ABSTRACT
BACKGROUND: The gradual increase in the global population has led to the rising demand for agricultural products worldwide. This required the introduction of environment- and public health-friendly advanced technologies for plant protection to guard yields from pest destruction in a sustainable way. Encapsulation technology is a promising procedure to increase the effectiveness of pesticide active ingredients while reducing human exposure and environmental impact. Despite the presumed favorable properties of encapsulated pesticide formulations on human health, it is necessary to systematically assess whether they are less harmful to human health than conventional pesticide products. OBJECTIVES: We aim to systematically review the literature to answer the question of whether micro- or nano-encapsulated pesticide formulations exert different degrees of toxicity than their conventional (not-encapsulated) counterparts in in vivo animal and in vitro (human, animal, and bacterial cell) non-target models. The answer is important to estimate the possible differences in the toxicological hazards of the two different types of pesticide formulations. Because our extracted data will come from different models, we also aim to perform subgroup analyses to investigate how toxicity varies across different models. A pooled toxicity effect estimate will also be performed by meta-analysis when appropriate. METHODS: The systematic review will follow the guidelines developed by the National Toxicology Program's Office of Health Assessment and Translation (NTP/OHAT). The protocol adheres to the Preferred Reporting Items for Systematic Reviews and meta-analyses Protocol (PRISMA-P) statement. PubMed (NLM), Scopus (Elsevier), Web of Science Core Collection (Clarivate), Embase (Elsevier), and Agricola (EBSCOhost) electronic databases will be comprehensively searched in September 2022 to identify eligible studies using multiple search terms of "pesticide", "encapsulation" and "toxicity" along with their synonyms and other words that are semantically related. The reference lists of all eligible articles and retrieved reviews will be manually screened to identify additional relevant papers. ELIGIBILITY CRITERIA: We will include peer-reviewed experimental (non-target in vivo animal model and in vitro human, animal, and bacterial cell cultures) studies published as full-text articles in English language that simultaneously investigate the effect of any micro- or nano-encapsulated pesticide formulation, applied in all ranges of concentrations, duration, and routes of exposure, and its corresponding active ingredient(s) or its conventional non-encapsulated product formulation(s) used in the same ranges of concentrations, duration, and routes of exposure on the same pathophysiological outcome. We will exclude studies that examine pesticidal activity on target organisms, cultures of cells isolated from target organisms exposed in vivo or in vitro, and those using biological materials isolated from target organisms/cells. STUDY APPRAISAL AND SYNTHESIS: Studies identified by the search will be screened and managed according to the review inclusion and exclusion criteria in the Covidence systematic review tool by two reviewers, who will also blindly extract the data and assess the risk of bias of included studies. The OHAT risk of bias tool will be applied to evaluate the quality and risk of bias in the included studies. Study findings will be synthesized narratively by important features of the study populations, design, exposure, and endpoints. If findings make it possible, a meta-analysis will be performed on identified toxicity outcomes. To rate the certainty in the body of evidence, we will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.