ICI Agrochemicals Jealott's Hill Research Station Bracknell, Berkshire, RG12 6EY UK
Summary. The paper addresses progress in agricultural practices and crop protection methodology in recent years and relates them to predicted future trends and prospects. It describes how the international agrochemical market overall is maturing and how agricultural practice might change in response.
With regard to crop protection, we believe that chemical products will continue to be the mainstay well into the next century and possibly much longer. However, the characteristics required for new chemicals will be more stringently defined and the research methods by which they are discovered will change markedly. In addition to biological and cost efficacy, future crop protection chemicals will need to be environmentally benign and toxicologically safe to operators, farmers and the public at large. Furthermore, there will be a requirement for new active ingredients to provide high added-value to the manufacturers since price erosion will reduce the margins on crop protection chemicals. Research and development methodologies will take increasing account of those characteristics of a product which are required for success in the marketplace, and the inventive process will be driven by test systems and screens which reflect these characteristics.
Biological products derived from biotechnology will meet with significant success in specific areas, but the major short term impact of biotechnology will be upon research and development of chemically-based products. Transgenic plant species will increase in importance, especially when useful traits such as herbicide tolerance or resistance to insects or viruses are expressed. Plants which are genetically engineered to express an enzyme which degrades a specific pesticide or class of pesticides should find utility in several markets. The development of biological control agents (e.g. bacteria, fungi, viruses) will also be greatly assisted by biotechnology, but inherent problems of unreliability will continue to inhibit market penetration in many situations. Increased emphasis will be placed upon methods of formulation, packing and application, driven both by the need to differentiate products and also by safety considerations. Progress with diagnostic kits to assist with decisions on timing and necessity of sprays has been somewhat disappointing to date. It will be interesting to note whether crop protection 'packages' involving diagnostic kits will become a part of common practice.
The paper concludes that for the foreseeable future, safe and effective crop protection chemicals will continue to be essential components of world agricultural systems, with biotechnology-based methodologies increasingly providing alternatives, albeit on a relatively minor scale.
The role of the agriculture industries is to produce a reliable supply of food to meet the needs of a burgeoning world population, safely and without deleterious effects on the environment at large. Over the past century or so, there has been an ever-increasing dependence upon the use of crop protection chemicals in combating the deleterious attentions of insect pests, weeds and fungal diseases. In spite of continued success, the industry finds itself faced with many paradoxes. In 1990, experts from numerous facets of the agriculture industries met at Hamburg for the 7th International Conference of Pesticide Chemistry, sponsored by IUPAC. With regard to crop protection chemicals, the first paper, presented by W K Moberg of Dupont and co-authored by myself, concluded that 'the second golden age of agricultural chemistry is at hand'. After an intensive week of science, involving approximately 2,000 people, 1,000 posters and 50 lectures (6), John Finney, Research and Development Director of ICI Agrochemicals, summarised the progress of the whole meeting in a closing lecture entitled, 'Where do we stand: where do we go?' (5). In his summary he stated:
`the historic achievements of the pesticide industry have been substantial, even remarkable, and those involved should take pride in their contribution to the well-being of their fellow men. Instead their activities are perceived by a majority of the general public to be unnecessary and unsafe, both to mankind and to the environment. It is not generally recognised that there will be at least 90 million new mouths to feed each year for the foreseeable future, an increase equivalent to the addition of the population of Hamburg every week. Nor is it recognised that there are no practicable alternative crop protection technologies which can reliably substitute for agrochemicals to control the vast majority of the world's most important pests, diseases and weeds. To pretend otherwise could have serious implications for mankind.'
This paper will attempt to address the paradoxes expressed in the statements above in terms of the changes which may be brought about by the impact of novel science and new technologies.
During 1989, the world's population increased by 106 million. If this rate is maintained into the future, the world's population will have more than doubled by 2050. Population growth will ensure an ever-increasing demand for food and materials such as natural fibres. Additionally, the consumer continues to seek higher quality and more variety in produce.
