The use of experimental studies to reveal suspected neurotoxic chemicals as occupational hazards: acute and chronic exposures to organic solvents.

The nervous system differs from many other body organs by its central control of vital functions and its low regeneration capacity. Organic solvents have, as a group, been suspected to have neurotoxic effects. Because of their similar physical properties and the fact that in industrial uses, they are often present in various mixtures, organic solvents have also been regarded, unfortunately, to induce common neurotoxic effects. However, it is evident from experimental studies using specified exposure conditions that different organic solvents have very diverse neurotoxic effects and also that the toxic mechanism may differ between acute and chronic exposure. No specific method used to describe a neurotoxic effect or single toxic response can be used for the overall occupational risk assessment of all organic solvents. Each solvent has to be considered as having its own unique toxic effects.     

The discriminative stimulus and subjective effects of d-amphetamine,phenmetrazine and fenfluramine in humans

The discriminative stimulus (DS) and subjective effects of d-amphetamine (AMP), phenmetrazine (PMT) and fenfluramine (FFL) were studied in a group of normal healthy adults. Subjects (N=27) were trained to discriminate between placebo and 10 mg AMP (PO). Fourteen of the subjects (discriminators) reliably learned the discrimination, whereas the other 13 did not. Nearly all discriminators labelled AMP as a stimulant, and AMP, relative to placebo, increased ratings of drug liking and general activity level, and produced typical stimulant-like subjective effects, as measured by the Profile of Mood States, the Addiction Research Center Inventory, and a series of visual analog scales. The discrimination accuracy of discriminators increased as a function of hour after drug ingestion, as did analog ratings of how certain subjects were that their discrimination responses were correct. Discriminators were tested with doses of PMT (25 and 50 mg) and FFL (20 and 40 mg) to determine whether the DS properties of these drugs would substitute for those of AMP. Both doses of PMT consistently substituted for AMP, and PMT produced subjective effects very similar to those of AMP. Conversely, neither dose of FFL consistently substituted for AMP, and FFL produced essentially no subjective effects. These findings are consistent with results from discrimination studies with other species, and provide further evidence of the validity of this procedure for studying the DS properties of drugs in humans. Offprint requests to: L.D. Chait     

Occurrence and Distribution of Bone Tumors in Beagle Dogs Exposed to 90Sr

Radiation-induced bone tumors in beagle dogs exposed to ⁹⁰Sr have been evaluated in terms of their incidence, time of appearance, occurrence as multiple tumors, anatomic distribution, and the influence of sex on their development. Among dogs fed ⁹⁰Sr during skeletal development, the incidence of bone tumors was dose dependent. Tumors thus appeared in 10 of 19 dogs receiving average skeletal doses of 130 Gy, 15 of 60 receiving 97 Gy, 5 of 61 receiving 61 Gy, 2 of 65 receiving 26 Gy, and 1 of 40 receiving 1.3 Gy. No tumors appeared among 66 dogs who received 8 Gy, 78 who received 0.3 Gy, and 80 non-irradiated controls, all of which have been observed for life. Among dogs given a single intravenous injection of ⁹⁰Sr in early adulthood, tumor production was somewhat higher than among ⁹⁰Sr-fed dogs at the same radiation dose: bone tumors were present in 6 of 25 dogs who received 62 Gy and 1 of 20 dogs who received 7.5 Gy. Bone tumors appeared sooner and were more often multiple in animals receiving the higher doses. Long bones were the sites of most of the tumors appearing after the highest dose level. Bones of the head, particularly the mandible, were the predominant site of tumors in the next highest dose level group.     

Score Statistic to Test for Genetic Correlation for Proband-Family Design

In genetic epidemiological studies informative families are often oversampled to increase the power of a study. For a proband‐family design, where relatives of probands are sampled, we derive the score statistic to test for clustering of binary and quantitative traits within families due to genetic factors. The derived score statistic is robust to ascertainment scheme. We considered correlation due to unspecified genetic effects and/or due to sharing alleles identical by descent (IBD) at observed marker locations in a candidate region. A simulation study was carried out to study the distribution of the statistic under the null hypothesis in small data‐sets. To illustrate the score statistic, data from 33 families with type 2 diabetes mellitus (DM2) were analyzed. In addition to the binary outcome DM2 we also analyzed the quantitative outcome, body mass index (BMI). For both traits familial aggregation was highly significant. For DM2, also including IBD sharing at marker D3S3681 as a cause of correlation gave an even more significant result, which suggests the presence of a trait gene linked to this marker. We conclude that for the proband‐family design the score statistic is a powerful and robust tool for detecting clustering of outcomes.     

Well-being (quality of life) in connection with hypertensive treatment

Quality of life is often considered to equate how the medical treatment is subjectively perceived by the patient, but ought to include the total impact of the disease/treatment on the patient's emotional, physical, and social well-being. Recently, a proposal for a generally applicable definition of quality of life in health care was put forward. This definition includes general well-being, health, and welfare (external factors), as three fundamental components, and the definition is based on both objective and subjective judgments. General well-being is exclusively and expression of the individual's subjective experience and is based on his or her own qualitative evaluation of well-being in relation to condition, treatments, and experiences. Health is according to the proposed definition, judged both objectively (signs) and subjectively (symptoms). Apart from health and well-being, there is also reason to include objectively registrable factors at the welfare level (external factors) such as the consumption of medicines, number of days in hospital, length of sick leave, need of in-home care, etc. This review is an attempt to elucidate the effects of antihypertensive pharmacotherapy on the patient's general well-being. The topic will be discussed from several points of views (e.g., aims of antihypertensive treatment, occurrence of symptoms in the population, compliance with prescribed treatment, symptom inventories, the concept of quality of life.     

