Applying the adverse outcome pathway concept for assessing non-monotonic dose responses: biphasic effect of bis(2-ethylhexyl) phthalate (DEHP) on testosterone levels.

Male reproduction is one of the primary health endpoints identified in rodent studies for some phthalates, such as DEHP (Bis(2-ethylhexyl) phthalate), DBP (Dibutyl phthalate), and BBP (Benzyl butyl phthalate). The reduction in testosterone level was used as an intermediate key event for grouping some phthalates and to establish a reference point for risk assessment. Phthalates, and specifically DEHP, are one of the chemicals for which the greatest number of non-monotonic dose responses (NMDRs) are observed. These NMDRs cover different endpoints and situations, often including testosterone levels. The presence of NMDR has been the subject of some debate within the area of chemical risk assessment, which is traditionally anchored around driving health-based guidance values for apical endpoints that typically follow a clear monotonic dose-response. The consequence of NMDR for chemical risk assessment has recently received considerable attention amongst regulatory agencies, which confirmed its relevance particularly for receptor-mediated effects. The present review explores the relationship between DEHP exposure and testosterone levels, investigating the biological plausibility of the observed NMDRs. The Adverse Outcome Pathway (AOP) concept is applied to integrate NMDRs into Key Event Relationships (KERs) for exploring a mechanistic understanding of initial key events and possibly associated reproductive and non-reproductive adverse outcomes.

Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study.

BACKGROUND: Hydroxyethylstarch used for volume restoration in brain-dead kidney donors has been associated with impaired kidney function in the transplant recipients. We undertook a multicentre randomised study to assess the frequency of acute renal failure (ARF) in patients with severe sepsis or septic shock treated with hydroxyethylstarch or gelatin. METHODS: Adults with severe sepsis or septic shock were enrolled prospectively in three intensive-care units in France. They were randomly assigned 6% hydroxyethylstarch (200 kDa, 0.60-0.66 substitution) or 3% fluid-modified gelatin. The primary endpoint was ARF (a two-fold increase in serum creatinine from baseline or need for renal replacement therapy). Analyses were by intention to treat. FINDINGS: 129 patients were enrolled over 18 months. Severity of illness and serum creatinine (median 143 [IQR 88-203] vs 114 [91-175] micromol/L) were similar at baseline in the hydroxyethylstarch and gelatin groups. The frequencies of ARF (27/65 [42%] vs 15/64 [23%], p=0.028) and oliguria (35/62 [56%] vs 23/63 [37%], p=0.025) and the peak serum creatinine concentration (225 [130-339] vs 169 [106-273] micromol/L, p=0.04) were significantly higher in the hydroxyethylstarch group than in the gelatin group. In a multivariate analysis, risk factors for acute renal failure included mechanical ventilation (odds ratio 4.02 [95% CI 1.37-11.8], p=0.013) and use of hydroxyethylstarch (2.57 [1.13-5.83], p=0.026). INTERPRETATIONS: The use of this preparation of hydroxyethylstarch as a plasma-volume expander is an independent risk factor for ARF in patients with severe sepsis or septic shock.

Differential effects of specific delta and kappa opioid receptor antagonists on the bidirectional dose-dependent effect of systemic naloxone in arthritic rats, an experimental model of persistent pain.

In an attempt to determine the opioid receptor class(es) which underly the two opposing effects of naloxone in models of persistent pain, we tested the action of the selective delta antagonist naltrindole, and that of the kappa antagonist MR-2266 on the bidirectional effect of systemic naloxone in arthritic rats. As a nociceptive test, we used the measure of the vocalization thresholds to paw pressure. The antagonists were administered at a dose (1 mg/kg i.v. naltrindole, 0.2 mg/kg i.v. MR-2266), without action per se but which prevents the analgesic effect of the delta agonist DTLET (3 mg/kg, i.v.) or the kappa agonist U-69,593 (1.5 mg/kg, i.v.) respectively, and does not influence the effect of morphine (1 mg/kg i.v.) or the mu agonist DAMGO (2 mg/kg, i.v.) in these animals. In arthritic rats injected with the delta antagonist, the paradoxical antinociceptive effect produced by 3 micrograms/kg i.v. naloxone was not significantly modified (maximal vocalization thresholds (% of control) were 146 +/- 9% versus 161 +/- 7% in the control group). By contrast, the hyperalgesic effect produced by 1 mg/kg i.v. naloxone was significantly reduced (maximal vocalization thresholds were 87 +/- 4% versus 69 +/- 5% in the control group). In rats injected with the kappa antagonist, the antinociceptive effect of the low dose of naloxone was almost abolished (mean vocalization thresholds were 115 +/- 3% versus 169 +/- 7%) whereas the hyperalgesic effect of naloxone 1 mg/kg i.v. was not significantly modified (mean vocalization thresholds = 70 +/- 3% and 65 +/- 3%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Gastric fluid pH and volume in gynaecologic out-patients. Influences of cimetidine and cimetidine-sodium citrate combination.

Eighty consecutive ASA physical status 1 women scheduled for day-case gynaecological laparoscopy under general anaesthesia were randomly allocated during the pre-operative visit to receive one of four premedication regimes. Patients in group 1 received hydroxyzine 100 mg; patients in group 2 received hydroxyzine 100 mg and cimetidine 400 mg; patients in group 3 received hydroxyzine 100 mg and effervescent cimetidine (cimetidine 200 mg + sodium citrate 1.8 g). All were given orally in 30 ml of water, 90 min before anaesthetic induction. Patients in group 4 received effervescent cimetidine orally in 30 ml of water 5 min before anaesthetic induction. Following induction of anaesthesia, gastric pH and residual volume (phenol red dilution technique) were measured. Gastric pH was higher (P < 0.05) in groups 2, 3 and 4 (medians: 5.71, 4.84, 6.07, respectively) than in group 1 (2.18). No patient had a gastric pH < or = 2.5 in group 4 compared with 13/14 n group 1, 1/15 in group 2 and 2/14 in group 3 (P < 0.0001). Mean gastric volumes were higher (P < 0.05) in group 4 (30.4 +/- 23.2 ml) than in groups 1, 2 and 3 (11.8 +/- 6.4, 15.8 +/- 11.2, 17.2. +/- 24.4 ml, respectively). Nine of the 19 patients in group 4 had a volume higher than 25 ml. Only one patient in group 1 had both gastric pH < or = 2.5 and volume > or = 25 ml. The administration of effervescent cimetidine 5 min prior to anaesthetic induction seems to be an easy and effective method of decreasing the acidity of gastric contents in day surgery.