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Long-term effects of radium exposure in female dial workers: Differential white blood cell count
ENVIROSMENI-AI.
RLSLAR(:H
15,
252-
261
(1978)
Long-Term Effects of Radium Exposure in Female Workers: Differential White Blood Cell Count
Dial
The long-term effects of bone-seeking radionuclides on bone marrow in humans seem worthy of exploration. Leukocyte counts (total white cells. polymorphonuclears, lymphocytes, eosinophils. and monocytes) were analyzed among 393 female radium dial workers who were first employed between 1913 and 1929 and most recently examined between 19.54 and 1975. Mean and median counts were compared by initial intake level (&i of radium per kg of skeleton) within three age-at-last-examination groups (45-54, 55-64. and 65-74 yr). Median estimated 40-yr average alpha doses to trabecular bone marrow in the highest intake levels compared were 9 rad. 104 rad. and 40 rad. in the three age groups. Spearman rank correlation coefficients between radium intake and white cell counts were also calculated. There was little evidence for long-term or late effects of radium exposure on white cell counts. In the younger age groups, lymphocyte count tended to increase with increasing radium intake. In 65-74 year olds. eosinophil count decreased with increasing intake (Spearman I’ = -0.14. P < 0.05). Continued follow-up of this population should help clarify the question of possible long-term effects (direct or indirect) of radium exposure.
INTRODUCTION
Studies of the hematological effects of exposure to ionizing radiation are of interest, since certain cells of blood and blood-forming organs are among the most radiosensitive cells of the body. Since radium and plutonium are bone-seeking radionuclides, the possibility of bone-marrow injury has been explored to some extenl. In beagles injected with ZzhRa and zX9Pu, reductions in white blood cells and differential leukocyte counts were evident in the first year (Dougherty and Rosenblatt, 1969). Depression of lymphocyte and eosinophil counts showed no recovery during the first year post-injection, and depression of the lymphocyte count persisted through 42 months post-injection at the highest injection levels (Dougherty and Rosenblatt. 1971). In humans, data on hematological effects of internal emitters are limited. Early studies of persons exposed to radium, either ingested, as by radium dial painters or injected for supposed therapeutic effects, reported bone marrow injury, as evidenced by blood dyscrasias (anemia, leukopenia, and, possibly, leukemia) (Martland, Conlon and Knef, 1925: Martland, 1929). The few deaths attributed to leukemia among female radium dial painters (1913- 1929) occurred a relatively short time after exposure. The long-term effects of radium exposure, especially at levels lower than those associated with early death, on bone marrow are not clear. The U.S. Government’s right to retain a nonexclusive covering this paper is acknowledged. I Work supported by the United States Energy Research 252 0013-9351/78/0152-0252$02.00/O Copyright All
rights
15 of
1978 reproduction
by
Academw in any
Press.
Inc.
form
reserved.
royalty-free
license
and Development
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Ra
EXPOSC‘RE
IN
FF.blALE
DIAL
\VORKERS
253
The present study examines leukocyte counts in relation to radium exposure in female radium dial workers first employed before 1930. These data should be relevant to disease susceptibility, in view of the crucial role of leukocytes in host defense against infectious and other agents. MATERIALS
AND METHODS
The present sample is comprised of females who were first employed before 1930 in the radium dial industry in the United States (mostly in Illinois, Connecticut, and New Jersey). Ascertainment was from various sources, including employment lists, company photographs of workers, statements of co-workers, and self-referral. Details on the characteristics of this group have been reported previously (Polednak, 1977a, 1977b). Radium body-burden measurements and clinical data on dial workers are derived mainly from studies done at the Massachusetts Institute of Technology and at the Argonne National Laboratory since about 1954. A small number of persons was studied as part of the New Jersey Radium Research Project (1957- 1967). The present study includes female dial workers examined clinically on one or more occasions between 1954 to 1975. At least one report of differential leukocyte count was available for 465 women aged 45 to 74; the small numbers of women under 45 and over 74 were excluded from analysis. Excluded also were 72 women who had a diagnosed malignant neoplasm. Of the remaining 393, the majority (i.e., 205) were last examined between 1970- 1975. All but 62 were still alive, as of the most recent contact (1974 or 1975). Methods of measurement of radium body burden have been described elsewhere (Evans, 1966; Maletskos et rrl.. 1964). Briefly, gamma radiation (from daughter products of retained radon) is measured by scintillation gamma-ray spectrometry using crystals of thallium-activated sodium iodide, and the measurement of radon emanating from the body is made on samples of exhaled breath, obtained in an underground vault (Marinelli et rrl., 1955: Stehney et (I/.. 1955). For this analysis, radiation dose was defined as the initial intake of zr6Ra and zz8Ra in microcuries per kilogram (&i/kg). This is the total amount of radium entering the blood initially, calculated from the measured radium body burden using the retention function of Norris et crl. (1955). divided by the skeletal weight (5 kg for females). The calculation assumed a constant rate of intake over the total exposure duration. For dial painters who worked before 1926 and whose work period extended into or beyond 1926, the calculation involved truncation of the exposure duration at 1936: this is justifiable because changes in work regulations around 1926. including prohibition of mouth-tipping of the brush, resulted in a marked reduction in the amount of radium ingested. The intake-dose levels used in this study (~0.20, 0.20-0.99. 21.00, and ~5.00 PCiikg) were selected primarily to provide nearly equal sample sizes in the groups. Differential leukocyte counts were done at several clinical laboratories (two laboratories at M.I.T. and one at Argonne), and procedures did not change over the years of study. Total (combined) white cell count was reported in hundreds of cells per cubic mm. Percentages of polymorphonuclears, lymphocytes, monocytes, and eosinophils were based on counts of cells in peripheral blood. using Wright’s stain. At Argonne. differential counts are based on 200 cells: at M.I.T.,
100 cells are counted unless “abnormalities” were found (in which case another 100 are counted). Basophils and stabs (juvenile neutrophils) were not considered in this study. Percentages were multiplied by total white cell count to obtain differential counts. Within each of three age (at most recent examination) categories (45-54. 55-64, and 65-74 yr), means and medians were tabulated by intake-dose category. For statistical analyses, nonparametric methods were used, due to the departure from the normal distribution shown by the variables (especially eosinophils and monocytes). In each age group, the relationships between intake dose and the differential leukocyte counts were examined by use of Spearman’s rank correlation test (two-tailed). Kendall’s rank correlation test was also used: coefficients were somewhat lower than Spearman I.-S. but significance levels were similar, so that the Kendall I.‘S are not reported here. RESULTS
Tables 1-4 show mean and median differential leukocyte counts by intake-dose category within four age groups. In the 45-54 yr olds (Table l), means and megroup than in the < 1.OO &i/kg dians are generally higher in the z 1.00 &i/kg group, except for eosinophils. None of the Spearman correlation coefficients between the intake dose and leukocyte counts, however, are statistically significant (P > 0.05 for all). A similar pattern holds for the 55-64-year-old group (Table 21, except that eosinophil levels are more similar in the four intake-dose groups. One of the Spearman ~.‘s is statistically significant, i.e.. that between intake dose and lym-
Initial
intake
dose (PCiikg)
11.00 (N = 41)
Total
white
cells
Polymorphonuclears Lymphocytes Eosinophils Monocytes As Year of examination Initial intake dose (pCi/kg)
31.00 (N = 18) Spearman
Mean
SD
Mean
SD
731 (7488)” 4188 (3995) 2660 (2373) I23 (80) 1.52 (954) 50.9 (X1.3) I959 (0.39)
1810
8056 (7650) 4650 (4114) 1989 (2885) 94 (0) 328 (238) 51.7 (52.3 1959 (2.65)
2026
+o. IS
I671
+0.09
‘1 Correlation coefficients between ‘j Medians are in parentheses.
