College of Health Sciences

Clinical Biochemistry Department

Theoretical toxicology 24-4- 2019

Dr. Ligia Eliya Matti

Target Organ Toxicity

 Introduction to Target Organ Toxicity

 Hematotoxicity
 Hepatotoxicity
 Nephrotoxicity

Target organ toxicity is defined as the adverse effects or disease states

manifested in specific organs in the body. The observed differences in target
organ toxicity are most likely due to structural and functional differences in
the cells that make up the tissues and organs.
Differences between cells: cells differ in many way including:
1- Energy consumption (e.g., use of ATP)
2- Rate of cellular division
3- Active and passive transport characteristics
4- Relationship to cell barriers (e.g., blood-brain barrier)
5- Extracellular matrices (e.g., hydroxyapatite, collagen)
6- Presence of intracellular components (e.g., contractile filaments in
muscle cells microtubules in neurons)
7- Repair mechanisms, and biotransformation capacity.

This cellular specialization means that each organ will respond to a toxicant in a
different way.

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Considerations of target organ toxicity

1- Not all organs are affected to the same extent by a toxicant

2- A single toxicant may have several target organs
3- Several toxicants may have the same target organ
4- The highest concentration of a toxicant is not always found in the target organ
5- The concentration of a toxicant in a target organ is the result of all
toxicokinetic processes.

Hematotoxicity

Stem cells found in bone marrow represent the source of all blood components
(erythrocytes, leukocytes, and thrombocytes). Poietins, or stimulating factors, regulate
the “fate” of a stem cell whether it becomes an erythrocyte (erythropoietin),
leukocyte, or thrombocyte.

Toxicity Mechanisms:

Hematotoxins cause quantitative and qualitative alterations of blood cells to produce

toxic symptoms. Hematotoxin occur when blood components subject to structural
changes that interfere with normal functions or when there is decreased or increased
number of the blood cells. For example, anemia characterizes by presence low
number of RBC that cannot meet their functions(oxygen transporting). Leukemia is
an increase in white blood cell. low thrombocytes, thrombocytopenia may lead to
loss blood either eternally or externally.

Qualitative changes in blood cell components can also result in disease. Microcytic
hypochromic anemia results when erythrocytes have a low hemoglobin content.

The number of RBC is normal but they are small, less colored that they cannot
achieve their functions sufficiently.

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Examples

Carbon monoxide (CO) changes the oxygen-carrying capacity of hemoglobin. This

will result in hypoxia or anoxia, which is an inadequate supply of oxygen to the
tissues.

Cyanide (HCN) and hydrogen sulfide (H2S) are capable of producing cytotoxic
hypoxia, a potentially lethal condition in which cells in the body cannot utilize O2
during normal cell metabolism associated with energy production.

Blood dyscrasias (i.e., disorders), it usually results in abnormal cellular

components— too many of one blood cell type, too few of another. Benzene
(an organic solvent) is known to cause thrombocytopenia and leukemia.
Agranulocytopenia, a decrease in the monocytes and lymphocytes which caused by
DDT ( an insecticide). Pancytopenia, a reduction in all blood cells that cause by
chlordane. Finally, hemolytic anemias result when erythrocytes are destroyed by a
toxicant, such as naphthalene.

Evaluating Hematotoxicity

Five tests are commonly used to measure the quantitative and qualitative aspects of
blood.

1- The red cell count

2- White cell count
3- Platelet count
4- Hemoglobin (Hb)
5- Hematocrit (HCT)

1, 2, and 3 testes are quantitative measurements, 4 and 5 testes are indicators of the
oxygen-carrying capacity of blood.

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  Hepatotoxicity

Hepatotoxicity means toxic effects in the liver. This largest gland in the body
performs many functions additionally of being the main organ of detoxification.
These include:

1- Synthesis many proteins (e.g., plasma albumin, coagulation proteins)

2- Excrete bile
3- Metabolize fats, carbohydrates, and proteins.

Toxicity Mechanisms

Liver toxicants can be cytotoxic or Cholestatic.

Cytotoxic mechanisms influence hepatocytes and these include fatty liver, liver
necrosis, and cirrhosis.

Cholestatic mechanisms impact the flow of bile. Intrahepatic cholestasis occurs when
the flow of bile is blocked within the liver.

