Reference value and annual trend of white blood cell counts among adult Japanese population
Environ Health Prev Med
Reference value and annual trend of white blood cell counts among adult Japanese population
Sonoko Sakuragi 0 1
Jiro Moriguchi 0 1
Fumiko Ohashi 0 1
Masayuki Ikeda 0 1
0 F. Ohashi M. Ikeda (&) Kyoto Industrial Health Association (Main Office) , 67 Nishinokyo-Kitatsuboicho, Nakagyo-ku, Kyoto 604-8472 , Japan
1 S. Sakuragi J. Moriguchi Kyoto Industrial Health Association (Mibu Office) , 4-1 Mibu-Shijaku-cho, Nakagyo-ku, Kyoto 604-8471 , Japan
Objectives This study was initiated to establish the reference values (the 95 % lower limit in particular) for white blood cell (WBC) counts in peripheral blood of general Japanese population. Additional attempts were made to examine whether the reference range had changed in the past 100 years, and which factors had induced such change in WBC counts. Methods Data employed were WBC counts of [100 thousand apparently healthy Japanese men, collected in 2002 and in 2010, respectively. Information on smoking habits was collected simultaneously. Results The distribution of WBC counts was essentially normal. Arithmetic mean (AM) WBC was 6,248 cells/mm3 in 2002 and 6,162 cells/mm3 in 2010. Based on the 2010 observation, 3 9 103 WBCs/mm3 (after rounding of the figure) was identified as the 95 % lower limit of the reference value for the population. No clear age dependency was detected. Smoking induced elevation in WBC, whereas WBC returned to the level of never smokers after quitting for 3 or more years. Conclusions Historical review disclosed a secular trend of decrease in WBC in the past 100 years, so that about 8 % of never-smoking men would be considered leukocytopenic according to the conventional cutoff of 4 9 103 cells/mm3 as a screening level. Decreased smoking rates and improved general hygiene are discussed as possible factors for WBC count reduction. Thus, WBC count of 3 9 103 cells/mm3 is recommended as the 95 % lower limit of the reference value for screening cases with reduced WBC counts.
Annual trend; Japanese; Leukocyte counts; Men; Reference value; White blood cell counts
Counting of leukocytes [white blood cells (WBCs)], a
classical method to detect hematological abnormalities, is
still an important item in occupational health examination.
For example, whereas benzene-induced leukocytopenia [
has seldom been encountered recently in industrialized
countries including Japan as industrial use of this
wellknown hematotoxic solvent has been severely controlled in
recent years [
], the WBC count stands as a critical
health effect marker in health examination for
radiationexposed subjects .
In preventive medicine, therefore, establishment of the
reference value for WBC counts together with clarification
of the range of distribution among Japanese general
population are of practical importance. It has been reported that
ethnic difference exists in WBC counts among adult women
] and presumably in general population as a whole, which
suggests the need for studies on local populations such as
Japanese for evaluation of Japanese subjects.
Substantial compilations of WBC count data for
apparently healthy men were available to this study group.
Taking advantage of these compilations, this study was
initiated to clarify the current levels of WBC counts in
general Japanese population. A secular trend of shift in the
WBC counts and possible age dependency were also
examined in comparison with retrieved reports on WBC
counts for the Japanese population in the past. Whereas the
materials examined were for men, it was expected that the
conclusions should be applicable also to women, as there
would be no gender difference in WBC counts [
Subjects and methods
The study protocol was approved by the Ethics Committee of
Kyoto Industrial Health Association. Each and all of the
subjects studied provided informed consent in writing, with
understanding that physicians and/or paramedical staff of the
Association might use the results of the health examinations
for medical education and research purposes under the
condition that the results be presented generally on a group
basis or with due respect to anonymity of the subjects.
The subjects were apparently healthy adult Japanese
men who underwent hematological examinations
(including WBC counting) as part of routine annual health
checkup in clinical facilities of this Association. Those who were
under medical treatments were excluded. In practice, more
than 100 and 130 thousand cases were available during the
1-year period from 1 August 2002 to 31 July 2003 (the
2002 data) and during another 1-year period from 1 April
2010 to 31 March 2011 (the 2010 data), respectively. Many
of the examinees were full-time employees of enterprises
of various sizes, but self-employed people, university
students, and local residents were also included.
Blood samples were taken by venopuncture of cubital
vein, and immediately heparinized. Hematological
examinations were conducted by use of automated blood cell
counters. Depending on the survey year, two types of
counters were used, i.e., Sysmex SE9000 (Sysmex, Kobe,
Japan) in 2002, and ABX PENTRA XL80 (Horiba, Kyoto,
Japan) in 2010. A preliminary study with human blood
samples to examine possible intercounter difference in the
] gave a regression line of Y = -361 ?
