anticholinesterase pesticides (metabolism, neurotoxicity, and epidemiology) || regulatory aspects of...

PART IV

REGULATORY ASPECTS

41REGULATORY ASPECTS OF ANTICHOLINESTERASEPESTICIDES

KAI SAVOLAINEN

New Technologies and Risks, Finnish Institute of Occupational Health, Topeliuksenkatu 41 a A, 00250 Helsinki, Finland

41.1 Introduction 569

41.2 Importance of Pesticides for the Protection of Cropsand Humans 570

41.3 The Importance of Regulation of Pesticides 571

41.4 Overall Principles, Goals and Implications of RiskAssessment and Science-Based Regulation ofPesticides and a Description of the RiskManagement Framework 572

41.5 Steps in Risk Assessment of Pesticides 57341.5.1 Hazard Identification 57341.5.2 Hazard Characterization 57341.5.3 Exposure Assessment 57441.5.4 Risk Characterization of Insecticides

and Other Pesticides 574

41.6 Risk Assessment and Management Framework ofPesticides within the European Union 575

41.7 Regulatory Actions for Management Risks ofPesticides within the European Union 57541.7.1 Acceptable Daily Intake and Maximum

Residue Limits (MRL) 57541.7.2 Occupational Exposure Levels (OEL)

for Pesticides 57541.7.3 Acceptable Operator Exposure Levels

(AOEL) for Pesticides 57641.7.4 Acute Reference Dose (ARfD) 57641.7.5 Bystander Exposure 577

41.8 Classification and Labeling of Pesticides:Carcinogenic, Mutagenic, and Reproductive Toxic(CMR) Compounds 577

41.9 Discussion and Conclusion 577

References 578

41.1 INTRODUCTION

This Chapter will discuss the general principles of theregulatory issues related to pesticides, with a special empha-sis on acetylcholinesterase insecticides where appropriate(Fenner-Crisp, 2001; Klaassen, 2007). It is important toremember that when used properly, pesticides confer remark-able benefits on agriculture and forestry, and thus for societyat large (CDC, 2005). They increase crop yields, can reducediseases in production animals, and may also be used incombating insect vector-mediated diseases. However, exces-sive exposures may cause serious damage not only tohighly exposed individuals but also to susceptible subgroupsof the population such as children and the elderly (seeChapter 40).

Because several pesticides, in particular anticholinesteraseorganophosphate (OP) and carbamate (CM) insecticides, actby inhibiting the activity of the crucial enzyme acetylcholin-esterase (Klaassen, 2007), these compounds may be highlytoxic to humans, so their use is strictly controlled in mostcountries. In addition to the anticholinesterase insecticides,halogen-containing insecticides such as lindane and DDTmay cause acute and chronic toxicity to humans and havemarked deleterious environmental effects (Klaassen, 2007).

National authorities and international organizations haveissued legislation and recommendations intended to guaran-tee the safe use of pesticides. In addition to these interna-tional regulations on pesticides, there have been evaluationsof these compounds and recommendations by several interna-tional organizations such as the World Health Organization

Anticholinesterase Pesticides: Metabolism, Neurotoxicity, and Epidemiology. Edited by Tetsuo Satoh and Ramesh C. GuptaCopyright # 2010 John Wiley & Sons, Inc.

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(WHO-UNEP, 2006), the International Program forChemical Safety (IPCS, 2004), and the Food and AgricultureOrganization (FAO, 2007). A report was also issued after theJoint Meeting on Pesticide Residues (JMPR, 2007), an organ-ization established jointly by WHO and FAO to address allissues relevant to the safe use of pesticides. These issueswill be briefly discussed. The recommendations or guidelinesdo not necessarily carry the same weight as national orregional legislation, such as that of the European Union.Instead, they reflect the international consensus on manyissues on pesticide risk assessment and management. It isthus not surprising that a number of countries have adoptedmany of the recommendations and guidelines of WHO andIPCS into their national legislation, either exactly as givenor only slightly modified.

The national or regional legislation or regulations onpesticides in the United States will be covered by Dr. AnnaFan (see Chapter 40). The standpoint of the EuropeanUnion (EEC, 1991; EFSA) will be described here in moredetail. Although the legislation on pesticides may vary fromcountry to country, the general panoramic principles aremuch the same. A description of individual national legis-lations on pesticides would be repetitive, so the EU hasbeen chosen to be representative. Special emphasis isplaced on the fact that OP-type cholinesterase inhibitorsand CM insecticides may be highly toxic, highlighting theneed for specific precautions when the use of such com-pounds is being regulated. The toxicity of OP-type and CMinsecticides has been described elsewhere in this book.Because European regulations on insecticides and otherpesticides are not dealt with in any detail in other chaptersof this work, the European Union regulations will be exam-ined in some detail here.

