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

ABSTRACT. The main objective of controlled field trials of pesticides in the EU and OECD countries is to identify (determine) the magnitude of the residual amounts of active ingredients of pesticide formulations in or on cultivated agricultural products, including animal feed, which should be designed to provide the maximum possible residues of active ingredients in the harvest of treated processed The data obtained on residues are then used to establish maximum residue concentrations (limits) of pesticide (mg/kg) in or on food products or animal feed recommended by the Codex Alimentarius Commission (Codex MRL). These values should not pose any risk to human health and take into account the requirements of international food products trade. Conduct of field trials of PPPs in Ukraine is regulated by Law of Ukraine “On Pesticides and Agrochemicals”, Decree of the Cabinet of Ministers of Ukraine No. 295  and Methodology Guidelines for the Hygienic Evaluation of New Pesticides. In accordance with Law of Ukraine “On Pesticides and Agrochemicals”, field trials are one of the stages of state testing of pesticides, which are conducted with the aim of establishing their biological efficacy, toxicological and hygienic and environmental evaluation and developing regulations for their application. The national action strategy to improve the assessment of safety of PPPs for human and animal health, and environment, which is one of the main elements taken into account when deciding on the registration of PPPs for use in Ukrainian agriculture, in accordance with OECD and EU requirements, depends entirely on the concept that should be the basis of this assessment. To date, plenty of data has been accumulated in the literature, indicating that the national concept of safety and hazard assessment of PPPs based on “complex hygienic rationing of pesticides in the environment” based on the maximum permissible concentrations used are out of date and should be replaced by the concept of “complex risk assessment”. The immediate task in increasing the reliability of the national field trials of PPPs and evaluation of their results in terms of their safety for humans, animals and environment is to bring them closer to European standards.

Key Words: plant protection products, domestic standards.

Before discussing the problem of evaluation of the results of national field trials of plant protection products (PPPs, pesticides) in terms of their safety for human and animal health and environment in accordance with the standards of the European Union (EU) and the Organization for Economic Co-operation and Development (OECD) , it is necessary to briefly consider how field trials of plant protection products are carried out in EU and OECD countries and in Ukraine.

Objectives and tasks of field trials      

The main objective of controlled field trials of pesticides in the EU and OECD countries is to identify (determine) the magnitude of the residual amounts of active ingredients of pesticide formulations in or on cultivated agricultural products, including animal feed, which should be designed to provide the maximum possible residues of active ingredients in the harvest of treated processed crops [1]. The data obtained on residues are then used to establish maximum residue concentrations (limits) of pesticide (mg/kg) in or on food products or animal feed recommended by the Codex Alimentarius Commission (Codex MRL) [2]. These values should not pose any risk to human health and take into account the requirements of international food products trade. Tasks of the field trials: 1) evaluation of the expected range of residual amounts of active ingredients of PPPs in a harvest of agricultural crops; 2) determination of the rate of reduction of residues of active ingredients of PPPs in products of interest; 3) determination of such values of the residues of the active ingredient of PPPs as the supervised trial median residue (STMR) and the highest residue (HR) to conduct a risk evaluation when the residue of the active ingredient of PPP penetrates human body with food. It should be emphasized that supervised field trials of pesticides in the EU and OECD countries are necessarily carried out in accordance with the principles of Good Agricultural Practice (GAP) [3], Good Plant Protection Practice (GPPP) [4] and Good Laboratory Practice (GLP) [5].

Good Agricultural Practice

Good Agricultural Practice is “a practice that relates to the ecological, economic and social sustainability of on-farm processes and which results in safe and high-quality food and non-food agricultural products” [3, 6]. The concept of Good Agricultural Practice lies in the application of modern knowledge, use of natural resources for the production of safe and healthy food and non-food agricultural products in a humane manner against the background of the achievements of economic and social stability.

At the end of 2007, upon the initiative of the Europe-Retailer Produce Working Group (EUREP), based on the concept of Good Agricultural Practice (GAP), a new version of the standard of safety of agricultural products and food quality was developed — Global GAP [7]. The main difference of this standard from the previously existing ones was to minimize the risks of agricultural production by tracking the entire production cycle, and not just checking the final product. To develop the Global GAP standard, HACCP (Hazard Analysis and Critical Control Point) system, which essentially became the basis of this standard, was used [8]. Compliance with the Global GAP standard eliminates the possibility of accumulation of harmful substances of chemical origin in products, as well as prevents mechanical and microbiological contamination. The main elements of the Global GAP standard are the condition of the soil and their fertilizing systems, seed, plant protection system, picking and storage of products, labour protection, industrial sanitation, environmental protection, production risk analysis, staff qualifications, complaints procedure, product tracking and return procedures.

Global GAP certification is voluntary, not requiring any legal documents for PPP users. However, according to current literary data, this system covers food producers in more than 90 countries and about 100 thousand farms that are certified by the Global GAP [9]. Ukraine also has a number of enterprises that are the members of the Global GAP.

Good Plant Protection Practice    

Plant Protection is one of 11 resource elements of Good Agricultural Practice (GAP) [3]. However, GPPP, its content and concept is much broader than the GAP, since it does not selectively relate only to the use of plant protection products, but covers all other aspects that lead to plant protection. Regulation (EC) No 1107/2009 of the European Parliament and of the Council of October 21, 2009 concerning the placing of plant protection products in the market and repealing Council Directives 79/117/EEC and 91/414/EEC in Article 3 “Terms” gives the definition of GPPP: “Good Plant Protection Practice” means a practice whereby the treatments with plant protection products applied to given plants or plant products, in conformity with the conditions of their authorised uses, are selected, dosed and timed to ensure acceptable efficacy with the minimum quantity necessary, taking due account of local conditions and of the possibilities for cultural and biological control [10].

Currently, GPPP is the main strategy and measures in the field of plant protection, namely:

• safety for humans, animals, and the environment from a scientific point of view;
• recognition by the competent authorities as suitable, appropriate and necessary in practical settings;
• recommendation by the official services responsible for the use of plant protection products;
• practical use by qualified operators.

