W T Rüegg, Syngenta Crop Protection AG, Schwarzwaldallee 215, PO Box, CH-4002 Basel, Switzerland. Tel: (+41) 61 323 11 10; Fax: (+41) 61 323 59 54; E-mail: firstname.lastname@example.org
The high adoption of chemical weed control and the broad range of solutions already available to manage most weed problems are significant hurdles to the development and launch of new herbicides. Business potentials are influenced by the high technical and biological standards provided by existing herbicides, as well as the intense competition in the marketplace. Other factors adding complexity are agronomic, structural and technological changes, including the introduction of herbicide-tolerant crops, and the high costs of development for new active ingredients, mainly due to increasing regulatory requirements. In the light of increasing weed resistance to widely used herbicides, securing diversity in agronomy as well as weed management is a key to efficient crop production in future. In order to support this objective, new herbicides, preferably with new modes-of-action, will need to be discovered and developed.
The agrochemical industry has been very successful in developing new herbicides. New chemicals with improved properties, especially providing significantly reduced use rates, and often new modes-of-action have been discovered, developed and launched for many different crops. This success has positively influenced agriculture as a whole. However, these days the introduction of new herbicides with either a new mode-of-action or novel chemical classes has slowed. Since 1991, when sulcotrione, an HPPD herbicide, was introduced in the marketplace, no new mode-of-action has been commercialised in Europe, while there were 10 new modes-of-action commercialised between 1970 and 1985 and five new ones between 1986 and 1991 (Schulte, 2004). Should this trend continue, it could impact the success of farming and agricultural production in the long term. This article aims at analysing the reasons for slower technical progress in the area of herbicide invention and to sketch potential opportunities for the future.
Drivers for technical progress
The main driver for technical progress – also in the herbicide area – is business potential. However, such business opportunities clearly need to be balanced against the excellent technical quality of existing (‘old’) herbicides, which set very high technical, regulatory and economic standards to be matched (or even to be exceeded). Due to their high market volume globally, the major food crops, such as maize, cereals and rice, have always been attractive targets for new active ingredients. This explains why in those crops a broad range of modes-of-action are available. In maize, for example, active ingredients discovered between 1950 and 1980 (e.g. triazines and acetanilides) still represent a significant portion of the market value. Other crops, like sugarcane, worth the development of a specific new active ingredient in the past, are today considered more of a minor crop, where new active ingredients rather need to be spin-offs from projects in a major crop like cereals or maize, which per se offer a bigger market potential (Quadranti & Nevill, 2004).
The introduction of (genetically engineered) herbicide-resistant crops, beginning in the mid-1990s, has provided a further solution offering broad-spectrum weed control as well as a ‘new’ mode-of-action for certain crops. Although the main compound, glyphosate, is old, due to the introduction of a seed ‘technology fee’, the value capture model for herbicides has been transformed, transferring value from chemicals to the seed business. However, glyphosate-resistant crops have lowered the costs of weed management in cotton and soyabean overall, including herbicide as well as increased seed costs for the grower. Today, conventional crop protection research competes with traits research for R&D resources. Nevertheless, herbicide-tolerant crops (and genetically modified organisms in general) are considered an agro-business opportunity, potentially allowing the use of one and the same herbicide across many crops.
The consolidation process in the agrochemical industry (Copping, 2003) has reduced the overall R&D resources. In 2005, there were only 11 companies with significant expenditure in crop protection research and development, compared with 35 companies in 1985. From published patents (Fig. 1), one might conclude that the number of chemistry laboratories worldwide has declined sharply, and therefore the research activities have declined. Thus, just by sheer probability, the chances of discovering totally new chemical classes (measured by numbers and patent diversity) appear to have been lowered in the last 10 years. Increasing cost of herbicide development (Fig. 2) represents a significant challenge to project prioritisation and ‘risk-taking’ at a very early stage of the R&D process, as it is not possible to maintain a broad diversification of research projects over a long period of development. Both effects have slowed down technical progress globally and decreased the discovery of new chemistries significantly.
