Hromas et al described AML1 gene translocations in persons who previously had experienced “high-level radiation exposure from nuclear explosions.”1(p4011) The authors indicated that they were describing a novel syndrome of radiation-associated acute myeloid leukemia involving AML1 gene translocations. There is no evidence, however, that any of the 3 persons in this study received “high-level radiation exposure” or, in fact, received any significant amounts of radiation exposure to the bone marrow, as judged from the brief descriptions of their exposures. The science of assigning a bone marrow radiation dose is precise, and without accurate and detailed radiation exposure information, it is virtually impossible to tell whether an individual was excessively exposed or possibly had received a bone marrow radiation dose in the leukemogenic range. For example, case 1 may have received trace amounts of downwind exposure and probably would not have been allowed close enough to an atomic bomb detonation to have received any appreciable radiation dose. The amount of radiation received by the second person, who allegedly took a picture of ground zero in Hiroshima 2 weeks after the nuclear explosion, would have been negligible, even if he had been standing at ground zero. Hypocenter radiation decayed rapidly during the first few hours after detonation. It has been reported that anyone working 10-20 hours a day at the Hiroshima hypocenter beginning at day 1 for the week following the bomb would have received a radiation dose of about 0.1 Gy, an amount of radiation well below the lowest significant dose shown to be leukemogenic for humans from the Hiroshima and Nagasaki atomic bomb exposures.2,3 Case 3 is said to have worked for a company that removed debris from ground zero. The nature and duration of his work with the company was not described, so that no meaningful radiation dose can be assigned. He most likely would have carried some type of radiation dosimeter if he had been at risk of excessive exposure.

The fact that all 3 cases of leukemia were preceded by a significant pancytopenic phase is much more consistent with the type of secondary leukemia induced by chemical or chemotherapeutic agents than those reported due to sublethal amounts of total body radiation exposure. The cases of acute leukemia in the atomic bomb survivors of Hiroshima and Nagasaki clinically resembled the primary types of acute leukemia that occur in nonexposed persons, and rarely did they experience a preleukemic pancytopenic phase.4,5 

Finally it is important to emphasize that it is not possible to identify any individual case of leukemia as radiation induced. To date no specific markers of radiation exposure have been described, and, even though some chromosomal and genetic abnormalities may be more prevalent in persons with leukemia and a history of exposure to excessive amounts of radiation than nonexposed persons with leukemia, none of the changes have been shown to be specific for radiation induction of the leukemia.

Translocations in radiation-associated leukemias

We agree with some of the points raised in Dr Finch's letter. First, we agree that one cannot be sure of the ionizing radiation dose that these 3 patients received from their exposure to nuclear explosions, because it was not quantitated at the time. Indeed, unless it was inhaled or ingested, it could have been small. We also agree that it is true that there is no known specific DNA abnormality that can prove a malignancy was the result of radiation exposure. Thus we acknowledge that it is within the realm of possibility that these patients' past exposure to radiation was small and coincidental, and not the cause of their acute myelogenous leukemia (AML). That is why we stated that these patients had radiation-associatedleukemia, as opposed to radiation-induced leukemia.

We respectfully disagree with other contentions of the letter. First, the postulate that there is a safe level of exposure to nuclear radiation is controversial: many investigators believe that even small doses of such radiation may still cause malignancy (reviewed in Nussbaum1-1). Second, myelodysplasia was indeed a well-described result of the nuclear explosions in Japan.1-2 In fact, there is evidence that it was underreported because the French-American-British (FAB) classifications for leukemia and myelodysplasia were not extant at the time the majority of cases occurred.1-3 Modern re-examination of the hematologic malignancies that occurred after the nuclear explosions in Japan finds a high incidence of myelodysplasia.1-3 Third, as opposed to what was mentioned in the above letter, our patients had no other risk factors for secondary AML besides the exposure to ionizing radiation.

Thus, even if their radiation exposure was small, it may still have played a role in these patients' AML. We found it especially intriguing that they all shared the nuclear radiation exposure, novelAML1 gene translocations, an identical cytometric phenotype, and an identical clinical course. The probability of all of these shared characteristics randomly occurring together is low. In addition, in vitro experiments have shown that the AML1locus to be the major target of radiation-induced translocations.1-4 Therefore, although it is difficult to prove absolutely, it is more probable that these patients hadAML1 locus mutations from their radiation exposure.

References

References
1-1
Nussbaum
RH
The linear no-threshold dose-effect relation: is it relevant to radiation protection regulation.
Med Phys.
25
1998
291
299
1-2
Nakanishi
M
Tanaka
K
Shintanti
T
Takahashi
T
Kamada
N
Chromosomal instability in acute myelocytic leukemia and myelodysplastic syndrome patients among atomic bomb survivors.
J Radiat Res (Tokyo).
40
1999
159
167
1-3
Matsuo
T
Tomonaga
M
Bennett
JM
et al. 
Reclassification of leukemia among A-bomb survivors in using the French-American-British (FAB) classification for acute leukemia.
Jpn J Clin Oncol.
18
1988
91
96
1-4
Deininger
MW
Bose
S
Gora-Tybor
J
Yan
XH
Goldman
JM
Melo
JV
Selective induction of leukemia associated fusion genes by high dose ionizing radiation.
Cancer Res.
58
1998
421
425

References

References
1
Hromas
R
Shopnick
R
Jumean
HG
et al. 
A novel syndrome of radiation-associated acute myeloid leukemia involving AML1 gene translocations.
Blood
95
2000
4011
4013
2
Schull
WJ
Effects of Atomic Radiation.
1995
121
John Wiley and Sons
New York, NY
3
Shimizu
Y
Kato
H
Schull
WJ
Studies on the mortality of A-bomb survivors. 9. Mortality, 1950-1985: part 2. Cancer mortality based on the recently revised doses (DS86).
Radiat Res.
121
1990
120
141
4
Hoshino
T
Finch
SC
Lamphere
JP
et al. 
Peripheral blood changes preceding the development of leukemia in atomic bomb survivors of Hiroshima and Nagasaki. Atomic Bomb Casualty Commission Technical Report 19-75.
1975
1
31
Atomic Bomb Casualty Commission
Hiroshima
5
Bizzozero
O
Jr
Johnson
KG
Ciocco
A
et al. 
Radiation-related leukemia in Hiroshima and Nagasaki 1946-1964. II. Observations on type-specific leukemia, survivorship, and clinical behavior.
Ann Int Med.
66
1967
522
530