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The Risk of Remote Consequences of Nuclear and Chemical Technologies

#2311


Evaluation of the Risk of Remote Consequences Caused by Dangerous Factors of Nuclear and Chemical Technologies Affecting the Population

Tech Area / Field

  • ENV-EHS/Environmental Health and Safety/Environment
  • ENV-MRA/Modelling and Risk Assessment/Environment
  • BIO-INF/Bioinformatics/Biotechnology
  • BIO-RAD/Radiobiology/Biotechnology

Status
8 Project completed

Registration date
21.09.2001

Completion date
15.10.2009

Senior Project Manager
Visser H

Leading Institute
State Research Center of Virology and Biotechnology VECTOR, Russia, Novosibirsk reg., Koltsovo

Supporting institutes

  • RAMS / Siberian Branch of Russian Academy of Medical Sciences / Institute of Internal Medicine, Russia, Novosibirsk reg., Novosibirsk\nSiberian Branch of RAS / Institute of Cytology and Genetics, Russia, Novosibirsk reg., Novosibirsk\nVNIITF, Russia, Chelyabinsk reg., Snezhinsk\nState Research Institute of Organic Chemistry and Technology, Russia, Moscow

Collaborators

  • Radiobiological Institute of the University of Munich, Germany, Munich

Project summary

A negative effect of the environmental pollution on the population health at the end of XX century has turned into a global problem for the entire mankind. A group of physical and chemical factors (radiation, mutagens, and cancerogens), whose effect on the human population even at small doses is capable of causing the morbidity rate growth and change in the gene pool structure during several generations, present the highest danger. The range of diseases caused is determined by the nature of a particular factor and specific features of the loci most vulnerable to the effect of this factor. The diseases of this group include cancer, diseases of the endocrine system, and congenital deformities. Conversion of the military-industrial complex, destroying and utilization of chemical warfare components, and nuclear waste reprocessing and disposal accentuate this problem to a considerable extent. A constant increase in the cancer morbidity rate is observed on the urbanized territories, where nuclear and chemical technologies, metallurgy, and oil processing objects are concentrated, despite a considerable decrease in their capacity rates. The logistics of these territories and the policy of ecological safety should be formed and maintained considering the specificity of each production object, including the possible remote biomedical consequences of their activities and possible catastrophes. The mathematical models recommended by the US Environmental Protection Agency may be used as a first approximation for assessing the potential adverse effects. However, these models have an essential disadvantage that can cancel out the calculations done. Here we mean a number of ambiguities in the parameters used in the models. For example, ambiguous are the following point: determinations of the factor-potential of a cancerogenic agent, appearing when the results of animal experiments are applied to humans; of the dose—effect parameters for small dose values; the immune status of population inhabiting different regions and countries; certain ambiguousness stem from the differences in social and climatic conditions; etc. To surpass these difficulties, it seems most adequate to apply ecological-epidemiological analysis and construct empiric models maximally considering the specific features of the population health and total environmental pollution. A great number of regions in Russia display one or another pronounced factor of physical or chemical nature that determine the adverse ecological situation. Such regions seem most appropriate objects for such modeling, satisfying the Hill’s principles for ecological-epidemiological analysis. The most general criterion for sampling while assessing the consequences of the effect of an exterior factor is either the fact of such effect or occurrence of its gradient in the experimental group and its absence in the control.

The basic aspect of this problem lies in detecting the specific changes in the human genome caused by the effect of cancerogenic and mutagenic factors. Up-to-date methods of molecular genetic analysis and the existing knowledge on the structure—function organization of the genome of macrocellular organisms allows us to come to grips with the clarification of the patterns of the effect of inpidual adverse ecological factors on the human organism and human population gene pool. Several major problems may be specified within the frames of this direction:


(1) Clarification of the genetic bases of inpidual sensitivity to an external factor and susceptibility to the diseases it causes;
(2) Evaluation of the pattern of hereditary material changes in somatic and as a result of the exterior effect generative cells;
(3) Determination of the pattern of gene pool changes of the population having experienced this adverse effect in a succession of generations.

