On the efficiency of age-adjusted tests in animal carcinogenicity experiments

Based on asymptotic relative efficiency calculations, Ryan (1985, Biometrics 41, 525-531) concludes that, in the analysis of animal carcinogenicity experiments, age-adjusted tests of tumor rates should be routinely preferred to simple proportions tests for both lethal and nonlethal tumors. We recalculate the asymptotic efficiencies of the simple proportions test relative to the log-rank test for the lethal tumor case. For a simplified model it is shown that the relative efficiency may be easily computed as a function of the crude tumor rate and the survival rate at the time of terminal sacrifice. More generally, we calculate by numerical quadrature the asymptotic relative efficiency for all models considered by Ryan and, using simulations, examine the relevance of asymptotic efficiencies to typical sample sizes. Contrary to the numerical results of Ryan, we find, for experiments with good survival and typical tumor rates, that the relative efficiencies are greater than 95%, usually about 99%. In the nonlethal tumor case, similar results follow from Ryan for tumor rates and survival rates typically encountered in practice. As it is often difficult to determine whether or not a tumor is lethal, we conclude for equal interim mortality rates, that the simple proportions test is usually adequate in evaluating animal carcinogenicity experiments.     

Estimating tumor incidence rates in animal carcinogenicity experiments

Tumor incidence is the primary measure of carcinogenesis. This article focuses on estimating time-dependent incidence rates in animal experiments with few sacrifices. When the context of observation is known for none or all of the animals dying with the tumor of interest, previous results are obtained under relaxed assumptions. The link with existing semiparametric and nonparametric procedures based on latent failure times is exploited by using these methods to compute maximum likelihood estimates of the incidence rates without introducing latent random variables. Nonparametric estimators that are appropriate when all contexts of observation are known are generalized to the case in which the contexts of observation are unknown for a subset of the tumor-bearing animals.     

The interpretation of equivocal or marginal animal carcinogenicity tests

Summary The interpretation of animal carcinogenicity tests traditionally rely almost exclusively upon a comparison of specific tumor rates in treated vs. matched and, perhaps, historical control animals. Yet, carcinogenicity tests yield much more biological and pathological data than simply final tumor rates. This additional data should also be considered as part of the total weight of evidence, particularly when analyzing a marginal or equivocal test result. If there are no positive findings among the data discussed here and listed in Table 1, it is unlikely that a marginal or equivocal increase in tumor incidence is actually treatment-related, irrespective of statistical analysis.     

An analysis by chemical class of Salmonella mutagenicity tests as predictors of animal carcinogenicity

For a number of years, investigators have recognized that humans potentially are exposed to large numbers of genotoxicants. Many efforts have attempted to validate various short-term bioassays for use as rapid, inexpensive screens for genotoxicants--especially carcinogens. In this analysis, we examine Salmonella mutagenicity as an indicator of potential carcinogenicity by comparing published (and when possible, evaluated) Salmonella results with the evaluated Gene-Tox animal carcinogen data base. The Salmonella bioassay does especially well in those cases where the level of evidence for carcinogenicity is the strongest. Analysis shows that except for specific classes of compounds, the plate-incorporation protocol and the preincubation protocol are equally efficient at detecting mutagens. This paper also demonstrates how validation values (sensitivity, specificity, etc.) vary with chemical class. Overall, this analysis demonstrates that when used and interpreted in a meaningful chemical class context, the Salmonella bioassay remains extremely useful in identifying potential animal carcinogens.     

Interpretation of two-stage experiments in animal studies

Two-stage experiments allow results to be analysed at the end of the first stage and the second stage to be omitted if the preliminary conclusions are clear-cut. They thus offer the potential to reduce the number of experimental animals. However, using standard P values to assess the significance of results at the end of either stage will lead to an increase in risk of false positive conclusions. This paper provides a possible protocol for two-stage experiments and a method for adjusting P values. It is shown that, for experiments with reasonable power (>80%), the expected reduction in animal numbers will be at least 20%.     

A magnetic field exposure facility for evaluation of animal carcinogenicity

Several animal studies have been carried out at the Institut Armand Frappier (IAF) to determine whether chronic exposure to 60 Hz linearly polarized sinusoidal magnetic fields might increase the risk of cancer development of female Fisher rats. The magnetic field exposure facility was developed to meet the requirements of the study protocol for chronic exposure of large number of animals to field intensities of sham < 0.2 microT, 2 microT, 20 microT, 200 microT, and 2000 microT. At each exposure level, including sham, the animals are distributed in a group of four exposure units. Each exposure unit contains two exposure volumes having uniform distribution of magnetic fields for the animals, while the magnetic field external to the unit falls off rapidly due to the "figure-eight" coil topography used. A program of "shake down" tests, followed by verification and calibration of the exposure facility, was carried out prior to starting the animal experiments. Continuous monitoring of the magnetic field and other environmental parameters was an important part in the overall quality assurance program adopted.     

New thinking on animal experiments

Animal experimentation is a perennial issue for many researchers, legislators and critics. A group of Britain's most senior politicians has now recommended changes to the country's rules, some of the strictest in the world, and others in Europe are thinking about future directions. Nigel Williams reports.     

Antioxidant therapy of purulent wounds in animal experiments

A new complex method for treating purulent wounds has been elaborated in the experiment on 22 mature chinchilla rabbits with a simulated abscess. It has been established that a combined use of a 2% alcohol solution of ionol, a 10% aqueous solution of urotropin for irrigation of the wound cavity and a single administration of nialamide cuts down the time two-fold for cleaning wounds and development of granulations and by 40% for the wound complete healing.     

Effects of T-activin in viral myocarditis in animal experiments

The efficacy of immunomodulating agent T-activin has been studied in adult BALB/C mice infected with Coxsackie B1 virus. Optical, electron microscopic and immunological tests have shown that T-activin protects myocardium and modulates immune disorders in mice with viral myocarditis.