Talk:Xenoestrogen

Bisphenol-A (BPA) is an organic compound composed of two phenol rings connected by a methyl bridge, with two methyl functional groups attached to the bridge. The hydroxy functional group on each phenol is para- to the connecting methyl bridge. A general synthesis for making BPA is a condensation reaction of acetone and phenol together with hydrochloric acid, which acts as a catalyst. This is a very exothermic reaction, with an enthalpy value of –368 kJ/mol. As a result, it is assumed that extensive cooling is required during BPA production. This mechanism was used in the production of 1.63 billion pounds of BPA in North America at the end of the third quarter of 1996. Due to increasing demand production is experiencing growth worldwide. This increased demand can be accounted for when considering the uses of BPA by the modern world. BPA is used in the production of epoxy resins and polycarbonate plastics. One type of epoxy is the product of the reaction between epichlorohydrin and BPA. These epoxies are used as food-contact surface coatings for cans, metal jar lids, coatings and finishes, automobile parts, adhesives, aerospace applications, and as a coating for PVC water pipe walls. Polycarbonate plastics are used with CD and CD-ROM manufacturing, in automotive parts, high-impact windows, household appliances, food packaging, and plastic bottles for water and baby milk. Some of the polymer forms are used as dental sealants and bonding agents. Bisphenol-a is not considered a major threat as a pollutant by most government standards, but recent research indicates that BPA can act as an estrogen analog in biological systems. Estrogen analogs have the effect of "femininizing" the male fetus in animals, as well as distrupting normal estrogen production in females. This mimicking occurs at levels far below recommended safe concentrations listed by the EPA and OSHA. Bisphenol-A has been found in significant levels in foods from cans. It has also been found in baby milk and bottled water. These contaminants arise because BPA leaches from polycarbonate and epoxy products used in the metal cans and bottles, especially when heated. In the autoclaving process (of all canned food production) BPA can leach into the processed product and contaminate the canned contents. Some bioconcentration of BPA has been found in autoclaved fatty foods. Bisphenol-A is also associated with weight loss in rats and increases in live weight in beagle dogs. Although BPA is not considered a pollutant and the Resource Conservation and Recovery Act does not regard BPA as a hazardous substance, the fact that BPA production uses phenol has raised some concern. Some people have expressed suspicion in regard to trace amounts of phenol contained in the BPA product. Phenol is listed as 158 out of the 250 top chemicals listed in the CERCLA Priority List of Hazardous Substances. Despite many scientists expressing concerns with levels of BPA concentrations in foods, industry is against using a BPA substitute. The reason cited is that most substitutes for BPA that exhibit the same properties are actually more toxic as well as more expensive. As a result, it is not expected to see any decrease in BPA demand in the near future, until another compound can be found that provides the versatility of BPA without the additional environmental consequences. In mice, a dosage of 1250 mg/kg/day was associated with fetotoxicity and maternal toxicity, but did not cause a significant increase in the incidence of malformations. The process used in the RAR for estimating oral exposure of consumers is highly conservative and predicts a cumulative daily exposure to bisphenol A with food of up to 0.6 mg/person, mainly from wine consumption and canned food. A recent dietary exposure assessment performed by the Scientific Committee on Food results in a much lower estimated intakes from dietary exposures. Repeated dose toxicity Dietary administration of bisphenol A in mice indicates that the liver is a target organ of bisphenol A in this species resulting in changes in size and nucleation of hepatocytes. A NOAEL for these effects could not be defined from the available data and a LOAEL of 120 mg/kg/day is derived. Genotoxicity Although there is some evidence for a genotoxic activity in vitro, bisphenol A was not genotoxic in vivo and there is no evidence from animal carcinogenicity studies for a significant carcinoenic effect. The DNA-adducts were considered as of no concern to human health as there were no positive results for gene mutation and clastogenicity in cultured mammalian cells.The CSTEE, therefore, agrees with the overall conclusion that bisphenol A has no significant mutagenic potential in vivo. Carcinogenicity Based on the overall evaluation of the available data, including those from repeated dose and mutagenicity studies, the CSTEE agrees with the assessor that bisphenol A does not have a significant carcinogenic potential Reproductive and developmental toxicity The conflicting data from studies using low doses, however, do raise uncertainities. The uncertainities on possible low dose effects of bisphenol A, albeit based on a limited number of studies using non-standard protocols, result in conclusion requesting further research. A recent report (NTP, 2001) comes to the same conclusion.

