This is a review of the research into endocrine effects of noise since the early 1980s at the Institute for Water, Soil and Air Hygiene. According to our knowledge, no other group has studied systematically the endocrine effects of acute and chronic noise exposure. Mechanisms of acute noise-induced stress reactions as well as long-term increase of stress hormones in animal and persons under chronic noise exposure were studied. Our theoretical background was Henry's psychophysiological stress model with the two reaction alternatives : (i) The fight­flight reaction, characterised by an increase in adrenalin and noradrenaline (ii) The defeat reaction with increased cortisol. Extremely intense acute noise exposure near the threshold of pain caused an increased release of cortisol from the suprarenal cortex but acute noise exposure with levels between 90 and 100 dB(A) caused an increase of catecholamines. Non­habituated noise increased primarily the release of adrenalin from the suprarenal medulla, whereas habituated noise caused a chronic increase of noradrenaline from the sympathetic synapses under longterm noise exposure at work. Environmental noise exposure (Leq > 60 dB(A)) caused catecholamine increase if activities such as conversation, concentration, recreation etc were disturbed through noise. In sleeping persons, traffic noise with only Leq > 30 dB (A) and Lmax > 55 dB(A) caused significant acute increase of cortisol, which developed into chronic increase if the noise exposure was repeated consistently. Parallel to cortisol, chronic noradrenaline increase was also observed. Based upon the empirical results, a noise stress model was developed which is a first step forward in the theoretical understanding of endocrine noise effects.

The hypothalamo-pituitary-adrenal (HPA) system is a most important mediator of the organism's response to stress. Secretory activity of this endocrine system displays a specific regulation during normal nocturnal sleep in humans. Pituitary release of adrenocorticotropin (ACTH) as well as adrenocortical release of cortisol decreases to a minimum during early sleep which is simultaneously characterized by maximum release of growth hormone (GH) and a predominance of slow wave sleep (SWS). In contrast, release of ACTH and cortisol reaches a maximum during late sleep which is simultaneously characterized by minimum plasma concentrations of GH and a predominance of rapid eye movement (REM) sleep. The nadir activity of the pituitary-adrenal system during early sleep reflects an active inhibition of this 'stress' system. One of the factors mediating this inhibition presumably is the sleep associated hypothalamic secretion of a release inhibiting factor of ACTH. In addition, limbic­hippocampal neuronal networks contribute to the inhibitory control over HPA activity during early sleep. Those structures appear to coordinate HPA inhibition and cortical activity (with prevalent SWS) during early sleep, thereby facilitating the formation of memories in sleep. As indicated by studies testing the effects of elevated plasma glucocorticoid levels, the inhibition of HPA activity during early sleep is an essential prerequisite for the memory function of sleep. Possibly, immunological memory formation likewise benefits from this inhibition. The suppression of pituitary-adrenal secretory activity during early sleep can be significantly weakened after profound acute stress as well as in states of chronic stress (including normal aging) which thereby disturb regular memory formation in sleep.

