Adrenal Toxicology: Molecular Targets, Endocrine Mechanisms, Hormonal Interactions, Assessment Models, and Species Differences in Toxicity
The adrenal gland is the most common toxicological target in the endocrine system (Colby and Longhurst, 1992; Ribelin, 1984; Rosol et al., 2001). In surveys based on in vivo toxicology studies, the order of endocrine organ toxicity by frequency of reported effects was adrenal testes thyroid ovary pancreas pituitary parathyroid (Colby and Longhurst, 1992; Ribelin, 1984) with the adrenal cortex, rather than the medulla, being the most frequent site of toxicity within the adrenal gland. Despite this, there has been a lack of recognition of the importance of adrenal function in a regulatory endocrine disruption evaluation context, and the need for an adrenal toxicology assessment strategy has been pointed out (Harvey and Everett, 2003; Harvey and Everett, 2006; Harvey and Johnson, 2002; Harvey et al., 2007; Hinson and Raven, 2006; Oskarsson et al., 2006). The lack of a regulatory strategy is surprising, given the experience in human medicine of the impact of adrenocortical suppression due to unrecognized drug side effects, the emerging evidence of the large range of compounds that produce adrenocortical toxicity, and also because environmental sentinel species, such as fish and birds, are showing evidence of adrenal dysfunction (Baos et al., 2006; Bisson and Hontela,
2002; Champoux et al., 2006; Dorval et al., 2005; Hontela et al., 1992; Norris et al., 1999; Quabius et al., 1997). Further, adrenocortical function is also known to modulate the response to, and tolerance of, toxic insult (Harvey et al., 1999; Harvey et al., 1994; Harvey, 1996a; Harvey, 1996b) and indeed glucocorticoid production is the single most important physiological response for survival of an organism postinfection or injury (Munck et al., 1984), including the stress resulting from chemical intoxication. Any impairment of this response is detrimental to health, and potentially, survival.