bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of metabolism in the endocrine-disrupting effects of chemicals in aquatic and terrestrial systems
Authors: van den Berg M. , Sanderson T. , Kurihara N. , Katayama A. 
Published: October 2007

This review describes the role of metabolism with endocrine active substances. Many modern synthetic compounds are readily metabolized to more polar forms that often contain hydroxy groups. This presence of polar groups and aromatic moieties in the parent compound or metabolite can play an important role in the mechanism of endocrine disruption. In addition, phase II metabolism (e.g., glucuronidation) can also lead to deactivation of the endocrine properties. In the case of bisphenol A and alkylphenols, metabolism can be considered as a detoxification mechanism as glucuronides decrease of inhibit binding to the estrogen receptors. In the case of phthalate esters, the primary metabolites, the monoesters, and further degraded metabolites do not interact with the estrogen receptor either. In contrast, the demethylation of methoxychlor in fish and other vertebrate species leads to metabolites with an increased affinity for the estrogen receptor. Certain PCB metabolites with hydroxy groups on the para position without vicinal chlorines have estrogenic activity, but these metabolites are not relevant for the environment. PCB metabolites with methylsulfonyl groups are commonly found in environmental biota and have been associated with several endocrine, developmental, and reproductive effects. Some DDT metabolites bind weakly to the estrogen receptor, but the major biotransformation product p,p-DDE is an androgen receptor (AR) antagonist. Vinclozolin is an anti-androgen and this effect appears to caused by two of its more water-soluble metabolites. The chloro-s-triazines exhibit an in vitro induction of aromatase, but their dealkylated metabolites show a decrease or lack of this effect. It is recognized that common metabolic processes can differ strongly among species that complicates ecotoxicological risk assessment of endocrine active substances. In conclusion, the testing of metabolites for endocrine-disrupting properties should be encouraged in the future to establish a better risk assessment process. An appendix containing levels and half-lives of various endocrine-disrupting chemicals in the environment and in wildlife is included at the end of this article.
Critical factors in exposure modeling of endocrine active substances
Authors: de Voogt P. , van Hattum B. 
Published: October 2007

Multimedia transport, partitioning, and degradation pathways are key processes in the probability of a substance to interact with target organisms. Biotic factors such as toxicokinetics, biotransformation capacity, and behavioral and life-cycle aspects of the organisms are determinants for final concentrations at target organs. The role of metabolites in endocrine disruption can be quite different from those of the parent compounds, and often this requires separate toxicokinetic evaluation. The exposure assessment of endocrine active substances (EASs) suffers from a huge lack of reliable data, of both values that are used as input parameters in exposure models, and field data that are needed for validation purposes. In general, for the more classic EASs, such as PCBs, p,p'-DDE, chlorinated dioxins, some pesticides, and organotins, reliable data are sufficiently available, but careful evaluation of the quality of databases is necessary. Several data quality evaluation systems have been proposed. For the "newer" compounds, only few data have been gathered so far. The latter compounds include alkylphenols, bisphenol A, brominated flame retardants, phytoestrogens, and in particular natural and synthetic hormones, which in view of their high estrogenic potency could be the most important compounds in terms of risk. The suitability of current exposure assessment models for EASs at this moment seems to be restricted to the persistent compounds such as PCBs, PCDDs, and PCDFs. Especially for the compounds subject to biodegradation and biotransformation, the lack of experimental data to derive model-input parameters and perform validation studies at this moment is one of the main obstacles for the further application of generic exposure models to other EASs. Most of the current models do not allow life stage-specific predictions. Although the mechanisms of endocrine disruption involve different types of action, the principle of additivity, based on the equivalent toxicity approach (using estrogen equivalent potencies relative to 17β-estradiol) seems promising for the design of integrated exposure and effect models for EASs. Research programs aimed at the endocrine disruption issue must focus on promoting experimental studies for generation of reliable, high-quality parameter data on the one hand, and surveys or monitoring campaigns for collection of representative field data on the other. The non-specificity of possible effects caused through endocrine mechanisms implies that in order to reveal dose-response relationships all potentially active agents, or at least as many as feasible, need be included in the risk assessments. Current regulatory monitoring programs should further be evaluated and harmonized with validation requirements of models used in exposure assessment.
Environmental fate and metabolism: Issues and recommendations
Authors: de Voogt P. , Halling-Sørensen B. , van Hattum B. , Holland P. T. , Ingerslev F. , Johnson A. , Jürgens M. , Katayama A. , Klein W. , Kurihara N. , Leblanc J. C. , Racke K. D. , Sanderson T. , Shemesh M. , Shore L. S. 
Published: October 2007