I.503 10x5 I I9 189 2.2 1.7
dose and the white
blood
cell counts.
835
to.21
I57
+0.01
257
10.07
2. I I.1
r”
Ka EXI’OSVRE
1h
FElI.ALE
DIAI.
Initial
Total
white
Mean
SD
7390
cells
(7500)” 4457 (‘II 17) 2293
Lymphocytes
0.20 (h’
I25
Monocytey
(Ill) 374
Age
(37X) 61.1
Year Initi;il
(61.9) I969
of examination intake dose
dose
SD
Mean
I697
7430
1970
1353
(7350) 4157
I446
796 I (8100) 3708
IO1 I
(4888) 3673
lb4
(26461 1x3
272
(123) 343
2.5
(2.59) 5X.8
790
(3611 I05
162
201
(114) 36.5
2.6
13201 61.1
6. I
(0.00)
(61.7) 1967
6.0
10.38)
(&Vlig)
>I.00 (,V = 44)
Mean
(2199) Eocinophils
intake
~ 0.99 = 401
(‘WI) 25s 1
255
\VORKERS
(~5.001 (N = 24)
SD
(57.9) 196’
I932 I481
Mean 8313 IXF(.sO) 4756
SD
Spearma p
I786
+o. I7
lJb5
-cO.ll
820
(50.50) 2179
843
-0.3
1x2
(2744) I68
IJX
t0.08
302
(1171 ‘$55
300
-0.05
?.I
(455) 58.9
3.1
4.n
(5X.1) I962
4.2
(h.70)
(19.65)
(&i/kg) ” Correlation ‘/ hledians are ,’ < 0.05.
coefficients
between
dose
and
the
white
blood
cell
counts.
in parentheses.
phocytes (,. = +0.23; p < .02). The correlation between dose and total white cells approached statistical significance (/’ = +O. 17: 0.05 < p < .lO). These results did not appear to be related to a terminal rise in white cell levels: i.e.. only 4 of the high-intake (3 1.00 &i/kg) women died within five yr of examination, and total white cell and lymphocyte levels were not unusual. In the 65-74 year age group (Table ?), means and medians are similar in the four intake-dose groups for all variables except eosinophils; mean and median eosinophil counts are relatively low in the highest intake groups (3 1.OO@/kg). The only statistically significant correlation is that between intake-dose and eosinophil count (Spearman I’ = -0.14, P < .05). It should be noted that in the two age groups with adequate sample sizes (Tables 2 and 3). means and medians for all variables are very similar in the co.20 and 0.20-0.99 &i/kg intake-dose groups. From medical examinations and hospital records, information on health status was obtained. The conditions most commonly diagnosed or reported (i.e., hypertension, cardiovascular diseases, osteoarthritis, diabetes mellitus) would not be expected to influence differential leukocyte count (Wallach. 1974). Since eosinophil count is increased in various allergic diseases, the correlation between eosinophil count and radium intake in 65-74 yr olds was reexamined, excluding 31 women with histories of allergic disorders (asthma, hay fever. allergic or vasomotor rhinitis. urticaria). The correlation was the same as that obtained previously, but the P value was higher due to the smaller sample size (Spearman I’ = -0.14. A’ = 180, P = 0.06).
256
ANTHONY
P. POLEDSAK
Initial
(N
<0.20 = 88)
Mean Total
white
cells
Polymorphonuclears Lymphocytes
7367 (7000)’ 41 I5 (3842)
0.20
= 66)
Mean
SD
7092
7229 (6983) 4182
102 I
7184 (7075)
207 I ISS?
751
4194 (4032) 2277
I56
(2101) 140
140
(109) 428
2.8
(406) 68.8
4.5
(68.3) 1972
1569
1498
(4174) 2303 (2396)
102
153
I89
Monocytes
273
(IS’) 117
68. I
2.6
(369) 68.5
3.5
(67.8) 1971
intake
dose
(35.00) (N = 3)
SD
( 158) 409 (375)
of examination
21.00 = 57)
Mean
Eosinophils
Initial
(N
(Kiikg)
SD
815
Year
dose
~ 0.99
(iv
2414 ( 22791
Age
intake
(67.3) 1972 (0.03)
(0.43)
Mean 7472
Spearmal p
SD 2459
-0.06
1848
-0.00
742
(7300) 4476 (4423) ‘13 I
741
-0.03
108
(2149) IS3
II8
-0.14’
233
(II?) 455
241
co.08
2.6
(453) 68.2
1.6
4.2
(67.9) 1971
5.4
(4.39)
(I 1.45)
(@Ii/kg) ” Correlation coefficients between Ir Medians are in parentheses. : ,’ < 0.05.
dose
and
the
white
blood
cell
counts
Since the only evidence for a depression in white cell counts in relation to intake dose was for eosinophils in 65-74 yr olds, this was examined in more detail. Table 4 compares the distribution of eosinophil counts in two intake-dose groups (< 1.OO and b 1.OO&i/kg) within the 65-74-year-old group, excluding women with allergic conditions. There is a higher proportion of lower counts and a lower propor-
Initial
intake
dose
(@G/kg)
count 49 99 149
10-249
21.00 (“?)
Number I’ 29 ‘6 29
Number
(9.0) (21.6) (19.4) (21.6)
x 12 13 8
2so+
3x
(2X.4)
5
Total
134
(100.0)
46
‘1 Excluding x2 = 8.42.
31 women d.f. = 4.0.05
with histories < ,I < .lO.