The oral Reference Dose (RfD) is based on the assumption that thresholds exist for certain toxic effects such as cellular necrosis. It is expressed in units of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Please refer to the Background Document for an elaboration of these concepts. RfDs can also be derived for the noncarcinogenic health effects of substances that are also carcinogens. Therefore, it is essential to refer to other sources of information concerning the carcinogenicity of this substance. In a 103-week dietary study, groups of 50 rats/sex were fed diets containing 0, 1000, or 2000 ppm bisphenol A. All treated groups of rats had reduced body weights, compared with controls, evident from the 5th week of exposure. Food consumption was also reduced, compared with controls, but this effect was not observed until the 12th week of treatment. Reduced body weights in rats, therefore, was considered a direct adverse effect of exposure to bisphenol A. In the same study (NTP, 1982), male mice (50/group) were fed diets containing 0, 1000, or 5000 ppm bisphenol A and female mice (50/group) were fed 0, 5000, or 10,000 ppm bisphenol A. Male mice at 5000 ppm and female mice at 5000 and 10,000 had reduced body weights. At 1000 and 5000 ppm, there was an increase in the number of multinucleated giant hepatocytes in male mice. This effect was not considered to be adverse, and this level is a NOAEL in mice. Assuming a food factor for mice of 0.13, this dietary concentration corresponds to a dosage of 130 mg/kg/day. Because the LOAEL of 50 mg/kg/day in rats is less than the NOAEL of 130 mg/kg/day in mice, the NOAEL in mice cannot be chosen as a basis for the RfD. The LOAEL of 50 mg/kg/day in rats, the lowest dosage used in either species in the chronic studies, is chosen as the basis for a chronic oral RfD A recent study investigated the modifications in endogenous antioxidant capacity, including superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, oxidative stress index, reduced glutathione (GSH), glutathione disulfide (GSSG), and thiobarbituric acid-reactive substance (TBARS) in the brain, liver, kidney, and testes of mice under bisphenol A (BPA), an endocrine disrupter, treated for 5 days. BPA was administrated intraperitoneally at doses of 25 and 50 mg/kg/day. The TBARS levels were not affected by BPA administrations. The SOD activities increased and the catalase activities decreased in the liver after BPA administration. The GPx activity decreased in the kidney. The levels of GSH+GSSG increased in the brain, kidney, liver, and testes, while, the levels of GSH decreased in the testes. Most of the composites and sealants used in dentistry are based on bisphenol A diglycidylether methacrylate (Bis-GMA). Reports revealed that in situ polymerization is not complete and that free monomers can be detected by different analytic methods. Concerns about the estrogenicity of bisphenol A (BPA) and other aromatic components leached from commercial products have been expressed. We studied biphenolic components eluted from seven composites and one sealant before and after in vitro polymerization using HPLC and gas chromatography/mass spectrometry and we investigated how pH modifications affect the leaching of these components. We found BPA (maximal amount 1.8 µg/mg dental material), its dimethacrylate derivative (Bis-DMA, 1.15 µg/mg), bisphenol A diglycidylether (6.1 µg/mg), Bis-GMA (2.0 µg/mg), and ethoxylate and propoxylate of bisphenol A in media in which samples of different commercial products were maintained under controlled pH and temperature conditions. Our results confirm the leaching of estrogenic monomers into the environment by Bis-GMA-based composites and sealants in concentrations at which biologic effects have been demonstrated in in vivo experimental models. The main issue with implications for patient care and dentist responsibility is to further determine the clinical relevance of this estrogenic exposure. These findings confirm reports that in vitro polymerization is not complete and that free monomers can be detected by different analytic methods. Several publications have appeared since our first report on BPA and Bis-DMA leaching from the Delton sealant that may help to define a position regarding monomer leachability and their hormonal activity in vivo. With respect to the implications for patient care and dentist responsibility, more data must be gathered before a complacent attitude toward this hazard is adopted. As Söderholm and Mariotti proposed, the main issue is to determine whether the estrogenic effects of dental sealant and composite monomers have any real clinical consequences. This concern should be addressed by new studies that focus on the toxicity--estrogenicity--of leached monomers, oligomers, and precursors, similar to the paper recently published by our group. It will be difficult to give an a priori prediction of the risk to human health posed by such exposures, but new data may help assess this exposure within the general risks attributable to xenoestrogens and especially BPA. Four recent observations have raised concern about the estrogenicity of bisphenols. First, a more potent in vivo BPA effect has been demonstrated as compared to previous in vitro assays. For instance, 3 days of exposure to microgram levels of BPA (60-100 µg/rat/day) released from capsules promoted cellular proliferation in rat uterus and vagina, which showed molecular and morphologic alterations nearly identical to those induced by estradiol . The biologic significance of the 179 µg BPA eluted from a 100-mg polymerized sample of commercial composite in our study should be considered from this standpoint. Second, BPA seems to act on other target organs as well as the obvious organs [breast and uterus. Third, genetic differences in susceptibility to the estrogenic effect of BPA have raised concerns about subpopulations with a higher sensitivity to this estrogen. Fourth, bisphenol A is not the only molecule with proven in vitro estrogenicity that is used by the plastics industry. The leaching of other components with estrogenic activity from polymerized composites and sealants cannot be ruled out because sparse information is available on their ingredients. For instance, commercial products use dibutylphthalate (35), dioctylphthalate, bis 2-ethylhexylphthalate, and dicyclohexylphthalate as catalyst components. Some of these phthalates are among the estrogenic chemicals described. On the other hand, guidelines have been issued by organizations such as the following, disputing the importance of the foregoing findings.

