Dose-response relationship action

The law of mass action has been successfully applied to many drug dose-response relationships since the early work of Clark. The systematic relation between the dose of a drug and the magnitude of its response is based on three assumptions (1) response is proportional to the level of receptor occupancy (occupancy theory), (2) one drug molecule combines with one receptor site, and (3) a negligible fraction of total drug is combined with the receptors. These assumptions must also apply to Beidler s equation. 

Stages in hazard characterization according to the European Commission s Scientific Steering Committee are (1) establishment of the dose-response relationship for each critical effect (2) identification of the most sensitive species and strain (3) characterization of the mode of action and mechanisms of critical effects (including the possible roles of active metabolites) (4) high to low dose (exposure) extrapolation and interspecies extrapolation and (5) evaluation of factors that can influence severity and duration of adverse health effects. 

Second, there are specific endpoint assays for which an adverse outcome clearly dictates the action to be taken. These endpoints include either immediate or delayed hypersensitivity reactions, because once the individual is sensitized a dose-response relationship may not apply. 

LSD, relatively little systematic testing of performance over a range of LSD dosage and throughout the duration of its action had been reported. We therefore undertook studies that would reveal the dose-response relationship with more precision, initially by the oral route and later by intravenous or inhalation routes of administration. A total of approximately 100 subjects were tested between 1961 and 1966, at... 

Dose-response assessment today is generally performed in two steps (1) assessment of observed data to derive a dose descriptor as a point of departure and (2) extrapolation to lower dose levels for the mmor type under consideration. The extrapolation is based on extension of a biologically based model (see Section 6.2.1) if supported by substantial data. Otherwise, default approaches that are consistent with current understanding of mode of action of the agent can be applied, including approaches that assume linearity or nonlinearity of the dose-response relationship, or both. The default approach is to extend a straight line to the human exposure doses. 

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. 

It is important to note that the T1 screening program will not determine dose-response relationships, mechanism of action, or the adversity of a chemical s effect, if any. Rather, it is designed to demonstrate interaction with components of the endocrine system. 

The chemical paradigm for risk management also is used in regulating exposures to hazardous chemicals that cause deterministic effects and exhibit a threshold in the dose-response relationship. For these substances, RfDs, which are often used to define acceptable exposures, represent negligible doses, because RfDs usually are well below assumed thresholds for deterministic responses in humans and action to reduce doses below RfDs generally is not required. This interpretation is supported by cases where doses above an RfD are allowed when achieving RfD is not feasible. A particular example... 

UK is nonantigenic and its mechanism of action is much more direct compared with that of streptokinase. UK cleaves plasminogen, by first-order reaction kinetics, to form plasmin. It is pH and temperature stable. The lack of circulating neutralizing antibodies and its direct mechanism of action allow for a predictable dose response relationship. 

In characterizing the database, a number of assumptions are applied when data are not available or are incomplete (USEPA, 1991 IPCS, 2005 Kimmel et al., 2006). These include uncertainties about toxicokinetics, mechanism of action, low-dose-response relationships, and human exposure patterns. Each of these assumptions is supported to some extent by the scientific literature. The following assumptions are generally accepted in risk assessment strategies ... 

The feasibility of informative experiments, whether in vitro or, if necessary, in vivo will depend mainly on the availability of model systems that are sufficiently well understood, and the coverage of the broad types of investigation, as in conventional toxicity experiments where the objective is to try to detect any effect and subsequently to decide whether it is toxic or pharmacological . The need to explore such major features as the concentration-response or dose-response relationship, speed of onset, duration of action and reversibility of effects and their upstream and downstream consequences on other physiological mechanisms, potential interactions with the physiological and pathophysiological status of the patient, and other treatments administered at the same time, will all affect the nature and number of the most relevant experiments. 

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