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Previous Page Bt genes have been introduced into potatoes, cotton, maize, and other plants The action mechanism is similar as described for Bt itself The class II EPSP synthase gene also called roundup ready gene induces tolerance to glyphosate When introduced into soybeans, cotton, maize, canola, and the like, these plants tolerate glyphosate That means that glyphosate can be used to control weeds in these crop plants without damaging them, although it is originally a total herbicide that kills all plants The advantage for the farmer is that he needs only one product, instead of several different selective (and more expensive) herbicides Roundup ready soybeans were launched in 1996 and today 50 percent of the soybean crop in the United States is derived from roundup ready seeds Other glyphosate-resistant transgenic crops introduced by Monsanto are maize and oil seed rape Competing companies also developed herbicideresistant plants or plants genetically modified to be protected against certain pests, but none has achieved a commercial breakthrough, mainly because of political reasons One controversial issue is that the farmers must buy transgenic seeds that are controlled by one monopolist supplier Local seed suppliers cannot produce seeds from harvested crops, because the transgenic plants are sterile and unable to produce new seeds for germination Another potential problem is that the resistance genes of the transgenic plants are released into the environment in an uncontrolled way leading to problems that are presently not foreseen The European Union has put a ban on all new transgenic plants and requires a clear labeling of all food that contains products from transgenic crops Europeans feel that it is an unacceptable risk, as it is not proven that genetically modified food is safe Many Americans on the other hand think that this is no problem at all, as there is no proof that genetically engineered food is not safe This illustrates the different perceptions of risk in different parts of the world 11.5 Testing Requirements for New Pesticides 11.5.1 General information and physical and chemical properties In the past, pesticides were optimized for efficacy, but sometimes with harmful side effects to man or the environment Today, modern pesticides have high selectivity for the target organism, and testing programs are mandatory to minimize risks and maximize benefits Before a pesticide can be sold, the supplier must ask the competent authorities of the respective countries for a permit, the marketing authorization The applicant must submit a dossier containing all information about the new substance that is needed to make a thorough risk or benefit analysis A complete registration dossier contains around 200 different scientific reports with over 20,000 pages, the equivalent of 25 books The studies are conducted under stringent quality control following the OECD guideline of GLP (Good Laboratory Practice) GLP is an internationally accepted quality standard It assures that the personnel are qualified, that the methods are validated and that the instruments are properly calibrated All data and reports are audited by an independent quality assurance unit The first part of a dossier contains basic information about the active substance and the applicant Here are some examples: name, structure, and route of synthesis of the substance must be described The typical purity of the technical material and the identity isomers and impurities is determined by the analysis of five production batches to assess the reproducibility of the process and to help to identify fake products In the next chapter the chemical and physical properties are described, determined according to official guidelines published by the OECD and other organizations This applies to the active substance, all significant metabolites, and all formulated products Some of the required studies are listed in Table 11.11 TABLE 11.11 Examples of Physical and Chemical Tests Required for the Registration of New Pesticides No Description of test Purpose of test or remarks Appearance (physical state, color, odor) Melting point, boiling point, density Vapor pressure Flammability, explosivity, corrosivity, oxidative properties Surface tension Solubility in water (at pH values) and organic solvents Spectra (UV/VIS, IR, NMR, Mass) Partition coefficient n-octanol or water Hydrolysis and photolysis in water Stability and photochemical degradation in air Stability upon storage or shelf life Analytical methods for purity and impurities in active substance and products Analysis of five production batches Analytical methods for residues in food Analytical methods for residues in soil, water, air Identification Identification, information Risk for evaporation Hazard during transport and storage Risk to surface water General information, risk for leaching Identification Risk for bioaccumulation Risk for persistence Risk for air pollution, persistence, and ozone depletion Quality of product Quality and risk of toxic impurities 10 11 12 13 14 15 Reproducibility of process Consumer safety Environmental monitoring Appearance, melting and boiling points, density, spectra, and solubility data serve to establish unambiguously the identity of the substance The vapor pressure value