Approximately 3% of the world's surface is presently used for agriculture. With regard to world land area, less than 25% is suitable for agriculture. This land area is under ever-increasing pressure from population growth and from alternative uses. The need for greater productivity per unit land area in those areas which are most suited to intensive sustainable agriculture will undoubtedly increase, requiring the use of the best available methodologies (3). It is thereby almost certain that crop protection chemicals will form one of the cornerstones of agricultural practice for at least the next 20 years. For this reason, a substantial part of this paper is given to improvements in the technologies relating to the use of chemicals.
There is currently considerable interest in research on a world-wide basis into alternative methods of pest and weed control. It is imperative that we continue to seek alternatives and to ensure that appropriate funding is available. We should also be realistic in our expectations for such technologies and should be careful never to confuse the public with over-optimistic and misleading statements. In particular, emerging technologies should seek to build upon existing successes (e.g. crop protection chemicals) and comparisons, including risks and benefits, should always be made on a scientific basis. Rancour amongst scientists who espouse different methodologies will inevitably lead to negative perceptions of science as a whole by the public (8).
If we take stock in 1991, we may conclude that the crop protection chemical industry has achieved a remarkably high degree of technical success. In each of the sectors of fungicides, herbicides and insecticides, chemical treatments are available today which act effectively at application rates as low as tens of grammes per hectare (7). The industry is overwhelmingly science and technology-based and the vital contribution of research and development to its success is beyond question. As mentioned above, the perception of the public towards the crop protection chemical industry is distinctly negative. This works its way through into the political arena where government food support policies and the requirements of regulatory authorities will impact very strongly upon the industry in the future years. However,the industry can be relied upon to provide satisfactory technical solutions to the regulatory strictures which it faces. Of course, all of this comes with costs as well as perceived benefits
Whereas the 1970s and '80s were characterised by steady growth in sales income in the markets for agrochemicals, most experts predict very little growth overall in the 1990s. The maturing industry is also facing the problem of price erosion in real terms, at least in the short term. At first sight, this situation seems at odds with the continued increased requirement for food, but intense competition in maturing markets provides the explanation. Whereas there can be expected to be several hotspots for growth, e.g. Southern Europe, South East Asia, the traditionally strong markets face modest declines in real terms.
In the last decade, the industry was characterised by a series of major acquistions. In 1988 it was estimated that 75% of the world market share was held by the top ten companies, whereas the corresponding figure for 1972 was 57%. The top fifteen agrochemical companies in 1990, together with sales value are shown in Table 1 (1).
Table 1. Top 15 agrochemical companies (1990)
The total world market in 1989 was estimated at US$24 billion and at US$26 billion in 1990. Three major sectors account for the 90% total market. The biggest sector is herbicides which makes up about 44% of the total. As we move into the future, we expect the herbicide sector to grow fastest in relative terms due to labour shortages caused by urbanisation in developing countries. The insecticide and acaricide market is estimated at 29%, whereas the fungicides sector, i.e. chemicals used to control plant diseases caused by pathogenic fungi, accounts for about 21% of the world market. The remaining 6% was comprised largely of chemicals which regulate plant growth and those which control nematodes in the soil.
It can be seen from Table 2 that monocotyledonous crops such as cereals and grains vastly outstrip the dicotyledonous crops such as soyabeans. This fact has major implications for the selectivity required in herbicides. In more detail, there are about seven major crop areas which contribute to the market for agrochemical treatments. These are maize, soyabeans, small grain cereals (e.g. wheat and barley), rice, cotton, vines and fruit and vegetables. A further major market is provided by the requirement for total vegetative control. Accordingly, most agrochemical companies focus upon the same targets. This has lead to a highly competitive situation in which the continued discovery and development of novel and effective crop protection chemicals is critical for survival in the industry. Additionally, patentability is a very important factor in securing a monopoly on a particular crop protection product and to exclude generic manufacturers who have not borne the high costs of research and development. These costs are presently estimated at around US$50-100 million to take a new active ingredient from discovery to the market place and over a typical timespan of seven to ten years (3).
Table 2. Major crop plantings worldwide in millions of hectares for 1989 and 1990 (2).
