Evaluation of urinary biomarkers of exposure to benzene: correlation with blood benzene and influence of confounding factors

Purpose   trans,trans-Muconic acid (t,t-MA) is generally considered as a useful biomarker of exposure to benzene. However, because of its lack of specificity, concerns about its value at low level of exposure have recently been raised. The aim of this study was (a) to compare t,t-MA, S-phenylmercapturic acid (SPMA) and benzene (B-U) as urinary biomarkers of exposure to low levels of benzene in petrochemical workers and, (b) to evaluate the influence of sorbic acid (SA) and genetic polymorphisms of biotransformation enzymes on the excretion of these biomarkers. Method  A total of 110 workers (including 24 smokers; 2–10 cigarettes/day) accepted to take part in the study. To assess external exposure to benzene, air samples were collected during the whole working period by a passive sampling device attached close to the breathing zone of 98 workers. Benzene was measured in blood (B-B) samples taken at the end of the shift, and was considered as the reference marker of internal dose. Urine was collected at the end of the shift for the determination of B-U, SPMA, t,t-MA, SA and creatinine (cr). B-U and B-B were determined by head-space/GC–MS, SPMA and SA by LC-MS, t,t-MA by HPLC-UV. Results  Most (89%) personal measurements of airborne benzene were below the limit of detection (0.1 ppm); B-B ranged from <0.10 to 13.58 μg/l (median 0.405 μg/l). The median (range) concentrations of the urinary biomarkers were as follows: B-U 0.27 μg/l (<0.10–5.35), t,t-MA 0.060 mg/l (<0.02–0.92), SPMA 1.40 μg/l (0.20–14.70). Urinary SA concentrations ranged between <3 and 2,211 μg/l (median 28.00). Benzene concentration in blood and in urine as well as SPMA, but not t,t-MA, were significantly higher in smokers than in non-smokers. The best correlation between B-B and urinary biomarkers of exposure were obtained with benzene in urine (μg/l r = 0.514, P < 0.001; μg/g cr r = 0.478, P < 0.001) and SPMA (μg/l r = 0.495, P < 0.001; μg/g cr r = 0.426, P < 0.001) followed by t,t-MA (mg/l r = 0.363, P < 0.001; mg/g cr r = 0.300, P = 0.002). SA and t,t-MA were highly correlated (r = 0.618, P < 0.001; corrected for cr r = 0.637). Multiple linear regression showed that the variation of t,t-MA was mostly explained by SA concentration in urine (30% of the explained variance) and by B-B (12%). Variations of SPMA and B-U were explained for 18 and 29%, respectively, by B-B. About 30% of the variance of B-U and SPMA were explained by B-B and smoking status. Genetic polymorphisms for biotransformation enzymes (CYP2E1, EPHX1, GSTM1, GSTT1, GSTP1) did not significantly influence the urinary concentration of any of the three urinary biomarkers at this low level of exposure. Conclusion  At low levels of benzene exposure (<0.1 ppm), (1) t,t-MA is definitely not a reliable biomarker of benzene exposure because of the clear influence of SA originating from food, (2) SPMA and B-U reflect the internal dose with almost similar accuracies, (3) genetically based inter-individual variability in urinary excretion of biomarkers seems negligible. It remains to assess which biomarker is the best predictor of health effects.     

Efficacy of 3,5-dibromo-L-phenylalanine in rat models of stroke,seizures and sensorimotor gating deficit

Background and purpose:

Abnormal glutamatergic activity is implicated in neurologic and neuropsychiatric disorders. Selective glutamate receptor antagonists were highly effective in animal models of stroke and seizures but failed in further clinical development because of serious side effects, including an almost complete set of symptoms of schizophrenia. Therefore, the novel polyvalent glutamatergic agent 3,5-dibromo-L-phenylalanine (3,5-DBr-L-Phe) was studied in rat models of stroke, seizures and sensorimotor gating deficit.

Experimental approach:

3,5-DBr-L-Phe was administered intraperitoneally as three boluses after intracerebral injection of endothelin-1 (ET-1) adjacent to the middle cerebral artery to cause brain injury (a model of stroke). 3,5-DBr-L-Phe was also given as a single bolus prior to pentylenetetrazole (PTZ) injection to induce seizures or prior to the administration of the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) to cause disruption of prepulse inhibition (PPI) of startle (sensorimotor gating deficit).

