H. A. RAGAN, P. L. HACKETT, B. J. MCCLANAHAN AND W. J. CLARKE 
927 
levels. The increase in blast and pro forms could 
be either a quantitative increase in the cell 
types or a relative increase if more distal cells 
have died. Also, Cooper et al.^o demonstrated a 
prolonged granulocyte generation time in six 
pigs ingesting 625 /uCi ^^'Sr/day. Beirman^i re- 
ports similar findings in human acute leukemia 
patients, along v^^ith defective maturation and 
altered release of cells to the peripheral blood. 
These effects would certainly upset the feed- 
back control mechanisms. 
An impaired immunologic competence, with 
either a viral or neoplastic clonal etiology, must 
also be considered in the development of these 
hematopoietic neoplasms and is under investi- 
gation at this time. Viruses with certain charac- 
teristics common to known leukemia viruses 
have been isolated from some of these leukemic 
pigs, but their role in the etiology is unknown. 
A scheme depicting the possible pathogenesis 
of ^*'Sr induced hematopoietic neoplasms is 
shown in Figure 5. Bone marrow irradiation 
may produce some subtle somatic mutation, re- 
sulting in an enzymatic change and a matura- 
tion defect. This clone of cells could then become 
the dominate cell line, by either progressive 
radiation effects on the normal cell line, or 
by a failing immune system which had pre- 
viously held the neoplastic cells in check. Proba- 
BONE MARROW IRRADIATION 
Direct Cell Death 
Hematopoietic Cell Damage 
Hemato Depression 
(Early Cell Death) 
/'(Maturation Defect) 
^Elevated Poietins^ 
" Reduced Chalone 
Somatic Mutation 
Neoplastic Clone 
-^/ith Enzyme Defect 
1^ Immune 
Competence 
/* 
Myeloid Metaplasia 
Leukemia 
bly both mechanisms would be active. In addi- 
tion, this clone of immature cells might be espe- 
cially susceptible to the cellular and humoral 
regulators that would be elevated from the con- 
stant marrow damage. It has been suggested 
that the spectrum of hematopoietic neoplasms 
in these pigs indicates that a pluripotent mar- 
row stem cell is probably affected."'^* This, 
however, does not seem reasonable since most 
neoplasms have been of a single cell type, which 
would indicate the affected cell is probably a 
committed stem cell. It should be noted from 
Figure 5 that myeloid metaplasia is not a part 
of the progression to neoplasia, but is probably 
a physiologic response to the pathologic process 
occurring in the bone marrow. 
SUMMARY 
The "gross" effects of ^^Sr have been well 
documented in several species. However, there 
needs to be additional studies of in-utero and 
neonatal exposure of the hematopoietic system, 
correlated with the subsequent development of 
hematopoietic neoplasia. These more definitive 
studies would include determination of stem cell 
kinetics, the influence of poietins and chalones, 
and alterations in leukocyte kinetics. These 
questions need answers not only for clarifica- 
tion of cellular radiation effects, but also be- 
cause non-radiation bone marrow insults may 
have a similar pathogenesis in the development 
of neoplasia. The miniature pig is particularly 
well suited for these studies because of life span 
and the ease of obtaining serial blood and bone 
marrow samples. 
ACKNOWLEDGMENTS 
The contributions of L, K. Bustad, R. 0. 
McClellan, M. E. Kerr, and many others to the 
early periods of this study are gratefully ac- 
knowledged. 
REFERENCES 
Figure 5 
90,. 
Proposed Scheme of Sr Induced 
Myeloid Metaplasia and Neoplasia 
IFigure 5. — Proposed Scheme of °°Sr Induced Myeloid 
Metaplasia and Neoplasia. 
1. Parmley, W. W., Jensen, J. B., and Mays, C. W. 
Skeletal self-absorption of beta-particle energy. In: 
Some Aspects of Internal Radiation, T. P. Dough- 
erty, W. S. S. Jee, C. W. Mays, and B. J. Stover 
(Eds.), Permagon Press, Oxford, pp. 437-451, 
1962. 
