ࡱ> u@ bjbj  @@@@@lAeCDDDDDDDKf$sRůʪEhDDhhʪDD{{{h DD{h{<{N{DC ln@ve&4)<e"LxL8D< P{Xl^) DDDʪʪ8@{ @AREHNA WORKSHOP 9 11 June 2005 Environmental impact on congenital diseases PILI Cultural Center Kos Island Aegean Sea Thursday 9 June 2005 Problem formulation. Overview of the problem of Environmental Impact on Health. Morning Session Coordinators: L. Hens, C. Sekeris 09:10Welcome address by project coordinatorP.Nicolopoulou Stamati09:1510:00Key note address: Sets the sceneJohn Peterson Myers10:45Coffee Break11:15Discussion 12:00Official Opening by the Mayor and Kos authorities12:30Lunch break Afternoon Session: Session Coordinators: C.V. Howard, A. Mantovani 13:30Male Dysgenesis SyndromeJorma Toppari13:45Endocrine disrupters, inflammation and steroidogenesisOlle Soder14.30Maternal exposure and cryptorchismPatrick Thonneau15.00Endocrine disrupter exposure and risk of male congenital malformationsNicolas Olea Serrano15:30Discussion 17:00 Departure by bus to hotel and then to Zia mountain for ouzo and dinner. Friday 10 June 2005 Morning Session Coordinators: C. Evangelides, C.V. Howard 09:00Congenital Diseases related to environmental exposure to dioxinsJanna Koppe09:35Endpoints for prenatal exposures in toxicological studiesAlberto Mantovani10.00Association of intra uterus exposure with drugs. Thalidomide effectMaurizio Clemente10:30Coffee Break11:00EUROCAT: surveillance of environmental impactHelen Dolk Martine Vrijheid11:30Do we have evidence from the wild lifeGwynne Lyons 12.30Lunch at the old spring Pigi13.30Departure for Asclepieion by bus (optional) * Guided visit to Asclepieion Afternoon Session: European Environmental Agency Multicausuality Round Table Discussion Session coordinators: David Gee, Vyvyan Howard 14:30Brain storming on Multicausality Reporteur: Nicholas LelosJohn Peterson Myers 15:0015.3016:00Coffee Break16.30Discussion17.30Departure by bus to Hotel and then to the Ancient Roman Odeon of Kos 20.00-21.00 Harp and Flute concert at the Roman Odeon, in the city of Kos Dinner * If you wish to visit the ancient Asclepieion, please contact Ms Alexandra Katsivelaki at the computer room, Thursday 9th June until 2.00 pm. Saturday 11 June 2005 Morning Session Coordinators: C.V. Howard, Nicolas Olea 09:00Raising awareness on impact to EU policies of Information Society RTD and deployment projects resultsVassilios Laopodis09.15Country report on Congenital diseases in GreeceEmmanuel Agapitos Manolis Brillakis Evaggelos Fousteris09.30Country report on Congenital diseases in BulgariaStoyan Stoyanov- Ekaterina Terlemesian09.50Environmental risk and new born sex ratioMiroslav Peterka10.30Coffee Break11.00Pesticides exposure in relation to congenital diseasesCatherine Wattiez11.30The point of view on congenital diseases of NGOs concerning environmental exposureGenon Jensen Marie Christine Dewolf12.00Congenital Diseases in ChinaYongtang Jin12.30Lunch13.30Conclusions-Closing Raporteur: Nguyen Thi ThucLuc Hens 15.00 Departure by bus to Hotel and then to Airport or Hot Springs Free afternoon 18.30-21.00 Dinner at the sea shore, Greek Dancing Evening " Every morning at 8.45, departure by bus from Hotel Marmari Beach to Pili Cultural Center " Internet Facilities in the computer Room next to library. SUMMARIES Congenital abnormalities in Greece Functional evaluation of statistical data (1981  1995) Authors BRILAKIS Emmanuel, Medical doctor, School of Medicine, National and Kapodistrian University of Athens FOUSTERIS Evangelos, Medical doctor, School of Medicine, National and Kapodistrian University of Athens PAPADOPULOS S. Jannis, Associate Professor of Medicine, School of Medicine, National and Kapodistrian University of Athens Summary Objective: This studys objective is to record the regional distribution of mortality and hospitalization caused by congenital abnormalities in Greece and to compare the mortality and the infantile mortality by congenital abnormalities between Greece and other countries. Study design: The data were obtained from the official issues of the National Statistical Service of Greece (N.S.S.G). The specific mortality and infantile mortality indexes by congenital abnormalities and the number of discharged patients with congenital abnormalities per 100.000 of population are evaluated for the whole of Greece and per each geographic region for the time period between 1981 and 1995. Greece was compared to other, randomly selected countries (Bulgaria, France, Italy, Japan, Portugal, Sweden, The Netherlands, and U.S.A.). The information data for these countries derive from the Annuals of the World Health Organization (W.H.O.). Results: The specific mortality and infantile mortality indexes by congenital abnormalities are considerably higher in Greece in relation to the countries studied. Among the 10 regions of Greece, Athens and Thrace have the highest mortality indexes, while Athens and Crete appear to have the highest number of hospitalized patients due to congenital abnormalities according to their population. In Thrace a disproportional high number of deceased in comparison to discharged patients was noted. Conclusions: Greece appears to have more deaths by congenital abnormalities compared to the other randomly selected countries. A significant difference at the distribution of the deaths and discharged patients among the geographic regions of Greece is observed. This study is unable to detect the reasons for this distribution. Association of intra uterus expore with drugs. Thaladomide effect Maurizio Clementi About 80% of pregnant women use prescribed or over-the-counter drugs. In many cases, however, drugs are unjustifiably used. Physicians and pregnant women need to develop awareness that drugs should be taken when essential in fertile period to avoid unnecessary