Systematic update to the mammalian relative potency estimate database and development of best estimate toxic equivalency factors for dioxin-like compounds.

The World Health Organization (WHO) assesses potential health risks of dioxin-like compounds using Toxic Equivalency Factors (TEFs). This study systematically updated the relative potency (REP) database underlying the 2005 WHO TEFs and applied advanced methods for quantitative integration of study quality and dose-response. Data obtained from fifty-one publications more than doubled the size of the previous REP database (∼1300 datasets). REP quality and relevance for these data was assessed via application of a consensus-based weighting framework. Using Bayesian dose-response modeling, available data were modeled to produce standardized dose/concentration-response Hill curves. Study quality and REP data were synthesized via Bayesian meta-analysis to integrate dose/concentration-response data, author-calculated REPs and benchmark ratios. The output is a prediction of the most likely relationship between each congener and its reference as model-predicted TEF uncertainty distributions, or the 'best estimate TEF' (BE-TEF). The resulting weighted BE-TEFs were similar to the 2005 TEFs, though provide more information to inform selection of TEF values as well as to provide risk assessors and managers with information needed to quantitatively characterize uncertainty around TEF values. Collectively, these efforts produce an updated REP database and an objective, reproducible approach to support development of TEF values based on all available data.

A high dose mode of action for tetrabromobisphenol A-induced uterine adenocarcinomas in Wistar Han rats: A critical evaluation of key events in an adverse outcome pathway framework.

TBBPA is a non-genotoxic flame retardant used to improve fire safety in a wide variety of consumer products. Estimated human exposures to TBBPA are very low (<0.000084 mg/kg-day), relative to the doses (500 and 1000 mg/kg-day of TBBPA) administered in a recent bioassay that resulted in uterine tumors in Wistar Han rats following chronic exposure. As part of an effort to characterize the relevance of the uterine tumors to humans, data and biological knowledge relevant to the progression of events associated with TBBPA-induced uterine tumors in female rats were organized in an adverse outcome pathway (AOP) framework. Based on a review of possible MOAs for chemically induced uterine tumors and available TBBPA data sets, a plausible molecular initiating event (MIE) was the ability of TBBPA to bind to and inhibit estrogen sulfotransferases, the enzymes responsible for sulfation of estradiol. Subsequent key events in the AOP, including increased bioavailability of unconjugated estrogens in uterine tissue, would occur as a result of decreased sulfation, leading to a disruption in estrogen homeostasis, increased expression of estrogen responsive genes, cell proliferation, and hyperplasia. Available data support subsequent key events, including generation of reactive quinones from the metabolism of estrogens, followed by DNA damage that could contribute to the development of uterine tumors. Uncertainties associated with human relevance are highlighted by potential strain/species sensitivities to development of uterine tumors, as well as the characterization of a dose-dependent MIE. For the latter, it was determined that the TBBPA metabolic profile is altered at high doses (such as those used in the cancer bioassay), and thus an MIE that is only operative under repeated high dose, administration. The MIE and subsequent key events for the development of TBBPA-induced uterine tumors are not feasible in humans given differences in the kinetic and dynamic factors associated with high dose exposures in rats relative to human exposure levels to TBBPA.

Lack of potential carcinogenicity for steviol glycosides - Systematic evaluation and integration of mechanistic data into the totality of evidence.

Steviol glycosides are present in the leaves of the Stevia rebaudiana plant, have a sweet taste, and have been used as a sweetener for centuries. To build on previous authoritative safety assessments of steviol glycosides, a systematic assessment of mechanistic data related to key characteristics of carcinogens (KCCs) was conducted. Over 900 KCC-relevant endpoints from peer-reviewed literature and high-throughput screening data (ToxCast/Tox21) were identified across individual steviol glycosides and derivatives, metabolites, and whole leaf extracts. Most data (both in vivo and in vitro, including human cells), showed inactivity. Studies were weighted according to quality and relevance. Although data were available for eight of the ten KCC, genotoxicity, oxidative stress, inflammation, and cell proliferation/cell death represent the KCCs with the most data. The data for these KCC primarily show beneficial activity (anti-inflammatory, antioxidant, and anti-proliferative). Following integration across all data, and accounting for study quality and relevance, the totality of the evidence demonstrated an overall lack of genotoxic and carcinogenic activity for steviol glycosides. This is in agreement with previous regulatory decisions, and is consistent with the lack of tumor response in two-year rodent cancer bioassays. The findings support prior conclusions that steviol glycosides are unlikely to be carcinogenic in humans.

