NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS .
NTP TECHNICAL REPORTON THETOXICOLOGY AND CARCINOGENESISSTUDIES IN Hsd:SPRAGUE DAWLEY SD RATSEXPOSED TO WHOLE-BODY RADIO FREQUENCYRADIATION AT A FREQUENCY (900 MHz) ANDMODULATIONS (GSM AND CDMA) USED BYCELL PHONESScheduled Peer Review Date: March 26 to 28, 2018NOTICEThis DRAFT Technical Report is distributed solely for the purpose of predissemination peer review under the applicable informationquality guidelines. It has not been formally disseminated by the NTP. It does not represent and should not be construed to representNTP determination or policy.NTP TR 595National Toxicology ProgramNational Institutes of HealthPublic Health ServiceU.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOREWORDThe National Toxicology Program (NTP) is an interagency program within the Public Health Service (PHS) of theDepartment of Health and Human Services (HHS) and is headquartered at the National Institute of EnvironmentalHealth Sciences of the National Institutes of Health (NIEHS/NIH). Three agencies contribute resources to theprogram: NIEHS/NIH, the National Institute for Occupational Safety and Health of the Centers for Disease Controland Prevention (NIOSH/CDC), and the National Center for Toxicological Research of the Food and DrugAdministration (NCTR/FDA). Established in 1978, the NTP is charged with coordinating toxicological testingactivities, strengthening the science base in toxicology, developing and validating improved testing methods, andproviding information about potentially toxic substances to health regulatory and research agencies, scientific andmedical communities, and the public.The Technical Report series began in 1976 with carcinogenesis studies conducted by the National Cancer Institute.In 1981, this bioassay program was transferred to the NTP. The studies described in the Technical Report series aredesigned and conducted to characterize and evaluate the toxicologic potential, including carcinogenic activity, ofselected substances in laboratory animals (usually two species, rats and mice). Substances selected for NTP toxicityand carcinogenicity studies are chosen primarily on the basis of human exposure, level of production, and chemicalstructure. The interpretive conclusions presented in NTP Technical Reports are based only on the results of theseNTP studies. Extrapolation of these results to other species, including characterization of hazards and risks tohumans, requires analyses beyond the intent of these reports. Selection per se is not an indicator of a substance’scarcinogenic potential.The NTP conducts its studies in compliance with its laboratory health and safety guidelines and FDA GoodLaboratory Practice Regulations and must meet or exceed all applicable federal, state, and local health and safetyregulations. Animal care and use are in accordance with the Public Health Service Policy on Humane Care and Useof Animals. Studies are subjected to retrospective quality assurance audits before being presented for public review.NTP Technical Reports are indexed in the NIH/NLM PubMed database and are available free of chargeelectronically on the NTP website (http://ntp.niehs.nih.gov). Additional information regarding this study may berequested through Central Data Management (CDM) at cdm@niehs.nih.gov. Toxicity data are available throughNTP’s Chemical Effects in Biological Systems (CEBS) database: ases/cebs/index.cfm.
