AROGYAKERALAM KASARAGOD District Programme Monitoring &Support Unit District Medical Office (Health), Kasaragod at Kanhangad, Chemmattamvayal, P.O. Balla, Pin-671531 Phone: 0467 2209466,Email:[email protected]

Doc.No.Endos./500/2011 Date: 20-08-11

Synopsis of published literatures on health effects of Dr. Mohammed Asheel Asst. Nodal Officer Endosulfan rehabilitation project, Kerala Mob: 09895989327, Email: [email protected] 1) NERVOUS SYSTEM 1.1 Title: Major Findings: Developmental exposure to zineb and/or endosulfan The study was to test the hypothesis renders the nigrostriatal dopamine that exposure to pesticides such as system more susceptible to these endosulfan and/or zineb during environmental chemicals later in life critical periods of postnatal development could result in neuronal Authors and their affiliations: dysfunction and enhance the impact Zhenquan Jia a, Hara P. Misra a,b,* of these pesticides during exposure as adults. a Department of Biomedical Sciences and Pathobiology, College of The findings support our hypothesis Veterinary Medicine, Virginia that exposure to pesticides such as Polytechnic Institute and State endosulfan and zineb during critical University, Blacksburg, VA 24061, periods of postnatal development USA contributes to neurotransmitter changes upon re‐challenge in b Edward Via Virginia College of adulthood. Osteopathic Medicine, Virginia Tech Corporate Research Center, 2265 Kraft Drive, Blacksburg, VA 24060, USA

Published in: NeuroToxicology 28 (2007) 727–735 1.2 Title: Major Findings: Endosulfan Poisoning and Chronic Brain Syndrome This report describes a case of chronic brain syndrome following poisoning Authors and their affiliations: by endosulfan; it is believed to be Dov R. Aleksandrowicz the first recorded case of such a Shalvata Psychiatric Center complication due to that compound. Hod Hasharon, Israel Published in: Arch. Toxicol. 43, 65‐68 (1979)

1.3 Title: Major Findings: Effects of in utero and lactational exposure to endosulfan in prefrontal The possible neurotoxic effects of the cortex of male rats organochlorine endosulfan have been evaluated on male Authors and their affiliations: offspring rats exposed in utero and Teresa Cabaleiro, Ana Caride, during lactation. Alejandro Romero, Anunciaci´on

כ Lafuente The developing nervous system is proposed to be a potentially sensitive Laboratorio de Toxicolog´ıa, Facultad target for pesticide exposure (Tilson, de Ciencias, Universidad de Vigo, 1998, 2000; Nakai and Satoh, 2002; Campus de Orense, Las Lagunas, Shafer and 32004 Orense, Spain Meyer, 2005)

Published in: Toxicology Letters 176 (2008) 58–67

Summarizing, in utero and lactational treatment to endosulfan induces several alterations in content and of amino acids and biogenic amines in prefrontal cortex in male rats during the development. These variations are age‐ and dose‐ dependent and they could be related to several alterations in the important functions in which the prefrontal cortex is involved such as cognitive tasks, selective attention, short term working memory, response inhibition, behavioural flexibility, etc.

1.4 Title: Major Points: Effects of endosulfan on brain acetyl‐ cholinesterase activity in juvenile The effects of endosulfan upon brain bluegill sunfish acetylcholinesterase (AChE) activity were measured in juvenile bluegill Authors and Affiliations: sunfish (Lepomis macrochirus). Hiran M. Dutta_ and Dane A. Arends Department of Biological Sciences, The duration of exposure was Kent State University, Kent, OH 44242, related to the reduction in the AChE USA activities which reflected the biotoxicity of endosulfan.

Published in: Environmental The changes in the AChE activities Research 91 (2003) 157–162 will certainly affect the normal behavior of the juvenile bluegill which is detrimental to their very existence in the natural habitat.

1.5 Title: Major Points: Selective involvement of basal We report a teenage girl with acute ganglia and occipital cortex in a endosulfan poisoning who developed patient with acute endosulfan psychosis, generalized tonic‐clonic poisoning seizures, myoclonic jerks, cortical blindness and limb rigidity. Serial Authors and Affiliations: magnetic resonance imaging (MRI) Department of Neurology, Sunjay showed bilateral reversible lesions Gandhi Postgraduate Institute of localized to caudate nucleus, Medical Sciences, Lucknow, India putamen and occipital cortex; internal capsule and thalamus were spared. Department of Radiology, Sunjay This selective involvement may have a Gandhi Postgraduate Institute of bearing on mechanisms underlying Medical Sciences, Lucknow, India endosulfan toxicity.

Department of Neuroophthalmology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

Published in: Journal of Neurological Sciences 147 (1997) 209‐213 1.6 Title: Major Findings: Association of selected persistent The case‐control study was performed organic pollutants in the placenta to explore the association between with the risk of neural tube defects placental levels of selected POPs and risks for neural tube defects (NTDs) in Authors and their affiliations a Chinese population with a high Ren, A. Qiu, X. Jin, L. Ma, J. Li, Z. prevalence of NTDs. Placental Zhang, L. Zhu, H. Finnell, R. H. concentrations were analyzed by gas Zhu, T. chromatography‐mass spectrometry.

Institute of Reproductive and Child The medians of polycyclic aromatic Health and Ministry of Health Key hydrocarbons (PAHs), o,pʹ‐isomers of Laboratory of Reproductive Health, dichlorodiphenyltrichloroethane Peking University Health Science (DDT) and metabolites, alpha‐ and Center, Beijing 100191, China. gamma‐hexachlorocyclohexane (HCH), and alpha‐endosulfan were significantly higher in case placentas Published in: than in controls. Concentrations above Proc Natl Acad Sci U S A. 2011 Jul 18 the median were associated with a 4.52‐fold [95% confidence interval (CI), 2.10‐9.74) increased risk for any NTDs, and 5.84‐ (95% CI, 2.28‐14.96) and 3.71‐fold (95% CI, 1.57‐8.79) increased risks for anencephaly and spina bifida, respectively. A dose‐ response relationship was observed for anencephaly and spina bifida subtypes. 1.7 Title: Endosulfan can induce convulsions The environmental pollutant that could lead to brain damage. The endosulfan disrupts cerebral cortical variability and lack of specificity of function at low doses neurological signs and symptoms in the pre‐convulsive stages makes early Authors and their affiliations diagnosis difficult. We sought to Scremin, Oscar U determine if electrophysiological Chialvo, Dante R exploration of the cerebral cortex Lavarello, Simona could yield objective signs of Berra, Hector H endosulfan intoxication at levels that Lucero, Miguel A do not elicit convulsions. Netherlands EEG power and the evoked potentials (EP) to electrical stimulation were Instituto de Toxicologia Agraria de studied over the contralateral (S1CL) Rosario, Facultad de Ciencias and homolateral (S1HL) cortical Medicas, UNR, Santa Fe 3100, Rosario somatosensory areas and the CP2000, Argentina. contralateral visual area (V1CL). [email protected] Endosulfan induced a dose‐related Published in: increase in EPs at all sites. Neurotoxicology. 2011 Jan;32(1):31‐7. Epub 2010 Dec 7. In conclusion, endosulfan induced a large increase of cortical evoked potentials amplitudes at doses that did not elicit convulsions. These responses could be used as a non‐ invasive diagnostic tool to detect low‐level endosulfan intoxication in humans and to help establish the NOAEL and LOAEL levels of this pollutant.

2) REPRODUCTIVE SYSTEM 2.1 Title: Major Findings: A method to determine residue levels of persistent A method has been developed for the organochlorine pesticides in analysis of organochlorine pesticides in human milk from human milk using solvent extraction, Indonesian women Florisil_ solid phase extraction clean‐up and analysis by gas chromatography with an Authors and their affiliations: electron capture detector. Emma R. Burke a, Alexis J. Holden a,*, Ian C. Shaw b There was no significant difference (at the 95% confidence level) in levels of a Department of Environmental pesticides between urban and rural areas Management, University of Central Lancashire, Preston PR1 2HE, UK

b Environmental Science &Research Institute, 27 Creyke Rd, Christchurch, New Zealand

Published in: Chemosphere 50 (2003) 529–535 2002 Elsevier Science Ltd 2.2 Title: Major Findings: Endosulfan sulphate interferes with reproduction, embryonic The aim of this study was to evaluate the development and sex possible effects promoted by endosulfan differentiation in Daphnia sulphate in changes on the life cycle, magna embryo development and sex differentiation of Daphnia magna.