of allergic
disorders
(see
text)
fCi) (17.4) (76. I) (28.3) (17.4) (1O.Y) (100.1)
Ka
EXPOSL’RE
IN
FEMALE
DIAL
WORKERS
257
tion of higher counts in the 2 1.OO pCi/kg group compared with the < 1.OO pCi/kg group; the x? value approaches statistical significance (0.05 < .I.J< .LO). These cross-sectional data suggest that the increase in eosinophil level from age 55-64 to age 65-74 in the lower intake-dose groups (< 1 .OO&i/kg) is not evident in the higher intake-dose group (2 1.OO&i/kg). Some limited longitudinal data on eosinophil levels support this conclusion. For 29 of the 57 women in the 31.00 pCi/kg group last examined at age 65-74 (Table 3), an eosinophil count was available for age 50-59 (mean age, 54.1 2 2.6 SD yr). The mean and median eosinophil counts were nearly identical, i.e.. the means were 120 2 83 SD at age 50-59 (median, 96) and 126 2 87 SD at age 65-74 (median, 108). A Wilcoxon matched-pairs signed-ranks test (two-tailed) yielded statistically insignificant results. In comparison, for 41 of the 154 women in the cl.00 ,&i/kg group last examined at age 65-74 (Table 3). an eosinophil count was also available for age 50-59 (mean age, 54.2 ? 3.2 SD yr). The mean and median eosinophil counts were higher in the older age groups, i.e.. the means were 129 t 132 SD (median, 94) at age 50-59 and 176 ? 141 SD (median. 135) at age 65-74. A Wilcoxon matched-pairs signed-ranks test (two-tailed) yielded statistically significant results (P < .05). The initial intake dose used in these comparisons can be used to obtain estimates of dose absorbed by the bone marrow, the target tissue at risk with respect to possible effects of bone-seeking radionuclides on leukocyte production. The average dose to marrow within trabecular bone in a person with I &i radium burden and 5000 g of skeleton is 2.23 radlyr (Spiers and Whitwell, 1972; Marshall and Hoegerman, 1974). The average 40-yr (trabecular) bone marrow dose for a person with an initial intake of 1 &i/kg of skeleton would be approximately 3.5 tad. This estimate was obtained by using the Norris at rrl. (1955) retention function (0.54 t”“. t >, 1 day), the 40-yr time integral of which is 0.31 yr. That is: 2.23 rad/yr.&i x (5 kg x I @/kg) x 0.31 yr =3.5 rad. The beta-particle dose is very small (Spiers and Whitwell, 1972) and is not considered here. The average dose to cortical (vs trabecular) bone marrow is also not considered, but the active marrow in the adult is Largely or entirely contained in predominantly trabecular regions (Woodard and Holodny, 1960; Holodny, Lechtman and Laughlin, 1961). Spiers and Whitwell (1972) have calculated that considerable fractions of bone marrow are irradiated by 226Ra alpha particles, especially in bones with small marrow cavities, i.e., 53% of marrow in the parietal bone. and 20-34% of marrow in trabecular bone areas. Using the median initial intake doses shown in Tables I-4. the estimated median 40-yr average (trabecular) bone marrow doses in the highest dose categories are: 9 t-ad (age group 45-54); 104 rad (age group 55-64); and 40 rad (age group 65-74). Only one woman had an initial intake dose of ~100yCilkg (i.e.. 105). Her estimated 40-yr average dose to trabecular bone marrow is 368 rad; a 50-yr dose was more appropriate in this case, as in some others, but the difference is negligible. These data on dosimetry will be useful in the interpretation of the findings. DISCUSSION Jt is recognized that difficulties are involved in analyzing differentiai leukocyte counts as biological variables. In addition to intrapersonal physiologic variability,
there are inaccuracies caused by sampling (i.e., counting a sample containing at most a few hundred of the many leukocytes circulating in the blood). The most rare leukocyte types (juvenile neutrophils and basophils), however, were excluded from our analyses. Also, the results of counting 200 cells (as in part of the present series) are considerably more accurate than those obtained with 100 cells (Rumke, Bezemer. and Kuik. 1975). It should be emphasized that the present study concerns only long-term or late effects of radium exposure on white blood cell counts. Apparent effects occurring earlier after exposure have been reported previously, although their interpretation (e.g., the true frequency of leukemia) is questionable (Loutit. 1970). Leukopenia, as well as anemia. was recognized in the 1920’s as a consequence of radium exposure (U. S. Bureau of Labor Statistics. 1929: Martland, 1929). The present sample of radium dial workers examined from 1954 to 1975 excludes some persons with high intake-doses (who died earlier) and a few deaths attributed to leukemia. Few of the correlations (Spearman r) between dose and white cell counts are statistically significant. There is little evidence for leukocyte depression, such as reported in beagles injected with high doses of 226Ra and Z39Pu. In beagle experiments with 2Z6Ra. however, leukocyte depression (in early months post injection) was followed by recovery to control levels for all variables (white cells, polymorphonculears. eosinophils, monocytes, and leukocytes) by 2-6 yr, except for lymphocytes in a high-intake group (3.5 PCiikg of body. or about 3.5 pCi/kg of skeleton) (Dougherty and Rosenblatt, 1971). Due to the greater retention of radium in the beagle relative to the human skeleton. the skeletal dose delivered (per unit of intake) in the beagle is several times that in man (Rowland, Keane, and Lucas, 1973). Thus, the present tindings on leukocyte levels some 30-50 yr after first exposure to radium may not be unexpected in view of the evidence from beagle experiments. In the 65-74 year olds (Table 3), the lower mean and median eosinophil counts in the highest intake-dose group ( 2 1.00 &i/kg), and the negative correlation (Spearman 1.) between intake dose and eosinophil count, suggest a possible doserelated depression in eosinophil level. Based on these cross-sectional data, and limited longitudinal data, the increase in eosinophil count from age 55-64 to age 65-74 in the lower intake-dose groups (< 1.OOPCiikg) is not evident in the higher intake-dose group (~1.00 &i/kg). If this effect is real, it would not appear to represent a depression persisting from an earlier time. External irradiation of most animal species depresses the eosinophil count. but sometimes causes eosinophilia in man and monkeys (Eldred, 1959; Kurohara rt trl.. 1964). The response depends upon the volume of tissues, and parts of the body. irradiated: radiation-related eosinophilia may be of prognostic significance in some types of cancer (Ghossein t’r irl., 197.5). Since internal emitters (?‘(‘Ra and Z39Pu) have been shown to produce at least transient depression of eosinophils in beagles (Dougherty and Rosenblatt, 1971), the present finding of lower eosinophil levels in the high intake-dose group of 65-74 yr olds should be further explored. The data in Table 4 suggest the possibility of a bone marrow effect, with destruction of eosinophil precursors and an eventual depletion of eosinophils. Continued follow-up of these women. preferably with more reliable methods of counting eosinophils. will be required. In
~g, ESPOSrRE
IS
FEMALE
Dl.AL
259
‘IVORKKRS
view of the possible role of eosinophils in immunological reactions (Speirs cutr/l., 1974). such data may be relevant to disease susceptibility. Comparisons of the means and medians by intake-dose group in Tables I and 2 (ages 45-64). and the Spearman 1.‘~. suggest a tendency toward slightly higher levels of some variables (i.e., total white cells and lymphocytes) in the higher intake-dose levels. After acute whole-body irradiation at lower doses, regenerative proliferation of hemopoietic cells may be pronounced. and may lead to temporary hypercellularity (Porteous and Lajtha, 1966; Upton, 1970). Conceivably. such compensatory proliferation may account for the present findings. The higher levels of lymphocytes at higher dose groups in the 45-54 and 55-64 year olds are noteworthy. Due to the low soft-tissue retention of radium, irradiation of lymphatic tissue is unlikely, except in the first few days after intake. With bone-seeking radionuclides that are ingested. the marrow is irradiated. but in the present study B-lymphocytes (bone-marrow derived) were not distinguished from T-lymphocytes. Recent experiments on mammalian cells (fibroblasts) i/l I~~YJ confirm previous findings that the mean lethal dose from alpha particles is about 100 rad (Lloyd et (I/.. 1976). The estimated average doses to trabecular bone marrow (noted above) of some women reached 100 rads. Thus. the compensatory proliferation shown after initial depletion of blood-forming cells with external irradiation may be expected in some of the women in this study. Also. the bone marrow dose estimates reported here are average doses to trabecular bone marrow. and doses to some areas (i.e.. near bone surfaces) may be considerably higher. In any event. at the initial intake doses (and estimated average trabecular bone-marrow rad doses) involved in this study of long-term survivors of radium exposure, there is little evidence for persistent depression, or significant compensatory proliferation. of leukocytes. The present data. however, concern only leukocyte counts: possible effects on leukocyte function (e.g.. phagocytic activity) have not been considered. It should be noted that the changes have been reported in membrane receptors of human lymphocytes exposed to radiation (Facchini rf (I/.. 1976). It is difficult to extrapolate from these data on radium exposure to possible hematological effects of plutonium exposure in humans. Among beagles injected with internal emitters. however. dose-dependent leukocyte depressions were more significant and more persistent with 239Pu than with 2z6Ra (Dougherty and Rosenblatr. 1971). It is possible, therefore. that the long-term effects on leukocyte counts of plutonium exposure in humans may be more pronounced than those reported for radium. ACKNOWLEDGMENTS The
2ittthol-
thanks
J. H.
M:ii-sh:tli.