risks. On the other hand, if drugs are needed during pregnancy because of chronic or acute maternal diseases, the therapy should be performed and the most known low-risk drugs should be preferred. The world wide awareness of the potential teratogenic effects of drugs has been introduced by the thalidomide disaster in the early 1960s. This substance, marketed in western countries since 1957, was considered a harmless therapeutic drug reputed to have efficacy as sedative and as antiemetic for use in early pregnancy. Thalidomide was considered safe as experimental studies in pregnant mice and rats did not show any side effect at large exposure. Unfortunately, thalidomide induces regularly only in rabbits and nonhuman primates the specific pattern of malformations observed in humans. It has been estimated that the total worldwide number of children affected with the thalidomide embryopathy which is characterized by variable degrees of reduction deformities of the limbs and many other skeletal and non-skeletal malformations, is more than 6000. The tragedy of thalidomide was a lesson for both health professionals and the public. Medicine, biology, genetics and embryology have developed new areas to study the environmental effects on the reproduction: the clinical teratology, the reproductive toxicology and the developmental toxicity. The basic principles for investigating the potentiality or the capacity of a drug to induce reproductive toxicity have been developed. It can be stated that the response depends upon the exposure to: a specific drug in a particular dose, with a dose-effect relationship a genetically susceptible species, because not all mammalians are susceptible or sensitive to a given drug there are different sensitive gestational period for different effects the mode of action of environmental agents. The assessment of the embryo-fetotoxic risk of therapeutic products is a long process, and, for the new drugs, is limited to animal studies, although it is accepted that predictive values from animal tests is not adequate to extrapolate results in term of human safety. For drugs on the market, large epidemiological (prospective or retrospective) studies are normally accepted. However, as in the case of thalidomide, most of the human teratogens have been discovered earlier in man than in animals. Alert physicians have hypothesized the teratogenicity of many substances from case studies or single observations. Specific epidemiological studies have provided the final evidence of such hypotheses. However, pertinent data about the possible teratogenic risks related to exposure to certain drugs are not available or difficult to interprete. For this reason, teratogen information services (TIS) were instituted in the 80s and their development continued into the late 80s and 90s as the request for information increased. The main objectives and functions of TISes are: to counsel in risk assessment in pregnancy, to recognize and detect risk factors in order to prevent birth defects, to increase knowledge by stimulating the exchange of experiences and providing training in counseling. Prevalence of Congenital Diseases among perinates in China from 1996 to 2002 Yongtang Jin, MD, PhD, professor (Dept of Environmental and Occupational Health, School of Public Health, Anhui Medical University, Hefei 230032, P.R.China E-mail address:  HYPERLINK "mailto:jinedu@163.com" jinedu@163.com, Tel number: +86 0551 5161177) SUMMARY BACKGROUND It was from Oct 1986 to Sep 1987 that a survey of the constitutional status of perinates was carried out in China and the incidence of congenital diseases among Chinese perinates was first notified accurately. Data of all categories of congenital diseases among live and still births from 28 weeks of gestation to a period within 7 days after delivery were collected. There were 1,243,284 perinates monitored in 945 hospitals of 29 provinces, cities and autonomous regions during a period of 12 months. 16,172 perinates were with congenital diseases, 101 categories of birth defects were noted, and the total incidence of the 101 categories of congenital diseases in China was 130.1 per 10,000. The 5 leading categories of major congenital diseases by frequency were: anencephaly, hydrocephaly, spina bifida, cleft lip with cleft palate, and congenital heart diseases. Perinatal deaths totaled 33,137 and the perinatal mortality was 26.7 per 10,000. Among the causes of perinatal death, congenital malformation accounted for 17.8%. There were 44,469 births (35.8%) of full-term low birth weight infants, and 1748 of them were with congenital diseases. The incidence of congenital diseases in full-term low birth weight infants was 393.1 per 10,000. On the base of those data, a population-based congenital diseases surveillance system across China was instituted in March 1992. OBJECTIVES The aim of the work is to assess the changes of incidence, disease types, sequence of congenital diseases and causal factors, unuaual trends of congenital diseases among perinates in China, 1996~2002. METHODS We collected the data of congenital diseases published by 17 provinces and cities (Chongqing, Tianjin, Gansu, Guangdong, Hebei, Guizhou, Hunan, Shanxi, Henan, Shandong, Hefei/Anhui, Guangxi, Jiaxing/Zhejiang, Nanjing/Jiangsu, Liaoning, Kunming/Yunnan and Inner Mongolia), but it could basically represent distribution of congenital diseases all over the China from 1996 to 2002 in according to economic, population and geographical features of those regions. Congenital diseases cases were diagnosed and reported for perinates from 28 weeks of gestational age to 7 days after delivery through a hospital based active surveillance system, and the types of congenital diseases were classed by standard