Authors and their affiliations: Endosulfan sulphate promoted a P. Palma a,c,_, V.L. Palmaa, R.M. significant decrease of the offspring Fernandes a, A.M.V.M. Soares b, number in all concentrations. Results I.R. Barbosa showed a reduction of the size of females, together with a decrease in moulting a Departamento de Cieˆncias do frequency. Furthermore, an increase in Ambiente, Escola Superior embryo deformities was observed at all Agra´ria de Beja, Beja 7800‐295, concentrations tested. Above a Portugal concentration of 91.7 mgL_1 there was an increased production of males. The results b CESAM & Departamento de suggest that endosulfan sulphate interferes Biologia da Universidade de with the life cycle and sex determination of Aveiro, Aveiro 3810‐193, the crustacean D. magna. Portugal

c Centro de Estudos Farmaceˆuticos, Faculdade de Farma´cia, Universidade de Coimbra, Rua do Norte, Coimbra 3000‐295, Portugal

Published in: Ecotoxicology and Environmental Safety 72 (2009) 344– 350 2.3 Title: Major Findings: Persistent Pesticides in Human Breast Milk and Cryptorchidism Eight organochlorine pesticides (including Endosulfan) were measured in all samples Authors and their affiliations: (medians; nanograms per gram lipid) for Ida N. Damgaard,1 Niels E. cases/controls. Skakkebæk,1 Jorma Toppari,2 Helena E. Virtanen,2 Heqing Statistical analysis showed that pesticide Shen,3 Karl‐Werner Schramm,3 levels in breast milk were significantly Jørgen H. Petersen,1,4 Tina K. higher in boys with cryptorchidism (p = Jensen,1 Katharina M. Main 0.032).

1University Department of In conclusion, our study suggests an Growth and Reproduction, association between congenital Copenhagen, Denmark; cryptorchidism and persistent 2Departments of Physiology and organochlorine pesticides present in Pediatrics, University of Turku, mothers’ breast milk. Turku, Finland; 3GSF‐National Research Center Prenatal exposure to persistent for Environmental and Health, organochlorine pesticides may adversely Institute for Ecological affect testicular descent in boys. Chemistry, euherberg, Germany; 4Department of Biostatistics, University of Copenhagen, Denmark

Published in: Environ Health Perspect 114:1133–1138 (2006). 2.4 Title: Major Findings: Organochlorine pesticide residue The aim of the present study was to analyze levels and oxidative stress in the OCP residues in maternal and cord preterm delivery cases blood of women and assess the levels of different non‐enzymatic oxidative stress Authors and their affiliations: markers as well as to establish correlation Rahul Pathak1, Sanvidhan G with OCP levels, if any. Suke1, Tanzeel Ahmed1, Rafat S Levels of OCPs like Hexachlorocyclohexane Ahmed1, AK Tripathi1, Kiran (HCH), endosulfan, and DDT were Guleria2, CS Sharma3, SD analyzed by gas chromatography. Non‐ Makhijani3 and BD Banerjee1 enzymatic oxidative stress was measured.

1 Environmental Biochemistry In conclusion, our results suggest that and Immunology laboratory, higher levels of some of the OCP (like Department of Biochemistry, Endosulfan) may be associated with University College of Medical Preterm Delivery and increased oxidative Sciences & G.T.B. Hospital stress. (University of Delhi), Delhi, India 2 Department of Obstetrics and Gynecology, University College of Medical Sciences & G.T.B. Hospital (University of Delhi), Delhi, India

3 Instrumentation and Bio‐Labs, Central Pollution Control Board, Ministry of Environment and Forest, Delhi, India

Published in: Human and Experimental Toxicology 29(5) 351–358

2.5 Title: Major Findings: Endosulfan and its metabolites in fertile women, placenta, cord The present study investigated the blood, and human milk presence of endosulfan I, endosulfan II, and endosulfan metabolites in fatty and Authors and their affiliations: non‐fatty tissues and fluids from women of Isabel Cerrilloa, Alicia Granadaa, reproductive age and children in Southern Marı´a‐Jose´ Lo´ pez‐Espinosaa, Spain. Begon˜ a Olmosa, Margarita Jime´neza, Africa Can˜ ob, The highest concentration of commercial Nicolas Oleaa,_, Marı´a Fa´ tima endosulfan I and endosulfan II was found in Olea‐Serranoc adipose tissue, with a mean value (I+II) of aLaboratory of Medical 17.72 ng/g lipid, followed by human milk, Investigations, Department of with a mean value (I+II) of 11.38 ng/mL Radiology, School of Medicine, milk. Hospital Clinico, University of Granada, 18071 Granada, Spain This study suggests that exposure from bGynecology & Obstetric Service, mother to child is a common event, both in Hospital Clı´nico, Granada, Spain utero and via breastfeeding, due to the high cFood Sciences Department, frequency of exposure of women of University of Granada, Granada, reproductive age. Spain

Published in: Environmental Research 98 (2005) 233–239

2.6 Title: Major Points: Effect of Endosulfan on Male A study to examine the relationship Reproductive Development between environmental endosulfan exposure and reproductive development in Authors and Affiliations: male children and adolescents. Habibullah Saiyed,1 Aruna The study population was composed of 117 Dewan,1 Vijay Bhatnagar,1 male schoolchildren (10–19 years of age) of a Udyavar Shenoy,2 Rathika village situated at the foothills of cashew Shenoy,2 Hirehall Rajmohan,3 plantations. Kumud Patel,1 Rekha Kashyap,1 The study parameters included recording of Pradip Kulkarni,1 Bagalur clinical history, physical examination, Rajan,3 and Bhadabhai Lakkad1 sexual maturity rating (SMR) according to Tanner stages, and estimation of serum 1National Institute of levels of , luteinizing hormone Occupational Health (Indian (LH), follicle‐stimulating hormone, and Council of Medical Research), endosulfan residues. Meghani Nagar, Ahmedabad, Our study results suggest that endosulfan India; exposure in male children may delay sexual maturity and interfere with sex 2Department of Pediatrics, hormone synthesis. Kasturba Medical College, Mangalore, India; 3Regional Occupational Health Research Centre, Bangalore, India

Published in: VOLUME 111 | NUMBER 16 | December 2003 • Environmental Health Perspectives 2.7 Title: Major Findings: Peripheral precocious puberty in A 4‐month‐old girl presented with sexual a 4‐month‐old girl: role of development, including breast enlargement, pesticides? menstruation, uterine length of 69?mm at ultrasonography, and dramatically high Authors and their affiliations bioactivity, but no growth Gaspari, L. acceleration, pubic hair, pelvis masses or Paris, F. O. adrenal tumors. Jeandel, C. Sultan, C. Gas chromatography with an electron capture detector and mass spectrometry Unit dʹEndocrinologie‐ detected pesticides (DDT, and Gyncologie Pediatrique, Service endosulfan sulpfate) in plasma from the de Pediatrie 1, Hospital Arnaud‐ infant, the mother, and the 38‐year‐old de‐Villeneuve, CHU Montpellier, father, who reported a dramatic decrease in University Montpellier I, libido, and in soil samples from their farm. Montpellier, France. The precocious sexual development was probably caused by the estrogen activity of Published in: the environmental contamination by tons of Gynecol Endocrinol. 2011 Feb 9. pesticides stored in the family farm.

3) ENDOCRINE SYSTEM 3.1 Title: Major Findings: Effect of pesticides on transactivation in vitro: A The estrogenic potential of four comparison of stable transfected pesticides (endosulfan, , MVLN and transient transfected tolchlofos‐methyl and propamocarb) MCF‐7 cells was compared in parallel with 17_‐ (E2) by reporter constructs in Authors and their affiliations: transient transfected MCF‐7BUS and in stable transfected MVLN cells.

Heidi ,כ Eva C. Bonefeld‐Jorgensen In MVLN cells, endosulfan, prochloraz, tolchlofos‐methyl and T. Gr¨unfeld, Irene M. Gjermandsen propamocarb caused cytotoxic responses at concentrations higher Unit of Environmental than 10, 25, 25 and 100 _M, Biotechnology, Department of respectively. Environmental and Occupational Medicine, University of Aarhus, Vennelyst Boulevard 6, DK‐8000 Aarhus, Denmark

