Table 4.

GEP Criteria for Assessing Dietary Exposures to Pesticides Using Environmental Sampling and Questionnaires/Interviews/Record Review.

Category	Criteria for Causal Inference and Quantitative Risk Assessment	Comments
Residue in Food (Environmental Sampling)
Study Protocol and QA/QC Procedures	An a priori protocol/study plan is required, including reference to a thorough Standard Operating Procedure (SOP) that details sampling protocols and addresses internal quality control. The protocol should include all the details regarding the design and implementation of the study. Any deviations should be noted. While all details of the protocol will not be included in a journal article, the documents should be available on request and submitted for any studies being considered for pesticide registration and policy-making.	▪Formal quality programs may be followed, such as the International Organization for Standardization (ISO). See WHO [17] guidance for further information. ▪In total diet studies (TDSs), the necessary processing and preparation of foods creates a risk of contamination or chemical losses; as such, QA methods are particularly important for these types of studies [32].
Representative Food Sampling	The selection of foods for sampling must include all types of foods that are generally consumed to assess total dietary exposure. Several batches or lots of each food must be sampled to determine the ranges of residue levels. Alternatively, bulk samples from multiple batches/lots can be used to assess average pesticide residue levels. If relying on existing samples (e.g., a market basket food survey, FDA pesticide residue monitoring program), the researchers must verify that the food sampling meets the criteria outlined here. When using a market basket (MB, also known as a TDS approach), the researcher must follow general guidance outlined by WHO et al. [33], which includes specifications for sampling and processing methodology.	▪See WHO et al. [33] for further information.
Validity and Reliability of Sampling	Exposure assessed via the same methods and within the same timeframe across all groups. Samples collected under controlled conditions; contamination assessed (e.g., via blanks analysis). Contamination from storage materials, the matrix (e.g., external contamination on toenail samples), and other sources fully considered and controlled via equipment selection, cleaning, etc. All glassware, reagents, organic solvents, and water should be checked for possible interfering contaminants. For MB or TDS methods, preparation and analysis of food as consumed is critical because preparation techniques, including peeling, washing, and heating, affect pesticide levels.	▪With regard to timeframe, while not all samples will necessarily be taken at the same time (e.g., studies with rolling enrollment), the researcher must evaluate whether pesticide concentrations may have changed over time (e.g., due to environmental degradation, changing pesticide use) and assess how any changes may impact results. For biological samples that are time-varying (within a person) due to chemical metabolism or other factors, particularly within a single day or across weeks, the researchers must assess and either standardize sample collection across participants or adjust/stratify results to account for differences. ▪In instances where timing affects results, stratification or other methods for evaluating inconsistencies across measures may be utilized [3]. ▪For MB and TDS methods, consult guidance by WHO et al. [33] and FDA [34,35].
Specificity	Metric is specific to the exposure of interest. The residue measured must be the parent compound of interest or a toxicologically relevant metabolite/degradation product that represents an internal dose that is well correlated with external exposure.
Sensitivity	Metric is sensitive (i.e., measurable down to a limit of detection that is low enough to estimate the chemical in a sufficient percentage of the samples to inform the causal or research question). There must also be high confidence in the ability of the instruments used to provide the needed level of sensitivity.	▪For TDS/MB surveys, pooled samples are usually used. Chemical concentrations may be altered in a pooled sample (concentrated or diluted). Therefore, the analytical methods used must be of a higher sensitivity compared with those used for food compliance monitoring.
Validity and Reliability of Analytical Methods	The analytical test methods must be suitable for the food type (e.g., raw food versus processed food, consideration of lipid/water content of the food) and the substance of interest. The analytical test methods have been validated (e.g., by assessment of repeatability within a laboratory and reproducibility of the method at multiple laboratory sites). In the case of a novel test, sufficient information must be provided regarding the within-laboratory validation, and any uncertainties should be discussed. Validity should be assessed via intraclass correlation coefficient (ICC) or similar assessment.
Number of Samples and Replicates	Ensure there are a sufficient number of total samples for the specific detection limit and/or to achieve sufficient power for the necessary statistical analysis. For screening TDS surveys, 20–30 samples may be sufficient. For refined analyses, as many as 200–300 samples may be needed [33]. A sufficient number of replicates per sample is required to ensure data validation and assessment of data variability.	▪See WHO et al. [33] for further information.
