What is Toxicokinetics?

Toxicokinetics is essentially the study of "how a substance gets into the body and what happens to it in the body". Four processes are involved in toxicokinetics.

The study of the kinetics (movement) of chemicals was originally conducted with pharmaceuticals and thus the term pharmacokinetics became commonly used. In addition, toxicology studies were initially conducted with drugs. However, the science of toxicology has evolved to include environmental and occupational chemicals as well as drugs. Toxicokinetics is thus the appropriate term for the study of the kinetics of all toxic substances.

Frequently the terms toxicokinetics, pharmacokinetics, or disposition may be found in the literature to have the same meaning. Disposition is often used in place of toxicokinetics to describe the time-course of movement of chemicals through the body (that is, how does the body dispose of a xenobiotic?).

The disposition of a toxicant along with its' biological reactivity are the factors that determine the severity of toxicity that results when a xenobiotic enters the body. Specific aspects of disposition of greatest importance are:

duration and concentration of substance at the portal of entry

rate and amount that can be absorbed

distribution in the body and concentration at specific body sites

efficiency of biotransformation and nature of the metabolites

the ability of the substance or it's metabolites to pass through cell membranes and come into contact with specific cell components (e.g., DNA).

the amount and duration of storage of the substance (or it's metabolites) in body tissues

the rate and sites of excretion

Examples of how toxicokinetics of a substance can influence its toxicity:

Absorption. A highly-toxic substance, which is poorly absorbed, may be no more of a hazard than a substance of low toxicity that is highly absorbed.

Biotransformation. Two substances with equal toxicity and absorption may differ in hazard depending on the nature of their biotransformation. A substance biotransformed into a more toxic metabolite (bioactivated) is a greater hazard than a substance that is biotransformed into a less toxic metabolite (detoxified).

Absorption, distribution, biotransformation, and elimination are inter-related processes as illustrated in the following figure.

The toxicokinetics literature is extensive and a listing of all the excellent toxicology and toxicokinetics textbooks 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.

Basic ToxicologyF. Lu. Taylor & Francis, Washington, D.C.

Casarett and Doull's ToxicologyC. Klaassen, editor. McGraw-Hill Companies, Inc., New York

Essentials of Environmental ToxicologyW. Hughes. Taylor & Francis, Washington D.C.

Essentials of Anatomy and PhysiologyV. C. Scanlon and T. Sanders. F. A. Davis, Philadelphia

Essentials of Human Anatomy and PhysiologyE. N. Marieb. Addison Wesley Longman, Inc. Menlo Park, California

Industrial ToxicologyP. Williams and J. Burson, eds. Van Nostrand Reinhold, New York

Modern ToxicologyE. Hodgson and P. Levi. Elsevier Science Publishing, Co., New York

Principles of Biochemical ToxicologyJ. A. Timbrell. Taylor & Francis LTD, London

Principles of ToxicologyK. Stine and T. BrownINTRODUCCION EN ESPAOL

Qu es la Toxicocinetica?

Toxicocinetica es esencialmente el estudio " de como una sustancia entra en el cuerpo y que lo pasa en el cuerpo". Cuatro procesos son implicados en toxicocinetica.

Absorcin.- La sustancia entra en el cuerpo

Distribucin.- La sustancia se mueve del sitio de donde entra a otras reas del cuerpo.

Biotransformacin.- El cuerpo cambia (transforman) la sustancia en sustancias qumicas nuevas Excrecin.- La sustancia o sus metabolitos dejan el cuerpo.

El estudio del la cintica (el movimiento) de sustancias qumicas al principio fue conducido con productos farmacuticos y as el trmino farmacocinetica se hizo comnmente usado. Adems, los estudios de toxicologa al principio fueron conducidos con medicinas (drogas). Sin embargo, la ciencia de toxicologa se ha desarrollado para incluir sustancias qumicas ambientales y ocupacionales as como medicinas (drogas). Toxicocinetica es as el trmino apropiado para el estudio de la cintica de todas las sustancias txicas. Con frecuencia los trminos (las condiciones) toxicocinetica, farmacocinetica, o la disposicin pueden ser encontrados en la literatura para tener el mismo significado. La disposicin a menudo es usada en el lugar de toxicocinetica describir el curso tiempo de movimiento de sustancias qumicas por el cuerpo (es decir cmo el cuerpo elimina un xenobioticos). La disposicin de un toxico con la reactividad biolgica es los factores que determinan la severidad de toxicidad que pasa cuando un xenobiotico entra en el cuerpo. Los aspectos especficos de disposicin de la mayor importancia son: Duracin y concentracin de sustancia en la entrada de entrada

La tarifa y la cantidad que puede ser absorbida

Distribucin en el cuerpo y concentracin en sitios de cuerpo especficos

Eficacia de biotransformacion y naturaleza de los metabolitos

La capacidad de la sustancia o sus metabolitos para pasar por membranas de clula y entrar en el contacto con componentes de clula especficos (por ejemplo, el ADN).

