Reference values of trace elements in blood and/or plasma in adults living in Belgium.

OBJECTIVES: Trace elements (TEs) from natural and anthropogenic sources are ubiquitous. Essential or not, their relevance for human health and disease is constantly expanding. Biological monitoring is a widely integrated tool in risk assessment both in occupational and environmental settings. However, the determination of appropriate and accurate reference values in the (specific) population is a prerequisite for a correct interpretation of biomonitoring data. This study aimed at determining the reference distribution for TEs (Al, As, Sb, Be, Bi, Cd, Co, Cu, Mn, Hg, Mo, Ni, Pb, Se, Tl, Sn, V, Zn) in the blood and/or plasma of the adult population in Belgium. METHODS: Blood and plasma samples were analyzed for 178 males and 202 females, recruited according to an a priori selection procedure, by inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: Reference values were established with high confidence for AsT, Cd, Cu, HgT, Mn, Mo, Pb, Sn, Se, Tl and Zn. Compared to previously published data in the Belgian population, a decreasing time trend is observed for Zn, Cd and Pb. Globally, the results also indicate that the current exposure levels to TEs in the Belgian population are similar to those from other recent national surveys. CONCLUSIONS: These reference values and limits obtained through validated analytical and statistical methods will be useful for future occupational and/or environmental surveys. They will contribute to decision-making concerning both public health policies but also exposure assessments on an individual scale.

Fulminant Hepatic Failure in the Course of an Outpatient Anesthetic Procedure: Sevoflurane among Other High-Risk Factors.

A 20-year-old man underwent an outpatient general anesthetic procedure with sevoflurane for the correction of a bilateral gynecomastia. The patient had been first exposed to sevoflurane two years before, without any complication. He presented an overweight with a body mass index (BMI) of 31.4 kg/m2 and had an episode of "binge" drinking a few days before anesthesia. He became icteric from postoperative day 9, and after the worsening of liver function tests, the liver biopsy revealed centrilobular necrosis. The patient became encephalopathic and required urgent liver transplantation on postoperative day 30. The possibility of a sevoflurane-related fulminant hepatic failure is discussed.

Do current OELs for silica protect from obstructive lung impairment? A critical review of epidemiological data.

Inhalation of respirable crystalline silica (RCS) can lead to serious health effects such as silicosis and lung cancer. There also seems to be a general consensus to consider that RCS exposure is associated with obstructive lung impairment or chronic obstructive pulmonary disease (COPD), a leading cause of mortality, morbidity, and disability worldwide. It is, however, not clear whether occupational exposure levels (OELs), generally set to prevent silicosis, also protect workers from developing an obstructive impairment. This review aims at clarifying the potential relationship between RCS exposure and obstructive lung impairment as defined by spirometry. Eleven studies that reported both silica exposure levels and spirometry results were identified. We systematically extracted data pertaining to (a) the population studied, (b) level of exposure to RCS and other pollutants, (c) spirometry procedure and interpretation, and (d) methodology used to investigate the relationship between RCS exposure and spirometry. These studies add supporting evidence in favor of a qualitative association between occupational activities exposing to RCS and obstructive lung dysfunction. However, no well-founded quantitative estimate can be drawn from these investigations; the available relevant literature does not allow defining a RCS exposure threshold associated with an increased risk of obstructive lung dysfunction, as defined by spirometry, in workers without silicosis. Further research is needed, but, as highlighted in this review, conducting epidemiological studies with both valid exposure and outcome measurements is a real challenge.

Urinary trace element concentrations in environmental settings: is there a value for systematic creatinine adjustment or do we introduce a bias?

