Radiation Effects On The Skin

20 REPORT OF A TASK GROUP OF COMMITTEE 1
(8) The upper papillary dermis is very well vascularised. About 90% of the blood flow is
associated with temperature regulation.
(9) The vascular supply to the skin of man (and the pig) is predominantly via segmental
musculocutaneous arteries which supply relatively small areas of skin. This is
distinctly different from small laboratory rodents where single direct cutaneous
arteries are the only blood supply to large areas of the dermis.
3. RADIATIONEFFECTS ON THE SKIN

3.1. Introduction
(57) There have been numerous experimental investigations into the effects of
radiation on the skin of small laboratory rodents, monkeys, pigs and man. Many of these
studies have involved the irradiation of the skin and subcutaneous tissues with
penetrating x or gamma rays and were aimed at resolving certain problems related to
cancer therapy, e.g., dose-fractionation effects, tissue oxygenation, and combined
treatment modalities. Although these studies have no direct relevance to radiological
protection, the investigations provided an understanding of the mechanisms of radiation
effects on the skin and are of value in the interpretation of the response of the skin to
non-uniform exposure to intermediate or high-energy /I irradiation to significant areas of
the body surface. Specific radiological protection problems, such as exposure to ‘hot’
radioactive particles, the effects of very low /I energy rays, and of alpha-particle effects
require special consideration (see Section 3.6).
(58) A review of the literature indicates a confusing terminology used to describe the
various changes seen in the skin after radiation exposure. Frequently, different terms are
used to describe the same phenomenon or conversely, and perhaps more confusing, the
same term might be used to identify reactions that are quite different in their aetiology.
For the purposes of this report a standard terminology has been adopted which is
outlined below. The criteria used have a strong pathophysiological basis but, in addition,
the time-scale of changes helps in the classification of lesions.
3.1.1. Terminology used to describe the responses of skin to radiation

(59) There are several phases of erythema observed in the skin after irradiation, some
of which are associated with significant deterministic responses with respect to radio-
logical protection. In the responses listed below their time of onset is given in
parentheses. The terminology for these responses was reviewed and discussed by
Hopewell (1990).
(i) Dry desquamation (3-6 weeks): an atypical keratinisation of the skin due to the
reduction in the number of clonogenic cells within the basal layer of the epidermis.
(ii) Moist desquamation (4-6 weeks): the loss of the epidermis due to the sterilisation
of a high proportion of clonogenic cells within the basal layer of the epidermis.
(iii) Secondary ulceration (>6 weeks): secondary damage to the dermis as a conse-
quence of dehydration and infection when moist desquamation is severe and
protracted due to the reproductive sterilisation of the vast majority of the
clonogenic cells in the irradiated area.
(iv) Dermal necrosis (> 10 weeks): necrosis of dermal tissues as a consequence of
vascular insufficiency.
THE BIOLOGICAL BASIS FOR DOSE LIMITATION IN THE SKIN 21
(v) Dermal atrophy (> 26 weeks): a thinning of the dermal tissues associated with the
contraction of the previously irradiated area.
(vi) Telangiectasia (> 52 weeks): an atypical dilatation of the superficial dermal
capillaries.
(vii) Invasive fibrosis: the method of healing associated with acute ulceration, secondary
ulceration and dermal necrosis that leads to scar tissue formation.
Special case
(viii) Acute ulceration (< 14 days): an early loss of the epidermis and to a varying degree
deeper dermal tissue that results from the death of fibroblasts and endothelial cells
in interphase.
(ix) Acute epidermal necrosis (< 10 days): interphase death of post mitotic keratino-
cytes in the upper viable layers of the epidermis. This type of lesion may occur with
high-dose, low-energy b irradiation.
3.1.2. Pathophysiology of radiation-induced changes in the skin

(60) Following radiation exposure, the skin shows several distinct phases of damage,
their frequency and severity depending largely on the conditions of the radiation
exposure. There are species, even strain differences, in the timing of the changes, some of
which can be explained by the different biological characteristics of the skin type exposed
to radiation. The principal phases of damage that have been recognised are:
(a) An early transient erythema seen within a few hours of irradiation which usually
subsides after 24-48 h.
(b) The main erythematous response reflects a varying severity of loss of the basal cells
from the epidermis and matrix cells from the hair follicle. Dry desquamation,
epithelial denudation (moist desquamation) or hair loss (epilation) may result after
3-6 weeks. With severe and prolonged moist desquamation secondary ulceration can
develop.
(c) A late phase of erythema which is associated with dermal ischaemia and possibly
necrosis between 8 and 20 weeks after irradiation.
(d) Late skin damage, i.e., atrophy, telangiectasia and necrosis.
The pathophysiology of each of these phases of damage will now be discussed in detail:
3.2. The Early Erythematous Reaction

(61) This is a well documented phenomenon which in man is seen within a few hours
after irradiation of large fields with acute doses of 22 Gy of x rays. Such dose levels are
commonly involved in radiotherapy treatment schedules. The response is believed to be
related to an early phase of inflammation in which the increased permeability of the
capillaries, as a result of the activation of a proteolytic enzyme (Jolles and Harrison,
1965), plays a major role. This increased permeability has been assessed using protein-
bound vital dyes. In the skin of rabbits increased permeability was found to be related to
the level of exposure up to 800 R (Jolles, 1972). Although some investigators have
proposed that these early changes are of importance and influence the subsequent course
of the skin reaction, this view is no longer held.
3.3. The Main Erythematous Reaction

(62) This is possibly the most documented and best understood of the different
phases of radiation-induced damage to the skin. The target cell population, damage to
which causes the response, is the basal cells of the epidermis. The reddening of the skin
(hyperaemia) represents a secondary inflammatory reaction to the death of basal cells
and the subsequent development of epidermal hypoplasia.
(63) Within a few days following irradiation a marked fall has been reported in both
the 3H-thymidine labelling index and the mitotic index of basal cells. The numbers of
degenerate cells were reported to be increased at this time but not markedly (Morris and
Hopewell, 1988). However, even if cells that do not remain reproductively viable after
irradiation, nor become pyknotic, merely mature and migrate in the usual way this would,
in the absence of cell divisions, still result in a denudation of the basal layer in a time-
course approximately equivalent to the turnover time of the unirradiated basal layer of
the epidermis. Thus it is the natural migration, differentiation, and loss of cells from the
basal layer that accounts for most of the decline in the basal cell density with time after
irradiation.
(64) In the skin of the flank of the Large White pig, the rate of cell loss from the basal
layer is 2.6 f 0.2%/day after doses of 15-20 Gy of x rays (Morris and Hopewell, 1988);
in the Yorkshire pig it was -4O/day (Archambeau et aZ.,1979). This rate of cell loss was
independent of the radiation doses used in the studies (Fig. 10) and was consistent with
the first appearance of a spotty moist desquamation, after higher doses, at 33.2 f 1.1
days (Hopewell and van den Aardweg, 1988) and 17-21 days after x irradiation
(Archambeau et al., 1968) in these two strains of pig. In guinea pigs and mice the rate of
cell loss is faster at 5-6%/day and &3%/day, respectively (Potten et al., 1983). Moist
desquamation develops in both these species earlier than in pig or man. The peak of the
main erythematous reaction in human skin, after a single dose of 12.5 Gy, was slightly
later than 30 days (Field et d., 1976). At doses just below the threshold for moist
‘\
\
‘\
07 \
0 10 20 30 LO
Time after Irradlatlonidaysl
Fig. 10. Comparison of the time-related changes in the density of basal cells of the epidermis of Large White
(-) and Yorkshire pigs (- - -) after irradiation with single doses of x rays. The curves for the loss of cells have
been extrapolated to estimate the time after irradiation with higher doses that moist desquamation would
occur. (Reproduced from Morris and Hopewell, 1988, with permission.)
desquamation a transient phase of dry desquamation may be observed over the same
time scale. This represents an atypical thickening of the stratum corneum.
(65) Following x irradiation with doses just above or just below the threshold for
moist desquamation in the pig, repopulation of the basal layer of the epidermis is
predominantly by the proliferation of surviving clonogenic cells from within the
irradiated area. These colonies of cells can be recognised in histological sections as
regions of the basal layer with a relatively normal basal cell density (Fig. 11) (Morris and
Hopewell, 1988). Labelling with 3H-thymidine has demonstrated that the labelling index
is as high as 40-50% in these regenerating cell colonies (Fig. 12).
(66) Similar time-related changes in the cellularity of the basal layer of the epidermis
of the pig to those reported above after x irradiation have also been noted after p
irradiation (Osanov, 1983). These studies were again carried out on the skin of immature
pigs, 9 weeks of age, with 90Sr/90Y and 14’Pm sources of 40 mm diameter. Following
irradiation with a skin surface dose of 70 Gy from a 90Sr/90Y source the cellularity of the
basal layer of the epidermis had declined by -50% after 14 days (Fig. 13). This suggests
a rate of cell loss in this strain of pig intermediate between that of the Large White and
Yorkshire pigs used in the investigations with x rays. By day 30 the density of cells in the
basal layer and that of the whole interfollicular epithelium was reduced to approximately
zero. This was associated with the clinical appearance of moist desquamation. Moist
desquamation was transient and by 45 days after irradiation hyperplasia of the epidermis
was seen; the density of cells in the basal layer and the cellularity of the whole epidermis
was increased by a factor of - 1.5. This is consistent with the reported 25% increase in
the number of viable cell layers in the epidermis of pigs at 2 35 days after 20 Gy of x rays
(Morris and Hopewell, 1988). After ‘OSr/““Y irradiation with a single dose of 70 Gy the
cellularity of the epidermis appeared to be reduced again after 62 days, but by the end of
the observation period (220 days) the cellularity was similar to that of normal skin.
However, this apparently normal macroscopic pattern should not be taken as evidence
that full recovery has occurred (Osanov, 1983). Following irradiation with 14’Pm, a low-
energy beta-ray emitter (E,,,,, 0.225 MeV), similar but less severe changes were observed
0 14 28 42 56
Time after Irrodlatlon (days)
Fig. 11. Time-related changes in the number of cells per mm (cell density) of the basal layer of the epidermis
of pigs after irradiation with single doses of 15 Gy (A ) and 20 Gy (0) of x rays. The open symbols represent
the cell density in regenerating colonies and the hatched area the unirradiated control values (*SE). Error bars
indicate *SE. (Redrawn from Morris and Hopewell, 1988.)
IO/ Basal Layer ,~
CO
2
x
8
5 20
F
‘=
xi
9
3
10
0
0 14 28 L2 56
Time after Irradiatlonldays)
Fig. 12. Time-related changes in the 3H-thymidine single pulse labelling index of cells in the basal layer of the
epidermis of pigs after irradiation with single doses of 15 Gy (A ) and 20 Gy (0) of x rays. The open symbols
represent the labelling indices of cells in regenerating cell colonies and the hatched area the unirradiated
control values (*SE). Error bars indicate *SE. (Redrawn from Morris and Hopewell, 1988.)
0
0 10 20 30 LO 50 60 70 22L
Time after Irradiation (days I

