UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

 WASHINGTON, D.C. 20460

 

 

OFFICE OF

PREVENTION, PESTICIDES AND

 TOXIC SUBSTANCES

MEMORANDUM

DATE: February 19, 2010

SUBJECT: Transmission of Bibliography for the 2010 Session of the FIFRA Scientific 

Advisory Panel (SAP) Entitled “Re-Evaluation of Human Health Effects of 

Atrazine: Review of Experimental Animal and In Vitro Studies and 

Drinking Water Monitoring Frequency”

FROM: Tina E. Levine, Ph.D.

Director

Health Effects Division

TO: Joseph Bailey

Designated Federal Official

FIFRA Scientific Advisory Panel

Office of Science Coordination and Policy (7201M)

On November 3, 2009, EPA presented its review plan for a year long re-evaluation 

of the human health effects of atrazine . This review plan involves three FIFRA 

Scientific Advisory Panel (SAP) meetings planned for 2010. In the report from the 

November, 2009 meeting, the SAP requested that review materials be provided “as 

early as possible in advance of each [SAP] meeting (SAP report, December 2, 2009).” 

This memo transmits the Agency’s list of references relevant for the second SAP 

meeting on the human health effects of atrazine. 

The second SAP meeting will focus on a variety of important scientific issues related 

to the toxicity and exposure profile of atrazine. The Agency will solicit comments from 

the Panel on issues such as potential toxicity to the hypothalamic-pituitary-adrenal 

(HPA) axis, immune system, prostate, brain, and alterations to the enzyme aromatase. 

In addition, the Agency plans to discuss the scientific issues associated with lifestage 

susceptibility and linking a chemically-induced activation of the HPA axis to other health 

outcomes and possible approaches to use key events in a mode of action in risk 

assessment. The Agency will also seek feedback about monitoring water exposure and 

guidance to help refine the sampling frequency for monitoring community water systems 

(CWS).
Page 2 of 15

 This second SAP meeting, the Agency’s scientific review of toxicology studies will 

focus on both those studies used to support the 2003 reregistration of atrazine and new 

studies. A review of the scientific literature of new data on atrazine and/or its 

metabolites available since the 2003 Interim Reregistration Eligibility Decision (IRED) 

has been conducted. The scope of this evaluation is restricted to articles reporting on 

effects in mammals or in vitro studies from mammalian or human cell lines that provide 

data on toxicity, pharmacokinetics, and/or mode of action (MOA) of atrazine and/or its 

metabolites. The purpose of this literature review was to determine the state-of-thescience since the 2003 atrazine IRED. To obtain peer reviewed references on atrazine, 

EPA conducted searches using three online bibliographic databases: PubMed, 

TOXLINE, and EMBASE. These searches encompassed studies on atrazine and/or its 

metabolites published between the years 2003 to 2009. Published articles excluded 

from the Agency’s preliminary analysis included: 

 Studies conducted on non-mammalian species;

 Commentaries or letters to the editor;

 Abstracts lacking sufficient detail on methods and results;

 Topic reviews that did not present original work;

The Agency’s scientific review encompasses toxicology studies will include

studies available up to January 30, 2010. Studies that become available after that date 

will be integrated into the Agency’s weight of the evidence (WOE) analysis scheduled 

for review by the FIFRA SAP in September 2010. The Agency is aware of a number of 

published studies on the effects of atrazine on the development of the mammary gland. 

The Agency is also aware of several new studies expected to be published in spring 

2010 which may further characterize the effects of atrazine on development of the 

mammary gland. Thus, evaluation of all studies on the development of the mammary 

gland will be deferred to the September 2010 SAP meeting where both toxicity studies 

and epidemiology studies will be considered.

EPA has evaluated approximately 100 studies for this upcoming SAP meeting. 

In addition to the studies published after the 2003 IRED, select references published 

before 2003 have been included to provide context and/or historical background. A 

bibliography of these relevant references is attached. 
Page 3 of 15

Bibliography

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mice to arsenate and atrazine in drinking water modulates gene expression and 

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Page 4 of 15

10.Dooley, G.P., Reardon, K.F., Prenni, J.E., Tjalkens, R.B., Legare, M.E., Foradori, 

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(2006). Identification of a novel hemoglobin adduct in Sprague-Dawly rats 

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13.Enoch, R.R., Stanko, J.P., Greiner, S.N., Youngblood, G.L., Rayner, J.L., & 

Fenton, S.E.(2007). Mammary gland development as a sensitive end point after 

acute prenatal exposure to an atrazine metabolite mixture in female Long-Evans 

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14.Fan, W., Yanase, T., Morinaga, H., Gonda, S., Okabe, T., Nomura, M., Hayes, 

T., Takayanagi, R., & Nawata, H.(2007). Herbicide atrazine activates SF-1 by 

direct affinity and concomitant co-activators recruitments to induce aromatase 

expression via promoter II. Biochemical and Biophysical Research 

Communications, 355:4 1012-1018.

