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International harmonization of food safety assessment of pesticide residues Árpád Ambrus J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/jf505854w • Publication Date (Web): 09 Feb 2015 Downloaded from http://pubs.acs.org on February 16, 2015

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Journal of Agricultural and Food Chemistry

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International Harmonization of Food Safety Assessment of Pesticide Residues

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Árpád Ambrus *#

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National Food Chain Safety Office, Tábornok u 2 u Budapest 1143 , Hungary.T: 36 1

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2263790, e-mail [email protected]

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ABSTRACT

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This article summarizes the development of principles and methods applied within the

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program of the FAO/WHO Codex Alimentarius during the past 50 years for the safety

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assessment of pesticide residues in food and feed and establishing maximum residue limits

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(MRLs) to promote free international trade and assuring the safety of consumers. The role of

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major international organizations in this process, the FAO capacity building activities and

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some problematic areas which require special attention are briefly described.

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KEYWORDS

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pesticide residues, maximum residue limit, MRL, JMPR, Codex Alimentarius, Good

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Agriculture Practice, quality control of analytical measurements

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1 ACS Paragon Plus Environment


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INTRODUCTION

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The continuously increasing volume of international trade in agricultural commodities

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requires the harmonization of quality and safety provisions to assure the free movement of

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goods and the protection of the consumers. The maximum permissible concentrations of crop

25

protection chemicals in various food and feed commodities are elaborated by the Codex

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Committee on Pesticide Residues (CCPR) and become voluntary international standards after

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adoption by the Codex Alimentarius Commission (CAC).1 The CCPR recommendations are

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based on the evaluations of the FAO/WHO Joint Meeting on Pesticide Residues (JMPR). The

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principles of the current methodology of the JMPR were described in another article2. In

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addition to the elaboration of Codex MRL, the Food and Agriculture Organization of the

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United Nations (FAO) and the World Health Organization (WHO) carry out wide range of

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activities including, but not limited to the training on evaluation and safety assessment of

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pesticide residues,3 analysis of pesticide residues and quality control of pesticide products,4

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code of conduct in the use of pesticides5 and principles of good agricultural practice. The

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IUPAC Commission on Pesticide Chemistry and its successors as well as the Organisation for

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Economic Cooperation and Development (OECD) Working Party on Chemicals, Pesticides

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and Biotechnology contributed significantly to the international harmonization of the use and

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safety evaluation of pesticides.

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The objectives of this article is to review the milestones of the evolving working principles of

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the CCPR and other key activities that contributed to the international harmonization of the

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consumers’ safety assessment related to the pesticide residues from the personal perspective

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of the author whose involvement in these activities had been recognized by the International

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Union of Pure and Applied Chemistry (IUPAC) International Award for Advances in

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Harmonized Approaches to Crop Protection Chemistry in 2014. In addition, some of the

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problematic areas where further work would be required are discussed.


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METHOD

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The reports of the CCPR have been reviewed and the actions taken or recommendations made

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in relation to those areas in which the author personally contributed were selected and

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summarized. The training activities were recalled from the personal records of the author.

51 52

RESULTS

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International Activities for establishing Codex MRLs

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The complex relationship between the international organizations and the Member States of

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the Codex Alimentarius is illustrated in Figure 1. Their role in elaboration of Codex

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maximum residue limits is briefly described hereunder.

58

The maximum residue limits are elaborated by the CCPR, holding its meetings annually since

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1966. The Members States have the opportunity to comment on the maximum residue levels

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and working principles recommended by the JMPR at three occasions and during the final

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adoption of the recommended maximum residue limits as Codex MRLs at the annual

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meetings of the CAC. The stepwise procedure is described in the Procedural Manual of

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CAC.6 In addition to the elaboration of MRLs, the CCPR develops its working principles and

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guidance documents.

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The JMPR is an independent expert body 7 responsible for establishing acceptable daily intake

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(ADI) and acute reference dose (ARfD) for pesticide residues and evaluation of the results of

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supervised residue trials and other relevant supporting documents for recommending

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maximum residue levels (mrl), highest residues (HR) and supervised trial median residues

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(STMR) to be considered by the CCPR. In addition, the JMPR calculates long- and short-term

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dietary intakes of residues applying the regional diets published by WHO. The members of



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the JMPR are invited by the FAO and WHO based on their personal capacity and they are not

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representing their governments. The compounds are scheduled by the JMPR Joint Secretaries

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taking into account the priority list prepared by the CCPR. The Member Countries of CCPR

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may express their reservation concerning the recommendations made by the JMPR either

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during the meeting of the Committee and or completing the ‘Concern Form’, introduced in

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2009, which is then sent back to JMPR for consideration.

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The Group of National Associations of Manufacturers of Agrochemical Products (GIFAP)

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and its successors Global Crop Protection Federation (GCPF) and the CropLife International

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(CLI) have prepared a number of guidelines and took part in the meetings of JMPR and

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CCPR as observer. Its members are preparing the comprehensive data packages, including

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also confidential proprietary data, to support the evaluation of pesticide residues.

