Air pollution-induced placental alterations: an interplay of oxidative stress, epigenetics, and the aging phenotype?

According to the "Developmental Origins of Health and Disease" (DOHaD) concept, the early-life environment is a critical period for fetal programming. Given the epidemiological evidence that air pollution exposure during pregnancy adversely affects newborn outcomes such as birth weight and preterm birth, there is a need to pay attention to underlying modes of action to better understand not only these air pollution-induced early health effects but also its later-life consequences. In this review, we give an overview of air pollution-induced placental molecular alterations observed in the ENVIRONAGE birth cohort and evaluate the existing evidence. In general, we showed that prenatal exposure to air pollution is associated with nitrosative stress and epigenetic alterations in the placenta. Adversely affected CpG targets were involved in cellular processes including DNA repair, circadian rhythm, and energy metabolism. For miRNA expression, specific air pollution exposure windows were associated with altered miR-20a, miR-21, miR-146a, and miR-222 expression. Early-life aging markers including telomere length and mitochondrial DNA content are associated with air pollution exposure during pregnancy. Previously, we proposed the air pollution-induced telomere-mitochondrial aging hypothesis with a direct link between telomeres and mitochondria. Here, we extend this view with a potential co-interaction of different biological mechanisms on the level of placental oxidative stress, epigenetics, aging, and energy metabolism. Investigating the placenta is an opportunity for future research as it may help to understand the fundamental biology underpinning the DOHaD concept through the interactions between the underlying modes of action, prenatal environment, and disease risk in later life. To prevent lasting consequences from early-life exposures of air pollution, policy makers should get a basic understanding of biomolecular consequences and transgenerational risks.

Manganese exposure and cognitive deficits: a growing concern for manganese neurotoxicity.

This symposium comprised five oral presentations dealing with recent findings on Mn-related cognitive and motor changes from epidemiological studies across the life span. The first contribution highlighted the usefulness of functional neuroimaging of the central nervous system (CNS) to evaluate cognitive as well as motor deficits in Mn-exposed welders. The second dealt with results of two prospective studies in Mn-exposed workers or welders showing that after decrease of Mn exposure the outcome of reversibility in adverse CNS effects may differ for motor and cognitive function and, in addition the issue of plasma Mn as a reliable biomarker for Mn exposure in welders has been addressed. The third presentation showed a brief overview of the results of an ongoing study assessing the relationship between environmental airborne Mn exposure and neurological or neuropsychological effects in adult Ohio residents living near a Mn point source. The fourth paper focused on the association between blood Mn and neurodevelopment in early childhood which seems to be sensitive to both low and high Mn concentrations. The fifth contribution gave an overview of six studies indicating a negative impact of excess environmental Mn exposure from air and drinking water on children's cognitive performance, with special attention to hair Mn as a potential biomarker of exposure. These studies highlight a series of questions about Mn neurotoxicity with respect to cognitive processes, forms and routes of exposure, adequate biomarkers of exposure, gender differences, susceptibility and exposure limits with regard to age.

Telomere biology in giant cell tumour of bone.

Giant cell tumour of bone (GCTB) is a benign bone tumour known for the unpredictable clinical behaviour of recurrences and, in rare instances, distant metastases. It consists of uniformly distributed osteoclastic giant cells in a background of mononuclear rounded and spindle-shaped cells. Cytogenetically, telomeric associations are the most common chromosomal aberrations, which, however, are normally almost exclusively found in high-grade malignancies. GCTB has often been regarded as a polyclonal tumour, but more recently a recurrent specific aberration was reported, which suggests a possible role for disturbed telomere maintenance. Here we further investigate telomere maintenance in GCTB using 19 samples from 19 patients. A combination of immunofluorescence and FISH was performed, applying antibodies directed against promyelocytic leukaemia body-related antigen and hTERT and using telomere peptide nucleic acid probes. The TRAP assay and telomere restriction fragment length analysis were performed for functional detection of telomerase activity and alternative telomere lengthening. Both osteoclastic giant cells and mononuclear cells showed positivity for hTERT and promyelocytic leukaemia body-related antigen. In most mononuclear cells, co-expression was present. The TRAP assay demonstrated heterogeneous telomerase activity, while telomere restriction fragment length analysis showed non-heterogeneous telomere lengths, indicating the absence of alternative telomere lengthening. Confocal microscopy showed stereometric co-localization of nucleolin with promyelocytic leukaemia body-related antigen in association with telomeres in the spindle-shaped cells. hTERT was more diffusely distributed throughout the nucleus. Our results show that GCTB demonstrates remarkable telomere maintenance of activated telomerase and inactivated alternative telomere lengthening in the presence of normal mean telomere restriction fragment lengths. These findings strongly suggest that these aggregates, while activating telomerase, are part of a structural telomere protective-capping mechanism rather than of a telomere-lengthening mechanism. Telomere maintenance could be considered an important key factor in the pathogenesis of GCTB.

