Dose-response relationship concept

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. 

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. 

Our assignment for EPA was to apply quantitative risk analysis methods to the determination of risk for a particular chemical. The health risks for perchloroethylene turned out to be highly uncertain, but by using decision analysis concepts we were able to display this uncertainty in terms of alternative assumptions about the dose response relationship. Similar methods might be used to characterize uncertainties about human exposure to a chemical agent or about the costs to producers and consumers of a restriction on chemical use. 

As an alternative to the traditional NOAEL approach, the BMD concept has been proposed for use in the quantitative assessment of the dose-response relationship, see the next section. 

The concept of categorizing carcinogens into threshold carcinogens and non-threshold carcinogens is a pragmatic approach that simplifies the reality of dose-response relationships. The observed dose-response curve for tumor formation in some cases represents a single rate-determining step however, in many cases it may be more complex and represent a superposition of a number of dose-response curves for the various steps involved in the mmor formation. It is therefore more realistic to assume that there is a continuum of shapes of dose-response relationships which cannot be easily differentiated by data and information usually available. 

An immunologic basis for chronic beryllium disease has been postulated and a hypersensitivity phenomenon demonstrated. Consistent with the concept of chronic berylliosis as a hypersensitivity pulmonary reaction are the following Persons with berylliosis also show delayed cutaneous hypersensitivity reactions to beryllium compounds their peripheral blood lymphocytes undergo blast transformation and release of macrophage inhibition factor after exposure to beryllium in vitro helper/suppressor T-cell ratios are depressed and there is lack of a dose-response relationship in chronic beryllium cases. Hypersensitization may lead to berylliosis in people with relatively low exposures, whereas nonsensitized individuals with higher exposures may have no effects. 

The preceding sections have explored classical pharmacological concepts based on the dose-response relationships in tissue or organ preparations. The enormous complexity of living systems and the remoteness of cause from effect (i.e., drug administration from pharmacological action) introduce many complications and artefacts into the study of such relationships. 

An underlying concept in risk assessment relies on the statement by Paracelsus (see above) and the fact that for most types of effect, there will be a dose-response relationship. Therefore, the corollary is that there should be a safe dose. Consequently, it should be possible to determine a level of exposure, which is without appreciable risk to human health or the ecosystem. 

There appear to have been few advances in either medicine or toxicology between the time of Galen (ad 131-200) and Paracelsus (1493-1541). It was the latter who, despite frequent confusion between fact and mysticism, laid the groundwork for the later development of modem toxicology by recognizing the importance of the dose-response relationship. His famous statement— All substances are poisons there is none that is not a poison. The right dose differentiates a poison and a remedy —succinctly summarizes that concept. His belief in the value of experimentation was also a break with earlier tradition. 

The explanation of the pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination processes is a highly specialized branch of toxicology, and is beyond the scope of this chapter. However, here we introduce a few basic concepts that are related to the several transport rate processes that we described earlier in this chapter. Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to xenobiotics. In addition these studies are essential to provide information on the fate of the xenobiotic following exposure by a define route. This information is essential if one is to adequately interpret the dose-response relationship in the risk assessment process. In recent years these toxicokinetic data from laboratory animals have started to be utilized in physiologically based pharmacokinetic (PBPK) models to help extrapolations to low-dose exposures in humans. The ultimate aim in all of these analyses is to provide an estimate of tissue concentrations at the target site associated with the toxicity. 

Although dose-response assessments for deterministic and stochastic effects are discussed separately in this Report, it should be appreciated that many of the concepts discussed in Section 3.2.1.2 for substances that cause deterministic effects apply to substances that cause stochastic effects as well. The processes of hazard identification, including identification of the critical response, and development of data on dose-response based on studies in humans or animals are common to both types of substances. Based on the dose-response data, a NOAEL or a LOAEL can be established based on the limited ability of any study to detect statistically significant increases in responses in exposed populations compared with controls, even though the dose-response relationship is assumed not to have a threshold. Because of the assumed form of the dose-response relationship, however, NOAEL or LOAEL is not normally used as a point of departure to establish safe levels of exposure to substances causing stochastic effects. This is in contrast to the common practice for substances causing deterministic effects of establishing safe levels of exposure, such as RfDs, based on NOAEL or LOAEL (or the benchmark dose) and the use of safety and uncertainty factors. 

Which of the following is generally credited with developing the early concept of the dose-response relationship ... 

The individual tolerance concept has some unrealistic properties (Kooijman 1996 Newman and McCloskey 2000). Most importantly, if there is a distribution in sensitivities, this would imply that the survivors from an experiment are the less sensitive individuals. Experiments with sequential exposure show that this prediction fails (at least as the dominant mechanism) (Newman and McCloskey 2000 Zhao and Newman 2007). There is sufficient reason to conclude that the individual threshold model is not sufficient to explain the observed dose-response relationships, and that mortality is a stochastic process at the level of the individual... 

The determination of susceptibility entails the presence of observable changes in biochemical or physiologic processes reflecting dose-response relationships unique to a chemical (e.g., sulfur dioxide) or class of chemicals (e.g., acid aerosols). Susceptibility and hypersusceptibility are not meaningful concepts outside of the context of specific exposures. "Dose-response relationships are chemical-specific and depend on modes of action people are not hypersusceptible to all kinds of exposures" (PCCRARM 1997). 

The fundamental principle of toxicology is the concept that the sixteenth century physician Paracelsus articulated in the 1500s sola dosis facit venenum or the dose makes the poison . The modem version of this observation is the dose-response relationship, which is experimentally and theoretically supported through pharmacokinetic and pharmacodynamic experimentation. Pharmacokinetics is concerned with the study of the time course of the disposition of drugs, specifically absorption, distribution, metabolism and elimination, often referred to as ADME. In non-technical terms it can be thought of as what the body does to the chemical. An understanding of the pharmacokinetic (in the case of dmgs) or toxicokinetic (all chemicals) profile is critical to estimate the... 

The concept of critical load is based on the dose-response relationship, the critical load being exceeded when the load causes harmful effects to the recep-... 

The public finds it difficult to understand the concept of dose-response relationships. 

The various ways that the dose-response relationship may be portrayed includes the simple, intuitive concept of a virtually safe dose . This has its roots in the portrayal of what is termed the margin of exposure , a concept itself derived from the pharmaceutical industry when portraying to the physician the ratio between the amount of a drug that produces a harmful effect and that which produces the desired beneficial one. 

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