Published in: Molecular and Cellular Endocrinology 244 (2005) 20–30 3.2 Title: Major Findings: ‐Induced ERK‐1 and The objective of the study was to ERK‐2 Activation via Multiple investigate the ability of some of the Membrane‐Initiated Signaling estrogen mimetics (belonging to major Pathways classes of environmental ) to produce rapid activation of ERKs via Authors and their affiliations: various signaling pathways in the Bulayeva, Nataliya N;Watson, GH3/B6/F10 prolactinoma cell lines. Cheryl S Endosulfan was able to produce Department of Human Biological phosphorylation at almost all tested Chemistry and genetics, University concentrations. of Texas Medical Branch, Galveston, Basically two patterns of stimulations Texas, USA were seen: Compounds active in both subpicomolar and nanomolar ranges Published in: (Endosulfan, and Environmental Health coumestrol) versus compounds active Perspectives; Nov 2004; 112, 15; only in the nanomolecular range (DDE ProQuest pg. 1481 and ). 3.3 Title: Major Findings: Effects of Currently Used Pesticides in Assays for Twenty‐four pesticides were tested for Estrogenicity, Androgenicity, and interactions with the estrogen receptor Activity in Vitro (ER) and the androgen receptor (AR) in transactivation assays. Authors and their affiliations: Helle Raun Andersen,* Anne Marie The two organochlor insecticides Vinggaard,† Thomas Høj dieldrin and Endosulfan increased cell Rasmussen,* Irene Marianne proliferation and ER transactivation Gjermandsen,‡ and Eva Cecilie gene response in MCF‐7 cells Bonefeld‐Jørgensen‡ significantly at 5 and 1 _M, respectively. Both compounds induced maximum *Environmental Medicine, Institute response at 25 _M, whereas higher of Public Health, University of concentrations resulted in a decreased Southern Denmark, Odense, response due to cytotoxicity. In both Winsløwparken 17, DK‐5000 Odense assays, the response induced by C, Denmark; endosulfan was higher than the †Institute of Food Safety and response induced by dieldrin. Toxicology, Division of Biochemical Endosulfan potentiated the 17_‐ and Molecular Toxicology, Danish estradiolinduced proliferation when it Veterinary and Food was tested together with a Administration, Mørkhøj Bygade 19, concentration of 17_‐estradiol causing a DK‐2860 Søborg, Denmark; and submaximum response. Dieldrin did ‡Department of Environmental and not enhance the 17_‐estradiol‐induced Occupational Medicine, Unit of response in any of the assays. Environmental Biotechnology, University of Aarhus, Building 260, Vennelyst Boulevard 6, DK‐8000 Aarhus C, Denmark

Published in: Toxicology and Applied Pharmacology 179, 1–12 (2002) 3.4 Title: Major Points: Endosulfan effects on pituitary The study was undertaken to hormone and both nitrosative and investigate in pubertal male rats oxidative stress in pubertal male possible effects of endosulfan rats administered throughout lactation and gestation on: (a) pituitary gene Authors and Affiliations: expression of prolactin, luteinizing hormone (LH), growth hormone (GH) and thyroid stimulating hormone T. Cabaleiro ,כA. Caride, A. Lafuente (TSH); and (b) circulating levels of these hormones. Laboratorio de Toxicología, Facultad de Ciencias, Universidad de Vigo, In pubertal male rat, prenatal and Campus de Orense, Las Lagunas, lactational exposure to endosulfan 32004 Orense, Spain modifies expression and release of prolactin, LH, GH and TSH, and Published in: pituitary NOS1 and NOS2 mRNA Toxicology Letters 197 (2010) 106– levels, suggesting that nitrosative stress 112 can be implicated in the endocrine toxicity of endosulfan at pituitary level. 3.5 Title: Major Points: Screening of some anti‐progestin endocrine disruptors using a About 7 different chemicals (mostly recombinant yeast based in vitro pesticides or their metabolites) like bioassay DDT and its metabolites, nonylphenol, endosulfan were screened in this assay Authors and Affiliations: system for their role in transactivation Shamba Chatterjee a,1, Vikas Kumar and they were all found to be anti‐ a,1, Chandrajeet B. Majumder b, progestative. Partha Roy a,* a Molecular Endocrinology Laboratory, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India

b Fluid Particle Research Laboratory, Department of Chemical Engineering, Indian Institute of Technology Roorkee, Roorkee 247 667, Uttarakhand, India

Published in: Toxicology in Vitro 22 (2008) 788– 798 3.6 Title: Major Points: Circulating thyroid hormone levels We evaluated the effects of two and iodothyronine deiodinase organochlorinated environmental activities in Nile tilapia contaminants, Endosulfan and Aroclor (Oreochromis niloticus) following 1254 on peripheral thyroid hormone dietary exposure to Endosulfan and metabolism and thyroid hormone Aroclor plasma levels in Nile tilapia (Oreochromis niloticus). Authors and Affiliations: Ana Maria Coimbraa,b,*, Maria It is concluded that dietary exposure of Armanda Reis‐Henriquesa,b, Veerle tilapia to Endosulfan or Aroclor 1254 M. Darrasc can lead to changes in circulating a) ICBAS‐Instituto de Cieˆncias thyroid hormone levels and/or in Biome´dicas de Abel Salazar, peripheral thyroid hormone Laborato´rio de Fisiologia Aplicada, metabolism. The changes in hormone Largo do Prof. Abel Salazar 2, 4099‐ metabolism differ between tissues, 003, Porto, Portugal eventually reflecting tissue‐specific b) CIIMAR‐Centro Interdisciplinar differences in adaptation. de Investigac¸a˜o Marinha e Ambiental, Laborato´ rio de Toxicologia Ambiental, Rua dos Bragas 289, 4050‐123, Porto, Portugal c) Laboratory of Comparative Endocrinology, Zoological Institute K.U. Leuven, Naamsestraat 61, B‐ 3000 Leuven, Belgium

Published in: Comparative Biochemistry and Physiology, Part C 141 (2005) 8 – 14 3.7 Title: Major Points: Human Exposure to Endocrine‐ Disrupting Chemicals and Prenatal In this study we aimed to determine Risk Factors for Cryptorchidism whether the combined effect of and Hypospadias: A Nested Case– environmental estrogens measured as Control Study total effective xenoestrogen burden (TEXB) is a risk factor for male Authors and Affiliations: urogenital malformations. Mariana F. Fernandez,1 Begoña Olmos,1 Alicia Granada,1 Maria José We found an increased risk for male López‐Espinosa,1 José‐Manuel urogenital malformations related to Molina‐Molina,1 Juan Manuel the combined effect of environmental Fernandez,2 Milagros Cruz,3 Fátima estrogens in placenta. Olea‐Serrano,4 and Nicolás Olea1

1Laboratory of Medical Investigations, 2Department of Pediatrics, and 3Department of Gynecology and Obstetrics, San Cecilio UniversityHospital, Granada, Spain; 4Department of Nutrition, University of Granada, Granada, Spain

Published in: VOLUME 115 | SUPPLEMENT 1 | December 2007 • Environmental Health Perspectives

3.8 Title: Major Points: Endocrine disrupters and human Epidemiological research studying the puberty effect of endocrine disrupters on the onset of puberty is summarized. Authors and Affiliations: In girls, earlier age at menarche was E. Den Hond and G. Schoeters reported after exposure to polychlorinated biphenyls (PCBs), poly Department of Toxicology, VITO brominated biphenyls (PBBs), persistent (Flemish Institute for Technological pesticides (DDT, endosulfan) and Research), Mol, Belgium esters. In boys, exposure to PCBs, PCDFs or Published in: the pesticide endosulfan was associated international journal of andrology with delayed puberty or decreased 29 (2006) 264–271 penile length. 3.9 Title: Major Points: Oxidative stress and loss of cortisol The effects of endosulfan on cortisol secretion in adrenocortical cells of secretion, cell viability, antioxidants and rainbow trout (Oncorhynchus) lipid peroxidation were investigated. exposed in vitro to endosulfan, an organochlorine pesticide The in vitro study identified endosulfan as a chemical inducing a Authors and Affiliations: loss of secretory responses in teleost J. Dorval, V.S. Leblond, A. Hontela * adrenocortical steroidogenic cells and alterations in the activity of enzymes De´partement des Sciences known to be involved in oxidative Biologiques, Universite´ du Que´bec stress pathways. a` Montre´al, TOXEN Research Moreover, the significant increase in Centre, C.P. 8888, succ. Centre‐ville, lipid hydroperoxides levels provided Montre´al, Que´., Canada H3C 3P8 further evidence for endosulfan‐ induced oxidative stress. Published in:

Aquatic Toxicology 63 (2003) 229_/241

3.10 Title: Major Points: Effect of in vitro estrogenic pesticides on human oestrogen Nine widely distributed pesticides were receptor _ and _ mRNA levels recently demonstrated to possess potential estrogenic properties in Authors and Affiliations: oestrogen receptor (ER) transactivation H.T. Grünfeld, E.C. Bonefeld‐ and/or E‐screen assays.

