Xenobiotic effects on leukocytes

1. Xenobiotic Effects On
Hematopoietic (Leucocytes).
Ph. Nisreen Sami Hasab
Higher Diploma in Toxicology & Pharmacology
Supervised by:-
Dr. Ammar Ali Hussein
2020

2.  White Blood Cells (WBCs) or Leukocytes :-
leukocytes are far less numerous than red blood cells, they are important to
body defense against disease. On average, there are 4000 to 11.000
WBCs/mm3, and they account for less than 1 percent of total blood volume.
White blood cells are the only complete cells in blood; that is; they contain
nuclei and the usual organelles.
Leukocytes form a protective, movable army that helps defend the body against
damage by bacteria, viruses, parasites, and tumor cells. As such they have some
very special characteristics.
White blood cells, by contrast, are able to slip into and out of the blood vessels
(by process called diapedesis).
WBCs can locate areas of tissue damage and infection in the body by
responding to certain chemicals that diffuse from the damaged cells. This
capability is called positive chemotaxis.

4.  Types of WBCs:-
WBCs are classified into two major groups, depending on
whether or not they contain visible granules in their cytoplasm.
 Granulocytes :-
are granule-containing WBCs. They have lobed nuclei, which
typically consist of several rounded nuclear areas connected by thin
strands of nuclear material. The granules in their cytoplasm stain
specifically with Wright's stain. The granulocytes include the
neutrophils, eosinophil and basophils.
1. Neutrophils:- have a multilobed nucleus (3-5lobes) and very fine
granules that respond to both acid and basic stains. Consequently,
the cytoplasm as a whole stains pink. Neutrophils are avid
phagocytes at sites of acute infection.

5. 2. Eosinophils :- have a bilobed blue-red nucleus that resembles an
oldfashioned telephone receiver and large red cytoplasmic granules.
Their number increases rapidly during allergies and infections by
parasitic worms (flat-worms, tapeworms, etc.).
3. Basophils :- the rarest of the WBCs, have S shaped nucleus
contain large histamine-containing granules that stain dark blue.
Histamine is an inflammatory chemical that makes blood vessels
leaky and attracts other WBCs to the inflammatory site.
 AGranulocytes :- lack visible cytoplasmic granules. Their nuclei
are spherical oval or kidney-shaped. The agranulocytes include
lymphocytes and monocytes .

6. 1. Lymphocytes :-have a large dark purple nucleus that occupies
most of the cell volume. Only slightly larger than RBCs, lymphocytes
reside in lymphatic tissues, where they play an important role in the
immune response. There are two types of lymphocytes:
• T lymphocytes: provide cell mediated immunity.mature in the
thymus.
• B lymphocytes: provide humoral immunity.
• Natural killer cells (NK cells) :NK cells arise from lymphoid precursor cells,
but receptors can be activated with or without binding antibodies or a major
histocompatibility complex. Detection and destruction of cells that do not
express MHC-I receptors.Cells infected with viruses (especially herpes
viruses)Tumor cells
Kill via : Induction of apoptosis (granzymes, perforin)
Antibody-dependent cell-mediated cytotoxicity (activated by binding of CD16)
Cytokine production: INF-γ and TNF-α ,Function enhanced by IFN-α and
IFN-β, IL-2, IL-12

7. 2. Monocytes:-
are the largest of the WBCs. Except for their more abundant
cytoplasm and indented (kidney like) nucleus, they resemble large
lymphocytes. When they migrate into the tissues, they change into
macrophages. Macrophages are very important in fighting chronic
infections, such as tuberculosis.
The granulocytes and the monocytes protect the body against invading
organisms by ingesting them by the process of phagocytosis. The
lymphocytes function mainly in connection with the immune system.
However, a function of certain lymphocytes is to attach themselves to
specific invading organisms and destroy them.

8.  Genesis of the Leukocytes :-two major
 lineages of white blood cells are also formed, the myelocytic and the
lymphocytic lineages. The lymphocytic lineage beginning with the
lymphoblast; that produce lymphoctes, and the myelocytic lineage beginning
with the myeloblast; which produce other WBCs.
 The granulocytes and monocytes are formed only in the bone marrow.
Lymphocytes are produced mainly in the various lymphogenous organs,
including the lymph glands, the spleen, the thymus, the tonsils, and various
lymphoid rests in the bone marrow, gut, and elsewhere.
 These colony stimulating factors (CSFs) and interleukins not only prompt
red bone marrow to turn out leukocytes, but enhancing the ability of mature
leukocytes to protect the body. Apparently, they are released in response to
specific chemical signals in the environment such as inflammatory chemicals
and certain bacteria or their toxins.

