Vitamin D is directly associated with favorable glycemic, lipid, and inflammatory profiles in individuals with at least one component of metabolic syndrome irrespective of total adiposity: Pró-Saúde Study, Brazil.

Vitamin D insufficiency has been suggested as a risk factor for several metabolic disorders. The objective of the study was to investigate the association between serum 25 hydroxyvitamin D [25(OH)D] and metabolic health markers of Brazilian individuals with normal-weight, overweight or obesity. We hypothesized that serum 25(OH)D would be inversely associated with glycemic, lipid and inflammatory markers indicative of metabolic abnormality. Data of 511 individuals (33-79 years), recruited from a longitudinal investigation (Pró-Saúde Study), were analyzed cross-sectionally. Anthropometric, biochemical, body composition, socio-demographic and lifestyle data were collected. Based on body mass index (BMI; normal weight, overweight, obesity) and metabolic health (metabolically healthy (MH) and metabolically unhealthy (MU)) categories, the participants were classified into 6 phenotypes. Individuals having zero components of the metabolic syndrome were considered as "MH". MH obesity was frequent in 2.0% of the participants and 56.0% exhibited vitamin D insufficiency (<20 ng/mL). In the subgroups of the same BMI category, there were no significant differences in 25(OH)D concentrations between individuals classified as MH and MU. After adjustments (including %body fat and BMI), an inverse association was observed between 25(OH)D and visceral adipose tissue (B = -6.46, 95% confidence interval, CI: -12.87, -0.04), leptin (B = -0.09, 95% confidence interval, CI: -0.14, -0.03), insulin (B = -0.21, 95%CI: -0.34, -0.07), HOMA-IR (B = -0.06, 95%CI: -0.10, -0.02), triglycerides (B = -2.44, 95%CI: -3.66, -1.22), and TNF-α (B = -0.12, 95%CI: -0.24, -0.005) only in MU individuals. Our results indicate that the association of 25(OH)D concentrations with a favorable biochemical profile (glycemic, lipidic and inflammatory) seems to depend on the individual's overall metabolic health, suggesting more benefits from higher serum vitamin D in MU individuals, regardless of their adiposity.

Association between circulating exhausted CD4+ T cells with poor meningococcal C conjugate vaccine antibody response in HIV-infected children and adolescents.

OBJECTIVES: To investigate the expression levels of surface markers of activation (CD38 and HLA-DR), inhibition (PD-1, TIGIT and CD57) and co-stimulation (CD28 and CD127) on CD4+ T cells of children/adolescents with vertical HIV infection (HI patients) and HIV-uninfected (HU) controls vaccinated with the meningococcal C conjugate vaccine (MCC). METHODS: HI patients (n=12), aged 8-17 years, were immunized with two MCC injections, while HU controls (n=9), aged 5.3-10.7 years, received a single MCC dose (as per national recommendation at the time of this study, a single MCC vaccine dose should be given for healthy children and youth aged 1-18 years). The HI patients were categorized according to the combined antiretroviral therapy (cART) treatment. Blood samples were obtained before vaccination, after priming, and after the administration of a booster dose of vaccine to determine the serum bactericidal antibody (SBA) titers and the expression levels of surface markers on CD4+ T cells by flow cytometry. The levels of serum cytokines, IL-4 and CXCL-13 were also measured using Luminex kits. RESULTS: The co-expression of the TIGIT-HLA-DR-CD38 molecules increased in the CD4+ T cells of HI patients/no-cART who also showed a lower frequency of CD127+CD28+ CD4+ T cells than HI patients/cART and HU group subjects. There were significant negative correlations between the frequency of exhausted CD4+ T cells and the SBA response. IL-4 levels were higher in HI patients/cART and positively correlated with SBA titers but negatively associated with the expression of exhaustion markers. Moreover, the CXCL-13 levels were positively correlated with the exhausted CD4+ T cells. CONCLUSION: The results of our study suggest that the co-expression of exhaustion markers and/or loss of co-stimulatory molecules influence the SBA response in HI patients.