This study demonstrated that כJorgensen organochlor and organo‐phosphorous pesticides possess the ability to Unit of Environmental Biotechnology, interfere with the ER_ and ER_ mRNA Department of Environmental and steady state levels. Occupational Medicine, University of Aarhus, Vennelyst Boulevard 6, DK‐8000 Aarhus, Denmark

Published in: Toxicology Letters 151 (2004) 467– 480 3.11 Title: Major Findings: The organochlorine chemicals Differential estrogenic effects of endosulfan, dieldrin, and gamma‐ the persistent organochlorine hexachlorocyclohexane (lindane) are pesticides dieldrin, endosulfan, persistent pesticides to which people and lindane in primary neuronal are exposed mainly via diet. Their cultures antagonism of the gamma‐aminobutyric acid‐A (GABA(A)) receptor makes them Authors and their affiliations convulsants. They are also endocrine Briz, Victor disruptors because of their interaction Molina‐Molina, Jose‐Manuel with the estrogen receptor (ER). Here, Sanchez‐Redondo, Sara we study the effects of dieldrin, Fernandez, Mariana F endosulfan, and lindane on ERs in Grimalt, Joan O primary cultures of cortical neurons Olea, Nicolas (CN) and cerebellar granule cells Rodriguez‐Farre, Eduard (CGC). Sunol, Cristina All the compounds tested inhibited the binding of [(3)H]‐estradiol to the ER in both CN and CGC, with dieldrin in Department of Neurochemistry and CGC showing the highest affinity. Neuropharmacology, Institut Moreover, extracts of CN treated with dʹInvestigacions Biomediques de endosulfan, dieldrin, or lindane Barcelona, Consejo Superior de induced cell proliferation in MCF‐7 Investigaciones Cientificas, Institut human ‐derived cells. dʹinvestigacions Biomediques Overall, the observed alterations on ER‐ August Pi i Sunyer, E‐08036 mediated signaling and ER levels in Barcelona, Spain. neurons might contribute to the neurotoxicity of these organochlorine Published in: pesticides.

Toxicol Sci. 2011 Apr;120(2):413‐27. Epub 2011 Jan 27.

3.12 Title: Major Findings: Prenatal exposure to OBJECTIVE: To investigate the organochlorine pesticides and TSH association between prenatal exposure status in newborns from Southern to organochlorine pesticides (OCPs) Spain and thyroid‐stimulating hormone (TSH) levels in male newborns. METHODS: Exposure to 17 OCPs was analyzed in Authors and their affiliations 220 placentas from a male birth cohort Freire, Carmen ,Lopez‐Espinosa, in Southern Spain, and TSH was Maria‐Jose,Fernandez, Marieta measured in the umbilical cord blood. Molina‐Molina, Jose‐Manuel OCP concentrations were quantified by Prada, Remedios, Olea, Nicolas gas chromatography and mass Netherlands spectrometry. Multivariate regression analysis was conducted to examine the Laboratory of Medical association between pesticide exposure Investigations, San Cecilio and neonatal TSH levels, adjusting for University Hospital, University of confounders. RESULTS: Newborn boys Granada, CIBER de Epidemiologia y with higher exposure to endrin in Salud Publica (CIBERESP), Av. placenta had higher odds of TSH cord Madrid s/n, 18071 Granada, Spain. blood levels ,higher prenatal exposure to endosulfan‐sulfate was associated Published in: with lower odds of TSH >/=5mU/L. A Sci Total Environ. 2011 Aug marginally significant negative 15;409(18):3281‐7. association was found between TSH and hexachlorobenzene levels. No association was found between TSH and the remaining pesticides.

CONCLUSIONS: Early exposure to certain environmental chemicals with endocrine‐disruption activity may interfere with neonatal thyroid hormone status; however, the pattern of interference is not yet clearly elucidated.

3.13 Title: Major Points: Estrogen‐like endocrine disrupting Estrogen‐like endocrine disrupting chemicals affecting puberty in chemicals (EEDC) are exogenous, man‐ humans‐‐a review made chemicals that alter the functions of the endocrine system and cause Authors and Affiliations: various health defects by interfering Roy, Jonathan R , Chakraborty, with the synthesis, metabolism, binding Sanjoy Chakraborty, Tandra R or cellular responses of natural estrogens. Major EEDCs found Department of Biology, Adelphi abundantly in our environment include; University, Garden City, New York, Endosulfan, DDT, dioxin, NY 11530, USA. polychlorinated biphenyls (PCBs), (BPA), polybrominated Published in: biphenyls (PBB), phthalate esters, Med Sci Monit. 2009 and . In girls, EEDCs Jun;15(6):RA137‐45. has been linked to earlier menarche, abnormal breast development in pre‐ pubertal, earlier menarche, thelarche and earlier pubic hair stage. In males, endosulfan affects pubertal boys by slowing down the timing of reproductive maturation. This article provides a possible structure‐function relation of the above mentioned EEDCs which interfere with sexual development during puberty.

3.14 Title: Major Points: Endosulfan effects on pituitary The present study was undertaken to hormone and both nitrosative and investigate the possible effects of oxidative stress in pubertal male endosulfan on: rats (a) pituitary gene expression of prolactin, luteinizing hormone (LH), Authors and Affiliations: growth hormone (GH) and thyroid Caride, A, Lafuente, A, Cabaleiro, T stimulating hormone (TSH); (b) circulating levels of these hormones; and Laboratorio de Toxicologia, Facultad (c) expression of nitric oxide synthase 1 de Ciencias, Universidad de Vigo, and 2 (NOS1 and NOS2), and heme Campus de Orense, Las Lagunas, oxygenase‐1 (HO‐1) at pituitary level. 32004 Orense, Spain We can conclude that in pubertal male Published in: rat, prenatal and lactational exposure to Toxicol Lett. 2010 Aug 16;197(2):106‐ endosulfan modifies expression and 12. Epub 2010 May 13. release of prolactin, LH, GH and TSH, and pituitary NOS1 and NOS2 mRNA levels, suggesting that nitrosative stress can be implicated in the endocrine toxicity of endosulfan at pituitary level.

4) IMMUNE SYSTEM 4.1 Title: Major Points:

Determination of the The effect of eight pesticides with different immunotoxic potential of chemical structure (atrazine, bentazone, pesticides on functional activity chloride‐zone, dichlofluanid, endosulfan, of sheep leukocytes in vitro MCPA, simazine, triallate) on sheep peripheral blood phagocytes and Authors and Affiliations: lymphocytes was examined. Juraj Pistl *, Nata´lia Kovalkovicˇova´, Vanda Three of the pesticides tested suppressed Holovska´, Jaroslav Lega´th, both, the metabolic activity of phagocytes Ivan Mikula and mitogenic activation of lymphocytes (dichlofluanid, endosulfan and simazine). Department of Microbiology and Immunology, University of Veterinary Medicine, 041 81 Kosˇice, Slovakia

Published in: Toxicology 188 (2003) 73_/81 4.2 Title: Major Points:

Toxic effects of endosulfan on The objective was to evaluate possible blood lymphocyte subsets in immune alterations induced by endosulfan adult rats exposure during pregnancy and lactation in both male and female adult rats. Authors and Affiliations: A. Lafuente, T. Cabaleiro, A. The results suggest that endosulfan Caride, A. Romero exposure during pregnancy and lactation Laboratorio de Toxicolog´ıa, Facultad could modify humoral immunity in de Ciencias, Universidad de Vigo, offspring adulthood, and that females are Campus de Orense, Las Lagunas s/n, more susceptible to this pesticide because 32004‐Orense, Spain their cellular immunity was also altered.