is an indication of the volatility of the substance If a substance is volatile it may evaporate and be transported through air and inhaled by people, thereby increasing the risk to bystanders or nontarget plants Flammability and explosivity are also safety parameters that show whether a substance may be dangerous when shipped or stored The partition coefficient is a very important property to assess possible accumulation of a substance in the food chain It is defined as the ratio of the solubility of a substance in n-octanol and in water Log (Kow) = log [(concentration in octanol) / concentration in water)] A high log (Kow) means that the substance dissolves better in octanol than in water (e.g., if log Kow = 6, a million times) In practical terms this means that there is a risk that the substance accumulates in fat On the other hand, a log (Kow) < -2 shows that the substance is a hundred times more soluble in water than in octanol This usually is a warning sign that the substance has a tendency to leach into ground water Hydrolysis and photolysis experiments allow conclusions on how stable a substance is and whether it may have a tendency to persist in the environment Here the rate constants and the half life of a substance in water are measured at different pH values and under irradiation with simulated sunlight The hydrolysis is tested at four different pH values: pH 4, pH 7, and pH simulate the natural situation in soil and water, while a pH 1.2 is used to simulate the acidity in the stomach and gives some indication about hydrolysis after accidental oral ingestion Organochlorines are often stable against hydrolysis Other compounds undergo complicated reactions leading to a variety of products that are difficult to analyze Methyl bromide is a compound that undergoes a straightforward hydrolysis resulting in the formation of methanol and hydrogen bromide (Eq 11.7) pH4 CH3Br + H2O ——* CH3OH + HBr (11.7) The storage stability (shelf life) of active substances and formulated products are studies under simulated climatic conditions to assure that they maintain their quality when stored or transported A product must be stable for at least years under the conditions on the climatic zone, where it is used The efficacy chapter contains the information directly related to the use of the active substance in the field, like mode of action, intended use, application rates, frequency of applications, efficacy against target organisms, and potential for development of resistance in target organisms Efficacy must be demonstrated for all target organisms and for all formulations intended for marketing Efficacy is evaluated in field studies under different climatic conditions Studies are conducted by specialized field trial contractors or by government affiliated agricultural research stations In all tests, the chemical analysis of the samples is a crucial step Modern chromatographic methods are applied, for example, HPLC, LCMS-MS, or GC-MS and all methods must be carefully validated This means that linearity, accuracy, precision, and selectivity must be proven Validations are required for methods used during the development phase and also for monitoring after a marketing authorization is granted Enforcement methods are intended for use by government laboratories to monitor product quality, worker exposure, or residues in food, feed, and the environment 11.5.2 Toxicity The toxicity of pesticides (and all other new chemical products) must be tested on animal models before a product can be sold in the market Toxicity tests have different levels of complexity and different objectives Acute toxicity studies are usually carried out on rats and the effect lasts up to days Their purpose is to determine how toxic a substance is after accidental exposure Tests are conducted not only through oral intake and inhalation, but also through exposure to the skin and eye The latter test was originally done on rabbits, but is now being replaced by in vitro alternatives The final result (end point) of the acute oral tests used to be the LD-50 value, the dose after which 50 percent of the animals die It is now being replaced by the acute reference dose (ARfD) This is the highest dose that is still safe for a human after a single exposure to the pesticide It is calculated from the highest dose that caused no harm in the acute animal studies (NOAEL = no observed adverse effect level) and a safety factor (F) The safety factor is usually 100 and it accounts for the uncertainty that is associated with the comparison of the toxic responses in animals and humans ARfD = NOAEL (in acute studies) * safety factor (F) Short-term toxicity studies simulate the exposure of workers or farmers to the products they use on a regular basis They are performed with rats and dogs and last to months Chronic and carcinogenicity studies last up to years and simulate the long-term exposure of consumers to small concentrations of pesticides in food Rats, mice, and dogs are used as animal models The final result is the acceptable daily intake (ADI), the highest exposure level that is still safe for humans ADI = NOAEL (in chronic studies) * safety factor (F) ADI and NOAL are given in mg/kg (body weight) That means they are normalized to the body weight to make the results of different species comparable Absorption, distribution, excretion, and