Fig. 13. Time-related changes in the number of cells in the epidermis of the pig after irradiation with a skin
surface dose of 70 Gy from a gOSr/yaY source relative to the number of cells in epidermis of control animals.
Data are given for the basal layer (A, A ) and the whole epidermis (0, 0). The open and closed symbols
represent the mean values for two animals. The hatched area represents fSE of the unirradiated control
values. (Redrawn from Osanov, 1983.)
(Osanov, 1983) even after a high skin surface dose of 100 Gy (Fig. 14). Following
irradiation with skin surface doses of lo-100 Gy there was a reduction in the density of
cells in the basal cell layer and in the total cellularity of the epidermis. This appeared, as
after x rays, to occur at a rate that was independent of the radiation dose at the doses
used and would have been consistent with the development of moist desquamation at
- 30 days after much higher doses. However, as indicated later in this report, because of
the rapid fall off in depth dose from 14’Pm j? irradiation the doses that could lead to the
THE BIOLOGICAL BASIS FOR DOSE LIMITATION IN THE SKIN 2.5
o 1 , , -Y‘.,, ,
0 10 20 30 60 90 120 150
Time after Irradiation (days 1
Fig. 14. Time-related changes in the relative cellularity of the epidermis of the pig after irradiation with
various skin surface doses from a 14’Pm source. Data are given for the basal layer (O---O) and the whole
epidermis (A---A ). Error bars and hatched area represent *SE. (-a-*-) indicates the initial rate of cell loss at
3.3’Wday.
development of moist desquamation results in very early (interphase) death of the viable
cells in the upper layers of the epidermis. This leads to the appearance of an early lesion
specific for exposures involving very low-energy /I irradiation (Hopewell, 1986).
Irradiation with skin surface doses of 10 Gy allowed for a very rapid repopulation of the
epidermis by 20-30 days (Osanov, 1983) and only after a dose of 100 Gy was there any
evidence of transient epidermal hyperplasia (Fig. 14).
(67) The identification and counting of labelled clusters of cells from epithelial
preparations of the skin of the mouse (Al-Barwari and Potten, 1976) or from histological
sections in the pig (Archambeau et al., 1979) have been used as a means of assessing the
radiosensitivity of clonogenic cells within the basal layer, Values of Do in the order of
1 .O-3.5 Gy were obtained. Counts of the increase in number of labelled cells per cluster,
as a function of time after irradiation, suggest a turnover time of -25 h for the
regenerating clonogenic cells of the skin of the mouse (Al-Barwari and Potten, 1976);
this compared with 16-25 h for the pig (Morris and Hopewell, 1988; Archambeau et al.,
1979) and 24-26 h for man (Dutreix et al., 1971). The latter study was based on clinical
measurements of the growth of macrocolonies of epithelial cells in areas of moist
desquamation in patients receiving radiotherapy, The macrocolony assay of reproductive
clonogenic cell survival for the epidermis was initially developed in the mouse (Withers,
1967).
(68) When an area of irradiated skin is completely denuded of clonogenic epithelial
cells then the healing of moist desquamation must occur totally as a result of the division
JAICRP22:2-c
and migration of viable cells from the edges of the irradiated area. The stimulus for such
an ingrowth is unknown but may well be initiated at approximately the same time and by
a similar mechanism to that responsible for the initiation of divisions in reproductively
viable clonogenic cells within an irradiated area. An epidermal cell migration rate of
1 mm in 6-7 days, as estimated from wound healing studies in the pig (Winter, 1972),
could have a significant effect on the acute epithelial radiation response of skin when
small areas are exposed. When larger areas of skin are irradiated with high doses and all
the clonogenic cells within that area are reproductively sterilised, cell migration from the
edges of the field will be relatively ineffective. Secondary ulceration, involving the loss of
dermal tissue, may develop in such situations as a consequence of infection and trauma.
(69) An important finding arising from the investigations involved in the use of the
microcolony assay of epidermal cell survival in mice was that a high proportion of the
microcolonies was associated with the hair follicle canals (Potten and Al-Barwari, 1985)
i.e., approximately 50% after 8 Gy and 70-80% after 20 Gy. Similar conclusions were
reached on, the basis of histological studies in pig skin after x irradiation (Morris and
Hopewell, 1989). The 2- to 3-fold increase in the mitotic index of the cells of the basal
layer, within the canal of hair follicles, by the 20th day after irradiation provides further
evidence for the important role played by these cells in the recovery of the epidermis
after irradiation (Osanov et aZ., 1976). These findings have important implications for
radiological protection because’of the presence of a significant proportion of epithelial
basal cells within the canal of hair follicles. These will be spared in exposures involving
low to intermediate-energy p-ray emitters.
(70) The time course for the development of the main erythematous reaction, and the
associated epithelial reaction, of pig skin after irradiation from a high-energy b-ray
emitter (gOSr/gOYE,,,,, 2.27 MeV) and an intermediate-energy /?-ray emitter (“OTrn: E,,,,,
0.97MeV), for sources of a similar size, are illustrated in Figs 15a and 15b. In each
instance the response of two representative areas of skin is given for the single doses
associated with a 95% incidence (ED,,)of moist desquamation. In each instance the
maximum level of erythema was seen between 3 weeks and 6 weeks after irradiation and
was classified as moderate to bright red (Score B-C). Moist desquamation (Score S or T)
developed after 4-6 weeks and was very transient, a residual dry, scaly, desquamation
was reported after 5-6 weeks (Score R). Moist desquamation was more prolonged after
gOSr/gOYirradiation despite the significantly lower skin surface dose. The more rapid
onset of repopulation after “OTrn irradiation can be explained by the high level of
epithelial cell survival within the hair follicle canals. This would also explain why a higher
surface dose was required to produce a similar incidence of desquamation after “OTrn
irradiation as compared with gOSr/gOYirradiation, The above differences appear to apply
generally for moist desquamation at doses above the ED,, (Hopewell, 1986).
(7 1) Radiation-induced changes in hair, seen over the period of the main
erythematous reaction, are related mainly to the reduction in the number of clonogenic
cells in the germinal zone, namely the cells of the hair matrix. However, a few cells may
be killed directly by the radiation as was deduced by the early rise in the number of
‘apoptotic fragments’ in the germinal region of follicles of mice (Potten, 1985b). The
cumulative effect of these processes is a dose-dependent reduction in the cell production
by the matrix, which is expressed as a reduction in the diameter of actively growing hairs.
The term hair dysplasia was used to describe this phenomenon by Griem and Malkinson
(1967). In studies on mice these authors reported that -20% of hairs were dysplastic
after 2 Gy, increasing to -80% of all hairs after 7 Gy. A dose of 10 Gy was the upper
1
E
ERYTHEMA
D Pig 1
Pig 2
2 4 6 8 10 12 14 16
Weeks post irradiation
Fig. 15a. Time-scale of changes in the severity of erythema and an indication of the presence or absence of
desquamation or dermal necrosis after irradiation from y0Sr/90Y with skin surface doses representing the ED,,
for moist desquamation. Individual fields on two pigs were assessed at weekly intervals. The severity of
erythema increased from minimal (A), moderate (B) and bright red (C) or to dusky (D) and mauve (E).
Desquamation was either dry (R) or moist over < i the irradiated area (S) or moist over >$ the irradiated
area (T).
limit of measurement in this system, since this represented the approximate epilation
dose.
(72) Measurements of the maximum transient reduction in diameter of actively
growing hairs in the pig (Sieber et al., 1986) and in the guard hairs of the mouse (Potten,
1985b) showed a similar dose-effect relationship for the percentage reduction in hair
diameter in each species; a detectable reduction in diameter was seen after 1 Gy with a
28 REPORT OF A TASK GROUP OF COMMITTEE I
ERYTHEMA
+ Pig 1
-+- Pig 2
0 2 4 6 a 10 12 14 16
DESQlJAhtATlON
AND
-
T
NECROSIS
0
0 2 4 6 a 10 12 14 16
Weeks post irradiation
Fig. Mb. Time-scale of changes in the severity of erythema and an indication of the presence or absence of
desquamation or dermai necrosis after irradiation from “OTm with skin surface doses representing ED,, for
moist desquamation. Individual fields on two pigs were assessed at weekly intervals. The severity of erythema
increased from minimal (A), moderate (B) and bright red (C) or to dusky (D) and mauve (E). Desquamation
was either dry (R) or moist over <t the irradiated area(S) or moist over >i the irradiated area (T).
30% reduction after 5 Gy. In the pig it was not possible to measure a > 50% reduction in
hair diameter since at this point the hairs tended to break at their narrowest point.
(73) With x-ray doses of >5 Gy to pig skin (Sieber and Hopewell, 1989) some hair
loss was seen. This effect was at a maximum after 4-6 weeks. Epilation was transient,
with full regrowth by 10 weeks, after doses of 512 Gy. Permanent hair loss was seen after
irradiation with 14 Gy, suggesting a threshoId dose for alopecia of slightIy greater than
12 Gy, a dose close to that suggested for man for acute single exposures. Hair growth is
asynchronous in both these species.
(74) In the mouse a threshold dose of - 12.5 Gy was reported for the partial loss of
fully formed but resting hair follicles. A varying degree of alopecia was seen after single
doses of 14 and 15 Gy (Vegesna et al., 1988). In the rat, complete epilation was reported
in anagen hairs after 12 Gy and by 24 Gy for telogen hairs (Geary, 1952).
3.4. Late Erythema, Dermal Ischaemia and Necrosis