The clinical correlate of chronic hypercortisolism is Cushing's syndrome (CS). After exclusion of an iatrogenic cause (glucocorticoid administration), two reliable laboratory methods for establishing the diagnosis are (i) measurement of "free" (unmetabolised) cortisol in a 24-hour urine (UFC) sample and (ii) the low-dose (1 or 1.5 mg) dexamethasone (Dex) test. For the latter, Dex is taken orally at midnight, and plasma cortisol is measured at 8 a.m. In normals and in the absence of CS, the morning cortisol (200-650 nmol/L) is suppressed to <80 nmol/L. In endogenous CS of all causes, cortisol suppression by Dex is absent or incomplete. In patients with severe mental depression or stress, suppression may also be incomplete ("false­positives"). However, UFC is normal or only slight increased in the latter group, while it is always markedly increased in clinically apparent CS. In CS, UFC rises proportionally more than plasma cortisol because the cortisol binding plasma protein (transcortin) can bind only about 500 nmol/L cortisol. Protein-bound cortisol is not excreted by the kidney. After establishing the diagnosis CS, the differentiation between its pituitary (ca. 70%), adrenocortical (ca. 20%) or "ectopic" (ACTH production by non-pituitary tumours) (ca. ^10%) origin is made by plasma ACTH measurement, a corticotropin releasing hormone injection test (with plasma ACTH/cortisol measurement) and a high-dose Dex (8 mg or more) suppression test. Chronic hypocorticolism can be primary (adrenal disease, Addison's disease) or secondary (pituitary or hypothalamic disorder). UFC measurement is not an established method for confirming hypocortisolism because most analytical methods are too unspecific and insensitive in the subnormal range. Low-normal or subnormal plasma cortisol plus elevated ACTH is the hallmark of Addison's disease. Injection of high doses of ACTH does not lead to a rise in plasma cortisol in these patients. A clearly subnormal cortisol plus low ACTH proves secondary hypocortisolism. Mild forms with low-normal plasma cortisol, however, are more difficult to prove. So-called "dynamic" tests stimulating the whole hypothalamo-pituitary­adrenal axis (insulin hypoglycemia test or metyrapone test) are necessary to confirm the diagnosis. Patients with hypocortisolism, depending on disease severity, must be treated permanently or only in stressful situations with hydrocortisone unless they may die after passing the clinical state of an "adrenal crisis".

Connections between thalamic structures of the auditory system and subcortical areas (amygdala, hippocampus, hypothalamus) had been hypothesized to act as a fast reacting "memory chain" establishing and enhancing adverse excitations during noise exposure. Recent studies prove that the lateral amygdala is an important part of a second separate pathway to the telencephalic projections of the auditory system. This fast, monosynaptic thalamo-amygdala tract is responsible for full-blown "fear responses" evoked by auditory stimuli as shownd by several conditioning experiments in animals: A fear memory system. The appertaining basic processes of plasticity in the amygdala are reductions of latencies of neuronal excitations and recruiting of more elements with shorter latency, long-term potentiation causing enhancement of auditory- evoked responses by repeated stimulation, as well as sharpening of primary broad tuning curves of elements. Very recently a study using Functional-Magnetic-Resonance-Imaging (fMRI) demonstrated that an amygdalar contribution to conditioned fear learning can be revealed in normal human subjects too. These findings were supported by Positron-Emission-Tomography (PET) studies in depressive persons showing that amygdala metabolic abnormality predicted the cortisol concentration in blood. Using connections via central amygdala, lateral and medial hypothalamus to parts named nuclei paraventriculares and regio arcuata, the sound evoked excitations reach two essential components of endocrine functioning: a) the well-known hypothalamic-pituitary-adrenal (HPA) system with a subsequent rise (via Corticotropin-Releasing Hormone: CRH) in Corticotropin (Adreno-CorticoTropin Hormone: ACTH) and the corticosterone levels; b) the synthesis of ACTH and beta-endorphine-like substances in the arcuate region being axonally transported to extrahypothalamic brain regions. Longer-lasting activation of the HPA-axis, especially abnormally increased or periodically elevated levels of cortisol and the widespread extrahypothalamically distributed CRF/ACTH may lead to disturbed hormonal balance and even to severe diseases.