0.993X (r = 0.997, p \ 0.01, n = 97), where X and Y are
the measures by Sysmex and PENTRA, respectively. This
close agreement was taken to suggest that no adjustment
was necessary in evaluation. By means of self-administered
questionnaires, the subjects were asked in addition on their
smoking habits, i.e., if they were current, former, or never
smokers; in case of former smokers, they were further
asked the duration of smoking abstinence, whether it was
less than 3 years or 3 years and longer.
For time trend analysis, literature was sorted by use of a
retrieval system, ‘‘Ichushi-Web,’’ a system founded by the
Japan Medical Abstracts Society (Tokyo, Japan) in 1983
specifically for Japan-based literature published in the
1980s and afterwards; it was found that the target literature
was usually in Japanese, for which search by PubMed was
not productive enough. Literature published in the 1970s
and earlier was traced by taking advantage of references
given in published articles. Thus, best efforts were made to
collect publications even in the period not covered by the
With regard to statistical analyses, normal distribution
was assumed for WBC counts, as discussed later in detail,
so that the distributions were expressed in terms of
arithmetic means (AMs) and arithmetic standard deviations
(ASDs). Unpaired t test and analysis of variance (ANOVA)
(followed by post hoc test, Scheffe´) were employed to
detect possible significance of differences in the
distributions. Possible difference in parameters between two
regression lines were examined after Ichihara [
Distribution patterns among total subjects, smokers,
Distribution histograms for total, never-smoking, and
currently smoking cases are depicted in Fig. 1a–c, respectively,
to show that the distributions were essentially normal. It
should be noted that the mode of WBC counts for never
smokers [WBC count, about 5.0 9 103 cells/mm3; Fig. 1b]
was slightly smaller than that for current smokers [WBC
count; about 6.0 9 103 cells/mm3; Fig. 1c].
WBC counts in 2002 and in 2010
In practice, 103,492 and 130,431 cases were available in
2002 and 2010, respectively. Breakdown of the total cases
by smoking habits to never, former, and current smokers
(Table 1) showed that former smokers were older than the
other two groups by about 5 years. When WBC counts
were compared, WBC counts for the total group in 2010
differed significantly from the counts in 2002 (p \ 0.01),
but the net difference (a decrease) in AM was as small as
86 cells/mm3. Similar comparison of WBC for the
neversmoker group in 2002 and in 2010 also showed a
significant (p \ 0.01) difference with a small net increase in AM
WBC of 57 cells/mm3. It was considered that both changes
were medically meaningless, although statistically
significant due to the large numbers of cases studied (i.e.,
[30,000 cases even for never smokers).
WBC counts for current smokers were significantly higher
(p \ 0.01) than those for never or former smokers in both
2002 and 2010. The net difference was about 1,000 cells/
mm3. In contrast, the net difference between former and never
smokers was quite smaller, e.g., about 100 cells/mm ,
although it was statistically significant (p \ 0.01).
Further calculation for 5 percentile values to find the
95 % lower limit of the WBC counts (Table 1) revealed
that, in 2010, the values were 2,899, 2,925, and 3,123 cells/
mm3 for never, former, and current smokers, respectively.
After rounding the figures, 3.0 9 103 cells/mm3 would be
the 95 % lower limit of the current reference for general
population including current smokers.
Effect of abstinence of smoking
Analysis of 2010 data on the duration of abstinence of
smoking showed that AM WBC counts for those with
abstinence for 3 years or longer (5,591 cells/mm3;
n = 603) did not differ significantly (p [ 0.10 by Scheffe´)
from the values for never smokers (5,666 cells/mm ;
n = 40,748), whereas AM WBC for those who had quit for
less than 3 years (5,753 cells/mm3; n = 35,438) was still
more than that for never smokers.
Possible effect of aging
To examine possible age-dependent changes in WBC
counts, total cases were divided by decades of age, and 7
age groups were subjected to ANOVA (Table 2). It should
be noted that the cases at 80? years of age were limited,
i.e., 48 and 11 cases in 2002 and 2010, respectively
(\0.05 % of the cases studied). It turned out that there was
a steady trend of decrease in the three youngest age groups
in both 2002 and 2010. For older ages, however, the
changes were in the opposite direction in the 50–59-year
group in 2002 and insignificant in 2010. In addition, the net
difference between the age groups was \150 cells/mm3. In
overall evaluation, therefore, it was concluded that the
agedependent changes should be not meaningful
medicobiologically, although statistically significant in some cases.