(75) A late phase of erythema is well characterised in pig skin after irradiation with
single doses or fractionated doses involving a small number of large doses per fraction of
photons or fast neutrons (Hopewell et al., 1988; Archambeau et al., 1985). This was
referred to as the mid-term reaction in the early studies by Fowler et al. (1963, 1965).
With increasing fractionation of the radiation dose this late phase of erythema becomes
relatively less significant when compared with the severity of the main erythematous
reaction and moist desquamation (Hopewell et al., 1978). This may account for the lack
of significance of this late phase of erythema in most radiotherapy patients. However, in
the Chernobyl accident victims this late phase of erythema was a significant complication
in a group of people exposed to high-energy fl irradiation (Barabanova and Osanov,
1990). In these patients the dose at a depth of 1500 pm, the level of the deep dermal
plexus of blood vessels was 220 Gy, i.e. approximately 30% of the dose at a depth of
70 pm.
(76) The late phase of erythema may vary in its severity but at its maximum it is
characterised by skin with a dusky or mauve appearance, i.e., an erythema with a distinct
bluish colouration. The reaction is associated with oedema and the probability of the
development of necrosis increases with increasing dose after a threshold dose of - 18 Gy
of x rays. The latency for the development of necrosis was lo-16 weeks in the Large
White pig (Hopewell and van den Aardweg, 1988), slightly shorter in the Yorkshire pig
(Archambeau et al., 1968), and approximately 10 weeks in man. In the pig the
development of necrosis was seen after a skin surface dose of 40 Gy of 90Sr/90Y but not
after skin surface doses of 130 Gy from “OTm (Fig. 15). At these late times, necrosis was
also seen in some of the Chernobyl accident victims exposed to high-energy /I irradiation
(Barabanova and Osanov, 1990).
(77) The development of the late phase of erythema and of dermal necrosis is
preceded by the loss of endothelial cells, a reduction in the capillary density and an
increased separation of the remaining endothelial cell nuclei (Archambeau et al., 1984).
This reduction in the density of nuclei indicates the loss of cells and the attempt to
compensate for the loss. At 12 weeks after the irradiation of the skin of Large White pigs
a dose-related reduction in dermal blood flow has been reported. This was based on the
results of isotope clearance studies (Moustafa and Hopewell, 1979).
(78) Oedema and impaired lymphatic clearance precedes the measured reduction in
dermal blood flow. The presence of oedema might contribute to a collapse of the
vasculature. However, vascular insufficiency as the result of the occlusion of a proportion
of the end arterioles, by the proliferation of reproductively viable endothelial cells, has
been reported (Hopewell, 1983). The vessels at the level of the deep dermal plexus,
between the dermis and the fatty layer, appear to be a specifically important target cell
population for the development of dermal necrosis (Hopewell, 1986).
3.5. Late Skin Damage

(79) Late skin damage is characterised by dermal atrophy, a thinning of dermal tissue,
and an associated reduction in the linear dimensions of an irradiated area. Late

epidermal atrophy may also be seen but this may be secondary to the dermal change.
Dermal atrophy has been well documented in pig skin (Hopewell et aZ., 1979,1987) and
clinically it is recognised as subcutaneous induration, although in the past it has
erroneously been referred to as subcutaneous fibrosis. After /3 irradiation with single
doses from 22.5 mm diameter 90Sr/90Y plaques, dermal atrophy in pig skin develops in
two distinct phases: the first phase was seen between 14 weeks and 20 weeks with a later
phase after 52 weeks (Fig. 16). Comparable phases of development of dermal thinning
Q
2 0.71 1
3
33 Gy
I
I 20 LO 60 80 loo
0 20 LO 60 80 la 0
Time after Xrradiationiweeks)
Fig. 16. Time-related changes in the relative thickness of dermal tissue compared with adjacent unirradiated
skin in the pig after irradiation with various single doses of B rays from a 22.5 mm diameter Y”Sr/YUYplaque
(from Rezvani et al., 1988).
have also been seen after x irradiation (Baker et d., 1989) but it is not known whether
/?-ray emitters of lower energy than that of 90Sr/90Y produce the same pattern of changes.
(80) The mechanisms leading to the two phases of injury are uncertain. It is probable
that the pathogenesis of the first phase of atrophy is similar to that already proposed for
the development of dermal necrosis after high doses. Alternatively it has been proposed
that the fibroblasts are the potential target cells (Withers et al., 1980). However, the time
course for the loss of fibroblasts comes later than that for the endothelial cell changes
(Hamlet and Hopewell, 1988), which suggest that fibroblasts are not the primary target
cell population.
(81) The underlying pathogenesis of the second phase of dermal thinning in pig skin is
more obscure. The degeneration of the smooth muscle cells of the tunica media of small
arterioles and their replacement by hyaline material has been reported in the skin and
other tissue at these late times (Hopewell et al., 1989). In the skin of pigs this was also
associated with the appearance of petechial haemorrhages and focal regions of dermal
necrosis. An additional observation in this animal model was the appearance of
histological change in blood vessels characteristic of telangiectasia.
(82) Telangiectasia is a well recognised late reaction in human skin in patients
receiving radiotherapy treatment with fractionated doses. These vascular abnormalities
are rarely seen earlier than 52 weeks after the completion of therapy but they then
increase in both incidence and severity for up to at least 10 years. The rate of progression
of telangiectasia is dose-related (Turesson and Notter, 1986).
(83) In addition to the above changes, late dermal injury to the skin may become
manifest as a necrotic ulcer which is slow to heal. Necrosis is usually precipitated by
trauma in atrophic skin where the recovery of the vasculature to injury may be markedly
impaired.
3.6. Radiation-Induced Skin Reactions Specific to Radiological Protection

(84) In radiological protection there are a number of specific responses of the skin
which cannot be explained adequately by extrapolation from results obtained from
experiments, the primary aim of which was related to cancer therapy. The problems
include irradiation with small highly radioactive particles (‘hot particles’) which range in
size from a diameter of a few microns up to a millimetre or two. These particles can
produce very high and localised doses to the skin. Exposures can also involve very
superficial irradiation with low-energy #?-ray emitters or alpha particles. In the latter
situation the primary energy absorption will be in the epidermis above the basal layer.
Radioactive fragments of neutron activated steel that arise from activities in the nuclear
industry may cause beta and gamma ray exposures. The activation product Vo is
particularly common and may occur with a wide range of activities, typically 40 Bq to
20 MBq, depending upon the source size and specific activity. Power reactors can also
give rise to mixed fission products from irradiated fuel rods and may potentially result in
exposures. Activity ranges of fission product sources have been reported to range from
about 40 Bq to 400 kBq (Warnock et al., 1987).
(85) The primary lesion resulting from irradiation with ‘hot particles’ is ‘acute
ulceration’. The depth and size of the ulcer will depend on the skin surface dose and the
energy of the emissions from the particle. The full lesion usually develops within 2 weeks
of irradiation (Hopewell, 1986). Prior to the development of an ulcer a small pale,
circular area with a slight bluish tinge can be detected; this is frequently surrounded by a
halo of erythema. This reaction is very different from that reported for large-field
irradiation with both x and gamma rays. However, in essence it is akin to the ‘bulls eyes’
phenomenon reported by Forbes and Mikhail(l969) after the irradiation of pig skin with
235UC2spheres of 140-328 ,um diameter.’
(86) Histological studies have shown that the underlying pathogenesis of these ulcers
seen after high doses is different from that already described for the lesions produced by
the irradiation of larger areas of skin with significantly lower doses. Within a few days of
irradiation, pyknosis of the nuclei of endothelial cells and fibroblasts can be seen in the
papillary dermis; cells at a greater depth may be involved if higher skin surface doses
and/or sources of higher energy are used. Within 5-7 days, the papillary dermis is largely
devoid of cell nuclei although a palely staining epidermis remains intact. Ulceration is
evident when the overlying epidermis separates from the then necrotic dermis and is lost.
The doses required to produce acute ulceration and the histological appearance of the
cells within a few days of irradiation are consistent with a mechanism related to the death
of cells in interphase. As was indicated above, the depth of the ulcer will depend, in part,
on the skin surface dose and energy of the /?-ray emitter. At doses just above the
threshold for the death of fibroblasts and endothelial cells in interphase (- 100 Gy) only
superficial ulcers may result. This may be covered by a dried serum exudate which could
give the appearance of dry desquamation. Acutely produced ulcers resulting from doses
close to the above threshold for interphase cell death tend to heal rapidly provided that
infection is avoided. (The probability of ulceration and the severity and duration of the
lesion increases with dose above the threshold.) The healed lesion may leave a small scar
with the appearance of a small dimple. Doses of > 150 Gy (at 70 pm depth) were found
to produce a severe necrotic or ulcerative lesion of the skin in the Chernobyl accident
victims after a latent interval of 5-10 days (Barabanova and Osanov, 1990). These
changes are again consistent with the death of fibroblasts and endothelial cells in
interphase albeit that large areas of skin were involved.
(87) Moist desquamation, which is associated with the loss of the reproductive
integrity of stem cells in the basal layer, is not seen after ‘hot particle’ irradiation. With
lower doses any clonogenic cells that may be reproductively sterilised will be rapidly
replaced by the migration of cells from outside the higher-dose region.
(88) Late dermal atrophy may develop after ‘hot particle’ irradiation at doses below
the threshold for ulcer formation (Hamlet et al., 1986). Although this has not been well
documented, atrophy could be represented by a thinning of the dermis by up to 30%,
over a small area of the skin surface.
(89) There may be about 80% reduction in the dose across the epidermis with
irradiation of the skin with p-ray emitters of very low energy, such as 14’Pm, E,,,,,
0.225 MeV. This results in significantly higher doses to the cells in the upper viable layer
of the epidermis than to the basal layer and in particular to the potential stem cells which
are largely distributed towards the bases of the rete ridges. In investigations involving
irradiation of pig skin with 14’Prn (Hopewell, 1986) the variation in dose across the viable
epidermis was such that the doses to the upper viable layers of the epidermis were
sufficient to result in interphase cell death, whereas at the maximum depth of the basal
layer the severity of the sterilisation of clonogenic cells was below that usually associated
with thedevelopment of moist desquamation. Biologically this resulted in a skin reaction
with the gross appearance of moist desquamation which developed after a very short
’ The spheres are fissioned microspheres of 93% enriched ?j5U carbide. and referred to as ZAFUCT.
latency of about ~2 weeks. Once established, the duration of the reaction was of the
order of a few days.
(90) Histological studies after 14’Pm irradiation (Hopewell, 1986) have demonstrated
an early pyknosis of cells in the upper viable layers of the epidermis after 3 days. This
initiated an inflammatory reaction with a subsequent disruption of the total epidermis.
The early and unique pattern of changes produced by irradiation from 147Pm went
unrecognised in an earlier publication reporting studies involving irradiation with this
isotope (Peel et al., 1984).
(91) It would seem reasonable to assume that similar reactions might result from
irradiation with lower energy p-ray emitters and irradiation from alpha particles. With
lower energy B-ray emitters the disparity in dose between the upper differentiated but
viable layers of the epidermis and the basal layer would be greater. After alpha-particle
irradiation, very high doses might be received by the upper viable layers of the epidermis
with no appreciable dose to the basal layer, specifically to those stem cells at the bases of
rete pegs. No late radiation-induced changes were seen after 14’Pm irradiation (Hamlet et
al., 1986).
3.7. Dose-Effect Relationships and Threshold Doses