Future technical requirements for crop protection chemicals
Against the backcloth of a world in which the population is expected to double in the next half century, in which there are demands for better quality and more variety in foodstuffs, and in which there are essentially no competing technologies, it is not difficult to be optimistic about the need for continued research into crop protection chemicals. It is equally clear that the future does not look like the past. In order to remunerate the rapidly increasing costs of research and development, the crop protection industries will be obliged to restrict developments to chemicals with high added value. There will be a strong drive for increased differentiation in emerging products so that premium pricing can reflect this added value. This approach will favour chemicals which inter alia meet the following criteria for new products (4):
- very highly active and effective in terms of treatment costs per hectare;
- higher margins of safety to the treated crop;
- safe to the environment, the user and the consumer;
- compatible with mixture partners and suitable for use in integrated pest management programmes; flexible in use with respect to crop growth, temperature, weather conditions;
- protected by broad patent coverage;
- simplicity in manufacture and formulation.
Compounds with novel modes of action will be highly prized in several areas since they will be useful in strategies to avoid resistance. The physico-chemical properties of molecules will be important, especially if they contribute to the positive factors listed above. In herbicides, the selectivity requirements will become ever more demanding, as the key weed targets increasingly resemble the crop (e.g. wild oats in barley; Johnson grass in maize). The success of R&D in the various companies will crucially depend on their ability to introduce the characteristics listed above into compounds which make up their portfolio of development candidates. For this reason, the traditional domination of agrochemical research by chemists and biologists will erode. Instead they will be joined by a partnership of ancillary scientists who will contribute better understanding of uptake and transport phenomena, behaviour of chemicals in soil, leaching of chemicals into ground water, etc. The multidisciplinary thinking of the discovery team will need to be based around a screening methodology which will reflect all those characteristics required in a successful product.
It was mentioned above that resistance will play a major part in shaping the progress in research in the coming years. In addition to the high value which will be placed upon novel modes of action, there will be continuing and increased interest in techniques and regimes used to prolong the lifespan of existing compounds. Whereas resistance to fungicides and insecticides has been a problem of commercial proportions for several decades, herbicide resistance will present itself as a major commercial problem in the 1990s.
The companies will also seek to further capitalize upon patent protected inventions already in hand. It may be expected that considerable effort will be expended upon achieving extensions in use of the existing product range. This will lead on to a requirement for more efficacious formulations, imaginative mixture useage and differentiation by packaging. Ease of disposal of packs, already a major environmental consideration, can be expected to become even more important in the coming years.
In spite of the continuing need for new product introductions, the mounting difficulties touched upon above in achieving new registrations will continue the trend to a reducing number of new product introductions per annum, seen over the past several years. This will be exacerbated by increasing environmental pressures on the industry. These will lead to even more stringent registration requirements for both new and old products (5). In the 1980s considerable heat was generated by the introduction of arbitrary and groundless restrictions by the regulatory authorities. The latter must deal with the unenviable task of providing a reasoned balance between benefit and risk in the face of both political pressure and the demands of the agriculture industries for introduction of more efficacious products. It is to be hoped that the 1990s will present a more fruitful picture. It is imperative that the regulatory scene is logically and scientifically based and that the regulators, together with industry scientists, will forge a constructive relationship centered positively upon the accelerated introduction of benign chemicals.
Biotechnology applied to crop protection can be expected to provide rapid advances in the coming years. Whereas these advances will undoubtedly lead to the introduction of novel microbial products and crop varieties, it is unlikely that they will constitute more than 5% of the total crop protection market by the year 2000. Nevertheless, some of these new technologies will be of very significant local importance.
A major role for molecular biology-based techniques is presently blossoming in the support of the discovery of traditional crop protection chemicals. Provision of large amounts of target proteins, for example by engineered overproduction in microorganisms is already commonplace. Biotechnology has also a major role to play in the validation of target sites for biorational design. The use of genetically engineered Arabidopsis mutants is already providing very useful screening data with regard to the lethality of specified biochemical lesions. Biotechnology is also contributing enormously at present to the development of rapid throughput microscreens.
It is hard to see how biotechnology could provide completely new methods of weed control, but the principles of genetically-engineered tolerance to herbicides are now well established. Arguably, most herbicides which are currently registered, and which have suitable weed control spectra, are already under study. There are, however, several uncertainties which may limit the impact of this technology.