NTP TECHNICAL REPORTON THETOXICOLOGY AND CARCINOGENESISSTUDIES OF GSM- AND CDMA-MODULATEDCELL PHONE RADIO FREQUENCY RADIATIONAT 900 MHz IN Hsd:SPRAGUE DAWLEY SD RATS(WHOLE-BODY EXPOSURE)Scheduled Peer Review Date: March 26 to 28, 2018NOTICEThis DRAFT Technical Report is distributed solely for the purpose of predissemination peer review under the applicable informationquality guidelines. It has not been formally disseminated by the NTP. It does not represent and should not be construed to representNTP determination or policy.NTP TR 595National Toxicology ProgramNational Institutes of HealthPublic Health ServiceU.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
2CONTRIBUTORSNational Toxicology ProgramExperimental Pathology Laboratories, Inc.Evaluated and interpreted results and reported findingsProvided pathology reviewM.E. Wyde, Ph.D., Study ScientistM.F. Cesta, D.V.M., Ph.D., Study PathologistC.R. Blystone, Ph.D.A.E. Brix, D.V.M., Ph.D.,M.H. Hamlin, II, D.V.M., Principal InvestigatorA.E. Brix, D.V.M., Ph.D.T.A. Crabbs, D.V.M.M.M. Gruebbel, D.V.M., Ph.D.J.F. Hardisty, D.V.M.R.R. Maronpot, D.V.M., M.S., M.P.H.R.A. Miller, D.V.M., Ph.D.C.C. Shackelford, D.V.M., M.S., Ph.D.Experimental Pathology Laboratories, Inc.J.R. Bucher, Ph.D.M.C. Cora, D.V.M.S. Elmore, D.V.MP.M. Foster, Ph.D.M.J. Hooth, Ph.D.A.P. King-Herbert, D.V.M.G.E. Kissling, Ph.D.D.E. Malarkey, D.V.M., Ph.D.G.K. Roberts, Ph.D.K.R. Shockley, Ph.D.R.C. Sills, D.V.M., Ph.D.S.L. Smith-Roe, Ph.D.M.D. Stout, Ph.D.N.J. Walker, Ph.D.K.L. Witt, M.S.IIT Research InstituteConducted studiesD.L. McCormick, Ph.D., Principal InvestigatorT.L. Horn, Ph.D., Study DirectorJ.R. Gauger, B.S., EngineerL.H. Brennecke, D.V.M.Charles River Laboratories, Inc.R.M. Kovatch, D.V.M.Charles River Laboratories, Inc.RTI InternationalProvided SMVCE analysisR.W. Tyl, Ph.D., Principal InvestigatorF.T. Les, M.S. (sperm motility)Charles River Laboratories, Inc.M.C. Marr, B.A.C.S. Sloan, M.S.CSS, Inc.Prepared quality assessment auditsS. Brecher, Ph.D., Principal InvestigatorS. Iyer, B.S.V.S. Tharakan, D.V.M.NTP Pathology Peer ReviewEvaluated slides and contributed to pathology reporton rats exposed to GSM- and CDMA-modulated cell phone RFRfor 28 Days (October 13, 2016)M.P. Jokinen, D.V.M., CoordinatorILS, Inc.Pathology Associates International,A Charles River CompanyEvaluated pathology findings and sperm motilityJ.S. Hoane, D.V.M., Ph.D., Principal InvestigatorJ.M. Pletcher, D.V.M., M.P.H., Principal InvestigatorL. Brennecke, D.V.M.C. Detrisac, D.V.M., Ph.D.F.T. Les, M.S. (sperm motility)NOT FOR ATTRIBUTIONE.T. Adams, D.V.M., Ph.D.ILS, Inc.M.F. Cesta, D.V.M., Ph.D.National Toxicology ProgramG.P. Flake, M.D.National Toxicology ProgramK.S. Janardhan, M.V.Sc., Ph.D.ILS, Inc.A.R. Pandiri, B.V.Sc. & A.H., Ph.D.National Toxicology ProgramPeer Review Draft
GSM- and CDMA-Modulated Cell Phone RFR, NTP TR 595NTP Pathology Peer Reviewand Pathology Working GroupsEvaluated slides and contributed to pathology reportson rats exposed to GSM- and CDMA-modulated cell phone RFRfor 2 Years (January 29, February 11, 12, and 25, March 3 and 23,and April 11, 2016, and April 26 and 27, 2017)Coordinators:M.F. Cesta, D.V.M., Ph.D.National Toxicology ProgramT.A. Crabbs, D.V.M.Experimental Pathology Laboratories, Inc.M.M. Gruebbel, D.V.M., Ph.D.Experimental Pathology Laboratories, Inc.G.A. Willson, D.V.M., M.S.3J.P. Morrison, D.V.M.Charles River Laboratories, Inc.M. Novilla, D.V.M., M.S., Ph.D.SNBL USAA.R. Pandiri, B.V.Sc. & A.H., Ph.D.National Toxicology ProgramC.C. Shackelford, D.V.M., M.S., Ph.D.Experimental Pathology Laboratories, Inc.A.K. Sharma, M.V.Sc., M.S., Ph.D.CovanceJ.A. Swenberg, D.V.M., Ph.D.University of North CarolinaSocial & Scientific Systems, Inc.Provided statistical analysesExperimental Pathology Laboratories, Inc.Participants:B.R. Berridge, D.V.M., Ph.D.GlaxoSmithKlineD. Bigner, M.D., Ph.D.Duke