metabolism (ADME) is a test to establish the fate of a substance in the body of a living organism This study type is also used to investigate the transfer into secondary products such as milk and eggs Animal models for ADME studies are rats, goats, and hens Distribution of the original active substance (parent) in the different organs is determined and the formed metabolites are identified and quantified The final result is a mass balance accounting for the fate of the applied substance, for example, how much is excreted via exhaled air, urine, or feces and how much stays in the body C-14 labeled test substance is often used for this type of study, because radioactivity can be followed more easily than unlabeled substances 11.5.3 Residues in food Food safety is a key issue in modern society, because we are exposed to food from birth to death Plant protection products are often used on food crops, biocides in food factories, or animal housing Therefore, tests are required to determine the risk of pesticide residues in the raw agricultural commodity (RAC) and the processed food products The first step is to identify the critical crops and the compounds for which residue studies must be conducted The breakdown and reaction products and metabolites in treated plants and products are often identified after treatment with a C-14 labeled test substance in plant metabolism studies The objective is to determine the fate of the parent substance and its metabolites in the crop plants and their processing products From the results of the studies, the relevant residues are defined {residue definition) For example, in plants glyphosate is converted to its main metabolite AMPA (= aminomethylphospohonic acid), which was also studied as part of the residue assessment metabolism Glyphosate After the significant residues are identified, field studies are designed to determine experimentally the level of residues in crops that were treated according to the label recommendation and to good agricultural practice Field trials are required in typical growth areas and in different climate zones The program must be repeated in a second year to account for climatic fluctuations Samples of the crop and the processed food are collected at various intervals after application of the pesticide and at the normal harvest day They are deep-frozen to < -20 C to avoid degradation of the residues and sent to the analytical laboratory, where they are analyzed for residues of all compounds included in the residue definition The result is a maximum residue level (MRL), the concentration that will not be exceeded when a product is used exactly as recommended by the manufacturer If a higher concentration is found in a crop, it can be concluded that the farmer did something wrong However, residues >MRL not mean that the food is unsafe, because the MRL is usually much lower than the level that would affect the health of the consumer Only if a residue exceeds the ADI (acceptable daily intake), the food poses an unacceptable health risk 11.5.4 Human safety risk assessment Risk, in its scientific meaning, has two components, namely hazard and exposure To swim in an ocean is hazardous, but people living inland are never exposed to swimming in the ocean This means that their personal risk of being harmed by the ocean is very small Risk = hazard x exposure The hazard of pesticides comes from their toxicity, exposure from their use, or from residues in food In principle every person can be exposed to pesticides, therefore, a large number of toxicity tests must be conducted before a pesticide gets a marketing authorization (See Table 11.12 for examples.) The toxicity of pesticides varies widely, as can be seen from the examples in Table 11.13 On acute exposure glyphosate, nicosulfuron, and mancozeb are essentially not toxic, whereas carbofuran is very toxic It is 50 times more toxic than imidacloprid, which has a similar use On the other hand, the application rate of carbofuran is three times higher than that of imidacloprid If we assume that the exposure of farm workers parallels the application rate, the exposure to carbufuran is three times that of imidacloprid Three times higher exposure together with 50 times higher acute toxicity leads to 150 times higher risk for workers using carbofuran than for workers using imidacloprid Chronic toxicity does not parallel the acute toxicity Chlorpyriphos and paraquat for instance, have medium acute toxicity, but a high TABLE 11.12 Examples of Toxicological Tests Required for the Registration of a New Pesticide Animal model No Description of test Acute oral and inhalation toxicity Acute dermal toxicity Skin and eye irritation, sensitization Short term toxicity up to months Long-term toxicity and carcinogenicity up to years Reproductive toxicity Neurotoxicity, endocrine disruption ADME (adsorption, distribution metabolism, and excretion studies) Rat Rat Rat, rabbit in vitro Rat, dog Rat, dog, mouse Rat, rabbit Rat, hen Rat, goat hen Purpose or remarks Accidental ingestion or inhalation Accidental exposure or skin Damage of eye or skin after accidental exposure Risk after multiple exposure (workers) Risk upon lifetime exposure (consumer via food) Risk for fertility and exposure during pregnancy Risk to nerve and hormone systems Assessment of fate in the body