Statistical evaluation of an acute dermal toxicity test using the dermal fixed dose procedure

The conventional method for the assessment of acute dermal toxicity (OECD Test Guideline 402, 1987) uses death of animals as an endpoint to identify the median lethal dose (LD50). A new OECD Testing Guideline called the dermal fixed dose procedure (dermal FDP) is being prepared to provide an alternative to Test Guideline 402. In contrast to Test Guideline 402, the dermal FDP does not provide a point estimate of the LD50, but aims to identify that dose of the substance under investigation that causes clear signs of nonlethal toxicity. This is then used to assign classification according to the new Globally Harmonised System of Classification and Labelling scheme (GHS). The dermal FDP has been validated using statistical modelling rather than by in vivo testing. The statistical modelling approach enables calculation of the probability of each GHS classification and the expected numbers of deaths and animals used in the test for imaginary substances with a range of LD50 values and dose-response curve slopes. This paper describes the dermal FDP and reports the results from the statistical evaluation. It is shown that the procedure will be completed with considerably less death and suffering than guideline 402, and will classify substances either in the same or a more stringent GHS class than that assigned on the basis of the LD50 value.

Statistical evaluation of the fixed concentration procedure for acute inhalation toxicity assessment

The conventional method for the assessment of acute inhalation toxicity (OECD Test Guideline 403, 1981) uses death of animals as an endpoint to identify the median lethal concentration (LC50). A new OECD Testing Guideline called the Fixed Concentration Procedure (FCP) is being prepared to provide an alternative to Test Guideline 403. Unlike Test Guideline 403, the FCP does not provide a point estimate of the LC50, but aims to identify an airborne exposure level that causes clear signs of nonlethal toxicity. This is then used to assign classification according to the new Globally Harmonized System of Classification and Labelling scheme (GHS). The FCP has been validated using statistical simulation rather than byin vivo testing. The statistical simulation approach predicts the GHS classification outcome and the numbers of deaths and animals used in the test for imaginary substances with a range of LC50 values and dose response curve slopes. This paper describes the FCP and reports the results from the statistical simulation study assessing its properties. It is shown that the procedure will be completed with considerably less death and suffering than Test Guideline 403, and will classify substances either in the same or a more stringent GHS class than that assigned on the basis of the LC50 value.

A statistical evaluation of the fixed dose procedure

The fixed-dose procedure (FDP) was introduced as OECD Test Guideline 420 in 1992, as an alternative to the conventional median lethal dose (LD50) test for the assessment of acute oral toxicity (OECD Test Guideline 401). The FDP uses fewer animals and causes less suffering than the conventional test, while providing information on the acute toxicity to allow substances to be ranked according to the EU hazard classification system. Recently the FDP has been revised, with the aim of providing further reductions and refinements, and classification according to the criteria of the Globally Harmonized Hazard Classification and Labelling scheme (GHS). This paper describes the revised FDP and analyses its properties, as determined by a statistical modelling approach. The analysis shows that the revised FDP classifies substances for acute oral toxicity generally in the same, or a more stringent, hazard class as that based on the LD50 value, according to either the GHS or the EU classification scheme. The likelihood of achieving the same classification is greatest for substances with a steep dose-response curve and median toxic dose (TD50) close to the LD50. The revised FDP usually requires five or six animals with two or fewer dying as a result of treatment in most cases.

The competitive dialogue procedure: Advantages, disadvantages, and its implementation into English and Dutch law