82

The OECD contributes significantly to the international harmonization of regulation and

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safety assessment of pesticides. The OECD Member Countries may delegate experts to

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various working groups which develop guidance documents under the auspices of the

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Environment, Health and Safety Division. Many of the 71 guidance documents published

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within the Series on Pesticides and Biocides8 had been prepared with the participation of

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experts who were also the members of the JMPR, or commented by the JMPR. The principles

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outlined in the OECD documents and followed by the JMPR had been partly aligned. Other

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OECD documents have been considered by the JMPR or fully incorporated in its working

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procedures.9

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The representative of IUPAC, which is a scientific, international, non-governmental body,

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took part in the meetings of the FAO Working Party and the FAO Panel of JMPR during the

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first 2 decades and advised the Panel and the CCPR on analytical methodology. A number of

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important projects directly related to the work of the JMPR10-13 and CCPR14-20 had been


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elaborated by the expert teams of the IUPAC Chemistry and the Environment Division and its

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predecessors.

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The FAO alone or in cooperation with WHO and United Nations Environmental Programme

98

(UNEP) has promoted the development of various guidelines and guidance documents on safe

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and efficient use of pesticides, international harmonization of pesticide registration

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requirements, dietary intakes of chemical contaminants. FAO also supports directly or within

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the frame of the joint program of FAO and International Atomic Energy Agency (IAEA)

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Training and Reference Centre for Food and Pesticide Control (TRC) numerous training

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programs related to evaluation of pesticide residues, safe use of pesticides. Training Courses

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are organized both at the FAO/IAEA laboratory at Seibersdorf (Austria) and in the Member

105

States. 21 The Food Contaminant and Residue Information System (FCRIS) of TRC includes a

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database of method protocols and information on methods of analysis provided by Codex

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Member States, collaborating institutions or the FAO/IAEA Food and Environmental

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Protection Laboratory.22

109 110

Milestones in the evolving working principles of CCPR.

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The major responsibilities of the CCPR include: establishing maximum limits for pesticide

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residues, environmental and industrial contaminants (showing chemical or other similarity to

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pesticides) in specific food items or in groups of food, and in certain animal feeding stuffs

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moving in international trade where this is justified for reasons of protection of human health;

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preparing priority lists of pesticides for evaluation by the JMPR; considering methods of

116

sampling and analysis for the determination of pesticide residues in food and feed, and other

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matters in relation to the safety of food and feed containing pesticide residues. 23

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The first meeting of the CCPR, attended by the delegates of 16 countries and 6 international

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organizations, took place in The Hague, The Netherlands, in 1966. The Meeting



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recommended tolerances, presently called maximum residue limits (MRLs), for three

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pesticides (malathion, inorganic bromide and hydrogen cyanide) to be considered by the

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Member States and the CAC, and identified 13 pesticides as first priority and 13 pesticides as

123

second priority which were allocated to some member states agreeing to supply information

124

on them. The expansion and the importance of its work is indicated by the fact that since the

125

first meeting 279 pesticide active ingredients have been evaluated by the JMPR and 25 new

126

compounds were included in the priority list of the 2014 CCPR, which was attended by

127

delegates of 56 countries and 14 international organizations.

128

The working principles of JMPR and CCPR have been continuously developed. New working

129

documents have been prepared and the old ones have been updated as deemed necessary to

130

reflect the knowledge and experience gained during the previous years, and to make best use

131

of available information. The progress made in the basic procedures is described in the

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following sections indicating the year when their elaboration had been started or amendments

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were made. The reports of the CCPR can be accessed on the Codex Alimentarius homepage

134

according to the years of the meetings,24 therefore they are not referenced separately.

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Elaboration of maximum residue limits (MRLs)

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Source of residues to be considered for establishing maximum residue limits. The 1966

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meeting recommended ‘tolerances’, currently called maximum residue limits, for pesticide

138

residues in food or on raw food materials including carryover from animal feeding stuffs. The

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scope was further expanded (1967) by including unintentional residues occurred in foods

140

from background or environmental contamination and if they result from the use of pesticides

141

at an earlier stage in the food chain. In the latter case the maximum likely occurring residue

142

was covered by "practical residue limits" which would be the subject of administrative

143

decisions based on residues actually found. It was recommended that the Committee should


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deal with all pesticide residues irrespective of their origin as well as industrial pollutants

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(1980).

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Clear distinction was made between the two situations, namely when a persistent pesticide

147

had been withdrawn from agricultural use and when it is still in use and its residues are taken

148

up by the follow-up crops (2007). In the first case extraneous residue limits (EMRL) had been

149

established, while in the latter case the residue taken up by the plant from the soil is added to

150

the residues derived from the direct use of pesticides or separate MRLs are established for

151

those commodities which are not treated directly with the pesticide.

