Hagen Scherb, Kristina Voigt, Magdalena Sigler, Ralf Kusmierz

Institute of Computational Biology HELENA Lecture Course in Scheyern, July 16th & 17th 2014

Genetic Effects in the Vicinity of Nuclear Facilities

France - Germany - Luxembourg - Switzerland - The Netherlands

Content

Background Genetic effects after Chernobyl Genetic effects near nuclear power plants (German KiKK-study) Chernobyl consequences + KiKK-study Newborns’ sex ratio – technically sex odds

Data + Methods

Studies: sample versus full registration Exposure: nuclear facilities Effect: Sex ratio – annual municipality level gender specific live birth data Models: linear and nonlinear logistic regression

Results Luxembourg: Dudelange (Effect by French NPP Cattenom ?) Switzerland: Beznau D + CH: 32 nuclear facilities France: 28 nuclear facilities Synopsis: D + CH + F

Summary and Outlook

Background Risk Perception

1990s increased incidences of childhood leukemia were reported near UK nuclear facilities Ian Fairlie 2014 (review, synopsis, hypothesis) 1992 No One Escapes Harm – The Essential Story of In-Utero Irradiation John W. Gofman 1992 2000/2010 we have shown that the human sex ratio at birth is distorted following exposure by ionizing radiation: Chernobyl, atomic bomb tests, nuclear facilities Scherb et al. 2000, Scherb&Voigt&Kusmierz 2010, Scherb&Voigt 2007, Scherb&Voigt 2011 Scherb&Kusmierz&Voigt 2013

Source: http://lesoufflecestmavie.unblog.fr/2014/02/13/

http://www.ncbi.nlm.nih.gov/pubmed/24054083http://www.ncbi.nlm.nih.gov/pubmed/24054083http://www.ncbi.nlm.nih.gov/pubmed/24054083http://www.ncbi.nlm.nih.gov/pubmed/24054083http://www.ibis-birthdefects.org/start/cache/No One Escapes Harm.pdfhttp://www.ibis-birthdefects.org/start/cache/No One Escapes Harm.pdfhttp://www.ibis-birthdefects.org/start/cache/No One Escapes Harm.pdfhttp://www.ibis-birthdefects.org/start/cache/No One Escapes Harm.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/10869337http://www.ncbi.nlm.nih.gov/pubmed/10869337http://www.ncbi.nlm.nih.gov/pubmed/10869337http://enviroinfo.eu/sites/default/files/pdfs/vol6516/0616.pdfhttp://enviroinfo.eu/sites/default/files/pdfs/vol6516/0616.pdfhttp://enviroinfo.eu/sites/default/files/pdfs/vol6516/0616.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/17482426http://www.ncbi.nlm.nih.gov/pubmed/17482426http://www.ncbi.nlm.nih.gov/pubmed/17482426http://www.ncbi.nlm.nih.gov/pubmed/21336635http://www.ncbi.nlm.nih.gov/pubmed/21336635http://www.ncbi.nlm.nih.gov/pubmed/21336635http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765590/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765590/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765590/http://lesoufflecestmavie.unblog.fr/2014/02/13/

Background

Hermann J Muller (1890-1967) discovered X-ray mutagenesis in 1927 The Nobel Prize in Physiology or Medicine 1946

Genetic effects

Cancer – childhood leukemia and thyroid cancer

Congenital malformation – cleft lip and palates

Chromosome anomalies – Down syndrome or trisomy 21

Stillbirths

Neonatal death – within 7-days, 28-days or 1 year

Sex ratio among newborn

http://en.wikipedia.org/wiki/Hermann_Joseph_Muller

Background Genetic effects after Chernobyl

Down syndrome or trisomy 21 Sperling et al. 1993, 2012

Congenital anomalies – heart, deformities, etc. Lazjuk et al. 1997

Congenital anomalies in Bavaria Scherb, Voigt 2014

Neural tube defects Wertelecki 2010

Stillbirths Scherb et al. 1999, Auvinen et al. 2001

Sex ratio in Europe vs. USA Scherb and Voigt 2007, 2011

Sex ratio in Cuba vs. Russia Scherb, Kusmierz, Voigt 2013

http://www.ncbi.nlm.nih.gov/pubmed/8044094http://www.ncbi.nlm.nih.gov/pubmed/22162022http://www.ncbi.nlm.nih.gov/pubmed/9368311http://www.ncbi.nlm.nih.gov/pubmed/9368311http://www.strahlentelex.de/Stx_14_652-653_S01-05.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/20308207http://www.ncbi.nlm.nih.gov/pubmed/9368311http://www.ncbi.nlm.nih.gov/pubmed/10597994http://www.ncbi.nlm.nih.gov/pubmed/11266330http://www.ncbi.nlm.nih.gov/pubmed/17482426http://www.ncbi.nlm.nih.gov/pubmed/21336635http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765590/

