Incorporating conceptual site models into national-scale environmental risk assessments for legacy waste in the coastal zone

Solid wastes deposited in the coastal zone that date from an era of lax environmental regulations continue to pose significant challenges for regulators and coastal managers worldwide. The increasing risk of contaminant release from these legacy disposal sites, due to a range of factors including rising sea levels, associated saline intrusion, and greater hydrological extremes, have been highlighted by many researchers. Given this widespread challenge, and the often-limited remedial funds available, there is a pressing need for the development of new advanced site prioritization protocols to limit potential pollution risks to sensitive ecological or human receptors. This paper presents a multi-criteria decision analysis that integrates the principles of Conceptual Site Models (Source-Pathway-Receptor) at a national scale in England and Wales to identify legacy waste sites where occurrence of pollutant linkages are most likely. A suite of spatial data has been integrated in order to score potential risks associated with waste type (Source), likelihood of pollutant release relating to current and future flood and erosion climate projections, alongside current management infrastructure (Pathway), and proximity to sensitive ecological features or proxies of human use in coastal areas (Receptors). Of the 30,281 legacy waste deposits identified in England and Wales, 3,219 were located within the coastal zone, with coastal areas containing a density of legacy wastes (by area) 10.5 times higher than inland areas. Of these, 669 were identified as priority sites in locations without existing coastal defences or flood management infrastructure, with 2550 sites identified in protected areas where contaminant transfer risks could still be apparent. The majority (63%) of the priority sites have either undefined source terms, or are classified as mixed wastes. Mining and industrial wastes were also notable waste categories, and displayed strong regional distributions in the former mining areas of north-east and south-west of England, south Wales, and post-industrial estuaries. The large-scale screening process presented here could be used by environmental managers as a foundation to direct more high-resolution site assessment and remedial work at priority sites, and can be used as a tool by governments for directing funding to problematic sites. List of Acronyms

Incorporating conceptual site models into national-scale environmental risk assessments for legacy waste in the coastal zone

Solid wastes deposited in the coastal zone that date from an era of lax environmental regulations continue to pose significant challenges for regulators and coastal managers worldwide. The increasing risk of contaminant release from these legacy disposal sites, due to a range of factors including rising sea levels, associated saline intrusion, and greater hydrological extremes, have been highlighted by many researchers. Given this widespread challenge, and the often-limited remedial funds available, there is a pressing need for the development of new advanced site prioritization protocols to limit potential pollution risks to sensitive ecological or human receptors. This paper presents a multi-criteria decision analysis that integrates the principles of Conceptual Site Models (Source-Pathway-Receptor) at a national scale in England and Wales to identify legacy waste sites where occurrence of pollutant linkages are most likely. A suite of spatial data has been integrated in order to score potential risks associated with waste type (Source), likelihood of pollutant release relating to current and future flood and erosion climate projections, alongside current management infrastructure (Pathway), and proximity to sensitive ecological features or proxies of human use in coastal areas (Receptors). Of the 30,281 legacy waste deposits identified in England and Wales, 3,219 were located within the coastal zone, with coastal areas containing a density of legacy wastes (by area) 10.5 times higher than inland areas. Of these, 669 were identified as priority sites in locations without existing coastal defences or flood management infrastructure, with 2550 sites identified in protected areas where contaminant transfer risks could still be apparent. The majority (63 %) of the priority sites have either undefined source terms, or are classified as mixed wastes. Mining and industrial wastes were also notable waste categories, and displayed strong regional distributions in the former mining areas of north-east and south-west of England, south Wales, and post-industrial estuaries. The large-scale screening process presented here could be used by environmental managers as a foundation to direct more high-resolution site assessment and remedial work at priority sites, and can be used as a tool by governments for directing funding to problematic sites

Pre-Existing Adenovirus Immunity Modifies a Complex Mixed Th1 and Th2 Cytokine Response to an Ad5/HIV-1 Vaccine Candidate in Humans

