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26-Jan-2007 Advanced Cancer Risk Assessment Methods 1. The objective of this study, co-directed by Italy and the United States, is to apply the biologically-based risk assessment procedures to analyse cases of main interest. 2.
3. The following Alliance countries are represented in this pilot study: Belgium, Czech Republic, Germany, Greece, Italy, Portugal, Spain, Turkey and USA. After the very positive outcome of the NATO ARW Workshop in Poland, a participation of Poland seems very desirable (this aspect has to be formally defined). The Partner countries represented are: Azerbaijan, Belarus, Lithuania, Moldova and Ukraine. Achievements 4. The first meeting (Rome, February 23-25, 1998) was mainly focused on organizational and planning aspects and on the research programme. The previous Pilot Study activity (Phase 1) was briefly summarized for new participants and new activities were discussed. Participants agreed on the idea of carrying out a research and producing a book including both general theoretical aspects and an extended number of case studies that illustrate the application and the results of advanced cancer risk assessment methods. The meeting was chaired by the Pilot Study Directors, Dr. G. A. Zapponi (Istituto Superiore di Sanità, Italy) and Dr. J. Cogliano (US Environmental Protection Agency, Washington D.C.). The possible topics which could be developed in the study were discussed in detail. This discussion pointed out some main arguments for future study. It was proposed that each topic would be treated by participants from different countries, and a leading country for each topic was proposed. 5. The second meeting was held in Rome on November 15, 1999. New participants were introduced and a short presentation was made on the activity and the results of Phase I of the Pilot Study as well as on the recently published book. 6. The items of the study already identified in the first meeting were confirmed, and some new topics were identified:
7. Moreover, the following further items were identified and proposed:
8. Some major aspects of the Chernobyl aspects consequences would be considered within the case studies. 9. The following points, to be considered in the above topics (chapters), were discussed during the meeting:
10. As far as the structure of different contributions is concerned, it was proposed and decided that each chapter should have a “standard” structure:
11. Several papers were presented and made available by participants at the meeting, representing a first contribution to the various chapters-topics:
12. Moreover, Dr. L. Edler (German Cancer Research Center, Heidelberg) presented a paper by A. Kopp-Schneider “Using a stochastic model to analyse the sequence of phenotypic changes in rat liver focal lesions” and Dr. Testai (Istituto Superiore di Sanità, Italy) presented data and evaluations concerning the effects of metabolism on cancers susceptibility. 13. The 3rd Meeting was held in Santorini, Greece, November 17-21, 2000. On this occasion, Dr. A. Mekhtiev (Physiology Inst., Baku, Azerbaijan) and Prof. P. Molchanov (Vinnytsia University, Ukraine) joined the Pilot Study team. A number of extended papers were presented. (a) “Risk assessment in perspective” (Dr. Chao Chen): 14. Dr. Chao Chen (US EPA, Washington), coordinator of a subgroup has presented an extended draft report, proposing the integration of already established modelling approaches with new ones. In particular, using the 2,3,7,8-TCDD case as an example, the complexity of pathways leading to the carcinogenic effect has been underlined (the whole processes triggered by the Ah receptor-mediated action, which include the activation other metabolic processes, as well as mitogenesis and other cellular events). Based on this and other examples, the proposal of multi-pathway models has been considered in such cases, in order to jointly describe the different processes that may coexist. Moreover, it has been underlined that in many cases the “initiation” event may result as consequence of various upstream events (included, for instance, the destabilization of genome), which are difficult to describe in terms of a simple transition to initiated stage, but, rather, require a more complex modelling. 15. The biological information generally available for risk assessment have been classified into (a) Information for developing a Physiologically Based Pharmacokinetic (PBPK) model, (b) Signaling pathway (signal transduction and cellular response) and (c) Cellular dynamics of tumor formation. These three aspects may be described by specific models, that may be combined. 16. Several applications to practical cases have been presented. (b) “The current state of biologically-based cancer risk assessment and new developments” (Dr. G. Luebeck, USA) 17. The proposed scheme of the whole contribution includes an introduction (carcinogenic risk assessment based on biological mechanisms and quantitative methods), the discussion of the 2-stage clonal expansion (TSCE) model, also in mathematical terms, its extensions to cover more biological aspects, theoretical considerations, illustrative-informative cases and examples, and applications. 