With a world population expected to reach nearly ten billion people by 2050, the demand for innovative tools to help meet our future food security needs has never been more urgent. Sustainable agriculture requires both the use of modern crop protection products (pesticides) to help farmers manage destructive pests and the protection of pollinators that contribute to our food productivity. To better address this requirement, scientists at Bayer have extended the environmental safety assessment to the early phases of new candidate products’ life cycle, to better understand its potential impact on bees. One of Bayer’s newest insecticides, Sivanto® prime, is a perfect example of meeting this dual goal of protecting both plants and bees.
// With a world population expected to reach nearly ten billion people by 2050, the need to increase crop productivity depends both on crop protection products (pesticides) and the preservation of pollinators.
// Only one out of 160,000 potential new compounds for crop protection products reaches commercialization, a process that, on average, requires long-standing profound expertise, costs approximately 250 million EUR and takes eleven to fourteen years to meet today’s standards of safety.
// Bayer is conducting honey bee and other environmental safety testing already during exploration of new chemistry, to more quickly evaluate a candidate’s potential impact on pollinators and the environment. The company is also participating in the development of new test methodologies to better assess potential risks to honey bees and other pollinators.
// The number of new studies performed to evaluate a product’s potential impact on pollinators is substantial.
// With its excellent crop performance and bee safety profile, Sivanto prime, a novel Bayer insecticide belonging to the new substance class of butenolides, exemplifies Bayer’s focus on pollinator safety during new product development.
// As part of its leading role in crop protection, Bayer continues to search for new products that meet high environmental compatibility standards and will help solve tomorrow’s critical food challenges.
“I was lucky to be part of the agronomic development of the new compound, flupyradifurone. Later introduced under the trade name Sivanto prime, this was exactly the type of product that our regulators and customers had been talking about.”
Dr Matthias Haas
Bayer Global Project Manager
Manufacturers have long realized that a safe work environment is foundational to higher production and a happier workforce. In the absence of an emphasis on safety, accidents are more likely to occur and with them comes a greater potential for worker injuries and a disruption in long-term productivity. In agriculture, protecting the pollinator “workforce” is critical to greater farm productivity, just as the use of new technologies is needed to protect valuable crops from destructive pests. It’s no stretch to say that safety is of paramount importance when it comes to developing new crop protection products. After all, the people who work in the crop protection industry are also consumers, eating the same foods and living in the same environment as do their friends and neighbors.
Nowhere is this emphasis on safety more evident than in the process underlying Bayer’s development of new products. However, before discussing the steps Bayer takes to develop new products, it is worth discussing why new product development is so critical to agricultural sustainability.
The development of innovative products is the life-blood of any Research and Development-based company, yet when it comes to food production, it’s not just the company that benefits from these discoveries. The use of new products and integrated technologies, coupled with best management practices, has enabled more food to be grown on less land than ever before, providing a bounty for farmers and for everyone who enjoys nutritious food at an affordable price. Despite this remarkable progress, the UN estimates that agricultural production must increase by 50 percent to meet our future food demand1. With most of the world’s suitable farmland already under cultivation, growth can only come from new innovations that can help farmers glean more from each existing hectare.
And yet sustainable agriculture is dependent on more than new growth-enhancing technologies. Producing more food on limited land must be accomplished without disrupting our natural resources and biodiversity. Preserving our environment includes safeguarding our soil and water, as well as the beneficial organisms that play a vital role in growing our food. Plant pollination is an essential component of crop production and no insect pollinator is more important to farming than the honey bee (Apis mellifera).
Balancing the need for crop protection with the need to protect these critical pollinators is a key criterion of Bayer’s product life cycle development.
Finding the right balance requires an eye for observation and an ear to listen to what is needed. During a new product’s development, feedback from all potential stakeholders is not only welcome, it is encouraged. As a global project leader, one of Dr Matthias Haas’ primary goals is to help drive the development of promising new candidates from research to market entry and he recalls one such product as being particularly noteworthy. “I was lucky to be part of the agronomic development of the new compound, flupyradifurone,” says Haas. “Later introduced under the trade name Sivanto prime, this was exactly the type of product that our regulators and customers had been talking about. The increased interest in protecting pollinators, coupled with our farmers’ need for reliable tools to protect their crops, shows that Sivanto prime was ahead of its time in anticipating our future safety standards.”
