Opportunities for reduction in acute toxicity testing via improved design

The conventional method for assessing acute oral toxicity (OECD Test Guideline 401) was designed to identify the median lethal dose (LD50), using the death of animals as an endpoint. Introduced as an alternative method (OECD Test Guideline 420), the Fixed Dose Procedure (FDP) relies on the observation of clear signs of toxicity, uses fewer animals and causes less suffering. More recently, the Acute Toxic Class method and the Up-and-Down Procedure have also been adopted as OECD test guidelines. Both of these methods also use fewer animals than the conventional method, although they still use death as an endpoint. Each of the three new methods incorporates a sequential dosing procedure, which results in increased efficiency. In 1999, with a view to replacing OECD Test Guideline 401, the OECD requested that the three new test guidelines be updated. This was to bring them in line with the regulatory needs of all OECD Member Countries, provide further reductions in the number of animals used, and introduce refinements to reduce the pain and distress experienced by the animals. This paper describes a statistical modelling approach for the evaluation of acute oral toxicity tests, by using the revised FDP for illustration. Opportunities for further design improvements are discussed.

The potential for the use of agent-based models in ecotoxicology

This chapter introduces ABMs, their construction, and the pros and cons of their use. Although relatively new, agent-basedmodels (ABMs) have great potential for use in ecotoxicological research – their primary advantage being the realistic simulations that can be constructed and particularly their explicit handling of space and time in simulations. Examples are provided of their use in ecotoxicology primarily exemplified by different implementations of the ALMaSS system. These examples presented demonstrate how multiple stressors, landscape structure, details regarding toxicology, animal behavior, and socioeconomic effects can and should be taken into account when constructing simulations for risk assessment. Like ecological systems, in ABMs the behavior at the system level is not simply the mean of the component responses, but the sum of the often nonlinear interactions between components in the system; hence this modeling approach opens the door to implementing and testing much more realistic and holistic ecotoxicological models than are currently used.

Sequentially testing for a gene-drug interaction in a genomewide analysis

Assaying a large number of genetic markers from patients in clinical trials is now possible in order to tailor drugs with respect to efficacy. The statistical methodology for analysing such massive data sets is challenging. The most popular type of statistical analysis is to use a univariate test for each genetic marker, once all the data from a clinical study have been collected. This paper presents a sequential method for conducting an omnibus test for detecting gene-drug interactions across the genome, thus allowing informed decisions at the earliest opportunity and overcoming the multiple testing problems from conducting many univariate tests. We first propose an omnibus test for a fixed sample size. This test is based on combining F-statistics that test for an interaction between treatment and the individual single nucleotide polymorphism (SNP). As SNPs tend to be correlated, we use permutations to calculate a global p-value. We extend our omnibus test to the sequential case. In order to control the type I error rate, we propose a sequential method that uses permutations to obtain the stopping boundaries. The results of a simulation study show that the sequential permutation method is more powerful than alternative sequential methods that control the type I error rate, such as the inverse-normal method. The proposed method is flexible as we do not need to assume a mode of inheritance and can also adjust for confounding factors. An application to real clinical data illustrates that the method is computationally feasible for a large number of SNPs. Copyright (c) 2007 John Wiley & Sons, Ltd.

T testing the immune system

Amid the flurry of grant writing and experimentation, statistical analysis sometimes gets less attention than it requires. Here, we describe fully the considerations that should go into the employment of the statistical two-sample t test.

Active-control trials with binary data: a comparison of methods for testing superiority or non-inferiority using the odds ratio

This paper considers methods for testing for superiority or non-inferiority in active-control trials with binary data, when the relative treatment effect is expressed as an odds ratio. Three asymptotic tests for the log-odds ratio based on the unconditional binary likelihood are presented, namely the likelihood ratio, Wald and score tests. All three tests can be implemented straightforwardly in standard statistical software packages, as can the corresponding confidence intervals. Simulations indicate that the three alternatives are similar in terms of the Type I error, with values close to the nominal level. However, when the non-inferiority margin becomes large, the score test slightly exceeds the nominal level. In general, the highest power is obtained from the score test, although all three tests are similar and the observed differences in power are not of practical importance. Copyright (C) 2007 John Wiley & Sons, Ltd.

The expected performance of single nucleotide polymorphism loci in paternity testing

We discuss the utility of single nucleotide polymorphism loci for full trio and mother-unavailable paternity testing cases, in the presence of population substructure and relatedness of putative and actual fathers. We focus primarily on the expected number of loci required to gain specified probabilities of mismatches, and report the expected proportion of paternity indices greater than three threshold values for these loci. (c) 2004 Elsevier Ireland Ltd. All rights reserved.