Association between circulating exhausted CD4+ T cells with poor meningococcal C conjugate vaccine antibody response in HIV-infected children and adolescents

OBJECTIVES: To investigate the expression levels of surface markers of activation (CD38 and HLA-DR), inhibition (PD-1, TIGIT and CD57) and co-stimulation (CD28 and CD127) on CD4+ T cells of children/adolescents with vertical HIV infection (HI patients) and HIV-uninfected (HU) controls vaccinated with the meningococcal C conjugate vaccine (MCC). METHODS: HI patients (n=12), aged 8-17 years, were immunized with two MCC injections, while HU controls (n=9), aged 5.3-10.7 years, received a single MCC dose (as per national recommendation at the time of this study, a single MCC vaccine dose should be given for healthy children and youth aged 1-18 years). The HI patients were categorized according to the combined antiretroviral therapy (cART) treatment. Blood samples were obtained before vaccination, after priming, and after the administration of a booster dose of vaccine to determine the serum bactericidal antibody (SBA) titers and the expression levels of surface markers on CD4+ T cells by flow cytometry. The levels of serum cytokines, IL-4 and CXCL-13 were also measured using Luminex kits. RESULTS: The co-expression of the TIGIT-HLA-DR-CD38 molecules increased in the CD4+ T cells of HI patients/no-cART who also showed a lower frequency of CD127+CD28+ CD4+ T cells than HI patients/cART and HU group subjects. There were significant negative correlations between the frequency of exhausted CD4+ T cells and the SBA response. IL-4 levels were higher in HI patients/cART and positively correlated with SBA titers but negatively associated with the expression of exhaustion markers. Moreover, the CXCL-13 levels were positively correlated with the exhausted CD4+ T cells. CONCLUSION: The results of our study suggest that the co-expression of exhaustion markers and/or loss of co-stimulatory molecules influence the SBA response in HI patients.

Quantitative bias analysis of the association of type 2 diabetes mellitus with 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153).

An association between serum concentrations of persistent organic pollutants (POPs), such as 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153), and risk of type 2 diabetes mellitus (T2DM) has been reported. Conditional on body mass index (BMI) and waist circumference (WC), a higher serum PCB-153 concentration may be a marker of T2DM risk because it reflects other aspects of obesity that are related to T2DM risk and to PCB-153 clearance. To estimate the amount of residual confounding by other aspects of obesity, we performed a quantitative bias analysis on the results of a specific study. A physiologically-based pharmacokinetic (PBPK) model was developed to predict serum levels of PCB-153 for a simulated population. T2DM status was assigned to simulated subjects based on age, sex, BMI, WC, and visceral adipose tissue mass. The distributions of age, BMI, WC, and T2DM prevalence of the simulated population were tailored to closely match the target population. Analysis of the simulated data showed that a small part of the observed association appeared to be due to residual confounding. For example, the predicted odds ratio of T2DM that would have been obtained had the results been adjusted for visceral adipose tissue mass, for the ≥90th percentile of PCB-153 serum concentration, was 6.60 (95% CI 2.46-17.74), compared with an observed odds ratio of 7.13 (95% CI 2.65-19.13). Our results predict that the association between PCB-153 and risk of type 2 diabetes mellitus would not be substantially changed by additional adjustment for visceral adipose tissue mass in epidemiologic analyses. Confirmation of these predictions with longitudinal data would be reassuring.

A cross-reacting material CRM197 conjugate vaccine induces diphtheria toxin neutralizing antibody response in children and adolescents infected or not with HIV.

