Marek Jakubowski

Renal and Neurologic Effects of Cadmium, Lead, Mercury, and Arsenic in Children: Evidence of Early Effects and Multiple Interactions at Environmental Exposure Levels

Lead, cadmium, mercury, and arsenic are common environmental pollutants in industrialized countries, but their combined impact on children’s health is little known. We studied their effects on two main targets, the renal and dopaminergic systems, in > 800 children during a cross-sectional European survey. Control and exposed children were recruited from those living around historical nonferrous smelters in France, the Czech Republic, and Poland. Children provided blood and urine samples for the determination of the metals and sensitive renal or neurologic biomarkers. Serum concentrations of creatinine, cystatin C, and β2-microglobulin were negatively correlated with blood lead levels (PbB), suggesting an early renal hyperfiltration that averaged 7% in the upper quartile of PbB levels (> 55 μg/L; mean, 78.4 μg/L). The urinary excretion of retinol-binding protein, Clara cell protein, and N-acetyl-β-d-glucosaminidase was associated mainly with cadmium levels in blood or urine and with urinary mercury. All four metals influenced the dopaminergic markers serum prolactin and urinary homovanillic acid, with complex interactions brought to light. Heavy metals polluting the environment can cause subtle effects on children’s renal and dopaminergic systems without clear evidence of a threshold, which reinforces the need to control and regulate potential sources of contamination by heavy metals.

Low-level environmental lead exposure and intellectual impairment in children--the current concepts of risk assessment.

Lead is an environmental contaminant. The majority of epidemiological research on the health effects of lead has been focused on children, because they are more vulnerable to lead than adults. In children, an elevated blood lead (B-Pb) is associated with reduced Intelligence Quotient (IQ) score. This paper summarizes the current opinions on the assessment of the health risk connected with the children’s environmental exposure to lead. The B-Pb level of concern of 100 μg/l proposed by the US Centers of Disease Control in 1991 was for a long time accepted as the guideline value. In the meantime there has been a significant worldwide decrease of B-Pb levels in children and present geometric mean values in the European countries range from 20 to 30 μg/l. The recent analyses of the association of intelligence test scores and B-Pb levels have revealed that the steepest declines in IQ occur at blood levels < 100 μg/l and that no threshold below which lead does not cause neurodevelopmental toxicity can be defended. European Food Safety Authority (EFSA) concluded in 2010, on the basis of results of Benchmark Dose (BMD) analysis, that an increase in B-Pb of 12 μg/l (BMDL01) could decrease the IQ score by one point. It seems that this value can be used as a “unit risk” to calculate the possible decrease of IQ and, consequently, influence of the low-level exposure to lead (< 100 μg/l) on the health and socioeconomic status of the exposed population.

Biological monitoring of exposure: trends and key developments.

Biological Monitoring of Exposure: Trends and Key Developments: Marek Jakubowski, et al. Nofer Institute of Occupational Medicine, Poland—The concept of biological monitoring (BM) has gained the special interest of individual scientists and international organizations. Today, when analytical problems have almost ceased due to new laboratory techniques and quality assurance systems, the methods for interpretation of results have become the most important issue. There are important discrepancies regarding the role of biological monitoring of occupational exposure between Europe and the United States. BM has been an important tool of medical health surveillance in the European countries. In the United States it belongs rather to the field of occupational hygiene. It seems that both the approaches can be accepted. More attention should be paid to the development of the truly health‐based biomarkers of exposure based on the dose‐effect and dose‐response relationships. New areas of application of BM of occupational exposure include determination of DNA and protein adducts, unchanged volatile organic compounds in urine, monitoring of exposure to pesticides, antineoplastic drugs, hard metals, and polycyclic aromatic hydrocarbons. In the general environment BM is the most valuable tool for acquiring knowledge of current levels of internal exposure to xenobiotics, identifying the hot spots and developments in trends of exposure. BM can provide policy makers with more accurate information on the control measures undertaken. At present, the main areas include heavy metals, persistent organic pollutants and pesticides. BM of chemical exposure has become increasingly important in the assessment of the health risk in occupational and environmental medicine. Therefore it would be worthwhile to include BM in the curricula for the training of occupational hygienists.

