Lead Poisoning From Home-Prepared Indian Spices in 3 Families.

Spice consumption, along with other environmental factors, can contribute to pediatric lead poisoning. Although public health efforts have increased awareness of contamination of spices, false assumptions regarding the safety of home-prepared spices have emerged. Here, we present the clinical features, family beliefs, and environmental toxicology of 3 spice-associated pediatric lead poisoning cases.

Endocrine profiling and prioritization of environmental chemicals using ToxCast data.

BACKGROUND: The prioritization of chemicals for toxicity testing is a primary goal of the U.S. Environmental Protection Agency (EPA) ToxCast™ program. Phase I of ToxCast used a battery of 467 in vitro, high-throughput screening assays to assess 309 environmental chemicals. One important mode of action leading to toxicity is endocrine disruption, and the U.S. EPA's Endocrine Disruptor Screening Program (EDSP) has been charged with screening pesticide chemicals and environmental contaminants for their potential to affect the endocrine systems of humans and wildlife. OBJECTIVE: The goal of this study was to develop a flexible method to facilitate the rational prioritization of chemicals for further evaluation and demonstrate its application as a candidate decision-support tool for EDSP. METHODS: Focusing on estrogen, androgen, and thyroid pathways, we defined putative endocrine profiles and derived a relative rank or score for the entire ToxCast library of 309 unique chemicals. Effects on other nuclear receptors and xenobiotic metabolizing enzymes were also considered, as were pertinent chemical descriptors and pathways relevant to endocrine-mediated signaling. RESULTS: Combining multiple data sources into an overall, weight-of-evidence Toxicological Priority Index (ToxPi) score for prioritizing further chemical testing resulted in more robust conclusions than any single data source taken alone. CONCLUSIONS: Incorporating data from in vitro assays, chemical descriptors, and biological pathways in this prioritization schema provided a flexible, comprehensive visualization and ranking of each chemical's potential endocrine activity. Importantly, ToxPi profiles provide a transparent visualization of the relative contribution of all information sources to an overall priority ranking. The method developed here is readily adaptable to diverse chemical prioritization tasks.

The endocrine effects of mercury in humans and wildlife.

Mercury (Hg) is well studied and research continues as our knowledge of its health risks increases. One expanding area of research not well emphasized to date is the endocrine effects of Hg. This review summarizes the existing literature on the effects of Hg on the endocrine system and identifies gaps in the knowledge. It focuses on the thyroid, adrenal, and reproductive systems, including the accumulation of Hg in the endocrine system, sex differences that are manifested with Hg exposure, reproductive effects in male and female animals including humans, and Hg effects on the thyroid and adrenal systems. We concluded that there are five main endocrine-related mechanisms of Hg across these systems: (a) accumulation in the endocrine system; (b) specific cytotoxicity in endocrine tissues; (c) changes in hormone concentrations; (d) interactions with sex hormones; and (e) up-regulation or down-regulation of enzymes within the steroidogenesis pathway. Recommendations for key areas of research to better understand how the endocrine effects of Hg affect human and wildlife health were developed, and include increasing the amount of basic biological information available about Hg and wildlife species, exploring the role of Hg in the presence of other stressors and chemicals, understanding sublethal and indirect effects of Hg on adverse outcomes, developing better methods to extrapolate effects across species, and understanding the effects of Hg on multiple organ systems following exposure of an animal. Greater inclusion of endocrine endpoints in epidemiological and field studies on humans and wildlife will also advance the research in this area.

History and genesis of the detailed review of thyroid hormone disruption assays.

This issue presents the detailed review paper (DRP) on thyroid hormone disruption assays that was prepared for the Organization for Economic Cooperation and Development (OECD) and that exists as an OECD monograph. However, this document is now available here in one issue of Critical Reviews in Toxicology as a series of published articles. The original document has been modified in several ways. First, an overview (now article 2) was added to discuss how new data and new directions for thyroid research will play an important role in shaping thyroid assays as they evolve. Second, each of the original chapters of the thyroid DRP have been separated into individual papers. The appendices of the original DRP were removed and will be merged and published separately.

