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LOOMIS'S ESSENTIALS of TOXICOLOGY FOURTH EDITION This Page Intentionally Left Blank LOOMIS'S ESSENTIALS of TOXICOLO. The newest edition of this basic toxicology text differs little from the previous edition in both form and content. The type is slightly larger and thus easier to read . PDF | On Jan 1, , Mary O. Amdur and others published Casarett and Doull's animals. However the LD50 is essential for characterizing the toxic effects of.


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Casarett & Doull's Essentials of oxicology NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge. Department of Pharmacology, Toxicology, and Therapeutics. University of Kansas mentation is essential in the examination of responses to chemicals. Casarett & Doull's Essentials of Toxicology, 3e. Curtis D. Klaassen, John B. Watkins III. Go to Review Questions. Search Textbook Autosuggest Results.

However, several other routes are commonly used, such as intramuscular IM , intraperitoneal IP , topical, and intravenous IV. The experimental determination of this range of doses is the basis of the dose-response relationship. Hence these data suggest that only a few chemicals or drugs 27 were responsible for a very high percentage of chemical-induced deaths. At 20 to 25 min NaHCOs 0. Updating Results.

A NOEL may be misleading since it commonly represents only the highest dose from a series of widely spaced doses used in the experiment. If the sequence of doses had been more closely spaced, the experimenter may have found a different NOEL. Numbers in Toxicology 19 In clinical toxicology additional forms of dosage are common. One highly useful dosage form is that which identifies the amount or concentration of a substance in the atmosphere to which humans may be exposed without adverse health effects.

Such a dose is called the threshold limit value TLV and is expressed as weight per cubic meter of air or as parts of chemical per million parts of air PPM. The data for TLVs may be obtained from human experience or experiment and animal studies, and represent the opinion of an expert committee who are suppUed with the animal and clinical data.

Further modification of TLVs with the addition of "safety factors" by expert committees has led to the appearance of dosage terms used for regulatory and legal purposes. Such terms are PELs permissable exposure levels , which represent the concentration of an agent in the atmosphere to which a person may be exposed without risk, and AD Is allowable daily intakes , which represent, in the case of food additives, the amount that can be taken daily in the diet, even for a lifetime, without risk.

These latter values may have httle relation to any actual experimental data. The nature of these differences is seldom obvious and becomes evident only when the biologic mechanism is challenged, such as by exposure to a chemical agent. For example, a group of single cells such as bacteria or a group of whole animals such as inbred mice may be considered as uniform populations of biologic mechanisms, and as such may be exposed to a suitably selected concentration or dose of a specific chemical agent.

If the chemical agent is capable of producing an observable effect, such as death of the organism, or an effect from which the cells or animals completely recover in a period of time, then the dose or concentration of the chemical could be selected so that it would produce that effect.

Furthermore, if the effect could be quantified, then the experiment would show that not all members of the group respond to the same dose or concentration of the chemical in a quantitatively identical manner. Rather, some of the animals would show an intense response, whereas others would show a minimal response to the same dose of the agent. Or, if the dose were properly selected, some of the animals or cells would die and others survive.

Thus, what has been considered as an all-or-none response appUes only to a single member of the test group and is found to be actually a 20 Loomis's Essentials of Toxicology graded response when viewed in regard to the entire group of members in the test. Such deviations in the response of apparently uniform populations of cells or animals to a given concentration of the chemical may be generally ascribed to biologic variation, a subject that is dealt with in detail in Chapter 6.

Frequency Response Experience has shown that biologic variation in response to chemicals within members of a species is generally small as compared to biologic variation between species. Since one of the criteria of our experiment is that the response can be quantified regardless of the effect that is measured, then by further experiment each animal in a series of supposedly uniform members of a particular species may be given an adequate dose of the chemical to produce an identical response.

The data obtained from such an experiment may be plotted in the form of a distribution or frequencyresponse curve. Such a representation for a hypothetical chemical agent is shown in Fig. The plot shown in Fig. The curve indicates that a large percentage of the animals that receive a given dose Dose X will respond in a quantitatively identical manner.

As the dose varies in either direction from Dose X, some animals will show the same response to a lower dose, and others require a higher dose. Such a curve follows the laws represented by the normal Gaussian distribution pattern. Numbers in Toxicology 21 and is of considerable interest because it permits the use of statistical procedures applicable to such curves. The dose identified as X is the mean dose, and the sum of all the animals responding to doses higher than the mean dose is equal to the sum of all the animals responding to doses of less than the mean dose.

In actual practice, the true Gaussian curve is rarely, if ever, obtainable. Rather, a skewed variation of the curve is usually obtained as the best fitting curve for the experimental data. Cumulative Response In toxicology, frequency-response curves are not commonly used. Rather, it is conventional to plot the data in the form of a curve relating the dose of the chemical to the cumulative percentage of animals showing the response such as death. Such curves are commonly known as doseresponse curves.

Figure 2. Only by experimentation can a dose be selected so that not all the animals die, nor do all of them survive. The initial dose may well be a dose so small that no effect is manifested by the animals.

