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Background: Recently, the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also for the approach used to perform these evaluations. Some critics have claimed that failures of IARC Working Groups to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans. oBjectives: The authors of this Commentary are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We examined criticisms of the IARC classification process to determine the validity of these concerns. Here, we present the results of that examination, review the history of IARC evaluations, and describe how the IARC evaluations are performed. discussion: We concluded that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various disciplines and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed. conclusions: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public’s health.

Phosphite () induces a range of physiological and developmental responses in plants by disturbing the homeostasis of the macronutrient phosphate. Because of its close structural resemblance to phosphate, phosphite impairs the sensing, membrane transport, and subcellular compartmentation of phosphate. In addition, phosphite induces plant defence responses by an as yet unknown mode of action. In this study, the acclimation of Arabidopsis thaliana plants to a sustained phosphite supply in the growth medium was investigated and compared with plants growing under varying phosphate supplies. Unlike phosphate, phosphite did not suppress the formation of lateral roots in several Arabidopsis accessions. In addition, the expression of well-documented phosphate-starvation-induced genes, such as miRNA399d and At4, was not repressed by phosphite accumulation, whilst the induction of PHT1;1 and PAP1 was accentuated. Thus, a mimicking of phosphate by phosphite was not observed for these classical phosphate-starvation responses. Metabolomic analysis of phosphite-treated plants showed changes in several metabolite pools, most prominently those of aspartate, asparagine, glutamate, and serine. These alterations in amino acid pools provide novel insights for the understanding of phosphite-induced pathogen resistance.

Phosphite (H2PO3 -, Phi) is an analog of phosphate (H3PO4 -, Pi) which is not metabolized by plants and therefore accumulates in the tissue. Because of their close steric resemblance Phi is able to mimic Pi, thus impeding Pi sensing and signalling mechanisms. In Pi limited plants Phi inhibits phosphate starvation responses, i.e. adaptations aimed at coping with limited Pi supply and increasing Pi uptake capacity. Thus, Phi has constrictive effects on plant growth under low P supply. Phi is also commercially marketed as a biostat against oomycete pathogens (e.g. Phytophthora spp.) for agricultural application and even used on an ecosystems scale. Phi directly inhibits pathogen growth through interference with phosphate-dependent metabolism and/or phosphate signaling which is paralleled in plants grown on high phosphite concentrations. In addition, Phi activates plant defense responses, e.g. by SA-dependent induction of defense gene expression or increased callose deposition, by a yet unknown mode of action. We have started to characterize the impact of prolonged phosphite treatment by analyses of growth responses, root development, gene expression and metabolic adjustments. We show that at low levels Phi has indirect impact on plant growth by inhibiting phosphate uptake whereas at elevated tissue contents Phi directly impairs growth. Phi is not able to suppress the induction of lateral roots under P limiting conditions and the up-regulation of a set of phosphate starvation induced genes. Furthermore, phosphite induces specific changes in the abundance of several metabolites, especially amino acids, which may have relevance for the understanding of phosphite induced resistance.

Phosphite (H2PO3 ‐) is a phosphate analog widely used to protect plants from oomycete pathogens such as Phytophthora and Pythium. Phytophthora species are prominent pathogens in agriculture, e.g. Phytophthora infestans causing potato late blight. Phytophthora cinnamomi has devastating effects on native ecosystems with over 4000 plant species at risk in Western Australia alone. Phosphite is a well‐known protectant of plants and exhibits a complex mode of action. I It directly inhibits the pathogen’s growth by interference with its phosphate‐dependent metabolism. At the same time it also inhibits the plant’s phosphate starvation response, e.g. the up‐regulation of high‐affinity phosphate transporters, and thus has constrictive effects on plant growth under low phosphate supply. In addition to these direct effects, phosphite also induces the plant’s defence responses with increased expression of defence genes. However, the underlying mechanism of this indirect effect is not understood. We have started to characterise the impact of phosphite on plant defence responses by analyses of transgenic plants, metabolic pathways and the natural genetic variation in the plant Arabidopsis thaliana.

Phosphite (H2PO3 -) is a phosphate analog that is not metabolised by plants but can interfere with the phosphate signalling pathway. It inhibits the plant’s phosphate starvation response, e.g. the up-regulation of high-affinity phosphate transporters, and thus has constrictive effects on plant growth under low phosphate supply. Phosphite has also been used widely to protect plants from oomycete pathogens such as Phytophthora and Phytium. Phytophthora species are prominent pathogens in agriculture, e.g. Phytophthora infestans being the causing agent of potato blight (Irish potato femine). Phytophthora cinnamomi has devastating effects ('dieback disease') on native ecosystems with over 3000 plant species at risk in Western Australia alone. Phosphite is the only known protectant of plants and exhibits a complex mode of action. At elevated concentrations it directly inhibits the pathogen’s growth by interference with its phosphate-dependent metabolism and/or phosphate signalling which is paralleled in plants grown on high phosphite concentrations. In addition to these direct effects phosphite also induces some of the plant’s defence responses, e.g. treatment of plants leads to increased expression of defence genes. However, the underlying mechanism of this indirect effect is not understood. We have started to characterise the impact of phosphite on plant defence responses by analyses of phenotypic changes, gene expression and metabolic pathways in the model plant species Arabidopsis thaliana. Transgenic plants have been generated that express a microbial phosphite dehydrogenase which converts phosphite into phosphate. These plants are a valuable tool to dissect direct from indirect phosphite effects.