However, the potential success of innovations also depends much on product price and cost. Operating a farm successfully is a complex task (Zoschke & Quadranti, 2002). Farmers are under pressure, commodity prices for most agricultural produce are low and subsidies are under scrutiny. The change in real agricultural income per worker in EU-25 has overall declined by 6.6% in 2005. Farmers suffered most in Hungary, Slovakia, Spain, Portugal, Slovenia, France and Italy where agricultural income per worker declined by 19%, 15%, 12%, 11%, and 10% respectively. But farmers’ incomes have also dropped in Germany by 4.9% (Agra Europe Weekly: http://www.agra-net.com/portal; 6 February 2006).
In order to reduce costs, farmers might think of cutting product rates, applying less than recommended on the label. However, this not only puts the success of a weed control programme at risk, but potentially favours the build-up of resistance of herbicides to weeds. Likewise, the intensive use of a single herbicide is likely to promote herbicide resistance development, but at an accelerated pace, and especially so, if used in various crops grown in the same rotation, as currently experienced with glyphosate in herbicide-tolerant crops in the United States (Powles & Preston, 2006). Applying full use rates, as recommended, is a critical success factor to keep herbicides effective for as long as possible.
In sharp contrast to industry’s limited R&D resources, regulatory requirements are increasing (Anonymous, 2005). Regulatory support work absorbs significant time and money, either directly by competition for biological and environmental test capacity in glasshouse, laboratory and field, or indirectly through resource allocation at external laboratories and contractors. Figure 2 clearly demonstrates how development cost has increased up to 1995, especially for regulatory demands, a trend which continues today.
Overall, industrial research has reacted to new regulatory requests by introducing additional screening systems/levels at earlier stages. On top of crop selectivity, the objective is now to fully investigate environmental, ecological (fish, birds, bees, etc.) and toxicological parameters, as well. However, this is not different for herbicides, fungicides or insecticides per se. Inclusion of more selection parameters slows down the success rate, while raising cost and complexity. Especially the latter has encouraged industry to focus work in ‘safe herbicide harbours’, such as ALS or ACCase chemistry. This can explain, at least partly, why there is little variation in recently launched new active ingredients, in terms of mode-of-action. To identify a way for regulation of new modes-of-action is a major challenge and can be easily demonstrated with the example of the introduction of HPPD chemistry. On the other hand, it is rather attractive to have exclusive rights on a new active ingredient with a new mode-of-action in a major crop, matching an important market segment.
The milestone of environmental hurdles from a research point of view has been the introduction of the 0.1 μg L−1 trigger value for water contamination in Europe, in the early 1990s. Since leaching of compounds is basically influenced by the same parameters that are important for herbicidal functionality, namely soil residuality (main factor degradation) and soil mobility (water solubility, soil adsorption), this trigger value had a major impact on the research and development of new herbicides. For environmental reasons, short residual, low water solubility and highly soil-adsorptive compounds are preferred. On the other hand, herbicides with a certain persistence and good soil mobility would make good agronomical sense for many crops. The chemical industry has adapted screening methods that allow the elimination of environmentally critical compounds early in the screening cascade. But the optimisation towards both acceptable weed control and acceptable leaching potential continues to be a tricky decision-making process in the early screening stages. Many resources continue to be invested into this area of concern, before a decision for development of a new active ingredient is taken. As ‘old’ compounds are no longer going through the EU Annex I re-registration process for active ingredients, this frees up room for new opportunities as such. However, it also slows down progress in delivering sustainable innovation, which bears a risk of inadequate compensation of those products dropped.
Are there still opportunities for new herbicides, and what are the main search targets? Is there still an incentive to invest into herbicide research?
The driver for profitability is and will continue to be crop yield (Fig. 3) and quality. The high impact of weed competition on yields makes weed control mandatory. In order to secure crop yields, chemical solutions for weed management will continue to be the preferred choice for the foreseeable future. And obvious alternatives are not in sight.
The increase in the global population has already led to an intensification of crop production (output/surface) and this must continue (Fig. 4) in order to secure world food supply.
