Application of the U.S. EPA Mode of Action Framework for Purposes of Guiding Future Research: A Case Study Involving the Oral Carcinogenicity of Hexavalent Chromium

Mode of action (MOA) analysis provides a systematic description of key events leading to adverse health effects in animal bioassays for the purpose of informing human health risk assessment. Uncertainties and data gaps identified in the MOA analysis may also be used to guide future research to improve understanding of the MOAs underlying a specific toxic response and foster development of toxicokinetic and toxicodynamic models. An MOA analysis, consistent with approaches outlined in the MOA Framework as described in the Guidelines for Carcinogen Risk Assessment, was conducted to evaluate small intestinal tumors observed in mice chronically exposed to relatively high concentrations of hexavalent chromium (Cr(VI)) in drinking water. Based on review of the literature, key events in the MOA are hypothesized to include saturation of the reductive capacity of the upper gastrointestinal tract, absorption of Cr(VI) into the intestinal epithelium, oxidative stress and inflammation, cell proliferation, direct and/or indirect DNA modification, and mutagenesis. Although available data generally support the plausibility of these key events, several unresolved questions and data gaps were identified, highlighting the need for obtaining critical toxicokinetic and toxicodynamic data in the target tissue and in the low-dose range. Experimental assays that can address these data gaps are discussed along with strategies for comparisons between responsive and nonresponsive tissues and species. This analysis provides a practical application of MOA Framework guidance and is instructive for the design of studies to improve upon the information available for quantitative risk assessment

Refinement of arsenic attributable health risks in rural Pakistan using population specific dietary intake values

Background: Previous risk assessment studies have often utilised generic consumption or intake values when evaluating ingestion exposure pathways. If these values do not accurately reflect the country or scenario in question, the resulting risk assessment will not provide a meaningful representation of cancer risks in that particular country/scenario. Objectives: This study sought to determine water and food intake parameters for one region in South Asia, rural Pakistan, and assess the role population specific intake parameters play in cancer risk assessment. Methods: A questionnaire was developed to collect data on sociodemographic features and 24-hour water and food consumption patterns from a rural community. The impact of dietary differences on cancer susceptibility linked to arsenic exposure was evaluated by calculating cancer risks using the data collected in the current study against standard water and food intake levels for the USA, Europe and Asia. A probabilistic cancer risk was performed for each set of intake values of this study. Results: Average daily total water intake based on drinking direct plain water and indirect water from food and beverages was found to be 3.5 L day-1 (95% CI: 3.38, 3.57) exceeding the US Environmental Protection Agency’s default (2.5 L day-1) and World Health Organization’s recommended intake value (2 L day-1). Average daily rice intake (469 g day-1) was found to be lower than in India and Bangladesh whereas wheat intake (402 g day−1) was higher than intake reported for USA, Europe and Asian sub-regions. Consequently, arsenic-associated cumulative cancer risks determined for daily water intake was found to be 17 in children of 3-6 years (95% CI: 0.0014, 0.0017), 14 in children of age 6-16 years (95% CI: 0.001, 0.0011) and 6 in adults of 16-67 years (95% CI: 0.0006, 0.0006) in a population size of 10000. This is higher than the risks estimated using the US Environmental Protection Agency and World Health Organization’s default recommended water intake levels. Rice intake data showed early life cumulative cancer risks of 15 in 10000 for children of 3-6 years (95% CI: 0.0012, 0.0015), 14 in children of 6-16 years (95% CI: 0.0011, 0.0014) and later life risk of 8 in adults (95% CI: 0.0008, 0.0008) in a population of 10000. This is lower than cancer risks in countries with higher rice intake and elevated arsenic levels (Bangladesh and India). Cumulative cancer risk from arsenic exposure showed the relative risk contribution from total water to be51%, from rice to be44% and wheat intake 5%. Conclusions: The study demonstrates the need to use population specific dietary information for risk assessment and risk management studies. Probabilistic risk assessment concluded the importance of dietary intake in estimating cancer risk, along with arsenic concentrations in water or food and age of exposed rural population

Cross-Sector Review of Drivers and Available 3Rs Approaches for Acute Systemic Toxicity Testing

Acute systemic toxicity studies are carried out in many sectors in which synthetic chemicals are manufactured or used and are among the most criticized of all toxicology tests on both scientific and ethical grounds. A review of the drivers for acute toxicity testing within the pharmaceutical industry led to a paradigm shift whereby in vivo acute toxicity data are no longer routinely required in advance of human clinical trials. Based on this experience, the following review was undertaken to identify (1) regulatory and scientific drivers for acute toxicity testing in other industrial sectors, (2) activities aimed at replacing, reducing, or refining the use of animals, and (3) recommendations for future work in this area

The emergence of circular economy: a new framing around prolonging resource productivity

In this article we use Hirsch and Levin’s (1999) notion of ‘umbrella concepts’ as an analytical lens, in order to articulate the valuable catalytic function the circular economy concept could perform in the waste and resource management debate. We realize this goal by anchoring the circular economy concept in this broader debate through a narrative approach. This leads to the insight that while the various resource strategies grouped under circular economy’s banner are not new individually, the concept offers a new framing of these strategies by drawing attention to their capacity of prolonging resource use as well as to the relationship between these strategies. As such, circular economy offers a new perspective on waste and resource management and provides a new cognitive unit and discursive space for debate. We conclude by discussing research opportunities for the IE community relating to the concept’s theoretical development and its implementation. Specifically, we pose that reinvigorating and growing the social science aspects of IE is required for both. After all, it is the wide adoption and collective implementation of an idea that shapes our material future

Evaluating the contribution of changes in isoprene emissions to surface ozone trends over the eastern United States

Reducing surface ozone (O3) to concentrations in compliance with the national air quality standard has proven to be challenging, despite tighter controls on O3 precursor emissions over the past few decades. New evidence indicates that isoprene emissions changed considerably from the mid-1980s to the mid-1990s owing to land-use changes in the eastern United States (Purves et al., 2004). Over this period, U.S. anthropogenic VOC (AVOC) emissions decreased substantially. Here we apply two chemical transport models (GEOS-CHEM and MOZART-2) to test the hypothesis, put forth by Purves et al. (2004), that the absence of decreasing O3 trends over much of the eastern United States may reflect a balance between increases in isoprene emissions and decreases in AVOC emissions. We find little evidence for this hypothesis; over most of the domain, mean July afternoon (1300–1700 local time) surface O3 is more responsive (ranging from −9 to +7 ppbv) to the reported changes in anthropogenic NOx emissions than to the concurrent isoprene (−2 to +2 ppbv) or AVOC (−2 to 0 ppbv) emission changes. The estimated magnitude of the O3 response to anthropogenic NOx emission changes, however, depends on the base isoprene emission inventory used in the model. The combined effect of the reported changes in eastern U.S. anthropogenic plus biogenic emissions is insufficient to explain observed changes in mean July afternoon surface O3 concentrations, suggesting a possible role for decadal changes in meteorology, hemispheric background O3, or subgrid-scale chemistry. We demonstrate that two major uncertainties, the base isoprene emission inventory and the fate of isoprene nitrates (which influence surface O3 in the model by −15 to +4 and +4 to +12 ppbv, respectively), preclude a well-constrained quantification of the present-day contribution of biogenic or anthropogenic emissions to surface O3 concentrations, particularly in the high-isoprene-emitting southeastern United States. Better constraints on isoprene emissions and chemistry are needed to quantitatively address the role of isoprene in eastern U.S. air quality