Dose-Response Relationship

Is there a known dose response human relationship for the toxic effects of the poison?

From: Practical Pharmacology , 2011

Clinical therapeutics and good prescribing

Stuart H Ralston Physician, FRCP, FMedSci, FRSE, FFPM(Hon) , in Davidson's Principles and Do of Medicine , 2018

Dose–response relationships

Plotting the logarithm of drug dose against drug response typically produces a sigmoidal dose–response bend (Fig. 2.2). Progressive increases in drug dose (which, for most drugs, is proportional to the plasma drug concentration) produce increasing response but only inside a relatively narrow range of dose; further increases in dose beyond this range produce niggling extra outcome. The following characteristics of the drug response are useful in comparing unlike drugs:

•

Efficacy describes the extent to which a drug tin can produce a target-specific response when all available receptors or binding sites are occupied (i.e. Emax on the dose–response bend). A full agonist can produce the maximum response of which the receptor is capable, while a partial agonist at the same receptor will take lower efficacy.Therapeutic efficacy describes the effect of the drug on a desired biological endpoint and tin exist used to compare drugs that act via different pharmacological mechanisms (due east.thou. loop diuretics induce a greater diuresis than thiazide diuretics and therefore have greater therapeutic efficacy).

•

Authority describes the amount of drug required for a given response. More potent drugs produce biological effects at lower doses, and so they have a lower EDfifty. A less potent drug can still have an equivalent efficacy if it is given in college doses.

The dose–response relationship varies between patients because of variations in the many determinants of pharmacokinetics and pharmacodynamics. In clinical exercise, the prescriber is unable to construct a dose–response bend for each individual patient. Therefore, well-nigh drugs are licensed for employ inside a recommended range of doses that is expected to accomplish close to the meridian of the dose–response bend for most patients. However, it is sometimes possible to achieve the desired therapeutic efficacy at doses towards the lower cease of, or even below, the recommended range.

Therapeutic alphabetize

The agin effects of drugs are often dose-related in a similar way to the beneficial effects, although the dose–response curve for these adverse effects is usually shifted to the right (Fig. 2.two). The ratio of the EDfifty for therapeutic efficacy and for a major adverse outcome is known as the 'therapeutic index'. In reality, drugs accept multiple potential adverse effects, but the concept of therapeutic alphabetize is usually based on adverse effects that might require dose reduction or discontinuation. For virtually drugs, the therapeutic alphabetize is greater than 100 simply at that place are some notable exceptions with therapeutic indices of less than ten (east.g. digoxin, warfarin, insulin, phenytoin, opioids). The doses of such drugs have to be titrated carefully for individual patients to maximise benefits but avoid agin effects.

Dose–Response Relationship

E.J. Calabrese , in Encyclopedia of Toxicology (Third Edition), 2014

Introduction

The dose–response relationship is a fundamental concept in toxicology. It is a framework around which all hazard assessment testing is performed and dose–response model extrapolations are based and from which environmental regulations are derived. In the expanse of toxicological machinery enquiry, such investigations are besides focused on attempting to clarify for the underlying footing for dose-dependent transitions. Thus, the dose–response relationship provides the principal focus about which and from which toxicological inquiry and applications emerge. Based on the central role that the dose–response human relationship has in the subject area of toxicology, it is non surprising that their history is inseparable.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B978012386454300991X

Biocompatibility

Chiayi Shen undefined , in Phillips' Science of Dental Materials , 2022

Dose–Response Relationship of Toxicity

Paracelsus (1493−1541), who is sometimes referred to every bit the "father of toxicology," stated, "All things are poison, and null is without poison; simply the dose permits something not to be poisonous." In short, "The dose makes the poison." The statement indicates that toxicity is dose dependent; the effect of a specific dose of a therapeutic substance may be toxic, nontoxic, or beneficial. The quantity of a substance (in milligrams) ingested by test animals is ofttimes expressed every bit milligrams per kilograms of body weight (mg/kg bw).

