The effect of chronic low level lead exposure on blood-brain barrier function in the developing rat.

Blood-brain barrier (BBB) function was assessed in 19-21-day-old rats exposed to low level lead from birth. Newborn rats received lead via milk from lactating dams given drinking water containing 0.1% lead acetate [Pb(Ac)2]. The treatment regime produced lead levels in the neonates within the range 20-80 micrograms dl-1 blood, without affecting growth. Cerebrovascular permeability (PS-product) to the diffusion-limited solute mannitol was unchanged in six regions of the cerebral hemisphere, the cerebellum and the brainstem, suggesting that barrier integrity was not affected by the low dose lead treatment. Regional cerebrovascular permeability to nutrient tracers representing seven BBB transport classes was not impaired by lead treatment. However, the PS estimates for the amino acids lysine and histidine and for thiamine were greater than control in some regions of the cerebral hemisphere. These alterations in nutrient supply to the brain may reflect altered substrate utilization associated with repair processes or delayed maturation of the CNS.

The effect of L-tryptophan on motor activity and its prevention by an extracerebral decarboxylase inhibitor and by 5-HT receptor blockers.

L-Tryptophan at moderately low dosage (20 mg/kg) reduced the activity of rats taken during a dark period (red light) and put into an open field illuminated by bright white light. Activity was not altered when the field was illuminated by red light. Tryptophan did not cause significant hypoactivity in rats pretreated with the 5-hydroxytryptamine (5-HT) receptor antagonists methysergide, cyproheptadine and metergoline. However, tryptophan did not alter brain 5-HT concentration and only increased 5-hydroxyindoleacetic acid (5-HIAA) slightly in rats killed shortly after behavioural observation. A further indication that the behavioural effect of tryptophan was not due to increased brain 5-HT was its prevention by R04-4602 at a dose sufficient to block peripheral but not central L-aromatic amino acid decarboxylase. The results suggest that the above behavioural effect of L-tryptophan is peripherally mediated. A number of potential mechanisms are discussed.

Safety evaluation of phytosterol esters. Part 4. Faecal concentrations of bile acids and neutral sterols in healthy normolipidaemic volunteers consuming a controlled diet either with or without a phytosterol ester-enriched margarine.

A study was conducted in 12 healthy males and 12 females (mean age 36 years) to assess the impact of a margarine enriched with phytosterol esters on faecal concentrations of bile acids and sterols. During the run-in period, volunteers consumed 40 g of a control margarine for 21 consecutive days if male, and for 28 days if female. Half of the volunteers were then randomly allocated to consume the control margarine for another 21 or 28 days, respectively. The remaining subjects consumed 40 g of a margarine containing 8.6 g vegetable oil phytosterol (46% (w/w) beta-sitosterol, 26% campesterol, 20% stigmasterol). Throughout the total study subjects consumed the same diet adjusted for individual energy requirements. The phytosterol ester-enriched spread significantly enhanced faecal neutral sterol concentrations from about 40 mg/g to 190 mg/g dry weight faeces. Faecal neutral sterol metabolites increased from about 30 mg/g to about 50 mg/g. The major parent sterols excreted were cholesterol, sitosterol, campesterol and stigmasterol. Sitosterol, campesterol and stigmasterol comprised 28%, 15% and 12% of the total faecal neutral sterols, reflecting the composition of the sterol enriched margarine. The major sterol metabolites excreted were metabolites formed by, predominantly, oxidation at the 3-position and metabolites saturated at the 5,6 position in a beta-configuration. Faecal secondary bile acid concentration was reduced by vegetable oil sterols from 7.6 mg/g dry faeces to 6.0 mg/g. Consumption of vegetable oil phytosterols slightly but significantly increased the faecal concentration of 4-cholesten-3-one. However, 4-cholesten-3-one concentration remained very low (< 2 mg/g) and in line with values reported in the literature for subjects fed high or low fat diets. No sterol oxides could be detected in the faeces. We conclude that in healthy adult males and females a high intake of vegetable oil phytosterol esters does increase the amount of neutral sterols in the faeces, as expected, but does not result in the increased formation of bile acids or sterol metabolites.

Safety evaluation of phytosterol esters. Part 5. Faecal short-chain fatty acid and microflora content, faecal bacterial enzyme activity and serum female sex hormones in healthy normolipidaemic volunteers consuming a controlled diet either with or without a phytosterol ester-enriched margarine.