In subsequent groups of animals the dose would be increased by a constant multiple such as 2, or on a logarithmic basis, until ultimately a sufficiently high dose of the compound would be administered so that all of the animals in the group would die as a consequence of the exposure to the chemical.

Thus, the only observation made in the experiment is that of death or survival of the animals. Under these conditions data would be obtained which may be plotted to give the results shown in graph form in Fig. Biologic experiments may be designed with the objective of determining the dose of a chemical required to produce any specific effect. When the experiments are done and a frequency distribution curve of the data is plotted, that curve is a visual representation of the differences among members of a test group of experimental subjects, a condition frequently referred to as "biological variation.

When the data from the above experiment are plotted as a cumulative dose-response curve, the slope of the curve then becomes a visual and mathematical index of the differences among members of the test group. The measured effect need not be death of the animal but may be any type of biologic effect that can be quantified.

The experiment need not be conducted on whole animals but may be conducted on a single cell system such as a bacterial cell or an isolated organ, tissue, or cell from any biologic system. There is no question that the compound may be considered harmful or safe, depending upon the dose given. The LD50 is a statistically obtained virtual value.

The limits of the probability range are arbitrarily selected by the experimenter to indicate that similar results would be obtained in 90 or 95 of tests performed in a manner identical to that described. Several methods are available for the performance of such a calculation. At the point of intersection, a vertical line is drawn and this line intersects the abscissa at the LD50 point.

The statistical procedures that are commonly involved in toxicology are the same procedures that are used in the other biological sciences. The progressive improvements in the statistical methods and the development of computer technology as well as the lowering of the cost of the software and hardware has made it readily accessible to students and indispensable to scientists.

The modern toxicologist needs mainly to understand which statistical procedures are applicable to his specific data and how to use modern computer technology to perform the mathematical chores involved. If the LD50 for compound B is greater than that of compound A, compound B may be said to be less potent than compound A. Furthermore, if dose and lethality are the only considerations, compound A can be said to be more toxic harmful than compound B.

This would indicate that potency in terms of quantity of chemical involved and toxicity in terms of harmfulness 24 Loomis's Essentials of Toxicology are relative terms that can be used only with reference to another chemical.

Therefore, one of the criteria that may be used to describe relative toxicities of two compounds is that of the relation of the doses required to produce an equal effect.

However, as far as evaluation of the toxicity of a single compound is concerned, the absolute value of the LD50 may be in terms of a few micrograms or as much as several grams of a particular compound. If the LD50 is only a few micrograms for one compound, and is several grams for a second compound, the difference between the two compounds becomes highly significant. It is common practice to use the term "potent" for a chemical if the dose required to produce any effect is small, i.

Table 2. Because of the fact that some chemicals will produce death in microgram doses, such chemicals are commonly thought of as being extremely toxic or poisonous.

Other chemicals may be relatively harmless following doses in excess of several grams. LDso's are listed according to averages of nearest round figures from many sources.

The principal sources are: Barnes, C. Press, Berkeley, ; Handbook of Toxicology, Vol. Saunders Co. Compilation of LD50 values in newborn and adult animals, Toxicol Appl.

An example of such a categorization, along with the respective lethal doses, is given below. Basically it is apparent that toxicity is relative and must be described as a relative dose-effect relationship between compounds. However, it is also apparent that the concept of toxicity as a relative phenomenon is true only if the slopes of the curves of the dose-response relationship for the compounds are essentially identical.

It is possible that the slopes of the dose-response curves for any two compounds could be distinctly different, as are those that are shown for compounds C and D in Fig.

If dose is the only consideration, it is apparent that compound C is less toxic than compound D because compound C has a higher LD5 than compound D. It is therefore apparent that the slope of the dose-response curve may be most significant with respect to comparing relative toxicities of two compounds.

Some of the commonly used drugs are the best examples of chemicals that can produce undesirable effects. Drugs that have as the basis of their action an abiHty to interfere with biologic processes are potentially harmful agents. This is particularly true if the primary action of the drug is concerned with a vital process.

With such a drug, the therapeutic use of the agent is based upon obtaining a graded response from given doses which would result only in a desirable effect. If the desirable effect is exceeded, then the vital process would be sufficiently influenced so that a significant, harmful effect may result. Many drugs have actions side actions or side effects in addition to the basic action of the drug.

The side actions may or may not be undesirable, and as a rule a chemical becomes a drug only if the undesirable actions are not significant in comparison to the desirable actions of the drug.

When morphine is given to produce analgesia, it also produces respiratory depression. When the anticholinergic agents are given for their effect on gastric motility, they also produce dryness of the mouth. AppUcation of the antihistamine compounds or penicillin to the skin may initiate immunologic mechanisms resulting in sensitization phenomena which can be so severe that they result in death. Undesirable effects of drugs are believed to be related to the dose of the drug.

In the case of side effects of drugs, e. That is, as the dose is increased, the intensity of the undesirable side effect also increases. In the case of sensitization to the drug appHed to the skin, there may be little, if any, relationship between the dose necessary to produce a therapeutic effect and the dose necessary to Numbers in Toxicology 27 induce sensitization, but there is usually a direct relationship between the dose, however small it may be, and the intensity of the sensitization response.

