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Article

Assessing the Validity of Normalizing Aflatoxin B1-Lysine Albumin Adduct Biomarker Measurements to Total Serum Albumin Concentration across Multiple Human Population Studies

by
Joshua W. Smith
1,
Derek K. Ng
2,
Christian S. Alvarez
3,
Patricia A. Egner
1,
Sean M. Burke
1,
Jian-Guo Chen
4,
Thomas W. Kensler
1,5,
Jill Koshiol
3,
Alvaro Rivera-Andrade
6,
María F. Kroker-Lobos
6,
Manuel Ramírez-Zea
6,
Katherine A. McGlynn
3 and
John D. Groopman
1,*
1
Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
2
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
3
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA
4
Department of Epidemiology, Qidong Liver Cancer Institute, Qidong 226200, China
5
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
6
Research Center for the Prevention of Chronic Diseases, Institute of Nutrition of Central America and Panama, Guatemala City 1188, Guatemala
*
Author to whom correspondence should be addressed.
Toxins 2022, 14(3), 162; https://doi.org/10.3390/toxins14030162
Submission received: 14 January 2022 / Revised: 14 February 2022 / Accepted: 15 February 2022 / Published: 23 February 2022
(This article belongs to the Special Issue Mycotoxin Biomarkers: Innovation and Utility)
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Abstract

The assessment of aflatoxin B1 (AFB1) exposure using isotope-dilution liquid chromatography-mass spectrometry (LCMS) of AFB1-lysine adducts in human serum albumin (HSA) has proven to be a highly productive strategy for the biomonitoring of AFB1 exposure. To compare samples across different individuals and settings, the conventional practice has involved the normalization of raw AFB1-lysine adduct concentrations (e.g., pg/mL serum or plasma) to the total circulating HSA concentration (e.g., pg/mg HSA). It is hypothesized that this practice corrects for technical error, between-person variance in HSA synthesis or AFB1 metabolism, and other factors. However, the validity of this hypothesis has been largely unexamined by empirical analysis. The objective of this work was to test the concept that HSA normalization of AFB1-lysine adduct concentrations effectively adjusts for biological and technical variance and improves AFB1 internal dose estimates. Using data from AFB1-lysine and HSA measurements in 763 subjects, in combination with regression and Monte Carlo simulation techniques, we found that HSA accounts for essentially none of the between-person variance in HSA-normalized (R2 = 0.04) or raw AFB1-lysine measurements (R2 = 0.0001), and that HSA normalization of AFB1-lysine levels with empirical HSA values does not reduce measurement error any better than does the use of simulated data (n = 20,000). These findings were robust across diverse populations (Guatemala, China, Chile), AFB1 exposures (105 range), HSA assays (dye-binding and immunoassay), and disease states (healthy, gallstones, and gallbladder cancer). HSA normalization results in arithmetic transformation with the addition of technical error from the measurement of HSA. Combined with the added analysis time, cost, and sample consumption, these results suggest that it may be prudent to abandon the practice of normalizing adducts to HSA concentration when measuring any HSA adducts—not only AFB1-lys adducts—when using LCMS in serum/plasma.
Keywords: aflatoxin; biomarker; albumin; adduct; normalization; dosimetry; mass spectrometry aflatoxin; biomarker; albumin; adduct; normalization; dosimetry; mass spectrometry

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MDPI and ACS Style

Smith, J.W.; Ng, D.K.; Alvarez, C.S.; Egner, P.A.; Burke, S.M.; Chen, J.-G.; Kensler, T.W.; Koshiol, J.; Rivera-Andrade, A.; Kroker-Lobos, M.F.; et al. Assessing the Validity of Normalizing Aflatoxin B1-Lysine Albumin Adduct Biomarker Measurements to Total Serum Albumin Concentration across Multiple Human Population Studies. Toxins 2022, 14, 162. https://doi.org/10.3390/toxins14030162

AMA Style

Smith JW, Ng DK, Alvarez CS, Egner PA, Burke SM, Chen J-G, Kensler TW, Koshiol J, Rivera-Andrade A, Kroker-Lobos MF, et al. Assessing the Validity of Normalizing Aflatoxin B1-Lysine Albumin Adduct Biomarker Measurements to Total Serum Albumin Concentration across Multiple Human Population Studies. Toxins. 2022; 14(3):162. https://doi.org/10.3390/toxins14030162

Chicago/Turabian Style

Smith, Joshua W., Derek K. Ng, Christian S. Alvarez, Patricia A. Egner, Sean M. Burke, Jian-Guo Chen, Thomas W. Kensler, Jill Koshiol, Alvaro Rivera-Andrade, María F. Kroker-Lobos, and et al. 2022. "Assessing the Validity of Normalizing Aflatoxin B1-Lysine Albumin Adduct Biomarker Measurements to Total Serum Albumin Concentration across Multiple Human Population Studies" Toxins 14, no. 3: 162. https://doi.org/10.3390/toxins14030162

APA Style

Smith, J. W., Ng, D. K., Alvarez, C. S., Egner, P. A., Burke, S. M., Chen, J.-G., Kensler, T. W., Koshiol, J., Rivera-Andrade, A., Kroker-Lobos, M. F., Ramírez-Zea, M., McGlynn, K. A., & Groopman, J. D. (2022). Assessing the Validity of Normalizing Aflatoxin B1-Lysine Albumin Adduct Biomarker Measurements to Total Serum Albumin Concentration across Multiple Human Population Studies. Toxins, 14(3), 162. https://doi.org/10.3390/toxins14030162

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