Published in: Toxicology Letters 164S (2006) S1–S324

5) GENOTOXICITY, CYTOTOXICITY AND TERATOGENICITY 5.1 Title : Major Findings: Comet assay in phytoplankton as Genotoxicity was observed from biomarker of genotoxic effects of 1 lg/L of endosulfan and was environmental pollution not concentration dependent. Authors and their affiliations: Akcha a,*, G. Arzul a, S. Rousseau a, M. Endosulfan exposure resulted in Bardouil b DNA strand breaks from the aIFREMER, Laboratoire d’Ecotoxicologie, concentration of 1 lg/L (p < 0.05), Rue de l’Ile d’Yeu, 44311 Nantes Cedex 03, but effect did not appear to be France concentration dependent b IFREMER, Laboratoire Phycotoxines, Rue de l’Ile d’Yeu, 44311 Nantes Cedex 03, France Published in: Marine Environmental Research 66 (2008) pg: 59–61 journal homepage: www.elsevier.com/locate/marenvrev _ 2008 Elsevier Ltd. 5.2 Title : Major Findings: Endosulfan Decreases Cell Growth and This study was designed to Apoptosis in Human HaCaT assess the mitogenic, Keratinocytes:Partial ROS‐Dependent apoptogenic, and genotoxic ERK1/2 Mechanism effects of endosulfan on the Authors and their affiliations: HaCaT cell line. SEBASTIEN ANTHERIEU,1* NATHALIE Endosulfan has been shown to LEDIRAC,1 ANNE‐PASCALE LUZY,2 PHILIPPE generate transient reactive LENORMAND,3 JEAN‐CLAUDE CARON,2 oxygen species (ROS), and AND ROGER RAHMANI1* blocking this oxidative stress by 1 INRA, UMR 1112 ‘‘Re´ponses des N‐acetyl cysteine (NAC) strongly Organismes aux Stress Environnementaux’’, prevented both persistent Equipe de Toxicologie Cellulaire, nuclear ERK1/2 phosphorylation Mole´culaire et Ge´nomique, Sophia‐ and cell growth decrease. Antipolis, France Additional experiments 2 Galderma R&D, Les Templiers, Biot, demonstrated that unchanged France endosulfan rather than its 3 Institute of Signaling, Developmental metabolites has mutagenic Biology and Cancer Research, CNRS‐UMR effects and increased DNA 6543, Centre Antoine Lacassagne, Nice, strand breaks in human France keratinocytes. In conclusion, the results show Published in: that human keratinocytes are J. Cell. Physiol. 213: 177–186, 2007. more affected by a chronic than an acute exposure to endosulfan. On the whole, our findings demonstrate that endosulfan disrupts epidermal homeostasis by two concomitant independent mechanisms: a ROS‐dependent mechanism responsible for DNA damage and decrease in cell proliferation, and a ROS‐independent inhibition of apoptosis that could contribute to mutant cell survival and therefore have possible carcinogenic effects. 5.3 Title : Major Findings: Analysis of Endosulfan and Its Metabolites A new analytical method in Human Serum Using Gas combining solid‐phase extraction Chromatography–Tandem and gas chromatography– Mass Spectrometry tandem mass spectrometry used to determine the insecticide Authors and their affiliations: endosulfan as well as its F.J. Arrebola1, J.L. Martínez Vidal1,*, and A. metabolites endosulfan‐ether, ‐ Fernández‐Gutiérrez2 lactone, and ‐sulfate in human 1 Department of Analytical Chemistry, serum. University of Almería, 04071 Almería, Spain The mean levels of the total 2 Department of Analytical Chemistry, endosulfan found in the farmers University ofGranada, 18071 Granada, Spain were significantly higher than Published in: the mean level present in the Journal of Chromatographic Science, Vol. non‐occupationally exposed 39, May 2001 people group. The results obtained revealed that the pesticide could be detected practically intact in human blood, the similarity of the results obtained from the serum samples of the two studied groups and the differences found when the urine samples were analyzed seemed to indicate that urine analysis offers information about a recent exposition of the individual and serum analysis shows that information can be attributed to less recent expositions. 5.4 Title : Major Findings: Oxidative stress responses in different Our present results demonstrate organs of Jenynsia multidentata exposed to that exposure to a sublethal Endosulfan concentration of Endosulfan Authors and their affiliations: results in oxidative stress in M.L. Ballesterosa, D.A.Wunderlinb, several organs of J. multidentata. M.A.Bistonia, The brain was the most sensitive a Universida Nacionalde Co´rdoba, Facult organ to oxidative damage. adde Ciencias Exacta sFı´sicasy Naturales,Ca´tedra DiversidadAnimalII,Avda.Ve´lez Sa´rsfield 299, 5000 Co´rdoba, Argentina b Universid Nacional deCo´rdoba‐ CONICET, Facultad de Ciencias Quı´micas, Dto.Bioquı´mica Clı´nica‐CIBICI Published in: Ecotoxicology and Environmental Safety 72 (2009) 199–205 2008 ElsevierInc.Allrightsreserved 5.5 Title : Major Findings: DNA Damage and Mutagenicity Induced Endosulfan and metabolites may by Endosulfan and Its Metabolites interact with DNA directly or Authors and their affiliations: through the production of ROS. MahimaBajpayee,1 AlokKumar Pandey,1 In conclusion, the present study SabinaZaidi,2 JavedMusarrat,2 Devendra is the first to compare endosulfan Parmar,1 NeerajMathur,3 PrahladKishore with its isomers and metabolites Seth,1 and AlokDhawan1* for their ability to induce 1) Developmental Toxicology Division, mutations in a conventional Industrial Toxicology Research Centre, bacterial test system and to Lucknow‐226001, India induce DNA damage in 2) Department of Microbiology, Faculty of mammalian cells. Endosulfan, its Agricultural Sciences, Aligarh Muslim isomers, and metabolites were University, Aligarh‐202002, India positive in both the bacterial and 3) Epidemiology Section, Industrial mammalian cell systems Toxicology Research Centre, Lucknow‐ 226001, India Published in: Environmental and Molecular Mutagenesis 47:682^692 (2006) VVC 2006Wiley‐Liss, Inc. 5.6 Title : Major Findings: Selective induction of the CYP3A family by This report clearly shows the endosulfan and DNA‐adduct formation in genotoxicity of endosulfan. This different hepatic and hepatoma cells chlorinated insecticide induces Authors and their affiliations: the formation of abundant DNA M. Dubois a, A. Pfohl‐Leszkowicz ‘, I. De adducts in both fetal rat Waziers ‘, P. Kremers S* hepatocytes and Hep G2 cells. a Universit P de Litge. Lahorcrtoire de Endosulfan strongly correlated to Chimie M:dicale, lnstitut de Pathologir, B35, the high induction of CYP3A Centre Hospitalier Unir~ersitaue. B‐4000 gene expression. Surf Tilman, Belgium Endosulfan has a major impact h E.N.S.A.T.. Lahorrrtoire de Toxicologic et on the human liver via induction SCcuritr’ Alimentaire. 145 Al,. de Muret. of CYP3A4 and CYP3A7. 31076 Toulouse. France ’ Uniti de Rerherche de Biochirnie Pharmacologique et MPtabolique (INSERM U751. CHU Necker‐Erzfant Malades. 156 rue de Vougirard. 75730 Paris Cedex 15. France Published in: Environmental Toxicology and Pharmacology 1 (1996) 249‐256 5.7 Title: Major Findings: Exposure to mixtures of endosulfan and A number of epidemiological zineb induces apoptotic and necrotic cell studies have demonstrated a death in SH‐SY5Y neuroblastoma cells, in strong association between the vitro incidence of Parkinson’s disease Authors and their affiliations: and pesticide exposure Zhenquan Jia1 and Hara P. Misra1,2,* In conclusion, our results help to 1 Department of Biomedical Sciences and better characterize pesticide‐ Pathobiology, College of Veterinary induced neuroblastoma cell Medicine, Virginia Polytechnic Institute and death. Both zineb and State University, Blacksburg, VA 24061, USA endosulfan were found to 2 Edward Via Virginia College of induce cytotoxicity in SH‐SY5Y Osteopathic Medicine, Virginia Tech cells via both apoptotic and Corporate Research Center, 2265 Kraft necrotic pathways. Drive, Blacksburg, VA 24060, USA Published in: Together, with evidence JOURNAL OF APPLIED TOXICOLOGY provided in this study, it appears J. Appl. Toxicol. 2007; 27: 434–446 likely that endosulfan and zineb Published online 16 February 2007 in Wiley alone or in combination play a InterScience role in the cell death in an in (www.interscience.wiley.com) DOI: vitro model system that may, at 10.1002/jat.1218 least in part, be involved in the degeneration of dopaminergic neurons and may be relevant for the pathogenesis of some of these neurodegenerative diseases. 5.8 Title: Major Findings: Advantages of Human Hepatocyte‐Derived Endosulfan was found to induce Transformants Expressing a Series of MN through the CYP3A4‐ Human Cytochrome P450 Isoforms for mediated pathway Genotoxicity Examination Endosulfan sulfate was the Authors and their affiliations: genotoxic metabolite to induce Tsuneo Hashizume,* Sumie Yoshitomi,† MN ; this metabolite was Satoru Asahi,* Rieko Uematsu,* Shigeo considered to be produced in the Matsumura,* Fumio Chatani,* and HepG2 transformant expressing Hiroaki Oda‡,1 human CYP3A4 by the treatment *Development Research Center and with b‐endosulfan. †Discovery Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17‐85 , Jusohonmachi 2‐chome, Yodogawa‐ku, Osaka 532‐8686, Japan; and ‡Laboratory of Nutritional Biochemistry, Nagoya University Graduate School of Bioagricultural Sciences, Furo‐cho, Chikusa‐ ku, Nagoya 464‐8601, Japan Published in: TOXICOLOGICAL SCIENCES 116(2), 488– 497 (2010) doi:10.1093/toxsci/kfq154 5.9 Title: Major Findings: Citrinin and endosulfan induced The present investigation was teratogenic effects in Wistar rats conducted to evaluate the Authors and their affiliations: teratogenic potential of citrinin Nittin D. Singh,† Anil K. Sharma,* (CIT) and endosulfan either Prabhaker Dwivedi, Rajendra D. Patil and alone or in combination in Manoj Kumar pregnant rats during gestational Division of Pathology, Indian Veterinary days 6–20. Research Institute, Izatnagar‐ 243122, India In the present study, endosulfan treatment induced Published in: fetal gross anomalies The JOURNAL OF APPLIED TOXICOLOGY internal hydrocephalus, J. Appl. Toxicol. 2007; 27: 143–151 cerebellar hypoplasia, Published online 22 December 2006 in microphthalmia, contracted and Wiley InterScience notched kidneys, (www.interscience.wiley.com) DOI: multilobulated liver, dilated 10.1002/jat.1185 renal pelvis, incomplete ossification of skull bones, rib 2006 John Wiley & Sons, Ltd anomalies and sacral and caudal vertebrae agenesis were the important fetal malformations The dose of endosulfan (1 mg kg−1 body weight) employed in the present study is lower than the dose established by the World Health Organization (WHO) for reproductive toxicity assessment in rats (WHO, 1984). Because of widespread use or contamination of CIT and endosulfan in the environment and its occurrence in the animal and human food (Anderson, 1995) and the presence of residues in the blood and milk samples of females (Sancewicz‐ Pach et al., 1997; Sanghi et al., 2003), these might pose a potential risk to developing fetuses during pre‐natal and post‐natal life 5.10 Title: Major Findings: Human health risk assessment of A primary risk assessment endosulfan. I: Toxicology and hazard concern for endosulfan is that identification effects resulting from exposure Authors and their affiliations: during critical developmental Marilyn H. Silva *, Sheryl L. Beauvais stages (in utero, or to infants Department of Pesticide Regulation, and children) will result in California Environmental Protection endocrine disruption and Agency, Sacramento, CA 95812, USA subsequent neurotoxicity, Published in: developmental or reproductive Regulatory Toxicology and Pharmacology adverse effects that are 56 (2010) 4–17 irreversible. 0273‐2300/$ ‐ see front matter Published by Elsevier Inc. doi:10.1016/j.yrtph.2009.08.013 5.11 Title: Major Findings: Genotoxicity evaluation of the insecticide The higher proportion of endosulfan in the wetland macrophyte laggards and vagrand Bidens laevis L chromosomes observed at 5 mg/L would indicate that endosulfan interacts with the Authors and their affiliations: spindle interrupting normal De´bora J. Pe´rez a,b,c, Mirta L. Menone chromosome migration. b,c,*, Elsa L. Camadro a,c, Vı´ctor J. Moreno b Endosulfan resulted genotoxic to B. laevis, a species of potential a) Laboratorio de Gene´tica, Estacio´n value for bioassays and in situ Experimental Agropecuaria Balcarce INTA e monitoring of environmental Facultad de Ciencias Agrarias e UNMdP,CC contamination by pesticides. 276, 7620 Balcarce, Argentina