diagnostic codes (ICD-9). The data were analysed and reviewed by this summary. RESULTS The results showed the overall incidence of congenital diseases in China was 10.03, the males and females was 9.62 and 10.94, respectively. Prevalence of congenital diseases for male perinates was statistically higher than the one for female perinates(P<0.01), and there were significant differences of congenital diseases among perinates between in urban and rural areas, the former was 8.02 and the later was 12.04. Compared to perinates whose mothers were at other age groups(20-,25-,30-,35-), the incidence of congenital diseases was the highest (14.22) among perinates whose mothers were 35 years old and over (P<0.01). The types of leading congenital diseases were orderly neural tube defect (2.96), congenital hydrocephalus (1.38), cleft lip and palate (0.80), polydactyly (0.75) and deformities of feet (0.58). The perinates mortality rate was 13.75,while the mortality rate of infants with congenital diseases was 492.35.The main risk factors of congenital diseases might related to pesticide exposure, drugs use, infection and chronic disease, other environmental pollution such as Lead, benzene and chemicals etc. CONCLUSIONS The incidence of congenital diseases in China was higher in the world, and congenital diseases had become one of the major causes of perinatal deaths. Many risk factors possibly play an important role in pathogenesis of congenital diseases. Dioxins and congenital malformations: a role for Vitamin A? Janna G. Koppe, Gavin W. Ten Tusscher, Marieke Leijs. University of Amsterdam, EKZ-AMC Dept. of pediatrics. NGO: Ecobaby Introduction: Congenital malformations and dioxins are supposed to be not relevant, since no increase was found after the Seveso accident in 1976. However there are indications that these chemicals might play a role by interfering with the mothers metabolism resulting in congenital malformations. In animal studies effects like cleft lip- and palate and renal agenesis are described. Reviewed will be studies in humans to dioxins and congenital malformations and a possibility for prevention with Vitamin A will be discussed. Methods: Studies in humans are reviewed in relation to hot spots like Seveso, Chapaevsk Russia, Vietnam, after spraying of pesticides and in the neighbourhood of landfill sites. Studies: The most severe acute dioxin poisoning took place in Seveso 1976, when 300 g -130 kg of pure dioxin was spread over the village after an explosion of a factory producing 2,4,5 trichlorophenol the ICMESA plant. The most striking immediate effect was chloracne. An abnormal sex ratio was described in relation to the exposure of the father. ADDIN REFMGR.CITE Mocarelli P2000427Paternal concentrations of dioxin and sex ratio of offspring.Journal427Paternal concentrations of dioxin and sex ratio of offspring.Mocarelli Pgertroux P.M.Ferrari E.Patterson D.G.Kieszak S.M.Brambilla P.Vincoli N.Signorini S.Tramacere PCarreri V..2000dioxinsexSex RatioNot in File18581863Lancet355Lancet1(1) In a hot spot of dioxin poisoning in the city of Chapaevsk Russia due to a factory producing lindane (hexachlorocyclohexane) severe problems with reproduction are described. More miscarriages, more congenital malformations especially congenital hydrocephalus and renal agenesis, more prematurity and more small for date babies. In adults there is an increase in lungcancer and breastcancer, more diabetes, hypertension, dyslipidemias, and cardiovascular diseases. ADDIN REFMGR.CITE Revich2001321BDioxin exposure and public health in Chapaevsk, RussiaJournal321BDioxin exposure and public health in Chapaevsk, RussiaRevich,B.Aksel,E.Ushakova,T.Ivanova,I.Zhuchenko,N.Klyuev,N.Brodsky,B.Sotskov,Y.2001/5abnormalitiesAdultadverse effectsageanalysisBirth Weightbloodbreast cancercancercancer mortalitycancer riskChemicalchemical industrychemicalschemistryChildChild,PreschoolchildrencongenitalDemographydioxinDioxinsdrinkingEnvironmentalEnvironmental ExposureEnvironmental PollutantsepidemiologyetiologyexposureFemalehealth statusHumanIncidenceInfantInfant,Low Birth WeightInfant,NewbornInfant,PrematurelevelsLow Birth WeightLunglung cancerMaleMaternal-Fetal ExchangeMedicalMilkMilk,HumanmortalityNeoplasmsNewbornpollutantPregnancyPublic HealthReproductionreproductive healthRiskRussiarussian federationSoilvinyl chlorideWaterWater SupplywomenNot in File951966Chemosphere434-71hc
Center for Demography and Human Ecology of Institute for Forecasting, Russian Academy of Sciences, Moscow, Russian Federation. revich@mail.ecfor.rssi.ru
PM:11372889Chemosphere1(2) After the Vietnam war in the offspring of veterans exposed to the herbicide Agent Orange, that contains quite a lot of dioxins an increase in oro-facial clefts is described. ADDIN REFMGR.CITE Sterling1986212Review of recent Vietnamese studies on the carcinogenic and teratogenic effects of phenoxy herbicide exposureJournal212Review of recent Vietnamese studies on the carcinogenic and teratogenic effects of phenoxy herbicide exposureSterling,T.D.Arundel,A.1986Abnormalities,Drug-InducedAbortion,Spontaneousadverse effectsAnimalCarcinogensCase-Control Studieschemically induceddrug effectsEnvironmental ExposureetiologyFemaleHerbicidesHumanHydatidiform MoleInfant,NewbornLeadLiverLiver NeoplasmsMaleMaternal ExposureOdds RatioPregnancyReproductionTeratogensUnited StatesUterine NeoplasmsVietnamNot in File265278Int.J.Health Serv.162PM:3699946Int.J.Health Serv.1(3) A same increase was found in the neighbourhood of a chemical combustion site near to Amsterdam.  