Figure 17-xv shows a typical dose–response curve from a jail cell-culture examination (cytotoxicity test), where cell viability, measured equally relative optical density, decreases with an increment in the dose of the applied chemic (eastward.g., ZnCltwo). Two important concepts evolved from the dose–response plot. A dose can be described either as a lethal dose (LD), in which the response is the death of animals or cells, or an constructive dose (ED), in which the response is some other observable consequence. The plot allows us to identify the doses that affect a percentage of the exposed population. For case, lethal dose fifty (LDl) is the dose that kills 50% of the test organisms. The plot also shows that in that location are doses of a substance that do not elicit any agin biological reaction, called thethreshold dosage, and the highest nontoxic dose is the so-called no-observed-agin-result level (NOAEL).

Not all biological reactions to dental materials follow this strict dose concept. Equally has been mentioned, allergic reactions can occur at much lower concentrations than toxic reactions, and they are rather insensitive to the concentration of allergen. Some even claim that allergic reactions are dose independent. Nevertheless, clinical feel shows that patients with proven contact dermatitis to nickel ions may, in certain cases, tolerate nickel-containing alloys in the mouth. One caption is the extremely depression concentration of Ni acquired by the diluting upshot of saliva.

Critical QUESTION

Why does test exposure time affair in conducting biocompatibility tests?

General Considerations

Daphne B. Moffett , ... Bruce A. Fowler , in Handbook on the Toxicology of Metals (4th Edition), 2015

two.four U-Shaped Curves and Essentiality

The dose-response human relationship for an essential substance such as a vitamin or essential trace element is U-shaped. At very low doses, there is a high-level adverse outcome, which decreases with increasing dose; similarly, at very high doses, in that location is a loftier-level adverse event that decreases with decreasing dose. The region of the dose-response relationship at very low doses of essential nutrients is commonly referred to as a deficiency (Tokar et al., 2013). As the dose is increased to the bespeak that the deficiency no longer exists, and no adverse response is therefore detected, the organism reaches a state of homeostasis.

In that location are eight metals mostly accepted to be essential: cobalt, copper, atomic number 26, magnesium, manganese, molybdenum, selenium, and zinc. The dose-response relationships for these substances are all U-shaped; nevertheless, the points at which deficiencies and, in contrast, poisoning occur are specific to each metal (Nordberg et al., 2000).

Read full chapter

URL:

https://world wide web.sciencedirect.com/science/commodity/pii/B978044459453200010X

General pharmacology

Morris J. Chocolate-brown MA MSc FRCP FAHA FBPharmacolS FMedSci , in Clinical Pharmacology , 2019

Dose–response relationships

Conventionally, the horizontal centrality shows the dose and the response appears on the vertical axis. The slope of the dose–response curve defines the extent to which a desired response alters equally the dose is inverse. A steeply rising and prolonged curve indicates that a small change in dose produces a large modify in drug outcome over a wide dose range, e.chiliad. with the loop diuretic furosemide (used in doses from 20 mg to over 250 mg/twenty-four hours). Past contrast, the dose–response curve for thiazide diuretics soon reaches a plateau, and the clinically useful dose range for bendroflumethiazide, for example, extends from 5 to 10 mg; increasing the dose beyond this produces no added diuretic effect, although it adds to toxicity.

Dose–response curves for wanted and unwanted effects can illustrate and quantify selective and non-selective drug action (Fig. eight.i).

Toxicology

Harrell East. Hurst , Michael D. Martin , in Pharmacology and Therapeutics for Dentistry (Seventh Edition), 2017

Factors That Alter Dose–Response Relationships

Dose–response relationships can vary with many factors, including differences within and amidst individuals. Factors responsible for dose–response variations within an individual over time may include age and nutritional status, environmental influences, functional status of organs of excretion, concomitant disease, and various combinations of factors. Changes in pharmacokinetics of toxicants are a frequent basis for altered dose–response relationships. Known influences include increased poison bioactivation by enzyme consecration, such every bit occurs in sure variants of cytochrome P450 with exposure to phenobarbital or polychlorinated biphenyls. Conversely, inhibition of metabolic clearance is possible with interacting chemicals, increasing the pharmacodynamic action of drugs and chemicals.