Systematic creatinine adjustment of urinary concentrations of biomarkers has been a challenge over the past years because the assumption of a constant creatinine excretion rate appears erroneous and the issue of overadjustment has recently emerged. This study aimed at determining whether systematic creatinine adjustment is to be recommended for urinary concentrations of trace elements (TEs) in environmental settings. Paired 24-h collection and random spot urine samples (spotU) were obtained from 39 volunteers not occupationally exposed to TEs. Four models to express TEs concentration in spotU were tested to predict the 24-h excretion rate of these TEs (TEµg/24h) considered as the gold standard reference: absolute concentration (TEµg/l); ratio to creatinine (TEµg/gcr); TEµg/gcr adjusted to creatinine (TEµg/gcr-adj); and concentration adjusted to specific gravity (TEµg/l-SG). As, Ba, Cd, Co, Cr, Cu, Hg, Li, Mo, Ni, Pb, Sn, Sb, Se, Te, V and Zn were analyzed by inductively coupled argon plasma mass spectrometry. There was no single pattern of relationship between urinary TEs concentrations in spotU and TEµg/24h. TEµg/l predicted TEµg/24h with an explained variance ranging from 0 to 60%. Creatinine adjustment improved the explained variance by an additional 5 to ~60% for many TEs, but with a risk of overadjustment for the most of them. This issue could be addressed by adjusting TE concentrations on the basis of the regression coefficient of the relationship between TEµg/gcr and creatinine concentration. SG adjustment was as suitable as creatinine adjustment to predict TEµg/24h with no SG-overadjustment (except V). Regarding Cd, Cr, Cu, Ni and Te, none of the models were found to reflect TEµg/24h. In the context of environmental exposure, systematic creatinine adjustment is not recommended for urinary concentrations of TEs. SG adjustment appears to be a more reliable alternative. For some TEs, however, neither methods appear suitable.

Parental occupational exposure to pesticides as risk factor for brain tumors in children and young adults: a systematic review and meta-analysis.

OBJECTIVE: To examine the potential association between parental occupational exposure to pesticides and the occurrence of brain tumors in children and young adults. METHODS: Studies identified from a MEDLINE search through 15 January 2013 and from the reference lists of identified publications were submitted to a systematic review and meta-analysis. Relative risk estimates were extracted from 20 studies published between 1974 and 2010. Most of the retrieved studies involved farm/agricultural jobs. Summary ratio estimates (SR) were calculated according to fixed and random-effect meta-analysis models. Separate analyses were conducted after stratification for study design, exposure parameters, disease definition, geographic location and age at diagnosis. RESULTS: Statistically significant associations were observed for parents potentially exposed to pesticides in occupational settings and the occurrence of brain tumor in their offspring after combining all case-control studies (summary odds ratio [SOR]: 1.30; 95%: 1.11, 1.53) or all cohort studies (summary rate ratio [SRR]: 1.53; 95% CI: 1.20, 1.95). Significantly increased risks were seen for prenatal exposure windows, for either exposed parent, for exposure defined as to pesticides as well as by occupational/industry title, for astroglial brain tumors and after combining case-control studies from North America or cohort studies from Europe. CONCLUSIONS: This meta-analysis supports an association between parental occupational exposure to pesticides and brain tumors in children and young adults, and adds to the evidence leading to the recommendation of minimizing (parental) occupational exposure to pesticides. These results must, however, be interpreted with caution because the impact of work-related factors others than pesticide exposure is not known.

Occupational exposure to cobalt is not associated with incipient signs of dilated cardiomyopathy in a Belgian refinery.

BACKGROUND: Excessive absorption of cobalt has been associated with cases of dilated cardiomyopathy in the past, but it is unclear whether occupationally exposed populations are at risk. OBJECTIVE: To assess the possible relationship between occupational exposure to cobalt and incipient signs of dilated cardiomyopathy. METHODS: A cross-sectional survey was conducted in a cobalt production facility in Belgium constituting one of the largest occupational populations worldwide (n=256 male workers). Exposure to cobalt was assessed by measuring urinary cobalt concentration (µg/gcreat), reflecting recent exposure, and by computing an integrated exposure index (µg/gcreat×years), reflecting long-term exposure. The effect on the myocardium was investigated by echocardiography and electrocardiography, and dose-effect relations with cobalt exposure were traced by multiple regression analysis. RESULTS: No dose-effect relationship between exposure to cobalt and parameters reflecting dilated cardiomyopathy was found in a population of workers characterised by a median recent cobalturia of 4 µg/gcreat and a median long-term cobalturia of 100 µg/gcreat×years. A reduction in the dimensions of the left ventricular internal cavity was associated with recent exposure to cobalt. CONCLUSIONS: Occupational exposure to cobalt does not appear associated with incipient signs of dilated cardiomyopathy within the gradient of exposure recorded in this population.

Reference values and upper reference limits for 26 trace elements in the urine of adults living in Belgium.

