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Somatic mutation by endogenous radiocarbon
1letters tow International Journalof NuclearMedicineand Biology,1974,Vol. 1, pp.227-228. PergamonPress. Printedin NorthernIreland
Somatic
Mutation
by Endogenous
Radiocarbon (Received 21 November 1973) occurring radiocarbon, produced by cosmic radiation secondary neutrons in the stratoIt is extensively sphere, permeates all living matter.(‘) diluted with stable carbon, the normal concentration being only 1.17 x lo-l2 g 14C/g carbon or, with respect to its radioactivity, 13.56 disintegrations/ mm/g carbon for materials in equilibrium with the atmosphere.(2) The half-life of radiocarbon is 5730 yr.(3) Concentrations have been approx. augmented during the past two decades because of nuclear weapon testing, but contamination is presently only 40 per cent above normal level and is decreasing.c4) Due to the long radiocarbon half-life, only a fraction of the actual amount of the nuclide present in a body undergoes radioactive disintegration during an animal’s lifetime. This fact, coupled with the minute concentrations of the radioisotope, has resulted in a general disregard for the possibility that endogenous radiocarbon could exert a significant effect on the life process. However, it can be shown that the probability of a radiocarbon decay occurring in a strategic location in a living cell is high. This would be the situation where the carbon isotope involved was part of a DNA base in a critical position on a gene. The radioactive transformation would not necessarily be lethal to the cell since only a low energy beta particle is emitted. Furthermore, the particular DNA base would not inevitably be dislodged from its position on the chain. 14C decays to 14N and this stable isotope could assume the place of the decayed atom in a significant percentage of the nuclear transformations. It has been demonstrated theoretically that there is a high probability of nonrupture of the bond in the C-r4C -+ C-14N + B- transformation. c5) In an actual case, it has been shown experimentally that in the disintegration of a 14C isotope in the ethane molecule, 47 per cent of the reactions produce a methyl amine in which the molecular entity is conserved.(s) NATURALLY
The possibility of this reaction occurring in a specific position in one of the genes in a human somatic cell is significant. Taking the spleen as representative, it is known that the whole cell contains This about 0.77 mg DNA-P/g fresh tissue.(‘) translates to 8.0, mg DNA/g fresh tissue or 1.4, mg DNA base carbon/g fresh tissue. A 70-kg person would have 99 g DNA base carbon in his cells. Of this, 1.3, x lo-log or 7.0 x 1012 atoms would be into account an estimated radiocarbon, taking 20 per cent excess due to nuclear weapon testing contamination. During a lifetime of 70 years there would be 5.9 x 1Oro DNA base ‘*C nuclear transformations. Since the human cell has approximately 1 .l x lOlo DNA nucleotides/cell(s) and there is a weighted average of 4.8 carbon atoms/DNA base, it is seen that a carbon atom of any chosen DNA base in at least one of the cells would undergo the ‘“C -+ 14N nuclide transmutation in 70 years. If 47 per cent of the transformations allowed the l*N to take the exact place of the original 14C, there would be a 53 per cent chance of this type of modification of any carbon atom of a specific DNA base in a gene. The change in the DNA base could cause a copy error during the proceeding replication, which would result in a somatic mutation of the affected cell that would be perpetuated in successive mitoses. This endogenous radiocarbon mechanism is distinct from that of the nuclear radiation induced mutations. Pauling has shown the significance of additional radiation burden from fallout radiocarbon on the human population. tg) He concluded that the radiation effect of the nuclear weapon produced ‘*C would be more important than that of a chemical transmutation mechanism for general damage to the cell DNA. Nevertheless, it now appears that nuclear radiation is an inefficient mutagenic agent. A recent study shows that a doubling of the normal radiation dose would only produce a 3 per cent increase in the frequency of genetic defects.(rO) Naturally occurring background radiation has not been observed to be the principal cause of any animal disease, although it might be a minor agent in some. This is seen from medical statistics in areas of high natural radiation, for example, in specific regions of Brazil.‘l’) The possible relevance of the chemical transmutation mechanism to the problem of the etiology of various diseases is evident. For example, if one of the initiating phases of carcinogenesis is a specific
227
228
Letters to the editor
somatic mutation, naturally occurring endogenous radiocarbon provides a reasonable mechanism for the particular irreversible alteration of a cell gene influencing growth regulatory mechanisms. This could be the first step in the production of the cancer. The 53 per cent probability of a specific nondisruptive mutation is greater than the one-in-four chance of contracting clinical cancer for man. But this presents no contradiction since the somatic mutation would be only an initiating step and ensuing conditions would still have to come into operation before the cancer could manifest itself. It would be feasible to experimentally test the radiocarbon effect. Laboratory animals could be raised on radiocarbon-free diet. This would be proteinaceous material obtained from yeast cultures on petroleum(12) and plants grown in an atmosphere containing fossil fuel-derived carbon dioxide. Low levels of the isotope in the animals’ bodies, achieved in the second generation, would be monitored by a If endogenous radiocarbon dating laboratory. radiocarbon does cause somatic mutations leading to oncogenic phenomena, a decrease in the rate of spontaneous neoplasia in the animals of the experiment would be observed. Furthermore, it would be interesting to determine at the same time whether the reduction in the burden of endogenous radiocarbon has a general effect on the longevity of the animals, since ageing could also be related to somatic mutations. M. A. TAMERS Nova University, Life Sciences Center Fort
1.
