Journal of Trace Elements in Medicine and Biology 68 (2021) 126830 Available online 31 July 2021 0946-672X/© 2021 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Multi-elemental determination of metals, metalloids and rare earth element concentrations in whole blood from the Canadian Health Measures Survey, 2009-2011 Innocent Jayawardene a,*, Jean-François Paradis b, Stéphane Bélisle b, Devika Poddalgoda a, Kristin Macey a a Existing Substances Risk Assessment Bureau, Health Canada, Ottawa, ON, Canada b Health Products Laboratory Longueuil, Regulatory Operations and Enforcement Branch, Health Canada, Longueuil, QC, Canada A R T I C L E I N F O Keywords: Biomonitoring ICP-MS Biobank Trace elements A B S T R A C T Background: As part of Government of Canada’s Chemical Management Plan, substances containing aluminum (Al), bismuth (Bi), cerium (Ce), chromium (Cr), germanium (Ge), lanthanum (La), lithium (Li), neodymium (Nd), praseodymium (Pr), tellurium (Te), titanium (Ti) and yttrium (Y) were identified as priorities for risk assessment. Generating exposure estimates from all routes of exposure from multiple sources using a traditional approach for these elements can be challenging. The use of human biomonitoring (HBM) data would allow for direct and more precise assessment of the internal concentrations from all routes and all sources of exposure. There are no Ca- nadian or North American population-level whole blood HBM data for the elements listed above. Therefore, this is the first biomonitoring project carried out to determine the concentrations of these elements from a nationally representative sample of Canadians. Objectives: The objective of this study was to generate whole blood concentrations for Al, Bi, Ce, Cr, Ge, La, Li. Nd, Pr, Te, Ti and Y in the Canadian population using biobank samples from the Canadian Health Measures Survey (CHMS) cycle 2 (2009–2011) for use in characterizing exposure in screening assessments and for establishing baseline concentrations to determine how exposures are changing over time. Methods: The sample analysis was conducted by ICP-MS. A rigorous quality control and quality assurance process was implemented in order to generate data with high accuracy and precision while measuring low concentrations and minimizing possible inadvertent contamination. Results: Of the elements analysed, the whole blood concentrations (μg/L) of Al, Ce, Cr, Ge, La, Nd, Pr, Te, Ti and Y in the Canadian population aged 3–79 years were below their respective method reporting limit (MRL). Two elements, Bi and Li were detected in 5 % and 66 % of the Canadian population. The median Li concentration was 0.47 μg/L. Conclusion: The results of this study provide information on concentrations of these elements in the Canadian population which can be utilized to characterize exposure in screening assessments and there by the potential for harm to human health. In addition, this study provides baseline HBM data which can be used as a comparative HBM dataset for other populations with similar exposure patterns. 1. Introduction Human biomonitoring (HBM), which is defined as the measure of concentrations of chemicals in biological matrices, such as blood and urine, has become a very important tool in assessing exposure to envi- ronmental chemicals [1]. In Canada, biomonitoring of environmental chemicals in the general population has been conducted since 2007 through the Canadian Health Measures Survey (CHMS). With the availability of nationally represen- tative HBM data over the past 10 years, the Government of Canada has conducted screening-level risk assessments for cobalt, selenium, zinc, silver and thallium utilizing HBM data under the Chemicals Manage- ment Plan (CMP), an initiative established in accordance with the Ca- nadian Environmental Protection Act, 1999 (CEPA) [2–6]. These * Corresponding author. E-mail address: innocent.jayawardene@canada.ca (I. Jayawardene). Contents lists available at ScienceDirect Journal of