Lack of potential carcinogenicity for aspartame - Systematic evaluation and integration of mechanistic data into the totality of the evidence.

Despite repeated confirmation of aspartame safety in a variety of foods and beverages, there continues to be interest in researching the potential carcinogenic risk associated with its consumption. The objective of this evaluation was to conduct a systematic assessment of available mechanistic data using a framework for quantitatively integrating the key characteristics of carcinogens (KCCs). For aspartame, 1332 endpoints were appraised for quality and relevance and quantitatively integrated using an algorithm to determine the potential for individual KCC activity based on all available evidence, and subsequently assessed in the context of human and animal evidence streams. An overall lack of activity (integrated scores <0 and no "strong" categorizations) was observed for all KCCs except oxidative stressor (#5), for which activity was determined to be unlikely to be related to a carcinogenic response. Overall, the KCC-based analysis, together with the lack of consistent evidence of carcinogenicity in experimental animals, continue to support lack of carcinogenicity from aspartame consumption. This comprehensive evaluation of available mechanistic data demonstrates the need for a systematic approach to identify and appraise all avaialble data as part of weight-of-evidence determinations related use of KCC in evaluations of potential human carcinogenicity.

Lack of potential carcinogenicity for acesulfame potassium - Systematic evaluation and integration of mechanistic data into the totality of the evidence.

The safety of low- and no-calorie sweeteners remains a topic of general interest. Substantial evidence exists demonstrating a lack of carcinogenicity of the no-calorie sweetener acesulfame potassium (Ace K). The objective of this evaluation was to conduct a systematic assessment of available mechanistic data using a framework that quantitatively integrates proposed key characteristics of carcinogens (KCCs) into the totality of the evidence. Over 800 KCC-relevant endpoints from a variety of in vitro and in vivo assays were assessed for quality, relevance, and activity, and integrated to determine the overall strength of the evidence for plausibility that Ace K acts through the KCC. Overall, there was a lack of activity across the KCCs (overall integrated score <0 and no "strong" categorization for evidence of activity) in which data were identified. Together with the absence of treatment-related tumor effects in rodent bioassays, these results support the conclusion that Ace K is unlikely to induce a carcinogenic response. This assessment employed a weight of the evidence analysis that includes the consideration of factors such as reliability, strength of the model system, activity, and dose in a complex and heterogeneous dataset, and the ultimate integration of multiple data streams in the cancer hazard evaluation.

Lack of potential carcinogenicity for sucralose - Systematic evaluation and integration of mechanistic data into the totality of the evidence.

Sucralose is widely used as a sugar substitute. Many studies and authoritative reviews have concluded that sucralose is non-carcinogenic, based primarily on animal cancer bioassays and genotoxicity data. To add to the body of knowledge on the potential carcinogenicity of sucralose, a systematic assessment of mechanistic data was conducted. This entailed using a framework developed for the quantitative integration of data related to the proposed key characteristics of carcinogens (KCCs). Data from peer-reviewed literature and the ToxCast/Tox21 database were evaluated using an algorithm that weights data for quality and relevance. The resulting integration demonstrated an overall lack of activity for sucralose across the KCCs, with no "strong" activity observed for any KCC. Almost all data collected demonstrated inactivity, including those conducted in human models. The overall lack of activity in mechanistic data is consistent with findings from animal cancer bioassays. The few instances of activity across the KCC were generally accompanied by limitations in study design in the context of either quality and/or dose and model relevance, highlighted upon integration of the totality of the evidence. The findings from this comprehensive and integrative evaluation of mechanistic data support prior conclusions that sucralose is unlikely to be carcinogenic in humans.

Benefit-risk analysis for foods (BRAFO): Evaluation of exposure to dietary nitrates.