In general, the goal of pesticide regulations is to ensurethe safe use of these compounds, some of which are sprayedon crops to increase agricultural yields, and in other casesare applied with the intent of protecting production animalsfrom diseases caused by insects and other animals. This inevi-tably leads to pesticide residues in raw food items or pro-cessed foods, and thus to consumer exposure. Similarly,workers, in particular pesticide operators, sprayers, and hand-lers, are exposed during their work activities. It is thereforethe aim to ensure that consumers and workers are not expo-sed to excessive doses of pesticides during their daily activi-ties. It is also desirable in pesticide risk assessment andmanagement to ensure that working conditions for agricul-tural, forestry, or orchard workers are safe, and that theworkers are not exposed to high levels of pesticides, thusendangering their health. The current discussion will featurethe following issues:

† the importance of pesticides for the protection of cropsand humans;

† the importance of regulation of pesticides;

† the overall principles, goals and implications of riskassessment- and science-based regulation of pesticidesand a description of the risk management framework;

† the steps in risk assessment of pesticides, includinghazard identification, hazard characterization, exposureassessment, risk characterization of insecticides andother pesticides;

† the risk assessment and management framework forpesticides within the European Union;

† regulatory actions for the management of risks frompesticides within the European Union, including accep-table daily intake and maximum residue limits (MRL),occupational exposure levels (OEL), acceptable oper-ator exposure levels (AOEL), acute reference dose(ARfD), and bystander exposure;

† the classification and labeling of pesticides into carcino-genic, mutagenic, and reproductive toxic (CMR) com-pounds; and

† a discussion and conclusions.

This chapter deals mainly with the regulation of insecti-cides, particularly OP-type anticholinesterase and CM insec-ticides. The principles of pesticide regulation in many casesapply to all types of pesticides, and no distinction betweeninsecticides and other pesticides will usually be made.However, there are exceptions related to OP-type insecticidesand CMs due to their high acute toxicity. As an example ofthe lethality of OP-type insecticides, mevinphos has a lethaldose 50 (LD50) value of 3 mg/kg in the rat, and the valuefor parathion, and especially its toxic metabolite paraoxon,is even lower (Savolainen and Kalliokoski, 2001). Fur-thermore, the LD50 value of the CM aldicarb is about1 mg/kg in rat (Klaassen, 2007; Savolainen and Kalliokoski,2001). The doses of these insecticides that can kill a humanbeing are also extremely low, and hence serious precautionsare necessary to prevent fatalities.

41.2 IMPORTANCE OF PESTICIDES FOR THEPROTECTION OF CROPS AND HUMANS

The most widely used groups of pesticides are herbicides,which are used around the world to destroy weeds andother plants that would reduce the yield of valuablecrops. This is extremely important, because in many areas,especially in subtropical and tropical areas, as much as halfof a crop can be lost due to weeds (FAO, 2007). Fungicidesrepresent another major group of pesticides, and are usedagainst plant diseases that can also cause marked lossesof crops. Insecticides are used to kill the insects that con-sume and destroy crops while in the field. Insects can beresponsible for losses of more than 50% of crop yields in cer-tain parts of the world, especially in subtropical and tropical

570 REGULATORY ASPECTS OF ANTICHOLINESTERASE PESTICIDES

regions. Thus, one can argue that pesticides play an extremelyimportant role in the protection of human health simply byensuring that people do not starve. The protection of cropsis also important in ensuring the health and nutrition ofproduction animals such as cows and sheep, and hence ulti-mately of humans, especially in areas subject to drought,flooding, and plagues of insects.

However, pesticides are a double-edged sword. Althoughthey have beneficial effects, pesticides can also cause harmto humans and damage the environment (Klaassen, 2007).Many OP-type anticholinesterase insecticides, such as mala-thion and parathion, which are used extensively all overthe world (Klaassen, 2007), or mevinphos (Kangas et al.,1993), commonly used in greenhouses, can induce serious,even lethal intoxications in exposed individuals at highdoses. Other classes of acutely highly toxic pesticides includethe chlorine-containing insecticides such as DDT and lin-dane. These latter types of pesticides are banned in mostindustrialized countries, although they can still be used forsome special purposes. For example, the use of DDT hasagain been permitted in South Africa to combat the spreadof malaria, because other insecticides have proved to be inef-ficient (WHO, 2007).

Pesticide poisonings continue to be a major healthhazard, especially in developing countries. For example, theWorld Health Organization (WHO, 1973) reported 500,000acute pesticide poisonings globally in 1972, including 5000deaths. The number was even higher in 1985, with1,000,000 cases and 20,000 deaths worldwide, according toWHO (Litchfield et al., 2005). In the same year, Jeyaratnamreported 220,000 deaths caused by exposure to pesticidesglobally (Jeyaratnam, 1985). More recently, Garcia reported500,000–1,500,000 poisonings, with 3000–28,000 deathsin 1998 (Garcia, 1998), while Goel and colleagues gave anestimate of 300,000 deaths in 2007 (Goel et al., 2007).These figures clearly indicate that pesticide poisonings andpesticide-induced lethality continue to be a major healthhazard that needs to be strictly controlled (see Chapter 24).

In addition to human poisoning and fatalities, pesticides,particularly the highly toxic insecticides such as OP-typeanticholinesterase agents, can cause harm to the environmentby killing insects, birds, and other animals, causing residuesin food crops or polluting the soil or groundwater. Since thepublication of the watershed book “Silent Spring” in 1962by Rachel Carson, attempts to control and restrict pesticiderisks have interested the public (WHO, 2007).