Anti-diphtheria antibody levels decrease with aging, and frequent booster vaccinations are required to maintain herd immunity. We analyzed the diphtheria toxin neutralizing antibody (DT-Nab) response induced by a conjugate vaccine (meningococcal C polysaccharide-CRM197) in HIV-vertically infected (HI) children and adolescents and healthy controls (HC) with matched age. We report the association of DT-Nab with the bactericidal antibodies to serogroup C meningococcus (MenC). Before vaccination, 21 HI patients (50%) had no protection against diphtheria (≤0.01IU/ml of antibody) and only 8 (19%) showed complete protection (≥0.1IU/ml). About half of the HC (56%) had complete protection before immunization and 6 subjects (12%) had no protection against diphtheria. After one and two vaccine injections, 96% of HC and 64% of HI vaccinees, respectively, showed full protection against diphtheria. These data indicate that CRM197 was able to induce primary and/or booster response in both groups of individuals.

Association of serum bactericidal antibody and opsonic antibody levels after Neisseria meningitidis serogroup C conjugate vaccine in Brazilian children and adolescents infected or not infected with HIV.

Neisseria meningitidis serogroup C (MenC) is the main causative agent of meningitis in Brazil. HIV infection affects the quality of the immune system. HIV+ children have an increased risk of infection to encapsulated bacteria such as N. meningitidis. We evaluated the opsonic antibody (OPA) levels and its correlation with serum bactericidal antibody (SBA) levels induced by one and two doses of a MenC conjugate vaccine in children and adolescents HIV+ and HIV-exposed but uninfected children (HEU) group. Overall the data show the importance of two doses of vaccine for HIV+ individuals. About 79% and 58% of HIV+ patients showed SBA and OPA positive response after two doses of vaccine, respectively. For HEU group, 62% and 41% of patients showed SBA and OPA positive response after one dose of vaccine, respectively. A positive and significant association between SBA and OPA levels was seen after two doses of vaccine in HIV+ patients.

Subsets of memory CD4+ T cell and bactericidal antibody response to Neisseria meningitidis serogroup C after immunization of HIV-infected children and adolescents.

Meningococcal disease is endemic in Brazil, with periodic outbreaks and case fatality rates reach as high as 18 to 20% of cases. Conjugate vaccines against meningococci are immunogenic in healthy children. However, we have previously shown a poor bactericidal antibody response to a Men C conjugate vaccine in Brazilian HIV-infected children and adolescents after a single vaccine administration. The goal of the present work was to investigate associations between bactericidal antibody response induced by MenC vaccine and the frequency and activation profile (expression of CD38, HLA-DR and CCR5 molecules) of total CD4+ memory T cell sub-populations in HIV-1-infected children and adolescents. Responders to vaccination against MenC had a predominance (about 44%) of CD4+ TINTERMEDIATE subset followed by TTRANSITIONAL memory subset (23 to 26%). Importantly, CD4+ TINT frequency was positively associated with bactericidal antibody response induced by vaccination. The positive correlation persisted despite the observation that the frequency TINT CD38+HLA-DR+ was higher in responders. In contrast, CD4+ TCENTRAL MEMORY (TCM) subset negatively correlated with bactericidal antibodies. In conclusion, these data indicate that less differentiated CD+ T cells, like TCM may be constantly differentiating into intermediate and later differentiated CD4+ T cell subsets. These include CD4 TINT subset which showed a positive association with bactericidal antibodies.

Neutral polyfluoroalkyl substances in the global atmosphere.

