Prof.Shizuyo Sutou , has won the Distinguished Scientist Award in Radiation biology

Prof. Shizuyo Sutou has won the Asia’s Distinguished Scientist Award in Radiation Biology. 2. Self introduction 2-1. Background and education Sutou was born in 1942 in Yokosuka, Kanagawa Prefecture, where the Yokosuka Naval Arsenal was located and where his father worked. In the spring of 1945, he and his mother were forced to evacuate to Yuki, Ibaraki Prefecture, the hometown of his parents, to avoid air raids by the US military. He attended elementary school, junior high school, and high school there. In 1962, he enrolled at the University of Tokyo and obtained bachelor’s, master’s, and Ph.D. degrees in Pharmaceutical Sciences. The title of his dissertation was “A Study on Detection Systems for Environmental Mutagens.” He lives in Okayama since 2003. 2-2. Occupational career Here is a brief summary of Sutou’s occupational career: Apr. 1968 – Mar. 1970: Researcher at Shionogi & Co., Ltd., Central Research Institute. Apr. 1970 – Dec. 1982: Researcher at Nomura Research Institute, Ltd. (Jan. 1971 – Sep. 1971: Researcher at the National Institute of Genetics.) (Apr. 1978 – Mar. 1981: Lecturer at the University of Tokyo, Faculty of Pharmaceutical Sciences.) (Aug. 1980 – Nov. 1981: Researcher at City of Hope National Medical Center, USA.) Jan. 1983 – Jun. 1988: Researcher at NRI Life Science, Ltd. Jul. 1988 – Dec. 1998: Researcher at Itoham Foods Inc., Central Research Institute. (Aug. 1988 [1 month]: Instructor at the Thailand National Institute of Health as an expert for Japan International Cooperation. (Sep. 1994 – Mar. 1995): Lecturer at Ibaraki University Graduate School.) Jan. 1999 – Mar. 2002: Researcher at the National Institute of Advanced Industrial Science and Technology. (Sep. 2001 – Mar. 2002: Lecturer at Aomori University.) Mar. 2003 – Mar. 2008: CEO of iGENE Therapeutics, Inc. Apr. 2015 – Mar. 2015: Professor at Shujitsu University, School of Pharmacy. (Apr. 2004 – Mar. 2005: Lecturer at Kurashiki University of Science and the Arts.) April 2015 – present: Prof. Emeritus at Shujitsu University and visiting researcher. (Dec. 2022: Lecturer at Tohoku Medical and Pharmaceutical University.) (Careers in parentheses are concurrent positions.) 3. Qualifications, Affiliated Societies, Experiences, Publications, etc. 3-1. Licenses and Certifications Sutou holds the following licenses and certification: 1) Pharmacist (1967, License No. 105001). 2) Principal radiation specialist (1967, License No. 2193). 3) Ph.D. in pharmaceutical sciences (1974, the University of Tokyo, No. 3250). 3-2. Affiliated societies Sutou used to be a member of several societies, including the Japanese Tissue Culture Association, the Molecular Biology Society of Japan, the Japanese Society of Animal Science, the International Conference on Biotechnology in Animal Reproduction, and the Japanese Environmental Mutagen and Genome Society (JEMS). He has been a member of JEMS since its inception in 1972 and is an honorary member now. 3-3. Activities Associated with Academic Societies and Occupations Sutou has been actively involved in various volunteer activities and professional roles, including: 1) Board member of the Yokohama Biotechnology Forum (1984-1999). 2) Editorial board member for the journal “BIOClinica” (1986-1988). 3) Council member of the Japanese Environmental Mutagen Society (1991-2001). 4) Member of the Committee for Discussing the Future of Yuki City (1995-2004). 5) Organizing committee member of the 8th International Environmental Mutagen Society (1997- 2002). 6) Editorial board member of the journal “Mutation Research” (1997-[?]). 7) Editor-in-chief of “Environmental Mutagen Research,” the official journal of JEMS (1998-1999). 8) Editorial board member of the journal “Mutagenesis” (2002-[?]). 3-4. Publications and Presentations Sutou’s contributions include: 1) Papers: 120 in English and 25 in Japanese. 2) Commentaries or reviews: 48. 3) Books: S. Sutou (Editor-in-chief), M. Doss, H. Tanooka (Eds): Fukushima Nuclear Accident: Global Implications, Long-Term Health Effects, and Ecological Consequences, Nova Science Publishers, Inc., N.Y., 2015. S. Sutou. A message to Fukushima: Don’t be afraid of radiation, Gentosha, Tokyo, 2017 (in Japanese). S. Sutou. A message to Fukushima: Long life and low cancer risk by low-dose radiation, Gentosha, Tokyo, 2019 (in Japanese). S. Sutou. Radiation has been an old friend of the Earth and humans, Gentosha, Tokyo, 2021 (in Japanese). S. Sutou. Contribution of a chapter or chapters to 10 books, 1985-2005 (in Japanese or English). 4) Presentations in academic meetings: 186. 