41.3 THE IMPORTANCE OF REGULATIONOF PESTICIDES

The regulation of pesticides is considered to be extremelyimportant in most societies, and the regulatory process isdetailed in national legislations. For example, in the United

States, pesticides are principally regulated under two majorstatutes: the Federal Insecticide, Fungicide and RodenticideAct and the Federal Food, Drug and Cosmetic Act. TheU.S. Environmental Protection (U.S. EPA) Agency’s Officeof Pesticide Programs evaluates ingredients and pesticideproducts proposed for registration and use in the UnitedStates. The regulation of pesticides in the United States isdescribed elsewhere in this book (see Chapter 40 on poison-ing and regulation in the United States). In the EuropeanUnion, pesticides are also considered a special group ofcompounds and are regulated at the Union level by CouncilDirective 91/414/EEC (EEC, 1991), which provides acommon regulatory framework for all regulatory activitieson pesticides. The assessment of the risks and safety of pes-ticides in the European Union is discussed at EuropeanPesticide Cooperation (EPCO) meetings organized by theEuropean Food Safety Authority (EFSA) established in 2003in Parma by Council Directive 178/2002/EC (EC, 2002).

Today, most risk assessment of pesticides within theEuropean Union is carried out by Scientific Committeesappointed by EFSA with experts nominated by all EuropeanUnion Member States. The Scientific Committees preparescientific opinions on questions drafted by the CompetentAuthorities in the European Union Member States or by theEuropean Commission. These opinions do not, however,carry any legal weight. They are, however, used as thescientific guidance for the European Commission, which isthe decision-making body on pesticide regulations at theEuropean Union level. Likewise, pesticides are tightlyregulated in all industrialized countries because of theirspecial use. As most pesticides are poisons that are usedintentionally on a great number of agricultural crops, pro-duction animals, in orchards and in forestry, this means thatworkers in such professions may run the risk of beingexposed to these highly toxic pesticides. In addition, whencrops are sprayed with pesticides, varying amounts of thesechemicals can be found subsequently in the food itemsmade from these crops. These levels of pesticides in foodsare called residues, and the goal of the regulatory activitiesis to ensure that consumer exposure to such food items doesnot cause health hazards to individuals because of overlyhigh pesticide residues. These activities are regulated bysetting residue limits for different pesticides in differentfood items in order to avoid exposures that are too high(EC, 2005).

The importance of tight regulations for pesticides isemphasized by the large number of pesticide poisonings,even in countries where regulations and their implementationis strict. For example, in the United States in 2007, theAmerican Association of Poison Control Centers, in itsNational Incidence Report, reported 102,754 pesticide inju-ries, stating that insecticide poisoning nationally accountedfor 4.2% of all poisonings in the United States (Sudakinand Power, 2007; see Chapter 40). Following recognition

41.3 THE IMPORTANCE OF REGULATION OF PESTICIDES 571

of the high number of insecticide injuries in the United States,U.S. EPA took stringent steps to reduce the harmful effectsof OPs. For example, chlorpyrifos and diazinon were foundto pose unacceptable risks to children, and hence pre-cautions have been taken to eliminate the use of manycommon OP-type insecticides from indoor and outdoor resi-dential environments. While efforts have been made toreduce health hazards caused by anticholinesterase insecti-cides the industrialized countries such as the United States,the challenges in the developing countries related to insecti-cide and other pesticide induced-health hazards are immense,and require continuous actions (Rantanen et al., 2004).

41.4 OVERALL PRINCIPLES, GOALS ANDIMPLICATIONS OF RISK ASSESSMENT ANDSCIENCE-BASED REGULATION OF PESTICIDESAND A DESCRIPTION OF THE RISKMANAGEMENT FRAMEWORK

The key principles in scientific risk assessment are the assur-ance of the transparency of the risk assessment process, thereliability and validity of the data used in risk assessment,and adequate assessment of the uncertainties in the resultingassessments. The overall goals of the process are to assuresafe handling of pesticides and to guarantee the productionof safe food items when pesticides have been used to protectthe crops. Furthermore, the risk assessment of pesticides, orany other chemicals to that end, has also wide implicationsbeyond the actual process itself. Risk assessment can haveimplications on the subsequent risk management, whichcan have an impact on different stakeholders, public auth-orities, scientific community, media, and naturally workers,employers, as well as consumers — in other words, everyone(IPCS, 2008) (Fig. 41.1)

Regulation of pesticides and other chemicals is currentlybased on a formalized risk assessment process, first devel-oped by the United States National Academy of Sciences(NRC, 1983) through its National Research Council. Riskassessment is a part of risk analysis that consists of riskassessment, risk management, and risk communication(IPCS, 2008) (Fig. 41.2). The important principle in thisprocess is the careful separation of risk assessment fromrisk management and risk communication to avoid non-science-driven influences on the risk assessment procedure,as will be discussed later in detail. In the risk assessmentprocess itself, the steps include (i) hazard identification,(ii) hazard characterization, including dose–effect anddose–response considerations, (iii) exposure assessment,and (iv) based on the previous steps, risk characterization ofa given pesticide with a goal of achieving a quantitativerisk assessment.