The phenomenon of sensitization to a chemical involves an abnormal response to the chemical; this phenomenon is discussed in greater detail in Chapter 9. Therefore, toxicity or harmful effects from certain drugs necessitate separate consideration, for it is common practice to refer to one drug as being more or less "toxic" than another drug. However, toxicity from drugs is also a relative term, for it is also common practice to speak of one drug as being less toxic than another because the incidence or severity of side effects is less than for similarly useful drugs.

The hope of the pharmacologist is to develop drugs which would be safe in all circumstances, but this is rarely, if ever, accomplished. To a pharmacologist, the term "potency" means the relative dose of the drug that is required to produce an effect equal to that produced by a similarly acting drug. Thus, if two drugs are capable of producing a quantitatively identical effect, the drug that produces the effect with the lower dose is said to be the more potent of the two drugs.

If the slopes of the dose-response curves for the two drugs are parallel, then the margin of safety between the two drugs may not be different. The margin of safety to a pharmacologist is the dosage range between the dose producing a lethal effect and the dose producing the desired effect.

This margin of safety is referred to as the therapeutic index and is obtained experimentally as follows: Two dose-response curves are obtained on a suitable biologic system such as mice or rats. One of the curves represents the data obtained for the therapeutic effect of the drug and the second curve represents the data obtained for the lethal effect of the drug. This is a useful concept in considering the margin of safety for practical use of the drug.

It is evident from Fig. When several drugs have similar actions and are used for similar therapeutic purposes, the drug with the greatest potency in terms of therapeutic dose is not necessarily either the safest or the most desirable drug.

Curve A represents the therapeutic effect for example, anesthesia and curve B represents lethal effect. Other factors were involved, the drug with the highest therapeutic index would be the safest or least toxic drug, since therapeutic doses of it would be less likely to produce lethal effects. However, additional factors are always involved because, as already indicated, few, if any, drugs have but a single action.

For example, since a margin of safety or therapeutic index is used to relate the therapeutic effect to the lethal effect, a similar margin of safety could also be calculated for the relationship between undesirable side actions and therapeutic actions. Such information is the aim of the drug toxicologist, who would like to develop drugs that have not only a high therapeutic index but also a high index in regard to freedom from all undesirable effects of the chemical.

The word safety basically implies the reciprocal of harmfulness.

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All chemical-induced biologic effects, some of which can be labeled as harmful, can be produced in the experimental laboratory. Harmful effects may be either reversible sublethal or irreversible lethal. Each of these effects, including the absence of any effect, can be expressed in the form of a dose-response curve. Thus the overall picture of the safety as well as harmfulness of any chemical is dose related and can be graphically demonstrated as shown in Fig. The figure shows that each effect would be represented by a curve with a specific slope and the range of doses applicable would be defined.

If one first defines the nature of the harmful effect, then 29 Numbers in Toxicology 0 0 c o Q. Reversible O Q. For illustrative purposes each curve is shown to have a different slope. The numbers that are used in toxicology are derived from appropriately conducted experimental studies.

These numbers are then subjected to statistical procedures that produce acceptable although virtual numbers.

Casarett and doulls essentials of toxicology third edition pdf

The virtual numbers are simply a concise form for expression of the results of an experiment and should be recognized as being appUcable only to the specific initial experiment. However, in clinical toxicology it is acceptable to conclude that data from studies on animals, properly qualified, are applicable to humans. The final extrapolation of data from animal to man takes various forms, one of which is to simply add a safety factor of from to fold.

Such a procedure results in numbers that are entirely virtual. Each point respresents response of a single animal. However, the virtual nature of a statistically obtained value, such as the LD50 or ED50 of a chemical, tends to obscure an important concept in toxicology, the concept that there is no fixed dose or concentration of a chemical that can be relied upon to produce a given biologic effect in a population.

This is evident from the frequency distribution curve shown in Fig. It is common practice to speak of normals, hypersensitive members, and hyposensitive members of a population.

The conditions that determine these categories of response are readily seen when the crude data for each contributing member are plotted on dose-response coordinates. Those subjects that deviate from the mean line B in the direction of line A are said to be hypersensitive to the chemical. Those subjects that deviate from line B toward line C are said to be hyposensitive to the chemical.

The graph also indicates that following a given dose or concentration , such as Dose X, the response may be below average or average in intensity, or the response may be maximum, i. The factors responsible for hypersensitivity of biologic systems to chemicals are an important part of the study of toxicology. For example, the normal human will be in a state of health only as long as the body is suppUed with nutrients and water as well as essential minerals and accessory food substances such as the vitamins.

In the absence of these compounds as well as in the presence of an excess of the compounds, the human will develop undesirable effects.

An example is shown in Fig. According to the figure, there is a concentration range for calcium between 9 and This normal concentration of calcium as well as comparable normal concentrations of numerous other substances i.

When there is a decrease in the level of the calcium, such as can occur when the body is not supplied adequate vitamin D or sources of calcium, the subject encounters muscle cramping due to the hypocalcemia.

Conversely, when the calcium concentration is elevated above normal, the subject suffers from hypercalcemic malfunction of the kidney. Death can occur because of exceptionally low or high calcium concentrations in the serum of humans.

