On the monitoring of radiation-induced germline mutation in humans: reply to Y. E. Dubrova
Яргин С. В. On the monitoring of radiation-induced germline mutation in humans: reply to Y. E. Dubrova // Молодой ученый. 2014. №3. С. 51-53.
Several publications overestimating medical consequences of the Chernobyl accident and nuclear testing at the Semipalatinsk Test Site were commented on previously [1–7]. Another example is provided by the paradox discussed in : the results of , based on the observations among the atomic bomb survivors in Japan, “may indicate that a single, acute exposure of spermatogonial cells in humans does not give rise to discernible effects on mutation induction at minisatellite loci. Although this finding appears to be in line with the results for mice, in which only a weak effect was observed after gamma irradiation of spermatogonial cells [10,11], any conclusion will require much further study given that Dubrova's studies indicate precisely the opposite, namely that spermatogonial cells are the sensitive cells for this type of mutation after either acute or chronic exposure [12,13].” .
I am very grateful to Yuri Dubrova for his response  to my letter ; but the following should be commented. It is written in : “The Author also makes a very serious accusation stating that ‘statistics with unknown levels of significance’ was used in our publications [15,16]. I would like to stress that the main result of these two studies, showing significantly elevated mutation rate in the germline of irradiated parents, was verified by means of the most conservative statistical test — Fisher’s exact test.” . To start with, the references in the corresponding sentence from my letter  were [15,17], not [15,16]. The correct references must be [16,17]; but all the arguments below pertain to . The following was written in my letter: “…statistics with unknown levels of significance are used in the argumentation in [15,17]. For example, a negative correlation between the mutation rate and a paternal year of birth among inhabitants of Semipalatinsk area is stated without giving the value of the correlation coefficient and its level of significance [15,17]. Considering the configuration of the diagram Fig. 2 in  this correlation may be insignificant. Nevertheless, a discussion is led on its basis, e.g.: ‘Most importantly, this correlation provides the first experimental evidence for change in human germline-mutation rate with declining exposure to ionizing radiation and therefore shows that the Moscow treaty banning nuclear weapon tests in the atmosphere (August, 1963) has been effective in reducing genetic risk to the affected population .’”  This latter passage was cited by Yuri incompletely and left without comment. The Fisher’s exact test is not used for evaluation of the level of significance of correlation coefficients. The dose comparisons concerning Chernobyl accident in my letter  were left without comment. Yuri concluded: “Another of the Author’s statements that the doses used in our mouse studies ‘were more than 100 times higher than average individual doses’ for the irradiated families is not correct.” . Note that the corresponding statement in my letter  was based on the above-mentioned dose comparisons, immediately following them in the text and accompanied by references to Dubrova’s publications about Chernobyl [15,17,18]. These dose comparisons , presented also in , generally agree with the data from  cited by Dubrova . In the mouse studies [10,11], mentioned above, the doses were higher: correspondingly 3 and 6 Gy vs. 1 Gy in the mouse study by Dubrova’s group . In a recent study, no evidence for mutation induction at pre-meiotic male germ cells following gamma-irradiation with the doses 0.5 and 1 Gy was found . No evidence for minisatellite mutation induction has been found after radiotherapy [22–24].
Furthermore it is written in the author’s reply  that “according to the results of numerous studies the doses for the families living in the Semipalatinsk District of Kazakhstan have been estimated as 0.5 Sv and higher” with a reference to . However, in the abstract of the article  it is written: “The village of Dolon, in particular, has been identified for many years as the most highly exposed location in the vicinity of the test site. Previous publications cited external doses of more than 2 Gy to residents of Dolon while an expert group assembled by the WHO in 1997 estimated that external doses were likely to have been less than 0.5 Gy.” The single historical measurement in the village of Dolon was likely performed at the axis of the radioactive trace . Accordingly, the dose estimates based on this measurement are considered as possible maximum external dose rather than the average dose for the residents of this village . Dolon was identified as the most exposed village in the vicinity of the Semipalatinsk Test Site [25,26]. It is stated in  that Dubrova et al. collected material in the rural areas around the Semipalatinsk nuclear test site, where, considering the above arguments, the average individual doses must have been lower than “0.5 Sv and higher” as per .
Finally, in the author's reply , an argument from  was reiterated: “Existing estimates of doses for the residents of contaminated areas around the Chernobyl Nuclear Power Plant reflect external and internal exposure to caesium-137 and caesium-134 . As discussed in [15,27], these estimates are often at odds with those obtained by retrospective biodosimetry, which may reflect the initial external and internal exposure to the short-lived radionuclides.”  It was however pointed out in  that the share of the short-lived radionuclides in the population exposure after the Chernobyl accident must have been lower than that after the atomic explosions in Japan, where no increase in the minisatellite mutations was found . After a nuclear power plant accident, predominantly those radionuclides are released into the environment, which had been accumulated in the reactor, i.e. relatively long-lived ones; whereas during an atomic explosion both short- and long-lived radionuclides are generated and can exert their biological action. This argument was dismissed by the remark: “Author’s belief that the 'share of short-lived isotopes in the population exposure must have been lower than that after the atomic explosions in Hiroshima and Nagasaki' is totally groundless.”  In conclusion, the arguments from  have not been adequately responded.
Several publications exaggerating medical consequences of elevated radiation background, emerged after the Chernobyl accident, were discussed in [1–7]. The following flaws can be found in many of such papers: interpretation of spontaneous conditions as radiation-induced, indication of radioactivity or doses without confrontation with the radiation background, conclusions about incidence increase of pathological conditions without an adequate comparison with a control. Correctness of scientific discussion is also of importance.
