Human biomonitoring reference values derived for persistent organic pollutants in blood plasma from the Canadian Health Measures Survey 2007–2011

International Journal of Hygiene and Environmental Health 220 (2017) 744–756

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Human biomonitoring reference values derived for persistent organic pollutants in blood plasma from the Canadian Health Measures Survey 2007–2011 Douglas A. Haines, Cheryl Khoury, Gurusankar Saravanabhavan, Kate Werry ∗ , Mike Walker, Morie Malowany Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada

a r t i c l e

i n f o

Article history: Received 31 October 2016 Received in revised form 7 March 2017 Accepted 8 March 2017 Keywords: Reference values Persistent organic pollutants Human biomonitoring Canadian Health Measures Survey Canada

a b s t r a c t Nationally representative human biomonitoring data on persistent organic pollutants (POPs) including organochlorine pesticides (OCs), polychlorinated biphenyls (PCBs) brominated flame retardants (BFRs) and perfluoroalkyl substances (PFASs) are available through the Canadian Health Measures Survey (CHMS). We have used a systematic approach building on the reference interval concept proposed by the International Federation of Clinical Chemistry and Laboratory Medicine and the International Union of Pure and Applied Chemistry to derive human biomonitoring reference values (RV95 s) for selected POPs in blood plasma in the general Canadian population. Biomarkers were chosen based on specific selection criteria including their detection in most Canadians (>66% detection rate). Age and sex were evaluated as possible partitioning criteria and separate RV95 s were derived for the sub-populations in cases where partitioning was deemed necessary. RV95 s for OCs, PCBs, and BFRs were derived both on a whole weight of blood plasma and on a lipid weight adjusted basis whereas they were derived only on a whole weight basis for PFASs. RV95 s ranged from 0.018 ␮g/L (PCB 201) to 21 ␮g/L (perfluorooctane sulfonate) and from 3.1 ␮g/kg lipid (PCB 201) to 1400 ␮g/kg lipid (p,p -DDE). The 22 RV95 s reported in this paper represent the first set of reference values for POPs in the Canadian general population against which individual and population human biomonitoring data may be compared. Crown Copyright © 2017 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/).

1. Introduction Human biomonitoring (HBM) is defined broadly as the measurement of biomarkers (parent chemical and/or its biotransformation products) in human biological fluids or tissues and is used as a tool for estimating human exposure to chemicals in order to inform public health, risk assessment, and risk management decisions (NRC, 2012). Several countries including Canada, the United States, Germany, Spain, Korea and France have conducted national-level human biomonitoring studies (CDC, 2009; Fréry et al., 2012; Haines et al., 2016; Park et al., 2016; Pérez-Gómez et al., 2013; Schulz et al., 2007). To facilitate the interpretation of clinical chemistry data, the concepts of reference intervals along with the relevant statistical methodologies have been developed by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) (Solberg,

∗ Corresponding author at: 269 Laurier Avenue West, Ottawa, Ontario, K1A 0K9, Canada. E-mail address: [email protected] (K. Werry).

1987) and the International Union of Pure and Applied Chemistry (IUPAC) (Poulson et al., 1997). The German Human Biomonitoring Commission (HBM Commission) adopted this approach to interpret HBM data using reference values to indicate background exposure to environmental chemicals in a reference population. The HBM Commission defines a reference value (RV95 ) as “the 95th percentile of the measured pollutant concentration levels in the relevant matrix of the reference population. To derive it, it is rounded off within the 95% confidence interval” (HBM Commission, 2016). The RV95 indicates the upper margin of the current background exposure of the general population to a given substance at a given time (Ewers et al., 1999). The IFCC and IUPAC provided recommendations on constructing reference populations, including sample selection, sample size, the use of the most recent data, inclusion and exclusion criteria, partitioning criteria, and quality of analytical methods (Solberg, 1987). HBM data from representative surveys are considered the most appropriate to derive population-level RV95 s for environmental chemicals in human biological materials (Ewers et al., 1999). The Canadian Health Measures Survey (CHMS) has been collecting nationally representative HBM data from the general population

http://dx.doi.org/10.1016/j.ijheh.2017.03.004 1438-4639/Crown Copyright © 2017 Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

D.A. Haines et al. / International Journal of Hygiene and Environmental Health 220 (2017) 744–756

since 2007 (Haines et al., 2016). Using the CHMS biomonitoring data, we previously derived RV95 s for metals and trace elements in blood and urine in the Canadian general population (Saravanabhavan et al., 2016). As a continuation of this effort, the purpose of this paper is to establish RV95 s for persistent organic pollutants (POPs) measured in plasma of the Canadian general population using the most recent HBM data available from the CHMS. POPs are a concern for human health primarily due to their persistence in both the environment and the human body.

2. Methods

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Triglycerides were measured using the VITROS TRIG Slide method based on the procedure described by Spayd et al. (1978) and TC was measured using the VITROS CHOL Slide method based on the procedure by Allain et al. (1974). Total lipids (TL) were estimated using the formula: TL (g/L) = 2.27 × TC (g/L) + TG (g/L) + 0.623 (Phillips et al., 1989; Bernert et al., 2007; Bergonzi et al., 2009). OCs, PCBs and BFRs were reported as weight of chemical per volume of plasma (whole weight, ␮g chemical/L plasma) and as weight of chemical per kilogram of total lipid (lipid weight, ␮g chemical/kg lipid). PFASs were reported as whole weight only. If a respondent’s TL and/or TG value was missing or below the limit of detection (LOD) then the estimate of that respondent’s lipid adjusted chemical was also set as missing.

2.1. Data source The HBM data on POPs were obtained from the datasets collected from the first (2007–2009) and second (2009–2011) cycles of the CHMS. These represent the most recent POPs datasets available from the CHMS. Detailed descriptions of the CHMS rationale, survey design, sampling strategy, mobile examination centre (MEC) operations and logistics, as well as ethical, legal, and social issues have been published elsewhere (Haines et al., 2016; Day et al., 2007). The CHMS is an ongoing survey designed to provide comprehensive direct health measures at the national level that collects information from the general population. The CHMS sample design covers 96% of the Canadian population (Giroux, 2007). The remaining 4% of the Canadian population not covered by the sample design include full-time members of the Canadian Forces and people living on reserves or in other Aboriginal settlements, in institutions and in some remote regions. CHMS 2007–2009 and 2009–2011 involved an in-person household interview and a subsequent visit to a MEC. The household interview gathered general demographic, labour force activity, and socio-economic data and detailed health, nutrition and lifestyle information. At the MEC visit, scheduled to take place a few days to a few weeks following the household interview, direct physical measurements were taken, including collection of blood and urine samples which were assessed for environmental chemicals including the following classes of POPs: organochlorine pesticides (OCs), polychlorinated biphenyls (PCBs), brominated flame retardants (BFRs), and perfluoroalkyl substances (PFASs). In order to obtain accurate national estimates for some blood measures such as glucose and serum cholesterol, subsamples of respondents were requested to fast prior to the MEC visit. The respondents were considered fasted if they did not eat or drink anything except water for ≥10 h prior to the appointment; otherwise, the respondents were categorized as non-fasted. The blood samples for individual measurements of OCs, PCBs and BFRs that were collected in the CHMS 2007–2009 and used in this analysis were all from the fasted subsample of participants aged 20–79 years. The most recent PFAS dpose of this study were collected from fasted and non-fasted 12–79 year old participants from CHMS 2009–2011. POPs were measured in plasma at the Centre de toxicologie du Québec (CTQ) of l’Institut national de santé publique du Québec (INSPQ) using validated analytical methods (Health Canada, 2013, 2010). The laboratory carried out quality control protocols during the batch processing of the samples and tested standard reference materials or certified reference materials when available. In addition, the laboratory analysed field blanks, replicate samples, and blind quality control samples over the course of each two year cycle to demonstrate the method performance. Moreover, CTQ leads the Arctic Monitoring and Assessment Program Ring Test for Persistent Organic Pollutants in Human Serum which is an external quality assessment scheme for PCB congeners, OCs, BFRs, and PFASs (INSPQ, 2016). Triglycerides (TG) and total cholesterol (TC) in serum were measured by enzymatic methods (Health Canada, 2009a, 2009b).

2.2. Statistical analysis Statistical analysis was conducted using R (R Core Team, 2015) and SUDAAN 10.0.1 software (RTI International, USA). Biomarker concentrations that were below LOD were assigned a value of LOD/2. Unlike RV95 s derived previously for metals and trace elements from CHMS data, no exclusion criteria were examined for any of the POPs in this analysis as no confounders were considered to sufficiently influence biomarker concentrations due to their ubiquitous presence and persistence in the environment and in humans. Reference populations were constructed for each biomarker based only on the partitioning criteria of age group (12–19, 20–39, 40–59, and 60–79 years) and sex. Information on age and sex were taken from the household and clinic questionnaire databases. Partition testing and extreme value removal followed the approach outlined in Saravanabhavan et al. (2016). Briefly, candidate partitions were tested by comparing the weighted percentage of each partition’s population that is above the overall population’s 95th percentile, declaring partitioning necessary if any such percentage was larger than 7.8% or smaller than 2.2%. These cutoff values are based on the approach described by Lahti et al. (2002), but adapted to the present one-sided context of the upper limit (defined at the 95th percentile), instead of the original two-sided context of the reference interval (defined by the 2.5th and 97.5th percentiles.) Within each such required partition, extreme values were then removed to ensure the resulting RV95 s are indicative of background levels of exposure. Extreme values were removed by applying either Tukey’s approach (Tukey, 1977) or Tukey’s adjusted approach (Hubert and Van der Veeken, 2008) to the natural log-transformed data, with the adjusted approach being applied if the data remained skewed after log-transformation. For the POPs analysed, less than 4% of the samples in any given partition were removed as extreme values except for the 60–79 years age group partition for perfluorodecanoic acid (PFDA)which had 8.4% removed. After extreme value removal, weighted 95th percentiles and associated confidence intervals were computed for each partition and reported as RV95 s. Variance estimation for all tests, models and percentile estimates used the Balanced Repeated Replicates (BRR) approach required by CHMS, using the supplied bootstrap weights. All results were rounded to two significant figures and assessed for publication quality based on the coefficient of variation (CV) as per the CHMS release guidelines (Statistics Canada, 2013). An estimate with a CV greater than 33.3% was deemed too high to publish, and an estimate with a CV between 16.6% and 33.3% must be interpreted with caution. RV95 s derived from estimates with CVs between 16.6% and 33.3% are considered provisional. These procedures of partition testing, extreme value removal, and RV95 calculation were carried out separately for whole-weight (␮g/L plasma) and lipid-adjusted (␮g/kg lipid) data for each of the POPs.

