State Enterprise “L.I. Medved’s Research Center of Preventive Toxicology, Food and Chemical Safety, Ministry of Health of Ukraine”, Kyiv, Ukraine

Abstract. This article explores aspects of EU-Ukraine Association Agreement, where an important part is a provision for the establishment of a free trade zone, which involves bringing Ukraine’s technical regulations and procedures in line with European ones. At the same time, special attention is paid to the requirements of harmonization of domestic statutory acts concerning placing of chemical products, including pesticides on the market, as well as quality and identity of their studies to assess the level of hazard to human health and environment.
According to the authors, the main element of the identity of the quality of data for the assessment of chemicals is the use of the principles of Good Laboratory Practice in conducting studies, approved by the Organization for Economic Cooperation and Development (OECD). Tasks for solving these issues during field studies of pesticides have been outlined.
Key words: OECD, plant protection products, Good Laboratory Practice, field studies, standard operating procedures.

With the advent of new technologies and the global deterioration of the environmental situation on the planet, the existing system of food safety requires constant modernisation [1]. Up to 70 % of toxins of different origin from the environment may penetrate the human body through food products [2].

Introduction of food safety management systems in connection with the dynamic growth of species of biological threats prompts the leading world countries to harmonize their legislation. The policy on biosafety provision is an integral part of the EU policy in the field of ecology, healthcare and consumer right protection. Today, we can state that European standards in this field are the highest in the world.

On July 27, 2014, the President of Ukraine and the leadership of the European Union, heads of states and government have signed the economic part of EU-Ukraine Association Agreement (hereinafter referred to as the “Agreement”) [3]. A key element of the Agreement is the provision for the establishment of an in-depth and comprehensive Free Trade Zone (FTZ). Actions on the creation of the FTZ will, among other things, consist in bringing own technical regulations, procedures, sanitary and phytosanitary measures and food safety measures in line with European ones.

In accordance with Article 56 of the Agreement, Ukraine will undertake the necessary steps to gradually achieve compliance with the EU technical regulations and systems of standardisation, metrology, accreditation, EU conformity assessment and market surveillance actions, and will adhere to the principles and practices set forth in the relevant EU Decisions and Regulation [4]. Cooperation in science and technology is also an important aspect of the Agreement. This cooperation will be carried out through the intensification of work with various multi-sectoral organisations, in particular the Organisation for Economic Cooperation and Development (OECD) [4]. OECD is an international organisation with 34 member countries. Seventy countries, including Ukraine, have the status of OECD partners, taking part in many areas of its activities. The OECD was established in 1961 on the basis of the European Organisation for Economic Cooperation, established for management with the help of the US and Canada under the Marshall Plan for European Recovery after the Second World War. Since its establishment, OECD activities have been aimed at strengthening and improving the efficiency of the economies of the participating countries. In addition, OECD has the functions of developing science and technology policy, as well as solving social issues [5]. The OECD, among other activities, pays much attention to harmonising the regulation of the circulation of chemical products, including pesticides.

The dissatisfaction of governments and industry representatives from different states in terms of quality of non-clinical studies, the results of which are the ground for assessment of the level of hazard of manufactured products in the case of human health care and environmental protection, has led to the establishment of criteria for conducting such studies by OECD member states.

To avoid the use of different schemes for conducting such studies that could interfere with international trade in chemicals, OECD member states have decided to make international harmonisation of test procedures and Good Laboratory Practice. In 1979–1980, an international expert group established under the special program on chemical control, using organisational and scientific methods and experience from various national and international sources, has developed the OECD Principles of Good Laboratory Practice. These Principles of Good Laboratory Practice were adopted by the OECD Council in 1981 and revised in 1997 as an addition to the decision of the OECD Council on the mutual acceptance of data in assessing the safety of chemicals [6].

Within the second consensus OECD Consensus Symposium on Good Laboratory Practices held in Vail, Colorado, on May 21–23, 1991, experts discussed and agreed on the application of principles of Good Laboratory Practice under field conditions (field studies). This symposium allowed reaching an agreement on the issues of field study management in the context of adherence to the GLP Principles and the interpretation of the following terms: study, a study place, study director, responsibilities of the study site administration, quality assurance, etc., and their application in this context. An agreed document is a guide to the interpretation of the relevant GLP Principles in relation to field studies [7]. The purpose of the Principles of Good Laboratory Practice is to promote the application of the principle of quality assessment of data obtained as a result of a study of chemicals.