15.Fan, W., Yanase, T., Morinaga, H., Gondo, S., Okabe, T., Normura, M., 

Komatsu, T., Moroashi, K., Hayes, T.B., Takayanagi, R., & Nawata, H. (2007). 

Atrazine-induced aromatase expression is SF-1 dependent: implications for 

endocrine disruption in wildlife and reproductive cancers in humans. Environ 

Health Perspect, May, 115:5, 720-727.

16.Filipov, N.M., Pinchuk, L.M., Boyd, B.L., & Crittenden P.L. (2005). Immunotoxic 

effects of short-term atrazine exposure in young male C57BL/6 mice. 

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17.Filipov, N.M., Stewart, M.A., Carr, R.L., & Sistrunk, S.C. (2007). Dopaminergic 

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18.Foradori, C., Hinds, L., Hanneman, W., & Handa, R. (2009a). Effects of atrazine 

and its withdrawal on gonadotropin-releasing hormone neuroendocrine function 

in the adult female Wistar rat. Biology of Reproduction, Dec, 81:6, 1099-1105.

19.Foradori, C., Hinds, L., Hanneman, W., Legare, M., Clay, C., & Handa, R. 

(2009b). Atrazine inhibits pulsatile luteinizing hormone release without altering 
Page 5 of 15

pituitary sensitivity to a gonadotropin-releasing hormone receptor agonist in 

female Wistar rats. Biology of Reproduction, 81:1, 40-45.

20.Foradori, C.D., Hinds, L.R., et al. (2009c). Effects of atrazine on GnRH 

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Biology of Reproduction, 81:6, 1099-1105.

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line in rats. Food Chem Toxicol, Dec, 41:12, 1711-1717.

22.Fukamachi, K., Han, B.S., Kim, C.K., Takasuka, N., Matsuoka, Y., Matsuda, E., 

Yamasaki, T., and Tsuda, H. (2004). Possible enhancing effects of atrazine and 

nonylphenol on 7,2-dimethylbenz[a]anthracene-induced mammary tumor 

development in human c-Ha-ras proto-oncogene transgenic rats. Cancer Sci., 

95:5, 404-410.

23.Giusi, G., Facciolo, R.M., Canoaco, M., Alleva, E., Santucci, D., Belloni, V., & 

Dessi-Fulgheri, F. (2006). The endocrine disruptor atrazine accounts for a 

dimorphic somatostatinergic neuronal expression pattern in mice. Toxicological 

Sciences, 89:1, 257-264.

24.Gojmerac, T., Pleadin, J., Zuric, M., Rajkovic-Janje, R., & Korsic, M. (2004). 

Serum luteinizing hormone response to administration of gonadotropin-releasing 

hormone to atrazine-treated gilts. Vet Hum Toxicol, Oct, 6:5, 245-247.

25.Hase, Y., Tatsuno, M., Nishi, T., Kabe, Y., Yamaguchi, Y., Hanada, H., Kataoka, 

K., Ozawa, N., Natori, M., Handa, H., & Wantabe, H. (2008). Atrazine binds to 

F1F0-ATP synthase and inhibits mitochondrial function in sperm. Biochemical 

and Biophysical Research Communications, 366:1, 66-72.

26.Heneweer, M., Van den Berg, M., & Sanderson, J.T. (2004). A comparison of 

human H295R and rat R2C cell lines as in vitro screening tools for effects on 

aromatase. Toxicol. Lett., 149:2, 183-194.

27.Higley, E.B., Newsted, J.L., Zhang, X., Giesy, J.P., & Hecker, M. (2010). 

Assessment of chemicals effects on aromatase activity using the H295R cell line. 

Environ Sci Pollut Res Int., Jan, 20, Epub ahead of print

28.Hocking, B. (2009). Melamine-contaminated powdered formula and urolithiasis. 

N Engl J Med., June, 360:25, 2676-2677.

