Systematic review of comparative studies assessing the toxicity of pesticide active ingredients and their product formulations.

Humans are exposed to complex chemical mixtures, such as pesticides. Although the need for the assessment of health and environmental hazards deriving from the interactions between various substances found in commercial pesticide formulations is becoming increasingly recognized, the approval of pesticide products is still mostly limited to determining the toxicity of the individual ingredients ignoring the possible combined effects in mixtures. The objective of this study was to systematically review the literature of in vitro and in vivo studies that simultaneously examine the toxicity of pesticide product formulations and their declared active ingredients to compare their toxicity to human health and to the environment. Two electronic databases were searched for studies that assessed the health effects of active pesticide ingredients and their product formulations. The literature search was performed with a combination of the following terms: "pesticide", "formulation", "commercial product", "commercial pesticide" and "health". After screening by predefined inclusion and exclusion criteria, quality and reliability assessment of eligible publications was conducted by use of the ToxRTool. Two investigators independently screened the identified publications and extracted results from eligible studies. Our search yielded 36 toxicity studies; 23 studies investigated herbicides, 15 examined insecticides and 4 focused on fungicides. Twenty-four studies reported increased toxicity of the product formulations versus their active ingredients, which, in most cases, were attributed to the presence of adjuvants in the formulations. A significant number (n = 10) of studies focused on the comparative testing of glyphosate and glyphosate-based herbicides, and six of them concluded that Roundup, the dominant product formulation of glyphosate, is more toxic than the active ingredient alone. We identified only 8 studies demonstrating reduced toxicity of product formulations in relation to the active ingredient that might be due to a potential antagonistic effect between the constituents. The results of this review demonstrate the inadequacy of current EU testing requirements for assessing the health hazards of pesticide product formulations based mainly on the evaluation of the individual ingredients and of at least one representative use and formulation. Ignoring the possible risks deriving from the interaction between the active and other ingredients of various commercial pesticide product formulations might result in the misinterpretation of its toxicological profile. At EU level efforts are currently made to address this issue. In this context, we recommend that all product formulations should be fully assessed during the authorization process.