Arterial structure and function and environmental exposure to cadmium.

OBJECTIVES: Few studies have addressed the effect of cadmium toxicity on arterial properties. METHODS: We investigated the possible association of 24 h urinary cadmium excretion (an index of lifetime exposure) with measures of arterial function in a randomly selected population sample (n = 557) from two rural areas with low and high environmental exposure to cadmium. RESULTS: 24 h urinary cadmium excretion was significantly higher in the high compared with the low exposure group (p<0.001). Even though systolic (p = 0.42), diastolic (p = 0.14) and mean arterial pressure (p = 0.68) did not differ between the high and low exposure groups, aortic pulse wave velocity (p = 0.008), brachial pulse pressure (p = 0.026) and femoral pulse pressure (p = 0.008) were significantly lower in the high exposure group. Additionally, femoral distensibility (p<0.001) and compliance (p = 0.001) were significantly higher with high exposure. Across quartiles of 24 h urinary cadmium excretion (adjusted for sex and age), brachial (p for trend = 0.015) and femoral (p for trend = 0.018) pulse pressure significantly decreased and femoral distensibility (p for trend = 0.008) and compliance (p for trend = 0.007) significantly increased with higher cadmium excretion. After full adjustment, the partial regression coefficients confirmed these associations. Pulse wave velocity (beta = -0.79+/-0.27; p = 0.004) and carotid (beta = -4.20+/-1.51; p = 0.006), brachial (beta = -5.43+/-1.41; p = 0.001) and femoral (beta = -4.72+/-1.74; p = 0.007) pulse pressures correlated negatively, whereas femoral compliance (beta = 0.11+/-0.05; p = 0.016) and distensibility (beta = 1.70+/-0.70; p = 0.014) correlated positively with cadmium excretion. CONCLUSION: Increased cadmium body burden is associated with lower aortic pulse wave velocity, lower pulse pressure throughout the arterial system, and higher femoral distensibility.

A battery of DNA effect biomarkers to evaluate environmental exposure of Flemish adolescents.

The present paper deals with the evaluation of a battery of genotoxicity biomarkers in healthy Flemish adolescents and their relation with common pollutants occurring in their life environment. DNA damage as reflected by the comet assay appeared to be most sensitive to ozone (partial r(2) = 0.102, p < 0.00001), and to a lesser extent to ortho-cresol (partial r(2) = 0.055; p = 0.001) and 1-hydroxy-pyrene (1-OH-pyrene, partial r(2) = 0.031; p = 0.013). 8-hydroxy-deoxyguanosine (8-OHdG) was only related to ortho-cresol (r(2) = 0.069; p < 0.007). Interestingly, the comet assay results and urinary 8-OHdG concentrations were positively correlated with a Pearson r = 0.21 (p = 0.003, N = 200). Logistic regression models revealed significant relations between chromatid breaks and 1-OH-pyrene (relative risk (RR): 1.58; p = 0.008), and t,t-muconic acid (RR: 1.71; p = 0.014). There was no correlation between micronucleus formation or occurrence of chromosomal or chromatid breaks on the one hand and comet or 8-OHdG results on the other hand. Thus, in this study the comet assay on whole blood samples and urine 8-OHdG measurements especially appeared sensitive biomarkers for assessing the genetic effects of environmental pollutants to which adolescents may be exposed.

Neurobehavioral functioning after cessation of manganese exposure: a follow-up after 14 years.