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3. Results and discussion Fifty-seven POPs biomarkers (14 OCs, 24 PCBs, 10 BFRs and 9 PFASs) were measured in individual blood samples collected from the CHMS participants between 2007 and 2011 (Table 1). We shortlisted biomarkers based on percent detect in the Canadian population; RV95 s were derived only for those biomarkers which were detected in at least 66% of Canadians. This was done to focus on chemicals with widespread exposure, provide sufficient sample size for statistical analysis, and minimize the effect of censored data (LOD/2) on the RV95 s. In total, RV95 s were derived for 21 POPs biomarkers (5 OCs, 10 PCBs, 1 BFR, and 5 PFASs). In addition, an RV95 was also established for the sum of PCBs 138, 153 and 180 (PCB(138 + 153 + 180)) as these three congeners are the most frequently detected di-ortho-chlorine-substituted PCBs in population studies and are dominant contributors to total PCB concentrations (CDC, 2017; Rawn et al., 2012). All biomarkers, except ␤-hexachlorocyclohexane (␤-HCH) and 2,2 ,4,4 -tetrabromodiphenyl ether (PBDE 47), required partitioning by age. Although both sex and age were tested as partitioning criteria, none of the biomarkers required partitioning by sex. The partitioning criteria used in this work were based on weighted proportions of distributions for partitions falling outside reference limits defined for the overall distribution, as suggested by Lahti et al. (2002). While CHMS POPs biomarkers did not warrant partitioning by sex according to these criteria, descriptive statistical estimates (such as geometric means and 95th percentiles (P95)) might still significantly differ between males and females in the Canadian population for the studied biomarkers. For example, in our earlier study based on the CHMS 2007–2009 dataset, we observed that the geometric mean concentrations in females of p,p- dichlorodiphenyldichloroethylene (p,p -DDE), hexachlorobenzene (HCB) and ␤-HCH were significantly higher than males while males had significantly higher concentrations of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) than females (Haines and Murray, 2012). Thus, partitioning decisions do not necessarily correlate with statistically significant differences among subpopulation concentrations. In the CHMS, approximately 50% of the participants were chosen randomly to fast prior to the MEC visit. Concentrations of OCs, PCBs and BFRs were measured in blood samples obtained only from fasted participants. Phillips et al. (1989) reported that on a serum whole weight basis, non-fasted samples had 22% to 29% higher concentrations of PCBs, HCB and p,p -DDE than did fasted samples. However, when corrected by total serum lipids, fasted and nonfasted concentrations were not statistically different. It is expected that the whole weight concentrations reported in the fasted CHMS participants in this study may be lower than would be observed in a non-fasted population. Nonetheless, fasted samples may be more reflective of background exposures as fasting may reduce the influence of recent food consumption on the blood concentrations of these persistent chemicals. In the literature, HBM concentrations for OCs, PCBs and BFRs are variably reported in whole weight and lipid weight values. In this study we derived RV95 s for these biomarkers both on a whole weight and lipid weight basis (Tables 2–4 , respectively). The establishment of Canadian reference values expressed in these two forms allows for broader current and historical comparisons of HBM data for these chemicals within Canada and internationally. Because PFASs do not tend to accumulate in fat tissue (de Vos et al., 2008; Kissa, 2001), the RV95 s for PFASs were derived as whole weight values only (Table 5). In general, RV95 s derived for all OCs and PCBs in this study increased with age. The RV95 s for the 60–79 year old age group were 2–9 times higher than those for 20–39 year olds. Comparable age trends in P95 serum and plasma concentrations of OCs and PCBs have been observed in other studies (Patterson et al., 2009;

Schettgen et al., 2015). Age group trends in RV95 s for the PFASs in this study were not as pronounced or consistent as those observed for OCs and PCBs. Inconsistent results have been reported in the literature with some studies indicating correlations between age and PFAS concentrations and others not (Kato et al., 2011; Haug et al., 2009; Kannan et al., 2004; Calafat et al., 2007). The lack of consistent age-related accumulation patterns of PFASs may be due to their affinity for lipoproteins rather than neutral lipids as with OCs and PCBs. The RV95 s and P95s for blood, serum or plasma concentrations of POPs from population representative national surveys are presented in Table 6. This table is restricted to RV95 s that have been derived according to the IFCC/IUPAC concepts (Schulz et al., 2012) or to P95s established from representative national surveys of general populations (CDC, 2009; InVS, 2011; Kato et al., 2011; Patterson et al., 2009) undertaken within 10 years of the start of the CHMS, and from the Canadian First Nations Biomonitoring Initiative (FNBI), (AFN, 2013). THE FNBI is a representative survey of Canadian First Nations living on-reserve and crown lands south of the 60◦ parallel that was carried out in 2011to address an important knowledge gap for a Canadian population not covered by the CHMS. Only RV95 s and P95s for age groups similar to those used in the CHMS and that combine males and females are presented in Table 6. In this table, German RV95 s are values in whole blood, P95s for Canada-First Nations are values in plasma, and P95s for all other surveys are in serum. Furthermore, to facilitate comparisons with national surveys, only studies that have reported 95 percent confidence intervals (CI) with their estimates are shown in this table. For the purposes of this paper, Canadian RV95 s were considered different than P95s of other national studies only if there was no overlap between the 95 percent CI upon which the RV95 s from this study were derived and the 95 percent CI of the P95s from the other studies. Point estimates were used to compare Canadian RV95 s with those from Germany. Since the removal of extreme values in the statistical analysis did not change appreciably the P95 values of the biomarker concentration in partitions, upon which the RV95 s in this study were derived, P95s of biomarker concentrations in corresponding age groups from other population representative studies are presumed suitable for comparisons. Caution is warranted when comparing RV95 s and P95s between various countries and populations due to differences in population sampling and analysis methods, matrices, sample sizes, age group categories, the data collection years upon which the reference values and percentiles were derived, and the variability associated with these values. 3.1. Organochlorine pesticides OCs pesticides are chlorinated hydrocarbons used extensively from the 1940s through the 1970s in agriculture, residential and industrial applications. OCs are structurally related compounds with one or more chlorine-substituted aliphatic or aromatic rings. Aldrin, chlordane, dichlorodiphenyltrichloroethane (DDT), HCB, HCH, mirex and toxaphene are among the compounds in this group. OCs are very persistent in the environment, bioaccumulate in biota, and biomagnify in the food web and in humans. Consequently, OCs have been banned, deregistered, or had their use severely curtailed in Canada since the mid-1970s and are subject to global control under the Stockholm Convention on Persistent Organic Pollutants (Environment Canada, 2013, 2006a; Stockholm Convention, 2009). The health effects of OCs have been studied extensively and assessments have evaluated the potential health effects from exposure (ATSDR, 1994, 1995, 2002a,b, 2005, 2008, 2012, 2013, 2014, 2015a). However, attributing health effects to specific OCs is complicated as exposure is often to more than one OC and the mode of action is similar for these chemicals. The International Agency for Research on Cancer has classified a number of OCs as Group 2A probable

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Table 1 Persistent organic pollutants measured in plasma in the Canadian Health Measures Survey between 2007 and 2011 and their respective limits of detection and detection rates. Chemical

Organochlorine pesticides Aldrin Chlordane ␣-Chlordane ␥-Chlordane cis-Nonachlor trans-Nonachlor Oxychlordane Dichlorodiphenyltrichloroethane (DDT) p,p’-Dichlorodiphenyltrichloroethane (p,p’-DDT) p,p’-Dichlorodiphenyldichloroethylene (p,p’-DDE) Hexachlorobenzene (HCB) Hexachlorocyclohexane ␤-Hexachlorocyclohexane (␤-HCH) ␥-Hexachlorocyclohexane (␥-HCH, Lindane) Mirex Toxaphene Toxaphene Parlar 26 Toxaphene Parlar 50

CAS No.

2007–2009

2009–2011

LOD (␮g/L)

Detection ratea (%)

LOD (␮g/L)

Detection ratea (%)

309-00-2

0.010

0

NA

NA

57-74-9 5103-71-9 5103-74-2 5103-73-1 39765-80-5 27304-13-8 50-29-3 72-55-9 118-74-1

0.010 0.005 0.005 0.010 0.005

0 0.30 50.96 96.00 97.42

NA NA NA NA NA

NA NA NA NA NA

0.050 0.090 0.040

9.36 99.64 75.30

NA NA NA

NA NA NA

319-85-7 58-89-9 2385-85-5 8001-35-2

0.010 0.010 0.010

93.05 0.66 52.64

NA NA NA

NA NA NA

0.005 0.005

26.29 47.69

NA NA

NA NA

Polychlorinated biphenyls 2,4,4’-Trichlorobiphenyl (PCB 28) 2,2’,5,5’-Tetrachlorobiphenyl (PCB 52) 2,3’,4,4’-Tetrachlorobiphenyl (PCB 66) 2,4,4’,5-Tetrachlorobiphenyl (PCB 74) 2,2’,4,4’,5-Pentachlorobiphenyl (PCB 99) 2,2’,4,5,5’-Pentachlorobiphenyl (PCB 101) 2,3,3’,4,4’-Pentachlorobiphenyl (PCB 105) 2,3’,4,4’,5-Pentachlorobiphenyl (PCB 118) 2,2’,3,3’,4,4’-Hexachlorobiphenyl (PCB 128) 2,2’,3,4,4’,5’-Hexachlorobiphenyl (PCB 138) 2,2’,3,4’,5,5’-Hexachlorobiphenyl (PCB 146) 2,2’,4,4’,5,5’-Hexachlorobiphenyl (PCB 153) 2,3,3’,4,4’,5-Hexachlorobiphenyl (PCB 156) 2,3,3’,4’,5,6-Hexachlorobiphenyl (PCB 163) 2,3’,4,4’,5,5’-Hexachlorobiphenyl (PCB 167) 2,2’,3,3’,4,4’,5-Heptachlorobiphenyl (PCB 170) 2,2’,3,3’,5,5’,6-Heptachlorobiphenyl (PCB 178) 2,2’,3,4,4’,5,5’-Heptachlorobiphenyl (PCB 180) 2,2’,3,4,4’,5’,6-Heptachlorobiphenyl (PCB 183) 2,2’,3,4’,5,5’,6-Heptachlorobiphenyl (PCB 187) 2,2’,3,3’,4,4’,5,5’-Octachlorobiphenyl (PCB 194) 2,2’,3,3’,4,5’,6,6’-Octachlorobiphenyl (PCB 201) 2,2’,3,4,4’,5,5’,6-Octachlorobiphenyl (PCB 203) 2,2’,3,3’,4,4’,5,5’,6-Nonachlorobiphenyl (PCB 206)

7012-37-5 35693-99-3 32598-10-0 32690-93-0 38380-01-7 37680-73-2 32598-14-4 31508-00-6 38380-07-3 35065-28-2 51908-16-8 35065-27-1 38380-08-4 74472-44-9 52663-72-6 35065-30-6 52663-67-9 35065-29-3 5266-69-1 52663-68-0 35694-08-7 40186-71-8 52663-76-0 40186-72-9

