UNITED STA TES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORA NDUM 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 W ater Monitoring Frequen cy” 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 re quested 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 (CW S).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 i s 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-the science since the 2003 atrazine IRED. To obtain peer reviewed referenc es 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 Age ncy’s scientific review encompasses toxicology studies will include studies available up to January 30, 2010. S tudies that become available after that date will be integrated into the Agency’s weight of the evidence (WO E) 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, evaluat ion 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 studie s 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 ba ckground. A bibliography of these relevant references is attached.Page 3 of 15

Bibliography Post 2003 References 1. Albanito, L., Lappano, R., Madeo, A., Chimento, A., Prossnitz, E.R., Cappello, A.R., Dolce, V., Abonante, S., Pezzi, V., & Maggiolini, M. (2008). G - protein coupled receptor 30 and estrogen receptor- alpha are involved in the proliferative effects induced by atrazine in ovarian cancer cells, Environ Health Perspect, 116:12, 1648 - 1655. 2. Belloni V, Alleva E, et al. (2007). Effects of low doses of atra zine on the neurobehavioural development of mice. Ethology Ecology & Evolution, 19, 309 - 322. 3. Benachour, N., Moslemi, S., Sipahutar, H., & Seralini G.E. (2007). Cytotoxic effects and aromatase inhibition by xenobiotic endocrine disrupters alone and in combination, Toxicology and Applied Pharmacology, 222:2, 129 - 140. 4. Betancourt, M., Resendiz, A., & Fierro, E.C, (2006). Effects of two insecticides and two herbicides on the porcine sperm motility patterns using computer- assisted semen analysis (CASA) in vitro. Reprod Toxicol, Oct, 22:3, 508 - 12. 5. Cimino - Reale, G., Ferrario, D., Casati, B., Brustio, R., Diodovich, C., Collotta, A., Vahter, M., & Gribaldo, L. (2008). Combined in utero and juvenile exposure of mice to arsenate and atrazine in drinking water modulates gene expression and colonogenicity of myeloid progenitors. Toxicol Lett, Jul 180:1, 59 - 66. 6. Coban, A, & Filipov, N.M. (2007). Dopaminergic toxicity associated with oral exposure to the herbicide atrazine in juvenile male C57BL/6 mice. J. Ne urochem, Mar, 100:5, 1177 - 87. 7. Coder, Pragati Sawhney (Syngenta) (2010). Atrazine -An oral developmental toxicity study of atrazine in the rat, including cross -fostering and pair-feeding. Unpublished data from Syngenta, 3000 pgs 8. Devos, S., Hooghe, R., Ho oghe - Peters, E.L., De Bosscher, K., Vanden Berghe, W. , Haegeman, G., Staels, B., Bauer, E., Roels, F., & Hooghe, R. (2003). Inhibition of cytokine production by the herbicide atrazine: Search for nuclear receptor targets. Biochemical Pharmacology, 65:2, 303 - 308. 9. Devos S, Van Den Heuvel R, et al. (2004). Limited effect of selected organic pollutants on cytokine production by peripheral blood leukocytes. Eur. Cytokine Netw, 15, 145 - 151.Page 4 of 15

10. Dooley, G.P., Reardon, K.F., Prenni, J.E., Tjalkens, R.B., Legare , M.E., Foradori, C.D., Tessari, J.E., & Hanneman, W. H. (2008). Proteomic analysis of diaminocholorotriazine adducts in W istar rat pituitary glands and LbetaT2 rat pituitary cells. Chem Res Toxicol, Apr, 21:4, 844 - 51. 11. Dooley, G., Prenni, J., Prentiss, P ., Cranmer, B., Anderson, M., & Tessari, J. (2006). Identification of a novel hemoglobin adduct in Sprague - Dawly rats exposed to atrazine. Chem Res Toxicol, 19, 692 - 700. 12. Dooley, G., Hanneman, W ., Carbone, D., Legare, M., Anderson, M., & Tessari, J. (200 7). Development of an immunochemistry detection method for atrazine induced albumin adducts. Chem Res Toxicol, 201, 1061 - 1066. 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 rats. Environ Health Perspect, Apr, 115:4, 541 - 547. 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. Toxicological Sciences, 86:2, 324 - 332. 17. Filipov, N.M., Stewart, M.A., Carr, R.L., & Sistrunk, S.C. (2007). Dopaminergic toxicity of the herbicide atrazine in rat striatal slices. Toxicology, 232:1 - 2, 68 - 78. 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 W istar 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 p ulsatile luteinizing hormone release without alteringPage 5 of 15