As briefly mentioned above, the overall goal of riskassessment, which is used to serve risk management, is toassure the safe use of pesticides when these compoundsare undergoing risk assessment. The key principles of riskassessment are (i) careful identification of the data requiredin the different steps of risk assessment, (ii) the validity andrelevance of the data, and (iii) transparency of the data; inother words, information about all data sources and meansby which the data have been generated must be available.Other important issues include data on the neutrality of riskassessors and possible conflicts of interest (Savolainen andKalliokoski, 2001).

A key issue in any risk assessment and subsequentlythe risk management procedure is the accuracy of the datathat are available. In assessing human risks, human data areoccasionally available, for example from epidemiological orfield studies. When dealing with new compounds, humandata are not usually available, and, hence, the risk assessment

Risk Analysis Framework

RiskAssessment

RiskManagement

RiskCommunication

*Interactive exchange of information and opinions

concerning risks

*Science based *Policy based

Figure 41.1 Relationship between the three components of riskanalysis. Adapted from IPCS, 2008.

ScienceMedia

Economy

Stakeholders

Publicauthorities

OthersExposure and uncertainty

assessment scientists

Risk management

Figure 41.2 Communication about exposure and risk: a selectionof possible actors and alliances surrounding those doing exposureassessment and uncertainty analysis. From IPCS, 2008.


has to be based on animal studies. The exposure assessment,in turn, will be based on different exposure estimates fromanimal studies, worst-case scenarios, and estimates providedby various exposure models. All these issues add uncertaintyto the risk assessment of a given pesticide. The exposureassessment is extremely important for OP-type insecticidesbecause of their high potential acute toxicity. Using datafrom experimental animal models such as rats, mice, orother animal species adds to the uncertainty because interspe-cies differences in terms of toxicokinetics and toxico-dynamics can be remarkable (Klaassen, 2007; WHO, 1999).The exposure assessment also includes several uncertainties.In many cases, the exposure assessment is made under theassumption that (i) an adequate model for exposure calcu-lation is available and that (ii) enough data about all influen-tial exposure factors are available. It needs to be emphasizedthat a high level of scientific agreement is required beforeone can devise an exposure assessment approach that willrealistically model a given exposure scenario and model(IPCS, 2008; WHO, 1999). Even though exposure modelsare increasingly used in assessing exposure to pesticides,the model-based exposure assessment is still often the fastestand in many cases the only possible way to achieve somedegree of accuracy. However, this approach uses a forecasttechnique that contains inherent uncertainty. Because thedifferent steps in the risk assessment process include varyingdegrees of uncertainty, it is important to ensure that uncer-tainty estimates of the different risk assessment of pesti-cides/insecticides are carried out carefully.

41.5 STEPS IN RISK ASSESSMENTOF PESTICIDES

The risk assessment process for pesticides does not differ inprinciple from the risk assessment process for other chemi-cals. The key steps are (i) hazard identification, (ii) hazardcharacterization, including dose–effect and dose–responseconsiderations, (iii) exposure assessment, often includingthe use of modeling of exposure, and (iv) risk characteriz-ation. Risk assessment is the overall assessment of all thesesteps. The ultimate goal of the risk assessment process isto be able to provide a quantitative assessment of a givenrisk as this provides the best possibilities for accurateand reliable risk management (EC, 2006b; Savolainen andKalliokoski, 2001).

41.5.1 Hazard Identification

In the hazard identification step, the goal is to identify pesti-cide hazards that might cause harm to health among exposedindividuals such as workers, consumers, children, and theelderly. In order to prevent overly high exposures to thesespecial groups, extra precautions such as controlling of

manufacturing practices or additional safety/uncertaintyfactors can be used. However, in general, similar sources ofinformation are used for hazard identification of pesticidesand insecticides. In the formalized hazard risk assessmentprocess, hazard identification data come from animal toxicitytesting, the most important of which are the following (EC,2006b; Klaassen, 2007).

† Acute toxicity tests with a single dose should becarried out that cover all important target organs,using an appropriate exposure route, with at least threedose levels in both sexes, and a 14-day follow-up forobservation of any delayed effects. Usually the testsare carried out in mice and rats.

† A short-term toxicity test with a duration of 28–90 daysshould be carried out in mice and rats, with multipledosing using oral, inhalational, or dermal exposureroutes, covering all relevant target organs and threerelevant doses in both sexes.

† A long-term or chronic toxicity test should be carriedout in mice (18 months duration) and rats (up to 24months duration), usually with oral dosing and coveringall relevant possible target organs and three relevantdose levels.

Carcinogenicity testing should be conducted in mice (18months) and rats (24 months), usually with oral dosingof both sexes, covering all relevant target organs and threerelevant dose levels.

† Three-generation reproductive toxicity studies shouldbe carried out, usually in two animal species, as wellas teratogenicity studies covering all relevant targetorgans in both sexes using three relevant dose levels.

† Genotoxicity studies should be conducted using in vitroand in vivo models to detect mutations and chromoso-mal aberrations.