In general, depletion of essential endogenous substances as well as excess of any essential endogenous substance results in toxicity to the subject. The specific nature of the endogenous substances that are essential to different biologic species will vary between species.

This simple fact constitutes a mechanism that is extensively utilized as a means of producing death in an undesirable species by the use of chemicals. The conclusion that is reached is that xenobiotic compounds show simple, essentially linear concentration-response relationships, whereas essential endogenous compounds show biphasic concentration-response relationships.

Chemicals that possess selectively harmful mechanisms of action represent the greatest contribution of toxicology to science.

Based on the theory that a chemical could be designed to be selectively toxic lethal to a biologic mechanism that is present only in that species which it is desirable to eliminate and provided the chemical is free of additional effects, such a compound would possess an infinitely high margin of safety for the biologic mechanisms which it is desirable to maintain.

The development of chemicals as antibacterial agents, as pesticides, as herbicides, as anticarcinogenic agents, and as insecticides is rapidly approaching this ideal relationship between safeness and harmfulness of chemicals. CHAPTER 3 Biologic Factors That Influence Toxicity JLn order for a chemical to produce an effect on a biologic mechanism, a reaction chemical or physical-chemical in nature usually occurs between the chemical and some reactant chemical in the biologic system under study.

It is also possible that an effect could be achieved solely on the basis of physical phenomena, such as a change in osmotic pressure, but such events are uncommon in toxicology. In all cases, the chemical agent under consideration must come in contact with some "reactant" chemical which is normally present at some location in the biologic system if a chemical reaction or interaction is going to occur.

The reactant chemical is commonly referred to as the "receptor. First, the chemicals must be suitably selected and placed in physical contact with each other so that a reaction will take place. Second, the chemicals must be mutually soluble to some degree in some vehicle, because the addition of two substances in dry form usually does not permit sufficient contact between the reactants for a reasonable rate of reaction to occur.

Third, unless a product of the reaction is removed, the reaction does not go to completion; rather, an equilibrium is obtained between the reactants and the products of the reaction. These criteria also must be met for a chemical reaction to take place in a biologic system. For example, if a chemical is given by mouth it may be carried into the gastrointestinal tract, from there into the blood, and subsequently into the tissues and cells.

Simultaneously while the processes of translocation are taking place, the chemical will be reaching incidental sites where it may be "chemically bound" or "adsorbed" or "biotransformed" to new chemical entities. Furthermore, the initial chemical and its products will reach sites that serve to "eliminate" or "excrete" them from the body.

Consequently chemicals that are taken into the body are eventually eliminated from the body. The processes of absorption from some site of administration, translocation, and elimination occur simultaneously and regulate the presence and concentration of each chemical in the various compartments of the body.

Casarett & Doull’s Essentials of Toxicology, 3e

Although it is common to discuss absorption of an agent from the site of administration separately from translocation, the mechanisms responsible for absorption and translocation are similar since both basically involve passage of the agent across biologic membranes. The kinetics of these processes can be mathematically described and have developed into a branch of toxicology known as "toxicokinetics" for non-drug chemicals and "pharmacokinetics" for drugs.

These kinetics are discussed in detail in treatises devoted entirely to that subject. For the purpose of the current discussion, the kinetics involved in the translocation and eUmination of a chemical agent supply the details of a fundamental concept in toxicology. This concept is that whenever a chemical is administered on multiple occasions over a period of time so that its rate of administration exceeds the rate of eUmination, the agent will accumulate in the animal and thereby influence the degree of toxicity that is produced.

The biologic factors that influence the processes of translocation, elimination, and accumulation of chemicals in the body are considered in this chapter and the chemical factors are presented in the following chapter.

These coverings give the structures their physical form and serve not only to protect their contents from temperature extremes, fluid loss, or mechanical insult but also to influence efficiently the free transfer of chemicals from access to their contents.

In order for a chemical to gain access to a receptor that Ues on or in an intracellular organelle, the chemical must effectively pass through a host of protective membranes. Figure 3. However, nonspecific binding is only temporary since it involves a readily reversible reaction; that is, as the concentration of the free drug diminishes with time there is a corresponding decrease in the concentration of the bound form.

This reaction is shown in Fig. The molecule may be altered biotransformed by specific or nonspecific enzymatic systems present in the various organs. It may be deposited in storage tissues. Almost any reactive chemical that is administered to the organism is almost immediately subjected to mechanisms that may confine its translocation within the organism or terminate its existence as a free chemical Fig. Since many foreign chemicals are capable of producing a specific effect on some biologic system or systems, such systems may be said to be the site or locus of action of the chemical.

The locus may be strictly confined in one anatomic location within the animal, or it may be diffusely located throughout the animal.

Since the effect of a chemical is a function of its concentration at the locus of action, it would be desirable to determine the concentration of the chemical at this site of action.

Of toxicology pdf essentials

In the intact animal, a limited amount of such information may be obtained by the use of agents tagged with isotopes which emit radiation energy or with heavy isotopes. More commonly the organ, tissue, or cells are prepared and analyzed by suitable chemical or physicochemical methods. Once the existence and amount of the chemical at the effector site are verified, this information may be compared to the blood concentration of the agent at the same time.