The increasing world population (United Nations, 2004) seems to be a major driver for the need to increase food production output per area. Though the acreage of arable land as such seems to remain stable (FAO: http://faostat.fao.org; 19 January 2006), the loss of ‘good’ arable land due to urbanisation and climatic changes must be taken into account. Mega cities sprawl into fertile arable land. Among other criteria, many historical cities were founded where economic success in good arable land was guaranteed. For example the urban expansion of Paris occurs today into the best agricultural land in the Paris basin (Megacity task force of the international geographical union (University of Köln: http://www.megacities.uni-koeln.de/documentation; 14 July 2006). To compensate for the loss of good arable land, the remaining production space needs to increase its output.
To cope with today’s regulatory requirements is a major task. Old compounds are under scrutiny for various reasons. Requirements are unlikely to decrease, even though it is costly to maintain compounds in the market. Less profitable compounds will be divested or completely given up by R&D-based companies, especially after patent expiry. In such a business environment, generic companies (with only limited or no R&D activities) have an advantageous cost position. However, this in turn indirectly limits overall technical progress.
What are the needs arising from the intensification of agriculture in different parts of the world, e.g. in Eastern Europe or China? And what are the consequences of various agro-political changes, e.g. subsidy systems, or biofuel production?
Irrespective of the anticipated changes, farms become larger and extend to thousands of hectares in the Americas and Eastern Europe. Therefore, farm management practices will change accordingly. Those farms not only expect reliable weed control, at the same time they also seek non-complex management tools. Speed, flexibility and efficiency are of key importance. One-shot products are wanted, delivering a complete weed spectrum and providing season-long weed control. Mainly for reasons of convenience, the market favours products combining several active ingredients into stable readymade products, as they provide higher performance and convenience for the end user.
In many parts of the world, farmers are confronted with the fact that their established weed control measures are beginning to lose effectiveness, due to weeds developing herbicide resistance. Even if they switch to newer products, they may still face problems with different levels of cross resistance. Among other reasons, this can be seen as a direct consequence of what has been stated above: a decrease in the range of active ingredients and modes-of-action available, reducing ‘diversity’, which is considered a crucial component of effective and sustainable weed management (Powles et al., 1997; Powles & Preston, 2006).
Further problems to be addressed are the expectations regarding weed shifts and/or the occurrence of (new) weed problems, due to the introduction of new weed species by global travel or international transport of goods. Will certain plants profit from climatic changes like global warming? Although the topic of climatic changes is controversial, meteorological statistics show an increase in environmental anomalies (Smith & Reynolds, 2005; National Climatic Data Center: http://www.ncdc.noaa.org; 6 February 2006): drought, flooding, heat, extreme frosts and mild winters. Some weeds might be affected differently by those weather conditions, and the behaviour of crops could also potentially change. Reports of new weed problems are frequent all over the world and do not occur only in the new world, but in Europe as well. Though Ambrosia artemisiifolia L., Cyperus esculentus L. and Sorghum halepense (L.) Pers. are common weeds worldwide and today are considered ‘standard’ in terms of weed control, their recent appearance in Europe north of the Alps has demanded adapted solutions, and countries may not have weed control strategies in place. Giant hogweed (Heracleum mantegazzianum Sommier & Levier) is not a particularly important weed in arable crops, but demonstrates clearly that invasive weeds can create major problems for European authorities (Hansen et al., 2006). While some of them are currently only of local importance, the question is whether we will be able to control those weed species, once some of them become widespread in our cropping systems? Or might even certain weed species regain commercial importance, once ‘old’ compounds are no longer registered?
Effective screening methods are in place. High-throughput screens, powerful databases for structure activity research and most recently, virtual screening technologies, allow users to search through in-house and commercially available compound libraries, to select compounds with diverse structures, but with the same biological functions. Compounds with a new mode-of-action are desired and necessary in the mid- to long term, in order to manage herbicide resistance. Ideally, they should also be highly active (with ‘low’ dosage). However, all other parameters, like very good crop tolerance (and possible multi-crop fit), broad weed spectrum, application flexibility, cost efficiency and favourable regulatory profile must be present. This is a challenge. However, in order to contribute to effective crop production, the R&D-based agrochemical industry aims at meeting the challenge of delivering successful herbicidal solutions for the future, in order to help sustain ‘diversity’ of weed management, and, therefore, effective crop production.
We thank Dr H.G. Brunner and Dr R. Hauck, Syngenta Crop Protection AG, respectively, for the patent analysis and for the economic data.