BACKGROUND: Little is known on the long-term course of early manganese (Mn) neurotoxic effects. Mn alloy workers were examined in a follow-up study 14 years after exposure ceased at a Canadian facility. METHODS: The same battery of neurofunctional tests used in the initial examination in 1990 was administered to 77 Mn-workers and 81 referents in 2004. RESULTS: Manganese-workers had poorer scores compared to referents both in the initial and follow-up examinations for several motor tasks of the Luria Motor Scale. At follow-up, older Mn-workers (>45 years at cessation of exposure) had poorer scores than referents for tests of cognitive flexibility. Cumulated exposure was associated with poorer test scores for certain neuromotor and cognitive tests and on a mood scale. Differences on certain tests observed at initial examination were not present at follow-up. CONCLUSIONS: Manganese exposure was associated with persistent deficits for certain neuromotor functions, cognitive flexibility, and adVerse mood states, while recovery occurred for other functions.

An epidemiological re-appraisal of the association between blood pressure and blood lead: a meta-analysis.

Studies on the possible association between blood pressure and blood lead have reached divergent conclusions. In a previous meta-analysis, a doubling of the blood lead concentration was associated with a 1.0/0.6 mm Hg increase in systolic and diastolic blood pressure (BP). This meta-analysis updates the analysis originally performed in 1994. Articles on the association between BP and blood lead were identified from computer searches from January 1980 to February 2001 using the Medical Literature Analysis and Retrieval System. Of the studies reviewed, 31 provided sufficient details to be considered. The meta-analysis included 58518 subjects recruited from the general population in 19 surveys and from occupationally exposed groups in 12 studies. In all but four studies, the results were adjusted for age, and most studies took into account additional confounding factors such as body mass index and the use of alcohol and medication. Weighted joint P-values were calculated using Stouffer's procedure. The association between BP and blood lead was similar in both men and women. In the combined studies, a two-fold increase in blood lead concentration was associated with a 1.0 mm Hg rise in the systolic pressure (95% CI +0.5 to +1.4 mm Hg; P < 0.001) and with a 0.6 mm Hg increase in the diastolic pressure (95% CI +0.4 to +0.8 mm Hg; P < 0.001). On balance, this meta-analysis suggests that there can only be a weak association between BP and blood lead.

Non invasive quantification of manganese deposits in the rat brain by local measurement of NMR proton T1 relaxation times.

Up to now, there is no reliable non invasive biomarker for the concentration of manganese (Mn) in the brain after intoxication to this metal. The aim of the present experimental study was to determine the predictive value of the localized measurement of the proton NMR relaxation time T1 as a quantitative estimation of the concentration of Mn in brain. The relationship of the proton relaxation rates (1/T1) was established in rat brain homogenates as a function of the Mn, iron, and copper concentration. Subsequently, an experimental model of Mn neurotoxicity was used: rats were stereotactically injected with increasing amounts of Mn2+ (as MnCl2) in the ventricles. After 3 weeks, local measurements of T1 were carried out in live rats. They were then sacrificed in order to sample the striatum, the cortex, and the cerebellum from the brain and to perform a quantitative determination of the concentration of Mn in these tissues by atomic absorption spectrometry (AAS). The results indicate excellent correlation coefficients between relaxation rates and tissue Mn concentrations (r= 0.84, 0.77 and 0.92 for the striatum, the cortex and the cerebellum, respectively). This methodology offers a unique toolfor monitoring the degree of Mn concentration in different areas of the brain in animal models of Mn intoxication. It will be useful for evaluating the efficacy of treatments aimed at decreasing the metal in the brain. The method could be potentially useful for being transposed in the clinical situation for monitoring Mn-exposed workers.

Renal function, cytogenetic measurements, and sexual development in adolescents in relation to environmental pollutants: a feasibility study of biomarkers.

BACKGROUND: Human exposure to chemicals is normally monitored by measurement of environmental pollutants in external media. We investigated whether biomarkers in adolescents can show exposure to, and health effects of, common environmental pollutants. METHODS: We recruited 200 17-year-old adolescents (120 girls) from a rural control area and from two suburbs polluted by a lead smelter and two waste incinerators. We measured biomarkers of exposure and of effect in blood and urine samples, and obtained questionnaire data. School doctors measured testicular volume and staged sexual maturation. FINDINGS: Internal exposure was mostly within current standards. Concentrations of lead and cadmium in blood, PCBs (polychlorinated biphenyls) and dioxin-like compounds in serum samples, and metabolites of VOCs (volatile organic compounds) in urine were higher in one or both suburbs than in the control area. Children who lived near the waste incinerators matured sexually at an older age than others, and testicular volume was smaller in boys from the suburbs than in controls. Biomarkers of glomerular or tubular renal dysfunction in individuals were positively correlated with blood lead. Biomarkers of DNA damage were positively correlated with urinary metabolites of PAHs (polycyclic aromatic hydrocarbons) and VOCs. Interpretation Biomarkers can be used to detect environmental exposure to pollutants and measure their biological effects before overt disease develops. Our findings suggest that current environmental standards are insufficient to avoid measurable biological effects.

