Appropriateness of the Critical Study

Evalrrate the body of evidence that led to the EPA-derived MeHg RfD. Htrman epidemiological and animal toxicity data should be the basis of the evaltration. The evaluation should determine the appropriateness of the critical study, end point of toxicity, and uncertainty factors used by EPA in deriving the RfD for MeHg. Sensitive populations should be considered. 

The methods the USEPA uses in the derivation of inhalation RfDs are similar in concept to those used for oral RfDs however, the actual analysis of initiation exposures is more comple.x tlian oral e. posurcs due to (1) the dynamics of the respiratory system and its diversity across species, and (2) difTcrcnces in the physiochcmical (both physical and chemical) properties of contaminants. Although the identification of the critical study and the determination of the NOAEL in theory are similar for oral and inlralalion e.xposures, several important differences should be noted. In selecting the most appropriate study, the USEPA considers differences in respiratory anatomy and physiology, as well as differences in the physicochemical characteristics of tire contaminant. Differences in respiratory anatomy and physiology may affect the pattern of contaminant deposition in the respiratory tract, and the clearance and redistribution of the agent. Consequently, the different species may not receive the same dose of the contaminant at the same locations within the respiratory tract even though both species were exposed to the same particle or gas concentration. Differences in the physicochemical characteristics of the contaminants, such as the size and shape of a particle or whether the contaminant is an aerosol or a gas, also influence deposition, clearance, and redistribution. 

The critical study (Bucci and Parker 1992) involved a relevant route of exposure (oral) for determining an RfD. Rats were administered GB by oral gavage, a route of administration that exaggerates the exposure that would normally occur from methods resulting in a slower rate of delivery (e.g., in feed or water). However, the study was subchronic in duration (13 weeks) rather than chronic (104 weeks), and ChE measurements varied and did not show a consistent dose-response relationship across ChE types and genders. Thus, the subcommittee believes that the study was too short in duration and that the results were too variable to form an ideal basis for determining a LOAEL. In addition, the methods used to measure ChE were not ideal (see Appendix G). However, in the absence of other well-conducted studies, the subcommittee agrees with ORNL that the study by Bucci and Parker (1992) is the most appropriate of the available studies for derivation of the RfD for GB. 

The critical studies of MeHg examined a range of neurodevelopmental outcomes. Selection of the most appropriate BMD requires consideration of the biological significance of the effects, including the sensitivity and severity of the outcomes, consideration of the abiUty to detect both exposure and effects, and selection of an appropriate dose-response model. To examine and compare the results of the critical studies, BMD calculations were conducted and compared for various end points. These results are presented and discussed in detail in Chapter 7. 

These have been few studies on the Malaysian automotive industry, especially DC. This study intends to study the current situation in Proton and its vendors PD practice and performance and investigate how vendors DC will enable the success of Proton internalization strategy. At the same time, it will examine the appropriateness of the critical success factors (CSFs) highlighted by prior research on Malaysian DC development. This study focuses on PD activities in Proton because... 

The FDA may request that the sponsor submit additional CRFs that the agency views as important to the drug s review. Typically, the agency will request all CRFs for the pivotal studies. In doing so, the agency s reviewers will attempt to designate the critical studies for which CRFs are required about 30 days after the application s receipt. If a sponsor fails to submit the CRFs within 30 days of the FDA s request, the agency may view the eventual submission as a major amendment and extend the review period as appropriate. 

Although the subcommittee agrees with ORNL that ChE inhibition is a valid end point on which to base the RfD for GA, the subcommittee s confidence in the data is undermined by the increased baseline RBC-AChE concentrations, which were attributed to laboratory errors, in the critical study. Eurthermore, confidence in the calculation of an equivalent oral NOAEL from an i.p. NOAEL is diminished because data from a secondary reference (i.e., RTECS 1995) were used to determine the ratio of the oral LD50 to the i.p. LD50. The subcommittee suggests that the data be verified from the primary source and cited appropriately. 

The fugacity coefficient 0 is generally calculated from an equation of state. However, many equations of state require a knowledge of the critical parameters of the solute, which may not always be available. Nevertheless, solubilities can be correlated, and sometimes extrapolated, using this approach. The addition of more solutes poses few problems from a thermodynamic viewpoint, as long as the appropriate solid-state fugacity is used in the calculations. This type of approach may also be used to study... 

The third criterion is critical in determining the appropriateness of the design of a bioequivalence study. 

This functional definition makes clear that the discipline of Statistics is Indeed multi-faceted and essential throughout clinical trials. It is critical at the start of the clinical trial process so that a study can be designed appropriately to facilitate the collection of optimum quality data, which then need to be organized and managed correctly. These data are then described and analyzed, and the numerical results of these analyses are interpreted in the context of the particular study. Finally, the numerical results of the analyses and the authors interpretation of these results are presented to regulatory agencies to request permission to market the drug, and published in clinical communications to provide Information to physicians. 

There are more examples for the application of these requirements If a study involves analytical procedures, the facility has to have an adequate power supply with adequate provisions for the case of power failures or breakdowns. The same provisions have to be taken for the air-conditioning system of the animal rooms. It is self-evident that the IT system of a test facility will have to be protected against this kind of event, too. Furthermore, an adequate ventilation system will be needed in order to protect test systems, equipment and technicians from noxious or corrosive gases and volatile solvents. In the area of in vitro test systems, a surveillance system for the facilities (i.e. the containers) used to store cell lines in a deep-frozen stage will have to assure that the level of liquid nitrogen does not fall below the critical minimal level. Many more examples could be cited and the appropriateness of the facility and its construction can be followed down to the small table on which the balance to be used in the study is placed Does this table have sturdy legs and a special. 

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