Individual and mixture associations of perfluoroalkyl substances on liver function biomarkers in the Canadian Health Measures Survey.

BACKGROUND: Perfluoroalkyl substances can disrupt hepatic metabolism and may be associated with liver function biomarkers. We examined individual and mixture associations of PFAS on liver function biomarkers in a representative sample of Canadian adults. We explored the potential for effect modification by sex and body mass index, as well as by physical activity level which may attenuate the deleterious effect of PFAS on metabolic disorders. METHODS: We analyzed data from participants aged 20-74 from the Canadian Health Measures Survey. We used linear regression to examine associations between plasma concentrations of PFOA, PFOS, PFHxS, PFNA, PFDA, and PFUDA on serum concentrations of aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and total bilirubin. We used quantile g-computation to estimate associations with a PFAS mixture for each simultaneous, one-quartile change in PFAS concentrations. RESULTS: Each doubling of PFOA, PFOS, PFHxS, or PFNA concentrations was associated with higher AST, GGT, and ALP concentrations. Each doubling of PFOA concentrations was associated with 16.5% (95%CI: 10.4, 23.0) higher GGT concentrations among adults not meeting Canada's physical activity guidelines vs. 6.6% (95%CI: -1.6, 15.5) among those meeting these guidelines. Sex and BMI also modified some associations, though to a lesser extent. We did not observe associations between ALT and PFOA (1.2% change; 95%CI: -2.5, 4.9), PFOS (2.2% change; 95%CI: -0.8, 5.3), or PFHxS (1.5% change; 95%CI: -0.4, 3.4). We also did not observe consistent associations for PFDA and PFUDA or with total bilirubin. In quantile g-computation models, each simultaneous one-quartile increase in the PFAS mixture was positively associated with AST (7.5% higher; 95%CI: 4.0, 10.4), GGT (9.7% higher; 95%CI: 1.7, 17.0), and ALP (2.8% higher; 95%CI: 0.5, 5.4). CONCLUSION: Higher plasma concentrations of PFOA, PFOS, PFHxS, and PFNA - both individually and as a mixture - were associated with higher serum concentrations of liver function biomarkers. These results contribute to emerging evidence suggesting that higher levels of physical activity appear to be protective against the hepatotoxic effects of PFOA. This work contributes to a growing body of evidence supporting the hepatotoxic effects of PFAS.

Direct LC-MS/MS and indirect GC-MS/MS methods for measuring urinary bisphenol A concentrations are comparable.

BACKGROUND: Bisphenol A (BPA) is typically measured in urine using an indirect method that involves enzymatic deconjugation and extraction. In contrast, the direct method measures free and conjugated BPA concurrently and sums them to estimate urinary BPA concentrations. Statistical comparison of total BPA results using the direct and indirect methods is necessary to accurately interpret biomonitoring data for risk assessments. OBJECTIVES: To compare urinary BPA concentrations estimated from the indirect and direct methods in duplicate first trimester urine samples collected from 1879 pregnant women from the MIREC Study. METHODS: For the indirect method, we measured urinary BPA concentrations using GC-MS/MS. For the direct method, we summed free and conjugated BPA concentrations measured using LC-MS/MS. We evaluated deviation between the two methods using the Bland-Altman analysis in the total sample and stratified (1) by specific gravity and (2) at the limit of quantification (LOQ). RESULTS: Median urinary BPA concentrations for the direct and indirect methods were 0.89 µg BPA equivalents/L and 0.81 µg/L respectively. Concentrations from the direct method were, on average, 8.6% (95% CI: 6.7%, 10.5%) higher than the indirect method in a Bland-Altman analysis. The percent differences between the two methods was 4.0% in urines with specific gravities < 1.02 (n = 1348, 72%) and 20.3% in urine with specific gravity ≥ 1.02. In values below the LOQ (n = 663, 35%), we observed smaller average percent deviation (4.8%) between the two methods but wider limits of agreement. DISCUSSION: Results from this study, based on the largest statistically rigorous comparison of the direct and indirect methods of BPA measurement, contrast previous findings reporting that the indirect method underestimates total BPA exposure. The difference in urinary BPA concentrations we observed with the indirect and direct methods is unlikely to alter the interpretation of health outcome data.

Exposure Load: Using biomonitoring data to quantify multi-chemical exposure burden in a population.