S. A.
Fry.
and
A. T. Keane
for
their
helpful
comment5
on
thi\
munuxripr.
REFERENCES Dougherty.
J. H. and
Rosenblatt.
I.. S. (1969).
Leuhocyte
depression
‘14P~1. I/I “Delayed Effects on Bone-Seeking Radiontlclide\:~ tC. University of Utah Pres\. Salt Lake c’ity. DoLIghter>. J. H. and Rosenblatt. L. S. ( 1971 I. Long-term hematological beaglea. Rd. RPS. 48. 319-331.
in beagles W.
May\ effects
injected
v,ith
v/
22fiRa
01
4.57~168. emitters
in
260
ANTHONY
P.
POLEDNAK
Eldred, E. (1959). The response of eosinophils to total-body X-irradiation of the monkey. ~/ood 14, l87- 193. Evans. R. D. (1966). The effects of skeletally deposited alpha-ray emitters in man. &;r. J. Rud;o/. 39, 881-895. Facchini, A.. Maraldi, N. M.. Bartoli, S., Farulla, A.. and Manzoli, F. A. (1976). Changes in membrane receptors of B and T human lymphocytes exposed to 6oCo gamma rays, &d. Res. 68, 339-348. Ghossein. N. A.. Bosworth, J. L.. Stacey, P.. Muggia. F. M., and Krishnaswamy, V. (1975). Radiation-related eosinophilia. Radiology 117, 4133417. Holodny. E.. Lechtman, H.. and Laughlin. J. S. (1961). Bone-marrow dose produced by radioactive isotopes. Radiology 77, 1 -I I. Kurohara, S. S.. Hempelmann. L. H.. Englander. C. L. S., Fuller. L. M.. and Rubin, P. (1964). Eosinophilia after exposure to ionizing radiation. Rud. Rex. 23, 357-368. Lloyd, E. L.. Gemmell. M. A., Henning, C. B.. Gemmell. D. S., and Zabransky. B. J. (1976). Cell survival following alpha particle irradiation: Critical sites and implications for carcinogenesis. Radiological and Environmental Research Division Annual Report, Argonne National Laboratory, pp. 1-11. Loutit. J. F. (1970). Malignancy from radium. Brir. J. Cnrrcer 24, 195-207. Maletskos. C. J., Braun. A. G.. Shanahan. M. M.. and Evans, R. D. (1964). Quantitative evaluation of dose-reponse relationships in human beings with skeletal burdens of radium-226 and radium-228. In “Assessment of Radioactivity in Man.” International Atomic Energy Agency. Vienna. Marinelli. L. D.. Miller, C. E.. Gustafson. P. F.. and Rowland. R. E. (1955). The quantitative determination of gamma-ray emitting elements in living persons, Amer. .I. Roentg~~nd. Rtrd. T/Iw. Nwl. Med. 73, 661-671. Marshall. J. H. and Hoegerman. S. F. ( 1974). Estimation of alpha-particle dose from LzhRa to blood. Radiological and Environmental Research Division Annual Report, Argonne National Laboratory, pp. 56-62. Argonne, Illinois. Marshall. J. H. rf crl. (1973). “Alkaline Earth Metabolism in Adult Man.” ICRP Publication No, 20, Pergamon Press, New York. Martland. H. S. (1929). Occupational poisoning in manufacture of luminous watch dials. J.A.M.A. 92, 466473. 552-559. Martland, H. S.. Conlon. P. and Knef. J. D. (1925). Some unrecognized dangers in the use and handling of radioactive substances. J.A.M.A. 85, 1769-1776. Norris, W. P.. Speckman, T. W., and Gustafson, P. F. (1955). Studies of the metabolism of radium in man. Amer. J. Roenfgenol. Rod. Ther. N/K/. Med. 73, 785-802. Polednak. A. P. (1977). Long-term effects of radium exposure in female dial workers: Hematocrit and blood pressure. Environ. Res. 13, 237-249. Polednak, A. P. (1977). Long-term effects of radium exposure in female dial workers: Serum proteins. Environ. Res. 13, 396-406. Porteous. D. D. and Lajtha. L. G. (1966). On stem-cell recovery after irradiation. Byit. .I. Hrnttrtc~l. 12, 177- 188. Rowland, R. E., Keane. A. T. and Lucas, H. F.. Jr. (1973). A preliminary comparison of the carCarcinogenesis.” (C. L. Sanders ef trl.. cinogenicity of 226Ra and ZzrRa in man, III “Radionuclide Eds.), pp. 406420. U. S. Atomic Energy Commission, Oak Ridge. Rumke, C. L., Bezemer. P. D., and Kuik. D. J. (1975). Normal values and least significant differences for differential leukocyte counts. J. Chronic Dis. 28, 661-668. N. M. (1974). Eosinophils in humoral and cell mediated Speirs, R. S., Speirs. E. E.. and Ponzio. responses. ~n “Developments in Lymphoid Cell Biology.” (A. Gottlieb. Ed.). pp. 51-73. CRC Press. Cleveland. Spiers. F. W. and Whitwell, J. R. (1972). Theoretical comparisons of dosage from ‘?Sr and L’hRa in human and beagle bone. In “Second International Conference on Strontium Metabolism.” PP. 1~ 15. U. S. Department of Commerce, Springfield. Virginia. Stehney. A. F., Norris. W. P.. Lucas, H. F.. Jr., and Johnston. W. H. (1955). A method for measuring the rate of elimination of radon in breath. Amer. J. Roerltgenol. Rod. Ther. Nwl. Med. 73, 774-784.
Ra EXPOSURE
United
IN
FEMALE
DIAL
WORKERS
261
States Bureau of Labor Statistics. (1929). Radium poisoning. A~ortrhl~ Ltrhor RcI,. 28. IZOO- 1175. Upton. A. C. (1970). Comparative observations on radiation-induced myeloproliferative disorders in animals and man. f,r “Myeloproliferative Disorders of Animals and Man.” (W. J. Clarke. E. B. Howard. P. L. Hackett. Eds.). pp. 149-170. U. S. Atomic Energy Commission. Oak Ridge, Tennessee. Wallach. J. (1974). “Interpretation of Diagnostic Tests.” 2nd ed. Little. Brown. Boston. Woodard, H. Q. and Holodny. E. (1960). A summary of the data of Mechanik on the distribution of human bone marrow. Physics in Med. & Biol. 5. 57-69.