1. Jargin S. V. On the overestimation of Chernobyl consequences: motives and mechanisms. Med. Radiol. Radiat. Safety (Moscow) 2011, V 56, N 5, p. 74–79 (Russian with English summary) http://www.fmbcfmba.org/default.asp?id=5100
2. Jargin S. V. Overestimation of medical consequences of increased background radiation. Med. Radiol. Radiat. Safety 2008, V 53, N 3, p. 17–22.
3. Jargin S. V. Non-confident publications regarding radiation cancerogenesis incidence found in Semipalatinsk area, Med. Radiol. Radiat. Safety 2007, V 52, N 5, p. 73–74.
4. Jargin S. V. Overestimation of Chernobyl consequences: poorly substantiated information published. Radiat. Environ. Biophys. 2010, V 49, p. 743–5.
5. Jargin S. V. Chernobyl-related cancer and precancerous lesions: incidence increase vs. late diagnostics. Dose-Response 2014 doi: 10.2203/dose-response.13–039.Jargin
6. Jargin S. V. Overestimation of medical consequences of nuclear testing in Semipalatinsk area. BMJ Response 10 June 2008 http://www.bmj.com/rapid-response/2011/11/02/overestimation-medical-consequences-nuclear-testing-semipalatinsk-area-exa
7. Jargin S. V. Overestimation of Chernobyl Consequences: Some Mechanisms. Molodoi Uchenyi - Young Scientist 2013, N 6, p. 810–9.
8. Jargin S. V. Some aspects of mutation research after a low-dose radiation exposure. Mutat. Res. 2012, V 749, p. 101–2.
9. Kodaira M., Izumi S., Takahashi N., Nakamura N. No evidence of radiation effect on mutation rates at hypervariable minisatellite loci in the germ cells of atomic bomb survivors. Radiat. Res. 2004, V 162, p. 350–6.
10. Sadamoto S., Suzuki S., Kamiya K., et al. Radiation induction of germline mutation at a hypervariable mouse minisatellite locus. Int. J. Radiat. Biol. 1994, V 65, p. 549–57.
11. Niwa O., Kominami R. Untargeted mutation of the maternally derived mouse hypervariable minisatellite allele in F1 mice born to irradiated spermatozoa. Proc Natl. Acad. Sci. U. S. A. 2001, V 98, p. 1705–10.
12. Dubrova Y. E., Plumb M., Brown J., et al. Stage specificity, dose response, and doubling dose for mouse minisatellite germ-line mutation induced by acute radiation. Natl. Acad. Sci. U. S. A. 1998, V 95, p. 6251–5.
13. Dubrova Y. E., Plumb M., Brown J., Jeffreys A. J. Radiation-induced germline instability at minisatellite loci. Int. J. Radiat. Biol. 1998, V 74, p. 689–96.
14. Dubrova Y. E. Reply to the letter by S. V. Jargin. Mutat. Res. 2012, V 749, p. 103–4.
15. Dubrova Y. E., Grant G., Chumak A. A., et al. Elevated minisatellite mutation rate in the post-Chernobyl families from Ukraine. Am. J. Hum. Genet. 2002, V 71, p. 801–9.
16. Dubrova Y. E., Bersimbaev R. I., Djansugurova L. B., et al. Nuclear weapons tests and human germline mutation rate. Science 2002, V 295, p. 1037.
17. Dubrova Y. E. Monitoring of radiation-induced germline mutation in humans. Swiss Med. Wkly. 2003, V 133, p. 474–8.
18. Dubrova Y. E., Nesterov V. N., Krouchinsky N. G., et al. Further evidence for elevated human minisatellite mutation rate in Belarus eight years after the Chernobyl accident. Mutat. Res. 1997, V 381, p. 267–78.
19. Likhtarev I. A., Kovgan L. N., Vavilov S. E., et al. Internal exposure from the ingestion of foods contaminated by 137Cs after the Chernobyl accident — report 2. Ingestion doses of the rural population of Ukraine up to 12 y after the accident (1986–1997). Health Phys. 2000, V 79, p. 341–57.
20. Abouzeid Ali H. E., Barber R. C., Dubrova Y. E. The effects of maternal irradiation during adulthood on mutation induction and transgenerational instability in mice. Mutat. Res. 2012, V 732, p. 21–5.
21. Beal M. A., Glenn T. C., Lance S. L., Somers C. M. Characterization of unstable microsatellites in mice: no evidence for germline mutation induction following gamma-radiation exposure. Environ. Mol. Mutagen. 2012, V 53, p. 599–607.
22. May C. A., Tamaki K., Neumann R., et al. Minisatellite mutation frequency in human sperm following radiotherapy. Mutat. Res. 2000, V 453, p. 67–75.
23. Rees G. S., Trikic M. Z., Winther J. F., et al. A pilot study examining germline minisatellite mutations in the offspring of Danish childhood and adolescent cancer survivors treated with radiotherapy. Int. J. Radiat. Biol. 2006, V 82, p. 153–60.
24. Tawn E. J., Rees G. S., Leith C., et al. Germline minisatellite mutations in survivors of childhood and young adult cancer treated with radiation. Int. J. Radiat. Biol. 2011, V 87, p. 330–40.
25. Simon S. L., Baverstock K. F., Lindholm C., et al. A summary of evidence on radiation exposures received near to the Semipalatinsk nuclear weapons test site in Kazakhstan. Health Phys. 2003, V 84, p. 718–25.
26. Gordeev K., Shinkarev S., Ilyin L., et al. Retrospective dose assessment for the population living in areas of local fallout from the Semipalatinsk nuclear test site Part I: External exposure. J. Radiat. Res. 2006, V 47 Suppl A, p. A129–36.
27. Baverstock K., Williams D. Chernobyl: an overlooked aspect? Science 2003, V 299, p. 44.