2. 3. 4. 5. 6. 7. 8. 9.
10. 11. 12.
International Journalof NuclearMedicineand Biology,1974, Vol. 1 pp. 228-229. PergamonPress. Printedin NorthernIreland
An Unexpected Complication in the Use of 169Yb-DTPA with Respect to Hospital Health Physics (Received 20 November 1973)
cisternography and ventriculography are performed today with 1311-Human Serum Albumin or with gvmT~ Serum Albumin. Both radionuclides have their drawbacks; Iodine- 13 1 requires previous thyroid blockage and delivers an unnecessary beta radiation to the patient, thus contributing to the total radiation burden. On the other hand, technetium-99m has better physical characteristics, but its short half life precludes scintigraphic studies at more than 2 days after administration. Recently the attention has been drawn towards the radionuclide ytterbium-169 which in chelated form proved to be valuable for cisternography and ventriculography(1-3) The radiopharmaceutical lsgYbDTPA appeared to be stable under various in vitro and in vivo conditions.(‘) The chelate is removed from the cerebrospinal fluid by absorption into the blood and excreted unchanged in the urine by glomendar filtration. Ytterbium-169 decays with photon emission in the range of 8-308 keV. Alpha and b&a emissions are essentially absent. Excellent images Lauderdale, Florida 33314, U.S.A. can be obtained detecting the 177- and 198-keV References photons. Their abundance is relatively high and ANDERSONE. C., LIBBY W. F., WEMHOUSE S., amounts to 0.57 photons per disintegration.t4) REID A. F., KIRSHENBAUMA. D. and GROSE The long physical half life of 32 days permits adequate testing for pyrogenicity and sterility. A. V. Science 105, 576 (1947). The radiation dose to the patient is relatively low KERLAN I., OLSON U., KALLBERG P. and due to the effective half life of 12 hr.c2) KILICCI S. Arkiv Geofysik 4, 465 (1964). During a period from Otober 1972 to March 1973, GODWIN H. Nature, Lond. 195, 984 ( 1962). NYDAL F., L~~VSETHK. and SYRSTAD0. Nature, we examined the flow of cerebrospinal fluid with the aid of lBSYb-DTPA in 27 patients, among which a Lond. 232, 418 (1971). 2-yr-old child, at the University Hospital of Leyden. WOLFSBERGM. J. them. Phys. 24, 24 ( 1956). Last February, a whole body 40K determination WOLFGANGR. L., ANDERSONR. C. and DODSON in an infant showed a small contamination of lsDYb. R. W. J. them. Phys. 24, 16 (1956). DAVIDSONJ. N. Cold Spring Harbor Symp. Quant. Several other babies undergoing the same examination in the whole body counter also showed lssYb Biol. 12, 50 (1947). contamination. The activity measured ranged from LEHN~GER A. L. BiochPnistry, p. 636. Worth, 1 to 4 nCi. N.Y. (1970). Further investigation showed that the lasYb PAULLNGL. Science 128, 1183 (1958). contamination was fixed to the cotton napkins of GRAHN D. Bioscience 22, 535 (1972). FREIRE-MAIA A. An. Acad. Brasil. Cienc. 43, 457 the babies. All the contaminated napkins had come to the whole body counter from the pediatric de(1971). KIHLBERG R. Ann. Rev. Microbioloa 26, 427 partment. It appeared that in our hospital napkins are sent to a central laundry, where also napkins (1972). RADIOISOTOPE
Somatic
Mutation
by Endogenous
Radiocarbon (Received 21 November 1973) occurring radiocarbon, produced by cosmic radiation secondary neutrons in the stratoIt is extensively sphere, permeates all living matter.(‘) diluted with stable carbon, the normal concentration being only 1.17 x lo-l2 g 14C/g carbon or, with respect to its radioactivity, 13.56 disintegrations/ mm/g carbon for materials in equilibrium with the atmosphere.(2) The half-life of radiocarbon is 5730 yr.(3) Concentrations have been approx. augmented during the past two decades because of nuclear weapon testing, but contamination is presently only 40 per cent above normal level and is decreasing.c4) Due to the long radiocarbon half-life, only a fraction of the actual amount of the nuclide present in a body undergoes radioactive disintegration during an animal’s lifetime. This fact, coupled with the minute concentrations of the radioisotope, has resulted in a general disregard for the possibility that endogenous radiocarbon could exert a significant effect on the life process. However, it can be shown that the probability of a radiocarbon decay occurring in a strategic location in a living cell is high. This would be the situation where the carbon isotope involved was part of a DNA base in a critical position on a gene. The radioactive transformation would not necessarily be lethal to the cell since only a low energy beta particle is emitted. Furthermore, the particular DNA base would not inevitably be dislodged from its position on the chain. 14C decays to 14N and this stable isotope could assume the place of the decayed atom in a significant percentage of the nuclear transformations. It has been demonstrated theoretically that there is a high probability of nonrupture of the bond in the C-r4C -+ C-14N + B- transformation. c5) In an actual case, it has been shown experimentally that in the disintegration of a 14C isotope in the ethane molecule, 47 per cent of the reactions produce a methyl amine in which the molecular entity is conserved.(s) NATURALLY
