Critical evaluation of current concepts in exposure assessment.

The exploitation of natural resources and the improper use and disposal of thousands of chemicals have resulted in environmental pollution and a potential threat to human health on a global scale. Increasing public concern about environmental exposure to and consequent ill health from contaminants demands informed answers based on valid risk assessment. By assessing internal exposure to pollutants, human biomonitoring focuses on early markers of potential risks to prevent serious adverse effects. Exposure assessment may provide a rational basis for risk assessment, with knowledge of the adequacy of limit values; it may also uncover long-term changes in body burdens and thus help identify the sources and transfer pathways of environmental pollutants. The techniques of biological exposure assessment should be incorporated into epidemiological studies if suitable specimens are available, such as exhaled air, blood, urine, breast milk, or adipose or keratinous tissue. Special precautions must be taken in sampling, storage, and analysis if the findings are to be interpreted correctly and reliable conclusions drawn.

Influence of hydralazine on the pharmacokinetics of orally administered d-propranolol and lidocaine in conscious dogs.

A study was conducted on the influence of oral coadministration of hydralazine (H) on the pharmacokinetics of d-propranolol (P) and lidocaine (L) in 6 conscious dogs. They were given an oral solution containing P (2 mg/kg) and L (15 mg/kg) alone or together with 25 mg H. Plasma concentrations of P and L and the metabolites monoethylglycinexylidide (MEGX) and glycinexylidide (GX) were measured by specific HPLC methods. Concomitant administration of H caused a significant (p less than 0.05) increase in P peak concentrations (Cmax, 34 +/- 5: 73 +/- 10 ng/ml) and the area under plasma concentration time curve (AUC, 142 +/- 18: 254 +/- 56 ng/ml X hr) of P with significant (p less than 0.05) 24% reduction of the apparent oral clearance. The time to reach peak concentrations (Tmax) and the terminal half life (t1/2 beta) were not altered. In contrast to the pattern seen with P the disposition of L was not affected by H. The change in presystemic clearance of P by H cannot be explained by a general underlying mechanism such as an alteration in liver blood flow alone or portal-systemic shunting, since then the pharmacokinetics of L should parallel those of P. It is speculated that other mechanisms, most likely alteration of P metabolism, are primarily responsible for the observed interaction between P and H.

Cardiac and pulmonary norepinephrine release and removal in the dog.

Norepinephrine extraction and spillover rates were determined in the heart and lungs of anesthetized dogs under resting conditions, during sympathetic stimulation, and during epicardial pacing. The fractional extraction of norepinephrine across the coronary and pulmonary vascular beds was measured from the venoarterial difference in tritiated norepinephrine after infusion of a tracer dose to a steady state level. Cardiac extraction averaged 0.299 +/- 0.03 and pulmonary extraction averaged 0.215 +/- 0.014; extraction was unaffected by sympathetic stimulation or pacing. Norepinephrine spillover from sympathetic nerve terminals in the heart and lungs was measured from the venoarterial difference in endogenous norepinephrine and plasma flow after correction for the extraction component. Cardiac norepinephrine spillover increased linearly with increasing frequency of sympathetic stimulation to 7.44 times resting levels at 2 Hz. During pacing, there was no change in cardiac norepinephrine spillover despite marked changes in heart rate. Norepinephrine spillover was demonstrated under resting conditions in the lung and was greater than observed in the heart. Pulmonary norepinephrine spillover increased with sympathetic stimulation to 4.15 times resting levels at 2 Hz. It is possible to separate the contributions of norepinephrine extraction and spillover to measured venoarterial differences of norepinephrine under physiological conditions in the dog.

Characterization of the clonidine receptor site.

At the cardiac sympathetic nerve terminal the alpha 2-adrenoceptor is presynaptic and appears to be located at an extrasynaptic site. This is suggested by (1) absence of evidence of autoinhibitory feedback at physiologic stimulus levels up to about 50 percent of the maximum chronotropic response in the isolated guinea pig right atrium, and (2) absence of significant competition between clonidine and synaptically released noradrenaline (NA) for the presynaptic site. In the central nervous system (CNS) cardiovascular alpha 2-receptors are probably located at a postsynaptic site in bulbospinal regions of the brain, since they produce effects identical to those of synaptic release of NA. Experiments with the clonidine analog alinidine (ST 567) suggest that there are differences in central receptor type subserving clonidine-mediated baroreflex heart rate and blood pressure changes.

Effects of alinidine (ST 567) on baroreceptor-heart rate reflexes and its interactions with clonidine on the baroreflex and on the sympathetic terminals of the isolated atrium.

Alinidine (ST 567), an N-allyl derivative of clonidine, slowed the heart rate of conscious rabbits by 41 +/- 2.3 (S.E.D.) b/min and reduced mean arterial pressure (MAP) by 6.4 +/- 1.4 mmHg (P less than 0.001). The cardiac slowing was considered to be a direct effect in agreement with previous findings by others, since it was present in rabbits without functioning autonomic nerves, but the fall in blood pressure did not occur in these animals. Alinidine produced no significant changes in the reflex tachycardia response evoked by infusing nitroprusside, or in the pressure-related parameters of the MAP-heart period (HP) curve of the baroreceptor-heart rate reflex (i.e. HP range, gain, or median blood pressure BP50). Intravenous (i.v.) clonidine produced characteristic rises in baroreflex HP range and gain, which were due to vagal facilitation, and also produced falls in BP50 and resting MAP. I.v. alinidine suppressed the clonidine-induced vagal facilitation, but had no effect on the blood pressure changes. Intracisternal alinidine could be given in only relatively low dose, but reduced the clonidine-induced rise in vagal component of HP range. The main site of antagonism between i.v. alinidine and clonidine was probably in the CNS. We studied the nature of the antagonism at the sympathetic nerve terminal of the isolated left guinea pig atrium. Clonidine depressed the inotropic response to field stimulation of the sympathetic nerves and this was competitively antagonised by phentolamine greater than yohimbine greater than alinidine at potencies of about 1200:80:1. Alinidine was considered to be a weak but specific alpha 2-antagonist; it has no alpha 1-antagonist properties since it was without effect on the contractile response to noradrenaline of the guinea pig aorta. The alpha 2-antagonist property explains the suppression by alinidine of the clonidine-induced facilitation of the vagal component of the baroreceptor-heart rate reflex.