18. The paper presented at the meeting constitutes a first draft of the presentation of the up-dated biologically-based modelling theory (that was originally developed by Dr. S. Moolgavkar from the Fred Hutchinson Cancer Research Centre, and has been further improved in the same Centre with the contribution of Dr. Luebeck). Some model applications have been discussed, together with their rationale and theoretical basis. 19. In particular, some specific processes predicted by the biologically-based model theory were examined, as, for instance, the effect of cancer promotion exposure of a population which includes subjects who have already undergone to a critical mutation of their somatic cells (initiation). In this case it expected that the age-specific cancer rates, described by the hazard functions, will reach a local maximum, dip and the reach the background level. This is explained by the consideration that the carriers of a high number of intermediate (initiated) cells are progressively eliminated from the population, and then the surviving individuals will be the ones carrying a smaller number of initiated cells, and therefore at a smaller risk attributable to the promoter action (this trend was already discussed in a previous meeting, when examining a population including susceptible and normal individuals: susceptible individuals are expected to be ill before normal ones, so that the remaining part of the population will include the more resistant individuals; this may affect the age-specific rates). 20. It has also been discussed an extension of the Two-stage and Clonal Expansion (TSCE) model including a pre-initiation condition/stage, that may be important in specific situations, as for example, in the case of “genomic instability” and/or a very poor DNA-repair efficiency. 21. The discussed applications of “Biologically-Based Models”, and, more specifically, of particular forms of the “Two-Stage Clonal Expansion Model”, include emissions from coke ovens and lung cancer, radon and lung cancer (the Colorado Plateau Miner cohort), cancer following exposure to low LET radiation, altered hepatic lesions in rats treated with TCDD. 22. The studies of radiation (radon and LET radiation) have suggested that this agent may cause not only cell initiation (basically, mutation process), but may also have a promotion action (stimulus to initiated cells to proliferate), that may predominate at high exposures. As discussed, this hypothesis needs more study; however, it seems to be in agreement with some experimental data. A possible explanation of the mechanism of action is that normal cells, when damaged by alpha particles, may send out signals capable of modifying (increasing) proliferation of nearby initiated (precancerous) cells. 23. As already discussed in the Final Report of Phase 1 of the Pilot Study (V. Cogliano, G. Luebeck and G.A. Zapponi, 1999), the Pilot Study team has underlined that one of the aims of biologically-base modelling is to generate some hypotheses on the processes under study; the report by G. Luebeck includes an application of this principle. 24. Dr. Griciute (Lithuanian Oncology Center, Vilnius) has presented two papers concerning the consequences of the Chernobyl accident. The one summarized here concerns the thyroid cancer in children. As is known, the Chernobyl accident in 1986 has caused the release of about 30-40 million curies of short-lived radioiodine isotopes and about 12-21 million curies of cesium, strontium and plutonium, that were unevenly distributed mainly in 25,000 km of Belarus, Ukraine and Russia territory. In the region around Chernobyl the childhood thyroid cancer incidence after the accident became about 100/1,000,000 versus a spontaneous incidence less than 1/1,000,000 in most countries. More than 1,300,000 persons received a thyroid irradiation dose exceeding the permissible values. The attributable risk at 1 Gy level has been estimated in the order of 88%. Almost all children of Belarus have been significantly exposed to 131J. Thyroid cancer has been diagnosed in 508 children in the 1986-1996 period, and in more than 800 children up to the end of 1997, with an average increase of incidence per year of about 50-fold. As far as Ukraine is concerned, during the first 5 years after the accident 59 cases of thyroid cancer were diagnosed in children and adolescents up to 18 years, and 513 cases in the 1986-1996 period (321 cases for the 0-15 age class and 192 cases in the 15-18 year age class). Before the accident (1981-1985 period) thyroid cancer morbidity index in children was 0.05/100,000, while it was 0.11/100,000, 0.39/100,000 and 0.54/100,000 respectively in the 1986-1990, 1991-1995 and 1996 periods. Most of the risk increase was observed in the northern regions of Ukraine, were the highest contamination (> 1 Gy) was detected. A higher risk was assessed for children who were younger at the time of accident (e.g., in 1996, 60% of cancer thyroid cases were identified in children with less than 4 years old at the time of accident). 