0.05 0.30 0.03 0.03 0.03 0.03 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01

1.38 0 1.80 46.94 29.44 0.60 28.90 90.35 1.26 98.56 62.89 97.48 71.22 78.66 24.52 85.13 38.43 98.62 51.08 80.40 70.50 69.12 64.39 43.11

NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA

NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA

Brominated flame retardants 2,2’,4,4’,5,5’-Hexabromobiphenyl (PBB 153) 4,4’-Dibromodiphenyl ether (PBDE 15) 2,2’,4-Tribromodiphenyl ether (PBDE 17) 2,3’,4-Tribromodiphenyl ether (PBDE 25) 2,4,4’-Tribromodiphenyl ether (PBDE 28) 2’,3,4-Tribromodiphenyl ether (PBDE 33) 2,2’,4,4’-Tetrabromodiphenyl ether (PBDE 47) 2,2’,4,4’,5-Pentabromodiphenyl ether (PBDE 99) 2,2’,4,4’,6-Pentabromodiphenyl ether (PBDE 100) 2,2’,4,4’,5,5’-Hexabromodiphenyl ether (PBDE 153)

59080-40-9 2050-47-7 147217-75-2 147217-77-4 41318-75-6 147217-78-5 5436-43-1 60348-60-9 189084-64-8 68631-49-2

0.02 0.03 0.03 0.03 0.03 0.03 0.03 0.02 0.02 0.02

3.44 0.18 0 0 3.25 0 74.76 26.79 26.02 41.35

NA NA NA NA NA NA NA NA NA NA

NA NA NA NA NA NA NA NA NA NA

Perfluoroalkyl substances Perfluorobutanoic acid (PFBA) Perfluorohexanoic acid (PFHxA) Perfluorooctanoic acid (PFOA) Perfluorononanoic acid (PFNA) Perfluorodecanoic acid (PFDA) Perfluoroundecanoic acid (PFUnDA) Perfluorobutane sulfonate (PFBS) Perfluorohexane sulfonate (PFHxS) Perfluorooctane sulfonate (PFOS)

375-22-4 307-24-4 335067-1 375-95-1 335-76-2 2058-94-8 45187-15-3 108427-53-8 45298-90-6

NA NA 0.3 NA NA NA NA 0.3 0.3

NA NA 98.89 NA NA NA NA 97.95 99.86

0.5 0.1 0.1 0.2 0.1 0.09 0.4 0.2 0.3

0.33 1.90 100 98.95 78.41 60.71 0 98.75 99.67

LOD: limit of detection; NA: not measured in those years of the Canadian Health Measures Survey. a The detection rate is defined as the percentage of the survey sample having plasma biomarker concentration above the LOD (Health Canada, 2010, 2013).

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Table 2 Reference values (RV95 s) for organochlorine pesticides in plasma for the general Canadian populationa from 2007 to 2009. Chemical

Age Group (years)

Whole Weight

Lipid Weight

N

P95 (CI) (␮g/L)

RV95 (␮g/L)

N

P95 (CI) (␮g/kg lipid)

RV95 (␮g/kg lipid)

trans-Nonachlor

20–39 40–59 60–79

524 594 545

0.054 (0.038–0.069) 0.11 (0.096–0.13) 0.22b (0.13–0.30)

0.054 0.11 0.22⊥

525 592 541

11 (7.1–14) 19 (15–23) 33 (23–44)

11 19 33

Oxychlordane

20–39 40–59 60–79

526 595 546

0.036 (0.030–0.043) 0.074 (0.064–0.085) 0.14 (0.11–0.17)

0.036 0.074 0.14

524 595 544

6.7 (5.0–8.3) 11 (9.7–13) 20 (16–25)

6.7 11 20

p,p’-DDE

20–39 40–59 60–79

526 596 545

c

5.5 (3.8–7.3) 9.1 (7.1–11)

NA 5.5 9.1

525 596 544

820b (240–1400) 890b (450–1300) 1400 (880–1800)

820⊥ 890⊥ 1400

HCB

20–39 40–59 60–79

525 596 538

0.12b (0.065–0.18) 0.16 (0.13–0.19) 0.21 (0.15–0.26)

0.12⊥ 0.16 0.21

525 596 537

23b (10–35) 25 (22–28) 32 (22–43)

23⊥ 25 32

␤-HCH

20–79

1624

0.33b (0.093–0.57)

0.33⊥

1658

75b (20–130)

75⊥

CI: 95% confidence interval; p,p’-DDE: p,p’-dichlorodiphenyldichloroethylene; HCB: hexachlorobenzene; ␤-HCH: ␤-hexachlorocyclohexane; N: number of participants; NA: not available; P95: 95th percentile; RV95 : the 95th percentile of the measured chemical concentration of the reference population, within the 95% confidence interval. a Based upon sampling of CHMS participants following ≥10 h of fasting. b Use data with caution as the coefficient of variation at the 95th percentile for the reference population is between 16.6% and 33.3%. c Coefficient of variation at the 95th percentile for the reference population is too high (>33.3%) for the estimate to be published. ⊥ Provisional reference values as RV95 s were derived from estimates with coefficients of variation between 16.6% and 33.3%. Table 3 Reference values (RV95 s) for polychlorinated biphenyls (PCBs) in plasma for the general Canadian populationa from 2007 to 2009. Chemical

Age Group (years)

Whole Weight

Lipid Weight

N

P95 (CI) (␮g/L)

RV95 (␮g/L)

N

P95 (CI) (␮g/kg lipid)

RV95 (␮g/kg lipid)

PCB 118

20–39 40–59 60–79

523 596 544

0.045 (0.032–0.058) 0.10 (0.076–0.13) 0.23 (0.17–0.29)

0.045 0.10 0.23

525 596 542

8.7 (6.4–11) 17 (12–22) 34 (25–43)

8.7 17 34

PCB 138

20–39 40–59 60–79

522 596 546

0.096 (0.075–0.12) 0.25 (0.20–0.30) 0.40 (0.33–0.47)

0.096 0.25 0.40

520 595 543

17 (12–22) 44 (35–53) 65 (50–81)

17 44 65

PCB 153

20–39 40–59 60–79

520 595 545

0.17 (0.12–0.21) 0.47 (0.31–0.64) 0.81 (0.64–0.98)

0.17 0.47 0.81

518 593 543

29 (19–39) 83b (50–120) 130 (95–170)

29 83⊥ 130

PCB 156

20–39 40–59 60–79

526 592 544

0.021 (0.015–0.027) 0.054b (0.033–0.075) 0.11 (0.092–0.12)

0.021 0.054⊥ 0.11

525 591 541

3.8 (2.6–4.9) 9.5 (7.9–11) 17 (13–22)

3.8 9.5 17

PCB 163

20–39 40–59 60–79

526 594 543

0.030 (0.022–0.039) 0.076b (0.038–0.11) 0.16 (0.13–0.18)

0.030 0.076⊥ 0.16

525 592 541

5.6 (3.8–7.4) 13b (6.1–19) 24 (19–29)

5.6 13⊥ 24

PCB 170

20–39 40–59 60–79

523 589 545

0.036b (0.014–0.058) 0.10 (0.081–0.12) 0.23 (0.19–0.28)

0.036⊥ 0.10 0.23

520 589 543

6.6b (4.0–9.1) 16 (12–20) 37 (24–50)

6.6⊥ 16 37

PCB 180

20–39 40–59 60–79

519 589 545

0.098b (0.058–0.14) 0.35 (0.29–0.41) 0.81 (0.66–0.97)

0.098⊥ 0.35 0.81

517 589 543

18 (13–24) 55 (42–68) 130 (92–170)

18 55 130

PCB 187

20–39 40–59 60–79

526 591 543

0.037 (0.027–0.048) 0.11 (0.073–0.15) 0.23 (0.17–0.28)

0.037 0.11 0.23

525 587 539

6.2b (3.3–9.1) 16b (9.5–22) 33 (27–39)

6.2⊥ 16⊥ 33

PCB 194

20–39 40–59 60–79

526 592 542

0.021b (
0.021⊥ 0.77 0.18

525 590 539

c

12 (10–14) 30 (22–38)

NA 12 30

PCB 201

20–39 40–59 60–79

526 593 536

0.018 (0.013–0.023) 0.071b (0.038–0.10) 0.16 (0.11–0.21)

0.018 0.071⊥ 0.16

520 592 531

3.1b (1.8–4.3) 11b (6.3–16) 21 (16–27)

3.1⊥ 11⊥ 21

PCB(138+153+180)

20–39 40–59 60–79

520 594 545

0.37 (0.26–0.48) 1.1b (0.62–1.6) 2.0 (1.6–2.3)

0.37 1.1⊥ 2.0

518 592 544

61b (34–88) 180b (98–270) 330 (260–410)

61⊥ 180⊥ 330

CI: 95% confidence interval; N: number of participants; NA: Not available; P95: 95th percentile; RV95 : the 95th percentile of the measured chemical concentration of the reference population, within the 95% confidence interval. a Based upon sampling of CHMS participants following ≥10 h of fasting. b Use data with caution as the coefficient of variation at the 95th percentile for the reference population is between 16.6% and 33.3%. c Coefficient of variation at the 95th percentile for the reference population is too high (> 33.3%) for the estimate to be published. ⊥ Provisional reference values as RV95 s were derived from estimates with coefficients of variation between 16.6% and 33.3%.

