The aim of the project is to identify the genetic background of radiation sensitivity

The aim of the project is to identify the genetic background of radiation sensitivity National Research and Development Program-1/008/2001

COMPLEX STUDY OF CARCINOGENIC EFFECTS FOR PREVENTION OF LUNG CANCER
Assessment and protection against environmental effects
2001-2004

Introduction

The health status of the Hungarian population is very poor in absolute terms and when it compared with other European countries. About 70-80% of cancer incidents could be prevented if environmental pollution, smoking, stress and work injuries were alleviated. The mortality from respiratory diseases is much higher than the European average, and besides of the lifestyle the environmental factors, the outdoor end indoor air quality plays considerable role. Many air-pollutants are known or presumed to have carcinogenic effect. Among leading causes of lung cancer are smoking but some poly-cyclic aromatic carbohydrates (PAH) and asbestos has also considerable role. The major indoor pollutants are smoke, asbestos and radon. In practice, people are exposed not only to a single agent, but also to joint effect of several ones, which may amplify the exposure. This is particularly true to pollution from air, ionising- and non-ionising radiation.

Purposes

The aim of the consortium is to study the combined effect of environmental air-pollution, ionising and non-ionising radiation bringing together wide area of disciplines. The complex study of the aethiological factors will lead us to the better understanding of pathomechanisms, to the collation of early indicators, to the elaboration of particular bio-markers and establishment of new therapeutical tools, respectively. Completing the detailed measurement of exposures with epidemiological data it will be possible to set up a versatile database. The risk of different affections can be predicted by models being developed and the assessing of recommendations will be conceivable the methods of risk reduction, the development of preventive principles.

To achieve our aim the tasks were divided into following sections.

MEASUREMENTS AND SURVEY - A versatile database will be set up for radiation burden originating from natural and man-made sources (electromagnetic fields) concerning the radiation burden of target population (employees and public). These data could serve as basis for future public health research (i.e. epidemiological surveys). In possession of exposure data and relying on research results it is possible to examine whether further regulative measures are needed, or not. To explore the associations between the incidence of lung cancer and exposure to occupational or environmental particles and fibres epidemiological study will be carried out. The main objective is to survey the adverse health effects of environmental pollutants to explore the combined effects (strengthening and/or weakening) of pollutants occurring in both the indoor and outdoor air in high concentration with the aim to understand the mode of action and to substantiate the preventive measures.

BIOMEDICAL RESEARCH – The combined effect of different pollutants (ionising and non-ionising radiation, heavy metals, asbestos, PAH-s etc.) will be studied. Individual sensitivity, toxicity of inhaled pollutants, induction of DNA damage, genomic instability, cellular defence and repair mechanisms will be studied as determining factors in biological damage caused by environmental pollutants. The influence of various modulating factors, such as the additive, synergistic and antagonistic interactions of chemical and physical exposures will be studied in vitro model systems to explore major mechanisms of carcinogenic process.

NUMERICAL MODELING OF THE INHALATION PROCESSES - LUNG CANCER AND RISK MODEL The main purposes of these theoretical efforts are: (i) to compute the local deposition distributions of compact, fibrous and radioactive particles in different regions of the human respiratory system; (ii) to introduce local deposition enhancement factors for the quantification of the distribution; (iii) to compute the clearance pattern of the deposited material; (iv) in case of radionuclides to calculate the hit probabilities with the DNA of sensitive cells; (v) applying in vitro data, transformation probabilities will be computed. As a second step, the results of our primary models will be built into a cancer and risk model developed by wide international collaboration of other research institutes and universities. The general objective of the numerical mathematical and biophysical models related to the project is to present a better estimation of the health risk of inhaled compact particles, fibers and radionuclides and to assure a clearer understanding about the mechanisms of the produced physical and biological processes.

Participants

The "Frederic Joliot-Curie" National Research Institute for Radiobiology and Radiohygiene /NRIRR/ (Fodor József National Center for Public Health, NCPH) is charged in the coordination of the project (head: Prof. Dr. Köteles, Gy., persons responsible: Dr. Bognar, G. Dr. Dám, A.M., Dr. Kerekes, A., Sáfrány, G., Thuróczy, Gy.,). Five department from the institute (cell biology, molecular biology, diagnosis of radiation effects, computing and measurements and non-ionising radiation) are involved in the fulfillment of the following tasks (i) Assessment of radiation burden originated from ionising and non ionising radiation; (ii) Application of molecular and cellular biological, cytogenetical methods in investigation of combined environmental hazards and patho-mechanisms (iii) The role of initial damage and genom instability in carcinogenesis.

The National Institute of Environmental Health /NIEH- NCPH /. Several departments of the NIEH will be directly involved in the project (persons responsible: Dr. Rudnai, P., Dr. Schocket, B.) In line with the present project, they are building up a complex molecular epidemiological project by using biochemical and molecular genetic methodologies for the biomarkers of exposure and genetic susceptibility to investigate the potential risk factors of human lung cancer in a patient population..

National Institute of Occupational Health /NIOH-NCPH/(person responsible: Dr. Tatrai E.) Their task to investigate the pulmonary toxicity of pollutants and the protective mechanisms in the lung on primary cultures of different lung cells (macrophages, pneumocytes etc.).