3.7.1. Field-size efsects
(92) It has been a long accepted practice in radiotherapy to reduce the total dose to
skin as the treatment area is increased. Based on clinical experience with orthovoltage
x rays several authors (e.g., Ellis, 1942; Paterson, 1948) proposed safe ‘tolerance’ doses
for human skin (Table 4). The doses proposed were in broad agreement with each other,
but the biological basis of the term clinical tolerance was not clearly defined and must
not be confused with iso-effect doses. Ellis (1942) did provide some broad guidelines;
small fields were said to tolerate the occurrence of moist desquamation which was
associated with prompt healing, whilst large fields only tolerated a dose that produced
dry desquamation (moist desquamation was said to be unacceptable over a larger area).
Considerable confusion was caused when these clinically derived ‘tolerance doses’ were
accepted as iso-effective doses for the skin by authors proposing mathematical formulae
for areas and volume effect relationships for the skin (e.g., von Essen, 1969). In an
experimental study in the pig no field-size effect could be demonstrated when the
responses of 4 cm x 4 cm and 4 cm x 16 cm skin fields were compared (Hopewell and
Young, 1982).
(93) In experiments related to radiological protection (Hopewell et al., 1986), circular
areas of pig skin, 5 mm to 40 mm diameter, were irradiated with 90Sr/90Y. The ED,,
values (f SE) for moist desquamation were derived from the dose-effect curves for the
incidence of moist desquamation against dose, where the doses represented the central
axis dose at 16 pm depth over an area of 1.1 mm2. The ED,, values were found to
decline markedly from about 70 Gy for a 5 mm diameter source to about 27 Gy for a
222.5 mm diameter source (Fig. 17). Irradiated areas of 15 mm diameter would appear
to be the upper limit at which cell migration from the edges of the irradiated area had a
significant influence. There was no change in the ED,, for sources of 22.5 mm and
40 mm diameter. It is perhaps of significance, from the point of view of mechanisms, that
the dose-effect curves for the 5, 11 and 15 mm diameter sources had a significantly
shallower slope than those for the two large sources. This implies a greater inhomo-
Table 4. Variation in the “tolerance dose” (Gy) for human skin with field size.
Studies based on the irradiation of cancer patients with orthovoltage x rays
(a) Ellis (1942)
Field size (cm x cm)

6X4 8X 10 15x20 Large/small
Treatment (Small) (Large) (%)
Single dose 20 14.5 11 55

3 week 50 31.5 29.0 58
5 week 58 43.5 33.5 58
(b) Patterson (1948)
Field size (cm X cm)

7x5 8x10 15x20 Large/small
Treatment (Small) (Large) (%)
Single dose 20 17 - -
3 week 52.5 45 30 57
5 week 60 50 35 58
(c) Von Essen (1969)
Field size (cm x cm)

6x4 15x20 Large/small
(7 x 5) (%)
(Small) (Large)
Dose = k (area)-“.16 67
Dose = k (area)-“.16 71
Skin Surface Dose (Gy)
Fig. 17. Dose-related changes in the percentage of skin sites showing either moist desquamation after
irradiation from 5-40 mm diameter Y?Sr/Y”Yplaques or acute ulceration from irradiation with 1 or 2 mm
diameter particles. The data are those of Hopewell er al. (1986) replotted by probit analysis. Error bars
indicate &SE on the ED,, values (O-40 mm; O-22.5 mm; A-15 mm; A-11 mm; W-5 mm; O-2 mm;
0-l mm) (with permission, Hopewell, 1991). The analysis takes into account more recent dosimetry.
geneity in the cell populations irradiated with the smaller sources. This might reflect an
increase in the stimulus for cell migration after higher doses. This would also help to
explain the reduced field-size effect at the ED,, and at the estimated threshold doses for
90Sr/90Y sources > 10 mm diameter (Table 5). Similar threshold doses were reported by
Moritz and Henriques (1952) and George and Bustad (1966) after the irradiation of pig
skin.
(94) The irradiation of skin with a B-ray emitter of significantly lower energy than
9oSr/90Y, for example “OTrn (EmaX0.97 MeV), would leave many reproductively viable
basal cells within the irradiated area, i.e., those basal cells situated in the hair follicle
canal. In such a situation cell migration from the edges of an irradiated area would be
expected to be of reduced significance in determining the response of areas of increasing
size to irradiation. The finding of a significantly reduced field-size effect and higher skin-
surface doses for the EDso, the ED,, and estimated threshold doses in pig skin after
irradiation with *‘OTm sources of 5-19 mm diameter (Fig. 18) provides major evidence
for the presence and importance of viable clonogenic cells within the hair follicle canal.
(95) A comparison of the radiation responses of the skin to 90Sr/90Y and “OTm with
that of 14’Pm is not entirely meaningful because of the change in the biological response
produced by very low-energy B-ray emitters. The dose-effect curves for acute epithelial
necrosis after 14’Prn are shown in Fig. 19. A small field size effect was seen. However, this
is of doubtful significance because of the difficulties associated with the recognition of
minor skin changes in very small areas.
Table 5. Acute breakdown of the skin of pigs after p irradiation, ED,,, values (&SE),
ED,,, and estimated threshold doses
Sources Estimated
diameter ED,,, ED,,, threshold dose Type of
Isotope (mm) (GY) GY) (GY) lesion
“‘l&,“‘Y 40 29f 1” 20*1 -18 MD

22.5 27&l 21fl -18
15 42f5 21f3 -18
11 45*5 22f3 -19
5 70f5 34f4 -25
2 179f 14 123* 15 -75 AU
1 368f45 151f36 - 102
I7”Tm 19 72f6” 48rt4 - 35 MD
9 74f3 49f3 - 35
5 86f5 57f4 - 39
2 250f21 109f 13 -70 AU
1 263f31 114f16 -85
0.5 339f36 147f20 -85
0.1 211f25 92f14 -64
266 f 23a,h 116f.10a,s - 750
““Pm 15 512f33’ 305 f 41 - 200 AEN
9 572 f 35 366 f 45 - 200
5 615f33 408 f 40 -250
2 717f39 510f40 - 350
a Dose at a 16 pm depth, averaged over 1.l mm2.