UniversityM.V. Smith, Ph.D., Principal InvestigatorL.J. Betz, M.S.S.F. Harris, B.S.J.D. Krause, Ph.D.C.G. Leach, M.S.B. Blankenship, D.V.M.Charles River Laboratories, Inc.B. Bolan, D.V.M., M.S., Ph.D.GEMpath, Inc.M.C. Boyle, D.V.M., Ph.D.AmgenA.E. Brix, D.V.M., Ph.D.Experimental Pathology Laboratories, Inc.S.A. Elmore, D.V.M., M.S.National Toxicology ProgramM.R. Elwell, D.V.M., Ph.D.CovanceG.P. Flake, M.D.National Toxicology ProgramBiotechnical Services, Inc.Prepared Technical ReportS.R. Gunnels, M.A., Principal InvestigatorK.K. Coker, Ph.D.P.A. Gideon, B.A.L.M. Harper, B.S.J.I. Irving, M.A.P.P.C. Nader, B.S.E.E.S. Rathman, M.S.D.C. Serbus, Ph.D.K. Frazier, D.V.M., Ph.D.GlaxoSmithKlineR.H. Garman, D.V.M.Consultants in Veterinary Pathology, Inc.J.R. Hailey, D.V.M.CovanceJ.F. Hardisty, D.V.M.Experimental Pathology Laboratories, Inc.R.A. Herbert, D.V.M., Ph.D.National Toxicology ProgramJ.S. Hoane, D.V.M.Charles River Laboratories, Inc.K.S. Janardhan, M.V.Sc., Ph.D.ILS, Inc.P.B. Little, D.V.M., M.S., Ph.D.Experimental Pathology LaboratoriesD.E. Malarkey, D.V.M., Ph.D.National Toxicology ProgramR.R. Maronpot, D.V.M., M.S., M.P.H.Maronpot Consulting, LLCR.A. Miller, D.V.M., Ph.D.Experimental Pathology Laboratories, Inc.R.A. Moore, D.V.M.ILS, Inc.Peer Review DraftNOT FOR ATTRIBUTION
4CONTENTSABSTRACT . 6EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY . 15PEER REVIEW PANEL . 16SUMMARY OF PEER REVIEW PANEL COMMENTS . 17INTRODUCTION. 18MATERIALS AND METHODS . 40RESULTS. 74DISCUSSION AND CONCLUSIONS . 151REFERENCES . 164APPENDIX ASummary of Lesions in Male RatsExposed to GSM-Modulated Cell Phone RFR for 2 Years . A-1APPENDIX BSummary of Lesions in Female RatsExposed to GSM-Modulated Cell Phone RFR for 2 Years . B-1APPENDIX CSummary of Lesions in Male RatsExposed to CDMA-Modulated Cell Phone RFR for 2 Years . C-1APPENDIX DSummary of Lesions in Female RatsExposed to CDMA-Modulated Cell Phone RFR for 2 Years . D-1APPENDIX EGenetic Toxicology. E-1APPENDIX FClinical Pathology Results . F-1APPENDIX GMean Body Temperatures, Organ Weights,and Organ-Weight-to-Body-Weight Ratios. G-1APPENDIX HReproductive Tissue Evaluations . H-1APPENDIX IGSM- and CDMA-Modulated Cell Phone RFR Exposure Data. I-1Peer Review DraftNOT FOR ATTRIBUTION
GSM- and CDMA-Modulated Cell Phone RFR, NTP TR 5955APPENDIX JIngredients, Nutrient Composition, and Contaminant Levelsin NTP-2000 Rat and Mouse Ration. J-1APPENDIX KSentinel Animal Program . K-1Peer Review DraftNOT FOR ATTRIBUTION
6GSM- and CDMA-Modulated Cell Phone RFR, NTP TR 595ABSTRACTGSM- AND CDMA-MODULATED CELL PHONE RADIO FREQUENCY RADIATIONSynonyms: Cell phone radio frequency radiation; mobile phone radio frequency radiationThe predominant source of human exposure to radio frequency radiation (RFR) occurs through the use of cellularphone handsets. The Food and Drug Administration nominated cell phone RFR emission for toxicology andcarcinogenicity testing in 1999. At that time, animal experiments were deemed crucial because meaningful humanexposure data from epidemiological studies were not available. Male and female Hsd:Sprague Dawley SD rats wereexposed to time-averaged whole-body specific absorption rates of Global System for Mobile Communications(GSM)- or Code Division Multiple Access (CDMA)-modulated cell phone RFR at frequencies of 900 MHz (hereinreferred to as “cell phone RFR”) in utero, during lactation, and after weaning for 28 days or 2 years. Genetictoxicology studies were conducted in rat peripheral blood erythrocytes and leukocytes, brain cells, and liver cells.STUDY DESIGN28-Day StudiesBeginning on gestation day (GD) 6, groups of 20 time-mated F0 female rats were housed in specially-designedreverberation chambers and received whole-body exposures to GSM- or CDMA-modulated cell phone RFR atpower levels of 0 (sham