Glyphosate results revisited: De Roos et al. respond.The reaction of Farmer et al. regarding our article on glyphosate glyphosate herbicide and desiccant for grains. Heavy doses to birds cause soft shells on their eggs. exposure and cancer incidence in the Agricultural Health Study (AHS AHS Assistant House Surgeon. ) (De Roos et al. 2005) is difficult to understand given the tentative nature of our conclusions. For the most part, we found no associations with the cancers we studied, and to quote from our abstract, Glyphosate exposure was not associated with cancer incidence overall or with most of the cancer subtypes we studied. There was a suggested association with multiple myeloma incidence that should be followed up as more cases occur in the AHS. Despite the fact that we believe our presentation of the data was quite fair and included a lengthy discussion of possible biases affecting our results, several comments by Farmer et al. necessitate a response. Farmer et al. had several criticisms of our review of the genotoxicity Genotoxic substances are a type of carcinogen, specifically those capable of causing genetic mutation and of contributing to the development of tumors. This includes both certain chemical compounds and certain types of radiation. literature (De Roos et al. 2005). Although the discussion of the toxicity studies is interesting, these studies only serve as background information in our article; the epidemiologic associations between glyphosate exposure and cancer incidence we observed are the empirical result of our investigation. Criticisms of our reference to the genotoxicity literature do not, of course, alter the human data we presented. We stated in our article the conclusion of the U.S. Environmental Protection Agency Environmental Protection Agency (EPA), independent agency of the U.S. government, with headquarters in Washington, D.C. It was established in 1970 to reduce and control air and water pollution, noise pollution, and radiation and to ensure the safe handling and (U.S. EPA EPA eicosapentaenoic acid. EPA abbr. eicosapentaenoic acid EPA, n.pr See acid, eicosapentaenoic. EPA, n. 1993) and the World Health Organization (1994) that glyphosate is not mutagenic mutagenic inducing genetic mutation. , but because that conclusion focused on the active ingredient, glyphosate, and not formulated products such as Roundup (Monsanto Company, St. Louis, MO), we also cited several studies which show potentially greater toxic effects of Roundup than glyphosate. Our article (De Roos et al. 2005) does not purport to be a comprehensive review of the toxicology literature, and because of space limitations imposed by the journal, we did not discuss several studies showing potentially toxic effects of several glyphosate-based pesticide products through disruption of cell-cycle control mechanisms, which may be relevant for cancer as well as noncancer health outcomes (Marc et al. 2002, 2004). The fact the some of the studies we cited did not use Good Laboratory Practices is irrelevant, because this system is used primarily in analytical chemistry and contract laboratories for routine support of pesticide regulation, and is not required by any of the principal funding agencies for research studies. Studies that are submitted to the U.S. EPA to support applications for licensing pesticides are required to meet specified guidelines for record keeping, data reporting, and protocol development. These Good Laboratory Practices provide some assurance that regulators can rely on the data they review and give them the ability to perform audits as needed as needed prn. See prn order. . Investigators who perform studies for research purposes are not required to follow these structured practices, but many may do so. Furthermore, it does not follow that work done in labs that do not strictly adhere to the U.S. EPA's testing and reporting requirements follow "bad" laboratory practices. Quality assurance for research studies is provided by the peer-review process and by replication. This is analogous to the distinction between clinical laboratory tests performed in the context of human research and tests performed for diagnostic purposes. In order for these tests to be covered by insurers, they must be performed in laboratories approved by the Clinical Laboratory Improvement Amendments Clinical Laboratory Improvement Amendments (CLIA) of 1988 are United States federal regulatory standards that apply to all clinical laboratory testing performed on humans in the United States, except clinical trials and basic research. (CLIA CLIA Clinical Laboratory Improvement Amendments of 1988 Congressional legislation that promulgated quality assurance practices in clinical labs, and required them to measure performance at each step of the testing process from the beginning to the end-point of a 2005). CLIA approval assures that the test results are valid but does not address the underlying science that led to the development of the test. In their letter, Farmer et al. used exposure information from a study by Acquavella et al. (2004) in which biomonitoring of farmers who applied glyphosate was used to determine a maximum dose calculation. The dose thresholds Farmer et al. cite as relevant for carcinogenicity carcinogenicity /car·ci·no·ge·nic·i·ty/ (kahr?si-no-je-nis´i-te) the ability or tendency to produce cancer. carcinogenicity the ability or tendency to produce cancer. are from mouse and rat models in which the active ingredient, glyphosate, was tested in feeding studies (Williams et al. 2000). Lower relevant doses may apply for Roundup and other formulated products containing glyphosate, or for glyphosate products used in combination with other active ingredients. In addition, epidemiology can provide direct information on the question of what happens in humans from more relevant routes of exposure. Some questions were raised about the possible associations we observed between glyphosate and multiple myeloma