Absence of genotoxic impact assessed by micronucleus frequency in circulating lymphocytes of workers exposed to cadmium.

PURPOSE: Cd is considered as a genotoxic carcinogen for which a threshold can be identified. This threshold has, however, not been established and the shape of the relationship between Cd exposure and genotoxic effects is unknown. The aim of the present study was to analyse the shape of the dose-response relationship for the genotoxic effects of Cd in occupational settings. METHODS: The study has a cross-sectional design and includes 60 healthy male and female workers with known Cd exposure selected from two plants manufacturing or recycling nickel-Cd batteries. The frequency of MN was measured in circulating lymphocytes, and related to internal Cd doses (Cd-B, Cd-U). Determinants of MN frequency were traced by multivariate regression analysis. RESULTS: Cd exposure covered a wide range as measured by Cd-B (0.02-1.26 µg/dL), Cd-U (0.26-15.80 µg/g creat) and seniority in the plant (1-42 years). Gender was the only parameter significantly associated with MN frequency, women having on average 8.5 additional MN/1000 BN cells compared to men. Cd-B, Cd-U or Ni-U did not influence MN frequency when adjusted for gender and other potential confounders. CONCLUSION: This finding is consistent with the existing knowledge on the mechanisms governing the genotoxic activity of Cd, which are all non-stochastic and thresholded. The threshold for systemic genotoxic effects of Cd is thus beyond the range of internal exposure considered in the present investigation.

Cobalt and its compounds: update on genotoxic and carcinogenic activities.

This article summarizes recent experimental and epidemiological data on the genotoxic and carcinogenic activities of cobalt compounds. Emphasis is on the respiratory system, but endogenous exposure from Co-containing alloys used in endoprostheses, and limited data on nanomaterials and oral exposures are also considered. Two groups of cobalt compounds are differentiated on the basis of their mechanisms of toxicity: (1) those essentially involving the solubilization of Co(II) ions, and (2) metallic materials for which both surface corrosion and release of Co(II) ions act in concert. For both groups, identified genotoxic and carcinogenic mechanisms are non-stochastic and thus expected to exhibit a threshold. Cobalt compounds should, therefore, be considered as genotoxic carcinogens with a practical threshold. Accumulating evidence indicates that chronic inhalation of cobalt compounds can induce respiratory tumors locally. No evidence of systemic carcinogenicity upon inhalation, oral or endogenous exposure is available. The scarce data available for Co-based nanosized materials does not allow deriving a specific mode of action or assessment for these species.

Co-exposure to lead increases the renal response to low levels of cadmium in metallurgy workers.

PURPOSE: Research on the effect of co-exposure to Cd and Pb on the kidney is scarce. The objective of the present study was to assess the effect of co-exposure to these metals on biomarkers of early renal effect. METHODS: Cd in blood (Cd-B), Cd in urine (Cd-U), Pb in blood (Pb-B) and urinary renal biomarkers, i.e., microalbumin (µ-Alb), beta-2-microglobulin (ß2-MG), retinol binding protein (RBP), N-acetyl-ß-d-glucosaminidase (NAG), intestinal alkaline phosphatase (IAP) were measured in 122 metallurgic refinery workers examined in a cross-sectional survey. RESULTS AND CONCLUSIONS: The median Cd-B, Cd-U, Pb-B were: 0.8 µg/l (IQR = 0.5, 1.2), 0.5 µg/g creatinine (IQR = 0.3, 0.8) and 158.5 µg/l (IQR = 111.0, 219.3), respectively. The impact of Cd-B on the urinary excretion of NAG and IAP was only evident among workers with Pb-B concentrations ≥ 75th percentile. The association between Cd-U and the renal markers NAG and RBP was also evidenced when Pb-B ≥ 75th percentile. No statistically significant interaction terms were observed for the associations between Cd-B or Cd-U and the other renal markers under study (i.e., µ-Alb and ß2-MG). Our findings indicate that Pb increases the impact of Cd exposure on early renal biomarkers.

Validation and clinical application of a high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the quantitative determination of 10 anti-retrovirals in human peripheral blood mononuclear cells.

