Transcript Hematotoxicity File

Hematotoxicit
y
Dr. Basma Damiri
Chapter 4
Direct effect on RBCs
1.
2.
Competitive inhibition of oxygen binding
to hemoglobin
Chemically induced anemia
Competitive inhibition of oxygen
binding to hemoglobin
 CO
→ binds to the heme iron in the hemoglobin
 Cyanide → binds to the heme iron in the
hemoglobin and inhibition of mitochondrial energy
production.
 H2S → binds to the heme iron in the hemoglobin
and inhibition of mitochondrial energy production.
Methemoglobin
 Does
not bind or transport O2.
 Its accumulation is detrimental and
prevented by the enzymatic reduction of
ferric to ferrous iron via enzyme
methemoglobin reeducates (diaphorase)
 Normal value is 0.5% or less.
Accumulation of Met-Hb
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Bluish discoloration of the skin and mucosa
membranes.
Levels less than 10 % may be asymptomatic except
for the bluish color.
10-20%  hypoxia
>20%  cardiovascular and neurological
complication related to hypoxia
>40 % combined with headache, dizziness,
nausea, and vomiting
>60%  leathal
causes
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Inorganic nitrite
Na-nitrite and chlorate (CIO3)
Oxidized ferric- hemoglobin (Fe ++)
Nitrate but once it is reduced to nitrite by bacteria in the
gut.
Aromatic amines and nitro compounds such as aniline
and nitrozbenze leading to hemolytic anemia
Dapsone and primazuine  leading to hemolytic
anemia
All can be found in contaminated drinking water 
Jericho
Redox cycle
The
oxidative
methemoglobin
conversion
by
of
nitrites
hemoglobin
and
to
chlorates,
combined with the reduction of methemoglobin
back to ferrous-hemoglobin
Chemicals -induced bone
marrow damage
Granulocytopenia is caused as following
administration of :
cancer chemotherapeutic drugs,
 antibiotic chloramphenicol,
 anti-inflammatory agents such as
butazolidin
 Exposure to benzene
Result: low granulocytes to maintain the first line
of defense against infectious agents, and
recurrent infection is likely.
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Blood Toxicants
1.
2.
3.
Benzene- induced bone marrow
suppression
Aniline and nitrobenzene induced
methemoglobinemia.
Hydrogen sulfide-induced effect
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Oh Yeah, by the way:
Hydrogen Sulfide Gas
is a toxic (poisonous) gas that
can kill you the first time you breath
it!
Hydrogen Sulfide is an extremely
toxic gas that is colorless,
flammable, heavier than air, soluble
in water, and has the smell of rotten
eggs at lower concentrations.
What is H2S?
S
H2S is naturally occurring chemical produced by
bacteria as it decomposes organic material.
Hydrogen Sulfide is generated as a common by-product of
industrial and manufacturing processes.
H
It may develop in low oxygen
environments, such as, sewers,
swamps and polluted water.
Hydrogen Sulfide is formed under low oxygen conditions when
sufficient amounts of sulfur and bacteria are present. H2S can be
formed in many places such as
• Oil and gas reservoirs.
• Sewers and sewage processing facilities.
• Dark damp places where bacteria is present.
H
It is a natural Product of
Decay or Putrefaction
You may find H2S in:
Dairies
Breweries
Chemical processes
Geothermal exploration
Fisheries
Tanneries
72 different Industries
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Physical Characteristics
Color – Clear/Transparent
Odor – Sweetish taste, unpleasant
odor; described as rotten eggs.
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Hazardous Characteristics
Toxic
H2S is the second most toxic gas
known to man.
The most toxic is Hydrogen Cyanide
PEL of H2S = 10 ppm
PEL of HCN = 10 ppm
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Target Organs
Lungs
Nose
Eyes
Respiratory
control
center
Liver
H2S Awareness
Concentration Levels & Effects
The following table below lists the health effects of
exposure to H2S.
Concentration
Health Effects
10 ppm
Beginning eye irritation
50-100 ppm
Slight respiratory tract irritation after 1 hour exposure.
100 ppm
Coughing, eye irritation, loss of sense of smell after 2-15 minutes. Altered
respiration, pain in the eyes, and drowsiness after 15-30 minutes followed by
throat irritation after 1 hour. Several hours exposure results in gradual
increase in severity of these symptoms and death may occur within the next
48 hours
200-300 ppm
500-700 ppm
Severe respiratory tract irritation after 1 hour of exposure. Possible
pulmonary edema (fluid in the lungs).