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30.Hossain, M. M. & Filipov, N. M.(2008). Alteration of dopamine uptake into rat 

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31.Juliani, C.C., Silva-Zacarin, E.C., Santos, D.C., & Boer, P.A.(2008). Effects of 

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32.Kandori, H., Suzuki, S., Asamoto, M., et al. (2005). Influence of atrazine 

administration and reduction of calorie intake on prostate carcinogenesis in 

probasin/SV40 T antigen transgenic rats. Cancer Sci., 96, 221-226.

33.Karrow, N.A., McCay, J.A., Brown, R.D., Musgrove, D.L., Guo, T.L., Germolec, 

D.R., & White, K.L. Jr (2005). Oral exposure to atrazine modulates cell-mediated 

immune function and decreases host resistance to the B16F10 tumor model in 

female B6C3F1 mice. Toxicology, Apr, 209:1, 15-28.

34.Kim, D., Breckenridge, C. (Syngenta) (2010). Atrazine - Derivation of the shortterm inhalation NOAEL using a physiologically-based pharmacokinetic model. 

Unpublished data from Syngenta

35.Kirby E.D., Geraghty A.C., Ubuka T., Bentley G.E., Kaufer D. (2009). Stress 

increases putative gonadotropin inhibitory hormone and decreases luteinizing 

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36.Kmetic, I., Gaurina Srcek, V., Silvac, I., Simic, B., Kniewald, Z., & Kniewald, J. 

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(CHO-K1) cell line. Bull Environ Contam Toxicol., Aug, 81:2, 205-209.

37.Kniewals, J., Kmetič, I., Gaurina Srček, V., Šimiċ,b., & Kniewald, Z. (2003) 

Cytotoxicity of Herbicide Atrazine On Chinese Hamster ovary cell Line In 

Monolayer. Toxicol Lett. 144 (Suppl 1 ):S111-S112

38.Laville, N., Balaguer, P., Brion, F., Hinfray, N., Casellas, C., Porcher, J.M., & AitAissa, S. (2006). Modulation of aromatase activity and mRNA by various 

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228, 98-108.

39.Laws, S.C., Ferrell, J.M., Stoker, T.E., & Cooper, R.L. (2003). Pubertal

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biotransformation by-products, diamino-S-chlorotriazine and hydroxyatrazine. 

Toxicological Sciences 76:1, 190-200.
Page 7 of 15

40.Laws, S.C., Hotchkiss, M., Ferrell, J., Jayaraman, S., Mills, L., Modic, W., Tinfo, 

N., Fraites, M., Stoker, T., & Cooper, R. (2009). Chlorotriazine Herbicides and 

Metabolites Activate an ACTH-Dependent Release of Corticosterone in Male 

Wistar Rats. Tox. Sci. 112(1), 78–87.

41.Lim, S., Ahn, S.Y., Song, I.C., Chung, M.H., Jang, H.C., Park, K.S., Lee, K., Pak, 

Y.K., & Lee, H.K. (2009). Chronic exposure to the herbicide, atrazine, causes 

mitochondrial dysfunction and insulin resistance. PLOS One, April, 4:4, 1-11.

42.Malik, S.I., Terzoudi, G.I., & Pantelias, G.E. (2004). SCE analysis in G2 

lymphocyte prematurely condensed chromosomes after exposure to atrazine: the 

non-dose-dependent increase in homologous recombinational events does not 

support its genotoxic mode of action. Cytogenet and Genome Research, 104:1-

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43.Manske, M., Beltz, L, and Dhanwada, K. (2004). Low-Level Atrazine Exposure 

Decreases Cell Proliferation in Human Fibroblasts. Arch. Environ. Contam. 

Toxicol., 46, 438-444.

44.Maravilla-Galvan, R., Fierro, R., Gonzalez-Marquez, H., Gomez-Arroyo, S., 

Jimenez, I., & Betancourt, M. (2009). Effects of atrazine and fenoxaprop-ethyl on 

capacitation and the acrosomal reaction in boar sperm. Int. J. Toxicol., Jan-Feb, 

28:1, 24-32.

45.McMullin T.S. (2003). Pharmacokinetic modeling of disposition and time-course 

studies with [14C]-atrazine. J. Toxicol. Environ. Health, 66:A, 941-964.

