No retraction, correction or concern found when last checked on Oct 23, 2026.

Optimal Exposure Biomarkers for Nonpersistent Chemicals in Environmental Epidemiology

Antonia M. Calafat, Matthew P. Longnecker, Holger M. Koch and 9 more

Environmental Health Perspectives · 2015 · Public domain

Abstract

Summary We discuss considerations that are essential when evaluating exposure to nonpersistent, semivolatile environmental chemicals such as phthalates and phenols (e.g., bisphenol A). A biomarker should be chosen to best represent usual personal exposures and not recent, adventitious, or extraneous exposures. Biomarkers should be selected to minimize contamination arising from collection, sampling, or analysis procedures. Pharmacokinetics should be considered; for example, nonpersistent, semivolatile chemicals are metabolized quickly, and urine is the compartment with the highest concentrations of metabolites. Because these chemicals are nonpersistent, knowledge of intraindividual reliability over the biologic window of interest is also required. In recent years researchers have increasingly used blood as a matrix for characterizing exposure to nonpersistent chemicals. However, the biologic and technical factors noted above strongly support urine as the optimal matrix for measuring nonpersistent, semivolatile, hydrophilic environmental agents.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 23, 2026. Paragraph numbers are ours, so an answer can point at one.

1Quantification of exposure biomarkers is increasingly used to provide an integrated measure of a person’s multiple chemical-specific exposures. Yet successful exposure characterization requires more than sophisticated analytical chemistry techniques—the biomarker and matrix are also key.

2For general-population exposures, persistent organic pollutants (POPs) are usually measured in blood, and metabolites of nonpersistent chemicals such as phthalates and bisphenol A (BPA) are best measured in urine. In recent years, however, investigators have increasingly characterized exposure to nonpersistent chemicals by using other tissue matrices, particularly blood. To illustrate this trend, we identified 80 scientific articles, published in 2000–2014, that reported measuring BPA or phthalates in blood serum/plasma and other nonaqueous matrices, and that addressed topics on etiology, exposure, or metabolism (Figure 1).

3Urine is the preferred matrix for most nonpersistent chemicals because of their pharmacokinetics. Nonpersistent chemicals are quickly transformed to hydrophilic, polar metabolites and excreted mainly in urine. The concentration of most urinary metabolites is 30–100 times greater than concentrations in blood. With existing analytical techniques, higher urinary concentrations facilitate quantification, whereas relatively low blood concentrations of polar biomarkers increase the likelihood that external contamination obscures true exposures.

4These are paramount considerations, given the increasingly recognized ubiquity of contamination. Controlled conditions of collection, storage, and processing of biospecimens are a long-acknowledged critical step for trace analyses of metals, volatile organic compounds, and POPs. Unfortunately, the importance of preanalytic contamination sources is not as well understood for semivolatiles such as phthalates, phenols (e.g., BPA, parabens, triclosan), and similar modern nonpersistent chemicals.

5Rather than reflecting a person’s usual exposure over months to years, detected biomarkers of chemicals such as phthalates and BPA can represent recent use of medical equipment or treatment near the time of biospecimen collection. Extraneous contamination may occur during both the preanalytical and analytical phases. Phthalates and BPA can be detected even in the cleanest laboratories, from reagents, sampling equipment, and analytical apparatus. Extraneous phenols may also come from sources such as plastics or paper products (BPA), soap (triclosan), moist towelettes (parabens), and preservatives (BPA, parabens). Moreover, in the field, during processing, or in the laboratory, beginning immediately after sample collection, phthalate diesters are hydrolyzed to monoesters by enzymes present in most biologic matrices (e.g., milk, serum, meconium, amniotic fluid, skin, saliva, sweat). These hydrolytic enzymes are not present in urine. In other words, monoesters are formed both from diesters absorbed in the body from a person’s general environment—the exposure we intend to assess—and from diesters introduced into the biospecimen itself from contaminated surfaces and medical devices.

6Phase I (e.g., phthalate oxidative metabolites) and phase II (e.g., phenol conjugates) metabolite biomarkers are least likely to arise from extraneous sources. Also, these metabolites exist at higher levels than the hydrolytic monoesters or free (unconjugated) phenols in urine. For many phenols, no specific oxidative metabolites that can exclude contamination are currently used for biomonitoring. Instead, conjugated phenols (rather than the unconjugated species) are the most valid exposure biomarkers.