The development of crop protection products is not for the faint-hearted. According to a recent study, only one out of every 160,000 compounds typically survives the grueling evaluation process to reach commercialization2. For those that do, the average development costs 250 million EUR and takes 11 to 14 years of testing to ensure it meets the highest standards of performance and safety before it can be sold. As part of a new candidate’s registration process, a wide variety of potential human health and environmental effects associated with the use of the product are assessed. Scientific data regarding the chemical and physical characteristics, composition, potential adverse effects and environmental fate of each product must be generated by the manufacturer and reviewed by the regulatory authorities to determine whether it
The creation of flupyradifurone, the active molecule in Sivanto prime, was inspired by the natural compound stemofoline – an isolate from Stemona japonica, a medicinal plant that grows mainly in Southeast Asia.
What made the development of Sivanto prime so exciting was its excellent ecotoxicological and safety profile, which matched today’s stringent regulatory requirements. In addition to its rapid control of some of the most destructive sucking pest species found in many crops, Sivanto prime was found to be fully compatible with honey bees and bumblebees. Field research showed that the application of Sivanto prime according to the prescribed, crop-specific application instructions does not interfere with honey bee health, specifically in terms of foraging activity, brood and colony development, colony vitality or overwintering success.
The development of a new crop protection product costs 250 million EUR on average and takes 11 to 14 years of testing to ensure it meets the highest standards of performance and safety before it can be brought to market.
1 UN report: How to Feed the World in 2050:
2 Philipps McDougall (2016). The Cost of New Agrochemical Product Discovery, Development and Registration in 1995, 2000, 2005-8 and 2010 to 2014.
“Today, regulators want to know the mechanism behind these new compounds in order to understand why they have a high margin of safety to bees.”
Dr Richard Schmuck
Head of Environmental Safety, Bayer
Dr Richard Schmuck, whose department is responsible for evaluating the environmental safety of crop protection products at Bayer, has been at the forefront of ecotoxicological research on honey bees for many years and has been a major proponent of how the company has shifted its approach to new product development. “While we have always checked new substances for inherent toxicity or persistence, today we already focus on optimizing the balance of new molecules between pest control efficacy and environmental compatibility during the synthesis phase,” Schmuck notes. “Pushing this screening and optimization forward by two years requires an earlier investment, but ultimately it reduces costs by allowing us to make a more informed decision about which molecule to select.” From a pragmatic research perspective, the sooner a company can eliminate a product that will not meet high performance and safety standards, the sooner it can invest in more promising ones.
This earlier screening of new candidates for bee safety is only part of Bayer’s extended development process with regard to environmental compatibility. New study protocols to assess bee health are evolving due to an increased public awareness of the importance of bees which made policy makers even more cautious when it comes to pesticide regulation. “It is not sufficient anymore to demonstrate that a product does not adversely impact bees under practical use conditions,” says Schmuck. “Today, regulators want to know the mechanism behind these new compounds in order to understand why they have a high margin of safety to bees.”
“We were very interested to learn what enzymes produced by honey bees are responsible for their inherent resistance to certain insecticides.”
Dr Ralf Nauen
Principal Scientist, Head of Resistance Management, Bayer
Understanding the complex mechanisms involved in insecticide toxicology and insect resistance has helped Dr Ralf Nauen, Principal Scientist at Bayer Pest Control, to gain insights into Sivanto’s selectivity to bees. “We were very interested to learn what enzymes produced by honey bees are responsible for their inherent resistance to certain insecticides, such as Sivanto prime,” acknowledges Nauen. “By defining these metabolic pathways, we can open the door to understanding how these products interact with other species.” For example, his team of scientists, together with external collaboration partners, identified the same detoxification mechanism present in honey bees in other pollinators, a promising discovery that could have profound implications for future environmental research.
Evaluating the mechanistic nature of a product’s potential impact on bees is only one of a complex set of tools designed to facilitate today’s ever more elaborate environmental compatibility assessment. While a certain amount of precautionary risk-avoidance can be useful, it can have negative implications for agriculture if taken too far. Beginning with the passing of Council Directive 91/414/EEC in 1991, which harmonized the registration of corp protection products across all Member States of the European Union, and continuing with more recent legislation, the number of compounds available to European farmers today has been reduced by more than half. The dramatic reduction in the tools available to EU farmers has increased the threat of pest resistance, as farmers are forced to rely on fewer products.
Sivanto's strong efficacy profile allows the control of severe sucking pests such as aphids (above left), hoppers and whiteflies (above right), while being inherently safe to honey bees.
In addition to the loss of existing products, the emphasis on hazard over true risk assessment (which includes the consideration of hazard and exposure) is negatively affecting the development of new active substances. A recent report2 found that since 1995, the number of new substances identified as potential candidates for the development of new pesticides screened by manufacturers has tripled, but the number of candidates in full development has declined by more than 60 percent. And the primarily precaution-driven extension of regulatory requirements is only adding to the difficulty in finding suitable candidates for new crop protection products – see graph below.