pituitary sensitivity to a gonadotropin - releasing hormone receptor agonist in female W istar rats. Biology of Reproduction, 81:1, 40 -45. 20. Foradori, C.D., Hinds, L.R., et al. (2009c). Effects of atrazin e on GnRH neuroendocrine function after its withdrawal in the adult female W istar rat. Biology of Reproduction, 81:6, 1099 - 1105. 21. Fujimoto, N. and Honda, H. (2003). Effects of environmental estrogenic compounds on growth of a transplanted estrogen respon sive pituitary tumor cell 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). Th e end o crine 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 hormon e 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., & Wa ntabe, 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. 29. Holloway, A.C., Anger, D.A., Crankshaw, D.J., W u, M., & Foster, W .G. (2008). Atrazine - induced changes in aromatase activity in estrogen sensitive target tissues. J. Appl. Toxicol., Apr, 28:3, 260 - 270.Page 6 of 15

30. Hossain, M. M. & Filipov, N. M.(2008). Alteration of dopamine uptake into rat striatal vesicles and synaptosomes caused by an in vitro exposure to atrazine and some of its metabolites. Toxicology, 248, 52 - 58. 31. Juliani, C.C., Silva -Zacarin, E.C., Santos, D.C., & Boer, P.A.(2008). Effects of atrazine on female Wi star rats: morphological alterations in ovarian follicles and immunocytochemical labeling of 90 kDa heat shock protein. Micron, Jul, 39:5, 607 - 616. 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., & Wh ite, K.L. Jr (2005). Oral exposure to atrazine modulates cell - mediated immune function and decreases host resista nce 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 pharm a cokinetic model. Unpublished d ata 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 hormone in male rats. Proc Natl Acad Sci USA , 106:27, 11324 - 11329. 36. Kmetic, I., Gaurina Srcek, V., Silvac, I., Simic, B., Kniewald, Z., & Kniewald, J. (2008). Atrazine exposure decreases cell proliferation in Chinese Hamster Ovary (CHO - K1) cell line. Bull Environ Contam Toxicol., Aug, 81:2, 205 - 209. 37. Kniewals, J., Km etič, I., Gaurina Srček, V., Šimi ċ,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 selected pesticides in the human choriocarcinoma JEG - 3 cell line. Toxicology, 228, 98 - 108. 39. Laws, S.C., Ferrell, J.M., Stoker, T.E., & Cooper, R.L. (2003). Pubertal development in female W istar rats following exposure to propazine and atrazine 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., Mil ls, 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 Wi star Rats. Tox. Sci. 112(1), 78

–87. 41. Lim, S., Ahn, S.Y., Song, I.C., Chun g, 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. (20 04). 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 - 4, 3 15 - 319. 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 - cou rse studies with [ 14 C] - atrazine. J. Toxicol. Environ. Health, 66:A, 941 - 964. 46. McMullin, T.S., Andersen, M.E., Hanneman, W .H., Nagahara, A., Lund, T.D., Pak, T., & Handa, R.J. (2004). Evidence that atrazine and diaminochlorotriazine inhibit the estrogen/progesterone induced surge of luteinizing hormone in female Sprague - Dawley rats without changing estrogen receptor action. Toxicological Sciences, Jun, 79:2, 278 - 286. 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 evaluated by physiologically modeling approaches. Toxicology, 240, 1 - 14. 48. Mizota, K. & Ueda, H. (2006). Endocrine disrupting chemical atrazine causes degranulation through Gq/11 protein - couple d neurosteroid receptor in mast cells. Toxicol Sci., Apr, 90:2, 362 - 368.Page 8 of 15