The general principles of Good Plant Protection Practice are as follows:

1. plant protection measures should be implemented in such a way as to correspond to the area to be treated, crop and situation, and the use of the necessary means must correspond to the absolutely necessary;
2. proven biological, mechanical and other non-chemical measures to reduce damage from pests and diseases should be used as far as possible in cases where it is practically and economically feasible;
3. the goal should not be the eradication of pests, but the reduction of invasion (infection) in such a way that there is no economic damage; however, there may be cases requiring zero tolerance for the pest;
4. those who use plant protection products are obliged to resort to the help of official and other consulting services, improving their skills in various specialized institutions.

Good Laboratory Practice

Due to the preparation of the dossier materials for PPP on the results of field trials in accordance with the requirements of Article 8 (1) of Regulation (EC) No. 1107/2009 of the European Parliament and of the Council which is considered when deciding on the registration of PPP for its use in agricultural practice, it is not [possible to pass by the issue of the use of the principles of Good Laboratory Practice (GLP) . Article 3 of the said Regulation contains the following statement: “Good Laboratory Practice” means a practice as defined in point 2.1 of Annex I to Directive 2004/10/EC of the European Parliament and of the Council of February 11, 2004 on the harmonisation of laws, regulations and administrative provisions relating to the application of the principles of good laboratory practice and the verification of their applications for tests on chemical substances [11].  Annex 1, OECD Principles of Good Laboratory Practice (GLP), of Directive 2004/10/EC provides the definition of GLP: Good laboratory practice (GLP) is a quality system concerned with the organisational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported.

The subject of these safety studies are substances contained in pharmaceuticals, pesticides, cosmetics, veterinary preparations, as well as in food additives, and industrial chemicals. The objective of these trials is to obtain data on the properties of the above-listed drugs and substances and/or their safety in relation to human and animal health and/or environmental.     Non-clinical health and environmental safety studies, covered by the GLP principles, include work that can be done in the laboratory, greenhouses and field conditions.

And finally, in Соmmission Regulation (EU) No. 283/2013 of March 01, 2013 setting out the data requirements for active ingredients in accordance with Regulation (EC) 1107/2009 of the European Parliament and of the Council 2009 concerning the placing of plant protection products in the market [12] and in Соmmission Regulation (EU) No. 284/2013 of March 01, 2013 setting out the data requirements for plant protection products in accordance with Regulation (EC) No. 1107/2009 of the European Parliament and of the Council 2009 concerning the placing of plant protection products in the market [13], it is stated that tests and analyses should be performed in accordance with the GLP principles set forth in Directive 2004/10/EC of the European Parliament and of the Council [11], when trials are carried out to obtain data on the properties or safety of the active ingredients of PPPs and/or PPPs in relation to human and animal health or environment. These Regulations state that tests or analyses can be carried out by official or officially authorised laboratories or organizations that must meet at least the following requirements:

• have at their disposal sufficient scientific and technical personnel with the necessary education, training, technical knowledge and experience to perform the functions assigned (official duties);
• have at their disposal the appropriate equipment necessary for the proper performance of tests and measurements, which are operated by competent performers; this equipment must be properly maintained and calibrated when it is necessary before it is put into operation and then when used in accordance with the program set;
• have at their disposal relevant experimental fields and, if necessary, greenhouses, growth cabinets and storage facilities; the environment in which the trials are carried out should not lead to the cancellation of the results or adversely affect their accuracy;
• provide access to all relevant personal standard operating procedures and protocols used for trials;
• provide, at the request of the competent authority information on its location and the test plant protection products prior to the start of the trial;
• ensure that the quality of the work performed corresponds to its type, range, scope, and purpose;
• keep records of all observations, calculations and obtained data and calibration records, and the final trial report, as long as the corresponding PPP is authorized in the member state;
• provide the relevant national authority with all the information necessary to demonstrate that they can meet all the requirements listed above;
• to allow inspections, which each member state must regularly organize on its territory, to carry out checks on compliance with all the above-listed requirements at any time.

Good Experimental Practice

It should be noted that in Regulation (EC) No. 1107/2009 of the European Parliament and of the Council [10] in Article 3 of the Terms, along with the term GLP, the term “Good Experimental Practice” (GEP) is given in the following context without any further comment: “Good Experimental Practice” means a practice in accordance with the provisions of the European and Mediterranean Plant Protection Organisation (EPPO) Guidelines 181 and 152. The emergence of the term “Good Experimental Practice” was largely contributed by the inaccuracy made by the European Commission in using the term “Good Laboratory Practice” in relation to conducting field (non-clinical) trials of pesticides [11], although it is clear that conditions of PPP trials in the laboratory significantly differ from field trials. However, it is impossible to recognize the use of the term “Good Experimental Practice” as absolutely impeccable exclusively for conducting field trials, since an experiment can be carried out both in the field and in the laboratory conditions.

 As it appears from the EPPO standards (EPPO PP1) [14, 15], the main objective of the GEP is to provide high-quality field trials conducted to evaluate the efficacy of PPPs for the control of specific pests, i. e. evaluation of PPP efficacy — one of the stages of field trials.  The term “efficacy evaluation” means the determination of the efficacy of PPPs against a target pest, which may include a degree of agronomic stability and economic benefits [16]. Conducting field trials in accordance with GEP should ensure that data on the efficacy of PPPs obtained in one country can be used for registration purposes in other countries and to allow the use of PPPs in the agricultural practices of these countries. GEP involves managing the efficacy evaluation of field trials and the conditions in which field trials should be planned, conducted, evaluated, recorded and interpreted so that their results are comparable and reliable. In this case, the GEP covers the following aspects: qualification of the staff, use of proper equipment and facilities, protocols, methods of work, recording of results. In the practical settings, GEP requires consideration of the following:   

• criteria that must be met by organizations responsible for conducting field trials to evaluate the efficacy of PPPs;
• methods of work (conducting field trials) of these organizations;
• internal procedures for checking and confirming the use of GEP by organizations.

The EPPO PP1 standards are based on FAO principles for evaluation of the efficacy [16] for registering plant protection products for a particular crop-pest combination according to field trial results. To date, more than 300 standards have been approved by EPPO.     