ADDIN REFMGR.CITE ten Tusscher G.W.2000437Open chemical combustions resulting in a local increased incidence of orofacial clefts.Journal437Open chemical combustions resulting in a local increased incidence of orofacial clefts.ten Tusscher G.W.Stam G.A.Koppe J.G.2000ChemicalcombustionIncidenceNot in File12631270Chemosphere40Chemosphere1(4) In the EUROHAZCON project covering 21 waste landfill sites in Europe a residence within 3 km of the site was associated with an increased risk for neural tube defects, malformations of the cardiac septa and anomalies of great arteries and veins while borderline significant increase were found for tracheo-oesophageal anomalies, hypospadias and gastroschizis. No increase was found in several such studies in the USA.  ADDIN REFMGR.CITE Dolk1998146Risk of congenital anomalies near hazardous-waste landfill sites in Europe: the EUROHAZCON studyJournal146Risk of congenital anomalies near hazardous-waste landfill sites in Europe: the EUROHAZCON studyDolk,H.Vrijheid,M.Armstrong,B.Abramsky,L.Bianchi,F.Garne,E.Nelen,V.Robert,E.Scott,J.E.Stone,D.Tenconi,R.1998/8/8abnormalitiesadverse effectsCase-Control StudiescongenitalepidemiologyetiologyEuropeFemaleFetal DeathHazardous WasteHumanLogistic ModelsMaternal AgeMaternal ExposuremethodsMothersOdds RatioPopulation SurveillancePregnancyPublic HealthResidence CharacteristicsRiskRisk FactorsSocioeconomic FactorsSupport,Non-U.S.Gov'tTeratogensNot in File423427Lancet3529126
Department of Public Health and Policy, London School of Hygiene and Tropical Medicine, UK
PM:9708749Lancet1(5)  Baby with congenital hydrocephalus of mother with type 1 diabetes. Congenital hydrocephalus characteristic for dioxin poisoning is also a characteristic anomaly for the offspring of mothers with type 1 diabetes, as was already described in 1895 by Lecorch. ADDIN REFMGR.CITE Lecorché Dr.1885490Du diabete.Dans ses rapports avec la vie utérine, lamenstruation et la grossess.Journal490Du diabete.Dans ses rapports avec la vie utérine, lamenstruation et la grossess.Lecorché Dr.1885congenital hydrocephalusNot in File257273Ann.Gynécol.24Ann.Gynécol.1(6) Abnormal glycosylation is assumed to be the cause of congenital malformations in children of mothers with diabetes. It is known that dioxin blocks the monoglycosylation regulated by vitamin A. An excess of this vitamin overcomes this blockade. Interesting in this respect is the publication about the role of retinoic acid during gastrulation by Keegan. ADDIN REFMGR.CITE Keegan B.|R.2005492Retinoic Acid Signaling Restricts the Cardiac Progenitor PoolJournal492Retinoic Acid Signaling Restricts the Cardiac Progenitor PoolKeegan B.|R.Feldman J.L.begemann G.Ingham P.W.Yelon D.2005cardiogenic progenitor cellsretinoic acidNot in File247249Science307Science1(7) One may hypothesize that in both, dioxin poisoning and in mothers with type 1 diabetes abnormal glycosylation might be overcome by vitamin A. In the Netherlands 48% of women that want to become pregnant use a diet insufficient in Vitamin A. Advice: For prevention of congenital anomalies both in relation with high dioxin levels and in mothers with type 1 diabetes a sufficient supply of Vitamin A periconceptionally seems to be warranted.  ADDIN REFMGR.REFLIST Reference List 1. Mocarelli P, gertroux P.M., Ferrari E., Patterson D.G., Kieszak S.M., Brambilla P., Vincoli N., Signorini S., Tramacere P, Carreri V., . Paternal concentrations of dioxin and sex ratio of offspring. Lancet 355:1858-1863 (2000). 2. Revich B, Aksel E, Ushakova T, Ivanova I, Zhuchenko N, Klyuev N, Brodsky B, Sotskov Y. Dioxin exposure and public health in Chapaevsk, Russia. Chemosphere 43:951-966 (2001). 3. Sterling TD, Arundel A. Review of recent Vietnamese studies on the carcinogenic and teratogenic effects of phenoxy herbicide exposure. Int J Health Serv 16:265-278 (1986). 4. ten Tusscher G.W., Stam G.A., Koppe J.G. Open chemical combustions resulting in a local increased incidence of orofacial clefts. Chemosphere 40:1263-1270 (2000). 5. Dolk H, Vrijheid M, Armstrong B, Abramsky L, Bianchi F, Garne E, Nelen V, Robert E, Scott JE, Stone D, Tenconi R. Risk of congenital anomalies near hazardous-waste landfill sites in Europe: the EUROHAZCON study. Lancet 352:423-427 (1998). 6. Lecorch Dr. Du diabete.Dans ses rapports avec la vie utrine, lamenstruation et la grossess. Ann Gyncol 24:257-273 (1885). 7. Keegan B.|R., Feldman J.L., begemann G., Ingham P.W., Yelon D. Retinoic Acid Signaling Restricts the Cardiac Progenitor Pool. Science 307:247-249 (2005).  Congenital defects in wildlife: The wildlife-human connection Gwynne Lyons, Toxics Science and Policy Advisor WWF UK Species from each of the 5 main phyla, are now believed to have been impacted by endocrine disrupting chemicals (EDCs). There are many similarities in the endocrine systems of all vertebrate animals, such that if EDCs were present at significant levels in the environment, effects would likely have occurred in many exposed species. Homo sapiens will also be vulnerable, although exposure profiles will be somewhat different to those of aquatic and terrestrial wildlife. This paper provides a review of some of the structural defects that have been reported in vertebrate wildlife, particularly those which have been noted in the last decade and which are suspected or known to be associated with chemicals that act by disruption of the endocrine system. The effects seen in wildlife living in polluted areas, may give clues as to possible effects to look for in humans. Conversely, because disease in humans is subject to greater study than wildlife disease, disease trends in the human population may provide a pointer to the mechanisms of action of contaminants of concern and possible effects in wildlife. This paper therefore comments on the potential connections between abnormalities in wildlife and human health. The effects reported in wildlife particularly include: impaired reproduction; deformities of the male reproductive tract; thyroid