Adrenal toxicology: a strategy for assessment of functional toxicity to the adrenal cortex and steroidogenesis.

The adrenal is the most common toxicological target organ in the endocrine system in vivo and yet it is neglected in regulatory endocrine disruption screening and testing. There has been a recent marked increase in interest in adrenal toxicity, but there are no standardised approaches for assessment. Consequently, a strategy is proposed to evaluate adrenocortical toxicity. Human adrenal conditions are reviewed and adrenocortical suppression, known to have been iatrogenically induced leading to Addisonian crisis and death, is identified as the toxicological hazard of most concern. The consequences of inhibition of key steroidogenic enzymes and the possible toxicological modulation of other adrenal conditions are also highlighted. The proposed strategy involves an in vivo rodent adrenal competency test based on ACTH challenge to specifically examine adrenocortical suppression. The H295R human adrenocortical carcinoma cell line is also proposed to identify molecular targets, and is useful for measuring steroids, enzymes or gene expression. Hypothalamo-pituitary-adrenal endocrinology relevant to rodent and human toxicology is reviewed (with an emphasis on multi-endocrine axis effects on the adrenal and also how the adrenal affects a variety of other hormones) and the endocrinology of the H295R cell line is also described. Chemicals known to induce adrenocortical toxicity are reviewed and over 60 examples of compounds and their confirmed steroidogenic targets are presented, with much of this work published very recently using H295R cell systems. In proposing a strategy for adrenocortical toxicity assessment, the outlined techniques will provide hazard assessment data but it will be regulatory agencies that must consider the significance of such data in risk extrapolation models. The cases of etomindate and aminoglutethimide induced adrenal suppression are clearly documented examples of iatrogenic adrenal toxicity in humans. Environmentally, sentinel species, such as fish, have also shown evidence of adrenal endocrine disruption attributed to exposure to chemicals. The extent of human sub-clinical adrenal effects from environmental chemical exposures is unknown, and the extent to which environmental chemicals may act as a contributory factor to human adrenal conditions following chronic low-level exposures will remain unknown unless purposefully studied.