Background Genetic effects near nuclear power plants (KiKK-study)

Childhood cancer near nuclear power plants

http://www.bfs.de/de/kerntechnik/kikk/kikk_studie.htmlhttp://www.bfs.de/de/kerntechnik/kikk/kikk_studie.htmlhttp://www.bfs.de/de/kerntechnik/kikk/kikk_studie.html

Background Chernobyl consequences + KiKK-study

Stillbirths, congenital malformations, and the secondary sex ratio are increased in Europe after Chernobyl

Childhood cancer and childhood leukemia is increased near nuclear power plants

Based on this, our colleague Ralf Kusmierz raised two questions

Is the natural human birth sex ratio of 1.05 disturbed near nuclear facilities?

Can we approach this issue methodologically similar to the KiKK-study by investigating gender specific municipality level birth data?

Sex ratio of newborns

m boys and f girls born in a spatiotemporal category, then m/f is the birth sex ratio 104/100 – 106/100 = 1.04 – 1.06 is the normal value in large „natural“ human populations

Determinants of the secondary sex ratio The sex ratio is remarkably constant Ein-Mor et al. 2010 Little proven but many suspected sex ratio determinants James 2012

„Sex selective abortion“ Ethnicity Season Genetic conditions Ionizing radiation Chemicals Diseases Example: Bavarian malformation data set (1984 - 1991) sex ratio = 17343/12516 = 1.39

Background Newborns’ sex ratio – technically sex odds

http://www.ncbi.nlm.nih.gov/pubmed/19159875http://www.ncbi.nlm.nih.gov/pubmed/22776504http://www.strahlentelex.de/Stx_14_652-653_S01-05.pdf

Background Missing girls

Lost girls or missing girls in Remlingen, Germany, Asse II, nuclear waste disposal site

Expected number of baby girls: 434 / 1.0557 = 411 Lost girls: Expected – observed baby girls = 411 – 336 = 75

SOR=1.2235 95%-CL=[1.0611, 1.4108]

Region male female Sex Odds SOR ln(SOR) | SE Chisq | pRemlingen/Asse 434 336 1.2917 1.22 0.2017 7.7053Germany without Remlingen 16683946 15803390 1.0557 0.0727 0.0055

Live births Germany 1971-2012

Sample versus entire population

Individual level studies Sample, small sample sizes Willingness to participate Expensive, elaborate Recall bias, large sampling errors No secular trends KiKK-Studie N = 6000

Population level studies Full registration (municipalities, countries, continents) Independent of collaboration Simple, quick, cheap Recall bias obsolete, small random errors Secular trends Municipality based sex ratio study N = 80 millions

Paradigmatic is John Snow’s defining ecological study (oikos=house) discovering the cause of the Cholera epidemic in London 1854 (contaminated table water). Our sex ratio studies are ecological studies in the spirit of John Snow with topical data processing tools and statistical methods.

Data + Methods – Studies

http://en.wikipedia.org/wiki/1854_Broad_Street_cholera_outbreak

Data + Methods – Exposure

Germany France

Switzerland

The Netherlands: Borssele

, Luxembourg: Cattenom

Data + Methods – Effect

• SO sex odds • LL 95% lower limit • UL 95% upper limit • Austria, Belgium not yet completely geo-coded

Country period municipalities(≈) male female total SO LL ULFrance 1968 - 2011 36,565 16,968,701 16,145,925 33,114,626 1.0510 1.0502 1.0517Germany 1957 - 2012 18,382 17,017,551 16,117,512 33,135,063 1.0558 1.0551 1.0566Luxembourg 1975 - 2013 137 100,431 94,851 195,282 1.0588 1.0495 1.0683Switzerland 1969 - 2012 2,770 1,799,508 1,704,440 3,503,948 1.0558 1.0536 1.0580The Netherlands 1988 - 2009 798 2,183,191 2,078,949 4,262,140 1.0501 1.0481 1.0521Austria 1973 - 2012 2,628 1,759,711 1,670,283 3,429,994 1.0535 1.0513 1.0558Belgium 1989 - 2007 584 1,141,451 1,088,579 2,230,030 1.0486 1.0458 1.0513Total 61,864 40,970,544 38,900,539 79,871,083 1.0532 1.0528 1.0537