49. Mu, H., Zhang, P., & Xu, J. (2008). Testicular toxicity and mechanisms of chlorotoluron compounds in the mouse. Toxicology Mechanisms and Methods, 18:5, 399 -403. 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 and Applied Pharmacology, Sept, 223:3, 206 -217. 51. Pogrmic, K., Fa, S., Dakic, V., Kaisarevic, S. & Kovacevic, R. (2009). Atrazine oral exposure of peripubertal male rats downregulates steroidogenesis gene expression in Leydig cells. Toxicol. Sci., 111:1, 189 - 197. 52. Pruett, S.B., Fan, R., Zheng, Q., Myers, L.P., & Hebert, P.(2003). Modeling and predicting immunologi cal 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). Pattern s 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., Wo lf , D.C., Rayner, J.L., Enoch, J.L. , Enoch, R.R., & Fenton, S.E. (2007). Atrazine - induced reproductive tract alterations after transplacental and/or lacational exposure in male Long - Evans rats. Toxicology and Applied Pharmacology, Feb, 218:3, 238 - 248. 56. Rodriguez, V.M., Thiruchelvam, M., & Cory- Slechta, D.A. (2005). Sustained exposure to the widely used herbicide atrazine: Altered function and loss of neurons in brain monoamine systems. Environmental Health Perspectives, Jun, 113:6, 708 - 715. 57. Rooney, A.A., Matulka, R.A., & Luebke, R. W. (2 003). Developmental atrazine exposure suppresses immune function in male, but not female Spragus - Dawley rats. Toxicol Sci., Dec, 76:2, 366 - 375. 58. Rosenberg, B.G., Chen, H., Folmer, J., Liu, J., Papadopoulos, V., & Zirkin, B.R. (2008). Gestational exposure to atrazine: effects on the postnatal development of male offspring. J Androl., May- June, 29:3, 304 - 311.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) a nd 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 immunotoxicity of atrazine in rodents. Basic and Clinical Pharmacology and Toxicology, Feb, 102:2, 139 - 145. 61. Rowe, A.M., Brundage, K.M., & Barnett, J.B. (2007). In vitro atrazine exposure inhibits human natural killer cell lytic granule release. Toxicology and Applied Pharmacology, Jun, 221:2, 179 - 188. 62. Rowe, A.M., Brundage, K.M., Schafer, R., & Barnett, J.B. (2006). Immunomodulatory effects of maternal atrazine exposure on male Balb/c mice. Toxicology and Applied Pharmacology, 214:1, 69 - 77 63. Rusiecki, J.A., De Roos, A., Lee, W. J., Dosemci, M., Lubin J.H., Hoppin, J.A., Blair, A., & Alavanja, M.C. (2004). Cancer incidence among pesticide applicators exposed to atrazine in the Agricultural Health Study. J Natl Cancer Inst, Sept, 96:18, 1375 - 1382. 64. Santucci, D., Belloni, V., Dess&ig rave, F., & Alleva, E. (2006). Perinatal exposure to low dose atrazine affects neurobehavioural development of CD - 1 mice. Reprod Toxicol, Aug, 22:2, 10. 65. Schwab, C L, Fan R, et al. (2005). Modeling and predicting stress - induced immunosuppression in mice using blood parameters. Toxicological Sciences, 83, 101 - 113. 66. Shibayama, H., Kotera, T., Shinoda, Y., Hanada, T., Kajhara, T., Ueda, M., Tamura, H., Ishibashi, S., Yamashita, Y., & Ochi, S. (2009). Collaborative work on evaluation of ovarian toxicity. 1 4) Two - or four-week repeated - dose studies and fertility study of atrazine in female rats. J toxicol Sci., 34,147 - 155. 67. Singh, M., Kaur, P., Sandhir, R., & Kiran, R. (2008). Protective effects of vitamin E against atrazine - induced genotoxicity in rats. Mutat Res, Jul, 654:2, 145 - 149. 68. Singh, M., Sandhir, R., & Kiran, R.(2008). Atrazine - induced alterations in rat erthrocyte membranes: ameliorating efect of vitamin E. J Biochem Mol Toxicol, Sept, 225, 363 - 369. 69. Singh, M., Sandhir, R., Kiran, R., & Kaur, P. (2008). Protective effects of vitamin E against atrazine - induced genotoxicity in rats Mutation Research. Genetic Toxicology and Environmental Mutagenesis, 654:2, 145 - 149.Page 10 of 15

