Systematic review of comparative studies assessing the toxicity of pesticide active ingredients and their product formulations
Introduction
The fast industrialization and development of agricultural technology over the past century have dramatically changed both the ways and the degree of human exposure to synthetic chemicals. Nowadays, one of the major challenges that our society has to face is simply to keep pace with knowing how many chemicals are produced and used in the world. This is an important starting point for identifying the hazards and estimating the risks that chemicals might pose to the environment and to human health. According to the world's largest chemical substance information centre (CAS Registry), more than 149 million unique organic and inorganic chemicals such as alloys, coordination compounds, minerals, mixtures, polymers and salts have been synthetized in the history of humanity (CAS Registry, 2019); from which at least 84,000 chemical substances, including pesticides, may possibly be in commerce (GAO, 2013). The European Commission's pesticide database currently registers 1387 active pesticide ingredients from which 466 are permitted to use in the European Union (EU) (European Commission, 2019). The approval of active pesticide ingredients is carried out on EU level; however, the authorisation process requires that at least one representative use and formulation is assessed and deemed acceptable. The subsequent toxicological assessment and the authorisation of formulations containing an EU approved active substance are the exclusive responsibility of individual Member States (European Commission, 2018). As one active ingredient can serve as a base for many pesticide product formulations (PPFs), which can also differ in composition from one Member State to another, the number of commercially available PPFs cannot be precisely estimated but is almost certainly larger by magnitudes than the number of active substances.
The primary route of exposure to pesticides for the general population is ingestion of food products that might be contaminated with residues of, for example, insecticides, herbicides or fungicides sprayed on the crops. PPFs are not only used in agriculture but also in public applications and domestically that provide additional routes of exposure for citizens, mainly through inhalation and direct skin contact. Moreover, all exposure pathways can affect workers, primarily pesticide handlers. It is well recognized that some pesticides can produce acute and chronic side effects in individuals when exposed, such as impairment of the central or peripheral nervous system, (neuro)endocrine effects, altered metabolic and reproductive functions, or even mutation and cancer (Mostafalou and Abdollahi, 2017).
PPFs are typically cocktails of one or more active ingredients and other substances that have no direct biocidal action, therefore labelled as “inerts”, “adjuvants“ or “co-formulants”. These other substances are added to the active ingredient in order to improve its dissolution, stability, absorption and pesticidal action of the active ingredient (Cox and Surgan, 2006). The main co-formulants are surfactants, including the most common non-ionic surfactants, such as ethoxylated alkylphenols, which increase the solubility of the active ingredient by forming micelles and protect it from natural degradation (Cserhati, 1995). Organic and inorganic solvents can also be used to boost the mobility of the active ingredient (Yusoff et al., 2016). The necessity of adding adjuvants depends on the physicochemical properties of the active ingredient, as well as on the state of the product formulation (suspension concentrate, solution, wettable powder, granules, etc.). The presence of adjuvants may not only promote the penetration of the active ingredient into the target organism, but also into the skin of exposed individuals. On the other hand, the supposedly “inert” adjuvants can have biological activity on their own and may be just as or even more toxic to humans than the active pesticide ingredients, or the components might have synergetic effects (Cox and Surgan, 2006). According to the US Environmental Protection Agency, it is expected that “on the order of 50% of inert ingredients would be of low or low/moderate risk” (U.S. EPA, 2002). Nonetheless, in the recent past, the exact composition of pesticide products and the identity of other ingredients in these formulations were often undisclosed because producer companies were not obligated by law to give out information on other ingredients to consumers, unless they intrinsically bore a hazardous potential to human health or to the environment. The hazards and related risks of PPFs were assessed by the toxicity of the active ingredient, largely neglecting the potential harm of other components and/or the possible combined effects of mixtures. Furthermore, formulations are not appropriately assessed since dose-dependent effects and the environmental fate of the formulants prior to reaching recipient's non-target receptors are not usually taken into account. Currently, the EU limits the amount of active ingredients of pesticides allowed in food or water; however, concerns are increasing that analysing the individual ingredients and only limited number of formulations does not provide sufficient information on the potential spectrum of health effects of the widely diverse PPFs and that the interactions of ingredients should be addressed in a more systematic way to allow for effective protection of human health.
To the best of our knowledge, no systematic review has been carried out to assess whether PPFs pose greater health risk than their active ingredients. Therefore, the objective of this review was to give an overview on the literature of in vitro and in vivo studies that simultaneously examine the toxicity of PPFs and their declared active ingredients to identify the possible differences in their toxicity to human health and to the environment.
Section snippets
Research question
A PECO (population, exposure, comparator, outcome) statement was developed to address and understand potential differences in the toxicity of PPFs and their declared active ingredients on human health and on the environment (Table 1).
Identification of studies
PubMed and Scopus electronic databases were systematically searched on July 08, 2019 to identify studies from the past four decades comparatively assessing, in some way, the adverse health effects of active pesticide ingredients and their product formulations. The
Identification of eligible studies
The process of the search is presented in a PRISMA flow diagram (Fig. 1). Our initial database search yielded 1094 studies, of which 37 met the inclusion and exclusion criteria after removing duplicates. No additional records were identified by hand-searching reference lists. Full texts of two studies were not available despite contacting the authors. The included studies were submitted to reliability and quality assessment. According to the Klimisch categories of ToxRTool, one study received
Discussion
In this systematic review, 36 studies have been identified dealing with the evaluation of the toxicity of product formulations compared to active ingredients. Among which, 24 studies found that at least one pesticide product formulation possesses higher toxicity than its corresponding active ingredient. Only 8 studies reported reduced toxicity of PPFs, which might be due to a potential antagonistic effect of the co-formulates and the active ingredient. Even if not all the active ingredients and
Conclusion
The results of this review suggest that the toxicological hazards posed by complex chemical mixtures such as formulated pesticide products should not be underestimated. For instance, we could highlight from the reviewed articles that glyphosate formulations can exert more pronounced cytotoxic and endocrine disruptive effects compared to that of pure glyphosate. Thus, ignoring the possible risks deriving from the interaction between the active and other ingredients of a commercial pesticide
Funding sources and ethical statement
The study was carried out with the support of the Diagnosis, Monitoring and Prevention of Exposure-Related Noncommunicable Diseases (DiMoPEx) COST Action project (CA15129). The contribution of Szabolcs Lovas was supported by the EFOP-3.6.1-16-2016-00022 “Debrecen Venture Catapult program”.
Declaration of conflict of interest
None.
Acknowledgments
This project is part of the EU Cost Action, CA 15129 (DiMoPEx) which is supported by the EU Framework Program Horizon 2020.
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The first two authors contributed equally to this work.