152

It was considered necessary (1978) to recommend specific maximum residue limits for some

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"processed foods" resulting from good manufacturing practices. Recommending MRLs for

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processed food was later limited to those cases where the residue level increased during

155

processing. In other cases the MRLs for raw agricultural commodities apply for processed

156

products.9

157

Recognizing that some of the spices are mainly grown together with the main crops by many

158

small scale farmers and therefore no use recommendations could be made, the Committee

159

accepted, the principle (2002) of the elaboration of MRLs for pesticide residues in spices

160

based on monitoring data provided by the spice producing countries. The Committee revised

161

the list of spices based on their growth classification; and agreed that for persistent

162

organochlorine pesticides EMRLs but not MRLs should be established (2003).

163

Basis for recommending maximum residue limits. The first meeting concluded that

164

establishing a tolerance for a pesticide residue in a particular crop would normally constitute a

165

formal recognition of the use of the pesticide on that crop. The Committee defined the term

166

"good agricultural practice" (GAP) in 1977-78, which should be based on the uses

167

recommended by the government authorities in each country from which information is

168

available. The established MRL was directly linked to the refined definition of GAP in 1989.



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These agricultural practices should take into account the quantities of pesticides needed to

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adequately control the pests concerned so as to leave a minimum of residues. Comprehensive

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data on the variation of residues in agricultural products, especially from countries or regions

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with special pest control problems would be needed to cover the residues from world-wide

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use of pesticides. The governments were invited to supply relevant data and also to explain a

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particular agricultural practice needed. In this way countries would be able to accept that

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agricultural practices which were justified elsewhere, and hence accept the consequences of

176

these practices. International tolerance levels should accommodate such residues providing

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they are considered to be safe and technologically justified.

178

In principle, only one MRL should be established for one commodity (1978), but "double

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MRLs" could be established where agricultural commodities moved in trade in more than one

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form (e.g. whole peanuts and shelled peanuts).

181

It was considered necessary (1992-93) to provide residue data derived from so called animal

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transfer studies to estimate maximum residue levels and establishing MRLs for edible animal

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commodities (e.g. milk, meat, eggs, etc.) reflecting the pesticide residues in animal feed

184

resulted from the use of pesticides according to GAP. It was agreed that results of studies

185

conducted with dairy cattle and laying hens could be extrapolated to mammals (except marine

186

mammals) and poultry, respectively.

187

The Committee agreed (2006) that when the ARfD is exceeded for a particular GAP and

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chemical/commodity combination, JMPR should identify, if sufficient information is

189

available, alternative GAPs with adequate supporting field trials resulting in the highest

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residue value for which the IESTI is below the ARfD.

191

As part of the comprehensive revision of the classification of food and feed, the electronic

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working group identified representative commodities for the extrapolation of maximum

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residue limits for pesticides to the whole commodity groups or sub-groups (2011-14).


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Periodic review of the evaluation of old compounds. Delegations to the 1991 CCPR expressed

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concern with respect to maintaining official Codex MRLs (CXLs) that may no longer reflect

196

the current use conditions and the supporting toxicological studies and residue trials may not

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meet the contemporary standards. Therefore it was decided that the old compounds should be

198

re-evaluated under the ‘CCPR Periodic Review Programme’. The criteria for selecting

199

compounds for periodic review and the procedures have been amended several occasions. The

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latest one was published as part of the revised Risk Analysis Principles applied by the CCPR

201

in the 2013 Report.

202

Definition of residue limits. "Tolerances" were proposed (1966) to be "the amount of a residue

203

internationally agreed upon as acceptable on the food resulting from the recommended use of

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pesticides at the point of entry into a country or entry into trade channels within a country",

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and these tolerances shall not be exceeded thereafter (1969). "Tolerances" should be set at the

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minimum level necessary, but the lowest level should not be less then that can be determined

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with internationally adopted analytical methods, and the tolerance should not be zero; the

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word "tolerance" when it is used alone should refer to the concentration that is permitted in

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and on food.

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No tolerance could be established if sufficient toxicological data enabling establishing an

211

acceptable daily intake, or acceptable analytical methods were not available (1967). The

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Committee defined the terms of temporary ADI and temporary tolerance (1967). Temporary

213

tolerances were recommended for a limited time period where the data on the disappearance

214

during processing or the amount and nature of residues in food as consumed were deemed to

215

be in adequate (1969).

216

In 1982, the Committee decided that guideline levels (GL) would be recommended instead of

217

temporary MRLs in cases if only temporary ADI could be established.



218

In 1991, the Governments were requested to provide residue data from monitoring programs

219

on aldrin, dieldrin and endrin for the proposal of extraneous residue limits (ERLs) to replace

220

MRLs. The concept was further applied for other persistent pesticides which had been

221

withdrawn from agricultural use for some time, but their residues in soil were taken up by

222

succeeding crops.

