Background There are reports of developmental and reproductive health effects associated with the widely used biocide triclosan. Objective Apply the Navigation Guide systematic review methodology to answer the question: Does exposure to triclosan have adverse effects on human development or reproduction? Methods We applied the first 3 steps of the Navigation Guide methodology: 1) Specify a study question, 2) Select the evidence, and 3) Rate quality and strength of the evidence. We developed a protocol, conducted a comprehensive search of the literature, and identified relevant studies using pre-specified criteria. We assessed the number and type of all relevant studies. We evaluated each included study for risk of bias and rated the quality and strength of the evidence for the selected outcomes. We conducted a meta-analysis on a subset of suitable data. Results We found 4,282 potentially relevant records, and 81 records met our inclusion criteria. Of the more than 100 endpoints identified by our search, we focused our evaluation on hormone concentration outcomes, which had the largest human and non-human mammalian data set. Three human studies and 8 studies conducted in rats reported thyroxine levels as outcomes. The rat data were amenable to meta-analysis. Because only one of the human thyroxine studies quantified exposure, we did not conduct a meta-analysis of the human data. Through meta-analysis of the data for rats, we estimated for prenatal exposure a 0.09% (95% CI: −0.20, 0.02) reduction in thyroxine concentration per mg triclosan/kg-bw in fetal and young rats compared to control. For postnatal exposure we estimated a 0.31% (95% CI: −0.38, −0.23) reduction in thyroxine per mg triclosan/kg-bw, also compared to control. Overall we found low to moderate risk of bias across the human studies and moderate to high risk of bias across the non-human studies, and assigned a “moderate/low” quality rating to the body of evidence for human thyroid hormone alterations and a “moderate” quality rating to the body of evidence for non-human thyroid hormone alterations. Conclusion Based on this application of the Navigation Guide systematic review methodology, we concluded that there was “sufficient” non-human evidence and “inadequate” human evidence of an association between triclosan exposure and thyroxine concentrations, and consequently, triclosan is “possibly toxic” to reproductive and developmental health. Thyroid hormone disruption is an upstream indicator of developmental toxicity. Additional endpoints may be identified as being of equal or greater concern as other data are developed or evaluated.

Restraint has been used as a procedure to study the effects of stress on gestation outcome in rodents. The effects of restraint could potentially be used as a model for the impact of general stress produced by high doses of toxicants and other interventions. In mice, restraint in the peri-implantation period leads to implantation failure, and restraint at appropriate times in organogenesis produces cleft palate, supernumerary ribs, and resorption. In rats, there is some evidence for an association with restraint for implantation failure, but not for the morphological anomalies. Restraint in late gestation alters adult sexual behavior of male rat offspring, but consequences for their fertility are not known. Intrauterine growth retardation is not commonly associated with gestational restraint. In the few studies where they have been directly compared, different restraint procedures produced graded, qualitatively different, or no effects. Adrenocortical hormones have been implicated as mediating the effect of restraint on cleft palate, but not on supernumerary ribs, implantation failure, or sexual differentiation. Given the variety of restraint procedures and the varying species-dependent consequences, it is not possible to infer a generalizable pattern of developmental effects due to gestational stress from the restraint literature. As an alternative approach, contemporary methods in gene expression and developmental biology could profitably be applied to understanding different patterns of stress-mediated effects of toxicant exposures on intrauterine development. Birth Defects Res B 71:26-36, 2004. r 2004 Wiley-Liss, Inc.

This review summarizes and discusses research on retinoblastoma (Rb) cells in tissue culture. Retinoblastoma is an intraocular tumor of early childhood which is believed to originate from the primitive multipotential neuroectoderm of the optic cup region. The application of tissue culture techniques to the study of Rb cells permits detailed studies of the biology of this tumor. Classic studies have primarily focussed on growth and metastatic potential of Rb cells. Y-79 Rb cells, for example, have a short doubling time in vitro as well as aggressively growing in the anterior chambers of athymic 'nude' mice. Such active growth may result from secretion of a Retinoblastoma Derived Growth Factor (RDGF) by the cells. Several natural agents have now been shown to halt Rb cell growth in vitro. Among these are the fatty acid, butyrate, and two retinoids: retinol and retinoic acid. Interestingly, the retinoids have different mechanisms of action. Cultured Y-79 and WERI cells appear to be multipotential in that they exhibit both neuronal- and glial-like characteristics. Natural agents such as cyclic AMP and butyrate can induce the cells to differentiate along either neuronal or glial cell lines as assessed morphologically and immunocytochemically. Of interest is that combination of agents such as butyrate and laminin, an extracellular attachment protein, yield totally different morphologies, in this case, pigment epithelial in nature. Tissue culture studies thus not only show the primitive, multipotential nature of the Rb cells but their great plasticity as well. Such studies are also useful in elucidating the multiple factors (e.g., substrata and soluble agents) which code for normal retinal development from embryo to adult.

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