The cytochrome P450 isozyme 3A4 is an important enzyme in homo drug metabolism, and its presence in the gut and liver subjects it to inhibition by many drugs and dietary components, such as grapefruit juice. Conversely, substances are often less toxic by the oral route when administered with food every bit a upshot of less rapid absorption. The fourth dimension and frequency of administration can be of import in altering dose–response relationships through functional changes. Many compounds induce tolerance upon repeated assistants, whereas others can go more toxic with closely repeated administration. Receptor densities and sensitivity may vary with fourth dimension or as a consequence of previous exposure. An example of the latter is the well-known tolerance that develops to long-term administration of opioids.

Responses among individuals differ as a issue of unlike genetic traits. Recognition and agreement of relevant aspects of man diversity derived from functional genomic analyses offer potential for therapeutic gains. The rationale is to utilize appropriate drugs in patients best suited to benefit and to reduce use in patients with genetic traits that might result in toxicity. These efforts have spawned new terms, including pharmacogenetics, representing characterized genetic differences in drug metabolism and disposition, and pharmacogenomics, used to draw the broad spectrum of genes that affect drug response (meet Chapter 4). A summary is available that describes progress in determining genetic polymorphisms relevant to drug action and disposition. Known variants linked to altered drug effects in humans include phase I cytochrome P450 enzymes, phase II enzymes such equally Due north-acetyltransferases and glutathione-S-transferases, small molecule transporters, drug and endogenous substrate receptors, and ion channel variants. Similar advances are likely to be practical to understand genetic differences that outcome in toxic furnishings aside from those that arise during drug therapy. Approximately 400 million individuals worldwide exhibit a heritable deficiency in the cytoplasmic enzyme glucose-6-phosphate dehydrogenase. Considering this enzyme is essential to the prison cell's capacity to withstand oxidant stress through production of reducing equivalents, sensitive individuals with this enzymatic deficiency accept chemically mediated hemolytic anemia when exposed to oxidants.

Of particular importance to the interpretation of toxicologic studies are interspecies differences, which may confound understanding and interpretation of results from fauna models. Well-known differences in physiology, metabolic rates, pharmacokinetics of toxicant metabolism and excretion, and sites of toxicant activeness mediate these interspecies differences. Advances involving physiologically based pharmacokinetic modeling and use of predictive, mechanistically based biomarkers offer promise of augmenting, or in some cases obviating, conventional toxicity testing.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780323393072000400

Full general Toxicologic Pathology

Shayne C. Gad , Colin One thousand. Rousseaux , in Handbook of Toxicologic Pathology (2d Edition), 2002

2. Probit/Log Transforms and Regression

Dose-response relationships are among the well-nigh mutual interpolation bug encountered in toxicologic pathology. As noted in the preceding section, these relationships are rarely elementary so that a valid linear regression often cannot be fabricated directly from raw data. The most common valid interpolation methods are based on probability ("probit") and logarithmic ("log") value scales, with percentage responses (death, tumor incidence, etc.) being expressed on the probit calibration while doses ( 10 i) are expressed on the log scale.

There are two strategies for such an approach. The first is based on transforming information to these scales and then calculating a weighted linear regression on the transformed data. However, if one does not have admission to a calculator or a high-powered programmable calculator, it is non applied to assign weights to data. The second strategy requires the use of algorithms for the probit value and regression process and is extremely burdensome to perform manually.