Integrating basic research on thyroid hormone action into screening and testing programs for thyroid disruptors.

Thyroid hormone signaling is highly conserved among all the vertebrates, and appears to be present in some invertebrates. Both the components that comprise the system and its general role in development and physiology are evolutionarily conserved, although specific events regulated by thyroid hormones, such as amphibian metamorphosis, may differ among taxonomic groups. The articles in this issue review the thyroid systems of mammals (specifically humans and rodents), fish, amphibians, and birds, and the states of the assays and endpoints used to detect disruption of the thyroid system within a toxicological paradigm. It must be noted that while reptiles represent an enormously important group, they were excluded because there was not enough information in the literature on thyroid toxicology in reptiles at the time that this series of reviews was drafted. Each review highlights the best assays for current regulatory use and those that may be considered for development for future use and research. However, it is important to remember that thyroid research is moving ahead at a fast pace. New thyroid research will impact the design of future thyroid assays used for the detection of thyroid system disruption in ways that may not be anticipated at the time of this writing. Several new areas of exploration are discussed that reveal potential sites of disruption in the thyroid system, including (1) the importance of the neural drive for TSH upregulation, (2) thyroid hormone transport, including cellular transporters like monocarboxylate anion transporter 8 (MCT8) that can regulate thyroid hormone action at the cellular level, and thyroid hormone-binding proteins in the serum that have been shown to differentially bind to environmental chemicals (e.g., certain PCB congeners), and (3) the deiodinases as a target for disruption of thyroid hormone activity in the peripheral thyroid system. The review papers in this issue represent the current state of thyroid assays and endpoints for detection of chemicals that disrupt the thyroid system.

General background on the hypothalamic-pituitary-thyroid (HPT) axis.

This article reviews the thyroid system, mainly from a mammalian standpoint. However, the thyroid system is highly conserved among vertebrate species, so the general information on thyroid hormone production and feedback through the hypothalamic-pituitary-thyroid (HPT) axis should be considered for all vertebrates, while species-specific differences are highlighted in the individual articles. This background article begins by outlining the HPT axis with its components and functions. For example, it describes the thyroid gland, its structure and development, how thyroid hormones are synthesized and regulated, the role of iodine in thyroid hormone synthesis, and finally how the thyroid hormones are released from the thyroid gland. It then progresses to detail areas within the thyroid system where disruption could occur or is already known to occur. It describes how thyroid hormone is transported in the serum and into the tissues on a cellular level, and how thyroid hormone is metabolized. There is an in-depth description of the alpha and beta thyroid hormone receptors and their functions, including how they are regulated, and what has been learned from the receptor knockout mouse models. The nongenomic actions of thyroid hormone are also described, such as in glucose uptake, mitochondrial effects, and its role in actin polymerization and vesicular recycling. The article discusses the concept of compensation within the HPT axis and how this fits into the paradigms that exist in thyroid toxicology/endocrinology. There is a section on thyroid hormone and its role in mammalian development: specifically, how it affects brain development when there is disruption to the maternal, the fetal, the newborn (congenital), or the infant thyroid system. Thyroid function during pregnancy is critical to normal development of the fetus, and several spontaneous mutant mouse lines are described that provide research tools to understand the mechanisms of thyroid hormone during mammalian brain development. Overall this article provides a basic understanding of the thyroid system and its components. The complexity of the thyroid system is clearly demonstrated, as are new areas of research on thyroid hormone physiology and thyroid hormone action developing within the field of thyroid endocrinology. This review provides the background necessary to review the current assays and endpoints described in the following articles for rodents, fishes, amphibians, and birds.

Current and potential rodent screens and tests for thyroid toxicants.