and the risk of transfer to milk or egg chronic toxicity as can be seen from their low NOAEL values A NOAEL value of 0.1 mg/kg/day means that test animal exposed to this dose did not show negative health effects Only after the intake of higher doses were adverse reactions observed The ADI is the maximum amount that is safe for human intake It is derived from the NOAEL and a safety factor For example, the NOAEL of glyphosate is 400 mg/kg/day and the ADI is 0.1 mg/kg/day This means that human beings with 60-kg body weight can eat mg glyphosate without risk for their health This is the toxicity TABLE 11.13 Oral Toxicity of Some Common Pesticides (Approximate Values) Compound Acute tox LD50 (rat) (mg/kg) Chronic tox NOAEL (rat) (mg/kg/day) ADI or RfD (mg/kg/day) Application rate (g/ha) Glyphosate Nicosulfuron Mancozeb Imidacloprid Carbofuran Chlorpyrifos Paraquat 2,4-D >5000 >5000 >5000 424 2680 112 640 400 1000 20 0.1 0.6 0.1 1.25 0.03 0.06 0.002 0.01 0.005 0.01 3000 50 8000 290 1000 600 500 1000 ADI = acceptable daily intake; RfD = reference dose SOURCE: J T Stevens (2001) consideration Consumers are exposed to pesticide via food Assuming a residue of mg glyphosate per kg bread and a consumption of 0.5 kg bread per day, the exposure is 0.5 mg/day This is well below the acceptable intake of mg/day, indicating that the risk of consuming bread with glyphosate residues is low The situation is different for paraquat, which has an ADI of 0.005 mg/kg/day Taking the 60-kg person as an example, the acceptable intake is 0.06 mg/day On the exposure side, let us assume a residue of 0.2 mg/kg in bread and a daily consumption of 0.5 kg This leads to an exposure of 0.1 mg/kg, which is about twice the acceptable intake The conclusion is that, in this example, the risk associated with the residues of paraquat is not acceptable In general, risk values 1 are not acceptable and require risk management The risk management must reduce either exposure or toxicity The latter would mean that a toxic substance is replaced by a different, less toxic compound Exposure can be reduced in different ways Protective clothes for farm workers, such as gloves, goggles, overalls, and boots, are well-known risk management tools that reduce exposure by preventing dermal or oral intake of the pesticide Another way to manage risk is to limit the use of a pesticide For instance, an insecticide may not be allowed on food crops, because high residues and chronic toxicity would lead to an unacceptable risk Its use for vector control in nonagricultural areas could be acceptable, because exposure through food is not important The concept of risk is a valuable tool to make responsible and scientifically sound decisions By definition risk is never zero It must be balanced by a benefit to make it acceptable 11.5.5 Environmental fate and environmental toxicology All pesticides that can come into contact with the environment are subject to a risk assessment The basis for this risk assessment is provided by data from environmental fate and environmental toxicity studies, which are carried out in the laboratory or under field conditions The fate (adsorption, degradation, and mobility) of the active substance must be studied in soil, air, water, and sediments The laboratory studies are frequently performed with 14C-labeled substances to make the mass balance easier It is important to know how a substance degrades in the environment, because sometimes the degradation products are more persistent than the parent substance DDT, for instance, is converted to metabolites by stepwise dechlorination (Eq 11.9) The metabolites (e.g., DDD or DDA) can be found in soil for many years after the DDT itself is degraded Examples of environmental fate studies: Adsorption and desorption equilibrium constants are determined in different soils The route and rate of degradation in water, sediments, and soil is studied under aerobic, anaerobic, and photolysis conditions and at different temperatures in the laboratory under standardized conditions If the experimental results show that there is a risk for leaching, semi-field and field studies become necessary Lysimeter is the name of a set-up, in which intact soil cores (e.g., 1-m diameter and 1-m depth) are installed in a container that allows collecting the water that leaches through the soil core This water (leachate) is analyzed for content of parent substance and metabolites If any substance exceeds a concentration of 100 ng/1 (= 0.1 ppb), high risk for leaching is established and the substance cannot be used in the field Also, here the formation of degradation products must be taken into account They are often more polar than the parent and are therefore more soluble in water This can lead to higher mobility Atrazine is a typical example The parent molecule has already a tendency to leach into groundwater where it has a half-life of 100 to 200 days Its metabolite desethylatrazine (DEA, Eq 11-10), however, is even more soluble and moves more readily through the soil Its high mobility was so much of a concern that atrazine was banned from use, in which it can come into contact with groundwater Atrazine Field soil dissipation and accumulation studies are carried out to determine the lifetime of a substance in soil and to see whether it has a tendency to accumulate The final result is