A study was conducted in 12 healthy males and 12 healthy females (mean age 36 years, mean body mass index 24 kg/m2), to determine the effect of a margarine enriched with phytosterol esters on faecal short-chain fatty acids (SCFAs) and faecal bacterial enzyme activities, viable faecal microflora count, female sex hormones and serum cholesterol concentrations. The study design was a two-period, parallel dosing, randomized, placebo-controlled dietary study. Under controlled dietary conditions, participants consumed 40 g of the control margarine for 21 and 28 consecutive days for males and females, respectively. This was followed immediately by the second part of the study where subjects were equally and randomly allocated to consume daily 40 g of either the control or the test margarine, containing 8.6 g vegetable oil phytosterols (a mixture of beta-sitosterol, campesterol and stigmasterol), also for 21 or 28 days. All females were shown to have a regular menstrual cycle and were on an established method of contraception not involving oral contraceptives. When compared with the control group values, the test group showed a significant reduction in serum total and LDL cholesterol concentrations of 18 and 23% (P < 0.001; P < 0.001) respectively, in faecal lactic acid concentration (P = 0.039) and in serum progesterone levels (P = 0.021). There were no other significant treatment effects. Within each group a number of significant changes occurred compared to baseline. In the test group, faecal lactic acid concentration and the ratio of acetic acid:total SCFA; and the ratio of butyric acid:total SCFA, in the control group were both significantly reduced (P = 0.016). Compared to baseline, azo-reductase activity was significantly reduced in the control group (P = 0.047). Total faecal aerobes (P = 0.028), lactobacilli (P = 0.003) and staphylococci (P = 0.025) content was also significantly reduced in the control group, while in the test group only lactobacilli content was reduced (P = 0.019). Of the significant findings reported in this study, none was considered to be of biological importance except the beneficial reduction in serum total and LDL-cholesterol concentrations. The daily consumption of a margarine enriched with 8.6 g vegetable oil phytosterols did not affect the bacterial profile or the metabolic activities of the gut microflora, nor did it result in biologically relevant effects on serum female sex hormone levels. The margarine enriched with the vegetable oil phytosterols was well tolerated by both male and female volunteers.

Toxicity threshold of quinine hydrochloride following low-level repeated dosing in healthy volunteers.

Following a double-blind, four-way crossover design, 32 healthy volunteers (20 males and 12 females) each consumed lactose placebo, or 80, 120 or 160 mg quinine HCl daily for 21 days. Before dosing and at regular intervals during dosing, blood and urine samples were collected and analysed for quinine HCl. Electrocardiography, heart rate, blood pressure, audiometry, peripheral field, funduscopy, colour vision, visual acuity, electronystagmography (ENG) and test for optokinetic nystagmus were all evaluated before dosing and at selected times during dosing. The results showed that daily consumption of up to 80 mg quinine HCl did not significantly alter physiological, ophthalmic or audiometric responses. ENG determination showed that 12.5% of volunteers given lactose placebo or 80 mg quinine HCl exhibited at least one transitory period of ocular motor oscillations. This phenomenon was observed in 18.8% (P < 0.05) of volunteers with a daily intake of 120 mg quinine HCl or more. However, there was not a significant dose-related correlation between nystagmus and daily intake of quinine HCl. Five volunteers consuming lactose placebo displayed an aberrant ocular flutter that decreased significantly (P < 0.05) as the daily intake of quinine HCl increased. One volunteer showed a change in perception of red/green colour vision after taking 160 mg quinine HCl for 21 days. This study demonstrated that the no-untoward-effect level of quinine HCl is at least 80 mg/day.

Plasma levels of aluminium after tea ingestion in healthy volunteers.

12 healthy volunteers on a controlled aluminium (Al) diet each consumed a tea infusion (500 ml/70 kg body weight), with either milk or lemon juice as additives, or mineral water, following a three-way crossover design. The concentrations of Al were determined in the diet, mineral water and tea infusions, and in plasma samples collected before and up to 24 hr after consumption of tea or water, using graphite-furnace atomic absorption spectrophotometry or inductively coupled plasma emission spectrometry. Consumption of up to 1.60 mg Al from tea with milk or lemon juice did not increase plasma Al levels compared with consumption of approximately 0.001 mg Al from mineral water. The results suggest that, in the short-term, drinking tea does not contribute significantly to the total body burden of Al.