D.A. Haines et al. / International Journal of Hygiene and Environmental Health 220 (2017) 744–756

749

Table 4 Reference values (RV95 s) for brominated flame retardants in plasma for the general Canadian populationa from 2007 to 2009. Chemical

PBDE 47

Age Group (years)

20-79

Whole Weight

Lipid Weight

N

P95 (CI) (␮g/L)

RV95 (␮g/L)

N

P95 (CI) (␮g/kg lipid)

RV95 (␮g/kg lipid)

1668

0.41 (0.33–0.49)

0.41

1666

67 (51–83)

67

CI: 95% confidence interval; N: number of participants; P95: 95th percentile; PBDE 47: 2,2’,4,4’-Tetrabromodiphenyl ether; RV95 : the 95th percentile of the measured chemical concentration of the reference population, within the 95% confidence interval. a Based upon sampling of CHMS participants following ≥10 h of fasting. Table 5 Reference values (RV95 s) for perfluoroalkyl substances in plasma for the general Canadian population from 2009 to 2011. Chemical

Age Group (years)

N

P95 (CI) (␮g/L)

RV95 (␮g/L)

PFOA

12–19 20–39 40–59 60–79

506 362 334 321

4.0 (3.6–4.5) 5.8 (3.9–7.6) 4.4 (3.9–5.0) 6.4 (4.6–8.1)

4.0 5.8 4.4 6.4

PFNA

12–19 20–39 40–59 60–79

498 362 332 321

1.5 (1.2–1.8) 1.6 (1.2–2.0) 2.7a (1.5–3.8)

1.5 NA 1.6 2.7⊥

PFDA

12–19 20–39 40–59 60–79

507 350 331 294

0.39a (0.22–0.55) 0.39 (0.34–0.44) 0.50 (0.36–0.64) 0.58 (0.48–0.67)

0.39⊥ 0.39 0.50 0.58

PFHxS

12–10 20–39 40–59 60–79

502 360 333 317

10a (5.7–14) 6.0a (2.2–9.8) 12a (3.5–21) 8.9 (6.3–12)

10⊥ 6.0⊥ 12⊥ 8.9

PFOS

12–19 20–39 40–59 60–79

504 361 333 320

11 (9.0–13) 17a (6.9–27) 16 (13–19) 21a (9.8–32)

11 17⊥ 16 21⊥

b

CI: 95% confidence interval; N: number of participants; NA: not available; P95: 95th percentile; PFDA: perfluorodecanoic acid; PFHxS: perfluorohexane sulfonate; PFNA: perfluorononanoic acid; PFOA: perfluorooctanoic acid; PFOS: perfluorooctane sulfonate; RV95 : the 95th percentile of the measured chemical concentration of the reference population, within the 95% confidence interval. a Use data with caution as the coefficient of variation at the 95th percentile for the reference population is between 16.6% and 33.3%. b Coefficient of variation at the 95th percentile for the reference population is too high (>33.3%) for the estimate to be published. ⊥ Provisional reference values as RV95 s were derived from estimates with coefficients of variation between 16.6% and 33.3%.

human carcinogens, including DDT and aldrin (IARC, 2016a, 2017); or Group 2 B possible human carcinogens, including chlordane, HCB, HCH, mirex and toxaphene (IARC, 1987, 2001). Technical grade chlordane consists of over 140 structurally related organochlorine compounds of which trans-nonachlor is a main component (Health Canada, 2010). Chlordane is metabolized to oxychlordane in the environment and in the body and is highly persistent (CDC, 2005). The Canadian RV95 s for both trans-nonachlor and oxychlordane are 62–74% less than the lipid weight P95 values reported from the 2003–2004 NHANES for the United States (Patterson et al., 2009). The whole weight Canadian RV95 for trans-nonachlor for 40–59 year olds is 39% less, and the trans-nonachlor and oxychlordane lipid weight Canadian RV95 s for 20–39 year olds are 100% and 94% greater respectively than the corresponding P95 values reported in the Canadian First Nations population (AFN, 2013). DDT breaks down in the environment to more stable chemical forms including DDE which is the major residue found in people (Health Canada, 2010). The Canadian RV95 s for p,p -DDE (5.5 ␮g/L and 9.1 ␮g/L) are within the range of RV95 s (7–11 ␮g/L) for similar age groups in Germany (Schulz et al., 2012). The Canadian RV95 s are similar to P95s reported for France (InVS, 2011) and 52% and 61% less than the lipid weight P95s for age groups 40–59 and ≥60 years respectively in the United States (Patterson et al., 2009). Since the 1970s, mean serum levels of DDT and DDE have declined by about fivefold to tenfold in the United States population (CDC, 2009).The P95s for Canadian First Nations are similar to the CHMS derived

RV95 s with the exception of 20–29 year olds whose lipid weight value is 84% less than the CHMS RV95 (AFN, 2013). The RV95 s for HCB from this study are similar to the P95s reported for the United States (Patterson et al., 2009) and Canadian First Nations (AFN, 2013). However, they are about 76% to 96% less than the RV95 s for Germany (Schulz et al., 2012) and 62% to 74% less than the P95s reported for 40–59 and 60–74 year olds in France (InVS, 2011). HCB has not been registered as a pesticide in Canada since 1976 whereas it has been prohibited in France since 1988 and in Europe since 1993 which may account for the differences observed in this study (Environment Canada, 2006a; InVS, 2011). HCH was originally produced and applied as an organochlorine pesticide as a mixture of alpha (␣-HCH), beta (␤-HCH), gamma (␥HCH, lindane) and delta isomeric forms. The production, use or sale of ␣-HCH and ␤-HCH as pesticides is prohibited in Canada and until 2016, the only allowable use of lindane has been in a pharmaceutical application for control of head lice and scabies (Environment Canada, 2013). Both ␤-HCH and ␥-HCH were measured in CHMS blood plasma to evaluate HCH exposure. ␤-HCH accumulates in fatty tissues and has a blood elimination half-life of approximately seven years whereas ␥-HCH has a shorter half life of 20 h (CDC, 2005) and was detected in few (0.66%) CHMS samples. The ␤HCH Canadian whole weight RV95 for 20–79 year olds (0.33 ␮g/L) is within the range of RV95 s (0.3–0.9 ␮g/L) for adult age groups in Germany (Schulz et al., 2012). Canadian RV95 s are similar to P95s for the United States (CDC, 2009) but 60% less (lipid weight) and

750

D.A. Haines et al. / International Journal of Hygiene and Environmental Health 220 (2017) 744–756

Table 6 Reference values (RV95 ) and 95th percentiles (P95) for blood concentrations of persistent organic pollutants from population representative national surveys. Chemical

Survey

Study Period

Matrix

Age group (years)

RV95 (␮g/L)

P95 (CI) (whole weight) (␮g/L)

P95 (CI) (lipid weight) (␮g/kg lipid)

Organochlorine pesticides trans-Nonachlor

Canada

2007–2009

Plasma

20–39 40–59 60–79

0.054 0.11 0.22⊥

0.054 (0.038–0.069) 0.11 (0.096–0.13) 0.22a (0.13–0.30)

11 (7.1–14) 19 (15–23) 33 (23–44)

Canada-First Nations (AFN, 2013)

2011

Plasma

20–39 40–59 60–99

0.03 (0.03–0.04) 0.18 (0.14–0.22) 0.29 (0.20–0.37)

5.48 (4.10–6.86) 22.07 (19.22–24.91) 40.09 (28.79–51.39)

United States (Patterson et al., 2009)

2003–2004

Serum

20–39 40–59 ≥60

Canada

2007–2009

Plasma

20–39 40–59 60–79

Canada-First Nations (AFN, 2013)

2011

Plasma

20–39 40–59 60–99

United States (Patterson et al., 2009)

2003–2004

Serum

20–39 40–59 ≥60

Canada

2007–2009

Plasma

20–39 40–59 60–79

Oxychlordane

p,p’-DDE

34.40 (27.60–41.90) 58.00 (46.00–68.30) 129.00 (90.00–229.00) 0.036 0.074 0.14

0.036 (0.030–0.043) 0.074 (0.064–0.085) 0.14 (0.11–0.17)

6.7 (5.0–8.3) 11 (9.7–13) 20 (16–25)

0.02 (0.02–0.03) 0.11 (0.07–0.14) 0.17a (0.11–0.23)

3.46 (2.44–4.47) 12.05 (9.78–14.33) 26.21a (17.63–34.80) 17.80 (14.60–19.50) 30.10 (26.70–35.50) 65.20 (50.30–75.60)

NA 5.5 9.1

b

5.5 (3.8–7.3) 9.1 (7.1–11)

820a (240–1400) 890a (450–1300) 1400 (880–1800)

Canada-First Nations (AFN, 2013)

2011

Plasma

20–39 40–59 60–99

0.78a (0.45–1.10) 4.29 (3.24–5.34) 8.10 (5.73–10.48)

129.75a (71.44–188.06) 511.69 (404.87–618.50) 1085.01 (943.38–1226.64)

France (InVS, 2011)

2006–2007

Serum

18–39 40–59 60–74

3.55 (1.07–4.63) 5.68 (2.76–9.75) 5.32 (2.66–12.39)

603 (168–809) 922 (396–1739) 790 (402–925)

Germany-West (Schulz et al., 2012)

1997–1999

Whole blood 20–29 30–39 40–49 50–59 60–69

United States (Patterson et al., 2009)

2003–2004

Serum

2 4 7 8 11 675.00 (435.00–1000.00) 1870.00 (1320.00–2790.00) 3630.00 (2340.00–4780.00)

20–39 40–59 ≥60

HCB

␤-HCH

0.12⊥ 0.16 0.21

0.12a (0.065–0.18) 0.16 (0.13–0.19) 0.21 (0.15–0.26)

23a (10–35) 25 (22–28) 32 (22–43)

20–39 40–59 60–99

0.06 (0.05–0.08) 0.14 (0.11–0.18) 0.20 (0.17–0.23)

10.81 (8.23–13.39) 17.98 (13.74–22.22) 29.53 (22.75–36.31)

18–39 40–59 60–74

0.20 (0.18–0.30) 0.61 (0.30–0.81) 0.58 (0.35–0.80)

34 (31–45) 81 (48–119) 84 (68–141)

Canada

2007–2009

Plasma

20–39 40–59 60–79

Canada-First Nations (AFN, 2013)

2011

Plasma

France (InVS, 2011)

2006–2007

Serum

Germany (Schulz et al., 2012)

1997–1999

Whole blood 20–29 30–39 40–49 50–59 60–69

United States (Patterson et al., 2009)

2003–2004

Serum

20–39 40–59 ≥60

Canada

2007–2009

Plasma

20–79

Canada-First Nations (AFN, 2013)

2011

Plasma

20–99

France (InVS, 2011)

2006–2007

Serum

18–74

Germany (Schulz et al., 2012)

1997–1999

Whole blood 20–29 30–39 40–49 50–59 60–69

0.5 1.0 2.5 3.3 5.8 23.70 (21.10–26.10) 27.00 (25.10–37.30) 35.50 (30.50–46.10) 0.33⊥

0.3 0.3 0.3 0.5 0.9

0.33a (0.093–0.57)

75a (20–130)

0.06 (0.05–0.07)

9.29 (8.25–10.32)

1.50 (1.09–1.94)

190 (160–260)

D.A. Haines et al. / International Journal of Hygiene and Environmental Health 220 (2017) 744–756

751

Table 6 (Continued) Chemical

Survey

Study Period

Matrix

Age group (years)

United States (CDC, 2009)

2003–2004

Serum

≥20

2007–2009

Plasma

20–39 40–59 60–79

2011

Plasma

20–39 40–59 60–99

Polychlorinated biphenyls PCB 118 Canada

Canada-First Nations (AFN, 2013)

PCB 138

PCB 153

PCB 156

PCB 163

PCB 170

United States (Patterson et al., 2009)

2003–2004

Serum

20–39 40–59 ≥60

Canada

2007–2009

Plasma

20–39 40–59 60–79

Canada-First Nations (AFN, 2013)