25. The risk appears to be clearly dose-related and dependent on the age at exposure. Children are confirmed as a susceptible group. A lower thyroid cancer increment has also been observed in adults. (d) “Chernobyl accident and the health of clean-up workers: Lithuanian aspects” (Dr. L. Griciute). 26. Dr. Griciute has also presented various data concerning the health conditions of about 7100 Lithuanian workers (civil and military, about 98% males and 2% females, most of them aging 30-34 years at that time) employed in the environmental clean-up following the Chernobyl accident. The activity of these people, which continued from 1986 to 1990, included the decontamination of the atomic power plant and of the surrounding area and the construction of the building containing the reactor. The permanence of workers in the contaminated area typically lasted from 1 to 6 months. Exposure levels were up to 25 cGy (25 rad) of external gamma radiation; the limit was 10 cGy after June 1987.. About 60% of subjects were exposed to levels < 100 mSv, about 22% to levels within 100 and 200 mSv, about 17% to levels within 200-300 mSv and about 1% at levels > 300 mSv. Dosimetry is mentioned to be still a problem in the study of health status; for about one third of exposed people (almost ~ 31%) the doses were not registered, and some doubts exist concerning the precision of measurements for the other 69%. 28. The number of patients with thyroid nodularity (detected by ultrasound) was 117 (3.7%) with a slight statistically non-significant increase (nodularity frequency in non-exposed was 2.5% - 3.3%); most of nodules were solid. The probability of nodularity was associated with the duration of permanence in the Chernobyl area, while it was not with the dose from external exposure. The results of follow-up do not exclude the possibility of an excess of thyroid nodularity and tumors in the future, as based on data from a relatively recent analysis. 29. For the 1986-1996 period , the epidemiological data concerning Lithuanian clean-up workers indicate a statistically significant increase of Standard Incidence Ratios (SIRs) for cancer of Pancreas (9 Observed vs. 2.7 Expected, SIR=2.6, 95% CI: 1.03-4.87) and thyroid (3 Observed vs. 0.5 Expected, SIR=5.6, 95% CI: 1.05-13.69), while some non-significant increase was observed for other tumors. The SIR for overall cancer was 1.1 (71 Observed vs. 63.8 Expected, 95% CI: 0.87-1.39). For the period from 1994 to 1997, these increases appeared to not reach a statistically significant level (e.g., Thyroid Cancer, 2 Observed, 0.3 Expected, SIR= 7.8, 95% CI: 0.73-22.32), while the increase of the overall cancer incidence was not too far from a significant level (55 Observed, 43.3 Expected, SIR=1.3, 95% CI: 0.96-1.63). It may be observed that at the moment the number of cancer cases in this cohort is not particularly high. The study is continuing. (e) “Some procedures for cancer risk assessment (Ukraine)” (Prof. P. Molchanov) 30. Prof. Molchanov (Ukraine) has presented an overview of the cancer risk assessment procedures adopted in his country, in particular for radiation exposure. Basically, the procedures recommended by the US National Academy of Science and US EPA were used as reference. Moreover, a procedure for multifactor cancer risk assessment, based on multifactor models, and the use of expert judgment has been presented. The “fuzzy knowledge base” represents the totality of inferences (IF-THAN) reflecting the experience of the specific expert and his understanding of the cause-effect relation in a specific decision-making (forecasting) problem. On this base “events-trees” are build up that express in logical and quantitative terms the expert evaluations (that may be qualitative and quantitative). Mathematical procedures allow for subjective estimations in terms of probability weighing parameters, and “tuning” procedures of models are foreseen. (f) “Correlation of cancer risk with depression condition and brain serotonin level” (Dr. A. Mekhtiev) 31. Dr. Mekhtiev, researcher at the Institute of Physiology of Baku, Azerbaijan, and new participant in the Pilot Study, discussed some points emerging from his studies in the field of neurophysiology. In particular he underlined the influence of depression condition and the possible role on cancer risk of Serotonin (5-hydroxytryptamine) level in the brain. According to the presented data and hypotheses, Serotonin, a compound that plays a role in neurotransmission, may act as significant factor in cancer risk reduction, by diminishing the rate of various processes, including the cell proliferation. This is a possible mechanism hypothesized for explaining some observed effects. Dr. Mekhtiev will further develop these topics. (g) “Mechanisms underlying Endocrine Disruption and cancer” (Prof. E. Pluygers and Prof. J. Amaral-Mendes) 32. In their presentation, Prof. Pluygers (Oncologie-Depistate du Cancer, La Louviere, Belgium) and Prof. Amaral-Mendes (University of Evora, Portugal) stressed the importance of “endocrine disrupter” agents (EDs) in causing cancer. As is well known this category of risk agents include may important risk agents as Polychlorodibenzo-p-Dioxins (PCDD), Polychlorodibenzo-p-Furans (PCDF), Polychlorobiphenils (PCB), DDT, Diethylstilbestrol (DES) and many other compounds as xenoestrogens. 