A non-linear approach, consistent with available mode of action (MOA) data, is most scientifically defensible for assessing the carcinogenicity of oral exposure to hexavalent chromium (CrVI). ...Accordingly, the current paper builds upon previous studies (Haney, 2015a, 2015b) to first develop a non-linear, non-threshold approach as well as a non-linear threshold approach for assessing the oral carcinogenicity of CrVI, and then utilizes available MOA analyses and information for selection of the most scientifically-supported approach. More specifically, a non-linear, non-threshold dose–response function was developed that adequately describes the non-linearity predicted for potential human excess risk versus oral dose due to the sub-linear relationship between oral dose and internal dose (added mg Cr/kg target tissue) across environmentally-relevant doses of regulatory interest. Additionally, benchmark dose modeling was used to derive a reference dose (RfD of 0.003 mg/kg-day) with cytotoxicity-induced regenerative hyperplasia as a key precursor event to carcinogenesis in the mouse small intestine. This RfD value shows remarkable agreement with that published previously (0.006 mg/kg-day) based on a more scientifically-sophisticated, physiologically-based pharmacokinetic modeling approach (Thompson et al., 2013b). The RfD approach is the most scientifically-defensible approach based on the weight-of-evidence of available MOA information and analyses conducted for the most scientifically-supported MOA.
•Non-linear approaches are most defensible for CrVI-induced tumorigenesis.•Two non-linear approaches are developed under different MOA assumptions.•The approach selected should be consistent with mode of action (MOA) data.•The weight-of-evidence supports a non-mutagenic/cytotoxic MOA.•An RfD of 0.003 mg/kg-day is derived to protect against carcinogenic effects.
An inhalation unit risk factor (URF) was developed for cadmium. The URF is based on excess lung cancer mortality in a key epidemiological study of cadmium smelter workers (Park et al., 2012). The ...Park et al. (2012) study is an update of the Thun et al. (1985) cohort that was previously used to derive a URF in USEPA (1985). Park et al. re-analyzed the cadmium smelter worker population (near Denver, CO) using more detailed work history information, a revised cadmium exposure matrix, a detailed retrospective exposure assessment for arsenic (potential confounder), and updated mortality data (through 2002). Grouped observed and expected number of lung cancer mortalities along with cumulative cadmium exposures were used in the current study to obtain the maximum likelihood estimate and asymptotic variance of the slope (β) for the linear multiplicative relative risk model using Poisson regression modeling. Life-table analyses were used to derive the final URF for cadmium of 4.9E-04 per μg Cd/m3. The corresponding lifetime air concentration at the 1 in 100,000 no significant excess risk level is 0.020 μg Cd/m3, which can be used to protect the general public in Texas against the potential carcinogenic effects from chronic exposure to cadmium and cadmium compounds.
•A new unit risk factor of 4.9E-04 per μg Cd/m3 has been developed for cadmium.•New dose–response analyses were conducted with the latest scientific methods.•The URF is based on Park et al. (2012), the latest update of Thun et al. (1985).•The corresponding 1 in 100,000 no significant excess risk level is 0.020 μg Cd/m3.•This value is protective of the potential carcinogenic effects from chronic exposure.
•Mouse target tissue absorption per unit dose decreases appreciably with dose.•It is about 10-fold lower at the dose at the MCL than at the draft SFo POD dose.•This toxicokinetic phenomenon is ...inconsistent with linear low-dose extrapolation.•The dose–response curve accounting for this would clearly be non-linear.•A non-linear approach is most defensible for a cancer-based oral toxicity factor.
Dose-dependent changes in target tissue absorption have important implications for determining the most defensible approach for developing a cancer-based oral toxicity factor for hexavalent chromium (CrVI). For example, mouse target tissue absorption per unit dose is an estimated 10-fold lower at the CrVI dose corresponding to the federal maximum contaminant level (MCL) than at the USEPA draft oral slope factor (SFo) point of departure dose. This decreasing target tissue absorption as doses decrease to lower, more environmentally-relevant doses is inconsistent with linear low-dose extrapolation. The shape of the dose–response curve accounting for this toxicokinetic phenomenon would clearly be non-linear. Furthermore, these dose-dependent differences in absorption indicate that the magnitude of risk overestimation by a linear low-dose extrapolation approach (e.g., SFo) increases and is likely to span one or perhaps more orders of magnitude as it is used to predict risk at progressively lower, more environmentally-relevant doses. An additional apparent implication is that no single SFo can reliably predict risk across potential environmental doses (e.g., doses corresponding to water concentrations⩽the federal MCL). A non-linear approach, consistent with available mode of action data, is most scientifically defensible for derivation of an oral toxicity factor for CrVI-induced carcinogenesis.