4. Profile Highlights 4-1. Endoreduplication and Sister-Chromatid Exchanges (SCEs) In 1971, Sutou delved into cytogenetics at the National Institute of Genetics. His initial paper revealed that 4-nitroquinoline 1 oxide (4-NQO), a water-soluble carcinogen, induces endoreduplication, a process in which a pair of chromosomes (4 chromatids) align in parallel, forming diplochromosomes (“Endoreduplication in cultured mammalian cells treated with 4-nitroquinoline 1-oxide.” Mutat. Res., 18, 171-178, 1973). Cell cycle analysis of endoreduplication showed that G2 and G1 cell cycles are connected by skipping M phase and consists of two S phases, S1 and S2 (S. Sutou & F. Tokuyama. “Induction of endoreduplication in cultured mammalian cells by some chemical mutagens.” Cancer Res., 34, 2615-2623,1974). When DNA is damaged, sister-chromatid exchanges (SCEs) occur, involving the exchange of two double-stranded DNAs within a chromosome. Bromodeoxyuridine (BrdU, B) can substitute thymidine (T) in DNA. In the presence of BrdU during DNA replication, two types of strands are formed: B-T:T-B strand in S1, and B-B:T-B and B-T:B-B strands in S2. Differential staining of diplochromosomes with Giemsa revealed that the outer two chromatids with a B-B strand appear pale, while the inner two chromatids with a T-B or B-T strand appear dark. The precise arrangement of chromosomes is particularly intriguing. In a diploid cell, DNA length is 2 m in G1 phase and 4 m in G2/M phase, which doubles to 8 m and 16 m, respectively, in an endoreduplicated cell. Despite the extended DNA strands, they remain accurately positioned without entanglement. Theoretically, the ratio of SCEs in S2 to SCEs in S1 is 2, but experimental results showed that the ratio is around 3. The reason for this is because BrdU itself is a weak SCE-inducer. When a ring chromosome is used, SCEs in S1 can be detected without BrdU as a symmetric dicentric ring chromosome. Experiments using cells with a ring chromosome showed that SCEs occur spontaneously, and the incidence is close to that detected with very low dose levels of BrdU, 0.1 μg/mL (“Spontaneous sister-chromatid exchanges in Chinese hamster cells in vivo and in vitro.” Mutat. Res., 82, 331-341, l981). 4-2. The Micronucleus Test Since around 1970’s, the relationship between metagenesis and carcinogenesis has been a deep concern and researchers tried to establish detection methods of mutagens. The Mammalian Mutagenesis Study Group of the Japanese Environmental Mutagen and Genome Society (MMS.JEMS) was established in 1982. Sutou was one of organizers of MMS.JEMS, which has biannual meeting since then and the 83rd meeting was held in June, 2023. Initially, Sutou and colleagues examined protocols for the micronucleus test (MN test) based on international and domestic guidelines. Since the protocols lacked solid data, they established the Collaborative Study Group for the Micronucleus Test (CSGMT) in 1983. Sutou proposed studying the sex difference in the MN test, with 20 organizations participating. The results indicated no difference between male and female mice, suggesting that using male mice alone suffices for the MN test. The findings were reported by the CSGMT, with Sutou serving as the organizer-in-chief (CSGMT. “Sex difference in the micronucleus test.” Mutat. Res., 172, 151-163, 1986). As the second topic, Sutou proposed investigating strain differences. Four strains, namely BDF1, CD-1, ddY, and MS/Ae, were employed, and 24 organizations tested six chemicals using one of the strains. All four strains showed positive results, leading to the conclusion that any strain could be used. The results were reported by the CSGMT, with Sutou as the author (CSGMT. “Strain difference in the micronucleus test.” Mutat. Res., 204, 307-316, 1988). Among the four strains, MS/Ae (MS stands for “mutagen sensitive”) exhibited the highest response. This strain could be useful for testing weak clastogens. N-nitrosodiethylamine, previously reported as negative or equivocal in the MN test, showed positive results when MS/Ae mice were used (N. Higashikuni, T. Morita, S. Sutou. “N-nitrosodiethylamine induces micronuclei at doses below the maximum tolerated dose.” MMS Commun., 2, 1-6, 1994). The high mutagen sensitivity of MS/Ae mice suggested a maternal effect (S. Sutou, S. Sato. “Maternal effect on micronucleus induction in MS/Ae mice,” Environ. Mol. Mutagen., 15, 125-130, 1990). Since mitochondria are maternally transmitted to offspring, Sutou determined the entire mitochondrial DNA sequence (19,300 bases) and identified 15 sites that differed from the C3H strain. However, these 