Dose response

The dose-response is sigmoidal for both test and standard. The distance (x) measures the efficiency (log potency ratio) of the test relative to the standard. If the two lines coincide then the poten y is identical 

Toxicologists tend to focus their attention primarily on c.xtrapolations from cancer bioassays. However, tlicrc is also a need to evaluate the risks of lower doses to see how they affect the various organs and systems in the body. Many scientific papers focused on tlic use of a safety factor or uncertainty factor approach, since all adverse effects other than cancer and mutation-based dcvclopmcnUil effects are believed to have a tlu cshold i.e., a dose below which no adverse effect should occur. Several researchers have discussed various approaches to setting acceptable daily intakes or exposure limits for developmental and reproductive toxicants. It is Uiought Uiat an acceptable limit of exposure could be determined using cancer models, but today tliey arc considered inappropriate because of tlircsholds.  

Dmigers arc not necessarily defined by tlic presence of a particuhu chemical, but rather by the amount of tluit substance one is exposed to, also 

Not all contaminants or chemicals are created equal in their capacity to cause adi ersc effects. Thus, cleanup standards or action levels are based in part on the compounds toxicological properties. Toxicity data are derived largely from animal experiments in which llie aninuils (primarily mice mid rats) are exposed to increasingly liighcr concentrations or doses. Responses or effects can vary widely from no obscn ablc effect to temporary and reversible effects, to permanent injury to organs, to chronic functional impairment to ultimately, death. 

Two examples of toxicity, where the target is known, are carbon monoxide, which interacts specifically with hemoglobin, and cyanide, which interacts specifically with the enzyme cytochrome a3 of the electron transport chain (see chap. 7). The toxic effects of these two compounds are a direct result of these interactions and, it is assumed, depend on the number of molecules of the toxic compound bound to the receptors. However, the final toxic effects involve cellular damage and death and also depend on other factors. Other examples where specific receptors are known to be involved in the mediation of toxic effects are microsomal enzyme inducers, organophosphorus compounds, and peroxisomal proliferators (see chaps. 5-7). 

The study of receptors has not featured as prominently in toxicology as in pharmacology. However, with some toxic effects such as the production of liver necrosis caused by paracetamol, for instance, although a dose-response relation can be demonstrated (see chap. 7), it currently seems that there may be no simple toxicant-receptor interaction in the classical sense. It may be that a specific receptor-xenobiotic interaction is not always a prerequisite for a toxic effect. Thus, the pharmacological action of volatile general anesthetics does not seem to involve a receptor, but instead the activity is well correlated with the oil-water partition coefficient. However, future detailed studies of mechanisms of toxicity will, it is hoped, reveal the existence of receptors or other types of specific targets where these are involved in toxic effects. 

The dose-response relationship is predicated on certain assumptions, however  

That the toxic response is a function of the concentration of the compound at the site of action 

That the concentration at the site of action is related to the dose 

The human mind is as driven to understand as the body is driven to survive. 

Compound B has a different shaped response. There is a range of dosages that result in no response or a response lower than a threshold amount consequently, there are safe dosages for compound B. 

One point of extreme interest with any toxin is whether or not there is a safe dose for that toxin. The answer to this question is very important technically and economically, because toxins that have no safe dose must be eliminated completely for perfect safety. A zero-level reference is never totally achievable because compliance depends on the detection sensitivity of instruments, and that usually continues to increase. Thus, a toxin thought to be totally eliminated in the present may be found in the future because monitoring instruments have changed. 

FIGURE 6.12.1 Two typical dose-response curves. Compound A has no threshold value. 

FIGURE 6.12.2 Diagram of responses of a cell to a toxic substance that can cause cancer. 

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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. 

Fig. 4. Dose response for blood glucose measurement using a dry chemistry system having a water-borne, tough coating film. The numbers represent...

Excellent correlation was found when results at 660 nm and 749 nm were compared using a reference hexokinase glucose method (27). The dose response was excellent up to 300 mg/dL glucose. In general, water-borne coatings do not lend themselves to ranging by antioxidants (qv). 

Fig. 8. Agonist, dose—response curves, (a) For an agonist where a value of 10 M is indicated at the concentration giving 50% response, (b) For an agonist alone, Aq, and in the presence of increasing amounts of irreversible receptor antagonists, B—F. There is a progressive rightward shift of the dose—response curve prior to reduction of maximum response. This pattern is consistent with the presence of a receptor reserve.

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). 

A critical component of the G-protein effector cascade is the hydrolysis of GTP by the activated a-subunit (GTPase). This provides not only a component of the amplification process of the G-protein cascade (63) but also serves to provide further measures of dmg efficacy. Additionally, the scheme of Figure 10 indicates that the coupling process also depends on the stoichiometry of receptors and G-proteins. A reduction in receptor number should diminish the efficacy of coupling and thus reduce dmg efficacy. This is seen in Figure 11, which indicates that the abiUty of the muscarinic dmg carbachol [51 -83-2] to inhibit cAMP formation and to stimulate inositol triphosphate, IP, formation yields different dose—response curves, and that after receptor removal by irreversible alkylation, carbachol becomes a partial agonist (68). 

Fig. 11. Dose—response curves for (A,A) inhibition of cyclic AMP formation and stimulation of IP formation by carbachol (A,D) before and (A,H) after reduction of receptor number by irreversible alkylation (carbachol) is in M. Error bars ( ) are shown for some studies.

R. J. Taharida and L. S. Jacob, The Dose—Response Curve in Pharmacology, Springer Vedag, New York, 1979. 

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 evaluation is used in describing the quantitative relationship between the amount of exposure to a substance and the extent of toxic injury or disease. Data may be derived from animal studies or from studies in exposed human populations. Dose—response toxicity relationship for a substance varies under different exposure conditions. The risk of a substance can not be ascertained with any degree of confidence unless... 

Risk characterization is defined as the integration of the data and analysis of the above three components to determine the likelihood that humans wiU. experience any of the various forms of toxicity associated with a substance. When the exposure data are not available, hypothetical risk is characterized by the integration of hazard identification and dose—response evaluation data. 

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. 

Fig. 5. Toxic chemical dose—response curves (a) no effect (b) linear effect (c) no effect at low dose and (d) beneficial at low dose.

Fig. 6. Dose—response regression line for mortaUty data (represented by x) expressed by log-probit plot.

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. 

There should be sufficient dose—response information to allow decisions on causal relationships and relevance. 

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. 

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