La cantidad y la duracin de almacenaje de la sustancia (o sus metabolitos) en tejidos de cuerpo La tarifa y los sitios de excrecinEjemplos de como la toxicocinetica de una sustancia puede influir en su toxicidad:

Absorcin. Una sustancia sumamente txica, que es mal absorbida, no puede ser ms riesgosa que una sustancia de toxicidad baja que es sumamente absorbida.

Biotransformacion. Dos sustancias con la toxicidad igual y la absorcin pueden diferenciarse en el riesgo segn la naturaleza de su biotransformacion. Una sustancia biotransformada en metabolito ms txico (bioactivada) es un mayor riesgo que una sustancia que es biotransformada en metabolitos menos txicos (detoxified).

Absorcin, distribucin, biotranformacin, y eliminacin son procesos interrelacionados como lo muestra la siguiente figura.

Introduction

Absorption is the process whereby toxicants gain entrance into the body. Ingested and inhaled materials are still considered outside the body until they cross the cellular barriers of the gastrointestinal tract or respiratory system. To exert an effect on internal organs it must be absorbed, although local toxicity, such as irritation, may occur.

Absorption varies greatly with specific chemicals and the route of exposure. For skin, oral or respiratory exposure, the exposure dose (outside dose) is only a fraction of the absorbed dose (internal dose). For substances injected or implanted directly into the body, exposure dose is the same as the absorbed or internal dose.

Several factors affect the likelihood that a xenobiotic will be absorbed. The most important are:

route of exposure

concentration of the substance at the site of contact

chemical and physical properties of the substance

The relative roles of concentration and properties of the substance vary with the route of exposure. In some cases, a high percentage of a substance may not be absorbed from one route whereas a low amount may be absorbed via another route. For example, very little DDT powder will penetrate the skin whereas a high percentage will be absorbed when it is swallowed. Due to such route-specific differences in absorption, xenobiotics are often ranked for hazard in accordance with the route of exposure. A substance may be categorized as relatively non-toxic by one route and highly toxic via another route.

The primary routes of exposure by which xenobiotics can gain entry into the body are:

Other routes of exposure - used primarily for specific medical purposes:

For a xenobiotic to enter the body (as well as move within, and leave the body) it must pass across cell membranes (cell walls). Cell membranes are formidable barriers and a major body defense that prevents foreign invaders or substances from gaining entry into body tissues. Normally, cells in solid tissues (such as skin or mucous membranes of the lung or intestine) are so tightly compacted that substances can not pass between them. This requires that the xenobiotic have the ability to penetrate cell membranes. It must cross several membranes in order to go from one area of the body to another.

In essence, for a substance to move through one cell requires that it first move across the cell membrane into the cell, pass across the cell, and then cross the cell membrane again in order to leave the cell. This is true whether the cells are in the skin, the lining of a blood vessel, or an internal organ (e.g., liver). In many cases, in order for a substance to reach the site of toxic action, it must pass through several membrane barriers.

As illustrated in the diagram below, a foreign chemical will pass through several membranes before it comes into contact with and can damage the nucleus of a liver cell.

Cell membranes (often referred to as plasma membranes) surround all body cells and are basically similar in structure. They consist of two layers of phospholipid molecules arranged like a sandwich, referred to as a "phospholipid bilayer". Each phospholipid molecule consists of a phosphate head and a lipid tail. The phosphate head is polar, that is it is hydrophilic (attracted to water). In contrast, the lipid tail is lipophilic (attracted to lipid-soluble substances).

The two phospholipid layers are oriented on opposing sides of the membrane so that they are approximate mirror images of each other. The polar heads face outward and the lipid tails inward in the membrane sandwich.

The cell membrane is tightly packed with these phospholipid molecules interspersed with various proteins and cholesterol molecules. Some proteins span across the entire membrane providing for the formation of aqueous channels or pores.

