bluuebunny/crossref_metadata_2025 huggingface dataset:
Need for establishing integrated programs to monitor endocrine active compounds
Authors: Segner H.
Published: October 2007

Environmental monitoring programs on endocrine active compounds (EACs) have been used to document the level of exposure and to assess the possible association to the occurrence of developmental and reproductive disorders in wildlife. The establishment of causal links between exposure and effect data, however, was found to be difficult due to, for example, the presence of confounding factors or limited understanding of EAC mechanisms and interactions, but also because of conceptual and methodological limitations of current monitoring strategies. In order to provide plausibility of an EAC etiology for a developmental or reproductive alteration in a wildlife population, integrated monitoring programs are needed that will use a combination of complementary approaches: methods for a targeted search for suspected EACs in an environmental mixture, analysis of internal EAC doses instead of external EAC concentrations, utilization of mechanism-based end-points in bioanalytical and effect monitoring, investigation of the basic biology and physiology of wildlife sentinel species, laboratory replication of field effects, as well as consideration of epidemiological and weight-of-evidence criteria in the design and data evaluation of monitoring programs.
Search for the evidence of endocrine disruption in the aquatic environment; Lessons to be learned from joint biological and chemical monitoring in the European project COMPREHEND
Authors: Eggen R. I. L. , Bengtsson B.-E. , Bowmer C. T. , Gerritsen A. A. M. , Gibert Michel , Hylland Kjetil , Johnson A. C. , Leonards Pim , Nakari T. , Norrgren L. , Sumpter J. P. , Suter M. J.-F. , Svenson A. , Pickering A. D.
Published: October 2007

Between January 1999 and December 2001, the European Community project COMPREHEND was performed. The overall aim of COMPREHEND was to assess endocrine disruption in the aquatic environment in Europe, consequent to effluent discharge, with emphasis on estrogenic activity. COMPREHEND demonstrated the widespread occurrence of estrogenic effluents across Europe and presented evidence of impacts on a range of wild fish species. Using a variety of bioassays in combination with chemical analytical methods, estrogenic steroids of human origin from domestic wastewater effluents were identified as the most pervasive problem, although alkylphenols may be important estrogenic components of some industrial effluents. New tools have been developed for the identification of estrogenic effluents, and recommendations are made for the improvement of existing techniques. We have shown that individual fish within natural populations may be feminized to varying degrees, but it has not been possible to show, using traditional fish population parameters, that the survival of fish populations is threatened. However, laboratory-based fish life-cycle studies demonstrate the sensitivity of fish to estrogen (and androgen) exposure and how this might lead to complex (and potentially damaging) genetic changes at the population level. New approaches to this problem, utilizing recent advances made in the field of molecular and population genetics, are recommended. Finally, a study of estrogenic and androgenic activity of waste waters during the treatment process has shown that some of the existing wastewater treatment technologies have the potential to eliminate or minimize the hormonal activity of the final effluent.
Biomonitoring: Integration of biological end-points into chemical monitoring
Authors: Seifert M. , Wen L. , Alberti M. , Kausch U. , Hock B.
Published: October 2007

Biomonitoring is currently performed at two levels, assessing exposure to pollutants and effects monitoring by bioassays. As an example for the first approach, vitellogenin (VTG) in male fish of Abramis brama as an endpoint for estrogen exposure is discussed. However, similar changes of VTG or VTG-like proteins in the hemolymph of mussels could not be detected. Enzyme-linked receptor assays for monitoring estrogenic effects at the molecular level serve as an example for the second category. Applications of the enzyme-linked receptor assay (ELRA) developed in our laboratory are presented. Detection limits of 0.02 μg/l 17β-estradiol were recently achieved with the chemiluminescent format. Although effect monitoring provides information in terms of toxicity equivalents, it is not possible to relate the signals to specific pollutants and their concentrations. For this purpose, chemical analysis is required. New approaches are reported for the direct coupling of bioassays and chemical analysis. This concept is defined as bioresponse-linked instrumental analysis. It combines biomolecular recognition, initiating a biological effect, and chemical analysis. In addition to the classical bioanalytical approaches, new strategies in genomics and proteomics have been developed. This may lead to multimarker approaches opening this area to environmental analytics.
Identifying the causative agents: The use of combined chemical and biological strategies in monitoring programs
Authors: Routledge E. J.
Published: October 2007