Comparison of the principles and requirements of GEP [14] with the principles and requirements of the GAP [3], GPPP [4] and GLP [11] leads to the conclusion that they are identical in relation to the conduct of field trials (with the exception of efficacy evaluation) of PPPs, therefore GEP cannot be considered as a replacement for the GAP, GPPP and GLP.

Field trial zones for PPPs in EU countries

When planning field trials of PPPs, EU countries are guided by Annex 1 of Regulation (EC) No. 1107/2009, which defines three zones in the EU where field trials are carried out for subsequent registration and authorization of the use of plant protection products:

• Zone A - North: Denmark, Estonia, Latvia, Lithuania, Finland, Sweden.
• Zone B - Centre: Belgium, the Czech Republic, Germany, Ireland, Luxembourg, Hungary, the Netherlands, Austria, Poland, Romania, Slovenia, Slovakia, the UK.
• Zone C - South: Bulgaria, Greece, Spain, France, Italy, Cyprus, Malta, Portugal.

The principle of mutual recognition of field trial results established by this Regulation allows the authorization holder to place plant protection products in the market of another member state if the agricultural conditions, growing conditions of the plants and environmental conditions are comparable to the region in question. However, a member state may temporarily limit or prohibit the placement of plant protection products on its territory if it poses a risk to human and animal health and/or to the state of the environment. It should be noted that Regulation (EC) No. 1107/2009 does not refer to climatic regions within individual EU member states, but to entire states, which eliminates the need for field trials of PPPs in different climatic regions of the same state.

Information to be obtained during field trials of PPPs in OECD and EU countries

When conducting field trials, the type of soil (e. G. sand, clay, loam, sandy loam) should be identified and indicated for all sites where these trials are carried out. If plant protection product is applied directly to the soil, field trials should include sites with different types of soil (at least 4 types of soil).

The number of field trials for any crops, the results of which are used to establish MRLs for all OECD countries, is 16. In some cases, this number can be reduced to 10. The minimum number of field trials is eight.   

Methods of sampling, number and size of crop samples (treated and control), which are sampled from each test and control sites for subsequent chemical analysis, are regulated.

When conducting field trials, the following information and data should be obtained with respect to the test plant protection product and its active ingredient(s), antidotes and synergists [12,13]:                                                                                 

• intended scope (agriculture, horticulture, forestry, viticulture);
• effect on harmful organisms (contact, gastric, inhalation, etc.);
• application rate (consumption rate) for PPP and its active ingredient in g or kg per treated unit (ha, m², m³);
• concentration of the active ingredient in the test PPP (g/L, g/kg, mg/kg, g/tonne);
• method of application of PPP with the specification of equipment used;
• maximum number of treatments and their timing;
• stages of growth of the agricultural crop or plant and stages of development of harmful organisms;
• waiting periods between the last use of PPP and seeding or planting of subsequent agricultural crops, which are necessary to avoid phytotoxic effects on subsequent agricultural crops;
• instructions for use of PPP, which must be printed on its label;
• PPP compatibility with the proposed packaging materials;  
• procedures for cleaning the equipment used;
• methods and precautions regarding the handling of PPP, its storage and transportation, as well as those associated with the occurrence of emergency situations (spill, fire, etc.);
• procedures for the destruction or decontamination of PPP and its package;
• pre-harvest intervals for each crop (in days), return time for agricultural workers to the cultivated areas (in days), return time (in days) for livestock to grazing areas, waiting period (in days) for feed for animals, waiting period (in days) between use and handling of treated products;
• analytical methods for post-authorization control and monitoring for the determination of residues of active ingredients and significant metabolites;
• analytical methods for determining the active ingredient and significant impurities in PPP;
• data on the efficacy of PPP that allow evaluation of the efficacy of PPP against the target pest, agronomic stability and economic benefits compared to appropriate reference products and untreated control, as well as determination of the conditions for PPP use;
• data on the quantitative determination of the highest probable level of residues of active ingredients of PPP and their significant metabolites in treated crops at harvesting, grown in accordance with the GAP;
• proposed maximum residue levels of active ingredients (MRLs) of PPP;
• non-extractable residues of active ingredients of PPP; 
• half-life (DT50) of the active ingredient and significant metabolites in the soil;
• 90 % half-life of the active ingredient and significant metabolites in the soil;
• levels of residues of the active ingredient and significant metabolites during harvesting in the soil;
• data on accumulation of the residues of the active ingredient and significant metabolites, products of decomposition and reaction in the soil;
• data on mobility in the soil and possibility of enleaching of the residues of the active ingredient and significant metabolites, products of decomposition and reaction; 
• lysimetric data of field enleaching of the residues of the active ingredient and significant metabolites, products of decomposition and reaction; 
• evaluation of expected concentrations of the active ingredient of PPP in the soil;
• aerobic mineralization of PPP in surface water;
• evaluation of the expected concentration of active ingredient of PPP, significant metabolites, products of decomposition and reaction in surface water;
• the predicted concentration of the active ingredient of PPP in the air and the level of residues that humans, animals and other non-target organisms may be exposed to.

Conduct of PPP field trials in Ukraine

Conduct of field trials of PPPs in Ukraine is regulated by Law of Ukraine “On Pesticides and Agrochemicals” [17], Decree of the Cabinet of Ministers of Ukraine No. 295 [18] and Methodology Guidelines for the Hygienic Evaluation of New Pesticides [19]. In accordance with Law of Ukraine “On Pesticides and Agrochemicals”, field trials are one of the stages of state testing of pesticides, which are conducted with the aim of establishing their biological efficacy, toxicological and hygienic and environmental evaluation and developing regulations for their application. The list of scientific and research institutions and organizations involved in conducting state trials of pesticides in Ukraine was approved by Order of the Ministry of Environmental Protection of Ukraine [20]. In accordance with this Order “toxicological and hygienic evaluation of drugs, development of hygienic norms and regulations, development and modification of methods for determining the residual quantities of drugs” is carried out by specialists of the State Enterprise “L. I. Medved’s Institute of Ecohygiene and Toxicology” of the Ministry of Health of Ukraine (now State Enterprise “L. I. Medved’s Research Center of Preventive Toxicology, Food and Chemical Safety of the Ministry of Health of Ukraine), State Enterprise “Institute of Occupational Health of the National Academy of Medical Sciences of Ukraine” (now State Institution “Yu. I. Kundiiev Institute of Occupational Health of the National Academy of Medical Sciences of Ukraine”) and O. O. Bohomolets National Medical University.

