926 
GENETIC AND BIOLOGICAL EFFECTS OF RADIATION 
tissues during the early period of the embryo 
could not result in an embryonal rest of neo- 
plastic propensity which might become mani- 
fest under proper stimulation later in life. 
Vaughan/^ in a review of the literature, con- 
cluded that even at the relatively low dose rates 
of diagnostic procedures the incidence of leuke- 
mia in exposed fetuses is increased. 
Comparison of radiation-induced deaths in 
the uterine-milk exposure study are particu- 
larly interesting. The greater than 3-fold in- 
crease in mortality in those exposed to ^S>r 
during nursing and then to radioisotope feeding 
seems too much to be coincidental. It is interest- 
ing to postulate the development of a relatively 
^"Sr resistant cell population during embryogen- 
esis, or simply a homeostatic increase in the 
hematopoietic stem cell compartment which 
would require a greater accumulated radiation 
dose for depletion. 
The low incidence of bone tumors in swine 
chronically ingesting ^^'Sr is in direct contrast 
to the high bone neoplasia observed in rats and 
dogs injected with soSr.^^i^ The latter 
method of administration results in uneven ske- 
letal distribution and areas of high irradiation 
intensity or "hot spots," which result in severe 
necrosis and tumor development in these areas. 
Generally, the bone tumors that developed in 
our swine were also in sites of most severe os- 
teonecrosis, where extensive destruction and ac- 
tive remodeling processes were occurring. 
Of particular interest is the observation that 
in those cases where it was possible to deter- 
mine the site of origin, the swine bone tumors 
appeared to arise from the periosteal surface. 
Following injection of ^^Sr in several other 
species, the bone tumors originated from the en- 
dosteal surface, ^'^ and in a study utilizing a sin- 
gle intravenous ^^Sr injection in miniature 
swine it was established that greater damage 
occurred to the endosteum and trabeculae than 
to the periosteal surface.^^ The more even 
skeletal distribution of the isotope following 
chronic ingestion results in a relatively greater 
dose rate to the periosteum than following 
injection, but evidently not great enough to kill 
the cells that have the potential of becoming 
neoplastic. 
The pathogenesis of the ^^Sr effects on hema- 
topoiesis must be very complex with this long- 
lived, bone-seeking radionuclide, since the deli- 
cate homeostatic balance between stimulatory 
and repressor feed-back mechanisms would be 
under constant perturbation from the continu- 
ous marrow damage. In addition to this direct 
radiation damage, the cells responsible for 
maintaining the microcirculation are probably 
injured and contribute to the hematopoietic cell 
changes. It has, in fact, been shown by Crosby 
and co-workers^^ that, in X-irradiated animals, 
delayed bone marrow aplasia from the deterio- 
ration of the microcirculation results in the he- 
matopoietic cells not being maintained. It is 
reasonable to presume that a similar situation 
could ultimately occur at higher ^''Sr dose lev- 
els, and could be primarily responsible for the 
terminal fall in peripheral blood elements, and 
contribute to the subsequent development of 
myeloid metaplasia. 
It is apparent that continuous ingestion of 
^^Sr, exclusive of the 125 ^Ci/day group, re- 
sults in either a rather severe hematodepression 
and a terminal hemorrhagic crisis (3100, 650, 
or 250 fiCi/day), or has no readily detectable 
effect on the formed blood elements (< 125 
ftCi/day). The leukemogenicity, especially at 
the 125 /iCi/day level, is particularly interest- 
ing and is in contrast to earlier studies in which 
^°Sr by injection indicated that bone tumor 
production would be the most prevalent neo- 
plasm encountered. This observation confirms 
the results of retrospective studies in the 
human by Vaughan,^* in that she found the la- 
tent period for leukemia induction was con- 
siderably shorter than that for osteosarcoma 
development. 
The sequence of events terminating in acute 
hematopoietic neoplasms in these pigs is un- 
known. There are, of course, several possible 
mechanisms which may act independently or in 
concert. The effects of chronic leukopenia would ' 
undoubtedly influence the humoral feed-back 
control mechanisms, presumably by elevating j 
"leukopoietin" levels. An elevated "poietin" 
level probably would also be related to a re- ; 
duced chalone effect if early cell death occurred. | 
There is some evidence from the bone marrow 
examinations of the uterine-milk study pigs i 
that this may be occurring at the higher ^°Sr 