The possibility of this reaction occurring in a specific position in one of the genes in a human somatic cell is significant. Taking the spleen as representative, it is known that the whole cell contains This about 0.77 mg DNA-P/g fresh tissue.(‘) translates to 8.0, mg DNA/g fresh tissue or 1.4, mg DNA base carbon/g fresh tissue. A 70-kg person would have 99 g DNA base carbon in his cells. Of this, 1.3, x lo-log or 7.0 x 1012 atoms would be into account an estimated radiocarbon, taking 20 per cent excess due to nuclear weapon testing contamination. During a lifetime of 70 years there would be 5.9 x 1Oro DNA base ‘*C nuclear transformations. Since the human cell has approximately 1 .l x lOlo DNA nucleotides/cell(s) and there is a weighted average of 4.8 carbon atoms/DNA base, it is seen that a carbon atom of any chosen DNA base in at least one of the cells would undergo the ‘“C -+ 14N nuclide transmutation in 70 years. If 47 per cent of the transformations allowed the l*N to take the exact place of the original 14C, there would be a 53 per cent chance of this type of modification of any carbon atom of a specific DNA base in a gene. The change in the DNA base could cause a copy error during the proceeding replication, which would result in a somatic mutation of the affected cell that would be perpetuated in successive mitoses. This endogenous radiocarbon mechanism is distinct from that of the nuclear radiation induced mutations. Pauling has shown the significance of additional radiation burden from fallout radiocarbon on the human population. tg) He concluded that the radiation effect of the nuclear weapon produced ‘*C would be more important than that of a chemical transmutation mechanism for general damage to the cell DNA. Nevertheless, it now appears that nuclear radiation is an inefficient mutagenic agent. A recent study shows that a doubling of the normal radiation dose would only produce a 3 per cent increase in the frequency of genetic defects.(rO) Naturally occurring background radiation has not been observed to be the principal cause of any animal disease, although it might be a minor agent in some. This is seen from medical statistics in areas of high natural radiation, for example, in specific regions of Brazil.‘l’) The possible relevance of the chemical transmutation mechanism to the problem of the etiology of various diseases is evident. For example, if one of the initiating phases of carcinogenesis is a specific
227
228
Letters to the editor
somatic mutation, naturally occurring endogenous radiocarbon provides a reasonable mechanism for the particular irreversible alteration of a cell gene influencing growth regulatory mechanisms. This could be the first step in the production of the cancer. The 53 per cent probability of a specific nondisruptive mutation is greater than the one-in-four chance of contracting clinical cancer for man. But this presents no contradiction since the somatic mutation would be only an initiating step and ensuing conditions would still have to come into operation before the cancer could manifest itself. It would be feasible to experimentally test the radiocarbon effect. Laboratory animals could be raised on radiocarbon-free diet. This would be proteinaceous material obtained from yeast cultures on petroleum(12) and plants grown in an atmosphere containing fossil fuel-derived carbon dioxide. Low levels of the isotope in the animals’ bodies, achieved in the second generation, would be monitored by a If endogenous radiocarbon dating laboratory. radiocarbon does cause somatic mutations leading to oncogenic phenomena, a decrease in the rate of spontaneous neoplasia in the animals of the experiment would be observed. Furthermore, it would be interesting to determine at the same time whether the reduction in the burden of endogenous radiocarbon has a general effect on the longevity of the animals, since ageing could also be related to somatic mutations. M. A. TAMERS Nova University, Life Sciences Center Fort
1.