How are the field trials of plant protection products practically implemented in Ukraine in terms of their safety assessment for human and animal health, the environment, what data are obtained during the conduct of these trials, and how their implementation and results can be assessed in accordance with the requirements of the EU and OECD?

First of all, it should be noted the most important feature of conducting field trials of PPPs in Ukraine, which lies in the fact that foreign PPPs are generally subjected to field trials, and they have already passed field supervised trials in the EU or OECD countries and, based on the results of these trials, they have been registered for use in the agricultural practices of these countries. It would seem that this circumstance, taking into account Principle of Mutual Recognition of the Results of Field Trials of Regulation (EC) No. 1107/2009 allows the placement of PPP authorised in the EU without conducting field trials in Ukraine if the agricultural conditions, vegetation conditions of plants and conditions of the environment of the EU country that holds permission to use PPP in agricultural practice are comparable to Ukrainian ones. However, this is not so for two reasons. First of all, Ukraine, unfortunately, is not yet a member of the EU. And secondly, as noted above, field trials of PPPs in the EU and OECD countries are necessarily carried out in accordance with the principles of GAP, GPPP, GLP and GEP, which suggests that the application of PPPs in the agricultural practice of these countries will be in accordance with these principles. The basic norm of food safety for human consumption in connection with the use of PPPs — the maximum residue limit (level) (MRL) is legal only in the case of PPP application in accordance with GAP, GPPP, GLP and GEP.

Disconcertingly, the documents regulating the field trials of PPPs in Ukraine and their further use in the practice of agriculture [17-19], have even no hint that these trials and the further use of PPPs should be in accordance with GAP, GPPP, GLP and GEP. In Ukraine, there are no national methodological documents that would regulate the field trials of PPPs and their further use in accordance with the principles of GAP, GPPP, GLP and GEP, and with a rare exception [21], there are virtually no staff who would be trained and certified appropriately.  The rare exception is Law of Ukraine “On Plant Protection” [22], which state “the obligation to implement plant protection measures by enterprises, institutions, organizations of all forms of ownership and citizens whose activities relate to the use of land, forest, water objects, cultivation agricultural and other purposes ...” and “implementation of state control over compliance with pesticide application regulations ...”    

Paradoxically, precisely the fact that the above-mentioned regulatory documents are not used in the agricultural practice of Ukraine, it makes it compulsory to carry out field trials of PPPs in accordance with the conditions of application of PPPs that currently exist in the agricultural practice of Ukraine.  Only such conduct of field trials of PPPs will allow obtaining real data on the behaviour and amount of active ingredients of PPPs in cultivated agricultural products and environmental objects, develop standards and regulations that would ensure the safe use of PPPs for human and animal health, and environment, and conduct an objective comparison of the proposed standards and regulations with the standards and regulations of the EU and OECD countries. Just this kind of field trials of PPPs allows determining real values of maximum residue levels (limits) of active ingredients of PPPs in the national agricultural raw materials and food products and assess the actual load (impact) of PPPs on the human and animal body, and environment in connection with their use in agricultural practice in Ukraine.

The lack of use of the EU and OECD regulations in the agricultural practice of Ukraine does not allow using maximum concentrations (limits) of pesticide residues (MRL) in or on food or animal feed set by the Codex Alimentarius Commission [2], despite the entry into force of Decree of the Cabinet of Ministers of Ukraine on ensuring the application of the Code in Ukraine from January 01, 2012. The use of Code’s MRL in Ukraine is possible only if PPP are used in the agricultural practice of Ukraine in accordance with the standards for use of PPPs and waiting periods established in the EU and OECD countries [23]. However, in international trade of agricultural and food raw materials and food products, Ukraine should be guided solely by the values of the Code.

The organization and conduct of field trials of PPPs in Ukraine should be within the competence of the central executive body that implements the state agricultural policy in the field of PPPs. This body should have at least the following:  1) scientific and technical personnel with appropriate education, training, technical knowledge and experience; 2) necessary equipment for the correct tests and measurements, which must be properly maintained and calibrated for use in accordance with the established program; 3) relevant experimental fields, hothouses and greenhouses.

Professionals of the Ministry of Health of Ukraine (chemists, toxicologists and hygienists) participate in field trials of PPPs to collect information and obtain data necessary for assessing the safety of regulations of the use of PPPs developed by plant protection professionals (rate of application of PPPs and the number of treatments) for human and animal health, and the environment. This information and data are then used to decide on the registration of PPP in Ukraine and include the following:

• Maximum permissible concentration (MPC) of the active ingredient (AS) of PPP in the water reservoirs.
• Maximum permissible concentration (MPC) or the tentative permissible concentration (TPC) of the AS of PPP in the soil.
• Maximum permissible concentration (MPC) or safe reference level of impact (SRLI) of the AS of PPP in the working air.
• Maximum permissible concentration (MPC) or SRLI of the AS of PPP in atmospheric air.
• Time for people to return to sites treated with PPPs.
• Waiting period.
• Methods for determining residual amounts of active ingredients of plant protection products.
• Levels of residues of AS of PPP in the working air.
• Levels of residues of AS of PPP in the soil at the time of harvest.
• Levels of residues of AS of PPP in planting crop.
• Maximum permissible level (MPL) of AS of PPP in food product or in agricultural or food raw materials.

The main difference between the type, nature and amount of most of the information and data that are acquired during field trials of PPPs in Ukraine, compared with the EU and OECD countries, is that assessment of the harmful effects of active ingredients on the health of human and animals, birds, fish and environment in Ukraine is carried out using the unreasonable and uninformative concept of rigidly fixed MPC values of active ingredients of PPPs [23]. In the EU and OECD countries, this assessment is carried out using the probabilistic approach of the risk assessment concept, which was initiated by US EPA (US Environmental Protection Agency) in terms of active ingredients [24].

