External Co-60 gamma-ray exposure, continued until death

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From 1968 to 1979 Bill Norris and Tom Fritz performed one of several Beagle Dog Experiments at Argonne National Laboratory. They administered external Co-60 gamma-ray exposure at dose rates ranging from 0.3 to 54 cGy/day, continued until death on 13 months old dogs of both sexes, placed on experiment in two series: "A" from 1968 to 1970, and "B" from 1976 to 1978.

Contents

Red Book Description

Copied from: Roy C Thompson. Life-Span Effects of Ionizing Radiation in the Beagle Dog (1989) (link pdf)

Results as of 1987:

Dose Rate (rad/day) Series and no. exposed No. of Dead Animals Mean survival of dead animals (years) Mean survival of living animals (years) Septicemia Anemia Myeloproliferative Disorder
Controls B 46 12 8.4 10.0 0 (0) 0 (0) 0 (0)
0.3 B 92 33 8.2 9.7 0 (0) 0 (0) 0 (0)
0.8 B 46 28 8.0 10.0 0 (0) 0 (0) 1 (4)
1.9 B 46 42 7.3 8.9 0 (0) 1 (2) 7 (17)
3.8 A 24 24 5.2 0 (0) 2 (8) 11 (46)
7.5 A 16 16 1.9 0 (0) 7 (44) 7 (44)
12.8 A 13 13 0.8 7 (54) 4 (31) 2 (12)
26.3 A 16 16 0.15 16 (100) 0 (0) 0 (0)
37.5 A 8 8 0.10 8 (100) 0 (0) 0 (0)
54.0 A 4 4 0.07 4 (100) 0 (0) 0 (0)

Dogs were irradiated 22 hours per day, 7 days per week, in a specially constructed facility (Grahn, 1986; Norris, 1976). Particular attention was given to dosimetry; all factors contributing to the dose rate and total dose were normalized in the irradiation field by migrating dogs through all positions and orientations with respect to the irradiation source. Dose rates shown above are average absorbed dose; doses in air were quoted in early publications.

Several recent papers have summarized the status of the total experiment (Fritz, 1985, 1986; Grahn, 1986; Seed, 1985); earlier papers reported results from the higher-dose, Series A, animals (Norris, 1972, 1976; Seed, 1984). Published papers on specialized aspects of this study include those dealing with hematological effects (Fritz, 1973, 1982; Seed, 1978, 1980, 1987; Tolle, 1982, 1983), myelogenous leukemia (Fritz, 1973; Seed, 1977), erythroleukemia (Seed, 1977; Tolle, 1977), electron microscopic studies of bone marrow (Seed, 1982, 1983, 1987b; Tolle, 1983b), and leukemogenesis modeling (Seed, 1978, 19823, 1985, 1987; Tolle, 1979b).

Results at higher dose rates defined three distinct radiation-induced causes of death; all involve the hematopoietic system and seem to be related more directly to dose rate than to total dose. At the highest dose rates, early death resulted from septicemia associated with granulocytopenia. At somewhat lower dose rates, anemia was the predominant cause of death, with survival times of a few hundred days. At still lower dose rates, myeloproliferative disorders (the majority of which were myelogenous leukemias) occurred between 400 and 2000 days after onset of exposure. Myeloproliferative disorders did not occur beyond 2000 days, regardless of dose rate or total dose. After 7 years of continuous irradiation there is no difference in survival rate between controls and the 0.3 rad/day group. Among all dogs still alive, except for testicular atrophy and aspermia, the only clinically detectable effect of irradiation is a depression of circulating blood cell levels.

Information relevant to this experiment will be found in the following Argonne National Laboratory periodic reports:

  • 1964 (Dec) ANL-6971 137-138 [1]
  • 1965 (Dec) ANL-7136 116-120
  • 1966 (Dec) ANL-7278 102-106
  • 1967 (Dec) ANL-7409 258-260
  • 1968 (Dec) ANL-7535 151-162
  • 1969 (Dec) ANL-7635 94-102
  • 1970 (Dec) ANL-7770 130-135
  • 1971 (Dec) ANL-7870 138-145
  • 1972 (Dec) ANL-7970 192-206
  • 1973 (Dec) ANL-8070 31-54
  • 1974 (Dec) ANL-75-30 9-14
  • 1975 (Dec) ANL-76-99 10-19
  • 1976 (Dec) ANL-77-55 34-42
  • 1977 (Dec) ANL-78-90 78-86
  • 1978 (Dec) ANL-79-90 6-12
  • 1980 (Dec) ANL-80-90 8-13
  • 1981 (Aug) ANL-81-50 8-13
  • 1982 (Jun) ANL-82-35 11-19
  • 1983 (May) ANL-83-40 27-36
  • 1984 (Aug) ANL-84-30 37-46
  • 1985 (Aug) ANL-85-30 63-72


Gray Book Description

Copied from: GB Gerber, CR Watson, T Sugahara, and S Okada. International Radiobiology Archives of Long-Term Animal Studies I. Descriptions of Participating Institutions and Studies (1996) ([2])

Institution: Argonne National Laboratory, Argonne IL

Scientists: Bill Norris; retired, Tom Fritz; retired

Purpose To investigate the effects of duration-of-life exposure at different dose rates on survival and cancer inductions in dogs.