Biologic Factors That Influence Toxicity 37 of the body. The ratio of the concentration of the agent in the tissue to the concentration of the agent in the blood at any given time would represent an index of the effectiveness or lack of effectiveness of the membranes to influence translocation of the compound. This technique may be used to demonstrate the translocation of a chemical between any of the systems of the animal.

It is not uncommon that a chemical may pass readily from the gastrointestinal tract to the blood or from the lungs to all parts of the body except to the brain. Therefore, evidence indicating that a chemical agent readily passes through one membranous system in the organism does not necessarily mean that it will readily pass through all membranous systems in the organism.

Current concepts indicate that any chemical that does pass through membranes must do so by one or more of three possible mechanisms: Fluid and its solutes are translocated between organs in the mammaUan organism primarily by the blood and lymph circulation systems. The larger vessels of these systems serve only as conduits for transport of their contents to the various organs.

It is only at the capillary division of the circulation system thatfluidpasses into and out of the blood. CapiUary walls structurally consist of a single layer offlatepitheUal cells held together by an ''intercellular cement substance," through which it is currently beUeved that water and its solutes may be passively filtered.

The process of filtration through a biologic membrane is not only a function of the hydrostatic pressure differential across the membrane, but also a function of the osmotic pressure differential on the two sides of the membrane. Shown in Fig.

At the arteriolar end of the capiUaries, the hydrostatic pressure minus the plasma protein osmotic pressure within the capillary would have to be greater than the tissue hydrostatic pressure minus the interstitial protein osmotic pressure outside the capiUary to permit the filtration offluidfrom the lumen of the capillary to the extracellular interstitial fluid. In contrast to this, at the venous end of the capiUary the reverse condition would have to prevaU, so that the quantity of fluid lost from the plasma at one end of the capiUary is returned to the plasma at the other end of the capiUary if the tissue is to maintain a constantfluidvolume or weight.

If a filterable foreign chemical is present in the plasma and is only passively carried along with the filtered water, simplefiltrationwould permit an equilibration to occur only between the plasma and the extracellular spaces in the tissue, but the filtration process could not account for the passage of foreign chemicals across the final cell membrane.

The mammalian cell membrane, which separates the contents of the cell from its environment, is composed of a thin layer of lipid or lipid-like material which is bounded on both sides by a protein layer, and the resultant membrane contains multiple pores. Most such membranes in mammals are of the order of approximately A in thickness, and the extremely small pores vary from 2 to 4 A in diameter.

Transfer of water-soluble foreign chemicals from extracellular tissue fluid to intracellular fluid must involve either the process of diffusion across the membrane in the direction of a concentration gradient or a transport mechanism which would permit transfer of the chemical through the lipoid portion of the membrane.

Organic solutes of low molecular weight such as urea, creatinine, and organic acids pass freely across most cell membranes by simple diffusion, whereas ions such as sodium and potassium are selectively partitioned by the cellular membrane. In the latter case, the ions are selectively partitioned by an active transport mechanism involving Biologic Factors That Influence Toxicity 39 energy expenditure to maintain electrochemical gradients on the opposing sides of the membrane.

The transfer of water across cell membranes probably occurs via the small-diameter water-filled pores in the membrane. Also, molecules that are sufficiently small may pass through the pores in the membrane. The pores of the membrane are relatively few in number per unit area of membrane.

Therefore, lipid-insoluble substances that gain access to the interior of the cell have necessitated the development of a concept involving a special lipid-soluble carrier molecule, which is present in the membrane and is capable of combining with water-soluble molecules and carrying them across the lipid membrane to the interior surface of the cell, where the complex dissociates in the intracellular fluid.

Thus, whereas some degree of water solubility appears to be desirable for the effective translocation of a chemical to the various organs in an organism, the cell membranes are only poorly permeable to such water-soluble substances. A water- and lipid-insoluble foreign chemical therefore would have difficulty gaining access to the intracellular fluid in an organism.

In normal humans, approximately two-thirds of aU body water is intracellular. Therefore, if a compound is water-soluble and is carried freely across membranes, approximately two-thirds of the total amount of the foreign chemical in the body would be expected to be in the intracellular water.

In contrast to this, the compound that could not pass the cellular membrane but was soluble in water would be partitioned in the extracellular water of the body. Thus, the addition of a foreign chemical, that is, a chemical not normally present in the cell, to an intact biologic system in its normal environment differs from the simple mixture of solutions of two or more chemicals.

It is commonplace to observe that the amount of the chemical that produces inhibition of an enzyme system when tested on the isolated purified enzyme may bear no relation to the amount of the chemical necessary to produce a similar effect on that same enzyme when administered to the intact biologic cell; in fact, there may be a several hundred-fold difference between the two concentrations.

Some xenobiotic chemicals are so reactive with membranes that they are "captured" at the site of exposure to the chemical and little or no translocation takes place. The importance of this in toxicology is demonstrated by two highly reactive compounds, formaldehyde and methyl isocyanate, which are volatile at ordinary temperatures, thereby making inhalation the route of administration.

