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The intention of this study was to determine the utility of high-throughput screening (HTS) data, as exemplified by ToxCast and Tox21, for application in toxicological read-across in food-relevant chemicals. Key questions were addressed on the extent to which the HTS data could provide information enabling (1) the elucidation of underlying bioactivities associated with apical toxicological outcomes, (2) the closing of existing toxicological data gaps, and (3) the definition of the boundaries of chemical space across which bioactivity could reliably be extrapolated. Results revealed that many biological targets apparently activated within the chemical groupings lack, at this time, validated toxicity pathway associations. Therefore, as means of providing proof-of-principle, a comparatively well-characterized end point - estrogenicity - was selected for evaluation. This was facilitated through the preparation of two exploratory case studies, focusing upon groupings of paraben-gallates and pyranone-type compounds (notably flavonoids). Within both, the HTS data were seen to reflect estrogenic potencies in a manner which broadly corresponded to established structure-activity group relationships, with parabens and flavonoids displaying greater estrogen receptor affinity than benzoate esters and alternative pyranone-containing molecules, respectively. As such, utility in the identification of out-of-domain compounds was demonstrated, indicating potential for application in addressing point (3) as detailed above.

The UK has, in common with many developed countries, a growing elderly population, and within this demographic, digital exclusion is now seen as social care issue. This has become a policy challenge for local government that has an equivocal track record, from e-government to smart cities, of implementing digital policy agendas. This failure has been attributed to a policy implementation approach rooted in a model of governance that is no longer fit for purpose. This has been acknowledged by some local policymakers who are now experimenting with new, more cost-effective ways of addressing this challenge. This article examines how one local authority developed a project to co-create digital applications for elderly people. It presents a case study of a new, more collaborative, and innovative approach with urban actors who have not traditionally been involved in delivering this policy agenda.

Tox21 and ToxCast are high-throughput in vitro screening programs coordinated by the U.S. National Toxicology Program and the U.S. Environmental Protection Agency, respectively, with the goal of forecasting biological effects in vivo based on bioactivity profiling. The present study investigated whether mechanistic insights in the biological targets of food-relevant chemicals can be obtained from ToxCast results when the chemicals are grouped according to structural similarity. Starting from the 556 direct additives that have been identified in the ToxCast database by Karmaus et al. [Karmaus, A. L., Trautman, T. D., Krishan, M., Filer, D. L., and Fix, L. A. (2017). Curation of food-relevant chemicals in ToxCast. Food Chem. Toxicol. 103, 174–182.], the results showed that, despite the limited number of assays in which the chemical groups have been tested, sufficient results are available within so-called “DNA binding” and “nuclear receptor” target families to profile the biological activities of the defined chemical groups for these targets. The most obvious activity identified was the estrogen receptor-mediated actions of the chemical group containing parabens and structurally related gallates, as well the chemical group containing genistein and daidzein (the latter 2 being particularly active toward estrogen receptor β as a potential health benefit). These group effects, as well as the biological activities of other chemical groups, were evaluated in a series of case studies. Overall, the results of the present study suggest that high-throughput screening data could add to the evidence considered for regulatory risk assessment of food chemicals and to the evaluation of desirable effects of nutrients and phytonutrients. The data will be particularly useful for providing mechanistic information and to fill data gaps with read-across.

Food chemical risk assessment characterizes the potential hazards and the associated health risks resulting from exposure of humans to chemicals present in food over a specified period. This requires the identification of points of departure, which are usually derived from apical toxicity endpoints in in vivo studies. However, a shift in the traditional paradigm in toxicity testing for risk assessment has started, and increasing attention is now being paid to the use of mechanistic-based and exposure-based approaches, including toxicogenomics and quantitative in vitro-to-in vivo extrapolation. This review outlines the most recent examples of application of these new approaches to derive points of departure in food chemical risk assessment, as well as the challenges limiting their full application and future directions.

Transfection of a murine colon adenocarcinoma cell line (MAC13) with DNA extracted from GM892 or Raii cells previously treated with either the methyl- (temozolomide) or ethyl- (CCRG82019) imidazotetrazinones caused a dose-related suppression of cell growth. The effect was proportional to the concentration of DNA transfected and the time of incubation of the donor cell lines with the drugs. It was not shown with X-irradiated DNA suggesting that the effect did not arise from non-specific damage to the DNA. Transfection of MAC13 cells with DNA extracted from GM892 cells was more effective in inhibiting growth than DNA from Raji cells, and temozolomide treated cellular DNA was a more potent growth inhibitor than that from CCRG 82019 treated cells. For both agents the growth inhibitory effect was most marked with DNA extracted 6 hr after drug addition and thereafter the effect decreased up to 24 hr after drug addition. This suggests that the growth inhibitory effect is due to a repairable lesion, and that the terminal mechanism of action of these agents involves targets after DNA.

Very few traditional foods that are consumed have been subjected to systematic toxicological and nutritional assessment, yet because of their long history and customary preparation and use and absence of evidence of harm, they are generally regarded as safe to eat. This &39;history of safe use&39; of traditional foods forms the benchmark for the comparative safety assessment of novel foods, and of foods derived from genetically modified organisms. However, the concept is hard to define, since it relates to an existing body of information which describes the safety profile of a food, rather than a precise checklist of criteria. The term should be regarded as a working concept used to assist the safety assessment of a food product. Important factors in establishing a history of safe use include: the period over which the traditional food has been consumed; the way in which it has been prepared and used and at what intake levels; its composition and the results of animal studies and observations from human exposure. This paper is aimed to assist food safety professionals in the safety evaluation and regulation of novel foods and foods derived from genetically modified organisms, by describing the practical application and use of the concept of &39;history of safe use&39;.

Methylation of Micrococcus lysodeikticus DNA by purified DNA methylase isolated from L1210 leukemia cells is potently and specifically inhibited by both hetero and homoribo and deoxyribonucleotides containing guanine residues. The inhibitory effect is unaffected by chain length, but is abolished when the O 6 residue of guanine is substituted as in poly[d(O 6 MeG)] 20 . Potent inhibition is also shown by polyinosinic and polyxanthylic acids, but not by polyadenylic acid or by heteropolymers containing adenine and thymine. These results suggest that the 6-position of the purine nucleus is important in binding of the DNA methylase to a particular region of the DNA duplex and that the hydrogen bonding properties of this group are important in enzyme recognition.

Background: Food legislation in the European Union and elsewhere includes both hazard- and risk-based approaches for ensuring safety. In hazard-based approaches, simply the presence of a potentially harmful agent at a detectable level in food is used as a basis for legislation and/or risk management action. Risk-based approaches allow consideration of exposure in assessing whether there may be unacceptable risks to health. Scope and approach: The advantages and disadvantages of hazard- and risk-based approaches for ensuring the safety of food chemicals, allergens, ingredients and microorganisms were explored at an ILSI Europe workshop. Key findings and conclusions: It was concluded that both types of approach have their place, depending on the context. However, problems can arise when both types of approach are used in regulation by separate agencies that address different aspects of the same agent/substance present in food. This separation of decision-making can result in hazard-based restrictions on marketing and use, whereas risk-based assessments for those exposed show there is reasonable certainty no harm will result. This in turn can lead to contradictory, confusing and ultimately unnecessary actions. Use of hazard-based approaches for foods also means that comparisons with benefits for nutrition and food security cannot be undertaken. This has the potential to lead to bias in the overall conclusions of regulators and risk managers, who may not have been presented with the benefits of particular foods. The value of risk-based approaches is becoming increasingly recognised. © 2015 ILSI Europe A.I.S.B.L.