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#0574


Delayed Neurotoxicity. Early Diagnostics and Non-Experimental Forcasting

Tech Area / Field

  • CHE-SYN/Basic and Synthetic Chemistry/Chemistry
  • CHE-ANL/Analytical Chemistry/Chemistry
  • BIO-OTH/Other/Biotechnology

Status
8 Project completed

Registration date
09.02.1996

Completion date
21.08.2006

Senior Project Manager
Genisaretskaya S V

Leading Institute
State Research Institute of Organic Chemistry and Technology, Russia, Moscow

Supporting institutes

  • Institute of Biomedical Chemistry, Russia, Moscow

Project summary

Increasing spread of various chemicals in the human activity spheres bring about to dangerous delayed consequences caused by chemical agents affecting the central and peripheral nervous systems. Now it has been revealed a number of substances, rather various in chemical structure, that are capable to induce progressing motor paralysis of the extremities or disorders indicative of central nervous system injury within late terms (after several weeks). Delayed neurotoxicity effect is the best known for organo phosphorus pesticides. Besides that, polyneuropathies induced by some drugs, heavy metals, solvents, plasticizers, solubilizers, hydraulic fluids, etc. are known. Because the delayed toxicity mechanism is not completely clear, the classification of potential neurotoxicants with regard to their chemical structures is absent, the diagnostics is complicated, the therapy is non-effective, research in this field is very actual. The aim of this Project is creation of a problem-oriented database, software for molecular simulation and forecasting of neurotoxic properties of chemicals, development of test-systems for the early diagnostics of delayed neurotoxicity. Three-step investigation aimed at the realization of this Project includes:
Step A-l. Development of criteria for evaluating delayed neurotoxicity, choice of the biological models with regard for neurotoxicant effect mechanism, classification of chemicals by their specific actions; formation of a problem-oriented database.
Step A-2. Study of relations between biochemical parameters and neuropathologic disorders degree; creation of a program system for non-experimental forecasting of delayed neurotoxicity.
Step A-3. Development of test-systems for the early diagnostics of delayed neurotoxic effects, screening of new and well-known compounds by means of these test-systems.

The specific feature of this Project consists in the use of an original software system for computer design of physiologically active substances in non-experimental (i.e., computer assisted) forecasting of delayed neurotoxicity. This system is designed to process computer analysis of similarities and analogy in structures of known neurotoxicants and to use this knowledge in forecasting of delayed neurotoxicity of new chemicals (i.e., the mentioned computer system realizes the discussed forecasting in the process of so called machine learning by examples and reasoning by analogy).

Combination of methods of non-experimental forecasting with biological experimental works in such a case is unique. Such versatile comprehensive investigation will let us to solve a task of creation of reliable and accessible test-systems so necessary for practical medicine, veterinary medicine, sanitary service, ecotoxicology. Creation of test-systems and programs for non-experimental forecast, later on will let us largely to refuse biological experiments, which now are very complicated, long and expensive. In Russia and some other countries with developed production of various chemicals, normative requirements for delayed neurotoxicity control are absent. This creates real threat of harmful effects of many various chemicals including pharmaceuticals.

Expected results:


1. Fundumental theoretical works related to action mechanism of neurotoxicants of various chemical structure.
2. Classification of neurotoxicants.
3. Database formation.
4. Determination of correlations between neuropathologic and biochemical manifestations of intoxication.
5. Creation of test-systems for the early diagnostics of delayed neurotoxicity.
6. Non-experimental forecasting of neurotoxic properties of substances.
7. Screening of new and common chemicals by their neurotoxicity.
8. Extrapolation of toxicological data to men.
9. Preparation of methodological documents for sanitary standardization.

As a process stock should be listed:


1. Experimental methods of delayed toxicity determination.
2. Bibliographic information necessary for database forming as well as methodology and procedures of database creation.
3. Methods for synthesis of chemicals needed for creation of experimental models.
4. Biochemical methods for determination of esterase activity and separation of esterases.
5. Instrumental means (i.e., problem-oriented software package) of intelligent system analysing delayed neurotoxicity effects in the process of learning by examples and reasoning by analogy.
6. Development of documents for sanitary standardization of ecotoxicants.

Tasks of Project and its expected results have a clear conversion orientation and correspond to the goals of the ISTC. Our qualification and unique scientific experience, technical equipment and a high methodic level of research will lead to successful realization of this Project.

The following (potential users) may be interested in the results of this work:


- firms, producing and saling pesticides, herbicides, pyrethroids, drugs including drugs for loosing flesh, veterinary, antihelminthic and acaricide drugs, disinfectants;
- industries using and producing lubricating and hydraulic fluids, polymeric materials, solvents, plasticizers on the base of organophosphorus compounds, used in production of nitrolacquers, nitromastics, artificial leather;
- industries related to using heavy metals, such as lead, mercury, arsenic (typographic art, instrument engineering).

Our developments are intended directly for sanitary supervision services which supervise the execution of sanitary standards of chemicals safety as well as for specialists in environment protection field.

Participation of foreign collaborators in the Project will be realized as expertises of results and consultations on work and commercial issues.


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