The mechanistic transfer of the MPC determination algorithm for chemicals in the working air and environmental objects, used in industry, for PPPs that are used in agriculture does not make it possible to realistically assess how safe are regulations of PPP use, developed by plant protection professionals, for human and environment (rate of application and number of treatments). This is due to the fact that when applying PPP in agricultural practice, the concentration of the active ingredient in the working air, soil, reservoir water, air surrounding the person and the cultivated food product or feed for farm animals exclusively depends on the rate of application of PPPs, which is set by plant protection professionals and which should provide efficient control of weeds and pests, therefore, any regulation of these concentrations on the basis of virtual MPCs is impossible [23].

It is important to note that the first who paid attention to the difference between the hygienic rationing of chemicals used in industry and agriculture was Academician Lev Ivanovich Medved, one of the largest scientists in the hygiene of the former USSR, the founder of the All-Union Scientific and Research Institute of Hygiene and Toxicology of Pesticides, Polymers and Plastic Masses (now State Enterprise “L. I. Medved’s Research Center of Preventive Toxicology, Food and Chemical Safety of the Ministry of Health of Ukraine”), and he was the changeless director of institution for many years. He stated that: “When considering the problem of the impairment of human health by chemicals in agriculture, the specifics of their use, which differs from the conditions in the industry should be taken into account. Air pollution at workplaces of enterprises is the result of the imperfection of technology and sanitary facilities. The causes of pollution of water bodies with industrial effluents and atmospheric air with emissions depend on the imperfection of sewage treatment plants and catching devices. All these reasons are removable. Another thing with pesticides. They are deliberately loaded into aircraft, tractor and other sprayers and sprayed on millions of hectares, and therefore they continuously circulate in the living environment of people. At present, they are found all over the world in the atmospheric air, in the water of open reservoirs, in the subsoil waters, in food, in the body of living organisms, including people ” [25].

It is ruefully to state that these insightful thoughts of Academician L. I. Medved were not embodied in national papers related to the hazard assessment of active ingredients of PPPs for humans and the environment. Until now, this assessment is performed on the basis of the “establishment” of MPC values for active ingredients of PPPs in the working air, atmospheric air, water of open reservoirs and soil, which have nothing in common with the values of real concentrations of active ingredients of PPPs in these environments as a result of the use of PPPs in agricultural practice. This situation leads to the fact that as a result of field trials of PPPs, it is impossible to adequately assess the real danger faced by workers entering agricultural plots after using PPPs to perform agricultural work, as well as to assess whether the amounts of PPPs reaching the surface of plants and soil are dangerous, whether they pollute air, surface and ground waters. Unfortunately, this completely eliminates the assessment of the risk of active ingredients of PPPs with a common toxicity mechanism to human health.    

National strategy for improving the assessment of safety of PPPs used in agricultural practice for human and animal health, and environment

The national action strategy to improve the assessment of safety of PPPs for human and animal health, and environment, which is one of the main elements taken into account when deciding on the registration of PPPs for use in Ukrainian agriculture, in accordance with OECD and EU requirements, depends entirely on the concept that should be the basis of this assessment. To date, plenty of data has been accumulated in the literature, indicating that the national concept of safety and hazard assessment of PPPs based on “complex hygienic rationing of pesticides in the environment” [19] based on the maximum permissible concentrations used are out of date and should be replaced by the concept of “complex risk assessment” [24].  

The first step in this direction should be the development of a Guideline on Assessment of PPPs which will incorporate the collective context of laws and regulations, policies and guidance documents describing the methodology for the assessment of PPPs and their active ingredients.  The current legislative and regulatory documents in this field in Ukraine [17–19] have long been hopelessly outdated and do not meet the requirements of the documents used for these purposes in EU countries [23].

First of all, it should be noted that in these national documents definitions (terms) are used that are outdated or do not exist in modern EU regulatory documents and glossaries intended for PPPs [27]. This refers to terms such as:

• pesticides and agrochemicals;
• Certificates of Quality;
• methods for determining the compliance of pesticides and agrochemicals with Certificates of Quality.

Initially, the division of chemical compounds that are used in agriculture in Ukraine into pesticides and agrochemicals [17] was not correct, since the vast majority of pesticides are chemical compounds by their nature and, therefore, belong to agrochemicals. Agrochemicals are a general term for agricultural agrochemicals that are used in crop production and food production, including pesticides, feed additives, chemical fertilizers, veterinary preparations and related compounds [27]. Therefore, the majority of agrochemicals, which are used in agriculture of Ukraine for their intended purpose, can be divided into two groups - pesticides and chemical fertilizers. In this regard, the name of the above mentioned Law of Ukraine [17] is incorrect.

Furthermore, it should be noted that in modern EU regulatory documents, the term “plant protection products” (PPP) is used instead of the term “pesticides”. The term “pesticides” is a broader term that covers products such as biocides that are not intended for plants, but are used to control pests and vectors of diseases such as insects, rats and mice and do not fall within the competencies of the central executive body, which implements the state agrarian policy in the field of PPPs.

The term “pesticides” in the national popular literature was associated mainly with agrochemicals, which are used to control insects (despite their actual purpose in accordance with the recommendations of IUPAC) [27]. This led to the appearance of such unacceptable phrases as “pesticides and herbicides” in many publications. In order to further avoid such misunderstandings, the term “plant protection products” should be used instead of the term “pesticides”. PPPs are pesticides that are mainly used to keep the crop intact and prevent its damage by diseases and pests. PPPs include herbicides, fungicides, insecticides, acaricides, nematicides, algicides, rodenticides, slimicides and growth regulators.