This paper reports the validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method that allows the quantification of 10 antiretroviral (ARV) drugs in peripheral blood mononuclear cells (PBMCs) using 6 different isotopic internal standards (IS) and its clinical application. PBMCs are isolated from blood by density gradient centrifugation and drugs are extracted with a 60% methanol (MeOH) solution containing the 6 IS. The cell extract is then injected in the HPLC system and analytes are separated on a Symmetry Shield RP18 2.1 mm x 50 mm column. The different molecules are then detected by MS/MS in electrospray positive or negative ionisation modes and data are recorded using the multiple reaction monitoring (MRM) mode. Calibration curves are constructed in the range of 0.25-125 ng/ml of cell extract by a 1/x(2) weighted quadratic regression. The regression coefficients obtained are always greater than 0.99 and back calculated values always comprised in the range of +/-15% from their nominal concentration. Mean extraction recoveries are greater than 80% for all analytes and the method is accurate and precise with CV and bias lower than 9.4%. The lower limits of quantification (LLOQ) of the different drugs range from 0.0125 to 0.2 ng/ml of cell extract. This method was successfully applied to a cohort of 98 HIV-infected patients treated with Kaletra (400/100 mg of lopinavir/ritonavir (LPV/RTV) twice a day, n=48) or with Stocrin (600 mg once a day, n=50) and has been tested for cellular quantification of tipranavir (TPV) in 2 patients treated with Aptivus (500 mg twice a day). The patients treated by Kaletra showed mean cell-associated concentrations (CC) of 1819.0 and 917.2 ng/ml, for LPV and RTV, respectively. Patients treated with Stocrin showed mean CC of 2388.11 ng/ml while both patients under Aptivus showed TPV CC of 4322.7 and 1078.0 ng/ml, respectively. This method can be used to analyze ARV drug concentrations within the target tissue.

Carcinogenic potential of formaldehyde in occupational settings: a critical assessment and possible impact on occupational exposure levels.

OBJECTIVES: To review epidemiological studies which led to a change in the classification of formaldehyde by the International Agency for Research on Cancer (IARC) in 2004 as well as studies published thereafter, with the objective to examine whether occupational exposure levels for formaldehyde should be adapted. METHOD: Cohort and case-control studies investigating the association between occupational exposure to formaldehyde and nasopharyngeal cancer (NPC) and reporting estimates of formaldehyde exposure as well as the most recent meta-analyses, published after 1994, were reviewed. RESULTS: Evidence of an association between occupational formaldehyde exposure and NPC appears debatable. Results of the cohort studied by Hauptmann et al. (Am J Epidemiol 159(12):1117-1130, 2004) were key findings in the IARC evaluation. In this study, mortality from NPC was elevated compared with that of the US general population. However, internal comparison analysis using alternative categorization revealed that none of the relative risk for NPC was statistically significantly increased in any category of exposure (Marsh and Youk in Regul Toxicol Pharmacol 42(3):275-283, 2005) and re-analyses of the data highlighted the inappropriateness of the exposure assessment used by Hauptmann et al. (Am J Epidemiol 159(12):1117-1130, 2004) and Marsh et al. (Regul Toxicol Pharmacol 47(1):59-67, 2007). Two other cohorts (Coggon et al. in J Natl Cancer Inst 95(21):1608-1615, 2003; Pinkerton et al. in Occup Environ Med 61(3)193-200, 2004) reported no increase in NPC. Two case-control studies brought some evidence of an increased risk of NPC but the assessment of exposure levels was uncertain. DISCUSSION: Human studies fail to raise a convincing conclusion concerning the carcinogenicity of formaldehyde and are not helpful to delineate a possible dose-response relationship. Experimental data indicate that in rats, the carcinogenic activity of formaldehyde is associated with cytotoxic/proliferative mechanisms. Therefore protecting from these effects associated with formaldehyde exposure should be sufficient to protect from its potential carcinogenic effects, if any in humans. CONCLUSION: Current occupational exposure levels to formaldehyde, set to protect against local irritation, should not be adapted.

CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: guidelines from an experimental study.

