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Aspartame has been studied extensively and evaluated for its safety in foods and beverages yet concerns for its potential carcinogenicity have persisted, driven primarily by animal studies conducted at the Ramazzini Institute (RI). To address this controversy, an updated systematic review of available human, animal, and mechanistic data was conducted leveraging critical assessment tools to consider the quality and reliability of data. The evidence base includes 12 animal studies and40 epidemiological studies reviewed by the World Health Organization which collectively demonstrate a lack of carcinogenic effect. Assessment of1360 mechanistic endpoints, including many guideline-based genotoxicity studies, demonstrate a lack of activity associated with endpoints grouped to key characteristics of carcinogens. Other non-specific mechanistic data (e.g., mixed findings of oxidative stress across study models, tissues, and species) do not provide evidence of a biologically plausible carcinogenic pathway associated with aspartame. Taken together, available evidence supports that aspartame consumption is not carcinogenic in humans and that the inconsistent findings of the RI studies may be explained by flaws in study design and conduct (despite additional analyses to address study limitations), as acknowledged by authoritative bodies.

Vaping is the process of inhaling and exhaling an aerosol produced by an e-cigarette, vape pen, or personal aerosolizer. When the device contains nicotine, the Food and Drug Administration (FDA) lists the product as an electronic nicotine delivery system or ENDS device. Similar electronic devices can be used to vape cannabis extracts. Over the past decade, the vaping market has increased exponentially, raising health concerns over the number of people exposed and a nationwide outbreak of cases of severe, sometimes fatal, lung dysfunction that arose suddenly in otherwise healthy individuals. In this review, we discuss the various vaping technologies, which are remarkably diverse, and summarize the use prevalence in the U.S. over time by youths and adults. We examine the complex chemistry of vape carrier solvents, flavoring chemicals, and transformation products. We review the health effects from epidemiological and laboratory studies and, finally, discuss the proposed mechanisms underlying some of these health effects. We conclude that since much of the research in this area is recent and vaping technologies are dynamic, our understanding of the health effects is insufficient. With the rapid growth of ENDS use, consumers and regulatory bodies need a better understanding of constituent-dependent toxicity to guide product use and regulatory decisions.

Studies of neonatal health risks of unconventional natural gas development (UNGD) have not included comprehensive assessments of environmental chemical exposures. We investigated a clustering of dysphagic cases in neonatal foals born between 2014 and 2016 in an area of active UNGD in Pennsylvania (PA),USA. We evaluated equine biological data and environmental exposures on the affected PA farm and an unaffected New York (NY) farm owned by the same proprietor. Dams either spent their entire gestation on one farm or moved to the other farm in late gestation. Over the 21-month study period, physical examinations and blood/tissue samples were obtained from mares and foals on each farm. Grab samples of water, pasture soil and feed were collected; continuous passive sampling of air and water for polycyclic aromatic hydrocarbons was performed. Dysphagia was evaluated as a binary variable; logistic regression was used to identify risk factors. Sixty-five foals were born, 17 (all from PA farm) were dysphagic. Odds of dysphagia increased with the dam residing on the PA farm for each additional month of gestation (OR = 1.4, 95% CI 1.2, 1.7, p = 6.0E-04). Males were more likely to be born dysphagic (OR = 5.5, 95% CI 1.2, 24.5, p = 0.03) than females. Prior to installation of a water filtration/treatment system, PA water concentrations of 3,6-dimethylphenanthrene (p = 6.0E-03), fluoranthene (p = 0.03), pyrene (p = 0.02) and triphenylene (p = 0.01) exceeded those in NY water. Compared to NY farm water, no concentrations of PAHs were higher in PA following installation of the water filtration/treatment system. We provide evidence of an uncommon adverse health outcome (dysphagia) in foals born near UNGD that was eliminated in subsequent years (2017–2019) following environmental management changes. Notably, this study demonstrates that domestic large animals such as horses can serve as important sentinels for human health risks associated with UNGD activities.

One of the most difficult challenges for risk assessment is evaluation of chemicals that predominately co-occur in mixtures like polycyclic aromatic hydrocarbons (PAHs). We previously developed a classification model in which systems biology data collected from mice short-term after chemical exposure accurately predict tumor outcome. The present study demonstrates translation of this approach into a human in vitro model in which chemical-specific bioactivity profiles from 3D human bronchial epithelial cells (HBEC) classify PAHs by carcinogenic potency. Gene expression profiles were analyzed from HBEC exposed to carcinogenic and non-carcinogenic PAHs and classification accuracies were identified for individual pathway-based gene sets. Posterior probabilities of best performing gene sets were combined via Bayesian integration resulting in a classifier with four gene sets, including aryl hydrocarbon receptor signaling, regulation of epithelial mesenchymal transition, regulation of angiogenesis, and cell cycle G2-M. In addition, transcriptional benchmark dose modeling of benzo[a]pyrene (BAP) showed that the most sensitive gene sets to BAP regulation were largely dissimilar from those that best classified PAH carcinogenicity challenging current assumptions that BAP carcinogenicity (and subsequent mode of action) is reflective of overall PAH carcinogenicity. These results illustrate utility of using systems toxicology approaches to analyze global gene expression towards carcinogenic hazard assessment.