From the perspective of an agrochemical company owning a broad-spectrum herbicide, there could be a commercial requirement to spread the resistance gene as widely as possible through the very fragmented seed market. For example, this is currently Du Pont's approach with their sulphonylurea resistance gene. However, this raises the question of competitive advantage, and hence profit for any individual seed company. For a seed company with a maximum market share of 10% (most are lower than this at present), it is questionable whether the return can justify additional registration costs. Attempts to develop transgenic plants showing commercially significant levels of resistance to established herbicides has met with mixed fortunes.
Resistance to herbicides which act at the enzyme acetolactate synthase (ALS) has been easy to achieve through pollen mutation (ICI Garst), somaclonal selection (Pioneer/Molecular Genetics Inc.), and gene mutation (Du Pont). However, this is also reflected by the rapidity with which weed resistance has arisen in the field, and the increased use in combination with genetic resistance will increase the selection pressure even further. With compounds such as glyphosate, where natural resistance has not been reported, resistance has proved much harder to engineer. This objective continues to be the subject of a great deal of excellent research due to the attractiveness of the commercial target.
The level of farmer acceptance is uncertain as farmer choice is more limited, and economic comparisons with selective herbicides need to be made through experience. The resistant crop varieties which are now close to sales will begin to resolve these questions. Notable progress has been made on viral resistance, significant both because of the new science and because there is no adequate chemical control available. For example, it has been shown that the introduction into the plant of viral coat protein gene, or antisense sequence to part of the viral genome, will give protection against viral infection. Examples include the economically important polyvirus class which includes potato virus Y. The identification of a gene in tobacco mosaic virus which codes for cellto-cell viral movement via the plasmodesmata, indicates that there may be at least one other mechanism for engineering viral resistance.
Introduction of insect resistance has been demonstrated, but the extent to which this could replace insecticides is not yet clear. To date most of the work has been on the introduction of the gene encoding the toxin from Bacillus thuringiensis (Btt). Several companies, including Monsanto and Plant Genetic Sciences are heavily involved, and have demonstrated that the introduction of Btt does provide practical insect resistance. However, resistance to Bit has already started to appear where it has been used in a more conventional approach as a biological control agent (BCA), and this may limit the utility of engineered plants. Recent work suggests that there may be a much larger pool of insect-specific protein toxins than had previously been thought, and it may be that the prognosis for the future is for seed companies to compete via introduction of a succession of toxins. However, appearance of commercial levels of resistance combined with the large number of cultivars presently in use will limit the overall impact. This leaves large opportunities for novel chemical insecticides.
Biological control agents
Biological control agents (i.e. pest control exploiting living organisms) present an alternative way to use biotechnology in agriculture. In practice, wild-type BCA's typically suffer from slow action, narrow spectrum and unreliable performance which has severely limited their use in practice. However, genetic engineering potentially offers a way of improving performance. For example, Btt has been introduced into a Pseudomonas strain by Monsanto for soil insect control, and there is an increasing amount of work to introduce insect-specific peptide toxins into baculoviruses. Given the well-known difficulty of discovering new insecticide toxophores, coupled with the rapid rate of development of resistance, recombinant insecticidal BCA's could generate a significant impact. In principle, a similar approach could be taken to produce fungicidal or viricidal BCA's, but much less work has been done in this area.
Although the technical performance of engineered insecticidal BCA's is markedly improved, it remains to be seen whether they will be sufficiently robust over a range of field conditions. The acceptability of releasing an engineered live organism into the environment has yet to be fully tested, either scientifically or emotionally.
In conclusion, every leading R&D-based agrochemical company will lean heavily on biotechnology. A major contribution to the traditional methods of crop protection chemical discovery will be enabled through molecular biology. Transgenic plants will be developed to express useful biological traits such as resistance to herbicides, insects and pathogens. The regulatory response to these engineered species will be key. In a related area, the seeds companies will increasingly use molecular biology methodology (e.g. RFLPs) to expedite their conventional breeding programmes, thus providing short cuts to the more successful crosses.
