Lead inhibits the conversion of vitamin D into its
• More commonly on top of chronic
1- GIT: anorexia, abdominal pain,
2- CNS: encephalopathy, behavioral
changes, lethargy, fatigue, seizures &
CHRONIC TOXICITY (PLUMBISM)
• Nonspecific: vague body aches, anorexia, constipation
and abdominal colic.
• Blue lines on the gums and around anal marginsdue to
bacterial action precipitating lead sulfide.
• Neuropathy: wrist drop and foot drop. Optic
neuropathy may occur.
• CNS: cognitive disturbances, headache and
• Anemia, reticulocytosis and hemolysis.
• Renal impairment.
• Bony aches and gouty arthritis.
2B. Agent is possibly carcinogenic
•Human epidemiology data weak
•Animal data positive
(NOAEL) NO OBSERVABLE ADVERSE EFFECT LEVEL
NOAEL: An exposure level at which there are no statistically or
biologically significant increases in the frequency or severity of
adverse effects between the exposed population and its control.
it is the highest tested dose or concentration of a substance at
which no such adverse effect is found in exposed test organisms
where higher doses or concentrations resulted in an adverse effect
NOAEL is absent in Lead toxicity
S1- Blood Lead level
• less than 5 µg/dL for children (before 2012 as 10 (µg/dl).
• less than 25 µg/dL for adults
• biological exposure index (a level that should not be exceeded) for
lead-exposed workers in the U.S. is 30 µg/dL in a random blood
2- Blood zinc protoporphyrin (ZPP) (Free erythrocyte Protoporphyrin
• The normal range for ZPP is 0-35
• Its gives clue about duration of toxicity
• can be used as screening test
3- Urine DALA
• 1 - 8 years: 2.3-6.2 mg/g creat
• 9 - 17 years : 1.5-5.3 mg/g creat
• ≥ 18 years:
• Females : <5.4 mg/g creat
• Males : <1.8 mg/g creat
All Australians should have BLL below
• “It was never intended that this goal of 10 µg/dL be interpreted as a
‘safe’ level of exposure or a ‘level of concern’”, rather, it is the level
at which sources of exposure to lead should be investigated.
RECOMMENDED BLOOD LEAD
• Update on BLLs in Children
• Reference BLLin children below 6 Ys is 5 µg/dL
• This new level is based on the U.S. population of
children ages 1-5 years who are in the highest 2.5%
of children when tested for lead in their blood.
• The new recommendation does not change the
guidance that chelation therapy be considered
when a child has a blood lead test result greater
than or equal to 45 µg/dL
CENTERS OF DISEASE
CONTROL & PREVENTION
2- A baseline hemogram
Typical pattern of iron-deficiency
anemia with hypochromia and
3- A chemistry profile including:
RFT, LFT & uric acid.
• Adults may have elevated uric avid
because of the disturbance of
enzymatic amino hydrolases
Removes intracellular & extracellular lead.
It is a lipid-soluble drug and must be administered
IM only as IV may cause fat embolism.
It is the first chelator used in encephalopathic
individuals. Rapidly crosses the BBB.
Calcium disodium edentate (Ca Na2
Allows extracellular lead to be renally
Once started CaNa2EDTA should be given in full 5-day course.
The first dose begins removing lead from extracellular fluid in
bone, if not followed by next doses free lead neurotoxicity.
In cases of lead encephalopathy, BAL should be given first to
avoid redistribution of lead mobilized by CaNa2EDTA to CNS.
• orally and has few adverse effects.
• Can chelate lead even in low blood levels.
• Effective in children with levels 20-40
Dimercaptosuccinic acid (Succimer or DMSA):
5- Dimerval (DMPS):
Has become antidote for most heavy metal intoxications. It is
available in the oral form and in a water-based parenteral form.
• Depends on whether
acute or chronic
poisoning according to
• The only metal that is liquid at room
• Elemental symbol is Hg: Greek word
hydrargyrias “water silver.”
• Found in 3 forms but all are toxic:
1) Elemental (metallic) mercury (Hg0)
3- Inorganic mercury:
Cosmetics, disinfectants, explosives, ink
manufacturing, mirror silvering, perfume
industry, photography, spermicidal jellies,
tattooing inks, and wood preservation.
Vaccine preservative to prevent bacterial
contamination. Most commonly vaccines
that contain Thimerosal are DTP,
Haemophilus influenzae, and hepatitis B.
Toxicity by inhalation exposure
Poorly absorbed from GIT (eg, thermometers) .
Once inhaled, it is mostly converted to inorganic Hg (limited permeability to BBB).
Acute toxicity might result in:
• Fever, fatigue, and clinical signs of pneumonitis.
Chronic exposure results in
• neurologic, dermatologic, and renal manifestations.