abnormalities, and depressed immune system function. Endpoints for prenatal exposures in toxicological studies Alberto Mantovani Dept. Food Safety and Veterinary Public Health Istituto Superiore di Sanit, Rome, Italy Tel. ++39 06 4990 2565, e-mail:  HYPERLINK "mailto:alberto@iss.it" alberto@iss.it, website:  HYPERLINK "http://progetti.iss.it/inte/" http://progetti.iss.it/inte/ The conventional approach to developmental toxicology includes: 1) studies targeting the organogenesis/pregnancy period, to assess birth defects, minor anomalies (that may be a signal of more severe effects at higher dose levels), fetal growth and viability (OECD guideline 414); 2) one- and two-generation studies (OECD guidelines 415 and 416) that provide an overall assessment of general parameters related to postnatal development and survival. The importance of studies investigating effects on organogenesis cannot be overlooked, since short-term, even single, exposures in susceptible developmental phases may rise the risk of birth defects and/or embryonic loss; such instances can occur with, e.g., pharmaceuticals and workplace exposures. Several interesting in vitro assays exist, using cultured rodent embryonic stem cells or whole embryos; they could be developed as a screening battery as well as to understand embryotoxicity mechanisms. Nevertheless, the science of risk assessment is more and more concerned with the subltle, but potentially important, effects of low exposure levels relevant to the general population, such as intakes of food contaminants. Under this respect, the 2-generation study receives considerable attention, as it is the only standard protocol where an organism is exposed during the whole development, from gamete stage through to sexual development. The wide group of endocrine disrupters (ED) are a good example of a challenge to developmental toxicologists from several standpoints, including: a) the potential to induce long term effects on upon exposure in susceptible developmental phases, including postnatal life up to puberty; b) due to the regulatory role of endocrine homeostasis, mechanisms of endocrine disruption may impact on immune (e.g., AhR agonists), neurobehavioural (e.g., thyroid inhibitors), reproductive development (e.g., antiandrogens), as well as on susceptibility to cancer (e.g., mammary or testicular germ-cell tumours). Therefore, tiered approaches have to be developed: screening in vitro/in vivo assays should identify the most relevant mechanisms/endpoints to be investigated by targeted two-generation assays; these would allow to follow-up late outcomes and identify relevant NOELs for the most sensitive effects. The progress of toxicological sciences are pointing out also other long-term effects of prenatal exposures that deserve careful attention: in particular, disruption of immune development and early predisposition to cancer may be considered as likely hot topics for the next wave of research projects on chemical safety. Neonatal exposure to endocrine disrupters and risk of cryptorchidism and hypospadias Nicolas Olea Lab. Medical Investigations University Hospital-University of Granada 18071 Granada. Spain Previous studies on chemical exposure have provided some indication of the extent and significance of childhood exposure to xenoestrogens, including pesticides. An ecological study on geographical variations in orchidopexy rates and on the relationships between these differences and the exposure to pesticides suggested that the incidence of cryptorchidism in southeastern Spain was higher in areas with greater use of pesticides than in areas with less pesticide exposure. Along the Mediterranean coast, extensive areas alongside residential zones are devoted to intensive farming in plastic greenhouses. A prospective cohort study included 668 boys recruited at the time of delivery from a target population that consisted of babies born at the University of Granada Hospital from October 1 2000, to June 1 2002. A nested case-control study was performed on these infants with two objectives: i) to identify the main risk factors for cryptorchidism and hypospadias and their possible association with environmental factors, with special emphasis on exposure to environmental chemicals with estrogenic activity (xenoestrogens), and ii) to determine whether the combined effect of environmental estrogens measured as the total effective xenoestrogen burden is a risk factor for cryptorchidism and hypospadias. Cases were defined as boys with cryptorchidism and/or hypospadias at birth, and controls as boys with no urogenital malformations, matched with cases for parity, day of birth, and gestational age. A total of 50 cases and 114 controls were included. A questionnaire adapted from a Danish-Finnish study was used to gather information on parental characteristics, pregnancy, delivery, and potential risk factors. Blood from umbilical cords and placentas were collected. We measured the levels of 16 organochlorine pesticides, including lindane, HCH, heptachlor, aldrin, dieldrin, endrin, endosulfan, o,p'-DDE, and o,p'-DDD. The E-Screen bioassay was used to assess the total effective xenoestrogen burden (TEXB) of placenta extracts. More lipophilic xenoestrogens (alpha fraction) were separated from endogenous hormones (beta fraction) by a high performance liquid chromatography technique using a previously developed methodology. Statistical study was performed with conditional and unconditional logistic regression analysis. Mean age of mothers was 29.5 yrs (range, 17-43 yrs); 57% had low educational level (similar to that of fathers); 40% were multiparous, 19.25% had preterm delivery, and 21% of deliveries were Cesarian. No differences in matching criteria (date of birth, gestational age, and