The threshold level of urinary cadmium associated with increased urinary excretion of retinol-binding protein and β2-microglobulin: a re-assessment in a large cohort of nickel-cadmium battery workers

OBJECTIVE: To evaluate the threshold value of urinary cadmium (CdU) for renal dysfunction on the basis of relationships unconfounded by protein degradation, diuresis and the renal effects associated with chronic smoking. Methods We studied 599 workers (451 men, mean age 45.4 years) who were employed in four nickel-cadmium battery plants for 18.8 years on average. After adjustment for covariates by multiple regression, the CdU threshold values for increased concentrations of retinol-binding protein (RBPU) and b(2)-microglobulin (b(2)-mU) were assessed by logistic regression and benchmark dose analyses using as referents workers with CdU10, respectively. The benchmark dose (BMD5) and the benchmark dose lower limit (BMDL5) for a 5% excess in the background prevalence of abnormal RBPU and b(2)-mU were estimated at 5.1/3.0 and 9.6/5.9. When excluding ever smokers, odds for abnormal RBPU and b(2)-mU were both increased only among workers with CdU>10 (OR, 21.8, 95% CI, 6.4-74.4 and OR, 15.1, 95% CI, 3.6-63.1, respectively). In never smokers, these BMD5/BMDL5 of CdU were estimated at 12.6/6.6 and 12.2/5.5 while in ever smokers they were 6.2/4.9 and 4.3/3.5. Conclusions On the basis of associations undistorted by smoking and adjusted for covariates, the BMDL5 of CdU for low-molecular-weight proteinuria induced by occupational exposure to Cd can be reliably estimated between 5.5 and 6.6 μg/g creatinine

Joint Belgian recommendation on screening for DPD-deficiency in patients treated with 5-FU, capecitabine (and tegafur)

Objectives: Fluoropyrimidines such as 5-Fluorouracil (5-FU), capecitabine and tegafur are drugs that are often used in the treatment of maliginancies. The enzyme dihydropyrimidine dehydrogenase (DPD) is the first and rate limiting enzyme of 5-FU catabolism. Genetic variations within the DPYD gene (encoding for DPD protein) can lead to reduced or absent DPD activity. Treatment of DPD deficient patients with fluoropyrimidines can result in severe and, rarely, fatal toxicity. Screening for DPD deficiency should be implemented in practice. Methods: The available methods in routine to screen for DPD deficiency were analyzed and discussed in several group meetings involving members of the oncological, genetic and toxicological societies in Belgium: targeted genotyping based on the detection of 4 DPYD variants and phenotyping, through the measurement of uracil and dihydrouracil/uracil ratio in plasma samples. Results: The main advantage of targeted genotyping is the existence of prospectively validated genotype-based dosing guidelines. The main limitations of this approach are the relatively low sensitivity to detect total and partial DPD deficiency and the fact that this approach has only been validated in Caucasians so far. Phenotyping has a better sensitivity to detect total and partial DPD deficiency when performed in the correct analytical conditions and is not dependent on the ethnic origin of the patient. Conclusion: In Belgium, we recommend phenotype or targeted genotype testing for DPD deficiency before starting 5-FU, capecitabine or tegafur. We strongly suggest a stepwise approach using phenotype testing upfront because of the higher sensitivity and the lower cost to society

Biological monitoring and health effects of low-level exposure to N -methyl-2-pyrrolidone: a cross-sectional study

Purpose: To examine the value of urinary 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI) in a population of workers exposed to N-methyl-2-pyrrolidone (NMP) and to look for health effects of exposure to this organic solvent. Methods: Airborne NMP was determined according to the NIOSH method. Urinary 5-HNMP and 2-HMSI (after and before next shift) were determined by liquid chromatography with tandem mass spectrometry. Outcomes were effects on lung, kidney, skin and mucous membranes, nervous system, haematopoiesis and liver determined by clinical examination and laboratory measurements. Univariate statistical methods and multiple regressions were used to analyse results. Skin resorption, smoking and other potential confounders were taken into account. Results: Three hundred twenty-seven workers were eligible out of which 207 workers (63%) participated. Ninety-one of these worked with NMP. Occupational exposure to NMP did often not occur daily and ranged from non-detectable to 25.8mg/m3 (median=0.18). Urinary 2-HMSI (mg/l; before next shift) was the best biomarker of exposure to NMP, explaining about 70% of the variance, but most likelihood ratios did not allow for ruling exposure in or out, at these low levels of exposure. Creatinine adjustment did not improve the results clearly. No clear and consistent health effects could be associated with NMP exposure. No indication for a bias due to non-participation was found. Conclusions: Biological monitoring, primarily urinary 2-HMSI (mg/l; before next shift), is of value to estimate exposure to NMP even when exposure is irregular and low. Likelihood ratios of urinary 5-HMNP or 2-HMSI are, however, not quite satisfactory at these low levels. No irritant or other health effects were found

