Food Quality Protection Act of 1996: A New Challenge for Data

Chapter 20

Food Quality Protection Act of 1996: A New Challenge for Data Generation and Submission

Downloaded by MONASH UNIV on May 21, 2018 | https://pubs.acs.org Publication Date: August 1, 2002 | doi: 10.1021/bk-2002-0824.ch020

W. T. Beidler and L . D. Bray Syngenta Crop Protection, Inc., 410 Swing Road, Greensboro, NC 27419

The Food Quality Protection Act of1996has fundamentally changed the procedures used to assess the safety of U.S. food tolerances. The new requirements for aggregate and cumulative risk assessments alone create a huge data deficiency and hence an urgent need for real world data on exposure from all plausible pathways including dietary, water, and residential. Tremendous amounts of useful information are already available from various sources, but the data must first be organized into linked data bases in order to conduct assessments which are coherent in terms of the demographic, temporal and spatial factors. In many cases, the requisite data simply do not exist. The results of a market basket survey designed to fill an existing FQPA data gap will be presented. The market basket survey typifies the kind of studies that will be necessary to support pesticide registrations in the future.

© 2002 American Chemical Society

Garner et al.; Capturing and Reporting Electronic Data ACS Symposium Series; American Chemical Society: Washington, DC, 2002.

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152 The Food Quality Protection Act of 1996 is the most important and complex environmental legislation promulgated by Congress in the last twenty years. The FQPA, which amended both FIFRA and FFDCA, passed both houses of Congress unanimously with virtually no debate. On August 3, 1996, the day the President signai the Act, all pesticide tolerances immediately became subject to the more stringent safety standard and data requirements embodied in the FQPA language. At the core of the new safety standard is a fondamental change in the definition of "safe" as it relates to pesticide exposure. Under FIFRA, prior to FQPA, a pesticide registration was considered safe if the legal use resulted in no unreasonable adverse effect on the environment or to human health. Subsequent to FQPA, a pesticide use will be considered safe only if it can be established that there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residues, including all anticipated dietary exposures and all other exposures for which there are reliable information. The requirements of the FQPA will result in major changes in the future development of pesticide safety profiles. Examples of the most important and complex new requirements include: assessment of aggregate risk (diet, water, and residential exposure for one chemical), assessment of cumulative risk (combining aggregate exposures for all pesticides sharing a common mechanism of toxicity), assessment of acute exposure (early risk assessments focussed on chronic exposure only), testing for endocrine effects (direct or indirect hormonal changes), and increased safety margins between exposure and toxicity (additional safety factors to account for a possible enhanced susceptibility to children). These new requirements trigger comprehensive risk assessments for all uses and based on the outcome, additional studies may be necessary. In addition, the FQPA stipulates that all current tolerances are to be reassessed within ten years with thefirstthird completed by August 1999, the second third in August 2002 and the remainder by 2006. The EPA was successful in completing the first round of reassessments, which resulted in approximately 1500 tolerance revocations. However, almost all of the revocations (1248) were for tolerances on unsupported uses (voluntary cancellations on the part of the registrant). Very few tolerance revocations were based upon the conclusions of risk assessments performed in compliance with the foil mandate of FQPA. A hallmark of the Clinton Administration has been the protection of the nation's children. The FQPA codified this theme by requiring that an additional ten-fold margin of safety shall be applied for infants and children to take into account potential pre- and post-natal toxicity and completeness of the data generated with respect to exposure and toxicity to infants and children. The statute goes on to state that notwithstanding such a requirement the



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Administrator may use a different margin of safety it on the basis of reliable data, such margin will be safe for infants and children. The FQPA safety actor consideration creates a number of fundamental and serious issues for the pesticide industry, as well as the chemical industry as a whole. First, what constitutes a reliable database for making a determination of children's susceptibility and how should studies be conducted and interpreted for the evaluation of susceptibility. Second, since much of the needed information is not now available (particularly in the area of exposure) what safety factor, if any, should be applied in the interim while data are under development. Third, how does the added safety factor designated for an individual chemical translate in the derivation of safety factor tailored for an entire class of chemicals with a common mechanism of toxicity (cumulative risk assessment). In order to address these questions, EPA established a 10X-Safety Factor task force in March of 1998. The task force recommended expansion of the core toxicology guideline requirements to include immunotoxicity studies in the rat as well as an in vitro system, developmental neurotoxicity, and acute and subchronic neurotoxicity studies. Also discussed by the task force in connection with fully evaluating the issue of infant toxicity were the following studies: pharmacokinetics in fetuses, direct dosing of offspring, enhanced developmental neurotoxicity tests (specialized testing of sensory and cognitive fonction), developmental immunotoxicity, developmental carcinogenicity, and potential endocrine induction effects. In addition to these newly required studies and the potential future studies related to hazard evaluation, there is also an urgent need for exposure data, particularly with respect to children. The number and complexity of the newly required studies and related information will certainly create a demand on the current methods of data generation, data handling, and reporting of data, FQPA directs, as part of the reassessment process involved with the establishment, modification, or revocation of a tolerance, that EPA should consider all available information regarding the cumulative effects of pesticides that have been demonstrated to have a common mechanism of toxicity. Several independent scientific panels have concluded that the organophosphates pesticides (OPs) belong to a class of compounds which cause the same critical effect, act by the same molecular mechanism, act on the same molecular target and thereby share a common mechanism of toxicity (inhibition of acetylcholinesterase). Due to a combination of factors, including the common mechanism determination, the demonstrated acute toxicity, and the relative abundance of historical data, the OPs have been the focus of FQPA implementation effortsfromthe outset. Accordingly, most of the aggregate and cumulative risk assessment methodologies currently in place were developed and validated with OPs as the model.