The toxicity identification and evaluation (TIE) approach that identified unconjugated natural and synthetic steroid estrogens to be the major estrogenic component in domestic sewage treatment work effluent is described. Given the increasing popularity of TIE-based approaches in ecotoxicology research, a number of important considerations, limitations, and possible future directions of TIE studies are also discussed.
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.
Testing of endocrine active substances using an enhanced OECD test guideline 407: Experiences from studies on flutamide and ethinylestradiol
Authors: Freyberger A. , Andrews Peter , Hartmann Elke , Eiben Rolf , Loof Ingo , Schmidt U. , Temerowski M. , Folkerts Andree , Becka Michael , Stahl B. , Kayser Martin
Published: October 2007

Groups of five male and five female Wistar rats were treated by gavage with 0, 1, 10, and 100 mg/kg body weight (b.w.) flutamide (FLU) or 0.01, 0.05, and 0.2 mg/kg b.w. of ethinylestradiol (EE2) for at least 28 days according to an enhanced Organization for Economic Cooperation and Development (OECD) test guideline (TG) 407 to investigate which of the current and/or additional parameters would detect effects on the endocrine system and to provide data on intralaboratory variability. Two identical studies were performed in parallel on each compound. Common enhancements were determination of thyroid hormones (T3, T4) and thyroid stimulating hormone (TSH), of the stage of the estric cycle to ensure necropsy of females in diestrus, of the number and morphology of epididymal sperm, and of additional organ weights (e.g., male accessory sex organs, MASO) and histopathology of additional organs (e.g., pituitary, vagina). Endocrine-mediated findings consistently observed in these studies were decreased relative weights of MASO at 100 mg/kg FLU and at 0.2 mg/kg EE2, histological changes in pituitary and testes at > or = 10 mg/kg and in MASO, epididymis and adrenals at 100 mg/kg in FLU-treated males, histological changes in the mammary gland at > or = 0.05 mg/kg and in testes, MASO and adrenals at 0.2 mg/kg in EE2-treated males, estrogenization of uterus and vagina (despite necropsy in diestrus) at > or = 0.01 mg/kg EE2, and changes in the ovary at 0.2 mg/kg EE2. Spermatology was insensitive (EE2) or revealed changes only at the maximum tolerated dose (MTD). Determination of T3, T4, and TSH did not contribute to the detection of the endocrine effects (FLU) or provided equivocal results. Doubling the group size to 10 animals by combining the studies run in parallel did not increase the sensitivity of detection of endocrine-mediated effects above the level obtained by histopathological examination of groups of five animals. Only some of the proposed enhancements evaluated were helpful in detecting the endocrine-mediated effects of FLU and EE2. Evaluation of studies according to an enhanced TG 407 on 10 compounds with different endocrine activities will identify the most appropriate enhancements.
Application of rat medium-term bioassays for detecting carcinogenic and modifying potentials of endocrine active substances
Authors: Imaida Katsumi , Tamano S. , Hagiwara Akihiro , Fukushima S. , Shirai T. , Ito Nobuyuki
Published: October 2007

Two in vivo bioassay methods, a rat medium-term liver bioassay and a rat multiorgan bioassay, can be used for detecting carcinogenic or modifying potentials of endocrine active substances (EASs) on endocrine disruption (ED). The first bioassay, the rat mediumterm liver bioassay, is fundamentally based on the two-step hypothesis of liver carcinogenesis; initiation with diethylnitrosamine (DEN, 200 mg/kg b.w., ip) is followed by test chemical administrations during the second stage, in combination with 2/3 partial hepatectomy. It requires only eight weeks for animal experimental treatment and a further few weeks for quantitative analysis of immunohistochemically demonstrated gluthathione-S-transeferase placental form positive hepatic foci. A total of 313 chemicals/substances have already been analyzed, and the efficacy of the system for hepatocarcinogenesis has thereby been well established. This bioassay also provides information concerning dose responses and inhibitory potentials of test chemicals. Several possible EASs, most of them categorized as pesticides, have already been examined in this bioassay, and dose-response studies of nonylphenol, bisphenol A, and styrene have also been tested. Another bioassay, a medium-term, multiorgan bioassay system, using five different chemical carcinogens -DEN, MNU, BBN, DMH, and DHPN- has also been established for rapid detection of not only hepatocarcinogens, but also other organ-targeted carcinogens. These medium-term bioassays are particularly useful and reliable methods for detecting carcinogenic or modifying potentials of low doses of test chemicals, such as EASs, and these methods can be used for the effects of chemical mixtures of EASs.
Enhanced one-generation reproductive toxicity study in rats for detecting endocrine-disrupting effects of chemicals
Authors: Aoyama H. , Suzuki K.
Published: October 2007