Genetic polymorphisms in biotransformation enzyme CYP3A5 (6986G > A, CYP3A5*3; 14690A > G, CYP3A5*6) and drug transporter ABCB1 (1236C > T; 2677G > T/A; 3435C > T) are known to influence tacrolimus (Tac) dose requirements and trough blood levels in stable transplant patients. In a group of 19 volunteers selected with relevant genotypes among a list of 221 adult renal transplant candidates, we evaluated whether consideration of CYP3A5 and ABCB1 genetic polymorphisms could explain the interindividual variability in Tac pharmacokinetics after the first administration of a standard dose (0.1 mg/kg body weight twice a day). Lower area under the time versus blood concentration curves (AUC) or lower trough concentrations were observed among CYP3A5 expressors (n = 9) than among nonexpressors (n = 10) using two different analytical methods for Tac determination (liquid chromatography with tandem mass spectrometry (LC-MS/MS) and immunoassay). The median AUC(0-infinity) was 2.6- and 2.1-fold higher in nonexpressors for LC-MS/MS and immunologic methods, respectively. No difference was observed in Tac pharmacokinetic parameters in relation to ABCB1 polymorphisms. In conclusion, our study confirms the very significant effect of CYP3A5 polymorphism early after the first administration of Tac. It also provides a strong argument for a doubling of the loading dose in patients early identified a priori on the transplantation list as possessing at least one CYP3A5*1 allele.

Cadmium, lead and endometriosis.

OBJECTIVES: Cadmium (Cd) and lead (Pb) have been demonstrated to exert endocrine disrupting activities. Their possible role in endometriosis, an oestrogen-dependent disease, is unknown. METHODS: We compared cadmium urinary excretion (CdU) and blood concentration of cadmium (CdB) and lead (PbB) in 119 patients with peritoneal endometriosis and/or deep endometriotic (adenomyotic) nodules of the rectovaginal septum and 25 controls. RESULTS: The mean levels of cadmium in urine and blood did not differ among the groups. Women suffering from endometriotic diseases showed lower levels of PbB than controls. CONCLUSIONS: These data do not support a role for cadmium in the onset or the growth of endometriotic diseases but suggest a possible relationship with lead.

Mercapturic acids revisited as biomarkers of exposure to reactive chemicals in occupational toxicology: a minireview.

A minireview is presented concerning the use of mercapturic acids as biological exposure index for electrophilic chemicals. Besides pure analytical aspects, this minireview considers possible issues in relation to (a) the added value of mercapturic acids as compared to other well validated biomarkers of exposure and (b) the high inter-individual variability in mercapturic acids excretion. Recent field and/or experimental studies confirm the usefulness of mercapturic acids as biological exposure index for electrophilic chemicals and suggest the interest of a toxicogenetic approach for a better interpretation of the results of biological monitoring.

Influence of hOGG1, XRCC1 and XRCC3 genotypes on biomarkers of genotoxicity in workers exposed to cobalt or hard metal dusts.

Identification of genetic polymorphisms responsible for reduced DNA repair capacity may allow better cancer prevention. We examined whether variations in genes involved in base-excision (hOGG1, XRCC1) and double strand break (XRCC3) DNA repair contribute to inter-individual differences in genotoxic effects induced in the lymphocytes of 21 cobalt (Co) exposed, 26 hard metal (WC-Co) exposed and 26 matched control male workers. Genotyping was performed by PCR-RFLP. DNA single strand breaks and alkali-labile sites were measured by the alkaline Comet assay. Chromosomal rearrangements resulting from chromosome loss or acentric fragments were assessed as micronucleated mononucleates (MNMC) and binucleates (MNCB) with the cytokinesis-block micronucleus test. Urinary 8-hydroxydeoxyguanosine (8-OHdG) levels were used as an indicator of systemic oxidative DNA damage. A significantly higher frequency of MNMC was observed in WC-Co exposed workers with variant hOGG1(326) genotype. Multivariate analysis performed with genotypes, age, exposure status, type of plant, smoking and their interaction terms as independent variables indicated that MNMC and Comet tail DNA (TD) were influenced by genetic polymorphisms. In the exposed and total populations, workers variant for both XRCC3 and hOGG1 had elevated MNMC frequencies. Further studies will demonstrate whether genotyping for hOGG1 and XRCC3 polymorphisms is useful for a better individual monitoring of workers.

Investigations on the liver toxicity of a blend of HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) and HCFC-124 (2-chloro-1,1,1,2-tetrafluoroethane) in guinea-pigs.

