Increased expression of individual genes in whole blood is associated with late-stage lung cancer at and close to diagnosis.

Lung cancer (LC) mortality rates are still increasing globally. As survival is linked to stage, there is a need to identify markers for earlier LC diagnosis and individualized treatment. The whole blood transcriptome of LC patients represents a source of potential LC biomarkers. We compared expression of > 60,000 genes in whole blood specimens taken from LC cases at diagnosis (n = 128) and controls (n = 62) using genome-wide RNA sequencing, and identified 14 candidate genes associated with LC. High expression of ANXA3, ARG1 and HP was strongly associated with lower survival in late-stage LC cases (hazard ratios (HRs) = 2.81, 2.16 and 2.54, respectively). We validated these markers in two independent population-based studies with pre-diagnostic whole blood specimens taken up to eight years prior to LC diagnosis (n = 163 cases, 184 matched controls). ANXA3 and ARG1 expression was strongly associated with LC in these specimens, especially with late-stage LC within two years of diagnosis (odds ratios (ORs) = 3.47 and 5.00, respectively). Additionally, blood CD4 T cells, NK cells and neutrophils were associated with LC at diagnosis and improved LC discriminative ability beyond candidate genes. Our results indicate that in whole blood, increased expression levels of ANXA3, ARG1 and HP are diagnostic and prognostic markers of late-stage LC.

Increased levels of microRNA-320 in blood serum and plasma is associated with imminent and advanced lung cancer.

Lung cancer (LC) incidence is increasing globally and altered levels of microRNAs (miRNAs) in blood may contribute to identification of individuals with LC. We identified miRNAs differentially expressed in peripheral blood at LC diagnosis and evaluated, in pre-diagnostic blood specimens, how long before diagnosis expression changes in such candidate miRNAs could be detected. We identified upregulated candidate miRNAs in plasma specimens from a hospital-based study sample of 128 patients with confirmed LC and 62 individuals with suspected but confirmed negative LC (FalsePos). We then evaluated the expression of candidate miRNAs in pre-diagnostic plasma or serum specimens of 360 future LC cases and 375 matched controls. There were 1663 miRNAs detected in diagnostic specimens, nine of which met our criteria for candidate miRNAs. Higher expression of three candidates, miR-320b, 320c, and 320d, was associated with poor survival, independent of LC stage and subtype. Moreover, miR-320c and miR-320d expression was higher in pre-diagnostic specimens collected within 2 years of LC diagnosis. Our results indicated that elevated levels of miR-320c and miR-320d may be early indications of imminent and advanced LC.

Pan-cancer analysis of pre-diagnostic blood metabolite concentrations in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations. METHODS: We analysed targeted metabolomics data available for 5828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data-shared lasso penalty. RESULTS: Out of the 50 studied metabolites, (i) six were inversely associated with the risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2, and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine, and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk. CONCLUSIONS: These results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types.

Plasma concentrations of persistent organic pollutants and pancreatic cancer risk.

BACKGROUND: Findings and limitations of previous studies on persistent organic pollutants (POPs) and pancreatic cancer risk support conducting further research in prospective cohorts. METHODS: We conducted a prospective case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants were 513 pancreatic cancer cases and 1020 matched controls. Concentrations of 22 POPs were measured in plasma collected at baseline. RESULTS: Some associations were observed at higher concentrations of p, p'-DDT, trans-nonachlor, ß-hexachlorocyclohexane and the sum of six organochlorine pesticides and of 16 POPs. The odds ratio (OR) for the upper quartile of trans-nonachlor was 1.55 (95% confidence interval 1.06-2.26; P for trend = 0.025). Associations were stronger in the groups predefined as most valid (participants having fasted >6 h, with microscopic diagnostic confirmation, normal weight, and never smokers), and as most relevant (follow-up ≥10 years). Among participants having fasted >6 h, the ORs were relevant for 10 of 11 exposures. Higher ORs were also observed among cases with microscopic confirmation than in cases with a clinical diagnosis, and among normal-weight participants than in the rest of participants. Among participants with a follow-up ≥10 years, estimates were higher than in participants with a shorter follow-up (for trans-nonachlor: OR = 2.14, 1.01 to 4.53, P for trend = 0.035). Overall, trans-nonachlor, three PCBs and the two sums of POPs were the exposures most clearly associated with pancreatic cancer risk. CONCLUSIONS: Individually or in combination, most of the 22 POPs analysed did not or only moderately increased the risk of pancreatic cancer.