15 sites were common to CD-1 mice, the maternal strain of MS/Ae mice, which were not mutagen- sensitive. Therefore, factors other than mitochondria are likely responsible for the high mutagen- sensitivity (“Entire nucleotide sequence of mitochondrial DNA of MS/Ae mice.” Environ. Mol. Mutagen., 28, 107-111, 1996). In the 3rd subject, application routes were investigated. The intraperitoneal route allowed MN induction at lower doses, oral gavage route showed similar micronucleus-inducing activity per LD50 (M. Hayashi, S. Sutou, et al. “Difference between intraperitoneal and oral gavage application in the micronucleus test, The 3rd collaborative study by CSGMT/JEMS.MMS,” Mutat. Res., 223, 329-344, 1988). In the 4th CSGMT study, dosing times were investigated. Mice were administered 1, 2, and 4 times and the bone marrow samples were taken 24 h and 48 h after dosing. In general, two doses and sampling 24 h after dosing seemed to be best (CSGMT, corresponding author, S. Sutou. “Single versus multiple dosing in the micronucleus test: The summary of the fourth collaborative study by CSGMT/JEMS.MMS. CSGMT.” Mutat. Res.,234, 205-222,1990). In the 5th CSGMT study, the peripheral blood was used instead of the bone marrow, and acridine orange supravital staining was employed instead of Giemsa staining (CSGMT. “The summary report of the fifth collaborative study by CSGMT/JEMS.MMS.” Mutat. Res., 278, 83-89, 1990). On July 10-15, 1989, the 5th International Conference on environmental mutagens (ICEM) was held at Case Western University, Cleveland, Ohio. Sutou presented a large body of CSGMT data on behalf of collaborators, which seemed to impress international audience. This presentation must have paved the way to international collaborative studies thereafter. On July 4th, 1989, Tiananmen Square incident occurred. The 6th ICEM was planned to be held in Chine in 1993, but the 5th ICEM committee canceled the plan, saying that the international conference could not be held in such a barbaric country as to kill compatriots. Instead, in 1993, the 6th ICEM was held at Melbourne under the auspices of the Australia and New Zealand Environmental Mutagen Society (ANZEMS). Before this in May, 1991, the International Symposium on Environmental Mutagenesis and Carcinogenesis was held in Shanghai, China which invited Sutou to make a speech on the MN test. In Sutou’s review, CSGMT studies from 1st to 10th were introduced (“Achievements by CSGMT/JEMSMMS: the Collaborative Study Group of the Micronucleus Test in the Mammalian Mutagenesis Study Group of the Environmental Mutagen Society of Japan.” Mutat. Res., 340, 151-174, 1996). CSGMT further developed the MS test from the bone marrow to the liver and gastro-intestinal MN tests. These studies have been achieved by younger researchers and are incorporated into international and domestic guidelines. MMS had its own journal “MMS Communications (MMSC)” which was changed from “MMS newsletter” that was firstly issued in 1988. Experimental data from CSGMT members were mainly published in MMSC. Sutou and his colleagues published 10 original papers in MMSC. MMSC was issued biannually until 1996, when MMSC was merged to Mutation Research. There was a route to publish papers in Mutation Research through MMSC. Researchers who wanted to use this route sent manuscripts to Sutou and he communicated them to Mutation Research after peer review. Around 10 papers were published through this route. 4-3. Sex determination in spiny country-rats without the Y chromosome Sutou stayed at Dr. Ohno’s laboratory in the City of Hope National Medical Center around 1981 and made research into sex determination mechanisms. In Southwestern Islands of Japan, there live three spiny country-rats, Tokudaia muenninki in Okinawa main Island, T. tokunoshimensis in Tokunoshima, and T. osimensis in Amami Oshima. The karyotype of T. muenninki is 2n=44 with the X and Y chromosomes, but that of T. tokunoshimensis is 2n=25 with only one X chromosome and that of T. osimensis is 2n=45 with one X chromosome. Both male and females of the latter two have the identical karyotype. The late Prof. K. Tsuchiya captured these rats and Sutou examined their genomes and showed that these Y-lacking rats also lack Sry, the primary sex-determining gene of most mammals (S. Sutou et al. “Sex determination without the Y chromosome in two Japanese rodents Tokudaia osimensis osimensis and Tokudaia osimensis spp.” Mamm Genome. 2, 17-21, 2001). These three country-rats are on the verge of extinction and capture of them is prohibited now; further research into the rats came to a deadlock. 