In an analogous fashion to the medical field, biotechnology can also be used to generate diagnostic aids. The earliest application of the technology provided immunoassays, later supplemented by DNA/RNA probes for plant viruses, and these have found limited utility in the certification of virus-free stocks of, for example, potato and strawberry. In a logical next step, diagnostic tests were produced for specific fungal diseases, so that the timing and need for a fungicide treatment could be scientifically judged. Possibly, the best known example is a kit for Pythium which has been sold to managers of high quality turf grass areas, especially golf courses. Technically, there is every reason to believe that antibody or DNA probes could be generated to essentially all fungal, bacterial and viral pests. Initially, tests were complex and unreliable in unskilled hands, but technology developed in the medical field has potentially solved this problem. However, the key limitation is that by their nature such tests are spot tests, and there are serious sampling issues in trying to judge uniformity, for example in relation to the occurence of a fungal disease over a large hectarage.
Furthermore, there is at least a theoretical possibility of using diagnostics to monitor a physiological parameter such as ripeness in fruit crops, or the occurrence of a resistance mechanism in fungi or insects. In the former, the critical issue appears to be the amount of work which is needed to reliably establish a useable correlation between the diagnostic result and the physiology at the gross field level. In the latter example, the multiplicity of mechanisms requires a battery of tests, and despite much academic work with diagnostics, it is more effective and convenient to rely on a conventional bioassay at present. Nevertheless, progress is likely in all these areas, and agricultural diagnostics will increase in importance.
Major advances in formulation technology can be expected in the next decade. An important driver for these advances will be the requirement for improved operator and environmental safety (10). Increased emphasis will be placed upon knowledge emerging from a better understanding of the formulation field on the basis of physico-chemical science.
Perhaps the major drive for the future will be the replacement of solvent-based products (e.g. emulsifiable concentrates) by water-based formulations or by solids, e.g. suspension concentrates and especially water dispersable granules. Part of the pressure to replace organic solvents is based upon undesirable toxicology problems. Solid formulations are much preferred in terms of skin adsorption following spilleage. We can expect to see more wettable powders and water dispersable granules provided in water soluble inner packs. In order to allay fears concerned with spray drift, there will be more use of granules and driftless dusts. In cases where liquids are preferred, (e.g. to obtain maximal biological efficacy against pests), handling will be managed by closed-transfer systems which are amenable to easy washing.
Farm-based operators are beginning to disfavour tank mixing. Pre-mixes and formulations with built-in adjuvants will become more common in many markets. With regard to surfactants, there is already significant pressure to replace these with biodegradeable equivalents. Greater use may be made of surfactants based on oligosaccharides. Granules based on biodegradeable materials (e.g. starch) will offer considerable environmental advantage.
The disposal of packs is already a major issue. It is very likely that plastic containers will need to be returnable and collapsability will be a great advantage. There is a clear outlet for biodegradeable plastics here. Mini-bulk containers, delivered and serviced by the manufacturer and returnable for filling after use, will increase in popularity. With regard to solids, cardboard boxes and paper bags will enjoy greater useage.
Seed treatment is an area of growing importance for the agrochemical industry. It offers advantages in efficacy, economy of materials, reduced dissipation of active ingredient into the environment and reduced exposure of non-target organisms to the pesticide.
The use of a film such as a biodegradable polymer around the seed coating gives a more robust coating and greater seed-to-seed uniformity. Bird repellents can also be incorporated. Seed coatings can be combined with controlled release formulations. This is ideal when a lag time is required between the application and the desired effect or when a sustained effect is required. For example, the ICI insecticide tefluthrin (Force), when applied as a flowable microencapsulated seed dressing, to sugar beet, maize or wheat at rates as low as 12-25g/ha gives excellent sustained control of insect pests.
In the past, seed dressings have been applied mainly as powders or as solutions in organic solvents. Powders are messy to apply and are poorly retained by the seed. Liquid dressing uses large quantities of organic solvent which is both undesirable and expensive, particularly for high-tonnage crops such as cereals. Newer water-based formulations for seed dressing are proving to be more acceptable, but are more technically challenging for the formulation scientist. However, it is undoubtedly the case that in the future we will see continued improvements in formulations for seed dressings and in the associated application equipment.