An enhanced one-generation reproductive toxicity study in rats without adjusting a litter size during the lactation period is proposed as a rapid and reliable bioassay for providing the data concerning adverse and/or low-dose effects of suspected endocrine disruptors. In this study, pregnant females are treated with the test substance from gestation day 0 through lactation day 21, in principle. F1 offspring from one-half of the litters in each dose group are killed and necropsied at weaning, while those from the remaining litters are examined for sexual maturation, estrous cyclicity, and/or sperm production. A series of pilot studies with ethynylestradiol as a reference chemical have suggested that the exposure of estrogenic chemicals during the early gestation period is critical for detecting effects on fertilization and/or implantation of eggs and survival of implants, and that expression of some genes including AR in the prostate and IGF-1 in the uterus of F1 offspring may be sensitive markers for monitoring potential estrogenic effects of the test compound.
Making decisions in the 21st century: Scientific data, weight of evidence, and the precautionary principle
Authors: Burger J.
Published: October 2007

Traditionally, science has progressed by slow steps involving the accumulation of studies showing particular effects, leading eventually to a general consensus. However, with increasing development and industrialization, environmental problems have escalated faster than the ability to collect sufficient data to form clear consensus among scientists. Since managers require scientific information to make decisions about management, regulation, and public policy, the gap has been partially filled by two approaches: weight of evidence and the precautionary principle. I suggest that both are useful for making decisions about endocrine active substances, although few papers in the refereed literature link the precautionary principle with endocrine active substances. As with most public policy decisions, these involve an iterative process whereby scientific inquiry must continue to fill data gaps, and to determine if the decisions made by these processes are still appropriate and protective of human and ecological health. The precautionary principle is most useful when it continues to inform and help direct research to fill data gaps in our understanding of environmental problems, such as the effect of endocrine active substances on endocrine disruption.
Precautionary principle and endocrine active substances
Authors: Goldstein B. D.
Published: October 2007

The precautionary principle has been central to many of the debates concerning the appropriate approach to the threat posed by endocrine active substances (EASs). This newly emerging principle has been applied to issues as diverse as persistent organic pollutants and the European trade barrier on beef from hormone-treated cattle.
Why epidemiology of endocrine disruptors warrants the precautionary principle
Authors: Gochfeld Michael
Published: October 2007

The precautionary principle is controversial, and critics invoke the need to wait for "sound science" before taking "costly" regulatory action. For human health effects, epidemiologic results are often considered more valuable than toxicologic studies in animals. Direct human evidence on the endocrine effects of environmental chemicals has been slow to accumulate because of inherent sample size limitations of exposed populations and over-conservative hypothesis testing approaches. Moreover, human health outcomes may take decades to emerge. Indeed, even huge population-based studies of hormone replacement therapy have been inconclusive regarding both benefits and risks. This paper argues that certain intrinsic standard epidemiologic methods are stacked to avoid making a type I error. Moreover, these combine with extrinsic limitations (long latency, high cost), leading me to conclude that reliance solely on epidemiology to provide definitive answers, will almost inevitably delay the discovery of meaningful associations warranting timely action for protection of public health. There are several ways in which the inherent conservatism of epidemiology is arrayed against preventative regulatory steps, hence a precautionary approach is warranted while awaiting the results of additional studies which for various reasons may be very long delayed or even impossible.
General process for the risk assessment of pesticides that interact with or affect the endocrine system
Authors: Hamernik Karen
Published: October 2007

