Abstract
Systematic creatinine adjustment of urinary concentrations of biomarkers has been a challenge over the past years because the assumption of a constant creatinine excretion rate appears erroneous and the issue of overadjustment has recently emerged. This study aimed at determining whether systematic creatinine adjustment is to be recommended for urinary concentrations of trace elements (TEs) in environmental settings. Paired 24-h collection and random spot urine samples (spotU) were obtained from 39 volunteers not occupationally exposed to TEs. Four models to express TEs concentration in spotU were tested to predict the 24-h excretion rate of these TEs (TEμg/24h) considered as the gold standard reference: absolute concentration (TEμg/l); ratio to creatinine (TEμg/gcr); TEμg/gcr adjusted to creatinine (TEμg/gcr-adj); and concentration adjusted to specific gravity (TEμg/l-SG). As, Ba, Cd, Co, Cr, Cu, Hg, Li, Mo, Ni, Pb, Sn, Sb, Se, Te, V and Zn were analyzed by inductively coupled argon plasma mass spectrometry. There was no single pattern of relationship between urinary TEs concentrations in spotU and TEμg/24h. TEμg/l predicted TEμg/24h with an explained variance ranging from 0 to 60%. Creatinine adjustment improved the explained variance by an additional 5 to ~60% for many TEs, but with a risk of overadjustment for the most of them. This issue could be addressed by adjusting TE concentrations on the basis of the regression coefficient of the relationship between TEμg/gcr and creatinine concentration. SG adjustment was as suitable as creatinine adjustment to predict TEμg/24h with no SG-overadjustment (except V). Regarding Cd, Cr, Cu, Ni and Te, none of the models were found to reflect TEμg/24h. In the context of environmental exposure, systematic creatinine adjustment is not recommended for urinary concentrations of TEs. SG adjustment appears to be a more reliable alternative. For some TEs, however, neither methods appear suitable.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Boeniger MF, Lowry LK, Rosenberg J . Interpretation of urine results used to assess chemical exposure with emphasis on creatinine adjustments: a review. Am Ind Hyg Assoc J 1993; 54: 615–627.
German Federal Environment Agency. Opinion of the human biomonitoring commission. Standardisation of substance concentrations in urine—creatinine. Bundesgesundheitsbl – Gesundheitsforsch – Gesundheitsschutz 2005; 48: 616–618.
Ryan D, Robards K, Prenzler PD, Kendall M . Recent and potential developments in the analysis of urine: a review. Anal Chim Acta 2011; 684: 8–20.
Alessio L, Berlin A, Dell'Orto A, Toffoletto F, Ghezzi I . Reliability of urinary creatinine as a parameter used to adjust values of urinary biological indicators. Int Arch Occup Environ Health 1985; 55: 99–106.
Akerstrom M, Lundh T, Barregard L, Sallsten G . Sampling of urinary cadmium: differences between 24- h urine and overnight spot urine sampling, and impact of adjustment for dilution. Int Arch Occup Environ Health 2012; 85: 189–196.
Buchet JP, Staessen J, Roels H, Lauwerys R, Fagard R . Geographical and temporal differences in the urinary excretion of inorganic arsenic: a Belgian population study. Occup Environ Med 1996; 53: 320–327.
Daniel J, Ziaee H, Pradhan C, McMinn DJ . Six-year results of a prospective study of metal ion levels in young patients with metal-on-metal hip resurfacings. J Bone Joint Surg Br 2009; 91: 176–179.
Heavner DL, Morgan WT, Sears SB, Richardson JD, Byrd GD, Ogden MW . Effect of creatinine and specific gravity normalization techniques on xenobiotic biomarkers in smokers' spot and 24- h urines. J Pharm Biomed Anal 2006; 40: 928–942.
Hinwood AL, Sim MR, de Klerk N, Drummer O, Gerostamoulos J, Bastone EB . Are 24- hour urine samples and creatinine adjustment required for analysis of inorganic arsenic in urine in population studies? Environ Res 2002; 88: 219–224.
Minoia C, Sabbioni E, Apostoli P, Pietra R, Pozzoli L, Gallorini M et al. Trace element reference values in tissues from inhabitants of the European community. I. A study of 46 elements in urine, blood and serum of Italian subjects. Sci Total Environ 1990; 95: 89–105.
Sieniawska CE, Jung LC, Olufadi R, Walker V . Twenty-four-hour urinary trace element excretion: reference intervals and interpretive issues. Ann Clin Biochem 2012; 49: 341–351.