Interest of genotyping and phenotyping of drug-metabolizing enzymes for the interpretation of biological monitoring of exposure to styrene

In the field of occupational and/or environmental toxicology, the measurement of specific metabolites in urine may serve to assess exposure to the parent compounds (biological monitoring of exposure). Styrene is one of the chemicals for which biological monitoring programs have been validated and implemented in environmental and occupational medicine. However, inter-individual differences in the urinary excretion exist both for the main end-products (mandelic acid and phenylglyoxylic acid) and for its specific mercapturic acids (phenylhydroxyethylmercapturic acids, PHEMA). This limits to a certain extent the use of these metabolites for an accurate assessment of styrene exposure. In a group of 26 volunteers selected with relevant genotypes, and exposed to styrene vapours (50 mg/m3, 8 h) in an inhalation chamber, we evaluated whether genotyping or phenotyping relevant drug-metabolizing enzymes (CYP2E1, EPHX1, GSTM1, GSTT1 and GSTP1) may help to explain the observed inter-individual variability in the urinary metabolite excretion. Peripheral blood lymphocytes were used for genotyping and as reporter cells for the phenotyping of CYP2E1 and EPHX1. The GSTM1 genotype was clearly the most significant parameter explaining the variance in urinary PHEMA excretion (6-fold lower in GSTM1 null subjects; P < 0.0001) so that systematic GSTM1 genotyping should be recommended routinely for a correct interpretation of PHEMA urinary levels. Variant alleles CYP2E1*6 (7632T>A) and His113EPHX1 were associated with a significant reduction of, respectively, the expression (P = 0.047) and activity (P = 0.022) of the enzyme in peripheral blood lymphocytes. In combination with GSTM1 genotyping, the phenotyping approach also contributed to improve the interpretation of urinary results, as illustrated by the combined effect of CYP2E1 expression and GSTM1 allelic status that explained 77% of the variance in PHEMA excretion and allows the recommendation of mercapturates as specific and reliable biomarkers of exposure to styrene.

Biological monitoring for exposure to volatile organic compounds (VOCs) (IUPAC Recommendations 2000)

This paper deals with the appropriate application of biological monitoring (BM) for exposure to volatile organic compounds (VOCs). Sampling guidelines, approved analytical procedures, quality control systems, detailed aspects for the interpretation of biomonitoring data, a compilation of international biological action values for VOC exposure at the workplace (e.g., BAT, BEI®), and state of the art reference values are outlined or referred to in this review for recommendation as guidelines for health professionals in occupational and environmental settings. VOCs are frequently encountered at the workplace, in daily routines and widely used consumer products. They cover a broad spectrum of chemical classes with different physicochemical and biological properties. Inhalation is a prominent route of exposure due to their volatility but many VOCs can quite readily be absorbed through the skin. BM allows assessment of the integrated exposure by different routes including inhalation and concomitant dermal and oral uptake—a helpful tool for relating exposure to body burden and possible health effects. Because of the different toxicological profiles of VOCs, no uniform approach for BM can be recommended. VOCs in blood and urinary VOC metabolites are most often applied for BM. Limit values for workplace exposure have been established for many VOCs. In this field, profound analytical methodology and extensive experience exist in numerous international scientific laboratories for reliable routine application. Contamination and loss of VOCs during specimen collection, storage and sample treatment, and applied calibration procedure are the most important uncertainties for analytical quantification of VOCs in blood. For interpretation of the analytical results appropriate time of sampling, according to toxicokinetics of the compound, is crucial due to VOC elimination with short but differing biological half-lives. Lifestyle factors (such as smoking habits, alcohol consumption, and dietary habits), workload, personal working habits, exposure to VOC mixtures and endogeous factors (as genetic polymorphism for VOC metabolizing enzymes, body mass) contribute to BM results and have to be considered in detail. Future analytical work should focus on the improvement of analytical methodology of VOC determination in body fluids at low-level environmental exposure and evaluation of corresponding reference intervals.