the DT-90 value This is the time after which 90 percent of the starting material has disappeared TABLE 11.14 Environmental Fate and Environmental Toxicity Studies Required for the Registration of Pesticides No Description of test Rate and route of degradation, laboratory studies Field soil dissipation and accumulation studies Column leaching, lysimeter, field leaching Toxicity to aquatic life Toxicity to birds Toxicity terrestrial life Effects on nontarget arthropods Test system Soil, sediment, water Soil Soil, ground water Purpose or risk Persistence, formation of dangerous degradation products Persistence, accumulation Mobility in soil, leaching into ground water Interruption of food chain Fish, daphnia, algae, microorganisms Quail, duck Accumulation in food chain Interruption of and Earthworm, accumulation in food chain microorganisms Protection of nontarget Honeybees, species predatory mites If the DT-90 is longer than months, there is a risk for accumulation and risk management procedures must be proposed One such procedure could be to apply a product only every second year The second component of an environmental risk assessment for plant protection products that can come into contact with the environment are environmental toxicology tests (Table 11.14) Toxicity to aquatic life is tested on bacteria, daphnia, fish, and algae representing the food chain of aquatic species Toxicity in terrestrial systems is studied with microorganisms, earthworms, nontarget plants, and other soil-dwelling organisms Birds and mammals that feed on worms, fish or treated plants are the last step in the food chain They are also included in the environmental toxicity program Toxicity to beneficial insects is tested to assess the risk for nontarget species Toxicity to honey bees is critical, as they are required to fertilize flowering plants and trees Sometimes it is not possible to make insecticides so selective that they kill pests (insects) but not honeybees In this case, the risk management provision is to avoid using the product during the honeybee season or on flowering plants The evaluation of the results from the environmental fate leads to a predicted environmental concentration (PEC) of the pesticide representing the exposure level The accumulation in the food chain of fish is expressed as BAF (bioaccumulation factor in aquatic environment), that of mammals and birds as BCF (bioconcentration factor in terrestrial environment) Accumulation increases the exposure The NOAEL (no observed adverse effect level) represents the hazard level It is the result of the environmental toxicology studies If the PEC is higher than the NOAEL multiplied by a safety factor, the risk is considered too high and the pesticide is not registered (see Table 11.14) 11.6 Social and Economic Aspects 11.6.1 Social consequences of pesticide use The benefits of pesticides are social and economic Social components are human health, availability of food, quality of life, and protection of the environment Economic factors are loss of harvest, profitability of agriculture, and revenue of the industry Some social factors are directly related to economic factors If a farmer cannot make a living on his farm, he and his family must leave the land and migrate to the city, a process that occurs very frequently everywhere in the world If the agrochemical industry does not make a profit, the factories must close down and the employees lose their jobs If food becomes scarce prices go up and people with low incomes cannot afford a balanced diet or may even starve From these statements it seems clear that we need pesticides, if we want people to lead a decent life There are, however, also a lot of social problems connected with pesticides All pesticides are, by definition, toxic to some living organism—insecticides to insects, herbicides to plants, fungicides to fungi, and so on In addition, they often have direct or indirect effects on nontarget organisms Some are more toxic or longer lasting than others Some accumulate in the environment and cause harm far away from the original site or purpose of application No pesticide can be considered safe Risks associated with the use of a pesticide must be outweighed by the benefits The perception of risks and benefits changes with time as the history of DDT illustrates DDT was first synthesized in 1874 by the German chemist Zeidler However, the insecticidal properties of DDT were discovered only later, in 1939, by Paul Mueller in Switzerland, who received the Nobel Prize for his discovery After it became available on the market, DDT was accepted immediately and used on a large scale For the first time in history, people could control insects effectively Mothers could relieve their children from lice, farmers could protect their livestock and harvest DDT has probably been responsible for saving more lives than any other synthetic chemical, perhaps with the exception of antibiotics It is estimated that around 1940 ca 300 million people suffered from malaria The mortality rate was about percent Thirty years later DDT and WHO (World Health organization) malaria program had eradicated malaria in many parts of the world DDT also controlled the vectors of other diseases, such as louse-borne typhus, the plague, yellow fever, viral encephalitis, cholera, and the like Around 1970, people