Dietary nitrate has been associated with health benefits as well as potential risks, thus presenting a paradox for consumers and health professionals. To address the issue, we applied the Benefit-Risk Analysis for Foods (BRAFO) framework to evaluate dietary exposure to nitrate by considering how the risks and benefits might vary under the reference scenario of the acceptable daily intake (ADI) set forth by JECFA (3.7 mg/kg-day), or under an alternative scenario of a higher ADI (independently developed herein). Results demonstrated that risk, as conservatively characterized by various toxicological benchmarks, was present at levels ranging from the current ADI value of 3.7 mg/kg-day (lowest end of the range) to >15 mg/kg-day. When these ADI values, both established by regulatory bodies as well as independently herein were compared to intakes associated with benefits (decreased blood pressure observed following repeated exposure to nitrates ∼4-18 mg/kg-day), along with considerations of current dietary exposures associated with healthy diets, the alternative scenario allowed for benefits without incurring additional risk. For consumers aged 12 weeks and older, ADI values ∼12-17 mg/kg-day-based on more reliable data than used to derive the current ADI-allow benefits to be realized while still protecting public health. The assessment serves as a case study in how benefits can be considered in a risk assessment paradigm for foods, thus providing useful information to decision makers.

Evaluation of impact of shale gas operations in the Barnett Shale region on volatile organic compounds in air and potential human health risks.

Shale gas exploration and production (E&P) has experienced substantial growth across the U.S. over the last decade. The Barnett Shale, in north-central Texas, contains one of the largest, most active onshore gas fields in North America, stretching across 5000 square miles and having an estimated 15,870 producing wells as of 2011. Given that these operations may occur in relatively close proximity to populated/urban areas, concerns have been expressed about potential impacts on human health. In response to these concerns, the Texas Commission on Environmental Quality established an extensive air monitoring network in the region. This network provides a unique data set for evaluating the potential impact of shale gas E&P activities on human health. As such, the objective of this study was to evaluate community-wide exposures to volatile organic compounds (VOCs) in the Barnett Shale region. In this current study, more than 4.6 million data points (representing data from seven monitors at six locations, up to 105 VOCs/monitor, and periods of record dating back to 2000) were evaluated. Measured air concentrations were compared to federal and state health-based air comparison values (HBACVs) to assess potential acute and chronic health effects. None of the measured VOC concentrations exceeded applicable acute HBACVs. Only one chemical (1,2-dibromoethane) exceeded its applicable chronic HBACV, but it is not known to be associated with shale gas production activities. Annual average concentrations were also evaluated in deterministic and probabilistic risk assessments and all risks/hazards were below levels of concern. The analyses demonstrate that, for the extensive number of VOCs measured, shale gas production activities have not resulted in community-wide exposures to those VOCs at levels that would pose a health concern. With the high density of active wells in this region, these findings may be useful for understanding potential health risks in other shale play regions.

5th International PCB Workshop--summary and implications.

A summation of new and novel findings presented at "The Fifth PCB Workshop: New Knowledge Gained from Old Pollutants" workshop is provided in this overview, along with discussion of data gaps and research needs in the future. Relative to the previous workshop, the scientific presentations had a decreased emphasis on toxicology; rather, more than half of the sessions dealt with environmental sources, fate and transport, or transformations. Approximately 100 presentations in the form of talks and posters were included in the workshop. The presentations were generally divided into: emissions and transport of PCBs in natural and urban settings; chiral aspects of PCB transport; metabolism and distribution; new aspects of environmental metabolism of PCBs--from microbes to plants to animals; reproduction, developmental and cardiovascular effects of PCBs; updates on Anniston--the most highly exposed PCB community in the U.S. to date; and new and novel approaches for evaluating PCB mixtures (e.g., PCB toxic equivalency factors, and TEFs)--and the implications of such for risk assessment. An overarching state-of-the-science view is important to the goal of preventing negative health consequences. Currently, there are still many roadblocks to evaluating risk associated with this large group of 209 congeners--all of which have different physiochemical properties, variable fate and transport mechanism in the environment, and a range of ability for persistence, bioaccumulation, and biological activity.