Animal experiments have shown that these compounds can be efficiently removed from the air by the nasal mucous membranes during inspiration. Hence it is questionable whether even small amounts of these compounds are translocated to other parts of the body by inhalation. Likewise, half the lung tissue in the rat may be removed without seriously endangering the life of the rat. Certainly, one kidney can be removed from any animal without harming the animal as long as a remaining kidney is in good functioning condition.

Demonstration of chemical-induced damage to a living organ usually involves the use of one or more forms of tests designed to measure the function of the organ. Since it has been indicated that a large portion of the organ may be damaged before the reserve capacity of the organ is sufficiently diminished to render it functionally impaired, it is quite likely that function tests would not show small amounts of chemical-induced damage.

In actual practice, this has been repeatedly demonstrated so that one must continue to rely on histologic or histochemical evidence to demonstrate the initial degrees of chemicalinduced damage to an organ.

Much research is currently directed at developing more specific and more sensitive tests of organ function in an attempt to detect small degrees of chemical-induced damage to organs. It is apparent that as long as the organ maintains a reserve excess capacity to carry on its overall function, such research attempts are ill directed unless a function of the organ is selected for which the organ maintains no reserve capacity, or unless the organ can be so stressed that it carries on the function at the maximal level.

The final concentration of the added chemical at various areas throughout the organ varies depending upon the ability of the membranes to be immaterial or to enhance or inhibit transfer of the chemical through the organ. In the process of the transfer of the chemical to a specific cell within the organ, the chemical must necessarily come in contact with nonspecific binding sites which functionally remove it from the system. Since it is postulated that a specific concentration of a chemical or its metabolites must be present if such a preparation is going to lead to toxicity of the organ, it is reasonable to conclude that some cells will be more or less affected than other cells for no reason other than the physical and biologic limitations placed on free transfer of the chemical uniformly throughout the organ.

Such limitations may be practically insignificant if the chemical has the property of being freely transferable through the membranes. On the other hand, such limitations may be most significant and not easily overcome with a poorly translocated chemical, for it would mean that a constant concentration of a chemical would have to be maintained in contact Biologic Factors That Influence Toxicity with the organ for a sufficient time for some degree of uniform distribution of the agent to take place.

Thus, an organ that has been insulted by minimal toxic concentrations of a foreign chemical agent on one occasion would not be expected to show the overall toxicity that would occur as a result of continuous insult by the same concentration of the chemical for an extended period of time.

If the cell is then removed from the environment of the chemical, in time the organism will be free of the foreign chemical.

The same mechanisms that are involved in the uptake of the chemical agent would be involved in the elimination of the agent from the cell, regardless of whether the cell is a single bacterial cell or one of a host of similar cells within an organ. In the case of the single bacterial cell, the act of removing the cell from the chemical-containing medium to a medium that is free of the chemical reverses the concentration gradient of the chemical, so that diffusion of the chemical could accomplish its elimination from the cell.

In the case of the experimental animal, additional mechanisms of eUmination are involved. If the chemical passes into the circulatory system, it must then be eliminated from the circulatory system before the animal is free of it. If the chemical is in solution as a gas at body temperature, it will appear in the expired air from the animal; if it is a nonvolatile substance, it may involve excretion by the kidney via the urinary system, or it may be chemically altered by the animal and excreted via any of the mechanisms available to the animal, such as excretion in the urine, in the sweat, or in the saliva.

The rate of elimination depends on the nature of the chemical and the mechanisms that are used to terminate the presence of the chemical in the organism. Generally chemicals that are metaboUcally converted by the animal to derivatives will have short lives within the body. A chemical that is both metabolized and deposited in fat has a short life span in the blood and the nonfatty tissues; thiopental, for example, has a brief anesthetic action 15 min or less following conventional single doses in man.

This is because that portion of the drug which is in the blood rapidly 41 42 Loomis's Essentials of Toxicology undergoes conversion to nonanesthetic forms of the drug; the remainder of the drug is deposited in fat and muscle.

Then as rapidly as the drug diffuses from the fat back to the blood, it is converted to inactive forms so that the blood remains essentially free of effective concentrations of the drug see Fig. Many chemicals are selectively adsorbed on or combined with proteins or enzymes or even components of bone.

Such chemicals may remain in the animal for years following a single dose. Ninety-eight percent of the drug dicumarol is carried in the blood in combined form with albumin, where it is not available to produce an effect on cells or for metaboUc attack by the animal. Atabrine is distributed in the dog so that the liver concentration of the drug after a single dose may be as high as times greater than the concentration in the plasma.

The tetracycline drugs combine with components of newly formed bone in most laboratory animals so that reabsorp. First drink at Time 0 and one drink each hour thereafter. Data from Forney and Hughes, Clin. Lower graph represents translocation of a single dose of intravenously administered thiopental, a compound which is rapidly redistributed in the body and accumulated in fat. The figure shows initial translocation to the lean tissue and subsequent transfer to the fat.