An approach to the kickoff strategy requires construction of a tabular array with the pairs of values of x i and y i listed in order of increasing values of Y i (percentage response). Beside each of these columns a set of blank columns remain so that the transformed values may be listed. Then the columns are added as described in the linear regression procedure. Log and probit values may be taken from any of a number of sets of tables in standard texts. The rest of the tabular array is then developed from the transformed x i and y i values (denoted as x′i and y′i). A standard linear regression is then performed.

The second strategy we discussed has been broached by a number of authors. All of these methods are computationally cumbersome. It is possible to approximate the necessary iterative process using the algorithms developed by Abramowitz and Stegun, but this process merely reduces the complexity to a indicate where the procedure may be readily programmed on a small-scale calculator or programmable reckoner.

Read full chapter

URL:

https://world wide web.sciencedirect.com/science/commodity/pii/B9780123302151500168

Experimental Design and Statistical Analysis for Toxicologic Pathologists

Colin G. Rousseaux , ... Shayne C. Gad , in Haschek and Rousseaux's Handbook of Toxicologic Pathology (Fourth Edition), 2022

Probit/Log Transforms and Regression

Dose–response relationships are amid the virtually common interpolation issues encountered in toxicologic pathology. Equally noted in the preceding department, these relationships are rarely simple, so a valid linear regression often cannot be made straight from the raw data. The near mutual valid interpolation methods are based upon probability (probit) and logarithmic (log) value scales, with percentage responses like death and tumor incidence (Y i ) being expressed on the probit scale (by and large placed on the Y-axis), while doses (X i ) are expressed on the log scale (located on the X-axis). Probit analysis is a blazon of regression used to analyze binomial response variables (Finney, 1971). It transforms the sigmoid dose–response curve to a direct line that tin can then be analyzed by regression either through least squares or maximum likelihood. A graphical representation of a probit/log transformation and regression is shown in Figure 16.14.

Figure xvi.14. A sample of a probit plot.

There are two strategies for such a modeling approach. The first is based on transforming the information to these scales, then calculating a weighted linear regression on the transformed data. Notwithstanding, if one does not have access to a computer or a high-powered programmable calculator, it is not applied to assign weights to the data. In the absence of calculating machines, a 2d strategy requires the use of algorithms for the probit value and regression process. This latter technique is performed manually, and thus is extremely burdensome.

An approach to the first strategy requires construction of a table. The pairs of values of x i and y i are listed in order of increasing values of y i (percentage response), and beside each of these columns, a set of blank columns remain so that the transformed values may be listed. The probits of a set value of P should exist approximately linearly related to x, the measure out of the treatment, and a line fitted past eye may be used to requite a respective prepare of expected probits, Y. Then, the columns are added as described above in the linear regression procedure. Log and probit values may be taken from whatever of a number of sets of tables in standard texts. The remainder of the table is and so developed from the transformed ten i and y i values (denoted as x′ i and y′ i ). A standard linear regression is so performed using the transformed values.

The 2nd strategy uses methods that are computationally cumbersome. Information technology is possible to judge the necessary iterative computational process using the algorithms, simply this process merely reduces the complexity to a betoken where the procedure may exist readily programmed on a small figurer or programmable calculator. The probit distribution so is derived from a common mistake part, with the midpoint (50% point) moved to a score of 5.00. A ordinarily distributed population is assumed, and the results are sensitive to outliers.

The underlying frequency distribution used by this method becomes asymptotic every bit it approaches the extremes of the range. In other words, the corresponding probit values alter gradually—the curve is relatively linear—in the range of 16%–84%. However, beyond this core range, the values change ever more than rapidly as they approach either 0% or 100%. In fact, there are no values for either of these two limiting numbers.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780128210444000029

