For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from...

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Hormones and endocrine-disrupting chemicals: Low-dose effects and nonmonotonic dose responses

Human exposure to bisphenol A (BPA).

Systematic review of the chemical composition of contemporary dental adhesives

Bisphenol A (BPA) is the monomer used to manufacture polycarbonate plastic, the resin lining of cans, and other products, with global capacity in excess of 6.4 billion lb/year. Because the ester bonds in these BPA-based polymers are subject to hydrolysis, leaching of BPA has led to widespread human exposure. A recent report prepared by the Harvard Center for Risk Analysis and funded by the American Plastics Council concluded that evidence for low-dose effects of BPA is weak on the basis of a review of only 19 studies; the report was issued after a delay of 2.5 years. A current comprehensive review of the literature reveals that the opposite is true. As of December 2004, there were 115 published in vivo studies concerning low-dose effects of BPA, and 94 of these report significant effects. In 31 publications with vertebrate and invertebrate animals, significant effects occurred below the predicted “safe” or reference dose of 50 μg/kg/day BPA. An estrogenic mode of action of BPA is confirmed by in vitro experiments, which describe disruption of cell function at 10−12 M or 0.23 ppt. Nonetheless, chemical manufacturers continue to discount these published findings because no industry-funded studies have reported significant effects of low doses of BPA, although > 90% of government-funded studies have reported significant effects. Some industry-funded studies have ignored the results of positive controls, and many studies reporting no significant effects used a strain of rat that is inappropriate for the study of estrogenic responses. We propose that a new risk assessment for BPA is needed based on a) the extensive new literature reporting adverse effects in animals at doses below the current reference dose; b) the high rate of leaching of BPA from food and beverage containers, leading to widespread human exposure; c) reports that the median BPA level in human blood and tissues, including in human fetal blood, is higher than the level that causes adverse effects in mice; and d) recent epidemiologic evidence that BPA is related to disease in women.

https://endocrinedisruptors.missouri.edu/pdfarticles/vomsaalHughesEHP2005.pdf

An extensive new literature concerning low-dose effects of bisphenol A shows the need for a new risk assessment.

http://endocrinedisruptors.missouri.edu/pdfarticles/richterbpainvivoreviewrtx2007.pdf

In vivo effects of bisphenol A in laboratory rodent studies

The aim of this investigation was to evaluate the effect of bisphenol A (BPA), a contaminant of resin-based dental composites and sealants, on the fertility of male mice. Forty adult male Swiss mice were divided into four groups of 10. BPA (5, 25 and 100 micro g kg(-1) [corrected] was administered intragastrically daily to the mice in the test groups and distilled water to the control group for 28 d. Male fertility was assessed by mating each mouse with two untreated females. Females mated with male mice having ingested 25 and 100 micro g kg(-1) [corrected] BPA showed a significant reduction in pregnancy rates. Furthermore, the total number of resorptions out of the total number of implantations was significantly increased in females impregnated with males having ingested all three doses of BPA. Males having ingested 25 and 100 micro g kg(-1) [corrected] BPA showed a significant reduction in testicular sperm counts and in the efficiency of sperm production. Epididymal sperm counts were also significantly reduced in males that had ingested BPA. There were significant reductions in the absolute weights of the testes and seminal vesicles. These results suggest that male fertility and reproduction is impaired by bisphenol A.

Effects of bisphenol A on adult male mouse fertility.

Background The decision between pulp capping and root canal therapy after pulp exposure is a clinical issue. The aim of the authors' study was to evaluate the outcome of direct pulp-capping procedures performed by dental students. Methods The authors followed the treatment outcomes of 193 patients with 204 pulp exposures with direct pulp capping. They determined the outcome of pulp capping radiographically using periapical radiographs taken at least three years after pulp exposure. The outcome was considered as successful if the tooth was present and not associated with periapical radiolucency or root canal treatment; otherwise, the outcome was considered as being a failure. Results Overall, the success rate of pulp capping was 59.3 percent. The success was associated more with mechanical exposure than with carious exposure (92.2 versus 33.3 percent) ( P P P = .009). Patients' age, sex, and tooth location and position had no significant effect on the outcome ( P > .05). Conclusion The success rate of direct pulp capping was 92.2 percent with mechanical exposure and 33.3 percent with carious exposure. Clinical Implications Direct pulp capping is recommended after mechanical exposure with immediate placement of permanent restoration, while root canal therapy would be the choice of treatment if the exposure was due to caries.

