Mode of action-based risk assessment of genotoxic carcinogens

The risk assessment of chemical carcinogens is one major task in toxicology. Even though exposure has been mitigated effectively during the last decades, low levels of carcinogenic substances in food and at the workplace are still present and often not completely avoidable. The distinction between genotoxic and non-genotoxic carcinogens has traditionally been regarded as particularly relevant for risk assessment, with the assumption of the existence of no-effect concentrations (threshold levels) in case of the latter group. In contrast, genotoxic carcinogens, their metabolic precursors and DNA reactive metabolites are considered to represent risk factors at all concentrations since even one or a few DNA lesions may in principle result in mutations and, thus, increase tumour risk. Within the current document, an updated risk evaluation for genotoxic carcinogens is proposed, based on mechanistic knowledge regarding the substance (group) under investigation, and taking into account recent improvements in analytical techniques used to quantify DNA lesions and mutations as well as “omics” approaches. Furthermore, wherever possible and appropriate, special attention is given to the integration of background levels of the same or comparable DNA lesions. Within part A, fundamental considerations highlight the terms hazard and risk with respect to DNA reactivity of genotoxic agents, as compared to non-genotoxic agents. Also, current methodologies used in genetic toxicology as well as in dosimetry of exposure are described. Special focus is given on the elucidation of modes of action (MOA) and on the relation between DNA damage and cancer risk. Part B addresses specific examples of genotoxic carcinogens, including those humans are exposed to exogenously and endogenously, such as formaldehyde, acetaldehyde and the corresponding alcohols as well as some alkylating agents, ethylene oxide, and acrylamide, but also examples resulting from exogenous sources like aflatoxin B$_{1}$, allylalkoxybenzenes, 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), benzo[a]pyrene and pyrrolizidine alkaloids. Additionally, special attention is given to some carcinogenic metal compounds, which are considered indirect genotoxins, by accelerating mutagenicity via interactions with the cellular response to DNA damage even at low exposure conditions. Part C finally encompasses conclusions and perspectives, suggesting a refined strategy for the assessment of the carcinogenic risk associated with an exposure to genotoxic compounds and addressing research needs

Mode of action-based risk assessment of genotoxic carcinogens

Abstract The risk assessment of chemical carcinogens is one major task in toxicology. Even though exposure has been mitigated effectively during the last decades, low levels of carcinogenic substances in food and at the workplace are still present and often not completely avoidable. The distinction between genotoxic and non-genotoxic carcinogens has traditionally been regarded as particularly relevant for risk assessment, with the assumption of the existence of no-effect concentrations (threshold levels) in case of the latter group. In contrast, genotoxic carcinogens, their metabolic precursors and DNA reactive metabolites are considered to represent risk factors at all concentrations since even one or a few DNA lesions may in principle result in mutations and, thus, increase tumour risk. Within the current document, an updated risk evaluation for genotoxic carcinogens is proposed, based on mechanistic knowledge regarding the substance (group) under investigation, and taking into account recent improvements in analytical techniques used to quantify DNA lesions and mutations as well as “omics” approaches. Furthermore, wherever possible and appropriate, special attention is given to the integration of background levels of the same or comparable DNA lesions. Within part A, fundamental considerations highlight the terms hazard and risk with respect to DNA reactivity of genotoxic agents, as compared to non-genotoxic agents. Also, current methodologies used in genetic toxicology as well as in dosimetry of exposure are described. Special focus is given on the elucidation of modes of action (MOA) and on the relation between DNA damage and cancer risk. Part B addresses specific examples of genotoxic carcinogens, including those humans are exposed to exogenously and endogenously, such as formaldehyde, acetaldehyde and the corresponding alcohols as well as some alkylating agents, ethylene oxide, and acrylamide, but also examples resulting from exogenous sources like aflatoxin B1, allylalkoxybenzenes, 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), benzo[a]pyrene and pyrrolizidine alkaloids. Additionally, special attention is given to some carcinogenic metal compounds, which are considered indirect genotoxins, by accelerating mutagenicity via interactions with the cellular response to DNA damage even at low exposure conditions. Part C finally encompasses conclusions and perspectives, suggesting a refined strategy for the assessment of the carcinogenic risk associated with an exposure to genotoxic compounds and addressing research needs