A typical cell membrane structure is illustrated below.

Some toxicants move across a membrane barrier with relative ease while others find it difficult or impossible. Those that can cross the membrane, do so by one of two general methods, passive transfer or facilitated transport.

Passive transfer consists of simple diffusion (or osmotic filtration) and is "passive" in that there is no cellular energy or assistance required.

Some toxicants can not simply diffuse across the membrane but require assistance or facilitated by specialized transport mechanisms. The primary types of specialized transport mechanisms are:

facilitated diffusion

active transport

endocytosis (phagocytosis and pinocytosis)

Passive transfer is the most common way that xenobiotics cross cell membranes. Two factors determine the rate of passive transfer:

difference in concentrations of the substance on opposite sides of the membrane (substance moves from a region of high concentration to one having a lower concentration. Diffusion will continue until the concentration is equal on both sides of the membrane)

ability of the substance to move either through the small pores in the membrane or the lipophilic interior of the membrane

Properties of the chemical substance that affect its' ability for passive transfer are:

lipid solubility

molecular size

degree of ionization

Substances with high lipid solubility readily diffuse through the phospholipid membrane. Small water-soluble molecules can pass across a membrane through the aqueous pores, along with normal intracellular water flow.

Large water-soluble molecules usually can not make it through the small pores, although some may diffuse through the lipid portion of the membrane, but at a slow rate. In general, highly ionized chemicals have low lipid solubility and pass with difficulty through the lipid membrane.

Most aqueous pores are about 4 in size and allow chemicals of molecular weight 100-200 to pass through. Exceptions are membranes of capillaries and kidney glomeruli which have relatively large pores (about 40) that allow molecules up to a molecular weight of about 50,000 (molecules slightly smaller than albumen which has a molecular weight of 60,000) to pass through.

The illustration below demonstrates the passive diffusion and filtration of xenobiotics through a typical cell membrane.

Facilitated diffusion is similar to simple diffusion in that it does not require energy and follows a concentration gradient. The difference is that it is a carrier-mediated transport mechanism. The results are similar to passive transport but faster and capable of moving larger molecules that have difficulty diffusing through the membrane without a carrier. Examples are the transport of sugar and amino acids into RBCs and the CNS.

Some substances are unable to move with diffusion, unable to dissolve in the lipid layer, and are too large to pass through the aqueous channels. For some of these substances, active transport processes exist in which movement through the membrane may be against the concentration gradient, that is, from low to higher concentrations. Cellular energy from adenosine triphosphate (ADP) is required in order to accomplish this. The transported substance can move from one side of the membrane to the other side by this energy process. Active transport is important in the transport of xenobiotics into the liver, kidney, and central nervous system and for maintenance of electrolyte and nutrient balance.

In the following figure, the sodium and potassium ions are moving against concentration gradient with the help of the ADP sodium-potassium pump.

Many large molecules and particles can not enter cells via passive or active mechanisms. However, some may still enter by a process known as endocytosis.

In endocytosis, the cell surrounds the substance with a section of its cell wall. This engulfed substance and section of membrane then separates from the membrane and moves into the interior of the cell. The two main forms of endocytosis are phagocytosis and pinocytosis.

In phagocytosis (cell eating), large particles suspended in the extracellular fluid are engulfed and either transported into cells or are destroyed within the cell. This is a very important process for lung phagocytes and certain liver and spleen cells. Pinocytosis (cell drinking) is a similar process but involves the engulfing of liquids or very small particles that are in suspension within the extracellular fluid.

The illustration below demonstrates endocytosis membrane transport.

Absorcin EN ESPAOL

Absorcin es el proceso por el cual toxicos entran de beneficio en el cuerpo. Los materiales Ingeridos e inhalados todava son considerados fuera del cuerpo hasta que ellos crucen las barreras celulares del tracto gastrointestinal o el sistema respiratorio. Para ejercer un efecto sobre rganos internos esto debe ser absorbido, aunque la toxicidad local, como la irritacin, puede ocurrir. La absorcin vara enormemente con sustancias qumicas especficas y la ruta de exposicin. Para la piel, la exposicin oral o respiratoria, la dosis de exposicin (fuera de la dosis) es slo una fraccin de la dosis absorbida (la dosis interna). Para sustancias inyectadas o implantadas directamente en el cuerpo, la dosis de exposicin es la misma como la dosis absorbida o interna.