Staessen J, Bulpitt CJ, Roels H, Bernard A, Fagard R, Joossens JV et al. Urinary cadmium and lead concentrations and their relation to blood pressure in a population with low exposure. Br J Ind Med 1984; 41: 241–248.
Miler M, Šimundić AM . Low level of adherence to instructions for 24- hour urine collection among hospital out-patients. Biochem Med 2013; 23: 316–320.
Araki S, Sata F, Murata K . Adjustment for urinary flow rate: an improved approach to biological monitoring. Int Arch Occup Environ Health 1990; 62: 471–477.
Greenberg GN, Levine RJ . Urinary creatinine excretion is not stable: a new method for assessing urinary toxic substance concentrations. J Occup Med 1989; 31: 832–838.
Vij HS, Howell S . Improving the specific gravity adjustment method for assessing urinary concentrations of toxic substances. Am Ind Hyg Assoc J 1998; 59: 375–380.
Bingham SA, Cummings JH . The use of creatinine output as a check on the completeness of 24- hour urine collections. Hum Nutr Clin Nutr 1985; 39: 343–353.
De Keyzer W, Huybrechts I, Dekkers AL, Geelen A, Crispim S, Hulshof PJ et al. Predicting urinary creatinine excretion and its usefulness to identify incomplete 24 h urine collections. Br J Nutr 2012; 108: 1118–1125.
Garde AH, Hansen AM, Kristiansen J, Knudsen LE . Comparison of uncertainties related to standardization of urine samples with volume and creatinine concentration. Ann Occup Hyg 2004; 48: 171–179.
Narayanan S, Appleton HD . Creatinine: a review. Clin Chem 1980; 26: 1119–1126.
Barr DB, Wilder LC, Caudill SP, Gonzalez AJ, Needham LL, Pirkle JL . Urinary creatinine concentrations in the U.S. population: implications for urinary biologic monitoring measurements. Environ Health Perspect 2005; 113: 192–200.
National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39: S1–266.
Soveri I, Berg UB, Björk J, Elinder CG, Grubb A, Mejare I et al. Measuring GFR: a systematic review. Am J Kidney Dis 2014; 64: 411–424.
Chaumont A, De WF, Dumont X, Haufroid V, Bernard A . The threshold level of urinary cadmium associated with increased urinary excretion of retinol-binding protein and beta 2-microglobulin: a re-assessment in a large cohort of nickel-cadmium battery workers. Occup Environ Med 2011; 68: 257–264.
Haddam N, Samira S, Dumont X, Taleb A, Lison D, Haufroid V, Bernard A . Confounders in the assessment of the renal effects associated with low-level urinary cadmium: an analysis in industrial workers. Environ Health 2011; 10: 37.
Nermell B, Lindberg AL, Rahman M, Berglund M, Persson LA, El Arifeen S, Vahter M . Urinary arsenic concentration adjustment factors and malnutrition. Environ Res 2008; 106: 212–218.
Kim DK, Song JW, Park JD, Choi BS . A comparison of the adjustment methods for assessing urinary concentrations of cadmium and arsenic: creatinine vs. specific gravity. J Environ Health Sci 2011; 37: 450–459.
Hoet P, Jacquerye C, Deumer G, Lison D, Haufroid V . Reference values and upper reference limits for 26 trace elements in the urine of adults living in Belgium. Clin Chem Lab Med 2013; 51: 839–849.
Berlin A, Alessio L, Sesana G, Dell'Orto A, Ghezzi I . Problems concerning the usefulness of adjustment of urinary cadmium for creatinine and specific gravity. Int Arch Occup Environ Health 1985; 55: 107–111.
Sauvé JF, Levesque M, Huard M, Drolet D, Lavoué J, Tardiff R, Truchon G . Creatinine and specific gravity normalization in biological monitoring of occupational exposures. J Occup Environ Hyg 2015; 12: 123–129.
Sorahan T, Pang D, Esmen N, Sadhra S . Urinary concentrations of toxic substances: an assessment of alternative approaches to adjusting for specific gravity. J Occup Environ Hyg 2008; 5: 721–723.
Suwazono Y, Akesson A, Alfven T, Jarup L, Vahter M . Creatinine versus specific gravity-adjusted urinary cadmium concentrations. Biomarkers 2005; 10: 117–126.
Cone EJ, Caplan YH, Moser F, Robert T, Shelby MK, Black DL . Normalization of urinary drug concentrations with specific gravity and creatinine. J Anal Toxicol 2009; 33: 1–7.