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

Complexo de parasitóides de Phyllocnistis citrella (Lepidoptera, Gracillariidae) em dois pomares de citros em Montenegro, RS, Brasil Phyllocnistis citrella (Lepidoptera, Gracillariidae) and its parasitoids in two citrus orchards in Montenegro, RS, Brazil

Diversas vespas parasitóides, especialmente Eulophidae e Chalcididae, têm sido registrados atuando sobre populações de Phyllocnistis citrella Stainton, 1856 (larva-minadora-dos-citros), uma das principais pragas da citricultura mundial. O presente trabalho objetivou identificar o complexo de parasitóides de P. citrella em dois pomares de citros situados em Montenegro, RS, um de tangerineira variedade Montenegrina e outro do híbrido tangor Murcott. Em amostragens quinzenais de julho de 2001 a junho de 2003, todos os brotos de plantas sorteadas aleatoriamente eram inspecionados. Todas as folhas com pupas de P. citrella foram coletadas e acondicionadas individualmente em placas de Petri até a emergência dos parasitóides ou dos adultos de P. citrella. No primeiro ano foram obtidos 101 parasitóides, dos gêneros Elasmus Westwood, 1833, Cirrospilus Westwood, 1832, Sympiesis Förster, 1856 e Galeopsomyia fausta LaSalle, 1997 (Eulophidae). Ageniaspis citricola Logvinovskaya, 1983 (Encyrtidae) foi registrada somente na área de 'Murcott'. Esta espécie foi intencionalmente introduzida em pomares próximos para o controle do minador. No segundo ano foi amostrado um total de 609 parasitóides e A. citricola foi também registrada na área de 'Montenegrina'. Com a introdução e o estabelecimento da espécie exótica nos pomares, houve uma grande mudança na freqüência relativa das espécies. Ageniaspis citricola representou mais de 75% dos indivíduos presentes em ambos pomares no segundo ano, diminuindo a freqüência relativa das espécies nativas. Estudos sobre a comunidade de inimigos naturais associados ao minador-dos-citros, e o efetivo impacto que a espécie exótica causa sobre as nativas, são necessários antes de tomarem-se quaisquer medidas de controle.Several parasitoid wasps, mainly from Eulophidae and Chalcididae families, have been registered acting upon the citrus leafminer Phyllocnistis citrella Stainton, 1856 populations, one of the most important citrus pest worldwide. The present work aimed to identify the parasitoid complex of P. citrella in two citrus orchards, located in Montenegro, RS: one of the Montenegrina cultivar and the other of the hybrid tangor Murcott. In fortnightly samplings from July 2001 to June 2003, all the buds of randomly rafted plants were inspected. All the leaves, with pupae of P. citrella, were collected and individually maintained in Petri dishes until the emergence of parasitoids or adults of P. citrella. In the first year, 101 parasitoid individuals of the genus Elasmus Westwood, 1833, Cirrospilus Westwood, 1832, Sympiesis Förster, 1856 and Galeopsomyia fausta LaSalle, 1997 (Eulophidae) were obtained. Ageniaspis citricola Logvinovskaya, 1983 (Encyrtidae) was registered only in the 'Murcott' orchard. This species was intentionally introduced in nearby orchards for the leafminer control. In the second year, a total of 609 parasitoid individuals were sampled, and A. citricola was also registered in the 'Montenegrina' area. With the introduction and establishment of the exotic species in the orchards, occurred a great change in the species relative frequency. Ageniaspis citricola represented more than 75% of the individuals occurring in both orchards in the second year, and the relative frequency of the native species decreasing. Studies on the community of natural enemies associated to the citrus leafminer, and on the actual impact that the exotic species cause on the native ones are necessary before taking any measure of control