10.  Xenobiotics: Sources and Types:-
Originally, the term xenobiotic comes from the Greek word xenos , which means
foreign or strange, and ‘bios’, which means life. Xenobiotics are chemical compounds
exhibiting abnormal structural characteristics .
The unusual presence of any substance in high concentrations, the presence of
antibiotic drugs in the human body which may not be produced by the body itself nor
is a normal part of diet.
At times, a natural substance can be defined as a xenobiotic if it found its way into
humans or other animals.
-Bonjoko (2014) proposed the word ‘xenobiotic’based on the physiological and
biological effects of exogenous substances whether natural or synthetic (drugs,
chemicals) on the cells, tissues or organs of the organisms.
Many xenobiotics are potientially hazardous to the organisms which are exposed to
them in the environment .
Xenobiotics may persevere for long term (months to years) in the environment. For
example, the polymer structure of lignin .

11. antithyroids, anticonvulsants, chemotherapy, sulfas or
other antibiotics, analgesic, drugs used in Immune
dysfunction(AIDS, rheumatoid arthritis), etc .
Medications
X_ray media ,free radical that increase oxidative stress
.
Radiation.
alcohol, benzenes.Toxins
Cadmium, Lead (Pb), Mercury (Inorganic), Arsenic.Heavy metals
Pesticides such as fungicides, herbicides and
rodenticides . Organophosphate and organochlorine
insecticides (synthetic pesticides).
Environment
pollution or
industrial

12.  Drug-Induced agranulocytosis:-
Agranulocytosis is defined as a reduction in the number of mature myeloid cells in
the blood (granulocytes and immature granulocytes ) to a total count of 500
cells/mm3 (0.5 × 109/L) or less. In Europe, the incidence rate is reported to range
from 1.6 to 9.2 cases per million population. In the United States, reported rates are
slightly higher, ranging from 2.4 to 15.4 cases per million population.
Geographic variability in incidence is related to both differences in reporting and
medication usage but could also suggest genetic differences in susceptibility.
Older patients are thought to be at greater risk for to drug-induced agranulocytosis,
probably because of increased medication use.
Drug-induced agranulocytosis also occurs more frequently in women than in men.
The mortality rate is highest among elderly adults and patients with renal failure,
bacteremia, or shock at the time of diagnosis. Symptoms of agranulocytosis arise
from the increased infection risk associated with the lack of WBCs and include sore
throat, fever, malaise, weakness, and chills. Symptoms may appear either
immediately or insidiously, depending on the time course of neutropenia
development.

13. Symptoms may appear either immediately or insidiously, depending on the time
course of neutropenia development. The median duration of exposure before the
development of agranulocytosis ranges from 19 to 60 days for most drugs associated
with this adverse event, but the time to onset is greater than 1 month for most of
these agents.
The cause of drug-induced agranulocytosis is not fully understood, but two
mechanisms—direct toxicity and immune-mediated toxicity—have been proposed.
Direct toxicity to myeloid cells, particularly neutrophils, has been shown with
medications such as:-
chlorpromazine, procainamide, clozapine, dapsone , sulfonamides, carbamazepine,
phenytoin, indomethacin, and diclofenac .
The toxicity may be due to either the parent drug or a toxic metabolite or by
product. The severity of neutropenia associated with these drugs is often dose
dependent, but the occurrence of reactions is still idiosyncratic

14. Within the immune-mediated subset of agranulocytosis, there are three proposed
mechanisms of toxicity. The hapten mechanism involves the drug or its metabolite
binding to the membrane of neutrophils or myeloid precursors. After binding,
antibodies are induced that destroy the cell. This is thought to be the mechanism
of agranulocytosis induced by aminopyrine, penicillin, and gold compounds.

15. In the immune-complex mechanism, antibodies form complexes with the causative
drug, and the immune complex adheres to the target cell, leading to cell destruction.
This is the proposed mechanism of agranulocytosis induced by quinidine and
quinine . The drug induces antibody formation. The antibodies and drug form a
complex in the serum, and the complex nonspecifically binds to the cell membrane.
Complement is activated, and the cell is lysed.

16. Protein carrier mechanism. The drug combines with a plasma protein. The
complex then attaches to the cell membrane, and antibody formation is stimulated.
Antibodies later attach to the complex and activate complement. The cell is then
lysed by the complement. Nearly all classes of drugs have been associated with
some incidence of acute neutropenia or agranulocytosis, although the risk is
exceedingly small. For some drugs, though, the risk may be higher. These agents
include antithyroid medications, sulfasalazine, trimethoprim–sulfamethoxazole,
and β-lactam antibiotics.