control), 3, 6 or 9 W/kg for 5 to 7 days per week, continuing throughout gestation andlactation. The daily exposure duration was 9 hours and 10 minutes over an 18-hour and 20-minute period, asexposures cycled between modulations every 10 minutes. There were seven exposure groups per sex, including ashared sham control and three exposure groups for each modulation. At weaning, 10 males and 10 females pergroup were selected across four litters for continuation. Weaning occurred on the day the last litter reachedpostnatal day (PND) 21, marking the beginning of the 28-day study. Male and female F1 offspring continued toreceive whole-body exposures to GSM- or CDMA-modulated cell phone RFR at the same power levels and underthe same exposure paradigm, 5 to 7 days per week for up to 28 days.NOT FOR ATTRIBUTIONPeer Review Draft
GSM- and CDMA-Modulated Cell Phone RFR, NTP TR 59572-Year StudiesBeginning on GD 5, groups of 56 time-mated F0 female rats were housed in reverberation chambers and receivedwhole-body exposures to GSM- or CDMA-modulated cell phone RFR at power levels of 0 (sham control), 1.5, 3, or6 W/kg for 7 days per week, continuing throughout gestation and lactation. The daily exposure duration was 9 hoursand 10 minutes over an 18-hour and 20-minute period, as exposures cycled between modulations every 10 minutes.There were seven exposure groups per sex, including a shared sham control and three exposure groups for eachmodulation. At weaning, three males and three females per litter from 35 litters were randomly selected perexposure group for continuation. Weaning occurred on the day the last litter reached PND 21, marking thebeginning of the 2-year studies. Groups of 105 male and 105 female F1 offspring continued to receive whole-bodyexposures to GSM- or CDMA-modulated cell phone RFR at the same power levels and under the same exposureparadigm, 7 days per week for up to 104 weeks. After 14 weeks of exposure, 10 rats per group were randomlyselected for interim histopathologic evaluation and five were designated for genetic toxicity evaluation.PERINATAL FINDINGS AND THERMAL EFFECTSConsistent perinatal effects were observed between modulations, and in both the 28-day and 2-year studies,including lower dam body weights in late gestation and lactation, lower pup body weights and lower pup survivalrates. Whole-body exposure to GSM- or CDMA-modulated cell phone RFR had no effect on survival of damsduring gestation or lactation and no effect on littering, litter size or live litter pup numbers on PND 1. Lower bodyweight gains were observed during gestation in dams exposed to GSM during the 28-day and 2-year studies and theCDMA 28-day studies, with body weight effects becoming more pronounced and persisting throughout lactation forboth modulations and studies. Lower pup survival was observed for GSM exposure at 9 W/kg in early lactation(before PND 4) and at 6 and 9 W/kg in CDMA-exposed animals, in early and late (after PND 4) lactation. Lowermale and female pup body weights were observed beginning in early lactation following exposure to 6 W/kg ofeither GSM- or CDMA-modulated cell phone RFR.Body weight decreases in RFR exposed groups persisted throughout the post-weaning period in the 28-day studies,were observed at the 14-week interim evaluation in the 2-year studies, but eventually resolved and were notPeer Review DraftNOT FOR ATTRIBUTION