Key results:

Brain damage caused by ET-1 was reduced by 52%, which is comparable with the effects of MK-801 in this model as reported by others. 3,5-DBr-L-Phe significantly reduced seizures induced by PTZ without the significant effects on arterial blood pressure and heart rate normally caused by NMDA antagonists. 3,5-DBr-L-Phe prevented the disruption of PPI measured 3 days after the administration of ET-1. 3,5-DBr-L-Phe also eliminated sensorimotor gating deficit caused by MK-801.

Conclusion and implications:

The pharmacological profile of 3,5-DBr-L-Phe might be beneficial not only for developing a therapy for the neurological and cognitive symptoms of stroke and seizures but also for some neuropsychiatric disorders.     

Ten-year antibody persistence induced by hepatitis A and B vaccine (Twinrix) in adults

BACKGROUND: Hepatitis A and B infections are prevalent worldwide and cause significant morbidity and mortality. A combined vaccine providing dual protection against hepatitis A and B is available (Twinrix, GlaxoSmithKline Biologicals). METHOD: Two cohorts of adults aged 17-43 years were vaccinated with Twinrix according to a 0, 1, 6 months schedule and followed up for 10 years. RESULTS: One month after the primary vaccination course (Month 7), all subjects were seropositive for anti-HAV and all had anti-HBs> or = 10 mIU/ml. At month 120, 100% of subjects (N=34; N=29) in both cohorts were seropositive for anti-HAV; 94.1% and 86.2% of subjects had anti-HBs > or = 10 mIU/ml. The geometric mean concentrations (GMC; mIU/ml) were 373.9 and 674.6 in the two cohorts for anti-HAV, and 103.8 and 320.0, respectively, for anti-HBs. None of the serious adverse events reported throughout the follow-up period were considered by the investigator to be causally related to vaccination. CONCLUSIONS: Combined hepatitis A and B vaccine, Twinrix, is safe, well-tolerated and has demonstrated a highly immunogenic profile. Persistence of anti-HAV and anti-HBs antibodies in adults remains high for at least 10 years after primary vaccination.     

Genetic implications and health consequences following the Chernobyl nuclear accident

Kozenko M, Chudley AE. Genetic implications and health consequences following the Chernobyl nuclear accident. It has been almost 25 years since the Chernobyl nuclear accident in Ukraine. We review relevant data derived from published reports originating in the Former Soviet Union. We cite census data from Ukraine and research studies from Western Europe that analyzed the effect of radiation on genetics and health outcome in the exposed populations. We also present philatelic materials that pictorially captured that fateful event in history.     

Treatment of vitiligo in children and adolescents by autologous cultured pure melanocytes transplantation with comparison of efficacy to results in adults

Background Transplantation of autologous cultured pure melanocytes is a well‐established procedure for the treatment of refractory and stabilized vitiligo. However, there was no report specifically comparing the efficacy with the regard to defined age groups (children‐adolescence‐adult). Objective We analysed the efficacy of this procedure in the treatment of vitiligo in children and adolescents and compare it with the results in adults treated during the same period and using identical procedures. Methods Melanocytes were isolated from the roof of suction blister, cultured and expanded with Hu16 medium in vitro, and transplanted to laser‐denuded receipt area. A total of 12 children (8–12 years), 20 adolescents (13–17 years) and 70 adults with vitiligo were treated using this procedure. Results The patients obtained satisfactory results (repigmentation of 50% or more) results in children, adolescents and adults were 83.3%, 95.0% and 84.0% respectively. The mean extent of repigmentation in children, adolescents and adults was 80.7%, 78.9% and 76.6% respectively. There was no statistical difference in repigmentation among these three groups. After adjusting for all factors (gender, type of vitiligo, period of stability, location of the lesion or transplanted cell density) individually or totally using multiple regression analysis, age still did not correlate to the extent of repigmentation. Conclusions The satisfactory results obtained in the treatment of vitiligo in children and adolescents by transplantation of cultured autologous pure melanocytes are comparable with the results in adults. Therefore, this procedure can be considered in refractory and stable vitiligo in children and adolescents, especially in patients with large vitiliginous lesions.