Pregnant Laboratory Animals Research Articles

Analysis of Clustered Binary Data With Unequal Cluster Sizes: A Semiparametric Bayesian Approach

The analysis of clustered binary data is a common task in many areas of application. Parametric approaches to the analysis of such data are numerous, but there has been much recent interest in nonparametric and semiparametric approaches. When cluster sizes are unequal, an assumption is often made of compatibility of marginal distributions in order for semiparametric approaches to be developed when there is little replication for different cluster sizes. Here, we use the marginal compatibility assumption to extend flexible semiparametric Bayesian methods able to shrink towards a “parametric backbone” to the situation where there are few replicated observations for distinct cluster sizes and each distinct value of a covariate. A motivating application is the analysis of developmental toxicology data where pregnant laboratory animals are exposed to a dose of some potentially toxic compound and interest lies in describing the distribution, as a function of the dose level, of the number of fetuses exhibiting some characteristic abnormality. Flexible semiparametric methods are required here, as the data typically exhibit overdispersion and complex structure. We also consider a further extension appropriate to the analysis of clustered binary data in the situation where there is little or no replication for distinct covariate values.

Effects of protein deficient diets on the developmental toxicity of inorganic arsenic in mice.

Inorganic arsenic, when given by injection to pregnant laboratory animals (mice, rats, hamsters), has been shown to induce malformations. Arsenic methylation may be a detoxification step, and diets deficient in protein are a poor source of methyl donors and may possibly result in impaired arsenic methylation. Human health effects from chronic arsenic exposure have been reported mainly in populations with low socioeconomic status. Individuals in such populations are likely to suffer from malnutrition, which can compromise embryonic/fetal development and diminish arsenic methylating capacity. We sought to determine if dietary protein deficiency affects the developmental toxicity of inorganic arsenic. Mated females were randomly assigned to one of 12 treatment groups. Experimental groups received either AsIII or AsV i.p. on Gestation Day 8 (GD 8, plug=GD 0) and were maintained on a 5%, 10%, or 20% protein custom mixed diet from GD 1 until sacrifice. Controls received the custom diets alone, were given AsIII or AsV i.p. on GD 8 with Teklad LM-485 rodent diet, or were fed the LM-485 diet alone. Test females were sacrificed on GD 17, and their litters were examined for mortality and developmental defects. Arsenic plus dietary protein deficiency decreased maternal weight gain and increased the incidences of exencephaly, ablepharia, and skeletal defects, such as malformed vertebral centra, fused ribs, and abnormal sternebrae (bipartite, rudimentary, or unossified). These results demonstrate that dietary protein deficiency enhances the developmental toxicity of inorganic arsenic, possibly by impairment of arsenic methylation.

Effect of progesterone on the cardiac electrophysiologic alterations produced by ropivacaine and bupivacaine.

Bupivacaine-induced cardiotoxicity is enhanced in pregnant laboratory animals and in progesterone-pretreated isolated cardiac tissues. Ropivacaine is a new local anesthetic chemically related to bupivacaine. Although clinically equipotent with bupivacaine, ropivacaine is less cardiodepressant. Progesterone levels are elevated during pregnancy, and exogenously increasing progesterone levels in rabbits has increased bupivacaine's depressive effects on excitability. In neural tissues, bupivacaine's increased onset of block and depression of compound action potentials in tissues from progesterone-treated animals was similar to its effect in nerves from pregnant animals. This study determined whether exogenously increased progesterone levels can increase myocardial sensitivity to ropivacaine. Female ovariectomized rabbits were pretreated with progesterone for 4 days. After killing, the hearts were removed and Purkinje fibers (PFs) and ventricular muscle (VM) action potential parameters recorded. Tissues from animals receiving either progesterone or placebo were exposed to either ropivacaine or bupivacaine at concentrations ranging from 3.5 to 18.7 microM. Preparations were routinely paced at 2 Hz except where rate-dependent effects on the maximal rate of depolarization of phase zero (Vmax) were determined. Progesterone increased depression of myocardial Vmax only to bupivacaine (P less than 0.05). Ropivacaine was generally 3-5 times less potent in depressing cardiac electrophysiologic parameters. Bupivacaine demonstrated rate-dependent depression of Vmax that at higher frequencies was greater than ropivacaine's effects (P less than 0.05). Ropivacaine is less cardiodepressant than bupivacaine in this isolated PF-VM preparation. Exogenously increasing progesterone levels in vivo does not increase ropivacaine's depression of myocardial Vmax in isolated PF-VM tissues as it does to bupivacaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of the adult developmental relationship in prescreening for developmental hazards.

The overwhelming majority of chemicals already in commerce or brought into use each year have not been evaluated for their potential to adversely affect in utero development. Data from those that have been evaluated thus far in pregnant laboratory animals establish that most, but not all, were no more hazardous to the conceptus than they were to adult homeostasis. Most did not need standard developmental toxicity testing because avoidance of adult toxic exposure levels would have precluded abnormal in utero development. The six general principles of teratology when modified, expanded, and placed into this type of context of contemporary developmental toxicology allow an updating of the present testing sequence which was devised prior to 1966. The developmental hazard index (A/D ratio) calculated from the adult and developmental NOELs of standard Segment II evaluations is predicted by in vitro means. This determination, when coupled with adequate considerations of exposure can be used to prioritize chemicals for more elaborate developmental toxicity tests. Those chemicals with large ratios, i.e., disruptive of embryogenesis at treatment levels too low to produce overt effects in the mother and/or with significant concern regarding exposure, can be identified and tested in pregnant laboratory animals as high priority items. Those with low ratios and those for which there is a low level of concern regarding exposure potential also can be identified and are not high priority items for testing in pregnant animals. The proposed tier system establishes priorities of testing based on exposure and the concept of target organ toxicity applied to the embryo. It provides intensive in vivo evaluations of those chemicals for which developmental effects testing is most needed and avoids use of resources and animals for unnecessary testing of agents that do not pose threats to the conceptus.

The developmental toxicity of xylene and xylene isomers in the hydra assay

Two laboratories tested multiple forms of xylene for their developmental toxicity hazard potential ( A D ratio) by means of the hydra assay. The three isomers, as well as a solution of mixed xylenes, all interfered with development (D) at or near to concentrations that also were toxic to adult (A) hydra. The A D ratios ranged from 1 to 2 in hydra as they had in conventional tests made in pregnant laboratory animals. Each testing laboratory concluded that xylenes were not primary developmental hazards but coaffective agents capable of disrupting development only at or near to concentrations also toxic to adults. In each instance every xylene tested interfered with the same stage or developmental sequence and in a concentration-related manner. The hydra assay may be useful for establishing priorities to test agents in a more elaborate system, but substances less soluble than xylene may exceed the test's applicability.

The science of teratology in a regulatory setting.

The science of teratology is discussed from a regulatory point of view. A brief history of this branch of toxicology is presented with emphasis on specific instances of the inadvertent production of birth defects in humans as a result of exposure to exogenous agents. The basic principles of teratology are elucidated as a means of understanding current test protocols and their scientific rationale. A typical, general protocol is given and some of the major shortcomings of such a bioassay are presented. Among these shortcomings are the problems of significance of fetal toxicity and lack of a postnatal component to the teratology test system. The teratogenic and/or fetotoxic potential of selected pesticides are examined with special reference to the bioassay problems alluded to. Pesticides discussed include cacodylic acid, endrin, benomyl, ETU, nitrofen, and mirex. Finally, a brief discussion of a proposed teratology screen using pregnant laboratory animals is presented.