• Signs and symptoms might include:
• neuropsychiatric disturbances (e.g., memory loss, irritability, or depression)
• flushing, discoloration and desquamation of the hands and feet
In January 2008, Norway and Sweden totally
banned mercury fillings. In April 2008,
Denmark banned mercury fillings Ingested Elemental Hg
• Ingestion is the main route of ingestion
• Largest outbreaks are related to organic mercury (fungicide, seed
dressing, contaminated fish)
• Marine animals convert elemental to organic mercury in their
• Minamata (1940) Japan
• Iraq (1974)
• Toxicity is mainly neurologic
• Visual field defects
• Hearing loss
• Mental deteriration
• Main absorption by ingestion and skin
• Can be corrosive to mucosal membranes
• Poor lipid solubility:
• causes a non-uniform distribution with
kidney accumulation, causing renal
• Limit CNS penetration, but chronic
exposure allow for CNS accumulation &
TOTAL AMOUNT OF MERCURY (ΜG) RECEIVED BY LIBYAN CHILDREN
FROM VACCINES IN FIRST 2 YEARS OF LIFE ACCORDING TO OLD AND
NEW IMMUNIZATION SCHEDULES (2007)
Vaccine LIBYA USA
Total 37.5 µg 112.5 µg ? 237.5 µg < 2.7 µg
• Mercury reacts with sulfhydryl (SH) groups,
resulting in enzyme inhibition and pathologic
alteration of cellular membranes.
• Elemental and methylmercury are particularly
toxic to the CNS. Metallic mercury vapor is
also a pulmonary irritant.
• Methylmercury is teratogenic.
• Inorganic mercuric salts are corrosive to the
skin, eyes, and gastrointestinal tract, and are
• An immune mechanism is attributed to
membranous glomerulonephritis and acrodynia.
1- Acute inhalation elemental
• Dyspnea and pleuritic chest pain.
• Lethargy, confusion.
• Fatal ARDS has been reported
following elemental mercury
2- Acute ingestion of inorganic mercury &
Its corrosive properties account for
most of the acute signs and
The presentation can include
a) Gray mucous membranes.
b) Vomiting, severe abdominal pain,
hematemesis, and hypovolemic shock.
c) Systemic effects usually begin several
hours postingestion and may last
3- Acute ingestion of organic mercury
• Contaminated food.
• Organic mercury targets specific sites in the brain,
including the cerebral cortex (especially visual
cortex), motor and sensory centers , auditory
center, and cerebellum.
• Onset of symptoms usually is delayed
(days-weeks). Depletion of enzymes must
occur before the onset of symptoms.
• Symptoms are typically neurological:
• visual (eg, scotomata), ataxia, paresthesias, hearing loss,
dysarthria, mental deterioration, muscle tremor, movement
Acrodynia (Pink disease):
• considered to be a mercury allergy
• erythema of the palms and soles
• edema of the hands and feet
• desquamating rash
• hair loss
• tachycardia, hypertension,
• poor muscle tone
• constipation or diarrhea
MERCURY WAS ADDITIVE FOR
TEETHING POWDER UNTIL 1950
• All forms are toxic to the
fetus, but methylmercury
most readily passes through
• Even with an asymptomatic
patient, maternal exposure
can lead to spontaneous
abortion or retardation.
Country No. of Subjects Mean level µg/L Level range µg/L References
Belgium 474 15 1.1-103 Lauwerys et al.
Italy 80 20 0-46 Pallotti et al. (1979)
Japan 11 6.6 2 – 16.4 Suzuki et al. (1984 b)
Norway 103 11.3 0.6 – 24 Lie et al. (1982)
Poland 270 11.3 2.5-24 Szucki & Kurys
Kuhnert et al. (1981)
Schober et al. (2003)
Jones et al. (2010)
South Korea 293 8.63 1.48 – 45.71 Eun-mi Jo (2010)
Canada 492 16 0.8 – 112 * Dewailly E et al.
Sweden 106 3.4 0.4 – 16 Johansson N et al.
1- Blood levels less than 2 µg/L in unexposed
individual (exceptions individuals with a high dietary intake of fish).
2- Urine mercury levels less than 10-20 µg/L.
3- Hg can be found in hair because high SH group
• False-positive results secondary to environmental exposure.
• Do not use hair analysis solely to confirm mercury toxicity.
Removal of contaminated clothing and skin irrigation
Do not induce emesis if the compound ingested is caustic
Gastric lavage is recommended for organic ingestion, especially if
the compound is observed on the abdominal x-ray series.
Whole bowel irrigation may be used until rectal effluent is clear
and void of any radiopaque material.
Use chelating agents if the patient is symptomatic or if increased
blood or urine levels.
1. Metallic (elemental) mercury: In acute or chronic
• Oral DMSA may enhance urinary Hg excretion.
• Penicillamine is an alternative oral treatment.
2. Inorganic mercury salts:
• BAL if begun within minutes to a few hours after
ingestion, may reduce severe renal injury.
• Oral DMSA is also effective.
3. Organic mercury:
• Oral DMSA may be effective in decreasing Hg in
tissues, including brain.
BAL should not be used in metallic or organic mercury as
it redistribute mercury to the brain from other tissue sites.
CaNa2EDTA is contraindicated. It makes with Hg a
• Hemodialysis is used in severe
cases of toxicity when renal
function has declined.