Status Exposure initiated between 1968 and 1978, death of last dog at ANL in 1990. Study terminated /22/91; 18 remaining lowest level (0.3 rad/d) dogs transferred to ITRI.

Treatment External cobalt-60 gamma-ray exposure, continued until death; dogs placed on experiment in two series: "A" from 1968 to 1970, and "B" form 1976 to 1978. Dogs were irradiated 22 h/d, 7 d/w, in a specially constructed facility. Particular attention was given to dosimetry; all factors contributing to the dose rate and total dose were normalized in the irradiation field by migrating dogs through all positions and orientations with respect to the irradiation source. Control dogs were similarly housed in cages and migrated through positions in the control animal room.

Dosimetry: Radiation was delivered with a cobalt-60 gamma beam apparatus equipped with steel attenuators which were changed every few mo to compensate for radioactive decay. Beagles were caged singly in two-tiered fiberglass cages placed at calculated distances from the source; cages were rotated 90 degrees daily to compensate for the propensity of the dog to occupy the rear of the cage. Dose rate at the center of the cage was measured and converted to absorbed dose.

Endpoints Dogs were provided with life-time clinical care, including annual physical examination and blood work-ups. At necropsy, a thorough gross examination was conducted, ant a preliminary cause of death was determined. After histopathological examination of tissues from suspected lesions and an extensive suite of representative tissues, a "final" cause of death was determined and entered into the database.

Animal 276 Beagle dogs (138 females, 138 males), 13 mo old, in 10 groups

Results Hazard models indicated that hematopoietic failure occurring early in life was positively associated with dose and dose rate. The risk of death from causes other than cancer that occurred later in the life span also depended on dose and dose rate but was lower than the cancer risk. Once a dog survived long enough to die from cancer, failure times depended only on dose.

References Carnes, B.A., T.E. Fritz. Continuous irradiation of beagles with gamma rays. Radiation Research 136 103-110, 1993.

Experimental Groups Study 103.05 Life-Span Health Risks: Duration-of-Life Gamma-Irradiation of Young Adult Beagles

Group Id Radiation Dose Rate (mGy/d) Initiation of Exposures Number of Dogs
01 caged controls 46
02 3 1976 to 1978 92 (18 terminated)
03 8 1976 to 1978 46
04 19 1976 to 1978 46
05 38 1968 to 1970 24
06 75 1968 to 1970
07 128 1968 to 1970 13
08 263 1968 to 1970 16
09 365 1968 to 1970 8
10 540 1968 to 1970 4
Total 295

Data

Data from this study is available freely from the Beagle Dog archive at northwestern [3] and from the European Radiobiology Archive [4] ( password required ).

Tissues

Tissues preserved from these studies are stored at the Beagle Dog Archive at Northwestern University. Tissues may be searched for using their website [5].


