Published by De Gruyter

Volume 75 Issue 11-12

Issue of Pure and Applied Chemistry

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Contents
Journal Overview

Most research to identify endocrine-disrupting chemicals and their impacts has relied on mammalian models or in vitro systems derived from them. But nuclear receptors (NRs), the proteins that transduce hydrophobic hormonal signals and are major mediators of endocrine disruption, emerged early in animal evolution and now play biologically essential roles throughout the Metazoa. Nonmammalian vertebrates and invertebrates, many of which are of considerable ecological, economic, and cultural importance, are therefore potentially subject to endocrine disruption by synthetic environmental pollutants. Are methods that rely solely on mammalian models adequate to predict or detect all chemicals that may disrupt NR signaling? Regulation of NRs by small hydrophobic molecules is ancient and evolutionarily labile. Within and across genomes, the NR superfamily is very diverse, due to many lineage-specific gene and genome duplications followed by independent divergence. Receptors in nonmammalian species have in many cases evolved unique molecular and organismal functions that cannot be predicted from those of their mammalian orthologs. Endocrine disruption is therefore likely to occur throughout the metazoan kingdom, and a significant number of the thousands of synthetic chemicals now in production may disrupt NR signaling in one or more nonmammalian taxa. Many of these endocrine disruptors will not be detected by current regulatory/scientific protocols, which should be reformulated to take account of the diversity and complexity of the NR gene family.

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.

The term "environmental estrogen" refers to chemical substances that exhibit some degree of estrogen-like activity. The primary emphasis for potential adverse effects resulting from exposure to environmental estrogens is on in utero exposure because such exposure can occur during critical periods of organogenesis. Assessment of biological plausibility can be based, in part, on the extensive data on the effects of diethylstilbestrol (DES). The available evidence is too limited to judge with any confidence whether sperm counts have declined during the past 50 years. Based on both animal and human data with DES, it is biologically plausible that in utero exposures to exogenous estrogenic compounds are capable of reducing sperm production in adult men. However, the apparent existence of a maternal dose threshold for DES-induced effects on sperm counts undermines the likelihood that environmental estrogens, which are substantially less potent, are capable of causing similar effects.

Probably the only thing that can be said with certainty about the future of this field of ecotoxicology is that predicting it is foolish; the chances of being right are very slim. Instead, it seems to me likely that unexpected discoveries will probably have more influence on the field of endocrine disruption than the outcomes of all the planned experiments. It is certainly true that chance discoveries, such as masculinized fish in rivers receiving paper-mill effluent, imposex in molluscs due to exposure to tributyltin and feminized fish in rivers receiving effluent from sewage-treatment works, have been pivotal in the development of the field of endocrine disruption in wildlife. I consider that further such discoveries are likely, but I do not know which species will be affected, what effects will be found, what chemical(s) will be the cause, or what endocrine mechanism(s) will underlie the effects. The recent realization that many pharmaceuticals are present in the aquatic environment only underscores the range of effects that could, in theory at least, occur in exposed wildlife. What is somewhat easier to predict is the research that will be conducted in the immediate future, which will build upon what is known already. For example, it is clear that wildlife is rarely, if ever, exposed to single chemicals, but instead is exposed to highly complex, ill-defined mixtures of chemicals, including many that are endocrine active in various ways. We need to understand much better how chemicals interact, and what overall effects will occur upon exposure to such mixtures. We also need to move from assessing effects at the individual organism level, to understanding the consequences of these effects at the population level. Then, we need to determine the significance of any population-level effects due to endocrine disruption in comparison with the impact of many other significant stressors (e.g., over-exploitation, habitat loss, climate change) that also negatively impact wildlife. Such research will be difficult, and time-consuming, and will probably produce many surprises. All I can be fairly certain about is that the next few years are likely to be as interesting and exciting as the last few have been.

We examined the published data for the binding affinity of typical ligands to the α-subtype of the human estrogen receptor with use of an approximate molecular orbital method applicable to interacting molecular clusters. An ab initio procedure for "molecular fragments" proposed recently to deal with such macromolecules as proteins was applied to the molecular orbital calculations. The receptor protein was primarily modeled using 50 amino acid residues surrounding the ligand. For a few ligand-receptor complexes, the binding energy was also calculated with use of 241 amino acid residues contained in the entire binding domain. No significant difference was found in the calculated binding energy between the complex modeled with ligand-surrounding 50 amino acids and that with residues of the entire domain. The calculated binding energy was correlated very well with the published relative binding affinity for typical ligands.

The use of gene expression data in predictive and mechanistic toxicology is hindered by a lack of information on the relationships between transcriptional events and physiological and pathological changes. We discuss the analysis of these relationships using the rodent uterotrophic response as a model experimental system for estrogen-induced uterine growth.

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.

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.

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.

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.

About this journal

Since 1960, the International Union of Pure and Applied Chemistry (IUPAC) has made available to chemists everywhere a large amount of important chemical information published in the journal Pure and Applied Chemistry.

We are sad to announce the passing of Hugh Burrows, Editor-in-Chief of PAC between 2014-2022, and offer our deepest condolences to his family and friends. Hugh passed away surrounded by his loved ones on March 12, 2023. He left a big gap in our community and will be sorely missed. To honor Hugh's many contributions to IUPAC and our journal we plan to publish a more extensive obituary in the next issue of PAC. Please join us for a minute of silence dedicated to Hugh.

In 2020 we celebrated Pure and Applied Chemistry's 60th anniversary!
As part of these celebrations, we are offering free access to the virtual issue of PAC: 60 seminal papers published in PAC over the past 60 years

Pure and Applied Chemistry is the official monthly Journal of IUPAC, with responsibility for publishing works arising from those international scientific events and projects that are sponsored and undertaken by the Union. The policy is to publish highly topical and credible works at the forefront of all aspects of pure and applied chemistry, and the attendant goal is to promote widespread acceptance of the Journal as an authoritative and indispensable holding in academic and institutional libraries.

The objectives of the Journal are:

to publish papers based upon authoritative lectures presented at IUPAC sponsored conferences, symposia and workshops.
to publish papers or collections of papers by invitation, as special topic features.
to publish IUPAC Recommendations on nomenclature, symbols and units.
to publish IUPAC Technical Reports on standardization, recommended procedures, collaborative studies, data compilations, etc.