70. Son, H.Y., Nishikawa, A., Okazaki, K., Lee, K., Imazawa, T., & Hirose, M. (2003 ). Lack of modifying effects of atrazine and/or tamoxifen on thyroid carcinogenesis in rat pretreated with N - bis(2 - hydroxypropyl)nitrosamine (DHPN). Food Chem Toxicol, Dec, 41:12, 1911 - 1916. 71. Suzawa, M. & Ingraham, H.A. (2008). The herbicide atrazine activates endocrine gene networks via non - steroidal NR5A nuclear receptors in fish and mammalian cells. PloS ONE, 3:5, 1 - 11. 72. Tanaka, T., Kohno, H., Suzuki, R., & Sugie, S. (2004). Lack of modifying effects of an estrogenic compound atrazine on 7,12 - dimet hylbenz(a)anthracene - induced ovarian carcinogenesis in rats. Cancer Lett, Jul, 210:2, 129 - 137. 73. Tinfo, N., & Laws, S.C. (2009). Understanding the Effects of Atrazine on Steroidogenesis in Wi star rats. Society of Toxicology, Itinerary Planner, Baltimore, MD. 74. Ueda, M., Imai, T., Takizawa, T., Onodera, H., Mitsumori, K., Matsul, T., & Hirose, M. (2005). Possible enhancing effects of atrazine on growth of 7,12 - dimethylbenze(a) anthracene - induced mammary tumors in ovariectomized Sprague - Dawley rats. Cancer Sci., Jan, 96:1, 19 - 25. 75. Victor- Costa, A.B., Carozzi Bandeira, S.M., Oliveira, A.G., Bohorquiz Mahecha, G.A. & Oliveira, C.A. (2010). Changes in testicular morphology and steroiodogenesis in adult rats exposed to atrazine. Reprod Toxicol, Doi:10.1016/

j.reprotox.2009.12.006 76. Wh alen M M, Loganathan B G, et al. ( 2003). Immunomodulation of human natural killer cell cytotoxic function by triazine and carbamate pesticides. Chemico - Biological Interactions, 145, 311 - 319. 77. Yi, K.D., Breckenridge, C.B., & Simpkins, J.W. (2010a). Evaluation of the potential mechanisms of action underlying the effect of triazines on aromatase expression in vitro: relevance to man and the environment. Unpublished data from Syngenta 78. Yi, K.D., Breckenridge, C.B., & Simpkins , J.W . (2010b). Cytotoxicity of atrazine and its metabolites in vitro. Unpublished data from Syngenta Crop Protection, Inc. 79. Yi, K.D., Breckenridge, C.B., & Simpkins, J.W. (2010c). Dose and time dependent effects of atrazine and metabolites on aromatas e mRNA in multiple cell types in vitro. Unpublished data from SyngentaPage 11 of 15

80. Yi, K.D., Perez, E.J., Breckenridge, C.B., & Simpkins, J.W . (2010d). Ex vivo assessment of the effects of atrazine or its metabolites on phosphodiesterase activity. Unpublished d ata from Syngenta 81. Zeljezic, D. & Garaj -Vrhovac, V. (2004). Genotoxicity evaluation of pesticide formulations containing alachlor and atrazine in multiple mouse tissues (blood, kidney, liver, bone marrow, spleen) by comet assay. Neoplasma, 51:3, 198 - 203

. 82. Zeljezic, D., Garaj -Vrhovac, V., & Perkovic, P. (2006). Evaluation of DNA damage induced by atrazine and atrazine - based herbicide in human lymphocytes in vitro using a comet and DNA diffusion assay. Toxicology in Vitro, Sept, 20:6, 923 - 935. 83. Zeljeciz D, & Garaj -Vrhovac, V. (2004). Atrazine genotoxicity evaluation in different mouse organs by comet assay. Periodicum Biologorum, 106:2, 155 - 159.