Principles of Good Laboratory Practice (GLP) are, above all, quality assurance system relevant to the processes of the organisation, planning, the procedure for conduct and control of studies of chemical substances in the field of human health care and environmental protection, as well as design, archiving and submitting the results of these tests. One of the most important elements of GLP is the development and implementation of standard operating procedures (SOPs). These are detailed written instructions that describe the processes of study conduct or other activities that are not generally presented in detail in study plans or study guidelines, and are intended to achieve uniformity in the performance of certain activities, including field studies of pesticides [6]. The GLP principles include recommended management standards for a wide range of studies of chemical substances conducted for regulatory purposes or other assessments. According to these principles, the following types of expert, laboratory and field studies of pesticides are foreseen:

- study of physicochemical properties;
- toxicological studies, aimed at the assessment of exposure to human health (short-term and long-term);
- ecotoxicological studies, aimed at the assessment of exposure to the environment (short-term and long-term);
- environmental studies, aimed at the assessment of the nature of chemical substance behaviour in the environment (transportation, biodegradation and bioaccumulation).

The general classification of environmental studies includes studies aimed at identification of the identity and residual amounts of pesticides, metabolites and related compounds for assessing the permissible limits and other effects on the diet.

The scope of studying pesticides in the field conditions, their residual amounts, and metabolism is a significant issue since the study plans, conditions, methods and results are significantly different from the traditional toxicological studies conducted at the study site [7].

Field studies of pesticides involves experimental activities carried out outside the usual laboratory environment, for example, on land plots, in external reservoirs or in greenhouses, often in combination with activities performed in the laboratory; or a study that is performed sequentially (one after the other) — first under field conditions, then in a laboratory or vice versa.

Pesticide studies under field conditions involve experiments at the study sites (but not limited to them) to determine the following:

- amount of residues;
- degree of photodegradation;
- metabolism in plants;
- metabolism in soil;
- consumption of substances by agricultural crops in crop rotation;
- degradation in soil;
- bioaccumulation;

The term “study site” in the context of the concept of “field study” may relate to several “study places” located at one or more geographical points, where the stages or components of a single study are conducted [6]. Different study places may include but are not limited to:

- the scientific and research laboratory(ies) where the determination of test/standard objects (including identification of identity, purity, concentration, stability, and other related activities) is carried out;
- one or several agricultural or other indoor and outdoor plots (e.g. greenhouses), where the test or standard object (sample) is used in the test system;
- in some cases, processing premises, where the crop is harvested for the production of other products, such as tomato processing for juice, puree, paste or sauce;
- one or several laboratories where the samples are collected (including samples obtained after processing) are analysed or otherwise evaluated for the presence of chemical or biological residues [7].

In the context of field studies of residues or the environmental state, the test object is generally an ingredient or mixture (composition) consisting of the active ingredient(s) and one or several inert components, such as emulsifiers. Other studies on plants and soil under field conditions are designed to study the change — metabolism of substances that are part of the tested object, for this purpose, chemicals with a radioactive label are used. The test object may be a substance of analytical grade or technical quality, prepared at the field study place immediately before use.

In conducting field studies, there may also be several legal entities that are the “study place administration”. They are primarily responsible for the presence of personnel, facilities, equipment and materials at each study place [7].

The main administration (the administration of the study site) must have a working contract with the administration of the study place and interact with them in terms of how and how will implement the quality assurance program.

The appointment of a study director is a key decision in the process of ensuring that the study is conducted in accordance with GLP principles.

In the framework of his/her duties, the director is responsible for timely preparation of the study plan and provides conditions for its implementation under field conditions:

1) properly described, tested and standard samples (objects) should be available at study places, if necessary;

2) ensures proper coordination between field (or production) places and analytical laboratories for sample analysis;

3) ensures proper comparison and archiving of data obtained from field, production and laboratory places.

As a rule, one person is not able to perform the function of ensuring study quality in the field, this requires the participation of several employees [6]. In some cases, all these persons can be employed in one single organisation (in which, for example, sponsor conducts the study), in others — they can be employed in several organisations (for example, partially participating in studies conducted by the sponsor and partially — contractors). In addition, effective communication between the study director and/or responsible investigators should be ensured to inform personnel about critical points of activity by the quality assurance. Study places and premises (facilities) intended for field studies, in general, are completely or partially agricultural or farm buildings, forest lands, mesocosms or other open experimental places [7]. The location of the study places should be chosen in such a way as to ensure the minimum probability of third-party intervention. It is desirable to place them in areas free of application of chemicals, or where the historical use of pesticides has not been documented (both for their study and under common use).