In addition to these key animal studies, information fromepidemiological studies, field studies, and information fromcase studies can also be used, if available. Almost invariably,when one attempts a risk assessment of a new chemical, nohuman data are available.

41.5.2 Hazard Characterization

Once a hazard has been identified, its careful characterizationis mandatory. Data for hazard characterization come from adetailed analysis of the data provided by the studies listedabove, with a special emphasis on dose–effect (response ofa given organ in an animal) relationships from animal studiescovering deterministic toxic endpoints such as liver damageor neurotoxicity. Dose–response relationships, that is, the

41.5 STEPS IN RISK ASSESSMENT OF PESTICIDES 573

response of the exposed population, are analyzed in detail forcarcinogenic and genotoxic endpoints that reflect stochasticeffects in populations (Klaassen, 2007). Analyses of dose–effect and dose–response relationships are extremely impor-tant in the risk assessment process because in this riskassessment step critical target organs will be identified indetail. At least equally important is the analysis of the doselevels that evoke a hazardous effect in a given target organor population. When identifying the critical target organ,the key selection criterion is which organ(s) demonstratesa relevant toxic response at the lowest exposure level (EC,2007b; Klaassen, 2007).

41.5.3 Exposure Assessment

There are multiple goals in the exposure assessment step andin the risk assessment process the goals are multifocal.Previous steps of the process have provided informationabout the toxic levels of pesticides/insecticides, in otherwords, which doses can cause toxic effects in critical targetorgans at relevant doses in experimental models. The chal-lenge in the exposure assessment step is to obtain informationon the true exposure levels to which humans are exposed intheir working conditions through inhalation, skin, or theoral route. For example, consumers are normally exposedby the oral route, because of the residues present in food.There is also the so-called bystander exposure of thosepeople who live close to fields in which insecticides havebeen sprayed. In this case the route of exposure is via thelungs, by inhalation, although oral or dermal routes are alsosometimes possible.

Thus, exposure assessment is a major challenge, becauseexposure can take place via so many different routes. Inthe occupational environment, exposure for most chemicalstakes place through inhalation, and the importance ofdermal exposure is not so great. However, with pesticides,in most cases, exposure by inhalation is less importantthan dermal exposure (Jauhiainen et al., 1992; Kangaset al., 1993; Klaassen, 2007; Kurttio et al., 1991, 1992;Savolainen and Kalliokoski, 2001). However, there are alsopesticides, especially insecticides, to which exposure in theoccupational environment may also be remarkable via theinhalational route (Storm et al., 2000). Typical examplesare OP-type insecticides, which may have a high acute tox-icity. For such agents, prevention of exposure via both theskin and the lungs may be extremely important to preventserious health hazards, especially in the working environment(Savolainen and Kalliokoski, 2001).

When one is considering consumer exposure, the mouthis the most important exposure route and the sources of insec-ticides and other pesticides are usually food or drinkingwater. In the European Union, EFSA has provided scientificguidance to allow the European Union to set residue limitsor tolerances for pesticides and drinking water to prevent

excessive exposure of consumers according to the Directiveissued for the regulation of safe use of pesticides within theEuropean Union (EEC, 1991).

More recently, the concept of threshold of toxicologicalconcern (TTC) has gathered more support in the EuropeanUnion as a way of controlling exposure through food anddrinking water. The concept is based on the assumptionthat “safe exposure levels” for humans can be identified forindividual chemicals with known toxicological profiles.The TTC is a concept that refers to the establishment of alevel of exposure for all chemicals, whether or not there arechemical-specific toxicity data, and below these levels onewould predict that there would be no appreciable risk tohuman health. The concept proposes that a low level ofexposure with a negligible risk can be identified for manychemicals, including those of unknown toxicity, based onknowledge of their chemical structures (Kroes et al., 2005).The TTC concept has been widely discussed in the contextof several applications such as the risk management ofaerosol ingredients in consumer products (Carthew et al.,2009) and extracts used in cosmetics (Kroes et al., 2007;Re et al., 2009). The concepts have been utilized successfullyin the risk management of flavoring agents (Kroes et al.,2005) and also in controlling concentrations of pesticideswithin the European Union (http://www.efsa.europa.eu).Considering the challenges of exposure assessment, findinga less laborious means to reliably assess exposure of differentpopulation groups to different pesticides, remains a highpriority for different national and regional authorities andregulatory bodies, especially for insecticides because oftheir high acute toxicity.

41.5.4 Risk Characterization of Insecticidesand Other Pesticides

Risk characterization is the final step in the risk assessmentprocess, and it aims to synthesize all the information provi-ded by the earlier steps in the risk assessment process.Once the process has provided information on critical targetorgans and dose–effects of a given chemical in experimentalmodels or in cases when a stochastic process, such as cancer,can occur in a target population, data on exposure have to beavailable. Based on these data it is possible to estimate howthe results on a chemical’s effects in experimental studiescan be related to the real-life exposure situation, and byusing linear or other extrapolation models one can calculatethe possible health risk at different exposure levels. Ifhuman epidemiological studies are available that providerisk ratios for health risks to a given chemical at differentexposure levels, then a quantitative risk assessment becomespossible. However, it is rare to possess a complete data setfor any given chemical, though in many cases sufficientexperimental data are available and hence one can attemptto devise a quantitative risk assessment. In order to achieve


an accurate and reliable quantitative risk assessment oneneeds not only experimental data, but also a mechanisticunderstanding of the given risk, and preferably also humanepidemiological studies providing risk data in the truetarget population. It is evident that, for a truly scientific riskmanagement, one needs a full set of data from differentsteps of the risk assessment process.