Molecular Trepidations—The Linear Nonthreshold Model

Aalt Bast , Jaap C. Hanekamp , in Toxicology: What Everyone Should Know, 2017

Abstract

The dose–response relationship between exposure to chemicals and observed furnishings is essential as information technology expresses the well-known empirical ascertainment that unlike dose levels outcome in dissimilar furnishings in organisms such every bit humans. Very roughly: "small" doses—no or minor effects; "large" doses—large effects. And of course, many intermediate doses and responses can exist imagined and scrutinized. These two extremes of a range of exposure levels raise important questions such as: How pocket-sized is small and how big is large? Are effects immediately visible later exposure? Tin doses be and so small that there can be no effects: a threshold value? What about long-term furnishings of modest doses: could that be dangerous? These are all questions to which the field of toxicology tries to formulate answers to and so some. One group of chemicals is regarded as an exception to the rules of toxicology: genotoxic carcinogens—compounds that interact with the hereditary material such equally DNA—are regarded as detrimental to our health at any level, upwardly to one molecule of exposure in a lifetime. This axiom is critically discussed in this affiliate using the metaphor of the Gilded Ratio.

Read total chapter

URL:

https://www.sciencedirect.com/science/article/pii/B9780128053485000065

Concepts and Terminology

Wayne Spoo , in Clinical Veterinary Toxicology, 2004

THE DOSE-RESPONSE RELATIONSHIP

The dose-response relationship is the virtually bones and most important fundamental concept in the field of toxicology because so many wellness and economic assessments, as well equally regulatory decisions, frequently depend on the integrity of this relationship. In a truthful dose-response relationship, in that location is some measurable result that is proportional to the amount of the chemical received. Iii general assumptions must be considered when evaluating the dose-response relationship:

1.

The chemic interacts with a molecular or receptor site to produce a response.

ii.

The production of the response, or the degree of response, is correlated to the concentration of the chemical at that receptor site.

3.

The concentration of the chemical at the receptor site is related to the dose of chemical received. ane

At that place is a varied response as to which or to how many receptor sites a given chemical will bear upon. Much of this response depends on the toxicokinetic backdrop of the chemical (see Chapter 2). Some chemicals may be captivated rapidly and distributed to a big number of tissues, simply they may simply bear upon one or a few specific tissues, whereas other chemicals may accept similar or identical properties but affect many cells and tissues throughout the body. Conversely, other chemicals may be poorly absorbed and distributed within the body, and may affect only 1, a few, or many tissues. Others may be captivated with petty or no firsthand consequence, but may increase the risk of cancer in some tissues many years after.

Exposure to a toxicant assumes that one or more than cells, tissues, or organs are susceptible to being disrupted by this chemic. The area of the body that is almost often affected by this chemic is usually referred to as the target organ and may or may not cause pathognomonic lesions that indicate its presence. The road of exposure also plays a role in determining the target organ. For example, oral exposure to cadmium results in renal lesions with piffling effect on the lungs, whereas inhalation exposure affects the lungs first, with possible involvement of the kidneys. Dermal exposure produces little if any toxicity, fifty-fifty after prolonged exposure. Again, toxicokinetics plays a role. More chemical is needed to produce more than upshot. 1 route of exposure may provide a larger amount of chemic over the same exposure period than another route of exposure, providing more chemical and hence more than effect and more toxicity. Species differences in assimilation, distribution, metabolism, and excretion, as well as interspecies susceptibility may play integral roles in determining the toxicity of a specific chemical.

For example, consider the dose-response to "chemic A" and "chemical B" shown in Table 1-1 and graphically represented in Fig. 1-2.

The cardinal question that must be answered is this: Does increasing the exposure dosages of these chemicals result in a corresponding increase in mortality? Dose-response curve A shows increasing corporeality of mortality as the dose of the chemical increases. Therefore, if the assumptions stated earlier in this section are true, then the logical conclusion is that this chemical causes increasing mortality as the dose increases. Dose-response curve B, however, suggests this is not the case. Mortality is not correlated to either increased or decreased amounts of this chemical, suggesting that mortality is not definitively linked to exposure to this chemical.