The pathobiology of Parkinson's disease (PD) is associated with the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) projecting to the striatum. Currently, there are no ...treatments that can halt or reverse the course of PD; only palliative therapies, such as replacement strategies for missing neurotransmitters, exist. Thus, the successful brain delivery of neurotrophic factors that promote neuronal survival and reverse the disease progression is crucial. We demonstrated earlier systemically administered autologous macrophages can deliver nanoformulated antioxidant, catalase, to the SNpc providing potent anti-inflammatory effects in PD mouse models. Here we evaluated genetically-modified macrophages for active targeted brain delivery of glial cell-line derived neurotropic factor (GDNF). To capitalize on the beneficial properties afforded by alternatively activated macrophages, transfected with GDNF-encoded pDNA cells were further differentiated toward regenerative M2 phenotype. A systemic administration of GDNF-expressing macrophages significantly ameliorated neurodegeneration and neuroinflammation in PD mice. Behavioral studies confirmed neuroprotective effects of the macrophage-based drug delivery system. One of the suggested mechanisms of therapeutic effects is the release of exosomes containing the expressed neurotropic factor followed by the efficient GDNF transfer to target neurons. Such formulations can serve as a new technology based on cell-mediated active delivery of therapeutic proteins that attenuate and reverse progression of PD, and ultimately provide hope for those patients who are already significantly disabled by the disease.
The ability to precisely upregulate genes in inflamed brain holds great therapeutic promise. Here we report a novel class of vectors, genetically modified macrophages that carry reporter and ...therapeutic genes to neural cells. Systemic administration of macrophages transfected ex vivo with a plasmid DNA (pDNA) encoding a potent antioxidant enzyme, catalase, produced month-long expression levels of catalase in the brain resulting in three-fold reductions in inflammation and complete neuroprotection in mouse models of Parkinson's disease (PD). This resulted in significant improvements in motor functions in PD mice. Mechanistic studies revealed that transfected macrophages secreted extracellular vesicles, exosomes, packed with catalase genetic material, pDNA and mRNA, active catalase, and NF-κb, a transcription factor involved in the encoded gene expression. Exosomes efficiently transfer their contents to contiguous neurons resulting in de novo protein synthesis in target cells. Thus, genetically modified macrophages serve as a highly efficient system for reproduction, packaging, and targeted gene and drug delivery to treat inflammatory and neurodegenerative disorders.
•Dose-dependent differences in the dose fraction absorbed are quantified.•The dose fraction absorbed at the draft SFo point-of-departure is relatively high.•Environmentally-relevant hexavalent ...chromium oral doses are significantly lower.•Lower dose fraction absorbed at more human-relevant doses needs consideration.•Draft SFo should be divided by at least 10 to be more predictive at lower doses.
The mouse dose at the lowest water concentration used in the National Toxicology Program hexavalent chromium (CrVI) drinking water study (NTP, 2008) is about 74,500 times higher than the approximate human dose corresponding to the 35-city geometric mean reported in EWG (2010) and over 1000 times higher than that based on the highest reported tap water concentration. With experimental and environmental doses differing greatly, it is a regulatory challenge to extrapolate high-dose results to environmental doses orders of magnitude lower in a meaningful and toxicologically predictive manner. This seems particularly true for the low-dose extrapolation of results for oral CrVI-induced carcinogenesis since dose-dependent differences in the dose fraction absorbed by mouse target tissues are apparent (Kirman et al., 2012). These data can be used for a straightforward adjustment of the USEPA (2010) draft oral slope factor (SFo) to be more predictive of risk at environmentally-relevant doses. More specifically, the evaluation of observed and modeled differences in the fraction of dose absorbed by target tissues at the point-of-departure for the draft SFo calculation versus lower doses suggests that the draft SFo be divided by a dose-specific adjustment factor of at least an order of magnitude to be less over-predictive of risk at more environmentally-relevant doses.
Several international conservation organizations have recently produced global priority maps to guide conservation activities and spending in their own and other conservation organizations. ...Surprisingly, it is not possible to directly evaluate the relationship between priorities and spending within a given organization because none of the organizations with global priority models tracks how they spend their money relative to their priorities. We were able, however, to evaluate the spending patterns of five other large biodiversity conservation organizations without their own published global priority models and investigate the potential influence of priority models on this spending. On average, countries with priority areas received greater conservation investment; global prioritization systems, however, explained between only 2 and 32% of the US$1.5 billion spent in 2002, depending on whether the United States was removed from analyses and whether conservation spending was adjusted by the per capita gross domestic product within each country. We also found little overlap in the spending patterns of the five conservation organizations evaluated, suggesting that informal coordination or segregation of effort may be occurring. Our results also highlight a number of potential gaps and mismatches in how limited conservation funds are spent and provide the first audit of global conservation spending patterns. More explicit presentation of conservation priorities by organizations currently without priority models and better tracking of spending by those with published priorities are clearly needed to help make future conservation activities as efficient as possible.