RLSLAR(:H
15,
252-
261
(1978)
Long-Term Effects of Radium Exposure in Female Workers: Differential White Blood Cell Count
Dial
The long-term effects of bone-seeking radionuclides on bone marrow in humans seem worthy of exploration. Leukocyte counts (total white cells. polymorphonuclears, lymphocytes, eosinophils. and monocytes) were analyzed among 393 female radium dial workers who were first employed between 1913 and 1929 and most recently examined between 19.54 and 1975. Mean and median counts were compared by initial intake level (&i of radium per kg of skeleton) within three age-at-last-examination groups (45-54, 55-64. and 65-74 yr). Median estimated 40-yr average alpha doses to trabecular bone marrow in the highest intake levels compared were 9 rad. 104 rad. and 40 rad. in the three age groups. Spearman rank correlation coefficients between radium intake and white cell counts were also calculated. There was little evidence for long-term or late effects of radium exposure on white cell counts. In the younger age groups, lymphocyte count tended to increase with increasing radium intake. In 65-74 year olds. eosinophil count decreased with increasing intake (Spearman I’ = -0.14. P < 0.05). Continued follow-up of this population should help clarify the question of possible long-term effects (direct or indirect) of radium exposure.
INTRODUCTION
Studies of the hematological effects of exposure to ionizing radiation are of interest, since certain cells of blood and blood-forming organs are among the most radiosensitive cells of the body. Since radium and plutonium are bone-seeking radionuclides, the possibility of bone-marrow injury has been explored to some extenl. In beagles injected with ZzhRa and zX9Pu, reductions in white blood cells and differential leukocyte counts were evident in the first year (Dougherty and Rosenblatt, 1969). Depression of lymphocyte and eosinophil counts showed no recovery during the first year post-injection, and depression of the lymphocyte count persisted through 42 months post-injection at the highest injection levels (Dougherty and Rosenblatt. 1971). In humans, data on hematological effects of internal emitters are limited. Early studies of persons exposed to radium, either ingested, as by radium dial painters or injected for supposed therapeutic effects, reported bone marrow injury, as evidenced by blood dyscrasias (anemia, leukopenia, and, possibly, leukemia) (Martland, Conlon and Knef, 1925: Martland, 1929). The few deaths attributed to leukemia among female radium dial painters (1913- 1929) occurred a relatively short time after exposure. The long-term effects of radium exposure, especially at levels lower than those associated with early death, on bone marrow are not clear. The U.S. Government’s right to retain a nonexclusive covering this paper is acknowledged. I Work supported by the United States Energy Research 252 0013-9351/78/0152-0252$02.00/O Copyright All
rights
15 of
1978 reproduction
by
Academw in any
Press.
Inc.
form
reserved.
royalty-free
license
and Development
in and to copyright Administration.
Ra
EXPOSC‘RE
IN
FF.blALE
DIAL
\VORKERS
253
The present study examines leukocyte counts in relation to radium exposure in female radium dial workers first employed before 1930. These data should be relevant to disease susceptibility, in view of the crucial role of leukocytes in host defense against infectious and other agents. MATERIALS
AND METHODS
The present sample is comprised of females who were first employed before 1930 in the radium dial industry in the United States (mostly in Illinois, Connecticut, and New Jersey). Ascertainment was from various sources, including employment lists, company photographs of workers, statements of co-workers, and self-referral. Details on the characteristics of this group have been reported previously (Polednak, 1977a, 1977b). Radium body-burden measurements and clinical data on dial workers are derived mainly from studies done at the Massachusetts Institute of Technology and at the Argonne National Laboratory since about 1954. A small number of persons was studied as part of the New Jersey Radium Research Project (1957- 1967). The present study includes female dial workers examined clinically on one or more occasions between 1954 to 1975. At least one report of differential leukocyte count was available for 465 women aged 45 to 74; the small numbers of women under 45 and over 74 were excluded from analysis. Excluded also were 72 women who had a diagnosed malignant neoplasm. Of the remaining 393, the majority (i.e., 205) were last examined between 1970- 1975. All but 62 were still alive, as of the most recent contact (1974 or 1975). Methods of measurement of radium body burden have been described elsewhere (Evans, 1966; Maletskos et rrl.. 1964). Briefly, gamma radiation (from daughter products of retained radon) is measured by scintillation gamma-ray spectrometry using crystals of thallium-activated sodium iodide, and the measurement of radon emanating from the body is made on samples of exhaled breath, obtained in an underground vault (Marinelli et rrl., 1955: Stehney et (I/.. 1955). For this analysis, radiation dose was defined as the initial intake of zr6Ra and zz8Ra in microcuries per kilogram (&i/kg). This is the total amount of radium entering the blood initially, calculated from the measured radium body burden using the retention function of Norris et crl. (1955). divided by the skeletal weight (5 kg for females). The calculation assumed a constant rate of intake over the total exposure duration. For dial painters who worked before 1926 and whose work period extended into or beyond 1926, the calculation involved truncation of the exposure duration at 1936: this is justifiable because changes in work regulations around 1926. including prohibition of mouth-tipping of the brush, resulted in a marked reduction in the amount of radium ingested. The intake-dose levels used in this study (~0.20, 0.20-0.99. 21.00, and ~5.00 PCiikg) were selected primarily to provide nearly equal sample sizes in the groups. Differential leukocyte counts were done at several clinical laboratories (two laboratories at M.I.T. and one at Argonne), and procedures did not change over the years of study. Total (combined) white cell count was reported in hundreds of cells per cubic mm. Percentages of polymorphonuclears, lymphocytes, monocytes, and eosinophils were based on counts of cells in peripheral blood. using Wright’s stain. At Argonne. differential counts are based on 200 cells: at M.I.T.,
100 cells are counted unless “abnormalities” were found (in which case another 100 are counted). Basophils and stabs (juvenile neutrophils) were not considered in this study. Percentages were multiplied by total white cell count to obtain differential counts. Within each of three age (at most recent examination) categories (45-54. 55-64, and 65-74 yr), means and medians were tabulated by intake-dose category. For statistical analyses, nonparametric methods were used, due to the departure from the normal distribution shown by the variables (especially eosinophils and monocytes). In each age group, the relationships between intake dose and the differential leukocyte counts were examined by use of Spearman’s rank correlation test (two-tailed). Kendall’s rank correlation test was also used: coefficients were somewhat lower than Spearman I.-S. but significance levels were similar, so that the Kendall I.‘S are not reported here. RESULTS
Tables 1-4 show mean and median differential leukocyte counts by intake-dose category within four age groups. In the 45-54 yr olds (Table l), means and megroup than in the < 1.OO &i/kg dians are generally higher in the z 1.00 &i/kg group, except for eosinophils. None of the Spearman correlation coefficients between the intake dose and leukocyte counts, however, are statistically significant (P > 0.05 for all). A similar pattern holds for the 55-64-year-old group (Table 21, except that eosinophil levels are more similar in the four intake-dose groups. One of the Spearman ~.‘s is statistically significant, i.e.. that between intake dose and lym-
Initial
intake
dose (PCiikg)
11.00 (N = 41)
Total
white
cells
Polymorphonuclears Lymphocytes Eosinophils Monocytes As Year of examination Initial intake dose (pCi/kg)
31.00 (N = 18) Spearman
Mean
SD
Mean
SD
731 (7488)” 4188 (3995) 2660 (2373) I23 (80) 1.52 (954) 50.9 (X1.3) I959 (0.39)
1810
8056 (7650) 4650 (4114) 1989 (2885) 94 (0) 328 (238) 51.7 (52.3 1959 (2.65)
2026
+o. IS
I671
+0.09
‘1 Correlation coefficients between ‘j Medians are in parentheses.