People are often concurrently exposed to numerous chemicals. Here we sought to leverage existing large biomonitoring datasets to improve our understanding of multi-chemical exposures in a population. Using nationally-representative data from the 2012-2015 Canadian Health Measures Survey (CHMS), we developed Exposure Load, a metric that counts the number of chemicals measured in people above a defined concentration threshold. We calculated Exposure Loads based on five concentration thresholds: the analytical limit of detection (LOD) and the 50th, 75th, 90th and 95th percentiles. Our analysis considered 44 analyte biomarkers representing 26 chemicals from the 2012-2015 CHMS; complete biomarker data were available for 1858 participants aged 12-79 years following multiple imputation of results that were missing due to sample loss. Chemicals may have one or more biomarkers, and for the purposes of Exposure Load calculation, participants were considered to be exposed to a chemical if at least one biomarker was above the threshold. Distributions of Exposure Loads are reported for the total population, as well as by age group, sex and smoking status. Canadians had an Exposure Load between 9 and 21 (out of 26) when considering LOD as the threshold, with the majority between 13 and 18. At higher thresholds, such as the 95th percentile, the majority of Canadians had an Exposure Load between 0 and 3, although some people had an Exposure Load of up to 15, indicating high exposures to multiple chemicals. Adolescents aged 12-19 years had significantly lower Exposure Loads than adults aged 40-79 years at all thresholds and adults aged 20-39 years at the 50th and 75th percentiles. Smokers had significantly higher Exposure Loads than nonsmokers at all thresholds except the LOD, which was expected given that tobacco smoke is a known source of certain chemicals included in our analysis. No differences in Exposure Loads were observed between males and females at any threshold. These findings broadly suggest that Canadians are concurrently exposed to many chemicals at lower concentrations and to fewer chemicals at high concentrations. They should assist in identifying vulnerable subpopulations disproportionately exposed to numerous chemicals at high concentrations. Future work will use Exposure Loads to identify prevalent chemical combinations and their link with adverse health outcomes in the Canadian population. The Exposure Load concept can be applied to other large datasets, through collaborative efforts in human biomonitoring networks, in order to further improve our understanding of multiple chemical exposures in different populations.

Exposure to tobacco smoke and validation of smoking status during pregnancy in the MIREC study.

Given that prenatal exposure to tobacco smoke can lead to increased risks of adverse health effects, having valid measures of exposure is important. In a Canadian cohort (n = 2000), maternal and infant biospecimens were analysed for cotinine. Sensitivity and specificity of self-reported active smoking status were estimated. Regression modelling was used to identify potential predictors of maternal and infant plasma cotinine in non-smoking women. During the first trimester, 60.6% of the women reported never smoking, 27.3% were former smokers, 6.1% had quit when they found out they were pregnant, 5.8% were smokers and 42% of the non-smokers reported exposure to secondhand smoke (SHS). Low detection of tobacco biomarkers in meconium limited its ability to identify exposure to SHS. The sensitivity and specificity for self-reported smoking during the 1st trimester were 85.37 and 99.45%, respectively. The lowest sensitivity was found in participants with the highest level of education and income, oldest women and those born outside Canada. Non-smoking women living in an apartment had 1.7 times higher odds of detectable plasma cotinine than those living in a single home after adjusting for other variables. Our results suggest that while self-reports are fairly accurate, they may be less so in populations with higher socio-economic status. This investigation underscores the need to consider the participant socio-economic characteristics and dwelling type when using questionnaires to estimate active and passive tobacco exposure.

Univariate predictors of maternal concentrations of environmental chemicals: The MIREC study.

BACKGROUND: The developing fetus and pregnant woman can be exposed to a variety of environmental chemicals that may adversely affect their health. Moreover, environmental exposure and risk disparities are associated with different social determinants, including socioeconomic status (SES) and demographic indicators. Our aim was to investigate whether and how maternal concentrations of a large panel of persistent and non-persistent environmental chemicals vary according to sociodemographic and lifestyle characteristics in a large pregnancy and birth cohort. METHODS: Data were analyzed from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a cohort of pregnant women (N=2001) recruited over four years (2008-2011) in 10 cities across Canada. In all, 1890 urine and 1938 blood samples from the first trimester (1st and 3rd trimester for metals) were analysed and six sociodemographic and lifestyle indicators were assessed: maternal age, household income, parity, smoking status, country of birth and pre-pregnancy body mass index (BMI). RESULTS: We found these indicators to be significantly associated with many of the chemicals measured in maternal blood and urine. Women born outside Canada had significantly higher concentrations of di-2-ethylhexyl and diethyl phthalate metabolites, higher levels of all metals except cadmium (Cd), as well as higher levels of polychlorinated biphenyls (PCBs) and legacy organochlorine pesticides (OCPs). Nulliparity was associated with higher concentrations of dialkyl phosphates (DAPs), arsenic, dimethylarsinic acid (DMAA), perfluoroalkyl substances (PFASs) and many of the persistent organic pollutants. Smokers had higher levels of bisphenol A, Cd and perfluorohexane sulfonate, while those women who had never smoked had higher levels of triclosan, DMAA, manganese and some OCPs. CONCLUSION: Our results demonstrated that inequitable distribution of exposure to chemicals among populations within a country can occur. Sociodemographic and lifestyle factors are an important component of a thorough risk assessment as they can impact the degree of exposure and may modify the individual's susceptibility to potential health effects due to differences in lifestyle, cultural diets, and aging.