2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) has been developed as a substitute for ozone-depleting chlorofluorocarbons (CFCs). It is a structural analogue of halothane and similarities in the metabolic pathways and liver toxicity of both compounds have been described. The present study was initiated after an accidental outbreak of hepatitis in an industrial setting to examine whether concomitant exposure to 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124), which is not hepatotoxic, could enhance the liver toxicity of HCFC-123. Male Hartley guinea-pigs were exposed for 4 h to 5,000 ppm HCFC-123 alone or blended with 5,000 ppm HCFC-124, either once (single exposure) or on 5 consecutive days (repeated exposure). The animals were killed either 24 or 48 h after the last exposure. A transient cytolytic action of HCFC-123 was evident by increased mean serum levels of alanine aminotransferase at 24 h and isocitrate dehydrogenase at 24 and 48 h, both after a single or repeated exposure. The liver toxicity of HCFC-123 was confirmed by pathological examination of liver tissue, which showed mild (foci of necrotic hepatocytes) to moderate (multifocal random degeneration and necrosis) damage. Steatosis was also observed and was more pronounced after repeated exposure than after single. One animal out of 6 that were repeatedly exposed to the blend and sacrificed at 24 h showed liver lesions similar to halothane hepatitis. Although a few other animals responded markedly in the blend-treated group, on average, no significant difference in the biochemical or pathological lesions was found between the groups treated with HCFC-123 alone or with the blend. Urinary excretion of trifluoroacetic acid and chlorodifluoroacetic acid increased dose-dependently upon exposure to HCFC-123 and indicated accumulation after repeated exposure. No difference in metabolite excretion was found between animals treated with HCFC-123 alone or blended with HCFC-124. Treatment with HCFC-123 depleted hepatic glutathione levels by about 40 and 25% after single and repeated exposure, respectively; the amplitude of this reduction was not modified by co-exposure to HCFC-124. In conclusion, this study confirmed the hepatotoxicity of HCFC-123, based on biochemical, histopathological and metabolite studies, and found only very limited indication of a potentiation by HCFC-124 of this hepatotoxic effect.

Update on the genotoxicity and carcinogenicity of cobalt compounds.

OBJECTIVE: To integrate recent understandings of the mechanisms of genotoxicity and carcinogenicity of the different cobalt compounds. METHOD: A narrative review of the studies published since the last IARC assessment in 1991 (genotoxicity, experimental carcinogenesis, and epidemiology). RESULTS: Two different mechanisms of genotoxicity, DNA breakage induced by cobalt metal and especially hard metal particles, and inhibition of DNA repair by cobalt (II) ions contribute to the carcinogenic potential of cobalt compounds. There is evidence that soluble cobalt (II) cations exert a genotoxic and carcinogenic activity in vitro and in vivo in experimental systems but evidence in humans is lacking. Experimental data indicate some evidence of a genotoxic potential for cobalt metal in vitro in human lymphocytes but there is no evidence available of a carcinogenic potential. There is evidence that hard metal particles exert a genotoxic and carcinogenic activity in vitro and in human studies, respectively. There is insufficient information for cobalt oxides and other compounds. CONCLUSION: Although many areas of uncertainty remain, an assessment of the carcinogenicity of cobalt and its compounds requires a clear distinction between the different compounds of the element and needs to take into account the different mechanisms involved.

Interstitial lung disease induced by exogenous agents: factors governing susceptibility.

The purpose of this review is to describe the present state of knowledge regarding host susceptibility factors that may determine the occurrence, development and severity of interstitial lung disease (ILD) caused by exogenous agents. First, host susceptibility may pertain to differences in the delivery and/or persistence of the noxious agent in the lung. The deposition and clearance of inhaled particles or fibres may vary depending on innate anatomical or physiological characteristics, and on acquired changes, such as nasal disease or smoking-induced alterations. Genetically- or environmentally-induced interindividual differences in the expression of pulmonary biotransformation enzymes may form the basis for, or contribute to the risk of, drug-induced interstitial lung disease. Secondly, there are genetic and acquired variations in various enzymatic and nonenzymatic defence systems that protect cells and tissues against oxidative stress, which is often involved in the pathogenesis of interstitial lung disease caused by particles, fibres, metals, organic agents and drugs. Thirdly, the occurrence of immunological sensitization is dependent on both genetic and environmental factors. This has been demonstrated in chronic beryllium lung disease and in hypersensitivity pneumonitis. Fourthly, the propensity of individuals to develop particular types of inflammation, such as granulomas, is probably under genetic control. The regulation and resolution of inflammation and fibrogenesis caused by dust particles are also partly determined by genetic factors, involving cytokine networks and growth factors. In conclusion, although the issue of genetics pervades the entire discussion of host susceptibility, genes are not the only determinants of health and disease. Environmental factors may be equally important in shaping host susceptibility. Therefore, research must be focused on both the genetic bases and the environmental determinants of interstitial lung disease, in order to provide mechanism-based prevention strategies, early detection of, and improved therapy for these conditions.