The dose-response curve for any number of chemicals tin can be contradistinct by a number of factors: selective toxicity, interspecies differences, and private (intraspecies) differences.

•

Selective Toxicity. This type of toxicity produces injury to one kind of organism (or function of an organism) and non to another. Selective toxicity may exist due to a number of reasons, including the presence or absence of the target receptor in i species and not some other. Selective toxicity can be used to a toxicologist'due south advantage when designing drugs and chemicals with specific species utilise in mind. For example, toxicologists in the agrochemical industry may take advantage of selective toxicity and manipulate test chemicals so as to enhance the selective toxicity of their pesticides toward a specific pest while minimizing (to the greatest extent possible) the toxic furnishings in nontarget species, such as pets, nutrient animals, wildlife, and humans. Many of the very early on forms of the organophosphate pesticides had powerful insecticidal furnishings only also produced toxicosis in animals that were not the intended target species, including humans. Today, chemical manipulations of the basic organophosphate molecules have resulted in college analogousness toward the target species and less toxic effects in workers exposed to these pesticides.

Some other classic example of selective toxicity is the sulfonamide class of antimicrobials. Bacteria cannot absorb folic acid, and so they must industry folic acid. Mammals, on the other manus, cannot synthesize folic acid, so they must absorb the needed folic acid from the diet. Veterinarians routinely accept advantage of this information when administering sulfonamides for susceptible bacterial infections. Sulfonamides act equally competitive antagonists with para-aminobenzoic acid, a critical intermediate in the formation of folic acid in the bacterial prison cell. Hence, sulfonamides block the production of folic acid in the bacterial cell, only because mammals derive their source of folic acid from the diet and non through intracellular manufacturing, normal cell processes can continue in the mammalian cell.

•

Interspecies Differences. Both quantitative and qualitative differences occur between species as to the toxicity of a particular chemic or drug, both in the intensity of the toxic response and perhaps fifty-fifty the target organ affected. A skillful case of species differences in toxicity is acetaminophen use in canines versus felines. The toxic dose of acetaminophen in felines is 50 to 100 mg/kg, whereas the toxic dose for the canine is 600 mg/kg. 2 Canines can tolerate 6 to 12 times the dose on a milligram per kilogram ground than can felines. Why such a dramatic difference between species? The increased sensitivity to acetaminophen in felines is related to how the drug is metabolized. In dogs (and humans), acetaminophen is metabolized via phase II metabolism past hepatic glucuronide, sulfate, or cysteine conjugation, with glucuronidation being the main form of conjugation. This conjugate is then excreted and toxicosis is averted. Felines, even so, possess limited glucuronidation metabolic capabilities, hence they must rely on the two other, less-efficient pathways. As more acetaminophen is captivated and taken to the liver for metabolism, hepatic necrosis ultimately occurs. Methemoglobinemia, Heinz body formation, cyanosis, anorexia, hemolysis, and icterus are all consequences of the feline's inability to glucuronidate acetaminophen to any appreciable extent. Conversely, dogs have a more than adult glucuronidation adequacy and can, therefore, withstand much higher doses of acetaminophen on a milligram per kilogram basis than felines.

•

Individual (Intraspecies) Differences. Whereas toxicity differences betwixt species can exist profound, differences betwixt individuals within a species can also be significant.

Few proficient examples of intraspecies variations in toxicity can be found in the veterinarian literature. Intraspecies differences in toxicity to a chemic or drug take drawn the nearly attention in human being toxicology and pharmacology. Hereditary polymorphism, or hereditary differences in a single gene, has been the subject of research in recent years. For case, transgenic mice that possess a copy of the mutated p53 factor (i.e., the "tumor suppressor cistron") are at increased risk of developing some types of cancer when compared with those mice with two normal copies of the aforementioned gene. As research expands in this area, intraspecies differences of veterinary importance volition no doubt surface.

Read full chapter

URL:

https://www.sciencedirect.com/science/article/pii/B032301125X500042