46.McMullin, T.S., Andersen, M.E., Hanneman, W.H., Nagahara, A., Lund, T.D., 

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inhibit the estrogen/progesterone induced surge of luteinizing hormone in female 

Sprague-Dawley rats without changing estrogen receptor action. Toxicological 

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47.McMullin, T.S., Hanneman, W.H., Cranmer, B.K., Tessari, J.D., and Andersen, 

M.E. (2007). Oral absorption and oxidative metabolism of atrazine in rats 

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48.Mizota, K. & Ueda, H. (2006). Endocrine disrupting chemical atrazine causes 

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Page 8 of 15

49.Mu, H., Zhang, P., & Xu, J. (2008). Testicular toxicity and mechanisms of 

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50.Pinchuk, L.M., Lee, S.R., & Filipov, N.M. (2007). In vitro atrazine exposure 

affects the phenotypic and functional maturation of dendritic cells. Toxicology 

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51.Pogrmic, K., Fa, S., Dakic, V., Kaisarevic, S. & Kovacevic, R. (2009). Atrazine 

oral exposure of peripubertal male rats downregulates steroidogenesis gene 

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52.Pruett, S.B., Fan, R., Zheng, Q., Myers, L.P., & Hebert, P.(2003). Modeling and 

predicting immunological effects of chemical stressors: characterization of a 

quantitative biomarker for immunological changes caused by atrazine and 

ethanol. Toxicol Sci., Oct, 75(2): Epub 2003 Jul 25, 343-354.

53.Pruett, S.B., Fan, R., Zheng, Q., & Schwab, C. (2009). Patterns of 

immunotoxicity associated with chronic as compared with acute exposures to 

chemical or physical stressors and their relevance with regard to the role of 

stress and with regard to immunotoxicity testing. Toxicological Sciences, June, 

109:2, 265-275.

54.Rayburn, A.L., Moody, D.D., and Freeman, J.L. (2005). Cytotoxicity of technical 

grade versus formulations of atrazine and acetochlor using mammalian cells. 

Bull. Environ. Contam. Toxicol., 75, 691-698.

55.Rayner, J.L., Wolf, D.C., Rayner, J.L., Enoch, J.L., Enoch, R.R., & Fenton, S.E. 

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and/or lacational exposure in male Long-Evans rats. Toxicology and Applied 

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56.Rodriguez, V.M., Thiruchelvam, M., & Cory-Slechta, D.A. (2005). Sustained 

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57.Rooney, A.A., Matulka, R.A., & Luebke, R.W. (2003). Developmental atrazine 

exposure suppresses immune function in male, but not female Spragus-Dawley 

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58.Rosenberg, B.G., Chen, H., Folmer, J., Liu, J., Papadopoulos, V., & Zirkin, B.R. 

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Page 9 of 15

59.Ross, M.K., Jones, T.L., and Filipov, M.N. (2009). Disposition of the herbicide 2-

chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine (atrazine) and its major 

metabolites in mice: a liquid chromatography/mass spectrometry analysis of 

urine, plasma, and tissue levels. Drug Metab. Dispos., 37:4, 776-786.

60.Rowe, A.M., Brundage, K.M., & Barnett, J.B. (2008). Developmental 

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61.Rowe, A.M., Brundage, K.M., & Barnett, J.B. (2007). In vitro atrazine exposure 

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62.Rowe, A.M., Brundage, K.M., Schafer, R., & Barnett, J.B. (2006). 

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64.Santucci, D., Belloni, V., Dessì, F., & Alleva, E. (2006). Perinatal 

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65.Schwab, C L, Fan R, et al. (2005). Modeling and predicting stress-induced 

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66.Shibayama, H., Kotera, T., Shinoda, Y., Hanada, T., Kajhara, T., Ueda, M., 

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67.Singh, M., Kaur, P., Sandhir, R., & Kiran, R. (2008). Protective effects of vitamin 

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78.Yi, K.D., Breckenridge, C.B., & Simpkins, J.W. (2010b). Cytotoxicity of atrazine 

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79.Yi, K.D., Breckenridge, C.B., & Simpkins, J.W. (2010c). Dose and time 

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80.Yi, K.D., Perez, E.J., Breckenridge, C.B., & Simpkins, J.W. (2010d). Ex vivo 

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81.Zeljezic, D. & Garaj-Vrhovac, V. (2004). Genotoxicity evaluation of pesticide 

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82.Zeljezic, D., Garaj-Vrhovac, V., & Perkovic, P. (2006). Evaluation of DNA 

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83.Zeljeciz D, & Garaj-Vrhovac, V. (2004). Atrazine genotoxicity evaluation in 

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