In spite of inherent cost penalty, controlled release technologies will find wider application. The additional cost will be outweighed by several factors:
- The biological effect will enjoy extended persistence;
- Reduction of toxicity in practical useage;
- Reduction in loss to the environment;
- Application possible during sowing to protect the plant after emergence.
Whereas tabletting is a very common form of formulation in the pharmaceuticals industry, this has been relatively uncommon to date with agrochemicals. However, the move to active ingredients of higher potency will render this technology applicable in the crop protection chemical field. One or two applications have begun to emerge into the market place in recent years, and these have elicited significant interest.
Formulations of biological control agents
A major impediment to date concerning the successful commercial introduction of biological control agents rests with the availability of successful formulation types. Inter alia, BCA formulations must maintain the viability of the microorganism over long storage times, promote rapid establishment following application and be effective in cost terms. To date, these requirements have been rarely achieved.
As stated above, the chemically-based crop protection industry can be expected to invest heavily in the differentiation of existing product ranges. One aspect of this differentiation will be the move to innovative mixtures. Aside from mixtures (e.g. of herbicides) which are intended to increase spectrum of control, we can also expect mixtures of fungicides with insecticides or pesticide/ fertiliser combinations. These can present very considerable formulation challenges since the components may have very different physical properties. Suspoemulsions are one answer and are likely to become more common. Advances in the basic physical understanding of phenomena involved in formulation technology will be particularly useful in developing solutions to such complex problems.
In summary, we conclude that chemicals will continue to provide the key crop protection methodology for at least two more decades. However, the characteristics required for new products will change significantly. Increased emphasis will need to be placed upon higher levels of activity (down to, or even below, grams per hectare), higher margins of safety to the treated crop, benign environmental profile, and flexibility in use. Freedom from hazard to farmers, operators and the public at large will continue to be a premium requirement. Compounds with novel modes of action will be highly prized in many areas since they will be employed extensively in strategies to avoid resistance.
Biotechnology has a bright future, both in terms of enabling present discovery methods and also in the provision of novel crop varieties and microbial products. Commercial penetration is unlikely to be major during this century. The rate of commercial introductions will be constrained not only by technical and economic factors, but also by the regulatory framework which is being established in many countries to govern their development. With regard to diagnostic tests, it is unlikely in the short term that technical successes will be matched by commercial importance.
Formulation technology has much to offer with regard to the improvements required in the usage of traditional crop protection chemicals and also biological control agents. In the latter context, formulation research takes on a crucial importance.
Perhaps the major task facing the industry in the next decade is the negative public perception of the products of the industry. Whereas the agrochemical companies undoubtedly deserve some of the bad press that they have received due to past failures to take steps to counter misplaced and exaggerated claims of pressure groups, the industry will need to be much more vocal in arguing for the consistent benefits provided over many decades. The industry can be expected to take many positive steps to effect a change in this negative perception. Appropriate information on crop protection chemicals will be much more widely available both to the public at large and to groups such as schools, colleges and teamed societies. The industry will need to seek closer involvement and collaboration with environmental agencies and pressure groups in order to show that its massive investment in regulatory and environmental work is producing a scientific database which can confidently assure the public of safety. Training and product stewardship will assume even greater importance and will ensure that the standards which are adopted in the developed world at present will also be applied universally to developing countries.
I hope that it is clear from the discussion above that the future both for the chemically-based crop protection industry and also for the emerging and exciting new technologies is one which is increasingly rooted in its base in science. Multidisciplinary science is essential in the understanding of the complex phenomena engendered in crop protection technology. Provided that we, as a community, whether in discovery, development, practical useage or environmental assessment, adhere to principles of good science and avoid the pressures of perception, then we will ensure that the remarkable benefits delivered by modern agricultural practice will endure well into the next century.
The authors are pleased to acknowledge the assistance of Dr D K Lawrence and Dr D A Griffin in the preparation of this paper. They are also deeply indebted to Mrs Ivy Dowling for her patience and diligence in preparing the manuscript.
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