Screens in Safety and Hazard Assessment

FIGURE 4.1. Decision-making for pharmaceutical candidates based on outcome of screening tests, (a) A 100% probability of efficacy means that every compound that has the observed performance in the model(s) used has the desired activity in humans, (b) A 0% probability of efficacy means that every compound that has the observed performance in the model(s) used does not have the desired activity in humans, (c) A 100% probability of a safety finding means that such a compound would definitely cause this toxicity in humans, (d) A 0% probability means this will never cause such a problem in humans. Note. These four cases (a, h, c, and d) are almost never found. 

The terminology involved in screen design and evaluation and the characteristics of a screen should be clearly stated and understood. The characteristics of screen performance are defined as 

These characteristics may be optimized for a particular use, if we also consider the mathematics underlying them and errors.  

A brief review of the basic relationships between error types and power starts with considering each of five interacting factors (Gad, 1982a, 1999) that serve to determine power and define competing error rates. 

the desired sensitivity in a screen (such as being able to detect an increase of 10% in mutations in a population)  

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Fourteen formulations of chemical alternatives were submitted to EPA under confidentiality and they were assessed based on numerous human health and ecotoxicity endpoints in addition to bioaccumulation potential and environmental persistence. They were also screened for potential exposure to workers, users and the aquatic environment. Where data gaps existed, EPA experts used models and chemical analogs to estimate the hazard for a particular endpoint. The literature and test data reviews were published in the final report, Environmentally Preferable Options for Furniture Fire Safety Low Density Furniture Foam . In addition, each hazard endpoint was ranked with a concern level (High, Moderate or Low) based on the criteria used by the EPA s New Chemicals Program to rate the concern level of new chemicals submitted under the Toxic Substance Control Act (TSCA). As seen in Figure 8.2, where the hazard endpoint rankings are bold, the value is based on experimental data. Where the hazard endpoints are presented in italic font, the value is estimated based on models or chemical analogs. In this way, detailed hazard information was summarized and presented in a clear and concise format. 

The appropriate level of personal protection necessary to safely perform the site characterization activities will depend on the assessment of site hazards that might pose a risk to the site characterization team. The hazard assessment may be further refined during the approach to the site, based on the results of the field safety screening and initial observations of site conditions. Two general scenarios are considered, one in which there are no obvious signs of immediate hazards, and one in which there are indicators of site hazards. 

In order to adequately develop a medical surveillance plan, one must perform a thorough assessment of the physical, biologic, and/or chemical hazards to which personnel may be exposed and which have the potential to cause adverse health effects. For certain chemical substances, medical surveillance is prescribed by law. The standards are set by the Occupational Safety and Health Administration (OSHA). Attention to sensitivity, specificity, and predictive value is particularly important in occupational screening programs. The primary purpose of medical surveillance is the elimination of exposures that cause disease. Medical surveillance s ultimate goal is prevention. 

Careful attention to such detail is necessary as a second line of defence against the effects of reactive hazards. The level of protection considered necessary may range from the essential and absolute minimum of effective eye protection, via the safety screen, fume cupboard or enclosed reactor, up to the ultimate of a remotely controlled and blast-resistant isolation cell (usually for high-pressure operations). In the absence of facilities appropriate to the assessed level of hazard, operations must be deferred until such facilities are available. 

A theme throughout this chapter is the difference between genotoxicity assessment in hazard profiling and safety assessment applications. This comes more acutely into focus in this section where the follow-up to positive profiling tests is considered. The default expectation is that the follow-up for a positive early profiling test would be removal of the compound from the collection going forward the aim of a screening... 

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