The radiographic outcomes of direct pulp-capping procedures performed by dental students: a retrospective study.

The release of components from dental composite into surrounding tissue may cause an adverse tissue reaction. Thus, this study investigated the cytotoxicity of three types of dental composites with their flowable derivatives and determined the compounds released from these materials by high-performance liquid chromatography (HPLC) analysis. Fifteen specimens from each composite (Admira, Z250, Tetric Ceram) with fifteen of their flowables (Admira Flow, Tetric Flow, Feltik Flow) were prepared in the form of discs and divided into two groups of 10 and 5 for each material. The first group (10 discs) was used to evaluate the cytotoxicity of the material on balb/c 3T3 fibroblasts by measuring cellular metabolic activity (3{4,5-dimethylthiazol-2-yl}-2,5-diphenyltetrazolium bromide [MTT] assay) relative to Teflon controls, while the second group (5 discs) was used to determine the leached components from each material into culture medium by HPLC analysis. The results revealed that Z250 and Tetric Ceram were less cytotoxic than their flowable derivatives. However, the ormocer, Admira, was significantly more cytotoxic than Admira Flow. Among the standard composites, Tetric Ceram was the least cytotoxic and Admira the most. Furthermore, Tetric flow was the most cytotoxic and Admira flow was significantly the least cytotoxic among the flowable materials tested. HPLC analysis revealed bisphenol A glycerolate dimethacrylate (bis-GMA) and triethylene glycol dimethacrylate (TEGDMA) in the eluates of all the materials, while urethane dimethacrylate (UDMA) was present in all eluates except that of Feltik Flow. In conclusion, the flowable derivatives are more cytotoxic than the traditional composites whereas the ormocer Admira Flow is less cytotoxic than the Admira composite.

Cytotoxicity evaluation of dental resin composites and their flowable derivatives.

Radiographic technical quality of root canal treatment performed by dental students at the Dental Teaching Center in Jordan

This study investigated the effects of leached components from a resin-based dental composite (Z-100) and bisphenol A (BPA) on female mouse fertility. Leached components or BPA (5, 25 and 100 microg kg(-1)) were administered intragastrically daily to the test and distilled water to the control groups for 28 d. Female mice were then mated with sexually mature untreated males and their fertility was assessed. The results revealed a significant reduction in the number of pregnancies--54.5% vs. 100% (control)--in mice treated with the leached components from the dental composite, which also showed an increase of 142% in relative ovary weights. Exposure to 25 and 100 microg kg(-1) BPA resulted in significant increases in the total number of resorptions out of the total number of implantations and significant increases in relative uterine weights. Relative ovarian weights were significantly increased at the highest dose. High performance liquid chromatography analysis showed that tri-(ethylene glycol)-dimethacrylate (TEG-DMA) was the major leached component (total: 5945 microg ml(-1)) from the composite, followed by bisphenol A glycerolate dimethacrylate (BIS-GMA) (total: 2097 microg ml(-1)) and BPA (total: 78 microg ml(-1)). The results suggest that leached components from the dental composite used and commercially purchased BPA have adverse effects on the fertility and reproductive system of female mice.

Ahmad S. Al-Hiyasat

Papers

Effects of bisphenol A on adult male mouse fertility.

The radiographic outcomes of direct pulp-capping procedures performed by dental students: a retrospective study.

Cytotoxicity evaluation of dental resin composites and their flowable derivatives.

Radiographic technical quality of root canal treatment performed by dental students at the Dental Teaching Center in Jordan

Leached components from dental composites and their effects on fertility of female mice.