Systemic inflammation markers and cancer incidence in the UK Biobank.

Systemic inflammation markers have been linked to increased cancer risk and mortality in a number of studies. However, few studies have estimated pre-diagnostic associations of systemic inflammation markers and cancer risk. Such markers could serve as biomarkers of cancer risk and aid in earlier identification of the disease. This study estimated associations between pre-diagnostic systemic inflammation markers and cancer risk in the prospective UK Biobank cohort of approximately 440,000 participants recruited between 2006 and 2010. We assessed associations between four immune-related markers based on blood cell counts: systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and risk for 17 cancer sites by estimating hazard ratios (HR) using flexible parametric survival models. We observed positive associations with risk for seven out of 17 cancers with SII, NLR, PLR, and negative associations with LMR. The strongest associations were observed for SII for colorectal and lung cancer risk, with associations increasing in magnitude for cases diagnosed within one year of recruitment. For instance, the HR for colorectal cancer per standard deviation increment in SII was estimated at 1.09 (95% CI 1.02-1.16) in blood drawn five years prior to diagnosis and 1.50 (95% CI 1.24-1.80) in blood drawn one month prior to diagnosis. We observed associations between systemic inflammation markers and risk for several cancers. The increase in risk the last year prior to diagnosis may reflect a systemic immune response to an already present, yet clinically undetected cancer. Blood cell ratios could serve as biomarkers of cancer incidence risk with potential for early identification of disease in the last year prior to clinical diagnosis.

Time trends of perfluoroalkyl substances in blood in 30-year old Norwegian men and women in the period 1986-2007.

Biomonitoring studies are helpful tools and can increase our knowledge on time trends in human blood concentrations of PFASs: how they relate to emission trends and the potential prenatal exposure for future generations. In this study, serum was sampled in cross-sections of men and women who were 30 years old in each of the years 1986, 1994, 2001, and 2007 in Northern Norway and analyzed for 23 PFASs. Differences in serum concentrations across sampling years were investigated graphically and with significance testing and compared with those observed in our previous longitudinal study using repeated individual measurements in older men in the same years. The results demonstrate overall increasing blood burdens of PFASs in men and women in reproductively active ages during 1986-2001 and decreases until 2007. However, longer chained PFASs were still increasing in 2007 indicating divergent time trends between the different PFASs, underlining the importance of continued biomonitoring. Comparisons between 30-year-old men and older men within the same population demonstrated variation in time trends in the exact same years, underlining that biomonitoring studies must regard historic exposures and birth cohort effects.

Methodological issues in a prospective study on plasma concentrations of persistent organic pollutants and pancreatic cancer risk within the EPIC cohort.

BACKGROUND: The use of biomarkers of environmental exposure to explore new risk factors for pancreatic cancer presents clinical, logistic, and methodological challenges that are also relevant in research on other complex diseases. OBJECTIVES: First, to summarize the main design features of a prospective case-control study -nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort- on plasma concentrations of persistent organic pollutants (POPs) and pancreatic cancer risk. And second, to assess the main methodological challenges posed by associations among characteristics and habits of study participants, fasting status, time from blood draw to cancer diagnosis, disease progression bias, basis of cancer diagnosis, and plasma concentrations of lipids and POPs. Results from etiologic analyses on POPs and pancreatic cancer risk, and other analyses, will be reported in future articles. METHODS: Study subjects were 1533 participants (513 cases and 1020 controls matched by study centre, sex, age at blood collection, date and time of blood collection, and fasting status) enrolled between 1992 and 2000. Plasma concentrations of 22 POPs were measured by gas chromatography - triple quadrupole mass spectrometry (GC-MS/MS). To estimate the magnitude of the associations we calculated multivariate-adjusted odds ratios by unconditional logistic regression, and adjusted geometric means by General Linear Regression Models. RESULTS: There were differences among countries in subjects' characteristics (as age, gender, smoking, lipid and POP concentrations), and in study characteristics (as time from blood collection to index date, year of last follow-up, length of follow-up, basis of cancer diagnosis, and fasting status). Adjusting for centre and time of blood collection, no factors were significantly associated with fasting status. Plasma concentrations of lipids were related to age, body mass index, fasting, country, and smoking. We detected and quantified 16 of the 22 POPs in more than 90% of individuals. All 22 POPs were detected in some participants, and the smallest number of POPs detected in one person was 15 (median, 19) with few differences by country. The highest concentrations were found for p,p'-DDE, PCBs 153 and 180 (median concentration: 3371, 1023, and 810 pg/mL, respectively). We assessed the possible occurrence of disease progression bias (DPB) in eight situations defined by lipid and POP measurements, on one hand, and by four factors: interval from blood draw to index date, tumour subsite, tumour stage, and grade of differentiation, on the other. In seven of the eight situations results supported the absence of DPB. CONCLUSIONS: The coexistence of differences across study centres in some design features and participant characteristics is of relevance to other multicentre studies. Relationships among subjects' characteristics and among such characteristics and design features may play important roles in the forthcoming analyses on the association between plasma concentrations of POPs and pancreatic cancer risk.

