IUPHAR/ISC resource:

There is global concern that the industrial scale use of pesticides, used to maintain intensive agriculture, is deleterious to the environment, may compromise food and water security and compromise populations of insect pollinators; a system of pestidovigilance (Milner 2017) was proposed, comparable to the testing of pharmaceuticals.

Acute toxicity risk to beneficial insect species is assessed using the LD50. However, the impact of non-lethal chronic exposure is difficult due to the high cost of generating statistically significant evidence in the field, with its multiple variables (eg. weather, environment quality and other chemicals present). The identification of exposure concentration or LD50 doses are of limited value where non-lethal effects impact pollinator performance or reproduction. More relevant, is to adopt the principles behind the clinical dosing regimen to achieve safe therapeutic activity in patients where exposure dose/ frequency, its level of absorption and distribution in vivo, its clearance rate and its bioactivity (EC50), the selectivity between its target site (eg. in pest species) and other sites (eg. in pollinators) and it’s contraindications (eg. potential interactions with other chemicals or diseases).

We propose the application of these pharmacological principles to predict pesticide sub-lethal toxicity and so, inform environmental safety. For pesticide exposure, the total dose/concentration would be defined as the steady-state levels detected within pollinators after exposure to field-relevant levels (eg. Moffat 2015). When related to the bioactivity of the chemical within the pollinator species under study, this approach would provide a quantitative assessment of risk and informs on the level of mitigation required to reduce pesticide exposure to sub-threshold steady-state levels in beneficial species (eg. by the reduction of dose/frequency/duration of application/co-application with other chemicals).

We (International Union of Basic and Clinical Pharmacology [IUPHAR]) have established specialist databases on drug targets (eg. guidetopharmacology.org) built by collaboration between academia and industries and this infrastructure could be extended to catalogue the effects of pesticides in insect (pest and beneficial) species, as the target sites and chemicals are similar. These databases can include knowledge on pesticide interactions, as we do for drug contraindications, that are essential in assessing risks that may arise from exposure to multiple chemical/disease hazards. Furthermore, knowledge on adaptive processes in vivo, such as increased vulnerability to future exposure (Moffat 2016) or preference seeking in honeybees (Kessler 2015). This becomes highly relevant when we consider that the risk from chronic exposure via chemically contaminated field margins is relatively unknown.

Support for unexpected chronic exposure hazard comes from several large-scale DEFRA and industry studies which inadvertently identified a background neonicotinoid contamination of control sites (eg. Thompson 2013), where the chemicals have not been used recently. These findings have been supported by a direct analysis of local wildflowers where it was demonstrated that 97% of neonicotinoid exposure to honeybees was not from flowering crops, but wildflowers (Botias 2015, 2016). Indeed, neonicotinoids have been detected also in the soil (Jones 2014) and local dandelions (Krupke 2012).

Importantly, this alternative exposure route is prolonged throughout the flowering season and so delivers a constant chronic dose of neonicotinoids (and other unknown chemicals). Therefore, this alternative route of exposure likely contributes to the global presence (up to 80% of samples tested) of neonicotinoids in honey sold for human consumption (commentary in Connolly 2017) and likely contributes to the hundreds of pesticides found within honeybee hives (Mullin 2010). Therefore, there is a considerable knowledge gap on the consequences to insect pollinators of their chronic exposure to individual pesticides via field margins. Moreover, the potential for additive/synergistic cocktail effects by the exposure to multiple chemicals via field margin exposure is unknown. This identifies a major confounding factor that compromises the use of field margins to enhance local ecosystems by the provision of native forage to key crop pollinators. Such practices may compound the threat to insect pollinators.


We propose a unique role for the IUPHAR, which is linked to the International Science Council (ISC), in providing access to thousands of expert cellular scientists and expert pharmacological curators of chemical databases to build an open access database of existing knowledge and to initiate key bioactivity studies (eg. ligand-binding assays on tissue from pollinator species) to fill key knowledge gaps on possible chemical hazards. This would form part of IUPHAR’s existing databases (guidetopharmacology.org, guidetoimmunopharmacology.org, guidetomalariapharmacology.org), which is quality controlled by 90 expert subcommittees of ~800 scientists.

To aid in the understanding of our basic pharmacovigilance concept, we describe the environment as the patient and the target is the pest species (Figure 1 [could not include]). A chronic health risk is the damage to non-target sites (eg. pollinators) that may result from an imbalance between exposure and clearance rates, with the impact being compounded by molecular adaptations (eg. environmental adaptations – pest species resistance against the drug (pesticide) (Wu 2018), increased sensitivity [Moffat 2016] and preference seeking in honeybees {Kessler 2015]).

‘Environmental pharmacology’ deals currently with the entry of chemicals or drugs into the environment after elimination from humans and animals. However, there is a much more fundamental role for the adoption of pharmacological principles in the design and monitoring of safety for pesticides released directly into the environment. The quantitative values possible by the application of environmental pharmacology, would enable this science base to move beyond the impact to single bees by integrating into environmental models of bee colony performance (eg. BEEHAVE, http://beehave-model.net/). Furthermore, pesticides act at distinct sites which are frequently those already established for human health (e.g. nicotinic receptors, or enzymes) where expert subcommittees already exist, and where it would be trivial to add experts on the equivalent insect receptors.


