Requirements indirect safety

The indirect safety norms may well be used in parallel with the direct norms. And there is little reason not to do that although the indirect norms may seem less potent than the direct norms as a means to achieve safety, they widen the range of tools available for the purpose. Rather than putting all bets on one horse - the detailed do s and don ts that are likely to affect safety directly - the safety regulation also requires the industry to establish procedures and expertise for handling and complying with the direct safety requirements. 

The most general indirect safety requirement is the provision that obliges the party responsible to establish, follow up and further develop a management system designed to ensure eompliance with requirements in the health, safely and environment legislation . This is the very basis for the internal control system. 

Norway does not restrict itself to influencing safety by laying down legal requirements in the form of direct and indirect safety norms. State safety management also includes checking that the party responsible actually complies with the norm. 

OSHA s Safety Pays Program (2009) is another example of how Bird s concept has been applied. The Safety Pays literature says that the program will, among other things, Generate a report of the costs and the sales needed to cover those costs. As computations required by Safety Pays are made, a profit percentage is to be entered to produce the amount of sales necessary to cover direct and indirect costs. 

These are addressed ind The Backfit Rule (10 CFR 50.109, and the NRC Safety Goal Policy Statement (SECY-89-102). The Backfit Rule applies not to the regulated industry, but to the NRC staff. It says that backfitting is required if it will result in substantial increase in safely and the direct and indirect costs of backfitting are justified. (This limitation does not apply if the modification is necessary for compliance with regulations). 

Causes of adverse effects over-dosage (A). The drug is administered in a higher dose than is required for the principal effect this directly or indirectly affects other body functions. For instances, morphine (p. 210), given in the appropriate dose, affords excellent pain relief by influencing nociceptive pathways in the CNS. In excessive doses, it inhibits the respiratory center and makes apnea imminent The dose dependence of both effects can be graphed in the form of dose-response curves (DRC). The distance between both DRCs indicates the difference between the therapeutic and toxic doses. This margin of safety indicates the risk of toxicity when standard doses are exceeded. 

For solid oral dosage forms, a reference to the appropriate indirect food additive regulation for each material of construction is typically considered sufficient evidence of safety. However, for a powder for reconstitution dosage form, reference only to the indirect food additive regulations as evidence of safety for the materials of construction is not recommended. Compatibility for solid oral dosage forms and for powders for reconstitution is typically addressed for plastics and glass by meeting the requirements of the Containers test. 

The responsibility of chemical process managers for preventing air, water, and soil pollution has indirectly influenced plant safety by requiring better control of plant processes to prevent releases of hazardous materials. Regulatory legislation was introduced by the Health, Education, and Welfare Department (Health and Human Services) and the U.S. Environmental Protection Agency (EPA) to require (/) improvements in air quality (1955 Air Pollution Act ... 

These revised regulations require the validation of computer systems. Systems covered by device GMP regulations include any system that directly or indirectly impacts the safety, effectiveness, or quality of materials, components, or the finished device. 

The major advantage of (fractional) oral clearance as a phenotypic trait is that its value is linearly related to the enzyme s catalytic activity, provided that first-order conditions are present. This requirement, along with any safety considerations, is the main reason the dose of an in vivo probe should be as low as possible, consistent with analytical considerations. Furthermore, it is possible to directly extrapolate this type of trait measure to the disposition of other drugs whose metabolism is mediated by the measured enzyme and also to place the trait value within a therapeutic context. On the other hand, estimation of oral clearance requires multiple blood and urine collections, often over many hours, that are an inconvenience for the study subject and require considerable amounts of analytical time and effort. Because of this, simpler and less time-consuming approaches have often been used. However, it is not always appreciated that such phenotyping tests provide only an indirect measure of metabolizing activity and may be affected by factors other than the enzyme s intrinsic clearance. In addition, it is difficult to relate an indirect trait measure to parameters that are of clinical importance, such as the drug s clearance. 

Selection of a comprehensive testing battery to record the rate of AChE inhibition is a crucial point. In addition to the estimation of AChE activity, other functions (e.g., sensory systems, reflexes, neuromotor development, locomotion, gait, reactivity to medication) require close monitoring to achieve chemical safety to OPs. In the case of children and workers exposed to very low doses of OPs, other tests should indirectly include parameters like learning, memory loss, social behavior, and reproductive behavior. To integrate behavioral data into the context... 

Another typical source of uncertainty in mixture assessment is the potential interaction between substances. Interactions may occur in the environment (e.g., precipitation after emission in water), during absorption, transportation, and transformation in the organism, or at the site of toxic action. Interactions can be either direct, for example, a chemical reaction between 2 or more mixture components, or indirect, for example, if 1 mixture component blocks an enzyme that metabolizes another mixture component (see Chapters 1 and 2). Direct interactions between mixture components are relatively easy to predict based on physical-chemical data, but prediction of indirect interactions is much more difficult because it requires detailed information about the processes involved in the toxic mechanisms of action. One of the main challenges in mixture risk assessment is the development of a method to predict mixture interactions. A first step toward such a method could be the setup of a database, which contains the results of mixture toxicity tests. Provided such a database would contain sufficient data, it could be used to predict the likelihood and magnitude of potential interaction effects, that is, deviations for CA and RA. This information could subsequently be used to decide whether application of an extra safety factor for potential interaction effects is warranted, and to determine the size of such a factor. The mixture toxicity database could also support the search for predictive parameters of interaction effects, for example, determine which modes of action are involved in typical interactions. 

---