Loss of consciousness and possibly death in 30 minutes to 1 hour.
700-1,000 ppm
Rapid unconsciousness, loss of respiration, and death after 1-3 minutes.
1,000-2,000ppm
Unconsciousness at once, loss of respiration and death in a few minutes.
Death may occur even if individual is removed to fresh air at once.
Benzene and Alkylbenzenes
CH3
CH3
CH3
Benzene
Toluene
CH3
CH2
Ethylbenzene
CH3
H3C
C
Cumene
Xylene
H
Occam’s Razor is Dull
Simplest Proposition:
One metabolite acting through one
mechanism attacking one target
Likely Truth:
Multiple metabolites acting through
multiple mechanisms attacking
multiple targets
Hematologic Effects of Benzene
Causality Proven
 Aplastic
Anemia
 Myelodysplasia
 Acute
Myelogenous leukemia
(Including Acute Myelomonocytic
Leukemia, Acute Promyelocytic Leukemia,
Erythroleukemia)
Evidence Supporting Benzene
Leukemogenesis
1.
Biomedical Plausibility
2.
Case Studies
3.
Epidemiology
A. Numerator Specific
B. Denominator Specific
Hematologic Effects of
Benzene
Causality Probable but Unproven
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Acute Lymphatic Leukemia
Non-Hodgkin’s Lymphoma
Multiple Myeloma
Paroxysmal Nocturnal Hemoglobinuria
Chronic Myelogenous Leukemia
Hematologic Effects of Benzene
Causality Possible
Hodgkin’s
Disease
Chronic Lymphocytic Leukemia
(and other Myeloproliferative
Disorders)
Multiple Myeloma
 Plasma
cell tumor, usually of bone marrow
 Plasma cells are related to B Lymphocytes and
have the function of producing antibody
 Diagnosis usually made based upon the presence
of a monoclonal protein spike on serum protein
electrophoresis, and on the presence a large
numbers of plasma cells in the bone marrow.
Normal
Monoclonal
Gammopathy
Non-Hodgkin’s
Lymphoma
 Lymphocytic
tumors diagnosed by
exclusion - not Hodgkin’s disease nor
lymphocytic leukemias
 Broad and overlapping range of disease
entities and etiologies.
 Immune suppression common to a
number of causative factors, including
HIV infection.
Biological Plausibility of Causal Relationship
of Benzene to Multiple Myeloma
 Multiple
myeloma is a tumor of plasma cells which
are a form of B lymphocytes
 Exposure to benzene destroys B lymphocytes and
causes chromosomal abnormalities in B lymphocytes
 Benzene is a known cause of leukemia, a bone
marrow cancer, through a mechanism that leads to
the presence of a carcinogenic metabolite within the
bone marrow.
 Multiple myeloma is a bone marrow tumor.
Role of Biological Plausibility in
Determining Causal Relations of
Benzene to Multiple Myeloma
Benzene
causes the formation
of a carcinogen that is specific
to the organ at risk and that
affects the basic cell type,
including producing
cytogenetic abnormalities.
Biological Plausibility of Causal Relationship
of Benzene to Non-Hodgkin’s Lymphoma
 Non-Hodgkin’s
Lymphoma is a lymphocytic tumor
 Exposure to benzene destroys lymphocytes and
causes chromosomal abnormalities in
lymphocytes
 Benzene is a known cause of leukemia, a bone
marrow cancer, through a mechanism that leads
to the presence of a carcinogenic metabolite
within the bone marrow.
 The bone marrow is a lymphoid organ.
 Rats exposed to benzene develop lymphomas
Pluripotential Bone Marrow Stem Cell(s)
Matures to precursors of:
 Red
blood cells
 Platelets
 Granulocytic white blood cells
 Lymphocytic white blood cells
Platelets aggregation
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Cigarette smoke-induced arteriosclerosis
A plaque composed of a complex mixture of
lipids (e.g cholesterol) form underneath the
normal smooth endothelial lining of the
artery/arterioles.
If the plaque rupture: damage of the
endothelial lining → platelets aggregation →
platelet clot → death of the muscle → vascular
disease, strokes, angina, and heart attack
Suppression of platelets
number (Thrombocytopenia)
 Alkylating
agents used to treat cancer