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Twenty-Eight- to Ninety-Day Tests Chemicals are usually tested by administration in the diet, less commonly in the drinking water, and only when absolutely necessary by gavage, because the last process involves much handling and subsequent stress Numerous experimental variables must be controlled and biologic variables evaluated In addition the number of end points that can be measured is large, and as a consequence record keeping and data analysis must be carefully planned If all is done with care, much may be learned from such tests Experimental (Nonbiologic) Variables Several environmental variables may affect toxicity evaluations, some directly and others by their effects on animal health Major deviations from the optimum temperature and humidity for the species in question can cause stress reactions Stress can also be caused by housing more than one species of experimental animal in the same room.

which again is identical, up to the C4 term, to what would be obtained asymptotically from Eq. (2.24) under ID2. The C4 term can be estimated for each octave using the sample moment estimators of the fourth and second moments of the details, combined as per the de nition. Due to the quasi-decorrelation in the wavelet plane, this simple estimator will have low bias. The above arguments clearly show that, in the limit of a large number of samples, the key statistical features of the estimator namely lack of bias and low variance are retained and are therefore not ID2 dependent. Numerical simulations, summarized in Table 2.1, show that this asymptotic behavior is moreover reached for a relatively small number of samples. The simulations were performed using 1000

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Many toxic or metabolic effects show diurnal variations that are related to photoperiod Cage design and the nature of the bedding have also been shown to affect the toxic response Thus the optimum housing conditions are clean rooms, each containing a single species, with the temperature, humidity, and photoperiod being constant and optimized for the species in question Cages should be the optimum design for the species, bedding should be inert (not cause enzyme induction or other metabolic effect), and cages should not be overcrowded, with individual caging whenever possible Dose selection, preparation, and administration are all important variables Subchronic studies are usually conducted using three (less often, four) dose levels The highest should produce obvious toxicity but not high mortality and the lowest no toxicity (NOEL), whereas the intermediate dose should give effects clearly intermediate between these two extremes.

Robustness with Respect to Gaussianity Bias 0.015 0.017 0.016 0.017 0.015 0.019 0.013 0.004 Variance 0.039 0.036 0.039 0.045 0.149 0.131 0.122 0.228 MSE 0.039 0.036 0.039 0.045 0.150 0.132 0.122 0.228

homologue model of the ACE2 structure;240 (2) identi cation of a peptide, CP-1, derived from the HR2 region in the S2 domain of SARS-CoV S protein to guide the design of fusion inhibitors;241 (3) identi cation of human monoclonal antibodies against the S1 domain of S protein;242 and (4) silencing S protein expression in cultured cells by RNA interference (RNAi).224,243 Other RNAi approaches targeting different sites on the genome were also reported.224,244,245

Although the doses can be extrapolated from acute test, such extrapolation is dif cult, particularly in the case of compounds that accumulate in the body, and frequently a 14-day range- nding study is made Although the route of administration should ideally mimic the expected route of exposure in humans, in practice, the chemical is usually administered ad libitum in the diet because this is, on average, most appropriate Diets containing known amounts of the test material are presented to the animals Measurement of food consumption is recommended to provide an estimate of the test material consumed In cases where a highly accurate measurement of dose is an important factor in the experimental design, the animals may be treated by gavage or by capsules containing the test material To avoid effects from nonspeci c variations on the diet, enough feed from the same batch should be obtained for the entire study.

Gaussian Uniform Exponential Lognormal Pareto a 1:75 Pareto a 1:25 a-stable a 1:75 a-stable a 1.25

a It can be seen that the residual bias and variance of the waveletbased estimator of the scaling exponent a are not very sensitive to the form of the marginal of the process X t . They are, moreover, very close to the theoretical performance derived assuming exact decorrelation of the wavelet coef cients and Gaussianity of X t .

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