Pre -2003 References 1. Cooper, R.L., Stoker, T.E., Tyrey, L., Goldman, J.M., & McElroy, W.K. (2000). Atrazi ne disrupts the hypothalamic control of pituitary- ovarian function. Toxicol Sci., Feb, 53:2, 297 - 307. 2. Cooper, R.L., Laws, S.C., Das, P.C., Narotsky, M.G., Goldman, J.M., Tyrey, E.L., & Stoker, T.E. (1997). Atrazine and Reproductive Function: Mode and M echanism of Action Studies. Birth Defects Research (Part B) 80:98

– 112. 3. Cooper, R.L., Stoker, T.E., Goldman, J.M., Parrish, M.B, & Tyrey, L. (1996). Effect of atrazine on ovarian function in the rat. Reprod Toxicol, Jul -Aug 10:4, 257 - 64. 4. Das, P.C., Mc Elroy, W.K. & Cooper, R.L. (2001). Alteration of Catecholamines in Pheochromocytoma (PC12) Cells in Vitro by the Metabolites of Chlorotriazine Herbicide. Toxicological Sciences, 59, 127

– 137. 5. Eldridge, J.C., We tzel, L.T., & Tyrey, L. (1999). Estrous cyc le patterns of Sprague - Dawley rats during acute and chronic atrazine administration. Reprod Toxicol, Nov- Dec, 13:6, 491 -499. 6. Friedmann, A.S. (2002). Atrazine inhibition of testosterone production in rat males following peripubertal exposure. Reprod. To xicol, 16, 275 - 279.Page 12 of 15

7. Kalra, S.P., & Kalra, P.S.(1983). Neural regulation of luteinizing hormone secretion in the rat. Endocr Rev., 4, 311 - 351. 8. Lyons, W .R., Berlin, I., and Friendlander, S. (1942) Cornification of balano preputial peithelium in normal rats and castrated rats treated with testosterone proprionate. Endocrinology, 31:659 9. Marshall, F. (1966) Marshall’s Physiology of Reproduction. Longmans, Green and Co. LTD 10. Matsumoto AM, Karpas AE, Southworth MB, Dorsa DM, Bremner WJ. (1986). Evidence for activation of the central nervous system - pituitary mechanism for gonadotropin secretion at the time of puberty in the male rat. Endocrinology , 119:1, 362 - 369. 11. Monosson E, Kelce WR, Lambright C, Ostby J, Gray LE Jr. (1999). Peripubertal exposure to the antiandrogenic fungicide, vinclozolin, delays puberty, inhibits the development of androgen - dependent tissues, and alters androgen receptor function in the male rat. Toxicol Ind Health , 15:1 - 2, 65 - 79. 12. Ojeda, S.R., and Urbanski, H.F. (1994). Puberty in the rat. In E. Knobil and J.D. Neill (Eds.): The Physiology of Reproduction, 2 nd ed. New York, Raven Press. 13. Rivest, .S & Rivier, C. (1995). The role of corticotropin - releasing factor and interleukin - 1 in the regulation of neurons controlling rep roductive functions. Endocr Rev, 16, 177 - 199. 14. Rivier, C. & Rivest, S. (1991). Effect of stress on the activity of the hypothalamicpituitary- gondal Role of endogenous corticotropin - releasing factor. Science, 231, 607 - 609. 15. Rivier, C., Rivier, J., & Val e, W. (1986). Stress - induced inhibition of reproductive functions:Peripheral and central mechanisms. Biol Reprod., 45, 523 - 532. 16. Selye, H. (1939). Effect to adaptation to various damaging agents on the female sex organs in the rat. Endocrinology, 25, 6 15 - 624. 17. Stoker, T.E., Guidici, D.L., Laws, S.C. & Cooper, R.L. (2002). The Effects of Atrazine Metabolites on Puberty and Thyroid Function in the Male Wistar Rat: An Evaluation in the Male Pubertal Protocol. Toxicol. Sci., 67:2, 198 - 206. 18. Stoker, T.E., Laws, S.C., Guidici, D., & Cooper, R.L. (2000). The effects of atrazine on puberty and thryroid function in the male wistar rat: An evaluation of a protocol for the assessment of pubertal development and thyroid function. Toxicol. Sci., 58, 50 - 59.Page 13 of 15