The U.S. Environmental Protection Agency's Office of Pesticide Programs evaluates human health risk associated with exposure to pesticide chemicals. Chemical hazard and exposure assessment are components of the risk assessment process. For the risk assessment of single chemical conventional-type pesticides, there may be multiple exposure scenarios depending on the use pattern. Examples include acute and chronic dietary, and short-, intermediate-, and long-term occupational/residential exposures. For hazard assessment, available toxicity data and a weight-of the-evidence approach are used in the process of selecting appropriate toxicity endpoints for relevant exposure scenarios. The pesticide registration process requires that certain types of supporting toxicity data be submitted by the registrant depending in part on the chemical use pattern (e.g., food use). Types of toxicity data that might be submitted and used in hazard assessment include acute, subchronic, chronic, carcinogenicity, mutagenicity, metabolism, reproduction, developmental, neurotoxicity, and mechanistic studies. There may be data from multiple exposure routes (e.g., oral, dermal, inhalation) and from the scientific literature to consider. Dose-response information is also taken into account. In endpoint selection for a chemical, endocrine system-related effect(s) and dose-response relationship(s) are assessed in context of other types of effects, toxicities, and dose-response relationships noted. Endocrine system-related endpoints may include frank effects (e.g., endocrine organ hyperplasia or cancer) or precursor events (blood hormone level elevations). Endocrine system-related endpoints are generally treated like other cancer or non-cancer toxicity endpoints (e.g., hepatic cancer, neurotoxicity) in the risk assessment process. For chemicals with evidence of endocrine system interaction(s), an endocrine system-related effect may or may not be the most sensitive or relevant endpoint for a particular risk assessment exposure scenario. Some chemical examples will be presented. In the final risk assessment, hazard assessment information is integrated with exposure information. The assessment may be adjusted, at some point, for uncertainties in hazard or exposure data. An aggregate risk assessment, in which multiple sources or routes of exposure are considered, is typically performed for occupational and residential exposure scenarios. A cumulative risk assessment may be considered for groups of chemicals with a common mechanism of toxicity.
Role of the precautionary principle in the EU risk assessment process on industrial chemicals
Authors: de Bruijn J. , Hansen Bjorn , Munn S.
Published: October 2007

This paper discusses the practical implementation of the precautionary principle in the area of management of industrial chemicals in the European Union. An analysis of a number of recent cases where the precautionary principle was invoked shows that the main reason for doing so were the uncertainties in the risk assessment (or the underlying effects or exposure data), which were, according to the scientific experts, so high that the "normal" level of certainty could not be obtained. The challenge for the future is to try to develop general guidance or rules that will support the policymakers in their decision as to whether this uncertainty is so large that action is warranted or whether it is acceptable to wait until further information has become available.
Differing perspectives on the use of scientific evidence and the precautionary principle
Authors: Burger J.
Published: October 2007

Different governments and agencies are approaching the use of scientific evidence, weight of evidence, and the precautionary principle in different ways. The European community has used the precautionary principle in situations where the consequences are great, data are unavailable or will be costly (in terms of money and time) to obtain, or data are difficult or impossible to obtain. Other countries, such as the United States, have a risk assessment process that has built-in safety or uncertainty factors which are themselves precautionary. Risk management decisions can be made on the basis of adequate studies, risk assessment, weight-of-evidence approaches, and the application of the precautionary principle. While weight of evidence has been used in the United States for increased research funding and regulator action with respect to some chemicals that are hormonally active, the European community has applied the precautionary principle.
Risk management options for endocrine disruptors in national and international programs
Authors: Lamb J. C. , Koëter H. B. W. M. , Becker R. , Gies A. , Davies Les , Inoue T. , Jacobs A. , Lyons G. , Matsumoto M. , Timm G.
Published: October 2007

This workshop was convened to address common issues and concerns associated with risk management of endocrine-disrupting chemicals (EDCs). The talks described the tools and policies for key Japanese, Australian, German, and U.S. regulatory agencies. The agencies participating in the workshop were responsible for the regulation of various substances including: chemicals, pesticides, environmental contamination, pharmaceuticals, and food additives. The panel also described the role of the Organization for Economic Cooperation and Development (OECD) in standardizing the tools and validation of testing and screening methods. The panel also included nongovernmental organizations presenting the views of the World Wildlife Fund, and the chemical industry from industrialized nations; each organization described its concerns and proposed approaches to risk management of EDCs. This summary highlights the most important areas of common points of view of government, industry, and environmentalists. We also try to identify issues upon which viewpoints diverge.
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.
Risk perception: A chemical industry view of endocrine disruption in wildlife
Authors: Webb S. , Taalman R. , Becker R. , Onuma K. , Igarashi Koichi
Published: October 2007

Manufactured chemicals are essential to the vast array of goods and services that contribute to modern life. Their benefits are innumerable, and society is entirely dependent upon them. At the same time, there is an increasing awareness of the concept of environmental impacts. The challenge is to achieve the appropriate balance between the benefits and risks from chemicals, so that we all may enjoy the benefits of chemicals without significant detriment to current and future human and wildlife health. Ecological risk assessment is the mechanism that allows potential environmental chemical exposure to be benchmarked against hazardous properties so that risk is acceptable and environmental health is not impaired. Chemical management decisions based on such assessments are said to be risk-based. Within the context of environmental risk assessment practice for endocrine disruption, industry would support a position that:

endorsed the risk assessment process;

recognized that endocrine disruption is not an adverse effect per se, but rather a potential mechanism of action;

gave precedent to population-level effects instead of individual-level effects;

employed a tiered approach to hazard assessment; emphasized standardized and validated effects testing methodologies;

recognized that exposure per se does not necessarily constitute a risk;

considered relative potency (i.e., evaluation of the dose levels and mechanisms producing toxic adverse effects and determining whether the critical effect arises via an endocrine mechanism or another mechanism);

benchmarked risk against loss of benefits; and

evaluated risk within the context of overall risk from both natural and anthropogenic substances with common modes of action.