7The short half-life of nonpersistent chemicals presents additional challenges, in that a biomarker must meet the criterion of temporality. Regardless of the matrix, intraindividual variability exists in exposure metrics over short time periods, particularly when such exposures are episodic in nature. However, metabolites are detectable longer in urine than in other matrices. Acceptable biomarker variability can exist because exposures arise from common, quotidian sources. Consequently, reasonable reproducibility over months to years has been found for urinary biomarker concentrations. To improve exposure assessment, studies can also incorporate pooling of specimens or repeated measurements across the time window of interest, such as trimesters of pregnancy.

8In population research, environmental agents are selected for study based on biological relevance and exposure prevalence. Exposure biomarkers should be based on pharmacokinetics of the target chemicals and a suitable sampling matrix. The design should incorporate appropriate control procedures for collecting and processing specimens, validated analytical methods, and statistical analyses that account for sampling issues such as urine dilution and collection times.

9Technology has made it analytically possible to measure polar biomarkers at trace concentrations in many media, but these endeavors risk exposure misclassification due to low biomarker concentrations, short biologic half-lives, and threat of external contamination. Greater reliance on phthalate and phenol biomarker concentrations in urine will improve the return on investment in environmental research.

10The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. This research was supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Department of Health and Human Services. We thank Sandra Chambers at the NIEHS for help in identifying articles listed in Figure 1.