Figure 1. The relationship between the clinical assessment of therapeutic dosing and the sub-lethal impact of pesticides to beneficial species. The host is either the patient or the environment, with the threat being either a disease (in man) or a pest species (in the environment). Delivery of the effective drug (man) or pesticide (environment) requires that a bioactive steady-state dose is achieved by the dosing regimen (concentration or frequency of dosing) but this does must be at a level below that causing toxicity from side-effects where the drug/pesticide can now act at off-target sites such as another organ (man) or a beneficial species (environment). However, chronic use needs to also consider where potential adaptations (eg. addiction/sensitisation in man or preference seeking/sensitisation in pollinators) may occur. Finally, there is a growing concern about the number of medications elderly patients take (called polypharmacy, (Tatonetti 2012)) where complex contraindications may occur in man. In contrast, the situation for the environment, where unknown chemical cocktails exist, its ‘off-target’ effects (eg. on pollinators and man) are not yet fully realised, from the perspective of the long-term health of the ecosystem and man.




Key references.

Botias, C., David, A., Horwood, J., Abdul-Sada, A., Nicholls, E., Hill, E. & Goulson D. (2015). Neonicotinoid residues in wildflowers, a potential route of chronic exposure for bees. Environ. Sci. Technol. 49, 12731-40.

Botias, C., David, A., Hill, E.M. & Goulson D. (2016) Contamination of wild plants near neonicotinoid seed-treated crops, and implications for non-target insects. Sci. Total Environ. 566-567: 269-278.

Connolly, C.N. (2017). Nerve agents in honey. Science 358, 38-39.

Jones, A., Harrington, P. & Turnbull, G. (2014). Neonicotinoid concentrations in arable soild after seed treatment applications in preceding years. Pest Manag. Sci. 70, 1780-4.

http://www.guidetopharmacology.org/nciuphar.jsp

Kessler, S. C. et al. Bees prefer foods containing neonicotinoid pesticides. Nature 521, 74–6 (2015).

Krupke, C. H., Hunt, G. J., Eitzer, B. D., Andino, G. & Given, K. Multiple routes of pesticide exposure for honey bees living near agricultural fields. Plos One 7, e29268 (2012).

Milner, A.M. & Boyd, I.L. (2017). Towards pestidovigilance. Can lessons from pharmaceutical monitoring help to improve pesticide regulation? Science 357, 1232-1234.

Moffat, C., et al. (2015) Chronic exposure to neonicotinoids increases neuronal vulnerability to mitochondrial dysfunction in the bumblebee (Bombus terrestris). FASEB J. 29, 2112-9.

Moffat, C., et al. (2016) Neonicotinoids target distinct nicotinic acetylcholine receptors and neurons, leading to differential risks to bumblebees. Sci. Rep. 6, 24764.

Mullin, C., et al. (2010)
High levels of miticides and agrochemicals in North American apiaries: implications for honey bee health. Plos One 5, e9754.

Tatonetti, N.P. et al. (2012) Data-driven prediction of drug effects and interactions. Sci. Transl. Med. 4, 125ra31.

Wu, S.F, et al. (2018) The evolution of insecticide resistance in the brown planthopper (Nilaparvata lugens Stål) of China in the period 2012-2016. Sci. Rep. 2018 Mar 15;8(1):4586.


Previous Research Track Record of IUPHAR

The IUPHAR is a unique worldwide academic and industrial group addressing clinical and preclinical pharmacology. The Nomenclature Committee (NC-IUPHAR) has set up the IUPHAR/BPS Guide to PHARMACOLOGY database (GtoPdb), based in Edinburgh, with joint funding from IUPHAR and The British Pharmacological Society (BPS) and Wellcome Trust – supported by a federate of >80 drug target subcommittees, representing ~800 expert pharmacologists worldwide, allowing an independent academic/industrial expert-driven system of data collation and giving recommendations on key pharmacological interactions. This has now been extended with a collaboration with the International Union of Immunological Sciences (IUIS), and the Guide to Medicines for Malaria with the Medicines for Malaria Venture (MMV, funded by Bill Gates).

NC-IUPHAR was set up 30 years ago to resolve controversial issues in receptor pharmacology and nomenclature with an expert-driven approach, as the data are too complex for a ‘data-trawling’ approach. NC-IUPHAR has three outputs: articles with recommendations, GtoPdb, and specific symposia to address key issues. The management structure of having core committee meetings twice yearly, with specific delegation/communication to multiple expert subcommittees and follow-up via detailed minutes, has proven to be both successful and sustainable. This allows public-spirited lead scientists to ensure that their research areas are scientifically ‘clean’ with appropriate nomenclature and defined proteins. Recent efforts have included defining the main experimental variables and clinical translatability in a given field. Only validated and reproduced data are used, and because of this, uniquely, both academic and industrial scientists work in harmony in subcommittees and the core committee. Thus, this may be the only way to generate a way forward between industry and environmental protection.

Thus, 125 IUPHAR publications have an h-index of >80 – the databases are visited by scientists from 160 countries, and many biotechs. Thus, this management structure could be extended to the urgent, complicated and contentious area of environmental pharmacology. In this respect, we have already made simple recommendations to the House of Commons subcommittee about the molecular targets and synergies between pesticides, in the honeybee debate and have support.

We hope that the EKLIPSE network finds this approach will highlight key knowledge gaps and provide unique expertise to collaborate with other members of the network to assess the hazard/risk of chemical exposure from field margins within the EU.


Yours Sincerely


Michael Spedding (Secretary General)
Christopher N. Connolly

International Union of Basic and Clinical Pharmacology (IUPHAR)