Reiko Watanuki, Yuko Yoshida and Kiyoko Futagami

1. Radioactive Contamination and the Health of Women and post-Chernobyl Children-Based on Comparative study of Chernobyl, Seveso and Hiroshima/Nagasaki Reiko Watanuki, Yuko Yoshida and Kiyoko Futagami Chernobyl Health Survey and Healthcare for the Victims - Japan Women’s Network The 20th anniversary of Chernobyl Catastrophe International Conference “Health Consequences of the Chernobyl Catastrophe. Strategy of Recovery” 29 May to 2 June 2006, Kiev

2. Background Our Ecological Philosophy “Human being is a part of Nature（eco-system), and is not more than a part of Nature” “Uterus is a smaller eco-system” Viewpoint of our research“Pollutants and Women and children’s health” Chernobyl Health Survey and Health Care for the Victims – Japan Women’s Network was established in 1990. R. Watanuki: Director, E-mail: r-watanuki@mug.biglobe.ne.jp Y. Yoshida: Secretary, E-mail: yosida-y@tkd.att.ne.jp , K. Futagami: Vice director

3. Major incidents which affected unborn generations

4. 1.2 Health Studies of women and children Reported health conditions among inhabitants in contaminated areas. Girls and/or women Thyroid dysfunction, autoimmune disease , disturbance of sexual development, disturbance of menstrual function, deteriorated immunity, disease of reproductive organs, etc. During pregnancy Pregnancy complications, thyroid disease, anemia, urogenital diseases, miscarriage, early amenorrhea, premature birth, stillbirth, etc. Fetus Fetal death, insufficient development, hypoxia, congenital malformation, etc. Newborns, children and/or adolescents Neonatal death, Unhealthiness, Allergy, Diseases of nervous, immune, endocrine and/or reproductive systems, etc.

5. 2. Emerging science of endocrine disruption T. Colborn et al. “discovered” an endocrine disrupting effect of some chemicals in early 1990s.(Colborn et al., Our stolen Future, 1996) Endocrine disrupting chemicals (EDCs) are chemicals that can disrupt thyroid hormones, androgens, estrogens and other endocrine processes. In some EDCs, they can act at far below dose than previously assumed “No Observed Adverse Effect Level”. Now, EDCs on developing organisms are of greatest concern, since the disruptive effects of developmental exposure can be irreversible.

6. Concept of developmental basis (origins) of diseases and endocrine disruption Recently, the focus of developmental toxicology has changed to an important and emerging area: the effect in utero exposures (to some environmental agents) that cause permanent functional changes,that results in increased susceptibility to disease/dysfunction later in life span. (Heindel, In the International Symposium on Environmental Endocrine Disrupters, 2003)

7. 3.Health condition of post-Chernobyl Children: Our hypothesis, Case of Ms.A

8. We hypothesize that in Chernobyl case, for example, I131 and Cs137 may have endocrine disrupting effect and it may disrupt programs of biological response or gene expression or other biological homeostasis that may lead susceptibility to subsequent exposure to environmental agents. Especially exposure to such agents in utero may induce more serious effect to developmental embryo/fetus. In contaminated area, exposure to radiation can continue after birth even they are low level. It may lead children’s vulnerability which are observed in even today. Fig. by Watanuki & Yoshida

9. Regarding a finding of “Endocrine Disrupting Effect”:A Japanese distinguished immunologist’s “Ecological view” A comment of Prof T.TADA (Immunologist, Tokyo Univ.) (2001) • “We have considered so far, that separate from the outer environment, there was a sort of internal environment within a living body, and the internal system as microcosm was WORKING INDEPENDENTLY from the outer macrocosm, that was the organism. Such assumed independent organism has been subjected by the medical science. …..

10. A Japanese distinguished immunologist’s “Ecological view” (cont.) • However, the issue of Ecology has turned the traditional idea upside down, the idea that organism is essentially an independent existence.” • Therefore “incorporation of environmental pollutants, which have endocrine disrupting effect, would obviously link the inner organism with outer environmental situation. I believe we have to look at it as a serious big problem for the science of Biology.”

