Hair as a Biomarker of Systemic Exposure to Polybrominated Diphenyl

Nov 11, 2014 - ... liver, and fat were collected from adult male Sprague–Dawley rats exposed to increasing doses of the PBDE mixture found in house ...
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Hair as a Biomarker of Systemic Exposure to Polybrominated Diphenyl Ethers Shirley Poon,†,‡,∇ Michael G. Wade,§,∇ Katarina Aleksa,†,∥ Dorothea F. K. Rawn,⊥ Amanda Carnevale,†,‡ Dean W. Gaertner,⊥ Amy Sadler,⊥ François Breton,⊥ Gideon Koren,†,‡,# Sheila R. Ernest,¶ Claudia Lalancette,¶ Bernard Robaire,¶ Barbara F. Hales,*,¶ and Cynthia G. Goodyer○ †

Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada Department of Pediatrics, Pharmacology, Pharmacy and Medical Genetics, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada § Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario K1A 0K9, Canada ∥ School of Pharmacy, University of Waterloo, Waterloo, Ontario N2G 1C5, Canada ⊥ Food Research Division, Bureau of Chemical Safety, Health Products and Food Branch, Health Canada, Ottawa, Ontario K1A 0K9, Canada # Western University, 339 Windermere Road, London, Ontario N6A 5A5, Canada ¶ Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montréal, Quebec H3G 1Y6, Canada ○ The Research Institute of McGill University Health Centre, 4060 Ste Catherine St West, Montreal, Quebec H3Z 2Z3, Canada ‡

S Supporting Information *

ABSTRACT: The efficacy of using hair as a biomarker for exposure to polybrominated diphenyl ether (PBDE) flame retardants was assessed in humans and an animal model. Paired human hair and serum samples were obtained from adult men and women (n = 50). In parallel, hair, serum, liver, and fat were collected from adult male Sprague−Dawley rats exposed to increasing doses of the PBDE mixture found in house dust for 70 days via the diet. All samples were analyzed by GC-MS for eight common PBDEs: BDE-28, -47, -99, -100, -153, -154, -183, and -209. Paired human hair and serum samples had five congeners (BDE-28, -47, -99, -100, and -154) with significant individual correlations (0.345−0.566). In rat samples, BDE-28 and BDE-183 were frequently below the level of detection. Significant correlations were observed for BDE-47, -99, -100, -153, -154, and -209 in rat hair, serum, liver, and fat across doses, with r values ranging from 0.803 to 0.988; weaker correlations were observed between hair and other tissues when data from the lowest dose group or for BDE-209 were analyzed. Thus, human and rat hair PBDE measurements correlate strongly with those in alternative matrices, validating the use of hair as a noninvasive biomarker of long-term PBDE exposure.

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rats with PBDEs affect the thyroid hormone axis,11−13 neurobehavior,14 androgen signaling, and reproductive system development.15−17 Similarly, chronic human exposures to PBDEs are associated with altered thyroid hormone balance,18−20 attention deficits and impaired motor development,21,22 altered male hormone levels and cryptorchidism,23,24 low birth weight,25,26 and earlier menarche.27 PBDEs will remain in our everyday environment for many more decades because they are persistent and bioaccumulative, and as yet, there is no known method to destroy them. The present use of serum for PBDE biomonitoring makes it difficult

INTRODUCTION Polybrominated diphenyl ethers (PBDEs) have been used worldwide as additive flame retardants in a variety of consumer products, including textiles, furniture, insulation, electrical equipment, household appliances, and electronics. PBDEs leach out of these products, primarily in the form of dust, and persist and bioaccumulate in the environment.1 Although PBDEs have now been removed from commercial use in many countries, the human population in North America still has the greatest nonoccupational exposures to PBDEs globally.2 Body burdens of PBDEs are present throughout the human life cycle, from the fetus to the elderly, with the highest in infants, children, and economically disadvantaged groups.3−10 This is of concern since animal and human studies have provided evidence for associations between PBDE exposures and several adverse health-related outcomes. Chronic dietary treatments of © XXXX American Chemical Society