parity) were observed between case-matched controls and overall cohort. Risk of cryptorchidism and hypospadias increased with lower birth weight, lower increase in maternal weight during pregnancy, previous history of abortion and parental exposure to pesticides. The risk decreased with mothers age. TEXB was positive in 72.8% of alpha fractions (mean 1.82 6.65 pM estradiol/g of placenta) and in 77.11% of beta fractions (mean 2.04 17.3 pM estradiol/g of placenta). Higher TEXB alpha and beta levels were found in cases than in paired controls. Conditional logistical regression analysis, adjusted for mothers age at delivery and weight of the newborn, showed that TEXB of the alpha fractions was a risk factor for cryptorchidism (p= 0.031; OR = 2.82, 95% CI 1.10-7.24). DDT and metabolites, endosulfan and metabolites, lindane, aldrin/dieldrin/endrin, hexachlorobenzene, methoxychlor and mirex were found in placentas. The most frequent pesticides detected were p,pDDE (84%), followed by lindane (61%). The number of residues found in placenta samples was significantly higher in cases (p = 0.002). The presence of lindane, DDTs and endosulfan I was associated with increased risk of malformation, with ORs of 3.38 (95%CI 1.3-8.4), 2.6 (95%CI 1.2-5.7) and 2.2 (95%CI 0.99-4.8), respectively. This risk was also associated with higher concentrations of lindane (p = 0.007) and dieldrin (p = 0.052). Although the power of this study is limited, its findings are consistent with those of other studies that suggested the involvement of environmental factors in cryptorchidism and hypospadias. Environmental risk and newborn sex ratio Peterka M, Likovsky Z, Peterkova R. Department of Teratology, Institute of Experimental Medicine, Academy of Sciences CR, Vidensk 1083, 142 20 Prague 4, Czech Republic E-mail: peterka@biomed.cas.cz Summary The detection of intrauterine exposure to environmental pollutants using incidence of malformation in newborn children was successful only in few teratogens. 1) The most harmful factors can cause embryonic death already before any structural defect can arise. 2) Gross structural malformations arise during weeks 3 -12 of pregnancy. Therefore, the gross structural malformations can be used as an indicator of exposure only during the first trimester. 3) Part of the malformed embryos can be later spontaneously aborted. Because of all the above reasons, the number of malformations in newborns is thus represents only part of the original structural defects and is called residual teratogenesis. The precise number of spontaneous abortions in man is difficult to monitor. The official register does not include the abortions out of hand of hospital, as well as the very early abortions that are considered for delayed menses. Therefore, we were searching for another way allowing detecting factors that are harmful prenatally. There is evident higher vulnerability of boys to prenatal damage and following abortions. The long-standing higher male birth fraction is considered an indicator of reproduction stability and health. In contrast, a decrease in the male birth fraction has been reported after prenatal exposure to environmental chemical factors. We checked whether the male birth fraction could not be changed in our country after the Chernobyl disaster. After the explosion in the Chernobyl power station on April 26, 1986, three waves of radioactive clouds passed above the territory of the Czech Republic (April 30, May 4, and May 7). Increasing of whole body radioactivity was detected in residents in Prague and also in another part of our country. Absolute number of newborn boys and girls was checked in each 600 consecutive month from 1950 to 1999. In 599 months, there were always more newborn boys than girls. The only exception was November 1986, when the number of newborn boys was significantly decreased. This implies that the missing boys passed 3rd of intrauterine development in the time of increased radioactivity. We can speculate on possible reasons for the miscarriages after the Chernobyl disaster. One reason might be the radionuclide iodine131, whose concentration in radioactive clouds was very high after explosion. It is known that the radioactive iodine administered to pregnant women after eight week of pregnancy can cause fetal death. Peterka M, Peterkov R, Likovsk Z. Chernobyl: prenatal loss of four hundred male fetuses in the Czech Republic. Reprod Toxicol. 18:75-79, 2004. Endocrine disrupters, inflammation and steroidogenesis Olle Sder, MD, PhD Professor of Pediatrics; Pediatric Endocrinology Unit, Karolinska Institute & University Hospital, Stockholm, Sweden Epidemiological data indicate an increased incidence of disorders of male prenatal sex differentiation such as cryptorchidism and hypospadia. Common to these conditions is that they may arise from a defective androgen action during embryonal and fetal life. Although inactivating mutation of the androgen receptor (AR) is a well established cause of poor androgen action affecting male sex differentiation, such aetiology is relatively rare in patient populations with the above conditions according to several studies. Therefore, other mechanisms must be sought and have indeed been suggested. These include transient AR antagonism and reduced androgen formation by Leydig cells prenatally. Unwanted actions of endogenous mediators or xenobiotics have been discussed as possible mechanisms. Such events may occur temporary during critical time windows of early development although biochemical evidence at birth supporting such a cause may be absent. Exposures that may contribute to such effects include certain xenobiotics collectively referred to as endocrine disrupting chemicals (EDC) as well as endogenous host-response mediators