8GSM- and CDMA-Modulated Cell Phone RFR, NTP TR 595observed at later time points in the 2-year studies. There were no clinical observations associated with exposures toeither modulation.In the 28-day studies, subcutaneously implanted microchips were used to record body temperatures of animalswithin 3 to 5 minutes of exposure pauses. Body temperatures were recorded in F0 females during gestation andlactation and in F1 offspring during the post-weaning phase. Higher body temperatures were observed duringgestation in 9 W/kg GSM dams and during lactation in 6 W/kg GSM dams and 9 W/kg CDMA dams. At powerlevels selected for the 2-year studies (up to 6 W/kg), body temperature elevations did not exceed 1 C in the 28-daystudy measurements. No exposure-related temperature effects were observed in F1 offspring.2-YEAR STUDIESIn the 2-year studies, there was significantly lower survival in the shared male sham control group compared toalmost all exposed groups, for both modulations. Survival began to decline at a faster rate than in exposed groupsafter week 75. In the sham control group, 28% of animals survived to study termination, compared to 48% to 68%for exposed groups across both modulations. Lower survival in sham control male rats was largely attributed tohigher severity of chronic progressive nephropathy and there was a spectrum of lesions in other organs consideredsecondary to chronic progressive nephropathy that occurred at higher incidences in male sham controls. Survival inthe shared female sham control group was significantly lower than the 6 W/kg CDMA-exposed group; however, itwas similar to all other exposure groups, across modulations. At study termination, there was no effect on bodyweight in male or female rats, and there were no exposure-related clinical observations.At the 14-week interim evaluation, there were increased incidences of right ventricular cardiomyopathy in the heartof male rats following exposure to GSM- and CDMA-modulated cell phone RFR compared to sham controls.At 14 weeks, sperm motility and counts were evaluated in male rats exposed to GSM or CDMA. Exposure towhole-body GSM- or CDMA-modulated cell phone RFR, up to 6 W/kg, did not result in significantchanges/differences in reproductive organ histopathology or sperm parameters in male rats compared to the shamcontrols.NOT FOR ATTRIBUTIONPeer Review Draft
GSM- and CDMA-Modulated Cell Phone RFR, NTP TR 5959At 2 years, there were similarities in neoplastic and nonneoplastic responses between modulations. Followingexposure to GSM- or CDMA-modulated cell phone RFR, there were increases in the incidences of malignantschwannoma in the heart of male rats, with a significant positive trend in the incidences in GSM- andCDMA-exposed males and a significant pairwise increased incidence in CDMA 6 W/kg males. Also observed inthe heart were significantly increased incidences of right ventricular cardiomyopathy in 3 and 6 W/kg GSM maleand female rats and 6 W/kg CDMA male rats.Several other, weaker, responses were observed in both modulations including malignant glioma in the brain,adenomas in the pituitary gland (pars distalis), and pheochromocytomas of the adrenal medulla. Additionally, inGSM male rats there were marginal responses in the prostate gland, granular cell tumors of the brain, and inpancreatic islets that were not observed in CDMA-exposed rats, and in CDMA-exposed male rats, there was aresponse in the liver. The relationship between these responses and exposure to GSM or CDMA RFR wasuncertain.In the brain, there were incide
STUDIES IN Hsd:SPRAGUE DAWLEY SD RATS EXPOSED TO WHOLE-BODY RADIO FREQUENCY RADIATION AT A FREQUENCY (900 MHz) AND MODULATIONS (GSM AND CDMA) USED BY CELL PHONES Scheduled Peer Review Date: March 26 to 28, 2018 NOTICE This DRAFT Technical Report is distributed solely for the purpose of predissemination peer review under the applicable information
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Completed NTP Reports and Publications . NTP studies are published in various NTP report series after undergoing peer review. NTP reports published in FY 2018 or expected for peer review in FY 2019 are listed. Full citations for NTP reports, journal publications, and book chapters published during FY 2018 are provided as an appendix to this .