This article reviews current rodent screens and tests to detect thyroid toxicants. Many points of disruption for thyroid toxicants are outlined and include: (a) changes in serum hormone level; (b) thyroperoxidase inhibitors; (c) the perchlorate discharge test; (d) inhibitors of iodide uptake; (e) effects on iodothyronine deiodinases; (f) effects on thyroid hormone action; and (g) role of binding proteins (e.g., rodent transthyretin). The major thyroid endpoints currently utilized in existing in vivo assay protocols of the Organization for Economic Cooperation and Development (OECD), Japanese researchers, and U.S. Environmental Protection Agency (EPA) include thyroid gland weight, histopathology, circulating thyroid hormone measurements, and circulating thyroid-stimulating hormone (TSH). These endpoints can be added into the existing in vivo assays for reproduction, development, and neurodevelopment that are outlined in this chapter. Strategic endpoints for possible addition to existing protocols to detect effects on developmental and adult thyroid endpoints are discussed. Many of these endpoints for detecting thyroid system disruption require development and additional research before they can be considered in existing assays. Examples of these endpoints under development include computer-assisted morphometry of the brain and evaluation of treatment-related changes in gene expression, thyrotropin-releasing hormone (TRH) and TSH challenge tests, and tests to evaluate thyroid hormone (TH)-dependent developmental events, especially in the rodent brain (e.g., measures of cerebellar and cortical proliferation, differentiation, migration, apoptosis, planimetric measures and gene expression, and oligodendrocyte differentiation). Finally, TH-responsive genes and proteins as well as enzyme activities are being explored. Existing in vitro tests are also reviewed, for example, thyroid hormone (TH) metabolism, receptor binding, and receptor activation assays, and their restrictions are described. The in vivo assays are currently the most appropriate for understanding the potential effects of a thyroid toxicant on the thyroid system. The benefits and potential limitations of the current in vivo assays are listed, and a discussion of the rodent thyroid system in the context of human health is touched upon. Finally, the importance of understanding the relationship between timing of exposure, duration of dose, and time of acquisition of the endpoints in interpreting the results of the in vivo assays is emphasized.

Implications of research on assays to characterize thyroid toxicants.

Many aspects of thyroid endocrinology are very well conserved across vertebrate taxa. These aspects include thyroid hormone chemistry, the mechanism of its synthesis, and the proteins involved in these processes. In addition, the system by which the hormone is delived from the thyroid gland to target cells, including transport and regulation within the hypothalamic-pituitary-thyroid (HPT) axis, and the proteins that regulate the different components of this delivery system appear to be highly conserved across the vertebrates. Finally, the receptors that mediate thyroid hormone action and the roles thyroid hormone plays are very similar among the vertebrates. Thus, the goal of this chapter is to provide a brief synopsis of the literature supporting existing screening and testing strategies in different vertebrate taxa, and to provide insight into the strengths, weaknesses, and likely changes over time. It was determined during this review that, because of the complexity of the thyroid system, it is unlikely that current in vitro assays for thyroid toxicity will be able to sufficiently replace in vivo assays for thyroid toxicants. However, the in vitro assays serve an important purpose in providing mode of action information and could provide potential screening tools, and should continue to be developed for use. Moreover, because in vivo assays are added on to preexisting reproductive or developmental screens and tests, there are no additional animals required for the in vivo assays. Specific in vitro assays were identified for development, including the thyroid receptor binding and activation assays, and in vitro assays to evaluate thyroid hormone action. Some in vivo endpoints suggested for further research included neuronal differentiation and migration, measures of histogenesis, and measures for thyroid gland thyroid hormone content, which may be more sensitive indicators of TSH stimulation. The most commonly used endpoints currently used to monitor thyroid function are thyroid hormone levels (T3 and T4), TSH, thyroid gland weight, and thyroid histology. Thyroid endocrinology is rapidly advancing and new discoveries will certainly warrant incorporation into future assays. The development of additional endpoints that measure thyroid hormone's actions peripheral to the HPT axis and the development of new reagents for nonmammalian vertebrate species will significantly improve the ability of today's assays to detect chemicals that disrupt the thyroid system in multiple vertebrate species. It is our hope that this series of thyroid articles will provide regulators and research scientists the information needed for each individual to identify the assays and endpoints most suited for their specific purposes.