2011

Plasma

RV95 (␮g/L)

0.045 0.10 0.23

P95 (CI) (whole weight) (␮g/L)

P95 (CI) (lipid weight) (␮g/kg lipid)

0.412 (0.308–0.587)

62.2 (48.2–87.6)

0.045 (0.032–0.058) 0.10 (0.076–0.13) 0.23 (0.17–0.29)

8.7 (6.4–11) 17 (12–22) 34 (25–43)

b

b

0.19a (0.08–0.31) 0.37a (0.19–0.56)

b

44.73 (36.93–52.53) 11.90 (9.45–14.71) 28.60 (21.13–40.36) 69.10 (47.26–86.77)

0.096 0.25 0.40

0.096 (0.075–0.12) 0.25 (0.20–0.30) 0.40 (0.33–0.47)

17 (12–22) 44 (35–53) 65 (50–81)

20–39 40–59 60–99

b

b

0.45a (0.22–0.68)

64.94a (34.64–95.24) 90.28a (35.80–144.76)

18–39 40–59 60–74

0.67 (0.52–0.68) 1.46 (1.13–1.55) 1.74 (1.35–2.78)

101.6 (89.8–119.3) 197.2 (155.5–255.9) 219.2 (170.9–278.9)

0.17 (0.12–0.21) 0.47 (0.31–0.64) 0.81 (0.64–0.98)

29 (19–39) 83a (50–120) 130 (95–170)

b

France (InVS, 2011)

2006–2007

Serum

Germany (Apel et al., 2016)

2010

Whole blood 20–29 30–39 40–49 50–59 60–69

0.20 0.45 0.70 0.85 1.10

Canada

2007–2009

Plasma

20–39 40–59 60–79

0.17 0.47 0.81

Canada-First Nations (AFN, 2013)

2011

Plasma

20–39 40–59 60–99

b

b

1.04a (0.59–1.50)

144.63a (73.96–215.30)

b

b

18–39 40–59 60–74

1.09 (0.82–1.18) 2.02 (1.82–2.51) 2.58 (2.08–4.28)

175.4 (143.0–206.2) 294.3 (265.0–403.5) 341.3 (255.5–432.8)

France (InVS, 2011)

2006–2007

Serum

Germany (Apel et al., 2016)

2010

Whole blood 20–29 30–39 40–49 50–59 60–69

United States (Patterson et al., 2009)

2003–2004

Serum

20–39 40–59 ≥60

Canada

2007–2009

Plasma

20–39 40–59 60–79

Canada-First Nations (AFN, 2013)

2011

Plasma

20–39 40–59 60–99

United States (Patterson et al., 2009)

2003–2004

Serum

20–39 40–59 ≥60

Canada

2007–2009

Plasma

20–39 40–59 60–79

Canada-First Nations (AFN, 2013)

2011

Plasma

20–39 40–59 60–99

Canada

2007–2009

Plasma

20–39 40–59 60–79

Canada-First Nations (AFN, 2013)

2011

Plasma

20–39 40–59 60–99

0.30 0.80 1.10 1.40 1.65 37.00 (32.25–49.54) 93.00 (68.31–121.00 160.00 (141.00–212.00) 0.021 0.054⊥ 0.11

0.021 (0.015–0.027) 0.054a (0.033–0.075) 0.11 (0.092–0.12)

3.8 (2.6–4.9) 9.5 (7.9–11) 17 (13–22)

0.03a (0.02–0.05) 0.14a (0.08–0.19)

b

b

b

17.79a (10.72–24.86) 5.50 (4.80–8.09) 14.35 (11.27–17.40) 26.66 (21.30–34.06)

0.030 0.076⊥ 0.16

0.036⊥ 0.10 0.23

0.030 (0.022–0.039) 0.076a (0.038–0.11) 0.16 (0.13–0.18)

5.6 (3.8–7.4) 13a (6.1–19) 24 (19–29)

b

b

0.19a (0.09–0.29)

23.12a (11.93–34.32)

b

b

0.036a (0.014–0.058) 0.10 (0.081–0.12) 0.23 (0.19–0.28)

6.6a (4.0–9.1) 16 (12–20) 37 (24–50)

b

b

0.33a (0.20–0.47)

45.27a (25.52–65.01)

b

b

752

D.A. Haines et al. / International Journal of Hygiene and Environmental Health 220 (2017) 744–756

Table 6 (Continued) Chemical

PCB 180

PCB 187

PCB 194

PCB 201

PCB(138+153+180)

Survey

Study Period

Matrix

Age group (years)

United States (Patterson et al., 2009)

2003–2004

Serum

20–39 40–59 ≥60

Canada

2007-2009

Plasma

20–39 40–59 60–79

Canada-First Nations (AFN, 2013)

2011

Plasma

P95 (CI) (lipid weight) (␮g/kg lipid) 10.70 (8.50–13.90) 25.50 (21.70–33.30) 42.34 (32.84–62.90)

0.098⊥ 0.35 0.81

18 (13–24) 55 (42–68) 130 (92–170)

20–39 40–59 60–99

b

b

18–39 40–59 60–74

2006–2007

Serum

Germany (Apel et al., 2016)

2010

Whole blood 20–29 30–39 40–49 50–59 60–69

United States (Patterson et al., 2009)

2003–2004

Serum

20–39 40–59 ≥60

Canada

2007–2009

Plasma

20–39 40–59 60–79

Canada-First Nations (AFN, 2013)

2011

Plasma

20–39 40–59 60–99

United States (Patterson et al., 2009)

2003–2004

Serum

20–39 40–59 ≥60

Canada

2007–2009

Plasma

20–39 40–59 60–79

0.037 0.11 0.23

0.021⊥ 0.77 0.18

United States (Patterson et al., 2009)

2003–2004

Serum

20–39 40–59 ≥60

Canada

2007–2009

Plasma

20–39 40–59 60–79

Canada-First Nations (AFN, 2013)

2011

Plasma

20–39 40–59 60–99

Canada

2007–2009

Plasma

20–39 40–59 60–79

0.37 1.1⊥ 2.0

Germany (Apel et al., 2016)

2010

Whole blood 20–29 30–39 40–49 50–59 60–69

0.67 1.6 2.6 3.2 3.9

2007–2009

Plasma

0.41

2011

Plasma

20–99

United States (CDC, 2009)

2003–2004

Serum

≥20

Canada

2009–2011

Plasma

12–19 20–39 40–59 60–79

b

0.87 (0.74–1.01) 2.08 (1.70–2.59) 2.08 (1.46–3.06)

151.8 (118.5–232.5) 280.6 (246.6–382.8) 295.8 (192.0–263.1)

0.037 (0.027–0.048) 0.11 (0.073–0.15) 0.23 (0.17–0.28)

6.2a (3.3–9.1) 16a (9.5–22) 33 (27–39)

b

b

0.34a (0.21–0.47)

52.85a (27.30–78.39)

b

b

9.41 (7.37–11.70) 19.87 (17.70–30.90) 45.82 (32.21–60.02)

20–39 40–59 60–99

Canada-First Nations (AFN, 2013)

144.27a (71.33–217.20)

b

30.70 (23.19–43.30) 75.00 (63.70–96.70) 132.00 (102.00–189.00)

2011

20–79

0.99a (0.60–1.38)

0.20 0.50 0.80 1.05 1.20

Canada-First Nations (AFN, 2013)

Plasma

P95 (CI) (whole weight) (␮g/L)

0.098a (0.058–0.14) 0.35 (0.29–0.41) 0.81 (0.66–0.97)

France (InVS, 2011)

Brominated flame retardants Canada PBDE 47

Perfluoroalkyl substances PFOA

RV95 (␮g/L)

0.021a (
b

12 (10–14) 30 (22–38)

b

b

0.22a (0.14–0.30) 0.67a (0.29–1.05)

31.49a (15.82–47.17) 85.07a (38.28–131.86) 7.26 (4.90–11.57) 17.50 (15.42–19.80) 30.21 (26.03–38.55)

0.018 0.071⊥ 0.16

0.018 (0.013–0.023) 0.071a (0.038–0.10) 0.16 (0.11–0.21)

3.1a (1.8–4.3) 11a (6.3–16) 21 (16–27)

b

b

0.24a (0.14–0.33) 0.71a (0.27–1.14)

32.91a (17.81–48.01) 91.53a (36.68–146.39)

0.37 (0.26–0.48) 1.1a (0.62–1.6) 2.0 (1.6–2.3)

61a (34–88) 180a (98–270) 330 (260–410)

0.41 (0.33–0.49)

67 (51–83)

a

0.25 (0.15–0.34)

31.75a (19.56–43.94) 163 (102–240)

4.0 5.8 4.4 6.4

4.0 (3.6–4.5) 5.8 (3.9–7.6) 4.4 (3.9–5.0) 6.4 (4.6–8.1)

D.A. Haines et al. / International Journal of Hygiene and Environmental Health 220 (2017) 744–756

753

Table 6 (Continued) Chemical

PFNA

PFDA

PFHxS

PFOS

RV95 (␮g/L)

P95 (CI) (whole weight) (␮g/L)

Survey

Study Period

Matrix

Age group (years)

Canada-First Nations (AFN, 2013)

2011

Plasma

20–39 40–59 60–99

4.34a (2.37–6.31) 3.59 (2.70–4.49) 3.25 (2.79–3.71)

United States (Kato et al., 2011)

2007–2008

Serum

12–19 20–39 40–59 ≥60

7.30 (6.20–8.00) 9.60 (8.70–10.1) 10.1 (8.40–11.9) 9.80 (8.20–12.7)

Canada

2009–2011

Plasma

12–19 20–39 40–59 60–79

1.5 NA 1.6 2.7⊥

1.5 (1.2–1.8) b

1.6 (1.2–2.0) 2.7a (1.5–3.8)

Canada-First Nations (AFN, 2013)

2011

Plasma

20–39 40–59 60–99

2.02a (1.03–3.02) 2.38 (1.91–2.85) 4.73 (3.77–5.69)

United States (Kato et al., 2011)

2007–2008

Serum

12–19 20–39 40–59 ≥60

3.10 (2.60–4.00) 4.00 (3.30–5.00) 3.90 (3.30–4.60) 4.80 (3.60–6.00)

Canada

2009–2011

Plasma

12–19 20–39 40–59 60–79

Canada-First Nations (AFN, 2013)

2011

Plasma

20–39 40–59 60–99

0.51a (0.30–0.73) 0.63a (0.41–0.85) 0.66 (0.46–0.86)

United States (Kato et al., 2011)

2007–2008

Serum

12–19 20–39 40–59 ≥60

0.600 (0.500–0.700) 1.00 (0.700–1.30) 0.900 (0.800–1.20) 0.900 (0.700–1.50)

Canada

2009–2011

Plasma

12–19 20–39 40–59 60–79

Canada-First Nations (AFN, 2013)