Semmelweis University, Faculty of General Medicine, 2^nd Department of Pathology (person responsible: Prof. Dr. Kerényi T.) The task of the department in the intended experiments: Animal experiments: instillation, histological diagnosis, electron microscopy and energy disperse X-ray analysis of the specimens to detect signs of tissue toxicity and biosolubility.

Technoorg-Linda Scientific Technical Development Ltd. Co. (persons responsible: Szigethy,D., Balásházy, I.,). is a SME, having an international reputation in the development and production of instruments for the measurement of the physical parameters of aerosols. They have participated in international projects several times mainly in the field of the development of microdozimetric models and investigation of the biological effects of inhaled radioactive aerosols. For a successful realization of the project they elaborate, develop and apply numerical models for the examination of the biological and physical mechanisms of the formation of human lung cancer caused by inhaled carcinogenic materials. In addition, they develop and construct aerosol particle analyzers and alpha particle irradiator according to the requirements of the consortium.

Some results

The new Hungarian legislation has also extended the dosimetric control to workplaces or activities, where elevated values of the external or internal dose from natural sources could occur. As a pilot study the radon concentration and external gamma dose-rate were measured at two underground and one surface mines. The values observed were in the range of 82 – 589 Bq× m^-3 and 23 – 308 nSv× h^-1, respectively, i.e. the radon concentration was below the 1000 Bq× m^-3 Hungarian action level.

Epidemiological survey of 50 Hz magnetic fields in residences located above transformer stations was performed in twenty-one ten-story panel buildings. The electricity company (ELMÛ) provided supervision and measured the amperage through the bus bars of the 10/04 kV transformers. Magnetic field measured with different methods was compared to the amperage, measured parallel according to correlation coefficient, and the proper magnetic field mapping method for future surveys was selected.

Low dose ionizing radiation induced some protective mechanisms termed Radio-Adaptive Response (RAR) in human cell cultures, which was experienced in a narrow dose range and took some time to develop. Further studies are in progress to identify the mechanisms responsible and also to clarify possible cross adaptation to other pollutants.

The aim of the project is to identify the genetic background of radiation sensitivity. For this, primary fibroblast cultures are established from skin biopsies of cancer patients undergoing radiation therapy. The in vitro radiation sensitivity of the fibroblasts are measured by clonogenic and single cell electrophoresis assay and compared to the development of radiation induced toxic reactions of the patients. We also test whether genomic instability contributes to the development of toxic reactions.

In the present study our purposes are to have a description of the individual radiosensitivity and to investigate the modifiability of this individual radiosensitivity. According to our results the degree of cytogenetic damage (detected by the analysis of interphase micronucleus frequency) is definitely dose-dependent, but numerous cell biological factors can influence. One of these is the serum antioxidant concentration. The quantity of the cytogenetic damage decreased by the increasing level of the serum antioxidant. It seems to be clear, that the antioxidant protection can be increased by proper/required vitamin supply, especially in the low-dose range, which can affect the population from operated artificial radio-sources.

In primary culture of alveolar macrophages and pneumocytes type 2, the enzymes of redox system (SOD, GSH-Px, GSH-Rd, GGT) was studied after exposure to UICC amosite, crocidolite and rockwool (fibres substituting asbestos). MCP-1 and MIP-1a production was examined after abovelisted exposure to alveolar macrophages and pneumocytes type 2. Our results showed that amosite and crocidolite, decreased the activity of redox enzymes already at the lowest concentration (1 ug/ml) whereas rockwool did not influence negatively these activities. Amosite, crocidolite and rockwool increased the production of the two chemokines, but the effect of rockwool was more moderate.

All sorts of the examined Hungarian glass fibres had smaller respirable fraction and less damaging effect on the lung parenchyma than the crocidolith asbestos and other non-glass man-made mineral fibres. A new problem emerged, however, in connection with the quick biosolubility of the newly developed glass fibres: the local effect of their toxic components, mainly arsen and antimon, may be toxic for the surrounding lung tissue

Three-dimensional realistic geometry of the central human airways was mathematically described and applied for computational fluid dynamics (CFD) simulations. The geometry presents a smooth transition between the airways and a curved carina ridge of the airway bifurcations. Computational fluid dynamic aerosol deposition model was elaborated and the deposition of inhaled spherical particles in central human airways was computed by this CFD model.

An aerosol-measuring device is under development to measure the size distribution and concentration of the inhaled aerosols.

The stochastic lung deposition model was developed to compute the surface of the different lung regions e. g. airway generations. Deposition densities of inhaled particles along the airways were computed by the new model. After development, the model has been applied for four different topics: (i) total-, regional- and local deposition of urban aerosols of Budapest, measured at five different places, were computed and analyzed at different flow rates; (ii) the deposition of aerosol particles of the atmosphere of a therapeutic cave in Budapest was simulated at different breathing parameters in the human respiratory system; (iii) the distribution of deposition of inhaled therapeutic aerosols in the bronchial and carina regions at different breathing patterns and particle sizes were calculated; (iv) deposition of inhaled radon and its progenies in the respiratory system were analyzed at different breathing patterns for adults and children.

Two alpha-irradiator devices have been developed for in vitro cell irradiations with 1 and 100 MBq activities. Po-210 has been selected as alpha particle source. It is monoenergetic and its radio-toxicity is low. The broad alpha beam of the irradiator is collimated.

The physical, chemical and biological parameters of asbestos and glass fibres were collected and a model has been developed to simulate their deposition in the human respiratory system.