discovered that DDT benefits had their price It is persistent in the environment and had accumulated over the years following its intensive use Birds and aquatic life were directly affected, humans indirectly through DDT accumulation in the food chain It deemed that risks outweighed the benefits and DDT was banned from most uses Other seemingly less harmful insecticides had become available and replaced DDT At the time organophosphates and carbamates were believed to be better alternatives, because they did not bioaccumulate Today, we know that they are often very toxic to humans and animals They harm the operators, when applied without proper protection, and they are the cause of many accidental poisonings Actually, they are to a large extent responsible for the bad reputation that pesticides have today The next step was the use of pyrethroids They were effective and their use had relatively low risks, but the insects developed resistance, leaving us with a new problem This shows how sometimes a known risk is simply replaced by another risk, often unknown at the time of the introduction of the product There is also a big gap between real and perceived risk In Europe and the United States the public is mainly concerned about residues and food safety With proper precautions, however, this is not a real problem, as residues in food are low and not contribute significantly to our total intake of chemicals Actually, there are no cases confirmed in which residues of modern pesticides in food were the cause of poisoning of humans As there is a large overproduction of agricultural commodities in western countries, people worry about minor risks, like pesticide residues, as they not have to worry about supply of food in principle The picture is strikingly different in other parts of the world, where food production does not match the growth of the population and where malnutrition and famine are well known The largest real risk of pesticides is associated with their use Farm workers and their families are often poisoned by pesticides as a consequence of improper protection during application A picture of a farm worker spraying a field with bare feet and hands, without eye protection, wearing his everyday clothes illustrates this (Fig 11.4) He holds the nozzle right in front of him and walks directly into the spray mist The cotton face mask is not of much use, because it was designed to retain bacteria and other large particles, not vapors or aerosols Also, there is skin exposure and inhalation His clothes absorb large amounts of pesticide product When he gets home, he takes home the pesticide and may expose his family and food supplies What a difference to the application methods (see Fig 11.5) used in modern farming Here the worker is wearing protective clothing and spraying behind himself He will Figure 11.4 Worker is applying pesticide without protection The face mask does not protect against vapors and aerosols The skin is directly exposed and neither goggles nor protective clothes are worn (Source: Courtesy of Gerald R Stephenson, University of Guelph.) (hopefully) remove his disposable garment before going home Improper application methods are the main reason for acute and chronic poisoning by pesticides The challenges are to develop better methods, applicable to hot climates and small farms, and to train the farm workers how to use them 11.6.2 Economic aspects The global crop protection market for the year 2000 was about US$32 billion Herbicides accounted for about 45 percent, insecticides 22 percent, and fungicides 20 percent of worldwide sales The top selling agrochemicals were glyphosate and paraquat as herbicides, chlorpyriphos and imidacloprid as insecticides, azoxystrobin and mancozeb as fungicides The most important uses were on cereals (except rice) with Figure 11.5 Proper application technique: The operator wears a gas mask, goggles and a protective coverall (Source: Courtesy T Kratz, Landis Kane Consulting, Switzerland.) 26 percent, fruits and vegetables 22 percent, rice 11 percent, soy beans 10 percent, cotton 10 percent, others 21 percent In terms of mass, the production of organic crop protection chemicals grew until 1980 Since then it is more or less constant, although the treated areas and number of applications are still increasing However, the amount of pesticide applied per hectare is decreasing, as the products become more efficacious and pest management procedures change The average application rate in 1980 was kg a.i./ha/treatment; for modern pesticides it is less then 0.3 kg a.i./ha/treatment (a.i = active ingredient) Nevertheless, altogether about million t of active ingredients are produced worldwide every year The sales of the different pesticide classes is illustrated in Figs 11.6, 11.7, and 11.8 The development of new pesticides is very expensive and costs more than US$100 per substance and the failure rate is high It takes to years from the time of discovery to bring a new substance to the market On the other hand, only the best-selling products have sales exceeding US$100 per year On average, new substances are patent protected for another 10 years after they are brought to the market Thereafter they can be produced by any company with much lower development cost and therefore at lower prices Off-patent compounds produced by nonresearch