Exposure assessment of the Walloon population to pesticides within the BMH-WAL study

peer reviewe

Confounders in the assessment of the renal effects associated with low-level urinary cadmium: an analysis in industrial workers

<p>Abstract</p> <p>Background</p> <p>Associations of proteinuria with low-level urinary cadmium (Cd) are currently interpreted as the sign of renal dysfunction induced by Cd. Few studies have considered the possibility that these associations might be non causal and arise from confounding by factors influencing the renal excretion of Cd and proteins.</p> <p>Methods</p> <p>We examined 184 healthy male workers (mean age, 39.5 years) from a zinc smelter (n = 132) or a blanket factory (n = 52). We measured the concentrations of Cd in blood (B-Cd) and the urinary excretion of Cd (U-Cd), retinol-binding protein (RBP), protein HC and albumin. Associations between biomarkers of metal exposure and urinary proteins were assessed by simple and multiple regression analyses.</p> <p>Results</p> <p>The medians (interquartile range) of B-Cd (μg/l) and U-Cd (μg/g creatinine) were 0.80 (0.45-1.16) and 0.70 (0.40-1.3) in smelter workers and 0.66 (0.47-0.87) and 0.55 (0.40-0.90) in blanket factory workers, respectively. Occupation had no influence on these values, which varied mainly with smoking habits. In univariate analysis, concentrations of RBP and protein HC in urine were significantly correlated with both U-Cd and B-Cd but these associations were substantially weakened by the adjustment for current smoking and the residual influence of diuresis after correction for urinary creatinine. Albumin in urine did not correlate with B-Cd but was consistently associated with U-Cd through a relationship, which was unaffected by smoking or diuresis. Further analyses showed that RBP and albumin in urine mutually distort their associations with U-Cd and that the relationship between RBP and Cd in urine was almost the replicate of that linking RBP to albumin</p> <p>Conclusions</p> <p>Associations between proteinuria and low-level urinary Cd should be interpreted with caution as they appear to be largely driven by diuresis, current smoking and probably also the co-excretion of Cd with plasma proteins.</p

Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCC2 and their impact on drug disposition

The ATP-binding cassette (ABC) transporter superfamily comprises membrane proteins that translocate a variety of substrates across extra- and intra-cellular membranes, and act as efflux proteins. ABC transporters are characterised by the presence of genetic polymorphisms mainly represented by single nucleotide polymorphisms (SNPs), some of which having an impact on their activity. Besides physiological substances, drugs are also substrates of some ABC transporters, mainly ABCB1, ABCC1, ABCC2, ABCC3 and ABCG2. Identifying the impact of these polymorphisms on the pharmacokinetics (PK) of these drugs may have important clinical implications, certainly for those characterised by a narrow therapeutic index and significant inter- and intra-patient PK variability. This review focuses specifically on ABCB1 and ABCC2 and critically analyses important publications dealing with the influence of ABCB1 and/or ABCC2 polymorphisms on drug disposition in humans. For different reasons discussed in this paper, the effect of ABCB1 and/or ABCC2 polymorphisms on drug concentrations in blood is not always easy to interpret and to correlate with pharmacological effects. In contrast, intracellular or target tissue drug concentrations appear more directly influenced by these polymorphisms, as illustrated with intralymphocyte concentrations for immunosupressants and antiretrovirals or with cerebrospinal fluid (CSF) concentrations for antiepileptics and antidepressants. Further research on intracellular and/or target tissue drug concentrations are still needed to better characterise the PK-PG (pharmacogenetics) relationship involving ABC transporters

Research Highlights : Highlights from the latest articles in pharmacogenomics: calcineurin inhibitors in solid organ transplantation