such as pro-inflammatory cytokines induced by infection and other pro-inflammatory stimuli. To test this concept we exposed rats in vivo to defined EDC and analysed the steroidogenic capacity and profiles in primary cultures of Leydig and adrenocortical cells ex vivo. Further, we also analysed the effects of EDC and defined pro-inflammatory cytokines on steroidogenic cells in primary cultures in vitro. Our data indicate that such exposure may have profound and long-lasting effects on steroidogenesis by Leydig and adrenocortical cells, including both stimulatory and inhibitory actions. The altered production of steroid hormones was accompanied by changes in the expression levels of steroidogenic enzymes in the cells. The results show that EDC and pro-inflammatory cytokines may affect the production of steroid hormones directly, and also create a linkage between disorders of prenatal sex differentiation, inflammatory states and infections. The described mechanisms may contribute to poor androgen action during critical maturational stages of male prenatal development and be of significance in the pathogenesis of disorders of male sex differentiation. CONGENITAL DISEASES IN BULGARIA E. Terlemesian, S. Stoyanov University of Chemical Technology and Metallurgy, Centre of Ecology, 8, blvd. Kl. Ohridski, 1756 Sofia, Bulgaria Summary Congenital anomalies are structure formation errors, or disturbed chemical function due to a metabolic deficiency. They are inherited through gene transmission or are started by some stimulus at the appropriate time in embryogenesis, when developing structures are vulnerable. Developmental hazards of chemical, physical or infectious agents on fetuses could be assessed with monitoring the rate of congenital anomalies. The paper presents data and analysis about the state of congenital anomalies in Bulgaria. Assessment is based on statistical data reported in the National Statistical Institute Yearbook: Health Protection and the Sofia registry of congenital anomalies in the period 1996 1999. Forty isolated congenital anomalies and congenital diseases, detectable at birth or to the end of the first year of live have been detected out of 34124 pregnancies, registered in the period As indicators the rates of live births, stillbirths and induced abortions because of anomalies per 10 000 pregnancies registered are selected. Results are compared with EUROPAC rates of cases per 10000 births of 85 congenital anomaly subgroups in 34 EUROCAT full member registers in the period 1996 2001. Analysis made by Simeonov and Dimitrov shows that only two per cent have purely environmental origin. Comparison is made with the experience of the TIS in Jerusalem and the data reported in the frame of OTIS. Trends of reduction in the total infants mortality rates and the mortality rates due to congenital anomalies and due to certain conditions, originating in the prenatal period are established for the period 1990 2003. It is shown that in 2003 these two reasons for infants death are ranked at the first two places between the causes of the infants deaths with rates 260/1000 live births and 386/1000 live births respectively. Territorial distribution of infants mortality in 2003 caused by congenital anomalies and due to reasons originating in the prenatal period is connected with the territorial distribution of some known teratogen agents. Increase in the first child delivery mothers age and the total livebirths mother age are established for the last years in Bulgaria in connection of the high rates of chromosomal anomalies. Testicular dysgenesis syndrome as a congenital disease Jorma Toppari Departments of Physiology and Pediatrics University of Turku, FI-20520 Turku, Finland  HYPERLINK "mailto:jorma.toppari@utu.fi" jorma.toppari@utu.fi Sex chromosome mosaicism (45,X0/46XY karyotype) is often associated with an intersex phenotype and testicular dysgenesis. Undescended testes (cryptorchidism), hypospadias, and later on, infertility or subfertility and testicular cancer can be signs of testicular dysgenesis syndrome (TDS). The underlying reason is rarely a chromosomal abnormality, and for most cases the etiology remains currently unknown. We have hypothesized that genetic and environmental (including life style) factors that disturb gonadal development during pregnancy cause TDS, and the outcome depends on the timing and extent of the disruption. In mild cases only spermatogenesis may be affected during adulthood, whereas in severe cases the child may have hypospadias or develop testicular cancer at young age. The hypothesis is supported by clinical and epidemiological evidence that shows a strong association of the risks for each of the TDS signs, i.e. a boy with cryptorchidism has an increased risk of infertility and testicular cancer. Experimentally we can induce TDS-like changes in animals by treating them with endocrine disrupting compounds. The challenge for the pediatricians, urologists, andrologists, endocrinologists, oncologists and other physicians treating TDS patients is to unravel the developmental mechanisms and causative agents. Supported by the funding from the Academy of Finland, the Juselius Foundation and the EU Quality of Life Programme. EUROCAT: surveillance of environmental impact Martine Vrijheid On behalf of EUROCAT EUROCAT is a European network of population-based registries for the epidemiologic surveillance of congenital anomalies. EUROCAT started in 1979 and now covers more than a quarter of all births in the European Union. Currently, 40 registries in 19 countries of Europe survey more than 1 million births per year. EUROCAT Central Registry holds a standardised database of more that 350,00 cases of congenital anomaly, which is updated every year. The