References 48

1.
Characterization of Phthalate Exposure among Pregnant Women Assessed by Repeat Air and Urine Samples · 2008
No notice
2.
Alcock RE Halsall CJ Harris CA Johnston AE Lead WA Sanders G 1994 Contamination of environmental samples prepared for PCB analysis.Environ Sci Technol281118381842;
Not in our library10.1021/es00060a013
3.
Ashley DL, Bonin MA, Cardinali FL, McCraw JM, Holler JS, Needham LL, et al. Determining volatile organic compounds in human blood from a large sample population by using purge and trap gas chromatography/mass spectrometry. Anal Chem. 1992;64(9):1021-1029.
Not in our library10.1021/ac00033a011
4.
Baird DD Saldana TM Nepomnaschy PA Hoppin JA Longnecker MP Weinberg CR 2010 Within-person variability in urinary phthalate metabolite concentrations: measurements from specimens after long-term frozen storage.J Expo Sci Environ Epidemiol202169175;
Not in our library10.1038/jes.2009.17
5.
Urinary Creatinine Concentrations in the U.S. Population: Implications for Urinary Biologic Monitoring Measurements · 2004
No notice
6.
Bolann BJ Rahil-Khazen R Henriksen H Isrenn R Ulvik RJ 2007 Evaluation of methods for trace-element determination with emphasis on their usability in the clinical routine laboratory.Scand J Clin Lab Invest674353366;
Not in our library10.1080/00365510601095281
7.
Variability and Predictors of Urinary Bisphenol A Concentrations during Pregnancy · 2010
No notice
8.
Calafat AM Needham LL 2009 What additional factors beyond state-of-the-art analytical methods are needed for optimal generation and interpretation of biomonitoring data?Environ Health Perspect1171014811485;
Not in our library10.1289/ehp.0901108
9.
Cantonwine DE Cordero JF Rivera-Gonzalez LO Anzalota Del Toro LV Ferguson KK Mukherjee B 2014 Urinary phthalate metabolite concentrations among pregnant women in Northern Puerto Rico: distribution, temporal variability, and predictors.Environ Int62111;
Not in our library10.1016/j.envint.2013.09.014
10.
Engel LS Buckley JP Yang G Liao LM Satagopan J Calafat AM 2014 Predictors and variability of repeat measurements of urinary phenols and parabens in a cohort of Shanghai women and men.Environ Health Perspect1227733740;
Not in our library10.1289/ehp.1306830
11.
Engel SM Wolff MS 2013 Causal inference considerations for endocrine disruptor research in children’s health.Annu Rev Public Health34139158;
Not in our library10.1146/annurev-publhealth-031811-124556
12.
Fankhauser-Noti A Grob K 2007 Blank problems in trace analysis of diethylhexyl and dibutyl phthalate: investigation of the sources, tips and tricks.Anal Chim Acta5822353360;
Not in our library10.1016/j.aca.2006.09.012
13.
Fisher M Arbuckle TE Mallick R LeBlanc A Hauser R Feeley M 2015 Bisphenol A and phthalate metabolite urinary concentrations: daily and across pregnancy variability.J Expo Sci Environ Epidemiol253231239;
Not in our library10.1038/jes.2014.65
14.
Frederiksen H Kranich SK Jorgensen N Taboureau O Petersen JH Andersson AM 2013 Temporal variability in urinary phthalate metabolite excretion based on spot, morning, and 24-h urine samples: considerations for epidemiological studies.Environ Sci Technol472958967;
Not in our library10.1021/es303640b
15.
Guidry VT Longnecker MP Aase H Eggesbo M Zeiner P Reichborn-Kjennerud T 2015 Measurement of total and free urinary phenol and paraben concentrations over the course of pregnancy: assessing reliability and contamination of specimens in the Norwegian Mother and Child Cohort study.Environ Health Perspect1237705711;
Not in our library10.1289/ehp.1408325
16.
Temporal Variability of Urinary Phthalate Metabolite Levels in Men of Reproductive Age · 2004
No notice
17.
Concentrations of Phthalate Metabolites in Milk, Urine, Saliva, and Serum of Lactating North Carolina Women · 2008
No notice
18.
Irvin EA Calafat AM Silva MJ Aguilar-Villalobos M Needham LL Hall DB 2010 An estimate of phthalate exposure among pregnant women living in Trujillo, Peru.Chemosphere801113011307;
Not in our library10.1016/j.chemosphere.2010.06.048
19.
Jaeger RJ Rubin RJ 1970 Plasticizers from plastic devices extraction, metabolism, and accumulation by biological systems.Science1703956460462; PMID:
Not in our library10.1126/science.170.3956.460
20.
Jusko TA Shaw PA Snijder CA Pierik FH Koch HM Hauser R 2014 Reproducibility of urinary bisphenol A concentrations measured during pregnancy in the Generation R Study.J Expo Sci Environ Epidemiol245532536;
Not in our library10.1038/jes.2014.23
21.
Koch HM Aylward LL Hays SM Smolders R Moos RK Cocker J 2014 Inter- and intra-individual variation in urinary biomarker concentrations over a 6-day sampling period. Part 2: personal care product ingredients.Toxicol Lett2312261269;
Not in our library10.1016/j.toxlet.2014.06.023
22.
Koch HM Calafat AM 2009 Human body burdens of chemicals used in plastic manufacture.Philos Trans R Soc Lond B Biol Sci364152620632078;
Not in our library10.1098/rstb.2008.0208
23.
Koch HM Kolossa-Gehring M Schroter-Kermani C Angerer J Bruning T 2012 Bisphenol A in 24 h urine and plasma samples of the German Environmental Specimen Bank from 1995 to 2009: a retrospective exposure evaluation.J Expo Sci Environ Epidemiol226610616;
Not in our library10.1038/jes.2012.39
24.
Larson DF, Mayall B, Anderson RM. Hemolysis due to chemical contamination of clinical perfusion apparatus. Ann Thorac Surg. 1977;23(4):374-375.
Not in our library10.1016/s0003-4975(10)64146-x
25.