BACKGROUND: Trace elements (TEs) are ubiquitous and their potential interest for human health has been constantly expanding. Biological monitoring is generally considered to be a useful tool to assess human exposure to chemical agents in risk assessment both at occupational and environmental levels. However, the knowledge of accurate reference values, which may vary across countries or regions, is a prerequisite for correct interpretation of biomonitoring data. This study aimed at determining the reference distribution and the upper reference limit for 26 TEs (Al, As, Sb, Ba, Be, Bi, Cd, Cr, Co, Cu, In, Li, Mn, Hg, Mo, Ni, Pd, Pt, Pb, Se, Te, Tl, Sn, U, V, Zn) in the urine of the general adult population residing in Belgium. METHODS: In total, 1022 adults not occupationally or extra-occupationally (mainly via hobbies, drugs) exposed to these TEs were recruited by occupational physicians and toxicologists according to an a priori selection procedure. Non-fasting spot urine samples were analyzed for 460 males and 541 females by inductively coupled plasma mass spectrometry (ICP-MS). Careful control was applied during collection, handling and analyses of the samples to avoid any contamination. RESULTS: Globally, the results indicate that the exposure levels of the Belgian population to these TEs are low and grossly similar to those recently published by other national surveys. CONCLUSIONS: These new reference values and upper reference limits will be useful for future occupational and/or environmental surveys.

Elevated blood lead levels and sources of exposure in the population of Kinshasa, the capital of the Democratic Republic of Congo.

The objective of this study was to determine blood lead levels (BLLs) and the possible sources of exposure in the population of Kinshasa, the capital of the Democratic Republic of Congo. A cross-sectional survey was carried out from January to May 2008 in a representative sample of the Kinshasan population. BLL was measured in 275 individuals (53.4% women) aged 1-70 years in the urban area of Kinshasa and from 60 additional subjects in the rural area. Pb was also determined in environmental specimens (air and soil, indoor and outdoor). BLL in the study population ranged from 2.9 to 49.3 µg/dl (median, 9.9 µg/dl). The median BLL among children aged <6 years was 11.5 µg/dl (range: 3.0-37.8 µg/dl). Of these children, 71% had elevated BLL (≥10 µg/dl) and 22% had BLL ≥20 µg/dl. The proportion of elevated BLL (≥10 µg/dl) was higher for children aged <3 years than for children aged 3 to 5 years (97% vs 56%). A higher prevalence of elevated BLL was observed in urban compared with rural children (71% vs 20%). Significantly higher BLLs were also found in children whose mother consumed fired clay during pregnancy. Residential informal activities in the recycling of car batteries also contributed to elevated BLL in children. The elevated background of Pb exposure in the Kinshasan population indicates a public health issue that requires corrective actions. Pb-contaminated dust and air in children's home is an issue of public health concern. The use of leaded gasoline and the activities of car battery recycling in certain residences appear to constitute the main sources of exposure in the city of Kinshasa. The traditional use of fired clay for the treatment of gastritis by pregnant women is another significant contributor for elevated BLL in children.

Occupational exposure to pesticides and Parkinson's disease: a systematic review and meta-analysis of cohort studies.

OBJECTIVES: To systematically review available cohort studies and estimate quantitatively the association between occupational exposure to pesticides and Parkinson's disease (PD). METHODS: Studies were identified from a MEDLINE search through 30 November 2011 and from the reference lists of identified publications. Relative risk (RR) estimates were extracted from 12 studies published between 1985 and 2011. Meta-rate ratio estimates (mRR) were calculated according to fixed and random-effect meta-analysis models. Meta-analyses were performed on the whole set of data and separate analyses were conducted after stratification for gender, exposure characterisation, PD cases identification, geographic location, reported risk estimator and cohort study design. RESULTS: A statistically significant increased risk of PD was observed when all studies were combined (mRR=1.28; 95% confidence interval [CI]: 1.03-1.59) but there was a high heterogeneity and inconsistency among studies. The highest increased risks were observed for studies with the best design, i.e. reporting PD diagnosis confirmed by a neurologist (mRR=2.56; CI: 1.46-4.48; n=4), for cohort studies reporting incidence of PD (mRR=1.95; CI: 1.29-2.97; n=3) as well as for prospective cohorts (mRR=1.39; CI: 1.09-1.78; n=6). A significant increased risk was also seen for banana, sugarcane and pineapple plantation workers (mRR=2.05; CI: 1.23-3.42; n=2). CONCLUSIONS: The present study provides some support for the hypothesis that occupational exposure to pesticides increases the risk of PD.