4-4. Cattle sexing AS NRI Life Science, Inc. was closed, Sutou moved to Itoham Foods Inc. (Itoham), a meat packer, to carry out sexing of cattle. His team cloned and characterized bovine SRY gene on the Y chromosome, but this is a single gene and disadvantageous to amplify by PCR (Y. Kato et al. “Cloning and characterization of bovine SRY gene.” Anim. Sci. Technol. (Jpn), 66, 994-1001,1995). So, they cloned Y-specific repetitive DNA by using the deletion-enrichment method, in which Y- chromosome specific DNA was selectively enriched (T. Kudo et al. “Sexing of bovine embryos with male-specific repetitive DNA by polymerase chain reaction: Cloning and characterization of bovine male-specific repetitive DNA.” J. Reprod. Dev., 39, 55-63,1993). Bovine ovaries were collected from slaughterhouses, and eggs were isolated and matured in vitro. These eggs were then fertilized in vitro, and the resulting fertilized eggs were cultured to develop into blastocysts. Under a microscope, a few cells were isolated from the trophectoderm and subjected to sexing using PCR. This involved the use of two pairs of primers, one for Y-specific DNA and the other for male/female common repeated DNA. Embryos with two PCR bands were identified as males, while those with a single band were identified as females. This sexing method achieved nearly 100% accuracy. By utilizing embryo transfer techniques, calves of the desired sex could be obtained. In the case of milk cows, females were preferred, while for the Japanese Black breed, males were favored due to their faster growth rate. Itoham obtained international patents for this method and commercialized it as “XY-Selector.” However, the success ratio of embryo transfer techniques was approximately 50% or less, limiting full use of this sexing method (Y. Itagaki et al. “Sexing of bovine embryos with male-specific repetitive DNA by polymerase chain reaction: Sexing of bovine embryos and production of calves with predicted sex.” J. Reprod. Dev., 39, 65-72, 1993). 4-5. International Congress on Biotechnology in Animal Reproduction (ICEBAR) Sutou and his colleagues have developed a sexing method of cattle. They then had practical training course at the National Livestock Breeding Center (NLBC) in Fukushima and at livestock research stations in several prefectures. One day, Prof. T. Suzuki of Yamaguchi University asked Sutou to teach the sexing methos to students and breeders. After training, Suzuki invited Sutou to join ICEBAR. Before moving to Yamaguchi University, Suzuki had taught livestock breeders from various countries about embryo transfer techniques at NLBC, and his disciples were active at their hometown. The disciples held ICEBAR at their places. G. Oguri, the owner of Oguri Ranch, supported ICBAR financially in part. He passed away in 2021 at 92. ICEBAR was held 19 times from 1994 to 2015, and Sutou participated and presented in 14 of them. These were Cairo, Egypt (twice); Kathmandu Nepal; Kunming China; Bernberg, Germany; Chennai, India; Ulaanbaatar, Mongolia; Prague, Czech Republic; Leipzig, Germany; Zipo City, Shandong Province, China; and Novi Sad, Serbia. He was looking forward to sightseeing trips after academic meetings. Some memories are as follows: At Kathmandu in 1999, attendants saw the Himalayas from a plane. In 2002, Sutou moved from Chennai to Bangkok and was able to meet some of the students he taught in 1988. In 2006, attendants visited Lhasa, Tibet, from Qinghai. In particular, at the 18th ICEBAR held at Zipo City in 2014, Sutou gave a plenary lecture on human evolution for about an hour. 4-6. Trial to obtain bovine spongiform encephalopathy (BSE)-free cattle In 2003, Prof. K. Taira at the University of Tokyo and the director of the Gene Discovery Center at AIST, asked Sutou to establish a company to provide the technology and information on RNA interference (RNAi). He established a company, iGene Therapeutics, Inc. (iGENE), and served as CEO. At that time, BSE was a high social concern, so he thought that if the expression of the gene PRNP responsible for BSE was knocked-down, BSE-free cattle could be produced. iGENE was selling small interfering RNA (siRNA) expression vectors. Sutou and his colleagues introduced a short DNA sequence that expresses a small interfering RNA (siRNA) against PRNP into a vector harboring types II RNA polymerase III. EGFP was used as a marker for gene transfer. The plasmid was introduced into primary cultured bovine cells. Transgenic embryos were produced by the somatic nuclear cell transfer technology (SNCT), in which transgenic cells with EGFP were introduced into bovine enucleated eggs. When