Response Relationship

The effect of a substance depends on the amount administered, i.e., the dose. If the dose chosen is below the critical threshold (subliminal dosing), an effect will be absent. Depending on the nature of the effect to be measured, increasing doses may cause the effect to increase in intensity. Thus, the effect of an antipyretic or hypotensive drug can be quantified in a graded fashion, in that the extent of fall in body temperature or blood pressure is being measured. A dose-effect relationship is then encountered, as discussed on p.54. 

The dose-effect relationship may vary depending on the sensitivity of the individual person receiving the drug i.e., for the same effect, different doses may be required in different individuals. The interindividual variation in sensitivity is especially obvious with effects of the all-or-none kind. 

The evaluation of a dose-effect-relation-ship within a group of human subjects is made more dif cult by interindividual differences in sensitivity. To account for the biological variation, measurements have to be carried out on a representative sample and the results averaged. Thus, recommended therapeutic doses will be appropriate for the majority of patients, but not necessarily for each individual. 

The variation in sensitivity may be based on pharmacokinetic differences (same dose — different plasma levels) or on differences in target organ sensitivity (same plasma level — different effects). 

To enhance therapeutic safety, clinical pharmacology has led efforts to discover the causes responsible for interindividual drug responsiveness in patients. This field of research is called pharmacogenetics. Often the underlying reason is a difference in enzyme property or activity. Ethnic variations are additionally observed. Prudent physicians will attempt to determine the metabolic status of a patient before prescribing a particular drug. 

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The aroma of fmit, the taste of candy, and the texture of bread are examples of flavor perception. In each case, physical and chemical stmctures ia these foods stimulate receptors ia the nose and mouth. Impulses from these receptors are then processed iato perceptions of flavor by the brain. Attention, emotion, memory, cognition, and other brain functions combine with these perceptions to cause behavior, eg, a sense of pleasure, a memory, an idea, a fantasy, a purchase. These are psychological processes and as such have all the complexities of the human mind. Flavor characterization attempts to define what causes flavor and to determine if human response to flavor can be predicted. The ways ia which simple flavor active substances, flavorants, produce perceptions are described both ia terms of the physiology, ie, transduction, and psychophysics, ie, dose-response relationships, of flavor (1,2). Progress has been made ia understanding how perceptions of simple flavorants are processed iato hedonic behavior, ie, degree of liking, or concept formation, eg, crispy or umami (savory) (3,4). However, it is unclear how complex mixtures of flavorants are perceived or what behavior they cause. Flavor characterization involves the chemical measurement of iadividual flavorants and the use of sensory tests to determine their impact on behavior. 

Thus, a drug may produce response either with low efficacy by occupying many receptors or with high efficacy by occupying few receptors. The issues of dealing with agonist—dose response relationships can be complex and reference should be made to detailed texts (44,45). 

Natural and synthetic chemicals affect every phase of our daily Hves ia both good and noxious manners. The noxious effects of certain substances have been appreciated siace the time of the ancient Greeks. However, it was not until the sixteenth century that certain principles of toxicology became formulated as a result of the thoughts of Philippus Aureolus Theophrastus Bombastus von Hohenheim-Paracelsus (1493—1541). Among a variety of other achievements, he embodied the basis for contemporary appreciation of dose—response relationships ia his often paraphrased dictum "Only the dose makes a poison."... 

If possible, there should be measurement of the toxic effect in order quantitatively to relate the observations made to the degree of exposure (exposure dose). Ideally, there is a need to determine quantitatively the toxic response to several differing exposure doses, in order to determine the relationship, if any, between exposure dose and the nature and magnitude of any effect. Such dose—response relationship studies are of considerable value in determining whether an effect is causally related to the exposure material, in assessing the possible practical (in-use) relevance of the exposure conditions, and to allow the most reasonable estimates of hazard. 

Dose—Response Relationships and Their Toxicological Significance... 

In addition to the effect of biological variabihty in group response for a given exposure dose, the magnitude of the dose for any given individual also determines the severity of the toxic injury. In general, the considerations for dose—response relationship with respect to both the proportion of a population responding and the severity of the response are similar for local and systemic effects. However, if metabohc activation is a factor in toxicity, then a saturation level may be reached. 

Dose—response relationships are useful for many purposes in particular, the following if a positive dose—response relationship exists, then this is good evidence that exposure to the material under test is causally related to the response the quantitative information obtained gives an indication of the spread of sensitivity of the population at risk, and hence influences ha2ard evaluation the data may allow assessments of no effects and minimum effects doses, and hence may be valuable in assessing ha2ard and by appropriate considerations of the dose—response data, it is possible to make quantitative comparisons and contrasts between materials or between species. 