Competitive Dialogue (CD) is a new contract award procedure of the European Community (EC). It is set out in Article 29 of the 'Public Sector Directive' 2004/18/EC. Over the last decades, projects were becoming more and more complex, and the existing EC procedures were no longer suitable to procure those projects. The call for a new procedure resulted in CD. This paper describes how the Directive has been implemented into the laws of two member states: the UK and the Netherlands. In order to implement the Directive, both lawmakers have set up a new and distinct piece of legislation. In each case, large parts of the Directive’s content have been repeated ‘word for word’; only minor parts have been reworded and/or restructured. In the next part of the paper, the CD procedure is examined in different respects. First, an overview is given on the different EC contract award procedures (open, restricted, negotiated, CD) and awarding methods (lowest price and Most Economically Advantageous Tender, MEAT). Second, the applicability of CD is described: Among other limitations, CD can only be applied to public contracts for works, supplies, and services, and this scope of application is further restricted by the exclusion of certain contract types. One such exclusion concerns services concessions. This means that PPP contracts which are set up as services concessions cannot be awarded by CD. The last two parts of the paper pertain to the main features of the CD procedure – from ‘contract notice’ to ‘contract award’ – and the advantages and disadvantages of the procedure. One advantage is that the dialogue allows the complexity of the project to be disentangled and clarified. Other advantages are the stimulation of innovation and creativity. These advantages are set against the procedure’s disadvantages, which include high transaction costs and a perceived hindrance of innovation (due to an ambiguity between transparency and fair competition). It is concluded that all advantages and disadvantages are related to one of three elements: communication, competition, and/or structure of the procedure. Further research is needed to find out how these elements are related.

Case studies to demonstrate the range of applications of the Southampton Hand Assessment Procedure

The Southampton Hand Assessment Procedure (SHAP) was devised to assess quantitatively the functional range of injured and healthy adult hands. It was designed to be a practical tool for use in a busy clinical setting; thus, it was made simple to use and easy to interpret. This paper describes four examples of its use: before and after a surgical procedure, to observe the impact of an injury, use with prostheses, and during recovery following a fracture. The cases show that the SHAP is capable of monitoring progress and recovery, identifying functional abilities in prosthetic hands and comparing the capabilities of different groups of injuries.

A procedure for the simultaneous determination of total nitrogen and total phosphorus in freshwater samples using persulphate microwave digestion

In the absence of a suitable method for routine analysis of large numbers of natural river water samples for organic nitrogen and phosphorus fractions, a new simultaneous digestion technique was developed, based on a standard persulphate digestion procedure. This allows rapid analysis of river, lake and groundwater samples from a range of environments for total nitrogen and phosphorus. The method was evaluated using a range of organic nitrogen and phosphorus structures tested at low, mid and high range concentrations from 2 to 50 mg l-1 nitrogen and 0.2 to 10 mg l-1 phosphorus. Mean recoveries for nitrogen ranged from 94.5% (2 mg I-1) to 92.7% (50 mg I-1) and for phosphorus were 98.2% (0.2 mg l-1) to 100.2% (10 mg l-1). The method is precise in its ability m reproduce results from replicate digestions, and robust in its ability to handle a variety of natural water samples in the pH range 5-8.

A coherent procedure for inferring conduct

We exploit a theory of price linkages that lends itself readily to empirical examination using Markovchain, Monte Carlo methods. The methodology facilitates classification and discrimination among alternative regimes in economic time series. The theory and procedures are applied to annual series (1955-1992) on the U.S. beef sector

The trial: how procedure shapes substance

The rules and the principles of the common law are formed from the cases decided in courts of common law. The unique nature of the evolution of the common law has long been the subject of study. Less frequently studied has been the impact of procedure upon the development of substantive law. This paper examines how the procedures applicable to the trial of a case can affect the substance of the resulting decision. The focus of the examination is the decision in Bell v Lever Bros [1932] AC 161. While the case has long been regarded as a leading, albeit confusing, contract law case it is also greatly concerned with the conduct of litigation. This paper argues that the substantive decision was largely determined by the civil procedure available. Different rules of civil procedure, it is suggested, would have resulted in a better decision in the English law of contract.

A sequential procedure for comparing two experimental treatments with a control

A procedure is described in which patients are randomized between two experimental treatments and a control. At a series of interim analyses, each experimental treatment is compared with control. One of the experimental treatments might then be found sufficiently superior to the control for it to be declared the best treatment, and the trial stopped. Alternatively, experimental treatments might be eliminated from further consideration at any stage. It is shown how the procedure can be conducted while controlling overall error probabilities. Data concerning evaluation of different doses of riluzole in the treatment of motor neurone disease are used for illustration.