Immune system endocrine function

Effects of the test substance on organ systems not investigated elsewhere should be assessed when there is a reason for concern. For example, dependency potential or skeletal muscle, immune and endocrine functions can be investigated. 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

Among vertebrate species, the neuro-endocrine-immime system is responsible for many complex, inter-related physiological processes including neuronal, homeostatic, reproductive and immune functions. There are four main types of hormone polypeptides, eicosanoids, steroids and thyroid hormones. Reflecting the inter-dependency of the neiiro-endocrine and immune systems, hormones, neuropeptides and other neiirotransmitters are known to be produced by some immune cells and play a role in the regulation of the immune system, while endocrine and nervous tissues express receptors for many substances produced by the immune system. The major focus of interest in endocrine disruption has... 

The circulatory system carries out many important functions that contribute to homeostasis. It obtains oxygen from the lungs nutrients from the gastrointestinal tract and hormones from the endocrine glands and it delivers these substances to the tissues that need them. Furthermore, it removes metabolic waste products, such as carbon dioxide, lactic acid, and urea, from the tissues. Finally, it contributes to the actions of the immune system by transporting antibodies and leukocytes to areas of infection. Overall, the circulatory system plays a vital role in maintenance of optimal conditions for cell and tissue function. 

Bone metabolism has quickly become a topic of fascinating research. The bone, far from being a metabolically inactive tissue, is a tissue where different cell types and different molecules carry out numerous and varied functions. This has been due largely to the discovery of the RANKL/RANK/OPG system of cytokines. These new molecules are decisive in OCS, bone metabolism, and bone loss, but they are also important for other tissues and cells. Indeed, these proteins are critical in several systems the immune system, where they have functions that affect cell survival and the immunomodulation of T-, B-, and dendritic cells the vascular system and the endocrine system. 

Bason CW, Colbom T. 1992. US. application and distribution of pesticides and industrial chemicals capable of disrupting endocrine and immune systems. In Chemically-Induced Alterations in Sexual and Functional Development The Wildlife/Human Connection, Vol XXI, M.A. Mehlman, Princeton Scientific Publishing Co. 

The ICH S7A guidance states that "supplemental" studies are meant to evaluate potential adverse pharmacodynamic effects on organ systems functions that are not acutely essential for the maintenance of human life and not addressed by the "core battery" or repeated dose toxicity studies when there is a cause for concern.25 Examples of physiological functions that fall into that category include, but are not limited to, the renal/urinary, immune, GI, endocrine and autonomic nervous systems. This section focuses on the renal and GI systems based on their potential impact on the clinical development program. 

In recent years, concern that chemicals might inadvertently be disrupting the endocrine system of humans and wildlife has increased. The concerns regarding exposure to these endocrine disrupters are based on adverse effects observed in certain wildlife, fish, and ecosystems increased incidences of certain endocrine-related human diseases and adverse effects observed in laboratory animals exposed to certain chemicals. The main effects reported in both wildlife and humans concern reproductive and sexual development and function altered immune system, nervous system, and thyroid function and hormone-related cancers. Endocrine dismption is not considered a toxicological endpoint in its own right, but a functional change or toxicological mode(s) of action that may lead to adverse effects. Endocrine dismpters are addressed further in Section 4.11. 

Indications or suspicions of effects on organ systems and functions that are especially vulnerable during development and maturation in early life (in particular the nervous, reproductive, endocrine, and immune systems and also the metabolic pathways) Experimental data on such effects in young animals are not available... 

The most important clinical application of glucocorticoids and their semisynthetic analogs is their anti-inflammatory activity, discovered in 1949 by Hench and co-workers. The profound anti-inflammatory effects of glucocorticoids arise from the combined effects of these steroids on both the cellular and molecular mediators of inflammation these effects are separate from the metabolic effects described above and further indication of the widespread diversity of macromolecules to which steroids can bind. Glucocorticoids suppress inflammation at the cellular level by downregulating the concentration, distribution, and function of leukocytes (white blood cells) that profoundly influence inflammation and response to infection within the body (In this way, steroids help to mediate the overlap between the endocrine systems [chapter 5] and the immune systems [chapter 6]). Glucocorticoids also suppress inflammation at the molecule level by suppressing inflammatory cytokines, chemokines, and other molecular mediators of inflammation. 

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