Comparison of some homogeneity tests in analysis of over-dispersed binomial data

This paper compares the procedures based on the extended quasi-likelihood, pseudo-likelihood and quasi-likelihood approaches for testing homogeneity of several proportions for over-dispersed binomial data. The type I error of the Wald tests using the model-based and robust variance estimates, the score test, and the extended quasi-likelihood ratio test (deviance reduction test) were examined by simulation. The extended quasi-likelihood method performs less well when mean responses are close to 1 or 0. The model-based Wald test based on the quasi-likelihood performs the best in maintaining the nominal level. The score test performs less well when the intracluster correlations are large or heterogeneous. In summary: (i) both the quasilikelihood and pseudo-likelihood methods appear to be acceptable but care must be taken when overfitting a variance function with small sample sizes; (ii) the extended quasi-likelihood approach is the least favourable method because its nominal level is much too high; and (iii) the robust variance estimator performs poorly, particularly when the sample size is small.     

Qualitative and quantitative assessment of the risk from the exposure to fetotoxic chemical compounds

A new mathematical dose-response model for the expected probability of toxic response and also for the expected measure of the overdispersion parameter for the reproductive and developmental risk assessment is proposed. The model for the expected probability of toxic response is an improvised Weibull dose-response model incorporating the litter-size effect while the model for the overdispersion parameter is a polynomial function of the dose level. A beta-binomial distribution for the number of offspring showing toxic responses in a litter satisfactorily accounts for the extra-binomial variation and the intralitter correlation of responses of these pups. Confidence limits for low-dose extrapolation are based on the asymptotic distribution of the likelihood ratio. The safe dose for human exposure is then calculated by simple linear extrapolation. The model for overdispersion allows us to obtain the estimates of the overdispersion parameter at these dosages. This was not possible in the earlier models. The proposed model is illustrated by an application to a study on the effect of exposure to diethylhexylphthalate in mice. The results are compared with those obtained by Chen and Kodell (1989) who have applied the simple Weibull dose-response model to the same data set.This paper was prepared with partial support from the United States Environmental Protection Agency under a Cooperative Agreement Number CR-815273. The contents have not been subject to Agency review and therefore do not necessarily reflect the views or policies of the Agency and no official endorsement should be inferred.     

Photomirex: A teratogenicity and tissue distribution study in the rabbit

Abstract

Adult New Zealand white does were intubated orally with single daily doses of 0, 5, or 10 mg of photomirex (8‐monohydromirex) per kg body weight from the 6th through to the 18th day of gestation. Pregnancies were interrupted at term by cesarian section and fetuses removed and evaluated by following routine teratologic methods. Both maternal and fetal tissues were analyzed for residues of photomirex. None of the treated does showed any sign of toxicity. Except for a significant reduction in the mean fetal weight of the 10 mg/kg group all other parameters which evaluated fetal survival and fetal development were within the control range. Photomirex was found in all tissues examined. In the doe, the highest levels were found in fat followed by liver, kidney, spleen, heart, brain and blood. Photomirex was readily transferred across the placenta and accumulated in the fetus. However, in the fetus the highest levels were found in the heart, followed by liver, brain and blood. There were no teratogenic effects at the doses used in this study.     

Litter-based methods in developmental toxicity risk assessment

Developmental toxicity experiments are designed to assess potential adverse effects of drugs and other exposures on developing fetuses from pregnant dams. Extrapolation to humans is a very difficult problem. An important issue here is whether risk assessment should be based on the fetus or the litter level. In this paper, fetus and litter-based risks that properly account for cluster size are defined and compared for the beta-binomial model and a conditional model for clustered binary data. It is shown how the hierarchical structure of non-viable implants and viable but malformed offspring can be incorporated. Risks based on a joint model for death/resorption and malformation are contrasted with risks based on an adverse event defined as either death/resorption or malformation. The estimation of safe exposure levels for all risk types is discussed and it is shown how estimation of the cluster size distribution affects variance estimation. The methods are applied to data collected under the National Toxicology Program and in large sample simulations.     

Teratogenic and biochemical effects of a formulation containing dicofol in the chick embryo

The insecticide formulation, dicofol (18.5% EC) was evaluated for its toxic potential in developing chick embryo. Fertilized eggs of Gallus domesticus on 4th day of incubation were immersed in aqueous emulsions of dicofol at concentrations of 250?mg?L^?1, 500?mg?L^?1, and 1000?mg?L^?1 for 60?min at 37°C. These concentrations were corresponding to those used in plant protection practice (500?mg?L^?1). Two control groups of eggs were used: one group was immersed in distilled water (vehicle) and the second group was kept as untreated to study background toxicity. On embryonic day 7; recovered embryos were evaluated for mortality rate, wet body weight, gross morphological malformations, and some biochemical changes. The result revealed that administration of dicofol did not result in significant changes in wet body weight of embryo but the survival rate of dicofol treated embryos were markedly reduced as compared with controls. Among the survivors, the number of malformations was exhibited by dicofol treated embryos in dose-dependent manner. Among biochemical changes, only total protein content of embryo significantly (p?≤?0.05) reduced to 500?mg?L^?1 and 1000?mg?L^?1. Among enzymes, alkaline phosphatase and glutamate pyruvate transaminase activities were affected, which showed significant elevations.