Two-generation reproduction studies in Rats fed di-isodecyl phthalate.

Di-isodecyl phthalate (DIDP) is a commercial plasticizer with low toxicity in many animal studies. The effects of dietary DIDP administration on fertility and developmental parameters were assessed in Sprague-Dawley rats utilizing two generation reproductive toxicity studies generally consistent with current regulatory guidelines. Dietary levels ranged from 0.02 to 0.8% (or approximately 15 to 600 mg/kg/day). In the reproductive studies, there were no effects on fertility, but there were decreases in adult body weight along with corresponding increases in liver and kidney weights and histopathologic changes indicative of peroxisomal proliferation. There were no effects on live birth index, but reduced offspring survival was observed at postnatal days 1 to 4. This reduced survival was more pronounced in the F2 generation in which statistical significance was achieved at levels of 0.2% DIDP and greater. There were also transient decreases in offspring body weights prior to weaning, corresponding to rapid offspring growth, and high levels of food consumption. There were no notable alterations in developmental landmarks. Overall, these studies provided experimentally defined No-Observed-Adverse-Effect Levels (NOAELs) of 0.06% (approximately 50 mg/kg/day) for F2 offspring survival and 0.8% (approximately 600 mg/kg/day) for fertility, other measures of reproductive function, and developmental landmarks. Statistical evaluation of the data from both studies identified 108 mg/kg/day with a 95% lower bound value of 86 mg/kg/day as a theoretical NOAEL for reduced F2 offspring survival.

Molecular basis of dioxin actions: evidence supporting chemoprotection.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin), a highly publicized environmental contaminant, was shown to be chemoprotective against breast cancer in both rats and mice in bioassays conducted in the late 1970s. This finding went largely unnoticed as investigators focused on animal tumors that were increased by dioxin. The position that dioxin causes human tumors remains a subject for debate; however, recent epidemiological studies of a population highly exposed to dioxin in 1976 as a result of an industrial accident suggest that women with higher dioxin body burdens may have a lower incidence of breast cancer. With the growth of new knowledge about the molecular basis of dioxin actions in humans and animals, it is clear that most of the responses produced by this agent are initiated by a specific recognition protein (designated the Ah receptor) found in almost all animal and human tissues and organs. The recognition event between the Ah receptor and environmental agents like dioxin is due to the formation of a complex. We have observed that in the presence of dioxin, the Ah receptor turns off proliferation in tumor cells and suppresses the ability of these cells to invade normal tissue. We believe that these findings provide a molecular and biochemical basis for understanding the chemoprotective mechanisms suggested by the findings of rodent bioassays and could lead to the development of novel therapeutic agents targeting the Ah receptor.

A tiered approach for assessing children's exposure.

Recently, intense attention has been given to children's health issues, particularly in the use of consumer products. Because of this attention, researchers have been planning and initiating studies specifically aimed at developing both toxicology data and exposure data directed to improve our understanding of industrial and consumer product chemical impacts on children's health. To ensure that this research is focused on the highest priority chemicals, we present a methodology for determining and prioritizing the higher hazard chemicals and scenarios for which children could be disproportionately or highly exposed. This tiered approach includes a screening step for initial chemical selection, a hazard assessment based on no- or lowest-observed-adverse-effect levels, and a margin of exposure (MOE) calculation. The initial chemical screen focuses on the chemical presence in specific media that are special to children, such as foods children regularly eat and drink, residential or school air, products children use, and soil and dust in and around residences. Data from the literature or from models serve as the initial exposure estimate. This methodology would allow us to focus on those chemicals to which children are most exposed that are also associated with, potentially, the highest risk. Use of the MOE calculation allows for comparison among chemicals, prioritization of chemicals for evaluation and testing, and identification of significant data gaps.

Characterization of 2,3,7,8-tetrachlorodibenzofuran-dependent suppression and AH receptor pathway gene expression in the developing mouse mammary gland.

The AH receptor (AHR) is a ligand-activated transcription factor and member of a growing family of homologous proteins implicated in development. In this study we have characterized the actions of 2,3, 7,8-tetrachlorodibenzofuran (TCDF), a well-studied AHR ligand, and the expression of AHR and selected AHR signal transduction pathway genes in the developing mouse mammary gland. High levels of AHR protein were observed in the mammary glands of C57Bl/6J (AHR +/+) mice during estrous-stimulated growth and branching of terminal end buds (TEBs). Comparative analysis of mammary gland development in AHR -/- and +/+ littermates revealed a 50% reduction in TEBs and an increase in blunt-ended terminal ducts in the AHR null animals. Treatment of mammary glands, removed from estrogen/progesterone-primed C57Bl/6J mice and maintained in organ culture, with TCDF suppressed lobule development (greater than twofold decreases in lobule number and size), with a concomitant suppression of DNA synthesis, as judged by a 35 to 45% decrease in [3H]thymidine incorporation in the TEBs. Immunohistochemical staining patterns for AHR, aryl hydrocarbon nuclear translocator (ARNT; the heterodimerization partner of AHR), and two AHR-regulated genes, Cyp1A1 and Cyp1B1, were similar and not altered by treatment of mammary glands in organ culture with TCDF. The observed differences in the development of mammary glands from AHR +/+ and -/- mice, associated expression of the AHR protein with hormone-dependent lobule development, and suppressive actions of TCDF support the position that, in C57Bl/6J mice, development of the mammary gland is at least in part AHR dependent. Development occurs in the absence of exogenous AHR ligand, suggesting that the unoccupied receptor may function to support the proliferative stages required for full lobule development.