Genetic determinants of calcineurin inhibitor concentration at the pharmacodynamic target. Tacrolimus dose adjustment according to CYP3A5 genotype. CYP3A5 as a genetic determinant of the clinical variability of CYP3A-mediated drug interactions involving tacrolimus

Genotyping and phenotyping of biotransformation enzymes : towards a more accurate interpretation of biological monitoring of exposure to chemicals

Introduction : En toxicologie industrielle et environnementale, l'évaluation de l'exposition à des substances chimiques s'appuie sur deux approches largement complémentaires : la mesure de la substance dans l'air ("surveillance d'ambiance") et la mesure d'un paramètre biologique reflétant l'exposition ("surveillance biologique de l'exposition") ; dans ce dernier cas il s'agit le plus souvent de la substance elle-même ou d'un de ses métabolites dans l'urine ou dans le sang. Quelle que soit l'approche choisie, le professionnel de la santé doit disposer de valeurs limites pour interpréter les résultats. Dans le domaine de la surveillance biologique de l'exposition, les valeurs limites sont le plus souvent établies sur base des corrélations entre l'exposition externe et la concentration du biomarqueur dans les milieux biologiques. La valeur limite, alors appelée "index biologique d'exposition" (IBE) correspond à la valeur limite atmosphérique. Ces IBE ont cependant été établis en postulant que tous les individus répondent de manière identique, ce qui n'est pas le cas puisque des variations inter-individuelles importantes sont habituellement constatées. Objectifs : L'hypothèse du travail est qu'une part de cette variabilité réside au niveau de différences dans les capacités individuelles de biotransformation des xénobiotiques. Pour la vérifier et évaluer l'importance potencielle de ces facteurs, nous avons sélectionné à titre de modèle deux composés pour lesquelles une surveillance biologique de l'exposition peut être réalisée (sévoflurane et styrène). Trois enzymes (ou familles d'enzymes) intervenant dans le métabolisme de ces substances (CYPE2E1, GSTs et EPHX1) ont été examiné(e)s et l'influence des polymorphismes génétiques et phonétiques (expression ou activité) sur la variabilité observée dans la relation exposition externe-biomarqueur a été étudiée. Résultats : Dans un premier temps, nous avons démontré que le génotypage, classiquement effectué sur des échantillons sanguins, peut aussi bien être réalisé au départ d'échantillons urinaires (facilement obtenus en surveillance biologique de l'exposition), de préférence en utilisant les premières urines du matin. Appliquée à des études de terrain (sévoflurane et styrène), la prise en compte de polymorphismes génétiques s'est avérée particulièrement importante dans le cas ou la surveillance biologique de l'exposition au styrène est réalisée sur la base des acides mercapturitiques spécifiques dans l'urine. Dans ce cas, deux IBE peuvent clairement être distingués en fonction du statut GSTM1 des individus.L'influence des autres polymorphismes génétiques (CYP2E1 et EPHX1) semble moins importante bien que leur prise en compte dans des modèles de régression multiple permette d'augmenter significativement la part expliquée de la variabilité inter-individuelle (classiquement supérieur à 70% pour les acides mercapturiques spécifiques). Pour évaluer l'intérêt de la prise en chambre d'inhalation, nous avons démontré que la prise en compte du phénotype CYP2E1, en association avec le génotypage GSTM1, permet d'expliquer 77% de la variabilité biologique des acides mercapturiques urinaires, rendant ainsi ces marqueurs très intéressant pour la surveillance biologique de l'exposition au styrène. Les tests de phénotypage sur lymphocytes ont également permis de confirmer les effets liés aux polymorphismes génétiques observés dans les études de terrain (réduction des activités CYP2E1 et EPHX1 en présence, respectivement, des allèles CYP2E1*6 et EPHX1 His¹¹³). Conclusions : L'ensemble de ces résultats démontre qu'il est possible d'améliorer l'interprétation des résultats de surveillance biologique d'exposition en tenant compte du génotype et du phénotype de certains enzymes de biotransformatin pertinents. Nous proposons le concept de "surveillance biologique individualisée" dans lequel chaque individu dispose de son propre IBE sur la base de ses caractéristiques génétiques et phénotypiques (p. ex. BMI, âge).Thèse de doctorat en Santé publique (toxicologie industrielle) -- UCL, 200