• Neostigmine may help motor
function in methylmercury
toxicity. This toxicity often
leads to acetylcholine
• Grayish corrosion of GIT
• Ulceration of large intestine
• Congestion of kidneys
• Homicidal agent
• Signs & symptoms mimic natural diseases
• Ease of administration; odorless, tasteless
• Foods: daily human intake of arsenic contained in
food 0.5-1 mg, with the greatest mainly from fish In
seafood, arsenic is mainly found in its less toxic
• Water: A 2007 study found that over 137 million
people in more than 70 countries are probably
affected by arsenic poisoning from drinking water.
WHO recommends a limit of 0.01 mg/L of arsenic in drinking water
• Industry: herbicide, fungicide, wood preservative.
FORMS OF ARSENIC
• Arsenic exists in:
1- Inorganic (arsenite)
2- Organic (arsine)
3- Elemental form
1. Arsenic distributes rapidly to erythrocytes and
binds to the globin portion of hemoglobin
2. Redistribution occurs within 24 hours to the
liver, spleen, kidney & GIT
3. Arsenic impairs cellular respiration by
inhibiting mitochondrial enzymes and oxidative
4. Blocks pyruvate dehydrogenase in Kreb’s cycle
5. Over a period of weeks, deposits may be found
in skin, hair, nails, bone.
Arsenic produces cellular damage by:
• binding to enzyme SH groups.
• Massive fluid transudation into the bowel.
• Arsenic blocks the conversion of pyruvate to acetyl
coenzyme A and inhibits gluconeogenesis.
• Long-term exposure results in nerve damage
and may lead to lung, skin, or liver cancer.
• Once inhaled, arsine gas combines with
hemoglobin severe hemolysis and anemia.
Proposed MOA for arsenic and examples of biochemical effects that result from this action.
Hughes M F et al. Toxicol. Sci. 2011;123:305-332
Published by Oxford University Press on behalf of the Society of Toxicology 2011.
1. It is cheap
2. Easily obtained
4. No smell
5. No taste
6. Small quantity is required to cause death.
7. Can be easily administered with food or drink.
8. Symptoms simulate those of Cholera.
Arsenic is a Homicidal poison
SIGNS AND SYMPTOMS
1.The Fulminant type
2.The Gastroenteric Type
THE FULMINANT TYPE
• Massive doses of arsenic when rapidly
absorbed cause death in one to three
hours from shock and peripheral
• All the capillaries are markedly dilated,
especially in the splanchnic area with a
marked fall of blood pressure.
THE GASTROENTERIC TYPE
• This is the common form of acute poisoning and resembles
bacterial food poisoning.
• Symptoms usually appear half to one hour after ingestion,
but may be delayed many hours especially when arsenic is
taken with food.
• Burning and colicky pain in the esophagus, stomach and
• Intense thirst and severe vomiting which may be projectile
are the common symptoms.
SIGNS AND SYMPTOMS
• Acute severe arsenic poisoning
• Vital signs - Tachycardia and hypotension, even shock
• CNS - Altered mental status, delirium, coma, and seizures
• Frequently, patients exposed to arsenic have a garlic smell
to their breath and tissue fluids.
SIGNS AND SYMPTOMS
• Acute exposures generally manifest with the cholera-
like gastrointestinal symptoms of
• vomiting (often times bloody) and
• severe diarrhea (which may be rice-watery in
character and often bloody);
• these patients will experience acute distress,
dehydration (often), and hypovolemic shock.
SIGNS AND SYMPTOMS
• Arsine gas exposure
manifests with an acute
hemolytic anemia and striking
• Hemoglobinuria causes the
urine to appear black, and the
patient becomes rapidly
obtunded and shocky.
• Shaking chills are often
described in these patients.
Frequently, patients exposed to arsenic have a
garlic smell to their breath and tissue fluids.
• Peripheral Neuropathy: it affects sensory part
more than the motor one, often present with the
complaint of painful paresthesias.
• Black Foot Disease: peripheral vascular disease
due to peripheral vascular obliteration appearing
with acrocyanosis, Raynaud’s phenomenon.
• Dermatologic Effects: alopecia, hypo- or
hyperpigmentation, palmoplantar keratosis.
• Mee’s lines: transverse white lines in the nails
appear several weeks after mercury exposure.
Chronic toxicity is more insidious and may manifest as a
classical dermatitis (hyperkeratosis with a classical "dew
drops on a dusty road" appearance) 75
whitish lines (Mees lines) that look
much like traumatic injuries are found
on the fingernails.
Contact dermatitis may also be
induced in occupational arsenic
poisoning. Arsenic dust coming
into contact with the skin
produces four main types of
3. Combined toxic and
4. Reactions characterized by
• Blood and urine arsenic levels
• Normal blood arsenic level is < 7 µg/dl
• Ideal urine test is 24-hour urine collection
• Hair & Nails
• Arsenic is normally found in higher
concentrations in human hair and nails than
in other parts of the body. This has been
explained by the high content of keratin in
these tissues .
• BAL (British Antilewisite)
•Lewisite is arsenic-
containing vesicant gas
• DMSA (Succimer)
1. Pigmentation of skin
2. Mees lines in finger nails
3. Garlic odor of gastric contents
4. Subendocardial hemorrhage
5. Fatty degeneration of liver