I.503 10x5 I I9 189 2.2 1.7
dose and the white
blood
cell counts.
835
to.21
I57
+0.01
257
10.07
2. I I.1
r”
Ka EXI’OSVRE
1h
FElI.ALE
DIAI.
Initial
Total
white
Mean
SD
7390
cells
(7500)” 4457 (‘II 17) 2293
Lymphocytes
0.20 (h’
I25
Monocytey
(Ill) 374
Age
(37X) 61.1
Year Initi;il
(61.9) I969
of examination intake dose
dose
SD
Mean
I697
7430
1970
1353
(7350) 4157
I446
796 I (8100) 3708
IO1 I
(4888) 3673
lb4
(26461 1x3
272
(123) 343
2.5
(2.59) 5X.8
790
(3611 I05
162
201
(114) 36.5
2.6
13201 61.1
6. I
(0.00)
(61.7) 1967
6.0
10.38)
(&Vlig)
>I.00 (,V = 44)
Mean
(2199) Eocinophils
intake
~ 0.99 = 401
(‘WI) 25s 1
255
\VORKERS
(~5.001 (N = 24)
SD
(57.9) 196’
I932 I481
Mean 8313 IXF(.sO) 4756
SD
Spearma p
I786
+o. I7
lJb5
-cO.ll
820
(50.50) 2179
843
-0.3
1x2
(2744) I68
IJX
t0.08
302
(1171 ‘$55
300
-0.05
?.I
(455) 58.9
3.1
4.n
(5X.1) I962
4.2
(h.70)
(19.65)
(&i/kg) ” Correlation ‘/ hledians are ,’ < 0.05.
coefficients
between
dose
and
the
white
blood
cell
counts.
in parentheses.
phocytes (,. = +0.23; p < .02). The correlation between dose and total white cells approached statistical significance (/’ = +O. 17: 0.05 < p < .lO). These results did not appear to be related to a terminal rise in white cell levels: i.e.. only 4 of the high-intake (3 1.00 &i/kg) women died within five yr of examination, and total white cell and lymphocyte levels were not unusual. In the 65-74 year age group (Table ?), means and medians are similar in the four intake-dose groups for all variables except eosinophils; mean and median eosinophil counts are relatively low in the highest intake groups (3 1.OO@/kg). The only statistically significant correlation is that between intake-dose and eosinophil count (Spearman I’ = -0.14, P < .05). It should be noted that in the two age groups with adequate sample sizes (Tables 2 and 3). means and medians for all variables are very similar in the co.20 and 0.20-0.99 &i/kg intake-dose groups. From medical examinations and hospital records, information on health status was obtained. The conditions most commonly diagnosed or reported (i.e., hypertension, cardiovascular diseases, osteoarthritis, diabetes mellitus) would not be expected to influence differential leukocyte count (Wallach. 1974). Since eosinophil count is increased in various allergic diseases, the correlation between eosinophil count and radium intake in 65-74 yr olds was reexamined, excluding 31 women with histories of allergic disorders (asthma, hay fever. allergic or vasomotor rhinitis. urticaria). The correlation was the same as that obtained previously, but the P value was higher due to the smaller sample size (Spearman I’ = -0.14. A’ = 180, P = 0.06).
256
ANTHONY
P. POLEDSAK
Initial
(N
<0.20 = 88)
Mean Total
white
cells
Polymorphonuclears Lymphocytes
7367 (7000)’ 41 I5 (3842)
0.20
= 66)
Mean
SD
7092
7229 (6983) 4182
102 I
7184 (7075)
207 I ISS?
751
4194 (4032) 2277
I56
(2101) 140
140
(109) 428
2.8
(406) 68.8
4.5
(68.3) 1972
1569
1498
(4174) 2303 (2396)
102
153
I89
Monocytes
273
(IS’) 117
68. I
2.6
(369) 68.5
3.5
(67.8) 1971
intake
dose
(35.00) (N = 3)
SD
( 158) 409 (375)
of examination
21.00 = 57)
Mean
Eosinophils
Initial
(N
(Kiikg)
SD
815
Year
dose
~ 0.99
(iv
2414 ( 22791
Age
intake
(67.3) 1972 (0.03)
(0.43)
Mean 7472
Spearmal p
SD 2459
-0.06
1848
-0.00
742
(7300) 4476 (4423) ‘13 I
741
-0.03
108
(2149) IS3
II8
-0.14’
233
(II?) 455
241
co.08
2.6
(453) 68.2
1.6
4.2
(67.9) 1971
5.4
(4.39)
(I 1.45)
(@Ii/kg) ” Correlation coefficients between Ir Medians are in parentheses. : ,’ < 0.05.
dose
and
the
white
blood
cell
counts
Since the only evidence for a depression in white cell counts in relation to intake dose was for eosinophils in 65-74 yr olds, this was examined in more detail. Table 4 compares the distribution of eosinophil counts in two intake-dose groups (< 1.OO and b 1.OO&i/kg) within the 65-74-year-old group, excluding women with allergic conditions. There is a higher proportion of lower counts and a lower propor-
Initial
intake
dose
(@G/kg)
count 49 99 149
10-249
21.00 (“?)
Number I’ 29 ‘6 29
Number
(9.0) (21.6) (19.4) (21.6)
x 12 13 8
2so+
3x
(2X.4)
5
Total
134
(100.0)
46
‘1 Excluding x2 = 8.42.
31 women d.f. = 4.0.05
with histories < ,I < .lO.