Determination of germanium in urine and its usefulness for biomonitoring of inhalation exposure to inorganic germanium in the occupational setting.

The present study aimed to assess whether urinary germanium concentration can be used as a biomarker of inhalation exposure to airborne dust from metallic germanium (Ge) or GeO2 in the occupational setting. A novel hydride generation-based method coupled with fow-injection graphite furnace atomic absorption spectrometry (HG/FI-GFAAS) was developed for the determination of urinary germanium. It was found that urinary germanium concentration could be reliably determined by a standard additions method after thorough digestion of the urine and careful pH adjustment of the digest. The limit of detection (LOD) in urine for the HG/FI-GFAAS method was 0.25 microg Ge L(-1). In Belgian control male subjects, the urinary germanium concentration was below this LOD. In 75 workers currently exposed to inorganic germanium compounds, respirable and inhalable concentrations of germanium in the aerosols were measured on Monday and Friday at the job sites using personal air samplers. Spot-urine samples were collected on the same days before and after the work shift. The germanium concentrations of respirable dust correlated very well with those of inhalable dust and represented 20% of the inhalable fraction. Workers exposed to metallic Ge dust were on average ten times less exposed to germanium than those whose exposure involved GeO2 (3.4 versus 33.8 microg Ge m(-3)). This difference was reflected in the urinary germanium concentrations (3.4 versus 23.4 microg Ge g(-1) creatinine). Regression analysis showed that the concentration of germanium in the inhalable fraction explained 42% of the post-shift urinary germanium concentration either on Monday or on Friday, whereas in a subgroup of 52 workers mainly exposed to metallic germanium dust 57% (r = 0.76) of the Monday post-shift urinary germanium was explained. Urinary elimination kinetics were studied in seven workers exposed to airborne dust of either metallic Ge or GeO2. The urinary elimination rate of germanium was characterised by half-times ranging from 8.2 to 18.1 h (on average 12 h 46 min). The present study did not allow discrimination between the germanium species to which the workers were exposed, but it showed fast urinary elimination kinetics for inhalation exposure to dust of metallic Ge and GeO2. It pointed out that urine samples taken at the end of the work shift can be used for biological monitoring of inorganic germanium exposure in the occupational setting.

Neurobehavioural changes and persistence of complaints in workers exposed to styrene in a polyester boat building plant: influence of exposure characteristics and microsomal epoxide hydrolase phenotype.

OBJECTIVES: To investigate neurobehavioural effects and the persistence of complaints in workers exposed to styrene relative to exposure characteristics and the enzyme microsomal epoxide hydrolase (mEH) activity. METHODS: A cross sectional study was performed in a retrospective cohort of workers of a polyester boat building plant 3 years after the main activity shut down in 1989. Workers still currently exposed to a much lower concentration of styrene in air than before (n=27) and formerly exposed workers (n=90) were compared with matched control workers (n=64). Currently and formerly exposed workers laminated 4700 and 3610 hours on average at mean exposure to styrene concentrations of 148 and 157 mg/m(3) respectively. A structured neurological anamnesis into former and present complaints, the NSC-60 questionnaire, and computer assisted neurobehavioural tests (NES) were administered. The mEH phenotype activity was measured in lymphocytes with a novel gas chromatography-mass spectroscopy (GC-MS) method. RESULTS: For the period before 1989, currently and formerly exposed workers reported more complaints than control workers which related well with the mean exposure to airborn styrene concentration (p=0.03). Most complaints disappeared after the end of exposure, although the chest, equilibrium, and somatic category scores of NSC-60 and the number of workers reporting diminished sense of smell remained increased in formerly exposed workers (p

Epidemiological survey of workers exposed to inorganic germanium compounds.

