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Pyrrolizidine alkaloids (PAs) are among the most potent natural toxins occurring in a broad spectrum of plant species from various families. Recently, findings of considerable contamination of teas/herbal infusions prepared from non-PA plants have been reported. These are obviously due to cross-contamination with minor amounts of PA plants and can affect both food and herbal medicines. Another source of human exposure is honey collected from PA plants. These findings illustrate the requirement for a comprehensive risk assessment of PAs, hampered by the enormous number of different PA congeners occurring in nature. Up to now, risk assessment is based on the carcinogenicity of certain PAs after chronic application to rats using the sum of detected PAs as dose metric. Because of the well-documented large structure-dependent differences between sub-groups of PA congeners with respect to their genotoxicity and (cyto)toxicity, however, this procedure is inadequate. Here we provide an overview of recent attempts to assess the risk of PA exposure and the available literature on the toxic effects and potencies of different congeners. Based on these considerations, we have derived interim Relative Potency (REP) factors for a number of abundant PAs suggesting a factor of 1.0 for cyclic di-esters and open-chain di-esters with 7S configuration, of 0.3 for mono-esters with 7S configuration, of 0.1 for open-chain di-esters with 7R configuration and of 0.01 for mono-esters with 7R configuration. For N-oxides we suggest to apply the REP factor of the corresponding PA. We are confident that the use of these values can provide a more scientific basis for PA risk assessment until a more detailed experimental analysis of the potencies of all relevant congeners can be carried out.

A panel of scientists discussed a variety of issues related to the development of physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models for toxicological risk assessment. The panel concluded that although there are a variety of potential technical problems associated with the use of these models for hazard identification and risk assessment, PBPK/PD modeling represents an important technical advance in risk assessment methodology that should continue to be developed and applied. In addition to the technical issues that were addressed, the necessity of providing additional education for toxicologists in the skills necessary for the development and evaluation of PBPK/PD models was stressed.

INTRODUCTION Flavours are an important aspect of the e-cigarette sensory experience. The e-cigarette aerosol is generated by a heating coil vapourising the e-liquid. The vapourisation temperature has been estimated to reach up to 350oC [1], higher coil temperatures have been reported in the absence of e-liquid [2]. Our toxicological risk assessment approach to flavours considers both the flavour itself and the identification, measurement and risk assessment of any potential thermal breakdown and/or reaction products.

Principles in toxicological risk analysis.Kleinjans JC.Department of Health Risk Analysis and Toxicology, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands. j.kleinjans@grat.unimaas.nlToxicological risk analysis comprises a process of hazard identification, dose-response assessment and exposure assessment, providing as an output the estimation of the incidence and severity of adverse effects likely to occur in a human population in relation to actual or eventual exposure to hazardous compounds. Within this respect, toxicological risk analysis represents a scientific activity, which uses data from toxicological research, and serves as a basis for risk management which is the decision-making process which is performed by regulators and politicians, considering also non-scientific aspects such as socioeconomic and political factors. The predominant step in hazard identification is the answer to the question whether a compound must be classified as a genotoxic carcinogen, epigenetic carcinogen or non-carcinogen. Additional important aspects concern the questions how to extrapolate from high to low dose, as well as how to deal with exposures to complex mixtures of carcinogens. Also, the question is addressed whether it is required in toxicological risk analysis to consider susceptible subgroups in the population, for instance on the basis of specific genetic predispositions

s / Toxicology Letters 229S (2014) S40–S252 S183 increased (20%) cell proliferation at lower concentration. No IC50 values were obtained. Combination of AOH+SSI no increased cytotoxicity respect AOH tested alone. ROS generation was determined by the H2-DCFDA probe up to 120min. The ROS produced by AOH (15, 30 and 60 M) was 1.2-fold higher than the control. While SSI (6.25, 12.5 and 25 M) and the combination of SSI (6.25 M)+AOH (15 M) did not produce ROS generation. In conclusion, the SSI decreased cytotoxicity produced by AOH. Thus, food commodities containing SSI (specially, legumes) could contribute to diminish the toxicological risk that natural contaminant as AOH in diet can produce to humans. http://dx.doi.org/10.1016/j.toxlet.2014.06.623

Safety assessment procedures still rely heavily if not exclusively on the results of tests carried out in laboratory animals, then extrapolated to man. There are few examples of environmental compounds examined extensively enough in both man and animals to permit a critical comparison of the accuracy of such risk assessment procedures. Chlordecone (Kepone) is a lipophilic, rodent liver carcinogen which now stands among the most extensively studied environmental agents in humans. More than five years of clinical investigations of workers heavily exposed to organochlorine pesticide have established the spectrum of human toxicity of Chlordecone, its dose-response relationships, tissue distribution, metabolic pathways, half-time for elimination, and the concentration at which its major toxic manifestations involving the central nervous system, the liver, and the testes are not observed (no observable effect level, NOEL). Taking advantage of this unique opportunity to proximately compare humans with experimental animals for a single compound administered at comparable doses, we find that none of the toxic effects produced in humans were unrepresented in animal testing. However, the animal testing produced numerous "false positive" results. Hence, accurately predicting the qualitative toxicity of chlordecone in man based on studies in rats would have been impossible. Indeed, proteinuria observed in rats fed small amounts of chlordecone for two years was chosen as a sensitive endpoint by the United States Environmental Protection Agency as the basis for establishing acceptable levels of human exposure. However, we never observed proteinuria even in humans whose dose of chlordecone was hundreds of times higher than that given to the rats. We conclude that greater emphasis should be placed on clinical investigation of humans exposed to environmental agents. A better understanding of the strength and also of the limitations of animal toxicity testing will improve the reliability of extrapolating results of animal testing to human exposure conditions.