902 RADIATION BIOLOGY 



B. NATURE OF THE PRIMARY DAMAGE AND INTERMEDIATE EFFECTS 



Assuming that at least a large part of the damage must be due to the 

 action of radiation on the embryo itself, there arises the more difficult 

 task of elucidating the nature of the primary damage and the pathways 

 that lead to the observed malformations. Although there is little direct 

 evidence on these points available for mammalian embryos, the hypoth- 

 eses are limited by two end results which have been discussed in preceding 

 sections and must now be considered well established: (1) irradiation at a 

 given stage causes observable changes only in certain specific characters, 

 and (2) a primordium affected at any given stage responds in consistent 

 ways. These points will be considered in turn. 



(1) The first end result must be due either to differential primary 

 damage, or, if the primary damage was randomly distributed throughout 

 the body, a differential intermediate effect. A few available facts indi- 

 cate a possible basis for selectiveness at either step. There is evidence to 

 show that some of the processes specifically affected at any given stage 

 are those engaged in a rapid rate of change at the time. A few examples 

 are: vertebral jumbling — beginnings of primitive streak activity (Russell, 

 1949) ; brain hernia and pseudencephaly — early brain differentiation 

 (Kaven, 1938b) ; microphthalmia — early optic evagination (Wilson and 

 Karr, 1951); coloboma — invagination of optic vesicles (Russell, 1950); 

 digital reductions — limb bud rudder formation (Russell, 1950); second 

 phase for tail reduction — tail bud formation (Russell, 1950). There are 

 also a few examples which show that sensitivity is not always predictable 

 from the visibly fastest rate of change in a primordium: e.g., the critical 

 periods for Polydactyly and the first phase of tail reduction occur before 

 limb buds and tail bud, respectively, have made their appearance (Russell, 

 1950) ; a high incidence of liver damage is produced by irradiating at a 

 stage when the hepatic primordium is not yet indicated morphologically 

 (Wilson and Karr, 1951). In these cases some process related develop- 

 mentally (e.g., an organizer), and not necessarily by cellular ancestry, 

 may be sensitive at the time of irradiation. 



It is conceivable that the primary intracellular damage — e.g., chromo- 

 some breakage, injury of the spindle-forming mechanism — occurs with 

 uneven distribution, possibly dependent on relative proportions of cells 

 in mitosis in various regions. In addition to differential distribution of 

 the primary intracellular (and the subsequent cellular) damage, various 

 intermediate selective mechanisms on a higher level can be postulated. 

 Thus, for example, the different degrees of differentiation reached by 

 various precursors at the time of irradiation may be correlated with 

 different capacities for regeneration. Or, even a slight upset in cellular 

 balance in a region providing trophic influences for a certain primordium 