With regard to PPPs, there is no such international document as a “Certificate of Quality”, which, according to some professionals, would have to accompany PPP when it is imported into Ukraine. Companies importing PPPs accompany their products with Certificates of Analysis, Certificates of Composition or other documents that indicate compliance with the requirements of the specifications (technical conditions) of FAO/WHO [28] of the product being imported. In this regard, the methods of “determining the compliance of pesticides and agrochemicals with Certificate of Quality”, which are stipulated by Law of Ukraine [29], cannot exist and do not exist. Establishing compliance of PPPs that are imported into Ukraine to FAO/WHO specifications should be carried out in accordance with international (including European) standards and requirements only using methods that are developed under the auspices of the Collaborative International Pesticides Analytical Council (CIPAC). It is possible to raise any claims to the manufacturing company of PPPs regarding the products it shipped to Ukraine regarding its non-compliance with the requirements of the FAO/WHO specifications only on the basis of the data obtained using the CIPAC methods. In this regard, in Ukraine, there is completely no practical need for the development and subsequent approval of the methods used to control the compliance of PPPs being imported into Ukraine with the FAO/WHO specifications.

It should also be noted that the provision of Article 16¹ of Law of Ukraine “On Pesticides and Agrochemicals” ascertaining that “the competence of the specially authorized executive body on environmental protection in the field of activities related to pesticides ..., includes: development and approval of the methods for determining the conformity of pesticides ... with Certificates of Quality, in agreement with the specially authorized central executive body on health issues", is outdated, does not meet modern requirements for international turnover and trade of PPPs, and should be excluded from the new version of Law of Ukraine on PPPs. In this regard, the provision of p. 8 of Decree of the Cabinet of Ministers of Ukraine No. 295 regarding “the development and approval of the methods for determining “product compliance with the Certificates of Quality” [18] is outdated.        

There is also a need for a certain improvement in the legislative framework in the field of plant protection, which should consist in an approximation of national legislation to EU requirements in this area, and not include such grotesque requirements as “preventing ... contamination of plant products and the environment with plant protection products” (see Law of Ukraine “On Plant Protection”, Article 4. Main requirements for plant protection [22]).

In order the global revision of the above documents, including Law of Ukraine “On Pesticides and Agrochemicals” results in obtaining national regulatory documents that would correspond to the modern level of achievements of world science and practice related to the use of PPPs in agriculture, it is required to engage professionals of the appropriate qualifications and relevant knowledge to this process.

The basis for the development of a new Guideline on PPP Assessment should be the main EU regulatory documents in this area: Regulation (EC) No. 1107/2009 of the European Parliament and of the Council of October 21, 2009 [10]; Commission Regulation (EC) No. 283/2013 of March 01, 2013 [12], Commission Regulation (EC) No. 284/2013 of March 01, 2013 [13] and Guideline for PPP Assessment - version 2.1/2.2/2.3 [30].

In parallel with the development of the National Guidelines for the Assessment of PPPs, it is necessary to start developing the National Guidelines for evaluating the results of field trials in terms of the safety of PPPs for human and animal health, and environment, since current legislative and regulatory documents in this area governing field trials of PPPs their subsequent evaluation in Ukraine [17–19, 26] have long been hopelessly outdated and do not meet the requirements of the documents used for these purposes in EU countries [23].

It should be emphasized that, in EU countries, guidelines for assessment of PPPs are based on European Regulation [10] and national rules, which provide for national requirements for permitting (registration) PPPs.  Thereforeе, the work on the drafting National Guidelines on the assessment of PPPs and field trial results for PPPs should in no case be considered an identical translation of EU laws, rules and regulations in these areas from English to Ukrainian. When drafting these documents, it is necessary to take into account that the agricultural practices and practices of plant protection currently existing in Ukraine differ from European ones (unfortunately, not for the better). Therefore, along with the drafting National Guidelines for the Assessment of PPPs and field trial results of PPPs, which should take into account the real state of agricultural and plant protection practices in Ukraine, it is necessary to provide for the development of an action plan aimed at bringing national agricultural production to European standards in the nearest future.            

It was mentioned above that the organization and conduct of field trials of PPPs in Ukraine should be within the competence of the central executive body that implements the state agricultural policy in the field of PPPs. It is important to remember that success is largely determined by the correct formulation of the tasks solved during these trials and an accurate assessment of the results obtained.

The formulation and setting of tasks for field trials of PPPs in terms of their safety for human and animal health, and environment, data collection and assessment are the responsibility of the central executive body on health issues and are carried out, as mentioned above, by professionals (chemists, toxicologists and hygienists) of scientific and research institutions and organizations in accordance with Order of the Ministry of Environmental Protection of Ukraine [20]. In order to successfully complete this part of the field trials of PPPs, it is necessary to clarify the number of tasks required for the solution, list the data to be obtained, and develop uniform principles for their assessment, taking into account the requirements of EU standards, which are mandatory for all participants of these PPP trials. It is also necessary to develop uniform guidelines for the preparation of reports on the results of the evaluation of data from field trials of PPPs in terms of their safety for human and animal health, and environment.  Many years of experience in reviewing reports on field trials of PPPs of the Institutes of the Ministry of Health of Ukraine participating in field trials show that certain adjustments should be included in the presentation and interpretation of the materials of these reports relating to the assessment of PPP safety for human and animal health, and environment. First of all, this refers to the wording of the report titles, objectives and tasks of the trials conducted.

As a rule, title of each report contains such formulation: “Justification of the regulations for the safe use of the product (product is indicated)”; typical formulation of the objectives and tasks of the study: “Justification of hygienic regulations for safe use of the product...”. Many titles of the Reports, wordings of objectives and tasks of the study contain the following formulation: “Justification of MPL (maximum permissible level) of the active ingredient of the product in ...” (food product is indicated).

 The invalidity of such formulations lies in the fact that for the contingent that applies PPPs, there can be no “rules” for the safe use of PPPs, which can somehow be regulated, except for the only condition: the contingent that uses PPPs must be reliably protected from any of penetration of PPP into the human body using personal protective equipment. And for agricultural workers who must enter the territory after applying PPPs for a variety of agricultural work, not the “safe use regulations”, indeed, must be justified, but the periods when agricultural workers can enter the treated areas for a variety of operations without any personal protective equipment and without damage for their health.

Taking into account the above, it should be emphasized again that there are no separately existing “safe use regulations of the product” from the developed regulations for the use of the product (rate of consumption and number of treatments) proposed by plant protection professionals, cannot exist, even if they are called “hygienic” . It is strictly forbidden to make any changes to these regulations since only these regulations, i. e. rates of application and number of treatments with PPPs ensure the expediency of applying this PPP for a certain crop.