41.6 RISK ASSESSMENT AND MANAGEMENTFRAMEWORK OF PESTICIDES WITHIN THEEUROPEAN UNION

In the European Union, it is the European Commission andthe Member States that take the management decisions onregulatory issues, including approval of substances and set-ting of residue limits. Risk assessment in the EuropeanUnion follows the general risk assessment and risk manage-ment principles described above. As it is concerned withconsumer protection, the European Commission is in akey position to set different types of regulatory thresholdvalues for foods and the environment as indicated in thePesticides Directive (EEC, 1991). The scientific guidanceof the activities of the Commission services, that is theEuropean Union, originates from different sources. TheEFSA, which has been located in Parma, Italy, since 2003,provides scientific guidance without regulatory authority tothe Commission in all issues related to pesticides. EFSA’sScientific Panel on Plant Protection Products and theirResidues (PPR Panel) provides scientific guidance on issuesthat cannot be resolved within the peer review of activesubstances, or when further scientific guidance is needed onmore generic issues, commonly in the field of the toxicology,fate and behavior of pesticides. The European Commissionmay also request the scientific opinions of the PPR panelon residues of pesticides in the fields outside the PRAPeRUnit of EFSA. The PRAPeR is the unit within EFSA whichprovides management support for the PPR panel.

41.7 REGULATORY ACTIONS FORMANAGEMENT RISKS OF PESTICIDESWITHIN THE EUROPEAN UNION

41.7.1 Acceptable Daily Intake and MaximumResidue Limits (MRL)

A number of regulations including acceptable daily intakevalues (ADI) of various foods have been issued by nationalor regional authorities. The ADI values indicate how largea daily intake of a given pesticide is acceptable for adultsand children. ADI values are usually meant to protect popu-lations against the intake of pesticides through their food orwater in a long-term exposure setting.

As well as setting ADI values, maximum residue limits(MRL) for the concentrations of pesticides in given fooditems will also be issued. The MRLs are based on carefulanalytical studies on a large number of different items in aneffort to determine the real concentrations in raw fooditems and in processed foods, and to work out the level ofpesticide intakes such concentrations, that is residues, wouldcause in consumers. These values are then compared withthe real food intake of different kinds of food items, whichare often based on food basket studies evaluating the averageamounts of different foods. The goal is that the MRLs shouldbe set in such a way that they ensure that the set ADI valuesare not exceeded, even though a consumer’s intake of a givenfood item might exceed the average consumption levels(for the preparation of MRLs, see EC, 1999; EC, 2005).

41.7.2 Occupational Exposure Levels (OEL)for Pesticides

Workers in agriculture and forestry, as well as those employedin orchards, need to be protected against occupationalexposure to pesticides, especially the OP-type acetylcholin-esterase inhibitors and carbamate (CM) insecticides becauseof their potential high acute toxicity. In many cases, thesetting of threshold limit values (TLV) (Storm et al., 2000)for pesticides is problematic because TLVs or OELs (EEC,1991) aim at controlling levels of a given chemical in theoccupational air.

In the case of pesticides, these values are often a challengebecause the main route of exposure to pesticides is usuallydermal (Kalliokoski and Savolainen, 2001; Kangas et al.,1993; Savolainen, 2001) which cannot be controlled usingthe TLV or OEL approach. Furthermore, there are a limitednumber of pesticides, including some of the acetylcholin-esterase inhibitors, that are so volatile that inhalationalexposure is also possible (The Scientific Committee onOccupational Exposure Limits (SCOEL); Kangas et al.,1993; Storm et al., 2000), and in these cases exposure tothese compounds can be partially controlled by the settingof TLVs or OELs. There are indeed a number of OP insecti-cides for which OELs have been set. Storm and colleagues(2000) carried out a careful evaluation of OELs for 30 OPsbased on inhibition of red blood cell (RBC) acetylcholine-sterase enzyme. These limit values were those set for theUnited States. In that analysis, the authors’ conclusion wasthat in most cases the analyzed data suggested a lower OELthan the existing permissible exposure limits (PEL) or TLVs.