Two separate approaches, a carcass sampling model and an exposure probability model, provided estimates of bird mortalities of 600 000 and 800 000, respectively, from the 2010 Deepwater Horizon MC ...252 oil spill in coastal waters of the Gulf of Mexico. Monte Carlo simulation of parameter uncertainty led to respective 95% uncertainty intervals of 320 000 to 1200 000 and 160 000 to 1900 000. Carcass sampling relied on expansion factors multiplied by counts of bird carcasses retrieved in shoreline surveys, whereas exposure probability estimated bird deaths as a product of estimated coastal bird density, average oil slick size, slick duration, and proportionate mortality due to oiling. The low proportion of small-sized carcasses recovered, compared with considerably higher proportions of small live birds in coastal Gulf habitats, indicate an especially low probability of recovery for small birds after oil spills at sea. Most mortality affected 4 species: laughing gull Leucophaeus atricilla (32% of the northern Gulf of Mexico population killed), royal tern Thalasseus maximus (15%), northern gannet Morus bassanus (8%) and brown pelican Pelecanus occidentalis (12%). Declines in laughing gulls were confirmed by ~60% reductions in National Audubon Society Christmas Bird Count data for 2010–2013 along the Gulf coast. Population-level effects in apex predators of this magnitude likely had effects on prey populations that warrant careful assessment.
The Gulf of Mexico supports many seabird species, yet data gaps describing species composition and habitat use are prevalent. We used vessel-based observations from the Gulf of Mexico Marine ...Assessment Program for Protected Species to identify and characterize distinct seabird assemblages in the northern Gulf of Mexico (within the U.S. Exclusive Economic Zone; nGoM). Using cluster analysis of 17 seabird species, we identified assemblages based on seabird relative density. Vessel-based surveys documented the location, species, and number of seabirds across the nGoM between 2017-2019. For each assemblage, we identified the (co-)dominant species, spatial distribution, and areas of greater relative density. We also assessed the relationship of the total relative density within each assemblage with environmental, spatial, and temporal covariates. Of the species assessed, 76% (n = 13) breed predominantly outside the nGoM basin. We identified four seabird assemblages. Two assemblages, one dominated by black tern and the other co-dominated by northern gannet/laughing gull, occurred on the continental shelf. An assemblage dominated by sooty tern occurred along the continental slope into pelagic waters. The fourth assemblage had no dominant species, was broadly distributed, and was composed of observations with low relative density ('singles' assemblage). Differentiation of assemblages was linked to migratory patterns, residency, and breeding location. The spatial distributions and relationships of the black tern and northern gannet/laughing gull assemblages with environmental covariates indicate associations with river outflows and ports. The sooty tern assemblage overlapped an area prone to mesoscale feature formation. The singles assemblage may reflect commuting and dispersive behaviors. These findings highlight the importance of seasonal migrations and dynamic features across the seascape, shaping seabird assemblages. Considering the potential far-ranging effects of interactions with seabirds in the nGoM, awareness of these unique patterns and potential links with other fauna could inform future monitoring, research, restoration, offshore energy, and aquaculture development in this highly industrialized sea.
Disease activity measurement is a key component of rheumatoid arthritis (RA) management. Biomarkers that capture the complex and heterogeneous biology of RA have the potential to complement clinical ...disease activity assessment.
To develop a multi-biomarker disease activity (MBDA) test for rheumatoid arthritis.
Candidate serum protein biomarkers were selected from extensive literature screens, bioinformatics databases, mRNA expression and protein microarray data. Quantitative assays were identified and optimized for measuring candidate biomarkers in RA patient sera. Biomarkers with qualifying assays were prioritized in a series of studies based on their correlations to RA clinical disease activity (e.g. the Disease Activity Score 28-C-Reactive Protein DAS28-CRP, a validated metric commonly used in clinical trials) and their contributions to multivariate models. Prioritized biomarkers were used to train an algorithm to measure disease activity, assessed by correlation to DAS and area under the receiver operating characteristic curve for classification of low vs. moderate/high disease activity. The effect of comorbidities on the MBDA score was evaluated using linear models with adjustment for multiple hypothesis testing.
130 candidate biomarkers were tested in feasibility studies and 25 were selected for algorithm training. Multi-biomarker statistical models outperformed individual biomarkers at estimating disease activity. Biomarker-based scores were significantly correlated with DAS28-CRP and could discriminate patients with low vs. moderate/high clinical disease activity. Such scores were also able to track changes in DAS28-CRP and were significantly associated with both joint inflammation measured by ultrasound and damage progression measured by radiography. The final MBDA algorithm uses 12 biomarkers to generate an MBDA score between 1 and 100. No significant effects on the MBDA score were found for common comorbidities.
We followed a stepwise approach to develop a quantitative serum-based measure of RA disease activity, based on 12-biomarkers, which was consistently associated with clinical disease activity levels.
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