2011

Plasma

20–39 40–59 60–99

7.69a (2.96–12.41) 4.34 (2.94–5.73) 6.38a (4.04–8.72)

United States (Kato et al., 2011)

2007–2008

Serum

12–19 20–39 40–59 ≥60

15.9 (11.1–21.5) 7.40 (4.60–12.0) 11.1 (5.10–20.5) 9.10 (6.80–11.7)

Canada

2009–2011

Plasma

12–19 20–39 40–59 60–79

Canada-First Nations (AFN, 2013)

2011

Plasma

20–39 40–59 60–99

9.55 (7.39–11.72) 19.49a (9.20–29.79) 23.02 (18.58–27.45)

United States (Kato et al., 2011)

2007–2008

Serum

12–19 20–39 40–59 ≥60

28.0 (22.0–32.2) 35.1 (28.4–40.8) 42.8 (36.3–58.0) 51.5 (43.2–67.1)

0.39⊥ 0.39 0.50 0.58

10⊥ 6.0⊥ 12⊥ 8.9

11 17⊥ 16 21⊥

P95 (CI) (lipid weight) (␮g/kg lipid)

0.39a (0.22–0.55) 0.39 (0.34–0.44) 0.50 (0.36–0.64) 0.58 (0.48–0.67)

10a (5.7–14) 6.0a (2.2–9.8) 12a (3.5–21) 8.9 (6.3–12)

11 (9.0–13) 17a (6.9–27) 16 (13–19) 21a (9.8–32)

CI: 95% confidence interval is provided when reported in the literature; p,p’-DDE: p,p’-dichlorodiphenyldichloroethylene; HCB: hexachlorobenzene; ␤-HCH: ␤hexachlorocyclohexane; NA: not available; P95: 95th percentile; PBDE: polybrominated diphenyl ether; PCB: polychlorinated biphenyl; PFDA: perfluorodecanoic acid; PFHxS: perfluorohexane sulfonate; PFNA: perfluorononanoic acid; PFOA: perfluorooctanoic acid; PFOS: perfluorooctane sulfonate; RV95 : the 95th percentile of the measured chemical concentration of the reference population, within the 95% confidence interval. a Use data with caution as the coefficient of variation is between 16.6% and 33.3%. b Coefficient of variation at the 95th percentile for the reference population is too high (>33.3%) for the estimate to be published. ⊥ Provisional reference values as RV95 s were derived from estimates with coefficients of variation between 16.6% and 33.3%.

78% less (whole weight) than the corresponding P95s in France (InVS, 2011). The Canadian First Nations P95s for ␤-HCH are 82% less (whole weight) and 88% less (lipid weight) than the RV95 s for the 20–79 year old Canadian general population (AFN, 2013). Differences in diet and implementation of regulations restricting the uses of HCH across Europe may be factors contributing to the differences in concentrations between France and North America.

3.2. Polychlorinated biphenyls (PCBs) PCBs are a group of synthetic chlorinated organic compounds of which there are 209 possible congeners. They are persistent in the environment and can magnify many fold in the food chain and diet is the predominant source of human exposure. Use of PCBs has been restricted in Canada since 1977 and Government of Canada

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regulations establish a prohibition on the release, manufacture, processing, use, import, export, and sale of PCBs and products that contain certain concentrations of PCBs, and also provide exceptions to these prohibitions. They also set storage requirements for PCBs and products containing PCBs across Canada (CEPA, 1999a). PCBs are listed under the Stockholm Convention on Persistent Organic Pollutants (Stockholm Convention, 2009). Many studies have examined the health effects of PCB exposure in the workplace and in the general population. Acne-like skin conditions have been associated with high exposure in adults and neurobehavioural and immunological changes have been observed in some studies with children following maternal exposure (ATSDR, 2000, 2011). The International Agency for Research on Cancer has classified PCBs as Group 1, carcinogenic to humans (IARC, 2016b). RV95 s have been derived for PCB 118, PCB 138, PCB 153, PCB 156, PCB 163, PCB 170, PCB 180, PCB 187, PCB 194, PCB 201 and PCB(138 + 153 + 180) (Table 3). Within each age group, the highest RV95 values were found for PCB 153, PCB 180 and PCB 138. The German HBM Commission has recently updated its reference values for PCB 138, PCB 153, PCB 180 and PCB(138 + 153 + 180) through factor-based estimation using 1997–2010 data from the German environmental specimen bank to account for reductions in general population exposure from major sources (Apel et al., 2016). Similar to the provisional RV95 s for Germany, the Canadian RV95 s for these PCBs increased with age but are between 40% and 80% less than the German values established for men and women combined which have been expressed on a whole weight basis in whole blood. German provisional RV95 s expressed on a whole weight plasma and on a lipid weight basis have also been derived for men and women separately (data not shown). Nonetheless, the Canadian whole weight and lipid weight RV95 s which have not been partitioned by sex are about 60% to 90% less than the German reference values for men and women. The Canadian RV95 s for individual PCB congeners in this study are similar to or less (PCB 118 51% for age 60–79 years; PCB 156 34%, PCB 170 37%, and PCB 194 31% for age 40–59 years) than the P95 values reported for the United States (Patterson et al., 2009) and 56% to 88% less than P95s reported for PCB 138, PCB 153, and PCB 180 for France (InVS, 2011). The higher concentrations in France and Germany compared to North America may be due partly to differences in regulations over time and in diet consisting of greater fish consumption, which is an important source of PCB exposure, and that European populations are more concentrated near PCB contaminated sites (InVS, 2011). P95 values for PCB 156 (whole weight, 40–59 year olds), PCBs 170, 180, and 187 (whole weight and lipid weight, 40–59 year olds), and PCBs 194 and 201 (whole weight and lipid weight, 40–59 and 60–99 year olds) from Canadian First Nations are between 159% and 344% greater than the RV95 s derived from the CHMS general population. However, comparisons must be made with caution due to the high sampling variability (i.e. CVs between 16.6% and 33.3%) associated with most of the First Nations PCBs P95s (AFN, 2013; Statistics Canada, 2010). 3.3. Brominated flame retardants Polybrominated diphenyl ethers (PBDEs) and polybrominated biphenyls (PBBs) are two structurally related classes of organic compounds which have been used as fire retardants. They are environmentally persistent, bioaccumulate and biomagnify in the terrestrial food chain (ATSDR, 2004, 2015b; Environment Canada, 2006b). BFRs have multiple exposure pathways with food and dust as important exposure sources (Health Canada, 2006; Lorber, 2008; Wilford et al., 2005). The use of PBDEs haselevated their concentrations in North American food and environmental compartments resulting in exposures to people (Domingo, 2012; Hites, 2004). In order to protect the environment, the Government of Canada has placed restrictions on PBDEs (Canada, 2016). This includes the

prohibition of the manufacturing of all PBDEs in Canada and the restriction of the import and sale of PBDEs in mixtures. The critical effects observed in animal studies are effects on the liver and neurobehavioural development (Health Canada, 2006). The International Agency for Research on Cancer has classified decaBDE as a Group 3 carcinogen, not classifiable as to its carcinogenicity to humans, and PBBs as Group 2A carcinogens, probably carcinogenic to humans (IARC, 1999, 2016b). PBDE 47 was the most frequently detected BFR congener in the CHMS, consistent with the 2003–2004 US NHANES study (Sjödin et al., 2008). The lipid weight RV95 for PBDE 47 for the 20–79 year old Canadian general population (67 ␮g/kg lipid) (Table 4) is 59% less than the P95 reported for the United States population ≥20 years of age (CDC, 2009). P95s for the Canadian First Nations population 20–99 years of age are similar on a whole weight and 53% less on a lipid weight basis than the corresponding RV95 s for the 20–79 year old Canadian general population (AFN, 2013). Studies have highlighted higher concentrations of PBDEs in house dust and among residents in regions with historically stricter flammability standards such as California which may account for the differences between Canadian and United Stated values observed in this study (Eskenazi et al., 2011; Zota et al., 2008). 3.4. Perfluoroalkyl substances PFASs are synthetic chemicals with high chemical and thermal stability and are able to repel water and oils. They have been used in industrial and commercial applications such as fabric protectors, non-stick cookware, wiper blades, wire and cable insulation, flame retardant foams, paper coatings and pharmaceutical packaging (Kissa, 2001). PFASs are persistent and resist degradation in the environment. Since the 2002 voluntary phase-out of production by the world’s largest producer, global manufacturing and use of PFOS and PFOS-related products has decreased (Paul et al., 2009). Except for certain exemptions, Canada prohibits the manufacture, use, sale, and import of PFOS, as well as products containing PFOS (CEPA, 1999b). Globally, voluntary efforts were initiated in 2006 to reduce PFOA emissions and product content by 95% by 2010 and to eliminate emissions and product content by 2015 (EPA, 2016). Possible linkages between exposure to PFASs and adverse human health effects have been examined in occupational studies and studies of populations exposed to contaminated drinking water (ATSDR, 2015c). The results have been inconsistent and no definitive links have been established. In animals, effects have been observed on the liver and immune system. Based on a limited evidence of carcinogenicity, the International Agency for Research on Cancer has classified perfluorooctanoic acid as Group 2B, possibly carcinogenic to humans (IARC, 2016c). RV95 s for PFOA, perfluorononanoic acid (PFNA), PFDA, perfluorohexane sulfonate (PFHxS) and PFOS have been derived for Canada (Table 5). The Canadian RV95 s for PFOA and PFOS (all age groups), PFNA (12–19 and 40–59 years), and PFDA (20–39, 40–59, and 60–79 years) are between 35% and 63% less than the P95s reported for the corresponding age groups from the United States in 2007–2008 (Kato et al., 2011). No differences were observed for PFHxS (all age groups), PFNA (60–79 years) and PFDA (12–19 years). Overall, the P95s for PFASs in Canadian First Nations are similar to or less (i.e. PFOA 49% less in the 60–99 year old age group) than the RV95 s derived from the CHMS. The German HBM Commission established an RV95 of 10 ␮g/L for PFOA for women, men and children <10 years of age and RV95 s for PFOS of 20 ␮g/L, 25 ␮g/L and 10 ␮g/L for women, men and children <10 years, respectively. However, these reference values were based on samples collected between 2003 and 2007 which were not strictly representative of the German population (Schulz et al., 2012). Nonetheless, the Canadian RV95 s for PFOA ranging from 4 to 6.4 ␮g/L are less than