2. 3. 4. 5. 6. 7. 8. 9.
10. 11. 12.
International Journalof NuclearMedicineand Biology,1974, Vol. 1 pp. 228-229. PergamonPress. Printedin NorthernIreland
An Unexpected Complication in the Use of 169Yb-DTPA with Respect to Hospital Health Physics (Received 20 November 1973)
cisternography and ventriculography are performed today with 1311-Human Serum Albumin or with gvmT~ Serum Albumin. Both radionuclides have their drawbacks; Iodine- 13 1 requires previous thyroid blockage and delivers an unnecessary beta radiation to the patient, thus contributing to the total radiation burden. On the other hand, technetium-99m has better physical characteristics, but its short half life precludes scintigraphic studies at more than 2 days after administration. Recently the attention has been drawn towards the radionuclide ytterbium-169 which in chelated form proved to be valuable for cisternography and ventriculography(1-3) The radiopharmaceutical lsgYbDTPA appeared to be stable under various in vitro and in vivo conditions.(‘) The chelate is removed from the cerebrospinal fluid by absorption into the blood and excreted unchanged in the urine by glomendar filtration. Ytterbium-169 decays with photon emission in the range of 8-308 keV. Alpha and b&a emissions are essentially absent. Excellent images Lauderdale, Florida 33314, U.S.A. can be obtained detecting the 177- and 198-keV References photons. Their abundance is relatively high and ANDERSONE. C., LIBBY W. F., WEMHOUSE S., amounts to 0.57 photons per disintegration.t4) REID A. F., KIRSHENBAUMA. D. and GROSE The long physical half life of 32 days permits adequate testing for pyrogenicity and sterility. A. V. Science 105, 576 (1947). The radiation dose to the patient is relatively low KERLAN I., OLSON U., KALLBERG P. and due to the effective half life of 12 hr.c2) KILICCI S. Arkiv Geofysik 4, 465 (1964). During a period from Otober 1972 to March 1973, GODWIN H. Nature, Lond. 195, 984 ( 1962). NYDAL F., L~~VSETHK. and SYRSTAD0. Nature, we examined the flow of cerebrospinal fluid with the aid of lBSYb-DTPA in 27 patients, among which a Lond. 232, 418 (1971). 2-yr-old child, at the University Hospital of Leyden. WOLFSBERGM. J. them. Phys. 24, 24 ( 1956). Last February, a whole body 40K determination WOLFGANGR. L., ANDERSONR. C. and DODSON in an infant showed a small contamination of lsDYb. R. W. J. them. Phys. 24, 16 (1956). DAVIDSONJ. N. Cold Spring Harbor Symp. Quant. Several other babies undergoing the same examination in the whole body counter also showed lssYb Biol. 12, 50 (1947). contamination. The activity measured ranged from LEHN~GER A. L. BiochPnistry, p. 636. Worth, 1 to 4 nCi. N.Y. (1970). Further investigation showed that the lasYb PAULLNGL. Science 128, 1183 (1958). contamination was fixed to the cotton napkins of GRAHN D. Bioscience 22, 535 (1972). FREIRE-MAIA A. An. Acad. Brasil. Cienc. 43, 457 the babies. All the contaminated napkins had come to the whole body counter from the pediatric de(1971). KIHLBERG R. Ann. Rev. Microbioloa 26, 427 partment. It appeared that in our hospital napkins are sent to a central laundry, where also napkins (1972). RADIOISOTOPE