OBJECTIVES: To assess occupational exposure to inorganic germanium (Ge) in workers from a producing plant, and to assess the health of these workers, with a special focus on respiratory, kidney, and liver functions. METHODS: Cross sectional study of 75 workers exposed to Ge and 79 matched referents. Exposure was characterised by measuring air and urine concentrations of the element during a typical working week, and health was assessed by a questionnaire, clinical examination, lung function testing, chest radiography, and clinical chemistry in serum and urine, including high and low molecular weight urinary proteins. RESULTS: Airborne concentrations of Ge (inhalable fraction) ranged from 0.03 to 300 micrograms/m, which was reflected by increased urinary excretion of Ge (0.12-200 micrograms/g creatinine, after the shift at the end of the working week). Lung, liver, and haematological variables were not significantly different between referents and workers exposed to Ge. A slightly higher urinary concentration of high molecular weight proteins (albumin and transferrin) was found in workers exposed to Ge, possibly reflecting subclinical glomerular changes. No relation was found between the intensity or duration of exposure and the urinary concentration of albumin. No difference between referents and workers exposed to Ge was found for other renal variables. CONCLUSIONS: Measurement of urinary Ge can detect occupational exposure to inorganic Ge and its compounds. It is prudent to recommend the monitoring of renal variables in workers exposed to Ge.

Exposure to cadmium and conventional and ambulatory blood pressures in a prospective population study. Public Health and Environmental Exposure to Cadmium Study Group.

This prospective population study investigated in a random sample of 692 subjects (age 20-83 years) how changing environmental exposure to cadmium influenced blood pressure (BP) and the incidence of hypertension. At baseline (1985 to 1989; participation rate, 78%) and follow-up (1991 to 1995; re-examination rate, 81%), blood pressure was measured by conventional sphygmomanometry (CBP; 15 readings in total) and, at follow-up, also by 24-h ambulatory blood pressure monitoring (ABP). Systolic/diastolic CBP at baseline averaged 128.4/77.3 mm Hg. At baseline, blood cadmium concentration (B-Cd) and urinary cadmium excretion (U-Cd) averaged (geometric means) 11.1 nmol/L and 10.2 nmol/24 h. Over 5.2 years (median follow-up), B-Cd fell by 29.6% and U-Cd by 15.2%. B-Cd fell less in subjects living closer to three zinc smelters and in premenopausal women. During follow-up, systolic CBP decreased by 2.2 mm Hg in men and remained unchanged in women, and diastolic CBP increased by 1.8 mm Hg in both sexes. No relationship could be demonstrated between the secular trends in CBP and B-Cd or U-Cd or between B-Cd or U-Cd at baseline and the incidence of hypertension. In addition, in cross-sectional analyses involving the average of all available CBP measurements in each participant or 24-h ABP at follow-up (mean, 119.1/71.4 mm Hg), blood pressure was not correlated with B-Cd or U-Cd. In conclusion, environmental exposure to cadmium was not associated with higher CBP or 24-h ABP or with increased risk for hypertension. The lesser fall in B-Cd in the residents living closer to the zinc smelters or in premenopausal women underscores the necessity to sanitize cadmium-polluted areas and to systematically reinforce the preventive measures to be adopted by exposed communities to reduce cadmium uptake.

Neurobehavioural effects of occupational exposure to cadmium: a cross sectional epidemiological study.