The results of the recent Step Study highlight a need to clarify the effects of pre-existing natural immunity to a vaccine vector on vaccine-induced T-cell responses. To investigate this interaction, we examined the relationship between pre-existing Ad5 immunity and T-cell cytokine response profiles in healthy, HIV-uninfected recipients of MRKAd5 HIV-1 gag vaccine (HVTN 050, ClinicalTrials.gov #NCT00849732). Participants were grouped by baseline Ad5 neutralizing antibody titer as either Ad5-seronegative (titer ≤18; n = 36) or Ad5-seropositive (titer >200; n = 34). Samples from vaccine recipients were analyzed for immune responses to either HIV-1 Gag peptide pools or Ad5 empty vector using an ex vivo assay that measures thirty cytokines in the absence of long-term culture. The overall profiles of cytokine responses to Gag and Ad5 had similar combinations of induced Th1- and Th2-type cytokines, including IFN-γ, IL-2, TNF-α, IP-10, IL-13, and IL-10, although the Ad5-specific responses were uniformly higher than the Gag-specific responses (p<0.0001 for 9 out of 11 significantly expressed analytes). At the peak response time point, PBMC from Ad5-seronegative vaccinees secreted significantly more IP-10 in response to Gag (p = 0.008), and significantly more IP-10 (p = 0.0009), IL-2 (p = 0.006) and IL-10 (p = 0.05) in response to Ad5 empty vector than PBMC from Ad5-seropositive vaccinees. Additionally, similar responses to the Ad5 vector prior to vaccination were observed in almost all subjects, regardless of Ad5 neutralizing antibody status, and the levels of secreted IFN-γ, IL-10, IL-1Ra and GM-CSF were blunted following vaccination. The cytokine response profile of Gag-specific T cells mirrored the Ad5-specific response present in all subjects before vaccination, and included a number of Th1- and Th2-associated cytokines not routinely assessed in current vaccine trials, such as IP-10, IL-10, IL-13, and GM-CSF. Together, these results suggest that vector-specific humoral responses may reduce vaccine-induced T-cell responses by previously undetected mechanisms

A Cell Permeable Peptide Inhibitor of NFAT Inhibits Macrophage Cytokine Expression and Ameliorates Experimental Colitis

Nuclear factor of activated T cells (NFAT) plays a critical role in the development and function of immune and non-immune cells. Although NFAT is a central transcriptional regulator of T cell cytokines, its role in macrophage specific gene expression is less defined. Previous work from our group demonstrated that NFAT regulates Il12b gene expression in macrophages. Here, we further investigate NFAT function in murine macrophages and determined the effects of a cell permeable NFAT inhibitor peptide 11R-VIVIT on experimental colitis in mice. Treatment of bone marrow derived macrophages (BMDMs) with tacrolimus or 11R-VIVIT significantly inhibited LPS and LPS plus IFN-γ induced IL-12 p40 mRNA and protein expression. IL-12 p70 and IL-23 secretion were also decreased. NFAT nuclear translocation and binding to the IL-12 p40 promoter was reduced by NFAT inhibition. Experiments in BMDMs from IL-10 deficient (Il10−/−) mice demonstrate that inhibition of IL-12 expression by 11R-VIVIT was independent of IL-10 expression. To test its therapeutic potential, 11R-VIVIT was administered systemically to Il10−/− mice with piroxicam-induced colitis. 11R-VIVIT treated mice demonstrated significant improvement in colitis compared to mice treated with an inactive peptide. Moreover, decreased spontaneous secretion of IL-12 p40 and TNF in supernatants from colon explant cultures was demonstrated. In summary, NFAT, widely recognized for its role in T cell biology, also regulates important innate inflammatory pathways in macrophages. Selective blocking of NFAT via a cell permeable inhibitory peptide is a promising therapeutic strategy for the treatment of inflammatory bowel diseases