Received: June 8, 2014 Revised: November 6, 2014 Accepted: November 11, 2014

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formulated to mimic the relative median concentrations observed in house dust samples.35,36 This mixture was prepared by combining commercially available technical mixtures of PBDEs (DE-71, 52.08%; DE-79, 0.36%; and BDE-209, 44.18%; the remaining 3.3% was hexabromocyclododecane). Details of the chemical sources, mixture formulation, and diet preparation are described in Ernest et al.11 The test diets, designated as control (0), A (0.25 mg of total mixture per kg diet), B (2.5 mg/kg), C (25 mg/kg), or D (250 mg/kg) were estimated to deliver nominal daily doses of 0, 0.02, 0.2, 2.0, and 20 mg of the PBDE mixture/kg body weight, respectively. It was estimated that the highest dose would cause increased liver weight based on published results with DE-71;17 lower doses were selected to provide a very broad range encompassing environmentally relevant exposures. Adult Sprague−Dawley male rats (Charles River Canada, St Constant, QC, Canada), maintained on a 12 h light/12 h dark cycle in the Animal Resources Centre of McGill University, were fed with control or PBDE-treated diets ad libitum for 70 days (n = 8−10 animals per diet group). On the first day of exposure, a patch of hair was removed from over the scapulae of each animal to ensure that hair used for analysis of PBDEs was regrown during the treatment period. After 70 days of exposure, rats were euthanized by CO2 asphyxiation and subjected to necropsy. Blood was collected by cardiac puncture, and serum was prepared using a serum separator Vacutainer tube. Regrown hair was collected from the previously shaven area (about 10 cm2) and retained for PBDE analyses. A piece from the caudate lobe of the liver and one perirenal fat pad were collected from each rat and frozen on dry ice. Serum and tissue samples were stored at −80 °C until analyzed for PBDE content. Human and Rat Hair PBDE Analyses. Hair PBDE levels were analyzed using a previously described method.30 In brief, hair samples were cut into 1−2 mm pieces; 10−35 mg was washed in Milli-Q water and then extracted in 2 mL of 4:1 hexane/dichloromethane to which 1.5 mL of 4N HCL was added. After a 14 h incubation at 40 °C, the organic phase was removed and applied to a hexane-conditioned Na2SO4/Florisil SPE column. Samples were eluted in hexane, dried, and resuspended in 30 μL of 4:1 isooctane/toluene and analyzed by GCMS. Quantification was performed using a 9-point calibration curve whereby standards were spiked into “blank” hair with negligible endogenous levels of PBDEs. Standards were analyzed in the same manner as samples. The peak area ratio of congeners BDE-28 through BDE-183 to their internal standard, F-BDE-69, and BDE-209 to its internal standard, 13 C12-BDE-209, was calculated. The area ratios in blank hair were subtracted from the sample area ratios prior to plotting against the calibration curve to quantify the PBDEs in hair. Hair PBDE levels were corrected for the dry weight of each sample. Feed, Tissue and Serum PBDE Analyses. Rat feed (0.1− 0.25 g), liver (∼0.1 g), adipose (∼0.1 g), and serum (∼1 g) samples were thawed and weighed into 50 mL glass centrifuge tubes. Each sample was fortified with surrogate standards (12 13 C12 labeled PBDE congeners: 15, 28, 47, 77, 99, 100, 126, 138, 153, 154, 183, 209; Cambridge Isotope Laboratories, Andover, MA, USA). Samples were homogenized with 20 mL of 2:1 HPLC/GC grade acetone/hexane (EMD, Ottawa, ON, Canada) for approximately 30 s using a Silverson homogenizer so that the analytes partitioned directly from the tissues into the solvent. The extracts were cleaned up initially by passing them through a bed of anhydrous sodium sulfate (Na2SO4) (VWR,