BACKGROUND: A patient with unexplained minor behavioural changes associated with an axonal sensorimotor polyneuropathy had a history of chronic occupational exposure to cadmium (Cd). Although animal studies have shown that Cd is a potent neurotoxicant, little is known about its toxicity for the human central nervous system. The aim of this study was to investigate the toxic potential of chronic occupational exposure to Cd on neurobehavioural functions. METHODS: A cross sectional epidemiological study was conducted ina group of Cd workers and an age matched control group. Eighty nine adult men (42 exposed to Cd and 47 control workers) were given a blinded standardised examination that consisted of computer assisted neurobehavioural tests (neurobehavioural examination system), a validated questionnaire to assess neurotoxic complaints (neurotoxicity symptom checklist--60, NSC-60), and a standardised self administered questionnaire to detect complaints consistent with peripheral neuropathy and dysfunction of the autonomic nervous system. Historical and current data on biomonitoring of exposure to Cd, either the highest value of Cd in urine (CdU in microgram Cd/g creatinine) of each Cd worker during work (CdUmax) or the current value (CdUcurrent) of each control, were available as well as data on microproteinuria. RESULTS: Cd workers (CdUmax: mean (range), 12.6 (0.4-38.4)) performed worse than the controls (CdUcurrent: mean (range), 0.7 (0.1-2.0)) on visuomotor tasks, symbol digit substitution (p = 0.008), and simple reaction time to direction (p = 0.058) or location (p = 0.042) of a stimulus. In multiple linear regression analysis, symbol digit substitution, simple direction reaction time test, and simple location reaction time test were significantly related to CdUmax, (beta = 0.35 (p < 0.001), beta = 0.25 (p = 0.012), and beta = 0.23 (p = 0.021) respectively). More complaints consistent with peripheral neuropathy (p = 0.004), complaints about equilibrium (p = 0.015), and complaints about concentration ability (p = 0.053) were found in the group exposed to Cd than in the control group, and these variables correlated positively with CdUmax (peripheral neuropathy: beta = 0.38, p < 0.001; equilibrium: beta = 0.22, p = 0.057; concentration ability: beta = 0.27, p = 0.020). CONCLUSION: Slowing of visuomotor functioning on neurobehavioural testing and increase in complaints consistent with peripheral neuropathy, complaints about equilibrium, and complaints about concentration ability were dose dependently associated with CdU. Age, exposure to other neurotoxicants, or status of renal function could not explain these findings. The present study also indicates that an excess of complaints may be detected in Cd workers before signs of microproteinuria induced by Cd occur.

Usefulness of biomarkers of exposure to inorganic mercury, lead, or cadmium in controlling occupational and environmental risks of nephrotoxicity.

A successful prevention of renal diseases induced by occupational or environmental exposure to toxic metals such as mercury (Hg), lead (Pb), or cadmium (Cd) largely relies on the capability to detect nephrotoxic effects at a stage when they are still reversible or at least not yet compromising renal function. The knowledge of dose-effect/response relations has been useful to control nephrotoxic effects of these metals through a "biological monitoring of exposure approach". Chronic occupational exposure to inorganic mercury (mainly mercury vapor) may result in renal alterations affecting both tubules and glomeruli. Most of the structural or functional renal changes become significant when urinary mercury (HgU) exceeds 50 micrograms Hg/g creatinine. However, a marked reduction of the urinary excretion of prostaglandin E2 was found at a HgU of 35 micrograms Hg/g creatinine. As renal changes evidenced in moderately exposed workers were not related to the duration of Hg exposure, it is believed that those changes are reversible and mainly the consequence of recently absorbed mercury. Thus, monitoring HgU is useful for controlling the nephrotoxic risk of overexposure to inorganic mercury; HgU should not exceed 50 micrograms Hg/g creatinine in order to prevent cytotoxic and functional renal effects. Several studies on Pb workers with blood lead concentrations (PbB) usually below 70 micrograms Pb/dl have disclosed either no renal effects or subclinical changes of marginal or unknown health significance. Changes in urinary excretion+ of eicosanoids was not associated with deleterious consequences on either the glomerular filtration rate (GFR)--estimated from the creatinine clearance (C(Cr))--or renal hemodynamics if the workers' PbB was kept below 70 micrograms Pb/dL. The health significance of a slight renal hyperfiltration state in Pb workers is yet unknown. In terms of Pb body burden, a mean tibia Pb concentration of about 60 micrograms Pb/g bone mineral (that is 5 to 10 times the average "normal" concentration corresponding to a cumulative PbB index of 900 micrograms Pb/dL x year) did not affect the GFR in male workers. This conclusion may not necessarily be extrapolated to the general population, as recent studies have disclosed inverse associations between PbB and GFR at low-level environmental Pb exposure. A 10-fold increase in PbB (e.g., from 4 to 40 micrograms Pb/dL) was associated with a reduction of 10-13 mL/min in the C(Cr) and the odds ratio of having impaired renal function (viz. C(Cr) < 5th percentile: 52 and 43 mL/min in men and women, respectively) was 3.8 (CI 1.4-10.4; p = 0.01). However, the causal implication of Pb in this association remains to be clarified. The Cd concentration in urine (CdU) has been proposed as an indirect biological indicator for Cd accumulation in the kidney. Several biomarkers for detecting nephrotoxic effects of Cd at different renal sites were studied in relation to CdU. In occupationally exposed males, the CdU thresholds for significant alterations of renal markers ranged, according to the marker, from 2.4 to 11.5 micrograms Cd/g creatinine. A threshold of 10 micrograms Cd/g creatinine (corresponding to 200 micrograms Cd/g renal cortex: the critical Cd concentration in the kidney) is confirmed for the occurrence of low-molecular-mass proteinuria (functional effect) and subsequent loss of renal filtration reserve capacity. In workers, microproteinuria was found reversible when reduction or cessation of exposure occurred timely when tubular damage was still mild (beta(2)-microglobulinuria < 1500 micrograms/g creatinine) and CdU had never exceeded 20 micrograms Cd/g creatinine. As the predictive significance of other renal changes (biochemical or cytotoxic) is still unknown, it seems prudent to recommend that occupational exposure to Cd should not allow that CdU exceeds 5 micrograms Cd/g creatinine.(ABSTRACT TRUNCATED)