Laboratories that carry out an analysis of the residual amount of pesticides must be aware of the potential contamination of both the test sample and the standard sample. Premises for storing test and standard samples (objects) at all study plots should, if necessary, be subjected to environmental monitoring to ensure that the established limits of stability of these substances are met. It is also necessary to have premises for the proper storage and disposal of pesticides and related waste to exclude the possibility of cross-contamination of test systems, test or standard samples or collected samples. Particular emphasis should be placed on key field study procedures, such as storage of test objects (samples), field data collection, calibration of equipment for entering substances, application of a test object (sample), collection and transport of samples. It is also necessary to include all the methods intended for use in the analysis of samples to the study plan. If prior to signing the original study plan, the methods have not been fully developed or validated, then changes to the approved study plan may be required. The study plan should also cover all special types of analysis, such as conformity assessment procedures. Given the importance of quality assurance measures when analysing pesticide residues and environmental analysis, they should be specified in the SOPs and/or in the study plan. The procedures for assessing reproducibility, lack of interference and confirmation of analytical identity, in general, are also included in the SOPs and/or in the study plan [7].

The reliability of conducting field studies is based on complete and comprehensive primary data. Primary data include worksheets, notes, memos, remarks, or their exact copies, which are the results of own observations and research activities and are necessary for the reconstruction and evaluation of the report of this study. In cases where true copies of primary data were prepared (for example, textually decoded dictation records, dated and verified with correct signature), a true copy or correct transcript may be the source of the original data. Examples of primary data include photographs, microfilms, microfiches and their copies, computer printouts, magnetic media, including dictation recordings of observations and recordings of automated devices. One of the potential problems associated with remote study places is the temporary storage of materials from ongoing study until they are transferred to the archive upon completion of the study. Temporary storages at all study places must meet the requirements of ensuring the integrity of the study materials [7].

The globalisation of the pesticide registration process in the OECD member states and in the European Union, in particular, manifests itself in the unification of regulatory and methodological support for the pesticide registration system and the methods of testing PPPs. Only using standard, unified experimental methods for determining the physiochemical properties of pesticides, their behaviour in the environment, human toxicity and ecotoxicity, reproducible and comparative data can be obtained for further classification of pesticide hazards and risk assessment. OECD guidelines on the test of chemicals are the most widely used in many countries for this purpose. Experimental methods recommended by the OECD for testing pesticides have been developed within the framework of a major program for the preparation of chemical test guides, which began to be implemented since the 1980s. Currently, about 150 testing methods have been prepared, many of which can be applied to pesticides [8].

It should be noted that in Europe there is a single principle of regulating Good Laboratory Practice that covers the requirements for laboratory data for pharmaceuticals, chemicals, biocides, and plant protection products. Laboratory data is used to assess the risks to human health and the environment.

Additionally, there is additional regulation in the EU that covers plant protection products — Good Experimental Practice (GEP), which was introduced specifically for biological evaluations, including field studies [9].

Article 60 of Regulation (EC) No. 1107/2009 of the European Parliament and Council “On the placing of plant protection products on the market and cancellation of Council Directives 79/117/EEC and 91/414/EEC” indicates the following: “... the list of test and study reports relating to the active ingredient of interest, antidote or activating synergist ... and plant protection products which are necessary for the initial authorisation, change of permit conditions or renewal of authorisation ... include all information whether the studies and their reports have been certified as being in accordance with the principles of Good Laboratory Practice or Good Experimental Practice” [10]. Principles of Good Experimental Practice were implemented in Europe in 1996 to provide the regulation of data from field studies of pesticides for their registration. GEP has been implemented to provide a basis and uniformity for carrying out experiments and reporting on pesticide assessment used under field conditions. As noted above, there are many factors in the field that are beyond the control of investigators — soil and climatic features, weather conditions, varietal and species composition of plants, peculiarities of cultivation agriculture, peculiarities of harmful objects, etc. As a result, field study results, unlike laboratory ones, are prone to many variables. Therefore, reliable statistical models are important for interpreting the results. (In Europe, GEP regulation is separate from GLP. In other territories of OECD member states such as Japan and the US — only GLP, covering all the experiments on regulated markets) [9]. The GEP structure is similar to GLP and requires similar formal documents such as protocols, SOPs, field logs for data collection, preparation of reports and job descriptions, as well as a formal system of independent quality control.

Conclusion

Therefore, considering the above, a number of urgent challenges to the preparation of a statutory base for the implementation of sanitary and phytosanitary measures on the basis of the EU-Ukraine Association Agreement, bringing its technical regulations and procedures in line with European and international requirements are set for our state. We believe that, one of the important tasks of this program is unification of testing methods for plant protection products in Ukraine based on OECD guidelines on chemical substances tests, implementation of principles of Good Laboratory Practice in research institutions of the country for the purpose of mutual recognition of data and uniformity in the assessment of the level of hazard to human health and environment.

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Надійшла до редакції 27.04.2018 р.