This main topic of the project and symposium includes the issue of releases of EASs and their monitoring in the environment, food, and feed in order to provide the full set of criteria, relevant for exposure assessment. Much less research has been devoted to these areas as compared to investigations on the effects. Issues of special importance regarding exposure to EASs, both from a research and risk management point of view, predominantly result from the fact that high-potency natural products are released as well as anthropogenic substances. In order to provide reliable information for risk assessment and risk management, substantial research, methodological improvements, and improvements in data interpretation are needed regarding the following: releases and technologies for their mitigation; monitoring; establishment of background levels; transport, partitioning, persistence, degradation, and metabolism of EASs; dealing with "joint toxicity"; and providing reliable analytical methodology conforming to the principles of quality assurance. Phytohormones play a special role in this whole area since they may be used as food amendments.
Toxicity vs. beneficial effects of phytoestrogens
Authors: Wanibuchi H. , Kang J. S. , Salim E. I. , Morimura K. , Fukushima S. 
Published: October 2007

Phytoestrogens are nonsteroidal plant-derived compounds possessing estrogenic activity. These include two major classes: isoflavonoids and lignans. Phytoestrogens have received recently great attention because of their beneficial effects, which include the prevention of cancer, atherosclerosis, and bone density loss. However, they have estrogenic activity and may affect as endocrine disruptors. In this review, we pay attention to both the toxic and beneficial effects of phytoestrogens. Epidemiological data support that isoflavonoids help prevent cancer of breast, prostate, stomach, and lung. However, there have been some reports about a positive association between some phytoestrogens (e.g., campesterol and stigmasterol) and prostate cancer risk. Animal experiments and in vitro experiments have shown that the biological effects of phytoestrogens may be organ-specific, inhibiting cancer development in some sites, yet showing no effect or an enhancing effect on tumorigenesis at other sites. Also, their effects may be dependent on the timing and duration of exposure. For example, several studies in rodents have established that the favorable effect of an isoflavone-rich diet on breast cancer risk may be significant only if consumption occurs before puberty or during adolescence. On the other hand, prenatal exposure of genistein was reported to have a carcinogenic effect on the uterus of rodents. Phytoestrogen, especially soy products, has been used as hormone-replacement therapy, reducing such symptoms as hot flashes, vaginal dryness, and mood changes while protecting women from osteoporosis and heart disease. However, the animal data suggest that the timing of exposure to such compounds is crucial, with neonatal exposure having the most pronounced effects. Given the exposure of neonates to phytoestrogens, this should be a cause for concern.
Closing the gap between exposure and effects in monitoring studies
Authors: Tillitt D. E. , Papoulias D. M. 
Published: October 2007

A major challenge to contaminant monitoring programs is the selection of an appropriate suite of measurements for assessing exposure and effects. Early monitoring programs relied solely on residue analysis to detect the organochlorine compounds that were in use at that time. A shift to the use of more transient, less persistent chemicals required that a new set of tools be developed to determine if an organism had been exposed. This led to the development of cellular and biochemical assays that could indicate the presence of these types of chemicals in biota and the environment. However, it was recognized that measures of contaminant presence alone were insufficient to assess the health of biota. As a result, considerable research began to be directed toward development of diagnostic tools for measuring chemical effects in fish and wildlife. Today, contaminant monitoring programs follow a paradigm for study design that emphasizes not only the use of measures of exposure, but also measures of effect. Using data from our monitoring and research studies for hormonally active substances, we discuss a variety of metrics of exposure and effects and their application to specific chemicals, and the current information gaps. We conclude that although several bioindicators of exposure and effect have been promoted and used, to date there continues to be a poor association between cause and effect for endocrine active substances. In part, this is due to the limited number of diagnostic tools that are available and to a lack of basic toxicological information concerning toxicokinetics and mechanisms of action of hormonally active chemicals in fish and wildlife species. In the foreseeable future, both tissue and environmental residue data, despite the many limitations, will continue to be an important component of monitoring programs for hormonally active chemicals as we continue to develop and validate more specific bioindicators of exposure and effects.
Simple, rapid assays for conventional definite testing of endocrine disruptor hazard: Summary and recommendations
Authors: Fukushima S. , Freyberger A. 
Published: October 2007