DNA methylation and associated gene expression in blood prior to lung cancer diagnosis in the Norwegian Women and Cancer cohort.

The majority of lung cancer is caused by tobacco smoking, and lung cancer-relevant epigenetic markers have been identified in relation to smoking exposure. Still, smoking-related markers appear to mediate little of the effect of smoking on lung cancer. Thus in order to identify disease-relevant markers and enhance our understanding of pathways, a wide search is warranted. Through an epigenome-wide search within a case-control study (131 cases, 129 controls) nested in a Norwegian prospective cohort of women, we found 25 CpG sites associated with lung cancer. Twenty-three were classified as associated with smoking (LC-AwS), and two were classified as unassociated with smoking (LC-non-AwS), as they remained associated with lung cancer after stringent adjustment for smoking exposure using the comprehensive smoking index (CSI): cg10151248 (PC, CSI-adjusted odds ratio (OR) = 0.34 [0.23-0.52] per standard deviation change in methylation) and cg13482620 (B3GNTL1, CSI-adjusted OR = 0.33 [0.22-0.50]). Analysis among never smokers and a cohort of smoking-discordant twins confirmed the classification of the two LC-non-AwS CpG sites. Gene expression profiles demonstrated that the LC-AwS CpG sites had different enriched pathways than LC-non-AwS sites. In conclusion, using blood-derived DNA methylation and gene expression profiles from a prospective lung cancer case-control study in women, we identified 25 CpG lung cancer markers prior to diagnosis, two of which were LC-non-AwS markers and related to distinct pathways.

Predicting human plasma concentrations of persistent organic pollutants from dietary intake and socio-demographic information in the Norwegian Women and Cancer study.

BACKGROUND: Concentrations of persistent organic pollutants (POPs) in humans are influenced by a large number of factors including birth year, reproductive history and diet. Accordingly, information on dietary habits and socio-demographic variables may predict plasma concentrations of POPs, thus enabling studies on health effects in large epidemiological studies, without performing time consuming and expensive chemical analyses on entire cohorts. AIMS: To develop and evaluate statistical models for predicting concentrations of POPs in participants of the Norwegian Women and Cancer (NOWAC) study, using questionnaire information and measured plasma POP concentrations. MATERIALS AND METHODS: Information on estimated dietary intakes and socio-demographic variables from four different questionnaires (in 1991, 1994, 2004 and 2005) were obtained from participants in the NOWAC study. We measured POP concentrations in a total of 367 blood samples from 2005 and built multivariable linear regression models for p,p'-DDE, PCB-118, -138, -153, -180 and summed PCB concentrations in one subsample (N = 259) and evaluated the models in another subsample (N = 108). Measured and predicted values were compared using correlation coefficients and inter-method agreement was evaluated using weighted Cohen's κ for tertile categorization. RESULTS: Median POP concentrations in the population ranged from 13 ng/g lipid to 162 ng/g lipid (lowest for PCB-118 and highest for p,p'-DDE). Common predictors for all POPs were birth year, breastfeeding and the weight-related variables (BMI or weight change), whereas influential dietary variables differed and were of varying importance. The predicted plasma concentrations were significantly correlated with the measured values (rs = 0.24, 0.33, 0.41, 0.50, 0.56, and 0.54 for p,p'-DDE, PCB-118, -138, 153, -180 and summed PCBs, respectively). Tertiles of predicted plasma concentrations displayed significant, but varying agreement with measured concentrations (Weighted Cohen's κ = 0.19, 0.22, 0.33, 0.42, 0.45, and 0.50 respectively). CONCLUSION: Predicted plasma concentrations of certain PCBs showed good precision (Kw > 0.4) when compared to measured concentrations. Thus, the models can be used to classify NOWAC participants into high, medium and low PCB exposure groups.