Acute kidney injury following acute liver failure: potential role of systemic cadmium mobilization?

OBJECTIVE: A significant fraction of patients with acute liver failure (ALF) suffer from a concomitant acute kidney injury (AKI), the mechanism of which is probably multifactorial. Cadmium (Cd) is a widespread environmental pollutant and a tubulotoxic metal that accumulates in the liver. We tested the hypothesis that a release of Cd during ALF may cause a redistribution of Cd from the liver to the kidneys and play a role in the occurrence of ALF-associated AKI. METHODS: Twenty patients with ALF (ALF-patients), 20 patients from the ICU with no liver damage at admission (ICU-controls) and 20 healthy controls were recruited to compare the 24-h urinary excretion rate of Cd with that of lead (Pb), a nephrotoxic metal that does not accumulate in the liver, and zinc (Zn), a non-nephrotoxic element found in high amounts in the liver. The excretion rates of the low-molecular-weight proteins (LMWPs) were monitored. RESULTS: ALF-patients excreted markedly more Cd than the healthy controls and ICU-controls. In ALF-patients, the four urinary LMWPs (RBP, ß2-MG, CC16 and α1-MG) increased as a function of Cd excretion, with high correlation coefficients. The prevalence of patients excreting a high amount of LMWPs also increased with increasing Cd excretion. No relationship was found between the other elements investigated and the LMWPs, with the exception of copper, which shares close toxicokinetic similarities with Cd. CONCLUSIONS: This study shows a strong association between urinary Cd levels and the excretion rates of LMWPs in patients with ALF. A causal relationship is possible but could not be fully demonstrated in this study.

Manganese in plasma: a promising biomarker of exposure to Mn in welders. A pilot study.

BACKGROUND: There is raising concern about the potential neurotoxic effects of manganese (Mn) inhalation exposure in welders. Because most of the airborne particles in welding fume are in the respirable fraction, their bioavailability is likely to be higher than for coarser dust exposure. No well-validated biomarker for Mn exposure is available. OBJECTIVES: To investigate the interest of measuring Mn in plasma (Mn-P) and urine (Mn-U) as biomarkers of exposure in a group of 28 welders whose tasks were only welding-related. METHODS: Ambient air exposure to Mn (Mn-air) was determined by personal full-shift measurements on Monday and Tuesday. On the same days, blood and urine samples were collected before and after the shift. RESULTS: Mn-air varied from 1.3 to 729 µg/m(3) (GM 27.7). For Mn-U 65% of the values in welders were below the LOQ (0.20 µg/L). Compared to controls, the welders' Mn-P averaged 33% higher (1.5 vs 2.0 µg/L). In welders, the after-shift Mn-P values correlated well with Mn-air above 10 µg/m(3). In spite of similar Mn-air exposure on Monday and Tuesday, the relationships between Mn-air and after-shift Mn-P strikingly differed on Tuesday in that the inflection in the relationship was less obvious and the slope of the regression line (Mn-P after-shift/logMn-air) for a doubling of logMn-air was 2.3 times lower than on Monday. On Monday (the first day of the workweek), a Mn-P value of 2 µg/L could distinguish Mn-air exposure above or below 20 µg/m(3) with a sensitivity of 69% and a specificity of 82%. CONCLUSIONS: This preliminary study indicates that Mn-P is a promising biomarker of current exposure to Mn in welders and lends biological plausibility to the intended change for the Mn TLV-TWA of 20 µg/m(3) proposed by ACGIH for respirable Mn particulate.

Occupational exposure to indium: what does biomonitoring tell us?