Lassen TH Frederiksen H Jensen TK Petersen JH Main KM Skakkebæk NE 2013 Temporal variability in urinary excretion of bisphenol A and seven other phenols in spot, morning, and 24-h urine samples.Environ Res126164170;
Not in our library10.1016/j.envres.2013.07.001
26.
Longnecker MP Harbak K Kissling GE Hoppin JA Eggesbo M Jusko TA 2013 The concentration of bisphenol A in urine is affected by specimen collection, a preservative, and handling.Environ Res126211214;
Not in our library10.1016/j.envres.2013.07.002
27.
Temporal Variability and Predictors of Urinary Bisphenol A Concentrations in Men and Women · 2007
No notice
28.
Marcus M Christensen KY Manatunga A Rudra CB Brock JW Small CM 2010 Variability of phthalate monoester levels in daily first-morning urine from adult women: a pilot study.Rev Environ Health254359368;
Not in our library10.1515/reveh.2010.25.4.359
29.
Marega M Grob K Moret S Conte L 2013 Phthalate analysis by gas chromatography-mass spectrometry: blank problems related to the syringe needle.J Chromatogr A1273105110;
Not in our library10.1016/j.chroma.2012.11.076
30.
Markham DA Waechter JM Jr Wimber M Rao N Connolly P Chuang JC 2010 Development of a method for the determination of bisphenol A at trace concentrations in human blood and urine and elucidation of factors influencing method accuracy and sensitivity.J Anal Toxicol346293303;
Not in our library10.1093/jat/34.6.293
31.
Meeker JD Calafat AM Hauser R 2012 Urinary phthalate metabolites and their biotransformation products: predictors and temporal variability among men and women.J Expo Sci Environ Epidemiol224376385;
Not in our library10.1038/jes.2012.7
32.
Meeker JD Cantonwine DE Rivera-Gonzalez LO Ferguson KK Mukherjee B Calafat AM 2013 Distribution, variability, and predictors of urinary concentrations of phenols and parabens among pregnant women in Puerto Rico.Environ Sci Technol47734393447;
Not in our library10.1021/es400510g
33.
Nepomnaschy PA Baird DD Weinberg CR Hoppin JA Longnecker MP Wilcox AJ 2009 Within-person variability in urinary bisphenol A concentrations: measurements from specimens after long-term frozen storage.Environ Res1096734737;
Not in our library10.1016/j.envres.2009.04.004
34.
Phthalates and Cumulative Risk Assessment: The Tasks Ahead. 2008.
Not in our library
35.
Prenatal Exposure to Environmental Phenols: Concentrations in Amniotic Fluid and Variability in Urinary Concentrations during Pregnancy · 2013
No notice
36.
Pirkle JL, Needham LL, Sexton K. Improving exposure assessment by monitoring human tissues for toxic chemicals. J Expo Anal Environ Epidemiol. 1995;5(3):405-424.
Not in our library
37.
Variability over 1 Week in the Urinary Concentrations of Metabolites of Diethyl Phthalate and Di(2-Ethylhexyl) Phthalate among Eight Adults: An Observational Study · 2010
No notice
38.
Quirós-Alcalá L Eskenazi B Bradman A Ye X Calafat AM Harley K 2013 Determinants of urinary bisphenol A concentrations in Mexican/Mexican-American pregnant women.Environ Int59152160;
Not in our library10.1016/j.envint.2013.05.016
39.
Predictors and Variability of Urinary Paraben Concentrations in Men and Women, Including before and during Pregnancy · 2012
No notice
40.
Teeguarden J Hanson-Drury S Fisher JW Doerge DR 2013 Are typical human serum BPA concentrations measurable and sufficient to be estrogenic in the general population?Food Chem Toxicol62949963;
Not in our library10.1016/j.fct.2013.08.001
41.
Teitelbaum SL Britton JA Calafat AM Ye X Silva MJ Reidy JA 2008 Temporal variability in urinary concentrations of phthalate metabolites, phytoestrogens and phenols among minority children in the United States.Environ Res1062257269;
Not in our library10.1016/j.envres.2007.09.010
42.
Townsend MK Franke AA Li X Hu FB Eliassen AH 2013 Within-person reproducibility of urinary bisphenol A and phthalate metabolites over a 1 to 3 year period among women in the Nurses’ Health Studies: a prospective cohort study.Environ Health12180;
Not in our library10.1186/1476-069x-12-80
43.
Valvi D Monfort N Ventura R Casas M Casas L Sunyer J 2015 Variability and predictors of urinary phthalate metabolites in Spanish pregnant women.Int J Hyg Environ Health2182220231;
Not in our library10.1016/j.ijheh.2014.11.003
44.
Vandenberg LN Gerona RR Kannan K Taylor JA van Breemen RB Dickenson CA 2014 A round robin approach to the analysis of bisphenol A (BPA) in human blood samples.Environ Health13125;
Not in our library10.1186/1476-069x-13-25
45.
Vandentorren S Zeman F Morin L Sarter H Bidondo ML Oleko A 2011 Bisphenol-A and phthalates contamination of urine samples by catheters in the Elfe pilot study: implications for large-scale biomonitoring studies.Environ Res1116761764;
Not in our library10.1016/j.envres.2011.05.018
46.
Yan X Calafat A Lashley S Smulian J Ananth C Barr D 2009 Phthalates biomarker identification and exposure estimates in a population of pregnant women.Hum Ecol Risk Assess153565578;
Not in our library10.1080/10807030902892554
47.
Variability of Urinary Concentrations of Bisphenol A in Spot Samples, First Morning Voids, and 24-Hour Collections · 2011
No notice
48.
Potential External Contamination with Bisphenol A and Other Ubiquitous Organic Environmental Chemicals during Biomonitoring Analysis: An Elusive Laboratory Challenge · 2013
No notice

Cited by papers we hold 1

Organophosphate pesticide dose estimation from spot and 24-hr urine samples collected from children in an agricultural community · 2021
Not checked

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.