223

The Committee recognized from the beginning that sampling and analysis of residues play an

224

important role in testing compliance with legal limits, but reference to the established limits

225

was only stated in 1978: "Codex MRLs apply to the residue content of the final sample

226

representative of the lot". Maximum Residue Limits apply to the whole commodity as it

227

moves in commerce, and in general the whole commodity should be analyzed unless

228

otherwise indicated in the guideline on Portion of Commodities to which Codex Maximum

229

Residue Limits Apply and which is Analyzed25 specified in the Definition and Classification

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of Food and Food Groups for the purpose of Codex Tolerances for Pesticide Residues

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accepted in 1977 and revised several times until 1993.26 The basic principle is that the whole

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commodity should be analyzed except in few cases where the homogenization of the sample

233

would be technically difficult (e.g. stone fruits (except cherries) without stone, nuts without

234

shell, etc.). Residue data on edible parts of commodities are valuable information for

235

refinement of the residue intake estimate. It is to be noted that the gradual complete revision

236

of the classification is ongoing, and the CCPR reports from 2011 include the revised versions

237

of various commodity groups including sub-groups.

238

As some pesticides are applied for plant protection and as a veterinary medicine, the different

239

terms used by the JMPR and JECFA had been harmonized, and the definitions of the terms in

240

the Codex Classification of Foods and Animal Feeds were subsequently amended.

241

Furthermore, it was agreed that where JMPR and JECFA had recommended MRLs for the

242

same chemical with the same residue/marker definition on the same commodity, the higher


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MRL should be recommended provided that intake of residues did not exceed the ADI. The

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harmonized commodity descriptions and MRLs have been used since 2000.

245

In 2001 the Committee agreed that a case by case approach should be followed in establishing

246

MRLs for genetically modified crops, metabolite residues and for isomeric mixtures.

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Expression of residue limits. In 1966, the Committee agreed in to use the progression of 0.01,

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0.02, 0.05, 0.1, 0.2, 0.5, 1, 2, 5, 10, 15, 20, 25 … mg/kg for expressing the established

249

maximum residue limits, with use of 3 and 7 in exceptional cases. This approach was in effect

250

until the OECD MRL calculator was developed and applied systematically by the JMPR

251

(2012).27 Since then the following principles are followed in recommending maximum

252

residue limits: "for numbers between 1 and 10, they are rounded to a single digit; for 10 to

253

100, they are rounded to multiples of 10; for 100 to 1000, they are rounded to multiples of

254

100 and so on. Intermediate values of 0.015, 0.15, 1.5, 15, etc, were introduced to avoid

255

doubling of MRLs on rounding".

256

Calculation of dietary intake

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The Committee considered of primary importance the estimation of intake of pesticide

258

residues from the beginning. In view of the large discrepancy between intakes calculated from

259

tolerances and those demonstrated by market basket surveys already undertaken, the

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Committee strongly recommended that Governments should arrange monitoring surveys, total

261

diet studies and market basket surveys which would enable the JMPR to make an assessment

262

of the actual intake of a pesticide. WHO initiated a pilot computerized program for the

263

calculation of the potential intake of pesticide residues in individual countries, using the

264

average food consumption figures and the appropriate residue levels (1969). FAO/WHO

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Consultation on Pesticide Residues Intake (1987) elaborated Guidelines for Predicting Dietary

266

Intake of Pesticide Residues, which was completed and accepted in 1989. Nine "cultural"

267

diets based on similarities in dietary patterns were developed using the most recent FAO Food



268

Balance Sheets. The cultural diets together with the Codex MRLs were used for calculating

269

Estimated Maximum Daily Intakes (EMDls). A "global" diet based on the nine cultural diets

270

was used for estimating Theoretical Maximum Daily Intake (TMDIs). It was emphasized in

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the Guidelines, that TMDI and EMDI calculations give only very rough estimates of

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maximum potential intake, and do not represent actual intake figures. Better estimates of

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intake can be calculated solely at the national level and through actual dietary intake studies.

274

The Revised Guidelines for Predicting Dietary Intake of Pesticide Residues developed by the

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FAO/WHO Expert consultation (York 1996), taking into account the conclusions of the report

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of IUPAC Commission on Agrochemical and the Environment,12 recommended to use the

277

supervised trial median residue values (STMR) for estimation of international estimated daily

278

intake (IEDI), which gave much more realistic estimated than the EMDI or TMDI. It was

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noted that for a number of reasons, including measurement of residues in whole commodity

280

instead of that what is actually consumed, the STMR should still be considered an

281

overestimate of residue levels. The intake estimates were further refined with the application

282

of 13 (2001) and 17 regional diets (2014).