Although acute lethal toxicity has been used as an example, the principles discussed apply ia general to other forms of toxicity capable of being quantitated ia terms of dose—response relationships. 

Acute Toxicity Studies. These studies should provide the following information the nature of any local or systemic adverse effects occurring as a consequence of a single exposure to the test material an indication of the exposure conditions producing the adverse effects, in particular, information on dose—response relationships, including minimum and no-effects exposure levels and data of use in the design of short-term repeated exposure studies. 

Reproductive Toxicity. No data are available that impHcate either hexavalent or trivalent chromium compounds as reproductive toxins, unless exposure is by way of injection. The observed teratogenic effects of sodium dichromate(VI), chromic acid, and chromium (HI) chloride, adininistered by injection, as measured by dose-response relationships are close to the amount that would be lethal to the embryo, a common trait of many compounds (111). Reported teratogenic studies on hamsters (117,118), the mouse (119—121), and rabbits (122) have shown increased incidence of cleft palate, no effect, and testicular degeneration, respectively. Although the exposures for these experiments were provided by injections, in the final study (122) oral, inhalation, and dermal routes were also tried, and no testicular degeneration was found by these paths. 

There are some basic differences between toxic and allergic reactions. The most important differences are (1) an allergic reaction always requires a prior exposure to the compound, and this reaction only occurs in sensitized individuals and (2) a dose-response relationship is characteristic to a toxic reaction, whereas such a relationship is much less clear for an allergic reaction. Even minute doses can elicit an allergic reaction in a sensitized individual (see Fig. 5.42). ... 

FIGURE 5.51 Dose-response relationships for methyl mercury.(Used with permission.)... 

Hazard characterization and delineation of dose-effect or dose-response relationships. 3. Assessment of exposure 4. Risk characterization... 

Scientific information for the process of establishing OELs may come from human or animal data obtained using different methods, from studies of acute, subacute, and chronic toxicity through various routes of entry. Human data, which is usually the best source, is not easily available, and frequently it is incomplete or inadequate due to poor characterization of exposure and clear dose-response relationships. Human data falls into one of the following categories ... 

Dose-response relationship 1 he toxicological concept that the toxicity of a substance depends not only on its toxic properties, but also on the amount of exposure or dose. 

After the critical study and toxic effect have been selected, the USEPA identifies the experimental exposure level representing the highest level tested at which no adverse effects (including the critical toxic effect) were demonstrated. This highest "no-obserx cd-adversc-effcct-lever (NOAEL) is the key datum obtained from the study of the dose-response relationship. A NOAEL obserx ed in an animal study in which the exposure was intermittent (such as five days per week) is adjusted to reflect continuous exposure. 

The administration of the remedy is subject to a dose-response relationship. 

Kenakin, T. P., and Beek, D. (1980). Is prenalterol (H 133/80) really a selective beta-1 adrenoceptor agonist Tissue selectivity resulting selective beta-1 adrenoceptor agonist Tissue selectivity resulting from difference in stimulus-response relationships. J. Pharmacol. Exp. Ther. 213 406—413. 

A potential pitfall with stop-time experiments comes with temporal instability of responses. When a steady-state sustained response is observed with time, then a linear portion of the production of reporter can be found (see Figure 5.15b). However, if there is desensitization or any other process that makes the temporal responsiveness of the system change the area under the curve will not assume the linear character seen with sustained equilibrium reactions. For example, Figure 5.16 shows a case where the production of cyclic AMP with time is transient. Under these circumstances, the area under the curve does not assume linearity. Moreover, if the desensitization is linked to the strength of signal (i.e., becomes more prominent at higher stimulations) the dose-response relationship may be lost. Figure 5.16 shows a stop-time reaction dose-response curve to a temporally stable system and a temporally unstable system where the desensitization is linked to the... 

Environmental benefits of Emission Controls. Information in Figure 5 illustrate that the emission of sulphur in eastern North America has declined over the past decade. This decline allows for a possible verification of the dose-response relationships on which the environmental concerns for emissions have been based. A decline in sulphate deposition in Nova Scotia has apparently resulted in a decrease in acidity of eleven rivers over the period 1971-73 to 1981-82 (47), In the Sudbury, Ontario area where emissions have dechned by over 50% between 1974-76 and 1981-83, a resurvey of 209 lakes shows that most lakes have now become less acidic. Twenty-one lakes that had a pH < 5.5 in 1974-76 showed an average decline in acidity of 0.3 pH units over the period (48), Surveys of 54 lakes in the Algoma region of Ontario have shown a rapid response to a decline in sulphate deposition. Two lakes without fish in 1979 have recovered populations as pH of the water moved above 5.5 (49). Evidence is accumulating to support the hypothesis of benefits that were projected as a consequence of emission controls. This provides increased confidence in the projections. 

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