Suggested Corrections to the Farm Family Exposure Study

Referencing: Glyphosate Biomonitoring for Farmers and Their Families: Results from the Farm Family Exposure Study

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Acquavella et al. (2004) reported glyphosate exposure analyses from the Farm Family Exposure Study (FFES) using biomonitoring. The authors "analyzed urine samples for creatinine to assess the completeness of daily samples," but inadvertently used as "the normal range" 0.8–1.4 mg/dL and 0.5–1.1 mg/dL for males and females, respectively, which are the normal ranges of serum creatinine [National Institutes of Health (NIH) 2003]. The NIH normal values for urine creatinine are 24-hr total excretion values ranging from "500 mg/day to 2000 mg/day" (NIH 2006). Thus, Acquavella et al. (2004) needed to compare the 24-hr creatinine collection (urine creatinine concentration urine volume) to each individual's normative value of daily creatinine excretion based on age, sex, and body surface area (Cockcroft and Gault 1976).

Acquavella et al. (2004) also did not correct for the initial conditions. Of 47 farmers, 7 had 24-hr urinary glyphosate concentrations above the minimum detectable value of 1 ppb immediately before the start of their application. Such a farmer who had zero exposure during the monitored application would have excreted glyphosate over the following 4-day collection period in an amount estimable from the measured individual excretion rates. For a truly unexposed applicator to be shown to have a dosage statistically similar to zero, this estimated total 4-day excretion with zero exposure must be subtracted from the 4-day collection value.

In addition, Acquavella et al. (2004) evaluated one application per family and called it only a "potential limitation," without realizing that this may vitiate their study. If all 47 FFES subjects with complete data had an identical exposure distribution, any single applicator sampled 47 different times would have an expectation of presenting exposure data with a statistically similar mean and variance as the FFES 47 sampled only once each. Therefore Acquavella et al. (2004) cannot reject the possibility that all 47 applicators have a similar exposure distribution by taking only one sample from each. This is because an applicator's pesticide exposure is a stochastic process (accidents happen) that varies wildly from day to day, unlike the applicator's weight that is a relatively constant process that barely varies from day to day. Therefore a single measured exposure provides no statistical information for estimating the applicator's mean exposure over any time period other than the day measured. Furthermore, farmers' pesticide exposures are not results of a stationary process, (defined as a time series in which the mean and variance of measured exposures, over a sufficiently long period from time 1 to time 2, are constants independent of choice for time 1). In an earlier study, we (Mage et al. 2000) successfully modeled the risk of accidental high pesticide exposure events in the Agricultural Health Study population as decreasing with the increasing lifetime number of application days. As one might expect, we showed that as an applicator gains experience, the risk of high exposure decreases. Therefore differences in lifetime experience of the FFES applicators prior to sampling introduce another variance component into the analysis.

In conclusion, Acquavella et al. (2004) treated a single sample at the end of a nonstationary time series—with declining mean and finite variance—as if it were actually the true mean value of a stationary process with zero variance. I recommend that Acquavella et al. (2004) consider revising their analyses by correcting properly for incomplete urine collection, correcting for the initial condition of prior glyphosate exposure, and adjusting for the experience of the applicator (lifetime number of application days) as an explanatory variable.

The authors declare they have no competing financial interests.

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The Farm Family Exposure Study: Acquavella et al. Respond

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We thank Mage for his comments. In our article on glyphosate in the Farm Family Exposure Study (FFES) (Acquavella et al. 2004), we used 24-hr urinary creatinine to assess the completeness of daily samples over 5 days for the 48 participating farmers. We erred by summarizing the results as micrograms per deciliter instead of micrograms per day. Using an expected daily excretion of 566 µg/day as the lower end of the normal range (Bingham et al. 1988; Forman 2003), only four 24-hr urine samples over 5 days were below that lower limit. Therefore, the completeness of urine collection for the applicators was exceptional. Further details of the urine collection and our assessment of completeness can be found in a related article (Baker et al. 2005).

Mage criticizes us for not subtracting preapplication urine values in our assessment of systemic dose related to on-study applications. Indeed, seven of the applicators had detectable glyphosate in their urine on the day before their on-study application (Acquavella et al. 2004). Values were 1.1, 2.6, 3.9, 5.3, 8.3, 9.8, and 15.4 ppb. We intentionally did not correct for these initial values for two reasons. First, from an epidemiologic and public health standpoint, it is instructive to know the total dose for farmers during and after an application, which, for example, could then be compared to levels of toxicologic significance. Second, the overestimate caused by this practice is trivial for glyphosate in both an absolute and relative sense. Consider that glyphosate has a U.S. Environmental Protection Agency (EPA) reference dose of 2 mg/kg/day (U.S. EPA 1999), and the highest systemic dose we estimated in our study was 0.004 mg/kg/day. The requested corrections would be to the ten thousandths of a milligram per kilogram per day or less.

Last, Mage calls the fact that we only evaluated one application per farm family a limitation that may vitiate our study. That is a strong indictment for a study that comprehensively assessed exposure for farm families related to a single application of three pesticides to an extent not seen before. We agree that characterizing intraperson variation in absorbed pesticide dose over several seasons would provide valuable information, but that was not the objective of the FFES. Nevertheless, Mage's claim that we cannot reject the possibility that all 47 applicators have the same exposure distribution is refuted by our observations that absorbed dose was related to specific practices (e.g., not wearing gloves) and by similar findings in the literature that practices dictate absorbed dose (e.g., Arbuckle et al. 2002).

At the time of this research, J.A. was an employee of Monsanto, the company that manufactures glyphosate; C.G. is currently employed by Monsanto. The Farm Family Exposure Study was funded by a contract between the FFES Industry Taskforce and the University of Minnesota; B.A. and J.M. received research support under that contract.

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