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Lipid and Creatinine Adjustment to Evaluate Health Effects of Environmental Exposures

  • Methods in Environmental Epidemiology (EF Schisterman and AZ Pollack, Section Editors)
  • Published:
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Abstract

Purpose of Review

Urine- and serum-based biomarkers are useful for assessing individuals’ exposure to environmental factors. However, variations in urinary creatinine (a measure of dilution) or serum lipid levels, if not adequately corrected for, can directly impact biomarker concentrations and bias exposure-disease association measures.

Recent Findings

Recent methodological literature has considered the complex relationships between creatinine or serum lipid levels, exposure biomarkers, outcomes, and other potentially relevant factors using directed acyclic graphs and simulation studies. The optimal measures of urinary dilution and serum lipids have also been investigated.

Summary

Existing evidence supports the use of covariate-adjusted standardization plus creatinine adjustment for urinary biomarkers and standardization plus serum lipid adjustment for lipophilic, serum-based biomarkers. It is unclear which urinary dilution measure is best, but all serum lipid measures performed similarly. Future research should assess methods for pooled biomarkers and for studying diseases and exposures that affect creatinine or serum lipids directly.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of outstanding importance

  1. 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(4):928–42.

    Article  CAS  PubMed  Google Scholar 

  2. Phillips DL, Pirkle JL, Burse VW, Bernert JT, Henderson LO, Needham LL. Chlorinated hydrocarbon levels in human serum: effects of fasting and feeding. Arch Environ Contam Toxicol. 1989;18:495–500.

    Article  CAS  PubMed  Google Scholar 

  3. • 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. 2004;113(2):192–200. This is a seminal paper that provided evidence that creatinine levels are associated with various other factors, including age, sex, race, fat free mass, and body mass index. This paper is highly cited as justification for adjusting for creatinine as a covariate when assessing the health effects of environmental exposures measured in urine

    Article  PubMed Central  Google Scholar 

  4. Christensen K, Sobus J, Phillips M, Blessinger T, Lorber M, Tan YM. Changes in epidemiologic associations with different exposure metrics: a case study of phthalate exposure associations with body mass index and waist circumference. Environ Int. 2014;73:66–76.

    Article  CAS  PubMed  Google Scholar 

  5. •• O'Brien KM, Upson K, Cook NR, Weinberg CR. Environmental Chemicals in Urine and Blood: improving methods for creatinine and lipid adjustment. Environ Health Perspect. 2016;124(2):220–7. With the aid of directed acyclic graphs and simulation studies, these authors compared existing methods for creatinine and lipid adjustment with a new method, called covariate-adjusted standardization. They show that the new method is appropriate for assessing urinary biomarkers and that classical standardization works well for lipophilic, serum-based biomarkers

    PubMed  Google Scholar 

  6. Buckley JP, Herring AH, Wolff MS, Calafat AM, Engel SM. Prenatal exposure to environmental phenols and childhood fat mass in the Mount Sinai Children's environmental health study. Environ Int. 2016;91:350–6.

    Article  CAS  PubMed  Google Scholar 

  7. Guo J, Su L, Zhao X, Xu Z, Chen G. Relationships between urinary antimony levels and both mortalities and prevalence of cancers and heart diseases in general US population, NHANES 1999-2010. Sci Total Environ. 2016;571:452–60.

    Article  CAS  PubMed  Google Scholar 

  8. Tsai HJ, Wu CF, Tsai YC, Huang PC, Chen ML, Wang SL, et al. Intake of phthalate-tainted foods and serum thyroid hormones in Taiwanese children and adolescents. Sci Rep. 2016;6:30589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang W, Schaumberg DA, Park SK. Cadmium and lead exposure and risk of cataract surgery in U.S. adults. Int J Hyg Environ Health. 2016.

  10. 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(10):615–27.

    Article  CAS  PubMed  Google Scholar 

  11. Hoet P, Deumer G, Bernard A, Lison D, Haufroid V. 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. 2016;26(3):296–302.

    Article  CAS  PubMed  Google Scholar 

  12. Suwazono Y, Akesson A, Alfven T, Jarup L, Vahter M. Creatinine versus specific gravity-adjusted urinary cadmium concentrations. Biomarkers. 2005;10(2–3):117–26.

    Article  CAS  PubMed  Google Scholar 

  13. Yeh HC, Lin YS, Kuo CC, Weidemann D, Weaver V, Fadrowski J, et al. Urine osmolality in the US population: implications for environmental biomonitoring. Environ Res. 2015;136:482–90.

    Article  CAS  PubMed  Google Scholar 

  14. Weaver VM, Kotchmar DJ, Fadrowski JJ, Silbergeld EK. Challenges for environmental epidemiology research: are biomarker concentrations altered by kidney function or urine concentration adjustment? J Expo Sci Environ Epidemiol. 2016;26(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  15. Hauser R, Meeker JD, Park S, Silva MJ, Calafat AM. Temporal variability of urinary phthalate metabolite levels in men of reproductive age. Environ Health Perspect. 2004;112(17):1734–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hays SM, Aylward LL, Blount BC. Variation in urinary flow rates according to demographic characteristics and body mass index in NHANES: potential confounding of associations between health outcomes and urinary biomarker concentrations. Environ Health Perspect. 2015;123(4):293–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Middleton DR, Watts MJ, Lark RM, Milne CJ, Polya DA. Assessing urinary flow rate, creatinine, osmolality and other hydration adjustment methods for urinary biomonitoring using NHANES arsenic, iodine, lead and cadmium data. Environ Health. 2016;15(1):68.