Importance of genetic polymorphisms of drug-metabolizing enzymes for the interpretation of biomarkers of exposure to styrene.

The objective of this study was to test the infiuence of genetic polymorphisms for metabolic enzymes (CYP2E1, mEH, GSTM1 and GSTT1) implicated in the biotransformation of styrene in humans on the interpretation of urinary biomarkers of exposure. Thirty workers from a fibreglass-reinforced plastics factory took part in the study. Ambient styrene concentration was determined during the whole workshift by passive sampling. Urine was collected at the end of the shift for the determination of mandelic acid (MA) and phenylglyoxylic acid (PGA) (major biotransformation pathway), N-acetyl-S-(1-phenyl-2-hydroxy)ethyl-L-cysteine (M1) and N-acetyl-S-(2-phenyl-2-hydroxy)ethyl-L-cysteine (M2) (minor metabolic pathway) and creatinine. The average airborne styrene concentration of 18.2 ppm (range: 0.9-68.9 ppm) was very close to the current threshold limit value (TLV-TWA) recently adjusted by ACGIH from 50 to 20 ppm. There was a better correlation between external and internal exposure as estimated by urinary MA + PGA (r=0.92; p<0.0001) compared with urinary M1 + M2 (r=0.74; p<0.0001). To investigate to what extent genetic polymorphisms in metabolic enzymes could explain interindividual variations observed in the concentration of urinary biomarkers related to a given external exposure, two 'metabolic indexes' (derived from the ratio between the sum of urinary metabolites for a specific pathway and ambient styrene concentration) were calculated for each worker and compared for different allelic combinations. Monovariate analyses showed that GSTM1 polymorphism was clearly the most significant parameter infiuencing urinary concentrations of mercapturic acids. Based on GSTM1 allelic status, two different biological exposure indexes (BEIs) for M1 + M2 in post-shift urinary samples corresponding to a 20 ppm styrene concentration are proposed (GSTM1null: 1330 µg g(-1) creatinine, GSTM1+: 2878 µg g(-1) creatinine). Multivariate regression analyses were also performed and revealed that the presence of the rare CYP2E1*1B allele linked to TaqI polymorphism (A1/A2) was associated with increased urinary concentrations of metabolites from both pathways. Two previously described polymorphisms for the EPHX gene were also tested but seemed not really relevant for interpretation of biomarkers. In conclusion, while CYP2E1 genotyping, particularly assessment of the CYP2E1*1B allelic status, is useful for a more accurate interpretation of the concentration of urinary biomarkers, GSTM1 genotyping is absolutely necessary when considering a biological monitoring programme based on determination of urinary mercapturic acids.

Absence of significant genotoxicity in lymphocytes and urine from workers exposed to moderate levels of cobalt-containing dust: a cross-sectional study.

Mortality studies have shown that, in the past, lung cancer occurred after exposure to mixtures of cobalt metal and metallic carbide particles, the main constituents of hard metals, but apparently not when exposure was to cobalt alone. The major objective of this biomonitoring study was to assess genotoxic effects as a measure for carcinogenic risk in workers from cobalt refineries and hard metal plants currently exposed to the threshold limit value/time-weighted average (TLV-TWA) for cobalt-containing dust. The study comprised three groups of workers: 35 workers exposed to cobalt dust from three refineries, 29 workers exposed to hard metal dust from two producing plants, and 35 matched control subjects recruited from the respective plants. The study design integrated complementary methodologies to assess biomarkers of effects that represent both initial DNA damage (8-hydroxydeoxyguanosine [8-OHdG] in urine and comet assay on lymphocytes) and definitive chromosome breakage/loss (micronuclei in lymphocytes). Cobalt and cotinine were determined in urine as a measure for cobalt exposure and recent smoking, respectively. No significant increase of genotoxic effects was detected in workers exposed to cobalt-containing dust as compared to controls. No difference in any genotoxicity biomarker was found between workers exposed to cobalt and hard metal dusts. Multiple regression analysis indicated that workers who smoked and were exposed to hard metal dusts had elevated 8-OHdG and micronuclei values. Because this observation is in line with a previous epidemiological study of an increased risk of dying from lung cancer in workers from the hard metal industry who smoked, it is concluded that this specific occupational group needs closer medical surveillance.