283

The delegation of Canada pointed out (1991) that intake estimates should include an

284

assessment of the intake of extreme consumers, especially in cases where the acute toxicity of

285

pesticide residues was of concern. WHO was asked to define toxicological parameters for

286

acute toxicity of pesticide residues which would indicate a need to utilize high as opposed to

287

average food consumption data when developing estimates of dietary exposure. The Joint

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FAO/WHO Consultation on Food Consumption and Exposure Assessment of Chemicals

289

(Geneva 1997) suggested a methodology for calculation of short-term intake based on

290

consumption of food within 24 hours. Taking into account the limited experimental data, 28 a

291

variability factor of 10 was recommended. The variability factor was reduced by the JMPR to


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3 in 2003, and this figure was confirmed in 2006 based on the results of statistical analysis of

293

large amount of residue data in crop units published since the Geneva consultation. 29,30

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Methods of analysis and sampling.

295

The importance of analytical methods have been recognized from the first CCPR meeting

296

which concluded if insufficient data were available for the JMPR to recommend an acceptable

297

analytical method, then the Committee would not be able to establish a tolerance. It was

298

recommended (1968) that the Codex Alimentarius should contain methods of analysis and

299

sampling for pesticide residues and a referee method should be available for each residue -

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food matrix combination which should be used in cases of dispute. Where a collaboratively

301

tested or internationally accepted method of analysis was available, it should be linked with

302

the appropriate tolerance as a referee method. Countries preparing information for the JMPR

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should provide suitable methods particularly for use as referee methods and should

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recommend international collaborative work where appropriate. An Ad-Hoc Analytical

305

Working Group (AWGA) was set up in 1969 to examine the problems related to sampling and

306

the analytical methods provided by the governments and the IUPAC; to make

307

recommendations for appropriate methods of analysis; and to suggest a procedure whereby

308

appropriate and suitable methods of analysis could be developed. This working group was

309

called upon by all meetings thereafter. It was agreed in 1974, that the selected methods would

310

be published in the reports of the Committee. In 2007 the Committee agreed that the list of

311

methods for determination of pesticides would not be developed as a Codex document in the

312

Step Procedure but would stay as repository list on the IAEA website.22

313

The AWGA requested the JMPR (1982) to give preference to the definition of residues in

314

terms of the parent compound or a single residue component over the inclusion of metabolites

315

which cannot be incorporated easily in standard analytical methods. Considerable savings in

316

time and effort could therefore be achieved if these metabolites were deleted from the



317

residues to be measured. The JMPR agreed with the proposal and has recommended

318

maximum residue levels for enforcement purposes based on a single residue component as far

319

as the supervised trials data enabled that.

320

The AWGA decided that particular weight should be given to multi-residue methods, gas-

321

liquid chromatographic methods and to methods which had been subjected to collaborative

322

studies (1975), however the latter ones should not be regarded as "obligatory methods"

323

(1982). It was considered that the fair practice in international trade depended, among many

324

other things, on the reliability of the analytical results which could be increased by regular

325

assessment of the performance of the method; confirmation of the identity of the pesticide

326

residue by independent tests and adequate replication of the analysis. As a follow up, the

327

elaboration of the concept of "good practice in the analysis of pesticide residues" was started

328

in 1977 and the guidelines were adopted by the CAC in 1983. The revised version of this

329

guidelines were called Guidelines on Good Laboratory Practice in Pesticide Residue

330

Analysis’ (CAC/GL 40-1993).31 The AWGA amended the CAC/GL 40-1993 and the

331

Introduction section of the ‘Recommended methods of Analysis for Pesticide Residues’ in

332

2000 to accommodate reference to single-laboratory method validation19 and performance

333

criteria of methods validated in a single laboratory. The revised guidelines were adopted by

334

CAC in 2003.

335

The AWGA initiated elaboration of guidance document for estimation of uncertainty of

336

measured residue concentrations in 2002, and the Guidelines on the Estimation of Uncertainty

337

of Results32 (CAC/GL 59-2006) were adopted in 2006.

338

The 2013 CCPR started to revise the Good Analytical Practice document under the title of

339

‘Proposed draft guidelines on performance criteria for methods of analysis for the

340

determination of pesticides residues’. The GLs, being in the initial preparatory phase, will

341

provide additional useful information especially in the area of mass spectrometric analyses,


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but it completely disregards the consideration of the error of sample size reduction and sample

343

processing. Its consequences are discussed in the section on critical areas.

344

Elaboration of sampling methods for determination of residues in plant and animal

345

commodities

346

With regard to the problem of sampling, the Committee agreed that determining whether or

347

not a single identifiable lot complied with a particular tolerance was a matter of great urgency

348

and decided to set up a Working Group to meet during the session for discussing the problem

349

of sampling (AWGS). Until 1975 the sampling and analytical issues were discussed by the

350

same working group, when two separate working groups were set up. The AWGS prepared

351

the draft Method of Sampling Foods for the Determination of Pesticide Residues which was

352

further discussed during the subsequent meetings. The group confirmed (1978) that "Codex

353

Maximum Residue Limits apply to the residue content of the final sample representative of

354

the lot". The ‘Recommended Method of Sampling for the Determination of Pesticide

355

Residues’ was adopted as Codex Standard in 1982. The recommended method of sampling

356

for meat, edible offals, milk and eggs was also elaborated and the CAC adopted it in 1995.