’ Average of the data for the sources 0.1-2 mm diameter.
’ Dose at the skin surface, averaged over 1.l mm*.
MD-moist desquamation; AU-acute ulceration; AEN-acute epidermal necrosis.
Skin Surface DoseIGyl
Fig. 18. Dose-related changes in the percentage of skin sites showing either moist desquamation after
irradiation from 5-12 mm diameter ““Tm plaques or acute ulceration from irradiation with 0.1-2 mm
diameter particles. The data are those of Hopewell ef al. (1986) replotted by probit analysis and including a
dosimetry correction for the 0.1-l mm diameter sources (O-19 mm; 0-9 mm; O-5 mm; A-2 mm; n -
1 mm; +-0.5 mm; O-O.1 mm) (with permission, Hopewell, 1991).
0
0 loo290lw&w5036no700wo 9m low ma 12w
Skin Surface DoseiGyl
Fig. 19. Dose-related changes in the percentage of skin sites showing acute epithelial necrosis (*SE) after
irradiation from 2-15 mm diameter “‘Pm plaques. The data are those of Hopewell et a/. (1986) replotted by
probit analysis (a-15 mm; m-9 mm; A-5 mm; O-2 mm). Error bars indicate *SE (with permission,
Hopewell, 1990).
(96) For irradiations with intermediate and higher-energy B-ray emitters, dermal
atrophy and possibly telangiectasia may prove to be the cosmetically unacceptable late
normal tissue changes that could determine the dose limit in radiological protection.
Measurements of dermal thickness at 2 years after the irradiation of pig skin showed that
significant dermal thinning was observed (Figs 20 and 21) at doses that did not produce
early epithelial desquamation or acute ulceration in the case of 52 mm diameter sources
(Hamlet et al., 1986). However, threshold doses for the atrophy of the skin have still to
be established for a severity of dermal thinning that might be considered to be
cosmetically unacceptable.
(97) Data for man, which have established a dose-effect relationship for late skin
damage, have come from studies on patients receiving fractionated radiotherapy
THE BIOLOGICAL BASIS FOR DOSE LlMlTATlON IN THE SKIN 37
Fig. 20. Dose-related reduction in dermal thickness (irradiated control) in pig skin 104 weeks after irradiation
from 9”Sr/90Y j3 rays from 22.5 mm (a), 1.5mm (O), 11 mm (0), 5 mm (O), 2 mm (A ) or 1 mm (V 1diameter
sources. Error bars indicate *SE. (Redrawn from Hamlet et al., 1986, taking into account more recent
dosimetry.)
021 . . . . . . . . . ..I..
0 KI 2a x1 La 50 60 70 00 90 lcdl 10 120 13c IL0
Skin Surface Dose IGy)
Fig. 21. Dose-related reduction in dermal thickness (irradiated/control) in pig skin 104 weeks after irradiation
from ““Tm /l rays from 19 mm (A ), 9 mm (0), 5 mm (0) and 2 mm (a) diameter sources. Error bars indicate
*SE (redrawn from Hamlet etaf., 1986, taking into account more recent dosimetry).
treatment. Examination of the incidence of clinically evident late atrophy in large fields
would suggest that the dose given in 30 fractions that was associated with a 50%
incidence of a visible effect (ED,,) was about 69 Gy (Reinhold ef al., 1990). The
corresponding value for ~12.5% linear contraction of skin fields on the pig at 26-52
weeks after irradiation, was about 68 Gy (Fig. 22). The corresponding threshold doses
were about 40 Gy and 35 Gy, respectively.
(98) These fractionated radiation doses can be used to calculate equivalent acute
single doses by assuming that the underlying cell survival curve of the target cells, the
death of which is responsible for the effect, can be described by a linear-quadratic (LQ)
equation i.e., surviving fraction = e- W + Do’); D is the dose per fraction and a and B are
constants related to the dose and dose-squared terms. Assuming the applicability of the
LQ model of cell survival and an a/p ratio of 3 Gy for late damage to the skin the
Induration
Dose (Gy)
Fig. 22. Dose-related changes in the percentage incidence of subcutaneous induration in man and zz12.5%
linear tield contraction in pig skin after fractionated irradiation (daily fractionation over 39/49 days).
(Reproduced from Reinhold et al., 1990, with permission.)
equivalent single doses, based on these data, would be about 17 Gy and about 10.5 Gy
for the ED,, value and the threshold dose, respectively. The extrapolation of the data for
thinning of the dermis after the 9oSr/90Y and “OTrn irradiation of pig skin suggest a
similar threshold dose of about 10 Gy (Figs 20 and 21). For late telangiectasia in human
skin, the ED,, for a moderate severity of telangiectasia at 5 years was about 65 Gy
(Fig. 23) for fractionated doses given as 2 Gy per fraction, 5 fractions per week
(Turesson and Notter, 1986), and the threshold dose was about 40 Gy.
Fig. 23. Dose-related changes in the percentage of patients with moderate telangiectasia of the skin 5 years
after fractionated irradiation (2 Gy per fraction/5 times per week). (Redrawn from Turesson and Notter,
1984.)
(99) Clinical experience, based on studies of human skin in patients receiving
radiotherapy treatment, has suggested that there may be both age, and body site, related
differences in radiosensitivity. However, these differences are relatively small; for
example, in patients showing skin with an aged or weathered appearance, a reduction in
dose of up to 10% will be made in some centres. There is no evidence to suggest that the
sex of a patient has any influence on the radiosensitivity of the skin.
(100) A factor having a major effect in the radiosensitivity of the skin is the linear
energy transfer (LET) of the radiation. When the effects of high-LET radiations are
compared with low-LET radiation a relative biological effectiveness (RBE) has to be
considered. This depends on the specific radiation. The RBE increases with decreasing
neutron energy. For very small doses/fraction the RBE ranged from 3-4 for high-energy
fast neutrons (42 MeV,,,, or 62 MeV,,,,, ) to about 8 for low-energy fast neutrons
(4 MeV,,,,). RBE values in the range 1.5-4.0 are applicable for large single doses of
r 10 Gy (Hopewell et& 1988; Joiner and Field, 1988).
3.7.2. Protraction of exposure

(101) The dose-response relationships for both early and late radiation-induced
damage to the skin will be significantly influenced by the exposure rate. For ‘acute’
radiation exposures the dose limit should be based on the response of the dermis in order
to prevent the development of what might be considered detrimental late effects such as
dermal atrophy or telangiectasia. Protraction of the dose over a period of 2-3 weeks,
either by irradiation at low dose rates or by using multiple small dose fractions, would
result in higher threshold doses for both early and late radiation-induced injury. Since
repopulation by epithelial cells would not be significant over this period (van den
Aardweg et at., 1988; Turesson and Notter, 1984) the sparing of the dose would be due
to the repair of sublethal injury from low-LET radiation. The repair capacity of the
dermal vascular/connective tissues is greater than that of the epidermis and hence the
response of the dermis would be reduced relative to that of the epidermis. Expressed in
terms of the linear-quadratic model of cell survival, the a/B ratio obtained for the
appropriate target cells is about 10 Gy and about 3 Gy for the early and late effects,
respectively.
(102) When the period of exposure is protracted for intervals of 26 weeks the
repopulation of surviving clonogenic cells from within the basal layer will reduce or
possibly eliminate the effects of radiation on the epidermis. Simple split-dose studies in
the pig, using two equal doses, have suggested that full recovery of the epidermis is
completed with a 6 week interval between doses (van den Aardweg et al., 1988).
However, after daily (5 per week) fractionation over 6 weeks, full recovery may be
delayed until at least 2 weeks after the completion of irradiation (Morris and Hopewell,
1986). Clearly, with extensive protraction of the dose, the epidermis will be considerably
spared due to repopulation and thus the late dermal changes will again predominate,
(103) For the late dermal changes, there is considerable uncertainty about the
significance of a time factor, which might be associated with cellular repopulation.
Therefore, it is uncertain as to how late dermal effects might be modified by an extended
protraction of the dose beyond what is known from the results of studies on patients
receiving radiation therapy. In the light of this uncertainty the threshold dose of about
40 Gy for telangiectasia and late atrophy obtained for human skin after irradiation with
2 Gy fractions would appear to be the most appropriate for radiological protection if late
effects of this type are to be avoided.
3.8. Experimental Studies on the Effects of Irradiation with ‘Hot Particles’

(104) A comparison of the various studies that have been carried out on pig, monkey
and human skin, to determine the dose-effect relationships or threshold doses for the
response to sources that can simulate ‘hot particle’ exposure, is complex. A number of
factors have confounded the comparison of the results from the earlier studies and those
obtained recently. The geometries of the sources were not identical and there was not as
complete an understanding of the pathogenesis as there is today, and therefore the
terminology used to describe the radiation-induced lesions has changed. Today the
terminology can be based on a reasonable understanding of the underlying mechanisms
whereas in the past there was a reliance, at least in part, on the experience from radio-
therapy. However, in radiotherapy the fields are large and quite unlike the special
situation with ‘hot particles’. The retrospective interpretation of earlier findings, on the
basis of more recent knowledge, is likely to be subjective. The other major problem is the
definition of the dose to the skin and the need for some normalisation of the dose so that
comparisons can be made more readily.
(105) In the subsequent review of the various experimental studies the terminology
used by the various individual authors is first cited. The doses are also those quoted by
the authors. However, in the full intercomparison that follows, a normalisation process
has been adopted for the expression of dose. Furthermore, the observations in the earlier
experiments can now be interpreted in the light of new information on the pathogenesis
of the lesions obtained (see paragraph 86).
3.8.1. Studies on skin of monkeys

(106) To expose the skin of the backs of monkeys (Mucaca speciosa) 235UC2
microspheres 100-200 pm in diameter were taped to the skin for <6 h in a series of
three experiments conducted at the Los Alamos Scientific Laboratory (Biological and
Medical Research Group, 1965; Dean et al., 1970). Radiation doses were measured
using an extrapolation chamber and were also calculated based on a model using the
estimated activity of the particles. The results, which were comparable, were expressed as
peak doses at a depth of 100 pm. The same approach was used in the dosimetry for the
human experiments. In addition the doses averaged over 1.1 mm*, at a depth of 16 pm,
are also quoted and are subsequently quoted in parentheses. Such a designation of dose
is used in a subsequent intercomparison.
(107) In the first experiment, 13 exposures were made with peak doses ranging from
12.7-96 Gy (the doses averaged over 1.1 mm* at a depth of 16 pm were 3.8-28.8 Gy);
the only reaction observed was a slight erythema, to an area l-2 mm in diameter, after
the highest dose. The maximum erythema occurred after 48 h and no evidence of the
effects of exposure was seen after 26 days.
(108) The second experiment involved 9 exposures with peak doses ranging from
158-521 Gy (47-156 Gy). Erythema was visible at all sites after 48 h and there was an
elevation of the stratum corneum on the two sites that were irradiated with the two
highest doses. At 28 days a shallow, dry desquamation was observed but only in the
single site irradiated with 521 Gy (156 Gy). The dry desquamation had disappeared by
36 days. It was claimed that no obvious ulceration or dermal necrosis was seen. No
lesions were visible or palpable by 90 days.
(109) In a third experiment, 11 sites were exposed to peak doses in the range 1570-
6640 Gy (471-1992 Gy). Erythema was reported at all sites, with a maximum diameter
of g mm after the highest dose. The stratum corneum was elevated with palpable nodules
5-g mm in diameter. The maximum reaction was observed after 15 days. Ulceration was
reported at eight sites irradiated with point doses of 22610 Gy (2783 Gy). The
ulcerated areas remained open for about 2 weeks before a dry scab was formed. The
epithelium had regrown in the ulcerated sites by 71 days at which time the sites were
represented by a dimple of about 3 mm in diameter. The remaining three sites irradiated
with lower doses of 1570-2417 Gy (471-725 Gy) showed what was termed a ‘dry
desquamation’ to an area 3-4 mm in diameter.
3.8.2. Studies on human skin