To help address uncertainty surrounding the risk from Endocrine Active Substances (EAS) to wildlife, the chemical industry -- via the Long-Range Research Initiative (LRI) -- has implemented a research program aimed at identifying and addressing knowledge gaps and establishing internationally harmonized testing methodologies in cooperation with other stakeholders. Details of individual projects within the current LRI research program are presented.
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.
Endocrine disruption and the USFDA's Center for Drug Evaluation and Research
Authors: Jacobs A. , Brown Paul , Farrelly James , Fisher J. E. , Morse D.
Published: October 2007

Drugs may have intended or unintended endocrine effects. Drug evaluation may include both in vitro and in vivo evaluations of toxicity and developmental/reproductive effects. After a signal is identified, human relevance is of utmost concern. An integration "tool" that formalizes a weight-of-evidence approach has been developed to assess concern about reproductive/ developmental toxicity to humans. This approach can be used to assess concern about an endocrine disruption signal. A signal alone does not mean a concern for humans. An effect needs to have biologic relevance, and exposure thresholds for effects may exist. Risk/benefit for a particular drug is a clinical decision and may vary by the drug indication. Risk management for an identified concern could include wording in patient communications, tracking distribution or limited distribution, and patient or pregnancy registries.
Relevant activities for risk management of endocrine disruptors in Japanese government agencies
Authors: Oikawa S. , Matsumoto M.
Published: October 2007

Similar to other countries, issues concerning endocrine disruptors have been attracting people's attention, as well as concerns, in Japan. Consequently, relevant ministries have been conducting several activities and projects. A summary of the current activities related to endocrine disruptors being conducted by Japanese government agencies is provided in this paper.
Advancing the testing and assessment of chemical substances for endocrine disruption: OECD activities
Authors: Koëter H. B. W. M.
Published: October 2007

This paper describes the establishment of a number of expert groups in the Organization for Economic Cooperation and Development (OECD) to manage the work related to the development and validation of test methods to identify and characterize the human health and aquatic environmental hazards of endocrine-disrupting chemicals. In addition, the concept of testing and assessment, using the most adequate testing tools without being prescriptive, is explained, and a coordinated approach for international work sharing under the OECD umbrella is described.
Models of liquid mixtures: Structure, dynamics, and properties
Authors: Durov V. A.
Published: October 2007

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

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

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

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.
Ab initio QM/MM MD simulations of the hydrated Ca2+ ion
Authors: Schwenk C. F. , Rode B. M.
Published: October 2007

The comparison of two different combined quantum mechanical (QM)/molecular mechanical (MM) simulations treating the quantum mechanical region at Hartree-Fock (HF) and B3-LYP density functional theory (DFT) level allowed us to determine structural and dynamical properties of the hydrated calcium ion. The structure is discussed in terms of radial distribution functions, coordination number distributions, and various angular distributions and the dynamical properties, as librations and vibrations, reorientational times and mean residence times were evaluated by means of velocity autocorrelation functions. The QM/MM molecular dynamics (MD) simulation results prove an eightfold-coordinated complex to be the dominant species, yielding average coordination numbers of 7.9 in the HF and 8.0 in the DFT case. Structural and dynamical results show higher rigidity of the hydrate complex using DFT. The high instability of calcium ion's hydration shell allows the observation of water-exchange processes between first and second hydration shell and shows that the mean lifetimes of water molecules in this first shell (<100 ps) have been strongly overestimated by conclusions from experimental data.
Solid-state proton conduction: An ab initio molecular dynamics investigation of ammonium perchlorate doped with neutral ammonia
Authors: Rosso L. , Tuckerman M. E.
Published: October 2007