In the European Union, even though the EFSA carries outmost risk assessments of pesticides, scientific guidance onoccupational exposure levels of pesticides is provided bySCOEL, which works under the Directorate General onEmployment. This body carries out an independent scientificassessment of the latest available data on a given hazardouschemical. This committee was established as an informal

41.7 REGULATORY ACTIONS FOR MANAGEMENT RISKS OF PESTICIDES WITHIN THE EUROPEAN UNION 575

group of scientists in 1990, and was later formalized bythe Decision of the Council in July 12, 1995 to become ascientific committee providing guidance to the Commissionon workplace risks. It prepared a harmonized proposalfor occupational exposure limits based on evaluation ofthe relationship between health effects and exposure tochemicals in the work environment (EC, 1995; EC, 1998).The Committee consists of 21 experts from 21 differentEuropean Union Member States. The expertise of themembers covers chemistry, toxicology, epidemiology, occu-pational medicine, industrial hygiene and a general com-petence in setting OELs. All of the appointed SCOELmembers act as independent experts and not as representa-tives of national governments (EC, 1995, 2006a). SCOELtasks include (i) carrying out scientific evaluations of chemi-cal agents as requested by DG Employment; (ii) givingadvice to DG Employment on the setting of OELs basedon scientific data, and where appropriate propose (a) theeight-hour time-weighted average, (b) short-term limits,(c) biological limit values; (iii) supplementing OELs byfurther notations for example on skin exposure; (iv) providingrecommendations including basic information about asubstance, a description of critical health effects, and therationale used to derive an OEL; (v) keeping under reviewall relevant scientific factors relating to the derivation ofOEL; and (vi) providing, at the end of the evaluationprocess, a recommendation for every individual substanceevaluated (EC, 1995). Overall, SCOEL can propose threedifferent types of limit values: (i) Indicative OccupationalExposure Limit Values (IOELV); (ii) Binding OccupationalExposure Limit Values (BOELV); and (iii) BiologicalLimit Values (BLV).

Community IOELVs are health-based, non-bindingvalues, derived from the most recent scientific data available,which take into account the availability of measurement tech-niques. They are set threshold levels of exposure belowwhich, in general, no detrimental effects are expected forany given substance after short-term or daily exposure overa working lifetime. These are intended to assist Europeanemployers in determining and assessing risks (EC, 1998).

The BOELVs take account socio-economic and technicalfeasibility factors as well as the factors considered whenestablishing IOELVs. Therefore, when setting a BOELV,policy considerations are of major importance. For anychemical agent for which a BOELV has been establishedat the European Union level, a Member States must estab-lish a corresponding national binding OEL value, which canbe stricter, but cannot exceed the Community limit value(EC, 1998).

The BLV is a reference value presented as the concen-tration in the appropriate biological medium of the relevantagent, its metabolite, or indicator effect. For any chemicalagent for which a binding BLV has been established at theEuropean Union level, Member States must establish a

corresponding national binding BLV based on, but notexceeding the Community limit value. To date, there isonly one binding BLV, which is for inorganic lead and itscompounds (EC, 1998).

41.7.3 Acceptable Operator Exposure Levels(AOEL) for Pesticides

Owing to the problematic assessment of exposure of workersto pesticides, the European Union also intends to use accep-table operator exposure levels (AOELs), which reflect theconcentrations of pesticides in the human body absorbed byany route, including dermal, inhalational, and oral routes.Usually such assessments cannot be carried out feasibly inoccupational settings, and mathematical models to assessthe exposure of workers to various pesticides have thereforebeen developed to ensure that there are acceptable practicesof pesticide handling in the field. AOELs are still not beingused, because their practical implementation remains a chal-lenge, as are the reliable assessment of true exposures and theestimation of the concentrations they may generate in biologi-cal fluids. However, this illustrates how the development ofthe workable concepts and practices of AOELs is a topicunder constant development, and it can be predicted thatnew regulations will be proposed in the future.

41.7.4 Acute Reference Dose (ARfD)

In addition to ADI values and pesticide tolerances in theEuropean Union, acute reference doses (ARfDs) have beendetermined for certain foods to avoid excessive short-termexposure and consequent possible health risks resultingfrom exposure to pesticide residues in food. ARfD is thedose that can in principle be obtained from the diet duringone meal in cases where the concentrations of pesticidesin certain food items are excessive. Thus, ARfDs repre-sent a way to increase consumer safety and encourage theimplementation of good agricultural practices, leading hope-fully to the reduced use of these dangerous, highly toxicpesticides (i.e., many of the OPs) in agriculture and orchards.Before one can devise an ARfD, the basis for the ADIvalues on lifelong exposure to a given exposure has to be con-sidered. In this setting, a single exposure exceeding the ADImay not pose any real human health risk if the ADI is notexceeded for a long period of time. However, certain pesti-cides may present such an acute hazard that even thesecases are of toxicological concern. Therefore, as part of stan-dard practice in the risk assessment procedure for residuesin food and drinking water, the case of setting an ARfD hasto be considered for all compounds. Because acute effectsmay occur after even a single dose, exposures above theARfD will result in a decreased margin of safety. The JointMeeting of Pesticide Residues (JMPR) defined ARfD as“an estimate of a substance in food or drinking water,


expressed on body weight basis, that can be ingested over ashort period of time, usually during one meal or one day,without appreciable health risk to the consumer on the basisof all known facts at the time of evaluation” (FAO/WHO,1999). Although establishment of an ARfD relies heavilyon expert judgment, it is essential to adopt a flexibleapproach, which needs to be described as transparently aspossible. Furthermore, ARfDs may need to be reassessedshould new data come to light (EC, 2001).