nuclear-transferred 64 eggs were cultured, 17 developed into blastocysts. When 12 of them were used for embryo transfer, 6 impregnated cows. Four of them had miscarriages, one was stillborn, and one was born by Caesarean section, all of which showed EGFP. The world-first bPRNP-knocked-down live-born calf was unable to stand up and was euthanized for further analyses on the 20th day after birth. Expression of the bovine PRNP gene in the brain, cerebellum, spinal bulb, spinal cord, lung, and screen of the born calf was examined using RT-PCR. It was 8% of the control in the spleen where expression was most suppressed, and 71% in the spinal cord where it was least suppressed. The mean expression in 4 nerve tissues (brain, cerebellum, spinal bulb, spinal cord) was 34% of the control. When the expression levels of the PRNP protein was examined by Western blotting, the levels in 4 abortions, 1 stillbirth, and 1 birth did not differ significantly from the control. Thus, the trial to produce BSE-free cattle was not successful (P. Wongsrikeao et al. “Combination of the somatic cell nuclear transfer method and RNAi technology for the production of a prion gene-knockdown calf using plasmid vectors harboring the U6 or tRNA promoter.” Prion, 5, 39 – 46, 2011). 4-7. Human evolution through a hairless mutation 4-7-1. The Importance of New Concepts for Scientists In around 1981, Sutou conducted research at Dr. Ohno’s laboratory in the City of Hope National Medical Center, which marked an exhilarating period in his scientific career. At the request of the Society of Chromosome Research, he composed a brief biography of Dr. Ohno (“Dr. Susumu Ohno. Natural selection has merely modified, while redundancy has created.” Chrom. Sci., 23, 55-56, 2020). Dr. Ohno’s words resonate: “The most important thing for scientists is to propose new concepts.” These concepts were realized in his seminal book, “Evolution by Gene Duplication” (Springer-Verlag, 1970). Building on this inspiration, Sutou ventured to introduce new concepts, specifically the notion of “creation by loss.” 4-7-2. The Hairless Mutation as a Trigger for Human Evolution Three major characteristics distinguish humans from other primates: bipedality, practical nakedness, and the family as a social unit. The three could be explained by a single hairless mutation. The hair is the baby-carrying tool for all primates except humans. If a hairless mutation occurred in the chimpanzee/human last common ancestor (CLCA) 6 million years ago (Mya), when human karyotype with 46 chromosomes separated form that of chimpanzee’s 48, it must have diverged hairless human and hairy chimpanzee lineages. A hairless mother would be forced to be a biped on trees holding a baby with hands. Her activities would be markedly limited. The male partner would have to collect food and carry it to her to keep her and their baby from starving; irresponsible and selfish males could not have left their offspring. The mother would have sexually accepted her partner at any time as a reward for food. Sexual relations irrespective of estrus cycles might have strengthened the pair bond, contributing to family formation. A mother holding her baby with both hands must have made the mother-infant bond, a part of the family bond, stronger than that of any other primate. A single mutation in animals with scalp hair is known to induce hairless phenotype (ectodermal dysplasia). Bipedalism and hairlessness were disadvantageous traits; only those who could survive trials and tribulations in cooperation with family members must have been able to evolve as humans (“Hairless mutation: a driving force of humanization from a human-ape common ancestor by enforcing upright walking while holding a baby with both hands.” Genes to Cells, 17, 264-272, 2012). 4-7-3. Bipedalism as a Factor in the Birth of Immature Babies Early hominins had the opposable hallux and remained as arboreal denizens. Climate changes probably forced them to terrestrial life, but the ground was full of danger and trees were indispensable for refuge and nesting. Consequently, archaic hominins had mosaic characteristics of the upper body adapted for arboreal life and the lower body for terrestrial life, for which a larger brain was advantageous. Alternative strategies became possible: development of a large pelvis with a big birth canal through which a baby with a big brain/head could pass, or delivery of an immature baby, with rearing after birth. The former was physically incompatible with an upright posture due to high possibility of miscarriage, and structurally unfavorable for swift movement. Upright hominins were able to hold the immature baby with hands and raise it after birth. The immature brain had a lot of room for development after birth thanks to use of fire and meat eating (“The hairless mutation hypothesis explains not only the origin of humanization from the human/ape common ancestor but also immature baby delivery.” Human Genet Embryol., 3 (111), 2161-0436, 2013, doi:10.4172/2161-0436.1000111). 