357

The two methods were combined and the revised Recommended Methods of Sampling for the

358

Determination of Pesticide Residues for Compliance with MRLs became Codex Standard

359

(CAC/GL 33-1999) in 1999.33

360

The CAC/GL 41-1993 was updated and after some amendments the recommended method

361

became Codex Standard in 2010,34 which has not been affected until now by the ongoing

362

revision of the Classification of Food and Feed.

363 364

Capacity building in Member States

365

The FAO and WHO supported a number of training workshops and sponsored several

366

technical cooperation projects, coordinated research programs to assist Member States



367

establishing or enhancing their capacity to control pesticide residues in food and to provide

368

data for JMPR/CCPR reflecting the authorized use of pesticides in their countries.

369

Technical assistance programs. Their aim was to provide financial support and expert advice

370

for setting up or upgrading pesticide residue and or pesticide formulation control laboratories,

371

and to give basic training for the staff on relevant areas. The on-site training was usually

372

complemented with fellowships of typically 1-3 months in experienced laboratories. During

373

the last 40 years over 30 medium or large scale projects were completed and more than 100

374

analysts received fellowship training.

375

Training workshops. In addition to fellowship programs, training workshops were organized

376

in three major areas.

377

Analysis of pesticide residues and control of the quality of pesticide products. The objectives

378

of these workshops were to refresh the technical and theoretical knowledge of the analysts

379

working in the official laboratories of Member States, and introduce new methods and

380

instrumental techniques. The training included theoretical lectures comprised of theory and

381

practice of sampling, individual steps of the analysis, and from the middle of the 90-ies

382

quality control, quality assurance and statistical evaluation of the results. Many of the

383

workshops also included laboratory exercises. The participants have been provided with the

384

full text of the lectures and exercises, but the training materials have not been published

385

except those of the 1st workshop organized in Eger, Hungary in 1983.35

386

Some of the major further workshop were held in Bangkok, Thailand (1984, 1988), Miskolc,

387

Hungary (1994, 1996, 1998), Vienna/Seibersdorf (1999, 2000, 2001, 2002, 2004, 2012),

388

Suwon, Democratic Republic of Korea (1995, 1997), Bejing China (1998, 2000, 2002),

389

Nairobi, Kenya (2005), Philippines (2006).

390

Introduction of the concept of Global GAP for decision making high level government

391

officials. The aim of the training program was to show how the provisions of Global GAP, as


Page 16 of 33

Page 17 of 33


392

an effective quality control system, can be used to produce food which satisfies requirements

393

of import partners and assures safety of produced food. The topics covered all aspects of

394

Global GAP including but not limited to: general principles from soil management to

395

preparing the produced food for marketing, components of plant protection affecting quality,

396

intended and proper use of sprayers, certification and verification, food safety hazards,

397

worked example demonstrating critical control points of production of longan, application of

398

GAP in small scale farms, etc. Two workshops were held in Bangkok, Thailand (2003) and in

399

Nairobi, Kenya (2004).

400

Evaluation of pesticide residues data for the estimation of maximum residue levels in food

401

and feed. The training manual36 was designed for guiding government officials to plan and

402

implement supervised residue trials, and evaluate their results to be submitted to JMPR for

403

recommending residue levels for pesticides applied on crops of specific interest of developing

404

countries. Training workshops were held in Budapest, Hungary (2010); Bangkok, Thailand;

405

(2011), Accra, Ghana; Sao Paolo, Brazil (2011), Philippines (2012) and China (2012, 2014).

406

Coordinated research projects (CRP) have been organized on various subjects with the

407

involvement of 10-15 laboratories from different countries. Their major objectives were to

408

introduce new techniques and use them to generate data which can be utilized by the

409

participating and other laboratories and building up networking among laboratories working

410

on the same or similar fields. Many of the CRPs resulted in very useful information. Two of

411

them could be directly utilized in assessment of food safety. The first one generated over 9000

412

residue data in crop units from 89 field trials from 15 countries for obtaining information on

413

the distribution of residues in unit crops.30 These results were also taken into account by the

414

JMPR37 to confirm the variability factor of 3 used in short-term dietary exposure assessment.

415

The second project investigated the stability of residues during sample homogenization and

416

revealed that up to 80% of the surface residues of some pesticides may decompose during the



417

first few minutes of homogenization. Where the test portion taken from the homogenized

418

sample matrix was spiked with standard solution such decomposition was not observed.

419

Therefore, the usual recovery tests do not reveal the instability of analytes. The results of this

420

CRP and other studies prompted several government laboratories to process all samples in the

421

presence of dry ice.

422

Critical areas requiring special attention.

423

There are a number of unresolved issues which should be further explored and elaborated. In

424

this article only two related to the reliability of the measurements of pesticide residues are

425

discussed.