41.7.5 Bystander Exposure

Other means to protect consumers in different countries areprovided by guidelines and recommendations, especiallyin European Union Member States, to avoid the so-calledbystander exposure — exposure of individuals that liveclose to fields where pesticides are being used to protectcrops or people who have to pass through such fields as apart of their daily activities. In cases where bystanderexposure may become excessively high, limitations may beimposed on the use of highly toxic pesticides; in most casesthis will refer to insecticides.

The process of risk analysis is followed by the regulationof risks, which in addition to scientific risk assessment alsotakes into consideration other issues such as cost/benefitanalysis of the use of pesticides, acceptability of the use ofpesticides in the target population, the acceptable level ofrisks in the exposed population, and also potential harmdirected to other species in addition to humans.

41.8 CLASSIFICATION AND LABELING OFPESTICIDES: CARCINOGENIC, MUTAGENIC,AND REPRODUCTIVE TOXIC (CMR)COMPOUNDS

An important part of regulatory activities of the use ofchemicals, especially pesticides, in the European Unionis the classification and labeling of these compounds toprotect consumers and workers from excessive exposures totoxic compounds. The classification and labeling activitieswithin the Union are especially concerned with carcinogenic,mutagenic, and reproductive toxic compounds. This activityis not made directly for risk assessment purposes, but fordeciding on classification and classification-based labelingdecisions for different chemicals. Classification and labelingdecisions are usually made by European Union MemberState experts. In cases where the national experts cannotreach a reasonable consensus, independent SpecializedExperts on CMR issues have been invited to draw conclu-sions on these classification issues. However, after 2006,when the REACH legislation came into force, these activitieshave being implemented by the European Chemicals Agencylocated in Helsinki, Finland (EC, 2006b).

The decisions on classification and labeling of chemicalsin different categories of carcinogenicity, mutagenicity, orreproductive toxicity are based on a careful evaluation ofthe weight of evidence for the data. The categories are asfollows: (1) human (e.g., carcinogen); (2) possible human(e.g., carcinogen); and (3) no classification possible (usuallybecause of lack of data). Classification to category 1 requiresa human data set supported by experimental animal data.Classification to Category 2 is based on experimental animaldata provided that it is sufficient to draw a conclusion. Classi-fication to Category 3 means that the data are too limitedto allow allocation to Categories 1 or 2. Evaluation of hazardsis involved in the classification and labeling process; thefocus of the activity is on the evaluation of the intrinsic pro-perties of the compounds. Other issues such as exposureassessment are not involved, because the goal is not to assessrisks but rather to weigh the evidence about whether theproperties of a given compound can potentially be a sourceof hazard to humans in cases where an exposure can takeplace. This process in chemical evaluation, even though nota part of risk assessment, is extremely important, because itdetermines the text and warnings on packages containing agiven chemical. Thus, it can have a tremendous impact onthe commercial success of a given chemical on the market.

41.9 DISCUSSION AND CONCLUSION

Insecticides and other pesticides are an extremely importantgroup of chemicals used all over the world in agricultureand forestry. Their intensive use, especially in developingcountries but also in industrialized countries, is of vitalimportance in protecting crops against insects and othertypes of pests. Crop losses due to these pests can exceed50% and this can cause food shortages and malnutrition inlarge areas of the globe. Many of the pesticides, especiallythe highly toxic insecticides such as OP and CM anticholines-terase agents, can cause serious toxicities and symptoms,even fatalities to exposed humans, and thus the strict regu-lation of exposure to these compounds is highly justified.

The goal of assessment and management of risks asso-ciated with the use of highly toxic pesticides such as manyOP and CM insecticides is the prevention of excessiveexposures to these compounds. Exposure to high doses oftoxic insecticides may cause harmful signs and symptoms,ill health, serious poisonings, and even death. Serious poison-ing is most likely to occur in occupational environments,but poisonings of consumers and special groups such aschildren also occur frequently around the world. There isevery reason to be concerned about pesticides, especiallythe acute toxicities of OP and CM insecticides.

The thorough risk assessment of these pesticidecompounds includes (i) hazard identification, (ii) hazardcharacterization and dose–effect and dose–response

41.9 DISCUSSION AND CONCLUSION 577

analysis, (iii) exposure assessment, and (iv) risk characteriz-ation. Adequate data sets should be available on effects andexposure in order to prepare reliable and quantitative assess-ment of the risks posed by these compounds, that is, ascience-driven management of the risks of pesticides. Theresults of risk assessments have been used to provide arange of regulatory values to prevent excessive exposure tothese compounds. These values in the occupational environ-ment include occupational exposure limits and acceptableoperator exposure limits. Consumers are protected by the set-ting of a maximum residue limit for different crops and accep-table daily intake values of different pesticides. The decisionon setting maximum limits for concentrations of pesticides infood and drinking water is an extremely important way toprotect large parts of the population from the health riskposed by pesticides.

Currently, the procedures for assessing and managingrisks of pesticides are well established and the main principleshave been internationally recognized. This is demonstratedby the national and regional legislation to protect humanhealth from pesticide-induced poisonings. The main chal-lenge in protecting human health regarding pesticide toxicityremains the effective implementation of these regulations.

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