11. 4. Comparative study: Chernobyl vs. Seveso(Chemical Accident in Italy, 1976)

12. 20 years after the accident, Seveso Women’s Health Study started with a new scientific concept Why we compare Chernobyl with Seveso case? “Seveso accident” (Chemical -dioxin- exposure case) • On 10 July 1976, as a result of a chemical explosion, residents of Seveso, Italy, experienced the highest levels of TCDD (dioxin) exposure. • Twenty years later(1996), the Seveso Women's Health Study (SWHS) was initiated with a new scientific concept -Endocrine disrupting effect of chemicals. It is a sex-based retrospective cohort study of female residents of the most contaminated areas, to determine whether the women were at higher risk for reproductive disease.

13. Major results • Doubling of endometriosis but not significant dose response • Longer menstrual cycle but only in women exposed pre-menarche • No increase in spontaneous abortion or birth defects (numbers too small) • No change in age of menarche • Possible small association with birth weight /SGA • Increased breast cancer incidence

14. Considerations on SWHS • Underestimate of effects possible due to potentially high background TEQ • Highest exposed women were the youngest at follow-up • Animal evidence suggests in utero exposure may be the more sensitive route for the developing fetus. • It is possible the effects of TCDD are yet to be observed. Continued follow-up of the SWHS cohort and their offspring is needed. by B. Eskenazi (in International Symposium on Endocrine Disruption 2005, Okinawa, Japan)

15. 5. Comparative study: Chernobyl vs. Hiroshima/Nagasaki Victims of Atomic bombs • Hiroshima: August 6, 1945 Died instantaneously or of acute effects of radiation exposure: about 120,000 • Nagasaki: August 9, 1945 Died instantaneously or of acute effects of radiation exposure: about 75,000 Victims include many civilians and children. And almost the same number of people could survive the acute effects but have faced to fear of late effects of irradiation. The number of second generation of survivors is thought to be between 300,000 – 500,000 (uncertain).

16. 5-1. New findings on radiation health effects after 60 years: Increased cancer risk • A-bomb survivors’ epidemiological survey showed an elevated incidence of myelodysplastic syndrome (MDS) during 1980-2004. MDS was previously called as pre-leukemia and is closely related to leukemia. • It also shows that the elevated incidences of solid cancers are still persisting in 1980-2004. • At WHO-Nagasaki University joint seminar in Geneva September 2005, Prof. M Tomonaga (Nagasaki Univ.) presented a hypothesis. He regards that A-bomb radiation effect has been lasting for 60 years. • It could be a reasonable hypothesis that the stem cells were irradiated and damaged at chromosome and eventually DNA by the atomic bomb irradiation in 1945 and they are persisting over half century, giving rise to cancers.

17. Persistent subclinical inflammation among survivors was revealed 43-47 years later • Neriishi et al. (RERF) revealed the persistent subclinical inflammation among survivors at the time of 43-47 after exposure. The associations with radiation dose were statistically significant for some inflammatory indicators. • Among inflammatory diseases, associations were the strongest for chronic thyroiditis. Such associations were seen regardless of the presence of clinically detectable inflammatory disorders. Authors concluded that the association might contribute, as an epigenetic and/or bystander effect, to development of several radiation-induced disorders (Int. J. Radiat. Biol., 2001).

18. Major studies 1.Pregnancy outcomes Major malformations, stillbirth and/or neonatal death (1948-53) (Exposed 31,150, Control 41,066)* 2. Sex ratioof children (1948-1962)Total 65,431 3. Chromosome mutations (1967-1987) (Exp. 8,322, Cont. 7,976)* 4. Mutations in blood proteins (1975-1988) (Exp. 11,364 Cont. 12,297)** Results 1. No statistically demonstrable increase in major birth defects. 2.The prediction of the effects of lethal mutations on the frequency of male birth is not possible. 3.No difference were observed for newly arisen mutations. 4. No statistically significance. 5-2. Genetic studies (1948-) by ABCC/RERF

19. 5. Mortality and cancer incidence(1960- ) Children born between 05.1946 – 12.1984 (Both or one of parents: exposed 31,150, control 41,066)*,** 6. DNA studies(1996- )** 1) Six minisatellite loci Exposed: 50 families, 64 children Control: 50 families, 60 children 2) Six microsatellite loci 3) DNA from various single-copy genes 7 x 10(6) base pairs 5. To date(2003), no evidence of increased risk. Mortality up to age 20 was not related to parental exposure. Additional follow-up is on going. 6. 1)Difference is not statistically significant. DNA fingerprints are currently examined. 2) Exposed=0%,Control=0.6% Further study is required. 3) No mutation was detected. Extended study is on going. Exposed (proximally exposed*, or parental gonadal dose≥0.01Sv by DS86**)Control (distally exposed or not exposed*, or gonadal dose<0.01Sv**)