17.  Treatment--Drug-Induced agranulocytosis:-
The primary treatment of drug-induced agranulocytosis is the removal of the
offending drug. After discontinuation of the drug, most cases of neutropenia resolve
over time, and only symptomatic treatment (e.g., antimicrobials for infection
treatment and prophylaxis).
Sargramostim (granulocyte-macrophage colony-stimulating factor [GM-CSF]) and
filgrastim (granulocyte colony-stimulating factor [G-CSF]) have been shown to
shorten the duration of neutropenia, length of antibiotic therapy, and hospital length
of stay.
A commonly reported regimen is G-CSF 300 mcg/day via subcutaneous injection.

18.  Leucopenia :-
A range of disorders can cause decreases in white blood cells. This type of white
blood cell decreased is usually the neutrophil. In this case the decrease may be
called neutropenia or granulocytopenia. Less commonly, a decrease in lymphocytes
(called lymphocytopenia or lymphopenia).
 Neutropenia :-
can be acquired or intrinsic. A decrease in levels of neutrophils on lab tests is due to
either decreased production of neutrophils or increased removal from the blood.
The following list of causes is not complete.
• Medications - chemotherapy, sulfas or other antibiotics, phenothiazenes,
benzodiazepines, antithyroids, anticonvulsants, quinine, quinidine,
indomethacin, procainamide, thiazides.
• Radiation.
• Toxins - alcohol, benzenes.
• Intrinsic disorders - Fanconi's, Kostmann's, cyclic neutropenia.
• Immune dysfunction - disorders of collagen, AIDS, rheumatoid arthritis.
• Blood cell dysfunction - megaloblastic anemia, myelodysplasia, marrow
failure, marrow replacement, acute leukemia.
• Any major infection.,Miscellaneous - starvation, hypersplenism.

19.  Lymphocytopenia:-
Defined as total lymphocyte count below 1.0x109/L, the cells most commonly
affected are CD4+ T cells. Like neutropenia, lymphocytopenia may be acquired or
intrinsic and there are many causes. One causes Medications - chemotherapy
(antilymphocyte globulin therapy, alemtuzumab,glucocorticoids),Radiation.
 Leukocytosis:-
An increase in the number of white blood cells in circulation is called leukocytosis.
 Neutrophilia :-
Neutrophilia is an increase in the absolute neutrophil count in the peripheral
circulation. Normal blood values vary by age. Neutrophilia can be caused by a direct
problem with blood cells (primary disease). It can also occur as a consequence of an
underlying disease (secondary).
One cause :-
Cigarette smoking – occurs in 25–50% of chronic smokers and can last up to 5 years
after quitting.
Medication induced – corticosteroids (for example, prednisone, β-agonists, lithium)
Cancer – either by growth factors secreted by the tumor or invasion of bone marrow
by the cancer.

20.  Eosinophilia :-
A normal eosinophil count is considered to be less than 0.65×109/L
.Eosinophil counts are higher in newborns and vary with age, time
(lower in the morning and higher at night), exercise, environment,
and exposure to allergens. Eosinophilia is never a normal lab
finding.
 Lymphocytosis :-
 Increase in number of lymphocytes in the blood to > 4000/μL
(absolute) or > 50% of all leukocytes causes by Acute viral
infections (e.g., rubella, infectious mononucleosis, mumps)
 Neoplasia (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma,
chronic lymphoid leukemia) ,Chronic infections (e.g.,
tuberculosis, syphilis, toxoplasmosis)

21.  Conclusion:-
Keywords Xenobiotics • Carcinogens • Degradation
Environmental contamination by xenobiotics is a worldwide phenomenon as a result
of human activities resulting from rise in urbanization and population growth.
There are numerous sources of xenobiotics ranging from pharmaceuticals to
agriculture.
In addition, the making of unlawful drugs has led to the discharge of harmful
carcinogens into the water system. The release of these harmful pollutants results in
numerous short- and long-term effects to the natural ecosystem.
Since the time of the Industrial Revolution, scientific and technological permitted
humans in the over utilization of resources creating disturbance to the natural
ecosystem.
The generation of huge amount of toxic substances released from industrial caused
widespread contamination of the ecosystem.
The major contaminants are halogenated and nitrated hydrocarbons ,Several
herbicides, insecticides and fertilizers.

22.  References :-
1-Ninth Edition Lewis S. Nelson, MD, Neal A. Lewin, MD, Mary Ann Howland,
PharmD, Robert S. Hoffman, MD, Lewis R. Goldfrank, MD, Neal E.
Flomenbaum, MD, 2015.
2- Coates TD. Drug-Induced Neutropenia and Agranulocytosis. In: Post TW, ed.
UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/drug-
induced-neutropenia-and-agranulocytosis. Last updated August 1, 2016. Accessed
May 7, 2017.
3- Environmental Xenobiotics and Its Effects on Natural Ecosystem , All content
following this page was uploaded by Asha Embrandiri on 07 March 2019 this
publication at: https://www.researchgate.net/publication/311978744 .