4-7-4. The Human Robber Hypothesis: The Essential Role of Fire in Human Evolution About 2.5 Mya, a climate shifted from a wet to a dry environment. Savannah became normal and wildfires occurred frequently. Initially, naked hominins might have approached fire for warming, but soon must have come across charred animals in the aftermath of wildfires. They learned the taste of burnt meat, which must have been a driving force compelling them to become meat-eaters. Hominins must have learned gradually how to control fire and how to repel hairy animals that abhor fire. Because they could neither run fast nor have muscles sufficiently strong to compete with large carnivores’ fangs and claws, they chose not to be hunters but robbers. When they found that a carnivore had killed a prey animal, they approached the predator and repulsed it using fire and stones, then claiming the prey intact. The timing of global climate changes with the normal state of savannahs, the appearance of transitional humans, decline of large predators, the manufacture of stone tools, and the start of cooking largely coincide at 2.5 Mya. They also smoked out animals from their dens or caves, and robbed them of shelter and territory. Cooked meat is both tasty and easily digested, providing hominins with rich nutrients sufficient to enlarge the brain, while most large carnivores were forced to extinction. Consequently, the use of fire, facilitated by hairlessness, must have played important roles in protecting hominins from cold, in repelling predators, in robbing large carnivores of prey and dwellings, and in providing the brain with nutrients. Development of a large number of eccrine glands must be a result of hairlessness (“The human robber hypothesis: humans used fire to steal prey from large carnivores, thereby providing the brain with nutrients to enlarge it after birth.” Genes Environ., 36 (3), 72-77, 2014). 4-8. Research into Radiation Biology: Linear No-Threshold Model (LNT) vs Radiation Hormesis 4-8-1. Motivation behind Research on Biological Effects of Radiation Sutou’s research into the biological effects of radiation was triggered by the accident at the Fukushima Daiichi Nuclear Power Plant (FDNPP) following the Great East Japan Earthquake on March 11, 2011. The Japanese government forcibly evacuated residents within 20 kilometers of FDNPP. However, many people left their valuables in their homes, so the government planned to temporarily return the evacuees to their homes. The government set up four off-site centers just outside the 20-km radius of FDNPP, and recruited volunteers all over Japan to examine radio-contamination of the returnees. The plan started in May 2011 and was implemented mainly in June and July until August. Sutou took a Geiger-Muller counter and conducted radio-inspections at the Baji Koen off-site center in Minamisoma City, Fukushima, for about a week in mid-July. The evacuation zone comprised 27,843 households with a population of about 70,800, of which 33,598 individuals (43%) temporarily returned home. There were no pollutants requiring decontamination. Although no direct radiation-related fatalities occurred, forced evacuation claimed approximately 2,000 lives, mainly the elderly and sick. During this time, Sutou also examined radio-contamination in Fukushima and other locations. The highest contamination was about 6,000 cpm. Having been taught LNT, Sutou worried that his cancer risk might have been increased. This was the impetus for studying intensively the biological effects of radiation. Is 6,000 cpm harmful? 