The charge-transport mechanism in solid ammonium perchlorate crystal exposed to an ammonia-rich environment is studied using ab initio molecular dynamics. Ammonium perchlorate is an ionic crystal composed of NH4
+ and ClO4
- ; units that possesses an orthorhombic phase at T < 513 K and a cubic phase at T > 513 K. Exposure to an ammonia-rich atmosphere allows ammonia molecules to be absorbed into the crystal at interstitial sites. It has been proposed that these neutral ammonias can form short-lived N2H7
+ complexes with the NH4
+ ions allowing proton transfer between them, thereby enhancing the conductivity considerably. To date, however, there has been no direct evidence of this proposed mechanism. In this paper, ab initio molecular dynamics techniques are employed to explore this mechanism. By comparing computed infrared spectra of the pure and ammonia-doped crystals, we observe a significant broadening of the NH stretch peak into a lower frequency region, indicating through an experimentally verifiable observable, the formation of hydrogen bonds between NH3 and NH4
+ units. This suggestion is confirmed by direct observation of N2H7
+ complexes from the trajectory. Comparison of the diffusion constants of NH4
+ in the pure and doped crystals yields a ratio that is comparable to the experimentally measured conductivity ratio and clearly shows an enhanced positive charge mobility. Finally, compelling evidence suggesting the possibility of an ammonia umbrella inversion following proton transfer from NH4
+ and NH3 is obtained.
Thermodynamical, structural, and dielectric properties of molecular liquids from integral equation theories and from simulations
Authors: Krienke H.
Published: October 2007

A survey is given on our attempts to calculate equilibrium properties of molecular liquids (pure solvents and electrolyte solutions) with the help of spatial pair correlation functions, starting from classical molecular pair interactions. The selection of potential models, especially the influence of molecular polarizability, is discussed as well as the limitations of the different methods of calculation of molecular pair correlation functions (e.g., from molecular and site-site Ornstein-Zernike theories, from MC and from MD simulations). We have performed simulations and integral equation calculations for spatial distribution functions in pure solvents with very low dielectric constants as dioxane and tetrahydrofurane, up to solvents with a very high dielectric constant like n-methylformamide. Ionic solvation is studied in pure solvent systems as well as in solvent mixtures. The general features of ion solvation and association, of the solvent structure around solutes, and their influence on solution properties, are discussed in the framework of the different theoretical approaches.
Polar solvation dynamics: A combination of the reference interaction-site model and mode-coupling theories
Authors: Nishiyama K. , Yamaguchi T. , Hirata Fumio , Okada T.
Published: October 2007

We employ the reference interaction-site model (RISM) theory for solvation dynamics of simple ions in acetonitrile. For the description of time evolution of solvent relaxation, we apply the mode-coupling theory recently developed by Yamaguchi and coworkers [Mol. Phys.
101, 1211 (2003)]. The combination of the RISM/mode-coupling theory is used for the calculation of the dynamic response function, SS(t), which measures the relaxation of average energy of the solute-solvent system. SS(t) decays with the Gaussian plus underdamped curves in the time duration of first 1 ps, followed by slow, long-tailed components down to tens of picoseconds. We show that the RISM/mode-coupling framework is applicable rather well for the detailed description of solvation dynamics at the molecular level.
Inelastic X-ray scattering and high-frequency dynamics of molecular liquids
Authors: Pontecorvo E. , Di Leonardo R. , Masciovecchio C. , Ruocco G. , Ruzicka B. , Scopigno T. , Sette F.
Published: October 2007

The recently developed inelastic X-ray scattering technique opens a new kinematic region at the observation of molecular liquids vibrational dynamics over the lengthscales of the interparticle separation. We illustrate the capabilities of this powerful technique through the results obtained from liquid glycerol. A detailed analysis of the high-frequency vibrational dynamics of this system at ambient temperature is reported. New results in the study of structural relaxational dynamics in the high-temperature range (up to T = 560 K) are also discussed.
Application of a compact synchrotron radiation facility to studies on the structure of solvated chloride and iodide ions in various solvents
Authors: Ozutsumi K. , Ohtaki H.
Published: October 2007

A beamline equipped on the compact superconductive synchrotron radiation (SR) facility at Ritsumeikan University was designed for performing extended X-ray absorption fine structure (EXAFS) analyses of solutions and solids. The introduction of three different crystals, Si(220), Ge(220), and InSb(111), as the monochromator of the EXAFS spectrometer covers the K-edge absorption energy range of elements with low atomic numbers from silicon (atomic number 14) through zinc (30). The LIII-edge of the iodide ion could be measured by Si(220) and Ge(220). It is, however, not possible to measure the absorption of the bromide ion with this equipment. Using this spectrometer, the solvation structure of Cl- and I- ions was investigated in water, methanol, and ethanol under atmospheric pressure.