Arsenic levels among pregnant women and newborns in Canada: Results from the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort.

Arsenic is a common environmental contaminant from both naturally-occurring and anthropomorphic sources and human exposure can be detected in various tissues. Its toxicity depends on many factors including the chemical form, valence state, bioavailability, metabolism and detoxification within the human body. Of paramount concern, particularly with respect to health effects in children, is the timing of exposure as the prenatal and early life periods are more susceptible to toxic effects. The Maternal-Infant Research on Environmental Chemicals (MIREC) cohort was established to obtain national-level biomonitoring data for approximately 2,000 pregnant women and their infants between 2008 and 2011 from 10 Canadian cities. We measured total arsenic (As) in 1st and 3rd trimester maternal blood, umbilical cord blood, and infant meconium and speciated arsenic in 1st trimester maternal urine. Most pregnant women had detectable levels of total arsenic in blood (92.5% and 87.3%, respectively, for 1st and 3rd trimester); median difference between 1st and 3rd trimester was 0.1124µg/L (p<0.0001), but paired samples were moderately correlated (Spearman r=0.41, p<0.0001). Most samples were below the LOD for umbilical cord blood (50.9%) and meconium (93.9%). In 1st trimester urine samples, a high percentage (>50%) of arsenic species (arsenous acid (As-III), arsenic acid (As-V), monomethylarsonic acid (MMA), and arsenobetaine (AsB)) were also below the limit of detection, except dimethylarsinic acid (DMA). DMA (>85% detected) ranged from

Maternal and fetal exposure to cadmium, lead, manganese and mercury: The MIREC study.

Given the susceptibility of the fetus to toxicants, it is important to estimate their exposure. Approximately 2000 pregnant women were recruited in 2008-2011 from 10 cities across Canada. Cd, Pb, Mn and total Hg were measured in maternal blood from the 1st and 3rd trimesters, umbilical cord blood, and infant meconium. Nutrient intakes of vitamin D, iron, and calcium (Ca) were assessed using a food frequency questionnaire and a dietary supplement questionnaire. Median concentrations in 1st trimester maternal blood (n = 1938) were 0.20, 8.79 and 0.70 µg/L for Cd, Mn and Hg, respectively, and 0.60 µg/dL for Pb. While the median difference between the paired 1st and 3rd trimester concentrations of Cd was 0, there was a significant decrease in Pb (0.04 µg/dL) and Hg (0.12 µg/L) and an increase in Mn (3.30 µg/L) concentrations over the course of the pregnancy. While Cd was rarely detected in cord blood (19%) or meconium (3%), median Pb (0.77 µg/dL), Mn (31.87 µg/L) and Hg (0.80 µg/L) concentrations in cord blood were significantly higher than in maternal blood. Significant negative associations were observed between estimated Ca intake and maternal Cd, Pb, Mn and Hg, as well as cord blood Pb. Vitamin D intake was associated with lower maternal Cd, Pb, and Mn as well as Pb in cord blood. Even at current metal exposure levels, increasing dietary Ca and vitamin D intake during pregnancy may be associated with lower maternal blood Pb and Cd concentrations and lower Pb in cord blood.

Concentrations of persistent organic pollutants in maternal and cord blood from the maternal-infant research on environmental chemicals (MIREC) cohort study.

