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Cellular Toxicology is the third tutorial on toxicology produced by the Toxicology and Environmental Health Information Program of the National Library of Medicine, U.S. Department of Health and Human Services. This tutorial covers the basic toxic mechanisms that operate at the cell level which includes those that interfere with normal biochemical functions. While the study of cells and biochemicals is immensely complex, our intent is to present this subject in terms and concepts that is understandable to introductory college students. These Toxicology Tutorials are intended to help students understand the toxicology literature contained in the National Library of Medicine's Chemical and Toxicological databases.
In order to understand how toxins cause a harmful change in organs, tissues, cells, or biochemicals, it is first necessary to have knowledge of normal physiology and anatomy. In the initial section, we present an overview of normal physiology, especially as related to the normal body components and how they function. While we indicate how some xenobiotics can damage the different body components, detailed examples of toxic cellular and biochemical reactions will be covered in later sections.
The body is immensely complex with numerous components, all which perform precise functions necessary for the body to maintain health and well being. Malfunction of any component can result in a breakdown of a portion of the body, commonly referred to as disease. Toxins can damage an organ or organ system so that it can not function properly, leading to death or sickness of the organism (for example, liver or kidney failure). However, in nearly all cases, the toxin actually exerts its harmful effect directly on specific cells or biochemicals within the affected organ. These cell and chemical changes in turn cause the tissue or organ to malfunction.
Most toxins are usually specific in their toxic damage to particular tissues or organs, referred to as the "target tissues" or "target organs". Toxic effects may in fact affect only a specific type of cell or biochemical reaction. For example, the toxic effect of carbon monoxide is due to its' binding to a specific molecule (hemoglobin) of a specific cell (red blood cell). Another example of a highly specific effect is that of organophosphate toxins, which inhibit an enzyme (acetylcholine esterase), responsible for modulating neurotransmission at nerve endings.
On the other hand, the effect of some toxins may be generalized and potentially damage all cells and thus all tissues and all organs. An example is the production of free radicals by whole body radiation. Radiation interacts with cellular water to produce highly reactive free radicals that can damage cellular components. The result can be a range of effects from death of the cell, to cell malfunction, and failure of normal division (e.g., cancer). An example of a multi-organ chemical toxin is lead, which damages several types of cells, including kidney cells, nerve cells, and red blood cells.
The body is a remarkable complex living machine consisting of trillions of cells and multitudes of biochemical reactions. Each cell has a specific function and they work in concert to promote the health and vitality of the organism. The number and types of toxic reactions is likewise very large. While this tutorial can not possibly present all these types of cellular and biochemical toxic reactions, it is our goal to provide an overview of the primary toxic mechanisms with a few examples that illustrate these mechanisms. It is important to understand that changes at one level in the body can affect homeostasis at several other levels.
The understanding of the cellular and chemical toxicity is growing rapidly and there is already extensive literature in that regard. A listing of all the excellent books pertaining to this subject is beyond the scope of this tutorial. While other references were occasionally consulted, the textbooks listed below have served as the primary resources for this tutorial.
F. Lu. Taylor & Francis, Washington, D.C. 1996.
Casarett and Doull's Toxicology.
C. Klaassen. McGraw-Hill Companies, Inc., New York. 1996.
Essentials of Environmental Toxicology.
W. Hughes. Taylor & Francis, Washington D.C. 1996
Essentials of Anatomy & Physiology.
V. Scanlon and T. Sanders. F.A. Davis Company, Philadelphia. 1995.
N. Stacey. Taylor & Francis, London, U.K. 1993.
Introduction to Chemical Toxicology.
E. Hodgson and P. Levi. Appleton and Lange, Norwalk, CT. 1994
Mechanisms and Concepts in Toxicology.
W. N. Aldridge. Taylor & Francis, London, U.K. 1996
Principles of Biochemical Toxicology.
J. A. Timbrell. Taylor & Francis LTD, London. 1987.
Principles of Toxicology.
K. Stine and T. Brown. CRC Lewis Publishers, Boca Raton, FL. 1996.
Encyclopaedia of Toxicology.
P. Wexler. Academic Press, Inc. 1998.
Health Effects of Hazardous Materials.
N. Ostler, T. Byrne, and M. Malchowski. Prentice-Hall, Inc. 1996.
Armed Forces Institute of Pathology.
Washington, D.C. 1999.
Homeostasis is the ability of the body to maintain relative stability and function even though drastic changes may take place in the external environment or in one portion of the body. Homeostasis is maintained by a series of control mechanisms, some functioning at the organ or tissue level and others centrally controlled. The major central homeostatic controls are the nervous and endocrine systems.
We are continually challenged by physical and mental stresses, injury, and disease, any which can interfere with homeostasis. When the body loses its homeostasis, it may plunge out of control, into dysfunction, illness, and even death. Homeostasis at the tissue, organ, organ system, and organism levels reflects the combined and coordinated actions of many cells. Each cell contributes to maintaining homeostasis.