BACKGROUND: The industrial uses of indium, a rare metal with no known physiological role in humans, have increased dramatically over the past 15 years. The results of animal toxicity studies showing pulmonary and systemic effects as well as some reports in workers have created a growing concern about the possible occurrence of toxic effects in exposed workers. Validated biomarkers to assess exposure to indium are not available. OBJECTIVES: This work aimed at investigating the kinetics of indium in urine (In-U) and plasma (In-Pl) in workers manufacturing In ingots and mainly exposed to hardly water-soluble In compounds. All nine workers from the In department of a large metallurgical concern participated in the study as well as 5 retired workers and 20 controls. METHODS: Personal breathing zone air was collected throughout the work shift on Monday and Friday. Blood and urine samples were collected, before and after the shift, on the same day as the air sampling and on preshift the next Monday after a non-working week-end. Moreover, rats were given either InCl(3) by intraperitoneal injection or In(2)O(3) by pharyngeal aspiration, In was followed in plasma during 120 days and measured in tissues 120 days after exposure. RESULTS: Higher In-Pl and In-U concentrations were found in both current (range 0.32-12.61 µg/L plasma; 0.22-3.50 µg/g creat) and former (0.03-4.38 µg/L plasma; 0.02-0.69 µg/g creat) workers compared with controls (<0.03 µg/L plasma; <0.02 µg/g creat). Both biological parameters were highly correlated but no correlation was found between In-air (10-1030 µg/m(3)) and In-Pl or In-U. Normalizing In-U by the urinary creatinine concentration reduced the inter- (from 90% to 70%) and intra-individual variability (from 54% to 35%). In-Pl remained remarkably stable along the working week (inter- and intra-individual variability: 89% and 10%, respectively). Neither In-U nor In-Pl significantly increased during the day or the week. A week-end without occupational exposure was not sufficient to reach the background In-Pl and In-U levels measured in controls. The results of the experimental investigations confirmed the hypothesis that inhalation of hardly soluble In compounds may cause accumulation of In in the body leading to a prolonged "endogenous exposure" from both a lung depot of "insoluble" particles that are progressively absorbed and from a retention depot in other internal organs. CONCLUSION: This study shows that in workers exposed to hardly soluble In compounds, In-U and In-Pl are very sensitive to detect exposure and mainly reflect long-term exposure. In-Pl levels are particularly stable for a given individual. In-U might be more influenced than In-Pl by recent exposure. Both parameters remained high years after withdrawal from exposure, indicating a possible endogenous exposure and a prolonged risk of pulmonary and systemic diseases even after work exposure has ceased.

Time trends in occupational asthma in Belgium.

OBJECTIVES: There is little information on the changes in the pattern of occupational asthma (OA) over time. The objective of this study was to evaluate the time trends in the incidence and causes of immunological OA in Belgium using workers' compensation data. METHODS: Cases of OA were identified through a retrospective review of all claims submitted by salaried workers to the Belgian Workers' Compensation Board from 1993 to 2002. The likelihood of OA was categorized as definite, probable, or possible based upon the results of from diagnostic procedures. Time trends were evaluated using Spearman's rank correlation for crude numbers of cases and through the negative binomial regression for incidence rates of OA per industry. RESULTS: From a total of 1852 claims, 971 were categorized as having definite, probable, or possible OA. There was a downward trend in the annual number of cases due to the main causes of OA (i.e. flour, isocyanates, woods, and enzymes) and an apparent increase in cases of latex-induced OA. The estimated average annual incidence of OA was 29.4 (95% CI: 27.6-31.3) new cases per million salaried workers during the 1993-2002 period. There was a significant decline in the overall incidence rate of OA throughout the study period from 35.5 new cases per million salaried workers in 1993 to 25.8 in 2002. CONCLUSIONS: These compensation-based data indicate that there has been a global downward trend in the incidence of OA during the nineties, although the factors that determined this reduced incidence should be further investigated.

Residential exposure to pesticides and childhood leukaemia: a systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review of published studies on the association between residential/household/domestic exposure to pesticides and childhood leukaemia, and to provide a quantitative estimate of the risk. METHODS: Publications in English were searched in MEDLINE (1966-31 December 2009) and from the reference list of identified publications. Extraction of relative risk (RR) estimates was performed independently by 2 authors using predefined inclusion criteria. Meta-rate ratio estimates (mRR) were calculated according to fixed and random-effect models. Separate analyses were conducted after stratification for exposure time windows, residential exposure location, biocide category and type of leukaemia. RESULTS: RR estimates were extracted from 13 case-control studies published between 1987 and 2009. Statistically significant associations with childhood leukaemia were observed when combining all studies (mRR: 1.74, 95% CI: 1.37-2.21). Exposure during and after pregnancy was positively associated with childhood leukaemia, with the strongest risk for exposure during pregnancy (mRR: 2.19, 95% CI: 1.92-2.50). Other stratifications showed the greatest risk estimates for indoor exposure (mRR: 1.74, 95% CI: 1.45-2.09), for exposure to insecticides (mRR: 1.73, 95% CI: 1.33-2.26) as well as for acute non-lymphocytic leukaemia (ANLL) (mRR: 2.30, 95% CI: 1.53-3.45). Outdoor exposure and exposure of children to herbicides (after pregnancy) were not significantly associated with childhood leukaemia (mRR: 1.21, 95% CI: 0.97-1.52; mRR: 1.16, 95% CI: 0.76-1.76, respectively). CONCLUSIONS: Our findings support the assumption that residential pesticide exposure may be a contributing risk factor for childhood leukaemia but available data were too scarce for causality ascertainment. It may be opportune to consider preventive actions, including educational measures, to decrease the use of pesticides for residential purposes and particularly the use of indoor insecticides during pregnancy.