Concentrations of neutral per- and polyfluoroalkyl substances (nPFAS) in the atmosphere are of interest because nPFAS are highly mobile percursors for perfluoroalkyl acids. Two calibration studies in Ontario, Canada and Costa Rica established the feasibility of using XAD 2-resin based passive air samplers (XAD-PAS) to reliably determine long term average air concentrations of nPFAS under temperate and tropical climatic conditions. The temporal and spatial distribution of nPFAS was investigated by analyzing XAD-PAS deployed for one year at between 17 and 46 sites on six continents between 2006 and 2011 as part of the Global Atmospheric Passive Sampling (GAPS) study. Higher levels of fluorotelomer alcohols (FTOHs) compared to fluorinated sulfonamides (FOSAs), and fluorinated sulfonamidoethanols (FOSEs) were observed at all sites. Urban sites had the highest levels of nPFAS compared to rural and remote sites, which is also apparent in a positive correlation of nPFAS levels with the proximity of a sampling site to areas of high population density. Levels of FOSAs and FOSEs tended to decrease during the six years of measurements, whereas an initial decline in the concentrations of FTOHs from 2006 to 2008 did not continue in 2009 to 2011. A comparison of nPFAS levels measured in national XAD-PAS networks in Costa Rica and Botswana revealed that the GAPS sites in Tapanti and the Kalahari are representative of the more remote regions in those countries. XAD-PAS derived absolute nPFAS levels at GAPS sites are lower than those measured using another PAS, but are within the range of levels measured with active air samplers. Agreement of relative nPFAS composition is better between samplers, suggesting that the discrepancy is due to uncertain sampling rates.

Inhibition of caspase-8 activity promotes protective Th1- and Th2-mediated immunity to Leishmania major infection.

We investigated how apoptosis pathways mediated by death receptors and caspase-8 affect cytokine responses and immunity to Leishmania major parasites. Splenic CD4 T cells undergo activation-induced apoptosis, and blockade of FasL-Fas interaction increased IFN-γ and IL-4 cytokine responses to L. major antigens. To block death receptor-induced death, we used mice expressing a T cell-restricted transgene for vFLIP. Inhibition of caspase-8 activation in vFLIP mice enhanced Th1 and Th2 cytokine responses to L. major infection, even in the Th1-prone B6 background. We also observed increased NO production by splenocytes from vFLIP mice upon T cell activation. Despite an exacerbated Th2 response, vFLIP mice controlled better L. major infection, with reduced lesions and lower parasite loads compared with WT mice. Moreover, injection of anti-IL-4 mAb in infected vFLIP mice disrupted control of parasite infection. Therefore, blockade of caspase-8 activity in T cells improves immunity to L. major infection by promoting increased Th1 and Th2 responses.

CD4+ T-cell activation impairs serogroup C Neisseria meningitis vaccine response in HIV-infected children.

OBJECTIVE: To investigate the influence of CD4 T-cell activation and regulatory populations in HIV-infected children antibody response to vaccination with a conjugate C polysaccharide vaccine. DESIGN: CD4 T-cell activation was evaluated by expression of CD38, HLA-DR and CCR5 molecules. Regulatory CD4 T cells (TReg) were characterized as FoxP3CD127CD25 and inducer T cells (TInd) as CD4FoxP3CD25CD39. METHODS: All patients (n = 36) were HIV-vertically infected, aged 2-17 years-old and were vaccinated with one vaccine injection. Blood samples were obtained before and after immunization to determine bactericidal antibody titers (SBA), CD4 T-cell activation and frequency of TReg and TInd subsets (multiparametric flow cytometry). RESULTS: Children not-responding (n = 18) to MenC vaccine expressed higher frequency of activated CD4 T cells (HLA-DRCD38CCR5) than responders (n = 18), both before and after vaccination (P < 0.05). A significant higher frequency of TReg was detected in responders compared with nonresponders (P = 0.0001). We also detected an inverse correlation between CD4DRCD38CCR5 (P = 0.01) or CD4DRCD38 (P = 0.02) T cells and TReg cell frequency after vaccination. CD4 T-cell activation negatively correlated (P = 0.006) with postvaccination SBA titers but a positive correlation (P = 0.0001) was detected between TReg cells and SBA. TReg and TInd subsets were inversely correlated (P = 0.04). CONCLUSION: Our findings suggest that higher CD4 T-cell activation leads to poor vaccine response in children living with HIV, which may be associated with a TReg/TInd disequilibrium.

Myeloid-derived suppressor cells help protective immunity to Leishmania major infection despite suppressed T cell responses.

