Overview: An Urgent Need for Environmental Pharmacology?

By: Michael Spedding, Secretary-General IUPHAR, Spedding Research Solutions, Le Vesinet, 78110, France, michael@speddingresearchsolutions.fr and Chris Connolly, c.n.connolly@outlook.com

This brief article features a potentially important new area for pharmacology, which IUPHAR has explored in the past, but failed to get funding for, despite the apparent importance of the subject. This article, and some others in finalisation, are therefore presented as a ‘teaser’ for reflection, and specifically to obtain feedback to the authors: if we don’t get any, we will be discouraged from advancing, if we do we will continue to push for partnerships. So please send comments to the emails below. An encouraging point is that when we have presented the concept to young pharmacologists, we have had enthusiastic returns. Nevertheless, the pharmacology and toxicology of the environment has many entrenched positions by very powerful lobbyists, and it will be impossible to make headway without obtaining funding.

Pharmacologists are the first link with chemists in drug discovery. However, the industrial synthesis of new chemical substances and release into the environment outstrips the capacity to test for safety (1,2). Furthermore, chemicals may have such high affinity for their sites of action, and also be concentrated in food chains, that they pose considerable risk to keystone species, and represent a cause of much of the widespread loss of biodiversity and insect populations which is now so evident. In this respect many pesticides interact with insect receptors (eg nicotinic or nuclear receptors) at concentrations not dissimilar from those affecting orthologue mammalian receptors. Furthermore, agonism and antagonism at such receptors follows classical pharmacological principles, at concentrations which may interfere with function which may be 100-fold lower than concentrations causing toxicity, and this may be modelled virtually, especially if crystal structures are known.

In this respect the European Food Safety Authority lowered the daily human recommended intake of bisphenol A, which is used in many food and drink containers, from 50 to 4 µg/kg body weight, but are now considering lowering it much further based on experimental animal studies (Bisphénol A | EFSA (europa.eu)). Recent data (3) have shown highly deleterious effects of synergies of perfluoroalkyl substances (PFSAs, which can have extraordinary persistence in the environment), phthalates and phenols (including bisphenol A), in mother-child pairs, with measurable levels of the substances in serum or urine from the tenth week of pregnancy.  Language delay was present in some of the offspring and the authors showed that relevant concentrations of the agents produced synergies which could negatively affect multiple genetic pathways in human cerebral organoids, Xenopus and zebrafish models.  The authors calculated that ~50% of babies had been exposed to pharmacologically active concentrations (3). Chemicals of environmental concern (CECs) occur in Swedish lakes, which are sources of drinking water, at an average concentration of 190ng/L, and in one such lake it was calculated that river water supplied 5kg/day of CECs (4). Thus, the total quantity of long-lasting CECs released into the environment is a critical factor.

Pharmacologists with experience in drug-receptor interactions can bring their knowledge to bear in a way which is not always evident in toxicological evaluations.  Receptor access may be via hydrophilic and hydrophobic (cell membrane) pathways, with immense differences in kinetics. Concentrations in in waste-water, rivers, seas, soil or even beehive wax may be known, but what dose should be considered? The massive amounts administered to a given environment may be considered as a dose, but the ensuing concentrations in specific microenvironments may well be sufficient to have pharmacological effects on multiple receptor systems, while field trials may not be sufficiently sensitive to pick up such effects. Thus, we may have to reconsider the total doses synthesized and how they can be disposed of, and also reconfigure and reinforce interactions between pharmacologists (IUPHAR) and toxicologists (IUTOX).

However, intensive agriculture requires a tight control on pests, disease and weeds, and the complexity of chemical exposure is enormous. At present, after toxicological analysis, industry proposes field trials to measure toxicity to insect populations, but these have massive variables associated with them which renders defining synergies between different agents very difficult to ascertain.  ).  IUPHAR via its nomenclature committee, NC-IUPHAR, has developed expert committees and websites for all drug receptors/targets (www.guidetopharmacology.org) listing Kis and IC₅₀s for key compounds and drugs.  However CECs may act by similar targets (examples : nuclear receptors, nicotinic and GABA receptors, sodium channels, etc for which expert committees are already constituted by NC-IUPHAR). A first step would be including affinities for CECs in the guides. Secondarily, championing validated pharmacological tests and challenging some of the accepted procedures for measuring toxicity. An example might be pharmacological modulation of nicotinic receptors in honeybees which may induce deleterious changes in behaviour.