References

  • Grahn D. and Fritz T.E. 1986. Chronic radiation injury with mice and dogs exposed to external whole-body irradiation at the Argonne National Laboratory. In Life-Span Radiation Effects Studies in Animals: What Can They Tell Us? (R.C. Thompson and J.A. Mahaffey, eds., CONF-830951, NTIS, Springfield, VA) 14-31.
  • Norris W.P., Tyler S.A. and Sacher G.A. 1976. An interspecies comparison of responses of mice and dogs to continuous 6 0 ~goam ma-irradiation. In Biological and Environmental Effects of Low-Level Radiation. Vol. 1 (International Atomic Energy Agency, Vienna) 147-1 56.
  • Fritz T.E., Tolle D.V. and Seed T.M. 1985. Chapter 7. The preleukemic syndrome in radiation-induced myelogenous leukemia .and related myeloproliferative disorders. In The Preleukemic Syndronze (Hemopoietic Dysplasia) (G.C. Bagby, ed., CRC Press, Cleveland) 87-100.
  • Fritz T.E., Seed T.M., Tolle D.V. and Lombard L.S. 1986. Late effects of protracted whole-body irradiation of beagles by cobalt-60 gamma rays. In Life-Span Radiation Effects Studies in Aninzals: What Can They Tell Us? (R.C. Thompson and J.A. Mahaffey, eds., CONF-830951, NTIS, Springfield, VA) 116-141.
  • Seed T.M., Kaspar L.V., Fritz T.E. and Tolle D.V. 1985. Cellular responses in chronic radiation leukemogenesis. In Carcinogenesis, Vol. 10 (E. Huberman and S.H. Barr, eds., Raven Press, New York) 363-379.
  • Fritz T.E., Norris W.P. and Tolle D.V. 1973. Myelogenous leukemia and related myeloproliferative disorders in beagles continuously exposed to 60Co gamma-radiation. In Unifying Concepts of Leukemia, Bibl. haemat. Vol. 39 (R.M. Dutcher and L. Chieco-Bianchi, eds., Karger, Basel) 170-188.
  • Fritz T.E., Tolle D.V., Doyle D.E., Seed T.M. and Cullen S.M. 1982. Hematologic responses of beagles exposed continuously to low doses of 60Co gamma radiation. In Experimental Henzatology Today 1982 (S.J. Baum, G.D. Ledney and S. Thierfelder, eds., S. Karger, New York) 229-240.
  • Seed T.M., Tolle D.V., Fritz T.E., Cullen S.M., Kaspar L.V. and Poole C.M. 1978. Haemopathological consequences of protracted gamma irradiation in the beagle: Pre-clinical phases of leukaemia induction. In Late Biological Effects of Ionizing Radiation, Vol. I. (International Atomic Energy Agency, Vienna) 531 -545.
  • Seed T.M., Cullen S.M., Kaspar L.V., Tolle D.V. and Fritz T.E. 1980. Hemopathologic consequences of protracted gamma irradiation: Alterations in granulocyte reserves and granulocyte mobilization. Blood 56:42-51. abstract
  • Tolle D.V., Fritz T.E., Seed T.M., Cullen S.M., Lombard L.S. and Poole C.M. 1982. Leukemia induction in beagles exposed continuously to 6 0 ~ goa mma irradiation: Hematopathology. In Experimental Hematology Today 1982 (S.J. Baum, G.D. Ledney and S. Thierfelder, eds., S. Karger, Basel) 241-249.
  • Tolle D.V., Cullen S.M., Seed T.M. and Fritz T.E. 1983. Circulating micromegakaryocytes preceding leukemia in three dogs exposed to 2.5 Rlday gamma radiation.. Vet. Pathol. 20:111-114.
  • Seed T.M., Tolle D.V., Fritz T.E., Devine R.L., Poole C.M. and Norris W.P. 1977. Irradiation-induced erythroleukemia and myelogenous leukemia in the beagle dog: Hematology and ultrastructure. Blood 50:1061-1079. pdf
  • Tolle D.V., Fritz T.E. and Norris W.P. 1977. Radiation-induced erythroleukemia in the beagle dog. A hematologic summary of five cases. Am. J. Pathol. 87:499-510. pdf
  • Seed, 1982, Seed T.M., Chubb G.T. and Tolle D.V. 1982. Sequential changes in bone marrow architecture during continuous low dose gamma irradiation. In Scanning Electron Microscopyll981/ZV. (0. Johari, ed., SEM Inc., AMF O'Hare, Chicago) 61-72. pubmed
  • Seed T.M., Chubb G.T., Tolle D.V., Fritz T.E., Poole C.M., Doyle D.E., Lombard L.S. and Kaspar L.V. 1983. The ultrastructure of radiation-induced endosteal myelofibrosis in the dog. In Scanning Electron Microscopy1 1982/1. (O.Johari, et al., eds., SEM Inc., AMF O'Hare, Chicago) 377-391. pubmed
  • Seed T.M. 1987b. Structure-function relationships in radiation-induced cell and tissue lesions: Special references to the contributions of scanning electron microscopy and hematopoietic tissue responses. Scanning Microsc. 1 :255-272. abstract
  • Tolle D.V., Seed T.M., Cullen S.M., Poole C.M. and Fritz T.E. 1983b. Aberrant megakaryocytopoiesis preceding radiation-induced leukemia in the dog. In Scanning Electron Microscopy 1198211 (0. Johari, R.M. Albrecht andT.,M. Seed, eds., SEM Inc., AMF O'Hare, Chicago IL) 367-376. pubmed
  • Seed T.M., Kaspar L.V., Fritz T.E. and Tolle D.V. 1985. Cellular responses in chronic radiation leukemogenesis. In Carcinogenesis, Vol. 10 (E. Huberman and S.H. Barr, eds., Raven Press, New York) 363-379.
  • Seed T.M., Kaspar L.V., Tolle D.V. and Fritz T.E. 1987. Chronic radiation leukemogenesis: Postnatal hematopathologic effects resulting from in-utero irradiation. Leukemia Res. 11:171-179.pubmed
  • Tolle D.V., Seed T.M., Fritz T.E. and Norris W.P. 1979b. Irradiation- induced canine leukemia: A proposed new model. Incidence and Hematopathology. In Experimental Hematology Today 1979. (S.J. Baum and G.D. Ledney, eds., Springer-Verlag, New York) 247-256.
  • Carnes, B.A., T.E. Fritz. Continuous irradiation of beagles with gamma rays. Radiation Research 136 103-110, 1993. jstor
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