The auditory system is permanently open - even during sleep. Its quick and overshooting excitations caused by noise signals are subcortically connected via the amygdala to the hypothalamic-pituitary-adrenal-axis (HPA-axis). Thus noise causes the release of different stress hormones (e.g. corticotropin releasing hormone: CRH; adrenocorticotropic hormone: ACTH) especially in sleeping persons during the vagotropic night/early morning phase. These effects occur below the waking threshold of noise and are mainly without mental control. Animal experiments show noise-induced changes in sensitivity of cellular cortisol receptors by increase of heat-shock proteins, and ultrastructural changes in the tissue of the heart and the adrenal gland. Increased cortisol levels have been found in humans when exposed to aircraft noise or road traffic noise during sleep. The effects of longer-lasting activation of the HPA-axis, especially long term increase of cortisol, are manifold: immuno suppression (e.g. eosinopenia), insulin resistance (e.g. diabetes), cardiovascular diseases (e.g. hypertension and arteriosclerosis), catabolism (e.g. ostoeporosis), intestinal problems ( e.g. stress ulcer) etc. Even worse may be the widespread extrahypothalamical effects of CRH/and/or ACTH which have the potential to influence nearly all regulatory systems, causing for example stress­dysmenorrhea etc. as signs of disturbed hormonal balance.

In this paper we discuss the risk of myocardial infarction induced by traffic noise within the conceptual framework for risk assessment suggested by the US National Research Council. The characterisation of cardiovascular risk is evaluated using a four-dimensional set of evaluation criteria: severity of health effect, frequency of exposures considered relevant for health, size of estimated risk, and validity of risk assessment. For quantification of risk we calculated lifetime risks using standard methods applied for quantitative cancer risk estimation. In evaluation of validity we refer to criteria that the International Agency for Research on Cancer has developed for classification of epidemiological evidence. Compared to other adverse effects regarded in regulatory toxicology, myocardial in-farction is a severe health effect. Assuming that sound pressure levels Leq, 6-22 hr above 65 dB(A) are associated with an increased cardiovascular risk, a major portion of the German population (about 16 %) is exposed to health relevant noise levels. Estimated lifetime risk amounts to 20 :1,000 and exceeds considerably the lifetime risk induced by other environmental hazards or tolerable risk levels suggested in other contexts. A causal association between noise exposure and infarction risk, however, cannot be taken as proven scientifically, because chance, bias or con-founding cannot be ruled out with reasonable confidence. Methodological quality of the studies performed, consistency of findings, dose-response relations, coherence with a recent occupational study and biological plausibility nevertheless support a causal interpretation. Thus, an integrative evaluation of all available information may justify the conclusion that a causal interrelationship is probable. The conclusions for regulation strongly depend on how the high risk potential is balanced against the uncertain causality assessment. This question cannot be answered by science but must be decided politically. From a public health perspective noise exposure should be reduced in order to protect human health.

In several recent investigations it could be demonstrated that the free cortisol response to awakening can serve as an useful index of the adrenocortical activity. When measured with strict reference to the time of awakening the assessment of this endocrine response is able to uncover subtle changes in hypothalamus-pituitary-adrenal (HPA) axis activity, which are, for instance, related to persisting pain, burnout and chronic stress. Furthermore, it has been suggested that the HPA axis might serve as an indicator of allostatic load in subjects exposed to prolonged environmental noise. In the present paper four separate studies with a total of 509 adult subjects were combined in order to provide reliable information on normal values for the free cortisol response to awakening. Corresponding with earlier findings, a mean cortisol increase of about 50% within the first 30 minutes after awakening was observed. The intraindividual stability over time was shown to be remarkably high with correlations up to r=.63 (for the area under the response curve). Furthermore, the cortisol rise after awakening is rather consistent, with responder rates of about 75%. Gender significantly influenced early morning free cortisol levels. Although women showed a virtually identical cortisol increase after awakening compared to men, a significantly delayed decrease was observed. Confirming and extending previous findings, the present study strongly suggests that neither age, nor the use of oral contraceptives, habitual smoking, time of awakening, sleep duration or using / not using an alarm clock have a considerable impact on free cortisol levels after awakening. The cortisol awakening response can be assessed under a wide variety of clinical and field settings, since it is non-invasive, inexpensive and easy-to-employ. The present data provide normal values and information on potential confounds which should facilitate investigations into the endocrine consequences of prolonged exposure to environmental noise.