of allergic
disorders
(see
text)
fCi) (17.4) (76. I) (28.3) (17.4) (1O.Y) (100.1)
Ka
EXPOSL’RE
IN
FEMALE
DIAL
WORKERS
257
tion of higher counts in the 2 1.OO pCi/kg group compared with the < 1.OO pCi/kg group; the x? value approaches statistical significance (0.05 < .I.J< .LO). These cross-sectional data suggest that the increase in eosinophil level from age 55-64 to age 65-74 in the lower intake-dose groups (< 1 .OO&i/kg) is not evident in the higher intake-dose group (2 1.OO&i/kg). Some limited longitudinal data on eosinophil levels support this conclusion. For 29 of the 57 women in the 31.00 pCi/kg group last examined at age 65-74 (Table 3), an eosinophil count was available for age 50-59 (mean age, 54.1 2 2.6 SD yr). The mean and median eosinophil counts were nearly identical, i.e.. the means were 120 2 83 SD at age 50-59 (median, 96) and 126 2 87 SD at age 65-74 (median, 108). A Wilcoxon matched-pairs signed-ranks test (two-tailed) yielded statistically insignificant results. In comparison, for 41 of the 154 women in the cl.00 ,&i/kg group last examined at age 65-74 (Table 3). an eosinophil count was also available for age 50-59 (mean age, 54.2 ? 3.2 SD yr). The mean and median eosinophil counts were higher in the older age groups, i.e.. the means were 129 t 132 SD (median, 94) at age 50-59 and 176 ? 141 SD (median. 135) at age 65-74. A Wilcoxon matched-pairs signed-ranks test (two-tailed) yielded statistically significant results (P < .05). The initial intake dose used in these comparisons can be used to obtain estimates of dose absorbed by the bone marrow, the target tissue at risk with respect to possible effects of bone-seeking radionuclides on leukocyte production. The average dose to marrow within trabecular bone in a person with I &i radium burden and 5000 g of skeleton is 2.23 radlyr (Spiers and Whitwell, 1972; Marshall and Hoegerman, 1974). The average 40-yr (trabecular) bone marrow dose for a person with an initial intake of 1 &i/kg of skeleton would be approximately 3.5 tad. This estimate was obtained by using the Norris at rrl. (1955) retention function (0.54 t”“. t >, 1 day), the 40-yr time integral of which is 0.31 yr. That is: 2.23 rad/yr.&i x (5 kg x I @/kg) x 0.31 yr =3.5 rad. The beta-particle dose is very small (Spiers and Whitwell, 1972) and is not considered here. The average dose to cortical (vs trabecular) bone marrow is also not considered, but the active marrow in the adult is Largely or entirely contained in predominantly trabecular regions (Woodard and Holodny, 1960; Holodny, Lechtman and Laughlin, 1961). Spiers and Whitwell (1972) have calculated that considerable fractions of bone marrow are irradiated by 226Ra alpha particles, especially in bones with small marrow cavities, i.e., 53% of marrow in the parietal bone. and 20-34% of marrow in trabecular bone areas. Using the median initial intake doses shown in Tables I-4. the estimated median 40-yr average (trabecular) bone marrow doses in the highest dose categories are: 9 t-ad (age group 45-54); 104 rad (age group 55-64); and 40 rad (age group 65-74). Only one woman had an initial intake dose of ~100yCilkg (i.e.. 105). Her estimated 40-yr average dose to trabecular bone marrow is 368 rad; a 50-yr dose was more appropriate in this case, as in some others, but the difference is negligible. These data on dosimetry will be useful in the interpretation of the findings. DISCUSSION Jt is recognized that difficulties are involved in analyzing differentiai leukocyte counts as biological variables. In addition to intrapersonal physiologic variability,
there are inaccuracies caused by sampling (i.e., counting a sample containing at most a few hundred of the many leukocytes circulating in the blood). The most rare leukocyte types (juvenile neutrophils and basophils), however, were excluded from our analyses. Also, the results of counting 200 cells (as in part of the present series) are considerably more accurate than those obtained with 100 cells (Rumke, Bezemer. and Kuik. 1975). It should be emphasized that the present study concerns only long-term or late effects of radium exposure on white blood cell counts. Apparent effects occurring earlier after exposure have been reported previously, although their interpretation (e.g., the true frequency of leukemia) is questionable (Loutit. 1970). Leukopenia, as well as anemia. was recognized in the 1920’s as a consequence of radium exposure (U. S. Bureau of Labor Statistics. 1929: Martland, 1929). The present sample of radium dial workers examined from 1954 to 1975 excludes some persons with high intake-doses (who died earlier) and a few deaths attributed to leukemia. Few of the correlations (Spearman r) between dose and white cell counts are statistically significant. There is little evidence for leukocyte depression, such as reported in beagles injected with high doses of 226Ra and Z39Pu. In beagle experiments with 2Z6Ra. however, leukocyte depression (in early months post injection) was followed by recovery to control levels for all variables (white cells, polymorphonculears. eosinophils, monocytes, and leukocytes) by 2-6 yr, except for lymphocytes in a high-intake group (3.5 PCiikg of body. or about 3.5 pCi/kg of skeleton) (Dougherty and Rosenblatt, 1971). Due to the greater retention of radium in the beagle relative to the human skeleton. the skeletal dose delivered (per unit of intake) in the beagle is several times that in man (Rowland, Keane, and Lucas, 1973). Thus, the present tindings on leukocyte levels some 30-50 yr after first exposure to radium may not be unexpected in view of the evidence from beagle experiments. In the 65-74 year olds (Table 3), the lower mean and median eosinophil counts in the highest intake-dose group ( 2 1.00 &i/kg), and the negative correlation (Spearman 1.) between intake dose and eosinophil count, suggest a possible doserelated depression in eosinophil level. Based on these cross-sectional data, and limited longitudinal data, the increase in eosinophil count from age 55-64 to age 65-74 in the lower intake-dose groups (< 1.OOPCiikg) is not evident in the higher intake-dose group (~1.00 &i/kg). If this effect is real, it would not appear to represent a depression persisting from an earlier time. External irradiation of most animal species depresses the eosinophil count. but sometimes causes eosinophilia in man and monkeys (Eldred, 1959; Kurohara rt trl.. 1964). The response depends upon the volume of tissues, and parts of the body. irradiated: radiation-related eosinophilia may be of prognostic significance in some types of cancer (Ghossein t’r irl., 197.5). Since internal emitters (?‘(‘Ra and Z39Pu) have been shown to produce at least transient depression of eosinophils in beagles (Dougherty and Rosenblatt, 1971), the present finding of lower eosinophil levels in the high intake-dose group of 65-74 yr olds should be further explored. The data in Table 4 suggest the possibility of a bone marrow effect, with destruction of eosinophil precursors and an eventual depletion of eosinophils. Continued follow-up of these women. preferably with more reliable methods of counting eosinophils. will be required. In
~g, ESPOSrRE
IS
FEMALE
Dl.AL
259
‘IVORKKRS
view of the possible role of eosinophils in immunological reactions (Speirs cutr/l., 1974). such data may be relevant to disease susceptibility. Comparisons of the means and medians by intake-dose group in Tables I and 2 (ages 45-64). and the Spearman 1.‘~. suggest a tendency toward slightly higher levels of some variables (i.e., total white cells and lymphocytes) in the higher intake-dose levels. After acute whole-body irradiation at lower doses, regenerative proliferation of hemopoietic cells may be pronounced. and may lead to temporary hypercellularity (Porteous and Lajtha, 1966; Upton, 1970). Conceivably. such compensatory proliferation may account for the present findings. The higher levels of lymphocytes at higher dose groups in the 45-54 and 55-64 year olds are noteworthy. Due to the low soft-tissue retention of radium, irradiation of lymphatic tissue is unlikely, except in the first few days after intake. With bone-seeking radionuclides that are ingested. the marrow is irradiated. but in the present study B-lymphocytes (bone-marrow derived) were not distinguished from T-lymphocytes. Recent experiments on mammalian cells (fibroblasts) i/l I~~YJ confirm previous findings that the mean lethal dose from alpha particles is about 100 rad (Lloyd et (I/.. 1976). The estimated average doses to trabecular bone marrow (noted above) of some women reached 100 rads. Thus. the compensatory proliferation shown after initial depletion of blood-forming cells with external irradiation may be expected in some of the women in this study. Also. the bone marrow dose estimates reported here are average doses to trabecular bone marrow. and doses to some areas (i.e.. near bone surfaces) may be considerably higher. In any event. at the initial intake doses (and estimated average trabecular bone-marrow rad doses) involved in this study of long-term survivors of radium exposure, there is little evidence for persistent depression, or significant compensatory proliferation. of leukocytes. The present data. however, concern only leukocyte counts: possible effects on leukocyte function (e.g.. phagocytic activity) have not been considered. It should be noted that the changes have been reported in membrane receptors of human lymphocytes exposed to radiation (Facchini rf (I/.. 1976). It is difficult to extrapolate from these data on radium exposure to possible hematological effects of plutonium exposure in humans. Among beagles injected with internal emitters. however. dose-dependent leukocyte depressions were more significant and more persistent with 239Pu than with 2z6Ra (Dougherty and Rosenblatr. 1971). It is possible, therefore. that the long-term effects on leukocyte counts of plutonium exposure in humans may be more pronounced than those reported for radium. ACKNOWLEDGMENTS The
2ittthol-
thanks
J. H.
M:ii-sh:tli.