b) Laboratorio de Ecotoxicologı´a, Departamento de Ciencias Marinas, Facultad de Ciencias Exactas y Naturales UNMdP, Funes 3350 (7600) Mar del Plata, Argentina c) Consejo Nacional de Investigaciones Cientı´ficas y Te´cnicas (CONICET), Rivadavia 1917, 1033, Buenos Aires, Argentina

Published in: Environmental Pollution 153 (2008) 695e698 _ 2007 Elsevier Ltd. All rights reserved. 5.12 Title: Major Findings: Genotoxicity evaluation of acute doses of endosulfan to freshwater teleost Channa The Indian freshwater air‐ punctatus (Bloch) by alkaline single‐cell breathing teleost fish Channa gel electrophoresis punctatus (Bloch) was exposed to acute concentrations of the Authors and their affiliations: organochlorine pesticide Sanjay Pandey, N.S. Nagpure_, Ravindra Endosulfan. Kumar, Shilpi Sharma, Satish K. Srivastava, Mahendra S. Verma The presence of DNA strand breakage in exposed specimens National Bureau of Fish Genetics Resources, indicated the genotoxic Indian council of Agriculture Research, potential of endosulfan. Lucknow 226002, Uttar Pradesh, India

Published in: Ecotoxicology and Environmental Safety 65 (2006) 56–61 2005 Elsevier Inc. 5.13 Title: Major Findings: Genotoxic Effects of a‐Endosulfan and f3‐ Endosulfan on Human HepG2 Cells In this study, we examined the genotoxicity of endosulfan in Authors and their affiliations: vitro with a HepG2 cell line.

Yuquan Lu,1 Kanehisa Morimoto,1 Tatsuya After treating HepG2 cells with Takeshita,1 Toru Takeuchi,1 and Takeshi a‐ or 13‐endosulfan for l hr, DNA Saito2 strand breaks were significantly induced by a‐endosulfan at 1Department of Social and Environmental concentrations fom 2 X 0o4 M to Medicine, Osaka University Graduate 1 x 10‐3 M, and by ,‐endosulfn at School of Medicine, Suita, Osaka, Japan; 1 x 10‐3 M.

2Laboratory of Environmental Biology, The results of this study suggest Department of Preventive Medicine, that both endosulfan is genotoxic Hokkaido University School of Medicine, to HepG2 cells. Sapporo, Japan

Published in: Environmental Health Perspectives * VOLUME 108 1 NUMBER 6 1 June 2000 5.14 Title: Major Findings: Micronucleus induction in erythrocytes of the Hyla pulchella tadpoles (Amphibia: Results obtained here showed a Hylidae) exposed to insecticide endosulfan genotoxic effect of the endosulfan on erythrocytes of Authors and their affiliations: H. puchella.

It important noticed that commercial formulations of Mariana Cabagna ,כ,Rafael C. Lajmanovich a endosulfan utilized, contains many ‘inert’ ingredients that can b, Paola M. Peltzer a, Gabriela A. Stringhini increase the toxicity of the c, Andr´es M. Attademo c product when compared to the a National Council for Scientific and technical‐grade material. Technical Research (CONICET), Faculty of Furthermore, ‘inert’ ingredients Biochemistry and Biological Sciences,FBCB‐ used in formulated pesticide UNL, Pje. El Pozo s/n (3000), Santa Fe, products are usually not Argentina disclosed and not included in b Cathedra of Normal Morphology, Faculty most of the testing required in of Biochemistry and Biological Sciences, order to register these pesticides. FBCB‐UNL, Moreover, although ‘inert’ Pje. El Pozo s/n (3000), Santa Fe, Argentina ingredients have no pesticide activity, they may be biologically c High School of Health, Faculty of active and sometimes the most Biochemistry and Biological Sciences, EES‐ toxic component of a pesticide FBCB‐UNL (3001), Santa Fe, Argentina formulation.

Published in: Mutation Research 587 (2005) 67–72 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.mrgentox.2005.08.001 5.15 Title: Major Findings: Effects of endosulfan on B cells of Langerhans islets in rat pancreas Chronic endosulfan administration for 2 months led Authors and their affiliations: to degenerative changes of various degrees of the pancreatic islets as well as the ,Suna Kalender b ,כ,Yusuf Kalender a exocrine acini.

Meltem Uzunhisarcikli a, Insufficiency of insulin hormone Ay˛se Ogutcu a, Fatma Açikgoz a, Dilek causes the increase of blood Durak c glucose level at the end of the 5th a Biology Department, Faculty of Arts and and 6th weeks, blood glucose Science, Gazi University, 06500 Ankara, level significantly increased. This Turkey shows that B cells couldn’t b Biology Department, Faculty of Education, secrete adequate insulin Gazi University, 06500 Ankara, Turkey Biochemical studies show that c Biology Department, Yozgat Faculty of endosulfan affects integral Arts and Science, Erciyes University, Yozgat, proteins and receptors of cell Turkey membrane.

Published in: In this study endosulfan caused Toxicology 200 (2004) 205–211 vacuoles and swelling of mitochondria. Blood glucose levels and ultrastructural changes in this study show that endosulfan affects B cells of pancreas in rats even if it is under the LD50 dose level. Endosulfan not only has toxic effects on mammalian and other animals but it causes pollution as well. Therefore, microbial insecticides which are effective on target organisms and don’t cause pollution should be used instead of endosulfan. 5.16 Title: Major Findings: Effect of pesticides on estrogen receptor transactivation in vitro: A comparison of The estrogenic potential of four stable transfected MVLN and transient pesticides (endosulfan, transfected MCF‐7 cells prochloraz, tolchlofos‐methyl and propamocarb) was Authors and their affiliations: compared in parallel with 17_‐ estradiol (E2) by reporter constructs in transient .Heidi T ,כ Eva C. Bonefeld‐Jorgensen transfected MCF‐7BUS and in stable transfected MVLN cells. Gr¨unfeld, Irene M. Gjermandsen Unit of Environmental Biotechnology, In MVLN cells, endosulfan, Department of Environmental and prochloraz, tolchlofos‐methyl Occupational Medicine, University of and propamocarb caused Aarhus, Vennelyst Boulevard 6, DK‐8000 cytotoxic responses at Aarhus, Denmark concentrations higher than 10, Published in: 25, 25 and 100 _M, respectively. Molecular and Cellular Endocrinology 244 (2005) 20–30

5.17 Title: Major Findings: Reactive oxygen species in in vitro pesticide‐induced neuronal cell (SH‐SY5Y) Our laboratory has demonstrated cytotoxicity: Role of NFκB and caspase‐3 that mice exposed to endosulfan (an organochlorine cyclodiene Authors and their affiliations: pesticide) and zineb (zinc (SH‐SY5Y) cytotoxicity: Role of NFκB and ethylene bisdithiocarbamate caspase‐3 (EBDC) fungicide) as juveniles Zhenquan Jia, Hara P. Misra and re‐exposed at 8 months of Edward Via Virginia College of Osteopathic age showed loss of dopamine Medicine, Virginia Tech Corporate Research (DA) in striatum. Mixtures of Center, 2265 Kraft Drive, Blacksburg, VA these pesticides also caused 24060, USA significantly increased levels of alphasynuclein, a major Published in: component of Lewy bodies and Free Radical Biology & Medicine 42 (2007) a hallmark of 288–298 neurodegenerative diseases such as PD and Alzheimerʹs disease (AD).

