Critical response

Separation Margin = Critical Response Envelope = Amplitude to = Amplitude to... 

A curious episode in 1973 characterizes the early time in this field. A pharmacological activity problem (discrimination between sedatives or tranquilizers) was related to mass spectral data without needing or using the chemical structures of the considered compounds (Ting et al. 1973). In a critical response (Clerc et al. 1973) it was reported that similar success rates—better than 95%—can be obtained for a classification of the compounds whether their names contain an even or odd number of characters, just based on mass spectral data Obviously, in both papers the prediction performance was not estimated properly. 

Sf/ -Separation margin CRE =Critical response envelope Nqj = Amplitude -Amplitude ... 

This dual responsibility can be enabled by the existence of a laboratory that operates with a certain degree of independence within the corporation (3). Such a laboratory has the following critical responsibilities (/) keep the science base renewed and vibrant, maintaining the base of science experts and... 

A summary of the response variables obtained in this preliminary study are shown in Table 14, and the order ranking for the influence of process variables on the critical responses associated with coating process efficiency and drug release are provided in Table 15. 

A summary of the response variables obtained in this preliminary study are shown in Table 14, and the order ranking for the influence of process variables on the critical responses associated with coating process efficiency and drug release are provided in Table 15. As can be seen from the summary provided in Table 14, there is clearly an influence of the processing conditions used on ultimate drug release characteristics. On further examination, it was concluded that the major causes of the magnitude of differences in drug release characteristics were primarily due to ... 

In addition to the principal studies, supporting studies are used in evaluating chemical toxicity. These studies provide supportive, rather than definitive, information and can include data from a variety of sources. For example, studies of different durations or in different species may confirm the choice of the critical response. Metabolic and other pharmacokinetic studies can provide insights into the mechanism of action of a chemical. By comparing the metabolism of the chemical in the laboratory animal and in humans, EPA might be able to estimate equitoxic doses. In vitro studies can provide insights into the chemical s potential for biological activity. The known toxicity of a structurally related compound and the use of structure-activity relationships can also provide clues to the chemical s possible toxicity. 

Dose-response concepts. Dose-response assessment for hazardous chemicals that can cause deterministic effects begins with the toxicology data developed during the hazard identification step described in Section 3.1.4.1.2. In many cases, hazard identification and dose-response assessment occur simultaneously. For each chemical, the critical response (a specific response in a specific organ) is identified in the hazard identification process. Using the available data for the critical response, one of the following is established ... 

A lowest-observed-adverse-effect level (LOAEL), which is the lowest administered dose of a chemical at which there is a biologically significant increase in frequency or severity of the critical response between the exposed population and its control. 

EPA bases its procedures for estimating RfD on several assumptions, the most basic of which is that a threshold exists in the dose-response relationship for the critical response. If the dose is above the threshold (not the same as RfD) and is of sufficient duration, EPA considers that the chemical will cause the response in some segment of the exposed population. The U.S. Food and Drug Administration uses a similar approach to identify safe levels of exposure to food additives and certain residues. Studies on many substances have shown that before toxicity occurs, the chemical must deplete a physiological reserve or overcome the various repair capacities in the human body (Klaassen et al., 1996). 

A third important assumption relates to selecting the critical response. EPA assumes that if the dose is below that required to cause the most sensitive response, then other deterministic responses will not occur. However, if other responses have shallower slopes in the dose-response curves near their thresholds, estimating RfD on the basis of the critical response may not be sufficiently protective to preclude a noncritical response from occurring. For this reason, EPA may use information on the slopes of dose-response curves to determine the critical response and the number of safety factors to be applied, although EPA rarely does so. 

EPA does not consider data on developmental toxicity, standing alone, as an adequate basis for estimating RfD. Investigators use acute or short-term exposures for these studies. Therefore, they are of limited use in estimating the threshold for deterministic responses. However, if developmental toxicity is the critical response for a chemical with a complete database, EPA will derive RfD from that study. 

The most appropriate NOAEL for the critical response from a well-conducted study in humans is identified. 

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. 