Childhood leukaemia and parental occupational exposure to pesticides: a systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis of published studies on the association between parental occupational exposure to pesticides and childhood leukaemia. METHODS: Studies were identified from a MEDLINE search through 31 July 2009 and from the reference lists of identified publications. Relative risk (RR) estimates were extracted from 25 studies published between 1985 and 2008. Meta-rate ratio estimates (mRR) were calculated according to fixed and random-effect meta-analysis models. Separate analyses were conducted after stratification for study design, definition of exposure (employment in a farm/agriculture assuming exposure to pesticides versus exposure to pesticides stipulated), exposed parent, window of exposure, type of leukaemia and biocide category. RESULTS: No statistically significant association between childhood leukaemia and parental occupation as farmers/agricultural workers was observed. When exposure to pesticides was stipulated, positive associations were reported for maternal exposure for all studies combined (mRR: 1.62; 95% CI: 1.22-2.16), in all exposure windows considered and for acute non-lymphocytic leukaemia (ANLL). There was no association with paternal exposure when combining all studies (mRR: 1.14; 95% CI: 0.76-1.69). However, significant increased risks were seen for paternal exposure, in some exposure windows as well as for the biocide category. CONCLUSIONS: The strongest evidence of an increased risk of childhood leukaemia comes from studies with maternal occupational exposure to pesticides. The associations with paternal exposure were weaker and less consistent. These results add to the evidence leading to recommend minimizing parental occupational exposure to pesticides. Our findings also support the need to rely more on studies that clearly stipulate exposure to pesticides rather than those that assume pesticide exposure because of farm/agriculture employment.

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 mug/l (median 0.405 microg/l). The median (range) concentrations of the urinary biomarkers were as follows: B-U 0.27 microg/l (<0.10-5.35), t,t-MA 0.060 mg/l (<0.02-0.92), SPMA 1.40 microg/l (0.20-14.70). Urinary SA concentrations ranged between <3 and 2,211 microg/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 (microg/l r = 0.514, P < 0.001; microg/g cr r = 0.478, P < 0.001) and SPMA (microg/l r = 0.495, P < 0.001; microg/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.

Ototoxicity of toluene and styrene: state of current knowledge.

Noise is the most common preventable cause of irreversible sensorineural hearing loss. During recent years, the results of experimental and human investigations have raised the level of concern about the potential ototoxicity of chemical agents and their interaction with noise. European Directive 2003/10/EC on the minimum health and safety requirements regarding the exposure of workers to the risks arising from noise specifies that the employer shall give particular attention, when carrying out the risk assessment, to, among others, any effects on workers' health and safety resulting from interactions between noise and work-related ototoxic substances. There is, however, currently very little awareness in the occupational health community of the chemical hazards to hearing. The main objective of this review was to analyze the available scientific literature on the ototoxic effects of styrene and toluene, in order to examine dose-response/effect relationships and the relevance of the prevention strategy for people exposed to these solvents. While both solvents appear clearly ototoxic in rats, human data are less straightforward and the existing evidence does not allow characterization of the dose-response/effect relationships; further research is needed. However, once hearing loss is incurred, it is irreversible, and one should be alert to the possible hearing loss induced by toluene and styrene and to the possible additive, potentiating, or synergistic ototoxic effects in case of combined exposure to several chemicals and in case of combined exposure to noise and chemical substances.

Clinical evaluation of a lead mobilization test using the chelating agent dimercaptosuccinic acid.