In summary, the results of the present study demonstrate that neuronal cells (SH‐SY5Y) exposed to endosulfan and zineb individually or in a mixture increase the production of hydrogen peroxide as well as superoxide anion, decrease SOD GPX, and CAT enzyme levels and increase lipid peroxide levels.

This holds tremendous implication for the derivation of risk assessment guidelines for human exposure to pesticides.

5.18 Title: Major Findings: Organochlorine pesticide residue levels and oxidative stress in preterm The aim of the present study was delivery cases to analyze the OCP residues in maternal and cord blood of Authors and their affiliations: women and assess the levels of Rahul Pathak1, Sanvidhan G Suke1, Tanzeel different non‐enzymatic Ahmed1, Rafat S Ahmed1, AK Tripathi1, oxidative stress markers as well Kiran Guleria2, CS Sharma3, SD Makhijani3 as to establish correlation with and BD Banerjee1 OCP levels, if any. 1) Environmental Biochemistry and Levels of OCPs like Immunology laboratory, Department of Hexachlorocyclohexane (HCH), Biochemistry, University College of Medical endosulfan, and DDT were Sciences & G.T.B. Hospital (University of analyzed by gas Delhi), Delhi, India chromatography. Non‐enzymatic 2) Department of Obstetrics and oxidative stress was measured. Gynecology, University College of Medical In conclusion, our results suggest Sciences & G.T.B. Hospital (University of that higher levels of some of the Delhi), Delhi, India OCP (like Endosulfan) may be 3) Instrumentation and Bio‐Labs, Central associated with Preterm Pollution Control Board, Ministry of Delivery and increased Environment and Forest, Delhi, India oxidative stress.

Published in: Human and Experimental Toxicology 29(5) 351–358 5.19 Title: Major Points: HUMAN RED BLOOD CELL MEMBRANE Endosulfan’s in vitro toxicity on DAMAGE BY ENDOSULFAN human red blood cell membrane was studied by staining with a Authors and Affiliations: fluorochrome dye, merocyanine‐ CLIVE SUNIL DANIEL, SARITA 540 (MC‐540) and Scanning AGARWAL and SHYAM S. AGARWAL Electron Microscopy (SEM).

ICMR Centrefor Advanced Research in Genetics, At a concentration of 0.001 Genetics Unit, Department of Medicine, K.G. pg/ml (1 ppb) endosulfan was Medical College, Lucknow (India) found to damage human red cell membranes as demonstrated by fluorescence of 30‐50% of red Published in: cells on staining with MC‐540. Toxicology Letters, 32 (1986) 113‐ 118 At concentration of 1 pg/ml (1 ppm) the cells were markedly damaged. 5.20 Title: Major Findings: Genotoxic evaluation of the insecticide In this work, a genotoxic testing endosulfan based on the induced system has been developed GADD153‐GFP reporter gene expression based on the induction of a HepG2/GADD153‐GFP reporter gene expression in response to Authors and their affiliations the DNA‐damaging agents. Li, Dahui, Liu, Jianzhang Methyl methanesulfonate, a Li, Jianzhong known carcinogenic and genotoxic agent, was used to test College of Life Sciences, Graduate the effects of damage dose and University of Chinese Academy of Sciences, post‐treatment incubation time Beijing, 100049, China. on GADD153‐GFP expression. [email protected] Subsequently, the system was applied to the genotoxicity evaluation of endosulfan. Endosulfan was able to cause Published in: the increase of GADD153‐GFP Environ Monit Assess. 2011 May;176(1‐ expression at a sublethal dose 4):251‐8. Epub 2010 Jul 14. (0.02‐20 mg/L). The results suggest that endosulfan has the potential genotoxicity for HepG2 cell line by inducing DNA damage.

5.21 Title: Major Findings: Ameliorating effect of N‐acetylcysteine and Subchronic exposure to curcumin on pesticide‐induced oxidative endosulfan commonly affects the DNA damage in human peripheral blood central nervous system, immune, mononuclear cells gastrointestinal, renal, and reproductive system. This study was conducted to Authors and their affiliations examine the role of oxidative stress in genotoxicity following Ahmed, Tanzeel, Pathak, Rahul pesticide exposure using human Mustafa, Md Kar, Rajarshi Tripathi, Ashok peripheral blood mononuclear K, Ahmed, Rafat S, Banerjee B cells (PBMC) in vitro. Further possible attenuation of Environmental Biochemistry and Molecular genotoxicity was studied using Biology Laboratory, Department of N‐acetylcysteine (NAC) and Biochemistry, University College of Medical curcumin as known modulators Sciences and G.T.B. Hospital (University of of oxidative stress. Lipid Delhi), Dilshad Garden, Delhi, 110 095, peroxidation was assessed by India. cellular malondialdehyde (MDA) level and DNA damage was quantified by measuring 8‐ hydroxy‐2ʹ‐deoxyguanosine (8‐ Published in: OH‐dG) using ELISA. Environ Monit Assess. 2011 Aug;179(1‐ 4):293‐9. Epub 2010 Nov 4. The results indicate that pesticide‐induced oxidative stress is probably responsible for the DNA damage, and NAC or curcumin attenuate this effect by counteracting the oxidative stress.

5.22 Title: Major Findings: Endosulfan‐induced hepatotoxicity is route Endosulfan is an important of exposure independent in rats hepatotoxic agent that generates free oxygen radicals in liver. With the widespread use of Authors and their affiliations endosulfan in agriculture, Friday Effiong, Uboh Ekpo Nya, Asuquo human beings are most likely to Mbeh Ubana, Eteng be exposed to it by eating food contaminated with endosulfan, Biochemistry Department, Faculty of Basic exposure to its low levels by skin Medical Sciences, College of Medical contact with contaminated soil, Sciences, University of Calabar, Calabar, smoking cigarettes made from Nigeria. [email protected]. tobacco that has endosulfan residues on it, or by nose and whole body inhalation exposure Published in: in the farms during its Toxicol Ind Health. 2011 Jul;27(6):483‐8. application. Since endosulfan is Epub 2011 May 4. a frequently used pesticide, and the incidence of toxic injury to the liver tissue in relation to its widespread use reported in the literature, we considered it necessary to investigate whether endosulfan‐induced liver injury could be route of exposure dependent.

The results of the enzyme and histological analyses showed that both oral and whole body inhalation exposure to endosulfan may cause liver tissue damage.