There also can be no substantiation of the MPL of the active ingredient of PPP in a food product, since PPP MPL is not substantiated but calculated from the results of physical determination of residual amounts of the active ingredient of PPP in food product harvest (mg/kg) during field trials [23]. Prior to carrying out supervised field trials of PPPs, the following parameters of active ingredients of PPPs are justified: acceptable daily intake of the active ingredient of PPP for a person (ADI [MPL]), acceptable operator exposure level (AOEL) and acute reference dose of the active ingredient of PPP (ARfD) [10].

The tasks of physicians in the course of conducting supervised field trials of PPP by protection professionals are only the following: 1) determine, on the basis of the data obtained by chemists, the return time (REI), i. e. time when agricultural workers, after the use of PPP, can enter the treated areas for various works without damage to their health; 2) establish, along with chemists and on the basis of the data obtained by chemists, on the content and behaviour of residues of the active ingredient of PPP in the soil of the treated areas and on the surface of vegetative plants, whether these residues are dangerous for pollution of ambient air and groundwater; 3) determine, on the basis of the data obtained by chemists, whether the amount of the residue of active ingredient in the food product corresponds with ADI of active PPP; 4) establish on the basis of the data obtained by chemists on the content of residues of the active ingredient of PPP in the food product during the growing season, the amount of pre-harvest interval (PHI) to exclude the possibility of consumption of food with residues of the active ingredient of PPP by population that would exceed set value of MPL.

The literature describes methods for calculating return periods used for various PPPs applied in agricultural practice [31–33], as well as methods for calculating the pre-harvest interval [34]: calculating the level of the maximum residue of the active ingredient of PPP for a given interval before harvesting and calculating the interval to harvest for a given maximum level of the residue of active ingredient of PPP.

The return periods of agricultural workers to the areas treated with PPP for manual or mechanized work should be established on the basis of data on the amounts of the active ingredient of PPP that can penetrate the human body through the respiratory organs and skin, as a result of eye exposure to evaporation, dust or mist or rubbing eyes with hand, glove or clothing that is contaminated with residues of the active ingredient. Different PPPs have different return periods. In turn, each PPP can have one or several different return periods depending on the type of future work, which must be performed after the application of PPP and during which human contact with the treated plants and soil may change: weeding, thinning, irrigation, loosening, etc. Unfortunately, materials of national Reports on the results of supervised field trials of PPPs contain no description of the ways in which the parameters necessary to establish return periods should be determined, and methods and formulas for calculating return periods are not given. Instead, data are presented on the determination of active ingredients of PPPs in washings from the surface of unprotected (open) skin and in stripes on workers’ overalls and then two values of return periods are provided on an absolutely empirical basis “for mechanized and manual work” without any identification of the type of work performed. In this regard, it is not possible to assess the reliability of the establishment of return periods when conducting domestic field trials, and it is also not impossible to assess how far these return periods are able to protect the health of agricultural workers from the harmful effects of PPPs during their use. It should be especially noted that people in overalls that do not fulfil their protective functions and leave the skin open should not be allowed to work with PPPs. In addition, such a primitive approach to the assessment of exposure to active ingredients of PPP as washings and stripes was not used long ago in the EU and OECD countries.  For this purpose, the values of the allowable exposure level (AEL), no-observed-effect level (NOEL), and the results of biological monitoring have been established.       

The situation is not the best with the establishment of a national standard — waiting period, which is similar to the EU standard — pre-harvest interval. A prerequisite for its determination is the availability of reliable data on the values of residues of the active ingredient of PPP in a crop during its growing season. It was noted above that in order to obtain reliable residual values, at least, statistical processing of the results of eight field trials of PPP on one agricultural crop is necessary, followed by a comparison of the obtained value with the allowed MPL. As with the standard “return period” in the materials of the National Reports on the results of supervised field trials of PPPs, there is no description of the method by which the waiting periods are established and the methods and formulas for calculating waiting periods are not provided. In this regard, it is not possible to assess the reliability of the establishment of waiting periods when conducting domestic field trials, and it is also not impossible to assess how far these waiting periods really prevent consumption of the national food products with residues of active ingredients of PPPs hazardous to human health.

When using a scholastic approach for complex risk assessment for humans, animals and the environment associated with the use of PPPs in agricultural practice [24], reliable determination of the residues of active ingredients of PPPs in agricultural raw materials, food products and environmental objects is of high priority.  The reliability of the results of field trials on the determination of the residues of active ingredients of PPPs in the above environments largely depends on the correct sampling for subsequent analysis. If the sample does not represent the whole product or the site from which it was sampled, all subsequent laborious and expensive analysis will be useless, because the result will not be reliable and therefore will not be valid. Unfortunately, we have to state that currently in Ukraine, sampling during conduct of the supervised field trials of PPPs is carried out in accordance with the Uniform Rules of Taking Samples of Agricultural Products, Food and Environmental Objects for Pesticide Microdetermination, which were developed and approved in the former USSR [35] and which long ago were hopelessly outdated and do not meet the modern requirements of the regulatory documents of leading international and national organizations — Codex Alimentarius Commission (CAC), Organization for Economic Co-operation and Development (OECD), US Environmental Protection Agency (US EPA), US Food and Drug Administration (US FDA, International Group of National Associations of Manufacturers of Agrochemical Products [GIFAP]) [36]. In this regard, it should be noted that Ukraine has developed and published Guide for sampling of agricultural raw materials, food products, water, soil and air for the determination of pesticide residues [37] long ago, which is compiled with regard to the requirements of the above organizations, which, for unknown reasons, is still not used when conducting supervised field trials of PPPs. Early corrections to the situation will contribute to obtaining reliable data when conducting supervised field trials.                   