20. Major studies on Human DNA minisatellite

21. On going genetic studies by RERF and the claims of children of the survivors against the Government On going studies • DNA studies • Mail survey (questionnaires) and clinical studies on adult onset type diseases. The claim of children of the survivors (2006) • Improvement of A-bomb Survivors Relief law, that is, national compensation and its application to the second generation. Especially, 1. Include a checkup for cancers into the general health examination for the second generations. 2. Perform medical treatments according to the result of the health examination 3. Investigate the actual conditions of second generations and issue “Second generations health record book”.

22. The movement of children of the survivors(First organization in Hiroshima was established in 1973)

23. 5-3. Osaka District Court in Japan recognized that diseases of 9 people were caused by Atomic bomb radiation (12 May 2006) Plaintiffs are between 69 and 81 years old. Seven of them were exposed to A-bomb radiation about 1.5 to 3.3 km from the hypocenters, and the other two were exposed to radiation when they entered in Hiroshima after the bombing. Later they suffered diseases such as cancers, cataract, thyroid hypofunction and etc. The Government had rejected to recognize that their disease were A-bomb radiation related.

24. The judge pointed out that Government’s dose estimating system is suspected to underestimate effects on people exposed further away from the hypocenter. Additionally, he said in the ruling it is needed to consider health problems caused by residual radiation, fallout and internal exposure, which has been neglected or very underestimated until now. This is an epoch-making ruling because that it pointed out the limitation of current dose estimation system created and conducted by ABCC and RERF. The Government appealed against the decision on 22 May.

25. Untoward pregnancy outcomes In utero exposure at time of bombing (Exp. 1630) Reproductive functions (1949-57, Hiroshima) Age of menarche (Exposed 1007, Control 993) Untoward pregnancy outcomes (aforesaid) In utero exposure has had significant effects on mental and physical growth and development. The effect seems particular pronounced for persons who were exposed during the period from 8 to 15 weeks after conception. Reproductive functions Almost same age between exposed group (age 14.71) and control group (14.57). 5-4. Studies on women’s reproductive health by ABCC

26. 2. Amenorrhea immediately after A-bomb exposure (Exposed. 880) 3. Menopause (Exp. 1000, Cont. 950) 4. Fertility (1962-64, Hiroshima/Nagasaki) (Exp. 2400) 2.Observed in half of the mature women. The frequency in women with ARS was significant higher (69%) than women without ARS (33.7%). In most (85.5%) of the cases, it was transient, but about 15% of them continued from amenorrhea to menopause. 3. A marked increase in the age groups 40-49. Its peak was seen in 1945. It was suggested that menopause is definitely accelerated by A-bomb exposure, but it cannot be attributed solely to direct effect on the ovary. 4. There was no evidence to suggest that those in the high radiation dose groups uniformly suffered impaired long-range fertility.

27. 5-5. Our questions for the A-bomb studies General • A-bomb studies were most of single, relatively high-dose exposure cases, and they were started 4 years after exposure. Data in early period is unknown or uncertain. • The control groups (zero Sv group) include those distally exposed or exposed less than 0.01Sv (by DS86), and may include those exposed from fall out. Exposure from fall out is thought to be insignificant dose, but actually, it is uncertain. Genetic • In the DNA studies, children of exposed group were born 10 years after parents’ exposure. Its result cannot be simply compare with the data of children whose parents were continuously exposed to low level radiation.

28. Reproductive health • In early study in Nagasaki, it suggested that radiation affects not only directly to the fetus but also indirectly as a result of its effect on the maternal tissue. It was of considerable importance in determining the outcomes of these pregnancies. However, these considerations were not followed by subsequent studies. • In pregnancy outcomes study, radiation effects to girls of adolescent age are uncertain. • In menarcheal age study, about 40% of girls remained pre-menarche stage, but follow-up study was not found. • Very few studies concerning women’s reproductive health and the study period is short. Insufficient follow-up. From our point of view, radiation effect to women’s reproductive health in Hiroshima/Nagasaki data should be re-evaluated.