Consideration of Matrix Effects	Adjust exposure estimate, as needed, based on the matrix. Both adjusted and un-adjusted concentrations and results should be reported.	▪For example, measurement in food using Liquid Chromatography-Mass Spectrometry (LC-MS) is complicated by compound and matrix-dependent response suppression or enhancement, otherwise known as matrix effect (see Niessen et al. [25]).
Sample Storage and Stability	Verify the stability of the pesticide residue in the samples, given the matrix, storage conditions, and duration of storage. Samples may have some known losses, but differences between low and high exposures can be assessed.	▪Stability of the substance of concern (e.g., the pesticide residue) in fresh or stored food must be verified. For example, recovery analysis using spiked samples should be employed or established prior to analysis. Storage conditions and duration should be reported.
Reporting Requirements	SOPs and the study protocol should be made publicly available. Details regarding the consideration and fulfillment of the above criteria (e.g., all sample collection, handling, processing, and storage; evidence of sample stability; analytical methods; method sensitivity, specificity, validity, and reliability; and QA/QC procedures) should be reported. Any deviations from the SOP/protocol and justifications for such deviations should be reported. While some of these details may need to be omitted for peer-reviewed publication, the information should be provided in supplemental material or made available upon request.
Food Consumption (Questionnaires, Interviews, Record Review)
Study Protocol	An a priori study protocol must include standard and detailed specifications for developing questionnaires (or using validated questionnaires) and conducting interviews; training personnel; extracting, coding, and processing data; keeping records and storing data; and quality assurance (QA) and quality control (QC) procedures that minimize the potential for bias and human error.
Exposure Window	1.The exposure metric should be assessed in the time period during which the exposure could have effects relevant to the outcome of interest. The selection of the exposure window should consider induction and latency and should be based on biological and clinical pathways.	▪Not applicable to case-control studies. For a developmental endpoint (e.g., congenital heart defects), the exposure metric should capture the exposure that occurred during the period of fetal development associated with that effect (e.g., fetal cardiac development). For cancer, the exposure must precede the diagnosis by a sufficient period of time (typically, at least 10 years).
Time Integration	The assessment of dietary intake should aim for habitual or long-term consumption of foods. For 24-hour dietary recall and food diaries, a sufficient and representative number of days should be used to estimate habitual consumption.	▪Because pesticide residues are typically present in foods at very low concentrations, long-term cumulative or cumulative average exposures are generally the most relevant metrics for any potential health effects. ▪For 24-hour recall and food diaries, multiple days are needed to sufficiently capture temporal variations in diet (e.g., week days vs. weekends; seasons).
Study Population	The study population should be representative of the target population with regard to the consumption distribution (i.e., include the range of consumption).
Design of Self-administered and Interview Questionnaires	The questions should clear and simple so as to avoid ambiguity and enhance recall. The questions should be sufficiently comprehensive and detailed to address specific research questions. For quantitative risk assessment, the questions should capture ordinal or semi-quantitative exposure information.	▪For 24-hour dietary recall, the interviewer should probe for information on food types, preparation methods, portion sizes, etc. ▪Self-administered questionnaires should include foods generally consumed and culturally specific to the target population. The questionnaires should also include questions regarding consumption behaviors (e.g., frequency, preparation methods, and portion size).
Blinding	Blinding of study participants and researchers should be implemented, if possible, to reduce the potential for information bias. Particularly for retrospective studies, exposure must be assessed independently of outcome.	▪The study participants should be blinded to the specific research question (i.e., the foods/pesticides of interest). ▪For retrospective studies, the person(s) conducting the interviews or reviewing questionnaires/records should be blinded to the outcome status of the study participants, if possible.
Validation of Dietary Assessment Methods	Dietary records/food diaries are the gold standard for dietary assessment. Food frequency questionnaires and 24-hour dietary recalls should be validated against dietary records.	▪Study participants should undergo training to ensure their dietary records are properly conducted and can provide robust information on food consumption.
Reporting Requirements	The study protocol should be made publicly available. Details regarding personnel training and credentials, questionnaire development, computer software employed, data extraction and processing, and methods used to estimate exposure should be reported. Any deviations from the study protocol and justifications for such deviations should be reported.

FDA = Food and Drug Administration; GEP = Good Epidemiology Practice; QA/QC = Quality Assessment/Quality Control; WHO = World Health Organization; Underlining indicates criteria that are needed for quantitative risk assessment.