to include the most vulnerable populations, pregnant women and infants; therefore, the development of noninvasive exposure biomarkers would be of great value. Moreover, serum levels of PBDEs represent only short-term exposure. In contrast, hair grows at a rate of ∼1 cm/month and, hence, segmental analyses can explore chronic exposure. Hair is a keratinous matrix, consisting of 88% protein and 3−4% lipid. This composition, combined with the ease of sampling, makes hair a suitable matrix to analyze for organic pollutants. D’Havé et al. reported significant correlations (r = 0.72− 0.77) between levels of ∑PBDEs in hair vs liver, kidney and muscle tissues in a terrestrial mammal, the European hedgehog.28 Moderately positive correlation coefficients of 0.37−0.56 were also reported for BDE-47 levels in hair vs liver, kidney, and muscle; however, due to detectability problems, correlation analyses for other individual congeners were not possible. Since this initial observation, several groups, including our own, have investigated the prevalence of PBDE congeners in human hair, improving techniques and detectability.29−31 The results from these previous studies have shown the presence of PBDEs in newborn, child, and adult hair and found significant increases in the PBDEs from proximal to distal segments from the scalp, making this matrix useful in examining exposure to PBDEs,30,32,33 yet none of these studies looked at associations between levels found in hair and systemic accumulations of PBDEs. More recently, another study done in the Philippines showed no correlation between breast milk and hair levels for major congener PBDE-47 (r = −0.057); however, limitations in this study include inconsistency in hair collection location on the scalp as well as the variability in time period between collecting hair and milk samples from the same individual.34 Thus, it is important to continue the investigation of the relationship and distribution of PBDEs between hair and other body matrices. Our objective here was to determine whether hair is an appropriate biomarker for predicting systemic PBDE exposure by evaluating congener levels in two species, in different matrices, and under various exposure scenarios. We compared PBDE congeners in paired human hair and serum samples from male and female adult volunteers in Montreal. In parallel, we determined whether chronic exposure to different PBDE levels resulted in similar changes in hair, serum, liver, and adipose PBDE concentrations in adult male rats fed a dietary PBDE mixture based on Boston house dust measurements, simulating North American daily exposures.11,35,36

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MATERIALS AND METHODS Human Study Design and Samples. Fifty volunteers (n = 27 women, n = 23 men; aged 20−65 years) from the Montreal area provided ∼100 mg of hair and 50 mL of blood for our study. The hair was cut within 1 cm from the scalp at the posterior vertex, and the whole length of hair was collected.30 The hair samples were stored in paper envelopes in the dark at 4 °C until assayed at the Toronto Hospital for Sick Children. The blood was centrifuged, and the ∼25 mL serum samples were kept frozen at −80 °C until processed at Health Canada. Ethics approval for the collection and use of the human hair and serum samples was obtained from McGill University and Health Canada. Animal Study Design and Samples. The animal study was approved by the McGill Institutional Animal Care Committee prior to the start of the study (Protocol #5862). Rats were fed a mixture of brominated flame retardants B

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Ottawa, ON, Canada) into a round-bottom flask (RBF), concentrated to near dryness using rotary evaporation, transferred to a preweighed 20 mL disposable scintillation vial, and allowed to sit in a well-ventilated area to come to dryness; the mass was recorded to determine the lipid content gravimetrically. Hexane (1 mL) was added to the extract and swirled until uniform. Each extract was then added to the top of a column packed with 6 g of 2% deactivated Florisil (60−100 mesh; Fisher Scientific, Ottawa, ON, Canada) and drained to within a few mm of the top of the Na2SO4, and enough hexane was added to wet the entire column (∼5 mL). PBDEs were eluted with 70 mL of hexane and collected in a 250 mL RBF. Extracts were reduced to ∼1 mL using rotary evaporation, transferred to a v-notch vial, and evaporated to dryness using a gentle stream of nitrogen. The dried samples were dissolved in isooctane and transferred to a chromatographic vial for analysis. For rats that had been fed the highest dose diet (D), a 10−20fold dilution of sample extracts was necessary to ensure that accurate concentration measurements could be achieved. PBDE analyses were done as previously described,37 using an Agilent 6890 gas chromatograph coupled to a 5973N mass selective detector (operated in electron ionization mode; Agilent, Mississauga, ON, Canada). The volume of the human serum samples was 25 mL to ensure as accurate a measurement of the endogenous levels of the eight congeners as possible and required more extensive cleanup and high resolution GC-MS; details of the methodology can be found in Rawn et al.38 Serum and tissue PBDE measurements were corrected for lipid levels as determined gravimetrically during extraction. Laboratory background was accounted for by removing the average of the PBDE concentrations observed in the two reagent blank samples for each set of samples analyzed. For all calculations and comparisons of PBDE levels in the hair, serum, and tissues, sample values that were below the level of detection (LOD) were substituted by the LOD divided by the square root of 2 to allow for comparison with US (National Health and Nutrition Examination Survey (2003−2004)) and Canadian (Canadian Health Measures Survey (2007−2009)) national data sets.38,41 Statistical Analyses. Data normality was tested on raw or log transformed data using the Shapiro-Wilk test. To determine correlations of values between matrices, the Spearman Rank Order Correlation was calculated for values and the significance of the correlation tested. Gender differences in PBDE levels in hair or serum were assessed using the Mann−Whitney U test. A p value limit of detection (LOD)