Pearson MA, Lu C, Schmotzer BJ, Waller LA, Riederer AM . Evaluation of physiological measures for correcting variation in urinary output: Implications for assessing environmental chemical exposure in children. J Expo Sci Environ Epidemiol 2009; 19: 336–342.
Waikar SS, Sabbisetti VS, Bonventre JV . Normalization of urinary biomarkers to creatinine during changes in glomerular filtration rate. Kidney Int 2010; 78: 486–494.
Health Canada. Report on human biomonitoring of environmental chemicals in Canada. Results of the Canadian Health Measures Survey Cycle 1 (2007–2009). August 2010. Available from http://www.healthcanada.gc.ca. Accessed June, 2014.
Centers for Disease Control and Prevention (CDC). Fourth national report on human exposure to environmental chemicals, updated tables, August 2014. Available from http://www.cdc.gov/exposurereport/. Accessed October, 2014.
Frery N, Saoudi A, Garnier R, Zeghnoun A, Falq G . Exposition de la population française aux substances chimiques de l'environnement. Institut de Veille Sanitaire: Saint-Maurice. 2011, 151 p.
WHO Biological Monitoring of Chemical Exposure in the Workplace Guidelines Vol 1 Contribution to the International Programme on Chemical Safety WHO/HPR /OCH 961. Geneva. 1996.
Bader M, Messerer P, Will W . Urinary creatinine concentrations in an industrial workforce and comparison with reference values of the general population. Int Arch Occup Environ Health 2013; 86: 673–680.
Moriguchi J, Ezaki T, Tsukahara T, Furuki K, Fukui Y, Okamoto S et al. Comparative evaluation of four urinary tubular dysfunction markers, with special references to the effects of aging and correction for creatinine concentration. Toxicol Lett 2003; 143: 279–290.
Akerstrom M, Barregard L, Lundh T, Sallsten G . The relationship between cadmium in kidney and cadmium in urine and blood in an environmentally exposed population. Toxicol Appl Pharmacol 2013; 268: 286–293.
Chaumont A, Nickmilder M, Dumont X, Lundh T, Skerfving S, Bernard A . Associations between proteins and heavy metals in urine at low environmental exposures: evidence of reverse causality. Toxicol Lett 2012; 210: 345–352.
Shelley R, Kim NS, Parsons PJ, Lee BK, Agnew J, Jaar BG et al. Uranium associations with kidney outcomes vary by urine concentration adjustment method. J Expo Sci Environ Epidemiol 2014; 24: 58–64.
Weaver VM, Vargas GG, Silbergeld EK, Rothenberg SJ, Fadrowski JJ, Rubio-Andrade M et al. Impact of urine concentration adjustment method on associations between urine metals and estimated glomerular filtration rates (eGFR) in adolescents. Environ Res 2014; 132: 226–232.
Basu A, Mitra S, Chung J, Guha Mazumder DN, Ghosh N, Kalman D et al. Creatinine, diet, micronutrients, and arsenic methylation in West Bengal, India. Environ Health Perspect 2011; 119: 1308–1313.
Gamble MV, Liu X . Urinary creatinine and arsenic metabolism. Environ Health Perspect 2005; 113: A442–A443.
Trevisan A, Nicoletto G, Maso S, Grandesso G, Odynets A, Secondin L . Biological monitoring of cadmium exposure: reliability of spot urine samples. Int Arch Occup Environ Health 1994; 65: 373–375.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Journal of Exposure Science and Environmental Epidemiology website
Supplementary information
Rights and permissions
About this article
Cite this article
Hoet, P., Deumer, G., Bernard, A. et al. Urinary trace element concentrations in environmental settings: is there a value for systematic creatinine adjustment or do we introduce a bias?. J Expo Sci Environ Epidemiol 26, 296–302 (2016). https://doi.org/10.1038/jes.2015.23
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/jes.2015.23
Keywords
This article is cited by
-
Association of obesity, diabetes, and hypertension with arsenic in drinking water in the Comarca Lagunera province (north-central Mexico)
Scientific Reports (2023)
-
Development of a multiplex mass spectrometry method for simultaneous quantification of urinary proteins related to respiratory health
Scientific Reports (2021)
-
Spot urine iodine levels below the WHO recommendation are not related to impaired thyroid function in healthy children and adolescents
European Journal of Nutrition (2021)
-
Urinary Concentration Correction Methods for Arsenic, Cadmium, and Mercury: a Systematic Review of Practice-Based Evidence
Current Environmental Health Reports (2019)
-
The physiological determinants of low-level urine cadmium: an assessment in a cross-sectional study among schoolchildren
Environmental Health (2017)