Blood lead in the general population in Poland

Lead concentration in venous blood (Pb-B) was investigated in 1122 inhabitants (including 555 children under 10 years of age) of five Polish towns with no large industrial lead emitters (group I) and in 1246 persons (707 children under 10 years of age) living in the vicinity of zinc and copper mills (group II). The samples were analysed using electrothermal atomic absorption spectrometry (ETAAS) and the performing laboratory participated in the external quality control scheme during the study period (1992–1994). In group I the mean geometric Pb-B concentrations ranged from 23.8 to 48.3μg/l in females, from 42.5 to 76.8 μg/l in males and from 29.9 to 62.5 μg/l in children. In group II, the mean geometric Pb-B concentrations were significantly higher and ranged from 49.4 to 105 μg/l in females, from 98.5 to 149 μg/l in males and from 73.7 to 114 μg/l in children, the values decreasing as the distance from the source of emission increased. Cigarette smoking was found to bring about a significant increase in Pb-B levels for both males and females. A significant correlation was noted between Pb-B concentrations in mothers and children. The ratio between child and maternal Pb-B concentrations amounted to approximately 1.0 for group I and to about 0.5 for group II. These findings indicate the necessity of undertaking preventive activities over the lead-contaminated areas. However, the lead hazard in Poland seems to be associated with point sources of emission and hence does not concern the whole population.

Calculating the retention of volatile organic compounds in the lung on the basis of their physicochemical properties

In the workplace, deliberate or accidental exposure to volatile organic compounds (VOCs) may occur by ingestion, but more usually through inhalation or dermal contact. The basic model of occupational exposure assumes repeated inhalation exposure during long periods of time, such as 8-h daily, 40-h per working week. Evaluation of the systemic health effects of industrial chemicals can be based on biological levels or internal doses absorbed in dermal or inhalation exposures. The lungs are the primary route of absorption in exposure to gases, vapors, and aerosols. In inhalation exposure, the dose absorbed can be calculated using the following equation: [formula in text] where C, concentration in the air; T, duration of exposure; V, lung ventilation; R, lung retention expressed as % of intake. As lung retention of VOCs has been studied on human volunteers in costly and time-consuming chamber-type experiments, available data are limited. To calculate dosage for the purpose of risk assessment, the default value of 100% is used. As the lung retention of VOCs in lungs can vary from less than 20 to more than 90%, a possibility of predicting the retention values on the basis of blood/air partition coefficients (K(B)) has been investigated. Lung retention data for 36 compounds were obtained from the existing scientific literature. These values derive from human volunteer studies lasting at least 2h. The K(B) values were either the already published experimental data or were calculated based on their physicochemical properties using a published solvation equation. The compounds under study were divided arbitrarily into two groups: water soluble (>10 g/l) and slightly soluble in water (<10 g/l) compounds. For water soluble compounds, the correlation between K(B) and lung retention was high (r=0.75 and 0.73 respectively); this referred both to K(B) values obtained experimentally or calculated in this report. For the compounds slightly soluble in water, the respective values amounted to 0.79 and 0.82. The obtained results indicate that VOC retention in the lung can be calculated solely on the basis of the partition coefficient K(B). As the descriptors used in the solvation equation can be predicted from chemical structure, this finding indicates that it is possible to assess lung retention for any chemical structure of VOC. The model described in the present report can be a practical alternative to the necessity costly and long-lasting chamber-type experiments which are also questionable on ethical grounds.