Trace Elements in Medicine and Biology journal homepage: www.elsevier.com/locate/jtemb https://doi.org/10.1016/j.jtemb.2021.126830 Received 19 March 2021; Received in revised form 15 July 2021; Accepted 30 July 2021 mailto:innocent.jayawardene@canada.ca www.sciencedirect.com/science/journal/0946672X https://www.elsevier.com/locate/jtemb https://doi.org/10.1016/j.jtemb.2021.126830 https://doi.org/10.1016/j.jtemb.2021.126830 https://doi.org/10.1016/j.jtemb.2021.126830 http://crossmark.crossref.org/dialog/?doi=10.1016/j.jtemb.2021.126830&domain=pdf http://creativecommons.org/licenses/by-nc-nd/4.0/ Journal of Trace Elements in Medicine and Biology 68 (2021) 126830 2 elemental moieties were assessed as they were part of 4300 substances identified as priorities for further evaluation under the CMP. Among the priorities identified for assessment were substances containing aluminum (Al), bismuth (Bi), cerium (Ce), chromium (Cr), germanium (Ge), lanthanum (La), lithium (Li), neodymium (Nd), praseodymium (Pr), tellurium (Te), titanium (Ti) and yttrium (Y). Some of these moi- eties, such as aluminium, are ubiquitous in environmental media and food. While others, including the rare earth elements (La, Ce, Nd, Pr, Y) have limited general population exposure potential due to their gener- ally low concentrations in environmental media, food and products, yet have been found indoor dust samples from Canadian homes. House dust is considered to be a sink for metal substances in consumer products and building materials [7–10]. All of these substances are in commerce in Canada. Generating exposure estimates for all routes of exposure from multiple sources using a traditional approach for these elements (i.e., deterministic exposure estimates based on algorithms and/or modelling and concentrations of a chemical in media such as water, food, air or products) can be challenging. The use of HBM data allows for a direct and more precise assessment of the internal exposure concentrations from all routes and all sources of exposure (e.g., environmental media, food, products) for the population [11]. Specially, the elements for which the main sources of exposure are environment media and diet, it is beneficial to use geographically representative biomonitoring data for characterizing exposure in the relevant population [12]. However, there are no Canadian or US population-level HBM data for the elements listed above. In the current study, whole blood samples from a nationally repre- sentative sample of Canadians collected during the CHMS cycle 2 (2009–2011) were obtained from the CHMS biobank with the objective of generating HBM data in the Canadian population for use in charac- terizing exposure in screening assessments of several remaining priority elements under the CMP. The multi-element analysis of whole blood samples was conducted using Inductively Coupled Plasma Spectrometry (ICP-MS). Considering the diversity of elements, the large volume of samples to be analysed, the complexity of the whole blood matrix and the potential spectral interference, challenges in obtaining low method reporting limits (MRLs) across all elements were anticipated. A rigorous quality control and quality assurance process was implemented in order to generate data with high accuracy and precision while measuring low concentrations and minimizing possible inadvertent contamination. These HBM data generated may also be useful in establishing baseline concentrations to determine how exposures are changing over time. 2. Materials and methods 2.1. Whole blood samples The Canadian Health Measures Survey, designed to be representative of approximately 96 to 97 % of the Canadian population aged 3–79, has Table 1 ICP-MS instrument operation parameters. Parameter Value RF Power 1500 W Carrier gas flow rate 0.90 L/min Auxiliary gas flow rate 0.90 L/min Plasma gas flow rate 14.9 L/min Make-up (booster) gas flow rate 0.26 L/min Nebulizer gas flow rate 0.90 L/min Helium gas flow rate (collision cell) 6.2 mL/min Integration time 0.9 s in standard mode, 4.5 s in high flow He mode Element/Isotope used for quantification Standard mode: 27Al, 209Bi, 140Ce, 139La, 7Li (6Li), 146Nd (143Nd, 144Nd), 141Pr, 125Te (126Te), 89Y. Considered the possible 142Nd interference on 142Ce. Octopole Reaction System (ORS) high He flow mode: 52Cr (53Cr), 74Ge, 49Ti. Internal standards 103Rh, 115In, 159Tb, 187Re Peristaltic pump flow rate 0.1 revolutions per second (rps) Table 2 Summary of QC/QA results obtained by analysing reference materials and/or spiked controls. Element Whole blood reference materials Expected concentration in the QC material (μg/L) Recovery (%) % RSD Statistical Evaluation of Method Trueness Al Seronorm L- 2 68.9 96 6 Unbiased Bi INSPQ reference blood 1.10 92 3 Unbiased Ce In-house spike 1.00 100 3 Unbiased Seronorm L- 2 0.086 112 6 NA Cr INSPQ reference blood 3.21 93 5 No evidence of bias Ge In-house spike 1.00 93 11 No evidence of bias La In-house spike 1.00 100 3 Unbiased Seronorm L- 2 0.090 112 6 NA Li In-house spike 1.00 94 11 No evidence of bias Nd In-house spike 1.00 100 4 Unbiased Seronorm L- 2 0.086 95 7 NA Pr In-house spike 1.00 100 3 Unbiased Seronorm L- 2 0.021 101 7 NA Te INSPQ reference blood 6.86 91 7 Unbiased Ti Seronorm L- 2 10.3 98 10 Unbiased Y In-house spike 1.00 99 3 Unbiased Seronorm L- 2 0.077 95 9 NA NA = Not Available (Trueness test not performed as Seronorm L-2 values were approximate (not certified). Table 3 Summary data - whole blood elemental concentrations (μg/L) for the Canadian population aged 3 to 79 years (n = 5752), Canadian Health Measures Survey Cycle 2 (2009 -2011). Element MDL (μg/L) MRL (μg/L) > MRL (%) 50th percentile (95% CI) 95th percentile (95% CI) Al 2.0 8.0 2.9 <8.0 <8.0 Bi 0.02 0.1 4.6 <0.1 <0.1 Ce 0.02 0.05 0.47 <0.05 <0.05 Cr 0.7 0.7 3.4 <0.7 <0.7 Ge 0.1 1 0 <1 <1 La 0.03 0.05 0.28 <0.05 <0.05 Li 0.2 0.4 66.4 0.47 (0.43− 0.51) 1.3 (1.2–1.4) Nd 0.01 0.05 0.12 <0.05 <0.05 Pr 0.01 0.02 0.09 <0.02 <0.02 Te 0.2 0.4 0 <0.4 <0.4 Ti 5.0 10 0.03 <10 <10 Y 0.02 0.06 0.12 <0.06 <0.06 CI = confidence interval, MDL = Method Detection Limit, MRL = Method Reporting Limit. Additional concentrations of Li, Al and Cr by age and sex are available in the appendix, Table A1 and A2. I. Jayawardene et al. Journal of Trace Elements in Medicine and Biology 68 (2021) 126830 3 a biobank for biospecimens (e.g., blood, urine) established at the Na- tional Microbiology Laboratory (NML) in Winnipeg, Canada for use in future health research studies [13]. The CHMS biobank was accessed in 2016 to obtain 5752 whole blood samples for analysis following approval from the Health Canada and Public Health Agency of Canada’s Research Ethics Board. These whole blood samples were collected from Canadians aged 3–79 years during the CHMS cycle 2 (2009–2011) at 18 sites across Canada [14] to be representative of 96.3 % of the Canadian population. The samples were collected in 6 mL Becton Dickinson plastic tubes containing K2EDTA as the anticoagulant. The blood sample was well mixed with the anti-coagulant, aliquoted into the specified cryo- genic Micronics tube, and refrigerated until the weekly shipment to the NML. Samples were stored at − 80◦C for approximately 5 years in the biobank prior to analysis [13]. Detailed descriptions of the CHMS project, rationale, survey design, sampling strategy, and mobile exami- nation centre (MEC) operations and logistics have been published [15, 16]. For this group of elements targeted in the present study (Al, Bi, Ce, Cr, Ge, La, Li, Nd, Pr, Te, Ti and Y), whole blood was the preferred matrix over urine. Most of these elements, with the exception of Ge, Li and Al, are predominantly excreted in feces [17–24]. As urine is a minor route of elimination, it is less likely that urine would be a sensitive enough biomarker to reflect exposure to these elements in the sampled popu- lation. In addition, blood has an added advantage as a biomarker of exposure over urine, as blood