S. A.
Fry.
and
A. T. Keane
for
their
helpful
comment5
on
thi\
munuxripr.
REFERENCES Dougherty.
J. H. and
Rosenblatt.
I.. S. (1969).
Leuhocyte
depression
‘14P~1. I/I “Delayed Effects on Bone-Seeking Radiontlclide\:~ tC. University of Utah Pres\. Salt Lake c’ity. DoLIghter>. J. H. and Rosenblatt. L. S. ( 1971 I. Long-term hematological beaglea. Rd. RPS. 48. 319-331.
in beagles W.
May\ effects
injected
v,ith
v/
22fiRa
01
4.57~168. emitters
in
260
ANTHONY
P.
POLEDNAK
Eldred, E. (1959). The response of eosinophils to total-body X-irradiation of the monkey. ~/ood 14, l87- 193. Evans. R. D. (1966). The effects of skeletally deposited alpha-ray emitters in man. &;r. J. Rud;o/. 39, 881-895. Facchini, A.. Maraldi, N. M.. Bartoli, S., Farulla, A.. and Manzoli, F. A. (1976). Changes in membrane receptors of B and T human lymphocytes exposed to 6oCo gamma rays, &d. Res. 68, 339-348. Ghossein. N. A.. Bosworth, J. L.. Stacey, P.. Muggia. F. M., and Krishnaswamy, V. (1975). Radiation-related eosinophilia. Radiology 117, 4133417. Holodny. E.. Lechtman, H.. and Laughlin. J. S. (1961). Bone-marrow dose produced by radioactive isotopes. Radiology 77, 1 -I I. Kurohara, S. S.. Hempelmann. L. H.. Englander. C. L. S., Fuller. L. M.. and Rubin, P. (1964). Eosinophilia after exposure to ionizing radiation. Rud. Rex. 23, 357-368. Lloyd, E. L.. Gemmell. M. A., Henning, C. B.. Gemmell. D. S., and Zabransky. B. J. (1976). Cell survival following alpha particle irradiation: Critical sites and implications for carcinogenesis. Radiological and Environmental Research Division Annual Report, Argonne National Laboratory, pp. 1-11. Loutit. J. F. (1970). Malignancy from radium. Brir. J. Cnrrcer 24, 195-207. Maletskos. C. J., Braun. A. G.. Shanahan. M. M.. and Evans, R. D. (1964). Quantitative evaluation of dose-reponse relationships in human beings with skeletal burdens of radium-226 and radium-228. In “Assessment of Radioactivity in Man.” International Atomic Energy Agency. Vienna. Marinelli. L. D.. Miller, C. E.. Gustafson. P. F.. and Rowland. R. E. (1955). The quantitative determination of gamma-ray emitting elements in living persons, Amer. .I. Roentg~~nd. Rtrd. T/Iw. Nwl. Med. 73, 661-671. Marshall. J. H. and Hoegerman. S. F. ( 1974). Estimation of alpha-particle dose from LzhRa to blood. Radiological and Environmental Research Division Annual Report, Argonne National Laboratory, pp. 56-62. Argonne, Illinois. Marshall. J. H. rf crl. (1973). “Alkaline Earth Metabolism in Adult Man.” ICRP Publication No, 20, Pergamon Press, New York. Martland. H. S. (1929). Occupational poisoning in manufacture of luminous watch dials. J.A.M.A. 92, 466473. 552-559. Martland, H. S.. Conlon. P. and Knef. J. D. (1925). Some unrecognized dangers in the use and handling of radioactive substances. J.A.M.A. 85, 1769-1776. Norris, W. P.. Speckman, T. W., and Gustafson, P. F. (1955). Studies of the metabolism of radium in man. Amer. J. Roenfgenol. Rod. Ther. N/K/. Med. 73, 785-802. Polednak. A. P. (1977). Long-term effects of radium exposure in female dial workers: Hematocrit and blood pressure. Environ. Res. 13, 237-249. Polednak, A. P. (1977). Long-term effects of radium exposure in female dial workers: Serum proteins. Environ. Res. 13, 396-406. Porteous. D. D. and Lajtha. L. G. (1966). On stem-cell recovery after irradiation. Byit. .I. Hrnttrtc~l. 12, 177- 188. Rowland, R. E., Keane. A. T. and Lucas, H. F.. Jr. (1973). A preliminary comparison of the carCarcinogenesis.” (C. L. Sanders ef trl.. cinogenicity of 226Ra and ZzrRa in man, III “Radionuclide Eds.), pp. 406420. U. S. Atomic Energy Commission, Oak Ridge. Rumke, C. L., Bezemer. P. D., and Kuik. D. J. (1975). Normal values and least significant differences for differential leukocyte counts. J. Chronic Dis. 28, 661-668. N. M. (1974). Eosinophils in humoral and cell mediated Speirs, R. S., Speirs. E. E.. and Ponzio. responses. ~n “Developments in Lymphoid Cell Biology.” (A. Gottlieb. Ed.). pp. 51-73. CRC Press. Cleveland. Spiers. F. W. and Whitwell, J. R. (1972). Theoretical comparisons of dosage from ‘?Sr and L’hRa in human and beagle bone. In “Second International Conference on Strontium Metabolism.” PP. 1~ 15. U. S. Department of Commerce, Springfield. Virginia. Stehney. A. F., Norris. W. P.. Lucas, H. F.. Jr., and Johnston. W. H. (1955). A method for measuring the rate of elimination of radon in breath. Amer. J. Roerltgenol. Rod. Ther. Nwl. Med. 73, 774-784.
Ra EXPOSURE
United
IN
FEMALE
DIAL
WORKERS
261
States Bureau of Labor Statistics. (1929). Radium poisoning. A~ortrhl~ Ltrhor RcI,. 28. IZOO- 1175. Upton. A. C. (1970). Comparative observations on radiation-induced myeloproliferative disorders in animals and man. f,r “Myeloproliferative Disorders of Animals and Man.” (W. J. Clarke. E. B. Howard. P. L. Hackett. Eds.). pp. 149-170. U. S. Atomic Energy Commission. Oak Ridge, Tennessee. Wallach. J. (1974). “Interpretation of Diagnostic Tests.” 2nd ed. Little. Brown. Boston. Woodard, H. Q. and Holodny. E. (1960). A summary of the data of Mechanik on the distribution of human bone marrow. Physics in Med. & Biol. 5. 57-69.