Th1/Th2 cytokines play a key role in immune responses to Leishmania major by controlling macrophage activation for NO production and parasite killing. MDSCs, including myeloid precursors and immature monocytes, produce NO and suppress T cell responses in tumor immunity. We hypothesized that NO-producing MDSCs could help immunity to L. major infection. Gr1(hi)(Ly6C(hi)) CD11b(hi) MDSCs elicited by L. major infection suppressed polyclonal and antigen-specific T cell proliferation. Moreover, L. major-induced MDSCs killed intracellular parasites in a NO-dependent manner and reduced parasite burden in vivo. By contrast, treatment with ATRA, which induces MDSCs to differentiate into macrophages, increased development of lesions, parasite load, and T cell proliferation in draining LNs. Altogether, these results indicate that NO-producing MDSCs help protective immunity to L. major infection, despite suppressed T cell proliferation.

Targeting caspases in intracellular protozoan infections.

Caspases are cysteine aspartases acting either as initiators (caspases 8, 9, and 10) or executioners (caspases 3, 6, and 7) to induce programmed cell death by apoptosis. Parasite infections by certain intracellular protozoans increase host cell life span by targeting caspase activation. Conversely, caspase activation, followed by apoptosis of lymphocytes and other cells, prevents effective immune responses to chronic parasite infection. Here we discuss how pharmacological inhibition of caspases might affect the immunity to protozoan infections, by either blocking or delaying apoptosis.

Inhibition of caspase-8 activity reduces IFN-gamma expression by T cells from Leishmania major infection.

Following infection with Leishmania major, T cell activation and apoptosis can be detected in draining lymph nodes of C57BL/6-infected mice. We investigated the mechanisms involved in apoptosis and cytokine expression following T cell activation. After two weeks of infection, apoptotic T cells were not detected in draining lymph nodes but activation with anti-CD3 induced apoptosis in both CD4 and CD8 T cells. Treatment with anti-Fas Ligand, caspase-8 or caspase- 9 inhibitors did not block activation-induced T-cell death. We also investigated whether the blockade of caspase-8 activity would affect the expression of type-1 or type-2 cytokines. At early stages of infection, both CD4 and CD8 T cells expressed IFN-gamma upon activation. Treatment with the caspase-8 inhibitor zIETD-fmk (benzyl-oxycarbonyl-Ile- Glu(OMe)-Thr-Asp(OMe)-fluoromethyl ketone) reduced the proportion of CD8 T cells and IFN-gamma expression in both CD4 and CD8 T cells. We conclude that a non apoptotic role of caspase-8 activity may be required for T cell-mediated type-1 responses during L. major infection.

Inhibition of caspase-8 activity reduces IFN-gamma expression by T cells from Leishmania major infection

Following infection with Leishmania major, T cell activation and apoptosis can be detected in draining lymph nodes of C57BL/6-infected mice. We investigated the mechanisms involved in apoptosis and cytokine expression following Tcellactivation. After two weeks of infection, apoptotic T cells were not detected in draining lymph nodes but activation with anti-CD3 induced apoptosis in both CD4 and CD8 T cells. Treatment with anti-FasLigand, caspase-8 or caspase- 9 inhibitors did not block activation-induced T-cell death. We also investigated whether the blockade of caspase-8 activity would affect the expression of type-1 or type-2 cytokines. At early stages of infection, both CD4 and CD8 T cells expressed IFN-gamma upon activation. Treatment with the caspase-8 inhibitor zIETD-fmk (benzyl-oxycarbonyl-Ile- Glu(OMe)-Thr-Asp(OMe)-fluoromethyl ketone) reduced the proportion of CD8 T cells and IFN-gamma expression in both CD4 and CD8T cells. We conclude that a non apoptotic role of caspase-8 activity may be required for T cell-mediated type-1 responses during L. major infection.