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the HBM Commission’s reference value of 10 ␮g/L. The Canadian RV95 s for PFOS in 20–29 (17 ␮g/L), 30–39 (16 ␮g/L) and 40–49 year olds (21 ␮g/L) compare to German reference values of 20 ␮g/L for women and 25 ␮g/L for men. Although exposure of general populations to several PFASs is widespread globally, demographic and geographic differences may exist (Fromme et al., 2009). 4. Conclusion RV95 s for several OCs, PCBs, BFRs and PFASs were derived for the Canadian general population using the concentration of their biomarkers in blood plasma obtained from the latest CHMS biomonitoring data. No exclusion criteria were examined for any of the POPs in this analysis. Partitioning criteria of age and sex were evaluated statistically and used to construct reference populations for each chemical. Although POPs have been measured in targeted studies for many years in Canada, the RV95 s in this study are the first ever established for the general Canadian population based on HBM data obtained from nationally representative surveys. Because these reference values are statistically derived and do not incorporate toxicological information of the environmental chemicals, they cannot be used to predict health effects. Nonetheless, RV95 s indicate the upper margin of the current background exposure of the general population to given substances and are reference points against which individual and population HBM data may be compared. It is of note that the RV95 approach presented here includes the removal of extreme values and, as a result, implies a more strict definition of background exposure than approaches that include extreme values. On the whole, the Canadian general population RV95 s for POPs are similar to or less than P95s or RV95 s from the United States and Europe, and with the exception of p,p DDE and some PCB congeners, are similar to or greater than P95s for First Nations populations in Canada. Acknowledgement Health Canada’s funding for Canadian Health Measures Survey biomonitoring is provided by the Monitoring and Surveillance component of the Government of Canada’s Chemicals Management Plan. References AFN (Assembly of First Nations), 2013. First Nations Biomonitoring Initiative: National Results (2011), http://www.afn.ca/uploads/files/afn fnbi en - 201306-26.pdf (Accessed 19 May 2016.). ATSDR (Agency for Toxic Substances and Disease Registry), 1994. Toxicological Profile for Chlordane. U.S. Department of Health and Human Services, Public Health Service. ATSDR (Agency for Toxic Substances and Disease Registry), 1995. Toxicological Profile for Mirex and Chlordecone. U.S. Department of Health and Human Services, Public Health Service. ATSDR (Agency for Toxic Substances and Disease Registry), 2000. Toxicological Profile for Polychlorinated Biphenyls (PCBs). U.S. Department of Health and Human Services, Public Health Service. ATSDR (Agency for Toxic Substances and Disease Registry), 2002a. Toxicological Profile for Aldrin/Dieldrin. U.S. Department of Health and Human Services, Public Health Service. ATSDR (Agency for Toxic Substances and Disease Registry), 2002b. Toxicological Profile for DDT, DDE, and DDD. U.S. Department of Health and Human Services, Public Health Service. ATSDR (Agency for Toxic Substances and Disease Registry), 2004. Toxicological Profile for Polybrominated Biphenyls. U.S. Department of Health and Human Services, Public Health Service. ATSDR (Agency for Toxic Substances and Disease Registry), 2005. Toxicological Profile for Hexachlorocyclohexane. U.S. Department of Health and Human Services, Public Health Service. ATSDR (Agency for Toxic Substances and Disease Registry), 2008. Addendum to the Toxicological Profile for DDT, DDE, DDD. U.S. Department of Health and Human Services, Public Health Servicee. ATSDR (Agency for Toxic Substances and Disease Registry), 2011. Addendum to The Toxicological Profile for Polychlorinated Biphenyls. U.S. Department of Health and Human Services, Public Health Service.

755

ATSDR (Agency for Toxic Substances and Disease Registry), 2012. Addendum to The Toxicological Profile for Mirex and Chlordecone. U.S. Department of Health and Human Services, Public Health Service. ATSDR (Agency for Toxic Substances and Disease Registry), 2013. Addendum to The Toxicological Profile for Chlordane. U.S. Department of Health and Human Services, Public Health Service. ATSDR (Agency for Toxic Substances and Disease Registry), 2014. Toxicological Profile for Toxaphene. U.S. Department of Health and Human Services, Public Health Service. ATSDR (Agency for Toxic Substances and Disease Registry), 2015a. Toxicological Profile for Hexachlorocyclohexane. U.S. Department of Health and Human Services, Public Health Services. ATSDR (Agency for Toxic Substances and Disease Registry), 2015b. Draft Toxicological Profile for Polybrominated Diphenyl Ethers (PBDEs). U.S. Department of Health and Human Services, Public Health Services, Atlanta, GA. ATSDR (Agency for Toxic Substances and Disease Registry), 2015c. Draft Toxicological Profile for Hexachlorocyclohexane. U.S. Department of Health and Human Services, Public Health Services, Atlanta, GA. Allain, C., Poon, L., Chan, C., Richmond, W., Fu, P., 1974. Enzymatic determination of total serum cholesterol. Clin. Chem. 20, 470–475. Apel, P., Angerer, J., Wilhelm, M., Kolossa-Gehring, M., 2016. New HBM values for emerging substances, inventory of reference and HBM values in force and working principles of the German Human Biomonitoring Commission. Int. J. Hyg. Environ. Health, http://dx.doi.org/10.1016/j.ijheh.2016.09.007 (in press). Bergonzi, R., De Palma, G., Tomasi, C., Ricossa, M.C., Apostoli, P., 2009. Evaluation of different methods to determine total serum lipids for normalization of circulating organocholorine compounds. Int. Arch. Occup. Environ. Health 82 (10), 1241–1247. Bernert, J.T., Turner, W.E., Patterson Jr., D.G., Needham, L.L., 2007. Calculation of serum total lipid concentrations for the adjustment of persistent organohalogen toxicant measurements in human samples. Chemosphere 68, 824–831. CDC (Centers for Disease Control and Prevention), 2005. Third National Report on Human Exposure to Environmental Chemicals. Department of Health and Human Services. CDC (Centers for Disease Control and Prevention), 2009. Fourth National Report on Human Exposure to Environmental Chemicals. Department of Health and Human Services. CDC (Centers for Disease Control and Prevention), 2017. Fourth National Report on Human Exposure to Environmental Chemicals, Updated Tables, January 2017, Volume Two, https://www.cdc.gov/biomonitoring/pdf/FourthReport UpdatedTables Volume2 Jan2017.pdf (Accessed 27 February 2017). CEPA (Canadian Environmental Protection Act, 1999), 1999a. PCB Regulations. Subsections 31(1) and (3), SOR/2008-273, http://laws.justice.gc.ca/eng/ regulations/SOR-2008-273/FullText.html (Accessed 31 August 2016). CEPA (Canadian Environmental Protection Act, 1999), 1999b. The Perfluorooctane Sulfonate and Its Salts and Certain Other Compounds Regulations. Subsection 93(1) and Section 319, SOR/2008-178, http://laws.justice.gc.ca/eng/ regulations/SOR-2008-273/FullText.html (Accessed 31 August 2016). Calafat, A.M., Wong, L.-Y., Kuklenyik, Z., Reidy, J.A., Needham, L.L., 2007. Polyfluoroalkyl chemicals in the U.S. population: data from the national health and nutrition examination survey (NHANES) 2003–2004 and comparisons with NHANES 1999–2000. Environ. Health Perspect. 115 (11), 1596–1602. Canada, 2016. Regulations Amending the Prohibition of Certain Toxic Substances Regulations, 2012. Canada Gazette, Part II: Official Regulations, 150(20), http:// www.gazette.gc.ca/rp-pr/p2/2016/2016-10-05/html/sor-dors252-eng.php (Accessed January 19 2017.). Core Team, R., 2015. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Available online at: http://www.Rproject.org/. Day, B., Langlois, R., Tremblay, M., Knoppers, B.M., 2007. Canadian health measures survey: ethical, legal and social issues. Health Rep. 18 (Suppl), 37–51. Domingo, J.L., 2012. Polybrominated diphenyl ethers in food and human dietary exposure: a review of the recent scientific literature. Food Chem. Toxicol. 50, 238–249. EPA (Environmental Protection Agency), 2016. Fact Sheet: 2010/2015 PFOA Stewardship Program, https://www.epa.gov/assessing-and-managingchemicals-under-tsca/fact-sheet-20102015-pfoa-stewardship-program (Accessed 31 August 2016). Environment Canada, 2006a. Canada’s National Implementation Plan Under the Stockholm Convention on Persistent Organic Pollutants, Cat. No.: En84-39/2006E, http://publications.gc.ca/Collection/En84-39-2006E.pdf (Accessed August 31 2016). Environment Canada, 2006b. Canadian Environmental Protection Act, 1999: Ecological Screening Assessment Report on Polybrominated Diphenyl Ethers (PBDEs), https://www.ec.gc.ca/lcpe-cepa/documents/substances/pbde/sar pbde-eng.pdf (Accessed 31 August 2016). Environment Canada, 2013. Update to Canada’s National Implementation Plan Under the Stockholm Convention on Persistent Organic Pollutants, https:// www.ec.gc.ca/lcpe-cepa/default.asp?lang=En (Accessed 31 August 2016). Eskenazi, B., Fenster, L., Castorina, R., Marks, A.R., Sjödin, A., Rosas, L.G., Holland, N., Guerra, A.G., Lopez-Carillo, L., Bradman, A., 2011. A comparison of PBDE serum concentrations in Mexican and Mexican-American children living in California. Environ. Health Perspect. 119 (10), 1442–1448.

756

D.A. Haines et al. / International Journal of Hygiene and Environmental Health 220 (2017) 744–756