Data according to Price et al, as predicted mathematically and compared with direct measurement in human blood and fat. Price et al, Clin. Pharmacol Ther. Biologic Factors That Influence Toxicity 43 tion of bone must take place before the drug can be eliminated from the animal. The insecticide DDT dichloro-diphenyl-trichloroethane is stored in fat and remains in the animal for months. The organophosphate agents as exemplified by diisopropylfluorophosphate are effectively bound to and inhibit the enzyme cholinesterase, and hydrolysis of the phosphorylated enzyme is so slow that the enzyme remains inhibited for weeks.

Such sites of deposition, adsorption, or reaction of chemicals within the body limit the ability of the body to excrete them from the body. Such sites therefore act as effective storage depots for chemicals that otherwise may be so effectively metabolized or excreted that they would have only a transient existence in the body. Such sites of storage also effectively prevent the occurrence of high concentrations of the free chemical so that toxic concentrations of the chemical are not normally achieved until the storage site become saturated with the chemical.

Thus, it would be reasonable to state that the potential toxicity of a chemical is influenced by the availability in the animal of an abundance of efficient nonspecific binding sites, or the presence or absence of efficient biotransformation mechanisms.

Animals lacking such mechanisms would be very susceptible to rapid rises in concentration of the active chemical in the body, and since toxicity is directly related to the available active concentration of a chemical, such animals would be expected to be highly susceptible to the toxic action of these chemicals. In general, single exposures of an experimental organism to a chemical result in uptake of the chemical by the organism and subsequent elimination of the chemical from the organism. The rate of elimination of the chemical is under the influence of the binding and storage mechanisms available for that chemical within the organism.

Some gases may have half-lives within the body as short as a few minutes, whereas some strongly bound chemicals may exist in the body for years. Therefore, repeated exposures to a chemical in which the interval between exposure is less than the life of the chemical within the organism would lead to accumulation of that chemical in the organism. Chemicals that are bound to protein or to sites on the cell not involved in the pharmacologic or toxicologic response to the chemical represent large storehouses for such chemicals within the body.

These bound forms of the chemical are generally not available for reaction with effector sites on the cells. However, it has been demonstrated that another chemical agent may displace the first chemical from the binding sites, making the first agent available in the free form.

In this way the administration of a 44 Loomis's Essentials of Toxicology second drug could induce toxicity from the first drug; for example, the strongly bound sulfonamide drugs can induce hypoglycemic coma by replacing antidiabetic drugs which are bound to protein. Also, when patients who have received quinacrine Atabrine for the treatment of malaria are given primaquine, the primaquine displaces the quinacrine, which rapidly reaches toxic concentrations in the blood.

Compounds that accumulate in the body because of repeated frequent ingestion as contaminants of food have occasionally caused insidious harm to sizable populations of humans. Among the various chemicals involved in this type of clinical toxicology, methyl mercury is an outstanding agent that is responsible for at least eight separate episodes of tragedy directly affecting a total of over humans.

Intoxication from this compound has resulted either from misuse, as food, of mercury-treated grain that was intended for seed purposes only, or because of industrial discharge of the compound or related mercury compounds that are subsequently converted to the alkyl mercury by the action of bacteria whereby it bioaccumulated in edible fish.

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The toxic manifestations of alkyl mercury methyl or ethyl intoxication in humans are loss of sensation, that is, paresthesia in the hands, feet, and the oral area, impairment of speech, and impairment of vision eventually leading to blindness.

These effects are probably related to the effect of the alkyl mercury on brain cells. As far as the paresthesia is concerned, there appears to be a direct relation between the concentration of methyl mercury in the blood and the incidence and severity of the paresthesia.

When a compound such as methyl mercury is taken by mouth as a contaminant of food, and when the particular food constitutes a staple item of the diet so that it is consumed daily, the compound has a good chance of accumulating in the body.

Under these conditions of repeated intake by the oral route, methyl mercury is particularly prone to accumulate since it is very slowly eUminated from the body and it is very readily absorbed from the gastrointestinal tract.

The half-life of methyl mercury is approximately 2 months. Since it has already been demonstrated that toxicity is related to concentration of a chemical at effector sites and since accumulation of a chemical is a mechanism of increasing the concentration of a chemical in the body, compounds that tend to accumulate are prone to produce toxicity.

Tolerance is the ability of an organism to show less response to a specific dose of a chemical than was shown on a prior occasion from Biologic Factors That Influence Toxicity 45 the same dose. It is as if the organism becomes partially refractory to the effect of the chemical by virtue of previous exposures to the chemical.

Tolerance could be due to any of at least three possible mechanisms. These are failure in translocation of the chemical to receptor sites, enhanced excretion or biotransformation systems, and elevation of the threshold of response at the receptor site. Currently there is little experimental evidence for or against the first mechanism. Biotransformation mechanisms are known to be altered by prior use of the same or related chemicals; this is discussed in the next chapter.

The third possibility involves the creation of an altered receptor system through a change in the numbers or types of receptors involved. In the toxicologic literature the term "tolerance" is frequently used incorrectly. For example, tolerance is different from resistance, as in the case of certain strains of rabbits which are known to be resistant to the effects of atropine because they have an enzyme in their gastrointestinal tract that inactivates atropine.