The present analysis has made it clear that WBC count of
3.0 9 103 cells/mm3 can be used as the cutoff level for
screening cases with reduced WBC counts. Taking a
conventional criterion of 4.0 9 103 WBCs/mm3 as the lower
limit of the normal range for WBC counts [
], 7,206 and
3,256 cases of total (5.52 %) and never-smoking men
(7.99 %) in 2010, respectively, would be below the limit.
With a tentative limit of 3.5 9 103 cells/mm3, the
prevalence would be 2,152 cases (1.65 %) and 984 cases
(2.41 %), respectively.
WBC counts have been a focus of medical attention
since as early as the 1910s. In practice, 15 articles reporting
WBC counts of Japanese men at the time of the study were
available through literature survey [
]; they are
tabulated in Table 3 in combination with the present
results. The target populations were men in many cases,
whereas WBC counts for women were reported either
separately or in combination with those for men. In most of
the reports, the results were presented in terms of AM and
ASD. Breakdown by decades of years of age were also
presented in selected cases [
], and the results of such
cases are presented as a range of AM values in Table 3.
Perusal of Table 3 suggests that WBC counts appear to
be reducing with time. For quantitative evaluation of a
possible secular trend of the decrease, one representative
value was selected for each article. In cases where AM
values were shown as a range, an arithmetic mean of the
Year of study
No. of cases Age (years)
White blood cell counts (cells/mm3)
Group by smoking
2.5 percentile 5.0 percentile 95.0 percentile 97.5 percentile p
a p for difference from never smokers by Scheffe´; for p B 0.01
b p for difference from former smokers by Scheffe´; for p B 0.01
a Number of cases
b p for difference from the immediately younger group by Scheffe´; two arrows, one arrow, and ns show p B0.01, B0.05, and[0.05, respectively.
The direction of arrows indicates an increase or a decrease
lower and upper limit values was taken. As sex difference
in WBC counts has been considered as insignificant among
Japanese populations (e.g., [
]), the values for men and
women in combination (shown as M ? W in Table 3) were
taken, whereas values for women only in Table 3 were not
taken up because values for women were always
accompanied by values for men.
WBC counting was conducted manually in early time
studies, whereas it is presently by use of automated cell
counters. Possible method-dependent difference was,
however, not taken into account as it was reported that no
differences in the results were observed between manual
and instrumental counting [
], while no information on
the method of counting was available for each report in the
A linear regression analysis was conducted, taking year of
publication and WBC counts on the horizontal and vertical
axis, respectively (Fig. 2a); the data cited from Asai et al.
] were prepared by Hibino in 1954–1955, and therefore
the year 1954–1955 was taken in preparing Fig. 2. The
publication year and WBC counts correlated significantly
(r = 0.581, p \ 0.05, n = 16) with a calculated regression
line of Y = 25518 - 9.538X, where X is the year of
publication and Y is the reported WBC counts. Worthy of note in
Fig. 1 is that the slope is negative (i.e., \0), and that the
present study results for 2002 and 2010 lie between the
regression line and the curve for the lower limit of the 95 %
range of the regression line. As a result, in 2010 for example,
the prevalence of those with less than 4,000 WBC/mm3 is as
high as 8 % among never-smoking men, as discussed above.
Thus, care should be practiced in making diagnosis of
leukocytopenia, e.g., for radiation-exposed subjects.
It was considered possible that concepts and practice of
statistical analysis made substantial progress in the late
a Variation by decades of age, with no consistent age-dependent trends
b The range of modes for each of decades of years of age (20–59 years)
c Data on smokers and nonsmokers were combined by the present authors for a whole group
1940s. Thus, the studies conducted in 1950? were
re-evaluated separately from previous studies. The
regression analysis (Fig. 2b) gave a calculated regression line of
Y = 12,544 - 3.023X (r = 0.150, p [ 0.05, n = 12),
where X is the year of publication and Y is the reported
WBC counts. Although the slope appeared to be less
steep (i.e., -3.023), it was negative (i.e., \0) and did not
differ significantly (p \ 0.05) from the slope (-9.538) for
total cases. The absence of the difference might be due to
wide variation around the regression line. The lack of
statistical significance of the correlation coefficient
(r = 0.150, p [ 0.05) may be attributable at least in part
Healthy medical students
Healthy army soldiers
Healthy men and women of various
occupations aged 20–60 years
Statement in a textbook
Citation of the study by Hibino which was
conducted in 1954–1955
Adult healthy workers; min. and max.
values are shown by ranges
Adult healthy workers; min. and max.
values are shown by ranges
Up to 59 years
Up to 59 years
Minimum and maximum values reported
for each of decades of years of age
See footnote c
20–60-year-old men (for details, see
20–60-year-old never-smoking men (for
details, see Table 1)
20–60-year-old men (for details, see
20–60-year-old never-smoking men (for
details, see Table 1)
to the narrowing of the study year range from 96 to
No reports were available on secular trend analyses
in WBC counts for other (i.e., non-Japanese)
populations. In the years around 2000, Bovill et al. [
6.2–6.4 9 103 cells/mm3 for men, and 6.1–6.2 9
103 cells/mm3 for women. In addition, van Oostrom et al.