EU member states, in accordance with Regulation (EC) No. 1107/2009 [10], when deciding on the use of active ingredient to create PPP, data describing its fate and distribution in the environment regarding possible pollution of surface waters, including estuarine and coastal waters, soil water (groundwater), soil and air, taking into account its possible transfer over long distances from the sites of use of plant protection products are obligatory reviewed. For this purpose, the EU has developed models for calculation of predicting environmental concentrations of active ingredients of PPPs in soil, surface and groundwater and air (PEC) [38–40] and guidelines for risk assessment using calculated predicting environmental concentrations [41–44]. Taking into account the fact that currently in Ukraine, data on pollution of ambient air and soil caused by the use of PPPs in agricultural practice are obtained as a result of a single supervised field trial using biased sampling methods, which, of course, does not allow judging about their reliability, and data on the pollution of surface and ground waters are completely absent, it is necessary to include model for calculation of predicting environmental concentrations of the active ingredients of PPPs in soil, water and air used in the EU in the national methodology in the shortest time possible.

When developing the National Guidelines for the Assessment of PPPs, it is necessary to develop a program for revising the values of ADI and MPL of active ingredients of PPPs that can have an additive effect on the human body. Further ignore of the obvious possibility of finding in the human diet, not one, but several active ingredients of PPPs with the same mechanism of biological action is impossible. Priority in this field belongs to the US supervising agency (US EPA) [24]. It should be noted that we have proposed a similar approach (under the influence of EPA works) to establish ADI of the active ingredients of organophosphorus pesticides and carbamates as early as in 2006 [45]. It was proposed, by analogy with polychlorinated dibenzo-para-dioxins, polychlorinated dibenzofurans and dioxin-like polychlorinated biphenyls [46], to express the toxicity of organophosphorus pesticides and carbamates using the toxicity factors with respect to parathion-methyl (metaphos), the most toxic among organophosphorus pesticides, the toxicity factor of which was taken as 1, and with respect to carbofuran, the most toxic among carbamates, the toxicity factor of which was also taken as 1. Toxicity factors for the active ingredients of organophosphorus pesticides and carbamates were calculated and it was suggested to proceed with the development of an MPL revision program for active ingredients of organophosphorus pesticides and carbamates considering the above. Unfortunately, this initiative has not found adequate support and has not yet received practical implementation.         

The national reports on field trial materials of PPPs include “Instructions for the safe use of the products ...” as a final section. Unfortunately, we have to admit that the presentation of the material in this section leaves much to be desired. In the EU countries, the requirements for such information included in the content of materials submitted for obtaining permission to use PPPs in agricultural practice are governed by the following documents: Regulation (EC) No. 1272/2008 of the European Parliament and the Council on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548 EEC and amending Regulation (EC) No. 1907/2006 [47], Regulation (EC) No .1107/2009 of the European Parliament and of the Council of October 21, 2009 [10] and Commission Regulation (EU) No. 547/2011 of June 08, 2011 implementing Regulation (EC) No. 1107/2009 of the European Parliament and the Council as regards labelling requirements for the plant protection products [48].

The requirements of the above regulatory documents are addressed to the manufacturers of PPPs, importers, distributors and consumers (users) and communicated to them by clearly applying them on a package of PPP, avoiding text washout from the package, as a separate leaflet (brochure) and label. Labelling of PPP should contain standard statements from the Commission Regulation (EC) No. 547/2011 [48] for particular risks to human or animal health and environment and standard statements for precautions.

In no case shall the PPP label contain such formulations as “non-toxic”, “harmless” or similar. However, information that PPP can be used when bees or other non-target species are active, or when agricultural crops or weeds are in the flowering stage, or statements with similar information relating to the protection of bees or other non-target species can be included in label, if permission to use PPP allows use in such conditions.

Returning to the national “Instructions for the safe use of the product...”, it should be noted that: 1) the text of the instructions does not indicate the persons for whom it is intended; 2) it is not allowed to use such statements as “therefore, the product can be attributed to the 3rd class of danger” in the text of the instructions; 3) the instructions should not include “provision of hygienic standards”; 4) it is categorically impossible not to give in the instructions the specific volume of the sprayer tank, the specific amounts of the calculated and weighted product and the rest amount of water.    

In accordance with the above, it is necessary to develop national requirements for the drafting “Instructions for the use of PPPs” and labels for PPPs taking into account EU requirements in this field.

The most important stage in the protection of human health and the environment in connection with the use of PPPs in agriculture is the monitoring of residues of active ingredients of PPPs in food stock and agricultural raw materials and food products. The European monitoring program in accordance with Regulation (EC) No. 400/2014 [49] allows monitoring the prediction of the safe use of PPPs in agriculture. Monitoring of the maximum residue levels of active ingredients of PPPs in food products (MRL) is the responsibility of the responsible authorities of the EU member states in accordance with the national monitoring programs and the European monitoring program for the analysis of cereal-based food product and baby formula. The results of the European monitoring program are annually presented by the European Food Safety Authority (EFSA) in their reports on the simulation and risk assessment of the residues of the active ingredient of PPPs in food products [50].

In this context, it should be noted that in the former USSR a unified control system (UCS) was in effect on the basis of All-Union Scientific and Research Institute of Hygiene and Toxicology of Pesticides, Polymer Materials and Plastic Masses which in essence was the all-union monitoring (15 union republics, about 2000 sanitary-epidemiological stations of different levels) for controlling pesticide residues in agricultural products, food products, drinking water, ambient air with data processing on computers and reverse information provision of sanitary-epidemiological stations with planning documents and a set of specialized tasks and sanitary and epidemiological recommendations on regarding the improvement of the sanitary situation in the country [51]. Taking into account the sad state of the civil service in Ukraine, which is obliged to control the quality of agricultural and food raw materials and food products consumed by humans and domestic animals in connection with the use of PPPs, it would be quite reasonable and justified to revive on the basis of the State Enterprise “L. I. Medved’s Research Center of Preventive Toxicology, Food and Chemical Safety of the Ministry of Health of Ukraine” Center for State Monitoring Over Residues of active ingredients of PPPs in Food Products and Animal Feed with simulation and risk assessment of these residues on the basis of short-term (acute) and long-term (chronic) exposure scenarios.

The immediate task in increasing the reliability of the national field trials of PPPs and evaluation of their results in terms of their safety for humans, animals and environment is to bring them closer to European standards.

 

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Надійшла до редакції 28.02.2019 р.