Data + Methods – Effect

Data + Methods – Models

Logistic regression for modeling and significance testing of determinants of the outcome of a binomial variable, e.g. boys among newborn children

Sample SAS code for logistic regression and nonlinear regression of log odds data Rayleigh function – spatial trend *Comment: m=male, f=female; data nlin; set nlin; x=km; so=m/f; z=log(so); var=1/m+1/f; w=1/var; run; proc nlin data=nlin; parms a=.00 b=.05 c=20; model z = a + b*(x/c)*exp(-((x/c)**2-1)/2); der.a=1; der.b=(x/c)*exp(-((x/c)**2-1)/2); der.c= -b*(x/c**2)*exp(-((x/c)**2-1)/2)+ b*(x**3/c**4)*exp(-((x/c)**2-1)/2); _weight_=w; run;

Simple jump function – time trend *Comment: m=male, f=female; data a; set a; d35=0; if km < 35 then d35=1; run; proc logistic data=a; model m/(m+f) = d35/scale=d; run;

Results Luxembourg: Dudelange (Effect by French NPP Cattenom?)

GK3

H-w

ert [

km]

5230

5240

5250

5260

5270

5280

5290

5300

5310

GK3 R-wert [km]

3400 3410 3420 3430 3440 3450 3460 3470 3480

Beznau

o municipalities D • municipalities CH

Results Switzerland: Beznau Nuclear Power Plant Beznau

Nuclear waste storage Würenlingen

Paul Scherrer Nuclear Research Institute

Results Switzerland: Beznau

Results Switzerland: Beznau

Results D + CH: 32 nuclear facilities (NF) Update of published results Scherb and Voigt 2011 Kusmierz, Voigt, Scherb 2010

http://www.ncbi.nlm.nih.gov/pubmed/21336635http://enviroinfo.eu/sites/default/files/pdfs/vol6516/0616.pdf

Results France: 28 nuclear facilities (NF) Publication submitted

Results France: 28 nuclear facilities (NF)

Results France: 28 nuclear facilities (NF)

Results Synopsis: France (red) Germany + Switzerland (blue) France base line adjusted !

Summary and Outlook

Childhood cancer and birth sex ratio are increased near nuclear facilities

DOGMA – UNSCEAR/ICRP/WHO/IAEA exclude such effects, because doses are much too low, allegedly. However „It‘s easy to find nothing“

Changed sex ratios (lost girls) is but one indicator among many others for false radiation protection principles for construction and approval of nuclear facilities

Operation, decommissioning, interim and “final” storage of nuclear waste are irresponsible and entail considerable harm to nature and mankind

Storage must be selected with utmost diligence and competence (optimum shielding), negative examples Asse II and Gorleben, Germany.

Intensifying research in the demonstrated effects is urgently needed

For the protection of the natural gene pools immediate action is required

No Installation of new NNPs, the German abandoning nuclear power is overdue

Thank your for your attention

Dr. Hagen Scherb, Dr. Kristina Voigt, M.Sc. (Math.) Magdalena Sigler, Dipl.-Ing. Ralf Kusmierz Institute of Computational Biology, Helmholtz Zentrum München – German Research Center for Environmental Health Ingolstaedter Landstr. 1, D-85764 Neuherberg, Germany scherb@helmholtz-muenchen.de Homepage

Genetic Effects in the Vicinity of Nuclear Facilities

http://www.helmholtz-muenchen.de/mailto:scherb@helmholtz-muenchen.demailto:scherb@helmholtz-muenchen.dehttp://www.helmholtz-muenchen.de/icb/institute/staff/staff/ma/2476/index.html

Foliennummer 1ContentBackground Risk Perception�� Background�� Background Genetic effects after Chernobyl�� Background Genetic effects near nuclear power plants (KiKK-study)Background Chernobyl consequences + KiKK-study�� Background Newborns’ sex ratio – technically sex oddsBackground Missing girls� Data + Methods – StudiesData + Methods – ExposureData + Methods – EffectData + Methods – EffectData + Methods – ModelsResults Luxembourg: Dudelange (Effect by French NPP Cattenom?)�Results Switzerland: Beznau Results Switzerland: BeznauResults Switzerland: BeznauResults D + CH: 32 nuclear facilities (NF)Results France: 28 nuclear facilities (NF)Results France: 28 nuclear facilities (NF)Results France: 28 nuclear facilities (NF)Results Synopsis: France (red) Germany + Switzerland (blue)Summary and OutlookFoliennummer 25