For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from...

/pdf/hormones-and-endocrine-disrupting-chemicals-low-dose-effects-2vn32zoqc8.pdf

Hormones and endocrine-disrupting chemicals: Low-dose effects and nonmonotonic dose responses

https://apps.who.int/iris/bitstream/10665/78102/1/WHO_HSE_PHE_IHE_2013.1_eng.pdf

State of the Science of Endocrine Disrupting Chemicals - 2012

Phenotypic development is the result of a complex interplay involving the organism’s own genetic make-up and the environment it experiences during development. The latter encompasses not just the current environment, but also indirect, and sometimes lagged, components that result from environmental effects on its parents that are transmitted to their developing offspring in various ways and at various stages. These environmental effects can simply constrain development, for example, where poor maternal condition gives rise to poorly provisioned, low-quality offspring. However, it is also possible that environmental circumstances during development shape the offspring phenotype in such a way as to better prepare it for the environmental conditions it is most likely to encounter during its life. Studying the extent to which direct and indirect developmental responses to environmental effects are adaptive requires clear elucidation of hypotheses and careful experimental manipulations. In this paper, I outline how the different paradigms applied in this field relate to each other, the main predictions that they produce and the kinds of experimental data needed to distinguish among competing hypotheses. I focus on birds in particular, but the theories discussed are not taxon specific. Environmental influences on phenotypic development are likely to be mediated, in part at least, by endocrine systems. I examine evidence from mechanistic and functional avian studies and highlight the general areas where we lack key information.

http://behav.zoology.unibe.ch/sysuif/uploads/files/esh/CUSO_LIT/Monaghan_PhilTrans2008.pdf

Early growth conditions, phenotypic development and environmental change.

Mercury exists naturally and as a man-made contaminant. The release of processed mercury can lead to a progressive increase in the amount of atmospheric mercury, which enters the atmospheric-soil-water distribution cycles where it can remain in circulation for years. Mercury poisoning is the result of exposure to mercury or mercury compounds resulting in various toxic effects depend on its chemical form and route of exposure. The major route of human exposure to methylmercury (MeHg) is largely through eating contaminated fish, seafood, and wildlife which have been exposed to mercury through ingestion of contaminated lower organisms. MeHg toxicity is associated with nervous system damage in adults and impaired neurological development in infants and children. Ingested mercury may undergo bioaccumulation leading to progressive increases in body burdens. This review addresses the systemic pathophysiology of individual organ systems associated with mercury poisoning. Mercury has profound cellular, cardiovascular, hematological, pulmonary, renal, immunological, neurological, endocrine, reproductive, and embryonic toxicological effects.

/pdf/environmental-mercury-and-its-toxic-effects-4es4isc9e9.pdf

Environmental Mercury and Its Toxic Effects

There is growing evidence that environmental chemicals can disrupt endocrine systems Most evidence originates from studies on reproductive organs However, there is also suspicion that thyroid homeostasis may be disrupted Several groups of chemicals have potential for thyroid disruption There is substantial evidence that polychlorinated biphenyls, dioxins and furans cause hypothyroidism in exposed animals and that environmentally occurring doses affect human thyroid homeostasis Similarly, flame retardants reduce peripheral thyroid hormone (TH) levels in rodents, but human studies are scarce Studies also indicate thyroid-disruptive properties of phthalates, but the effect of certain phthalates seems to be stimulative on TH production, contrary to most other groups of chemicals Thyroid disruption may be caused by a variety of mechanisms, as different chemicals interfere with the hypothalamic-pituitary-thyroid axis at different levels Mechanisms of action may involve the sodium-iodide symporter, thyroid peroxidase enzyme, receptors for THs or TSH, transport proteins or cellular uptake mechanisms The peripheral metabolism of the THs can be affected through effects on iodothyronine deiodinases or hepatic enzymes Even small changes in thyroid homeostasis may adversely affect human health, and especially fetal neurological development may be vulnerable It is therefore urgent to clarify whether the animal data showing effects of chemicals on thyroid function can be extended to humans

/pdf/environmental-chemicals-and-thyroid-function-1qd1i2eam1.pdf

Environmental chemicals and thyroid function

This article reviews thyroid function and its hypothalamic-pituitary-thyroid (HPT) axis control in birds with emphasis on the similarities and differences in thyroid function compared to mammals and other vertebrate classes. Thyroid hormones are important in metabolism and the thermogenesis required for homeothermy in birds, as in mammals, the other homeothermic class of vertebrates. Thyroid hormones play important roles in development and growth in birds, as is the case for all vertebrate classes. The developmental effects of thyroid hormones in birds are presented in the context of differences in precocial and altricial patterns of development and growth with emphasis on oviparous development. The sections on thyroid hormone actions include discussion of effects on the development of a number of tissue types as well as on seasonal organismal processes and interactions of the thyroid axis with reproduction. The current picture of how environmental chemicals may disrupt avian thyroid function is relatively limited and is presented in the context of the assessment endpoints that have been used to date. These endpoints are categorized as thyroid and HPT axis endpoints versus target organ endpoints. The final section discusses two recommended assay protocols, the avian two-generation toxicity assay and the avian one-generation assay, and whether these protocols can evaluate thyroid disruption in birds.

The hypothalamic-pituitary-thyroid (HPT) axis in birds and its role in bird development and reproduction.

Much of the research on sublethal, adverse effects of mercury (Hg) has focused on impairment of neurological function and reproduction in fish and fish-eating vertebrates. Here we examined the associations between Hg and endocrine function (adrenocortical responses and plasma thyroid hormone concentrations) of insectivorous tree swallow nestlings adjacent to a Hg-contaminated river and nearby reference rivers in Virginia. Nestlings from the contaminated sites had blood Hg concentrations that exceeded those from the reference sites by more than an order of magnitude (354 ± 22 vs 17 ± 1 ppb wet weight). A regression of age and Hg concentrations suggested dietary Hg at the contaminated sites exceeded the nestlings’ capacity to eliminate Hg through deposition into growing feathers. Although blood Hg concentrations among nestlings at the contaminated sites were lower than those typically associated with abnormal behavior or altered physiology in young birds, adrenocortical responses, plasma triiodothyronine, a...

F.M.Anne McNabb

Papers

The hypothalamic-pituitary-thyroid (HPT) axis in birds and its role in bird development and reproduction.

Suppressed adrenocortical responses and thyroid hormone levels in birds near a mercury-contaminated river.

Maternal Thyroid Hormones in Japanese Quail Eggs and Their Influence on Embryonic Development

17 – Thyroid Hormone Effects on Growth, Development, and Metabolism

Avian thyroid development and adaptive plasticity.