Study protocols for the characterization of endocrine active compounds presented in Workshop 4 included the enhanced Organization for Economic Cooperation and Development (OECD) test guideline (TG) 407, the medium-term rat liver and rat multi-organ carcinogenicity assays, and an enhanced one-generation reproduction study.
The outcome of rat studies on flutamide and ethinylestradiol indicated that these strongly active compounds can readily be detected even with a low animal number using the enhanced OECD TG 407. Both newly added (such as male accessory sex organ weights, histology of pituitary, vagina and male mammary gland) and already included parameters contributed to the detection of endocrine effects. Thorough evaluation of the results of 20 studies conducted with 10 compounds thought to interfere with the endocrine system by different mechanisms will identify the most appropriate enhancements to the current OECD TG 407.
Medium-term rat liver and rat multi-organ carcinogenicity assays are well recognized in the International Conferences on Harmonization for Pharmaceutical Chemicals. They have been successfully used to detect carcinogenic and modifying potentials of new chemicals within a relatively short time and can be applied to endocrine active compounds. Dose-response studies on nonylphenol, bisphenol A, and styrene using the rat liver carcinogenicity assay did not reveal effects of any of these compounds on the development of preneoplastic lesions in rat liver.
The enhanced one-generation reproduction study protocol included treatment of pregnant female rats from gestation day 0 through to lactation day 21, and examination of all offspring. Half of the animals were necropsied at weaning, the remaining animals were examined for vaginal opening, preputial separation, estrous cyclicity, and sperm characteristics and were necropsied at adulthood. In a pilot study ethinylestradiol inhibited maternal fertility at dose levels similar to those effective in the uterotrophic assay.
It is recommended to rapidly evaluate the conducted enhanced OECD TG 407 studies and to enhance the current OECD TG 407 appropriately. Further compounds with different mechanisms of action should be studied in the one-generation reproduction study to further investigate the usefulness of this protocol. The established medium-term carcinogenicity assays can be used to study carcinogenic potential rapidly. Use of female animals and inclusion of carcinogens targeting at breast and uterus should be considered in order to explore further the predictibility of this model.
Hormonally active agents and plausible relationships to adverse effects on human health
Authors: Inoue T. 
Published: October 2007

A hormonally active compound was first identified in the book Silent Spring by Rachel Carson in 1962, implicating the effect of pesticides such as DDT and the derivatives. Nearly four decades later, the book Our Stolen Future by Theo Colborn et al., and other pertinent publications have revisited and broadened the issue regarding a variety of possible chemicals and the area exposed. Translation and publication became available in Japan within the last four years. Since then, Japan joined the member countries involved in the global issue of endocrine disruptors, the "environmental hormone". Although a significant number of chemicals possessing a hormone-like action have been recognized for many years, and the action of their biological plausibility related to the receptor-mediated effects strongly suggests possible human effects comparable to hormonal changes in wildlife, little is known about evidences or adversities in experimental animals and humans. The most essential key to resolving these dilemmas may be to understand the mechanism of actions (i.e., a possible low-dose issue). In other words, the mechanism at the low-dose effect may be resolved simultaneously by the mechanism of three major questions linked to the low-dose issue; namely, threshold, possible oscillation, and additive and/or synergistic action.
Government view of endocrine disruption in wildlife
Authors: Gies A. 
Published: October 2007

Like hardly any other issue in ecotoxicology, endocrine disruption has given rise to public concern. Reproductive, behavioral, and immunological effects in wildlife were publicly not only understood as possible threats to wildlife populations, but also as early warning signals that human health could be at risk. Above all, the public has been concerned about negative outcomes in reproductive health, and effects like feminization in fish were regarded as evidence for the biological plausibility of the hypothesis that environmental levels of hormonally active chemicals are high enough to affect human reproductive health.
Public concern has been mirrored by several parliamentary and governmental decisions emphasizing the need for extensive research and rapid measures to reduce the risk associated with endocrine-disrupting substances.
Endocrine disruption in wildlife is clearly a priority issue. At least in densely populated areas like Europe, symptoms of endocrine disruption in wildlife cannot only be detected in areas with abnormally high levels of pollution, but have also occurred in main river systems, estuaries, and even in the open sea. Imposex in mollusks and feminization in fish that were clearly related to disturbances in the hormonal system of these organisms by exogenous substances have been used as markers in monitoring programs. Though symptoms of endocrine disruption can be clearly identified, it is much more difficult to link these outcomes to causative chemicals or mixtures of substances. Natural and pharmaceutical hormones, phytoestrogens, pesticides, and industrial chemicals may all play a role to a different degree depending on the site under study. This means that several different risk-reduction strategies have to be applied, including bans of substances, use restrictions, and installation and optimization of sewage treatment works embedded in a strategy for the overall reduction of chemical input into the environment.
It should be noted that, in addition to national and international regulatory actions taken by state authorities, a considerable reduction of the environmental input could be achieved in several countries by voluntary actions taken by industry.
Regulatory bodies are still facing major problems in the field of risk assessment and risk reduction. Association between effects and causative agents or mixtures are in many cases weak. Important tools for risk assessment such as dose-response relationships or the existence of thresholds are not yet agreed on. These uncertainties are the reason that many national governments and the European Commission have identified precaution as the main element in chemicals policy for the management of endocrine disruptors.
This paper is based on documents of the German Federal Environmental Agency, but solely represents the view of the author from a regulatory perspective and emphasizes the wildlife aspects of endocrine disruption.
Endocrine active substances and the need to improve environmental protection: An environmentalist's perspective
Authors: Lyons G. 
Published: October 2007