Likewise, immunity that is developed to certain chemicals, such as the protein and polysaccharide toxins of bacteria, involves development within the animal of an antibody; this antibody then reacts directly with and inactivates the toxin on subsequent exposure so that the animal develops a resistance immunity and not a tolerance, to the toxin. A significant component of the phenomenon of tolerance is that if a sufficient concentration of the chemical is presented to the organism, it responds by showing the conventional pharmacologic and toxicologic effects of the chemical.

Tolerance is usually acquired over a period of time by exposure to an agent, but resistance to an agent may be acquired rapidly following only a few doses of the agent over a period of a few hours.

In pharmacology this phenomenon is known as ''tachyphylaxis. When ephedrine is administered to a cat or dog by the intravenous route it promptly produces a rise in blood pressure.

With proper doses, this effect subsides within a half-hour, at which point a second dose will produce less effect. Each subsequent dose produces less and less effect until no response occurs, even if the dose is increased to virtually lethal levels. Hence, tachyphylaxis is not synonymous with tolerance to chemicals. Tolerance occurs with most habit-forming drugs and in this respect acquires considerable significance in toxicology.

In man as well as other animals repeated administration of morphine and related drugs results in tolerance to these drugs; a highly tolerant subject may require 20 to 40 times the usual dose of morphine in order to achieve the same degree of pharmacologic effect.

However, even subjects with extensive tolerance to these drugs not infrequently take lethal overdoses of the drugs. Minor 46 Loomis's Essentials of Toxicology changes in absorption and translocation of morphine in the tolerant subject do not account for the tolerance.

Rather, altered receptor sites in the brain, which have been described, appear to be responsible for the tolerance to morphine and related compounds. Tolerance to many of the drugs that affect the human brain is accompanied by a compulsion to take the drug. If the compulsion is sufficiently strong so that the drug is taken repeatedly, a cycle of events leading to progressive increase in tolerance is established.

Withdrawal of the drug may then lead to severe physical incapacitation and even death of such subjects. Such subjects are said to be addicted to the drug. Tolerance is a constant factor in addiction. The withdrawal effects that occur obviously constitute a type of harmful effect that is an exception to the basic concept that harmful effects of chemicals are directly related to concentration of the chemical present at the effector site.

Withdrawal effects, as exempUfied by delirium tremens in alcoholics or the hallucinating and convulsive effects in narcotic addicts, appear to be inversely related to the concentration of the drug in the tissue. In fact, administration of the drug reUeves these effects. This represents perhaps the only condition whereby a type of harmful effect results from withdrawal of a xenobiotic chemical and is therefore inversely related to the concentration of the chemical at effector sites in the animal.

Nonpolar compounds, as exemplified by ethyl alcohol, appear to pass readily across all biologic membranes in the living organism. The degree of ionization of a chemical in solution is a determinant of the ability of compounds to traverse membranes.

Likewise, the solubility of the compounds in lipid material is an important factor with respect to transfer of chemicals across membranes. The chemical structure of a compound determines the ability of the compound to have a biologic action, and around this fact is built the science of structure-activity relationship SAR. Since all living tissues or cells are capable of carrying on metabolic processes, such cells possess the ability to alter biotransform many normally existing compounds as well as some foreign compounds with which the organism may come in contact.

The biotransformation mechanisms are in many cases the result of enzymatic reactions which generate not only energy and products from nutrient chemicals, but also products of many foreign chemicals to which the tissue or organism may be exposed. Furthermore, certain laboratory animals as well as humans possess additional enzyme systems which may exist solely for the purpose of altering the structure of foreign chemicals.

Therefore, the chemical factors that influence 47 48 Loomis's Essentials of Toxicology toxicity fall into two categories. The first category is composed of those chemical and physicochemical properties of compounds which individually and collectively determine the abiUty of the compounds to pass across biologic membranes. Such properties are important because they regulate the translocation of the chemical throughout the biologic tissue.

The second category comprises the chemical structure of compounds which enables them to produce specific actions on the tissues and to be susceptible to transformation by mechanisms present in the biologic specimen. Such biotransformation mechanisms are important because they may result in the formation of products possessing less toxicity than the parent compound or in the production within the organism of products possessing greater toxicity than the parent compound.

The mechanisms by which harmful effects are produced vary from a generalized destruction of protein to specific action on single-enzyme systems.

Thus, strong acids or bases in high concentrations produce generalized destruction of all living cells, probably by precipitation of proteins with the consequent denaturation of the proteins and disruption of the integrity of the cell membranes. This nonspecific action is induced by concentrated solutions of all caustic or corrosive chemicals and involves partial to complete indiscriminate destruction of all parts of biologic cells.

A generalized overwhelming action of this type is no different from that which results from "cooking" or "burning" the tissue, so that such chemically induced effects are commonly referred to as "chemical burns. The intensity of such nonspecific toxicity is directly related to the concentration of the chemical which comes in contact with the biologic cell.

Generalized destruction of cells can be produced by any chemical that is sufficiently soluble in tissue fluids to gain access to the cells in high concentrations. SlideShare Explore Search You. Submit Search. Successfully reported this slideshow. We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads.

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