The impacts of emission trends of POPs on human concentration dynamics: Lessons learned from a longitudinal study in Norway (1979-2007).

BACKGROUND: In this short communication, our focus is on the relationship between human concentrations of select persistent organic pollutants (POPs) and environmental emissions. It is based on a longitudinal study (1979-2007) conducted in Norway. OBJECTIVES: Our aim was to extract general insights from observed and predicted temporal trends in human concentrations of 49 POPs to assist in the design and interpretation of future monitoring studies. DISCUSSION: Despite considerable decline for polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) since 1986, the sum of the targeted POPs increased from 1979 until 2001, with per- and polyfluorinated alkyl substances (PFASs) dominating recent blood burden measurements. Specifically, the time trends in serum concentrations of POPs, exemplified by PCB-153, 1,1'-(2,2,2-Trichloroethane-1,1-diyl)bis(4-chlorobenzene) (DDT) and perfluorooctane sulfonic acid (PFOS), resembled the trends in available data on their emissions, production or use. These observations suggest that interpretations of human biomonitoring data on persistent compounds must consider historic emissions, which likely vary spatially across the globe. Based on the different temporal trends observed across POP groups, it is evident that generalizations regarding temporal aspects have limitations. CONCLUSION: The discussion herein underscores the importance of understanding temporal variations in environmental emissions when designing and interpreting human biomonitoring studies.

Persistent Organic Pollutants and the Association with Maternal and Infant Thyroid Homeostasis: A Multipollutant Assessment.

BACKGROUND: Disruption of thyroid homeostasis has been indicated in human studies targeting effects of persistent organic pollutants (POPs). Influence on the maternal thyroid system by POPs is of special interest during pregnancy because such effects could impair infant thyroid homeostasis. OBJECTIVES: We investigated the association between POPs and thyroid-stimulating hormone (TSH) and thyroid hormones (THs) in mother and child pairs from the Northern Norway Mother-and-Child Contaminant Cohort Study (MISA). METHODS: Nineteen POPs and 10 thyroid parameters were analyzed in serum from 391 pregnant women in their second trimester. In addition, TSH concentrations in heel-prick samples from the infants were analyzed by the Norwegian Newborn Screening program. Association studies with a multipollutant approach were performed using multivariate analyses; partial least squares (PLS) regression, hierarchical clustering, and principal component analysis (PCA). RESULTS: Several POPs were significantly associated with TSH and THs: a) PFOS was positively associated with TSH; b) PCBs, HCB, and nonachlors were inversely associated with T3, T4, and FT4; and, c) PFDA and PFUnDA were inversely associated with T3 and FT3. After mutual adjustments for the other contaminants, only PFDA and PFUnDA remained significantly associated with T3 and FT3, respectively. Infants born to mothers within the highest TSH quartile had 10% higher mean concentrations of TSH compared with children born to mothers in the lowest TSH quartile. CONCLUSION: The present results suggest that background exposures to POPs can alter maternal thyroid homeostasis. This research contributes to the understanding of multipollutant exposures using multivariate statistical approaches and highlights the complexity of investigating environmental concentrations and mixtures in regard to maternal and infant thyroid function. Citation: Berg V, Nøst TH, Pettersen RD, Hansen S, Veyhe AS, Jorde R, Odland JØ, Sandanger TM. 2017. Persistent organic pollutants and the association with maternal and infant thyroid homeostasis: a multipollutant assessment. Environ Health Perspect 125:127-133; http://dx.doi.org/10.1289/EHP152.

Levels and trends of contaminants in humans of the Arctic.

The Arctic Monitoring and Assessment Programme (AMAP) is one of the six working groups established under the Arctic Council. AMAP is tasked with monitoring the levels of contaminants present in the Arctic environment and people as well as assessing their effects on a continuous basis, and reporting these results regularly. Most of the presented data have been collected over the last 20 years and are from all eight Arctic countries. Levels of contaminants appear to be declining in some of the monitored Arctic populations, but it is not consistent across the Arctic. Most Arctic populations continue to experience elevated levels of these contaminants compared to other populations monitored globally. There are certain contaminants, such as perfluorinated compounds and polybrominated diphenyl ethers, which are still increasing in Arctic populations. These contaminants require more investigation to find out the predominant and important sources of exposure, and whether they are being transported to the Arctic through long-range transport in the environment.