This paper reviews the existing concerns and presents conclusions and recommendations for action. The first section outlines an environmentalist's perspective and predicts that endocrine active substances (EASs) pose a high risk for wildlife populations. The second section explains that risk assessment, as currently practiced for individual chemicals, does not adequately protect the environment, and suggests several improvements that should be made. However, it is argued that the properties of endocrine disruption lead to increased uncertainty in the risk assessment, such that countries wishing to achieve a high level of protection would be justified in implementing precautionary controls. The third section outlines some conclusions and additionally provides an appraisal of the responses of governments and industry. Furthermore, several recommendations are made, particularly the imperative for research funding to be substantially increased and guaranteed for many years to come. Also highlighted is the need to hasten the development of screens and tests for ecotoxicity, and for governments to commit to a comprehensive sorting, screening, and toxicity testing program for all chemicals to which significant exposure occurs.
Models of liquid mixtures: Structure, dynamics, and properties
Authors: Durov V. A. 
Published: October 2007

Abstract
Models of the structure and properties of liquid mixtures are outlined. The main focus is on quasichemical models for the modeling of supramolecular ordering in mixtures, self-organized by H-bonds, leading to a unified description of their physicochemical properties. Models of polyvariable supramolecular species are discussed with respect to structure and composition of the mixtures, taking into account the cooperativity of H-bonding, and leading to a description of electric (dipole moment) and optic (polarizability) properties. We analyze the interrelations of thermodynamic functions (Gibbs energy, enthalpy, entropy), dielectric (permittivity) and optical properties (refractive index and its fluctuation derivatives, defining Rayleigh light scattering) of nonideal mixtures as well as the microscopic characteristics of the aggregates. Methods are developed in order to obtain both integral and differential parameters of aggregation. Models for the description of supramolecular reorganization, intramolecular transitions, and energy transfer during molecular thermal motion as well as fluctuation and relaxation phenomena are considered. Applications both to liquids and mixtures are outlined. The supramolecular assemblies in liquids with long-range molecular correlations are established. Macroscopic manifestations of the supramolecular organization in the properties of liquids are characterized.
Are isotopic mixtures ideal?
Authors: Jancsó G. 
Published: October 2007

Abstract
Isotopic mixtures have long been considered as textbook examples of ideal solutions. High-precision vapor pressure measurements have shown that even these very simple mixtures exhibit deviations from the ideal behavior. The small, but still significant nonideality of isotopic mixtures can be accounted for in terms of the difference in the molar volumes of isotopic molecules. Theoretical analysis demonstrates that the internal vibrations of the molecules significantly contribute to the excess Gibbs energy, and the proper consideration of the volume dependence of molecular vibrations of the component molecules is essential to the understanding of the properties of isotopic mixtures.
Structure and criticality of ionic fluids
Authors: Schröer W. , Weingärtner H. 
Published: October 2007

Abstract
Two properties render electrolyte theories difficult, namely the long-range nature of the Coulomb interactions and the high figures of the Coulomb energy at small ion separations. In solvents of low dielectric constant, where the Coulomb interactions are particularly strong, electrical conductance and dielectric spectra suggest that the ion distribution involves dipolar ion pairs, which then interact with the free ions and with other dipolar pairs. The dipole-dipole interactions between ion pairs lead to an increase of the dielectric constant, which in turn stabilizes the free ions, thus leading to redissociation at high salt concentrations. An equation of state that accounts for ion pairing, ion-ion pair, and ion pair-ion pair interactions rationalizes the basic features of the ion distribution. It also predicts a fluid-phase transition at low reduced temperatures, which closely corresponds to simulation results and to experimentally observed liquid-liquid phase transitions. The long-range nature of the Coulomb potential driving these transitions raises questions concerning their universality class. Experiments suggest that the Ising universality class applies, but there is cross-over to mean-field behavior rather close to the critical, not yet well explained by theory.
"Morphing" of ab initio-based interaction potentials to spectroscopic accuracy: Application to Cl-(H2O)
Authors: Bowman J. M. , Xantheas S. S. 
Published: October 2007

Abstract
We present anharmonic vibrational calculations for the Cl-(H2O) cluster and their convergence with the n-mode representation of the interaction potential. Extension of this representation up to 4-mode couplings produces results that appear to be converged to within 10 cm-1 or less relative to the exact 6-mode representation for this system. This methodology, in conjunction with the "morphing" technique, which is based on the scaling of the internal coordinates, provides an effective means of fitting intermolecular potentials to measured vibrational spectra. Application of this approach to the chloride-water interaction produces a revision of a previously developed empirical interaction potential that reproduces the measured fundamental and first overtone frequencies to within an average absolute deviation of 1.75 cm-1 in the 4-mode coupling representation.