426

Reducing the test portion size to ≤ 1 g. The high sensitivity of present MS/MS detection

427

systems makes possible to detect pesticide residues at 0.01-0.001 mg/kg or even lower level

428

from the extracts of ≤ 1 g portions of laboratory sample. Consequently, there is a continuously

429

increasing tendency to reduce test portion size, which led to a dedicated symposium titled

430

Going from Macro to Micro: Sample Processing in Residue Analytical Methods at the 13th

431

IUPAC Congress of Pesticide Chemistry.38 The authors of posters and recent scientific papers

432

demonstrated the reproducibility of the measurements with the results of recovery tests

433

performed with spiking of test portions with known amount of analytes. There was only a

434

very few presentations where the effect of test portion size reduction on the combined

435

uncertainty of the results were partly investigated. The draft 'Guidelines on Performance

436

Criteria Specific for Methods of Analysis for the Determination of Pesticide Residues' being

437

prepared by an electronic WG of CCPR specify the acceptable mean recovery values obtained

438

with minimum 5 replicates at each spiking level, and the "within-laboratory reproducibility,

439

which may be determined from on-going quality control data in routine analyses, should be ≤

440

20%, excluding any contribution due to sample heterogeneity".39 The Guidelines on the


Page 18 of 33

Page 19 of 33


441

Estimation of Uncertainty of Results (CAC/GL 59-2006)32 are listed under references, but no

442

specific criteria for the uncertainty deriving from the heterogeneity of the sample is specified.

443

The combined uncertainty of the laboratory phase of the determination of pesticide residues

444

(CVL) derived from three major sources: sample size reduction/sub-sampling (CVSS),

445

homogenization of the reduced portion of laboratory sample (CVSp) and analysis of the test

446

portion withdrawn from the homogenized sample (CVA):

447

CV = CV + CV

+ CV

Equ. 1

448

The previous research results indicate that the homogenization of the plant materials can be

449

one of the major contributors to the combined uncertainty of the results40 depending on the

450

equipment and the physical properties of the sample material. A CVSp of 34% was obtained

451

on an average when of apple surface treated with 14C-chlorpyrifos was homogenized at room

452

temperature, then 15 g test portions were extracted and the residues were detected with liquid

453

scintillation (CVA~2%). When the sample was homogenized in deep-frozen state in the

454

presence of dry ice, the CVSp was reduced to about 10%.41 In addition, the relative uncertainty

455

of sub-sampling of large crops should be added42 which may be as large as 17% depending

456

primarily on the uniformity of pesticide deposit on the surface of the fruits.

457

Assuming 15 g test portion and taking into account the average uncertainties of sub-sampling

458

(17%), sample processing (34%) and analysis (20%), the equation 1 gives a combined

459

uncertainty CVL of 43% for the laboratory phase of the determination of pesticide residues,

460

which is much higher than the default value of 25% specified by the European Commission.43

461

Let's assume that the homogenization process is sufficiently efficient to obtain well mixed

462

sample according to the criterion specified by Wallace and Kratochwil.44 If the laboratory

463

sample is statistically well mixed, the relationship between the relative uncertainty of sample

464

processing (CVSp) and the test portion size (m) can be described as:



Page 20 of 33

465

=

466

where m1 and m2 are the masses of test portions withdrawn from the homogenized laboratory

467

sample, and CVSp1 and CVSp2 are the corresponding relative uncertainties of sample

468

processing. It follows from equation 2 that the uncertainty of sample processing would be

469

about 130% and 39% in case of withdrawing 1 g test portion from the homogenized apple

470

samples at room temperature and in deep-frozen conditions.

471

The efficiency of sample processing can be substantially improved by applying two-step

472

sample processing.41,45 In this case a relatively large portion of the comminuted material (e.g.

473

200-500 g) is further homogenized with Ultra Turrax, and a small portion (1-5 g) is taken

474

from the turraxed material for extraction.

475

Experience gained in previous studies indicate that obtaining well mixed sample relative to 1

476

g test portion is very difficult, if possible at all. Therefore the combined uncertainty of sample

477

processing and analysis shall always be determined experimentally. It can most conveniently

478

be done, as part of the internal quality control program, with the reanalysis of retained test

479

portions of samples containing pesticide residues in well detectable concentration. The CVL

480

can be calculated as: ∑∆

CV = /1.128

481 | | !