multiple myeloma A malignant proliferation of abnormal plasma cells that populate the marrow-containing bones of the body. The affected plasma cells produce myeloma protein, a monoclonal antibody that replaces normal antibodies in the blood, thereby increasing susceptibility concerning the discrepancy between the age-adjusted relative risk of 1.1 [95% confidence interval confidence interval, n a statistical device used to determine the range within which an acceptable datum would fall. Confidence intervals are usually expressed in percentages, typically 95% or 99%. (CI), 0.5-2.4] and the relative risk adjusted for selected demographic and lifestyle variables of 2.6 (95% CI, 0.7-9.4) (De Roos et al. 2005). Farmer et al. question whether the discrepancy may be due to confounding or the selection of subjects into the more restricted analysis. This is plausible, and we discussed these issues at length in our article. The association only appeared within the subgroup with complete data on all the covariates; even without any adjustment, there was a 2-fold increased risk of multiple myeloma associated with glyphosate use among the smaller subgroup with covariate data. We acknowledged that this could be due to selection bias, effect modification effect modification Epidemiology An interaction among multiple possible cause-and-effect relationships, where the estimate of the effect of one factor on a disease process depends on other factors in the study , or confounding within this subgroup. We would point out, however, that confounding can be both positive and negative. The type of analysis suggested by Farmer et al., in which the data are stratified stratified /strat·i·fied/ (strat´i-fid) formed or arranged in layers. strat·i·fied adj. Arranged in the form of layers or strata. by each covariate individually in order to identify covariates for which missing data and/or adjustment made the biggest impact on the estimated relative risk, would be unreliable for such a small number of cases. Each estimate would be subject to small sample bias (Greenland 2000), which was cited by Farmer et al. as an issue with our overall estimate for myeloma myeloma /my·elo·ma/ (mi?e-lo´mah) a tumor composed of cells of the type normally found in the bone marrow. giant cell myeloma see under tumor (1). . The most reliable approach will be to reanalyze the data after more cases accumulate, both to assess whether the association with myeloma persists and to further evaluate confounding and selection bias using a larger case group to support analyses. Following up initial observations with more comprehensive epidemiologic data from the AHS has been our plan since the inception of the study. REFERENCES Aquavella JF, Alexander BH, Mandel JS, Gustin C, Baker B, Chapman P, et al. 2004. Glyphosate biomonitoring for farmers and their families: results from the Farm Family Exposure Study. Environ Health Perspect 112:321-326. CLIA. 2005. Clinical Laboratory Improvement Amendments Homepage. Available: http://www.cms.hhs.gov/clia/ [accessed 27 April 2005]. De Roos AJ, Blair A, Rusiecki J, Hoppin JA, Svec M, Dosemeci M, et al. 2005. Cancer incidence among glyphosate-exposed pesticide applicators in the Agricultural Health Study cohort. Environ Health Perspect 113:49-54. Greenland S, Schwartzbaum JA, Finkle WD. 2000. Problems due to small samples and sparse data in conditional logistic regression. Am J Epidemiol 151: 531-539. Marc J, Mulner-Lorillon O, Durand G, Belle R. 2002. Pesticide Roundup provokes cell division dysfunction at the level of CDK Cdk cyclin-dependent protein kinase. 1/cyclin B activation. Chem Res Toxicol 15:326-331. Marc J, Mulner-Lorillon O, Belle R. 2004. Glyphosete-based pesticides affect cell cycle regulation. Biol Cell 96:245-249. U.S. EPA. 1993. Reregistration Eligibility Decision (RED). Glyphosate. EPA-738-R-93-014. Washington, DC:U.S. Environmental Protection Agency. Williams GM, Kroes R, Munro IC. 2000. Safety evaluation and risk assessment of the herbicide herbicide (hr`bəsīd'), chemical compound that kills plants or inhibits their normal growth. A herbicide in a particular formulation and application can be described as selective or nonselective. Roundup and its active ingredient, glyphosate, for humans. Regul Toxicol Pharmacol 31:117-165. World Health Organization. 1994. Glyphosate. Environmental Health Criteria 159. Geneva Geneva, canton and city, Switzerland Geneva (jənē`və), Fr. Genève, canton (1990 pop. 373,019), 109 sq mi (282 sq km), SW Switzerland, surrounding the southwest tip of the Lake of Geneva. :World Health Organization. The authors declare they have no competing financial interests. Anneclaire J. De Roos and Megan A. Svec Program in Epidemiology Fred Hutchinson Cancer Research Center and the Department of Epidemiology, University of Washington Seattle, Washington E-mail: deroos@u.washington.edu Aaron Blair, Jennifer A. Rusiecki, Mustafa Dosemeci, and Michael C. Alavanja Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Department of Health and Human Services Noun 1. Department of Health and Human Services - the United States federal department that administers all federal programs dealing with health and welfare; created in 1979 Health and Human Services, HHS Bethesda, Maryland Jane A. Hoppin and Dale P. Sandler Epidemiology Branch National Institute of Environmental Health Sciences National Institutes of Health Department of Health and Human Services Research Triangle Park Research Triangle Park, research, business, medical, and educational complex situated in central North Carolina. It has an area of 6,900 acres (2,795 hectares) and is 8 × 2 mi (13 × 3 km) in size. Named for the triangle formed by Duke Univ. , North Carolina North Carolina, state in the SE United States. It is bordered by the Atlantic Ocean (E), South Carolina and Georgia (S), Tennessee (W), and Virginia (N). Facts and Figures Area, 52,586 sq mi (136,198 sq km). Pop. |
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