A ativação e a morte por apoptose de linfócitos T foram observadas em linfonodos drenantes de camundongos C57BL/6 infectados com Leishmania major. Investigamos os mecanismos envolvidos na apoptose e na expressão de citocinas após a ativação de linfócitos T. Após duas semanas de infecção, embora as células apoptóticas ainda não sejam detectadas em linfonodos drenantes, células T CD4 e CD8 sofrem apoptose após ativação com anti-CD3. O tratamento com anticorpo antagonista anti-Ligante de Fas, ou com inibidores das caspases-8 e 9, não bloqueou a morte induzida por ativação das células T. Investigamos também se a inibição da atividade da caspase-8 poderia afetar a expressão de citocinas tipo-1 ou tipo-2. Nos estágios iniciais da infecção, células T CD4 e CD8 de animais infectados com L. major expressaram IFN-gama após ativação. O tratamento com o inibidor de caspase-8 zIETD (benzoil-oxicarbonil-Ile-Glu(OMe)-Thr-Asp(OMe)-fluorometilcetona) durante a estimulação de células T reduziu a proporção de células T CD8 e a expressão de IFN-gama por células T CD4 e CD8. Concluimos que a atividade não apoptótica de caspase-8 pode ser necessária para o estabelecimento da imunidade mediada por células T durante a infecção por L. major.

Histological approaches for high-quality imaging of zooplanktonic organisms.

The investigation of the internal organization of zooplankton communities provides important information on the plankton biology with special interest for the study of ecological processes. Zooplanktoners can play a structural function as indicators for ecosystem health or stress, but their study using histological techniques is still limited. Here we report that the internal structure of zooplanktonic organisms can be facilely observed by a histological approach that combines optimal fixation and processing with a plastic resin (glycol methacrylate) embedding, resulting in increased tissue resolution. Using copepods, organisms that can dominate zooplankton assemblages, as models, collected from a tropical ecosystem (Paraibuna river, Brazil), we showed fine histological details of their muscular, nervous and digestive systems, structure of appendages and cell features. Critical advantages of this approach are that it permits optimal preservation and adequate handling of the organisms (embedded in agar after fixation) for further histological processing and investigation. This is important because it prevents both mechanically induced artifacts and loss of these diminutive organisms during the different steps of processing. Moreover, embedding in plastic resin showed a superior imaging of copepod internal structures compared to paraffin embedding. The use of glycol methacrylate is advantageous over paraffin/paraplast embedding by avoiding heat damage, tissue retraction and allowing faster embedding procedure and better tissue resolution. The value of histological approaches in enabling high-quality imaging of the internal structure of copepods is particularly important because these organisms can be used as indicators of environmental changes.

The Fas death pathway controls coordinated expansions of type 1 CD8 and type 2 CD4 T cells in Trypanosoma cruzi infection.

We investigated the role of the Fas ligand (FasL)/Fas death pathway on apoptosis and cytokine production by T cells in Trypanosoma cruzi infection. Anti-FasL, but not anti-TNF-alpha or anti-TRAIL, blocked activation-induced cell death of CD8 T cells and increased secretion of IL-10 and IL-4 by CD4 T cells from T. cruzi-infected mice. CD4 and CD8 T cells up-regulated Fas/FasL expression during T. cruzi infection. However, Fas expression increased earlier in CD8 T cells, and a higher proportion of CD8 T cells was activated and expressed IFN-gamma compared with CD4 T cells. Injection of anti-FasL in infected mice reduced parasitemia and CD8 T cell apoptosis and increased the ratio of CD8:CD4 T cells recovered from spleen and peritoneum. FasL blockade increased the number of activated T cells, enhanced NO production, and reduced parasite loads in peritoneal macrophages. Injection of anti-FasL increased IFN-gamma secretion by splenocytes responding to T. cruzi antigens but also exacerbated production of type 2 cytokines IL-10 and IL-4 at a late stage of acute infection. These results indicate that the FasL/Fas death pathway regulates apoptosis and coordinated cytokine responses by type 1 CD8 and type 2 CD4 T cells in T. cruzi infection.