4-8-2. Experiencing 20,000 Hits of Radiation per Second The Earth was formed 4.6 billion years (By) ago, during a time of intense radiation. Radionuclides with long half-lives (τ), such as U-238 (τ: 4.5 By), U-235 (τ: 0.45 By), K-40 (τ: 1.25 By), and others, still exist today. Radioactivity has reduced to 1/5 now. K-40 is one of the constituents of living organisms. Ra-222 (τ: 3.8 days), a daughter nuclide of U-238, is abundant. C-14 and tritium are constantly produced in the air by the action of cosmic rays and incorporated into our bodies. Therefore, every living organism, every food is radioactive. Taking these into account, we are exposed to approximately 20,000 hits of radiation per second from the inside and outside. The highest radioactivity at Fukushima was 6,000 cpm, meaning 100 counts per second (cps). This is negligible compared with 20,000 hits/second. The radiation dose at Okayama is 100 cpm (2 cps) or less, and it is necessary to receive 10,000 times that dose to receive 20,000 hits/second. This estimation made Sutou feel relieved. It can be said that the level of contamination in Fukushima is such that there was no need to evacuate, decontaminate soils, and stockpile tritiated water. The Fukushima accident was a big accident. However, what made it a huge accident was the LNT (“Low-dose radiation effects.” Curr. Opin. Toxicol., 30:100329, June 2022). 4-8-3. Radiation Hormesis Radiation hormesis refers to a biological phenomenon that stimulates effects at low doses and represses them at high doses. In 1885 Roentgen discovered X-rays. Since there were no good medicines in these days, sick people were often irradiated with X-rays. X-rays had been found to be effective in many diseases. Sulfa drugs were developed in the 1930s, and penicillin in the 1940s. Pushed by chemicals, radiation therapy has fallen into decline. However, many subsequent experimental and clinical studies have revealed that radiation hormesis is a widespread phenomenon in living organisms. A good example is that workers at nuclear shipyards in the United States tended to live longer when they received a higher dose of radiation. LNT was recommended by the US National Academy of Sciences (NAS) in 1956 using Drosophila data, ignoring human data. In 2006, NAS used data of A-bomb survivors to support the LNT, but Sutou pointed out that NAS’s assertion has many drawbacks and could not support the LNT. LNT and hormesis are mutually exclusive, and numerous data support hormesis (“Low-dose radiation from A-bombs elongated lifespan and reduced cancer mortality relative to un-irradiated individuals.”Genes Environ. 2018 Dec 19;40:26. doi: 10.1186/s41021-018-0114-3). 4-8-4. Many of the Hiroshima and Nagasaki survivors live longer and have a lower cancer risk In general, 50% of the energy of an A-bomb is blast, 35% is heat, and the remaining 15% is radiation. Of the 15%, 5% was direct radiation and 10% was residual radiation, which fell to the ground as black rain. Sutou found an old Japanese paper on the Hiroshima A- bomb survivors by Dr. Obo and introduced it in English. Obo showed there that the black rain was highly radioactive (“Rediscovery of an old article reporting that the area around the epicenter in Hiroshima was heavily contaminated with residual radiation, indicating that exposure doses of A-bomb survivors were largely underestimated.” J. Radiat. Res., 2017, pp. 1–10. doi: 10.1093/jrr/rrx029). Once every five years, the Radiation Effects Research Foundation (RERF) publishes the results of the Life Span Study (LSS) of A-bomb survivors. When we look at the cancer risk of people who entered the cities after the A-bomb, A-bomb survivors, and Japanese people in general, the risk increases in this order. This can be explained by radiation hormesis (“Black rain in Hiroshima: a critique to the Life Span Study of A-bomb survivors, basis of the linear no-threshold model. Genes Environ. 2020 Jan 1;42:1. doi: 10.1186/s41021-019-0141-8). The same can be applied to life expectancy. People who were exposed to low doses lived longer, and people who were exposed to higher doses lived shorter lives. However, since only about 5% of people were exposed to high doses, the average survivor lived longer. This can also be explained by radiation hormesis (S. Sutou, op. cit.) 4-9. Chemical Hormesis Sutou and his colleagues are conducting a collaborative study of thresholds for mutagens. When cultured mammalian cells were treated with some mutagens and cellular activities were measured, lower doses stimulated the activities, while higher doses repressed them. (Sutou et al. “Collaborative study of thresholds for mutagens: proposal of a typical protocol for detection of hormetic responses in cytotoxicity tests.” Genes and Environment volume 40, Article number: 20 (2018)). Similarly, cell proliferation was studied, hormetic responses were observed (Sutou et al. “Collaborative Study of Thresholds for Mutagens: Hormetic Responses in Cell Proliferation Tests Using Human and Murine Lymphoid Cells.” Dose Response. 2021 Jun 29;19(2):15593258211028473). Hormetic responses were also observed in the MN test (unpublished). These results indicate that effects of mutagens are hormetic as well as radiation hormesis

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