C

congener

serum

hair

Spearman R

p

BDE-28 BDE-47 BDE-99 BDE-100 BDE-153 BDE-154 BDE-183 BDE-209

100 100 100 100 100 100 100 94

54 100 100 94 72 58 22 100

0.373 0.566 0.554 0.372 0.230 0.345 0.252 −0.083

0.0078 50-fold higher than those in our cohort, reflecting a unique context. In contrast, our serum PBDE levels are comparable to those observed in two large studies representative of the general North American population: the Canadian Health Measures Survey (2007−2009)38,40 and the US National Health and Nutrition Examination Survey (2003−2004).41 Despite the differences in our two cohorts, Zheng et al.31 found moderately positive correlations (r = 0.36−0.53) for BDE-28, -47, -100, -153, -154, and -183 but not -99 or -209, results that are quite similar to ours. Although they reported a gender difference in the hair (but not serum) ΣPBDE levels, with females 3-fold higher than males, our Canadian cohort did not show any gender differences in either hair or serum samples. Recently, several groups have published human hair PBDE analyses. Aleksa et al. analyzed hair samples from Canadian newborns and children aged 1−14 yr.30 The major congener in newborn hair was BDE-153 while in the older children BDE-47 and -99 were predominant; BDE-209 was often undetectable regardless of age. Tadeo et al. reported that, in Spain, the hair levels of BDE-47, -99, -100, -190, and -209 in children (1−11 yr) were similar to the levels in adults (24−44 yr); BDE-209 was the predominant congener, closely followed by BDE-47.29 In a study from Belgium, the levels of PBDEs in human hair were very low, below the limit of quantification in most samples.42 Finally, several Chinese researchers have assessed PBDE levels in hair from adult male and female workers in ewaste recycling sites; BDE-209 was always the major congener (several-fold higher than all other congeners together).42−45 These data suggest that exposure location (North America vs Europe vs Asia) and stage in development (pre- vs postnatal) as well as occupation will affect hair PBDE profiles. Hair offers several advantages as a biomarker for environmental exposures. First, hair is relatively stable and samples can be conveniently collected and stored.46,47 In addition, sampling is noninvasive which means that hair can be collected from vulnerable groups, such as pregnant women, newborns, the elderly, and chronically ill.48 Finally, unlike other matrices that represent only recent exposure (hours to days), hair reflects a longer detection window (months to years).47 This wider time frame allows for the retrospective assessment of chronic and past exposure over a defined time period, including in utero development.46,49 A recent study has provided two important facts about hair PBDE analyses. Carnavale et al.33 found a significant increase in total PBDEs from the proximal (at root end) to distal segments along the hair shaft. They also found that the use of coloring agents at least once during the previous year resulted in hair samples with a significantly lower median ΣPBDE level when compared to hair from individuals who did not use hair dyes. Because our study analyzed an aliquot of a whole hair segment, our measurements reflect median levels indicative of total

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ASSOCIATED CONTENT

S Supporting Information *

The median values and ranges of PBDE congeners measured in human hair (ng/g hair) and serum (ng/g lipid) (Table S1), the individual human serum and hair congener profiles (Figures S1 and S2), and the means and standard deviations of PBDE levels in liver, serum, adipose tissue, and hair from male rats exposed to an environmentally relevant combination of flame retardants (Table S2). This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Tel: 514-398-3610; e-mail: [email protected]. Author Contributions ∇

S.P. and M.G.W. contributed equally.

Funding

This study was supported by a grant (RHF100625) from the Institute for Human Development, Child and Youth Health (IHDCYH), Canadian Institutes of Health Research (CIHR) and by the Chemicals Management Plan Research Fund of Health Canada. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We would like to thank Veronica Atehortua for human subject recruitment and Devon Johnstone for initial human database analyses.

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ABBREVIATIONS PBDE polybrominated diphenyl ether BDE brominated diphenyl ether LOD limit of detection

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dx.doi.org/10.1021/es502789h | Environ. Sci. Technol. XXXX, XXX, XXX−XXX