33. In the paper presented by Prof. Pluygers that dealt with the mechanism underlying endocrine disruption and breast cancer, it has been underlined that it is not acceptable to base the evaluation of the effect of these compounds only on their property to bind to specific receptors, because other mechanisms also exist that may contribute in inducing estrogenic response. These other mechanisms include, for instance, the effect of serum on the xenoestrogen access to the estrogen receptor, the xenoestrogen binding to carrier proteins, the disturbance of metabolic pathways, the impact of several organo-chorinated pesticides, the action of PCBs and PBBs on gap-junctional intercellular communication. Moreover, the observation of a significant world-wide increase of breast cancer incidence and, at a lower level, of prostate cancer has been underlined. It has been observed that the results of some epidemiological studies indicate a positive correlation between organochlorine concentrations in adipose tissue or in blood and the development of breast cancer. The assessment and prevention of risks in this field was indicated as a major objective. 34. Prof. V. Bencko (University of Prague, Czech Republic) presented various epidemiological data concerning the TCDD and dioxin-like effects, that make part of this topic. (h) “Perspectives in biologically-based risk assessment: some molecular aspects” (Prof. C.E. Vorgias) 35. Prof. Vorgias (Athens University, Greece) has presented a contribution by the Greek biologist team (also including Prof. A. Kappas, from the National Center for Scientific Research Demokritos, Greece, who could not be present at the meeting) covering a large number of molecular and gene-related aspects of cancer risk. This is the main topic treated by these colleagues, already cared in the past. The effects of mutations in p53 gene, that acts as tumor suppressor, and that is mutated in over the 50% of almost all tumors, have been discussed. These include genomic instability, as a consequence of loss or inactivation of p53 (e.g., aneuploidy, amplifications or deletions observed in p53 deficient transgenic mice). The consequences of mutations in the BRCA1 suppressor gene and their weight in hereditary breast cancer in women have been also discussed, together with the impact of mutation of Rb tumor suppressor gene and other genes. methods and parameters useful to assess these mutations were also presented. Some important aspects concerning the joint action of the exposure to different carcinogens were also discussed from the molecular point of view. 36. Prof. Kitsos (Athens University, Greece) has presented his contribution in the field of experimental design based on theoretical mathematical-statistical considerations. This study is aimed at providing practical criteria for optimising the experimental design of animal studies in order to obtain the maximum information about metabolic parameters relevant to carcinogenic risk assessment. The method has been applied to the Michaelis-Menten model on the Pharmacokinetics. The principle of sequential design has been introduced, based of a two-stage design, in order to overcome difficulties in the estimation of parameters, of which some prior knowledge is needed for better organize experiments. Moreover, the application of statistics to mutation spectra and other relevant aspects has also been studied. These arguments are developed in cooperation with colleagues expert of biology of cancer risk. (j) “Physiological and metabolic parameters” (Dr. L. Edler, Dr. K. Watanabe) 37. This topic is cared by several participants, including Prof. Kitsos and Dr. Testai, and coordinated by Dr. Edler and Dr. Watanabe (Tulane University, New Orleans, USA). The item examined included the examination of the steady-state assumption in the Michaelis-Menten kinetic model and its impact on the physiologically-based toxicokinetic models (PBTK models), a review of the PBTK model-related interspecies extrapolation criteria, as well as some cases studies. In particular, an analysis of various xenobiotic metabolism reactions (reactions involving xenobiotic chemical agents) has been presented. Mathematical criteria for the parameter estimation have been presented. Some