companies are called generics or generic products Others 13% Herbecides Fungicides Insecticides Figure 11.6 Sales of the most important crop protection chemicals {Source: Cramer, H.H., 2003.) Generics are low-cost alternatives to new substances and are widely used in many parts of the world The problem is that many generics are still used in Asia, Africa, Eastern Europe, and South America, which are banned in economically advanced countries, because of unacceptable risks According to UN Food and Agriculture Organization (FAO) and World Health organization (WHO), about one-third of the pesticides sold in the developing countries, representing a market value of US$900 million, not comply with international regulations Those low-quality pesticides often contain hazardous active compounds or are impure In 2000, of the pesticide sales of US$32 billion worldwide, the Europe North America Rest of the world East Asia Latin America Figure 11.7 Regional distribution of crop protection product sales (2002) (Source: Castle, D., 2003.) Billion US $ Conventional Biotech Figure 11.8 Global sales of conventional and biotech crop protection (in billion US dollars at distributor level) (Source: Uttley, K, 2003.) Poor countries Population % change over decade Yield Population Yield Rich countries % change over decade Yield Population Population Figure 11.9 Comparison of agricultural productivity and population growth in poor and rich countries In poor countries the population grows faster than the yield per hectare; in rich countries it is the opposite (Source: Castle, D., 2003.) market share of developing countries was just $US3 billion or about 10 percent The reason for this imbalance is economic Many farmers in poor countries cannot afford modern efficient pesticides, although they would need them urgently This is illustrated in Fig 11.9 In the poor countries the population and the yield per hectare grew at about an equal rate in the 1980s In the 1990s, however, the population grew more rapidly than the agricultural production If this does not change soon, the next food crisis is inevitable In the rich, rapidly developing countries, on the other hand, productivity increases faster than population, leading to overproduction and to economic problems for farmers The most obvious solution to the problem would be to import food from countries with overproduction to those with food deficit However, this is not feasible, because the cost of transportation is too high Bibliography Anderson, T M., Industrial fermentation processes, Encyclopedia of Microbiology, Vol 2, Academic Press, 2000 Appleby, A P., F Muller, and S Carpy, Weed control, in Ullmann's Encyclopedia of Industrial Chemistry, 6th ed., Vol 39, p 199, 2003 Castle, D., in Registration of Agrochemicals in an Enlarged Europe, HR Conference, Brussels 2003 Copping, L G (Ed.), The BioPesticide Manual, British Crop Protection Council, 1998 Cramer, H H., Crop protection, in Ullmann's Encyclopedia of Industrial Chemistry, 6th ed., Vol 9, p 677-700, 2003 Hirose, Y., Production and isolation of enzymes, Enzyme Catalysis in Organic Synthesis, Vol 1, 41-66, Drauz, K., and Waldmann, H (Eds.), Wiley-VCH, Weinheim, Germany, 2002 Huber, D., J Jeong, and M Ritenour, Use of 1-Methylcyclopropene (1-MCP) on Tomato and Avocado Fruits, Potential for Enhanced Shelf Life and Quality Retention, Document HS-914, Florida Cooperative Extension Service, Institute of Food and Agricultural Sciences, University of Florida Available at EDIS Web site, http://edis.ifas.ufl.edu, January 2003 Maisch, W F., Fermentation processes and products, Corn Chemistry and Technology, 2nd ed., White, P J and Johnson, L A (Eds.), AACC Monographic, 695-721, 2003 Notermans, S and F Rombouts, (Eds.), Frontiers in Microbial Preservation and Fermentation, Elsevier Science Ltd., Oxford, 2002 OECD, Guidelines for the Testing of Chemicals, ISSN 1607-310X, 2002, available at www.sourceoecd.org Praeve, P., U Faust, W Sittig, D A Sukatsch (Eds.), Handbuch der Biotechnologie, Akademische Verlagsgesellschaft, Wiesbaden, 1982 Sanchez, S., and Demain, A L., Metabolic regulation of fermentation processes, Enzyme and Microbial Technology, 31, 895-906, 2002 Stephenson, G R., Pesticides use and world food production: Risks and benefits, Chap 15, 261-270, in Environmental Fate and Effects of Pesticides, J R Coats, Coats and H Yamamoto (Eds.), Symposium Series 853, American Chemical Society, Washington, DC Stevens, J T and C B., Breckenridge, Crop protection chemicals, in Principles and Methods of Toxicology, 4th ed., A W Hayes, (Ed.), Taylor & Francis, Philadelphia, 2001 Synthesis and Chemistry of Agrochemicals VI, ACS Symposium Series No 800, American Chemical Society, 2002 Tomlin, C D S (Ed.), The Pesticide Manual, 12th ed., British Crop Protection Council, 2000 Uttlejf, N., in Registration of Agrochemicals in an Enlarged Europe, HR Conference, Brussels, 2003 Vert, M., Polymers from fermentation, Poly(lactic acid)s and their precursors, the lactic acids, Actualite Chemique, 11, 12, 79-82, 2002, (in French) Waites, M J., N L Morgan, J S Rockey and G Higton, Industrial Microbiology, Blackwell Scientific, Oxford, 2001 Internet sites with information about agrochemicals: www europa eu int/publications/en www.epa.gov/pesticides www.pesticides.gov.uk www.wwf.org www.oecd.org/document www.fao.org