Examples

A number of organic chemicals are toxic to hepatocytes. These include:

a) Trichloroethylene
b) Carbon tetrachloride
c) Dichlorodiphenyltrichloroethane (DDT)

These may cause liver necrosis(death of cell), inflammation, or cirrhosis (the

replacement of hepatocytes by fibrous tissue during the repair of damaged
hepatocytes). Chronic ethanol toxicity involves the accumulation of excess fat
within hepatocytes, which can lead to fatty liver disease and cirrhosis.

The cholestatic mechanisms may result from blocked transport mechanisms in the
cell membrane of hepatocytes. Agents that cause hepatic cholestatic

include bile, steroid and a-naphthylisocyanate.

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 Evaluating Hepatotoxicity

Typically three types of tests conducted.

1- Testing blood serum (i.e., the noncellular portion), involves measuring

particular enzymes that may increase in damaged liver.
2- Test performed on blood as well, examines liver function for its ability to
remove routinely encountered substances (e.g., bilirubin). The time for clot
formation can be examined as an indicator of liver function.
3- The liver scan, is used to examine both liver anatomy (e.g., size) and function
(e.g., flow of blood and bile). This can be done by intravenously injecting a
radiopharmaceutical.

Nephrotoxicity

There are three processes occurring in the kidney, these include:

1- Glomerular filtration
2- Tubular reabsorption
3- Tubular secretion

These processes are involved in urine formation. Nephrotoxins are known to

affect each of these processes.

Toxicity Mechanisms

Two toxic responses may occur during filtration.

1- Large amount of filtrate is formed between glomerulus and bowman's capsule,

toxicant may accumulate at this region leading to toxicity.
2- This may in turn increase or decrease the rate of filtration or alter
characteristics of the glomerular apparatus (the filter).

The substances that normally excluded by the filter will be able to cross and
enter the filtrate.

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Nephrotoxicity mechanisms affect also the reabsorptive process. Most of the
salts and water are selectively reabsorbed, all amino acids and glucose are
reabsorbed as well in the proximal tubule. Any changes or disturbances induced
by toxicants this region will substantially affect reabsorption.

Tubular secretion, involves actively secretion of H+, K+ and xenobiotic from

the blood into tubular lumen. When toxicants or their metabolites alter these
transport mechanisms nephrotoxicity may result.

Examples

Two major responses may be recognized when the glomerular filtration

apparatus is injured:

1- Nephrotic syndrome is usually characterized by heavy proteinuria.

2- Nephritic syndrome is typically characterized by hematuria.

Lead and heroin toxicants cause nephrotic syndrome which resulting in heavy
proteinuria.

Heavy metals, antibiotics, and organic solvents are known to cause acute
tubular necrosis.

Cadmium (Cd), lead (Pb), and mercury (Hg) affect tubular reabsorption.

Cadmium is capable of producing glycosuria (loss of glucose in the urine) and

aminoaciduria (loss of amino acids in the urine). Lead cause the same effect of
cadmium.

Inorganic mercury (Hg2+), a powerful tubular nephrotoxin, may cause renal

failure

Accumulation of toxicants or their metabolites in the body due to oliguria (little

urine) or anuria (no urine) can lead to death.

Ethylene glycol, a commonly used antifreeze or coolant, is metabolized by the

body to calcium oxalate. This insoluble salt accumulates in the proximal tubule,

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both in the lumen and in the epithelial cells lining the lumen, forming an
intratubular obstruction to the normal flow of urine.

Evaluating Nephrotoxicity

There are many tests are involved in assessing renal function, these include:

1- Glomerular filtration rate (GFR)

2- Blood urea nitrogen (BUN)
3- Creatinine

GFR is defined as the amount of glomerular filtrate (mL) per unit of time
(min). Inulin, a fructose polymer is given IV to determine GFR. It is filtered
and does not reabsorbed or secreted by the nephron.

GFR(UI) (V)/PI=CI

GFR 0.3 mg/mL=125 mL/min (the normal rate with inulin)

Decrease in this rate means decrease in elimination of toxicants that could be

toxic to other organs.

The organic acid PAH (p-aminohippuric acid) is used to evaluate kidney

function. It is filtered and actively secreted into the urine.

Together, inulin and PAH studies provide information about glomerular

filtration and tubular secretion.

Regarding the second and third tests, Urea is endogenous toxicant formed
from the catabolism of proteins) and creatinine is a product of muscle
metabolism, are distributed in the blood. In adults, normally functioning
kidneys will eliminate urea (25 g/day) and creatinine (1.8 g/day) into urine.