objectives of EUROCAT are: To provide essential epidemiologic information on congenital anomalies in Europe To facilitate the early warning of teratogenic exposures To evaluate the effectiveness of primary prevention To assess the impact of developments in prenatal screening To act as an information and resource centre for the population, health professionals and managers regarding clusters or exposures or risk factors of concern To provide a ready collaborative network and infrastructure for research related to the causes and prevention of congenital anomalies and the treatment and care of affected children To act as a catalyst for the setting up of registries throughout Europe collecting comparable, standardised data EUROCAT approaches the surveillance of environmental impacts in the causation of congenital anomalies in the following 3 main ways: 1) Routine monitoring of temporal trends in congenital anomalies. This type of surveillance has for example been used to study the effects of folic acid supplementation on trends in neural tube defects throughout Europe; to evaluate reports of rising prevalence of hypospadias; and to detect important temporal trends of increasing prevalence of gastroschisis. 2) Detection and response to temporal and spatial clusters. Examples include the routine statistical monitoring to detect temporal clusters carried out by EUORCAT; studies of geographic heterogeneity of congenital anomalies in the UK, and of anophthalmia in England; and the EUROCAT Cluster Advisory Service:  HYPERLINK "http://www.eurocat.ulster.ac.uk" www.eurocat.ulster.ac.uk. 3) Evaluation of specific environmental exposure hypotheses. Examples are the evaluation of congenital anomaly prevalence after the Chernobyl accident; the study of risk of congenital anomalies in the vicinity of landfill sites; and the study of risk of hypospadias in relation to maternal occupational exposures to endocrine disrupting chemicals. At present, there are relatively few environmental exposures for which strong conclusions can be drawn about their potential to cause congenital anomalies; the proportion of congenital anomalies attributable to environmental exposures may not be high. However, fetal life is an especially sensitive period to environmental exposures and crucial exposures occur before the pregnancy is recognised. EUROCAT, covering a quarter of all births in Europe, can play an important role in a European environmental health surveillance strategy. Links between in utero exposure to pesticides and effects on the human progeny Does European pesticide legislation protect our health? Catherine Wattiez, Dr .Sc. Pesticides Action Network (PAN) Europe Links between pesticide exposure in the womb with various congenital diseases (limb, nervous system and musculoskeletal defects, cryptorchidism, hypospadias, cardiovascular defects, oral cleft), intrauterine growth retardation and various neurodevelopmental effects as shown by the reviewed scientific literature will be highlighted. Major sources of information are the Systematic review of pesticide human health effects, April 2004 from the Ontario College of Family Physicians (Toronto), the Collaborative on Health and Environment Group of the Institute for Agriculture and Trade Policy (Minneapolis) 2004 publication entitled Chemical contaminants and human disease: a summary of evidence and the May 2000 report In Harms way: toxic threats to child development by Greater Boston Physicians for social responsibility (Cambridge , MA) Contamination can occur as a consequence of mother pesticide exposure through food, water and other drinks and/or by professional father and mothers exposure directly or indirectly as pesticides can be brought back at home on clothing and on vehicles and/or as a consequence of pesticide home and garden use and/or as a consequence of living in the vicinity of sprayed fields. Moreover, since the female ova are formed at the fetal stage and environmental contaminants have been found in follicular fluid, the next generation of children born may be affected by their grandmothers exposure. We then will argue that the current European pesticide legislation fails to protect our health and environment and that forecasted modifications to the pesticide policy will much probably continue to do so. The European Environment and Health Action Plan - criticised by the European Parliament in its 23 February 2005 Resolution for being at best a research action plan failing to consider the precautionary principle, the risks for fetuses, infants and children and immediate exposure reduction actions leaves, as far as pesticides are concerned, environment and health risk reduction initiatives to the pesticides autorisation Directives (Plant Protection Products (PPP) and biocides) and to some complementary measures aimed at addressing the use phase of pesticides. Modifications of the Directive 91/414/EEC on the placing on the market of PPP and a new Thematic Strategy on the sustainable use of pesticides addressing, for the first time, the use phase of PPP are expected to be published by the Commission in September of this year. However still much lacunes persist in the draft proposal for modifications of Directive 91/414/EEC (risk assessment not properly evaluated due to lack of data on toxicity and exposure: specific tests not required for detection of hormone disrupting properties nor systematic tests for detection of immunotoxic and neurotoxic (except for OP and OP like) properties nor for detection of developmental toxicity endpoints later in life as a consequence of in utero exposure, combination effects are not considered and extensive review of the existing literature is not required) . 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