Estimating Time-Varying PCB Exposures Using Person-Specific Predictions to Supplement Measured Values: A Comparison of Observed and Predicted Values in Two Cohorts of Norwegian Women.

BACKGROUND: Studies on the health effects of polychlorinated biphenyls (PCBs) call for an understanding of past and present human exposure. Time-resolved mechanistic models may supplement information on concentrations in individuals obtained from measurements and/or statistical approaches if they can be shown to reproduce empirical data. OBJECTIVES: Here, we evaluated the capability of one such mechanistic model to reproduce measured PCB concentrations in individual Norwegian women. We also assessed individual life-course concentrations. METHODS: Concentrations of four PCB congeners in pregnant (n = 310, sampled in 2007-2009) and postmenopausal (n = 244, 2005) women were compared with person-specific predictions obtained using CoZMoMAN, an emission-based environmental fate and human food-chain bioaccumulation model. Person-specific predictions were also made using statistical regression models including dietary and lifestyle variables and concentrations. RESULTS: CoZMoMAN accurately reproduced medians and ranges of measured concentrations in the two study groups. Furthermore, rank correlations between measurements and predictions from both CoZMoMAN and regression analyses were strong (Spearman's r > 0.67). Precision in quartile assignments from predictions was strong overall as evaluated by weighted Cohen's kappa (> 0.6). Simulations indicated large inter-individual differences in concentrations experienced in the past. CONCLUSIONS: The mechanistic model reproduced all measurements of PCB concentrations within a factor of 10, and subject ranking and quartile assignments were overall largely consistent, although they were weak within each study group. Contamination histories for individuals predicted by CoZMoMAN revealed variation between study subjects, particularly in the timing of peak concentrations. Mechanistic models can provide individual PCB exposure metrics that could serve as valuable supplements to measurements.

Combining plasma measurements and mechanistic modeling to explore the effect of POPs on type 2 diabetes mellitus in Norwegian women.

The number of studies on persistent organic pollutants (POPs) and type 2 diabetes mellitus (T2DM) is growing steadily. Although concentrations of many POPs in humans have decreased substantially, only some studies consider temporal and inter-individual changes in POP concentrations when assessing exposure. Here we combined plasma measurements with mechanistic modeling to generate complementary exposure measures to our single blood draw after disease diagnosis. Blood was collected between 2003-2006 from 106 subjects with T2DM and 106 age-matched controls, and POP concentrations were compared after adjustment for relevant risk factors and multiple testing. Area under the curve (AUC) of PCB-153 from birth until age 18, representing early-life exposure, and AUC from birth until time of diagnosis were generated as well as examples of life-time exposure trajectories using a mechanistic exposure model. The rank sum of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs, OR=16.9 (95% CI: 3.05-93.6)) as well as ß-hexachlorocyclohexane (ß-HCH, OR=203.8 (95% CI: 11.5-3620)) and 1, 1-dichloro-2,2-bis(p-chlorophenyl) ethylene (p,p'-DDE, OR=11.3 (95% CI: 2.55-49.9)) were associated with T2DM. Neither of the AUCs reflecting early life exposure and total life-time exposure at the time of diagnosis were associated with the disease. The predicted life course trajectories display clear differences within and between individuals in the past and suggest that a single blood draw provide limited information on POP exposure earlier in life. The predicted AUCs for PCB-153 did not support the positive association between T2DM and measured blood concentration of certain POPs. This may suggest that the model is either too simplistic and/or that strength of the association may vary through life and with time to/past diagnosis.

Assessing the relationship between perfluoroalkyl substances, thyroid hormones and binding proteins in pregnant women; a longitudinal mixed effects approach.

