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.

Bisphenol A (BPA) exposure has been documented in pregnant women, but consequences for development are not yet widely studied in human populations. This review presents research on the consequences for offspring of BPA exposure during pregnancy. Extensive work in laboratory rodents has evaluated survival and growth of the conceptus, interference with embryonic programs of development, morphological sex differentiation, sex differentiation of the brain and behavior, immune responsiveness, and mechanism of action. Sensitive measures include RAR, aryl hydrocarbon receptor, and Hox A10 gene expression, anogenital distance, sex differentiation of affective and exploratory behavior, and immune hyperresponsiveness. Many BPA effects are reported at low doses (10-50 µg/kg d range) by the oral route of administration. At high doses (>500,000 µg/kg d) fetal viability is compromised. Much of the work has centered around the implications of the estrogenic actions of this agent. Some work related to thyroid mechanism of action has also been explored. BPA research has actively integrated current knowledge of developmental biology, concepts of endocrine disruption, and toxicological research to provide a basis for human health risk assessment.

It seems that the endocrine system including the testis in marmosets has some unique features that have not been observed in rodents, Old World primates, and humans, but detailed comparison in these features among these species will be presented in another review. Based on the data available, marmoset seems to be an interesting model for comparative studies. However, interpretation of experimental findings on the testicular effects in marmosets should be made with serious caution. Depending on potential mode of testicular actions of the chemical under investigation, marmoset may have very limited value in predicting potential testicular or steroid hormone-related endocrine effects of test chemicals in humans.

Toluene is a widely used industrial solvent, and humans may also have high exposures to toluene from the deliberate inhalation ("sniffing") of paint reducer, paint thinner, or paint for their narcotic effects. A number of case reports describe neonatal effects that have been attributed to toluene abuse during pregnancy. These effects may include intrauterine growth retardation, premature delivery, congenital malformations, and postnatal developmental retardation. The possibility of exposures to other fetotoxic agents, either as impurities or admixtures in toluene-containing products, or by deliberate or accidental exposures to other chemicals or drugs, cannot be excluded in these cases. The fetotoxic effects of toluene have been demonstrated in controlled studies in animals and are comparable to those observed in humans who have abused toluene-containing products before or during pregnancy. Intrauterine developmental retardation is the most clearly established effect in animals, as evidenced by decreased late fetal weight and retarded skeletal development. There is also limited evidence in rodents for skeletal and kidney abnormalities, as well as some evidence for effects on postnatal physical and possibly neurobehavioral development. Estimated daily exposures from experimental studies in animals are compared to estimated human daily intakes at the occupational permissible exposure level and at the level reported to produce euphoria in humans. Acceptable human intakes under California's Proposition 65 and under U.S. Environmental Protection Agency procedures are discussed.

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.