American Dental Association Statement on Bisphenol A Leaching From Dental Sealants Estrogenic Effects of Bisphenol A Lacking in Dental Sealants An American Dental Association Statement A 1996 study conducted by researchers in Spain and published in Environmental Health Perspectives found that a chemical, bisphenol A (BPA), which can potentially mimic human estrogen, leached out of dental sealants.1 Although the study did not show any causal effect between the presence of BPA and any health condition, the ADA was sufficiently concerned about this research to conduct its own evaluation. Of the 12 brands of dental sealants that currently carry the ADA Seal of Acceptance, 11 of the 12 materials leached no detectable BPA on first analysis; on second analysis, one sealant leached a trace amount of BPA within the test sensitivity (5 parts per billion). The manufacturer of this sealant was contacted. After additional quality control procedures were implemented in the manufacturing process, detectable BPA was successfully eliminated in the final product. (BPA is not a direct ingredient of dental sealants; it is a starting raw chemical that appears in the final product only when the raw materials fail to fully react.2) Hence, none of the dental sealants that carry the ADA Seal release detectable BPA, although it must be emphasized that there is no evidence to suggest a link between any adverse health condition and BPA leached out of dental sealants. The ADA also looked beyond product chemistry for the presence of BPA in dental sealants. The Association tested the blood of dentists who had dental sealants on their teeth and those who did not. The ADA examined 40 blood samples: 30 were from dentists with one to 16 sealed surfaces, and ten samples were from dentists who had no sealants. BPA was not found in any of the blood samples from either group, suggesting that if BPA is leached from dental sealants it is not detectable in blood tests; thus, it does not present an estrogenic hazard.3 In addition to its laboratory studies, the ADA worked with researchers at University of Nebraska Dental School on a clinical project to measure BPA exposure during and after sealant application. Dental sealants were applied to test subjects, then saliva and blood samples were collected at various time intervals after sealant application. This study showed that BPA released orally from a dental sealant may either not be absorbed or is not detectable at or above 5ppb when measured in systemic circulation.

Detection and resistance

Paragraph 6 states: "A 2005 study by Belcher and coworkers demonstrated that even very low levels of a xenoestrogen, in this case Bisphenol A could affect fetal neural development more than higher levels ..." Is that because the host organism is unable to detect and therefore resist xenoestrogens below some threshold level? Wavelength 20:55, 14 June 2006 (UTC)