concentrations represent the fraction systemically available at the target site. Whole blood was preferred over plasma or serum as it comprises all of the blood components (e.g., proteins, erythrocytes, platelets) and therefore an element has a higher chance of detection regardless of which fraction of the blood it parti- tioned into. 2.2. Elemental analysis The sample analysis was conducted at Health Canada’s Health Products Laboratory in Longueuil, Québec. Blood samples were diluted with a solution containing 0.7 % v/v nitric acid and 0.1 % v/v Triton X- 100, and Rhodium (Rh) and Terbium (Tb) at 1 ppb as internal standards. The content was mixed, centrifuged, and the supernatant was analysed by ICP-MS. Concentrations of Al, Bi, Ce, Cr, Ge, La, Li, Nd, Pr, Te, Ti and Y were simultaneously measured using Agilent lCP-MS 7500cx system (Agilent, Hachioji, Tokyo, Japan), with Chemstation ICP-MS software (version B.0306) for multi-element determination. Rhodium was used as the internal standard for the determination of Al, Cr, Ge, Li, Ti, and Y, while Tb was used as the internal standard for Bi, Ce, La, Nd, Pr, and Te determination. All elements were acquired in the peak alternation mode (Full Quant 3). When possible, at least one qualifier ion (secondary isotope) was used along with the quantification ion (primary isotope) during acquisition (Table 1). Element concentrations were determined using calibration curves with each series. The calibration curve for each element had its own quantification ion selected to limit interference. The calibration curve was prepared using the curve blank standard solution containing nitric acid, Triton X-100, potassium and isopropyl alcohol (IPA) and three or four multi-element calibration standards, depending on the concentra- tion of the element. Multi-element (Al, Bi, Ce, Cr, Ge, La, Li, Nd, Pr, Te, Ti and Y) calibration standards were prepared using 1000 μg/mL single element standards purchased from SCP science (Baie-d’Urfé, Québec, Canada). Calibration standards were reconstituted in a solution con- taining nitric acid, Triton X-100, potassium and IPA to simulate certain matrix effects present in blood [25,26]. Calibration curve ranged for low concentration elements (Bi,Ce, Cr, Ge, Li, Nd, Pr, Te, and Y) from 0.0025 ng/mL to 2 ng/mL and for Al and Ti, calibration curves ranged from 2 to 9 ng/mL. There was re-analysis of the calibration curve if the correlation coefficient (r) of the standard curve was lower than the acceptability criteria of r ≥ 0.996 (or r2 ≥ 0.992). The measured intensities of all standards were curve blank subtracted using the calibration curve to ensure background correction and minimize any possible contamina- tion. During the sequence of sample analysis, calibration controls of 0.01, 0.1, 0.5 and 1 ppb, were prepared using 1000 ng/mL single element standards purchased from Inorganic Ventures (Christiansburg, Virginia, USA) were tested in every 15 samples for continuous verifi- cation of the calibration curve. Verification of the calibration curve was conducted at the beginning and at the end of every analytical series. The method detection limit (MDL) for each of the elements was calculated from 7 replicate measurements of method blanks and control blood samples (spiked or neat) conducted on 7 days using three times standard deviation. For low level quantification, the method reporting limits (MRLs) were based on the in-house Standard Operating Procedure established using multiple guides to method validation (such as Eur- achem, Royal Society of Chemistry, and other guides [27–30]), to have a reproducibility (RSD <30 % during the long time frame of the analytical project (approximately 2 years) and analysing large numbers of samples (n = 5752). As ICP-MS is prone to interference, modifications were made to the analytical method to overcome certain polyatomic and other in- terferences during the whole blood analysis. The use of a collision cell in helium mode significantly