Clues and uncertainties in the risk assessment of arsenic in drinking water.

On the basis of studies of the prevalence of skin cancer among users of As-rich well water in Taiwan, WHO experts recommended in 1984 a maximum As concentration of 50 microg/litre in drinking water. Since that time, a plethora of non-cancer as well as cancer effects has been observed in several other populations sustaining a chronic exposure to various As concentrations in drinking water. This prompted a revision of the standard and a provisional guideline of 10 microg/litre was recommended in 1993. While the uncertainty linked to the statistical inferences leading to the guideline are reduced by the fact that they are directly estimated from human data and result from extrapolations made relatively close to observed exposure levels, developed guideline depends strongly on the choice of the dose-response model (linear, quadratic, hockey-stick) and the accuracy of the exposure data. The potential exposure to As sources other than drinking water, dietary habits and genetic characteristics of the populations may also make more difficult the inference of a recommendation for As concentration in drinking water. Owing to the huge cost of strongly reducing the current As in water standard, many efforts are presently made to clarify the quantitative aspects of As-induced cancers, particularly at low dose levels. New data on the metabolism and carcinogenic mechanism of As in humans along with the results of epidemiological studies presently under way in several countries will help to reduce the uncertainty in the risk assessment of As.

Sulfur mustard upregulates the expression of interleukin-8 in cultured human keratinocytes.

Although the morphological description of sulfur mustard (SM) injury is well characterised, little is known of the molecular mediators involved in cutaneous toxicity. Since infiltration by lymphocytes and PMNs represents one of the very first events observed in vivo upon exposure to SM, this study examined whether SM exposure can modify the expression by cultured human keratinocytes of interleukin-8, one of the most important chemoattractants for polymorphonuclear leukocytes (PMNs) in humans. Conditioned medium harvested from control keratinocyte cultures showed a gradual accumulation of this cytokine over time followed by a levelling off after 12 hours. Upon treatment with 10(-6) and 10(-5) M SM, no significant difference compared to the control situation was observed. After 6 h, a significantly higher amount of IL-8 was secreted by human keratinocytes treated with 10(-4) M SM and the accumulation of the cytokine persisted up to 24 h after exposure. The expression of IL-8 mRNA was assessed semi-quantitatively (RT-PCR) at the same time points in control and SM-treated (10(-4) M) human keratinocytes. When compared to control cultures, a clear upregulation of IL-8 mRNA levels was observed 6 and 12 h after SM exposure, which is consistent with the secretion pattern of the protein. The present observation indicates that increased secretion of IL-8 by human keratinocytes represents an early event of the inflammatory reaction following SM which is coherent with the reported delay in the recruitment of lymphocytes and PMNs observed in vivo.

Renal effects of low-level environmental cadmium exposure: 5-year follow-up of a subcohort from the Cadmibel study.

BACKGROUND: The clinical relevance of renal effects of cadmium in people exposed in the environment remains uncertain. This study examined the evolution of renal effects observed in a population exposed to cadmium in the environment. METHODS: 208 men and 385 women surveyed in 1985-89 (Cadmium in Belgium study [Cadmibel]; baseline) were re-examined on average 5 years later (Public health and environmental exposure to cadmium study [PheeCad]; follow-up). Urinary and blood cadmium and markers of renal tubular dysfunction and glomerular effects were measured. The association between cadmium body burden and renal factors was examined by multivariate logistic and linear regression. FINDINGS: In men, mean urinary cadmium excretion and blood cadmium concentration measured at follow-up were 7.5 nmol/24 h (SD 1.9) and 6.1 nmol/L (2.2), reductions of 16% and 35% from baseline, respectively. In women, the corresponding values were 7.6 nmol/24 h (1.9) and 7.8 nmol/L (2.1), reductions of 14% and 28% from baseline. No indication of progressive renal damage was found and the overall results suggest that the effects of low environmental exposure to cadmium on the kidney are weak, stable, or reversible. INTERPRETATION: Subclinical renal effects that have been reported in Belgium in patients with increased cadmium body burden are not associated with progressive renal dysfunction and most likely represent non-adverse manifestations.