19. Trentacoste, S.V., Friedmann, A.S., Youker, R.T., Breckenridge, C.B. & Zirkin, B.R. (2001). Atrazine effects on testosterone levels and androgen - dependent reproductive organs in peripubertal male rats. J. Andrology, 22, 142 - 148. 

### Water Monitoring/Modeling References 1. Blomquist, J.D., J.M. Denis, J.L. Cowles, J.A. Hetrick, R.D. Jones, and N.B. Birchfield. 2001. Pesticides in Selected Wa ter- Supply Reservoirs and Finished Drinking Wa ter, 1999 - 2000: Summary of Results from a Pilot Monitoring Program. U.S. Geol ogical Survey Open - File Report 01 -456. Published in cooperation with the U.S. Environmental Protection Agency. 2. Brown, L.C., Berthouex, P.M. 2002. Statistics for Environmental Engineers. CRC Press. 3. Conover, W .J. 1980. Practical Nonparametric Sta tistics. New York: W iley. 4. Crawford, C.G. 2004. Sampling Strategies for Estimating Acute and Chronic Exposures of Pesticides in Streams. Journal of the American Wa ter Resources Association (JAW RA) 40(2):485 - 502. 5. Deutsch, C.V., and A.G. Journel. 199 8. GSLIB: Geostatistical Software Library and User’s Guide. Second Edition. Ox ford University Press (New York, Oxford). 6. FIFRA Scientific Advisory Panel (FIFRA SAP). 2009. A Set of Scientific Issues Being Considered by the Environmental Protection Ag ency Regarding: The Ecological Significance of Atrazine Effects on Primary Producers in Surface Water Streams in the Corn and Sorghum Growing Region of the United States (Part II). SAP Minutes No. 2009 - 06. May 12

– 14, 2009 FIFRA Scientific Advisory Panel . Document available at http://www.epa.gov/scipoly/sap/meetings/2009/051209meeting.html 7. Gilliom R.J., J.E. Barbash, C.G. Crawford, P.A. Hamilton, J.D. Martin, N. Nakagaki , L.H. Nowell, J.C. Scott, P.E. Stackelberg, G.P. Thelin, and D.M. W olock. 2006. The quality of our Nation’s waters

— Pesticides in the Nation’s streams and ground water, 1992

–2001. U.S. Geological Survey Circular 1291, 172 p. Available at http://pubs.usgs.gov/circ/2005/1291/pdf/circ1291.pdf 8. Lee, H.K. 2004. Bayesian Nonparametrics via Neural Networks. Philadelphia: ASA/SIAM. 9. ILSI (International Life Sciences Institute), 1999. A Framework for Estimating Pesticide Concentrations in Drinking W ater for Aggregate Exposure Assessments. International Life Sciences Institute Risk Science Institute Wo rking Group Report, Wa shington, D.C., 61 pp. Available atPage 14 of 15

http://www.ilsi.org/ResearchFoundation/Publications/Estimating%20Pesticide%20Conce ntrations.pdf 10. Isaaks, E.H., and R.M. Srivastava. 1989. Applied Geostatistics. Oxford University Press (New York, Oxford). 11. Larson, S.J., C.G. Crawford, and R.J. Gilliom. 2004. Development and application of W atershed Regressions for Pesticides (WA RP) for estimating atrazine concentration distributions in streams. U.S. Geological Surve y W ater- Resources Investigations Report 03