(110) A human volunteer was exposed on the inner forearm to 3 different point doses
of 142 Gy (42.6 Gy), 400 (120 Gy) and 540 Gy (162 Gy) using 235UC2 microspheres
similar to those described above (Dean and Langham, 1969; Dean et al., 1970). The
lowest dose produced only a slight erythema, the intermediate dose produced an
erythematous reaction and the highest dose produced a possible small area of dry
desquamation after the development of erythema. No ulceration was said to occur. Two
years after the exposure the sites could not be detected.
3.8.3. Studies on skin ofpigs

(111) Forbes and Mikhail (1969) exposed the skin of pigs to radiation from 235UC2
microspheres similar to those used for the monkey and human studies. The microspheres
were sandwiched between two layers of polyethylene of 10 pm thickness and taped to the
skin. A total of 19 exposures were made with point doses ranging from 2400 to
74,000 Gy (720-22,000 Gy). Exposure times were typically in the range of 2-3 h. All
doses were large enough to produce early lesions described by the authors as ulcers. The
maximum diameter of the ulcers ranged from 0.5 mm at the lower doses to 8 mm at the
highest dose. Ulcer diameter was defined by the authors as the diameter of the denuded,
oozing sore, and in turn, the diameter of the dry scab which subsequently filled the
denuded space. The development of lesions was most rapid at the sites receiving the
highest dose; healing occurred more rapidly after the lowest doses. After the highest
dose, lesions appeared as early as the second day after exposure. These lesions were
initially inappropriately described as moist desquamation but it was said that the area of
involvement gradually spread outward to form an ulcer, which had a maximum size after
2-4 weeks. Scab formation commenced within 3 days of the appearance of the ulcer and
6 weeks after exposure all lesions were dry. Healing, with scar tissue formation, was
usually complete by 12 weeks. Due to circumstances outside their control the authors
were forced to terminate the studies before lower dose exposures could be carried out to
define the threshold dose for this effect.
(112) In an extensive series of experiments, the effects of different sizes of sources
(0.1-2.0 mm diameter), of different B-ray energy were studied on pig skin. All but one of
the sources used were plain sources attached to perspex rods which resulted in a back-
scatter component to the quoted dose. The 1 mm diameter gOSr/gOY source was of
different construction, consisting of a glass bead sealed in the end of a stainless steel tube
and as such this source was partly collimated. A partly collimated source does not
simulate exposure to ‘hot particles.’ The results of these studies were summarised by
Hopewell (1990); however, for the purposes of this report the data have been re-
analysed taking into account a recent re-evaluation of the dosimetry for these small
sources (Darley et al., 1991). The re-assessment only modifies the dose quoted when
JAICRP22: 2-D
averaged over 1.1 mm2, at a depth of 16 pm and does not change doses averaged over a
larger area of 1 cm*. The revised results are included on Figs 17 and 18. These studies
were different from those previously reported for the monkey, man and pig with 235UC2
in that multiple exposures with a range of doses were made so that plots representing the
probability of acute ulceration, as a function of dose, could be constructed for 90Sr/90Y
and 170Tm sources. For example, for studies with the 1 mm diameter 90Sr/90Y source,
doses in the range 22-3750 Gy (over 1.1 mm2 at 16 pm depth) were used with 17-18
sites being irradiated at each dose level. This approach enabled the determination of the
doses required to produce the effect in 10% and 50% of the exposed sites and allows an
estimate to be made of the threshold dose (Table 5).
(113) The end-point used to assess the effect in these studies was designated initially
by the author (Hopewell, 1986) as acute necrosis. This may be equated with the term
ulceration used by previous authors and referred to in this report as acute ulceration. It
was explicitly stated (Hopewell, 1986) that moist desquamation, again a term used by
earlier investigators, was always avoided with source sizes <2 mm in diameter for
reasons explained earlier. The time course for acute ulceration varied with dose level; for
doses which induced the effect in >50% of sites, acute necrosis was usually visible after
about 2 weeks and persisted for 4-5 weeks. However, for doses that induced the effect in
<50% of sites (ED,,) the effect was very transient, so much so that scoring the animals
twice a week resulted in many more positive observations than when they were examined
once a week. This produced an apparent reduction in the estimated ED,, value from
650 Gy to 400 Gy although this difference was not statistically significant (Hopewell et
al., 1986). The originally quoted doses of 450 Gy and 275 Gy were revised upwards by a
factor of 1.45 as a result of a correction in the dosimetry (Darley eta& 1991).
( 114) On the basis of the present re-analysis of the data of Hopewell (1990) the dose-
effect relationships for the 0.1-2 mm diameter “OTrn sources were similar, suggesting an
average ED,, value for acute ulceration for these sources of -270 Gy. The
corresponding average ED,o and estimated threshold doses for these small i70Trn sources
were -115 Gy and -75.0 Gy, respectively. These were not significantly different from
those for the 2 mm diameter 90Sr/90Y source: the lower ED,, value for the 2 mm
diameter 90Sr/90Y source reflects the steeper dose-effect curve for this source as
compared with the small 170Tmsources. The higher EDSO, ED,, and estimated threshold
doses for the 1 mm diameter 90Sr/90Y source as compared with the other sources used to
simulate ‘hot particle exposure’ may reflect the partial collimation resulting from the
specific design of this source. Collimation of a small source under-estimates the effect of
a ‘hot particle’ on the skin surface, and the results from this source have not been used in
the subsequent intercomparison of the various experimental studies.
3.8.4. Comparison of the studies

(115) The data from the studies described above, using the end-points and doses as
designated by the authors, are plotted in Fig. 24. The data from the studies on monkeys,
humans and pigs by Forbes and Mikhail (1969) showed a consistent pattern. All studies
were conducted with 235UC2 fuel particles, 100-200 pm in diameter, and peak doses at a
depth of 100 pm were always quoted. Where observed, the authors reported mild
erythema, erythema, dry desquamation and ulceration on an escalating dose scale.
(116) The points plotted on Fig. 24 from the pig studies with 170Trn by Hopewell
(1990) indicate the ED,, values and the range, ED,,-ED,,, for what was termed acute
ulceration. These differ from the results of Forbes and Mikhail in several important
p,~~_____________“_
10 lo2 3
10' 105
DOS&l
Fig. 24. Biological effects of small radioactive particles on the skin; the increasing scale of effect and the doses
are as reported by the investigators. For further explanation see the text. (Scale of effect: A-no effect; B-mild
erythema; C-erythema; D-dry desquamation; E-acute necrosis, based on the data of Hopewell et af., 1986;
F-ulceration based on the data from Los Alamos Scientific Laboratory, 1965 and Dean et al., 1970. The
lesions described as acute necrosis and ulceration by the different investigators are considered to be the same
and are termed acute ulceration in this report-paragraph 113.) 235UC2particles: monkey skin: thirteen points,
one at each dose in the range of 12.7 to 96 Gy showed no response and one area that received 96 Gy which
showed erythema. At higher doses the responses were more severe as indicated on the scale for the reaction
level. The dashed lines indicate the range of doses over which the response was reported to be the same.
Human skin: 0 (Dean el al., 1970); monkey skin: q(Dean et al., 1970); pig skin: A (Forbes and Mikhail,
1970); and pig skin, r70Tm: (+) (Hopewell, 1990), the symbols represent the ED,, values and the bars the
ED,,-ED,, range. (Redrawn from NCRP Report 1061989.)
respects. In the experiments by Hopewell (1990) the doses were delivered by 2.0, 1.0,
0.5 and 0.1 mm diameter 170Trn sources which gave essentially the same result. In
addition, the reported doses, which were intended to approximate to point doses, were
actually measurements made with an extrapolation chamber with an effective window
thickness of 16 pm and a collecting electrode of area 1.1 mm’. The ED,, doses were 2-3
times less than the dose required to produce an effect in 50% of the areas irradiated.
(117) There is an obvious discrepancy between the data derived from Hopewell
(1990) and the other studies. In an effort to reconcile these differences, the doses from
the 235UC2 microspheres were re-evaluated by calculating the doses they would have
produced had they been measured using the extrapolation chamber of the dimensions
used by Hopewell (1990). This calculation resulted in a change of the estimate of the
peak doses from the microspheres by a factor of 0.3 (see Appendix A in NCRP Report
106,1989).
(118) The results of this re-evaluation are given in Fig. 25 and Table 6. When the
doses were averaged over l.lmm* at a depth of 16 pm there was very good agreement as
to the dose range over which acute ulceration was always seen. In the case of the studies
with 235UC2 on the skin of the monkey and pig all individual fields irradiated with doses
of 2720 Gy developed lesions which the authors termed ulceration (now termed ‘acute
ulceration’ in this report, para 113). Doses of 2780 Gy were reported to represent
ZED,,, for ‘acute necrosis’ (acute ulceration) after the irradiation of pig skin with small
17’Tm sources. It can also be seen that at doses associated with the ED,, to ED,, for
acute necrosis (acute ulceration) in pig skin, i.e. approximately 115-660 Gy, dry
desquamation was reported in monkey and in man. Recent developments in the
understanding of the pathophysiology of the different skin changes seen after irradiation
would strongly question the use of the term dry desquamation for a lesion developing
44
Fig. 25. Biological effects of small radioactive particles on the skin, the increasing scale of effect is as reported
by the investigators. The doses have been normalised to those averaged over 1.1 mm* at a depth of 16 pm. For
further explanation see the text (for key to symbols see Fig. 24).
Table 6. Summary of dose levels associated with the

development of acute ulceration (2 ED,,,) of the skin of the
monkey and pig after irradiation with ‘hot particles’
Author Species Dose (Gy) n
Dean et al. (1970) b Monkey 783-1992