reduced polyatomic interferences including argon-carbon (ArC) and chloride oxide (ClOH) on Cr, iron oxide (FeO) on 74Ge, and phosphate oxide and other polyatomic interfering species such as PO+, SO, CCl, and ArCH on 49Ti. The carbon effect on Te resulting in a signal enhancement was reduced by the addition of IPA as a carbon source in the calibration standards. The ICP-MS instrument operating parameters are given in Table 1. Additional precautions were taken to minimize contamination dur- ing the sample pre-treatment and analysis to ensure accuracy of the reported results, in particular for those elements with known laboratory contamination (Al, Cr and Ti) and for those elements where parts-per- trillion concentrations were anticipated. These measures included using polystyrene centrifuge tubes (instead of glass tubes made with Al- borosilicate or polypropylene), pre-rinsing containers and accessories (e.g., automatic pipette tips, vials) with a dilute nitric acid solution followed by ultrapure water, using a teflon perfluoroalkoxy (PFA) automatic solution dispenser to prevent contamination during liquid transfer, pre-soaking polystyrene centrifuge tubes with ultrapure water and drying prior to use, and the use of high or ultra-pure reagents, powderless nitrile gloves, and lint-free tissue (Kimwipe™). The auto- sampler was placed inside a Plexiglas enclosure along with the use of additional Plexiglas cover sheets (placed approximately 30 cm from ceiling ventilation near workspace) to minimize airborne contamination of the samples during handling and analysis. To reduce Al contamina- tion occurring within the instrument, the ICP-MS inlet tubing was rinsed with an acid solution after replacement and an acid solution was pum- ped for at least one hour to allow the Al signal to stabilize prior to carrying out the sample analysis. 2.3. Quality control and quality assurance methods Sample collection materials used in the CHMS cycle 2 (e.g., butterfly needles, K2EDTA vacutainers, PTFE transfer pipette, cryovials) were tested for leaching or adsorption at different intervals (day one, and at months 1.5, 7 and 12) to ensure accuracy in the elemental concentra- tions measured in the whole blood samples. Accuracy, recovery, reproducibility, and efforts to minimize contamination of the whole blood samples were ensured through the use of method blanks (deionized pure water), whole blood reference mate- rials, and control blood samples. Three method blanks were required per series of up to 50 samples to verify purity of the reagents, tubes and other accessories used in the analysis. The average concentration in the blanks was subtracted from the results of the samples and reference materials. Three whole blood based reference materials were used for quality control and quality assurance purposes: Seronorm™[LGC standards, I. Jayawardene et al. Journal of Trace Elements in Medicine and Biology 68 (2021) 126830 4 Manchester, NH, USA], Institut National de Santé Publique du Québec (INSPQ) reference samples used in their inter-laboratory proficiency testing program for metals, and an in-house fortified blood sample created by reference blood obtained from INSPQ. Given the limited sample volume received, analysis of spiked samples were performed using a control sample from INSPQ. The elemental concentration in the control sample was considered for the recovery of spike samples. Reference materials were included with each sample series to verify inter-day and intra-day accuracy and precision of each series. Depending on the expected elemental concentrations in whole blood, reference materials were selected for quality control and quality assurance pur- poses (Table 2). For all elements tested, the acceptability criteria for accuracy was 70 to 130 % of expected concentrations. Precision, char- acterized by the % Relative Standard Deviation (% RSD) of the elemental concentrations of reference materials, was charted along the duration of the project. Percent