Estimating the influence of forests on the overall fate of semivolatile organic compounds using a multimedia fate model.

On the basis of recently reported measurements of semivolatile organic compound (SOC) uptake in forest canopies, simple expressions are derived that allow the inclusion of a canopy compartment into existing non-steady-state multimedia fate models based on the fugacity approach. One such model is used to assess how the inclusion of the canopy compartment in the model affects the calculated overall behavior of SOCs with specific physical--chemical properties. The primary effect of the forest is an increase in the net atmospheric deposition to the terrestrial environment, reducing atmospheric concentrations and accordingly the extent of deposition to the agricultural and aquatic environments. This effect was most pronounced for chemicals with log KOA around 9-10 and log KAW -2 to -3; their average air concentrations during the growing season decreased by a factor of 5 when the canopy compartment was included. Concentration levels in virtually all compartments are decreased at the expense of increased concentrations in the forest soil. The effect of the forest lies not in a large capacity for these chemicals but in the efficiency of pumping the chemicals from the atmosphere to the forest soil, a storage reservoir with high capacity from which the chemicals can return to the atmosphere only with difficulty. Because of seasonal variability of canopy size and atmospheric stability, uptake into forests is higher during spring and summer than in winter. The model suggests that this may dampen temperature-driven seasonal fluctuations of air concentrations and in regions with large deciduous forests may lead to a temporary, yet notable dip in air concentrations during leaf development in spring. A sensitivity analysis revealed a strong effect of forest cover, forest composition, and degradation half-lives. A high degradation loss on the plant surface has the effect of preventing the saturation of the small plant reservoir and can cause very significant reductions in atmospheric concentrations of those SOCs for which uptake in the canopy is limited by the size of the reservoir.

Contaminants in the Canadian Arctic: 5 years of progress in understanding sources, occurrence and pathways.

Recent studies of contaminants under the Canadian Northern Contaminants Program (NCP) have substantially enhanced our understanding of the pathways by which contaminants enter Canada's Arctic and move through terrestrial and marine ecosystems there. Building on a previous review (Barrie et al., Arctic contaminants: sources, occurrence and pathways. Sci Total Environ 1992:1-74), we highlight new knowledge developed under the NCP on the sources, occurrence and pathways of contaminants (organochlorines, Hg, Pb and Cd, PAHs, artificial radionuclides). Starting from the global scale, we examine emission histories and sources for selected contaminants focussing especially on the organochlorines. Physical and chemical properties, transport processes in the environment (e.g. winds, currents, partitioning), and models are then used to identify, understand and illustrate the connection between the contaminant sources in industrial and agricultural regions to the south and the eventual arrival of contaminants in remote regions of the Arctic. Within the Arctic, we examine how contaminants impinge on marine and terrestrial pathways and how they are subsequently either removed to sinks or remain where they can enter the biosphere. As a way to focus this synthesis on key concerns of northern residents, a number of special topics are examined including: a mass balance for HCH and toxaphene (CHBs) in the Arctic Ocean; a comparison of PCB sources within Canada's Arctic (Dew Line Sites) with PCBs imported through long-range transport; an evaluation of concerns posed by three priority metals--Hg, Pb and Cd; an evaluation of the risks from artificial radionuclides in the ocean; a review of what is known about new-generation pesticides that are replacing the organochlorines; and a comparison of natural vs. anthropogenic sources of PAH in the Arctic. The research and syntheses provide compelling evidence for close connectivity between the global emission of contaminants from industrial and agricultural activities and the Arctic. For semi-volatile compounds that partition strongly into cold water (e.g. HCH) we have seen an inevitable loading of Arctic aquatic reservoirs. Drastic HCH emission reductions have been rapidly followed by reduced atmospheric burdens with the result that the major reservoir and transport agent has become the ocean. In the Arctic, it will take decades for the upper ocean to clear itself of HCH. For compounds that partition strongly onto particles, and for which the soil reservoir is most important (e.g. PCBs), we have seen a delay in their arrival in the Arctic and some fractionation toward more volatile compounds (e.g. lower-chlorinated PCBs). Despite banning the production of PCB in the 1970s, and despite decreases of PCBs in environmental compartments in temperate regions, the Arctic presently shows little evidence of reduced PCB loadings. We anticipate a delay in PCB reductions in the Arctic and environmental lifetimes measured in decades. Although artificial radionuclides have caused great concern due to their direct disposal on Russian Shelves, they are found to pose little threat to Canadian waters and, indeed, much of the radionuclide inventory can be explained as remnant global fallout, which was sharply curtailed in the 1960s, and waste emissions released under license by the European reprocessing plants. Although Cd poses a human dietary concern both for terrestrial and marine mammals, we find little evidence that Cd in marine systems has been impacted by human activities. There is evidence of contaminant Pb in the Arctic, but loadings appear presently to be decreasing due to source controls (e.g. removal of Pb from gasoline) in Europe and North America. Of the metals, Hg provokes the greatest concern; loadings appear to be increasing in the Arctic due to global human activities, but such loadings are not evenly distributed nor are the pathways by which they enter and move within the Arctic well understood.