Forbes and Mikhail(l969) b Pig 720-22,000
Hopewell ( 1990)c Pip 780-1925
BDoses quoted are those averaged over 1.1 mm* at 16 pm

depth.
b 23sUC2 microspheres 140-328 pm diameter which
includes 25 pm thick coating.
c ““Tm particles of 0.1-2.0 mm diameter.
very rapidly after exposure. It is doubtful whether this lesion reported to be seen in
human and monkey skin after exposure from 235UC2 particles can be equated with this
classical reaction seen after radiotherapy treatment to larger areas. It is possible,
although speculative, that these superficial lesions represent the dried serum exudate
resulting from a shallow acute ulcerative lesion. The doses used were in the range usually
associated with the death of cells in interphase. An additional disadvantage of the
investigations in man and monkey was that insufficient fields were irradiated to ascertain
whether the probability of the occurrence of specific lesions varied with dose. In man of
the three areas studied only a single area was irradiated with a dose of 162 Gy, while in
the monkey of the many used only three areas were used for studies involving doses in
the range 471-725 Gy and a single site was irradiated with a lower dose of 156 Gy. Such
data are instructive but inadequate for radiological protection purposes. Studies in which
the probability of a given reaction (i.e. acute ulceration) can be assessed are required for
setting dose limits. For doses of cl00 Gy erythema was the only reaction reported in
monkey, man and pig (Fig. 25). This was also the case in the studies of Hopewell ef al.
(1986) although this was not initially reported.
(119) In the studies on pig skin (Hopewell et al, 1986; Hopewell, 1990) where the
probability of developing acute ulceration was assessed, doses of 220 Gy usually
produced small and transient lesions. However, for doses of 220-660 Gy a range of
responses was seen for a specific dose. Acute ulceration may be either absent, present
but transient, or present and show a considerable delay in healing. For “OTm particles
and gOSr/gOYparticles of 2 mm diameter a similar threshold dose should be applied to
avoid acute ulceration. In the Chernobyl accident victims (Barabanova and Osanov,
1990) similar acutely developing lesions were seen over much larger areas of skin than in
the experiments designed to simulate ‘hot particle’ exposure. This was seen after doses of
> 150 Gy. However, effects related to interphase death in the skin would not seem to be
dependent on the area of skin exposed (Coggle, 1990).
(120) Despite the limitations of the data of Forbes and Mikhail (1969), in the sense
that all skin sites exposed to 235UC2 particles of 144-328 pm diameter developed acute
ulceration, it has formed the basis for a recent re-analysis by Baum and Kaurin (1991). In
this re-analysis it was found that the uncertainties associated with a simple linear
regression fit of dose against ulcer size produced an intercept for ulcers of ‘zero’ size
which extended to zero dose. However, based on the depth dose distribution from
235UC2 particles of different size a new model was developed for predicting the threshold
dose for acute ulceration from 235UC2 particles ranging from 144 pm to 328 pm in
diameter. This model suggests that acute ulceration would occur with a central axis dose
of 27 Gy at an estimated depth of 1330 pm. The general applicability of the model is not
clear since the quotation of a dose at a depth of 1330 pm would suggest major
differences in iso-effective doses with /?-ray energy if the dose was to be prescribed close
to the skin surface. This is not the case when the response to p-ray sources of “OTm and
90Sr/90Y, which differ considerably in the B-ray energy, are compared (Hopewell, 1990).
The doses associated with the threshold for acute ulceration, assessed at 16 pm depth
(averaged over 1.1 mm*) are comparable, not markedly different as would be predicted
on the basis of the above model. There would also appear to be no sound biological basis
for the quotation of a dose at 1330 pm depth; lesions are produced by the death of cells
in the upper dermis, in interphase, a phenomenon that is usually associated with doses of
> 100 Gy. However, based on the model developed by Baum and Kauri (1991) it was
estimated that a 5% probability of acute ulceration would occur with an exposure of
6 x lo9 /? particles from a point source of mixed fission product /I particles on the skin
which, when averaged over 1.1 mm2, could be equated with a dose of about 210 Gy.
(121) In view of the availability of the studies on pig skin (Hopewell et al., 1986;
Hopewell, 1990) where the possibility of assessing the probability of developing acute
ulceration exists, and the reasonable degree of agreement between all the data as
expressed in Fig. 25, it is appropriate to explore the use of this more extensive pig skin
data for the derivation of an exposure limit based on dose which takes into account the
depth and area over the skin over which dose can be evaluated.
(122) The ED values for acute breakdown of the skin in the pig resulting from
exposure to various sizes of sources of 90Sr/g0Y, 170Tmand 14’Pm are shown in Table 5.
The doses are expressed as the average over 1.1 mm* at 16 ,um in the case of Y”Sr/yOY
and I’OTrn and at skin surface in the case of 14’Pm. It can be seen that the type of lesion
depends on the size of the source and b-ray energy. These results may be compared with
estimates of dose averaged over 1 cm*. Where direct measurements of dose over 1 cm*
were not available they were evaluated directly by evaluating the ratio between doses
over 1 cm* and 1.1 mm* on the basis of interpolation using calculations from the codes
VARSKIN (Traub et al., 1987) and BETA (Bailey, 1973) and the values are shown in
Table 7. Combining the data in Tables 5 and 7 provides estimates of ED values for
evaluation over areas of 1.1 mm* and 1 cm*. For all sources below a diameter of - 2 mm
Table 7. Acute breakdown of pig skin after B-ray exposure. The ratio between
measured doses* and doses averaged over an area of 1 cm*
Average Dose Over 1.1 mm* at 16 pm

Average dose over 1 cm*
Source Ratio based on
diameter Measurementb CalculationC Ratio use for
Isotope (mm) of average dose over 1 cm* 1 cm* evaluationd
9nSr/90Y 40 1 1 1
22.5 1 1 1
15 - 1.03 1
11 - 1.1 1.04
5 - 5 2.5
2 - 28 11.3
““Tm 19 1 1 1
9 - 1.6 1.2-1.4’
5 - 5 2.6-3.6e
2 12.2 28.7 12.2
1 45 70 45
0.5 - 75 30-48’
0.1 - 75 30-48”
r4’Pm 15 1 1 1
9 1.6 1.6 1.6
5 5 5 5
2 32 32 32
BThe majority of dose measurements were made using an extrapolation chamber

with an electrode of area 1.1 mm* at a depth of 16 pm.
b This ratio is based on extrapolation chamber measurements at an equivalent tissue
depth of 16 pm, using several different sized electrodes (Wells, 1986, 1988). Ratios
have been corrected compared to previous data on the basis of a non-linear (quadratic)
fit to the current vs. chamber spacing for the smaller sources. Since the actual dose over
1.1 mm2 and the ratio are corrected by the same amount the evaluated doses over 1
cm* remain essentially unchanged (see Charles, 1991).
c The ratio is based on a simplified calculation of doses at a depth of 16 pm, using a
plane source geometry, neglecting self absorption (Traub et al., 1987; Bailey, 1973).
Based on such calculations the ratio is increased by factors of about <2, zG2and 510 for
9%/Y”Y, ““Tm and r4’Pm respectively, when the average dose over an area of 1 cm2 is
calculated at a depth of loo-150 pm.
d Measured values are used where available. The ratio of calculated values for
various source sizes has been used to guide interpolation of measured values.
c Range based on measurements for 1.0 and 2.0 mm diameter sources.
the values for EQO are about 100 Gy and below about 10 Gy when averaged over areas
of 1.1 mm2 and 1 cm2, respectively. For sources with a diameter of 51 mm the data
limited to I’OTm; then the ED,, values are about 100 Gy and 2 Gy averaged over areas of
1.1 mm2 and 1 cm2, respectively. It is well known that dose-response data such as these
are not reliable indicators of specific ED values much below a few percent. However,
doses which are approximately two-thirds of the EDlovalues are often considered to be
appropriate threshold doses. If the doses averaged over 1 cm2 were evaluated at a depth
in the region of loo-150 pm, rather than 16 pm, then these doses would be further
reduced by factors (see Table 7) of about 2 for “‘Trn and 90Sr/g0Y and about 10 for
i4’Pm. The use of this depth could be justified on the basis that it represents the
approximate depth of the superficial dermal cells involved in the pathogenesis of acute
ulceration for a source of 52 mm diameter. The use of this depth for large area sources
also brings the rather high ED,, values for 14’Pm into line with values for the higher-
energy B-ray emitters. However, the acute epidermal necrosis produced by i4’Pm is
initially less severe (see para 89) than the acute ulceration characteristic of the higher
energy /? rays and dose limitation criteria should be based primarily on the latter. An
alternative and acceptable monitoring depth would be the Commission’s well established
nominal basal layer depth of 70 pm. In view of all these considerations a dose threshold
of 1 Gy over an area of 1 cm2 at a depth in the vicinity of 100 pm would appear to be an
appropriate rounded value for the prevention of acute ulceration from hot particle
sources, certainly where the radiation field is dominated by /I radiation with E,,,,, up to
about 2 MeV. Based on the data of Hopewell (1990) it has been suggested that a dose of
1 Gy averaged over an area of 1 cm2 at a depth between 100 pm and 150 pm where the
radiation is dominated by #I particles with an E,,.,,, up to about 2 MeV would be an
appropriate threshold (Charles, 1990). Other estimates based largely on the results from
studies with 235UC2 particles suggest that the threshold for what was termed by NCRP as
acute deep ulceration may be higher, about 5 Gy (NCRP, 1989; Baum and Kaurin, 1991).
3.9. Radiation Effects on Langerhans Cells