BACKGROUND: Pregnant women are an especially important population to monitor for environmental exposures given the vulnerability of the developing fetus. During pregnancy and lactation chemical body burdens may change due to the significant physiological changes that occur. Developmental exposures to some persistent organic pollutants (POPs) have been linked with adverse health outcomes. METHODS: First trimester maternal and cord blood plasma concentrations of several POPs including polychlorinated biphenyls (PCBs), organochlorine pesticides (OCs), polybrominated diphenyl ethers (PBDE)s and perfluoroalkyl substances (PFASs) were measured in samples from 1983 pregnant women enrolled in the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort. Predictors of exposure were also identified. RESULTS: In maternal plasma, there was >90 % detection for the perfluoroalkyl substances (PFASs) perfluorooctanoic acid (PFOA), perfluoroctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), and dichlorodiphenyldichloroethylene (DDE), oxychlordane and PCB 138 and 153. Cord blood plasma had much lower detection rates with low or very limited detection for most PCBs and PBDEs. The PFASs were the most frequently detected (23-64 %) chemical class in cord plasma. In a subset of 1st and 3rd trimester paired samples, PFAS concentrations were found to be strongly correlated and had ICCs ranging from 0.64 (PFOA) to 0.83 (PFHxS). The cord:maternal plasma concentration ratios ranged from 0.14 (PFOS) to 0.87 (oxychlordane, lipid adjusted). Similar to other studies, we found parity, maternal age, income, education, smoking status, pre-pregnancy BMI and fish consumption to be significant predictors for most chemicals. Those participants who were foreign-born had significantly higher concentrations of organochlorinated pesticides and PCBs. CONCLUSIONS: In the MIREC study, multiple chemical contaminants were quantified in the plasma of pregnant women. In cord plasma PFOA had the highest detection rate. However, compared to other Canadian and international population studies, the MIREC participants had lower contaminant concentrations of these substances.

Assessing determinants of maternal blood concentrations for persistent organic pollutants and metals in the eastern and western Canadian Arctic.

Aboriginal peoples in the Canadian Arctic are exposed to persistent organic pollutants (POPs) and metals mainly through their consumption of a traditional diet of wildlife items. Recent studies indicate that many human chemical levels have decreased in the north, likely due to a combination of reduced global chemical emissions, dietary shifts, and risk mitigation efforts by local health authorities. Body burdens for chemicals in mothers can be further offset by breastfeeding, parity, and other maternal characteristics. We have assessed the impact of several dietary and maternal covariates following a decade of awareness of the contaminant issue in northern Canada, by performing multiple stepwise linear regression analyses from blood concentrations and demographic variables for 176 mothers recruited from Nunavut and the Northwest Territories during the period 2005-2007. A significant aboriginal group effect was observed for the modeled chemicals, except for lead and cadmium, after adjusting for covariates. Further, blood concentrations for POPs and metals were significantly associated with at least one covariate of older age, fewer months spent breastfeeding, more frequent eating of traditional foods, or smoking during pregnancy. Cadmium had the highest explained variance (72.5%) from just two significant covariates (current smoking status and parity). Although Inuit participants from the Northwest Territories consumed more traditional foods in general, Inuit participants from coastal communities in Nunavut continued to demonstrate higher adjusted blood concentrations for POPs and metals examined here. While this is due in part to a higher prevalence of marine mammals in the eastern Arctic diet, it is possible that other aboriginal group effects unrelated to diet may also contribute to elevated chemical body burdens in Canadian Arctic populations.

Persistent organic pollutants (POPs) and metals in primiparous women: a comparison from Canada and Mexico.

Under the North American Commission for Environmental Cooperation (CEC) and its Sound Management of Chemicals (SMOC) program, a tri-national human contaminant monitoring initiative was completed to provide baseline exposure information for several environmental contaminants in Canada, Mexico and the United States (U.S). Blood samples were collected from primiparous women in Canada and Mexico, and were analysed for a suite of environmental contaminants including polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene(p,p'-DDE),beta-hexachlorocyclohexane (ß-HCH), mercury and lead. A multiple stepwise linear regression analysis was conducted using data from Canadian and Mexican primiparous mothers, adjusting for ethnicity group, age, pre-pregnancy BMI, years at current city and ever-smoking status. Concentrations of p,p'-DDE, ß-HCH, and lead were found to be higher among Mexican participants; however, concentrations of most PCBs among Mexican participants were similar to Canadian primiparous women after adjusting for covariates. Concentrations of total mercury were generally higher among Mexican primiparous women although this difference was smaller as age increased. This initial dataset can be used to determine priorities for future activities and to track progress in the management of the selected chemicals, both domestically and on a broader cooperative basis within North America.

Comparing plasma concentrations of persistent organic pollutants and metals in primiparous women from northern and southern Canada.