–4047, 68 p. Available at http://pubs.usgs.gov/wri/wri034047/ 12. Stone, W. W. ,and R.J. Gilliom. 2009. Update of watershed regressions for pesticides (WA RP) fo r predicting atrazine concentration in streams. U.S. Geological Survey Open - File Report 2009

– 1122, 22 p. Available at http://pubs.usgs.gov/of/2009/1122/ 13. Stone, W. W. , R.J. Gilliom, and C.G. Crawford. 2008. W atershed Regressions for Pesticides (WA RP) for Predicting Annual Maximum and Maximum Moving -Average Concentrations of Atrazine in Streams. U.S. Geological Survey Open - File Report 08 - 1186, 19 p. Available at http://pubs.usgs.gov/of/2008/1186/ 14. U.S. Environmental Protection Agency (USEPA). 2000. FIFRA Scientific Advisory Panel Briefing Document for a Consultation on: Monitoring Strategies for Pesticides in Surface Derived Drinking W ater. Prepared for June 6 - 9, 2000 FIFRA Scientific Advisory Panel. Document available at http://www.epa.gov/scipoly/sap/meetings/2000/june/drinkingwatersurvey.pdf 15. U.S. Environmental Protection Agency (USEPA). 2002. Organophosphate Pesticides: Revised Cumulative Risk Assessment. Current as of June 10, 2002. Documents available through the USEPA Office of Pesticide Programs web site at http://www.epa.gov/pesticides/cumulative/rra - op/

. 16 U.S. Environmental Protection Agency (USEPA). 2007a. Acetochlor Registration Agreement and Monitoring Program. Documents are available through the Federal docket. Docket ID : EPA- HQ - OPP - 2007 - 0725. Available at http://www.regulations.gov/search/Regs/home.html#docketDetail?R=EPA- HQ - OPP 2007 - 0725 17. U.S. Environmental Protect ion Agency (USEPA). 2007b. N - methyl Carbamate Revised Cumulative Risk Assessment. Available through the USEPA Office of Pesticide Programs web site at http://www.epa.gov/oppsrrd1/REDs/n mc_revised_cra.pdf

. 18. U.S. Environmental Protection Agency (USEPA). 2007c. Preliminary Interpretation of the Ecological Significance of Atrazine Stream -Wa ter ConcentrationsPage 15 of 15

Using a Statistically- Designed Monitoring Program. Prepared for the December 4

– 7, 2007 FIFRA Scientific Advisory Panel. Document available at http://www.epa.gov/scipoly/sap/meetings/2007/120407_mtg.htm 19. U.S. Environmental Protection Agency (USEPA). 2009a. The Ecological Significance of Atrazine Effects on Primary Producers i n Surface Water Streams in the Corn and Sorghum Growing Region of the United States (Part II). Prepared for the May 12

– 15, 2009 FIFRA Scientific Advisory Panel. Document available at http://www.epa.gov/scipoly/sap/meetings/2009/051209meeting.html 20. U.S. Environmental Protection Agency (USEPA). 2009b. The Ecological Significance of Atrazine Effects on Primary Producers in Surface Water Streams in the Corn and Sorghum Growi ng Region of the United States (Part II). Addendum to Section VI: Additional Analysis of the 40 AEEMP Sampling Sites to Identify Additional Areas That May Exceed the LOC. Prepared for the May 12

– 15, 2009 FIFRA Scientific Advisory Panel. Document availabl e at http://www.epa.gov/scipoly/sap/meetings/2009/051209meeting.html 21. Wh itmore, R.W ., Mosquin, P.L. Investigation of Statistical Confidence in Upper Quantiles and “Peak” Concentrations of Currently Available Atrazine Drinking W ater Monitoring Data. January 29, 2010. RTI International report Submitted to the U.S. Environmental Protection Agency by Syngenta Crop Protection, Inc. MRID #479728 - 04.