On the origin of elevated levels of persistent chemicals in the environment.

In general, contamination levels tend to be highest close to sources of a chemical and decline with increasing distance as a result of dilution, dispersion and degradation. However, contrary to this, circumstances have been described when contamination levels are higher further away from sources than at the sources themselves. Examples are elevated levels of persistent, hydrophobic, organic chemicals in the Arctic, in mountain regions and in forest soils. In order to address the questions of why and when such an inversion of environmental levels is occurring, this paper seeks to identify, name and categorise principles of general validity leading to such behaviour. By compiling and analysing various causes of elevated contamination levels in the environment, three main categories became apparent, 1. equilibrium partitioning effects, 2. effects resulting from changes in phase composition, volume or temperature, and 3. dynamic or kinetic effects. These principles are illustrated with several examples. The case can be made that understanding, quantifying and predicting these causes could provide a general conceptual framework for studying the fate of chemicals in the environment.

The evolution of mass balance models of persistent organic pollutant fate in the environment.

Current approaches to modelling the fate of persistent organic pollutants (POPs) in the environment have evolved in response to four dominant characteristics of these substances; namely: (1) the presence of POPs in virtually all environmental phases and the ease with which they move from one to the other requires multi-compartmental modelling. Describing transport across phase boundaries becomes as, or even more, important as quantifying transport within the phases; (2) POPs may persist in the environment for many decades. For chemicals that 'have time', concepts such as equilibrium partitioning and steady-state become more important than for short-lived substances whose fate is more controlled by the rates of transformation; (3) measuring POPs is difficult and expensive and observed concentrations of POPs are not available in high spatial or temporal resolution. Consequently, high resolution tends not to be a high priority in POP models; and (4) detrimental effects of POPs often manifest themselves in top predators, which has led to a focus on modelling biotic uptake and transfer within food chains. The task of building a POPs model is viewed as combining the four 'building blocks' of partitioning, transport, transformation and source data with the help of the law of the conservation of mass. Process models, evaluative models, models of real local, regional and global fate, as well as biological uptake models are presented and references to numerous examples are provided. An attempt is made to forecast future directions in the field of POPs modelling. It is expected that modelling techniques that do not rely on quantitative emission estimates as well as approaches that take into account spatial, temporal and climatic variability as well as parameter uncertainty will increase in importance. Finally, the relationship between modelling POPs and models of other pollutant issues is addressed, as are potential interactions between POPs and pollutant issues such as eutrophication, acidification and global climate change.