Prospective study on the reversibility of neurobehavioral effects in workers exposed to manganese dioxide.

In 1987, a cross-sectional study in a dry-alkaline battery plant in Belgium revealed subclinical neurobehavioral dysfunctions associated with inhalation exposure to manganese dioxide (MnO2) particulate. The overall geometric mean of the time-weighted average concentration of manganese (Mn) in "total" dust (MnT) amounted, at that time, to 1 mg Mn/m3 and the duration of exposure was 5.5 years on average. An 8-year longitudinal investigation was conducted in this cohort (n = 92) in order to find out whether early effects on eye-hand coordination (EHC), hand steadiness (HST), and simple visual reaction time (VRT) were reversible when the airborne manganese concentration at the workplace was abated. During the observation period from 1988 to 1995, MnT monitoring was implemented on a monthly basis producing more than 1300 personal air samples, EHC tests were given yearly to assess the precision of the hand-forearm movement (PN1), and HST and VRT tests were carried out yearly since 1991. By the end of the study, the cohort size had dropped to 34 subjects. The model of unbalanced repeated measurements with unstructured covariance matrix and a time-varying covariate (log MnT) was the most appropriate to analyze the data. Wald chi 2 statistic was used for testing time-trends. The reduction of MnT over time was significantly associated with an improvement of the PN1 values (total cohort: Wald chi 2 = 8.5, p = 0.004; beta log MnT = -6.098 +/- 2.096). Like in the total cohort, time-trends were also found in the three exposure subgroups which could be identified in the cohort (average MnT over 1987-1992 were about 400, 600, and 2000 micrograms Mn/m3 for the low, medium, and high exposure subgroups, respectively). Only in the low exposure subgroup the PN1 value normalized when MnT (provisional estimates) decreased from about 400 to 130 micrograms Mn/m3 by the end of the study. Solely the reduction in MnT explained these findings on PN1, while a "healthy-worker-effect" mechanism was unlikely to have operated. The prognosis for the medium and high exposure subgroups remains uncertain as the improvement of their EHC performance may have been affected by past MnO2 exposure to such an extent that the persistence of a partial loss of EHC ability is suggested. The time courses of the HST and VRT test results, however, indicated the absence of any improvement, suggesting irreversible impairment of hand stability (postural tremor) and simple visual reaction time. A separate examination in a group of 39 control subjects, re-tested 10 years after the first test in 1987, virtually precluded age as confounding factor in this prospective study. The findings of the longitudinal study are corroborated by the outcome of a separate follow-up study in a group of 24 ex-Mn employees, who showed in 1996 a significant improvement of eye-hand coordination after at least three years with no MnO2 exposure; as to HST and VRT, there was no significant change in the deficit of these two neurobehavioral markers.

Environmental exposure to cadmium, forearm bone density, and risk of fractures: prospective population study. Public Health and Environmental Exposure to Cadmium (PheeCad) Study Group.