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Recognizing the need for industry to play a significant role in the development of methodology to accomplish the FQPA assessments, representativesfromsix companies agréai on a collaborative effort to conduct a multiple compound cumulative assessment using a small group of OPs as the case study. The chemicals chosen for the case study were chlorpyrifos, diazinon, azinphos-methyl, acephate, and malathion which collectively represent over 500 tolerances of the approximate 1500 tolerances established for all OPs. The six-company task force, known as the OP Case Study Group, has met on a regular basis throughout 1998 and 1999 with a focused effort toward advancing the science of the aggregate and cumulative risk assessment process. The Case Study divided into four sub teams which focused on the following areas of the risk process: use and usage, dietary, non-dietary, water, and toxicology. As stated above, the initial objective of the Case Study Team was to conduct an aggregate and cumulative risk assessment for the registrant's OPs. It became apparent early in 1998 that adequate methodology was simply not available for assessing risk per the FQPA mandate so thefirsttwo years of effort were devoted to method development. The key accomplishments of the Case Study subteams are discussed below. The initial objective of the non-dietary subteam was to develop an exposure assessment software tool to estimate exposures from residential uses of pesticides. Thefinalwork product, an Excel-based spreadsheet called REx, can be used to calculate exposures to individuals applying pesticides in and around the home. The software can also calculate the exposure to adults and children re-entering pesticide treated lawns, gardens, and homes. REx can aggregate exposure from all routes (oral, dermal, inhalation) for multiple exposure scenarios and can be employed for both deterministic point estimates of exposure and probabilistic estimates of exposure when linked to a statistical program such as Crystal Ball. The water sub team has completed two major projects. The first project involved an exhaustive survey of the existing inventory of historical occurrences of the five Case Study OPs in U.S. waters during the period 1990 to 1997. The data sources included state lead agencies responsible for enforcing the Safe Drinking Water Act compliance monitoring program, the U.S. Geological Survey (USGS) National Water Quality Assessment program (NAWQA), EPA's Water Quality Information System (STORET) water database, universities, and a literature search. Thefinalreportfromthis survey collated 114,529 individual analytical results for finished drinking water (27,300 samples) and imfinished/non-drinking water (87,299 samples). In addition to the retrospective analysis of historical water data, the subteam developed a protocol for the prospective monitoring of drinking water. During 1998 a multiresidue method was developed to detect the five OPs and corresponding oxygen analogs at levels of 0.050 ppb. Samples of finished



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water were taken weekly during pesticide use periods and monthly at other times for a period of 12 months. Community water systems (CWS) originating from surface water in areas with an OP use history were targeted for the study. A total of 44 C WSs participated in the study. It should be emphasized that all of the participating water supplies were very likely to drawfroma water source exposed to runoff from agricultural and urban use of the specific OPs. The finalized study report details the resultsfroma total of 1,115 samples analyzed for ten active ingredients and accompanying metabolites (22,300 individual analytical determinations). The dietary subteam has explored several areas of the risk assessment process focusing primarily on development of a probabilistic cumulative acute dietary exposure estimate for five OPs on a limited number of crops. Since there is virtually no existing data on co-occurring residues on individual samples, industry currently relies upon compliance monitoring datafromFDA and market basket data generated by USDA from its ongoing Pesticide Data Program (PDP). However, nearly all of the data on real world residues are for composited samples. In order to use the composite data in an acute dietary assessment, the residue information must first be statistically decomposited transforming the distribution of composite values into an estimate of the underlying single-serving residue distribution. The dietary subteam has developed a new statistical procedure called MaxLIP (Maximum Likelihood Imputation Procedure) which uses maximum likelihood estimation and Monte Carlo simulation to impute thefrequencydistribution of single-serving residue concentrations from a distribution of composite residue concentrations. The procedure was validated by a peach study conducted by Novartis Crop Protection. In the study, an orchard was treated with diazinon and 200 peaches were randomly sampled. Each peach was extracted with solvent and analyzed individually. Aliquots of each solvent extract were also combined to form a composite extract that was also analyzed. (The 200 peaches were randomly combined into 20 composites.). The 20 composite values were provided to the authors of MaxLIP and a blind imputation of the single-serving residue distribution was performed. The distribution of the imputed single-serving residues and the distribution of the actual measured single-serving residues matched closely. Another inter-industry coalition was founded for the purpose of addressing specifically the issue of OPs in the food supply. The Qrganophosphate Market Basket Survey Task Force (OPMBSTF) was organized in 1998 for the purpose of assessing organophosphate pesticide residues in the nation's food supply. The task force (comprised of seven pesticide registrants) designed, funded, and conducted the project in collaboration with a third party Study Director, a Principal Investigator (responsible for the statistical design, data handling and reporting), andfivecontract analytical laboratories. Sample collection began in