6) CARCINOGENCITY 6.1 Title: Major Findings: Carcinogenic potential of endosulfan and .The aim of the present study was its metabolites based on a quantum to investigate the carcinogenic chemical model potential of endosulfan and its Authors and their affiliations: metabolites through electronic C.N.G. Bedor a,, R.J.L. Morais a, L.S. parameters that characterize the Cavalcanti a, J.V. Ferreira b, A.C. Pavão action of carcinogens, the findings Universidade Federal do Vale do São of the present study indicate that Francisco, Av. José de Sá Maniçoba, S/N, the use of this pesticide Centro, 56304‐205, Petrolina, PE, Brazil represents a risk to the health of b Instituto Federal de Alagoas, Rua Mizael the general population, Domingues, 75, Poço, 57020‐600, Maceió, especially rural workers. AL, Brazil The data from the present study c Universidade Federal de Pernambuco, indicate that endosulfan and all Av. Prof. Moraes Rego, 1235, Cidade its metabolites have carcinogenic Universitária, 50670‐901, Recife, PE, Brazil potential, based on the Published in: computational quantum chemical Science of the Total Environment 408 model. This places human health (2010) 6281–6284 at risk, which is especially true for 2010 Elsevier B.V. All rights reserved. agriculture workers who are most exposed to this compound and therefore the most vulnerable. 6.2 Title: Major Findings: Breast cancer risk and the combined The estrogenicity of adipose effect of environmental estrogens tissue extracts due to Authors and their affiliations: bioaccumulated Jesuｴ s M. Ibarluzea1, Mariana F. was associated with a higher risk of breast cancer in the leaner Fernaｴndez2, Loreto Santa‐Marina1, Maria women, especially in the F. Olea‐Serrano2, Ana M. Rivas2, Juan J. postmenopausal leaner group. Aurrekoetxea1, Joseｴ Expoｴ sito3, Miguel Lorenzo4, Pablo Torneｴ 5, Mercedes Complex interactions between Villalobos6, Vicente Pedraza6, Annie chemicals, endogenous or J. Sasco7 & Nicolas Olea2,* exogenous hormones and their 1Department of Health Guipuzkoa, San natural ligands and receptors may Sebastia´n, Basque Country, Spain; alter the internal homeostasis of 2Laboratory of Medical Investigations, the estrogenic environment of Hospital Clı´nico University of Granada, mammary tissue, leading to Granada, Spain; malignant transformation and 3Department of Oncology, Virgen de las cancer. Nieves University Hospital,m Granada, Spain; 4Department of Surgery, Torreca´rdenas Hospital, Almerı´a, Spain; Published in: Cancer Causes and Control 15: 591–600, 2004. 591 _ 2004 Kluwer Academic Publishers. Printed in the Netherlands. 6.3 Title: Major Findings: Modulation of aromatase activity and Some pesticides may induce mRNA by various selected pesticides in aromatase activity through the human choriocarcinoma JEG‐3 cell transcriptional activation of the line CYP19 gene Authors and their affiliations: When considering the physiologic Nathalie Laville a, Patrick Balaguer b, consequences of the modulating Franc¸ois Brion a, Nathalie Hinfray a, effects on aromatase by pesticides, Claude Casellas c, Jean‐Marc Porcher a, it is important to relate the present findings to the levels of כ,S´elim A¨ıt‐A¨ıssa a human exposure We found out new inducers of a INERIS, Ecotoxicological Risk aromatase activity, namely aldrin, Assessment Unit, BP 2, F‐60550 Verneuil‐ chlordane, cypermethrine, en‐Halatte, France methylparathion, endosulfan, , oxadiazon and b INSERM, U540, Molecular and Cellular metolachlor. Endocrinology of Cancers, F‐34090 The present study strengthens the Montpellier, France view that these chemicals may contribute to the occurrence of c CNRS UMR 5569, University of reproductive adverse effects in Montpellier 1, BP 14 491, F‐34093 both human and aquatic Montpellier Cedex 5, France organisms. Published in: Toxicology 228 (2006) 98–108 © 2006 Elsevier Ireland Ltd. All rights reserved. 6.4 Title: Major Findings: Relation of Prediagnostic Serum Estrogen Results support the hypothesis and Androgen Levels to Breast Cancer that prediagnostic serum Risk. estrogens and androgens are related to the subsequent Authors and their affiliations: diagnosis of breast cancer in CJoanne F. Dorgan,’ Christopher postmenopausal woman Longcope, Hugh E. Stephenson, Jr., Roni T. Falk, Rosetta Miller, Charlene Franz, Lisa Kahle, William S. Campbell, Joseph A. Tangrea, and Arthur Schatzkin Division of Cancer Prevention and Control, National Cancer Institute,Bethesda. Maryland 20892‐7326 Departments of Obstetrics and Gynecology and Medicine. University of Massachusetts Medical School, Worcester, Massachusetts 01655 Published in: Cancer epidemiology biomarkers and prevention Cancer Epidemiol Biomarkers Prev 1996;5:533‐539. Published online July 1, 1996. 6.5 Title: Major Findings: The insecticide endosulfan and its two Endosulfan was studied for its stereoisomers promote the growth of ability to act as a tumour promoter altered hepatic foci in rats in a two‐stage, altered hepatic foci Authors and their affiliations: bioassay in male Sprague‐Dawley Ronny Fransson‐Steen1ʹ2ʹ3, Sten rats. Flodstrdm1 and The results show that endosulfan Lars WMrngard1 and its two stereoisomers promote ʹinstitute of Environmental Medicine, the development of altered hepatic Karolinska Institutet, Box 60208, S‐104 01 foci, suggesting that endosulfan is Stockholm and 2Department of a tumour‐promoting agent acting Toxicology, Karolinska Institute*, Box by clonal expansion of initiated 60400, S‐104 01 Stockholm, Sweden cells. Published in: Our results show that the Carcinogenesis vol.13 no. 12 pp.2299‐ insecticide endosulfan is a 23O3, 1992 potential liver tumour promoter in a similar manner to structurally‐ related chlorinated cyclodienes. 6.6 Title: Major Findings: Effects of Pesticides on the Ratio of Xenobiotic estrogens are external 160c/2‐ hydroxyestrone: A Biologic compounds with estrogenic Marker of Breast Cancer Risk activity that may thereby affect the Authors and their affiliations: risk of breast cancer. This paper H. Leon Bradlow,1 Devra Lee Davis,2 describes a mechanism by which Gong Lin,1 Daniel Sepkovic,ʹ and Raj xenoestrogens may affect the Tiwari development of breast cancer. 1Strang‐Cornell Cancer Research Laboratory, New York, New York; 20ffice These pesticides significantly of the Assistant Secretary for Health, increase the ratio of 16ct‐OHE1/2‐ Department of Health and Human OHE, metabolites to values Services, Washington, DC comparable to or greater than Published in: those observed after DMBA (the Environ Health Perspect 103(Suppl 7):147‐ known rodent carcinogen 7,12‐ 150 (1995) dimethylbenzyl anthracene (DMBA)). The ratio of 16a‐ OHEl/2‐OHEl may provide a marker for the risk of breast cancer. 6.7 Title: Major Findings: Serum Levels After In conclusion, this study has and Subsequent Breast produced two important findings. Cancer First, in our population, high Authors and their affiliations: levels of sex hormones F. Berrino, P. Muti, A. Micheli, V. Krogh, were found to be powerful G. Secreto, Istituto Nazionale Tumori, predictors of breast cancer. Milan, Italy; Second, although the association G. Bolelli, Istituto di ClinicaOstetrica e between breast cancer risk and Ginecologica ʺP Sfameni,ʺ Universita di testosterone levels was already Bologna, Italy; known from case‐control studies R. Sciajno, Istituto Nazionale Tumori, these results prospectively Milan, and Istituto di Clinica Ostetrica e confirm this association. Ginecologica ʺP Sfameni,ʺ Universita di Bologna; P. Pisani, Unit of Descriptive Epidemiology, International Agency for Research on Cancer, Lyon, France; S. Panico, Istituto di Medicina Intema e Malattie Dismetaboliche, Facolta di Medicina, Universita Federico II, Naples, Italy. Published in: Journal of the National Cancer Institute. Vol. 88. No. 5. March 6, 1996 6.8 Title: Major Findings: Estrogen Receptor Activation via This report describes an in vitro/in Activation Function 2 Predicts Agonism vivo system for identifying the of Xenoestrogens in Normal and effects of Estrogen receptor Neoplastic Cells of the Uterine ligands in the myometrium and Myometrium elucidating their mechanism of action. Authors and Affiliations: Deborah S. Hunter, Leslie C. Hodges, Peter The results suggest that some M. Vonier, Robin Fuchs‐Young, Marco M. exogenous Estrogens (like Gottardis, and Cheryl L. Walker2 endosulfan) may mimic the effects The University of Texas M. D. Anderson of endogenous estrogens on Cancer Center, Science Park Research uterine leiomyoma and may Division, Smithville, Texas 78957 [D. S. H., contribute to a complex hormonal L. C. H., R. F‐Y., C. L. W.]; milieu that impacts both normal and neoplastic myometrium. The Tulane‐Xavier Center for Bioenvironmental Research, Tulane University, New Orleans, Louisiana 70112 [P. M. V.]; and Bristol Myers Squibb, Endocrine Oncology Pharmaceutical Research Institute, Princeton, New Jersey 08543 [M. M. G.] Published in: CANCER RESEARCH 59, 3090–3099, July 1, 1999 6.9 Title: Major Findings: cancer risk and exposure to Several epidemiologic studies pesticides in British Columbia farmers have reported an increased risk of prostate cancer among farmers. Authors and their affiliations Our aim was to assess the risk of Band, Pierre R, Abanto, Zenaida, Bert, Joel, developing prostate cancer in Lang, Barbara, Fang, Raymond,Gallagher, relation to exposure to specific Richard P, Le, Nhu D active compounds in pesticides. A case‐control approach was used with 1,516 prostate cancer patients Cancer Control Research, BC Cancer and 4,994 age‐matched internal Agency, Vancouver, British Columbia, controls. Conditional logistic Canada. regression was used to assess prostate cancer risk, adjusting for potential confounding variables Published in: and effect modifiers. Prostate. 2011 Feb 1;71(2):168‐83. doi: CONCLUSIONS: The significant 10.1002/pros.21232. Epub 2010 Aug 26. association between prostate cancer risk and exposure to DDT, simazine , lindane, endosulfan, 2,4‐D, 2,4‐DB, and carbaryl.

All the articles were reviewed and only relevant points were included in the synopsis.

This synopsis is not exhaustive and only forms a part of scientific evidences available in this office about the health effects of endosulfan.

Sd/

Dr. Mohammed Asheel Asst. Nodal Officer Endosulfan Rehabilitation Project