Semi-field (tunnel) studies with honey bees: foliar application at full bloom. When applied at proposed label rates, Sivanto prime causes no adverse effects to honey bees – even on flowering crops.
Considering the difficulty in bringing any pesticide to the market today, discovering and successfully developing a new insecticide that is easy on bees but tough on pests is a particularly significant accomplishment. Yet what first drew Nauen to Sivanto prime was not its inherent bee safety but its potential in insect resistance management programs. As the first product from a novel class of chemistry known as the butenolides, Sivanto prime has become critically important to modern pest management. “Having a new product with a distinct chemical nature gives farmers a much-needed tool in their fight against destructive insect pests,” notes Nauen. “This new butenolide will be a key component of Iintegrated Pest Management (IPM) practices, which depend in part on alternating different modes of action to help delay insect resistance development.”
“One of our main challenges is to align the different requirements and set up a global strategy for bee testing and risk assessment.”
Dr Maria Teresa Almanza
Head of Bee Testing and Risk Assessment Team of Environmental Safety, Bayer
Dr Maria Teresa Almanza, the head of the Bee Testing and Risk Assessment Team in Bayer’s Environmental Safety Department, is well-acquainted with the new bee testing requirements in Europe and in other regions around the world. “One of our main challenges is to align these different requirements and set up a global strategy for bee testing and risk assessment,” she notes. “There has been a huge shift in evaluating risks to bees, which includes increasing the number of species to be assessed, covering all possible routes of exposure (e.g. sprays, systemic residues in nectar and pollen, dust from seed treatment), different life stage responses (adults and larval developmental stages) and whole colony impact, such as overwintering success or other complex, chronic (long-term) endpoints. Creating new testing procedures for these factors is much easier said than done.”
Knowing this makes the discovery and development of Sivanto prime all the more satisfying: It has a complete range of uses (e.g. foliar, soil, drip irrigation) and can even be sprayed during full bloom in a wide range of crops according the product instructions.
2 Philipps McDougall (2016). The Cost of New Agrochemical Product Discovery, Development and Registration in 1995, 2000, 2005-8 and 2010 to 2014.
“We’d like to engage in joint sessions with all parties when we meet with the authorities, as this will help establish the transparent process we need to create meaningful new environmental safety testing protocols.”
Dr David Fischer
Director of Pollinator Safety at Bayer in the USA
Trying to harmonize bee safety testing methods among different regions is quite difficult when the area of research is rapidly evolving. Thirty years ago, most research focused on answering the question whether or not spray applications would kill bees. While this understanding is still important, today’s emphasis is on bee reproduction, colony-level effects and potential long-term impact. To be truly meaningful, new testing protocols must deliver reproducible results. A good example of this involves how scientists validate new studies on honey bee larvae: “Just recently, a newly validated study protocol to test pesticide toxicity to honey bee larvae toxicity following repeated exposure became an OECD guidance document (OECD 239). Working with other scientists of regulatory agencies, research institutes, industry and contract research organizations, Bayer participated in a ‘ring test’ with 16 other testing facilities across the world to make sure that the methodology yields consistent and reproducible results,” notes Almanza.
Some countries are considering requesting studies on pollinators other than honey bees, which presents an entirely different set of challenges for new product development and registration.
With more than 20,000 bee species in the world, it is impractical to develop testing protocols on all of them, so new research is addressing those which are of economic importance and which can readily be reared in sufficient quantities for testing, including bumble bee (Bombus spp.) and certain solitary bee (e.g. Osmia spp.) species.
Once again, Sivanto prime passes the test: Laboratory studies show that bumblebees are not more susceptible to flupyradifurone than honey bees and field trials found no effect on pollination efficiency of bumblebees when flupyradifurone was applied according to the use directions. Nonetheless, honey bees will remain the prime target of research for the foreseeable future. As Schmuck is quick to observe, “There is no other individual organism in the ecotoxicological arena for which so many tests are conducted as for the honey bee.”
The challenge of feeding a rapidly growing world population requires the use of innovative crop protection technologies and the preservation of natural resources, including insect pollinators.
Recognizing the need for both, Bayer scientists are conducting bee safety studies already in an early phase of a new product’s development and are participating in developing new testing protocols to better assess potential risks to pollinators. One product that exemplifies Bayer’s new development approach is Sivanto prime, a bee-friendly insecticide from a novel chemical class, which is critically important to integrated pest management programs in many crops.
Since 1995, the number of potential candidates screened by manufacturers has tripled but the number of candidates in full development has declined by more than 60 percent.
Source: ECPA 2013, R&D Trends for Chemical Crop Protection Products and the Position of the European Market