Ewers, U., Krause, C., Schulz, C., Wilhelm, M., 1999. Reference values and human biological monitoring values for environmental toxins. Int. Arch. Occup. Environ. Health 72, 255–260. Fréry, N., Vandentorren, S., Etchevers, A., Fillol, C., 2012. Highlights of recent studies and future plans for the French human biomonitoring (HBM) programme. Int. J. Hyg. Environ. Health 215, 127–132. Fromme, H., Tittlemier, S.A., Völkel, W., Wilhelm, M., Twardella, D., 2009. Perfluorinated compounds −Exposure assessment for the general population in western countries. Int. J. Hyg. Environ. Health 212, 239–270. Giroux, S., 2007. Canadian health measures survey: sampling strategy overview. Health Rep. 18, 31–36. HBM Commission, 2016. Reference and HBM Values, http://www. umweltbundesamt.de/en/topics/health/commissions-working-groups/ human-biomonitoring-commission/reference-hbm-values (Accessed 31 August 2016). Haines, D.A., Murray, J., 2012. Human biomonitoring of environmental chemicals—early results of the 2007–2009 Canadian Health Measures Survey for males and females. Int. J. Hyg. Environ. Health 215 (2), 133–137. Haines, D., Saravanabhavan, G., Werry, K., Khoury, C., 2016. An overview of human biomonitoring of environmental chemicals in the Canadian Health Measures Survey: 2007 to 2019. Int. J. Hyg. Environ. Health, http://dx.doi.org/10.1016/j. ijheh.2016.08.002 (in press). Haug, L.S., Thomsen, C., Becher, G., 2009. Time trends and the influence of age and gender on serum concentrations of perfluorinated compounds in archived human samples. Environ. Sci. Technol. 43 (6), 2131–2136. Health Canada, 2006. State of the Science Report for a Screening Health Assessment − Polybrominated Diphenyl Ethers (PBDEs) [Tetra-, Penta-, Hexa-, Hepta-, Octa-, Nona-, and Deca- Congeners] [Cas Nos. 40088-47-9, 32534-81-9, 36483-60-0, 68928-80-3, 32536-52-0, 63936-56-1, 1163-19-5]. Minister of Health, Ottawa, ON, http://www.hc-sc.gc.ca/ewh-semt/pubs/ contaminants/pbde/index-eng.php (Accessed 31 August 2016). Health Canada, 2009a. Total (CHOL), NRDCHMS Laboratory Technical Manual SOP#: NRD.CHMS. 2009-2.200. Health Canada, 2009b. Triglyceride (TRIG), NRDCHMS Laboratory Technical Manual SOP#: NRD.CHMS. 2009-2.360. Health Canada, 2010. Report on Human Biomonitoring of Environmental Chemicals in Canada. Minister of Health, Ottawa, ON, Canada, http://www.hcsc.gc.ca/ewh-semt/pubs/contaminants/chms-ecms/index-eng.php (Accessed 31 August 2016). Health Canada, 2013. Second Report on the Human Biomonitoring of Environmental Chemicals in Canada. Minister of Health, Ottawa, ON, http:// www.hc-sc.gc.ca/ewh-semt/pubs/contaminants/chms-ecms-cycle2/indexeng.php (Accessed 31 August 2016). Hites, R.A., 2004. Polybrominated diphenyl ethers in the environment and in people: a meta-analysis of concentrations. Environ. Sci. Technol. 38, 945–956. Hubert, M., Van der Veeken, S., 2008. Outlier detection for skewed data. J. Chemometr. 22, 235–246. IARC (International Agency for Research on Cancer), 1987. IARC monographs on the evaluation of carcinogenic risks to humans ?Supplement 7: Overall evaluations of carcinogenicity: An updating of IARC Monographs volumes 1–42. World Health Organization, Lyon. IARC (International Agency for Research on Cancer), 1999. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans −Volume 71: Re-evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide. World Health Organization, Lyon. IARC (International Agency for Research on Cancer), 2001. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans −Volume 79: Some Thyrotropic Agents. World Health Organization, Lyon. IARC (International Agency for Research on Cancer), 2016a. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans −Volume 113: 2,4-Dichlorophenoxyacetic Acid (2,4-D) and Some Organochlorine Insecticides. World Health Organization, Lyon. IARC (International Agency for Research on Cancer), 2016b. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans −Volume 107: Polychlorinated Biphenyls and Polybrominated Biphenyls. World Health Organization, Lyon. IARC (International Agency for Research on Cancer), 2016c. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans −Volume 110: Perfluorooctanoic Acid, Tetrafluoroethylene, Dichloromethane, 1,2-dichloropropane, and 1,3-propane Sultone. World Health Organization, Lyon. IARC (International Agency for Research on Cancer), 2017. List of classifications, volumes 1–117. World Health Organization, Lyon. INSPQ (Institut national de santé publique du Québec), 2016. AMAP Ring Test for Persistent Organic Pollutants in Human Serum. Centre de toxicologie du Québec, https://www.inspq.qc.ca/node/1729 (Accessed 31 August 2016). InVS (Institut de veille sanitaire), 2011. Exposition de la population franc¸aise aux substances chimiques de l’environnement. Tome 2: Polychlorobiphényles (PCB-NDL); Pesticides. Kannan, K., Corsolini, S., Falandysz, J., Fillman, G., Kumar, K.S., Loganathan, B.G., Mohd, M.A., Olivero, J., Van Wouwe, N., Yang, J.H., Aldous, K.M., 2004. Perfluorooctanesulfonate and related fluorochemicals in human blood from several countries. Environ. Sci. Technol. 38, 4489–4495. Kato, K., Wong, L.-Y., Jia, L.T., Kuklenyik, Z., Calafat, A.M., 2011. Trends in exposure to polyfluoroalkyl chemicals in the U.S. population: 1999–2008. Environ. Sci. Technol. 45, 8037–8045.

Kissa, E., 2001. Fluorinated Surfactants and Repellents. Marcel Dekkaer Inc., New York, NY. Lahti, A., Hyltoft Petersen, P., Boyd, J.C., Fraser, C.G., Jorgensen, N., 2002. Objective criteria for partitioning Gaussian-distributed reference values into subgroups. Clin. Chem. 48, 338–352. Lorber, M., 2008. Exposure of Americans to polybrominated diphenyl ethers. J. Expo. Sci. Environ. Epidemiol. 18 (1), 2–19. NRC (National Research Council), 2012. Exposure Science in The 21st Century: A Vision and a Strategy. National Academies Press, Washington, DC. Pérez-Gómez, B., Pastor-Barriuso, R., Cervantes-Amat, M., Esteban, M., Ruiz-Moraga, M., Aragonés, N., Pollán, M., Navarro, C., Calvo, E., Román, J., ˜ A., 2013. BIOAMBIENT.ES study protocol: rationale López-Abente, G., Castano, and design of a cross-sectional human biomonitoring survey in Spain. Environ. Sci. Pollut. Res. 20 (2), 1193–1202. Park, C., Hwang, M., Kim, H., Ryu, S., Lee, K., Choi, K., Paek, D., 2016. Early snapshot on exposure to environmental chemicals among Korean adults—results of the first Korean National Environmental Health Survey (2009–2011). Int. J. Hyg. Environ. Health 219 (4–5), 398–404. Patterson, D.G., Wong, L.-Y., Caudill, S.P., Dipietro, E.S., McClure, P.C., Cash, T.P., Osterloh, J.D., Pirkle, J.L., Sampson, E.J., Needham, L.L., 2009. Levels in the U.S. population of those persistent organic pollutants (2003–2004) included in the Stockholm Convention or in other long-range transboundary air pollution agreements. Environ. Sci. Technol. 43, 1211–1218. Paul, A.G., Jones, K.C., Sweetman, A.J., 2009. A first global production, emission, and environmental inventory for perfluorooctane sulfonate. Environ. Sci. Technol. 43, 386–392. Phillips, D.L., Pirke, J.L., Burse, V.W., Bernert Jr., J.T., Henderson, L.O., Needham, L.L., 1989. Chlorinated hydrocarbon levels in human serum: effects of fasting and feeding. Arch. Environ. Contam. Toxicol. 18, 495–500. Poulson, O., Holst, E., Christensen, J., 1997. Calculation and application of coverage intervals for biological reference values (technical report). Pure Appl. Chem. 69, 1601–1612. Rawn, D.F.K., Ryan, J.J., Sadler, A.R., Sun, W.-F., Haines, D., Macey, K., Van Oostdam, J., 2012. PCDD/F and PCB concentrations in sera from the canadian health measures survey (CHMS) from 2007 to 2009. Environ. Int. 47, 48–55. Saravanabhavan, G., Werry, K., Walker, M., Haines, D., Malowany, M., Khoury, C., 2016. Human biomonitoring reference values for metals and trace elements in blood and urine derived from the Canadian Health Measures Survey 2007–2013. Int. J. Hyg. Environ. Health, http://dx.doi.org/10.1016/j.ijheh.2016. 10.006 (in press). Schettgen, T., Alt, A., Esser, A., Kraus, T., 2015. Current data on the background burden to persistent organochlorine pollutants HCB, p,p -DDE as well as PCB 138, PCB 153 and PCB 180 in plasma of the general population in Germany. Int. J. Hyg. Environ. Health 218, 380–385. Schulz, C., Conrad, A., Becker, K., Kolossa-Gehring, M., Seiwert, M., Seifert, B., 2007. Twenty years of the German Environmental Survey (GerES): human biomonitoring–temporal and spatial (West Germany/East Germany) differences in population exposure. Int. J. Hyg. Environ. Health 210, 271–297. Schulz, C., Wilhelm, M., Heudorf, U., Kolossa-Gehring, M., 2012. Reprint of Update of the reference and HBM values derived by the German Human Biomonitoring Commission. Int. J. Hyg. Environ. Health 215, 150–158. Sjödin, A., Wong, L.Y., Jones, R.S., Park, A., Zhang, Y., Hodge, C., Dipietro, E., McClure, C., Turner, W., Needham, L.L., Patterson Jr., D.G., 2008. Serum concentrations of polybrominated diphenyl ethers (PBDEs) and polybrominated biphenyl (PBB) in the United States population: 2003–2004. Environ. Sci. Technol. 42 (4), 1377–1384. Solberg, H., 1987. Approved recommendation (1986) on the theory of reference values: part 1. The concept of reference values. Clin. Chim. Acta 165, 111–118. Spayd, R., Bruschi, B., Burdick, B., Dappen, G., Eikenberry, J., Esders, T., Figueras, J., Goodhue, C., LaRossa, D., Nelson, R., Rand, R., Wu, T., 1978. Multilayer film elements for clinical analysis: applications to representative chemical determinations. Clin. Chem. 24, 1343–1350. Statistics Canada, 2010. Canadian Health Measures Survey (CHMS) Data User Guide: Cycle 1. Statistics Canada, Ottawa, ON. Statistics Canada, 2013. Canadian Health Measures Survey (CHMS) Data User Guide: Cycle 2. Statistics Canada, Ottawa, ON. Stockholm Convention, 2009. Stockholm Convention on Persistent Organic Pollutants as Amended in 2009, http://chm.pops.int/TheConvention/Overview/ tabid/3351/Default.aspx. (Accessed 31 August 2016). Tukey, J.W., 1977. Exploratory Data Analysis. Addison-Wesley, Boston. Wilford, B.H., Shoeib, M., Harner, T., Zhu, J., Jones, K.C., 2005. Polybrominated diphenyl ethers in indoor dust in Ottawa, Canada: implications for sources and exposure. Environ. Sci. Technol. 39 (18), 7027–7035. Zota, A.R., Rudel, R.A., Morello-Frosch, R.A., Brody, J.G., 2008. Elevated house dust and serum concentrations of PBDEs in California: unintended consequences of furniture flammability standards? Environ. Sci. Technol. 42 (21), 8158–8164. de Vos, M.G., Huijbregts, M.A.J., van den Heuvel-Greve, M.J., Vethaak, A.D., Van de Vijver, K.I., Leonards, P.E.G., Van Leeuwen, S.P.J., De Voogt, P., Hendriks, A.J., 2008. Accumulation of perfluorooctane sulfonate (PFOS) in the food chain of the Western Scheldt estuary: comparing field measurements with kinetic modeling. Chemosphere 70, 1766–1773.