estimation criteria and optimal design principles are cared by Prof. Kitsos, as already discussed. Lastly, it has been stressed by several participants that PBTK modelling (the term PBPK model, i.e., physiologically-based pharmacokinetic modelling, is also used) has to be included in biologically-based modelling. In fact, the toxicokinetic of the involved agent and the kinetic of related metabolic processes (e.g., formation of active metabolites, detoxification and other processes) may significantly influence the dose-response relationship and other parameters relevant to risk assessment, and, in particular, the dose at the target. A correct estimation of the carcinogenic process parameters (i.e., mutation and clonal expansion rates) may be carried out only when the relevant toxicokinetics is known and quantitatively expressed. (k) “Individual susceptibility and genetic polymorphism” (G. A. Zapponi) 38. Some further consideration have been presented, concerning the concepts of the “inherited” and “acquired” susceptibility. This latter kind of susceptibility may be related to age at exposure (as, for instance, shown by the higher cancer risk of atomic bomb survivors exposed at younger age), to some pathological conditions (e.g., viral hepatitis associated to an increased liver cancer risk), to previous exposures, to nutritional conditions and to the adoption of diets that may reduce or increase cancer risk. 39. The genetically acquired susceptibility may be due to individual differences in the toxicokinetics of hazardous agents (e.g., a decreased detoxification capability, an increased rate of activation of xenobiotics, an increased half-life of carcinogenic compound in the body, etc.). It may be also due to individual differences in the toxicodynamics of hazardous agents, as differences in DNA-repair efficiency, the case of the “mutator” phenotype, differences in the processes regulating cell proliferation, differences concerning the “natural killer” cells, etc. 40. The genetically acquired susceptibility may also concern some aspects of the whole carcinogenic process: a typical example is the inheritance of a mutated gene, that may lead to a reduction of the mutation steps toward carcinogenesis (“inherited initiation”). Many tumors of infancy and childhood children may be considered in this paradigm. 41. As far as the cancer susceptibility related to inherited increased mutation rates is concerned, a review of the available epidemiological data indicate that reduced DNA- repair efficiency may be associated with significantly increased relative risks, expressed by odds ratios (ORs) ranging from 1.2 to 75.3, most of them being in the 2 - 10 interval. Higher values were observed in the case of tobacco smoking and alcohol consumption habits. These data concern the general population and may provide a suitable base for assessing the weight of this parameter. 42. The TCDD (considered to be a cancer promoter) and dioxin-like data may provide useful indications about the susceptibility to the promotion process. In this case, available data are mainly experimental. Other relevant experimental data concern the strain variability in cancer risk related to cell proliferation rates. (l) Other contributions 43. All the participants have participated in the development of some of the above arguments, so that the mentioned presentations should be considered as the result of collaborative activity. Moreover, Dr. Cogliano is studying the cancer risk assessment procedures adopted in Alliance and Partner countries. Participants who could not be present are in touch with the coordinators of the various topics. The way ahead 44. Gratitude to CCMS direction has been expressed by all participants for the help provided. 45. During the last discussion of the activity carried out up to this moment it has been observed that, also due to the difficulties of having no more than one meeting per year, the group needs more time for completing the work, also because of important specific items to be developed in detail such as the risk induced by the Chernobyl accident consequences (this year is the 15th after the accident, which is a typical latency period for cancer risk). 46. Moreover, due to the interest and the importance of a study concerning the risk assessment of the Chernobyl accident consequences, it has been proposed to organize a specific workshop on this item, inviting the main experts of the directly involved countries, also in order to correctly start a collaborative scientific activity with the scientists that had the responsibility of managing the accident consequences. 47. The proposed period for the completion of the project is 2002 or beginning of 2003. At least 3 further meetings are highly desirable and needed for the original Pilot Study objectives; the extension to the Chernobyl accident-related risk assessment implies other specific meetings. |
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