Copyright © 2005 by the Johns Hopkins Bloomberg School of Public Health
LETTERS TO THE EDITOR |
RE: "CANCER INCIDENCE AMONG PESTICIDE APPLICATORS EXPOSED TO ALACHLOR IN THE AGRICULTURAL HEALTH STUDY"
1 Department of Epidemiology, University of North Carolina School of Public Health, Chapel Hill, NC 27599-7435
2 Yale Occupational and Environmental Medicine Program, Yale University School of Medicine, New Haven, CT 06510
3 Molecular Toxicology and Environmental Health Sciences Program, University of Colorado Health Sciences Center, Denver, CO 80262
4 Monsanto Company, St. Louis, MO 63167
In a recent Journal article, Lee et al. concluded, "Our findings suggest a possible association between alachlor application and incidence of lymphohematopoietic cancers among applicators in the Agricultural Health Study" (1, p. 373). This interpretation, based on p values of 0.02 and 0.03 from trend analyses of unweighted and intensity-weighted alachlor use days, requires qualification in several ways. We describe two of them here.
First, "among applicators" does not mean "among licensed pesticide applicators," a description that would fit every cohort member. It means that the analysis was confined to the cohort members who reported alachlor use. The participants who did not report using alachlor, nearly half of the cohort, were excluded. They easily could have been included as the reference group. Sound textbook advice from Greenland (2, p. 316), who cites another reference in the following quotation (noted in brackets), holds that "a number of context-specific factors must be evaluated in order to offer a rationale for retaining or deleting the unexposed [3] ... [I]t is not difficult to perform analyses both with and without the unexposed group to see if the results depend on its inclusion. If such dependence is found, this fact should be reported as part of the results."
The authors’ rationale for excluding the alachlor nonusers was a suspicion of confounding by unknown but "important occupational and environmental exposures not explicitly identified by our study questionnaire" (1, p. 376). This possibility was based on slight differences between the nonusers and the highest three fourths of users combined (a group not used in any other analyses) on measured variables such as age, gender, smoking, and alcohol intake. These variables were used for adjustment, even though some of them are not suspected risk factors for the cancers in question.
The authors raised unknown confounders again, as a possible explanation for an association with a p value of 0.03: the reduced rate of all non-Hodgkin’s lymphomas combined among the alachlor users in comparison with the nonusers. When the potentially responsible confounder or confounders cannot be named, confounding is a weak explanation for the presence or absence of an association (4) and a poor rationale for deleting the unexposed group from an exposure-response analysis.
Second, the trend analysis in question focused on an aggregation of disparate diseases of the blood and blood-forming organs: all "lymphohematopoiteic cancers." This conglomeration is not a meaningful outcome pathologically, clinically, etiologically, or epidemiologically. Scholarly works on cancer epidemiology and prevention (5) do not lump multiple myeloma, Hodgkin’s disease, all non-Hodgkin’s lymphomas, and all leukemias together. Important etiologic distinctions are drawn among the leukemias (6) and the even more diverse non-Hodgkin’s lymphomas (7). Incidence rates for all "lymphohematopoietic cancers" combined are not even reported in the National Cancer Institute’s SEER Cancer Review (8).
The fact that this collection of diverse neoplasms produced trend p values of 0.02 and 0.03 when the alachlor nonusers were excluded from the analysis does not render it meaningful. Arguments can show that lumping diseases together increases or decreases statistical power, but any such argument requires one to assume which causal hypotheses are true and which are not. Decisions about lumping and splitting are always necessary. "Lymphohematopoietic cancers" clearly constitutes excessive lumping.
The Agricultural Health Study has the potential to make solid contributions to the epidemiologic literature on alachlor. The alachlor results from the study’s first round of follow-up for cancer incidence are just now entering the most important phase of their peer review: the postpublication phase (9, 10). As that phase progresses, trend analyses with the alachlor nonusers included will shed important light on what this valuable study has to say about cancer categories that are specific enough to be meaningful.
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REFERENCES |
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- Lee WJ, Hoppin JA, Blair A, et al. Cancer incidence among pesticide applicators exposed to alachlor in the Agricultural Health Study. Am J Epidemiol 2004;159:373–80.
[Abstract/Free Full Text] - Greenland S. Analysis of polytomous exposures and outcomes. In: Rothman KJ, Greenland S, eds. Modern epidemiology. 2nd ed. Philadelphia, PA: Lippincott-Raven, 1998:316.
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- Scherr PA, Mueller NE. Non-Hodgkin’s lymphomas. In: Schottenfeld D, Fraumeni JF Jr, eds. Cancer epidemiology and prevention. 2nd ed. New York, NY: Oxford University Press, 1996:920–95.
- Ries LAG, Eisner MP, Kosary CL, et al, eds. SEER cancer statistics review, 1975–2001. Bethesda, MD: National Cancer Institute. (http://seer.cancer.gov/csr/1975_2001/, http://seer.cancer.gov/csr/1975_2004).
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[Free Full Text] - Horton R. Postpublication criticism and the shaping of clinical knowledge. JAMA 2002;287:2843–7.
[Abstract/Free Full Text]
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