29. 6. New concept of “genetic” effect ofenvironmental agents (chemicals and radioactive substances) Fig.A Endocrine disruptors Fig. A shows a contrast of traditional with new formulations of the interactions of genes and environment in the determination of phenotype.(by Myers, In International Seminar on Nuclear War and Planetary Emergencies, 2003) Fig. B shows a new mechanism of biological effect of environment stress through genomic instability.(by Niwa, Environment and Health, 1998) Fig.B Radiation effect

30. Health condition of children, who experienced antenatal exposure in different period after Chernobyl Accident All subjects were born and are living in contaminated areas (1st zone: less than 15 Ci/km2, 2nd zone: 15-45 Ci/km2 ) Subjects: Children at age from 4 to 17, were divided into 3 groups. • 1st group: 105 children born in 1986-87. They were in utero at time of the accident • 2nd group: 100 children born in 1990. • 3rd group: 96 children born in 1995. Their parents were in pubertal period at time of the accident • Control group: 120 children born in 1986-87, 1991 and 1995

31. Peculiarities of each group • 1st group: Higher incidence of children with congenital developmental anomaly, nervous and endocrine diseases, and lower physical development. • 2nd group: Higher incidence of children with endocrine diseases and lower physical development. • 3rd group: Higher incidence of children with psychiatric disorder, congenital developmental anomaly, dominant genetic diseases and disbalance of physical development. They also have a peculiarity having mental retardation and multi minor developmental anomalies. (Bondarenko, 2005)

32. Conclusion This sort of situation has significance in suggesting problems related to ecological ethical norm. The alarm bell given by the soundless voices of Chernobyl children has revealed the responsibility of our generation. More specifically, it is our responsibility NOT to ‘produce’, NOT to ‘use’ or NOT to ‘discharge’ such pollutants that might affect future generations’ eco-system irreversibly, and that might cause genetic disorder. In other words, we must seek a society that values the principle of ‘non intervention to gene’ as ‘better and preferred option’, even it means we have to give up some material wealth or convenience.

33. Therefore, I would like to emphasise that we really have to see through the situation of Chernobyl children how much we, as current generation, are at the risk of forcing unbearable “suppression” to the future generations’ life and health. I believe that it indicates a significant challenge human history is facing in this 21st century.

34. Chernobyl children’s 20 years of radiation exposure experience is suggesting that world societies should convert its nuclear policy as soon as possible. By this conversion, not only nuclear weapons, but also technological dependence such as nuclear power generation should be reduced. This direction is the only way out of suppressing the life of future generations.

35. Comments of Japanese distinguished scientists in the field of radiation effects Prof. M. Tomonaga(Biomedical sciences, Nagasaki Univ.)The atomic bomb irradiation-induced genetic damage persist over half century and probably whole lives of survivors. This finding provides discrete evidence that all nuclear weapons must be considered more dangerous because of emitting radiation and should be abandoned.(In WHO-Nagasaki Univ. joint seminar, Geneva, Switzerland, 2005) Prof. T. Nomura(Radiation biology and medical genetics, Osaka Univ.)My experiments with mice anticipated the suggestion that parental exposure to radiation and chemicals could induce heritable tumors in the next generation. It is important to follow all the human subjects throughout their lives, especially adult type cancer and chronic diseases. (In International symposium: Transmissible Genetic Risk and Our Future, Osaka, Japan, 2005)

36. Acknowledgements Russia Larisa S. Bareva and doctors in Children center of antiradiational protection (Federal Children Center of Antiradiational Protection) Elena B Burlakova (Institute of Biochemical Physics RAS) Margarita I Mikhanlenko (Chernobyl Global Security Fund) Valentina M Kozeikina (Chernobyl Global Security Fund) Belarus Researchers of Institute of Genetics and Cytology BAS Olga Alenikova (Children’s Center for Oncology and Hematology) Sergey P. Chunikhovskiy (ex- Mogilev regional Children’s Hospital) Tamara Kravtsova (“Children in Trouble” in Mogilev) Ukraine Researchers of Institute of Molecular Biology and Genetics ASU Angelina I. Nyagu (Association “Physicians of Chernobyl”) Irina G. Ivasenko (Union “Kiev-Chernobyl”) U.K. Late Alice Stewart (ex-Birmingham Univ.) Japan Taisei Nomura (Osaka Univ.) Masao Tomonaga (Nagasaki Univ.) Otsura Niwa (Kyoto Univ.) And especially, children of Chernobyl and their mothers