BACKGROUND: Chronic low-level exposure to cadmium may promote calcium loss via urinary excretion. We undertook a prospective population study to investigate whether environmental exposure to cadmium lowers bone density and increases risk of fractures. METHODS: We measured urinary cadmium excretion, a biomarker of lifetime exposure, in people from ten districts of Belgium, of which six districts bordered on three zinc smelters. We also measured cadmium in soil and in vegetables from the districts, and collected data on incidence of fractures and height loss. Bone density was measured at the forearm just above the wrist by single photon absorptiometry, and calculated as the mean of six proximal and four distal scans. FINDINGS: Mean cadmium excretion at baseline was 8.7 nmol daily. Across the ten districts, mean cadmium concentration in soil ranged from 0.8 to 14.7 mg/kg, and from 0.1 to 4.0 mg/kg dry weight in vegetables. Median follow-up was 6.6 years. Mean forearm bone density in proximal and distal scans was 0.54 g/cm2 and 0.43 g/cm2 in men, and 0.44 g/cm2 and 0.34 g/cm2 in women. In postmenopausal women, a twofold increase in urinary cadmium correlated with 0.01 g/cm2 decrease in bone density (p<0.02). The relative risks associated with doubled urinary cadmium were 1.73 (95% CI 1.16-2.57; p=0.007) for fractures in women and 1.60 (0.94-2.72, p=0.08) for height loss in men. Cadmium excretion in districts near smelters was 22.8% higher (p=0.001) than in other districts, with fracture rates of 16.0 and 10.3 cases per 1000 person-years, respectively, and a population-attributable risk of 35.0%. INTERPRETATION: Even at a low degree of environmental exposure, cadmium may promote skeletal demineralisation, which may lead to increased bone fragility and raised risk of fractures.

Cadmium: a possible etiological factor in peripheral polyneuropathy.

Uncovering the exact cause of polyneuropathies seems to be impossible in up to 24% of the cases. Experimental studies have shown that cadmium (Cd), which is a well-known occupational and environmental hazard, can be a potent neurotoxicant for the peripheral nervous system. Moreover, Cd has a half-life of more than 15 years in humans. We hypothesize that older workers may be more susceptible to an increased Cd body burden, and may develop a peripheral polyneuropathy (PNP) over time. A blinded epidemiological survey was performed in 13 retired, long-term Cd-exposed workers and 19 age-matched controls. Historical Cd biomonitoring data were available over the last two decades. A neurological clinical examination, nerve conduction studies, and needle EMG were performed, and a standardized questionnaire was given to evaluate polyneuropathy complaints. If two of the following four criteria, i.e. complaints of polyneuropathy, neurophysiological changes compatible with polyneuropathy, distal symmetrical areflexia, or distal symmetrical anesthesia for vibration sense, temperature or blunt-sharp discrimination were present, the diagnosis of PNP was made. Two (11%) of the control and seven (54%) of the retired Cd workers met the PNP criteria OR: 9.92 (95%CI 1.60-61.6), Fisher exact test p=0.015. The existence of a polyneuropathy was related to the level of the Cd body burden as reflected by urinary Cd multiple logistic regression p=0.016, OR=1.26, (95%CI, 1.04-1.51), but not to blood lead (p=0.352). Our findings favour the hypothesis of a promoting role of increased cadmium body burden in the development of PNP at older age.

Adverse effects of chronic low level lead exposure on kidney function--a risk group study in children.

BACKGROUND: Children have been considered a risk group for lead (Pb) toxicity, mainly because of neurophysiological or neuro-cognitive deficits following Pb exposure. Blood Pb levels (b-Pb) of 100 microg/l currently have been defined as the lowest adverse effect level. The aim of this study was to compare, with the help of urinary markers, the kidney function of children with b-Pb just above this threshold with that of unexposed children, to assess from a nephrological point of view whether the current threshold is justified and whether children really are a particularly vulnerable risk group in terms of Pb-induced kidney damage. METHODS: In a cross-sectional study, 112 children, either from unexposed areas (controls, n=50) or Pb-contaminated areas (n=62), the latter partly with a known history of elevated b-Pb, were examined. Twenty nine urinary or serum markers mostly related to the function or integrity of specific nephron segments were determined (e.g. filtered plasma proteins, tubular enzymes, tubular antigens, eicosanoids). RESULTS: b-Pb were 39+/-13 microg/l in controls and 133+/-62 microg/l in exposed children. The main findings were increased excretion rates of prostaglandins and thromboxane B2, epidermal growth factor, beta2-microglobulin and Clara cell protein in the exposed children. A relationship between b-Pb and the prevalence of values above the upper reference limits was observed. CONCLUSIONS: With the help of urinary markers, nephron segment-specific effects of chronic low-level Pb exposure could be detected in children. The pattern of effects on glomerular, proximal and distal tubular and interstitial markers was similar to that previously observed in adults. The changes, however, occur at lower b-Pb levels than in adults. The current threshold appears to be justified also from a nephrological point of view, and children can indeed be considered a special risk group.