The exposure of Aboriginal peoples in the Canadian Arctic to persistent organic pollutants (POPs) and metals through the consumption of traditional food items is well recognized; however, less information is available for Canadian immigrants. The direct comparison of blood chemical concentrations for expectant primiparous women sampled in the Inuvik and Baffin regions of the Canadian Arctic, as well as Canadian- and foreign-born women from five southern Canadian centers (Halifax, Vancouver, Hamilton, Ottawa, and Calgary), provides relative exposure information for samples of northern and southern mothers in Canada. Based on our analyses, Canadian mothers are exposed to a similar suite of contaminants; however, Inuit first birth mothers residing in the Canadian Arctic had higher age-adjusted geometric mean concentrations for several legacy POPs regulated under the Stockholm Convention, along with lead and total mercury. Significant differences in exposure were observed for Inuit mothers from Baffin who tended to demonstrate higher blood concentrations of POPs and total mercury compared with Inuit mothers from Inuvik. Conversely, northern mothers showed a significantly lower age-adjusted geometric mean concentration for a polybrominated diphenyl ether (PBDE-153) compared to southern mothers. Furthermore, southern Canadian mothers born outside of Canada showed the highest individual concentrations measured in the study: 1700 µg/kg lipids for p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and 990 µg/kg lipids for ß-hexachlorocyclohexane (ß-HCH). Data from Cycle 1 (2007-2009) of the nationally-representative Canadian Health Measures Survey (CHMS) places these results in a national biomonitoring context and affirms that foreign-born women of child-bearing age experience higher exposures to many POPs and metals than their Canadian-born counterparts in the general population.

Cohort profile: the maternal-infant research on environmental chemicals research platform.

BACKGROUND: The Maternal-Infant Research on Environmental Chemicals (MIREC) Study was established to obtain Canadian biomonitoring data for pregnant women and their infants, and to examine potential adverse health effects of prenatal exposure to priority environmental chemicals on pregnancy and infant health. METHODS: Women were recruited during the first trimester from 10 sites across Canada and were followed through delivery. Questionnaires were administered during pregnancy and post-delivery to collect information on demographics, occupation, life style, medical history, environmental exposures and diet. Information on the pregnancy and the infant was abstracted from medical charts. Maternal blood, urine, hair and breast milk, as well as cord blood and infant meconium, were collected and analysed for an extensive list of environmental biomarkers and nutrients. Additional biospecimens were stored in the study's Biobank. The MIREC Research Platform encompasses the main cohort study, the Biobank and follow-up studies. RESULTS: Of the 8716 women approached at early prenatal clinics, 5108 were eligible and 2001 agreed to participate (39%). MIREC participants tended to smoke less (5.9% vs. 10.5%), be older (mean 32.2 vs. 29.4 years) and have a higher education (62.3% vs. 35.1% with a university degree) than women giving birth in Canada. CONCLUSIONS: The MIREC Study, while smaller in number of participants than several of the international cohort studies, has one of the most comprehensive datasets on prenatal exposure to multiple environmental chemicals. The biomonitoring data and biological specimen bank will make this research platform a significant resource for examining potential adverse health effects of prenatal exposure to environmental chemicals.

Circulating metals and persistent organic pollutant concentrations in Canadian and non-Canadian born primiparous women from five Canadian centres: results of a pilot biomonitoring study.

The developing foetus is thought to be at increased risk from exposure to environmental contaminants; however, developmental exposure data is notably lacking for many contaminants. Moreover, potential regional differences or effect of place of birth on residue levels measured in pregnant women is also unknown. Therefore, as part of a multinational biomonitoring study, 125 primiparous pregnant Canadian women were recruited from five Canadian centres (Vancouver, Calgary, Hamilton, Ottawa, and Halifax). Metals in whole blood and persistent organic pollutants (POPs) in plasma were measured by inductively coupled plasma mass spectrometry (ICPMS) and gas chromatography-mass spectrometry (GCMS), respectively. Of the 125 women recruited to this study, complete data sets were available for 123 of which 103 were Canadian born. Data were analysed by analysis of covariance and linear mixed models using age and body mass index as covariates. The metals cadmium (Cd), cobalt (Co), lead (Pb), nickel (Ni), selenium (Se), and total mercury (Hg) were detected in more than 93% of the samples tested. ß-Hexachlorohexane (ß-HCH), oxychlordane, trans-nonachlor, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), polybrominated diphenyl ether (PBDE) congeners (PBDE-153, PBDE-47), polychlorinated biphenyl (PCB) congeners (PCB-138, -153, and -180), and the dioxin-like PCB congener PCB-118 were quantified in greater than 70% of the samples tested. Significant differences in the concentrations of Cd, Ni, PCB-153, and p,p'-DDE were found between the centres studied. Furthermore, foreign-born pregnant women had significantly higher concentrations of Cd, ß-HCH, PBDE-47, PCB-138, -153, -180, and p,p'-DDE compared to Canadian born pregnant women. Taken together, the data suggest that there are potential regional differences in contaminant body burden and place of birth may also contribute to differences in maternal residue concentrations.