Hematotoxicit y Dr. Basma Damiri Chapter 4

Direct effect on RBCs 1. Competitive inhibition of oxygen binding to hemoglobin 2. 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  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  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 conversion of hemoglobin to methemoglobin by nitrites and 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.

Blood Toxicants 1. Benzene- induced bone marrow suppression 2. Aniline and nitrobenzene induced methemoglobinemia. 3. Hydrogen sulfide-induced effect

10 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. Oh Yeah, by the way:

What is H2S? 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. 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 H H S Dark damp places where bacteria is present. Oil and gas reservoirs. Sewers and sewage processing facilities.

12 You may find H2S in: Dairies Breweries Chemical processes Geothermal exploration Fisheries Tanneries 72 different Industries It is a natural Product of Decay or Putrefaction

13 Physical Characteristics Color – Clear/Transparent Odor – Sweetish taste, unpleasant odor; described as rotten eggs.

14 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

15 Target Organs Nose Lungs Respiratory control center Eyes Liver

Concentration Levels & Effects The following table below lists the health effects of exposure to H 2 S. ConcentrationHealth Effects 10 ppmBeginning eye irritation ppmSlight respiratory tract irritation after 1 hour exposure. 100 ppmCoughing, eye irritation, loss of sense of smell after 2-15 minutes. Altered respiration, pain in the eyes, and drowsiness after 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 ppmSevere respiratory tract irritation after 1 hour of exposure. Possible pulmonary edema (fluid in the lungs) ppmLoss of consciousness and possibly death in 30 minutes to 1 hour ,000 ppmRapid unconsciousness, loss of respiration, and death after 1-3 minutes. 1,000-2,000ppmUnconsciousness 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 CH 3 3 H 3 C C H CH 3 Benzene CH 3 Toluene Xylene Cumene Ethylbenzene CH 2 3

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  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.

Monoclonal Gammopathy Normal

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  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