] reported 5.41 9 103 cells/mm3 for healthy adult men.
Compared with these levels, surveys in the years around
1980 reported somewhat higher levels. For example,
Godwin et al. [
] observed in a large-scale survey that the
means were 6.0–6.5 9 103 cells/mm3 (with small
agedependent variations) and that the minimum and the
maximum were 3.5 and 12.0 9 103 cells/mm3,
respectively. Barrett et al. [
] found that the mean and the range
for WBC counts were 6.3 (4.2–11.2) 9 103 cells/mm3 for
men and 6.8 (4.0–10.4) 9103 cells/mm3 for women. Galen
] reported that mean WBC counts were 6.7 to
7.0 9 103 cells/mm3 (3.5 and 11.9 9 103 cells/mm3 for
2.5 and 97.5 percentile, respectively). According to Giorno
et al. [
], WBC counts were in ranges of 3.13–
10.84 9 103 cells/mm3 for men and 3.28–11.05 9 103
cells/mm3 for women. Thus, it appears likely that higher
WBC counts were reported in the years about 20 years ago
than at present time, although the ethnic backgrounds of
the populations studied might vary.
With regard to possible explanations for the secular
decrease in WBC counts in Japan, it is quite conceivable
that at least two factors have been involved, i.e., infectious
diseases and smoking. First, the decrease may be
associated with reduced prevalence of infectious diseases, as
WBC counts are known to increase in response to
infections. For example, the Ministry of Health, Labor, and
Welfare, Japan recorded 533 9 103 cases of patients with
infectious diseases (including parasitosis and tuberculosis)
in 1953. The number stayed at a high level of 563 9 103
cases in 1963, but was reduced to 219 9 103 cases in 2008
]. No separate statistics are available for parasitosis
among adult population. School health statistics, however,
suggest an even more dramatic improvement in hygienic
conditions. Namely, the percentage for 6–8-year-old
children in primary schools who had eggs of gastrointestinal
tract parasites was 50.7 % in 1953, which dropped to
17.9 % in 1963 and 0.4 % in 2008 [
Another possible cause of reduction in WBC counts is
the increase in the never-smoking ratio, as previously
pointed out by Schwartz et al. [
]. Articles are
accumulating to report that smoking induces an increase in WBC
counts, although this may not be due to inflammation of the
respiratory tract [
]. Thus, Smith et al. [
] observed that
WBC counts were higher (7.4 9 103 cells/mm ) among
839 male current smokers than among 2,421 male never
smokers (6.2 9 103 cells/mm3). The value for 3,597
former smokers (6.4 9 103 cells/mm ) was between the
current and never smokers. A similar difference was
observed among 925 current, 2,688 former, and 4,721
never-smoking women (7.4, 6.3, and 6.2 9 103 cells/mm3,
Ishizaka et al. [
] also showed higher WBC counts
(6.3 9 103 cells/mm3) among 1,158 current smokers (men
and women combined) as compared with the counts in
1,130 former smokers (5.3 9 103 cells/mm3) and 1,399
never smokers (5.1 9 103 cells/mm3). The WBC counts
correlated significantly (p \ 0.01) with current smoking
after logistic regression analysis [
Al-Awadhi et al. [
] found in a small-scale epidemiology study
with 49 smokers (31 men and 18 women) and 43
nonsmokers (24 men and 19 women) that WBC counts were
higher in smokers than in nonsmokers (p \ 0.05). Lee
et al. [
] made a survey of community residents near
nuclear power plants. WBC counts were higher for
smokers (6.7 9 103 cells/mm3 for 1,054 men and 86
women) than for nonsmokers (6.3 9 103 cells/mm3 for
649 men and 6.1 9 103 cells/mm3 for 1,813 women),
although the effect of distance from the plants appeared to
be negative (i.e., those who lived closer to the plants had
higher WBC counts).
Thus, it appears to be prudent to conclude that smoking
induces an increase in WBC counts, and that smoking
cessation most probably results in reduction in WBC
counts. During the period 1998–2008, for example, the
smoking rate among male Japanese population gradually
decreasing from 52.8 % in 1998 [
] to 46.8 % in 2003
] and 36.8 % in 2008 [
Acknowledgments The authors are grateful to the administration
and staff of Kyoto Industrial Health Association for their interest in
and support of this work.
Conflict of interest The authors declare that they have no conflicts
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