The mechanisms involved in thyroid homeostasis are complex, and perfluoroalkyl substances (PFASs) have been indicated to interfere at several levels in this endocrine system. Disruption of the maternal thyroid homeostasis during early pregnancy is of particular concern, where subclinical changes in maternal thyroid hormones (THs) may affect embryonic and foetal development. The present study investigated associations between THs, thyroid binding proteins (TH-BPs) and PFAS concentrations in pregnant women from Northern Norway. Women participating in The Northern Norway Mother-and-Child contaminant Cohort Study (MISA) donated a blood sample at three visits related to their pregnancy and postpartum period (during the second trimester, 3 days and 6 weeks after delivery) in the period 2007-2009. Participants were assigned to quartiles according to PFAS concentrations during the second trimester and mixed effects linear models were used to investigate potential associations between PFASs and repeated measurements of THs, TH-BPs, thyroxin binding capacity and thyroid peroxidase antibodies (anti-TPOs). Women within the highest perfluorooctane sulfonate (PFOS) quartile had 24% higher mean concentrations of thyroid stimulating hormone (TSH) compared to the first quartile at all sampling points. Women within the highest quartiles of perfluorodecanoate (PFDA) had 4% lower mean concentrations of triiodothyronine (T3) and women within the highest quartile of perfluoroundecanoate (PFUnDA) had 3% lower mean concentrations of free triiodothyronine (FT3). Further, the difference in concentrations and the changes between three time points were the same for the PFAS quartiles. Thyroxin binding capacity was associated with all the THs and TH-BPs, and was selected as a holistic adjustment for individual changes in TH homeostasis during pregnancy. Finally, adjusting for maternal iodine status did not influence the model predictions. Findings in the present study suggest modifications of TH homeostasis by PFASs in a background exposed maternal population. The variation in levels of THs between PFAS quartiles was within normal reference ranges and may not be of clinical significance in the pregnant woman. However, subtle individual changes in maternal THs may have significant consequences for foetal health.

Maternal serum concentrations of per- and polyfluoroalkyl substances and their predictors in years with reduced production and use.

Determining maternal concentrations of per- and polyfluoroalkyl substances (PFASs) and the relative impact of various demographic and dietary predictors is important for assessing fetal exposure and for developing proper lifestyle advisories for pregnant women. This study was conducted to investigate maternal PFAS concentrations and their predictors in years when the production and use of several PFASs declined, and to assess the relative importance of significant predictors. Blood from 391 pregnant women participating in The Northern Norway Mother-and-Child Contaminant Cohort Study (MISA) was collected in the period 2007-2009 and serum analyses of 26 PFASs were conducted. Associations between PFAS concentrations, sampling date, and demographic and dietary variables were evaluated by multivariate analyses and linear models including relevant covariates. Parity was the strongest significant predictor for all the investigated PFASs, and nulliparous women had higher concentrations compared to multiparous women (10 ng/mL versus 4.5 ng/mL in median PFOS, respectively). Serum concentrations of PFOS and PFOA of women recruited day 1-100 were 25% and 26% higher, respectively, compared to those women recruited in the last 167 days of the study (day 601-867), and the concentrations of PFNA, PFDA and PFUnDA increased with age. Dietary predictors explained 0-17% of the variation in concentrations for the different PFASs. Significantly elevated concentrations of PFOS, PFNA, PFDA and PFUnDA were found among high consumers of marine food. The concentrations of PFHxS, PFHpS and PFNA were also increased in high consumers of game and elevated concentrations of PFHpS and PFOS were detected in high consumers of white meat. Study subjects with a high intake of salty snacks and beef had significantly higher concentrations of PFOA. The present study demonstrates that parity, sampling date and birth year are the most important predictors for maternal PFAS concentrations in years following a decrease in production and use of several PFASs. Further, dietary predictors of PFAS concentrations were identified and varied in importance according to compound.

Repeated measurements of per- and polyfluoroalkyl substances (PFASs) from 1979 to 2007 in males from Northern Norway: assessing time trends, compound correlations and relations to age/birth cohort.