Exposure determinants of cadmium in European mothers and their children

The metal cadmium (Cd) is a widespread environmental pollutant with documented adverse effects on the kidneys and bones from long-term environmental exposure, but with insufficiently elucidated public health consequences such as risk of cardiovascular disease, hormone-related cancer in adults and developmental effects in children. This study is the first pan-European human biomonitoring project that succeeded in performing harmonized measurements of Cd in urine in a comparable way in mother-child couples from 16 European countries. The aim of the study was to evaluate the overall Cd exposure and significant determinants of Cd exposure. A study population of 1632 women (24-52 years of age), and 1689 children (5-12 years of age), from 32 rural and urban areas, was examined within a core period of 6 months in 2011-2012. Women were stratified as smokers and non-smokers. As expected, smoking mothers had higher geometric mean (gm) urinary cadmium (UCd; 0.24 µg/g crea; n=360) than non-smoking mothers (gm 0.18 µg/g crea; n=1272; p<0.0001), and children had lower UCd (gm 0.065 µg/g crea; n=1689) than their mothers at the country level. Non-smoking women exposed to environmental tobacco smoke (ETS) at home had 14% (95% CI 1-28%) higher UCd than those who were not exposed to ETS at home (p=0.04). No influence of ETS at home or other places on UCd levels was detected in children. Smoking women with primary education as the highest educational level of the household had 48% (95% CI 18-86%) higher UCd than those with tertiary education (p=0.0008). The same observation was seen in non-smoking women and in children; however they were not statistically significant. In children, living in a rural area was associated with 7% (95% CI 1-13%) higher UCd (p=0.03) compared to living in an urban area. Children, 9-12 years had 7% (95% CI 1-13%) higher UCd (p=0.04) than children 5-8 years. About 1% of the mothers, and 0.06% of the children, exceeded the tolerable weekly intake (TWI) appointed by EFSA, corresponding to 1.0 µg Cd/g crea in urine. Poland had the highest UCd in comparison between the 16 countries, while Denmark had the lowest. Whether the differences between countries are related to differences in the degree of environmental Cd contamination or to differences in lifestyle, socioeconomic status or dietary patterns is not clear.

Internal standardization in the head space analysis of organic solvents in blood

SummaryThe determination of toluene, benzene, ethylbenzene and trichloro-ethylene in blood by means of a gas chromatographic head space technique is presented. Internal standards are added to the blood samples in the form of water solutions of volatile hydrocarbons in proportion 2:1. This enables application of the internal standard within the broad range of concentrations and in addition increases significantly the concentrations of investigated compounds in the gas phase of incubation vessel.Elaborated methods were applied for determinations of ethylbenzene in blood samples collected after experimental inhalation exposure and for evaluation of the rate of disappearance of benzene, toluene and trichloro-ethylene from blood after acute accidental or suicidal intoxications.

Unmetabolized VOCs in urine as biomarkers of low level occupational exposure

OBJECTIVES To compare the usefulness of determining unchanged forms of volatile organic compounds (VOCs), namely toluene (TOL), ethylbenzene (EB) and xylene (XYL), in urine with the effectiveness of the already used biomarkers of occupational exposure. MATERIALS AND METHODS Surveys were conducted in two workplaces (paint factory and footwear factory). In total, 65 subjects participated in the study. Air samples were collected using individual samplers during work shift. Urine and blood samples were collected at the end of work shift. Urine samples were analyzed for unchanged compounds and selected metabolites, while blood samples were tested for unchanged compounds. VOCs in blood and urine were determined by solid phase microextraction gas chromatography (SPME-GC-MS). RESULTS In the paint factory, the geometric mean (GM) concentrations of VOCs in the air ranged as follows: 0.2-4.7 mg/m(3) for TOL, 0.4-40.9 mg/m(3) for EB and 0.1-122.6 mg/m(3) for XYL. In the footwear factory, the GM concentration of TOL in the air amounted to 105.4 mg/m(3). A significant correlation (p < 0.05) was observed between VOCs in blood, urine and air. The regression analyses performed for paint factory workers showed that TOL-U and TOL-B were better biomarkers of exposure (r = 0.72 and r = 0.81) than benzoic acid (r = 0.12) or o-cresol (r = 0.55). CONCLUSION The findings of the study point out that the concentration of unchanged VOCs in urine can be a reliable biological indicator of low level occupational exposure to these compounds.