Equ. 2

Equ. 3

482

Where ∆=

483

from the whole bulk (aggregate) or laboratory sample, "! is the average of replicate

484

measurements and n is the number of duplicate samples analyzed preferably on different days

485

and from different bulk samples. The CVL defined by equation 1 should be equal to or less

486

than the 25% relative uncertainty of the measurement results specified by the European

487

Commission43, otherwise the laboratory could wrongly reject a lots based on the analysis of

488

residues in the sample taken from the lot.

and R1 and R2 are the results of analyses of independent tests obtained


Page 21 of 33


489

Stability of pesticide residues during sub-sampling and sample processing. The instability of

490

some pesticide residues such as dithiocarbamtes, chlorothalonil have been known for a long

491

time. Therefore the Recommended Methods of Sampling for the Determination of Pesticide

492

Residues for Compliance with MRLs specifies33 that "Where units may be damaged (and thus

493

residues may be affected) by the processes of mixing or sub-division of the bulk sample, or

494

where large units cannot be mixed to produce a more uniform residue distribution, the units

495

should be allocated randomly to replicate laboratory samples at the time of taking the primary

496

samples". Further on, a "sampling device, quartering, or other appropriate size reduction

497

process may be used but units of fresh plant products or whole eggs should not be cut or

498

broken. The results of the CRP mentioned above confirmed that several pesticide residues

499

may decompose at various extent during the first few minutes of cutting and homogenization.

500

Consequently, cutting large fruits or vegetables at the experimental field site or in an auxiliary

501

laboratory before shipping the samples to the testing laboratory is considered inappropriate,

502

because the contact of surface residues with the internal parts of the crops may result in

503

decomposition of residues. The 2013 JMPR recognized the difficulties and extra expenses

504

resulted from deep-freezing and shipping large crops, such as for instance a head of cabbage

505

or watermelon. A simple procedure for pre-testing the stability of residues before

506

commencing the supervised field trials was recommended46 based on the methodology

507

elaborated within the CRP.47 The procedure recommended by the JMPR should be used in all

508

cases where the whole plants are intended to be cut before shipping to the testing analytical

509

laboratory. However, it should only be applied for really large crops, as there is always the

510

possibility of decomposition of residues or contamination of the samples.

511 512 513

AUTHOR INFORMATION



514

Corresponding Author:

515

*E-mail: [email protected]

516

Notes

517

The author declares no competing financial interest.

518

# Retired Scentific Adviser

519

ABBREVIATION USED

520

ADI: Acceptable Daily Intake; ARfD: Acute Reference Dose; AWGA: Ad Hoc Working

521

Group on Methods of Analysis; AWGS: Ad Hoc Working Group on Methods of Sampling;

522

CAC: Codex Alimentarius Commission; CCPR: Codex Committee on Pesticide Residues;

523

CLI: CropLife international; CVA: relative uncertainty of the analysis phase of the

524

determination of residues; CVL; relative uncertainty of the laboratory phase of the

525

determination of residues including sub-sampling, sample processing and the analysis phase

526

of the determination; CVSp: Relative uncertainty of sample processing including chopping,

527

grinding, mincing, mixing the laboratory sample or part of it; CVSS: Relative uncertainty of

528

the sub-sampling of a large crop or a large bulk (aggregate) sample; EMDI; Estimated

529

Maximum Daily Intake; FAO: Food and Agriculture Organization of the United Nations;

530

FCRIS: Food Contaminant and Residue Information System; GCPF: Global Crop Protection

531

Federation; GIFAP: Group of National Associations of Manufacturers of Agrochemical

532

Products; HR: Highest residue; IAEA: International Atomic Energy Agency; IEDI:

533

International Estimated daily Intake; IUPAC; International Union of Pure and Applied

534

Chemistry; JMPR; FAO/WHO Joint Meeting on Pesticide Residues; MRL; Maximum

535

Residue Limit; mrl; maximum residue level; NEDI: National Estimated Daily Intake; OECD:

536

The Organisation for Economic Co-operation and Development; STMR: Supervised Trial

537

Median Residue; TMDI: Theoretical Maximum Daily Intake; TRC: FAO/IAEA Training and 22 ACS Paragon Plus Environment

Page 22 of 33

Page 23 of 33


538

Reference Centre for Food and Pesticide Control; UNEP: United Nations Environmental

539

Programme; WHO: World Health Organization.

540

ACKNOWLEDGMENT

541

The author is grateful to C. Hapeman, L. McConnell, K. Racke, organizers of the Plenary

542

Session on Crop, Environment, and Public Health Protection: Technologies for a Changing

543

World of the 13th IUPAC International Congress of Pesticide Chemistry for invitation to

544

present his personal experience in international harmonization of food safety assessment of

545

pesticides. The assistance of E. Dorogházi, Zs. Farkas and A. Zentai in the preparation of the

546

manuscript is greatly appreciated.

547 548

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549

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45. European Committee for Standardization (CEN) Foods of plant origin - Determination

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219. 2013, 5-6.

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FIGURE CAPTIONS

746 747

Figure 1. Relationship of Codex Member States and International Organizations related to elaboration of Codex Maximum Residue Limits (MRLs) for pesticide residues

748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781

FIGURE GRAPHIC

FAO

WHO

Exe. Com.

MRL EMRL

CAC

TRC

Training workshops Technical documents

CCPR

JMPR IUPAC GIFAP CLI

Member States

OECD

administration information exchange action recommendation result


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GRAPHIC FOR TABLE OF CONTENTS

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International Harmonization of Food Safety ... - ACS Publications

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