I read it with great interest [...] My impression is, however, that this expert report is an important contribution to a very important question which, since the Leuchter Report, needs to be answered urgently. [...] One can only very much hope that the well-known tactics of hushing up is not applied to your expert report, but that critical responses and comments will be made. Prof. Dr. Ernst Nolte, Historian, January 28,1992... 

Whenever a small number of qualified individuals manage an array of critical responsibilities within an organization, it is imperative to develop innovative strategies for managing changes that invariably impact quality and com-... 

In addition to case studies, a course journal has also been an effective tool. Students were asked to complete problems related to basic chemistry topics and internet resources in the journal. For example, end-of-chapter problems in the textbook12 were often assigned and completed in the journal. Students were also asked to record comments and questions related to course materials and to maintain a project log. Specifically, journal entries included responses to and analysis of internet resources, responses to and analysis of lecture material, critical responses to periodical articles and government documents, project ideas, and project progress including data, interviews, and event logs. The journals were collected at least one time during the quarter and at the end of the quarter. 

In addition, the Aviation Disaster Family Assistance Act of 1996 (ADFAA) mandated that the NTSB identify a human service organization to coordinate family assistance and mental health services to surviving victims and the families of the deceased and to coordinate a nondenominational memorial service. The NTSB, in turn, named the American Red Cross to oversee the coordination of these services. In the event an aviation disaster meets these criteria and the ADFAA is enacted, the national headquarters of the American Red Cross will deploy a Critical Response Team to engage the Federal Family Assistance Plan for Aviation Disasters. This team will work with local, state, and federal resources to meet the mental health and spiritual care needs of those involved (NTSB, 2007). 

This need for as complete a dataset as possible underscores the importance of the clinical monitor. Two related and critical responsibilities of clinical monitors are to ensure that all sites in the trial follow the study protocol, and to check that the required data are recorded as and when they should be. A good monitor will spot the absence of recorded data sooner rather than later, which considerably increases the likelihood of locating and subsequently recording those data. 

The work of Forbes and Battersby [46] is an integrated study of the relations among the chemical structures of the dialkyl phosphites, their adsorption on and reaction with iron, and their behavior in four-ball bench testing of lubricant additive effectiveness. The four-ball data in Table 11-17 for solutions of additive in white oil show that both the wear/load index (mean Hertz load) and the initial seizure load are critically responsive to concentration, with a strong effect when the concentration increases from 0.01 to 0.04 molal (0.031% to 0.124% P). The initial seizure load is an uncomplicated criterion with a straightforward interpretation, whereas the wear/load index is contrived, both in concept and performance. The low-load 50 minute wear data show inconsistencies in the influence of additives that have not been explained. 

Because the U.S. groups were not given an opportunity to view and comment on the accuracy of any draft reports from the TWG after their visit to Berkeley in 1998 and their subsequent visit to Dubna in 1999, they were totally taken aback by this rapid publication of the TWG conclusions without the iterative process that they had understood would take place with the involved groups at LBL in the United States, GSI in Darmstadt, Germany, and JINR in Dubna, USSR. In an attempt to counteract this criticism, responses from the Berkeley, Dubna, and GSI groups were invited and published in the IUPAC journal immediately following the TWG Discovery article of 1993 (Barber et al., 1993). The IUPAC then stated that this TWG report could now be considered by the CNIC, which had the responsibility for recommending names. However, it was pointed out that the TWG report had not been subjected to the external and internal review required by the IUPAC prior to publication. 

Given the highly dramatic nature of the times that he lived through, it is hardly surprising that the narrative of Synge s life is often condensed into a simplified and manageable version of a complicated set of events and contexts. Students of Synge need to be somewhat wary of the standard account which has informed much of the critical response to his work since his death in 1909. The conventional narrative usually follows a familiar pattern an... 

Equation (2.25) is an important relationship if one desires to plot the confidence intervals that surround the least squares regression line. The upper confidence limit for the particular case where x = 0 is obtained from Eq. (2.25) in which a 1 — a probability exists that the Normal distribution of instrument responses falls to within the mean y at x = 0. Mathematically, this instrument response y, often termed a critical response, is defined as... 

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