BACKGROUND: Longitudinal biomonitoring studies can provide unique information on how human concentrations change over time, but have so far not been conducted for per- and polyfluoroalkyl substances (PFASs) in a background exposed population. OBJECTIVES: The objectives of this study were to determine: i) serum PFAS time trends on an individual level; ii) relative compositions and correlations between different PFASs; and iii) assess selected PFAS concentrations with respect to periodic (calendar year), age and birth cohort (APC) effects. METHODS: Serum was sampled from the same 53 men in 1979, 1986, 1994, 2001 and 2007 in Northern Norway and analysed for 10 PFASs. APC effects were assessed by graphical and mixed effect analyses. RESULTS: The median concentrations of perfluorooctane sulphonic acid (PFOS) and perfluorooctanoic acid (PFOA) increased five-fold from 1979 to 2001 and decreased by 26% and 23%, respectively, from 2001 to 2007. The concentrations of PFOS and PFOA peaked during 1994-2001 and 2001, respectively, whereas perfluorohexane sulphonic acid (PFHxS) increased to 2001, but did not demonstrate a decrease between 2001 and 2007. Perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) displayed increasing trends throughout the entire study period (1979-2007). Although PFOS comprised dominating and stable proportions of PFAS burdens during these years, the contributions from PFOA and PFHxS were considerable. The evaluation of APC effects demonstrated that calendar year was the dominating influence on concentrations of PFOA, PFUnDA, and PFOS, although time-variant and weaker associations with age/birth cohort were indicated. CONCLUSIONS: The concentration changes of 10 PFASs in the repeated measurements from 1979 to 2007 demonstrated divergent time trends between the different PFASs. The temporal trends of PFASs in human serum during these 30years reflect the overall trends in historic production and use, although global transport mechanisms and bioaccumulation potential of the different PFASs together with a varying extent of consumer exposure influenced the observed trends. Sampling year was the strongest descriptor of PFOA, PFUnDA and PFOS concentrations, and the calendar-year trends were apparent for all birth year quartiles. Discrepancies between the trends in this current longitudinal study and previous cross-sectional studies were observed and presumably reflect the different study designs and population characteristics.

Persistent organic pollutants in Norwegian men from 1979 to 2007: intraindividual changes, age-period-cohort effects, and model predictions.

BACKGROUND: Longitudinal monitoring studies of persistent organic pollutants (POPs) in human populations are important to better understand changes with time and age, and for future predictions. OBJECTIVES: We sought to describe serum POP time trends on an individual level, investigate age-period-cohort effects, and compare predicted polychlorinated biphenyl (PCB) concentrations to measured values. METHODS: Serum was sampled in 1979, 1986, 1994, 2001, and 2007 from a cohort of 53 men in Northern Norway and analyzed for 41 POPs. Time period, age, and birth cohort effects were assessed by graphical analyses and mixed-effect models. We derived the predicted concentrations of four PCBs for each sampling year using the CoZMoMAN model. RESULTS: The median decreases in summed serum POP concentrations (lipid-adjusted) in 1986, 1994, 2001, and 2007 relative to 1979 were -22%, -52%, -54%, and -68%, respectively. We observed substantial declines in all POP groups with the exception of chlordanes. Time period (reflected by sampling year) was the strongest descriptor of changes in PCB-153 concentrations. Predicted PCB-153 concentrations were consistent with measured concentrations in the study population. CONCLUSIONS: Our results suggest substantial intraindividual declines in serum concentrations of legacy POPs from 1979 to 2007 in men from Northern Norway. These changes are consistent with reduced environmental exposure during these 30 years and highlight the relation between historic emissions and POP concentrations measured in humans. Observed data and interpretations are supported by estimates from the CoZMoMAN emission-based model. A longitudinal decrease in concentrations with age was evident for all birth cohorts. Overall, our findings support the relevance of age-period-cohort effects to human biomonitoring of environmental contaminants.

Climate change and the potential effects on maternal and pregnancy outcomes: an assessment of the most vulnerable--the mother, fetus, and newborn child.

In 2007, the Intergovernmental Panel on Climate Change (IPCC) presented a large amount of evidence about global warming and the impact of human activities on global climate change. The Lancet Commission have identified a number of ways in which climate change can influence human health: lack of food and safe drinking water, poor sanitation, population migration, changing disease patterns and morbidity, more frequent extreme weather events, and lack of shelter. Pregnant women, the developing fetus, and young children are considered the most vulnerable members of our species and are already marginalized in many countries. Therefore, they may have increased sensitivity to the effects of climate change. Published literature in the fields of climate change, human health, tropical diseases, and direct heat exposure were assessed through the regular search engines. This article demonstrates that climate change will increase the risk of infant and maternal mortality, birth complications, and poorer reproductive health, especially in tropical, developing countries. Thus, climate change will have a substantial impact on the health and survival of the next generation among already challenged populations. There is limited knowledge regarding which regions will be most heavily affected. Research efforts are therefore required to identify the most vulnerable populations, fill knowledge gaps, and coordinate efforts to reduce negative health consequences. The effects of malnutrition, infectious diseases, environmental problems, and direct heat exposure on maternal health outcomes will lead to severe health risks for mothers and children. Increased focus on antenatal care is recommended to prevent worsening maternal health and perinatal mortality and morbidity. Interventions to reduce the negative health impacts caused by climate change are also crucial. Every effort should be made to develop and maintain good antenatal care during extreme life conditions as a result of climate change.