BACKGROUND: The lead mobilization test reflects the mobilizable and likely toxicologically active fraction of the lead body burden. We propose a safe and convenient protocol for this test, to assess concomitant copper and zinc excretion and to determine the size of the chelatable lead pool in nonoccupationally exposed adults. METHODS: The study population included 80 white adults: 40 controls [median blood lead concentration (PbB), 25 microg/L] and 40 lead-exposed individuals (315 microg/L). After collection of 4- and 24-h baseline urine specimens and a blood sample, dimercaptosuccinic acid (DMSA) was administered orally (1 g), and additional 4- and 24-h urine specimens were obtained. Determinants of the chelatable urinary lead (DMSA-PbU) were traced by linear regression analysis. RESULTS: Urinary DMSA and lead excretion peaked within 2-3 h after DMSA administration. The amounts of DMSA, lead, copper, and zinc recovered in the 4-h urinary collections were highly correlated with those in 24-h collections (r = 0.857, 0.859, 0.958, and 0.757, respectively). At PbB concentrations >300 microg/L, the relationship between DMSA-PbU and PbB showed a steep increase and a widespread dispersion of DMSA-PbU around the regression line. After DMSA, copper and zinc excretion rates were increased up to 91- and 33-fold, respectively. No side effects were reported after DMSA. CONCLUSIONS: Determination of DMSA-PbU in a 4-h collection after DMSA is convenient, apparently safe, and inexpensive. An upper reference limit value of 22 microg/4 h is proposed for Belgian reference individuals. The diagnostic value of DMSA-PbU is likely to be contributive for PbB >300 microg/L.

Potentiation of 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123)-induced liver toxicity by ethanol in guinea-pigs.

HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane), a substitute for the banned chlorofluorocarbons (CFCs), is a structural analogue of the well-known hepatotoxicant halothane. The objectives of these experiments were to investigate (1) whether, like halothane, multiple exposure increases the risk of HCFC-123-induced liver toxicity, and (2) whether ethanol, a potent CYP2E1 inducer, potentiates the liver toxicity of HCFC-123. In experiment 1, male Hartley guinea-pigs were exposed twice a week to 5000 ppm HCFC-123 (4 h) during 3 weeks followed by 2 weeks recovery, and then re-exposed or not during 4 h to 5000 ppm HCFC-123. A group with a single exposure to 5000 ppm HCFC-123 and a control group were also included. In experiment 2, guinea-pigs received 5 or 10% ethanol in drinking water during 12 days before a single 4-h exposure to 5000 ppm HCFC-123. A group receiving 10% only, a group exposed once to 5000 ppm HCFC-123 but not pre-treated with ethanol and a control group were also included. In both experiments, the liver toxicity was assessed, 24 h post-exposure, by the serum activities of alanine aminotransferase (ALT) and isocitrate dehydrogenase (ICDH) as well as by histopathology. In experiment 2 the urinary excretion rate of the main metabolites trifluoroacetic acid (TFA) and chlorodifluoroacetic acid (CDFA) was assessed and CYP2E1 activity was measured by the chlorzoxazone metabolic ratio. Multiple exposure to 5000 ppm HCFC-123 did not cause greater liver damage than a single exposure (ALT, ICDH 3-fold control values). At this level of exposure the liver lesions were totally reversible within two weeks. Ethanol consumption produced CYP2E1 induction, increased urinary excretion of both HCFC-123 metabolites (more than 2-fold the rate measured in the non-induced group) and markedly increased the liver toxicity of HCFC-123 as shown by the serum liver enzyme activities (ALT 8.5-fold increase, ICDH 13-fold increase), and the histopathology. The necrosis was predominantly localised in the intermediate zone of the hepatic lobules with vacuolisation of the centrilobular zones. The effects associated with 10% ethanol pre-treatment were less marked than those observed with ethanol 5% and could be explained by the remaining blood ethanol levels causing an inhibition of HCFC-123 biotransformation. Significant correlations were obtained between the serum enzyme activities, the histopathology, the excretion rate of the metabolites and CYP2E1 activity. It can be concluded that (1) multiple exposure to HCFC-123 did not increase the liver toxicity of HCFC-123 in this experimental model, and (2) chronic ethanol consumption, known to be CYP2E1 inducer, strongly enhanced the biotransformation of HCFC-123 and its liver toxicity.