(123) It is now established that exposure to UVR and especially UV-B radiation
(280-320 nm) can modify a number of immunological responses in experimental animals
(Haniszko and Suskind, 1963; Noonan et al., 1981; Toews et al., 1980; Parrish, 1983).
For example, UVR reduces the capability of animals to react to various antigenic stimuli.
The precise mechanism is unclear but involves the presence of suppressor lymphocytes.
The question is whether chronic exposures of humans to UVR induces suppressor T
cells that in turn reduce the host’s ability to control the growth of skin cancers which has
been reported to be the case in mice (Kripke, 1981; Fisher et al., 1982). It is possible that
interaction of ionising radiation and UVR could be accounted for by the chronic
exposure to UVR depressing the immune response to cells initiated by ionising radiation.
This scenario would be consistent with both the clinical and experimental findings.
(124) The effects of x irradiation on the Langerhans cells in mice have been studied
by Cole and coworkers (1984, 1985) who reported a 50% loss of Langerhans cells 10
days after 14.4 + 1.3 Gy x rays. The number of ATPase positive cells in the epidermis of
the mouse foot pad was equated with the number of Langerhans cells. Irradiation could
reduce the number of apparent Langerhans cells by either cell killing or altering the
identification by the ATPase method. In Fig. 26 the number of Langerhans cells as a
function of exposure to 25 kVp x rays is shown and indicates a 50% reduction after about
1250 R (Fry, 1990). This result suggests a greater radiosensitivity than that reported by
Cole and Townsend (1985). The results shown in Fig. 26 were obtained from the skin on
the back of hairless mice whereas Cole et al. studied the thick foot pad.
(125) There is no evidence of mitotic death and therefore if such doses of radiation
kill Langerhans cells the death must be in interphase. Also, there is no evidence of split-
dose repair. A return either to the control number of Langerhans cells or to a normal
ATPase reaction takes about 3 weeks after exposure to a wide range of doses.
(126) The information about the effect of ionising radiation on the function of cells in
the skin associated with the immune system is very sparse. Irradiation with soft x rays
decreases the delayed-type hypersensitivity response, a measure of cellular immunity, in
a parallel fashion to the reduction of Langerhans cells (Fry, 1990).
Longerhans Cells per mm2

(Mean f S. D)
10 Days After Exposure
IO 25 kVp Xroys
I I I
0 500 1000 1500 2000

EXPOSURE (R)
Fig. 26. The number of Langerhans ceils/mmS as a function of exposure to 25 kV x rays. The Langerhans cells
were assayed at 10 days post exposure using the ATPase method of staining. (Redrawn from Fry, 1990.)
3.10. Radiation Effects on Melanocytes

(127) The proliferative capacity of melanoblasts appears to be limited and both
melanoblasts and melanocytes are relatively radioresistant. Interestingly, two opposite
effects can occur with irradiation. After irradiation the skin may appear less pigmented
and the hair become grey or white, effects which are usually associated with the killing or
inactivation of melanocytes. In contrast, increased pigmentation of the skin may occur at
lower doses with both ionising radiation and exposure to sunlight. Hyperpigmentation
that involves the hair follicles occurs only with photon and particle radiation because
ultraviolet radiation does not penetrate sufficiently deep. The increase in pigmentation is
probably due to increased synthesis of melanin rather than an increase in the number of
melanoblasts.
(128) Potten (1985a) has summarised the responses of hair pigmentation to
irradiation based on studies of a number of mammals including humans; much of the
information has come from studies of mice, in particular from the studies of Chase (e.g.,
Chase, 1949, 1951). The effect on pigmentation appears only in hairs that grow
subsequent to irradiation. The degree of effect is influenced by the stage of the hair
growth cycle, the most sensitive being the resting stage. The depigmentation effect is
permanent with a threshold in mice of about 3.0 Gy and a 50% effect dose of somewhat
more than 4 Gy. In the range of 3-10 Gy the loss of pigmentation appears to be
exponential with dose and with a D, of about 3 Gy. Survival curves for melanoblasts have
been published (Potten, 1968) and are characterised by a threshold of about 4.0 Gy, a D,
of about 2 Gy and an extrapolation number of 6-7.
3.11. Summary
(129) The major deterministic effects on the skin are as follows:
(130) Moist desquamation is the reaction to be prevented after acute exposure of an
area of 2 5 mm diameter of the skin to radiations of moderate to high energy.
(131) The early skin reaction in the epidermis, i.e., dry desquamation after moderate
doses, moist desquamation after high doses, results from radiation damage to the basal
cells. Erythema is the secondary, inflammatory response in the dermis to the radiation-
induced epidermal reactions.
(132) The rate of the development of the early skin reaction is independent of the
total radiation dose but may vary with excessive protraction of the radiation exposure.
After a single dose or a conventional fractionation schedule the peak reaction occurs
between 3 and 6 weeks and is related to the natural turnover rate of the basal cell layer.
The severity and the rate of recovery of the early reaction is dose-related.
(133) The estimated threshold doses for moist desquamation increase slightly with a
reduction in the area of skin irradiated with 90Sr/90Y due to cell migration from the edges
of the exposed sites (i.e., 17.5-25 Gy for 40-5 mm diameter sources, respectively).
Higher estimated threshold doses and a reduced area dependence was noted for
comparable sized “OTm sources (35-39 Gy) due to the migration of cells from within the
hair follicle sheaths.
(134) The migration of viable basal cells from lower dose areas prevents the
development of moist desquamation after exposure to discrete highly radioactive
particles, ‘hot particles’ (52 mm diameter).
(135) Acute ulceration develops within 2 weeks after ‘hot particle’ irradiation as a
result of the interphase death of fibroblasts and endothelial cells. The estimated
threshold doses for 2 and 51 mm particles is - 75 Gy, measured over an area of 1.l mm2
at a depth of 16 ,um. The corresponding threshold dose, expressed as an average over an
area of - 1 cm2 at a depth of loo-150 pm, is in the region of 1 Gy. Doses below 220 Gy
(at 16 pm depth over 1.1 mm*) result in ulcers that are likely to last for less than 1 week.
Erythema over a larger area will also occur.
(136) Irradiation with /3 particles of very low energy (SO.225 MeV) produces acute
epithelial necrosis as a consequence of the interphase death of post mitotic suprabasal
cells in the epidermis < 10 days after skin surface doses of > 200 Gy.
(137) For protracted doses of moderate and high-energy radiations late dermal
atrophy or telangiectasia are the detrimental effects to be avoided. Based on animal and
patient studies involving fractionated irradiation these effects are seen with an increasing
frequency after a single dose equivalent of - 10 Gy, i.e., doses of 35-40 Gy given in
- 2 Gy fractions.
(138) Irradiation reduces the number of Langerhans cells in a dose-dependent
manner. It is not clear whether the surface markers are altered or the cells undergo
interphase death. Delayed-type hypersensitivity appears to be reduced by soft x rays.
(139) Radiation can induce depigmentation. In mice the threshold is about 3.0 Gy.
The survival curve for melanoblasts has a wide shoulder and a D0 of about 2 Gy.
4. EXPERIMENTAL RADIATION CARCINOGENESIS
4.1. Introduction
(140) Experimental studies have been carried out on the induction of both epidermal
and dermal tumours. Most of the human data are for the induction of epidermal tumours,
basal and squamous cell carcinomas, and it is these types of tumour that are of particular
interest experimentally. Epidermal skin cancers are very rare in rats and mice that have
not been exposed to UV or ionising radiation. The commonest dermal tumour is
fibrosarcoma and in mice, at least, the natural incidence and the susceptibility for

Radiation Effects On The Skin

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20 REPORT OF A TASK GROUP OF COMMITTEE 1

3. RADIATIONEFFECTS ON THE SKIN

3.1.1. Terminology used to describe the responses of skin to radiation

3.1.2. Pathophysiology of radiation-induced changes in the skin

3.2. The Early Erythematous Reaction

3.3. The Main Erythematous Reaction

Time after Irradlatlonidaysl

IO/ Basal Layer ,~

Time after Irradiation (days I

Weeks post irradiation

3.4. Late Erythema, Dermal Ischaemia and Necrosis

3.5. Late Skin Damage

and an associated reduction in the linear dimensions of an irradiated area. Late

3.6. Radiation-Induced Skin Reactions Specific to Radiological Protection

3.7. Dose-Effect Relationships and Threshold Doses

Field size (cm x cm)

Single dose 20 14.5 11 55

(b) Patterson (1948)

Field size (cm X cm)

(c) Von Essen (1969)

Field size (cm x cm)

Skin Surface Dose (Gy)

“‘l&,“‘Y 40 29f 1” 20*1 -18 MD

a Dose at a 16 pm depth, averaged over 1.l mm2.

Skin Surface DoseIGyl

Skin Surface DoseiGyl

3.7.2. Protraction of exposure

3.8. Experimental Studies on the Effects of Irradiation with ‘Hot Particles’

3.8.1. Studies on skin of monkeys

3.8.2. Studies on human skin

3.8.3. Studies on skin ofpigs

3.8.4. Comparison of the studies

Table 6. Summary of dose levels associated with the

Author Species Dose (Gy) n

Dean et al. (1970) b Monkey 783-1992

BDoses quoted are those averaged over 1.1 mm* at 16 pm

Average Dose Over 1.1 mm* at 16 pm

BThe majority of dose measurements were made using an extrapolation chamber

3.9. Radiation Effects on Langerhans Cells

Longerhans Cells per mm2

0 500 1000 1500 2000

3.10. Radiation Effects on Melanocytes

4. EXPERIMENTAL RADIATION CARCINOGENESIS

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