    Article  PubMed  PubMed Central  Google Scholar 

  18. • Schisterman EF, Whitcomb BW, Buck Louis GM, Louis TA. Lipid adjustment in the analysis of environmental contaminants and human health risks. Environ Health Perspect. 2005;113(7):853–7. This is the first paper to apply a directed acyclic graph and simulation approach to the issue of serum lipid adjustment. This paper is highly cited as justification for adjusting for serum lipids as a covariate or using a two-stage model when assessing the health effects of lipophilic, environmental exposures measured in serum

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hunter DJ, Hankinson SE, Laden F, Colditz GA, Manson JE, Willett WC, et al. Plasma organochlorine levels and the risk of breast cancer. N Engl J Med. 1997;337(18):1253–9.

    Article  CAS  PubMed  Google Scholar 

  20. Li D, Longnecker MP, Dunson DB. Lipid adjustment for chemical exposures: accounting for concomitant variables. Epidemiology. 2013;24(6):921–8.

    Article  PubMed  Google Scholar 

  21. Costanza MC, Cayanis E, Ross BM, Flaherty MS, Alvin GB, Das K, et al. Relative contributions of genes, environment, and interactions to blood lipid concentrations in a general adult population. Am J Epidemiol. 2005;161(8):714–24.

    Article  PubMed  Google Scholar 

  22. Bernert JT, Turner WE, Patterson Jr DG, Needham LL. Calculation of serum “total lipid” concentrations for the adjustment of persistent organohalogen toxicant measurements in human samples. Chemosphere. 2007;68(5):824–31.

    Article  CAS  PubMed  Google Scholar 

  23. Bergonzi R, De Palma G, Tomasi C, Ricossa MC, Apostoli P. Evaluation of different methods to determine total serum lipids for normalization of circulating organochlorine compounds. Int Arch Occup Environ Health. 2009;82(10):1241–7.

    Article  CAS  PubMed  Google Scholar 

  24. Rylander L, Nilsson-Ehle P, Hagmar L. A simplified precise method for adjusting serum levels of persistent organohalogen pollutants to total serum lipids. Chemosphere. 2006;62(3):333–6.

    Article  CAS  PubMed  Google Scholar 

  25. 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(3):279–90.

    Article  CAS  PubMed  Google Scholar 

  26. Goncharov A, Haase RF, Santiago-Rivera A, Morse G. Akwesasne task force on the E, McCaffrey RJ, et al. high serum PCBs are associated with elevation of serum lipids and cardiovascular disease in a native American population. Environ Res. 2008;106(2):226–39.

    Article  CAS  PubMed  Google Scholar 

  27. Patel CJ, Cullen MR, Ioannidis JP, Butte AJ. Systematic evaluation of environmental factors: persistent pollutants and nutrients correlated with serum lipid levels. Int J Epidemiol. 2012;41(3):828–43.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Engel LS, Buckley JP, Yang G, Liao LM, Satagopan J, Calafat AM, et al. Predictors and variability of repeat measurements of urinary phenols and parabens in a cohort of shanghai women and men. Environ Health Perspect. 2014;122(7):733–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Meeker JD, Calafat AM, Hauser R. Urinary phthalate metabolites and their biotransformation products: predictors and temporal variability among men and women. J Expo Sci Environ Epidemiol. 2012;22(4):376–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Perrier F, Giorgis-Allemand L, Slama R, Philippat C. Within-subject pooling of biological samples to reduce exposure misclassification in biomarker-based studies. Epidemiology. 2016;27(3):378–88.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lyles RH, Mitchell EM, Weinberg CR, Umbach DM, Schisterman EF. An efficient design strategy for logistic regression using outcome- and covariate-dependent pooling of biospecimens prior to assay. Biometrics. 2016.

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Author information

Authors and Affiliations

  1. Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, 111 TW Alexander Dr, Research Triangle Park, Durham, NC, 27709, USA

    Katie M. O’Brien

  2. Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Dr, Research Triangle Park, Durham, NC, 27709, USA

    Kristen Upson

  3. Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Jessie P. Buckley

Authors
  1. Katie M. O’Brien
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  2. Kristen Upson
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  3. Jessie P. Buckley
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Corresponding author

Correspondence to Katie M. O’Brien.

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Conflict of Interest

Katie M. O’Brien, Kristen Upson, and Jessie P. Buckley declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

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This article is part of the Topical Collection on Methods in Environmental Epidemiology

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O’Brien, K.M., Upson, K. & Buckley, J.P. Lipid and Creatinine Adjustment to Evaluate Health Effects of Environmental Exposures. Curr Envir Health Rpt 4, 44–50 (2017). https://doi.org/10.1007/s40572-017-0122-7

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  • DOI: https://doi.org/10.1007/s40572-017-0122-7

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