156 January 1999 and continued for 12 months. The objective of this study was to determine the distribution and incidence of OP residues on single unit serving sizes (e.g., apples and peaches) and multiple unit serving sizes (e.g., grapes and green beans) commodities with a focus on foods commonly consumai by children. The commodities were sampledfromretail grocery stores and were prepared prior to analysis as they would be prior to consumption (e.g., apples were washed and cored, cucumbers were washed with one inch removed from each end, oranges were washed and peeled, etc.). A multiresidue analytical procedure was developed capable of detecting a total of twenty two active ingredients and twenty three toxicologically relevant metabolites. However, only those OPs with tolerances supported by a registrant on a specific crop were included in the analytical procedure for that crop. The limit of quantitation (LOQ) for each analyte was predetermined to be 1 ppb using gas chromatography withflamephotometric detection (GC/FPD) in the phosphorous selective mode. The limit of detection (LOD) was statistically determined for each analytical run and for each analyte. All detects above the LOQ were confirmed by either mass spectrometry (GC/MS) or GC/FPD using a column with different polarity than the primary column. Residues between the LOD and the LOQ were designated as trace. Upon evaluation of confirmation/de-confirmation results conducted on samples with quantifiable residues, it became evident that a potentially large percentage of trace samples may have infeetbeen false positives, as was observed with the quantifiable residues. Consequently, a Trace Confirmation Analysis (TCA) program was incorporated into the study design to evaluate the relative occurrence of false positives among trace detects. Twenty samples of each of thirteen commodities were sampled every two to three weeks (total of 25 shops) with a target of 500 individual samples per commodity over the one-year period. An A and Β replicate was taken at each sampling, so a total of nearly 13,000 samples were coded and tracked through the final report phase. Samples of the thirteen commodities were purchased from approximately 500 different locations throughout the contiguous United States. The sampling phase of the study employed a stratified systematic sampling protocol, which was statistically designed to assure sampling from retail stores that would be most representative of the nation's food supply. The stratification took into account such factors as geographical location, urban/rural nature of the surrounding population, and the size of the retailer. Each of the analytical contract laboratories was assigned the analytical responsibility for three or four specific commodities throughout the course of the project. An Excel spreadsheet "workbook" was developed specifically for use by all of the laboratories. The workbook was comprised of worksheets for each analyte and included entryfieldsfor sample code, initial injection volume, subsequent dilution volumes, second column confirmation, GC/MS



157 confirmation, and all other information necessary to correlate an individual single-serving sample and corresponding analytical results. The workbook was structural such that each parameter would only be enteral once to minimize the potential for data entry errors. As data were generated, the individual laboratories completed a preliminary internal QA/QC of the results. Preliminaryfindingswere reported to the Study Director for a "spot check" conducted by comparing verified chromatograms with the raw data. After verification by the Study Director, a locked version of the results was forwarded to the Principal Investigator, where data were uploaded into separate commodity files. During the upload, an automated QC routine was performed to check for formatting and data entry errors. Finally, master files for each commodity were developed which contained all of the residue information for all 500 samples. From the master files for each commodity, a summary file was compiled. The compilation of this summary file employed MACROS which perform summary statistics for various report formats and includes outputs like % trace, % non-detects, % greater than LOQ, minimum/maximum, average, and standard deviation. Throughout the entire course of the study an independent QA auditor conducted running QA/QC of the raw data. The auditor also performed quarterly in-life phase audits and assumed responsibility for thefinalreport audit. Upon completion of the project, the OPMBSTF will have generated a total of approximately 130,000 individual analytical results, stemmingfromnearly 250,000 analyses (i.e., dilutions, re-analyses, etc.). These data can be used to estimate the cumulative exposure to OP residues on the thirteen commodities chosen for the study as well as commodities similar in nature (surrogation). The chromatogramsfromjust one single shop (20 samples of each commodity) constitute a stack of paper four linear feet in height and the total chromatogram volume for the entire study amounts to about 700 cubic feet. All of the data will be submitted to the EPA on CD's and include all workbooks. Hardcopies of representative chromatograms will be provided for half of one shop (ten samples of each commodity). (Electronic versions of the chromatograms will not be submitted to the EPA.) The paper raw data will be permanently archived in limestone caverns in Hutchinson Kansas. The previous examples of the FQPA-inspired joint scientific efforts represent just a small portion of the total effort on the part of both EPA and the pesticide industry to folly interpret and implement the Food Quality Protection Act. As implementation proceeds, the requirements for supporting the registration of individual compounds have continued to expand as science policies evolve in the various risk assessment areas. Also, the need to generate simultaneous cumulative data on entire classes of chemistries, as in the examples for the OPs discussed above, will present a challenge for data capture and reporting in the future.


Food Quality Protection Act of 1996: A New Challenge for Data

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