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The endocrine system and toxicity

The endocrine system is one of the most common targets for toxicity and within the endocrine system the adrenal gland is the most common target organ for toxicity. There are few physiological processes not influenced by the function of this system, its constituent glands and hormones. Aberrant hormone secretion is implicated in adverse effects on processes as diverse as reproduction; all stages of development; carcinogenesis; inflammation; cardiovascular tone, electrolyte, glucose and water balance and basal metabolic rate to name a few. Consequently every organ, tissue and cell is affected to some extent by hormones. It is therefore of considerable importance to detect endocrine toxicity accurately and early in a toxicology programme, and due to the complexity of endocrine control, properly identify mechanisms of action to determine the relevance and strategic significance for compound development.

For example, a common finding in toxicology studies is enlarged adrenal (this may express as heavier adrenal weights and may translate into microscopically obvious cellular or zonal hypertrophy). Adrenocorticotrophic hormone (ACTH; corticotrophin) secretion from the pituitary is the major cause of enlarged adrenal, indeed the hormone was named because of its trophic effect on adrenal growth. In turn, there can be several reasons for excess ACTH secretion, from benign physiological stress-related mechanisms, through to the toxicologically significant loss of adrenal functionality and steroid production resulting in loss of pituitary feedback control. It is not possible to distinguish the mechanism by histopathology alone, and standard toxicology study designs do not allow mechanism identification. Expert evaluation of findings and, if necessary, specialist investigative study design, are required to elucidate the mechanism and significance of findings in the context of the overall regulatory development strategy of the compound.

Although tiered testing strategies are in place for the typical reproductive endpoints of current “endocrine disruptor” strategies (eg in vitro and in vivo assays for oestrogenicity, anti-androgens etc), regulatory agencies are increasingly questioning and demanding evidence for the mechanism of action of changes throughout the non-reproductive endocrine system seen in regulatory toxicology studies. Most commonly this has involved thyroid or adrenal function testing.

With over 30 years experience in industrial regulatory toxicology, and as an internationally recognised authority in endocrine toxicology (especially the adrenal and thyroid) Dr Harvey is uniquely placed to provide expert scientific input into endocrine toxicology problems in strategic regulatory development of novel compounds in the chemical, agrochemical and pharmaceutical sectors. Consultancy outputs include advice on data interpretation, relevance/significance of findings, design and monitoring of mechanistic studies, expert reports, and regulatory rebuttals.

Dr Harvey can be contacted at JSC International philip.harvey@jsci.co.uk.

Published 8th September 2015
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