Safety: assessments terms used

The terms verification, validation, and functional safety assessment are used in ANSI/ISA-84.00.01-2004-1. Each term implies that specific activities are taking place or that specific requirements are being met. Annex D provides an overview of these three terms. 

The preclinical trials are performed in in vitro and animal studies to assess the biological activity of the new compound. In phase 1 of the clinical trials the safety of a new drug is examined and the dosage is determined by administering the compound to about 20 to 100 healthy volunteers. The focus in phase II is directed onto the issues of safety, evaluation of efficacy, and investigation of side effects in 100 to 300 patient volimteers. More than 1000 patient volunteers are treated with the new drug in phase 111 to prove its efficacy and safety over long-term use. 

This section is devoted to the definition and comparison of the three nonrodent animal models (dog, ferret, and monkey) in terms of experimental procedures, environmental and dietary requirements, as well as advantages and disadvantages of use in safety assessment testing. 

Guillouzo et al. (1988) developed a coculture system of rat or human hepatocytes with rat liver epithelial cells that maintains the hepatocytes in a differentiated state for extended periods of time, thereby allowing studies involving chronic treatment with the test substance to be conducted. Primary cultures of hepatocytes can therefore provide a useful model for short- and long-term studies involving the safety assessment of xenobiotics. 

A survey in 2000, carried out in Los Angeles by a group at the University of Southern California School of Medicine, found a link with bladder cancer. It involved 1541 people with this condition and they were compared to 897 people who were not so afflicted. Adjustments were made to take into account smokers, who are liable to be more at risk of this disease in any case, and it found that those who used permanent hair dyes every month had a slightly higher risk of bladder cancer, especially if they had used hair dyes continuously for 15 or more years. Hairdressers had an even higher risk. This revelation prompted the Scientific Committee on Cosmetic Products and Non-Food Products ofthe EU (SCCNFP) to issue a discussion paper in February 2002. This was followed in December that year by a requirement that manufacturers must submit by July 2005 all their data on hair dyes together with studies to assess their safety in terms of cancer and toxicity. The outcome of this has yet to be published, but it will take the form of an approved list of hair dyes which will be issued in 2007. 

The humanized mouse model is used for safety assessment of drugs that affect lipid profiles as a side effect (and thereby possibly influence the risk of atherosclerosis and, subsequently, myocardial infarction). A typical example is the disturbed lipid profile and increased risk of myocardial infarction experienced by AIDS patients following the long-term use of HIV-l-protease inhibitors [16,17]. 

The term margin of safety is sometimes used to compare exposure levels to NO(A) EL and then this margin is compared with assessment factors. DNEL already include these assessment factors in the equation, so this thesis uses the term level of safety . 

For non-threshold effects, the term margin of exposure rather than margin of safety is sometimes used if assessment factors are excluded from the assessment and a unit descriptor system used to characterise the effect. 

It is difficult to assess the benefits and risks of smart drugs, because not enough research exists on tliein Although doctors question their salety, especially when used in the combinations that their fans prefer, safety may be less of a concern than efficacy, ft is not at all clear that these substances really have the beneficial effects claimed by their promoters, and we do not have enough information to know iust what are the effects of long-term use. 

SEVERIN I, DAHBI L, LHUGUENOT J-C, ANDERSSON MA, HOORNSTRA D, SALKINOJA-SALONEN M, TURCO L, ZUCCO F, STAMMATI A, DAHLMAN O, CASTLE L, SAVOLAINEN M, WEBER A, HONKALAMPI-HAMALAiNEN u and VON WRIGHT A. (2005) Safety assessment of food-contact paper and board using a battery of short-term toxicity tests European Union BIOSAFEPAPER project. Food Additives and Contaminants 22 1032-1041. 

The political decision to build and take into use a deep geological repository for long term storage of spent nuclear fuel will largely depend on the outcome of thorough scientifically-based safety assessments. Given the very long operational time span for the repository, the... 

The topic of preclinical assessment of a clinical candidate has been reviewed in Chapter 29. The topic is mentioned here because the decision as to whether it is safe to take a candidate drug into humans is ultimately a medical judgment that can only be made by individuals responsible for clinical drug development. Preclinical safety assessments are designed to provide the knowledge needed to decide whether it is reasonably safe to study a drug candidate in humans. The term reasonably safe is used in this context because that is what an FDA reviewer must answer when reviewing an IND application. 

The ideal test to answer a safety assessment question should have an endpoint measurement that provides data such that dose-response relationships can be obtained. Furthermore, any criterion of effect must be sufficiently accurate in the sense that it can be used to reliably resolve the relative toxicity of two test chemicals that produce distinct yet similar responses (in terms of hazard to humans). In general, it may not be sufficient to classify test chemicals into generic toxicity categories. For instance, if a test chemical falls into an intermediate toxicity category but is borderline to the next, more severe toxicity category, it should be treated with greater concern than another test chemical that falls at the less toxic extreme of the... 

Glacier-permafrost coupling creates a distinctive hydraulic regime, dominated by transient processes, which must be understood for long term safety assessments. In principle, the problem should be solved by a thermo-mechanically coupled model of the whole ice-water-rock system, driven by an external climate function. As an interim step, we use two separate models, one for... 

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