To maintain homeostasis, the body reacts to an abnormal change (induced by a toxin, biological organism, or other stress) and makes certain adjustments to counter the change (a defense mechanism). The primary components responsible for the maintenance of homeostasis are:
An example of a homeostatic mechanism can be illustrated by the body's reaction to a toxin that causes anemia and hypoxia (low tissue oxygen) (See illustration). Erythropoiesis (production of red blood cells) is controlled primarily by the hormone, erythropoietin. Hypoxia (the stimulus) interacts with the heme protein (the receptor) that signals the kidney to produce erythropoietin (the effector). This, in turn, stimulates the bone marrow to increase red blood cells and hemoglobin, raising the ability of the blood to transport oxygen and thus raise the tissue oxygen levels in the blood and other tissues. This rise in tissue oxygen levels serves to suppress further erythropoietin synthesis (feed back mechanism). In this example, it can be seen that cells and chemicals interact to produce changes that can either perturb homeostasis or restore homeostasis. In this example, toxins that damage the kidney can interfere with production of erythropoietin or toxins that damage the bone marrow can prevent the production of red blood cells. This interferes with the homeostatic mechanism described resulting in anemia.
Organ Systems and Organs
Before one can understand how xenobiotics affect these different body components, knowledge of normal body components and how they function is necessary. For this reason, this section provides a basic overview of anatomy and physiology as it relates to toxicity mechanisms. The basic structure and functional organization of the human body can be thought of as a pyramid or hierarchical arrangement in which the lowest level of organization (the foundation) consists of cells and chemicals. Organs and organ systems represent the highest levels of organization. This is illustrated below.
Simplified definitions of the various levels of organization within the body are:
The following figure illustrates the hierarchical organization of these body components.
The human body consists of eleven organ systems, each which contains several specific organs. An organ is a unique anatomic structure consisting of groups of tissues that work in concert to perform specific functions. Listed below are the eleven organ systems and their specific organs.
There are only four types of tissues that are dispersed throughout the body. A type of tissue is not unique for a particular organ and all types of tissue are present in most organs, just as certain types of cells are found in many organs. For example, nerve cells and circulating blood cells are present in virtually all organs.
Tissues in organs are precisely arranged so that they can work in harmony in the performance of organ function. This is similar to an orchestra that contains various musical instruments, each of which is located in a precise place and contributes exactly at the right time to create harmony. Like musical instruments that are mixed and matched in various types of musical groups, tissues and cells also are present in several different organs and contribute their part to the function of the organ and the maintenance of homeostasis.
Kinds of Tissues in the Body:
The four types of tissues:
The four types of tissues are similar in that each consists of cells and extracellular materials. They differ however, in that they have different types of cells and differ in the percentage composition of cells and the extracellular materials. The following figure illustrates how tissues fit into the hierarchy of body components.
Epithelial tissue is specialized to protect, absorb and secrete substances, as well as detect sensations. It covers every exposed body surface, forms a barrier to the outside world and controls absorption. Epithelium forms most of the surface of the skin, and the lining of the intestinal, respiratory, and urogenital tracts. Epithelium also lines internal cavities and passageways such as the chest, brain, eye, inner surfaces of blood vessels, and heart and inner ear.
Epithelium provides physical protection from abrasion, dehydration, and damage by xenobiotics. It controls permeability of a substance in its effort to enter or leave the body. Some epithelia are relatively impermeable; others are readily crossed. This epithelial barrier can be damaged in response to various toxins. Another function of epithelium is to detect sensation (sight, smell, taste, equilibrium, and hearing) and convey this information to the nervous system. For example, touch receptors in the skin respond to pressure by stimulating adjacent sensory nerves. The epithelium also contains glands and secrets substances such as sweat or digestive enzymes. Others secrete substances into the blood (hormones), such as the pancreas, thyroid, and pituitary gland.
The epithelial cells are classified according to the shape of the cell and the number of cell layers. Three primary cell shapes exist: squamous (flat), cuboidal, and columnar. There are two types of layering, simple and stratified. These types of epithelial cells are illustrated in the following figure.
Connective tissues are specialized to provide support and hold the body tissues together (i.e., they connect). They contain more intercellular substances than the other tissues. A variety of connective tissues exist, including blood, bone and cartilage, adipose (fat), and the fibrous and areolar (loose) connective tissues that gives support to most organs. The blood and lymph vessels are immersed in the connective tissue media of the body. The blood-vascular system is a component of connective tissue. In addition to connecting the connective tissue plays a major role in protecting the body from outside invaders. The hematopoietic tissue is a form of connective tissue responsible for the manufacture of all the blood cells and immunological capability. Phagocytes are connective tissue cells and produce antibodies. Thus, if invading organisms or xenobiotics get through the epithelial protective barrier, it is the connective tissue that goes into action to defend against them.
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