RSD < 30 % was considered acceptable for the re- sults from reanalysed blood samples. Both these acceptability criteria; for precision, percent RSD equal or below 30 % and for accuracy, % recovery to be between 70 % and 130 %, were based on the above mentioned in-house Standard Operating Procedure. The authors considered both these criteria as acceptable for the measurements done in this complex whole blood matrix and the low concentration levels at which they are detected. In addition, the metrological compatibility of the quality control measurement results of certified reference materials and of in-house quality control materials was done by a statistical evaluation of method trueness. This was performed according to the method described in the National Institute of Standards and Technology (NIST) practical guide [31]. Statistical evaluation of bias was conducted using results of the QC materials obtained on approximately 150 anal- ysis days with the certificate value and the expanded uncertainty [31, 32]. There was re-analysis of the reference material or the analytical series when results were outside of this range for accuracy (70 to 130 %) or RSDs >30 %. The laboratory participated and demonstrated satisfactory results in three inter-laboratory proficiency testing programs led by the INSPQ during this time period (2015–2017). 2.4. Statistical analysis Population-weighted descriptive statistics for the total population aged 3–79, and by age and sex, were generated by Statistics Canada using the Statistical Analysis System software (SAS Institute Inc., version 9.4m3, 2015) and the SUDAAN® (SUDAAN Release 11.0.3, 2018) sta- tistical software package. To account for the complex survey design of the CHMS, the set of bootstrap weights included with the data set was used to estimate the 95 % confidence intervals (CIs) for percentiles and detection frequencies [33,34]. Values MRL (%) Aluminium 95th (95 % CI) Chromium > MRL (%) Chromium 95th (95 % CI) Total 3− 79 5752 2.90 MRL = greater than method reporting limit, 33.3 % are suppressed. I. Jayawardene et al. 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Table A2 Arithmetic means, geometric means and selected percentiles of blood lithium concentrations (μg/L) for the Canadian population aged 3 to 79 years, by sex and age group, Canadian Health Measures Survey Cycle 2 (2009 to 2011): MRL = 0.4 μg/L. Sex Age n > MRL (%) GM (95 % CI) 50th (95 % CI) 95th (95 % CI) Total 3− 79 5752 66.43 0.36 (0.32− 0.41) 0.47 (0.43− 0.51) 1.3 (1.2− 1.4) Total 3− 5 475 70.95 0.34 (0.29− 0.40) 0.45 (0.39− 0.51) 1.0 (0.90− 1.2) Total 6− 11 921 60.91 0.29 (0.24− 0.35) 0.41 (0.28− 0.54) 1.0 (0.89–1.1) Total 12− 19 960 55.52 _ F 0.90 (0.81− 0.99) Total 20− 39 1214 60.87 0.31 (0.27− 0.36) 0.43 (0.35− 0.51) 1.1 (1.0− 1.2) Total 40− 59 1148 68.73 0.37 (0.30− 0.46) 0.47 (0.42− 0.52) 1.3 (0.89− 1.6) Total 60− 79 1034 83.37 0.57 (0.50− 0.66) 0.63 (0.57− 0.69) 2.0 (1.5− 2.5) Males 3− 79 2801 68.37 0.39 (0.34− 0.44) 0.49 (0.43− 0.54) 1.2 (0.96− 1.4) Females 3− 79 2951 64.59 0.33 (0.30− 0.38) 0.45 (0.41− 0.49) 1.4 (1.2− 1.6) >MRL = greater than method reporting limit, n = number of samples. Source: Statistics Canada, Canadian Health Measures Survey, Cycle 2, 2009–2011. Notes: Statistics Canada uses the term LOD (limit of detection) instead of MRL. 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https://doi.org/10.5731/pdajpst.2016.006577 https://doi.org/10.1007/BF02788968 https://doi.org/10.1007/BF02788968 Multi-elemental determination of metals, metalloids and rare earth element concentrations in whole blood from the Canadian ... 1 Introduction 2 Materials and methods 2.1 Whole blood samples 2.2 Elemental analysis 2.3 Quality control and quality assurance methods 2.4 Statistical analysis 3 Results and discussion 3.1 Quality control and quality assurance 3.2 Whole blood concentrations 3.3 Limitations 4 Conclusion Author statement Declaration of Competing Interest Acknowledgements Appendix A References