Systemic effects of two nasally administered glucocorticosteroids

Two topical corticosteroids, budesonide (BUD) and beclomethasone dipropionate (BDP), both administered as suspensions in water, were investigated in healthy volunteers regarding influence on cortisol in plasma and urine (U-cortisol) after nasal application. In the first study, single doses of 200, 400, and 800 μg of BDP and BUD were given at 10:00 pm. In the second study, 100, 200, and 400 μg were given mornings and evenings for 4 days. In the single-dose study, none of the drugs or doses showed any significant influence on cortisol in plasma. However, U-cortisol decreased significantly after BUD 400 and 800 μg. In the multidose study, U-cortisol values were significantly reduced after all doses of BUD and the highest dose of BDP. The compounds tested showed different ability to cause measurable systemic effects after nasal application. The clinical implication is that the prescriber, when choosing a compound, should take the application site into consideration and should also be encouraged to find the lowest effective dose.     

化学染发剂和冷烫精的毒性及对人体健康影响的调查研究

本文通过化学染发剂和冷烫精对大白鼠骨髓多染红细胞，毛囊细胞的微核实验及人群健康影响调查，结果表明化学染发剂，冷烫清具有较强致突变作用，两者同时使用致突变明显增强，并提出研制高效无毒染发剂和加强防护的重要性。     

Sexual sequelae of antihypertensive drugs: Treatment effects on self-report and physiological measures in middle-aged male hypertensives

Antihypertensive drugs are commonly associated with adverse side effects in both clinical and laboratory studies. We investigated the sexual sequelae of several major classes of antihypertensive drugs (e.g., beta blockers, central alpha agonists, diuretics) in normal males and in hypertensive patients. We compared the effects of four widely used agents (methyldopa, propranolol, atenolol, hydrochlorothiazide-triamterene) and placebo, in a selected sample of 21 sexually dysfunctional male hypertensives, 13 of whom completed all five phases of the study. Each study drug was administered for a 1-month treatment period, followed by a 2-week, single-blind washout phase, according to a randomized, Latin square crossover design. Dependent variables for the study included a broad range of hormonal, NPT, and self-report measures of sexual response. Results indicated a lack of consistent drug effects on measures of sexual response, although more frequent sexual and nonsexual side effects were observed with methyldopa and propranolol. As in our previous studies, age was negatively correlated with both hormonal and NPT measures, whereas changes in blood pressure were not significantly related to sexual function scores. Results do not support the hypothesis that sexually dysfunctional males are at greater risk for adverse sexual sequelae when treated with centrally active agents or diuretics.     

Super-reactivity to amphetamine toxicity induced by schedule of reinforcement

The chronic exposure of rats to a schedule of operant water reinforcement coupled with chronically restricted access to water sensitized the animals to intermittentd-amphetamine injections (0.31–2.5 mg/kg with intervals of 12–23 days between any two injections) in such a way that this drug came to produce catastrophic losses of body weight (32.4% of control levels). In the sessions whend-amphetamine was administered, the rats were also given a total of 12 brief electric shocks. Loss of body weight was unaccompanied by parallel changes in operant behavior performance, or in food or water intake. Remarkably, in other studies with the same interventions (sham schedule sessions, water deprivation, and foot shocks), with the exception that reinforcers were never delivered,d-amphetamine did not produce catastrophic falls in body weight. This super-reactivity tod-amphetamine toxicity may be mediated by a possible stressor action of the schedule of reinforcement. Its mechanism might be analogous to the known sensitization produced by classical experimental stressor stimuli to the repeated administration ofd-amphetamine.     

Comparative effects of enoximone and theophylline on plasma catecholamines and haemodynamics in cardiosurgical patients

Summary The release of endogenous catecholamines in aorto-coronary bypass graft patients receiving either 0.5 mg/kg enoximone (n=10), 4.0 mg/kg theophylline (n=10) or saline solution (control,n=10) has been studied, as well as certain haemodynamic parameters. Adrenaline (A) and noradrenaline (NA) concentrations were not significantly changed by the administration of enoximone. Theophylline caused a small increase in NA (+ 40% in the 1st min) and a marked increase in A (approximately + 7000% in the 1st min), which still remained elevated at the end of the investigation period (+ 220% in the 30th min). The major haemodynamic effects of enoximone were a significant increase in cardiac index (CI; + 35%) and a decrease in pulmonary capillary wedge pressure (PCWP; −27%), pulmonary artery pressure (PAP; −21%), RVEDV and RVESV, while the heart rate (HR) remained almost unchanged. The dominant haemodynamic effects of theophylline were an increase in HR (+ 26%; arrhythmia in 3 patients), PAP (+ 22%), and RVEDV (+ 19%), while REVESV (+ 26%), MAP (−16%), CI (−14%), and RVEF (−15%) fell significantly. It is concluded that the haemodynamic actions of enoximone are not mediated by catecholamine release, whereas the adverse cardiovascular effects of theophylline might partly be explained by the significant increase in plasma adrenaline.