The potential synergies between CECs are difficult yet crucially important to understand. In the UK, 17,303,251 Kg of pesticide is used on 78,513,286 ha (over 3 times the size of the UK), giving an average coverage of 220 g/ha. An average field may be treated with approximately 22 applications of pesticides, making the chemical load on intensively farmed land around 5 Kg/ha (0.5 g/m²). Given that the average 22 chemicals could be selected from a UK repertoire of 334 compounds and mixed prior to application, the chemical complexity is enormous and beyond the capacity of field tests to disentangle. Toxicological investigations are limited in providing mechanistic or pathological synergies and the impact on the decline of sole species (e.g. honeybees), but pharmacology has provided clear mechanistic evidence that, for example, neonicotinoids affects bees nicotinic receptors at much lower concentrations than affect overall toxicology. . The devastating decline in insect populations (75% decline in 27 years) is impacting the entire food chain, as evidenced by the coincident bird decline (5–7).

The need for target-based drug-interaction data.

Given the complexity of chemical exposures and the failure of governments to collect data on local pesticide use, it remains possible that a particular combination of CECs/pesticides may create an unforeseen risk to the environment or human health (3). Pharmacological interactions can lead to mechanistic synergies. These can be addressed using classic pharmacological techniques.

A number of studies have reported an increased incidence of cancers, Amyotropic Lateral Sclerosis, (ALS) and Parkinson’s Disease (PD) with pesticide use. Pesticide use associated with genetic variation of enzymes such as paraoxonase (e.g. PON1-55) may be linked to Parkinson’s disease (8).

Timing is now right, with the advent of health informatics, a large database of disease incidence is becoming available and this is recorded with geographical information (postcodes). For pesticide exposure compared to clinical exposure, total dose/concentration would be to the environment, compared to clinical dose and plasma level. This approach would provide a quantitative assessment of risk and informs on the level of mitigation (reduced dose or frequency of exposure) required to maintain pesticide exposure to sub-threshold levels in beneficial species, taking into account synergies. Specialist databases (eg guidetopharmacology.org) have been evolved between academia and industries for drug targets and could be extended to pesticides, as targets are similar. Further consideration is required for contraindications that may arise from exposure to multiple hazards (other chemicals/diseases) and adaptive processes in vivo that alter future vulnerability.

Thus the industrial scale use of pesticides in intensive agriculture, may have major deleterious effects in the environment with dangers for food and water security, insect pollinators and aquatic environments, impacting human health and wellbeing. Collapse of endangered species, and of entire ecosystems may be due to an underlying loss of insects. In response to these threats, a system of pestidovigilance was proposed, with total doses applied to ecosystems being controlled(9) . We would welcome feedback as to IUPHAR’s role in propagating environmental pharmacology.

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2. Diamond ML, de Wit CA, Molander S, Scheringer M, Backhaus T, Lohmann R, et al. Exploring the planetary boundary for chemical pollution. Environ Int. 2015 May;78:8–15.
3. Caporale N, Leemans M, Birgersson L, Germain P-L, Cheroni C, Borbély G, et al. From cohorts to molecules: Adverse impacts of endocrine disrupting mixtures. Science. 2022 Feb 18;375(6582):eabe8244.
4. Malnes D, Ahrens L, Köhler S, Forsberg M, Golovko O. Occurrence and mass flows of contaminants of emerging concern (CECs) in Sweden’s three largest lakes and associated rivers. Chemosphere. 2022 Jan 31;294:133825.
5. Harvey JA, Heinen R, Armbrecht I, Basset Y, Baxter-Gilbert JH, Bezemer TM, et al. International scientists formulate a roadmap for insect conservation and recovery. Nat Ecol Evol. 2020 Feb;4(2):174–6.
6. Hallmann CA, Sorg M, Jongejans E, Siepel H, Hofland N, Schwan H, et al. More than 75 percent decline over 27 years in total flying insect biomass in protected areas. PloS One. 2017;12(10):e0185809.
7. Hallmann CA, Foppen RPB, van Turnhout CAM, de Kroon H, Jongejans E. Declines in insectivorous birds are associated with high neonicotinoid concentrations. Nature. 2014 Jul 17;511(7509):341–3.
8. Manthripragada AD, Costello S, Cockburn MG, Bronstein JM, Ritz B. Paraoxonase 1, agricultural organophosphate exposure, and Parkinson disease. Epidemiol Camb Mass. 2010 Jan;21(1):87–94.
9. Milner AM, Boyd IL. Toward pesticidovigilance. Science. 2017 Sep 22;357(6357):1232–4.