Toxicity testing of groundwater quality

Groundwater is an important resource in the UK, with 45% of public water supplies in the Thames Water region derived from subterranean sources. In urban areas, groundwater has been affected by onthropogenic activities over 0 long period of time and from a multitude of sources, At present, groundwater quality is assessed using a range of chemical species to determine the extent of contamination. However, analysing a complex mixture of chemicals is time-consuming and expensive, whereas the use of an ecotoxicity test provides information on (a) the degree of pollution present in the groundwater and (b) the potential effect of that pollution. Microtox (TM), Eclox (TM) and Daphnia magna microtests were used in conjunction with standard chemical protocols to assess the contamination of groundwaters from sites throughout the London Borough of Hounslow and nearby Heathrow Airport. Because of their precision, range of responses and ease of use, Daphnia magna and Microfox (TM) tests are the bioassays that appear to be most effective for assessing groundwater toxicity However, neither test is ideal because it is also essential to monitor water hardness. Eclox (TM) does not appear to be suitable for use in groundwater-quality assessment in this area, because it is adversely affected by high total dissolved solids and electrical conductivity.

Testing white line strength in the dairy cow

The tensile strength of 576 pieces of white line horn collected over 6 mo from 14 dairy cows restricted to parity 1 or 2 was tested. None of the cows had ever been lame. Seven cows were randomly assigned to receive 20 mg/d biotin supplementation, and 7 were not supplemented. Hoof horn samples were taken from zones 2 and 3 (the more proximal and distal sites of the abaxial white line) of the medial and lateral claws of both hind feet on d 1 and on 5 further occasions over 6 mo. The samples were analyzed at 100% water saturation. Hoof slivers were notched to ensure that tensile strength was measured specifically across the white line region. The tensile stress at failure was measured in MPa and was adjusted for the cross-sectional area of the notch site. Data were analyzed in a multilevel model, which accounted for the repeated measures within cows. All other variables were entered as fixed effects. In the final model, there was considerable variation in strength over time. Tensile strength was significantly higher in medial compared with lateral claws, and zone 2 was significantly stronger than zone 3. Where the white line was visibly damaged the tensile strength was low. Biotin supplementation did not affect the tensile strength of the white line. Results of this study indicate that damage to the white line impairs its tensile strength and that in horn with no visible abnormality the white line is weaker in the lateral hind claw than the medial and in zone 3 compared with zone 2. The biomechanical strength was lowest at zone 3 of the lateral hind claw, which is the most common site of white line disease lameness in cattle.

Verification of design calculations of a wind catcher/tower natural ventilation system with performance testing in real building

A wind catcher/tower natural ventilation system was installed in a seminar room in the building of the School of Construction Management and Engineering, the University of Reading in the UK . Performance was analysed by means of ventilation tracer gas measurements, indoor climate measurements (temperature, humidity, CO2) and occupant surveys. In addition, the potential of simple design tools was evaluated by comparing observed ventilation results with those predicted by an explicit ventilation model and the AIDA implicit ventilation model. To support this analysis, external climate parameters (wind speed and direction, solar radiation, external temperature and humidity) were also monitored. The results showed the chosen ventilation design provided a substantially greater ventilation rate than an equivalent area of openable window. Also air quality parameters stayed within accepted norms while occupants expressed general satisfaction with the system and with comfort conditions. Night cooling was maximised by using the system in combination with openable windows. Comparisons of calculations with ventilation rate measurements showed that while AIDA gave reasonably correlated results with the monitored performance results, the widely used industry explicit model was found to over estimate the monitored ventilation rate.

Design, testing, and simulation of fibre composite leaf springs for heavy axle loads

This paper summarizes the design, manufacturing, testing, and finite element analysis (FEA) of glass-fibre-reinforced polyester leaf springs for rail freight vehicles. FEA predictions of load-deflection curves under static loading are presented, together with comparisons with test results. Bending stress distribution at typical load conditions is plotted for the springs. The springs have been mounted on a real wagon and drop tests at tare and full load have been carried out on a purpose-built shaker rig. The transient response of the springs from tests and FEA is presented and discussed.

Development of a method fon non-destructive testing of fruits using scanning laser vibrometry (SLV)

Quality control on fruits requires reliable methods, able to assess with reasonable accuracy and possibly in a non-destructive way their physical and chemical characteristics. More specifically, a decreased firmness indicates the presence of damage or defects in the fruit or else that the fruit has exceeded its “best before date”, becoming unsuitable for consumption. In high-value exotic fruits, such as mangoes, where firmness cannot be easily measured from a simple observation of texture, colour changes and unevenness of fruits surface, the use of non-destructive techniques is highly recommendable. In particular, the application of Laser vibrometry, based on the Doppler effect, a non-contact technique sensitive to differences in displacements inferior to the nanometre, appears ideal for a possible on-line control on food. Previous results indicated that a phase shift can be in a repeatable way associated with the presence of damage on the fruit, whilst a decreased firmness results in significant differences in the displacement of the fruits under the same excitation signal. In this work, frequency ranges for quality control via the application of a sound chirp are suggested, based on the measurement of the signal coherence. The variations of the average vibration spectrum of a grid of points, or of point-by-point signal velocity allows the go-no go recognition of “firm” and “over-ripe” fruits, with notable success in the particular case of mangoes. The future exploitation of this work will include the application of this method to allow on-line control during conveyor belt distribution of fruits.