Comparative population genetic analysis, studying the pattern the polymorphism level changes of the candidate genes in the populations or samples having experienced the effect of an adverse factor relative to the control populations or samples is the main approach to solving ecological—genetic problems. The data available in the pertinent literature demonstrate that at least several mutagens cause strictly specific changes in the structure of certain oncogenes in cancer cells. p53 gene is presently most studied in this respect. It was shown that the pattern of p53 mutations in somatic cells differs essentially in different countries and ethnic groups. It has been suggested that that the specific mutation patterns in certain cases may be due to the effect of particular mutagens. It has been also shown that a considerable number of cancer patients exhibit mutations in p53 gene. p53 is believed to be a good marker of certain cancer types. The databases on point mutation in p53 gene represent a pool of information obtained in different places with different pattern of cancerogenic factors. The question of whether there is a specific dependence of position and frequency of certain mutation on the nature of the affecting factor is still open. Confirmation of the occurrence of causal interactions between the nature of a mutagen and the mutation pattern it causes in the gene structure would allow the algorithms for unambiguous identification of the cancerogenic factors in inpidual regions to be developed. The data on specific mutation patterns recorded in the liver cancer patients that have contacted with aflatoxin B [Coursaget, P., et al, 1993, High prevalence of mutation at codon 249 of the p53 gene in hepatocellular carcinomas from Senegal. Br. J. Cancer, 67(6), 1995-1997] suggest that the problem can be solved. In addition to p53 gene and other oncogenes, certain genes coding for cell surface proteins, reacting specifically to this or that environmental factors, might be promising as markers for ecological genetic studies. A sufficient expanding of the list of the candidate genes will form the basis for development of early diagnostics, detection of inclination to a particular cancer type, and determination of the risk groups.

Studies carried out by the SRC VB Vector in Kuzbass allowed us to demonstrate that the method of ecological-epidemiological analysis is effective for detecting the causative interconnections between the rate of cancer diseases and a set of polyaromatic compounds at different doses. The principle of biological gradient, revealing the dependence of certain pathology type on the dose of a substance studied, was used in this experiment. Databases on radionuclide pollution of territories, water bodies, and foodstuff were created at the Research Institute of Technical Physics (Snezhinsk). They also calculated irradiation doses for different population cohorts. Specialists of the State Research Institute of Organic Chemistry and Technology have developed a set of simulation methods based on statistical approach. These methods consider different variants of efflux of dangerous substances and allow the fields of toxicant doses that affected different population cohorts during certain periods to be reconstructed retrospectively. At the Institute of Cytology and Genetics SB RAS and Institute of Internal Medicine SBB RAMS, data on mutations of p53 gene in the population cohorts (Novosibirsk) subjected earlier to a combined effect of chemical and radiation factors have been obtained.

GOAL OF THE PROJECT: Development of the model for assessing the risk of remote consequences (cancer diseases) that is adapted to the conditions of concrete regions with adverse ecological situation, and determination of the variability and mutation pattern in p53 gene and the polymorphism of several other candidate genes (c-fms, CCR-2, CCR-5, etc.) depending of the nature of the acting factor.

The work within the Project will be carried out at two levels: macrolevel and molecular genetic level. The macrolevel investigation comprises the integrated studies on determining the causal connections of cancer pathologies and the nature of an acting factor. To solve the macrolevel problem, certain areas (around the Volga River, in Ural, and Siberia) with either one dominating factor or a combined effects will be selected as well as the areas for comparison, which allow to consider the background corresponding to a factor in question. Once the areas with different values of certain factor are selected, the principle of biological gradient is used to construct the dose-effect curves for chronic and subchronic doses of a factor under study, corresponding to the concrete areas and actual morbidity rate. These data on the correspondence of cancer rate and the constant doses of the acting factor will be used to develop an empiric model of cancer risk. This model, thus, will take into consideration the actual factor-potentials for different population cohorts and other factors. Efficacy and applicability range of the model obtained will be checked on the test sites selected. The macrolevel studies will create a unique possibility for molecular genetic studies, since they allow biosamples of population cohorts affected by a thoroughly characterized factor to be collected and examined. In turn, this will provide for answering a basic question of whether there exists a specific dependence of mutation pattern of the p53 oncogene and other candidate genes on the nature of the acting factor. Thus, the project proposed is a first attempt to carry out a systematic investigation of a number of key problems of modern ecological genetics and molecular bases of carcinogenesis.


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